Abstract of the 35th Scandinavian Congress of Rheumatology, September 20-23, 2014, Stockholm, Sweden.

CONTENTS

VOLUME 43

Sunday Symposium

Scand J Rheumatol Downloaded from informahealthcare.com by Chinese University of Hong Kong on 02/03/15 For personal use only.

1

OP01/PP209 Initial infliximab is not cost-effective added on to a remission-targeted combination therapy in early rheumatoid arthritis: the 2-year results of the randomized clinical NEO-RACo trial V Rantalaiho, J Martikainen, H Kautiainen, K Puolakka, M Leirisalo-Repo; and the NEO-RACo Study Group

SUPPLEMENT 127

7

2

OP02/PP125 Impact of physicians’ activity and adherence to treat-to-target strategy on outcomes in early rheumatoid arthritis: a subanalysis of the Neo-RACo trial L Kuusalo, V Rantalaiho, H Kautiainen, M Korpela, K Puolakka, M Leirisalo-Repo

OP09/PP141 Fatigue fluctuates substantially in patients with stable rheumatoid arthritis treated with biological agents EL Esmose, R Cordtz, OR Madsen

Monday Workshop 7

OP10/PP151 Atherosclerosis in systemic lupus erythematosus (SLE) and controls: an analysis of SLE subgroups J Gustafsson, K Jensen-Urstad, M. Herlitz-Lindberg, S Mo€ller, S Pettersson, I Gunnarsson, A Larsson, E Svenungsson

8

OP11/PP156 Good response on tumour necrosis factor inhibitors is associated with a decreased risk of acute coronary syndrome in patients with rheumatoid arthritis L Ljung, L Jacobsson, SR Dahlqvist, J Askling; and ARTIS Study Group

Session A1 1

2014

OP03/PP130 Does disease activity at start of biologic therapy influence productivity losses in patients with RA? K Johansson, T Olofsson, J Eriksson, R van Vollenhoven, H Miller, I Peterson, J Askling, M Neovius

Session A3 Session A2 3

OP04/PP110 Characterization of lung inflammation and identification of shared citrullinated targets in the lungs and joints of early rheumatoid arthritis V Joshua, G Reynisdottir, J Ytterberg, M Engstro€m, A Eklund, M Skold, P-J Jakobsson, J Ro€nnelid, V Malmstro€m, L Klareskog, J Grunewald, AI Catrina

4

OP05/PP112 When does the female predominance in RA start - does sex influence the risk of ACPA development? AH Hensvold, T Frisell, PK Magnusson, J Askling, AI Catrina

9

OP12/PP149 The association between antibody levels before and after 7-valent pneumococcal conjugate vaccine immunization and subsequent pneumococcal infection in arthritis patients J Nagel, T Saxne, P Geborek, G Jo€nsson, M Englund, IF Petersson, J-Å Nilsson, L Truedsson, MC Kapetanovic

Session A4 9

OP13/PP243 CD28null T cells are myotoxic to autologous muscle cells from patients with polymyositis J Pandya, P Venalis, L Al-Khalili, M Hossain, V Stache, IE Lundberg, V Malmstro€m, A Fasth OP14/PP253 Interferon (IFN)-λ1/3, but not IFN-α, is a marker of poor response to treatment in lupus nephritis A Zickert, V Oke, I Parodis, E Svenungsson, I Gunnarsson

Session B1 4

OP06/PP132 The relationship between pain and inflammation in early rheumatoid arthritis: long-term follow-up in the Swedish population-based EIRA and SRQ register M Sandberg, S Saevarsdottir, R Altawil, L Alfredsson, L Klareskog, J Lampa

10

5

OP07/PP136 Pain in adult idiopathic inflammatory myopathies C Gonzalez-Echavarri, I Lundberg, H Alexanderson

Session B4 10

OP15/PP232 To which extent may the familial risk of rheumatoid arthritis (RA) be explained by established RA risk factors? X Jiang, T Frisell, J Askling, L Klareskog, L Alfredsson, H Källberg

11

OP16/PP233 Parity and severity of ACPA-positive/-negative rheumatoid arthritis. Results from the Swedish EIRA study M Pikwer, C Orellana, H Källberg, A Pikwer, C Turesson, L Klareskog, L Alfredsson, S Saevarsdottir, C Bengtsson

Session B2 6

OP08/PP143 The association of fatigue, comorbidity burden, disease activity, disability, and gross domestic product in patients with rheumatoid arthritis. Results from 34 countries participating in the QUEST-RA programme KL Grøn, L Ørnbjerg, M Hetland, T Sokka; and Quest-RA investigators

www.scandjrheumatol.dk

Contents

Session C3 12


12

OP17/PP214 Long-term 52-week results of PALACE 1, a phase 3, randomized, controlled trial of apremilast, an oral phosphodiesterase inhibitor, in patients with psoriatic arthritis A Adebajo, J Gomez-Reino, P Mease, J Wollenhaupt, C Hu, K Shah, R Stevens, A Kavanaugh OP18/PP222 Aortic regurgitation is common in ankylosing spondylitis and justifies routine echocardiographic screening E Klingberg, BG Sveälv, M Scharin Täng, O. Bech-Hanssen, L. Bergfeldt, H Forsblad-d’Elia

18

PP105 Dietary impact on treatment results of MTX in patients with RA C Lourdudoss, A Wolk, C Bengtsson, L Alfredsson, R van Vollenhoven

19

PP106 In early RA, the multi-biomarker disease activity score at different time points is predictive of subsequent radiographic progression K Hambardzumyan, R Bolce, S Saevarsdottir, K Forslind, I Petersson, P Geborek, S Ernestam, E Sasso, D Chernoff, S Cruickshank, R van Vollenhoven

20

PP107 Using the multi-biomarker disease activity score as a complementary inclusion criterion for clinical trials in rheumatoid arthritis may enhance recruitment K Hambardzumyan, R Bolce, S Saevarsdottir, K Forslind, S Ernestam, I Petersson, E Sasso, CC Hwang, O Segurado, P Geborek, R van Vollenhoven

21

PP108 Anti-citrullinated protein antibodies facilitate migration of synovial tissue-derived fibroblasts M Sun, V Joshua, AH Hensvold, M Engstro€m, IR Botusan, SB Catrina, V Malmstr€o m, AI Catrina, H Wähämaa

21

PP109 The presence of anti-carbamylated protein antibodies prior to onset of symptoms of rheumatoid arthritis (RA) is associated with radiological progression in early RA M Brink, MK Verheul, J Ro€nnelid, R Holmdahl, RE Toes, L Klareskog, LA Trouw, SR Dahlqvist

22

PP111 Patterns of isotype distribution in circulating antibodies in the pre-clinical phase of rheumatoid arthritis and their relationship to smoking C Turesson, U Bergstro€m, L Truedsson, A Sohrabian, L Jacobsson, J R€o nnelid

22

PP113 Autoantibodies to citrullinated proteins are associated with bone destruction marker and are modulated by first anti-rheumatic treatment in early rheumatoid arthritis AH Hensvold, V Joshua, W Li, M Larkin, F Quresh, L Israelsson, N Defranoux, S Saevarsdottir, AI Catrina

23

PP114 High serum cholesterol predicts rheumatoid arthritis in women C Turesson, U. Bergstro€m, M Pikwer, J-Å Nilsson, L Jacobsson

24

PP115 High prevalence of metabolic syndrome in early rheumatoid arthritis patients with normal weight: a case–control study R Müller, M Kull, T Eglit, A Aart, K Põlluste, M Lember, R Kallikorm

24

PP116 Recent infections and risk of rheumatoid arthritis: results from the population-based EIRA case–control study M Sandberg, C Bengtsson, L Klareskog, L Alfredsson, S Saevarsdottir

25

PP117 Self-reported physical activity and the risk of rheumatoid arthritis: a prospective study S Hagel, E Lindqvist, U Bergstro€m, M Pikwer, J-Å Nilsson, LT Jacobsson, C Turesson

Session C4 13

OP19/PP226 The diagnostic utility of hand and wrist fluorescence optical imaging in evaluating active synovitis Y Kisten, N Gyo€ri, H Rezaei, A Karlsson, E af Klint, R van Vollenhoven

Modern imaging - clinical and molecular 14

15

OP20/PP223 Magnetic resonance imaging (MRI) assessment of early response to certolizumab pegol in rheumatoid arthritis: a randomized, doubleblind, placebo-controlled Phase IIIb study applying MRI at weeks 0, 1, 2, 4, 8, and 16 M Østergaard, L Jacobsson, C Schaufelberger, M Sejer-Hansen, J Bijlsma, A Dudek, M Rell-Bakalarska, F Staelens, R Haake, B Sundman-Engberg, H Bliddal OP21/PP228 Diagnostic utility of musculoskeletal ultrasound in patients with suspected arthritis: a probabilistic approach H Rezaei, S Torp-Pedersen, E af Klint, Y Kisten, N Gyo€ri, RF van Vollenhoven

Poster Session Monday Pre-clinical and early phases of rheumatoid arthritis 15

16

PP101 The association between postmenopausal hormone therapy and the risk of rheumatoid arthritis: results from the Swedish EIRA study C Orellana, S Saevarsdottir, L Klareskog, L Alfredsson, C Bengtsson PP102 What is the predictive value of a family history of arthritis-related conditions on the risk of rheumatoid arthritis, and does it differ between seropositive and seronegative disease? T Frisell, K Hellgren, J Askling

16

PP103 Subclinical synovitis of the hands and wrists detected by fluorescence optical imaging and ultrasound Y Kisten, N Gyo€ri, H Rezaei, A Karlsson, E af Klint, R van Vollenhoven

17

PP104 The role of oestrogen in regulating LPS-induced inflammation in NADPH oxidase 2-deficient mice A Stubelius, A Andersson, R Holmdahl U Islander, H Carlsten



Contents Treatment strategies for rheumatoid arthritis

Pain in rheumatic diseases - clinical and molecular aspects

25

33

PP131 The relationship between sleep quality and pain, mood status and clinical symptoms in the patients with fibromyalgia syndrome: preliminary results of cross-sectional study A Bilgici, G Alayli, Y Ulus, N Hezer, O Kuru

33

PP133 Decreased risk for severe persisting pain in elderly patients with early rheumatoid arthritis: results from the Swedish population-based EIRA and SRQ register M Sandberg, R Altawil, L Alfredsson, L Klareskog, S Saevarsdottir, J Lampa

34

PP134 Effect of a thin dynamic insole on pain and walking ability in rheumatoid arthritis BH Linberg, AM Mengshoel

34

PP135 Kaltenborn’s manual mobilization method for pain relief in RA hand joints: clinical and ultrasound findings in a pilot study S Lind, P Nordstro€m, Y Kisten, A Levitsky, N Vivar, R van Vollenhoven

35

PP137 Remaining pain despite inflammation control in rheumatoid arthritis: long-term increased risk for widespread pain and fatigue ME Sandberg, S Saevarsdottir, R Altawil, L Klareskog, L Alfredsson, J Lampa; and the EIRA working group

PP119 Adalimumab (Humira®) normalizes melanocortin receptor subtype 2, 3, and 4 expression in CD8+, CD14+, and CD19+ leucocyte subsets in rheumatoid arthritis M Andersen, MK Olesen, I Nagaev, O Nagaeva, J Wikberg, L Mincheva-Nilsson, GN Andersen; and The Scandinavian Melanocortin Study Group

26

PP120 Methotrexate therapy without initial dose escalation V Sigurdardottir, T Husmark, J Lysholm, A Svärd

27

PP121 Impact of tumour necrosis factor inhibitor treatment on hand bone loss in rheumatoid arthritis patients treated in clinical practice: results from the nationwide Danish DANBIO registry LMM Ørnbjerg, M Østergaard, P Bøyesen, T Jensen, A Thormann, U Tarp, W Bøhme, D Dencker, H Lindegaard, UE Poulsen, A Hansen, V Ringsdal, A Schlemmer, N Graudal, AR Andersen, J Espesen, G Kollerup, T Christensen, R Pelck, B Glintborg, O Madsen, DV Jensen, O Majgaard, M Hetland

28

29

PP122 The tissue-selective oestrogen complex efficiently inhibits experimental arthritis and inflammation-induced bone loss with minimal uterine side-effects A Andersson, A Bernardi, A Stubelius, M Nurkkala-Karlsson, L Grahnemo, H Carlsten, U Islander PP123 Methotrexate in rheumatoid arthritis and psoriasis/psoriatic arthritis: a comparative study of hepatotoxicity J Karlsson Sundbaum, V Berglund, J Back, N Lehto, I Vikman, O Rollman, E Baecklund

Osteoarthritis- molecular and clinical aspects 36

PP138 Heparin-binding protein (HBP) in joint fluid distinguishes rheumatoid arthritis from osteoarthritis A Linder, A Gülfe

36

PP139 Bone mineral density in postmenopausal women with hip osteoarthritis N Grygorieva, V Povoroznyuk, S Krochak

29

PP124 The reliability of the Disease Activity Score in 28 joints (DAS28) might be overestimated RA Andreasen, MNVB Hansen, IMJ Hansen

30

PP126 In rheumatoid arthritis patients with stable low disease activity on etanercept plus methotrexate, continuation of etanercept is clinically and radiographically superior to discontinuation: results from a randomized, double-blind clinical trial M Østergaard, K Franck-Larsson, M Leirisalo-Repo, T Uhlig, M Jansson, E Larsson, F Brock, R van Vollenhoven

Fatigue and cognitive dysfunction in rheumatic diseases 37

PP140 The prevalence of pernicious anaemia, cobalamine and folic acid deficiency among patients newly diagnosed with rheumatoid arthritis: a descriptive cross-sectional study N Lomborg, SA Just, R Gildberg-Mortensen, RA Andreasen, IMJ Hansen

31

PP127 NORD-STAR: a multicentre, randomized, open-label, blindedassessor, phase 4 study in patients with early rheumatoid arthritis M Seddighzadeh; for the NORD-STAR investigators

37

PP142 Fatigue correlates with mental health and quality of life in primary Sj€ogren’s syndrome R Kiani, LVasaitis, A Svanberg, G Nordmark

32

PP128 Variations in the interval between dispensed doses were observed between self-administered TNF inhibitors A Berglund, E Larsson

38

PP144 Fatigue in adult idiopathic inflammatory myopathies Å Bjo€rklund, I Lundberg, H Alexanderson

32

PP129 TNF inhibitor therapy and risk of breast cancer recurrence in patients with rheumatoid arthritis P Raaschou, T Frisell, J Askling; and The ARTIS Study group

Comorbidities and rheumatic diseases 39

PP146 Does rheumatoid arthritis protect against multiple sclerosis, and if so, when? A population-based study E Arkema, T Frisell, T Olsson, J Askling


Contents 39

PP147 Dietary nutrients and carotid atherosclerosis in SLE patients C Lourdudoss, R van Vollenhoven, J Frostegård

40

PP148 Heart involvement in systemic sclerosis patients and mice models P Venalis, G. Kumańovics, H Schulze-Koops, A Distler, C Dees, P Zerr, K Palumbo-Zerr, L Czirja´k, Z Mackevic, IE Lundberg, O Distler, G Schett, JH Distler


41

PP150 Expression of HMGB1 and its receptors in hearts of patients with coronary artery disease with or without inflammatory rheumatic disease: a biopsy study M Zong, I Hollan, H Xiao, C Wick, H Harris, I Lundberg

42

PP152 A comparison between patients with rheumatoid arthritis in the western part of Sweden with or without treatment with biologics K Bengtsson, M Dehlin, E Hilme, G Kvist, B Rydberg, T Torstenson, A Lindhe´, SM Wallerstedt, H. Forsblad-dE´lia

43

PP153 Frequency of metabolic syndrome in patients with gout: a retrospective cross-sectional study M Morillon, IMJ Hansen

43

PP154 Increased incidence of low-energy fractures in RA patients from northern Sweden € SR Dahlqvist, K Wiberg, U Bergstro€m, M-L Ohman

44

45

PP155 The value of the QuantiFERON TB Gold In-Tube test in the identification of latent tuberculosis in rheumatic patients before treatment with TNF-α blockers in Vilnius University Hospital Santariskiu Clinics I Arstikyte, I Butrimiene, R Zablockis, A Venalis PP157 Prevalence of comorbidities in rheumatoid arthritis: does gross domestic product matter? Results from 34 countries in the QUEST-RA programme KL Grøn, L Ørnbjerg, M. Hetland, T Sokka; QUEST-RA investigators

49

PP162 Low CD4/CD8 ratio is associated with lower immunoglobulin levels in granulomatosis with polyangiitis patients receiving rituximab E Besada, JC Nossent

49

PP163 Chronic nasal carriage of Staphylococcus aureus in granulomatosis with polyangiitis patients receiving rituximab maintenance: friend or foe? E Besada, W Koldingsnes, JC Nossent

50

PP164 Late-onset neutropaenia in ANCA-associated vasculitis after rituximab treatment A Knight, A Bruchfeld, I Gunnarsson

51

PP165 The use of positron emission tomography (PET) imaging as a diagnostic procedure when vasculitis is suspected S Salomäki, K Taimen, J Silvola, J Kemppainen, U Hohenthal, A Saraste, A Roivainen, L Pirilä

51

PP166 The impact of clinical features and corticosteroids on biopsy findings in giant cell arteritis K Jakobsson, L Jacobsson, A Mohammad, J-Å Nilsson, K Warrington, E Matteson, C Turesson

52

PP167 The diagnostic performance of FDG PET-CT in patients with polymyalgia rheumatica and giant cell arteritis RA Gildberg-Mortensen, E Øster-Jørgensen, S Hess, IMJ Hansen

Molecular aspects on pathogenesis in arthritis/bone destruction 53

PP168 Cathepsin S and cathepsin L in serum and synovial fluid in rheumatoid arthritis with and without autoantibodies T Weitoft, A Larsson, V Manivel, J Lysholm, A Knight, J Ro€nnelid

53

PP169 Chemokine-mediated regulation of Th17-cell migration as a novel mechanism for oestrogen-induced amelioration of experimental arthritis A Andersson, A Stubelius, M Nurkkala-Karlsson, C Engdahl, M Erlandsson, L Grahnemo, MK Lagerquist, U Islander

Autoinflammatory diseases - clinical and molecular aspects 46

PP158 Gout: an old disease in a new phenotype M Fiene, B Fiene, V Karnebeck

Vasculitis 46

PP159 Inflammation, vitamin D, and bone mineral density in patients presenting with giant cell vasculitis and/or polymyalgia rheumatica SA Just, RA Andreasen, R Gildberg-Mortensen, N Lomborg, P Weihe, IMJ Hansen

53

PP170 CD25+CD39+ Tregs are enriched at the site of inflammation of patients with rheumatoid arthritis and impaired in suppressing IL-17A secretion J Herrath, K Chemin, I Albrecht, AI Catrina, V Malmstrom

47

PP160 Carcinoma of the prostate, RS3PE and polymyalgia rheumatica: a case study RA Gildberg-Mortensen, LK Nielsen, E Øster-Jørgensen, S Hess, IMJ Hansen

54

PP171 Alternatively spliced isoform expression of PTPN2 in rheumatoid arthritis M Houtman, K Shchetynsky, L Padyukov

54

48

PP161 Clinical and laboratory characteristics associated with visual complications in patients with biopsy-proven giant cell arteritis M Saleh, C Turesson, M Englund, PA Merkel, AJ Mohammad

PP172 Lasofoxifene and bazedoxifene suppress bone marrow B-cell development differently than 17β-oestradiol and do not increase peripheral B-cell activity A Bernardi, A Andersson, L Grahnemo, M Nurkkala Karlsson, H Carlsten, U Islander



Contents 55

PP173 B-cell responses to de novo identified citrullinated fibrinogen peptides are associated with the PTPN22 risk allele V Joshua, L Schobers, L Israelsson, M Hansson, J Ro€nnelid, AI Catrina, GJ Pruijn, V Malmstro€m

60

PP204 Costs in relation to disability, disease activity, and health-related quality of life in rheumatoid arthritis JA Karlsson, J Eriksson, J-Å Nilsson, T Olofsson, L-E Kristensen, M Neovius, P Geborek

55

PP174 Osteoclastogenesis is enhanced by anti-citrullinated proteins antibodies in rheumatoid arthritis A Krishnamurthy, V Joshua, H Wähämaa, N Tarasova, C Cerqueira, E Ossipova, N Vivar, K Amara, K Lundberg, V Malmstro€m, P-J Jakobsson, G Schett J Ytterberg, A Catrina

61

PP205 Patient characteristics in the Prospective International Register of Biologics in SLE (IRBIS-II): year 1 data M Mild, DJ Wallace, AE Clarke, SR Bernatsky, C Peschken, S Jacobsen, G. Ruiz-Irastorza, JG Hanly, D Kamen, R Ramsey-Goldman, MA Petri, P Fortin, R van Vollenhoven; and the SLICC group

56

PP175 HIF-2α-dependent RANKL induction and osteoclastogenesis is augmented by inflammatory cytokines S Revu, A Krishnamurthy, X Zheng, VG Sunkari, IR Botusan, M Korotkova, S-B Catrina, A Catrina

62

PP206 Sick leave and disability pension in relation to first initiation of biologic therapy across indications: a nationwide cohort study J Eriksson, L Jacobsson, L-E Kristensen, J Askling, M Neovius

63

57

PP176 Identification of a new citrullinated collagen type II T-cell epitope in HLA-DRB1*1001-positive rheumatoid arthritis patients K Chemin, E James, J Herrath, I Albrecht, C Anca, L Padyukov, L Ro€nnblom, L Klareskog, V Malmstr€o m

PP207 How good is the coverage and how accurate are data in the Swedish biologics register (ARTIS)? H Wadstrom, J Askling, M Neovius, J Eriksson

64

PP208 Drug survival in patients receiving golimumab treatment 2010–2013: results from the Swedish Rheumatology Quality register S Saevarsdottir, M Santacatterina, L Stawiarz, C Turesson, H Forsblad-d’Elia, L Jacobsson, S Lindblad

57

PP177 Anti-TNF therapy with adalimumab restores the bone metabolism balance through a dual mechanism in rheumatoid arthritis A Krishnamurthy, S Revu, A Hensvold, P Neregård, M Engstro€m, E af Klint, D Makrygiannakis, A Catrina

58

PP178 Differences in the autoreactive T-cell pool when restricted by the highly related rheumatoid arthritis-associated HLA-DRB1 alleles *04:01, *04:04, and *01:01 C Sandin, C Gerstner, H Uchtenhagen, E James, J Pieper, M Rieck, A Achour, JH Buckner, T Sandalova, V Malmstr€o m

58

PP179 Endogenous B-cell-targeted antigen expression induces tolerance to collagen type II arthritis in mice S Andersson, T Eneljung, S Tengvall, L Mårtensson, K Gustafsson, H Rikard, J Kihlberg, A Stern, P Jirholt, I Gjertsson

Spondyloarthritis - pathogenesis and management 64

PP210 Effect of secukinumab on psoriasis symptoms and physical functioning compared with placebo and etanercept in subjects with moderate-to-severe plaque psoriasis and concomitant psoriatic arthritis: a subanalysis from the phase 3 fixture study B Sigurgeirsson, A Gottlieb, R Langley, S Philipp, R Martin, C Papavassilis, S Mpofu

65

PP211 A number of autoimmunity-related gene polymorphisms are not associated with ankylosing spondylitis in a Latvian population J Zepa, L Zepa, I Bulina, A Sarbantovica, V Lavrentjevs, E Sikora, J Arajs, A Lejnieks, D Andersone, J Klovins, L Nikitina-Zake

66

PP212 A rare case of Pott’s disease in Denmark A Osmanagic, JC Bang, R Ramoskiene, IMJ Hansen

66

PP213 Comparison of sociodemographic characteristics, clinical variables, and depression in patients with psoriasis and psoriatic arthritis O Kuru, S Ketenci, A Bilgici, G Alayli, Y Akyol, Y Ulus

67

PP215 Long-term 52-week results of PALACE 3, a phase 3, randomized controlled trial of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with psoriatic arthritis and current skin involvement C Edwards, F Blanco, J Crowley, C Hu, R Stevens, C Birbara

68

PP216 Long-term safety and tolerability of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with psoriatic arthritis: pooled safety analysis of three phase 3, randomized controlled trials A Adebajo, P Mease, A Kavanaugh, D Gladman, J Gomez-Reino, J Wollenhaupt, M Cutolo, G Schett, E Lespessailles, K Shah, C Hu, R Stevens, C Edwards, C Birbara

Poster Session Tuesday Comparative effectiveness of treatments for rheumatic diseases 59

59

60

PP201 Baricitinib, an oral janus kinase inhibitor, in the treatment of rheumatoid arthritis: safety and efficacy in an open-label, long-term extension study P Taylor, M Genovese, E Keystone, D Schlichting, S Beattie, W Macias, J Lundmark (presenter only) PP202 In early RA patients with non-response to methotrexate monotherapy the change in multi-biomarker disease activity score is differentially associated with subsequent response to non-biological vs. biological therapy K Hambardzumyan, R Bolce, S Saevarsdottir, K Forslind, I Petersson, P Geborek, S Ernestam, E Sasso, D Chernoff, S Cruickshank, R van Vollenhoven PP203 Utilization of Nordic registries to support health economics research in rheumatic diseases H Miller



Contents 69

PP217 Inflammatory bowel disease-associated arthropathy: characteristics of the disease and validity of diagnoses based on ICD coding in Sweden P Drivelegka, N Papachrysos, I Petterson, A Bremander, L Jacobsson

69

PP218 Disease severity as measured by PROMs or need for second-line treatment in inflammatory bowel disease-associated arthropathy: comparison to other spondyloarthritis subgroups P Drivelegka, N Papachrysos, I Petersson, A Bremander, L Jacobsson

70

PP219 Comparison of non-radiographic axial spondyloarthritis and ankylosing spondylitis patients: baseline characteristics and development of clinical variables during 3 years of anti-TNF therapy in clinical practice JA Karlsson, MC Kapetanovic, IF Petersson, P Geborek, L-E Kristensen

71

71

PP220 The use of the mSASSS method by different specialists J Zepa, I Bulina, V Lavrentjevs, S Kadike, L Nikitina-Zake, A Lejnieks, D Andersone

72

PP224 Trabecular bone score in patients with rheumatoid arthritis V Povoroznyuk, T Karasevska, R Povoroznyuk, B Aubry-Rozier, D Hans

73

PP225 Influence of glucocorticoids on trabecular bone score in patients with rheumatoid arthritis V Povoroznyuk, T Karasevska, B Aubry-Rozier, N Dzerovych, R Povoroznyuk, D Hans

73

PP227 Dual-energy CT (DECT) imaging of tophi and monosodium urate deposits in a patient with longstanding anorexia nervosa JP Weihe, MB Morillon, J Lambrechtsen, IMJ Hansen

75

PP235 Smoking functions as a negative regulator of IGF-1 levels and the adipokine network in patients with rheumatoid arthritis M Bokarewa, M Erlandsson, RD Medina, ST Silfverswärd, A Ioan-Facsinay

77

PP236 An outsourced health-enhancing physical activity programme for people with rheumatoid arthritis. Feasibility, adherence and response: the PARA 2010 study B Nordgren, C Frideń, I Demmelmaier, G Bergstro€m, I Lundberg, A Dufour, C Opava; and The PARA study group

78

PP237 Smoking cessation in patients with rheumatic disease M-L Karlsson, S Pettersson, I Lundberg

78

PP238 Effect of exercise and lifestyle interventions on an outpatient rehabilitation programme for patients with hip or knee OA I Tollefsrud, E Askmann

79

PP239 Development of a Web and Mobile Application (WeMApp) to support physical activity in rheumatoid arthritis: results from the second step of a co-design process Å Revenäs, CH Opava, I Demmelmaier, C Keller, P Åsenlo€f

80

PP240 The Swedish Exercise Self-Efficacy Scale (ESES-S): reliability and validity in a rheumatoid arthritis population T Nessen, I Demmelmaier, B Nordgren, CH Opava

80

PP241 Serum 25-hydroxyvitamin D below 75 nmol/L in 75% of healthy Swedish adults during 75% of the year E Klingberg, G Oler€o d, J Konar, M Petzold, O Hammarsten

PP221 Hyaluronan is related to TNF in patients with ankylosing spondylitis D Hedqvist, U Hellman, L Do, B Sundstro€m, S Wållberg-Jonsson

Modern imaging - clinical and molecular

74

76

PP229 Whole-body and conventional magnetic resonance imaging for assessing inflammation and structural damage in psoriatic arthritis and axial spondyloarthritis RPP Poggenborg, SJ Pedersen, I Eshed, IJ Sørensen, OR Madsen, JM Møller, M Østergaard

Inflammatory systemic diseases - immunological mechanisms and clinical phenotypes 81

PP242 Detection of antinuclear antibodies: a comparison of indirect immunofluorescence on HEp-2 cells and fluoroenzymeimmunoassay (EliA CTD screen, Thermo Fisher) LN Troelsen, S Jacobsen

81

PP244 Autoantibodies against high mobility group box protein-1 in systemic lupus erythematosus: association with disease activity and other antinuclear antibodies C Sjo€wall, L Wirestam, J Wettero€, L Ottosson, E Sundberg, T Skogh, H Schierbeck

82

PP245 Development of IgG antibodies to streptavidin may explain a case of false-positive autoantibody screening test for connective tissue disease (CTD) PH Duhn, T Skovsted, B Kristensen, H Locht

83

PP246 Comparison of lymphomas in primary and secondary Sj€ogren’s syndrome L Vasaitis, G Nordmark, J Askling, K Ekstrom-Smedby, C Backlin, C Sundstro€m, E Theander, E Baecklund

PP230 MRI of the hand and wrist as a tool for detection of joint damage in early rheumatoid arthritis K Forslind, B Svensson

Life-style factors and intervention in rheumatic diseases 75

PP231 Comparison of a 12-week partly supervised exercise programme with a self-administered exercise programme for patients with newly diagnosed rheumatoid arthritis T Seneca, EM Hauge, T Maribo

76

PP234 Screening and simple counselling affect traditional cardiovascular risk factors in patients with early rheumatoid arthritis J Isaksson, S Wållberg-Jonsson, G-M Alenius, A S€o dergren


Contents 83

PP247 Sex ratio of offspring born to women with lupus E Arkema, J Salmon, JF Simard

84

PP248 Initial symptoms of sarcoidosis can be neurological: a case study J Henriksen, KE Olsen, R Ramoskiene, IMJ Hansen


85

85

PP249 Maternal and foetal outcomes in pregnant systemic lupus erythematosus patients: an incident cohort from a stable referral population followed during 1990–2010 IM Jakobsen, RB Helmig, K Stengaard-Pedersen PP250 Angiogenesis factors: markers for paraneoplastic rheumatic syndromes . . I Taliju¯niene , P Venalis, J Dadoniene, A Venalis, J Distler, I Lundberg, . R Rugiene

86

PP251 High serum levels of IFN-λ1/3 and IFN-α characterize two separate subgroups among SLE patients V Oke, J Gustafsson, S Brauner, A Zickert, I Gunnarsson, E Svenungsson

87

PP252 An NFKB1 gene promoter polymorphism is associated with primary Sj€ogren’s syndrome G Nordmark, L Vasaitis, E Theander, M Kvarnstro€m, SJ Johnsen, JG Brun, MV Jonsson, C Sjo€wall, H Forsblad-d’Elia, M Wahren-Herlenius, R Omdal, R Jonsson, M-L Eloranta, P Eriksson

88

88

PP254 Work ability in patients with polymyositis and dermatomyositis: an exploratory and descriptive study M Regardt, EWHenriksson, J Sandqvist, I Lundberg, M-L Schult PP255 Activated T cells enhance interferon-α production by plasmacytoid dendritic cells stimulated by RNA-containing immune complexes D Leonard, M-L Eloranta, N Hagberg, O Berggren, K Tandre, G Alm, L Ro€nnblom

90

PP259 Decreased disease activity and corticosteroid usage and no renal flares during belimumab treatment in patients with systemic lupus erythematosus I Parodis, E Svenungsson, M Axelsson, I Gunnarsson

91

PP260 Microcirculation and macrovascular disease in systemic sclerosis: a nailfold capillary study A Nordin, L Bj€o rnådal, E Roubi, K Jensen-Urstad, E Svenungsson

92

PP261 Effect of single-nucleotide polymorphisms on type I interferon production by plasmacytoid dendritic cells stimulated with SLE-associated immune complexes O Berggren, A Alexsson, K Tandre, A-C Syvänen, L R€o nnblom, M-L Eloranta

92

PP262 A new method for evaluating the extent of pulmonary fibrosis in patients with systemic sclerosis E Roubi, S Nyreń, L Bjo€rnådal, E Svenungsson, A Nordin

93

PP263 Characterization of histidyl-tRNA synthetase specific Th-cell response in blood and bronchoalveolar lavage (BAL) cells of myositis patients I Albrecht, E James, M Fathi, M Dastmalchi, J Herrath, K Chemin, J Wahlstro€m, J Grunewald, V Malmstro€m, I Lundberg

93

PP264 Diagnostic value of ANA and ENA among patients with paraneoplastic rheumatic syndromes . G Kapleryte , R Rugiene, J Dadoniene, E Aleknavicius, J Distler, A Venalis, P Venalis

94

PP265 An uncommon cause of dyspnoea B Fiene, M Fiene

94

PP266 Epilepsy in systemic lupus erythematosus L Hopia, M Andersson, E Svenungsson, F Piehl, T Tomson

95

PP267 Proteomics and metabolomics in the classification of SLE subsets P-J Jakobsson, E Svenungsson, H Idborg, P Nilsson, C Wheelock, I Gunnarsson, J Trygg, J Lehtio€, I Schuppe Koistinen; Identification of subphenotypes and biomarkers in systemic autoimmune diseases, an academic Karolinska–AstraZeneca joint programme

95

PP268 Renal microangiopathy in SLE with renal involvement: a biopsy study J Gerhardsson, B Sundelin, L Padyukov, A Zickert, E Svenungsson, I Gunnarsson

89

PP256 Indirect immunofluorescence on HEp-2 cells vs. ELIA CTD screen for the detection of antinuclear antibodies T Korsholm, A Troldborg, BD Nielsen

89

PP257 Increased levels of thrombin-activatable fibrinolysis inhibitor (TAFI) correlate with complement activation in patients with the antiphospholipid syndrome A Antovic, A Vikerfors, E Svenungsson

96

PP269 Bone mineral density and predictors thereof in a population-based cohort of individuals with juvenile chronic arthritis 17 years after disease onset L Bertilsson, BA Gäre, A Fasth, IF Petersson, H Forsblad-d’Elia

90

PP258 Profile of T-cell subsets in peripheral blood from idiopathic inflammatory myositis patients F Espinosa, K De Anda, D Gomez

96

PP270 Socioeconomic consequences of juvenile chronic arthritis: a population-based study 22 years after disease onset L Bertilsson, BA Gäre, A Fasth, IF Petersson, H Forsblad-d’Elia

Adolescent rheumatology


Scand J Rheumatol 2014;43 Suppl 127:1–97

How to apply current knowledge comparing the effectiveness of treatments for rheumatic diseases OP01/PP209


Initial infliximab is not cost-effective added on to a remission-targeted combination therapy in early rheumatoid arthritis: the 2-year results of the randomized clinical NEO-RACo trial V Rantalaiho1, J Martikainen2, H Kautiainen3,4,5, K Puolakka6, M Leirisalo-Repo7,8; and the NEO-RACo Study Group 1

Department of Internal Medicine, Centre for Rheumatic Diseases, Tampere University Hospital, 2Pharmacoeconomics and Outcome Research Unit, School of Pharmacy, University of Eastern Finland, Kuopio, 3Unit of Primary Health Care, Helsinki University Central Hospital, 4Department of General Practice, University of Helsinki, 5Unit of Primary Health Care, Turku University Hospital, 6Department of Medicine, South Karelia Central Hospital, Lappeenranta, 7Department of Medicine, Division of Rheumatology, Helsinki University Central Hospital, and 8Department of Clinical Medicine, University of Helsinki, Finland

Background: We have recently published the clinical results of the double-blind NEO-RACo trial (1, 2), in which 99 patients with early, DMARD-naïve RA were treated with a triple combination of DMARDs and prednisolone (FIN-RACo treatment strategy), and were randomized to receive either infliximab (INFL) or placebo (PLA) infusions during the first 6 months. Here we study the incremental cost-effectiveness of the addition of INFL to the remission-targeted combination treatment with DMARDs. Method: In the NEO-RACo trial, the treatment goal of all patients was strict remission; predefined treatment modifications and intra-articular glucocorticoids were applied in active disease. The resource use including all RA-related visits, medications, and intra-articular injections collected from the 99 patients during the 2-year follow-up. The unit costs of the resources used were obtained from the national list of health care unit costs and other published sources. Utility was assesses by SF-6D and quality-adjusted lifeyears (QALYs) gained were estimated. Results: At 24 months, 66% and 53%, respectively, of the patients in the FIN-RACoþINFL and FIN-RACoþPLA groups were in tight remission and 82% in both groups were in remission by the 28-joint disease activity score. The average total costs of treatment for 2 years were 15 347€ for the patients in the FIN-RACoþINFL group and 5481€ for those in the FIN-RACoþPLA group. Incremental costs were 9866€ (bootstrapped 95% CI 8750–11 124). Utility at baseline in the FINRACoþINFL and FIN-RACoþPLA groups was 0.61 (SD 0.13) and 0.60 (SD 0.11), respectively. QALYs

1

gained were 0.76 and 0.73 in 2 years, and the difference was 0.031 (95% CI 0.02 to 0.09) QALYs. The 2-year incremental cost-effectiveness ratio (ICER) was 320 032€ per additional QALY gained. Conclusions: In early RA, adding a 6-month course of INFL into a targeted treatment with combination DMARDs and prednisolone is not cost-effective. References 1. Leirisalo-Repo M, Kautiainen H, Laasonen L, Korpela M, Kauppi MJ, Kaipiainen-Seppänen O, et al. Infliximab for 6 months added on combination therapy in early rheumatoid arthritis: 2-year results from an investigator-initiated, randomised, double-blind, placebocontrolled study (the NEO-RACo Study). Ann Rheum Dis 2013;72:851–7. 2. Rantalaiho V, Kautiainen H, Korpela M, Hannonen P, KaipiainenSeppänen O, Möttönen T, et al. Targeted treatment with a combination of traditional DMARDs produces excellent clinical and radiographic long-term outcomes in early rheumatoid arthritis regardless of initial infliximab. The 5-year follow-up results of a randomised clinical trial, the NEO-RACo trial. Ann Rheum Dis. Published online: 28 October 2013. doi:10.1136/annrheumdis-2013-203497.

A1. Treatment strategies for RA: today and tomorrow OP02/PP125 Impact of physicians’ activity and adherence to treat-totarget strategy on outcomes in early rheumatoid arthritis: a subanalysis of the Neo-RACo trial L Kuusalo1, V Rantalaiho2, H Kautiainen3, M Korpela2, K Puolakka4, M Leirisalo-Repo5,6 1 Satakunta Central Hospital, Rauma, 2Department of Internal Medicine, Centre for Rheumatic Diseases, Tampere University Hospital, 3Unit of Primary Health Care, Helsinki University Central Hospital, 4South Karelia Central Hospital, Lappeenranta, 5 Department of Medicine, Division of Rheumatology, Helsinki University Central Hospital, and 6Institute of Clinical Medicine, University of Helsinki, Finland

Background: We have previously shown that, in early RA, remission-targeted, intensified initial FIN-RACo combination treatment, regardless of initial infliximab for 6 months, results in remission in most patients (1, 2). We wanted to explore whether physicians’ activity and adherence to a treat-to-target strategy affected the outcomes of early RA in these very aggressively treated patients. Method: In the Neo-RACo study 99 patients with early, active RA were treated with methotrexate, sulfasalazine, hydroxychloroquine, and low-dose prednisolone for 2 years. Patients were randomized to receive either infliximab or placebo for the initial 6 months. Therapy was unrestricted after 2 years and aimed at strict remission. Physicians’ (n ¼ 30) activity during 15 study visits between 0 and 24 months was evaluated

© 2014 Informa Healthcare on license from Scandinavian Rheumatology Research Foundation DOI: 10.3109/03009742.2014.946235


SCR 2014 – abstracts

2

References

100

1. Leirisalo-Repo M, Kautiainen H, Laasonen L, Korpela M, Kauppi MJ, Kaipiainen-Seppanen O, et al. Infliximab for 6 months added on combination therapy in early rheumatoid arthritis: 2-year results from an investigator-initiated, randomised, double-blind, placebocontrolled study (the NEO-RACo Study). Ann Rheum Dis 2013;72:851–7. 2. Rantalaiho V, Kautiainen H, Korpela M, Hannonen P, KaipiainenSeppänen O, Möttönen T, et al. Targeted treatment with a combination of traditional DMARDs produces excellent clinical and radiographic long-term outcomes in early rheumatoid arthritis regardless of initial infliximab. The 5-year follow-up results of a randomised clinical trial, the NEO-RACo trial. Ann Rheum Dis 2013. Published online: 28 October 2013. doi:10.1136/ annrheumdis-2013-203497.

90 80


Remission, %

70 60 50 40 30

OP03/PP130 20

Does disease activity at start of biologic therapy influence productivity losses in patients with RA?

10 p = 0.018

p = 0.048

p = 0.025

p = 0.40

2

3

4

5

0 Years

with a scoring system. The maximum for inactivity was 1 point/visit. Patients were divided into tertiles according to the activity of treatment. After follow-up of 5 years, strict Neo-RACo remission rates, 28-joint disease activity score (DAS28) levels, radiological changes, cumulative work disability, and antirheumatic medication after 2 years were evaluated. Neo-RACo strict remission was defined as no swollen or tender joints and five out of the following six criteria: morning stiffness 24 000 US dollars (USD) per capita] and 18 with low GDP (24 000 USD per capita) or low GDP ( 10 mg/L, the number of eligible patients can be increased while maintaining the ability to detect treatment responses. Method: In the SWEFOT trial, DMARD-naïve patients with early RA were enrolled, without a CRP requirement, and received methotrexate (MTX) monotherapy from baseline; at 3 months, non-responders to MTX (NR, DAS28 > 3.2) received treatment intensification. We analysed: (i) patients from baseline to 3 months and (ii) MTX non-responders; for the latter population we used data from month 3 as the de facto baseline and changes from month 3 to 12 as the measured response. In both analyses patients were grouped according to CRP ( 10 vs. > 10 mg/L) or MBDA score ( 44 vs. > 44) and assessed for clinical outcomes from baseline to 3 months following treatment with MTX, and from 3 to 12 months for add-on therapy (triple therapy or anti-TNF). Radiographic progression was assessed by change in SHS from baseline to 1 year for both analyses. Results: For the DMARD-naïve population (n ¼ 220), baseline values and changes from baseline for disease activity measures and DSHS were similar for patients with CRP > 10 mg/L vs. MBDA score > 44. Moreover, by adding the 37 patients with an MBDA score >44 and CRP 10 mg/L to the group with CRP > 10 mg/L (n ¼ 154), the combined group (n ¼ 191) had 24% more patients and similar clinical and radiographic outcomes. Similarly, for the MTX non-responder population (n ¼ 127), values at month 3 and changes to month 12 were similar for the CRP > 10 mg/L and MBDA >44 groups, and adding the 23 patients with month 3 MBDA score > 44 and CRP 10 mg/L to the group with CRP > 10 mg/L (n ¼ 49) created a combined group (n ¼ 72) with 47% more patients and similar outcomes. The results are summarized in Table 1. Conclusions: These data suggest that, if a clinical trial of DMARD-naïve or MTX non-responder patients were to include all patients with an MBDA score > 44 and/or CRP > 10 mg/L, the number of eligible patients can be increased by 24% and 47%, respectively, compared with enrolment based on CRP > 10 mg/L alone, while maintaining clinical and radiographic outcomes.

Table 1. DMARD naïve (n ¼ 220)

N MBDA DAS28 TJC SJC Patient global CRP (mg/dL) DSHS > 3 BL to 12 months (%)


MTX non-responders (n ¼ 127)

CRP > 10 mg/L

MBDA > 44

CRP > 10 mg/L or MBDA > 44

CRP > 10 mg/L

MBDA > 44

CRP > 10 mg/L or MBDA > 44

154 –16.4 –1.8 –4.6 –5.8 –20.2 –27.0 33

186 –15.7 –1.8 –4.7 –5.9 –18.9 –22.4 33

191 –15.6 –1.8 –4.6 –5.8 –18.7 –22.1 34

49 –23.2 –2.0 –4.0 –6.7 –18.5 –25.9 53

69 –21.4 –1.8 –4.5 –6.2 –16.8 –16.9 49

72 –20.7 –1.8 –4.1 –5.9 –16.2 –17.0 49


PP108

PP109

Anti-citrullinated protein antibodies facilitate migration of synovial tissue-derived fibroblasts

The presence of anti-carbamylated protein antibodies prior to onset of symptoms of rheumatoid arthritis (RA) is associated with radiological progression in early RA

1 Rheumatology Unit, Department of Medicine and 2Department of Molecular Medicine and Surgery, Diabetes Centre Karolinska, Karolinska Institute, Stockholm, Sweden

Background: Anti-citrullinated proteins antibodies (ACPAs) are highly specific for RA and are associated with a more aggressive disease phenotype leading to joint destruction. RA synovial fibroblasts (SFs) are the cellular key players in promoting both synovial inflammation and bone destruction and have been shown to transmigrate through the bloodstream in a mouse model. In this study we aimed to investigate the effects of ACPAs on RASF migration. Method: Human dermal fibroblasts (HDFs) were obtained from PromoCell. SFs were isolated from synovial tissue of RA patients by enzymatic digestion. ACPAs were isolated from peripheral blood of RA patients and monoclonal anti-citrullinated antibodies were obtained from synovial fluid by single B-cell cloning. Both RASFs and HDFs were analysed in migration assays (scratch test) with or without ACPAs. Cells were cultured and grown to 80–90% confluence in collagen-coated 24-well plates and serum starved (DMEM) for 1–2 h. After a linear scratch on the plate, cells were incubated with or without ACPAs IgG and control IgG (at a final concentration of 1000 ng/mL) in the presence of mitomycin. The effect of PI3K inhibition by wortmannin was also tested. Light microscopy images are taken immediately and 6 h after scratching. At the end of the experiment, the culture medium was collected for cytotoxicity testing. The light microscopy images were analysed using NIH ImageJ. The closure areas were normalized to medium control, and this value presents the migration index. Results: ACPAs but not control IgG induce a 3.92 0.45 (mean SD) fold increase in dermal fibroblasts migration and a 2.63 0.47 (mean SD) fold increase in RASF migration. PI3K blocking almost completely abolished ACPA effects, although a minimal residual effect of ACPAs compared to control IgG could still be observed even in the presence of wortmannin (a mean SD 1.39 0.38 fold increase). This effect was not mediated through cell death induction as demonstrated by LDH assay. Further testing of monoclonal antibodies with different reactivity profiles demonstrated that some but not all of these antibodies have similar migration promoting effects. Conclusions: Enhanced RASF migration effects on exposure to ACPAs are at least partly mediated through RTK and integrin pathways.

M Brink1, MK Verheul2, J Rönnelid3, R Holmdahl4, REM Toes2, L Klareskog5, LA Trouw2, SR Dahlqvist1 1 Public Health and Clinical Medicine, Rheumatology, Umeå University, Sweden, 2Department of Rheumatology, Leiden University Medical Centre, The Netherlands, 3Department of Immunology, Genetics and Pathology, Uppsala University, Sweden, and Departments of 4Medical Biochemistry and Biophysics and 5Medicine, Karolinska Institute, Stockholm, Sweden

Background: The presence of a new autoantibody system, anti-carbamylated protein (anti-CarP) antibodies, has been identified in rheumatoid arthritis (RA) and to predate disease onset (1–3). The presence of anti-CarP antibodies was evaluated in samples from individuals who subsequently developed RA sampled before and after onset of symptoms and related to previously analysed antibodies against citrullinated peptides (ACPA specificities) and anti-CCP2. The concentration of anti-CarP antibodies and radiological progression was evaluated after disease onset. Method: In this study, 252 individuals, with 423 samples, sampled before onset of symptoms of RA, and 197 population controls were identified as donors to the Medical Biobank of Northern Sweden. Of these, 192 were also sampled at the time of diagnosis. All samples were analysed for anti-CarP IgG and antiCCP2 antibodies using ELISAs. Ten different antibody reactivities against citrullinated antigens (ACPA specificities) were analysed using a custom-made microarray based on the ImmunoCAP ISAC system (Phadia) (4). Radiographs of hands and feet was graded according to the Larsen score. Results: The concentration of anti-CarP antibodies was significantly increased in the pre-symptomatic individuals compared with controls (p < 0.001) and also increased significantly after disease onset (p < 0.001) (Figure 1). The sensitivity for anti-CarP antibodies in p < 0.001 p < 0.001

2000 anti-CarP (AU/mL)

M Sun1, V Joshua1, AH Hensvold1, M Engström1, IR Botusan2, SB Catrina2, V Malmström1, AI Catrina1, H Wähämaa1


21

1000 800 600 400 Cut-off 100 0

Controls

Pre-symptomatic individuals

Patients



22


the pre-symptomatic individuals was 13.9% (95% CI 11– 17.6), and following development of RA 42.2% (95% CI 35.4–49.3). Anti-CarP antibody positivity was found in 5.1–13.3% of individuals negative for anti-CCP2 or ACPA specificities. The presence of anti-CarP antibodies was significantly related to radiological destruction at baseline, at 24 months, and also to progression (p < 0.05, all). Conclusions: The results indicate that anti-CarP antibodies evolve independently from anti-CCP2 antibodies and presently available ACPA specificities and identify a subset of patients with worse radiological progression of the disease independent of ACPA. References 1. Shi J, Knevel R, Suwannalai P, van der Linden MP, Janssen GMC, van Veelen PA, et al. Autoantibodies recognizing carbamylated proteins are present in sera of patients with rheumatoid arthritis and predict joint damage. Proc Natl Acad Sci USA 2011;108:17372–7. 2. Shi J, van de Stadt LA, Levarht EWN, Huizinga TWJ, Toes REM, Trouw LA, et al. Anti-carbamylated protein antibodies are present in arthralgia patients and predict the development of rheumatoid arthritis. Arthritis Rheum 2013;65:911–15. 3. Shi J, van Veelen PA, Mahler M, Janssen GMC, Drijfhout JW, Huizinga TWJ, et al. Carbamylation and antibodies against carbamylated proteins in autoimmunity and other pathologies. Autoimmun Rev 2014;13:225–30. 4. Brink M, Hansson M, Mathsson L, Jakobsson PJ, Holmdahl R, Hallmans G, et al. Multiplex analyses of antibodies against citrullinated peptides in individuals prior to development of rheumatoid arthritis. Arthritis Rheum 2013;65:899–910.

PP111 Patterns of isotype distribution in circulating antibodies in the pre-clinical phase of rheumatoid arthritis and their relationship to smoking C Turesson1, U Bergström1, L Truedsson2, A Sohrabian3, L Jacobsson1,4, J Rönnelid3 1 Rheumatology, Department of Clinical Sciences, Lund University, Malmö, 2Section of Microbiology, Immunology and Glycobiology, Department of Laboratory Sciences, Lund University, 3Department of Immunology, Genetics and Pathology, Uppsala University, and 4Department of Rheumatology and Inflammation Research, Sahlgrenska Academy at the University of Gothenburg, Sweden

Background: Previous studies indicate that several different isotypes of circulating anti-citrullinated peptide antibodies (ACPAs) and rheumatoid factor (RF) can be detected years before onset in individuals who later develop rheumatoid arthritis (RA), and that smoking is a predictor of RA. The objective was to investigate isotypes of antibodies to cyclic citrullinated peptides (CCPs) and RF, and their relationship to smoking, before the onset of RA. Method: Incident cases of RA were identified among participants (n ¼ 30 447) in a community-based health survey that was linked to local and national registers,


followed by a structured review of the medical records. One control from the health survey, matched for age, sex, and year of inclusion, was selected for each validated case. IgG anti-CCP2 antibodies were determined by standard ELISA methods (Euro-Diagnostica; locally defined cut-off 20 U/L). IgA and IgM anti-CCP2, and IgA, IgM, and IgG RF were detected using the EliA assay on the Phadia 2500 (Phadia/Thermo Fisher AB, Uppsala, Sweden). The standard anti-CCP antigen (the same as for the IgG anti-CCP2 measurements) was used. Cutoffs for these assays were set at the 98th percentile, based on investigation of sera from the matched controls. Analyses were stratified by time from inclusion in the health survey to RA diagnosis (1–3, 4–5, 6–8, and 9–13 years, respectively), and by history of current or ever smoking. Results: Serum was available from 166 cases (78% women) who were diagnosed with RA a median of 5 years (IQR 3–8; range 1–13) after inclusion in the health survey. The most frequently detected isotypes in the preRA individuals were IgM RF (24%) and IgG anti-CCP2 (22%). Among the IgM RF-positive individuals who later developed RA, 56% were positive for IgA RF and 46% were positive for IgG RF, and among those positive for IgG anti-CCP2, 73% were IgA anti-CCP2 positive and 19% were IgM anti-CCP positive. All isotypes were observed in a limited number of cases sampled > 9 years before RA diagnosis (n ¼ 33) (anti-CCP2: 12% IgG, 12% IgA, 6% IgM; RF: 18% IgM, 15% IgG, 12% IgA). The proportions with positive tests increased significantly with shorter time to diagnosis for IgG anti-CCP2 (p ¼ 0.026), IgA anti-CCP2 (p ¼ 0.046), and IgM RF (p ¼ 0.029), with a similar trend for IgA RF (p ¼ 0.09). Current (p < 0.001) and ever smoking (p ¼ 0.003) were associated with subsequent development of RA. There were no major differences in detected anti-CCP2 or RF isotypes before RA diagnosis between current smokers and current nonsmokers, whereas ever smokers were more likely than never smokers to be positive for IgG anti-CCP2 (28% vs. 13%; p ¼ 0.02) and IgG RF (15% vs. 6%; p ¼ 0.09), but not for the other isotypes. The time to RA diagnosis was similar in ever smokers and never smokers. Conclusions: Different patterns in isotype distribution are seen for anti-CCP2 antibodies and RF in the preclinical phase of RA. A history of smoking may contribute to the development of, in particular, IgG ACPA and IgG RF before the clinical onset of RA, suggesting a role for smoking in the very early pathogenesis of the IgG seropositive RA phenotype. PP113 Autoantibodies to citrullinated proteins are associated with bone destruction marker and are modulated by first anti-rheumatic treatment in early rheumatoid arthritis AH Hensvold1, V Joshua1, W Li2, M Larkin1, F Quresh2, L Israelsson1, N Defranoux2, S Saevarsdottir1, AI Catrina1



1 Rheumatology Unit, Department of Medicine, Karolinska Institute and Karolinska University Hospital, Stockholm, Sweden and 2Crescendo Bioscience, Inc, San Francisco, CA, USA

Background: There is an increased risk of bone destruction in anti-citrullinated protein antibody (ACPA)positive rheumatoid arthritis (RA). Recently, a cellular mechanism by which ACPA increase bone destruction in RA has been suggested. Receptor activator of nuclear factor kappa B ligand (RANKL) is a key molecule in the normal regulation but the presence of RANKL in serum in novel ACPA-positive and ACPA-negative RA has not been yet been thoroughly studied in early RA. The aim was to investigate RANKL in relation to the presence of antibodies to citrullinated proteins in a cohort of earlyuntreated RA patients. Method: Treatment with methotrexate was initiated in 183 patients with newly diagnosed untreated RA and symptoms for less than 1 year and analyses were conducted at baseline and after 3 months. Serum levels of total RANKL (ELISA; Biovendor Human sRANKL, Brno, Czech Republic) were determined. We also screened for ACPA by the anti-CCP2 test and for antibodies against citrullinated (cit) alpha-enolase (CEP-1) aa5-21, cit vimentin aa60-75, and cit fibrinogen aa563583 peptides (ELISA). Synovial RANKL expression was investigated by immunohistochemistry in a subgroup of patients (n ¼ 15). Results: RANKL levels were increased in synovia and serum in ACPA-positive (n ¼ 7/125) as compared to ACPA-negative RA (n ¼ 8/58) patients. The risk of RF interference made us restrict the continuing analysis of serum levels to the RF-negative patients (n ¼ 59) and similar results were found, as well as a 279 pmol/L increase (p < 0.05) after adjusting for patient characteristics (age, sex, and smoking). RANKL and all four different ACPAs were decreased at follow-up after the methotrexate treatment. X-ray hand and feet bone erosions at baseline were more frequent in anti-cit vimentin-positive (32%) than anticit vimentin-negative (15%) patients and this accumulation was not present in anti-cit enolase and anti-cit fibrinogen compared to negative patients. Conclusions: Our data indicate a role for RANKL in the early pathogenesis of ACPA-positive RA. We suggest that our results should be added to the increasing knowledge of a direct link between ACPA (and RANKL) and the bone destructive processes in RA. PP114 High serum cholesterol predicts rheumatoid arthritis in women C Turesson1, U Bergström1, M Pikwer1,2, J-Å Nilsson1, L Jacobsson1,3 1 Rheumatology, Department of Clinical Sciences, Lund University, Malmö, 2Rheumatology Unit, Mälar Hospital, Eskilstuna, and 3Department of Rheumatology and

23 Inflammation Research, Sahlgrenska Academy at Gothenburg University, Sweden

Background: Patients with active rheumatoid arthritis (RA) tend to have low cholesterol levels because of the effects of inflammation on lipid metabolism. However, several prospective studies have indicated that a high serum cholesterol level may be associated with increased risk of RA. Metabolic pathways in the development of RA may be affected by hormonal factors, and have a different impact in men and women. The purpose of this study was to examine sex-specific effects of total serum cholesterol on the future risk of RA. Method: Between 1974 and 1992, subjects (n ¼ 33 346; 22 444 men and 10 902 women) from a defined catchment area were included in a Preventive Medicine Programme (PMP). Information on lifestyle factors was obtained using a self-administered questionnaire. Blood samples were taken in the morning, after an overnight fast. Serum cholesterol was assessed immediately by an enzymatic method routinely used by the local hospital laboratory. From this population, we identified individuals who developed RA after inclusion by linking the PMP register to the local community-based RA register and to local and national patient administrative databases. In a structured review of the medical records, patients were classified according to the 1987 American College of Rheumatology (ACR) criteria for RA. Four controls for each validated case, matched for sex, year of birth and year of screening, who were alive and free of RA when the index person was diagnosed with RA, were selected from the PMP register. The impact of serum cholesterol on the risk of RA was examined in conditional logistic regression models, stratified by sex. Results: Two hundred and ninety patients [151 men and 139 women; median time from inclusion to RA diagnosis 12 years (interquartile range 8–18, range 1– 28); mean age at diagnosis 60 years] were diagnosed with RA and fulfilled the ACR criteria after inclusion in the PMP. There was no difference in cholesterol levels between men who subsequently developed RA and controls (mean 5.66 vs. 5.64 mmol/L). By contrast, women with a diagnosis of RA during the follow-up had higher cholesterol levels at baseline compared to controls [mean 6.04; standard deviation (SD) 1.16 vs. 5.71 (SD 1.11) mmol/L; odds ratio (OR) 1.47 per SD, 95% confidence interval (CI) 1.16–1.86, adjusted for smoking]. A higher cholesterol level was predictive of RF-positive RA (p ¼ 0.014) as well as RF-negative RA (p ¼ 0.004) in women. The association between higher cholesterol and subsequent development of RA in women remained significant in multivariate analyses adjusted for early menopause (at age < 46 vs. 46 years) (p ¼ 0.01). The association with future RA was statistically significant among those included 1–12 years before RA diagnosis (p ¼ 0.034) as well as among those included 13–28 years before RA diagnosis (p ¼ 0.001). Women with cholesterol levels in the



24

highest quartile (6.50–9.70 mmol/L) had an increased risk of RA compared to those in the second quartile (4.95–5.65 mmol/L) (smoking-adjusted OR 2.72, 95% CI 1.44–5.14). There was no similar pattern in men. Conclusions: A high serum cholesterol level was associated with increased risk of RA in women but not in men. This suggests that sex-specific exposures modify the impact of lipids on the risk of RA. The strong association with higher cholesterol among women surveyed long before RA diagnosis implicates early metabolic pathways in the aetiology of RA.


PP115 High prevalence of metabolic syndrome in early rheumatoid arthritis patients with normal weight: a case–control study R Müller, M Kull, T Eglit, A Aart, K Põlluste, M Lember, R Kallikorm Department of Internal Medicine, Tartu University, Estonia

Background: The term ‘metabolic syndrome’ (MetS) refers to a cluster of specific cardiovascular disease (CVD) risk factors: abdominal obesity, hypertension, hyperglycaemia, high triglycerides, and low HDL. MetS begins with the development of central adiposity. Rheumatoid arthritis (RA) is known to raise CVD risk but the pathogenesis of CVD in RA patients is not well explained by traditional risk factors (1, 2). It is known that the prevalence of MetS is raised in established RA but evidence in early arthritis is controversial (1). The aim of this study was to evaluate the prevalence of MetS in the early stage of RA. Method: MetS was diagnosed according to the National Cholesterol Education Program Adult Treatment Panel III criteria (3). The prevalence of MetS was evaluated in 71 patients with early RA and 213 (1:3 ratio) healthy sexand age-matched controls from a population sample ( 3 years). Both groups were divided into subgroups according to BMI: normal weight (BMI 24.9 kg/m2), overweight (BMI 25 kg/m2), obese (BMI 30 kg/m2). The χ 2 test was used to compare differences in prevalence of MetS in groups, the Mann–Whitney U test to compare means. SPSS version 22 was used in the data analysis. Table 1. Cardiovascular risk factors in early RA and controls.

2

BMI (kg/m ), mean (SE) Normal weight, % (n) Overweight, % (n) Obese, % (n) Metabolic syndrome, % (n) BMI 24.9 kg/m2 BMI 29.9 kg/m2 BMI 30 kg/m2


Early RA n ¼ 71

Controls n ¼ 213

p-value

26.8 (0.57) 40.0 (28) 60.0 (42) 23.9 (17) 32.4 (28) 17.9 (5) 31.5 (17) 64.7 (11)

28.1 (0.41) 31.8 (67) 68.2 (144) 35.8 (76) 39.4 (69) 1.5 (1) 15.4 (21) 61.8 (47)

NS NS NS NS NS 0) was 9/20 (45%) for PBO, 6/24 (25%) for ETN25, and 2/20 (10%) for ETN50. Radiographic progression was limited to 2 points in all but one patient in the PBO group (SHS D ¼ 3). Adverse events were similar between the groups; no unexpected safety signals were noted. Conclusions: More patients in the PBO group had radiographic progression than those in the ETN50 and ETN25 groups. These radiographic data plus the clinical findings suggest that discontinuing ETN after achieving a stable

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LDA/REM state may lead to clinical worsening and radiographic damage.

PP127 NORD-STAR: a multicentre, randomized, open-label, blinded-assessor, phase 4 study in patients with early rheumatoid arthritis M Seddighzadeh; for the NORD-STAR investigators Department of Medicine, Unit for Clinical Research Therapy, Inflammatory Diseases (ClinTRID), Karolinska Institutet, Stockholm, Sweden

Background: The optimal treatment for patients with early rheumatoid arthritis has not yet been fully defined. Specifically, it remains unclear whether the early initiation of a biologic therapy (anti-TNF, T-cell costimulation modulation, or anti-IL-6) is superior to optimized conventional therapy, and whether such early intervention might also allow for subsequent withdrawal of the biologic. Method: NORD-STAR is a multicentre, randomized, open-label, blinded-assessor, phase 4, Nordic trial in patients with early rheumatoid arthritis (symptom duration < 24 months). The global aim was to compare (i) the proportion of subjects who achieve remission with active conventional therapy vs. three biologic treatments, and (ii) two de-escalation strategies in patients who respond to treatment. The characteristics and clinical course of the first 81 enrolled patients are available and described. Clinical disease activity was evaluated using the disease activity score in 28 joints (DAS28) and the clinical disease activity index (CDAI). The change in mean DAS28 (ESR and CRP) and median CDAI, between day 1 and weeks 4, 12, and 24, was evaluated in the whole group of patients and after stratification for anti-cyclic citrullinated peptide (anti-CCP) antibody status. Moreover, the proportion of patients in remission according to CDAI ( 2.8) at week 24 was assessed. Results: The first 81 patients in the NORD-STAR trial had a mean age of 57 years and a median symptom duration of 6 months; 70.4% were female (57/81 patients) and 74.1% (60/81 patients) were anti-CCP antibody positive. Following enrolment and treatment initiation, DAS28 and CDAI decreased steadily between day 1 and week 24 and the change from baseline was highly significant (p < 0.001). Moreover, the greatest change in DAS28 and CDAI was observed during the first month of treatment. For patients with a completed week 24 visit (n ¼ 40), the anti-CCP antibody-negative group of patients demonstrated a greater reduction in CDAI compared to the anti-CCP antibodypositive group. Furthermore, in this subgroup of patients, 32.5% (n ¼ 13) were in remission according to CDAI criteria.



Conclusions: The NORD-STAR trial has commenced and more than 100 patients have been enrolled, proving the feasibility of this large Nordic investigator-initiated trial. The patients’ characteristics are as expected in this setting. The clinical improvements following enrolment have been excellent, underscoring the fact that four very good therapeutic strategies can be compared head-to-head for the first time.


PP128

Mean number of days

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60 55 50 45 40 35 30 25 20 15 10 5 0

Enbrel Simponi Humira Cimzia

0 2 4 6 8 10 13 16 19 22 25 28 31 34 37 40 Number of Prescriptions

Variations in the interval between dispensed doses were observed between self-administered TNF inhibitors A Berglund, E Larsson Pfizer AB, Sollentuna, Sweden

Background: Among prescribed TNF inhibitors, the interval between dosages is sometimes shortened because of insufficient effect for the whole interval between dosing. This can occur from the beginning or develop over time. For the latter case, production of neutralizing antibodies can have an impact. In other cases the interval can be prolonged, for example by a dose down strategy initiated by the doctor or the patient in case of remission. The aim of the present study was to study the time interval between dosages between TNF blockers among adult rheumatoid arthritis (RA) patients in Sweden. Method: This retrospective study retrieved information from the Swedish National Patient Registry and the Swedish Prescribed Drugs Registry and included adult patients diagnosed with RA (ICD-10 M05.8, M05.9, M06.0, M06.9) and first-time prescribed etanercept, adalimumab, golimumab, and certolizumab pegol between May 2010 and December 2013. Results: Among the adult patients diagnosed with RA with at least 365 days of follow-up, 921 patients on etanercept, 569 on adalimumab, 257 on golimumab, and 303 certolizumab pegol were analysed. The time interval between the first two dosages was a mean of 36.6 days for etanercept, 38.7 days for adalimumab, 34.1 days on golimumab, and 44.9 days for certolizumab pegol. The mean number of days between dosages varied over time, the longest time was observed among certolizumab pegol (Cimzia) patients, and in total the number of days between dosages was reduced over time (Figure 1). Conclusions: Among adult patients diagnosed with RA with at least 365 days of follow-up, the mean number of dosages varied between TNF inhibitors and over time. An increased number of days following the first dosages were observed; thereafter the mean number of days between the dosages was reduced over time.


PP129 TNF inhibitor therapy and risk of breast cancer recurrence in patients with rheumatoid arthritis P Raaschou1, T Frisell1, J Askling1; and the ARTIS study group Department of Medicine, Karolinska Institute, Stockholm, Sweden

Background: Based on concerns that TNFi might increase the risk of cancer recurrence, in combination with limited evidence, most clinical guidelines advice against the use of TNFi in patients with a history of cancer during the past 5 or 10 years. We investigated the risk of breast cancer recurrence in female patients with RA and a history of breast cancer starting treatment with TNFi, taking RA, breast cancer, and comorbidity-related factors into account. Method: A total of 143 female TNFi-treated patients (1999–2010) with RA and a history of breast cancer prior to TNFi start were identified through register linkages, and matched 1:1 from a cohort of 1598 comparable biologic-naïve individuals. One hundred and twenty TNFi-treated and 120 matched biologicnaïve individuals with a history of equally recent/ distant breast cancer met the eligibility criteria and comprised the final study population. The primary outcome was first recurrence of breast cancer. Through register linkages and chart review, individuals were followed until 2011. Hazard ratios for recurrence were calculated using Cox regression. Results: The median time from breast cancer diagnosis until TNFi treatment/start of follow-up was 9.4 years. Modest differences in breast cancer characteristics and/ or treatment among TNFi-treated and biologic-naive patients were noted at the time of breast cancer diagnosis. The median follow-up was 4.9 years from TNFi start (4.6 years among biologic-naïve patients). Among the TNFitreated, nine developed breast cancer recurrence (crude incidence rate 15/1000 person-years) during follow-up, compared to nine among the matched biologic-naïve


(16/1000 person-years). The adjusted corresponding hazard ratio was 1.1 (95% CI 0.4–2.8). Conclusions: Among patients with RA and a history of breast cancer, those who started TNFi treatment did not experience more breast cancer recurrences than RA patients treated otherwise. The generalizability of our findings to women with a very recent or a poor prognosis breast cancer remains unknown.

Pain in rheumatic diseases - clinical and molecular aspects Scand J Rheumatol Downloaded from informahealthcare.com by Chinese University of Hong Kong on 02/03/15 For personal use only.

PP131 The relationship between sleep quality and pain, mood status and clinical symptoms in the patients with fibromyalgia syndrome: preliminary results of crosssectional study A Bilgici, G Alayli, Y Ulus, N Hezer, O Kuru Department of Rheumatology, Ondokuz Mayis University, Samsun, Turkey

Background: Fibromyalgia (FM) is a generalized chronic pain condition that is often accompanied by symptoms such as fatigue, sleep disturbances, psychological and cognitive alterations. Sleep disturbances play an important role in the exacerbation of pain and other troubling symptoms reported by patients with FM (1–3). Method: Thirty-eight female patients with FM were enrolled in the study. Disease severity measures included pain visual analogue scale (VAS), the Fibromyalgia Impact Questionnaire (FIQ), and an FM symptom severity scale (SSS). Patients were asked to complete the Beck Depression Inventory (BDI). The Pittsburgh Sleep Quality Index (PSQI) was applied to assess sleep quality. The PSQI includes 19 items that explore subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. The subscale scores ranged from 0 to 3 and the sleep quality total score ranged from 0 to 21. Scores of 0–5 indicate good sleep quality, scores > 6 indicate poor sleep quality. Results: All participants were aged between 26 and 53 years, with a mean age of 41.75 6.35 years. The mean disease duration was 7.27 4.95 years. While poor sleep quality was associated with higher depression (r ¼ 0.439, p < 0.01), VAS rest pain (r ¼ 0.843, p < 0.01), FIQ (r ¼ 0.290, p < 0.001), and SSS (r ¼ 0.590, p < 0.001) scores, there was no correlation with VAS motion pain score. Twenty-six (70%) of the FM patients had poor sleep quality. When the patients were divided into two groups of poor sleep quality (n ¼ 26) and good sleep quality (n ¼ 11), there was a statistically significant difference for depression, VAS rest pain, and SSS between the groups. Except for the VAS motion pain score, poor sleep quality was associated with higher depression, VAS rest pain, and SSS scores (p < 0.001, p < 0.01, and p < 0.001,

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respectively). FIQ subscores were found to be significantly higher in patients with poor sleep quality than in patients with good sleep quality (p < 0.05), except for being unable to work and work difficulty subscores. This may be explained by the fact that 21 of the patients were housewives. Conclusions: These findings show a high frequency of sleep problems in patients with FM and suggest that sleep quality may influence pain, mood state, and daily functioning in patients with FM. Indeed, the quality of sleep can also be impaired by pain, depression, and disease activity in such patients. However, it is not clear whether sleep disturbance is the primary reason of FM symptoms or the result of chronic pain and depression. References 1. Martínez MP, Miró E, Sánchez AI, Díaz-Piedra C, Cáliz R, Vlaeyen JW, et al. Cognitive-behavioral therapy for insomnia and sleep hygiene in fibromyalgia: a randomized controlled trial. J Behav Med 2014;37:683–97. 2. Orlandi AC, Ventura C, Gallinaro AL, Costa RA, Lage LV. Improvement in pain, fatigue, and subjective sleep quality through sleep hygiene tips in patients with fibromyalgia [in Portuguese]. Rev Bras Reumatol 2012;52:666–78. 3. Affleck G, Urrows S, Tennen H, Higgins P, Abeles M. Sequential daily relations of sleep, pain intensity, and attention to pain among women with fibromyalgia. Pain 1996;68:363–8.

PP133 Decreased risk for severe persisting pain in elderly patients with early rheumatoid arthritis: results from the Swedish population-based EIRA and SRQ register M Sandberg1, R Altawil2, L Alfredsson1, L Klareskog2, S Saevarsdottir2, J Lampa2 1

Institute for Environmental Medicine and 2Department of Medicine, Rheumatology Unit, Karolinska Institute, Stockholm, Sweden

Background: Pain is common in rheumatoid arthritis (RA) and a significant portion of patients also report pain after adequate disease suppression and achievement of low detectable inflammation. To optimize pain and anti-rheumatic treatment, there is a need for early identification of patients with pain that is independent of inflammation. The aim of this study was to investigate the prevalence and potential predictors for a severe persistent pain phenotype of early RA. Method: We used the cases from a Swedish populationbased case–control study, the EIRA study. In total, 1802 incident RA patients aged 18–70 years were recruited during 1996–2009 and followed in the Swedish Rheumatology Quality register for up to 5 years. We defined the RA severe persisting pain phenotype as having pain measured on a visual analogue scale (VAS) 50 at diagnosis and VAS 50 together with CRP < 10 mg/L at the 2-year follow-up visit. Logistic regression was used to calculate the effect of sex, age at diagnosis, and




34

calendar period of diagnosis on this outcome. We also further adjusted our model for smoking and socioeconomic status (based on education). Results: Out of 1733 patients with data on both time points, we found 123 patients with the severe persisting pain phenotype, generating a prevalence for this condition of 7.1%. Sex and calendar period of diagnosis did not affect persisting pain significantly, but age at diagnosis did. Compared to the reference group (aged 50–60 years), the oldest age group (aged 65–70 years) had a lower risk (OR 0.54, 95% CI 0.29–1.00); also for the youngest patients (aged < 40 years) there was an indication of a lower risk, albeit not statistically significant (OR 0.58, 95% CI 0.33–1.04). Further adjustments for smoking and socioeconomic status enhanced the effect of older age (for patients aged 65–70 years: OR 0.46, 95% CI 0.24–0.90), but smoking and socioeconomic status were not significant predictors themselves. There were no significant differences between the age groups concerning pain at diagnosis or correlation between pain and DAS28, either at diagnosis or after 2 years. Conclusions: In a population-based cohort of incident RA cases, older patients seem to have a lower risk for development of persisting pain in early disease, independent of sex, calendar period of diagnosis, smoking, and socioeconomic status. These data indicate that age is important to consider in further investigations of non-inflammatory coupled pain development in RA.

PP134 Effect of a thin dynamic insole on pain and walking ability in rheumatoid arthritis 1

References 1. Otter SJ, Lucas K, Springett K, Moore A, Davies K, Young A, et al. Comparison of foot pain and foot care among rheumatoid arthritis patients taking and not taking anti-TNFalpha therapy: an epidemiological study. Rheumatol Int 2011;31:1515–19. 2. Hennessy K, Woodburn J, Steultjens MP. Custom foot orthoses for rheumatoid arthritis: a systematic review. Arthritis Care Res (Hoboken) 2012;64:311–20.

PP135

2

BH Linberg , AM Mengshoel 1

Rehabilitation, Revmatismesykehuset Lillehammer and 2 Institute for Health and Society, University of Oslo, Norway

Background: Forefoot pain occurs frequently in rheumatoid arthritis (RA), and also among patients that are in remission (1). Such pain may limit walking and activities of daily life. Earlier studies on different insoles have shown the effect on pain, but there are various results concerning walking ability (2). The objectives of this study were to investigate the immediate effects of a customized dynamic insole on pain and walking ability in patients with RA and forefoot pain and whether the insoles were in use 1 year later. The insole in this study was thin and could fit into most shoewear. Method: An experimental study was performed on 21 patients with RA and forefoot pain in either one or both feet. Eighty-one per cent of the participants were women. Their mean age (SD) was 54 (11) years and median (range) disease duration was 4 (0.25–25) years. The


patients walked as fast as they could in 6 minutes (6MWT) with insoles (situation A) or without insoles (situation B). The order of situations A and B was randomized, and the assessor was blinded to the order of the two situations. Both tests were conducted on the same day. Walking ability was assessed by the 6MWT. Foot pain was assessed by a 10-cm visual analogue scale (VAS) anchored with no or worst pain immediately after situations A and B. A 1-year follow-up was conducted by a telephone interview. Results: The median (IQR) in VAS pain was 19 (15) in situation A and 36 (27) in situation B (p < 0.001). The effect size was 0.6, and the result is considered to be of clinical relevance. The difference between the two situations in 6MWT was not statistically significant (p ¼ 0.07). After 1 year, 86% of the participants were still using the insoles, 71% found that the insoles relieved their foot pain and 57% of the participants reported increased walking ability using the insoles. Conclusions: The use of a thin dynamic insole showed an immediate forefoot pain relief during walking. The pain-modifying effect of the insoles can be supported by the high number of patients still using the insoles after 1 year.

Kaltenborn’s manual mobilization method for pain relief in RA hand joints: clinical and ultrasound findings in a pilot study S Lind1, P Nordström1, Y Kisten2, A Levitsky2, N Vivar2, R van Vollenhoven2 Scandinavian College of Naprapathic Medicine and 2Unit for Clinical Therapy Research, Inflammatory Diseases (ClinTRID), Department of Medicine, Karolinska University Hospital, Karolinska Institute, Solna, Stockholm, Sweden 1

Background: Hand pain is an important manifestation of rheumatoid arthritis (RA) and although multifactorial in origin, pain has both central and peripheral components. Pain is only in part related to disease activity and shows striking individual variability. The Kaltenborn manual mobilization method is based on gentle traction and passive motion that has been tested extensively in osteoarthritic joints and found to provide pain relief, but there are no published studies on the use of this method in RA.


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PP137 Remaining pain despite inflammation control in rheumatoid arthritis: long-term increased risk for widespread pain and fatigue ME Sandberg1, S Saevarsdottir2, R Altawil2, L Klareskog2, L Alfredsson1, J Lampa2; and the EIRA working group


1 Institiute of Environmental Medicine and 2Department of Medicine, Rheumatology Unit, Karolinska Institutet, Stockholm, Sweden

Method: Five female RA patients (age 40–80 years) on stable anti-rheumatic therapy were studied. The wrist, MCP and PIP joints were examined clinically, and patient-reported outcomes (PROs) were collected. Synovitis, tenosynovitis, and disease activity were evaluated using an ultrasound Doppler quantification method. Using Kaltenborn’s technique, the MCP2–5 joints in one randomly selected hand (for 4/5 patients) were manually mobilized. Three treatment sessions were carried out every second day for 1 week. Clinical examination, blood tests, PROs, and ultrasound evaluations were acquired before and after the first and third treatment sessions. Results: Out of the 20 MCP joints treated in the test hand, 75% (15/20) were self-reported as tender, while 25% (5/20) were not. Of these tender joints at baseline, 67% (10/15) were non-tender after the third treatment session. In the control hand, 60% (12/20) were self-reported as tender. Of these tender joints at baseline, 50% (6/12) were non-tender after the third treatment. The mean VAS score ( SD) for the test hand at baseline was 60.0 ( 22.1) and after the last treatment 40.0 ( 24.2). The mean VAS score ( SD) for the control hand was 50.4 ( 25.0) at baseline and 31.0 ( 23.9) after the last treatments. Pearson correlation tests for tenderness among patient self-reports (1.0, n ¼ 40) and physician assessments (0.419**, n ¼ 40) of both treated and untreated hands demonstrated highly significant and clinically relevant (Rho >0.3) results for bilateral pain. (MeanSD) There was a statistically significant decrease in quantitative Doppler activity in the 20 treated joints from baseline (51.535.7) to the final post-test treatment session (30.5 30.8) (p < 0.002). Conclusions: Our data demonstrate an overall pattern of pain reduction from baseline to post-treatment, and a highly significant decrease in Doppler activity by ultrasound quantification analysis. The remarkable ultrasound findings may indicate possible physiological microcirculatory changes as a result of joint mobilization therapy. These results support further studies of Kaltenborn’s manual mobilization as a complementary treatment option for RA patients with tender hand joints despite anti-rheumatic therapy.

Background: Pain is common in rheumatoid arthritis (RA), even after achievement of low detectable inflammation. Important long-term health effects of RA are fatigue and sleeping problems and a significant portion of patients also develop generalized pain. The aim of the present study was to investigate the remaining pain dimension in RA, the distribution, which patients that may be at increased risk, and whether it is a risk factor for long-term generalized (widespread) pain and fatigue. Method: We used the cases (incident RA patients aged 18–70 years recruited 1996–2009) from the Swedish population-based EIRA study, linked to the Swedish Rheumatology Quality Register (n ¼ 1633). Three years after diagnosis, an additional questionnaire was sent out, assessing fatigue, pain outside joints and sleeping problems (n ¼ 186). Remaining pain was defined as pain on visual analogue scale (VAS) 20 mm and CRP < 10 mg/L at the 12-month follow-up visit. Logistic regression was used to calculate the odds ratio (OR) of remaining pain by baseline clinical parameters, adjusted for sex, age, and period, and OR of widespread pain (WSP)/pain outside joints/sleeping problems/fatigue, as effects of remaining pain. Results: At 12 months, 35% of the patients had remaining pain, and at 3 years 7% had WSP, 36% had pain outside joints, 17% had sleeping problems, and 26% had significant fatigue (VAS 40). We found a higher HAQ score, tender joint count, and patient global assessment at diagnosis to all significantly and independently increase the risk for remaining pain at 12 months: ORs were 1.28 (95% CI 1.02–1.60), 1.04 (95% CI 1.02–1.06), and 1.25 (95% CI 1.12–1.38) per 20 units, respectively. A higher CRP, ESR, and swollen joint count all significantly and independently decreased the risk for remaining pain: OR 0.84 (95% CI 0.76– 0.92) per 10 units, OR 0.89 (95% CI 0.80–0.99) per 10 units, and OR 0.97 (95% CI 0.94–1.00) per joint, respectively. Regarding the effect of remaining pain at 12 months on WSP/pain outside joints/sleeping problems/fatigue, we found, despite our few observations, a strongly increased risk for these conditions with remaining pain: OR for WSP was 3.48 (95% CI 1.24– 9.73), for pain outside joints 2.67 (95% CI 1.44–4.94), for sleeping problems 3.82 (95% CI 1.61–9.06), and for fatigue 2.43 (95% CI 1.25–4.72). All results remained after excluding patients with very high baseline pain



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(3.62–15.1) ng/mL. This difference was statistically significant (Mann–Whitney U test, p < 0.0001) (Figure 1). Conclusions: In this pilot study, to our knowledge the first to investigate HBP in body fluids other than plasma and cerebrospinal fluid, measurement of HBP in joint fluid was shown to be feasible. Significantly higher levels were demonstrated in RA than in OA. Reference 1. Tapper H, Karlsson A, Mörgelin M, Flodgaard H, Herwald H. Secretion of heparin-binding protein from human neutrophils is determined by its localization in azurophilic granules and secretory vesicles. Blood 2002;99:1785–93.

Osteoarthritis- molecular and clinical aspects PP139

PP138 Heparin-binding protein (HBP) in joint fluid distinguishes rheumatoid arthritis from osteoarthritis

Bone mineral density in postmenopausal women with hip osteoarthritis N Grygorieva, V Povoroznyuk, S Krochak

A Linder1, A Gülfe2 1

Department of Clinical Sciences, Infectious Diseases and Department of Clinical Sciences, Rheumatology, Lund University, Sweden 2

Background: Heparin-binding protein (HBP, azurocidin, cationic anti-microbial protein of 37 kDa), a serine protease abundant in neutrophil granulocytes, has shown promise as a plasma marker of severe sepsis but it has not been studied in joint fluid. Method: Knee joint fluid was drawn from patients with rheumatoid arthritis (RA) or osteoarthritis (OA) in need of a local steroid injection and stored at 80 C after centrifugation. HBP concentrations were determined using ELISA (1). A few of the RA patients were on diseasemodifying anti-rheumatic drugs but none were on biologics. Results: In RA (n ¼ 54), HBP median (interquartile range) concentration was 172 (6.43–448) ng/mL and in OA (n ¼ 22) the corresponding values were 5.80

1000

HBP (ng/mL)


levels (VAS > 70 mm), indicating that the presence of WSP/fibromyalgia at diagnosis had no major impact on the results. We further found that remaining pain led to significantly increased odds of having worsened pain according to VAS, worse sleeping problems, and more areas affected by pain. Conclusions: More than a third of all RA patients have remaining pain despite satisfactory inflammatory control 12 months after diagnosis. This condition is a strong predictor for widespread pain 3 years after diagnosis and also for non-joint-related pain, sleeping problems, and fatigue. These observations stress the importance of acknowledging and optimizing pain treatment in patients with adequate inflammatory control early in RA.

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10

1 RA


OA

Department of Locomotor Apparatus, Institute of Gerontology NAMS of Ukraine, Kyiv, Ukraine

Background: Osteoporosis and osteoarthritis (OA) are common diseases in women in the postmenopausal period. The reasons why osteoporosis and OA do not affect all women during their postmenopausal period have not yet been ascertained, and the mechanisms of bone loss and cartilage degeneration when ageing have not been studied completely. Some literature data have confirmed that indices of X-ray absorptiometry in women with hip osteoarthritis (HOA) are higher, but others have not confirmed this point. The aim was to study the relationship between bone state and development of HOA in postmenopausal women. Method: Sixty-nine women in the postmenopausal period aged 50–79 years with HOA were examined (mean age 65.6 0.6 years, weight 74.1 0.8 kg, height 158.6 0.4 cm, age of menopause 49.2 0.4 years, duration of postmenopausal period 16.2 0.6 years). The control group consisted the 60 healthy women without HOA. A diagnosis of OA was obtained according to ACR criteria. Women with primary knee OA were excluded from the study. Bone state was measured by Prodigy dual-energy X-ray absorptiometry (DXA) and Sahara calcaneus quantitative ultrasound (QUS) densitometry. Results: We found a significant correlation between indices of DXA and QUS densitometry and the presence and stage of HOA in postmenopausal women. X-ray absorptiometry data were significantly higher in patients with HOA than in healthy women [bone mineral density (BMD) of the trunk: F ¼ 7.71, p ¼ 0.006; spine: F ¼ 6.32, p ¼ 0.01; neck: F ¼ 4.08, p ¼ 0.04; Ward’s area: F ¼ 4.69, p ¼ 0.03; and total



BMD: F ¼ 5.61, p ¼ 0.02]. Indices of QUS densitometry in women with HOA were also significantly higher than in healthy women [estimated BMD: F ¼ 6.49, p ¼ 0.01; broadband ultrasound attenuation (BUA): F ¼ 9.8, p ¼ 0.002; SOS: F ¼ 3.45, p ¼ 0.05]. In postmenopausal women we did not found a significant relationship between some indices of DXA (L1–L4, total hip and radius) and the presence of HOA. Conclusions: The presence and stage of HOA had a significant influence on ultrasound densitometry and DXA indices. This is important in the assessment of bone state in women in the postmenopausal period with HOA.

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PA, one with known B12 deficiency, five with a family history of B12 deficiency, four with macrocytosis and one with microcytic anaemia, one with B12 as well as FA deficiency, four with FA deficiency, and five with B12 deficiency. Conclusions: The possible presence of PA or B12 and FA deficiencies among patients newly diagnosed with RA might influence the fatigue and hence the DAS28. We are planning to examine our patients further, with homocysteine and methylmalonic acid together with gastric parietal cell and intrinsic factor antibodies. References

Fatigue and cognitive dysfunction in rheumatic diseases PP140 The prevalence of pernicious anaemia, cobalamine and folic acid deficiency among patients newly diagnosed with rheumatoid arthritis: a descriptive cross-sectional study. N Lomborg, SA Just, R Gildberg-Mortensen, RA Andreasen, IMJ Hansen Department of Rheumatology, OUH Svendborg Hospital, Svendborg, Denmark

Background: Rheumatoid arthritis (RA) is an autoimmune disease with polyarthritis. RA is associated with other autoimmune diseases within the patient (1). Pernicious anaemia (PA) is an autoimmune disease characterized by autoimmune destruction of the parietal cells. Anaemia due to cobalamin (vitamin B12) deficiency (B12 199 pmol/L)) and folic acid (FA) deficiency (FA 6 nmol/L) has been shown in RA (2). Fatigue is the most common symptom. The co-occurrence of RA and PA has been reported in very few cases (3–6). An unrecognized PA, B12, or FA deficiency might contribute to a false high disease activity score (DAS28). The overall objective of this study was to investigate the prevalence of PA in a cohort of patients newly diagnosed with RA. Method: A cross-sectional study was carried out in which 108 patients diagnosed with RA from 2011 to 2014 at Svendborg Hospital Denmark were evaluated with blood tests at the first visit, including B12, FA, and mean cell volume. At follow-up in March 2014, all patients were interviewed and records were evaluated for known PA or B12 deficiency, family members with B12 deficiency, alcoholism, gastrostomy, small bowel disease, vegetarian diet, or medication with proton pump inhibitors. Results: There were 29 drop-outs due to unwillingness, death, severe somatic or psychiatric condition, or a revision of the diagnosis. We found one patient with known

1. Somers EC, Thomas SL, Smeeth L, Hall AJ. Are individuals with an autoimmune disease at higher risk of a second autoimmune disorder? Am J Epidemiol 2009;169:749–55. 2. Segal R, Baumoehl Y, Elkayam O, Levartovsky D, Litinsky I, Paran D, et al. Anemia, serum vitamin B12, and folic acid in patients with rheumatoid arthritis, psoriatic arthritis, and systemic lupus erythematosus. Rheumatol Int 2004;24:14–19. 3. Abraham Z, Rozenbaum M, Gluck Z, Feuerman EJ, Lahat N, Kinarty A. Vitiligo, rheumatoid arthritis and pernicious anemia. J Dermatol 1993;20:418–23. 4. Itoh H, Kitagawa T, Kitaoka K, Nishiyama M, Hosogi H, Nishiya K. A case of rheumatoid arthritis associated with pernicious anemia and bronchiolitis obliterans organizing pneumonia [in Japanese]. Ryumachi 1995;35:920–6. 5. Nakao E, Mitsunaga A, Hamano T, Shirato M, Shirato I, Nishino T. Case report of rheumatoid arthritis associated with type A gastritis and Hashimoto thyroiditis [in Japanese]. Nihon Shokakibyo Gakkai Zasshi 2010;107:927–32. 6. Wang PL, Liou LB, Dunn P. Development of rheumatoid arthritis in a patient with pernicious anemia: case report. Chang Gung Med J 2001;24:125–9.

PP142 Fatigue correlates with mental health and quality of life in primary Sjögren’s syndrome R Kiani1, L Vasaitis2, A Svanberg1, G Nordmark2 1

Department of Public Health and Caring Sciences and 2Section of Rheumatology, Department of Medical Sciences, Uppsala University, Sweden

Background: Overwhelming fatigue is common in patients with primary Sjögren’s syndrome (pSS). Although one-third of patients have manifestations from different organs such as joints, skin, lungs, and kidneys, fatigue is often the most disturbing symptom. One cause of fatigue might be a treatable condition such as depression. Fatigue can lead to impaired quality of life and reduced working capacity, and can influence relationships with family and friends. The aim of this investigation was to identify the prevalence of fatigue in a group of patient with pSS and study the correlation with depression, anxiety, quality of life, clinical manifestations, autoantibodies, inflammatory parameters, and anaemia.




38

Method: Eighty-two patients were invited to participate in the study and 62 accepted (75.6%). Patients completed four instruments: VAS fatigue, the EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI), the Hospital Anxiety and Depression Scale (HADS), and Short Form-36 (SF-36). Information on the presence of clinical manifestations and anti-SSA/SSB antibodies was extracted from patient files. Blood for analysis of ESR, CRP, and haemoglobin levels was sampled at the visit. Results: A total of 72.6% of the patients reported a high degree of fatigue ( 50 mm) measured by the VAS. The VAS scores correlated with ESSPRI fatigue scores (r ¼0.89). There were no differences in age, gender, clinical manifestations or frequency of anti-SSA/SSB antibodies between patients with high or low fatigue. Overall, 19% of the patients scored > 8/21 points for depression (HADSD) and 26% scored > 8/21 points for anxiety (HADS-A), indicating clinically relevant morbidity. VAS fatigue correlated significantly with HADS-D (r ¼ 0.51) and HADSA (r ¼ 0.41; both p < 0.0001). The patients rated their quality of life in SF-36 as low compared with published data on healthy individuals (1). VAS fatigue correlated with all eight domains in SF-36 (r ¼ 0.37 to 0.61; p < 0.01). There were no relationships between VAS fatigue and ESR, CRP, or haemoglobin levels. Conclusions: Fatigue occurred in approximately threequarters of our patients with pSS and correlated with depression, anxiety, and impaired quality of life. There was no relationship between fatigue and autoantibodies, clinical manifestations, ESR, CRP, or anaemia. Identification and treatment of depression and anxiety may possibly reduce fatigue in patients with pSS. Reference 1. Segal B, Bowman SJ, Fox PC, Vivino FB, Murukutla N, Brodscholl J, et al. Primary Sjogren’s syndrome: health experiences and predictors of health quality among patients in the United States. Health Qual Life Outcomes 2009;7:46.

PP144 Fatigue in adult idiopathic inflammatory myopathies Å Björklund1, I Lundberg2, H Alexanderson3 1

Hälsopoolen, 2Department of Medicine, Rheumatology Unit, Karolinska Institutet, and 3Department of Neurobiology, Health Care Sciences and Society, KI/Physiotherapy Clinic, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

Background: Adult polymyositis (PM), dermatomyositis (DM), and inclusion body myopathy (IBM) are rare disorders presenting with muscle impairment. Patients with these diseases also have reduced quality of life (1, 2). Fatigue is often a disabling symptom in other inflammatory rheumatic conditions such as rheumatoid arthritis; however, few studies have focused on studying fatigue in myositis and the knowledge of fatigue myositis and how fatigue changes over time is sparse. The objectives of this


study were to evaluate (i) fatigue severity and frequency in PM, DM, and IBM in comparison with populationbased reference values, (ii) a possible difference in fatigue between the myositis entities, (iii) correlations between fatigue and muscle function, disease activity and other aspects of quality of life, and (iv) how fatigue develops over time. Method: All patients registered in the Swedish Myositis Register at Karolinska University Hospital (n ¼ 80: 46 PM, 27 DM, and seven IBM; 55 women and 25 men) who had completed the SF-36 survey in 2013 during a yearly check-up were included in this study. They had a median age of 62 years, a median diagnosis duration of 8 years, and a median disease activity of 6 (Q1–Q3, 0–15) mm (physician’s global assessment on a VAS, 0–100). Data on fatigue (SF-36 vitality, 0–100 where 100 equals no fatigue) and muscle function (Functional Index 2, FI-2) were also collected. All patients who had completed the SF-36 survey at both 2009 and 2013 (n ¼ 41) were included so as to study how fatigue changed over time. Results: Median (Q1–Q3) fatigue for the whole group was 50 (30–70), only one rated no fatigue. There was no statistically significant difference in fatigue between patients with PM, DM, and IBM: medians of 48 (30– 70), 50 (35–80), and 45 (35–50), respectively. Patients had significantly more fatigue compared to reference values (p < 0.001). Correlations between the SF-36 vitality and the other SF-36 domains varied between rs ¼ 0.54 and rs ¼ 0.75, with the highest correlations to mental health (rs ¼ 0.75) and social function (rs ¼ 0.66). Correlations between SF-36 vitality and the FI-2, the HAQ score and the physician global assessment of disease activity were rs ¼ 0.46, 0.47, and 0.48, respectively, with lower correlations to prednisolone dose, diagnosis duration, and age (rs ¼ 0.35, 0.01, and < 0.01, respectively). There was no statistically significant change in fatigue at 2013 compared to scores from 2009, with median scores of 50 (35–72.5) and 45 (20–60), respectively. Conclusions: Patients with PM, DM, and IBM were found to experience equal fatigue severity and there were no differences between men and women. There was a high correlation between fatigue and self-reported mental health and a moderate-to-high correlation to social function, with moderate correlations to other aspects of health and to muscle impairment, daily activities, and disease activity and lower correlations to prednisolone dose, diagnosis duration, and age. Fatigue scores were unchanged over 5 years. References 1. Regardt M, Welin Henriksson E, Alexanderson H, Lundberg IE. Patients with polymyositis or dermatomyositis have reduced grip force and health-related quality of life in comparison with reference values: an observational study. Rheumatology (Oxford) 2011; 50:578–85. 2. Sadjadi R, Rose MR; Muscle Study Group. What determines quality of life in inclusion body myositis? J Neurol Neurosurg Psychiatry 2010;81:1164–6.


Comorbidities and rheumatic diseases

39 Table 1. Before RA onset

PP146 Does rheumatoid arthritis protect against multiple sclerosis, and if so, when? A population-based study E Arkema1, T Frisell1, T Olsson2, J Askling1


Departments of 1Medicine and 2Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

Background: Experimental data suggest shared susceptibilities but also an ‘either/or’ pattern of risk for RA and multiple sclerosis (MS). Observational data have suggested a possible reduced occurrence of MS among patients with RA (1). Other reports have suggested a possible increase in the occurrence of demyelinating events in RA treated with TNF inhibitors (2). A proper understanding of the co-occurrence of RA and MS is thus of both aetiological and clinical importance. Our aim was to estimate the risk of RA among patients who had had a demyelinating event and/or MS, and the risk of MS/ demyelinating events in patients with prior RA diagnosis, compared to the general population. Method: Cases with incident RA were identified from the National Patient Register (NPR; Swedish inpatient and outpatient care) and the Swedish Rheumatology Quality (SRQ) Register. General population comparators were selected from the Swedish Population Register matched to the RA patients by age, sex, and county. Data on demyelinating disease and MS among RA patients and their population comparators were extracted from the NPR. We used logistic regression models to calculate the odds ratio (OR) of having a history of MS by the time of RA diagnosis, and Cox regression models to calculate the hazard ratio (HR) of MS following RA diagnosis, in both analyses compared to the general population. Results: We included 8170 incident RA cases from the SRQ register and 40 728 general population-matched controls. The OR for RA associated with a history of MS was 0.68 (95% CI 0.38–1.21) and the OR for RA associated with a history of a demyelinating event was 0.48 (95% CI 0.17–1.33) (Table 1). Counting from RA diagnosis and onwards, we observed only one MS case in the RA population and 24 MS cases among the population comparators, corresponding to an HR of 0.27 (95% CI 0.04–1.97). RA was associated with an increased risk of a subsequent demyelinating event (HR 2.76, 95% CI 1.32–5.76). When the same analyses were performed using RA identified in the Patient Register, the numbers increased but all associations remained of similar strength. Conclusions: The risk of RA among patients with a history of MS was reduced by a third. Cases of MS after RA onset were rare, suggesting shared but opposing or exclusive susceptibilities of the two diseases. By contrast, the risk for demyelinating events was reduced before RA onset but not thereafter, indicating a cause-and-effect association with the RA disease.

MS cases RA (SRQ) RA (NPR) General population Demyelinating events RA (SRQ) RA (NPR) General population

After RA onset

n

OR (95% CI)

n

HR (95% CI)

13 22 96

0.68 (0.38–1.21) 0.49 (0.32–0.76) 1 (ref)

1 11 24

0.27 (0.04–1.97) 0.68 (0.37–1.27) 1 (ref)

4 15 42

0.48 (0.17–1.33) 0.80 (0.46–1.38) 1 (ref)

10 18 25

2.76 (1.32–5.76) 1.27 (0.76–2.11) 1 (ref)

References 1. Somers EC, Thomas SL, Smeeth L, Hall AJ. Are individuals with an autoimmune disease at higher risk of a second autoimmune disorder? Am J Epidemiol 2009;169:749–55. 2. Seror R, Richez C, Sordet C, Rist S, Gossec L, Direz G, et al. Pattern of demyelination occurring during anti-TNF-α therapy: a French national survey. Rheumatology (Oxford) 2013;52:868–74.

PP147 Dietary nutrients and carotid atherosclerosis in SLE patients C Lourdudoss1, R van Vollenhoven1, J Frostegård2 Departments of 1Medicine and 2Environmental Medicine, Karolinska Institutet, Stockholm, Sweden

Background: The prevalence of atherosclerosis is increased in SLE. Disease-specific and treatment-related factors have been implicated. We hypothesized that diet may also play an important role. However, relatively little is known about dietary habits in patients with SLE. The aim of this study was to investigate the dietary nutrient levels in SLE patients with and without carotid atherosclerosis. Method: This study included 111 SLE patients from the SLE vascular impact cohort (SLEVIC) study, Karolinska University Hospital, Stockholm, Sweden. Data on diet were linked with data on unilateral and bilateral plaque. Dietary data were based on food frequency questionnaires. Data on plaque were scored as absence or presence of unilateral and bilateral plaque detected by B-mode ultrasound. Daily mean intake of dietary nutrients was compared between patients (a) with and without bilateral plaque and (b) with and without plaque in the left carotid. Data on plaque were adjusted for age and low density lipoprotein (LDL) levels through logistic regression. Results: The results are shown in Table 1. Significant differences were found in the mean intake of several nutrients between patients with and without bilateral plaque. Overall, patients with carotid plaque had lower



40 Table 1.

Nutrient


Energy (kcal) Fatty Acid C20:5 (E%) Fatty Acid C22:6 (E%) Disaccharides (E%) Sucrose (E%) Fiber (E%) Thiamin (mg) Niacin (mg)

Energy (kcal) Fatty Acid C20:5 (E%) Fatty Acid C22:6 (E%) Disaccarides (E%) Sucrose (E%) Vitamin B6 (mg) Riboflavin (mg) Thiamin (mg) Niacin (mg) Niacin equivalent (mg) Phosphorus (mg) Sodium (mg) Zinc (mg)

Mean SD

Mean SD

No plaque left þ right (n ¼ 63)

Plaque left þ right (n¼48)

p value

2104.84 725.46 0.06 0.05 0.13 0.09 14.61 5.08 10.31 4.55 2.44 0.89 1.43 0.51 17.62 5.20

1785.34 547.14 0.08 0.05 0.16 0.10 12.59 4.29 8.02 3.70 2.84 0.99 1.24 0.38 15.61 4.44

0.013 0.031 0.025 0.030 0.007 0.029 0.031 0.035

No plaque left (n ¼ 72)

Plaque left(n ¼ 39)

2092.09 695.74 0.06 0.05 0.13 0.09 14.51 4.90 9.94 4.41 2.27 0.82 2.09 1.00 1.43 0.49 17.55 5.08 35.55 11.11 1800.67 707.27 3173.35 948.69 12.48 4.35

1734.50 556.95 0.08 0.05 0.16 0.11 12.31 4.42 8.15 3.98 1.95 0.64 1.69 0.76 1.19 0.38 15.28 4.43 30.82 9.60 1532.03 569.23 2778.32 951.70 10.61 3.54

caloric intake of macronutrients and lower intake of various B vitamins and some other micronutrients. However, the dietary intake of fibre and of fatty acids C20:5 and C22:6 was higher in patients with carotid plaque. After data adjustments for age and LDL, energy, niacin, phosphorus, and zinc remained significant. Conclusions: We found nutritional differences between SLE patients with and without carotid atherosclerosis. The increased intake of certain fatty acids and decreased intake of micronutrients including B vitamins may have aetiological importance and will be investigated further.

PP148 Heart involvement in systemic sclerosis patients and mice models P Venalis1, G Kumánovics2, H Schulze-Koops3, A Distler4, C Dees4, P Zerr4, K Palumbo-Zerr4, L Czirják2, Z Mackevic5, IE Lundberg1, O Distler6, G Schett4, JHW Distler4 1

Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden, 2Department of Rheumatology, University of Pécs, Hungary, 3Division of Rheumatology, Medizinische Poliklinik, University of Munich, Germany, 4Department of Internal Medicine 3, University of Erlangen-Nuremberg, Germany, 5State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania, and 6Department of Rheumatology, Centre for Experimental Rheumatology, University Hospital Zurich,Switzerland

Background: Fibrosis and vasculopathy are the hallmarks of systemic sclerosis (SSc). There has been a shift


0.007 0.028 0.018 0.022 0.026 0.032 0.018 0.012 0.021 0.028 0.045 0.040 0.023

in opinion over the causes of SSc-related death in recent years. Cardiomyopathy was identified as a major cause of death. However, the pathogenesis of SSc-related cardiomyopathy is poorly understood. New therapies as well as platforms for testing are needed. We aimed to characterize cardiomyopathy in patients and mice models of SSc, and identify the best animal model for SSc-related cardiomyopathy. Method: Six patients with definite SSc were enrolled in the project. Disease duration was 7 2 years. Patients with clinical evidence for cardiovascular disease were excluded from the study. Three systemic disease models of scleroderma were chosen: the Fra-2 transgenic mice model (Fra-2), the sclerodermatous chronic graft-versus-host disease (cGvHD) model, and the tight skin 1 mutation model (Tsk-1). Formalin-fixed and paraffin-embedded heart sections were used for IHC. Heart sections from SSc patients, controls, and mouse models were stained for α-SMA, CD31, and CD45 active caspase-3 with picrosirius and haematoxylin–eosin. Results: Significant collagen accumulation was observed in hearts of SSc patients. The fibrotic area was increased by 8.8 2.3-fold compared to controls (p < 0.001). The same pattern was found in Fra-2 mice with a 8.9 2.8-fold increase (p ¼ 0.0002). By contrast, no significant changes were observed in cGvHD and in Tsk-1 mice. To detect differentiation towards myofibroblasts we stained for α-SMA. SSc samples presented with increased numbers of myofibroblasts 2.5 0.6 vs. 0.5 0.8 (p ¼ 0.01) per high


41

Fra-2 tg mice

Control mice

Fra-2 tg mice

Control mice

power field in controls. The same pattern was found in all mice models of SSc, although the highest mimicry to SSc hearts was observed in the Fra-2 model (3.0 1.1 vs. 0.5 0.6 p ¼ 0.0005). CD31 stainings revealed a significant loss of capillaries in SSc hearts (2.16 0.17-fold change vs. controls; p < 0.0001). A prominent capillary loss was also observed in Fra-2 and cGvHD models: 2.0 0.2-fold (p < 0.0001) and 2.1 0.3-fold (p < 0.0001) change, respectively. No changes were observed in Tsk-1 mice. Apoptosis of endothelial cells was increased in Fra-2 transgenic mice vs. controls (2.5 0.9 vs. 0.17 0.43; p ¼ 0.0001). Apoptosis was observed in cGvHD mice although it was also elevated in controls (2.6 0.7 vs. 1.2 0. 5, p ¼ 0.003). No apoptosis was detected in capillaries of Tsk-1 mice. Endothelial apoptosis was also elevated in SSc hearts with 1.2 0.4 vs. 0.2 0.4 (p ¼ 0.0018) in controls. Higher numbers of perivascular leucocytes were detected in SSc patients (5.8 1.8-fold change, p ¼ 0.0001), which strengthened the hypothesis of vascular damage. Conclusions: We have demonstrated that heart changes were detectable in all models of SSc, but the typical features of cardiac disease in SSc, namely loss

*

10 5 0

n.s.

n.s.

* 15 10 5 0

Fr

Ts k Co 1 nt ro l

0.0

15

SS c H ea lth y

X-fold change in fibrotic area

0.5

vH Co D nt ro l

0.0

n.s.

1.0

cG

0.5

*

*

a2t Co g nt ro l

1.0

1.5

Fr

*

Ts Co k 1 nt ro l

Healthy

a2 Co tg nt ro l cG vH Co D nt ro l

SSc patients

X-fold change in fibrotic area

Healthy

X-fold change in capillar; count

1.5

Collagen deposition is strongly enhaced in myocardial tissue of SSc patients

SSc patients

S H Sc ea lth y

X-fold change in capillar; count


The capillary counts are decreased in the myocard of SSc patients

of capillaries due to apoptosis of endothelial cells and fibrosis, were closely mimicked only by Fra-2 transgenic mice. The cGvHD and Tsk-1 mice lacked some features of scleroderma-related cardiomyopathy and were less representative. Thus, Fra-2 transgenic mice are a promising preclinical model for studying the mechanisms and therapeutic approaches of heart involvement in SSc.

PP150 Expression of HMGB1 and its receptors in hearts of patients with coronary artery disease with or without inflammatory rheumatic disease: a biopsy study M Zong1, I Hollan2, H Xiao3, C Wick1, H Harris1, I Lundberg1 1

Department of Medicine, Karolinska Institutet, Stockholm, Sweden, 2Lillehammer Hospital for Rheumatic Diseases, Lillehammer, Norway, and 3Oxford University, UK

Background: Inflammatory rheumatic diseases (IRD) are associated with increased risk of cardiovascular diseases. High mobility group protein B1 (HMGB1), an alarmin involved in the pathogenesis of IRD, can mediate myocardial dysfunction in vitro. Therefore, we wanted to




42

investigate the expression HMGB1 signalling in cardiac muscles of humans with coronary artery disease (CAD) with or without IRD. Method: We examined HMGB1 and its three receptors: receptor for advanced glycation end products (RAGE), Toll-like receptor (TLR) 4, and TLR2 by immunohistochemistry on frozen myocardial specimens from the right atria taken during coronary artery bypass grafting from 18 patients with CAD: eight without IRD, 10 with IRD (five rheumatoid arthritis, two polymyalgia rheumatica, one psoriatic arthritis, one giant cell arteritis, one ankylosing spondylitis). In addition, we examined total HMGB1 protein levels in heart muscle samples from right atria from six patients (three patients with IRD, three without IRD) by Western blot. Results: HMGB1 was expressed in the nuclei of cardiomyocytes in all patients. However, cytosolic HMGB1 in cardiomyocytes was recorded in all patients with IRD (strongly in six, weakly in four) but was only weakly present in one of the eight patients without IRD. In addition, HMGB1 was detected in mesothelial cells, endothelial cells, and large vessels. The total HMGB1 protein levels were lower in the heart muscle samples of patients with IRD compared to those without IRD. Of the receptors, RAGE and TLR4 occurred in most cardiomyocytes in all patients, while TLR2 was observed only in sporadic cardiomyocytes in all patients. All the receptors were also detected in mesothelial cells but only RAGE was recorded clearly in endothelial cells and large vessels. Conclusions: HMGB1 and its receptors are expressed in cardiomyocytes of CAD patients with or without IRD. However, the HMGB1 signalling pathways may be more easily activated in IRD patients as a more extranuclear staining pattern for HMGB1 was evident in these patients. Extranuclear HMGB1 might contribute to the increased risk of heart diseases in IRD

patients, and this risk might be reversed by HMGB1 targeting therapy.

PP152 A comparison between patients with rheumatoid arthritis in the western part of Sweden with or without treatment with biologics K Bengtsson1, M Dehlin1, E Hilme2, G Kvist3, B Rydberg4, T Torstenson5, A Lindhé6, SM Wallerstedt7, H Forsblad-dÉlia1 1

Rheumatology, Sahlgrenska University Hospital, Göteborg, Rheumatology, Alingsås Hospital, 3Rheumatology, Borås Hospital, 4Rheumatology, Skövde Hospital, 5Rheumatology, Uddevalla Hospital, 6Regional Health Care, Västra Götalands Region, and 7Clinical Pharmacology, Sahlgrenska University Hospital, Göteborg, Sweden 2

Background: The aim of this study was to investigate the use of biologics in patients with rheumatoid arthritis (RA) in western Sweden and to determine whether characteristics and comorbidity differed between patients receiving biologics and patients who did not. Method: Patients aged 18 years, diagnosed with RA and attending a specialist care unit at least once from 2009 to 2010, were identified in the regional health care database, Vega. Data for these patients were extracted for the period 2006–2010. Patients on biologics at 31 December 2010 were identified in the national register AntiRheumatic Treatment in Sweden (ARTIS) and also by linkage in Vega. Data from ARTIS were validated against medical records. Descriptive, comparative, and multiple logistic regression analyses were used to identify significant factors associated with biological treatment. Results: A total of 7712 patients with RA were identified, of whom 1137 (14.7%) were on biologics. Initially, another 390 patients were identified as taking biologics, but the validation process revealed that they had stopped

Table 1. Patients on biologics (n ¼ 1137) Female, n (%) Age (years), mean SD Inpatient care, n (%) Inpatient occasions, mean SD Days in hospital, mean SD Comorbidity, n (%) Diabetes mellitus Ischaemic heart disease Cerebrovascular disease Congestive heart disease Chronic respiratory disease Depression Cancer Infectious disease Pneumonia Sepsis


Patients without biologics (n ¼ 6185)

p-value

880 (77.4) 58.9 12.3 571 (50.2) 2.4 2.0 14.5 26.7

4559 (73.7) 66.2 15.1 3201 (51.8) 2.45 2.2 20.6 30.2

0.0090 < 0.0001 0.3414 0.6544 < 0.0001

97 (8.5) 93 (8.2) 46 (4.1) 33 (2.9) 132 (11.6) 110 (9.7) 90 (7.9) 840 (73.9) 145 (12.8) 20 (1.8)

745 (12.1) 954 (15.4) 577 (9.3) 671 (10.9) 991 (16.0) 752 (12.2) 936 (15.1) 4248 (68.7) 956 (15.5) 187 (3.0)

0.0006 < 0.0001 < 0.0001 < 0.0001 0.0001 0.0169 < 0.0001 0.0005 0.0191 0.0181



43

or planned to begin a biologic and they were therefore excluded from further analyses. In all, 60% of the patients on biologics were treated with their first biologic agent and 28% their second one. Infliximab (36%), etanercept (28%), and rituximab (16%) were the three most used biologics. The patients on biologics had disease duration of (mean SD) 16 11 years, a 28-joint disease activity score (DAS28) of 3.0 1.3, and a follow-up time of 41 33 months on their present biologics. The characteristics of the patients are shown in Table 1. In multiple logistic regression, higher age, the presence of cerebrovascular, congestive heart and chronic respiratory disease, and depression and malignancy were associated with not taking biologics. Infectious disease was associated with taking biologics. Sex, presence of diabetes, and ischaemic heart disease were not found to be of importance. Conclusions: In western Sweden, 14.7% of RA patients had biological treatment recorded on 31 December 2010. Patterns of comorbidity and age, but not sex, differed between patients receiving biological drugs and patients who did not.

M Morillon, IMJ Hansen

registered. Metabolic syndrome was defined according to the International Diabetes Federation (IDF) definition (3). Thus, to establish a diagnosis of metabolic syndrome, one of the following two must be met: waist measure (> 80 cm for women and 94 cm for men) or BMI > 30; plus two of the following: blood pressure > 130/85 mmHg or treatment for hypertension; triglyceride >1.7 mmol/L; HDL < 1.3 mmol/L for women and < 1.0 mmol/L for men or specific treatment for dyslipidaemia; raised fasting glucose > 1.7 mmol/L. Results: Fifty patients were seen in our clinic, four were excluded (incorrect diagnosis/missing data). Data from 46 patients (nine women and 37 men) were available (Table 1). The mean age for women was 69.3 (range 63–84 years) and the mean age for men was 63.9 (range 43–90 years). Eighty-nine per cent of the women and 59% of the men had metabolic syndrome according to the IDF definition. Serum urate levels before treatment were initially: 0.58 mmol/L for women and 0.56 mmol/L for men, and creatinine levels were 102 g/L for women and 105 g/L for men. Conclusions: Metabolic syndrome in patients with gout is frequent. More than half of the patients, both men and women, were diagnosed with metabolic syndrome. Patients with gout and metabolic syndrome are at high risk of cardiovascular comorbidity and should be treated in accordance with national guidelines for prevention of cardiovascular disease.

Department of Rheumatology, University Hospital of Odense, Svendborg Sygehus, Svendborg, Denmark

References

PP153 Frequency of metabolic syndrome in patients with gout: a retrospective cross-sectional study

Background: Gout and hyperuricaemia are the most common inflammatory diseases among men and postmenopausal women. An American study in 2007–2008 (1) estimated the prevalence to be 3–4%. Gout is associated with an increased risk of type 2 diabetes and cardiovascular disease (2). Patients with metabolic syndrome are twice as likely to die from a heart attack and three times as likely to die from a stroke. Thus it is essential to be attentive to cardiovascular risk factors in patients with gout. We wanted to estimate the frequency of metabolic syndrome in patients diagnosed with gout. To our knowledge there is no study describing the frequency of metabolic syndrome in these patients. Method: In a cross-sectional retrospective study design, all patients with the diagnosis of gout attending our Rheumatology Clinic as of 1 September 2013 were included. The patients were examined in our clinic over a period of 4 months. Data regarding gender, age, serum urate level, creatinine, and metabolic syndrome were

1. Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperuricemia in the US general population: the National Health and Nutrition Examination Survey 2007-2008. Arthritis Rheum 2011;63:3136–41. 2. Bhole V, Choi JW, Kim SW, de Vera M, Choi H. Serum uric acid levels and the risk of type 2 diabetes: a prospective study. Am J Med 2010;123:957–61. 3. Alberti KG, Zimmet P, Shaw J. Metabolic syndrome - a new worldwide definition. A Consensus Statement from the International Diabetes Federation. Diabet Med 2006;23:469–80.

PP154 Increased incidence of low-energy fractures in RA patients from northern Sweden SR Dahlqvist1, K Wiberg1,2, U Bergström3, M-L Öhman1 1

Public Health and Clinical Medicine, Rheumatology, Umeå University, 2Rheumatology, Östersunds Reumatikersjukhus, and 3Surgical and Perioperative Science, Umeå University, Sweden

Table 1.

Women (n ¼ 9) Men (n ¼ 37)

Mean age (years)

Mean s-urate (mmol/L) before treatment

Mean creatinine (g/L) before treatment

Metabolic syndrome (%)

693 (63–84) 639 (43–90)

0.58 (0.46–0.7) 0.56 (0.19–0.99}

102 (61–184) 105 (58–483)

89 59




44

Background: Periarticular bone loss is an early sign of joint involvement in rheumatoid arthritis (RA) (1). Patients with RA also have an increased generalized bone loss with development of osteoporosis. Osteoporosis and related fractures constitute an important extra-articular complication in RA. Osteoporosis per se is a known risk factor for fracture in the general population. In addition to general background factors (e.g. old age, low body mass, female gender, immobility) treatment with glucocorticoids and disease activity increase the risk of fractures in osteoporotic patients with RA (1, 2). However, the incidence of fracture is not well explored. The aim of this study was to estimate the incidence of low-energy fractures in RA patients identified within a population-based register of fractures in northern Sweden. Method: The register of patients with RA (1987 ACR criteria), consecutively included since 1995 (n ¼ 1178), was co-analysed with the Umeå register of injury data base with regard to low-energy fractures. This data base was constructed in 1993 and covers six districts with a population of 118 000 at-risk adults. All individuals admitted to the emergency ward with fractures are included consecutively. The individuals in this study were followed until fracture or to 1 January 2011. The standard incidence ratio (SIR) was calculated. SIR calculations were performed using the method of indirect standardization relative to the standard population of the geographic origin as the RA patients. Confidence intervals were obtained by treating the observed number of events as Poisson variables with expectation equal to the expected number. Results: Among the RA patients, 329 individuals (246 females and 83 males) were identified with a fracture. The corresponding figures among the controls were 14 102 females and 13 313 males with fractures. The odds ratio (OR) for a fracture in the RA patients was 1.38 (95% CI 1.21–1.57) in females and 1.85 (95% CI 1.46–2.32) in males. Stratification for age showed an increased SIR in the individuals aged > 65 years: OR 1.41 (95% CI 1.20– 1.64) in females and OR 1.97 (95% CI 1.48–2.57) inmales. The highest SIR was for hip fracture (females OR 2.51, 95% CI 1.21–4.61 and males OR 3.95, 95% CI 1.28–9.23), with a similar mean age for cases and controls (72–75 years). The duration of time from diagnosis of RA to the first fracture was, during the follow-up, mean (SD) 18.7 (14.0) years in females and 14.4 (11.7) years in males. The RA patients had a similar frequency of fractures indoors as outdoors compared with controls, who had a significantly higher frequency of fractures outdoors. Conclusions: RA is associated with a higher incidence of fractures. Stratification for age showed increased SIR in those above 65 years of age. The highest SIR was for hip fractures in both females and males. References 1. Roux C. Osteoporosis in inflammatory joint diseases. Osteoporos Int 2011;22:421–33.


2. Weiss RJ, Wick MC, Ackermann PW, Montgomery SM. Increased fracture risk in patients with rheumatic disorders and other inflammatory diseases - a case-control study with 53,108 patients with fracture. J Rheumatol 2010;37:2247–50.

PP155 The value of the QuantiFERON TB Gold In-Tube test in the identification of latent tuberculosis in rheumatic patients before treatment with TNF-α blockers in Vilnius University Hospital Santariskiu Clinics I Arstikyte1,2, I Butrimiene1,2, R Zablockis3, A Venalis1,2 1

State Research Institute, Centre for Innovative Medicine, 2Vilnius University, Centre of Rheumatology, and 3Vilnius University, Centre of Pulmonology and Allergology, Vilnius, Lithuania

Background: Interpretation of the QuantiFERON TB Gold In-Tube (QFT) test and the tuberculin skin test (TST) remains complicated in countries with a high prevalence of tuberculosis (TB) and previous BCG vaccination. TB prevalence in Lithuania is the highest in the European Union (57.37 cases/100 000 inhabitants in 2013) and 98% of population are BCG vaccinated (1). Most of the studies focus on general populations, although data in autoimmune diseases and immunosuppressive patients are scarce. Tumour necrosis factor-α blockers (TNFb) modulate the immune system and may increase the risk of latent tuberculosis (LTB) reactivation (2). The purpose of this study was to analyse the value of the QFT test in LTB identification in rheumatic patients before treatment with TNFb. Method: A total of 220 patients (39.1% males, age 34.58 12.74 years; 60.9% females, age 36.83 14.47 years), of whom 100 (45.5%) had RA, 63 (28.6%) AS, 42 (19.1%) PsA, and 15 (6.8%) JIA [all patients treated with methotrexate and 196 (89.1%) with low or medium doses of corticosteroids], treated with TNFb [adalimumab (2.3%), etanercept (76.4%), infliximab (16.8%), and golimumab (0.5%)] were tested for active TB or LTB before initiation of treatment with TNFb from April 2009 to January 2014. All patients were checked for respiratory symptoms, TB history was obtained, and QFT, TST, and radiological examination [chest X-ray for all patients and chest computer tomography (CT) after recommendation by a radiologist for 15 (6.8%) patients] were performed before starting TNFb. Results: Before starting TNFb, QFTþ was found in 14 (6.4%) patients, QFT in 203 (92.3%), QFT indeterminate in three (1.4%), TSTþ in seven (3.2%), and TST in 213 (96.8%). X-rays revealed no pathological findings in 212 (96.4%), although LTB signs were found in eight (3.6%) patients. Coincidence of QFT and TST was found: QFTþ/TSTþ for three patients (1.4%), QFTþ/TST for 13 (5.9%), QFT/TSTþ for four (1.8%), QFT/TST for 199 (90.5%), and QFT indeterminate/TST for three (1.4%) patients (concordance kappa 0.1967, 95% CI



0–0.4121). In total, 205 (93.2%) patients were not diagnosed for LTB, although in three (1.4%) cases TSTþ, QFT, chest X-ray and CT were without changes; for the remaining patients, QFT, TST, and X-ray were negative. In 15 (6.8%) cases LTB was diagnosed (99 days; 95% CI 38.5–106.4 before initiation of TNFb); in three patients QFTþ/TSTþ, 10 patients QFTþ/TST, one patient QFT/TSTþ, and one patient was QFT/TST, but X-ray and CT scans revealed pathology; for seven patients CT was abnormal despite a normal X-ray (three patients QFTþ/TSTþ, one QFT/TSTþ, and three QFTþ/TST), in six cases X-ray and CT were normal (all QFTþ/TST). Prophylactic treatment with rifampicin and isoniazid therapy was given to all LTB patients for 3 months. Conclusions: Although QFT is useful for diagnosing LTB, complex screening (QFT, TST, and radiological examination) for TB is recommended before starting TNFb therapy in countries with high TB prevalence and BCG vaccination rates. References 1. World Health Organization – surveillance report. Tuberculosis surveillance and monitoring in Europe 2013. Available from: www. ecdc.http://www.euro.who.int/__data/assets/pdf_file/0004/185800/ Tuberculosis-surveillance-and-monitoring-in-Europe-2013.pdf? ua¼1 (accessed July 2014). 2. Solovic I, Sester M, Gomez-Reino JJ, Rieder HL, Ehlers S, Milburn HJ, et al. The risk of tuberculosis related to tumor necrosis factor antagonist therapies: a TBNET consensus statement. Eur Respir J 2010;36:1185–205.

PP157 Prevalence of comorbidities in rheumatoid arthritis: does gross domestic product matter? Results from 34 countries in the QUEST-RA programme KL Grøn1, L Ørnbjerg2, M Hetland1, T Sokka3; QUEST-RA investigators 1

Copenhagen University Hospital at Glostrup, Denmark, 2Centre for Rheumatology and Spine Diseases (VRR), Glostrup, Denmark, and 3Centre for Rheumatology, Jyvaskyla Central Hospital, Finland

Background: Comorbid medical conditions are common in patients with RA. It is unknown how the comorbid burden is distributed in countries with different economic status. The objectives were to investigate how comorbidities in patients with rheumatoid arthritis (RA) are distributed and if the distribution is affected by the gross domestic product (GDP) of their resident country. Method: A total of 9874 patients from 34 countries [16 with high GDP (> 24 000 USD per capita) and 18 with low GDP (< 24 000 USD)] participated in the Quantitative Standard Monitoring of Patients with RA (QUEST-RA) study. The prevalence of 31 comorbid

45

conditions was assessed by interview of patients and review of patients files. Results: The most frequent comorbid conditions were hypertension (31.5%), osteoporosis at scan (17.6), osteoarthritis (15.5%), hyperlipidaemia (14.2%), obesity (14.1%), chronic back pain (13.4%), thyroid disease (10.4%), and peptic ulcer (8.5%) (Table 1). Overall, patients had a median of two comorbid conditions and 25.8% had no comorbidities, 23.1% had one comorbidity, 17.9% had two, 12.6% had three, 8.0% had four, 5.2% had five, and 7.4% had between six and 17 comorbidities. In high-GDP countries patients had a median of two comorbidities while patients in low-GDP countries had one (p < 0.001). Peptic ulcer and impaired renal function were evenly distributed in high- and low-GDP countries. As to the rest of the comorbidities, the percentage of patients with comorbidities was higher in high-GDP countries except for chronic back pain, osteoporosis at scan, and hypertension (Table 1). Table 1. Distribution of comorbidities in low- and high-GDP countries.

Comorbidities Hypertension Angina Heart attack Coronary artery disease Other heart disease Hyperlipidaemia Peripheral vascular disease Peptic ulcer Inflammatory bowel disease Impaired renal function Asthma Chronic bronchitis Diabetes mellitus Thyroid disease Cancer Stroke Parkinson’s disease Chronic back pain Musculoskeletal trauma Low energy fractures Osteoporosis at scan Osteoarthritis Infection requiring hospitalization Herpes zoster/ shingles Fibromyalgia Psoriasis Cataracts Psychiatric disease AIDS Alcoholism Obesity (BMI > 30 kg/m2)

Total %

High-GDP Low-GDP % %

p-value (high-GDP vs. low-GDP countries)

31.5 4.4 2.5 4.6

29.7 4.0 3.6 4.8

32.8 4.7 1.6 4.4

< 0.001 0.058 < 0.001 0.436

4.8 14.2 2.9

5.8 16 3.6

3.9 12.7 2.4

< 0.001 < 0.001 < 0.001

8.5 1.2

8.6 1.3

8.6 1.1

0.724 0.226

2.6

2.6

2.6

0.876

4.5 4.0 7.5 10.4 3.4 1.4 0.4 13.4 4.5

6.4 4.3 8.9 11.4 6.1 2.0 0.3 12.3 5.8

3 3.8 6.9 9.6 1.9 0.9 0.4 14.3 3.5

< 0.001 0.272 0.008 0.008 < 0.001 < 0.001 0.808 0.002 < 0.001

4.5 17.6 15.5 6.3

5.1 16.6 15.7 7.6

4.0 18.4 15.3 5.3

0.012 0.008 0.856 < 0.001

3.8

5.3

2.5

< 0.001

3.4 1.9 6.8 4.5 0.1 0.6 14.1

3.8 3.2 7.8 5.8 0.0 0.7 15.3

3.0 0.8 6.0 3.5 0.1 0.5 13.2

0.033 < 0.001 < 0.001 < 0.001 0.824 0.191 0.128



46

Vasculitis PP159 Inflammation, vitamin D, and bone mineral density in patients presenting with giant cell vasculitis and/or polymyalgia rheumatica

Autoinflammatory diseases - clinical and molecular aspects

SA Just, RA Andreasen, R Gildberg-Mortensen, N Lomborg, P Weihe, IMJ Hansen

PP158

Department of Medicine, Svendborg Hospital, Odense University Hospital, Svendborg, Denmark

Gout: an old disease in a new phenotype

Background: Patients presenting with giant cell vasculitits (GCA) and/or isolated polymyalgia rheumatica (PMR) are at high risk of developing osteoporosis (1, 2). Both the active inflammation itself and the glucocorticoid treatment are risk factors for bone mineral density (BMD) loss. In rheumatoid arthritis, a low S-25(OH)D level has been found to be a predictor for low BMD and high disease activity (3). In addition, in patients undergoing orthopaedic surgery, the S-25(OH)D level was found to be a negative phase reactant, while this could not be found in myocardial infarction patients (4, 5). In the current study we hypothesized that the inflammation level measured by sedimentation rate (SR) in patients presenting with GCA and/or PMR would be correlated positively to BMD and negatively to S-25(OH)D. Method: In a cross-sectional retrospective study design, all patients with a diagnosis of GCA and/or PMR attending our rheumatology clinic as of 1 December 2013 were included. At the time of disease presentation, the T-score for BMD at the lumbar spine and/or hip measured by dual-energy X-ray absorptiometry (DXA) was obtained, and SR and S-25(OH)D levels were registered. Correlations were calculated using Pearson’s test and comparisons of means by the t-test. Results: A total of 119 patients were investigated, 83 with isolated PMR and 36 with GCA. In 63 patients we

Klinik und Poliklinik für Innere Medizin A, Ernst-Moritz-ArndtUniversität, Greifswald, Germany

Background: The prevalence of gout has been increasing in recent years. Acute exacerbations of this chronic disease are often caused by changes in medication. Mainly elderly people with cardiovascular comorbidities present with a systemic inflammatory response syndrome (SIRS), posing a diagnostic challenge. Dual-energy computed tomography (DECT) may help to identify patients with exacerbation of chronic tophaceous gout even if arthritis is not the leading symptom. Method: We report a case series of patients with chronic tophaceous gout who presented to our tertiary hospital with a highly inflammatory disease and fever, and who did not respond to various antibiotic therapy regimes. After ruling out infectious causes, DECT revealed deposits of monosodium urate crystals so therapy with lowdose colchicine according to Terkeltaub was initiated after exclusion of contraindications. Results: Within a few days of initiating the colchicine therapy, signs and symptoms improved. We did not observe any adverse effects in our patients. Therefore, a low-dose colchicine therapy seemed to be effective and safe in people with exacerbation of chronic tophaceous gout. Additive therapy of prednisolone was necessary only in a minority of the patients. Because of underlying cardiovascular comorbidities, we avoided therapy with NSAIDs. Exacerbations of gouty arthritis mostly occurred due to body fluid changes or changes in medication. The majority of our patients were on low-dose acetylsalicylic acid (ASS) after a cardiovascular or cerebrovascular event. Conclusions: Older patients who present with SIRS should be evaluated for exacerbation of chronic tophaceous gout after infections are excluded, especially if there were medication changes that alter renal uric acid excretion. Antihypertensives, diuretics, and low-dose ASS are possible causative agents that are common medications in older people with cardiovascular comorbidities. DECT can help to identify these patients at risk. The role of DECT has to be evaluated in well-designed clinical trials.


Correlation between S-25(OH)D and SR in early GCA/PMR Sedimentionrate (mm/h) 50 100

M Fiene, B Fiene, V Karnebeck

0


Conclusions: The percentage of patients with comorbidities was overall higher in high-GDP than in low-GDP countries but comorbidities may be underdiagnosed, especially in low-GDP countries.

0

150 50 100 S-25(OH)D-vitamin (nmol/L)

200



found both SR and DXA results at presentation of disease, in 62 we found both S-25(OH)D and SR, and in 47 S-25 (OH)D and DXA. No correlation was found between SR at presentation and hip or vertebral T-score. A significant positive correlation (r ¼ 0.27, p ¼ 0.03) was found between SR and S-25(OH)D in patients presenting with GCA/PMR. This group contained 18 GCA and 44 isolated PMR patients. There was no difference in vitamin D level, hip T-score or lumbar spine T-score between isolated PMR and AT patients. A significant negative correlation between S-25(OH)D and hip T-score (r ¼ 0.38, p ¼ 0.007) was found, although there was no correlation to vertebral T-score. Conclusions: Hip and vertebral T-scores were not correlated with overall level of inflammation in patients presenting with GCA and/or PMR. There was a positive correlation between S-25(OH)D and SR in patients with the early GCA/PMR group. This observational study suggests that S-25(OH)D could be a positive phase reactant in presenting GCA/PMR, although further studies are needed to confirm this finding. References 1. Mazzantini M, Torre C, Miccoli M, Baggiani A, Talarico R, Bombardieri S, et al. Adverse events during longterm low-dose glucocorticoid treatment of polymyalgia rheumatica: a retrospective study. J Rheumatol 2012;39:552–7. 2. Duru N, van der Goes MC, Jacobs JW, Andrews T, Boers M, Buttgereit F, et al. EULAR evidence-based and consensus-based recommendations on the management of medium to high-dose glucocorticoid therapy in rheumatic diseases. Ann Rheum Dis 2013;72:1905–13. 3. Chen J, Liu W, Lin Q, Chen L, Yin J, Huang H. Vitamin D deficiency and low bone mineral density in native Chinese rheumatoid arthritis patients. Int J Rheum Dis 2014;17:66–70. 4. Waldron JL, Ashby HL, Cornes MP, Bechervaise J, Razavi C, Thomas OL, et al. Vitamin D: a negative acute phase reactant. J Clin Pathol 2013;66:620–2.

PP160 Carcinoma of the prostate, RS3PE and polymyalgia rheumatica: a case study RA Gildberg-Mortensen1, LK Nielsen1, E Øster-Jørgensen1, S Hess2, IMJ Hansen1 1 Department of Rheumatology, Svendborg Hospital, Odense University Hospital, Svendborg and 2Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark

Background: Remitting seronegative symmetrical synovitis with pitting oedema (RS3PE) has been reported as a paraneoplastic syndrome, often found together with adenocarcinomas (1). RS3PE is controversially associated with polymyalgia rheumatica (PMR) (2). PMR is characterized by inflammatory pain of the shoulder and/or limb girdle, together with biochemical evidence of inflammation in patients older than 50 years. However, single parameters are non-specific and many diseases can

47

mimic PMR (3). The incidence of cancer diagnosis is increased by 69% up to 6 months after the diagnosis of PMR (4). Method: Medical record evaluation. Results: A male patient born in 1932 was diagnosed with prostate cancer (PSA: 16 mg/L) in 2007. Biopsy revealed adenocarcinoma, Gleason score 5. During watchful waiting until April 2010, PSA increased to 67.9 mg/L, and he received treatment with Zoladex every third month, replaced by Eligard for every 6 months in January 2011. PSA was normalized within the first 3 months of treatment. About 1 year before cancer treatment was started, the patient complained of painful hands, with pitting oedema on the backs, compatible with RS3PE. This phenomenon disappeared when the prostate cancer was in remission. In April 2011 the patient was seen at the day hospital because of anaemia and an elevated erythrocyte sedimentation rate (ESR). Haemoglobin was 5.7 mmol/L, ESR 106 mm/h. The patient was now complaining of stiffness and aching of the shoulder and hip girdles especially in the morning. Biochemistry revealed CRP of 100 mg/L, IgM RF negative, anti-CCP negative, ANA negative, no monoclonal proteins in serum or urine were detected, and PSA was 1.2 mg/ L. A temporal artery biopsy was negative. A PET/CT scan visualized a high 18FDG uptake in the soft tissues around the shoulders and hips. There was no evidence of bone metastasis. After initiation of prednisone therapy (15 mg/day), the patient became asymptomatic and his biochemistry normalized. In March 2012 he was discharged from the rheumatology outpatient clinic, and in January 2014 he was discharged from the urological department. Conclusions: In this case RS3PE syndrome was perceived as a paraneoplastic syndrome because of the disappearance of symptoms as soon as the cancer was in remission. When the patient was referred with suspected PMR, a condition mimicking PMR was suspected, in this case metastatic prostate cancer. However, this was ruled out. In this case the diagnosis of PMR was seen as an independent phenomenon in relation to RS3PE, although the consecutive appearance was remarkable, possibly signalling a common background for the two symptom complexes. References 1. Sibilia J, Friess S, Schaeverbeke T, Maloisel F, Bertin P, Goichot B, et al. Remitting seronegative symmetrical synovitis with pitting edema (RS3PE): a form of paraneoplastic polyarthritis? J Rheumatol 1999;26:115–20. 2. Racanelli V, Prete M, Minoia C, Favoino E, Perosa F. Rheumatic disorders as paraneoplastic syndromes. Autoimmun Rev 2008; 7:352–8. 3. Soubrier M, Dubost JJ, Ristori JM. Polymyalgia rheumatica: diagnosis and treatment. Joint Bone Spine 2006;73:599–605. 4. Muller S, Hider SL, Belcher J, Helliwell T, Mallen CD. Is cancer associated with polymyalgia rheumatica? A cohort study in the General Practice Research Database. Ann Rheum Dis. Published online 10 July 2013. doi:10.1136/annrheumdis-2013-203465.



48

Method: Data from 840 patients with biopsy-proven GCA in Skåne, the southernmost region in Sweden, diagnosed between 1997 and 2010, were used for this analysis. Patients with GCA were identified in the regional register of the Department of Pathology in Skåne using established methods (1). The occurrences of acute visual complications after the onset of GCA were identified by linking the GCA cohort to the Skåne Health Care Register using ICD-10 codes as described previously (2). A nested case–control study was performed within the GCA cohort in which cases with visual complication were compared to age- and sex-matched patients with GCA without visual complications. In a structured review of all medical records, the presence of ophthalmological disease was validated, and we also recorded the use of selected medications at GCA onset, and histopathology findings (Table 1). Results: One hundred of the 840 patients (12%) with GCA had an assigned diagnosis code for at least one visual complication. Upon detailed case record review, eight patients with an ophthalmological complication that pre-dated the diagnosis of GCA and seven cases with either incomplete records or incorrectly assigned ICD codes were excluded. Eighty-five patients were found to have visual

PP161 Clinical and laboratory characteristics associated with visual complications in patients with biopsy-proven giant cell arteritis M Saleh1, C Turesson2, AJ Mohammad6,7

M

Englund3,4,

PA

Merkel5,


1

Department of Internal Medicine, Section of Rheumatology, Helsingborg Hospital, Sweden, 2Department of Rheumatology, Clinical Sciences, Lund University, Malmö, Sweden, 3Department of Orthopaedics, Lund University, Sweden, 4Clinical Epidemiology Research and Training Unit, Boston University School of Medicine, Boston, MA, USA, 5Division of Rheumatology, University of Pennsylvania, Philadelphia, PA, USA, 6Department of Renal Medicine, Vasculitis and Lupus Clinic, Cambridge University Hospitals, UK, and 7Department of Rheumatology, Clinical Sciences, Lund University, Sweden

Background: Early diagnosis of giant cell arteritis (GCA) and prompt initiation of high-dose glucocorticoid treatment is important to avoid permanent organ damage. One of the most feared outcomes in GCA is ischaemic complications, especially visual impairment or irreversible blindness. The aim was to compare the clinical and laboratory characteristics of patients with biopsy-proven GCA who develop visual complications to patients with GCA with no visual complications.

Table 1. Copmarisons between patients with biopsy-proven GCA with and without visual complications

Age at GCA diagnosis, years Median(IQR) Sex (F/M) Headache Jaw-claudication Fever* Temporal a. tenderness PMR-symptoms at GCA onset PMR-diagnosis prior to GCA onset Comorbidities Hypertension Diabetes Mellitus Hyperlipidaemia Ischemic heart diseases Cerebrovascular accident Thromboembolic disease Histopathology findings Granuloma Giant cells Atherosclerosis Drugs at GCA onset ACE/ARB Anticoagulant Platelet inhibitor Statin Non-steroidal anti-inflammatory drugs Beta-Blocker Laboratory data at GCA diagnosis (median, IQR) Erythrocyte sedimentation rate, mm/h C-reactive protein, mg/L

GCA with visual complications n ¼ 85 (%)

GCA without visual complications n ¼85 (%)

p-value

80 (74–84) 59/26 64 (75) 37 (44) 12 (21) 26 (31) 52 (61) 21 (25)

80 (75–83) 61/24 76 (89) 27 (32) 25 (42) 44 (52) 65 (77) 12 (14)

0.980 0.736 0.016 0.113 0.019 0.005 0.031 0.081

43 (51) 12 (14) 8 (9) 14 (17) 8 (9) 15 (18)

42 (49) 14 (17) 7 (8) 19 (22) 5 (6) 10 (12)

0.878 0.670 0.787 0.332 0.387 0.279

15 (18) 48 (57) 11 (13)

18 (21) 49 (58) 6 (7)

0.561 0.877 0.201

21 (25) 6 (7) 20 (24) 15 (18) 3 (4) 31 (37)

12 (14) 2 (2) 29 (34) 12 (14) 3 (4) 16 (19)

0.081 0.147 0.153 0.529 1.000 0.010

75 (57–92) 75 (50–105)

80 (57–96) 98 (65–174)

0.760 0.011

IQR¼inter-quartile range, PMR¼polymyalgia rheumatica, *Data available for 56 cases and 60 controls, ACE/ARB¼Angiotensin converting enzyme inhibitor/angiotensin II blocker.




complications; 72 patients had unilateral and 13 had bilateral visual impairment. Compared to patients without visual impairment, patients with GCA with new-onset visual impairment were less likely to have headache, fever, palpable abnormal temporal artery, polymyalgia rheumatica, and lower CRP at diagnosis compared with controls. The use of beta-blockers was associated with visual complication (Table 1). Conclusions: Patients with GCA with visual complications as a group have lower inflammatory responses compared to patients with GCA and no visual problems, as found in previous studies. Patients with visual complications are more likely to be treated with beta-blockers than patients with GCA without visual changes. The role of beta-blockers in end-organ ischaemia related to GCA should be further studied. References 1. Mohammad AJ, Nilsson JA, Jacobsson LT, Merkel PA, Turesson C. Incidence and mortality rates of biopsy-proven giant cell arteritis in southern Sweden. Ann Rheum Dis. Published online: 17 January 2014. doi:10.1136/annrheumdis-2013–204652. 2. Bremander A, Petersson IF, Bergman S, Englund M. Population-based estimates of common comorbidities and cardiovascular disease in ankylosing spondylitis. Arthritis Care Res (Hoboken) 2011;63:550–6.

PP162 Low CD4/CD8 ratio is associated with lower immunoglobulin levels in granulomatosis with polyangiitis patients receiving rituximab E Besada1, JC Nossent2 1 Institute of Clinical Medicine, UiT the Arctic University of Norway, Tromsø, Norway and 2Division of Medicine, Royal Darwin Hospital, Casuarina, Australia

Background: Rituximab (RTX) is an effective B depleting agent for inducing and maintaining remission in patients with granulomatosis with polyangiitis (GPA). RTX-induced late-onset neutropaenia and hypogammaglobulinaemia potentiate the risk of common infections, but infections mediated by T-cell dysfunction have also been described during RTX treatment. The aim of this study was to describe the course of CD4 cells and the CD4/CD8 ratio in GPA patients during long-term RTX treatment. Method: Prospectively collected data in 35 GPA patients treated with RTX between April 2004 and September 2011 at one centre were analysed. Total immunoglobulin (Ig) levels and immunophenotyping of lymphocytes were measured at RTX initiation and then after 3, 6, 12, 18, and 24 months. CD4 < 0.3 109/ L and CD4/CD8 ratio < 1 were defined as low count and ratio. Patients [median age 50 (14–79) years, 46% women] had received a cumulative dose cyclophosphamide of 14.8 g (0–250) and were treated with a median RTX cumulative dose of 4 g (2–6). Results are expressed

49 Table 1. Total immunoglobulin level (g/L) Patients at baseline

Baseline

12 months

24 months

Low CD4 Normal CD4 p-value Low ratio Normal ratio p-value

10.8 11.8 0.283 11.8 11.2 0.461

8.0 9.2 0.158 7.6 9.3 0.021

7.4 8.3 0.179 7.1 8.4 0.063

as means, unless stated otherwise. The student’s t-test and the Mann–Whitney U test were used as appropriate. Results: The CD4 cell count decreased from 0.46 at baseline to 0.38 (p ¼ 0.331) and 0.41 (p ¼ 0.183) 109/L at 3 and 6 months, respectively, and then increased to 0.57 (p ¼ 0.034) at 24 months. The CD4/CD8 ratio decreased from 1.31 to 0.99 (p ¼ 0.007) at 3 months and increased gradually to 1.62 (p ¼ 0.057) at 24 months. The proportion of patients with low CD4 decreased from 43% at baseline to 18% at 24 months while the proportion of patients with a low ratio remained stable between 34% and 50% (at 3 months) throughout the study period. Patients with low CD4 at baseline had an increase in their CD4 cell count at 3 months (0.18 vs. 0.28 109/L; p ¼ 0.003) while patients with a normal CD4 cell count had a decrease. Consequently, there were no statistical differences in CD4 cell count between the two groups at 3 months (0.36 vs. 0.40 109/L; p ¼ 0.064). Patients with low CD4 at baseline did not have a lower level in total Ig throughout RTX maintenance, whereas patients with a low ratio at baseline did (Table 1). Two patients had severe infections in the first 24 months of RTX maintenance and one had an infection due to T-cell dysfunction (Pneumocystis jiroveci) 4 months after RTX initiation. Conclusions: RTX treatment in GPA patients results in a temporary decrease in CD4 cell count and in the CD4/ CD8 ratio for about 6 months. Patients with a low baseline ratio remain low during RTX maintenance and are prone to lower Ig levels. The risk of infection due to T-cell dysfunction appears low in the first 2 years of RTX maintenance. PP163 Chronic nasal carriage of Staphylococcus aureus in granulomatosis with polyangiitis patients receiving rituximab maintenance: friend or foe? E Besada1, W Koldingsnes2, JC Nossent3 1

Institute of Clinical Medicine, UiT the Arctic University of Norway, Norway, 2Department of Rheumatology, University Hospital of North Norway, Tromsø, Norway, and 3Division of Medicine, Royal Darwin Hospital, Casuarina, Australia

Background: Chronic nasal carriage of Staphylococcus aureus (SA) has been shown to increase the risk of relapse



in patients with granulomatosis with polyangiitis (GPA). B-cell depletion with rituximab (RTX) is effective in inducing and maintaining remission in GPA. However, B-cell depletion and hypogammaglobulinaemia during RTX could increase the risk of chronic SA nasal carriage. The aim of this study was to investigate the effect of longterm RTX treatment on chronic SA nasal carriage, the risk of relapses, severe infections and hypogammaglobulinaemia in GPA patients. Method: This was a cohort study with prospectively collected nasal swab data in 29 GPA patients on RTX (median RTX dose of 9 g) treatment for a median period of 49 months. Patients [52% men, median age 50 (19–75) years at RTX initiation, 86% PR3-ANCA positive, 3% MPO-ANCA positive, and 10% ANCA negative; 66% and 59% with pulmonary and renal involvement, respectively] had received a cumulative dose of cyclophosphamide of 17 (0–250) g. Nasal swabs were collected prior and during RTX treatment with a median of three and nine swabs, respectively. Persistent SA nasal carriage was defined as the presence of SA in more than 75% of nasal swabs. Results: The frequency of persistent SA nasal carriage did not change before (20%) and after RTX (28%) (p ¼ 0.562). Persistent SA nasal carriage did not increase the risk of relapses (p ¼ 0.646), severe infections (p ¼ 0.357) or hypogammaglobulinaemia (p ¼ 1.00), but reduced the risk of chronic infections (p ¼ 0.033) during RTX. Patients without nasal SA carriage during RTX maintenance were at increased risk of discontinuing RTX due to hypogammaglobulinaemia (p ¼ 0.048) (Figure 1). They had less lung involvement (p ¼ 0.032), more disease activity at baseline (p ¼ 0.010), lower CD4 cell count after RTX 2 g (p ¼ 0.023), and

1,0

0,8 Cumulative Survival


50

0,6

0,4 Logrank p = 0.048 0,2

No-SA carrier SA carrier No-SA-censored SA-censored

0,0 ,00

100,00

200,00

300,00

400,00

TIME FROM RITUXIMAB INITIATION (weeks) Figure 1. Kaplan–Meier analysis of the probability of developing hypogammaglobulinaemia according to nasal carriage of Staphylococcus aureus during RTX maintenance.


larger decline of total Ig after RTX 2g (p ¼ 0.045) and at last visit (p ¼ 0.021). Conclusions: Long-term RTX maintenance therapy in GPA patients did not influence SA nasal carriage status. Persistent SA carriage during long-term RTX treatment did not increase the risk of relapses and infections and was associated with a lower risk of developing hypogammaglobulinaemia. Our results suggest that long-term RTX treatment is better tolerated in GPA patients with chronic SA nasal carriage.

PP164 Late-onset neutropaenia in ANCA-associated vasculitis after rituximab treatment AKnight1, A Bruchfeld2, I Gunnarsson3 1 Department of Medical Sciences, Unit of Rheumatology, Akademiska Hospital, Uppsala, 2Department of Renal Medicine, CLINTEC, Karolinska Institutet, and 3Department of Medicine, Rheumatology Unit, Karolinska University Hospital, Stockholm, Sweden

Background: Rituximab (RTX) is being used increasingly in anti-neutrophil cytoplasmatic antibody (ANCA)associated vasculitis (AAV), both as a single treatment course and as repeated therapy. Late-onset neutropaenia (LON) has been observed following RTX therapy in rheumatic diseases such as rheumatoid arthritis, systemic lupus erythematosus, and granulomatosis with polyangiitis (GPA), but so far data on microscopic polyangitis (MPA) are not available. Neutropaenia is associated with an increased risk of infection but studies on the prevalence and consequences of LON in AAV are scarce. Method: We studied the occurrence of LON in 59 AAV (47 GPA/12 MPA) patients treated with RTX. The patients were included in the AAV cohorts at Karolinska University Hospital in Stockholm and at Uppsala University Hospital. Patient charts were retrospectively reviewed for the occurrence of LON as well as for information on disease duration, and previous and concomitant medications. LON was defined as a neutrophil count < 1.5 109 with onset at least 1 month after treatment where other causes of neutropaenia had been excluded. For inclusion in the study, a minimum followup time of 6 month after RTX was required. Results: In all patients, the mean age at treatment start of RTX was 52.6 (18–83) years. A majority of patients were given RTX as second-line treatment after relapse or failure on DMARDs including cyclophosphamide (CYC), but three patients received RTX as first-line treatment. Two had been given plasmapheresis before RTX only. The most common dose regimen for RTX was 1000 mg administered twice 2 weeks apart. Sixteen patients had received a single course of RTX and 41 had been retreated at least once. Seven of the total 59 patients (11.9%) developed LON after a median time of 13 months (2–29) since the first dose of



RTX. Of the seven LON patients, 5/47 (10.6%) had a diagnosis of GPA and 2/12 (16.7%) of MPA. The median neutrophil count at LON was < 0.1 109, seen in 4/7 patients [range < (0.1–0.7) 109]. Three of the patients developed LON after the first RTX treatment and four had received repeated courses before LON development. Six of seven LON patients had been previously treated with CYC with a median cumulative dose of 10 g (0–55 g). One patient had ongoing CYC treatment, and three had treatment with azathioprine or mycophenolat mofetil at the time of LON. There was no difference in total CYC dose before RTX when comparing LON and non-LON patient groups (NS). Five of the LON patients developed infectious symptoms, the other two patients were identified at routine blood sampling. Six of the patients were hospitalized. Retreatment with RTX was given in two cases without further LON development. Conclusions: LON is a potentially severe but not uncommon side-effect of AAV and may occur in both GPA and MPA. In this study it was seen following both single and repeated treatment courses, and repeated RTX courses did not seem to increase the risk of LON development. The patients who developed LON did not differ with respect to previous or ongoing treatment with DMARDs compared to the non-LON patients. LON in AAV carries the risk of infection, requiring hospital care, and increased surveillance and awareness of the risk for LON in patients with GPA or MPA is recommended.

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Results: In seven out of 12 patients with non-specific vasculitis, FDG-PET showed signs of vasculitis and in seven patients there was a clarifying finding. Eight out of 13 patients with polymyalgia or suspicion of large vessel vasculitis had a clinically relevant finding in FDG-PET. In three out of six AAV patients, FDG-PET showed signs of vasculitis and helped to localize the site of disease. Four out of six patients with suspicion of sarcoidosis had a positive finding in FDG-PET, although only one turned out to be sarcoidosis. In the FUO group (10 patients), FDG-PET findings were positive in six cases, two which of were cholecystitis and one malignancy. Conclusions: As shown previously, FDG-PET is useful in detecting large vessel vasculitis and infection (1). It is also useful for clarifying the diagnostic process when there is a suspicion of vasculitis. Reference 1. Blockmans D. PET in vasculitis. Ann NY Acad Sci 2011;1228:64–70.

PP166 The impact of clinical features and corticosteroids on biopsy findings in giant cell arteritis K Jakobsson1, L Jacobsson1,2, A Mohammad3,4, J-Å Nilsson1, K Warrington5, E Matteson5, C Turesson1 1

PP165 The use of positron emission tomography (PET) imaging as a diagnostic procedure when vasculitis is suspected S Salomäki1, K Taimen1, J Silvola2, J Kemppainen3, U Hohenthal1, A Saraste3, A Roivainen2, L Pirilä1 1 Division of Medicine, Turku University Hospital, 2Turku PET Centre, University of Turku, and 3Turku PET Centre, Turku University Hospital, Finland

Background: Suspicion of vasculitis is a clinical challenge because the symptoms and laboratory findings can be very non-specific. We conducted an observational study to determine whether 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) can be used to clarify the diagnosis and whether it can help to localize the site of inflammation. Method: Between November 2011 and October 2013, in a total of 46 patients, FDG-PET was performed as a diagnostic procedure. We examined the following series of patients: 12 with non-specific vasculitis, six with suspected ANCA-associated vasculitis (AAV), 13 with suspected large vessel vasculitis, five with suspected sarcoidosis, and 10 with fever of unknown origin (FUO). The PET scans based on clinical evaluation and their interpretation were performed as part of the usual diagnostic process in Turku University Hospital.

Rheumatology, Department of Clinical Sciences, Lund University, Malmö, Sweden 2Department of Rheumatology and Inflammation Research, Sahlgrenska Academy at Gothenburg University, Sweden, 3Rheumatology, Department of Clinical Sciences, Lund University, Lund, Sweden, 4Department of Renal Medicine, Vasculitis and Lupus Clinic, Addenbrooke’s Hospital, Cambridge, UK, and 5Division of Rheumatology, Mayo Clinic, Rochester, MN, USA

Background: Temporal artery biopsy (TAB) is often used to confirm or reject the diagnosis both in uncertain cases and when the clinical picture indicates giant cell arteritis (GCA). There are conflicting data on the impact of corticosteroid treatment on TAB findings in patients with GCA. The objective of this study was to investigate the impact of baseline clinical characteristics and corticosteroid treatment on TAB findings in patients with GCA. Method: Individuals who developed GCA after inclusion in two population-based health surveys were identified by linking the health survey databases to the local patient administrative register and the national patient register. In addition, other patients diagnosed with GCA at the Departments of Internal Medicine and Rheumatology at a hospital in the area during the same period were also included. A structured review of medical records and TAB pathology reports was performed. The presence or absence of giant cells, granuloma, fragmented internal elastic




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lamina, fibrosis and grade of inflammatory infiltrates were recorded. The relationships between reported histopathological features, time from treatment start to TAB and clinical parameters were investigated. Results: In 183 included cases with a confirmed clinical diagnosis of GCA, the median time from start of corticosteroid treatment to TAB was 2 days [interquartile range (IQR) 1–4; total range 22–253]. The proportions with a positive biopsy in relation to timing of biopsy and in relation to treatment start did not differ significantly: 86% ( 0 days), 69% (1–3 days), 79% (4–7 days), and 80% (8–28 days) (p ¼ 0.17). Patients with a positive biopsy (77%) had significantly higher CRP (p ¼ 0.007) and ESR (p ¼ 0.03) at the time of clinical diagnosis. In logistic regression analysis, comparing biopsies performed before or on the same day as initial treatment to those 1–3 days after treatment start, the former was associated with a positive biopsy (OR 2.86, CI 1.06– 7.70) and the occurrence of inflammatory infiltrates (OR 3.74, CI 1.31–10.71). Minor inflammatory infiltrates were still seen, although less frequently, among those with longer time on corticosteroid treatment prior to TAB (p for trend: 0.03), whereas there was no such trend for major inflammatory infiltrates. The proportions with other histopathological features did not differ significantly across categories of time on corticosteroids. Patients with pre-treatment biopsy had lower ESR levels (p ¼ 0.04) and were less likely to have visual symptoms at diagnosis (36% vs. 54%; p ¼ 0.04). Conclusions: Biopsies were more likely to be positive and have characteristic histopathological features in patients with high CRP and ESR, and prior to start of corticosteroid treatment, whereas TAB performed a week or more after initiation of therapy still yields clinically useful information for the diagnosis of GCA.

PP167 The diagnostic performance of FDG PET-CT in patients with polymyalgia rheumatica and giant cell arteritis RA Gildberg-Mortensen1, E Øster-Jørgensen1, S Hess2, IMJ Hansen1

claudication, visual impairment, and tenderness of the temporal arteries. Temporal artery biopsy (TAB) is considered the gold standard in the diagnosis of GCA, despite a false negative rate up to 25% due to skip lesions. Fluoro-18-deoxyglucose (FDG) PET-CT is a non-invasive imaging technique that visualizes increased metabolic activity as it is seen in cancer and inflammation, including vasculitis. Our objective was to evaluate the diagnostic performance of FDG PET-CT in patients with PMR and GCA as a supplement to a smaller study we conducted previously. Method: We performed a retrospective review of all patients registered in the Department of Rheumatology within Svendborg Hospital, Odense University Hospital, in whom PMR or GCA was first diagnosed between 2008 and 2013, who had underwent a FDG PET-CT scan and TAB at the time of diagnosis. Results: Fifty-seven patients (28♀, 29♂) were included in the study. Twenty-seven patients (47.4%) presented with isolated PMR and 25 (43.9%) had a clinical diagnosis of GCA. Four patients (7.0%) presented only with constitutional symptoms and one patient (1.8%) was examined due to incidental finding of high inflammatory markers. Increased vascular uptake of FDG on PET-CT was detected in 23 of the 57 patients (40.4%). TAB was negative in six of those patients (26.1%). However, three3 patients had received high doses of prednisone before biopsy. TAB was positive in 21 of the 57 patients (36.8%). In four (19.0%) of these patients, PET-CT showed no increased vascular uptake, but two of the patients received steroids before the scan. Cohen’s kappa coefficient for a measure of interagreement was 0.63, corresponding to substantial agreement between biopsy and PET-CT findings. The sensitivity of detecting vasculitis on PET-CT was 81% and specificity 83%, while the positive and negative predictive values were 74% and 88%, respectively (included those patients who received steroid treatment prior to the PET-CT scan). Conclusions: This study supports our previous findings that PET-CT is a good second approach for detecting GCA and should be considered in patients with negative TAB. Furthermore, our findings support the theory that PMR and GCA are probably different facets of the same disease.

1

Department of Rheumatology, Svendborg Hospital, Odense University Hospital, Svendborg, and 2Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark

References

Background: Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are closely related disorders characterized by a systemic inflammatory response with elevated inflammatory markers and constitutional symptoms including fatigue, weight loss, and fever. Patients with PMR typically present with proximal muscle pain and stiffness while GCA is a vasculitis, causing cranial symptoms such as new-onset headache, jaw

1. Kermani TA, Warrington KJ. Polymyalgia rheumatica. Lancet 2013;381:63–72. 2. Blockmans D, Maes A, Stroobants S, Nuyts J, Bormans G, Knockaert D, et al. New arguments for a vasculitic nature of polymyalgia rheumatica using positron emission tomography. Rheumatology (Oxford) 1999;38:444–7. 3. Ray-Chaudhuri N, Kiné DA, Tijani SO, Parums DV, Cartlidge N, Strong NP, et al. Effect of prior steroid treatment on temporal artery biopsy findings in giant cell arteritis. Br J Ophthalmol 2002;86:530–2.



Molecular aspects on pathogenesis in arthritis/ bone destruction PP168 Cathepsin S and cathepsin L in serum and synovial fluid in rheumatoid arthritis with and without autoantibodies


T Weitoft1, A Larsson2, V Manivel3, J Lysholm4, A Knight5, J Rönnelid3 1 Section of Rheumatology, Centre for Research and Development Uppsala University/County Council of Gävleborg, Gävle, 2Section of Clinical Chemistry, Department of Medical Sciences, 3Department of Genetics, Immunology and Pathology, Uppsala University, 4Clinic of Rheumatology, Falu hospital, Falun, and 5Section of Rheumatology, Department of Medical Sciences, Uppsala University, Sweden

Background: Cathepsin S and cathepsin L are endosomal proteolytic enzymes involved in the degradation of extracellular matrixes, angiogenesis, and antigen presentation. Cathepsins could thus play several roles in the pathogenesis of rheumatoid arthritis (RA). The objectives of the present study were to study cathepsin S and cathepsin L levels in serum and synovial fluid of RA patients with and without autoantibodies against citrullinated peptides (ACPA) and rheumatoid factor (RF). Method: This study recruited 121 patients with RA and clinical signs of knee synovitis. Patient characteristics were collected and matched samples of serum and synovial fluid were analysed for cathepsin S, cathepsin L, ACPA, IgA and IgM RF, C-reactive protein (CRP), and matrix metalloproteinase 3 (MMP3). Results: Synovial fluid levels of cathepsin L, cathepsin S, and MMP3 were significantly higher than in serum. Serum levels of both cathepsins were significantly higher in patients with ACPA, IgM RF, and IgA RF compared with patients without these antibodies. Synovial fluid levels of both cathepsins correlated with DAS28 and CRP in ACPA- and RF-positive but not in seronegative patients. No such correlation was found for serum cathepsins. Conclusions: The differences in cathepsin S and cathepsin L between RA patients with and without autoantibodies indicate a unique role for cathepsins in the pathogenesis of seropositive RA. In this phenotype cathepsin serum levels may reflect the autoimmune activity, whereas the levels in synovial fluid may reflect the local inflammatory and matrix degrading process in the joint. PP169 Chemokine-mediated regulation of Th17-cell migration as a novel mechanism for oestrogen-induced amelioration of experimental arthritis A Andersson1, A Stubelius1, M Nurkkala-Karlsson1, C Engdahl2, M Erlandsson1, L Grahnemo1, MK Lagerquist2, U Islander1

53 Departments of 1Rheumatology and Inflammation Research and 2 Internal Medicine and Clinical Nutrition, Centre for Bone and Arthritis Research, Sahlgrenska Academy, University of Gothenburg, Sweden

Background: The incidence and progression of many autoimmune diseases are gender biased, which may be partially explained by the immune-modulating properties of endocrine hormones. Oestrogen treatment, as in hormone-replacement therapy, has been shown to be beneficial in rheumatoid arthritis (RA), although the mechanisms involved are mostly unknown. Pro-inflammatory T helper 17 (Th17) cells have emerged as key players in driving RA, although whether oestrogen modulates Th17 cells in this disease has not yet been studied. Therefore, the aim of this study was to investigate the effects of oestrogen on Th17 cells in experimental arthritis. Method: Female ovariectomized DBA/1 mice, treated with 17β-oestradiol (E2; 0.83 μg/day) or placebo, were subjected to collagen-induced arthritis (CIA) and Th17 cells in joints and lymph nodes were studied at several time points using flow cytometry and IL-17 ELISPOT. Results: The E2-treated mice with established CIA showed reduced severity and incidence of arthritis and fewer Th17 cells in joints compared to placebo controls. Of note, the mice treated with E2 displayed an accumulation of Th17 cells in lymph nodes during the induction phase of CIA, which was associated with an up-regulation of chemokine receptor 6 (CCR6) on lymph node Th17 cells as well as increased expression of the corresponding chemokine CCL20 within the lymph nodes. Conclusions: The E2-induced retention of Th17 cells within the lymph nodes in CIA, caused by interference with the CCR6–CCL20 pathway, suggests a novel mechanism in oestrogen-mediated inhibition of arthritis. Our study presents new important perspectives on the effects of oestrogen on the immune system, and the CCR6–CCL20-induced retention of Th17 cells in lymph nodes per se could be implicated in the development of new treatment strategies in RA.

PP170 CD25þCD39þ Tregs are enriched at the site of inflammation of patients with rheumatoid arthritis and impaired in suppressing IL-17A secretion J Herrath, K Chemin, I Albrecht, AI Catrina, V Malmstrom Department of Medicine, Karolinska Institutet, Stockholm, Sweden

Background: Regulatory T cells (Tregs) are important for the maintenance of self-tolerance and are implicated in the origins of autoimmunity. Despite enrichment of Tregs in joints of rheumatoid arthritis (RA) patients, local inflammation persists and becomes chronic. Recently, CD39 expression was described on FOXP3þ Tregs and




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was suggested as a novel mechanism of Treg suppression by producing anti-inflammatory adenosine together with CD73. Of note, the capacity of CD39þ Tregs to suppress Th17 responses is impaired in multiple sclerosis. Whether this defect is a general feature found in autoimmune diseases is currently unknown. In this study, we first aimed to better characterize the CD39þ Treg compartment in blood and synovial fluids from RA patients. We then further addressed their capacity in suppressing T effector cell responses, especially Th17 responses. Method: Multi-parameter flow cytometry was used to assess the ex vivo frequencies of FOXP3þCD39þ and FOXP3þCD39– Tregs in blood of healthy controls (n ¼ 11) and RA patients (n ¼ 15) as well as at the site of inflammation of RA (n ¼ 15) and spondylarthropathy patients (n ¼ 10). In addition, the differential suppressive capacity of synovial CD39þ and CD39– Tregs was investigated by conventional co-culture systems (n ¼ 6). Proliferation and cytokine secretion was measured by thymidine incorporation and luminex, respectively. Results: FOXP3þCD39þ Tregs were enriched at the site of inflammation (p ¼ 0.0007) whereas synovial FOXP3þCD73þ Tregs were reduced compared to the circulation (p < 0.001). The same pattern for CD39 and CD73 expression was also seen for the total population of synovial CD4þ T cells (p < 0.0001). Furthermore, synovial CD25þCD39þ Tregs were able to suppress proliferation of T effector cells (p ¼ 0.0313), in contrast to their CD39– counterparts that proliferated instead (p ¼ 0.026). Finally, cytokine suppression was exerted by the CD25þCD39þ Treg subset (and not by CD39–) for many cytokines but not for IL-17A. Conclusions: Our data suggest that FOXP3þCD39– and FOXP3þCD39þ Tregs are distinct subsets with different functions as exemplified by synovial CD39– T cells, which proliferate in vitro and secrete pro-inflammatory cytokines instead of suppressing them. CD39– Tregs could represent plastic Tregs that converted to IL-17 producers under inflammatory conditions. Furthermore, we demonstrate that, in synovial fluid, CD39þ Tregs are impaired in suppressing IL-17A secretion, a cytokine that may contribute to disease pathogenesis. This finding could partly explain why accumulation of Tregs is seen at the site of inflammation without facilitating remission.

remains unclear. Expression analysis is one of the tools to link findings from genetic epidemiology studies with biological mechanisms of the disease. Variations within the gene encoding the intracellular protein tyrosine phosphatase non-receptor type 2 (PTPN2), which has been implicated in T-cell receptor signalling, have recently been associated with a number of chronic inflammatory diseases, including RA. The PTPN2 gene codes for at least two alternatively spliced isoforms, TC45 and TC48, which differ in their C-termini and localize differentially to the nucleus and the cytoplasm. In this study, we investigated mRNA expression of PTPN2 isoforms in peripheral blood cells of RA patients and healthy controls. Method: We studied the relative mRNA expression of all PTPN2 splice forms combined and the specific PTPN2 splice forms by TaqMan real-time PCR in relation to the housekeeping gene ZNF592 in whole-blood samples from 75 RA patients and 77 healthy controls of Caucasian ancestry. The Mann–Whitney U test was used to evaluate differences and p < 0.05 was considered to be significant. Results: There was no significant difference in total PTPN2 expression in whole-blood samples from RA patients and healthy controls. However, the PTPN2 splice forms were differentially expressed in these samples. We saw an increase in expression for TC45 [median relative quantity (RQ) ¼ 1.119 (interquartile range, IQR 0.664); p ¼ 0.0259] and TC48 (median RQ ¼ 1.047 (IQR 0.529); non-significant) in RA patients. This difference was more pronounced when comparing the ratio of splice forms (p < 0.0001). Conclusions: Our study shows that PTPN2 expression of the canonical and the alternatively spliced isoforms in whole-blood samples of RA patients is different compared to healthy controls, although expression of total PTPN2 did not show this clearly. This is an example of expression analysis where the detection of overall gene expression without considering transcription/translation diversity may generate false negative results. Our results suggest that the structural differences between the two isoforms might affect events in the pathogenesis of RA.

PP172 PP171 Alternatively spliced isoform expression of PTPN2 in rheumatoid arthritis M Houtman, K Shchetynsky, L Padyukov Rheumatology Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden

Background: Rheumatoid arthritis (RA) is a prototype autoimmune disease with unknown aetiology. Despite extensive genetic association studies, the mechanism of disease in relation to putative function of found loci


Lasofoxifene and bazedoxifene suppress bone marrow B-cell development differently than 17β-oestradiol and do not increase peripheral B-cell activity A Bernardi, A Andersson, L Grahnemo, MN Karlsson, H Carlsten, U Islander Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, Gothenburg University, Sweden

Background: Lasofoxifene (las) and bazedoxifene (bza) are new selective oestrogen receptor modulators (SERMs) indicated for treatment of postmenopausal



osteoporosis. The inhibitory effects of 17β-oestradiol (E2) on B lymphopoiesis and its stimulatory effect on antibody production are well documented. The traditional SERM raloxifene (ral) also reduces B-cell development but does not increase antibody-producing cells. However, third-generation SERMs have not been studied from an immunological perspective. Therefore, the aim of this study was to investigate the effects of las and bza on B-cell development and function. Method: C57BL/6 mice were ovariectomized (ovx) or sham operated and treated with las, bza, ral, E2, or vehicle. Bone marrow and spleen cells were phenotyped by flow cytometry and antibody-producing cells were quantified using ELISPOT assay. Serum B-cell activating factor (BAFF) was measured by ELISA. Results: As expected, E2 treatment decreased B-cell numbers at all developmental stages from pre-BI cells (in bone marrow) to transitional B cells (in spleen) and increased marginal zone (MZ) B cells. Treatment with las or bza only decreased two distinct B-cell populations (immature B cells in bone marrow and T1 B cells in spleen) and had no effect on MZ B cells. Furthermore, E2, but not las or bza, increased serum levels of BAFF and numbers of antibody-producing cells. Conclusions: Las and bza differ from E2 by retaining normal numbers of cells at most B-cell stages during B lymphopoiesis and maturation and by not increasing antibody-producing cells or serum BAFF. PP173 B-cell responses to de novo identified citrullinated fibrinogen peptides are associated with the PTPN22 risk allele V Joshua1, L Schobers1, L Israelsson1, M Hansson1, J Rönnelid2, AI Catrina1, GJM Pruijn3, V Malmström1 1 Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden, 2Department of Immunology, Genetics and Pathology, Uppsala University, Sweden, and 3 Department of Biomolecular Chemistry, Radboud University, Nijmegen, The Netherlands

Background: Antibodies against citrullinated proteins are common in patients with rheumatoid arthritis (RA) and appear prior to the onset of the disease (1). Many of the citrullinated epitopes have been identified and studied in detail. Using an unbiased mass spectrometric approach, the levels of citrullinated fibrinogen (cit-Fib) peptides were demonstrated to be elevated in the synovial fluid of RA patients compared to non-RA patients (2). In this study we aimed to identify the presence of autoantibodies against these citrullinated peptides. Method: An in-house ELISA was established against five cit-Fib epitopes (cit-Fib α-35, cit-Fib α-216,218, cit-Fib α-263,271, cit-Fib α-425,426, and cit-Fib β-60,72,74) and serum samples from a cohort of patients with established RA (n ¼ 347) and from disease controls with psoriatic arthritis (PSA) or ankylosing spondylitis

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(AS) (n ¼ 268) were analysed. Cut-off for the ELISA was set at the 98th percentile, based on reactivity in a cohort of healthy controls (n ¼ 152). The RA patients were genotyped with regard to HLA-DR alleles and PTPN22 R620W. The RA cohort has previously been screened for anti-CCP2 antibodies and antibodies against cit-Fib protein (3). Results: Autoantibodies against the different cit-Fib epitopes were present in the following frequencies in the RA patients compared to the PSA/AS patients: cit-Fib α-35 (RA 20%, PSA/AS 2%), cit-Fib α-216,218 (13%, 2%), cit-Fib α-263,271 (21%, 2%), cit-Fib α-425,426 (17%, 2%), and cit-Fib β-60,72,74 (4%, 0%). The presence of autoantibodies against these epitopes was associated with the presence of anti-CCP2 antibodies and antibodies against whole cit-Fib. No genetic association was found between the presence of the HLA shared epitope and antibodies to the different cit-Fib epitopes, while an association was observed between the PTPN22 risk allele and positivity to cit-Fib α-35 and cit-Fib α-263,271. Conclusions: Fibrinogen is readily citrullinated in the rheumatic joint and our data show that several of the citrullinated epitopes are targeted by autoantibodies in the context of RA but not in PSA/AS. Our data further emphasize that the anti-citrulline response is broad with many parallel immune responses. Association between the presence of these autoantibodies with the PTPN22 risk carriers suggest that cit-Fib-reactive B cells would normally be deleted during the B-cell tolerance checkpoints (4). References 1. Rantapää-Dahlqvist S, de Jong BA, Berglin E, Hallmans G, Wadell G, Stenlund H, et al. Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum 2003;48:2741–9. 2. Raijmakers R, van Beers JJ, El-Azzouny M, Visser NF, Božič B, Pruijn GJ, et al. Elevated levels of fibrinogen-derived endogenous citrullinated peptides in synovial fluid of rheumatoid arthritis patients. Arthritis Res Ther 2012;14:R114. 3. Snir O, Widhe M, Hermansson M, von Spee C, Lindberg J, Hensen S, et al. Antibodies to several citrullinated antigens are enriched in the joints of rheumatoid arthritis patients. Arthritis Rheum 2010;62:44–52. 4. Menard L, Saadoun D, Isnardi I, Ng YS, Meyers G, Massad C, et al. The PTPN22 allele encoding an R620W variant interferes with the removal of developing autoreactive B cells in humans. J Clin Invest 2011;121:3635–44.

PP174 Osteoclastogenesis is enhanced by anti-citrullinated proteins antibodies in rheumatoid arthritis A Krishnamurthy1, V Joshua1, H Wähämaa1, N Tarasova2, C Cerqueira1, E Ossipova1, N Vivar1, K Amara1, K Lundberg1, V Malmström1, P-J Jakobsson1, G Schett3, J Ytterberg2, A Catrina1 1 Rheumatology Unit, Department of Medicine and 2Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden, and 3Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany




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Background: Antibodies against modified citrullinated vimentin (MCV) isolated from peripheral blood (PB) of rheumatoid arthritis (RA) patients induce osteoclast (OC) formation of PB-derived monocytes from healthy individuals. Recently, dendritic cells (DCs) have been proposed as potent OC precursors. We aimed to characterize DC- and macrophage (MΦ)-derived osteoclastogenesis in ACPAþ RA and furthermore to explore the effect of polyclonal anti-CCP2 antibody on osteoclastogenesis. Method: Synovial fluid (SF) (n ¼ 26) and plasma (n ¼ 38) samples were collected from RA patients. Total IgG was isolated on Protein G followed by ACPA IgG affinity purification on CCP2 columns. CD14þ monocytes were isolated from PB of ACPAþ RA patients or healthy individuals and cultured in the presence of GM-CSF and IL-4 to generate DCs or M-CSF to generate MΦ. DCs and MΦ were further differentiated to OCs in the presence of RANKL and M-CSF, with or without ACPA IgG or flow through control IgG (at a final concentration of 100 and 1000 ng/mL). OCs were counted as multinucleated (more than three nuclei) TRAPþ cells. In parallel, cells were grown on osteoassay surfaces and the bone resorption area was quantified by computer-assisted image analysis. Additionally, experiments were performed by using inhouse generated monoclonal citrulline IgG antibodies obtained from synovial fluid single B-cell cloning technology. Cytometric bead array was used to measure cytokines in the OC culture supernatants. Mass spectrometry was used to identify citrullinated proteins during different stages of OC maturation. Immunohistochemistry (IHC) was used to stain the OCs with ACPA IgG and monoclonal citrulline antibodies. Results: SF and plasma ACPA IgG significantly increased the number of TRAPþ OCs and bone resorption, we also observed a dose-dependent increase of RANKL-driven osteoclastogenesis from both DC and MΦ assay. A similar effect of ACPA-mediated OC induction was observed when the precursor cells were used from both healthy and CCPþ RA patients. Principal component analysis on proteomic profile during different stages of OC maturation from DCs and MΦ suggested that they exhibited different proteomic profiles. We found a significant increase in native vimentin levels during dendritic-derived OC maturation with identification of citrullinated vimentin peptides in the matured OCs. We determined an increase in the IL-8 levels during the OC maturation on the ACPA IgG-treated supernatants. We also found the monoclonal citrulline antibodies to induce osteoclastogenesis and their binding on citrulline targets on OCs were confirmed using IHC. Conclusions: SF- and plasma-derived ACPA IgG with broad specificities and monoclonal citrulline antibodies enhance RANKL-driven osteoclastogenesis. While citrullinated vimentin is a potential target in mature


OCs, the exact contribution of each distinct ACPA specificity remains to be determined. We propose a novel mechanism that ACPA binding on the citrullinated proteins expressed by OC precursors could lead to enhanced IL-8 production, which in turn may increase the osteoclastogenesis.

PP175 HIF-2α-dependent RANKL induction and osteoclastogenesis is augmented by inflammatory cytokines S Revu1, A Krishnamurthy1, X Zheng2, VG Sunkari2, IR Botusan2, M Korotkova1, S-B Catrina2, A Catrina1 1 Rheumatology Unit, Department of Medicine and 2Department of Molecular Medicine and Surgery, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

Background: The hypoxic environment of a chronically inflamed joint plays an important role in mediating local inflammation, but the exact molecular pathways modulated by hypoxia are still largely unexplored. We aimed to investigate the contribution of hypoxia to inflammationassociated bone loss. Method: Osteoblasts were cultured in normoxia (21% O2) or hypoxia (1% O2) in the presence/absence of tumour necrosis factor (TNF)-α. Receptor activator of nuclear factor (NF)-kappaB ligand (RANKL) and osteoprotegerin (OPG) levels were determined by rtPCR, Western blot and ELISA. Hypoxia-associated factor (HIF)-1α, HIF-2α, and VHL siRNA silencing was performed in osteo-blasts. A direct influence of HIF on RANKL was investigated by promoter chromatin immunoprecipitation (ChIP). Osteoblast-conditioned media, chemical hypoxia (dimethyloxalylglycine), and TNF-α were tested on osteoclast formation from peripheral blood (PB) mononuclear cells and on osteologic bone discs. Results: Hypoxia increased RANKL and decreased OPG mRNA and protein expression in osteoblasts and was additive to TNF. HIF-2α but not HIF-1α silencing abolished the hypoxia-induced RANKL expression. ChIP confirmed the interaction between HIF-2α and hypoxia responsive elements in the RANKL promoter. RANKL and OPG changes induced by concomitant exposure to hypoxia and TNF resulted in increased osteoclast formation by osteoblast-conditioned media. Chemical hypoxia and TNF had a similar additive effect to promote osteclastogenesis and bone destruction despite excess amounts of exogenous RANKL. Conclusions: Hypoxia has an additive effect with TNF to increase osteoclastogenesis, through dual mechanisms: (1) induction of RANKL expression through a HIF-2α- dependent mechanism and (2) activation and maturation of osteoclasts through a direct cellular effect.


PP176 Identification of a new citrullinated collagen type II T-cell epitope in HLA-DRB1*1001-positive rheumatoid arthritis patients

57

As such, this allele represents a good prototype for studying citrulline immunity. Our overall aim was to understand which aberrant immune responses may precipitate into RA.

K Chemin1, E James2, J Herrath1, I Albrecht1, C Anca1, L Padyukov1, L Rönnblom3, L Klareskog1, V Malmström1 1

Rheumatology Unit, Karolinska Institute, Stockholm, Sweden, Benaroya Research Institute, Seattle, WA, USA, and 3Section of Rheumatology, Department of Medical Sciences, Stockholm, Sweden

PP177


2

Background: Antibodies against the cartilage protein collagen type II (CII) are present in sera and synovial fluid from RA patients. Some of them are directed against the native protein, while others are directed against citrullinated CII. A dominant MHC class II restricted CII T-cell epitope has long been studied in the context of both human HLA-DR4 and mouse I-Aq, but this epitope is not dependent on citrulline. We postulated that some RA-associated HLA molecules could present citrullinated CII peptides and we aimed to identify and perform functional characterization of anti-citrullinated CII CD4þ T cells in RA patients. Method: The entire CII protein was screened for peptides capable of binding RA-associated HLA molecules (ProImmune Reveal assay). Three unique citrullinated type II collagen peptides binding to the RA-associated HLA-DR*1001 allele were identified. We screened these citrullinated peptides and their unmodified counterparts in functional T-cell assays using PBMCs from HLAmatched RA patients (n ¼ 13) and healthy donors (n ¼ 5). Multiparameter flow cytometry was performed to detect CD40L up-regulation and cytokine production was assessed through luminex technology. Enrichment of activated T cells was conducted with the use of antiCD40L beads to further study the function of autoreactive T cells. Results: In PBMCs from RA patients, one citrullinated CII peptide was found to induce a specific response, as it could be blocked by anti-HLA-DR antibodies. Strikingly, the native (non-citrullinated) peptide did not elicit any responses. Autoreactive T cells could also be detected in PBMCs isolated from two healthy donors. Upon stimulation with the cit-peptide, T cells secrete pro-inflammatory cytokines such as IFN-γ, IL17A, and TNF-α. Conclusions: We have identified a novel citrullinated CII-derived T-cell epitope that is presented by HLADRB1*1001. Whether HLA-DRB1*0401 alleles can also present this peptide is currently under investigation. While much work has been focused on the 0401 allele, only a few studies have focused on the *1001 allele. These studies suggest that HLA-DRB1*1001 would favour the presentation of citrullinated epitopes.

Anti-TNF therapy with adalimumab restores the bone metabolism balance through a dual mechanism in rheumatoid arthritis A Krishnamurthy, S Revu, A Hensvold, P Neregård, M Engström, E af Klint, D Makrygiannakis, A Catrina Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden

Background: Large clinical studies have demonstrated that TNF blockade delays radiological progression in rheumatoid arthritis (RA) independent of the clinical response. We aimed to investigate the mechanisms by which adalimumab, a human anti-TNF antibody, affects osteoclastogenesis in vivo and in vitro. Method: Expression of OPG, RANK, and RANKL was evaluated by immunohistochemistry and semiquantitative double-blind analysis of serial synovial biopsies obtained from 12 RA patients treated with adalimumab before and 8 weeks after treatment initiation. The in-vitro effect of adalimumab on RANKL and OPG expression in osteoblast-like cells with or without TNF priming was evaluated by RT-PCR and Western blots. Further investigation of the direct effect of adalimumab on osteoclast formation (TRAP staining) and function was tested in a bone resorption assay using blood-derived CD14-positive monocytes. Resorption area was analysed by computer-assisted image analysis. Results: Treatment with adalimumab significantly decreased the RANKL/OPG ratio and RANK expression in synovial tissue in parallel with a reduction in the number of synovial macrophages, while no changes were seen in the number of synovial lymphocytes. No significant differences were observed between EULAR responders and non-responders. In-vitro adalimumab mimicked the in-vivo effect inducing a decrease in the RANKL/OPG ratio in osteoblast-like cells (SaOS2). In addition, adalimumab was able to inhibit in-vitro osteoclast formation and bone resorption even in the presence of RANKL. Conclusions: Therapy with adalimumab regulates not only synovial inflammation but also bone metabolism through direct modulation of the RANKL/RANK/OPG pathway and inhibition of osteoclasts formation. These effects might explain the bone-sparing effect seen with TNF blockade even in the presence of ongoing inflammation.



58

PP178

PP179

Differences in the autoreactive T-cell pool when restricted by the highly related rheumatoid arthritisassociated HLA-DRB1 alleles *04:01, *04:04, and *01:01

Endogenous B-cell-targeted antigen expression induces tolerance to collagen type II arthritis in mice

C Sandin , C Gerstner , H Uchtenhagen , E James , J Pieper , M Rieck3, A Achour1, JH Buckner3, T Sandalova1, V Malmström1

S Andersson1, T Eneljung1, S Tengvall1, L Mårtensson1, K Gustafsson2, H Rikard3, J Kihlberg4, A Stern1, P Jirholt1, I Gjertsson1

1

1

1

1

1

2

1


Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden, 2Tetramer Core and 3Translational Research Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA

Background: The shared epitope (SE) alleles HLADRB1*04:01, *01:01, and *04:04 are associated with risk for rheumatoid arthritis (RA) positive for autoantibodies against, for example, citrullinated α-enolase. Recent studies identified specific citrullinated epitopes presented by *0401 that are associated with disease and provided molecular evidence for how citrullination could break tolerance. So far, the risk conferred by *01:01 and *04:04 is less well characterized. Here, we aimed at the identification and functional characterization of citrullinated α-enolase T-cell epitopes presented by these alleles. Method: Overlapping peptides covering the length of α-enolase were synthesized with every argininecontaining peptide being duplicated by a citrulline version. Tentative HLA-binding peptides were identified by in-vitro competition assays. Candidate epitopes were then used for functional assays with peripheral blood mononuclear cells (PBMCs) from RA patients and healthy donors positive for the HLA-DR alleles under investigation. T-cell responses were evaluated in in-vitro cultures as up-regulation of CD154 (CD40L) expression and intracellular cytokine staining as assessed by multi-parameter flow cytometry. Results: By screening the overlapping peptides, several novel α-enolase epitope candidates were identified. A large, but not complete, overlap was observed between *0401, *0404, and *0101. Surprisingly, the binding of native and citrullinated epitopes indicated that the bias for citrullinated epitopes of *04:01 appears less pronounced in *0404 or *0101. In-vitro stimulation of PBMCs demonstrated that a number of the epitope candidates are indeed immunogenic in RA patients and elicit a proinflammatory cytokine response. However, and in agreement with the peptide binding, a significant preference for citrullinated epitopes was only observed for *04:01. Conclusions: While this study confirms the compelling bias of *04:01 for citrullinated epitopes, it demonstrates its absence in *0404 and *0101. Our data suggest that, despite their name and shared amino acids, significant differences exist in how these HLA-DR alleles confer risk to RA. Altogether, this demonstrates how even subtle changes in the MHC peptide-binding groove can have significant immunological impacts and has prompted ongoing structural characterization of the different properties of *04:01 vs. *01:01 and *04:04.


Department of Rheumatology and Inflammation Research, Gothenburg University, Sweden, 2Molecular Immunology Unit, University College London, UK, 3Medical Inflammation Research, Karolinska Institute, Stockholm, Sweden, and 4Astra Zeneca, R&D, Mölndal, Sweden

Background: A safe and effective therapy in rheumatoid arthritis (RA) would be to re-establish tolerance. To achieve tolerance in a clinical setting, the underlying immunological mechanisms need to be better understood. Collagen-induced type II arthritis (CIA) is an established mouse model of human RA. We have previously shown that endogenous antigen presentation of a collagen type II (CII) peptide on all types of antigen-presenting cells induces tolerance to CIA (1, 2). The aim of this study was to test the hypothesis that presentation of the CII peptide on B cells alone could mediate tolerance. Method: B-cell-specific expression of CII was achieved by lentiviral-based gene therapy. Amino acids 259–270 in the CII peptide were cloned into the CLIP position of invariant chain to allow presentation on MHC II under control of the B-cell-specific IgK promoter (IgK-CII). In the control vector the original CLIP sequence was kept (IgK-Ctrl). Haematopoietic stem cells were transduced with vectors in vitro using lentiviral particles and injected into irradiated mice, which were later immunized. Results: Presentation of the CII peptide on B cells in IgK-CII mice reduced the severity of arthritis. The frequency of plasmablasts in draining lymph nodes was decreased and there were lower levels of CII-specific IgG antibodies in IgK-CII mice. The B-cell-specific presentation of CII in IgK-CII mice increased both number and suppressive function of regulatory T cells. Finally, adoptive transfer of regulatory T cells from IgK-CII mice to naïve recipients ameliorated the recipients’ development of CIA. Conclusions: Our data suggest that the endogenous presentation of the CII peptide on B cells is a key contributor to arthritis tolerance induction and maintenance. The effects are in part mediated by T regulatory cells and by reduced levels of CII-specific IgG antibodies.

References 1. Gjertsson I, Laurie KL, Devitt J, Howe SJ, Thrasher AJ, Holmdahl R, et al. Tolerance induction using lentiviral gene delivery delays onset and severity of collagen II arthritis. Mol Ther 2009;17:632–40. 2. Eneljung T, Tengvall S, Jirholt P, Henningsson L, Holmdahl R, Gjertsson I. Antigen-specific gene therapy after immunisation reduces the severity of collagen-induced arthritis. Clin Dev Immunol 2013;2013:345092.


Poster Session Tuesday Comparative effectiveness of treatments for rheumatic diseases PP201 Baricitinib, an oral janus kinase inhibitor, in the treatment of rheumatoid arthritis: safety and efficacy in an open-label, long-term extension study P Taylor1, M Genovese2, E Keystone3, D Schlichting4, S Beattie5, W Macias4, J Lundmark (presenter only)6

59 Table 1. Disease improvement/ activity measure ACR20 ACR50 ACR70 CDAI Remission SDAI Remission DAS28 ESR < 2.6 DAS28 ESR 3.2 DAS28 CRP < 2.6 DAS28 CRP 3.2 Boolean remission

24 weeks

52 weeks

149/201 (74%) 83/201 (41%) 43/201 (21%) 34/200 (17%) 30/195 (15%) 35/200 (18%) 55/200 (28%) 59/195 (30%) 93/195 (48%) 19/195 (10%)

139/196 (71%) 96/197 (49%) 53/197 (27%) 40/195 (21%) 42/194 (22%) 47/195 (24%) 82/195 (42%) 80/194 (41%) 116/194 (60%) 32/194 (16%)

1

Kennedy Institute of Rheumatology, University of Oxford, UK, Immunology and Rheumatology Clinic, Stanford University, Stanford, CA, USA, 3The Rebecca MacDonald Centre for Arthritis and Autoimmune Diseases, Mount Sinai Hospital, Toronto, Canada, 4Eli Lilly and Company, Corporate Ct, Indianapolis, IN, USA, 5Global Statistical Sciences/Autoimmune Platform, Eli Lilly, Indianapolis, IN, USA, and 6Bio-Medicines, Eli Lilly Sweden AB, Solna, Sweden


2

Background: Baricitinib (formerly LY3009104/ INCB028050) is a novel, oral inhibitor of JAK1 and JAK2 in the JAK-STAT signalling pathway being investigated as a treatment for rheumatoid arthritis (RA). The aim of this study was to report 52-week safety and efficacy findings of an open-label extension of the phase 2b study. Method: Patients (pts) were initially randomized to placebo (PBO) or one of four once-daily (QD) baricitinib doses (1, 2, 4, or 8 mg) for 12 weeks. Pts assigned to 2, 4, or 8 mg continued assigned treatment and pts assigned to PBO or 1 mg were reassigned to 4 mg QD or 2 mg BID for an additional 12 weeks of blinded treatment. In the openlabel portion of the study, patients in the 8 mg group continued to receive 8 mg QD and all other patients received 4 mg QD. Doses could be escalated to 8 mg QD at 28 or 32 weeks at the investigator’s discretion when > 6 tender and swollen joints were present. Analyses reported here include data over 52 weeks for patients treated in the open-label extension (nonresponder imputation used for discontinued pts). Results: Of the 212 pts eligible to participate, 201 (95%) entered the open-label extension, 184 completed 52 weeks of treatment, 15 discontinued, and two had not yet completed 52 weeks. Among pts who remained on 4 mg (n ¼ 108), TEAEs occurred in 57 (53%), SAEs in 11 (10%), infections in 34 (31%), and serious infections in four (4%). Among pts who received 8 mg at any time (n ¼ 93), TEAEs occurred in 59 (63%), SAEs in eight (9%), infections in 37 (40%), and serious infections in two (2%). No opportunistic infections or TB cases were observed. There was one death due to myocardial infarction in the 8 mg group. Among all patients combined in the open-label extension, the proportions of pts achieving ACR20, ACR50, ACR70, CDAI remission, SDAI remission, DAS28CRP 3.2, DAS28CRP < 2.6, DAS28ESR 3.2, DAS28CRP < 2.6, or the ACR/EULAR Boolean remission at the

start of the open-label extension (week 24) were similar or increased at week 52 (Table 1). Conclusions: Among pts completing 52 weeks of a phase 2b study, clinical improvements observed at week 24 were maintained or improved during the open-label extension. Safety signals observed over the open-label extension were consistent with previously reported results of baricitinib. Reference 1. Taylor P, Genovese MC, Keystone E, Schlichting D, Beattie S, Macias W. Baricitinib, an oral janus kinase inhibitor, in the treatment of rheumatoid arthritis: safety and efficacy in open-label, long-term extension study Ann Rheum Dis 2013;72(Suppl3):65, abstract [OP0047]

PP202 In early RA patients with non-response to methotrexate monotherapy the change in multi-biomarker disease activity score is differentially associated with subsequent response to non-biological vs. biological therapy K Hambardzumyan1, R Bolce2, S Saevarsdottir3, K Forslind4, I Petersson4, P Geborek4, S Ernestam5, E Sasso2, D Chernoff2, S Cruickshank6, R van Vollenhoven1 1 Unit for Clinical Therapy Research, Inflammatory Diseases, Karolinska Institute, Stockholm, Sweden, 2Crescendo Bioscience, South San Francisco, CA, USA, 3Medicine, Karolinska University Hospital, Stockholm, Sweden, 4Section of Rheumatology, Institution of Clinical Sciences, Lund University Hospital, Sweden, 5Institution LIME Medical Management Centre, Karolinska Institute, Stockholm, Sweden, and 6Scott Cruickshank and Associates, Santa Barbara, CA, USA

Background: For patients with early RA (eRA), methotrexate (MTX) is recommended as first-line treatment, and in non-responders the addition of both conventional non-biological disease-modifying anti-rheumatic drug therapy (triple DMARD therapy) and biological (antiTNF) therapy is supported by data. The objective was to evaluate the change in the multi-biomarker disease activity (MBDA) score during MTX therapy as a predictor of response to subsequent triple vs. biological therapy.




60

Method: Patients with eRA and DAS28 > 3.2 entered the SWEFOT clinical trial and received MTX monotherapy for 3 months, at which time clinical non-responders (DAS28 > 3.2) were randomized to receive non-biological triple DMARD therapy (arm A) or anti-TNF (infliximab) therapy with MTX (arm B). For this study, 129 non-responders at month 3 (n ¼ 62 from arm A and n ¼ 67 from arm B) were analysed by MBDA score at baseline (BL) and month 3. The assessment of changes in the MBDA score (DMBDA) from BL to month 3 as a predictor for response to triple or anti-TNF therapy at year 1 was done by defining small ( 6), moderate (7–20), and large (>20) decreases by tertiles. Small and moderate decreases were combined (small/moderate) and compared vs. large decreases for arms A and B. The proportion of patients in arm A vs. arm B with response at year 1 was evaluated by the odds ratio (OR) for patients with small/moderate vs. large decreases. Homogeneity of the ORs between the two cohorts was assessed by the Breslow–Day test. Results: The mean (median) decreases in MBDA score from BL to month 3 for year 1 responders (n ¼ 66) and non-responders (n ¼ 63) were 12.9 (10) and 10.8 (9), respectively (NS), and month 3 mean (median) MBDA scores were 47.1 (45) and 50.3 (47), respectively (NS). Among patients who had small/moderate decreases in MBDA score during MTX monotherapy, 43% responded to subsequent triple therapy and 57% responded to antiTNF (OR 0.577). By contrast, among patients with a large decrease in MBDA score from BL to month 3, 67% responded to subsequent triple therapy and 37% to anti-TNF treatment (OR 3.33). Thus the relative treatment effect of arm A vs. arm B differed according to the degree of change in the MBDA score from BL to 3 months (p ¼ 0.032). Conclusions: Among patients with eRA who did not achieve low disease activity on MTX monotherapy, those patients with the greatest decreases in MDBA score were more likely to respond to triple therapy whereas patients with lesser decreases of the MBDA score were more likely to respond to anti-TNF therapy. These findings suggest that, in MTX non-responders, the changes in MBDA score may help guide subsequent therapy. PP203 Utilization of Nordic registries to support health economics research in rheumatic diseases H Miller Unit for Clinical Therapy Research, Inflammatory Diseases (ClinTRID), Karolinska Institutet, Stockholm, Sweden

Background: Rheumatic diseases are often characterized by pain and disability. Many pharmaceuticals are available for their treatment and a considerable number of health economic (HE) studies have been published. Nordic countries maintain long-term comprehensive disease and drug registries. HE analyses, particularly those


that are based on registry data, can provide important information for health-care decision makers. The primary objective of this study was to systematically review HE analyses of rheumatic diseases that use Nordic registry data, and to provide a descriptive and critical analysis of this application. Method: Published literature was identified by searching the following databases: Medline; Embase through Ovid; Cochrane Library and the Health Economic Evaluations Database (HEED) through Wiley; and PubMed. Search terms were pertinent to rheumatic diseases and HE. One reviewer screened and subsequently extracted data from studies that fulfilled inclusion/exclusion criteria. Results: Forty-five HE studies used Nordic registry data. Studies were relevant to Sweden (n ¼ 26), Norway (n ¼ 12), Finland (n ¼ 4), and Denmark (n ¼ 4). Study types were modelling (n ¼ 13), costing (n ¼ 8), work/productivity (n ¼ 6), quality of life (n ¼ 13), and a combination of HE outcomes (n ¼ 5). Registry data were used within the studies to characterize patients with regard to clinical (n ¼ 29), demographic (n ¼ 20), utility (n ¼ 18), and cost/burden of disease (n ¼ 17). Registry data were used in three studies to validate/assess generalizability. All modelling studies combined registry with non-registry data (e.g. RCTs). Conclusions: Registries provide a rich source of information on real-world patient groups that are being incorporated into HE analyses. Although Nordic registry data are being used in HE studies, many analyses important to HE are not represented. These preliminary findings suggest that health economists should continue to broaden their use and application of registry data in the field of rheumatic disease. Given the gap in data required for an economic evaluation (e.g. modelling), researchers must also continue to be aware of potential issues associated with the synthesis of RCTs and registry data.

PP204 Costs in relation to disability, disease activity, and health-related quality of life in rheumatoid arthritis JA Karlsson1, J Eriksson2, J-Å Nilsson1, T Olofsson1, L-E Kristensen1, M Neovius2, P Geborek1 1 Department of Clinical Sciences Lund, Section of Rheumatology, Lund University, and 2Department of Medicine, Clinical Epidemiology Unit, Karolinska Institutet, Stockholm, Sweden

Background: RA is associated with high societal costs. While disability predicts costs in RA, little is known about the relationships between costs and disease activity or health-related quality of life. Thus, we aimed to study the associations between costs, disability, disease activity, and health-related quality of life. Method: RA patients receiving anti-TNF therapy in southern Sweden (n ¼ 2504; median disease duration 11 years) were monitored between July 2005 and December 2010. At each visit (n ¼ 15 732), HAQ,

n

74 448 519 461 221 64

17

n

89 553

50

25 193 816 354 174 115 70

6000 3000

3000

624

348

135

407 403 1265 349

31 268 1088 511 252 160 110

2000

HAQ category

DAS28, and EQ-5D scores were collected, while costs of anti-rheumatic drugs, health-care use, and productivity losses were calculated from 30 days before to 30 days after the visit using nationwide registers. Associations between the clinical measures and health-care (all patients, applying individual means) and work-loss costs (patients < 65 years; n ¼ 1806) were studied by linear regression, adjusting for demographics and disease characteristics, and by Spearman correlation. Confidence intervals were estimated by non-parametric bootstrapping. Because of the inclusion criteria, anti-TNF cost varied little between patients and was excluded from the analyses. Results: Over 60 days, the mean (SD) health-care cost of patients with ongoing anti-TNF therapy was €3189 (1290), encompassing an anti-TNF cost of €2470 (502; 77%). In patients aged 60 days prior to, and 4% > 60 days after, the registered start date in ARTIS. Eight per cent of patients had anti-TNF prescriptions filled > 90 days after the registered stop date in ARTIS. Conclusions: We observed a high coverage and accuracy of ARTIS data on biologics exposure, for both



64

spondyloarthropathies and rheumatoid arthritis. The combination of data from clinical registers such as ARTIS with data from national health registers offers a high quality measurement of de facto treatment.

Spondyloarthritis - pathogenesis and management

PP208

PP210

Drug survival in patients receiving golimumab treatment 2010–2013: results from the Swedish Rheumatology Quality register

Effect of secukinumab on psoriasis symptoms and physical functioning compared with placebo and etanercept in subjects with moderate-to-severe plaque psoriasis and concomitant psoriatic arthritis: a subanalysis from the phase 3 fixture study

S Saevarsdottir1, M Santacatterina1, L Stawiarz1, C Turesson2, H Forsblad-d’Elia3, L Jacobsson3, S Lindblad1 Scand J Rheumatol Downloaded from informahealthcare.com by Chinese University of Hong Kong on 02/03/15 For personal use only.

Bio-naïve patients generally have higher drug survival than patients previously treated with biologicals.

1

Karolinska Institutet, Stockholm, 2Lund University, Malmö, and University of Gothenburg, Sweden

B Sigurgeirsson1, AB Gottlieb2, RG Langley3, S Philipp4, RLM Martin5, C Papavassilis5, S Mpofu5

Background: Golimumab (Simponi®) is a TNFinhibiting biological drug that was approved in Sweden in 2010 for the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS). In observational studies, the 24-month adhesion to therapy of TNF inhibitors in bio-naïve patients has ranged from 50% to 70%. The aim of the current study was to evaluate cumulative survival probability of golimumab in clinical practice for patient with RA, PsA, and AS, as well as other spondyloarthritidies (SpA). Method: Data were retrieved for all patients initiating golimumab treatment from 2010 until 30 April 2013 from the nationwide Swedish Rheumatology Quality (SRQ) register. Survival analysis (Kaplan–Meier) was performed with right censoring and log-rank testing of equality across strata. Results: Of 1681 patients initiating golimumab treatment during the study period, 678 (40%) had RA, 364 (22%) PsA, 240 (14%) AS, 194 (12%) SpA, and 205 (12%) other diagnoses. The proportions of women in RA/PsA/AS/SpA patient groups were 80/50/28/52%, respectively, and their median age at baseline was 58/ 50/45/43 years. In patients with RA/PsA/AS/SpA, the proportions receiving golimumab as the first biological treatment were 47/45/41/37%, and the proportions receiving concurrent disease-modifying anti-rheumatic drugs (DMARDs) were 70/58/22/38%. When stratified by previous exposure to biological treatment (0/1–2/3 biologicals), the 24-month cumulative survival probability of golimumab in patients with RA was 56/52/ 32%, PsA 56/51/53%, AS 65/57/40%, and SpA 60/49/ 47%. In RA, significant difference was observed between bio-naïve patients and those who had previously received 1 biological drugs (p ¼ 0.0018); a similar trend was observed in AS patients (p ¼ 0.069) but not in PsA (p ¼ 0.6). Conclusions: The 24-month adhesion rates to golimumab in clinical practice appear to be comparable to other TNF inhibitors, whereas further studies are necessary to evaluate the long-term performance of golimumab.

Department of Dermatology, University of Iceland, Iceland, Tufts Medical Center, Boston, MA, USA, 3Dalhousie University, Halifax, Canada, 4Charité Universitätsmedizin, Berlin, Germany, and 5Novartis Pharma AG, Basel, Switzerland

3


1

2

Background: IL-17A is a proinflammatory cytokine that is considered central to psoriasis pathogenesis. Secukinumab (SEC; AIN457), a fully human anti-IL17A monoclonal antibody, has demonstrated efficacy in phase 3 trials for treatment of plaque psoriasis (1). Preliminary results also support efficacy in the treatment of psoriatic arthritis (PsA) (2). Here we report the efficacy and safety of SEC vs. placebo (PBO) and etanercept (ETN) in patients with moderate-to-severe plaque psoriasis and concomitant PsA. Method: Subjects aged 18 years were randomized 1:1:1:1 to SEC sc 150 or 300 mg, PBO, or ETN sc 50 mg. Subjects received treatment at baseline and weeks 1, 2, 3, and 4 and every 4 weeks from week 4 to week 48. At week 12, PBO-treated subjects not achieving Psoriasis Area and Severity Index (PASI) 75 were re-randomized 1:1 to SEC 150 or 300 mg. Subjects in the ETN arm received ETN 50 mg twice per week from baseline to week 12, and 50 mg once a week thereafter up to week 51. The co-primary objectives were to show superiority of SEC vs. PBO for PASI 75 and five-point investigator’s global assessment (IGA) 0 or 1 response at week 12. A pre-specified subanalysis of PASI responses and changes from baseline in the Health Assessment Questionnaire– Disability Index (HAQ-DI) up to week 52 in subjects with concomitant PsA is reported here. Results: The overall study population consisted of 1306 subjects. In subjects with concomitant PsA (n ¼ 192), significant improvements in PASI 75 response rates were observed with SEC 150 mg and 300 mg from week 4. PASI 75 responses at week 12 were: SEC 300 mg, 72%; SEC 150 mg, 59%; ETN, 39%; and PBO, 2%. PASI 90 responses were 44, 39, 18, and 2%, respectively (p < 0.01 for SEC 150 and 300 mg vs. PBO; p < 0.01 for SEC 300 mg vs. ETN) and responses were sustained through 52 weeks (Figure 1). Improvements in physical functioning as measured by change from baseline in HAQ-DI score

SCR 2014 – abstracts 80% 70% 60% 50% 40% 30% 20% 10% 0%

65 SEC 300 mg (N = 50)

* †

SEC 150 mg (N = 49)

Etanercept (N = 44) Placebo (N = 47)

* * †

Week 12

Week 52 PASI 75

A number of autoimmunity-related gene polymorphisms are not associated with ankylosing spondylitis in a Latvian population

*

Week 12

J Zepa1, L Zepa2, I Bulina1, A Sarbantovica2, V Lavrentjevs1, E Sikora1, J Arajs1, A Lejnieks3, D Andersone1, J Klovins2, L Nikitina-Zake2

Week 52 PASI 90

Mean change from baseline


Figure 1. Percentage of patients with PASI 75/90 response at weeks 12 and 52. All PSA subjects (non-responder imputation). *p < 0.01 vs. placebo, †p < 0.01 vs. etanercept.

0.1 0 –0.1 –0.2 –0.3 –0.4 –0.5 –0.6 –0.7 –0.8

SEC 150 mg (N = 20)

Etanercept (N = 20)

SEC 300 mg (N = 27)

Placebo (N = 12)

* * 0

4

8

12

16

20

24 28 Week

32

PP211

36

40

44

48

52

Figure 2. Mean change from baseline in HAQ-DI score to week 12 (placebo comparison/last observation carried forward) and week 52 for patients with baseline HAQ-DI 0.5. *p < 0.05 vs. placebo.

(n ¼ 158 with evaluable HAQ-DI data) were significantly improved with SEC 300 mg from week 4. HAQ-DI reductions from baseline at week 12 were SEC 300 mg, 0.41 (p < 0.01 for 300 mg vs. PBO); SEC 150 mg, 0.19; ETN, 0.29; PBO, 0.02; and reductions were sustained to week 52. HAQ-DI reductions were more pronounced in subjects with greater disability (baseline scores 0.5) (Figure 2). Both SEC and ETN were well tolerated with no unexpected safety findings. Conclusions: In patients with psoriasis and concomitant PsA, SEC improved skin symptoms and physical functioning vs. placebo, with benefits evident from week 4 and sustained to week 52. SEC 300 mg demonstrated significantly improved PASI 75/90 responses and greater reductions in HAQ-DI scores compared with ETN. These data strongly support continued evaluation of SEC in patients with PsA. References 1. Langley R, Reich K, Griffiths C, Puig L, Spelman L, Rivas Zaldivar E, et al. Secukinumab compared with placebo and etanercept: a head-to-head comparison of two biologics in a phase 3 study of moderate-to-severe plaque psoriasis (FIXTURE). Oral presentation at: 22nd EADV Congress, Istanbul, Turkey, 2–6 October 2013. 2. McInnes IB, Sieper J, Braun J, Emery P, van der Heijde D, Isaacs JD, et al. Efficacy and safety of secukinumab, a fully human antiinterleukin-17A monoclonal antibody, in patients with moderate-tosevere psoriatic arthritis: a 24-week, randomised, double-blind, placebo-controlled, phase II proof-of-concept trial. Ann Rheum Dis 2014;73:349–356.

1

Rheumatology, Pauls Stradins Clinical University Hospital, Biomedical Research and Study Centre of Latvia, and 3Riga East Clinical University Hospital, Riga, Latvia 2

Background: Ankylosing spondylitis (AS) is a chronic systemic disease of unknown aetiology that is characterized by back pain caused by inflammation of the sacroiliac joints and the axial skeleton. The heritability of AS is estimated to be more than 90%. Family studies suggest that less than 50% of the overall genetic risk is due to HLA-B27, meaning that other genes also contribute to disease susceptibility (1). Several immune-related genes such as ERAP1 and IL23R have been associated with AS (1). As a substantial number of autoimmunity-related genes have pleiotropic effects, we decided to test whether some genes that have been previously studied in AS and other inflammatory diseases confer susceptibility to AS in Latvian population. Ten single nucleotide polymorphisms (SNPs) [rs10499194 (TNFAIP3), rs3087243 (CTLA4), rs4810485 (CD40), rs13031237 (REL), rs3890745 (MMEL1), rs6684865 (MMEL1), rs2736340 (BLK), rs7574865 (STAT4), rs30187 (ERAP1), and rs26653 (ERAP1)] were selected for this study. The aim was to determine whether there are differences in allele frequencies of the studied polymorphisms in AS patients compared to controls in a Latvian population. Method: DNA samples from 102 AS patients classified by the modified New York criteria, recruited in P. Stradins Clinical University Hospital by a rheumatologist, were included in this study. DNA from 262 ethnically related healthy subjects from the Genome Database of the Latvian Population were included as a control group. DNA was isolated by the standard phenol/chloroform method. Samples were genotyped by real-time PCR using TaqMan pre-designed SNP genotyping assays. Association analysis was performed in a toolset Plink. Results: All genotyping results fit Hardy–Weinberg equilibrium. Two SNPs showed statistically significant differences between allele frequencies in AS patients and the control group. The frequencies of allele C of rs26653 (ERAP1) and allele T of rs4810485 (CD40) in AS patients differed significantly from those in the control group (p ¼ 0.02, OR 1.55, 95% CI 1.07–2.25 and p ¼ 0.01, OR 1.63, 95% CI 1.12– 2.39, respectively). However, after adjusting for multiple comparisons there were no statistically significant differences in allele frequencies of all the studied SNPs.



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Conclusions: The study revealed significant differences in allele frequencies of rs26653 (ERAP1) and rs4810485 (CD40) between patients and controls, but results were not statistically significant after correction for multiple comparisons. This might indicate that the studied polymorphisms do not confer susceptibility to AS in a Latvian population or that the association has to be studied in a larger group. Reference


1. Thomas GP, Brown MA. Genetics and genomics of ankylosing spondylitis. Immunol Rev 2010;233:162–80.

PP212 A rare case of Pott’s disease in Denmark A Osmanagic1, JC Bang2, R Ramoskiene1, IMJ Hansen1 Departments of 1Internal Medicine and 2Clinical Radiology, Odense University Hospital, Svendborg, Denmark

Background: Back pain is a very common complaint in patients. When it is present with signs of infection, a diagnosis of spondylitis must be considered. In the western world a less common agent of spondylitis is tuberculosis. Tuberculosis of the spine is also called Pott’s disease, and only a few cases of Pott’s disease have been registered in Denmark. The following case is one of the few. Case study: A 78-year-old woman, originally from Eastern Europe, complaining of lower back pain registered at the emergency department. The pain had lasted for 2 months but had worsened over a period of a few days. There was no trauma and we found no significant neurological deficits. The patient had a fever and blood tests showed signs of infection. A spine X-ray showed signs of osteolysis on vertebrae Th11 and Th12, presumed to be due to malignancy. Chest and abdominal CT scans showed signs of pneumonia but not of malignancy. The imaging also showed signs of osteolysis Th11 and Th12, involving the epidural space. An MRI scan of the vertebral spine showed signs of spondylitis Th10– Th12, with multiple epidural abscesses. This rather characteristic radiological finding, along with the patient’s Eastern European descent, was indicative of the diagnosis of Pott’s disease. The patient had been exposed to tuberculosis in early childhood. Initial testing of blood and sputum was negative. After PCR of the patient’s stomach fluid, signs of tuberculosis bacteria were found and treatment for tuberculosis was initiated. A biopsy of the vertebrae also confirmed the diagnosis of tuberculosis, the patient continued the treatment and is now in remission. Conclusions: Pott’s disease is a very rare diagnosis in the western world but, especially because of immigration, the


presence of tuberculosis should not be overlooked. Fortunately, there are distinct radiological signs of Pott’s disease that, along with a detailed medical history, can help find the correct diagnosis, rare as it may be.

References 1. Jain R, Sawhney S, Berry M. Computed tomography of vertebral tuberculosis: patterns of bone destruction. Clin Radiol 1993;47:196–9. 2. Pui MH, Mitha A, Rae WI, Corr P. Diffusion-weighted magnetic resonance imaging of spinal infection and malignancy. J Neuroimaging 2005;15:164–70. 3. Turgut M. Spinal tuberculosis (Pott’s disease): its clinical presentation, surgical management, and outcome. A survey study on 694 patients. Neurosurg Rev 2001;24:8–13.

PP213 Comparison of sociodemographic characteristics, clinical variables, and depression in patients with psoriasis and psoriatic arthritis O Kuru, S Ketenci, A Bilgici, G Alayli, Y Akyol, Y Ulus Department of Rheumatology, Ondokuz Mayis University, Samsun, Turkey

Background: Psoriatic diseases have substantial detrimental effects on patients’ quality of life, increasing depressive symptoms, reducing functionality and productivity, and impairing work productivity (1–3). Psoriatic arthritis (PsA), a manifestation of psoriatic disease, involves inflammation of the peripheral/axial joints, enthesis and usually concomitant skin/nail psoriasis (Ps).



Method: Thirty-four patients with a diagnosis of Ps and 48 patients with PsA diagnosed according to the criteria described by CASPAR were included in the study. In both Ps and PsA, the SPARCC enthesis index, BECK depression scale, HAQ disability index, FACIT fatigue scale, Psoriasis Area and Severity Index (PASI), and Nail Psoriasis Severity Index (NAPSI) were assessed. The Disease Activity Index for Psoriatic Arthritis (DAPSA) was calculated for disease activity in PsA. In group comparisons, the Mann–Whitney U test and the χ 2 test were used. Correlations between clinical parameters and depression were analysed by Spearman’s rho or Spearman’s rank correlation coefficient. Results: The mean ages of Ps and PsA patients were 38.35 12 and 46.50 10.93 years, respectively. In PsA, the average arthritis duration was 6.19 6.52 years. There were no significant differences in terms of education levels, cigarette or alcohol use, and other demographic factors between the groups. PASI and NAPSI scores were higher in PsA patients than Ps patients. However, this difference was not statistically significant, nor was there a significant relationship between the BECK and PASI or NAPSI in both groups. Female patients had significantly higher scores on the HAQ (p < 0.05). DAPSA scores were significantly lower in patients with higher education levels (p < 0.05). In Ps patients, NAPSI scores correlated positively with annual total cigarette consumption (pack-year) (r ¼ 0.37, p < 0.05) but NAPSI scores did not correlate with PASI scores. In both groups, depression correlated significantly with FACIT and HAQ scores (p < 0.001, for each). There was also a significant correlation between BECK and DAPSA scores in PsA (r ¼ 0.35, p < 0.01). In PsA patients with severe depression, HAQ, DAPSA, and SPARCC scores were significantly higher than those without depression (p < 0.01, p < 0.05, and p < 0.01, respectively). Conclusions: We could not find any significant differences between Ps and PsA patients in terms of depression, skin disease severity, and nail involvement. Depression demonstrated a strong correlation with arthritis severity and functional disability. References 1. Husted JA, Tom BD, Farewell VT, Gladman DD. Longitudinal study of the bidirectional association between pain and depressive symptoms in patients with psoriatic arthritis. Arthritis Care Res (Hoboken) 2012;64:758–65. 2. Kotsis K, Voulgari PV, Tsifetaki N, Machado MO, Carvalho AF, Creed F, et al. Anxiety and depressive symptoms and illness perceptions in psoriatic arthritis and associations with physical health-related quality of life. Arthritis Care Res (Hoboken) 2012;64:1593–601. 3. Han C, Lofland JH, Zhao N, Schenkel B. Increased prevalence of psychiatric disorders and health care-associated costs among patients with moderate-to-severe psoriasis. J Drugs Dermatol 2011;10:843–50.

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PP215 Long-term 52-week results of PALACE 3, a phase 3, randomized controlled trial of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with psoriatic arthritis and current skin involvement C Edwards1, F Blanco2, J Crowley3, CC Hu4, R Stevens5, C Birbara6 1

Rheumatology, University Hospital Southampton, UK, Rheumatology, INIBIC-Hospital Universitario A Coruña, Galicia, Spain, 3Rheumatology, Bakersfield Dermatology, Bakersfield, CA, USA, 4Biostatistics, Celgene Corporation, Warren, NJ, USA, 5Clinical Research and Development, Celgene Corporation, Warren, NJ, USA, and 6Rheumatology, University of Massachusetts Medical School, Worchester, MA, USA 2

Background: The PALACE 3 trial was conducted to compare the efficacy and safety of apremilast (APR) with placebo in patients with active psoriatic arthritis and at least one psoriatic lesion 2 cm at baseline despite prior conventional disease-modifying anti-rheumatic drugs (DMARDs) and/or biologics. Method: Patients were randomized (1:1:1) to placebo, APR 20 mg BID (APR20), or APR 30 mg BID (APR30) stratified by baseline DMARD use (yes/no) and baseline psoriasis involvement of body surface area ( 10 years 1.173 0.155; p ¼ 0.336). However, total radius BMD (0.600 0.178 vs. 0.695 0.213 g/ cm2; p ¼ 0.03) significantly decreased when RA lasted more than 3 years, spine (0.983 0.192 vs. 1.115 0.181 g/cm2; p ¼ 0.008), and femoral neck (0.654 0.224 vs. 0.783 0.245 g/cm2; p ¼ 0.04) BMD when RA lasted more than 10 years, as



compared to patients whose duration of RA did not exceed 3 years. Conclusions: Age influences both TBS and BMD to the same extent, and these parameters significantly decrease from 50 years onwards. TBS reacts rapidly to the changing hormonal status that is observed during menopause, and declines significantly after 3 years. The duration of RA influences only BMD, and its significant decrease is observed when the disease lasts for more than 5 years.

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PP225

differences in BMD of the PA spine and hip among the groups. Only forearm BMD in the second group was significantly lower in the first group (0.583 0.176 g/cm2 vs. 0.675 0.229 g/cm2; t ¼ 2.18; p ¼ 0.032). Spine TBS decreased by 1.4% after 1 year for G1 and by 5.8% for G2. Conclusions: For patients who are GC users, TBS but not BMD reflects bone microarchitecture deterioration, which is an indicator for those patients of a higher vertebral and non-vertebral risk of fracture. TBS is a determinant of bone state and must be monitored during longterm treatment with GC therapy.

Influence of glucocorticoids on trabecular bone score in patients with rheumatoid arthritis

PP227

V Povoroznyuk1, T Karasevska1, B Aubry-Rozier2, N Dzerovych1, R Povoroznyuk1, D Hans2 1 Department of Locomotor Apparatus, Institute of Gerontology NAMS of Ukraine, Kyiv, Ukraine, and 2Centre of Bone Diseases, Lausanne University Hospital, Lausanne, Switzerland

Background: Bone disorders are the main extra-articular complications of rheumatoid arthritis (RA). Patients with RA have a greater risk of osteoporosis and fracture than the general population. RA is a chronic inflammatory rheumatic disease and a frequent cause of secondary osteoporosis induced by the chronic inflammatory condition and long-term glucocorticoid (GC) therapy. The aim of this study was to evaluate the influence of GCs on the trabecular bone score (TBS), bone mineral density (BMD), and TBS dynamics over 1 year in patients with RA. Method: In this study 134 women with RA (age 52.5 12.8 years, height 162.6 6.4 cm, weight 68.2 13.7 kg, duration of disease 9.1 7.5 years, duration of postmenopausal period 7.6 7.2 years) were divided into three groups: the first group (G1) included 37 patients who did not use GCs; the second group (G2) comprised 50 patients who used GCs in a dose of more than 5 mg of prednisolone for more than 3 years; and the third group (G3) comprised 47 patients who took GCs only at the exacerbated stage for less than 6 months. All patients had been taking methotrexate as a basic treatment. BMD of total body, PA lumbar spine, proximal femur, and forearm were measured using the DXA method (Prodigy, GEHC Lunar, Madison, WI, USA) and PA spine TBS was assessed by means of the TBS iNsight® software package installed on our DXA instrument (Med-Imaps, Pessac, France). Evaluation of TBS dynamics in the patients in groups G1 and G2 over the year was conducted on the background of ongoing therapy that included doses of GCs (for the patients of G2) and/or without any osteotropic treatment. Results: The three groups did not differ with regard to age, basic anthropometric parameters, duration of disease, and duration of postmenopausal period. TBS in G2 was significantly lower compared to G1 (TBSL1– L4: 1.147 0.168 vs. 1.250 0.135; t ¼ 3.07; p ¼ 0.003), and G3 compared to G1 (TBS L1–L4: 1.274 0.138; t ¼ 3.95; p ¼ 0.0002). However, there were no

Dual-energy CT (DECT) imaging of tophi and monosodium urate deposits in a patient with longstanding anorexia nervosa JP Weihe1, MB Morillon1, J Lambrechtsen2, IMJ Hansen1 Departments of 1Rheumatology and 2Cardiology, Odense University Hospital, Svendborg, Denmark

Background: Gout is the most common inflammatory arthritis among men aged > 40 years. Microscopic examination by polarized compensated light microscopy of the joint fluid or of tophi is the gold standard for verifying the diagnosis (1). However, it is not always possible to perform a joint aspiration to verify the diagnosis. Consequently, clinicians often base their diagnosis on secondary criteria. Tophi in patients without gout have been reported in patients with anorexia nervosa (2). In previous studies, dual-energy CT (DECT) imaging has been shown to be a useful tool to confirm the presence of monosodium urate crystals within joints, tophi, and tendons (3). Recent improvements in DECT technology have initiated interest in non-invasive examination and detection of crystal deposits. The major benefit of DECT is spectral decomposition, which permits recognition of the types of tissues based on their characteristic energydependent photon attenuation. We describe a case based on a 48-year-old female with anorexia nervosa for the past 30 years. At clinical examination no swollen and tender joints were found, either in her hands or feet. In both hands plenty of tophi were seen by clinical examination. Biochemistry gave a serum urate level of 0.57 mmol/L and estimated GFR of 60 mL/min/1.73 m2. The patient weighed 39 kg. Microscopic examination of material aspirated from a tophus confirmed the diagnosis of gout. We wanted (i) to visualize the presence of monosodium urate crystals within tophi by using DECT imaging and (ii) to determine whether urate crystals were located elsewhere in the hands of a patient known to have microscopically verified tophaneus gout. Method: We used an HD 750 General Electric CT scanner to visualize the urate crystals. Results: Using DECT we visualized monosodium urate crystal deposits in tendons and soft tissue of the hands of




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our patient. Localization of the colour coding corresponded to the localization of the tophi seen on the clinical photographs and also showed crystals in relation to the tendons. Conclusions: DECT is a non-invasive procedure that, in our patient, showed monosodium urate crystals in soft tissues and tendons. The outlook for use of DECT is not yet known. DECT can become a useful tool for evaluating the diagnosis and extent of disease in patients presenting with arthralgia and/or arthritis. It can differentiate between pyrophosphate arthritis, and monosodium crystals and DECT can thereby be important in the detection of subclinical disease. To our knowledge, this is the first time monosodium urate crystals have been visualized in a patient diagnosed with anorexia nervosa. References 1. Hamburger M, Baraf HS, Adamson TC 3rd, Basile J, Bass L, Cole B, et al. 2011 Recommendations for the diagnosis and management of gout and hyperuricemia. Postgrad Med 2011;123:3–36. 2. Garcia-Porrua C, Canedo C, Argueso R, Gonzalez-Gay MA. Superficial collections of fluid tophaceous material as clinical presentation of anorexia nervosa. Ann Rheum Dis 2005;64:1658–9. 3. Choi HK, Al-Arfaj AM, Eftekhari A, Munk PL, Shojania K, Reid G, et al. Dual energy computed tomography in tophaceous gout. Ann Rheum Dis 2009;68:1609–12.

PP229 Whole-body and conventional magnetic resonance imaging for assessing inflammation and structural damage in psoriatic arthritis and axial spondyloarthritis RPP Poggenborg1, SJ Pedersen1, I Eshed2, IJ Sørensen1, OR Madsen3, JM Møller4, M Østergaard1 1

Rheumatology, Copenhagen University Hospital Glostrup, Copenhagen, Denmark, 2Radiology, Sheba Medical Centre, Tel Hashomer, Israel, 3Rheumatology, Copenhagen University Hospital Gentofte, Denmark, and 4Radiology, Copenhagen University Hospital Herlev, Copenhagen, Denmark


Background: Whole-body magnetic resonance imaging (WBMRI) is a new imaging modality where patients are scanned from ‘head to toe’ in one single scan, but with a lower resolution than conventional MRI (cMRI). The purpose was to investigate the ability of WBMRI to detect inflammation and structural damage in psoriatic arthritis (PsA) and spondyloarthritis (SpA), and to compare findings with dedicated cMRI. Method: Patients with clinically active peripheral PsA (Moll and Wright, n ¼ 18) or axial SpA (ESSG, n ¼ 18) and healthy subjects (HS, n ¼ 12) were included. WBMRI was assessed for synovitis, bone marrow oedema (BME), and bone erosions at sites included in the 78-tender joint count (TJC). Furthermore, WBMRI fat infiltration, BME, and bone erosions were evaluated in 23 discovertebral units (DVUs) in posterior and anterior parts separately, and in sacroiliac joints (SIJ) (eight quadrants). Whole-body imaging was performed on a 3-T MRI unit with a built-in bodycoil (sagittal and coronal T1-weighted pre/post-contrast and STIR sequences), and 1.½-T cMRI (SpA and HS: of spine and SIJ; PsA and HS: unilateral hand) was performed using T1-weighted pre/ post-contrast and STIR sequences. The PsAMRIS-hand method (1) was used for scoring synovitis in the finger joints in PsA and HS (scored 0–36). Results: Characteristics were for PsA/SpA/HS median (interquartile range, IQR) age 49 (37–58)/42 (32–51)/32 (27–47) years. PsA/SpA disease duration: 3 (1–19)/4 (2– 8) years; 78-TJC: 13 (7–30)/4 (0–17), 76-swollen joint count: 5 (3–11)/1 (0–2), and BASDAI score: 44 (19–70)/ 56 (46–68) mm. By WBMRI, more than 91% of inflammatory and structural lesions in the spine and SIJ could be evaluated, while readability was lower in distal peripheral joints, particularly in elbow and foot DIP joints (5–61%). BME assessed by WBMRI was significantly more frequent in PsA/SpA than in HS (p < 0.05, see Table 1). We found no statistically significant difference between groups in WBMRI synovitis assessed in all 78 joints, or only assessed in hand joints. By contrast, PsAMRIS-hand synovitis assessed by cMRI was higher in PsA than HS [2

Table 1. Median (IQR) scores of WBMRI findings in joints, DVUs, and SIJ quadrants. Psoriatic arthritis

Spondyloarthritis

Healthy subjects

78-joints: BME (0–78) 6 (1–9.5)* 5 (0–10) 2 (0–3) 78-joints: synovitis (0–78) 12 (7–14) 10 (3–17) 10.5 (5–18.5) 78-joints: erosion (0–78) 0 (0–2) 0 (0–2) 0 (0–1) Spine: BME (0–46) 1.5 (0–4) 1 (0–4) 0.5 (0–1.5) SIJ: BME (0–8) 0 (0–0) 0 (0–3) 0 (0–0) Total BME (0–132) 7 (3–15)* 8 (2–14)* 2.5 (1–4.5) Total structural damage 4 (0–6) 7 (3–12)* 1.5 (0–4.5) (0–194) The Mann–Whitney test was used for comparing PsA/SpA with HS. *p < 0.05.


(1–5) vs. 0 (0–0.5), p < 0.05]. cMRI scores of structural damage were higher in SpA than in HS [spine: 5 (1–15) vs. 0 (0–4); SIJ: 2.5 (0–6) vs. 0 (0–0), both p < 0.05]. Conclusions: WBMRI allows simultaneous assessment of peripheral and axial joints in PsA and SpA. The study strongly encourages further development and longitudinal testing of WBMRI techniques and assessment methods in PsA and SpA.


Reference 1. Ostergaard M, McQueen F, Wiell C, Bird P, Bøyesen P, Ejbjerg B, et al. The OMERACT psoriatic arthritis magnetic resonance imaging scoring system (PsAMRIS): definitions of key pathologies, suggested MRI sequences, and preliminary scoring system for PsA hands. J Rheumatol 2009;36:1816–24.

PP230 MRI of the hand and wrist as a tool for detection of joint damage in early rheumatoid arthritis K Forslind1, B Svensson2 1

Department of Clinical Sciences, Section of Rheumatology, Lund University, Section of Rheumatology, Helsingborg and 2 Department of Clinical Sciences, Section of Rheumatology, Lund University, Lund, Sweden

Background: It is vital to establish the diagnosis of rheumatoid arthritis (RA) before radiographic damage and functional disability occurs so that modern potent drugs may be instituted before the ‘window of opportunity’ is closed. To accomplish this, sensitive and specific tools for assessing disease activity and joint damage are needed. Magnetic resonance imaging (MRI) enables more sensitive assessment of both joint inflammation and structural damage than what is achieved by clinical measures and conventional radiography. The aim was to study the evolution of joint damage (synovitis, tenosynovitis, bone oedema, and erosions) in patients with RA as visualized by MRI and radiography during the first 3 years of treatment. Method: Thirteen patients with RA with disease symptoms for 0.05). Aerobic capacity according to Åstrand remained unchanged (p > 0.05). Conclusions: Several traditional risk factors for CVD were improved at the 9-month follow-up. This suggests that this model of screening according to the SRF guidelines and simple counselling according to national guidelines might be useful in primary prevention of CVD in patients with RA.

PP234 Screening and simple counselling affect traditional cardiovascular risk factors in patients with early rheumatoid arthritis

PP235

J Isaksson, S Wållberg-Jonsson, G-M Alenius, A Södergren

Smoking functions as a negative regulator of IGF-1 levels and the adipokine network in patients with rheumatoid arthritis

Department of Public Health and Clinical Rheumatology, University of Umeå, Sweden

M Bokarewa1, M Erlandsson1, RD Medina1, ST Silfverswärd1, A Ioan-Facsinay2

Medicine,

Background: Patients with rheumatoid arthritis (RA) have an increased risk of cardiovascular disease (CVD) and increased mortality in CVD. The cause of this increase has not been completely established, but chronic inflammation is thought to play a role. Traditional cardiovascular risk factors also appear to be important and may be potentiated by this inflammation. The Swedish Society for Rheumatology (SRF) has developed a set of guidelines for screening and primary prevention of CVD in patients with RA. The aim of this study was to evaluate these guidelines in a clinical setting. Method: Forty-seven patients newly diagnosed with RA during 2012 at the Department of Rheumatology, University Hospital of Umeå were recruited. Three months after initial diagnosis of RA, patients were examined physically and blood samples were collected with regard to traditional cardiovascular risk factors according to the guidelines from the SRF. Tests of cardiorespiratory fitness were also performed. Additionally, patients received simple counselling regarding matters of diet, tobacco use and exercise from a nurse and a physiotherapist, respectively. The counselling session, based upon national guidelines from the National Food Agency and the Public Health Agency, was performed once per patient and lasted for approximately 45 minutes. A follow-up was performed 9 months after the first


1

Rheumatology and Inflammation Research, University of Göteborg, Sweden, and 2Rheumatology, Leiden University Medical Centre, The Netherlands

Background: Smoking is important in the pathogenesis of rheumatoid arthritis (RA), being tightly connected to the genetic (carriage of HLA-DRB1 shared epitope) and serological (production of autoantibodies) risk factors for the development of RA. The molecular events connecting cigarette smoking to joint inflammation and low efficacy of anti-rheumatic drugs are poorly understood. Adipokines, short signalling peptides originating from adipose tissue, regulate carbohydrate metabolism and soft tissue regeneration. In RA, adipokines are connected to the disease activity and progressive radiological joint damage. Numerous effects of adipokines are mediated through the insulin-like growth factor-1 receptor (IGF-1R) complex. The aim of the study was to better understand potential connections between cigarette smoking and changes in IGF-1 signalling and adipokine network functions in patients with RA. Method: This observational study included 543 patients from two independent RA cohorts (Göteborg, n ¼ 350 and Leiden, n ¼ 193). Patients were divided by their smoking habits as present smokers (n ¼ 126), exsmokers (n ¼ 177), and never smokers (n ¼ 240).



Serum levels of total IGF-1 and adipokines (adiponectin, leptin, resistin, and visfatin) were measured with sandwich ELISAs. The patient groups were compared by quantitative statistics and the association between smoking and serum parameters were evaluated by bivariate and multivariate correlation analysis. Age, gender, disease duration, DAS28, smoking, BMI, VAS-pain, and serum levels of adipokines were included as candidate variables in the logistic regression model with backward elimination to evaluate their predictive power for low levels of IGF-1. Results: The two studied cohorts differed in disease duration, where the Leiden cohort consisted of early RA patients (DD median 0.4 years), higher disease activity (DAS28 median 5.1), and higher VAS-pain (median 46 mm), while the Göteborg cohort consisted of patients with established RA (DD median 7.5 years), low DAS28 (median 3.0), and VAS-pain (median 27 mm). In both cohorts the smokers were more often men (p < 0.001). Serum levels of IGF-1 were significantly lower in the present smokers followed by ex-smokers. RA patients who never smoked had significantly higher serum levels of IGF-1 (p < 0.001). Levels of adiponectin were also higher in never smokers (p ¼ 0.002). The present smokers had stronger correlations between IGF-1 and leptin (rho ¼ 0.233, p ¼ 0.009) and resistin (rho ¼ 0.210, p ¼ 0.018). These correlations were not observed in the never smokers or the ex-smokers. The logistic regression analysis showed that low levels of IGF-1 were associated with low levels of leptin and visfatin and with current smoking. Neither age, gender, DAS28, nor BMI contributed significantly in the regression model. Conclusions: Smoking is associated with lower serum levels of IGF-1 in RA patients. The low levels of IGF-1 in RA patients could be predicted by smoking and the levels of leptin and visfatin, potentially affecting pain perception and reducing regeneration processes in the damaged arthritic joints in RA patients. References 1. Klareskog L, Malmström V, Lundberg K, Padyukov L, Alfredsson L. Smoking, citrullination and genetic variability in the immunopathogenesis of rheumatoid arthritis. Semin Immunol 2011;23:92–8. 2. Scotece M, Conde J, Lopez V, Lago F, Pino J, Gomez-Reino JJ, et al. Leptin in joint and bone diseases: new insights. Curr Med Chem 2013;20:3416–25.

PP236 An outsourced health-enhancing physical activity programme for people with rheumatoid arthritis. Feasibility, adherence and response: the PARA 2010 study B Nordgren1, C Fridén1, I Demmelmaier1, G Bergström2, I Lundberg3, A Dufour4, C Opava1; and the PARA study group 1

Department of Neurobiology, Health Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden, 2Department

77 of Environmental Medicine, Karolinska Institutet, Solna, Sweden, 3Department of Medicine, Karolinska Institutet, Solna, Sweden, and 4Institute for Aging Research, Harvard Medical School, Boston, MA, USA

Background: Rheumatoid arthritis (RA) confers disability, poor health perception and increased risk of comorbidity and premature death, mainly due to cardiovascular disease. New drugs and new treatment principles have dramatically improved inflammation control but do not seem to fully alleviate pain, the development of disability, or the risk of cardiovascular disease (1–3). Thus, health-enhancing physical activity (HEPA) might be a valuable complement to drug therapy in rheumatic diseases. However, HEPA programmes are poorly investigated in RA and never in contexts entirely outside health care. Furthermore, dose–response issues related to physical activity in RA are seldom explored in depth, identification of the intervention elements influencing the outcome most efficiently is not done, and the characteristics of individuals responding best to a certain intervention are poorly described. Our objectives were to describe the feasibility of an outsourced HEPA programme, changes in HEPA levels, self-reported and assessed functioning as well as to explore aspects on adherence and response during the first year of a 2-year intervention study. Method: Two hundred and twenty patients participated in the programme, which included daily physical activity, twice-weekly circuit training, and support group meetings every 2 weeks. Self-reported data included sociodemographics, disease-related and psychosocial factors, and current and maintained HEPA levels. Tests of aerobic capacity and muscle function were performed and anthropometric data collected (4). Results: Eighty-eight per cent of the participants completed the 1-year assessments. The mean number of support group meetings attended was nine, circuit training sessions were performed a mean of 48 times, and the mean number of days with HEPA was 189. Self-reported current and maintained HEPA increased from 55% to 82% (p ¼ 0.0004) and from 0% to 37% (p ¼ 0.0495), respectively. General health perception and a number of other self-reported disease-related and psychosocial factors improved, while exercise self-efficacy was reduced. Aerobic capacity, timed standing and grip strength improved after 1 year and waist circumference was reduced. Better adherence to circuit training improved health perception, and better attendance at group meetings improved timed standing. Exercise self-efficacy improved among those adhering more to circuit training and support group meetings. Conclusions: The outreach HEPA programme was feasible, as indicated by high retention and reasonable attendance. Those adhering to circuit training and support group meetings gained the most benefits.



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References


1. Krishnan E, Lingala B, Bruce B, Fries JF. Disability in rheumatoid arthritis in the era of biological treatments. Ann Rheum Dis 2012;71:213–18. 2. Symmons DP, Gabriel SE. Epidemiology of CVD in rheumatic disease, with a focus on RA and SLE. Nat Rev Rheumatol 2011;7:399–408. 3. Taylor P, Manger B, Alvaro-Gracia J, Johnstone R, Gomez-Reino J, Eberhardt E et al. Patient perceptions concerning pain management in the treatment of rheumatoid arthritis. J Int Med Res 2010;38:1213–24. 4. Nordgren B, Friden C, Demmelmaier I, Bergstrom G, Opava CH. Long-term health-enhancing physical activity in rheumatoid arthritis - the PARA 2010 study. BMC Public Health 2012;12:397.

PP237 Smoking cessation in patients with rheumatic disease M-L Karlsson, S Pettersson, I Lundberg

6 (3–12) cig/day (p ¼ 0.012). There were no significant differences for pain, GH, or HAQ in the QS or CS between 0 and 24 months. However, a tendency of improved pain was noted in the QS group, where pain decreased from 37.5 (11–68) to 3.0 (0–65), compared to the CS group, from 60.0 (range 0–100) to 40 (range 2– 80). The GH decreased in the QS group from 37.5 (10– 65) to 3.5 (0–65) and in the CS from 56.5 (0–100) to 29 (10–80). Regarding the HAQ, the QS improved from 0.57 (0–1) to 0.0 (0.0–1.0) and the CS from 0.75 (0.13–2.13) to 0.26 (0.0–2.5). Conclusions: In this pilot study, 43% of patients with RA within the smoking cessation programme stopped smoking, which is a good result compared to other studies (1, 2). This study was an attempt to implement smoking cessation routines into clinical practice. More patients need to be included, and considering that behavioural change takes time, long-term outcomes have to be followed to further evaluate the effects of smoking cessation.

Department of Rheumatology, Karolinska University Hospital, Stockholm, Sweden

References Background: During the past decade, smoking has become of significant focus in the field of rheumatology. In rheumatoid arthritis (RA), several studies have indicated that smoking has an important link with disease outcome, and counselling against smoking is suggested to be mandatory in rheumatological care. In the general population only 2–3% quit smoking on their own but over 30% quit with structured counselling (1). The aim of this study was to develop and evaluate a method of smoking cessation support to be used in a rheumatology clinic. Method: From April 2011 to December 2013, patients with RA attending an early RA clinic or starting a first biological treatment were screened for smoking habits. Daily smokers were offered smoking cessation support, conducted by a rheumatology nurse with special training in motivational interviewing (MI) and smoking cessation. The support was individualized, but the participants were provided contact every 4 weeks over 2 years. The patients were followed in the Swedish Rheumatology Quality Register, with HAQ (score 1–3), pain intensity (pain, score 0–100), and global health (GH, score 0–100). Cigarette consumption (cig/day) was assessed at 0 and 24 months. Here we present preliminary data for 24 months of follow-up. Results: In total, 383 patients were screened, current smokers (n ¼ 84, 21.9%) were identified and 40 individuals accepted the smoking cessation support. To date, 14 patients have been in the programme for more than 2 years, six participants (43%) have quit smoking (QS), and eight (47%) continued smoking (CS). At enrolment, the median number of cigarettes smoked per day (cig/day) was 10 (range 5–25). The QS group smoked less at enrolment [8 (5–12) cig/day] compared to the CS [15 (10–25) cig/day; p ¼ 0.02]. At 24 months the CS had decreased cigarette consumption from 15 (10–25) to


1. Hom Ivarsson.B. [Smoking cessation. A booklet on health risks of smoking and the need to quit smoking], in Swedish. 2009. Institute of Public Health, Stockholm. Available from: www.hotellrevyn.se/ files/1001271607206/R2009-17-Tobak-och-avvanjning.pdf (accessed July 2014). 2. Naranjo A, Bilbao A, Erausquin C, Ojeda S, Francisco FM, RúaFigueroa I, et al. Results of a specific smoking cessation program for patients with arthritis in a rheumatology clinic. Rheumatol Int 2014;34:93–9.

PP238 Effect of exercise and lifestyle interventions on an outpatient rehabilitation programme for patients with hip or knee OA I Tollefsrud, E Askmann Rehabilitation, Revmatismesykehuset AS Lillehammer, Norway

Background: Among musculoskeletal conditions, osteoarthritis (OA) is the most common joint disease and, on a population basis, the most consequential in terms of impact on function, costs, and societal burden. Lifestyle modification, particularly exercise and weight reduction, is a core component and a key predictor of response in the management of OA. There is highquality evidence that exercise and weight reduction reduce pain and improve physical function in patients with OA of the knee. Based on these facts one physical therapist and one dietician started an outpatient rehabilitation programme for a group of patients with hip or knee OA. The main objective of this outpatient rehabilitation programme was to give these patients a chance to improve their lifestyle and to stay at work, despite their illness.



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Method: In this study 129 outpatients [91% women, median age 56.7 (34–66) years] with OA participated in groups (9–12 per group) one day on a weekly basis, for a total of nine sessions. They were tested individually at the beginning of the treatment and then after 6 months. Two tests were used: the Index of Muscle Function and the Submaximal Treadmill Test. The participants were introduced to different types of exercises and training, and they had to try to exercise three times a week. During each session, diet advice was given, the participants were weighed and tried out different types of training. In addition, we had multidisciplinary health personnel educating in a variety of aspects related to either work issues or OA. Six to 12 months after finishing the programme, the first 40 participants received a questionnaire. Results: The mean increase in aerobic capacity was 1 mL O2/kg/min, the mean increase in functional status was 2 points, and the mean weight loss was 5.3 kg (11.7 pounds). Based on the questionnaire, 88.8% reported that they were at work, although 45% had some kind of sick leave. Forty-seven per cent reported that they went to see their general practitioner less often than they used to. Conclusions: Our findings indicate that exercise and diet advice, combined with multidisciplinary patient education, can help these patients to improve their physical function and their BMI, and to maintain a working relationship. Their need to see their general practitioner also seems to be reduced. References 1. Jamtvedt G, Holm I, Hagen KB. Physical therapy interventions for patients with osteoarthritis of the knee: an overview of systematic reviews. Phys Ther 2008;88:123–36. 2. Kvien TK. The burden of osteoarthritis and the associated benefit and risks of current therapeutic options. In: Optimising the management of osteoarthritis: emerging therapies. London BMJ Group 2010: 13–18. 3. Wilkie R, Phillipson C, Hay E, Pransky G. Frequency and predictors of premature work loss in primary care consulters for osteoarthritis: prospective cohort study. Rheumatology (Oxford) 2014;53:459–64.

PP239 Development of a Web and Mobile Application (WeMApp) to support physical activity in rheumatoid arthritis: results from the second step of a co-design process 1

1

1,2

3

Å Revenäs , CH Opava , I Demmelmaier , C Keller , P Åsenlöf

2

1

Department of Neurobiology, Health Care Sciences and Society, Karolinska Institutet, Stockholm, 2Department of Neuroscience, Uppsala University, and 3Jönköping International Business School, Jönköping, Sweden

Background: Long-term adherence to physical activity recommendations is still a challenge for most individuals

with rheumatoid arthritis (RA), despite the evidence for health benefits. Various interventions have been developed but maintenance and long-term effects have not been achieved or demonstrated. New strategies to integrate physical activity into the everyday life of individuals with RA are needed (1). The overall aim was to provide basic data for a system requirement specification of a Web and Mobile Application (WeMApp) for self-management of physical activity. Specific objectives were to explore the future target user group, features of the future WeMApp and the correspondence between identified system requirements, that is what the WeMApp should provide for, arrange for or do, and established behaviour change techniques (BCTs). Method: We used a participatory action research design. Qualitative data were collected with multiple methods in connection to four workshops. Participants were five individuals with RA, a clinical physiotherapist, an officer from the Swedish Rheumatism Association, a web designer, and two physiotherapy researchers. A BCT taxonomy (2) was used to determine the extent of correspondence between the system requirements and established BCTs. Results: The proposed name of the WeMApp was ‘tRAppen’, which means ‘stairs’ in English and refers to physical activity, RA, and application in Swedish. Participants agreed that tRAppen should be based on two major components important for the maintenance of physical activity: (i) ‘My self-monitoring’, a calendar feature for goal setting, planning and recording of physical activity and progress, and (ii) ‘My peer group’, a small community feature for positive feedback and support from peers with RA. All system requirements corresponded to 24 established BCTs. Conclusions: To our knowledge, this is the first study involving individuals with RA as co-designers, collaborating with clinicians, researchers, web designers, and a patient organization, to produce basic data for a system requirement specification of a WeMApp for self-management of physical activity. The system requirements corresponded to theoretically derived BCTs. This may improve the possibility to replicate and also evaluate the future WeMApp.

References 1. Revenas A, Opava C, Asenlof P. Lead users’ ideas on core features to support physical activity in rheumatoid arthritis: a first step in the development of an internet service using participatory design. BMC Med Inf Decis Making 2014;14:21. 2. Michie S, Richardson M, Johnston M, Abraham C, Francis J, Hardeman W, et al. The Behavior Change Technique Taxonomy (v1) of 93 hierarchically clustered techniques: building an international consensus for the reporting of behavior change interventions. Ann Behav Med 2013;46:81–95.



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PP240

PP241

The Swedish Exercise Self-Efficacy Scale (ESES-S): reliability and validity in a rheumatoid arthritis population

Serum 25-hydroxyvitamin D below 75 nmol/L in 75% of healthy Swedish adults during 75% of the year

1

1

1

T Nessen , I Demmelmaier , B Nordgren , CH Opava

1,2

1


Department of Neurobiology, Health Care Sciences and Society, Karolinska Institutet and 2Department of Rheumatology, Karolinska University Hospital, Stockholm, Sweden

Background: It is important to identify determinants relevant for an individual’s decision to initiate, adopt, and maintain lifestyle-related behaviours. Health professionals’ work to support lifestyle changes includes the promotion of self-efficacy, that is the belief in one’s own ability to complete tasks and goals, which is one the psychological determinants of, for example, exercise. To evaluate such promotional measures, it is crucial to use valid and reliable assessment methods. The ESES has not yet been validated in Swedish for use among people with rheumatoid arthritis (RA). The aim of the present study was to investigate aspects of reliability and validity of the Swedish ESES (ESES-S) in an RA population. Method: A total of 244 people with RA participating in a physical activity study were included. The six-item ESES-S, exploring confidence in performing exercise, was assessed for test–retest reliability over 4–6 months and for internal consistency. Concurrent validity was investigated by calculating correlations between the ESES-S and age, gender, pain, activity limitation, healthenhancing physical activity, exercise, outcome expectations, and fear avoidance beliefs. Results: An ICC of 0.59 (95% CI 0.37–0.73) indicated moderate test–retest reliability for the 84 participants with stable ( 20/100 mm change on VAS) health perception, pain and fatigue, or unchanged EQ-5D scores between measurement occasions. Cronbach’s alpha coefficients of 0.87 and 0.89 at the first and second measurements, respectively, indicated a adequate internal consistency for the total sample. Corrected item-total correlations on single ESES-S items ranged between 0.53 and 0.73. Concurrent convergent validity for the ESES-S was partly confirmed by correlations with health-enhancing physical activity and outcome expectations, respectively (Pearson’s r ¼ 0.18, p < 0.01). Concurrent divergent validity was confirmed by the absence of correlations with age or gender. No floor or ceiling effects were found for the ESES-S total score. Conclusions: The results indicate that the ESES-S has moderate test–retest reliability and respectable internal consistency in people with RA. Concurrent validity was only partially supported in the present sample. Further research on the concurrent and predictive validity of the ESES-S is recommended.


E Klingberg1, G Oleröd2, J Konar2, M Petzold3, OHammarsten2 1

Department of Rheumatology and Inflammation Research, Department of Clinical Chemistry and Transfusion Medicine and 3Academic Centre for Applied Biostatistics, Occupational and Environmental Medicine, Sahlgrenska Academy at the University of Gothenburg, Sweden 2

Background: Numerous observational studies associate vitamin D insufficiency (VDI) with chronic illnesses, including rheumatic diseases. There are two definitions of VDI: serum 25-hydroxyvitamin D [25 (OH)D] 10 U/mL, and for RNA Pol III > 15 μg/mL. Results: We found that 448 (24%) samples were IIF positive and 232 (12%) were EliA CTD screen positive. When examined with EliA single antigen assays (Table 1), 56 samples did not exceed cut-off levels. One hundred and fifteen samples were double positive (IIF and EliA single antigen). Agreement between ANA IIF patterns and EliA antigen specificity was found in 58%, partial agreement in 30%, and disagreement in 12% of the samples. Among the IIF-negative and EliA CTD screenpositive samples (n ¼ 99), 38 samples were negative when examined for antibodies against single antigens, 30 samples were positive for antibodies against SSA

and/or SSB, and 25 were positive for dsDNA antibodies. The dsDNA antibody concentration was significantly lower in samples that were IIF negative compared to samples with an IIF homogeneous pattern (T-test: p ¼ 0.019) Conclusions: A positive test result by IIF was twice as frequent as a positive result by the EliA CTD screen. Disagreement between ANA IIF patterns and reactivity to specific antigens could only partly be explained by a low expression of SSA/SSB on Hep-2 cells. The sensitivity and specificity of the two methods for the diagnosis of CTD are currently being examined.

PP244 Autoantibodies against high mobility group box protein1 in systemic lupus erythematosus: association with disease activity and other antinuclear antibodies C Sjöwall1, L Wirestam1, J Wetterö1, L Ottosson2, E Sundberg2, T Skogh1, H Schierbeck2 1 IKE, AIR/Reumatologi, Linköping and 2Paediatric Unit, Department of Women’s and Children’s Health, Karolinska Institute, Stockholm, Sweden

Background: Systemic lupus erythematosus (SLE) is a systemic autoimmune condition characterized by reduced ability to degrade and eliminate apoptotic cells. This probably contributes to the excessive production of antinuclear autoantibodies (ANA), including anti-doublestranded (ds) DNA, which is a hallmark of SLE. The non-histone nuclear protein high mobility group box protein-1 (HMGB1) can act as a pro-inflammatory mediator in many inflammatory diseases when released extracellularly. In SLE, HMGB1 may leak out from inefficiently degraded apoptotic cells and be involved in the pathogenesis (1). Serum levels of HMGB1 correlate with SLE disease activity (2), and HMGB1 has also been shown to contribute to anti-dsDNA antibody production (3). Anti-HMGB1 antibodies have been reported in SLE (2, 4), although their pathogenetic role remains elusive. We aimed to detect and evaluate anti-HMGB1 antibodies in relation to other autoantibodies and to disease activity, phenotypes, and organ damage in a well-characterized cohort of Swedish SLE patients.




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Method: Sera from 188 SLE patients (89% female; mean age 49 years/range 18–88; mean duration 11 years/range 0–45) meeting the 1982 ACR and/or the 2012 SLICC classification criteria and 112 healthy controls (91% female; mean age 47 years/range 19–84) were included. Anti-HMGB1 antibody levels were analysed by an inhouse ELISA using recombinant HIS-tagged HMGB1. The cut-off value (300 AU) was set 2 standard deviations above the mean value among healthy controls. SLE sera were also analysed by immunofluorescence microscopy with regard to ANA (IF-ANA) using fixed HEp-2 cells (ImmunoConcepts, Sacramento, USA). Fluoroenzymeimmunoassay was used to evaluate antidsDNA antibodies (EliA, Thermo Fisher, Uppsala, Sweden), and line-blot technique (ANA profile-5, Euroimmun, Lübeck, Germany) was used for other ANA specificities. Results: Twenty-three per cent (43/188) of the SLE patients were judged to be anti-HMGB1 antibody positive vs. 4% (5/112) of the controls. The levels of anti-HMGB1 were significantly higher in patients than in controls. Anti-HMGB1 antibodies were associated with anti-dsDNA antibody (EliA) levels (r ¼ 0.49, p < 0.001) whereas correlations were less pronounced regarding SLEDAI-2K (r ¼ 0.15, p ¼ 0.04) and albuminuria (r ¼ 0.18, p ¼ 0.02), classical complement function (r ¼ 0.24, p ¼ 0.002) and complement protein C4 (r ¼ 0.23, p ¼ 0.002). The presence of anti-HMGB1 was not associated with organ damage or distinct disease manifestations. Sera containing anti-HMGB1 antibodies were more likely to contain IF-ANA yielding chromatin staining (homogeneous) on HEp-2 cells, compared to antiHMGB1 negative samples (p ¼ 0.009). Conclusions: We confirm that anti-HMGB1 antibodies occur in SLE and that they are associated predominantly with a homogeneous IF-ANA staining pattern. We did not find any association with renal disease. Anti-HMGB1 levels were correlated with both clinical and serological signs of disease activity. References 1. Urbonaviciute V, Fürnrohr BG, Meister S, Munoz L, Heyder P, De Marchis F, et al. Induction of inflammatory and immune responses by HMGB1-nucleosome complexes: implications for the pathogenesis of SLE. J Exp Med 2008;205:3007–18. 2. Abdulahad DA, Westra J, Bijzet J, Limburg PC, Kallenberg CG, Bijl M. High mobility group box 1 (HMGB1) and anti-HMGB1 antibodies and their relation to disease characteristics in systemic lupus erythematosus. Arthritis Res Ther 2011;13:R71. 3. Wen Z, Xu L, Chen X, Xu W, Yin Z, Gao X, et al. Autoantibody induction by DNA-containing immune complexes requires HMGB1 with the TLR2/microRNA-155 pathway. J Immunol 2013;190:5411–22. 4. Hayashi A, Nagafuchi H, Ito I, Hirota K, Yoshida M, Ozaki S. Lupus antibodies to the HMGB1 chromosomal protein: epitope mapping and association with disease activity. Mod Rheumatol 2009;19:283–92.


PP245 Development of IgG antibodies to streptavidin may explain a case of false-positive autoantibody screening test for connective tissue disease (CTD) PH Duhn1, T Skovsted2, B Kristensen3, H Locht1 Departments of 1Rheumatology and 2Clinical Biochemistry, Frederiksberg Hospital, København K and 3Phadia ApS, Allerød, Denmark

Background: The simultaneous occurrence of rare autoantibodies directed against fibrillarin, PCNA, RNA polymerase I–III, Mi-2, and PmScl is very unlikely to be found in the same patient. We describe a case where the EliA CTD Screen test (Thermo Fisher Scientific) was positive for autoantibodies to all of these antigens. The test system used streptavidin in the wells as linker for the recombinant antigens. The patient was examined by a rheumatologist and did not show any signs or symptoms of a CTD. Method: The patient was admitted to hospital with clinical symptoms of pneumonia. To exclude an underlying autoimmune condition, a CTD screening test was performed. Subsequent testing for IgG antibodies against 15 specific autoantigens was performed. Because the patient’s serum reacted to most of the antigens, a test for IgG antibodies against streptavidin was also undertaken. Serum was analysed before and after adsorption with plates coated with steptavidin to absorb anti-steptavidin antibodies. Serum samples drawn from the patient on three occasions (during a 6-month period) were investigated. Results: The CTD screening test remained positive when tested three times during the 6-month follow-up. In all test wells where streptavidin was used as linker molecule to the recombinant antigens, we obtained a positive reaction, that is against fibrillarin, PCNA, RNA polymerase I–III, and Mi-2. All other test wells without streptavidin coating were negative. Repeated testing at 8 weeks and 6 months showed similar positive results with decreasing levels of reactivity. When steptavidin antibodies were absorbed from the serum, the EliA CTD Screen test was clearly negative. Conclusions: The detection of antibodies to streptavidin in the patient could be due to microbial infection with, for example, streptomyces species. We were unable to investigate this further as the patient recovered rapidly from his infection. We propose that the presence of IgG antibodies to streptavidin can act as an interfering antibody in an autoantibody test system using streptavidin as linker. This can lead to a false-positive reaction in the CTD test and thereby misguide the clinician to search for a non-existing autoimmune condition. The frequency of these immune reactions might be rare, but should be considered when the serological results are incompatible with the clinical findings.


PP246 Comparison of lymphomas in primary and secondary Sjögren’s syndrome L Vasaitis1, G Nordmark1, J Askling2, K Ekstrom-Smedby2, C Backlin3, C Sundström3, E Theander4, E Baecklund1


1 Department of Medical Sciences, Section of Rheumatology, Uppsala University, 2Clinical Epidemiology Unit, Department of Medical Sciences, Karolinska Institutet, Stockholm, 3Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, and 4Department of Rheumatology, Skåne University Hospital, Malmö, Lund University, Malmö, Sweden

Background: It is well known that primary Sjögren’s syndrome (pSS) is associated with an increased lymphoma risk, in particular extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue type (MALT) developing at the site of inflammation in pSS, the salivary glands. Secondary SS (sSS), occurring in many of the rheumatic diseases, has also been linked to an increased risk of lymphoma (1), but it is not known whether these lymphomas share characteristics with pSS lymphomas. The aim of the study was to compare clinical characteristics, lymphoma subtypes, and sites of lymphoma in patients with pSS and sSS. Method: Patients registered with a diagnostic code of SS in the Swedish Patient Register 1964–2007 and lymphoma in the Cancer Register 1990–2007 were identified (n ¼ 224). Through a survey of medical records and lymphoma specimens, we identified 108 pSS lymphoma cases (57 fulfilling 2002 AECG criteria for pSS and 51 with all available information supporting pSS but with some AECG information missing) and 54 cases with sSS according to the AECG criteria (35 secondary to RA, 15 to SLE, and four to systemic sclerosis). Clinical data were collected from medical records, and lymphomas were reviewed and classified. Patients were followed for survival until 30 October 2013. Fisher and Mann– Whitney tests were used for statistical analyses. Results: MALT lymphoma was present in 26 (24%) of 108 pSS cases and in one of 54 (2%) cases with sSS (p < 0.001). The MALT lymphomas were situated in the salivary glands in 21 (51%) of the pSS cases, and the MALT lymphoma in the sSS case (associated disease RA) was situated in the lung. Follicular lymphoma was more common in sSS (20%) than in pSS (2%) (p < 0.001). The proportion of diffuse large B-cell lymphoma (DLBCL) was similar: 27% in pSS and 35% in sSS. In total, 36 (34%) of the pSS lymphomas and two (4%) of the sSS lymphomas were situated in salivary glands. The median age at lymphoma diagnosis (64 vs. 65 years) and overall median survival (7 vs. 6.5 years) were similar in pSS and sSS lymphoma patients. Conclusions: MALT lymphoma in the salivary glands seems to be associated only with pSS and not with sSS. This could support different mechanisms behind

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sicca development in pSS and sSS. DLBCL is common and occurs with a similar frequency in both pSS and sSS. Reference 1. Kauppi M, Pukkala E, Isomäki H. Elevated incidence of hematologic malignancies in patients with Sjögren’s syndrome compared with patients with rheumatoid arthritis (Finland). Cancer Causes Control 1997;8:201–4.

PP247 Sex ratio of offspring born to women with lupus E Arkema1, J Salmon2, JF Simard1,3 1 Karolinska Institutet, Stockholm, Sweden, 2Hospital for Special Surgery Weill Cornell Medical College, New York, NY, USA, and 3 Stanford School of Medicine, Stanford, CA, USA

Background: Women with SLE are at increased risk for pregnancy complications, and specific autoantibodies may result in preferential loss of female offspring. Studies on the male to female sex ratio of births in the SLE population have been contradictory (1, 2). We used a large national population-based cohort of patients with SLE to determine whether the sex ratio of births to mothers with SLE is different than the general population. Method: SLE was defined as 2 visits in inpatient or outpatient care (National Patient Register; 1969–2011) listing an SLE ICD code, with 1 SLE-coded visit to a specialist. A sample of general population comparators was identified from the Total Population Register. Women with a delivery were identified from the Swedish Medical Birth Register 1973–2011. We used logistic regression to calculate the odds ratio (OR) for having a male offspring associated with an SLE diagnosis adjusted for age, year, and country of birth. In our primary analysis, we restricted to first singleton births only. In secondary analyses, we examined all births and restricted to live births only. Results: We identified 604 women with SLE before their first delivery and 1289 singleton deliveries in total. Women with prevalent SLE at delivery had a lower proportion of male offspring compared to the general population. The OR for male offspring associated with prevalent SLE at delivery was 0.90 (95% CI 0.77–1.06) for first births and 0.91 (95% CI 0.81–1.02) for all births. ORs did not change with adjustment by age, year, or country of birth. The results were similar among live births only and when multiples were included. Conclusions: We observed a lower proportion of male offspring born to women with prevalent SLE at delivery compared to the general population, which was not statistically significant. In this large study using similar techniques to identify patients as that of a group in Canada (1), we did not confirm their findings of a male dominance in offspring.



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Table 1. Maternal characteristics and male to female sex ratio among deliveries in Sweden, 1973–2011, comparing mothers with SLE at delivery to mothers from the general population restricted to singleton births. First births


N Male baby, n (%) Male to female ratio Mother born in Sweden, n (%) Mother’s age, mean (SD) Stilllbirth*, n (%) Male baby, of live births, n (%) OR‡ (95% CI)

All births

Prevalent SLE at delivery

General population

Prevalent SLE at delivery

General population

604 293 (48.5) 0.94 542 (89.7) 28.7 (4.6)† 7 (1.2)† 290 (48.6) 0.90 (0.77–1.06)

18,226 9,303 (51.0) 1.04 16,314 (89.5) 26.5 (5.1) 75 (0.41) 9,265 (51.0) 1.0 (ref)

1,289 631 (49.0) 0.96 1,145 (88.8) 30.4 (4.8)† 12 (0.93)† 627 (49.1) 0.91 (0.81–1.02)

45,185 23,204 (51.4) 1.06 39,927 (88.4) 28.8 (5.3) 173 (0.4) 23,113 (51.4) 1.0 (ref)

* Foetal death before delivery or during delivery. † Significant at alpha ¼ 0.05, χ 2 test for proportions, two-sided t-test for means. ‡ OR for having a male offspring associated with a maternal SLE diagnosis.

References 1. Vinet É, Bernatsky S, Pineau CA, Clarke AE, Nashi EP, Scott S, et al. Increased male-to-female ratio among children born to women with systemic lupus erythematosus: comment on the article by Lockshin et al. Arthritis Rheum 2013;65:1129. 2. Lockshin MD, Cohn E, Aslam A, Buyon JP, Salmon JE. Sex ratios among children of lupus pregnancies. Arthritis Rheum 2013;65:282.

PP248 Initial symptoms of sarcoidosis can be neurological: a case study J Henriksen1, KE Olsen2, R Ramoskiene1, IMJ Hansen1 1

Medicin, OUH, Svendborg and 2OUH, Odense, Denmark

Background: Sarcoidosis is a multisystem granulomatous disease. Five per cent of patients with sarcoidosis have or develop neurological complications (1). The disease can affect all parts of the nervous system (1– 3). The neurological symptoms are treated by treating the primary disease. Corticosteroids are the primary treatment, supplemented with immunosuppressives if necessary. Case study: A 76-year-old woman was hospitalized with dizziness, episodes of falling, incontinence, and peripheral right-sided facial palsy. This was followed by progressive muscle weakness, pharyngeal palsy, and respiratory insufficiency. CT of the cerebrum was normal. In the first spinal fluid test, the leucocyte count was 114 106/L and the protein content was 3.7 g/L. Spinal glucose was normal. A repeated spinal fluid test was negative for HSV types 1 and 2, EBV, CMV, VZV, mycobacterium tuberculosis, and borrelia. A third spinal fluid test showed no malignant cells but the T4/T8 ratio had increased. Blood tests were normal for S-Ca and C-reactive protein. MRI of the cerebrum showed vascular encephalopathy and infarction sequelae. ENG showed axonal sensorimotor polyneuropathy. During the course of the disease, several differential diagnoses were evaluated including neuroinfections, Guillain–Barré,


CADASIL, and paraneuroplastic syndromes. A PET-CT showed increased fluorodeoxy glucose uptake in pulmonary infiltrates and mediastinal lymph nodes. Biopsies from these showed granulomatous inflammation with epithelioid cells without necrosis, consistent with sarcoidosis (Figure 1). The patient was treated for neurosarcoidosis with a high-dose corticosteroid, and later with the addition of methotrexate. She improved initially with regard to respiratory and neurological symptoms, with disappearance of pulmonary infiltrations, but relapsed a few weeks after the diagnosis. She died of respiratory insufficiency. Conclusions: As shown in this case, symptoms of neurosarcoidosis is far from specific, and a wide range of differential diagnoses were considered. It is imperative, in the initial investigation, that diagnostic imaging and lumbar puncture are performed. MRI has high sensitivity. However, the specificity is low (4). Spinal fluid deviations could be due to elevated protein, low glucose, or increased angiotensin-converting enzyme (2). Diagnosis of sarcoidosis is by histological detection of granulomatous inflammation with epithelioid cells, clinically relevant manifestations and radiographic findings. Biopsy material is usually from lymph nodes, lungs, and skin, as in this case study, resulting in a probable diagnosis (2,


3). A more definite diagnosis of neurosarcoidosis would have required a biopsy directly from nerve tissue. Neurosarcoidosis must be considered when neurological symptoms appear in a patient with sarcoidosis. If the patient has no known sarcoidosis, it is only when a variety of other diseases are excluded, particularly infection and malignancy, that sarcoidosis may be considered.


References 1. Krumholz A, Stern BJ. Neurologic manifestations of sarcoidosis. Handb Clin Neurol 2014;119:305–33. 2. Pawate S, Moses H, Sriram S. Presentations and outcomes of neurosarcoidosis: a study of 54 cases. Q J Med 2009;102:449–60. 3. Joseph FG, Scolding NJ. Neurosarcoidosis: a study of 30 new cases. J Neurol Neurosurg Psychiatry 2009;80:297–304. 4. Lury KM, Smith JK, Matheus MG, Castillo M. Neurosarcoidosis – review of imaging findings. Semin Roentgenol 2004;39:495–504.

PP249 Maternal and foetal outcomes in pregnant systemic lupus erythematosus patients: an incident cohort from a stable referral population followed during 1990–2010 IM Jakobsen1, RB Helmig2, K Stengaard-Pedersen1 1

Rheumatology, Aarhus University Hospital, Aarhus C and Obstetrics and Gynaecology, Aarhus University Hospital, Skejby, Denmark 2

Background: Systemic lupus erythematosus (SLE) primarily affects women of childbearing age and remains an important contributor to maternal and foetal morbidity and mortality (1), despite advances in the treatment of both SLE and obstetric complications over the past decades. Antiphospholipid syndrome and the presence of antiphospholipid antibodies, decreased kidney function and disease activity in general have been shown to be risk factors for spontaneous abortion, premature delivery, IUGR, and foetal death (1–3). The reported frequency of SLE flares during and after pregnancy varies in the literature from 25% to 68%. In Danish patients the impact of pregnancy on SLE activity and foetal complications have not been studied, and Scandinavian data on the subject are scarce (4). Therefore, the objective was to assess the impact of SLE and the presence of autoantibodies on pregnancy outcome in a cohort of incident pregnant lupus patients referred to a Danish university hospital during 1990–2010. Method: All pregnant lupus patients were referred to the university hospital from a stable referral area with approximately 1.4 million inhabitants. Eighty-four pregnancies in 39 women were registered using the Danish National Registry and by retrospective review of medical records, laboratory results, and midwives’ records from the Department of Rheumatology and the Department of Obstetrics and Gynaecology and possible other

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departments. Data were compared to data from 29 059 births during 2005–2010, covering all births from the referral area. Results: The 84 SLE pregnancies resulted in 62 live births. SLE flares developed in 46.4%, pre-eclampsia in 8.3%, and HELLP syndrome in 4.8% of cases. Significantly higher rates of premature delivery (p ¼ 0.0032), Caesarean section (p ¼ 0.015), hypertension (p ¼ 0.025), and IUGR (p ¼ 0.003) were found. Disease activity significantly (p ¼ 0.021) increased the risk of prematurity threefold. The presence of antiphospholipid antibodies significantly (p ¼ 0.002) increased the risk of spontaneous abortion threefold. Two babies died after extreme preterm birth. Two had neonatal lupus syndrome and one had congenital heart block. Birthweight and birth length were significantly lower in the SLE cohort. An unexpectedly high number of cardiac septum defects in the babies was observed. Conclusions: Danish women with SLE have a higher frequency of adverse pregnancy outcome for both the baby and the mother compared to the general population, but most SLE pregnancies were successful. A high number of babies born with cardiac septum defects were found and this needs further research. References 1. Ostensen M, Clowse M. Pathogenesis of pregnancy complications in systemic lupus erythematosus. Curr Opin Rheumatol 2013;25:591–6. 2. Empson M, Lassere M, Craig J, Scott J. Prevention of recurrent miscarriage for women with antiphospholipid antibody or lupus anticoagulant. Cochrane Database Syst Rev 2005;(2): CD002859. 3. Cortés-Hernández J, Ordi-Ros J, Paredes F, Casellas M, Castillo F, Vilardell-Tarres M. Clinical predictors of fetal and maternal outcome in systemic lupus erythematosus: a prospective study of 103 pregnancies. Rheumatology (Oxford) 2002;41:643–50. 4. Julkunen H, Jouhikainen T, Kaaja R, Leirisalo-Repo M, Stephansson E, Palosuo T, et al. Fetal outcome in lupus pregnancy: a retrospective case-control study of 242 pregnancies in 112 patients. Lupus 1993;2:125–31.

PP250 Angiogenesis factors: markers for paraneoplastic rheumatic syndromes I Taliju¯niene·1, P Venalis2, J Dadoniene·1,3, A Venalis1,3, J Distler4, I Lundberg2, R Rugiene·1,3 1

Rheumatology Centre, Vilnius University, Lithuania, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden, 3State Research Institute Centre for Innovative Medicine, Vilnius University, Lithuania, and 4 Department of Internal Medicine 3, University of ErlangenNuremberg, Erlangen, Germany 2

Background: Differential diagnoses between undifferentiated rheumatic syndromes and cancer are the subject of extensive investigations. Among newly diagnosed cancer patients, the prevalence of paraneoplastic rheumatic




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syndromes was reported to be 2.65% (95% CI 0.21–3.20) (1). Factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and endostatin are important in both the pathogenesis of cancer and inflammation. We aimed to evaluate VEGF, FGF, and endostatin as markers for paraneoplastic arthritis and Raynoud’s syndrome. Method: In this cross-sectional study the sera concentrations of VEGF, bFGF, and endostatin from patients with paraneoplastic arthritis and paraneoplastic Raynaud’s syndrome (n ¼ 28 and 23, respectively) were compared to those from patients with early arthritis and Raynaud’s syndrome secondary to systemic/inflammatory diseases (n ¼ 32 and 17, respectively) as well as to patients with newly diagnosed solid tumours only (n ¼ 32). Commercially available ELISA was used. The results are presented as median values. Results: Paraneoplastic arthritis patients presented with higher VEGF concentrations (38.95 pg/mL) compared to early arthritis (1.77 pg/mL, p < 0.001) and solid tumour (0.1 pg/mL, p < 0.001) patients. The same pattern was found in paraneoplastic Raynaud’s syndrome (31 pg/mL) when compared to secondary Raynaud’s (0.1 pg/mL, p < 0.001) and solid tumour (0.1 pg/mL, p < 0.001) patients. Similarly, endostatin concentrations were higher in paraneoplastic arthritis patients (6.92 pg/mL) than in early arthritis (1.89 pg/mL, p < 0.001) and solid tumour (1.58 pg/mL, p < 0.001) patients and in paraneoplastic Raynaud’s syndrome (6.2 pg/mL) when compared to secondary Raynaud’s (1.7 pg/mL, p < 0.001) and solid tumour (1.58 pg/mL, p < 0.001) patients. By contrast, paraneoplastic arthritis patients had significantly lower bFGF concentrations (0.12 pg/mL) in comparison to early arthritis (1.18 pg/mL, p < 0.001) and solid tumour (1.64 pg/mL, p < 0.001) patients. Paraneoplastic Raynaud’s syndrome patients also presented with significantly lower bFGF concentrations (0.16 pg/mL) when compared to secondary Raynaud’s (1.99 pg/mL, p < 0.001) and solid tumour (1.64 pg/mL, p < 0.001) patients. Conclusions: We have demonstrated that sera concentrations of angiogenic factors (VEGF, bFGF, and endostatin) in paraneoplastic arthritis and paraneoplastic Raynaud’s syndrome patients differ significantly from early arthritis and secondary Raynaud’s patients as well as from patients with newly diagnosed solid tumours. Thus these factors could serve as biomarkers for paraneoplastic arthritis and paraneoplastic Raynaud’s syndromes. However, larger cohort, longitudinal and immunohistochemical studies are required.

Reference 1. Rugiene· R, Dadoniene· J, Aleknavičius E, Tikuišis R, Distler J, Schett G, et al. Prevalence of paraneoplastic rheumatic syndromes and their antibody profile among patients with solid tumours. Clin Rheumatol 2011;30:373–80.


PP251 High serum levels of IFN-λ1/3 and IFN-α characterize two separate subgroups among SLE patients V Oke1, J Gustafsson2, S Brauner1, A Zickert2, I Gunnarsson2, E Svenungsson2 1 Rheumatology Unit, Department of Medicine and 2Karolinska Institutet, Stockholm, Sweden

Background: SLE is a systemic autoimmune disease with heterogeneous clinical manifestations and a pathogenesis that is still not completely understood. IFN-α is known as an important cytokine driving disease manifestations in a subgroup of patients, and type III IFNs (IFN-λ1, –2, and –3) have recently been described to be associated with renal involvement (1). The aim of this study was to measure the circulating levels of IFN-α and IFN-λ1/3 in a large cohort of SLE patients, and explore their association with clinical and laboratory manifestations. Method: This study included 261 SLE patients and 276 population controls, identified through the population registry and matched for age, sex, and region of living. All participants were investigated clinically by a rheumatologist regarding present and previous organ manifestations. Sera were collected after overnight fasting at inclusion and stored at 70 C until analysis. IFN-α and IFN-λ1/3 levels were measured in sera by a commercial ELISA (pan IFN-α and IFNλ1/3, lowest detection limits 0.022 and 0.3 pg/L, respectively). Results: IFN-α was detected in 154 (59%) patients and IFN- λ1/3 in 76 (29.1%), and 79 patients (30%) had no detectable levels of any of these cytokines. In comparison to controls, patients had higher levels of both IFNα and IFN-λ1/3 (p < 0.01). IFN-λ1/3 levels did not correlated to the levels of IFN-α (Figure). Two patient groups were identified, one with high (>1.3 pg/L) levels of IFN-λ1/3 (n ¼ 37) and the other with high (>0.112 pg/L) levels if IFN-α (n ¼ 39) (Figure 1). There were only five patients (cross symbol in the figure) who had high levels of both cytokines. For further statistical analysis patients were grouped accordingly to the figure. Patients with high IFN-λ1/3 levels were compared to the patients with high IFN-α and to the rest of the patients. Statistical analysis included the occurrence of common clinical SLE manifestations and autoantibodies. Both groups with high IFN-α and IFN-λ1/3 had leucopaenia [likelihood ratio (LR), p < 0.05] and thrombocytopaenia (LR, p < 0.01) at a higher proportion in comparison to the rest of the patients but they did not differ regarding the occurrence of malar rash, photosensitivity, discoid LE, arthritis, or nephritis. Patients with high IFN-α were more often positive for SSA, SSB (LR, p < 0.01), and anti-C1q autoantibodies (LR, p < 0.05) and had a tendency for less frequent occurrence of any antiphospholipid

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antibodies (LR, p ¼ 0.06). Both the IFN-λ1/3 and IFNα high groups had lower C3 levels than the other patients (LR, p < 0.05 and 0.005, respectively). There were less smokers among patients with high IFN-λ1/3 levels in comparison to high IFN-α and to the rest of the patients (LR, p < 0.01). Notably, three patients with active carditis and four with organic brain syndrome, as assessed by SLAM/SLEDAI, were in the high IFN-α group (LR, p < 0.05). Conclusions: Our study demonstrates that, among SLE patients, high levels of IFN-α and high levels of IFN-λ1/3 reside in two different subgroups with minimal overlap. Both cytokines may independently drive SLE disease manifestations, and could be considered for future drug development.

IFN-alpha vs IFN-lambda 1/3 High

1,0 0,8 IFN-alpha pg/L



+

0,6 0,4

+ +

0,2

+ +

0,0

High 0

5 10 15 IFN-lambda 1/3 pg/L

20

Reference 1. Wu Q, Yang Q, Lourenco E, Sun H, Zhang Y. Interferon-lambda1 induces peripheral blood mononuclear cell-derived chemokines secretion in patients with systemic lupus erythematosus: its correlation with disease activity. Arthritis Res Ther 2011;13:R88.

PP252 An NFKB1 gene promoter polymorphism is associated with primary Sjögren’s syndrome G Nordmark1, L Vasaitis1, E Theander2, M Kvarnström3, SJ Johnsen4, JG Brun5,6, MV Jonsson7,8, C Sjöwall9, H Forsblad-d’Elia10, M Wahren-Herlenius3, R Omdal4, R Jonsson5,7, M-L Eloranta1, P Eriksson9 1

Section of Rheumatology, Department of Medical Sciences, Uppsala University,Sweden, 2Department of Rheumatology, Skåne University Hospital Malmö, Lund University, Malmö, Sweden, 3Rheumatology Unit, Department of Medicine, 4 Clinical Karolinska Institutet, Stockholm, Sweden, Immunology Unit, Department of Internal Medicine, Stavanger

University Hospital, Norway, 5Department of Rheumatology, Haukeland University Hospital, Norway, 6Section for Rheumatology, Department of Clinical Science and 7 Department of Clinical Science, Broegelmann Research Laboratory, Norway, 8Section for Oral and Maxillofacial Radiology, Department of Clinical Dentistry, University of Bergen, Norway, 9Division of Rheumatology, Department of Clinical Experimental Medicine, Linköping University, Sweden, and 10Department of Rheumatology and Inflammation Research and the Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Sweden

Background: Activation of the transcription factor NFκB results in inflammation and autoimmunity. Studies in epithelial cells stimulated with anti-SSA antibodies from patients with primary Sjögren’s syndrome (pSS) have shown an activation of NF-κB (1). The p50/p65 heterodimer is the most common where NFKB1 encodes the p50 subunit. An association between an NFKB1 single nucleotide polymorphism (SNP) and anti-SSA/SSBpositive patients with pSS has been described (2). A four base-pair insertion/deletion (ins/del) in the promoter region, 94ATTG, of NFKB1 has been associated with ulcerative colitis and decreased survival in colorectal cancer (3). The aim of this investigation was to analyse the association between the NFKB1 ins/del promoter polymorphism and pSS, anti-SSA/SSB positivity, and clinical manifestations. Method: A total of 684 patients with pSS (92.8% females, mean age 58 years, 73.8% anti-SSA and/or anti-SSB positive) from Sweden (n ¼ 488) and Norway (n ¼ 196) and 1601 healthy controls (Sweden, n ¼ 1383, Norway, n ¼ 218) participated in this study. The NFKB1 ins/del was genotyped with TaqMan PCR (3). The insertion (ins, 2ATTG) is wild-type and the deletion (del, 1ATTG) is the minor allele. Association analyses were performed in PLINK. Data on antibodies and clinical manifestations were extracted from the patient files. Results: There was an association between the NFKB1 del allele and pSS (allele frequency pSS 0.42, controls 0.38), p ¼ 0.01, OR 1.18, 95% (CI 1.04–1.34). The genotype was associated in a dominant model (del/ delþdel/ins vs. ins/ins), with p ¼ 0.02, OR 1.25 (95% CI 1.04–1.51). All patients and 979 controls were genotyped for the NFKB1 SNP rs4648022 (2). A haplotype of NFKB1 del and SNP rs4648022 was associated with pSS, p ¼ 0.03, OR 1.35 (95% CI 1.04–1.76). There were no associations between the NFKB1 del allele and the presence of anti-SSA/SSB antibodies or any of the following clinical manifestations:; Raynaud’s phenomenon, arthritis, dermal vasculitis, major salivary gland swelling, lymphadenopathy, lymphoma, hypothyroidism, hypergammaglobulinemia or germinal centre formations in the minor salivary gland biopsies. Conclusion: Genetic variation in the NFKB1 -94ATTG ins/ del promoter polymorphism is for the first time shown to be associated with pSS. How this gene variant affects the NF-κ B signaling pathway, disease development and clinical



88

manifestations in pSS is unknown and an important topic for further studies.


References: 1. Lisi S, Sisto M, Lofrumento DD, D’Amore M. Sjögren’s syndrome autoantibodies provoke changes in gene expression profiles of inflammatory cytokines triggering a pathway involving TACE/NFκB. Lab Invest 2012;92:615–24. 2. Nordmark G, Wang C, Vasaitis L, Eriksson P, Theander E, Kvarnström M, et al. Association of genes in the NF-κB pathway with antibody-positive primary Sjögren’s syndrome. Scand J Immunol 2013;78:447–54. 3. Ungerbäck J, Belenki D, Jawad ul-Hassan A, Fredrikson M, Fransén K, Elander N, et al. Genetic variation and alterations of genes involved in NFκB/TNFAIP3- and NLRP3-inflammasome signaling affect susceptibility and outcome of colorectal cancer. Carcinogenesis 2012;33:2126–34.

work-related risk factors, and opportunities and constraints in the work environment. Conclusions: Poor self-rated work ability is common in patients with PM/DM, indicating a need to identify interfering risk factors and support patients to enhance work performance.

PP255 Activated T cells enhance interferon-α production by plasmacytoid dendritic cells stimulated by RNAcontaining immune complexes D Leonard1, M-L Eloranta1, N Hagberg1, O Berggren1, K Tandre1, G Alm2, L Rönnblom1 1

Department of Medical Sciences, Uppsala University and Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Uppsala, Sweden 2

PP254 Work ability in patients with polymyositis and dermatomyositis: an exploratory and descriptive study M Regardt1, EW Henriksson2,3, J Sandqvist4, I Lundberg5, M-L Schult6 1 Department of Occupational Therapy, Karolinska University Hospital, Stockholm, 2Department of Neurobiology, Health Care Sciences and Society, Karolinska Institutet, Stockholm, 3 Department of Medicine, Rheumatology Unit, Karolinska University Hospital at Solna, Karolinska Institutet, Stockholm, 4 Department of Social and Welfare Studies, Faculty of Health Sciences, Linkoping University, Norrkoping, 5Department of Medicine, Rheumatology Unit, Karolinska University Hospital at Solna, Karolinska Institutet, Stockholm, and 6Department of Clinical Sciences, Danderyd Hospital, Division of Rehabilitation Medicine, Karolinska Institutet, Danderyd, Sweden

Background: This study aimed to investigate the work situation, work ability, work-related risk factors, and influence of the physical and psycho-social work environment in patients with polymyositis (PM) and dermatomyositis (DM). Method: Patients with PM/DM were assessed using the Work Ability Index (WAI), and the Work Environment Impact Scale (WEIS). Results: Forty-eight patients (PM n ¼ 25 and DM n ¼ 23) participated (women/men: 29/19) with a mean age of 54 years (range 28–67 years, SD ¼ 10) and mean disease duration of 9 years (SD ¼ 9). Forty-four per cent worked full time, 31% part-time, and 25% were on full-time sick leave. More than 50% self-rated work ability as ‘poor’ or ‘less good’. Physically strenuous work components were present ‘quite to very often’ in 23–79% and more in patients on sick leave 2 years. For those working, the interfering factors in the work environment concerned task and time demands. Supporting factors concerned meaning of work and interactions with co-workers and others. Self-rated work ability correlated moderately to highly positive with percentage of full-time employment,


Background: A prominent interferon-α (IFN-α) signature is seen in several autoimmune diseases including systemic lupus erythematosus (SLE). Plasmacytoid dendritic cells (pDCs) are the main IFN-α-producing cells and produce large amounts of IFN-α in response to certain immune complexes (ICs). This IFN-α activates the immune system in several ways including polarization of naïve T helper (TH) cells to Th1 cells, expansion and activation of cytotoxic CD8þ T cells, and enhances B-cell differentiation and antibody production. Thus, once pDCs are activated they strongly promote the adaptive immune response. However, much less is known about the effects on pDCs by the different adaptive immune cells. Therefore, we aimed to determine whether T cells could promote the IFN-α production by pDCs stimulated by RNA-containing immune complexes. Method: Human T cells were activated by anti-CD3/ CD28 antibodies. T cells or supernatants from T-cell cultures were co-cultured with pDCs stimulated with immune complexes containing U1 snRNP particles and SLE-IgG (RNA-IC). Cells were analysed by flow cytometry and cytokines in supernatants were depleted or blocked by monoclonal antibodies. Supernatants were analysed for IFN-α and other cytokines. Results: Activated T cells or supernatants from activated T cells increased the IFN-α production >20-fold. GMCSF and IL-3 increased the IFN-α production. The stimulatory effect of supernatants was significantly reduced after depletion of GM-CSF (81%), blocking of GM-CSF (92%) or its receptor subunits CD131 and CD116 (55– 81%) (all p < 0.05). Furthermore, supernatant from activated T cells increased the frequency of CD80 and CD86 expressing pDCs from 6% to 35% (p < 0.05) and from 10% to 26% (p < 0.01), respectively. Activated SLE T cells enhanced IFN-α production to the same extent as T cells did from healthy controls. Conclusions: Activated T cells enhance IFN-α production by RNA-IC-stimulated pDCs through GM-CSF and


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IL-3, which induce maturation of the pDCs. This finding, together with previous observations in SLE of activated T cells and increased levels of GM-CSF and IL-3, suggests that T cells contribute to the activated type I interferon system in SLE. References 1. Rönnblom L, Elkon KB. Cytokines as therapeutic targets in SLE. Nat Rev Rheumatol 2010;6:339–47. 2. Willeke P, Schlüter B, Schotte H, Erren M, Mickholz E, Domschke W, et al. Increased frequency of GM-CSF secreting PBMC in patients with active systemic lupus erythematosus can be reduced by immunoadsorption. Lupus 2004;13:257–62.

Estimated from samples of incident CTD patients and diseased controls ECS

IIF HEp-2

Combined

n ¼ 211

>0.7

>1.0

1:>160

ECS þ IIF

Sensitivity Specificity LRþ LR–

88 93 13 0.13

80 96 18 0.21

85 88 7 0.16

90 80 4.5 0.12

Agreement of IIF HEp-2 and ECS In CTD patients (prevalent and incident patients)


ECS

PP256 Indirect immunofluorescence on HEp-2 cells vs. ELIA CTD screen for the detection of antinuclear antibodies

Negative

Negative Positive Total

17 17 34

>0.7

>1.0

Total

21 111 132

19 103 122

38 128 166

In controls (diseased controls and blood donors)

T Korsholm1, A Troldborg2, BD Nielsen2 Departments of 1Clinical Immunology and Aarhus University Hospital, Denmark

IIF HEp-2

2

ECS

Rheumatology,

Background: Indirect immunofluorescence (IIF) on HEp-2 cells (IIF Hep-2) is still the reference method of choice for detection of autoantibodies to cellular antigens known as antinuclear antibodies (ANA). However, its limitations should be kept in mind, as it is a laborious technique requiring highly qualified laboratory personnel and has low specificity, making it unsuitable for the highthroughput screening of relatively unselected populations with a low prevalence of connective tissue disease (CTD). Quantitative automated solid-phase methods are increasingly replacing IIF methods for the detection of antinuclear antibodies. To increase sensitivity, additional purified or recombinant antigens are added. We estimated the diagnostic performance of IIF HEp-2 vs. the EliA CTD Screen (ECS) for ANA detection in patients suspected of CTD, and also evaluated the agreement between the two methods. Method: For performance estimates 211 samples received for testing of ANA from patients suspected of CTD (42 subsequently diagnosed with CTD) were analysed. The patients who were later diagnosed with CTD were used in this project as incident patients (n ¼ 42). Another 124 samples from patients already diagnosed with CTD and 100 blood donors were analysed for further comparison of methods (agreement). All patients were diagnosed according to current consensus criteria. Information on diagnosis was retrieved from patient records. CTD diagnoses included systemic lupus erythematosus (SLE), primary Sjögren’s syndrome (pSS), systemic sclerosis (SSc), mixed connective tissue disease (MCTD), and polymyositis/dermatomyositis (PM/DM). Samples were analysed simultaneously by IIF HEp-2 (Immuno Concepts) and ECS (Thermo Fisher), each well coated with dsDNA, Ro52, Ro60, SSB, U1RNP (RNP70, A, C), Sm, centromere B, Jo-1, Scl70, Rib-P,

IIF HEp-2

Negative

Negative Total Total

232 26 258

>0.7

>1.0

10 1 11

6 1 7

Total 242 27 269

fibrillarin, RNA Pol III, PM-Scl, PCNA, and Mi-2. All reactive samples were further analysed for antibody specificity (EliA). Results: Diagnostic performance shown in the table. Conclusions: The results of this study indicate that the ECS with a cut-off of 0.7 is superior in performance to IIF HEp-2. However, the agreement analysis reveals a substantial fraction of CTD patients in whom ANA was detected by only one of the methods, substantiating that IIF HEp-2 is more sensitive for some diseases but, for some specific antibodies, the ECS demonstrates better recognition. IIF HEp2 and ECS complement each other, and if either is used alone, negative samples should be analysed by the other method if clinically indicated. We propose an algorithm for optimal detection of ANA in various patient populations suspected of having CTD. PP257 Increased levels of thrombin-activatable fibrinolysis inhibitor (TAFI) correlate with complement activation in patients with the antiphospholipid syndrome A Antovic, A Vikerfors, E Svenungsson Department of Medicine Solna, Rheumatology Unit, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

Background: The antiphospholipid syndrome (APS) is diagnosed when arterial/venous/small vessel thrombosis or obstetric morbidity occur together with positive




90

laboratory tests for antiphospholipid antibodies [aPL, including anticardiolipin (aCL) and/or antiβ2glycoprotein-I (a β2GPI) and/or the functional lupus anticoagulant (LA) test]. The pathophysiology behind aPL-associated thrombosis is complex. Thrombinactivatable fibrinolysis inhibitor (TAFI) represents a link between coagulation and fibrinolysis. The active form of the enzyme removes carboxyl-terminal lysine residues from partially degraded fibrin, thus maintaining fibrin clots and having a prothrombotic function. TAFI has been considered a potential acute phase protein while it may mediate anti-inflammatory effects by regulating complement anaphylatoxins C3a and C5a. The aims of this study were to investigate TAFI levels in relation to the fibrin clot tightness and fibrinolytic function as well as complement activation in patients with APS. Method: Fifty patients with APS and 15 controls were included. The levels of pro-TAFI (proenzyme) and TAFIa/ TAFIai (complex of active and inactive forms that corresponds to the concentration of the active form, which cannot be measured because of instability) were analysed with a chromogenic assay for TAFI and a specific ELISA for TAFIa/ai (both from Diagnostica Stago, Asnieres, France). Fibrin permeability was assessed by flow measurement and clot lysis time (CLT) was analysed by a turbidimetric lysis assay. C5a was analysed by a specific ELISA (Becton Dickinson Bioscience, NJ, USA). Results: The levels of the proenzyme pro-TAFI (%) as well as the levels of the active enzyme TAFIa/TAFIai (ng/ mL) were significantly increased in patients with APS compared to controls (114 2.7 vs. 88.7 16.5; p < 0.001 and 18.9 1.6 vs. 12.2 0.7; p < 0.001, respectively). Fibrin permeability expressed as permeability coefficient K (cm2 109) was lower in samples from APS patients compared to controls (6.4 0.6 vs. 9.8 0.8 cm2 109; p < 0.001) indicating a tighter fibrin structure. CLT (seconds) was longer in APS samples than in controls (374 34.3 vs. 278 42.2; p < 0.001). TAFI levels did not correlate with CLT or with K values in the investigated samples. However, moderately significant correlation was found between pro-TAFI and C5a (r ¼ 0.37, p < 0.01). Conclusions: Increased levels of pro-TAFI were found in patients with APS as a potential response to increased complement activation. Despite the increased TAFI activation it does not seem that the active form of TAFI significantly contributes to fibrinolysis impairment in APS. However, further studies are required to elucidate the role of TAFI in the pathophysiology of APS. PP258 Profile of T-cell subsets in peripheral blood from idiopathic inflammatory myositis patients F Espinosa1, K De Anda2, D Gomez2


1

Rheumatology, South Central High Specialty Hospital, PEMEX and 2Rheumatology, National Institute of Medical Science and Nutrition Salvador Zubiran, Mexico City, Mexico

Background: The role of T cells in idiopathic inflammatory myopathies (IIM) is not yet clear. Some alterations in certain subsets have been reported in inflamed muscle cells. However, a broad quantitative assessment of peripheral T-cell subsets has not yet been carried out. The aim of this study was to address the quantitative profile of potential pathogenic T-cell subsets, namely follicular helper T cells (Tfh), Th17, CD28 null, and regulatory T cells (Tregs) in peripheral blood from IIM patients. Method: Thirty IIM patients and 30 age- and gendermatched healthy donors were included. Peripheral blood mononuclear cells were isolated. T-cell subsets were evaluated by flow cytometry, as follows: Tfh (CD4þ CXCR5þ) and its subsets Tfh1 (CXCR3þCCR6–), Tfh2 (CXCR3–CCR6–), Tfh17 (CXCR3þCCR6þ), Th17 (CD4þIL17Aþ), CD28null (CD4þCD28– CD244þ), and Tregs (CD4þCD25highþFOXP3; CD8þ CD25highFOXP3). Percentages, absolute numbers, and mean fluorescence intensities were analysed. Results: We found increased numbers of total Tfh cells (28 8.16 vs. 6.64 1.29, p ¼ 0.031) in IIM patients when compared to healthy controls. Moreover, this increment was dependent on Tfh2 and Tfh17 (Tfh2: 14.61 3.07 vs. 5.52 0.92, p ¼ 0.014; Tfh17: 0.59 0.13 vs. 0.08 0.06, p ¼ 0.005). IIM patients also showed higher numbers of Th17 cells (30.25 6.49 vs. 13.46 2.95, p ¼ 0.031) as well as decreased numbers of Tregs (5.98 1.61 vs. 30.82 8.38, p ¼ 0.009). We also found an expansion of CD28 null cells (162.88 32.29 vs. 64 17.35, p ¼ 0.015). Conclusions: Our data suggest that IIM patients are characterized by an expansion of peripheral pro-inflammatory T cells, such as Tfh and Th17, as well as pro-apoptotic CD28 null cells, and a deficiency of suppressor populations of Tregs (CD4þ and CD8þ). PP259 Decreased disease activity and corticosteroid usage and no renal flares during belimumab treatment in patients with systemic lupus erythematosus I Parodis1, E Svenungsson1, M Axelsson2, I Gunnarsson1 1 Department of Medicine, Rheumatology Unit, Karolinska Institutet, Stockholm and 2AlbaNova, Stockholm University, Sweden

Background: B cells have a central role in systemic lupus erythematosus (SLE) and autoantibody production. Blymphocyte stimulator (BLyS) is important for the activation and maintenance of B cells. Belimumab is a recombinant monoclonal antibody that specifically binds to



soluble BLyS, and is the only biologic agent approved for treatment of SLE. Its effects in patients with lupus nephritis (LN) are poorly known. The aim of this study was to investigate the effects of belimumab given as an add-on to patients with active SLE despite standard-of-care therapy, with focus on patients with renal involvement. Method: Twenty-three patients (mean age 39.5 years) who have been treated with belimumab at Karolinska University Hospital were included in this prospective observational study. Clinical data were acquired at baseline and at weeks 12, 26, 52, and 104. Disease activity was assessed using the SLE Disease Activity Index 2000 (SLEDAI-2K) and the Systemic Lupus Activity Measure (SLAM). C3 and C4 levels were determined by nephelometry. The predominant organ manifestations to motivate treatment with belimumab were mucocutaneous (n ¼ 14) and musculoskeletal (n ¼ 14). Thirteen patients with a history of LN, five of them with signs for nephritis and low-grade proteinuria at baseline, were included. Results: At baseline, all but two patients were receiving oral prednisolone (mean dose 9.1 mg/day, range 0–20 mg/day), 17 patients were receiving antimalarials, six azathioprine, four mycophenolate mofetil, one methotrexate, and one cyclosporin. The median SLEDAI and SLAM scores were 9 (range 2–24) and 12 (range 5–26), respectively. Significant decreases in both SLEDAI-2K and SLAM scores were seen at weeks 12 (p ¼ 0.018 and p ¼ 0.003, respectively; n ¼ 18), 26 (p ¼ 0.008 and p ¼ 0.002, respectively; n ¼ 15), 52 (p ¼ 0.003 and p ¼ 0.044, respectively; n ¼ 12), and 104 (p ¼ 0.042 and p ¼ 0.042, respectively; n ¼ 5), compared to baseline. Prednisolone dosages were significantly decreased compared to baseline at weeks 12 (p ¼ 0.012, n ¼ 18), 26 (p ¼ 0.002, n ¼ 16), 52 (p ¼ 0.005, n ¼ 12), and 104 (p ¼ 0.043, n ¼ 5). Eighteen patients had low complement at baseline. We observed no significant increases in C3 or C4 levels, with the exception of a significant increase in C4 levels at week 12 (p ¼ 0.047, n ¼ 18). The patients with a history of nephritis had at baseline a mean 24-h albuminuria of 0.25 g/day (range 0.01–1.16 g/day). No renal flare was observed during the study. The grade of proteinuria remained unchanged compared to baseline at all follow-up occasions. One patient withdrew due to an allergic reaction. The treatment with belimumab was discontinued in four patients after 12 months of follow-up due to inadequate or uncertain effect, and in one patient after 6 months of follow-up due to plans for pregnancy. No severe adverse events were noted during the observation period. One male patient was diagnosed with prostate cancer (age at diagnosis 55 years) 15 months after discontinuation of belimumab. Conclusions: Belimumab treatment decreased SLE disease activity and reduced corticosteroid usage. Despite the limited number of patients, our observations indicate that belimumab may prevent renal flares and may be used

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in patients with renal involvement and persistent lowgrade proteinuria.

PP260 Microcirculation and macrovascular disease systemic sclerosis: a nailfold capillary study

in

A Nordin1, L Björnådal1, E Roubi2, K Jensen-Urstad3, E Svenungsson1 1 Department of Medicine, Rheumatology Unit, Karolinska Institutet, Stockholm, 2Department of Rheumatology, Sundsvalls Hospital, Karolinska Institutet, Sundsvall, and 3 Department of Clinical Physiology, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden

Background: Patients with systemic sclerosis (SSc) suffer from both micro- and macrovascular disease. Structural changes in nailfold capillaries, assessed by nailfold capillaroscopy (NFC), have been associated with microvascular manifestations, such as digital ulcers and pulmonary arterial hypertension. We investigated the association between NFC changes and macrovascular ischaemic arterial events (IAEs), including ischaemic heart disease, cerebrovascular disease, and peripheral vascular disease. Method: A total of 163 consecutive patients fulfilling the new 2013 EULAR/ACR classification criteria for SSc participated. Mean nailfold capillary density, presence of enlarged capillary loops and avascular regions were assessed by widefield NFC. Disease characteristics, autoantibodies, IAEs, digital ulcers, duration and severity of Raynaud’s phenomenon (RP), and echocardiographic/Doppler estimated systolic pulmonary arterial pressure (ePAP) were recorded after interview and file review. Results: The mean age of the patients was 61 13 years, and 83% were female. The mean capillary density was 13.5 4.5 loops/3 mm, and enlarged capillary loops or avascular regions were found in 52% and 55%, respectively. A history of IAEs and digital ulcers was present in 13% and 39%, respectively. ePAP >34 mm occurred in 17%. A low capillary density was associated with a higher ePAP, anticentromere antibodies (ACA), digital ulcers, and IAEs, and enlarged capillary loops with shorter disease duration and the presence of ACA. The occurrence of avascular regions prevailed in patients with a longer disease and RP duration, ACA, digital ulcers, and limited cutaneous SSc (p < 0.05 for all comparisons). Conclusions: We demonstrate, for the first time, that ischaemic macrovascular disease in patients with SSc is associated with structural impairment of the nailfold microvasculature. Moreover, we confirm previous reports that a loss of nailfold capillaries is associated with digital ulcers and a higher ePAP.



92 1

PP261 Effect of single-nucleotide polymorphisms on type I interferon production by plasmacytoid dendritic cells stimulated with SLE-associated immune complexes 1

1

1

2

O Berggren , A Alexsson , K Tandre , A-C Syvänen , L Rönnblom1, M-L Eloranta1


1 Department Medical Sciences and Science for Life Laboratory and 2Department of Molecular Medicine and Science for Life Laboratory, Uppsala University, Sweden

Background: Systemic lupus erythematosus (SLE) and many other systemic autoimmune diseases have a persistently activated type I interferon (IFN) system, displayed as elevated serum levels of IFN-α and increased expression of type I IFN inducible genes (an IFN signature). Recent studies have shown an association between the susceptibility to SLE and several gene variants within the type I IFN system, and we have shown that IFN-α production by the plasmacytoid dendritic cell (pDC) was enhanced by cross-talk with natural killer (NK) cells and B cells. In this study we investigated whether single nucleotide polymorphisms (SNPs) associated with SLE and other autoimmune diseases have an impact on the IFN-α production by pDCs from healthy individuals. Method: pDCs, B and NK cells were isolated from peripheral blood obtained from healthy individuals. pDCs, alone or in co-culture with NK or B cells, were stimulated with RNA-containing immune complexes (ICs), herpes simplex virus (HSV), or the oligonucleotide ODN2216. IFN-α production was measured in the cell cultures after 20 h by an immunoassay. All blood donors were genotyped with a 200K ImmunoChip and a 5-bp CGGGG length polymorphism in the IFN regulatory factor 5 gene (IRF5) by PCR. Results: In total, 506 SNPs representing 240 loci were associated with IFN-α production (p < 0.001) for the different cell combinations. However, only three of these associated SNPs were shared between the cell type combinations or IFN inducers. Several of the SNPs have not been reported to be associated with type I IFN production, whereas some loci have been described earlier for their genetic association with SLE. Furthermore, we found that the SLE risk variant of the 5-bp IRF5 CGGGGindel was associated with lower IFN-α production. Conclusions: We found a large number of genetic variants affecting the IC-mediated type I IFN production that highlight the intricate regulation of the type I IFN system and could be important for understanding the dysregulated type I IFN system in SLE and other autoimmune diseases.

Department of Rheumatology, Sundsvalls Hospital, Karolinska Institutet, Sundsvall, 2Department of Diagnostic Radiology, Karolinska Hospital, Stockholm, and 3Department of Medicine, Rheumatology Unit, Karolinska Institutet, Stockholm, Sweden

Background: Pulmonary fibrosis is a major cause of severe morbidity and mortality in systemic sclerosis (SSc). With high-resolution computer tomography (HRCT), fibrotic lesions have been reported in up to 80% of patients, but only a minority of these will develop severe respiratory dysfunction. Patients with fibrosis on HRCT are often categorized into one group when risk factors and SSc disease characteristics are described. The aim of this study was to evaluate the extent of pulmonary fibrosis detectable on HRCT. Method: From a database consisting of 137 SSc patients from Stockholm County, we investigated all patients categorized as having pulmonary fibrosis (signs of pulmonary fibrosis on one or more HRCT scans). A rheumatologist (ER) and a radiologist (SN) examined the first HRCT scan performed in these patients. Three slices, located just above the diaphragm, at the carina junction and located intermediate between these two locations, on each side were examined for signs of pulmonary fibrosis. Results: The scoring system is shown in Table 1. Each score represents a fixed percentage. Scores were summed and divided by six (number of examined slices) to obtain an average fibrosis score (AFS). Fifty-six patients (41%) were categorized as having pulmonary fibrosis. Of these, seven patients had no signs of pulmonary fibrosis on the first HRCT, 34 patients had 15% AFS. The autoantibody profile differed between patients with vs. patients without fibrosis. Patients with pulmonary fibrosis had anti-topoisomerase 1 antibodies (ATA) (p < 0.001) and anti-Sjögren syndrome antigen A (SSA) antibodies (p ¼ 0.05) more frequently, but were less often anticentromere antibody (ACA) positive (p < 0.001). ATA were more common in patients with >15% AFS vs. patients with 15% AFS was ACA positive. There were no differences regarding age, gender, smoking habits, diffuse/limited skin involvement, or reflux between patients with or without fibrosis or between patients with >15% vs. 30 sphingolipids demonstrated a specific group of these lipids at significantly higher concentrations in SLE compared to controls. Following treatment, these differences were normalized.

Background: Renal involvement is one of the most severe complications in systemic lupus erythematosus (SLE) and is present in approximately 30–50% of patients. Moreover, 15–20% of SLE patients develop the anti-phospholipid syndrome (APS), characterized by the occurrence of anti-phospholipid antibodies in combination with thrombotic manifestations, including acute and chronic findings of APS nephropathy (APSN). Currently there are no specific guidelines for treatment of APSN, but antihypertensive and anticoagulative treatment is usually given. Our aim was to examine the occurrence of vascular pathology consistent with APSN in renal biopsies from SLE patients, and to investigate the renal findings in association with pathological findings in the renal tissue, autoantibody specificities, clinical manifestations, genetics, and long-term renal outcome. Method: Consecutive renal biopsies from 112 patients with SLE and renal involvement were investigated and evaluated for findings of APSN. In total, 236 renal biopsies were available from study start in 1995. Data from biopsy reports, serum creatinine (mmol/L), and clinical information concerning hypertension were collected. Autoantibodies against cardiolipin (aCL) and β2glycoprotein-1 (β2GP1) were measured by enzymelinked immunosorbent assay (ELISA) according to clinical routines used at the laboratory at the time of biopsy. A lupus anticoagulant (LA) test was determined with the modified dilute Russell viper venom method. Long-term renal outcome was determined at study end. HLA genotyping was performed by polymerase chain reaction with sequence-specific primers. Results: We detected vascular pathology in accordance with APSN in 14.3% of the patients and in 7.6% of the total number of biopsies. There was a positive association between APSN and aCL antibodies and triple aPL positivity and a clear trend towards a positive association with anti-β2GP1 antibodies and LA positivity. Patients with APSN were more likely to be hypertensive and they had higher levels of creatinine as well as more severe histopathological findings on renal biopsies. Furthermore, we found APSN to be associated with the development of



96

end-stage renal disease. A genetic predisposition to APSN associated with the HLA-DRB1*13 allele was also observed. Conclusions: APSN is a severe, but not uncommon, presentation among SLE patients with renal disease, and thus is important to identify at an early stage, which requires a renal biopsy. Considering the increased risk for development of impaired renal function, randomized trials are needed to explore which treatment regiments are optimal to preserve renal function in this subgroup of SLE patients.


Adolescent rheumatology PP269 Bone mineral density and predictors thereof in a population-based cohort of individuals with juvenile chronic arthritis 17 years after disease onset L Bertilsson1, BA H Forsblad-d’Elia1

Gäre2,

A

Fasth3,

IF

Petersson4,

1 Department of Rheumatology and Inflammation Research, Sahlgrenska Academy, University of Gothenburg, 2Jönköping Academy for Improvement of Health and Welfare, School of Health Sciences, Jönköping University, 3Department of Paediatrics, Sahlgrenska Academy, University of Gothenburg, and 4Department of Orthopaedics, Clinical Sciences, Lund University, Sweden

Background: Juvenile chronic arthritis (JCA) is characterized by arthritis and onset before 16 years of age. JCA it of unknown aetiology but has an annual incidence between 7/ 100 000 and 23/100 000 in the Nordic countries. Several studies have indicated lower bone mineral density (BMD) in individuals with JCA. The aim was to investigate BMD in a population-based cohort of JCA and to identify possible predictors 17 years after disease onset. Method: BMD was measured with the calcaneal dualenergy X-ray absorptiometry and laser technique in 85 individuals with JCA, aged 23.3 4.6 years, 17 years after disease onset. The cohort was followed from disease onset with clinical, laboratory, and functional assessments. Z-scores for height and weight were calculated from a reference population. Results: The BMD Z-score was (mean SD) 0.55 0.95 (0.41 0.86 in women and 0.89 1.08 in men), which for both sexes were significantly lower than in the reference population (p¼ 0.001 and p < 0.001, respectively). Height and weight were lower in the men compared to the reference group (p ¼ 0.006 and p ¼ 0.011, respectively). In multiple linear regression, low BMD was for women determined by low weight and the use of hormonal contraceptives (R2 ¼ 0.32) and for men continuously active disease during the first 3 years of disease (R2 ¼ 0.49). In multiple logistic regression, a BMD Z-score < 1 SD was associated with the use of hormonal contraceptives in women (OR 4.9, 95% CI 1.4–


17.2) and the juvenile arthritis disease activity score 10 (JADAS-10) >1 at the 17-year follow-up in men (OR 16.7, 95% CI 2.3–122.2). Conclusions: BMD was reduced in this JCA cohort 17 years after disease onset. Low BMD was associated with low weight and hormonal contraceptives in women, and continuous disease activity in the first 3 years of disease and JADAS-10 at the 17-year follow-up in men. References 1. Haugen M, Lien G, Flato B, Kvammen J, Vinje O, Sorskaar D, et al. Young adults with juvenile arthritis in remission attain normal peak bone mass at the lumbar spine and forearm. Arthritis Rheum 2000;43:1504–10. 2. Lien G, Flato B, Haugen M, Vinje O, Sorskaar D, Dale K, et al. Frequency of osteopenia in adolescents with early-onset juvenile idiopathic arthritis: a long-term outcome study of one hundred five patients. Arthritis Rheum 2003;48:2214–23. 3. Thornton J, Pye SR, O’Neill TW, Rawlings D, Francis RM, Symmons DP, et al. Bone health in adult men and women with a history of juvenile idiopathic arthritis. J Rheumatol 2011;38:1689–93. 4. Zak M, Hassager C, Lovell DJ, Nielsen S, Henderson CJ, Pedersen FK. Assessment of bone mineral density in adults with a history of juvenile chronic arthritis: a cross-sectional long-term followup study. Arthritis Rheum 1999;42:790–8. 5. French AR, Mason T, Nelson AM, Crowson CS, O’Fallon WM, Khosla S, et al. Osteopenia in adults with a history of juvenile rheumatoid arthritis. A population based study. J Rheumatol 2002;29:1065–70.

PP270 Socioeconomic consequences of juvenile chronic arthritis: a population-based study 22 years after disease onset L Bertilsson1, BA Gäre2, A Fasth3, IF Petersson4, H Forsbladd’Elia1 1 Department of Rheumatology and Inflammation Research, Sahlgrenska Academy, University of Gothenburg, 2Jönköping Academy for Improvement of Health and Welfare, School of Health Sciences, Jönköping University, 3Department of Paediatrics, Sahlgrenska Academy, University of Gothenburg, and 4Department of Orthopaedics, Clinical Sciences, Lund University, Sweden

Background: Juvenile chronic arthritis (JCA) and the most recent designation juvenile idiopathic arthritis (JIA) are broad terms that describe a clinically heterogeneous group of arthritides that begin before 16 years of age. Knowledge of socioeconomic consequences of the disease is limited and there are few studies that concern the long-term socioeconomic consequences for adults with juvenile arthritis. The aim of this study was to investigate the long-term socioeconomic consequences of JCA in a population-based cohort of individuals with JCA, 28 to 35 years of age, compared to the general population, and to identify possible predictors of socioeconomic outcomes based on the earlier disease course.



Method: The patients were recruited from a prospective population-based epidemiological study of JCA in southwestern Sweden. The cohort had two follow-ups with clinical, laboratory, and functional assessments carried out on average 7 and 22 years after disease onset. At the second follow-up the participants also answered a questionnaire concerning education, income, disability benefits, marital/civil status, and children. They were then compared to the general population in the region. Results: Ninety-five participants (71% of the original cohort) were examined in the second follow-up. The men in the JCA cohort had borderline lower education compared to the general population (p ¼ 0.051); there was no difference for the women (p ¼ 0.491). Among the

97

women 5.3% had full disability pension and 9.6% partial compared to 2.2% and 0.8% for the general population, respectively (p < 0.001); there was no difference for the men (p ¼ 0.51). Concerning income, marital/civil status, and reproduction, no difference could be identified, either for men or women, in comparison with the general population. There were no associations between earlier disease-related variables and socioeconomic outcome in the second follow-up. Conclusions: We found that women more frequently had disability pension and that men tended to have lower education than the general population. We did not find any early predictors for long-term socioeconomic consequences of JCA.


98

Author Index


Author Index Åsenlöf P, 79 Aart A, 24 Achour A, 58 Adebajo A, 12 Adebajo A, 68 af Klint E, 13 af Klint E, 15 af Klint E, 16 af Klint E, 57 AKnight, 50 Akyol Y, 66 Al-Khalili L, 9 Alayli G, 33 Alayli G, 66 Albrecht I, 53 Albrecht I, 57 Albrecht I, 93 Aleknavicius E, 93 Alenius G-M, 76 Alexanderson H, 5 Alexanderson H, 38 Alexsson A, 92 Alfredsson L, 4 Alfredsson L, 10 Alfredsson L, 11 Alfredsson L, 15 Alfredsson L, 18 Alfredsson L, 24 Alfredsson L, 33 Alfredsson L, 35 Alm G, 88 Altawil R, 4 Altawil R, 33 Altawil R, 35 Amara K, 55 Anca C, 57 Andersen AR, 27 Andersen GN, 25 Andersen M, 25 Andersone D, 65 Andersone D, 71 Andersson A, 17 Andersson A, 28 Andersson A, 53 Andersson A, 54 Andersson M, 94 Andersson S, 58 Andreasen RA, 29 Andreasen RA, 37 Andreasen RA, 46 Antovic A, 89 Arajs J, 65 Arkema E, 39 Arkema E, 83 Arstikyte I, 44 Askling J, 2 Askling J, 4 Askling J, 8 Askling J, 10 Askling J, 16 Askling J, 32 Askling J, 39 Askling J, 62 Askling J, 63 Askling J, 83 Askmann E, 78 Aubry-Rozier B, 72 Aubry-Rozier B, 73 Axelsson M, 90 Bøhme W, 27 Bøyesen P, 27 Back J, 29 Backlin C, 83


Baecklund E, 29 Baecklund E, 83 Bang JC, 66 Beattie S, 59 Bech-Hanssen O, 12 Bengtsson C, 11 Bengtsson C, 15 Bengtsson C, 18 Bengtsson C, 24 Bengtsson K, 42 Bergfeldt L, 12 Berggren O, 88 Berggren O, 92 Berglund A, 32 Berglund V, 29 Bergström G, 77 Bergström U, 22 Bergström U, 23 Bergström U, 25 Bergström U, 43 Bernardi A, 28 Bernardi A, 54 Bernatsky SR, 61 Bertilsson L, 96 Bertilsson L, 96 Besada E, 49 Besada E, 49 Bijlsma J, 14 Bilgici A, 33 Bilgici A, 66 Birbara C, 67 Birbara C, 68 Björklund Å, 38 Björnådal L, 91 Björnådal L, 92 Blanco F, 67 Bliddal H, 14 Bokarewa M, 76 Bolce R, 19 Bolce R, 20 Bolce R, 59 Botusan IR, 21 Botusan IR, 56 Brauner S, 86 Bremander A, 69 Bremander A, 69 Brink M, 21 Brock F, 30 Bruchfeld A, 50 Brun JG, 87 Buckner JH, 58 Bulina I, 65 Bulina I, 71 Butrimiene I, 44 Carlsten H, 17 Carlsten H, 28 Carlsten H, 54 Catrina A, 55 Catrina A, 56 Catrina A, 57 Catrina AI, 21 Catrina AI, 22 Catrina AI, 3 Catrina AI, 4 Catrina AI, 53 Catrina AI, 56 Catrina S-B, 56 Catrina SB, 21 Cerqueira C, 55 Chemin K, 53 Chemin K, 57 Chemin K, 93 Chernoff D, 19

Chernoff D, 59 Christensen T, 27 Clarke AE, 61 Cordtz R, 7 Crowley J, 67 Cruickshank S, 19 Cruickshank S, 59 Cutolo M, 68 Czirják L, 40 Dadoniene· J, 85 Dadoniene J, 93 Dahlqvist SR, 8 Dahlqvist SR, 21 Dahlqvist SR, 43 Dastmalchi M, 93 De Anda K, 90 Dees C, 40 Defranoux N, 22 Dehlin M, 42 Demmelmaier I, 77 Demmelmaier I, 79 Demmelmaier I, 80 Dencker D, 27 Distler A, 40 Distler J, 85 Distler J, 93 Distler JHW, 41 Distler O, 40 Do L, 72 Drivelegka P, 69 Drivelegka P, 69 Dudek A, 14 Dufour A, 77 Duhn PH, 82 Dzerovych N, 73 Edwards C, 67 Edwards C, 68 Eglit T, 24 Eklund A, 3 Ekstrom-Smedby K, 83 Eloranta M-L, 87 Eloranta M-L, 88 Eloranta M-L, 92 Eneljung T, 58 Engdahl C, 53 Englund M, 9 Englund M, 48 Engström M, 3 Engström M, 21 Engström M, 57 Eriksson J, 2 Eriksson J, 60 Eriksson J, 62 Eriksson J, 63 Eriksson P, 87 Erlandsson M, 53 Erlandsson M, 76 Ernestam S, 19 Ernestam S, 20 Ernestam S, 59 Eshed I, 74 Esmose EL, 7 Espesen J, 27 Espinosa F, 90 Fasth A, 9 Fasth A, 96 Fasth A, 96 Fathi M, 93 Fiene B, 46 Fiene B, 94 Fiene M, 46 Fiene M, 94 Forsblad-dÉlia H, 42

Forsblad-d’Elia H, 12 Forsblad-d’Elia H, 64 Forsblad-d’Elia H, 87 Forsblad-d’Elia H, 96 Forsblad-d’Elia H, 96 Forslind K, 19 Forslind K, 20 Forslind K, 59 Forslind K, 75 Fortin P, 61 Franck-Larsson K, 30 Fridén C, 77 Frisell T, 4 Frisell T, 10 Frisell T, 16 Frisell T, 32 Frisell T, 39 Frostegård J, 39 Gäre BA, 96 Gäre BA, 96 Gülfe A, 36 Geborek P, 9 Geborek P, 19 Geborek P, 20 Geborek P, 59 Geborek P, 60 Geborek P, 70 Genovese M, 59 Gerhardsson J, 95 Gerstner C, 58 Gildberg-Mortensen R, 37 Gildberg-Mortensen R, 46 Gildberg-Mortensen RA, 47 Gildberg-Mortensen RA, 52 Gjertsson I, 58 Gladman D, 68 Glintborg B, 27 Gomez D, 90 Gomez-Reino J, 12 Gomez-Reino J, 68 Gonzalez-Echavarri C, 5 Gottlieb AB, 64 Grøn KL, 45 Grøn KL, 6 Grahnemo L, 28 Grahnemo L, 53 Grahnemo L, 54 Graudal N, 27 Grunewald J, 3 Grunewald J, 93 Grygorieva N, 36 Gunnarsson I, 7 Gunnarsson I, 10 Gunnarsson I, 50 Gunnarsson I, 86 Gunnarsson I, 90 Gunnarsson I, 95 Gunnarsson I, 95 Gustafsson J, 7 Gustafsson J, 86 Gustafsson K, 58 Györi N, 13 Györi N, 15 Györi N, 16 Haake R, 14 Hagberg N, 88 Hagel S, 25 Hambardzumyan K, 19 Hambardzumyan K, 20 Hambardzumyan K, 59 Hanly JG, 61 Hans D, 72 Hans D, 73


Author Index Hansen A, 27 Hansen IMJ, 29 Hansen IMJ, 37 Hansen IMJ, 43 Hansen IMJ, 46 Hansen IMJ, 47 Hansen IMJ, 52 Hansen IMJ, 66 Hansen IMJ, 73 Hansen IMJ, 84 Hansson M, 55 Harris H, 41 Hauge EM, 75 Hedqvist D, 71 Hellgren K, 16 Hellman U, 71 Helmig RB, 85 Henriksen J, 84 Henriksson EW, 88 Hensvold A, 57 Hensvold AH, 4 Hensvold AH, 21 Hensvold AH, 22 Herlitz-Lindberg M, 7 Herrath J, 53 Herrath J, 57 Herrath J, 93 Hess S, 47 Hess S, 52 Hetland M, 6 Hetland M, 27 Hetland M, 45 Hezer N, 33 Hilme E, 42 Hohenthal U, 51 Hollan I, 41 Holmdahl R, 17 Holmdahl R, 21 Hopia L, 94 Hossain M, 9 Houtman M, 54 Hu CC, 12 Hu CC, 67 Hu CC, 68 Husmark T, 26 Hwang CC, 20 Idborg H, 95 Ioan-Facsinay A, 76 Isaksson J, 76 Islander U, 17 Islander U, 28 Islander U, 53 Islander U, 54 Israelsson L, 22 Israelsson L, 55 Jönsson G, 9 Jacobsen S, 61 Jacobsen S, 81 Jacobsson L, 8 Jacobsson L, 14 Jacobsson L, 22 Jacobsson L, 23 Jacobsson L, 51 Jacobsson L, 62 Jacobsson L, 64 Jacobsson L, 69 Jacobsson L, 69 Jacobsson LTH, 25 Jakobsen IM, 85 Jakobsson K, 51 Jakobsson P-J, 3 Jakobsson P-J, 55 Jakobsson P-J, 95 James E, 57 James E, 58 James E, 93 Jansson M, 30

99 Jensen DV, 27 Jensen T, 27 Jensen-Urstad K, 7 Jensen-Urstad K, 91 Jiang X, 10 Jirholt P, 58 Johansson K, 2 Johnsen SJ, 87 Jonsson MV, 87 Jonsson R, 87 Joshua V, 3 Joshua V, 21 Joshua V, 22 Joshua V, 55 Joshua V, 55 Just SA, 37 Just SA, 46 Källberg H, 10 Källberg H, 11 Kadike S, 71 Kallikorm R, 24 Kamen D, 61 Kapetanovic MC, 70 Kapetanovic MC, 9 Kapleryte· G, 93 Karasevska T, 72 Karasevska T, 73 Karlsson A, 13 Karlsson A, 16 Karlsson JA, 60 Karlsson JA, 70 Karlsson M-L, 78 Karlsson MN, 54 Karnebeck V, 46 Kautiainen H, 1 Kautiainen H, 1 Kavanaugh A, 12 Kavanaugh A, 68 Keller C, 79 Kemppainen J, 51 Ketenci S, 66 Keystone E, 59 Kiani R, 37 Kihlberg J, 58 Kisten Y, 13 Kisten Y, 15 Kisten Y, 16 Kisten Y, 34 Klareskog L, 3 Klareskog L, 4 Klareskog L, 10 Klareskog L, 11 Klareskog L, 15 Klareskog L, 21 Klareskog L, 24 Klareskog L, 33 Klareskog L, 35 Klareskog L, 57 Klingberg E, 12 Klingberg E, 80 Klovins J, 65 Knight A, 25 Knight A, 53 Koistinen IS, 95 Koldingsnes W, 49 Kollerup G, 27 Komendantova N, 39 Konar J, 80 Korotkova M, 56 Korpela M, 1 Korsholm T, 89 Krishnamurthy A, 55 Krishnamurthy A, 56 Krishnamurthy A, 57 Kristensen B, 82 Kristensen L-E, 60 Kristensen L-E, 62

Kristensen L-E, 70 Krochak S, 36 Kull M, 24 Kumánovics G, 40 Kuru O, 33 Kuru O, 66 Kuusalo L, 1 Kvarnström M, 87 Kvist G, 42 Lagerquist MK, 53 Lambrechtsen J, 73 Lampa J, 4 Lampa J, 33 Lampa J, 35 Langley RG, 64 Larkin M, 22 Larsson A, 25 Larsson A, 53 Larsson A, 7 Larsson E, 30 Larsson E, 32 Lavrentjevs V, 65 Lavrentjevs V, 71 Lehtiö J, 95 Lehto N, 29 Leirisalo-Repo M, 1 Leirisalo-Repo M, 1 Leirisalo-Repo M, 30 Lejnieks A, 65 Lejnieks A, 71 Lember M, 24 Leonard D, 88 Lespessailles E, 68 Levitsky A, 34 Li W, 22 Linberg BH, 34 Lind S, 34 Lindblad S, 64 Lindegaard H, 27 Linder A, 36 Lindhé A, 42 Lindqvist E, 25 Ljung L, 8 Locht H, 82 Lomborg N, 37 Lomborg N, 46 Lourdudoss C, 18 Lourdudoss C, 39 Lundberg I, 5 Lundberg I, 38 Lundberg I, 41 Lundberg I, 77 Lundberg I, 78 Lundberg I, 85 Lundberg I, 88 Lundberg I, 93 Lundberg IE, 9 Lundberg IE, 40 Lundberg K, 55 Lundmark J, 59 Lysholm J, 25 Lysholm J, 26 Lysholm J, 53 Mårtensson L, 58 Møller JM, 74 Möller S, 7 Müller R, 24 Macias W, 59 Mackevic Z, 40 Madsen O, 27 Madsen OR, 7 Madsen OR, 74 Magnusson PK, 4 Majgaard O, 27 Makrygiannakis D, 57 Malmström V, 3 Malmström V, 9

Malmström V, 21 Malmstrom V, 53 Malmström V, 55 Malmström V, 55 Malmström V, 57 Malmström V, 58 Malmström V, 93 Manivel V, 53 Maribo T, 75 Martikainen J, 1 Martin RLM, 64 Matteson E, 51 Mease P, 12 Mease P, 68 Medina RD, 76 Mengshoel AM, 34 Merkel PA, 48 Mild M, 61 Miller H, 2 Miller H, 60 Mincheva-Nilsson L, 25 Mohammad A, 51 Mohammad AJ, 48 Morillon M, 43 Morillon MB, 73 Mpofu S, 64 Nagaev I, 25 Nagaeva O, 25 Nagel J , 9 Neovius M, 2 Neovius M, 60 Neovius M, 62 Neovius M, 63 Neregård P, 57 Nessen T, 80 Nielsen BD, 89 Nielsen LK, 47 Nikitina-Zake L, 65 Nikitina-Zake L, 71 Nilsson J-Å, 9 Nilsson J-Å, 23 Nilsson J-Å, 25 Nilsson J-Å, 51 Nilsson J-Å, 60 Nilsson P, 95 Nordgren B, 77 Nordgren B, 80 Nordin A, 91 Nordin A, 92 Nordmark G, 37 Nordmark G, 83 Nordmark G, 87 Nordström P, 34 Nossent JC, 49 Nossent JC, 49 Nurkkala-Karlsson M, 28 Nurkkala-Karlsson M, 53 Nyrén S, 92 Ørnbjerg L, 6 Ørnbjerg L, 45 Ørnbjerg LM, 27 Øster-Jørgensen E, 47 Øster-Jørgensen E, 52 Østergaard M, 14 Østergaard M, 27 Østergaard M, 30 Østergaard M, 74 Öhman M-L, 43 OHammarsten, 80 Oke V, 10 Oke V, 86 Oleröd G, 80 Olesen MK, 25 Olofsson T, 2 Olofsson T, 60 Olsen KE, 84 Olsson T, 39



100 Omdal R, 87 Opava C, 77 Opava CH, 79 Opava CH, 80 Orellana C, 11 Orellana C, 15 Osmanagic A, 66 Ossipova E, 55 Ottosson L, 81 Põlluste K, 24 Padyukov L, 54 Padyukov L, 57 Padyukov L, 95 Palumbo-Zerr K, 40 Pandya J, 9 Papachrysos N, 69 Papachrysos N, 69 Papavassilis C, 64 Parodis I, 10 Parodis I, 90 Pedersen SJ, 74 Pelck R, 27 Peschken C, 61 Peterson I, 2 Petersson I, 19 Petersson I, 20 Petersson I, 59 Petersson I, 70 Petersson IF, 9 Petersson IF, 70 Petersson IF, 96 Petersson IF, 96 Petri MA, 61 Petterson I, 69 Pettersson S, 7 Pettersson S, 78 Petzold M, 80 Philipp S, 64 Piehl F, 94 Pieper J, 58 Pikwer A, 11 Pikwer M, 11 Pikwer M, 23 Pikwer M, 25 Pirilä L, 51 Poggenborg RPP, 74 Poulsen UE, 27 Povoroznyuk R, 72 Povoroznyuk R, 73 Povoroznyuk V, 36 Povoroznyuk V, 72 Povoroznyuk V, 73 Pruijn GJM, 55 Puolakka K, 1 Puolakka K, 1 Quresh F, 22 Rönnblom L, 57 Rönnblom L, 88 Rönnblom L, 92 Rönnelid J, 21 Rönnelid J, 22 Rönnelid J, 25 Rönnelid J, 3 Rönnelid J, 53 Rönnelid J, 55 Raaschou P, 32 Ramoskiene R, 66 Ramoskiene R, 84 Ramsey-Goldman R, 61 Rantalaiho V, 1 Rantalaiho V, 1 Regardt M, 88


Author Index Rell-Bakalarska M, 14 Revenäs Å, 79 Revu S, 56 Revu S, 57 Reynisdottir G, 3 Rezaei H, 13 Rezaei H, 15 Rezaei H, 16 Rieck M, 58 Rikard H, 58 Ringsdal V, 27 Roivainen A, 51 Rollman O, 29 Roubi E, 91 Roubi E, 92 Rugiene· R, 85 Rugiene R, 93 Ruiz-Irastorza G, 61 Rydberg B, 42 Sørensen IJ, 74 Södergren A, 76 Saevarsdottir S, 4 Saevarsdottir S, 11 Saevarsdottir S, 15 Saevarsdottir S, 19 Saevarsdottir S, 20 Saevarsdottir S, 22 Saevarsdottir S, 24 Saevarsdottir S, 33 Saevarsdottir S, 35 Saevarsdottir S, 59 Saevarsdottir S, 64 Saleh M, 48 Salmon J, 83 Salomäki S, 51 Sandalova T, 58 Sandberg M, 4 Sandberg M, 24 Sandberg M, 33 Sandberg ME, 35 Sandin C, 58 Sandqvist J, 88 Santacatterina M, 64 Saraste A, 51 Sarbantovica A, 65 Sasso E, 19 Sasso E, 20 Sasso E, 60 Saxne T, 9 Saxne T, 25 Schaufelberger C, 14 Schett G, 40 Schett G, 55 Schett G, 68 Schierbeck H, 81 Schlemmer A, 27 Schlichting D, 59 Schobers L, 55 Schult M-L, 88 Schulze-Koops H, 40 Seddighzadeh M, 31 Segurado O, 20 Sejer-Hansen M, 14 Seneca T, 75 Shah K, 12 Shah K, 68 Shchetynsky K, 54 Sigurdardottir V, 26 Sigurgeirsson B, 64 Sikora E, 65 Silfverswärd ST, 76

Silvola J, 51 Simard JF, 83 Sjöwall C, 81 Sjöwall C, 87 Skogh T, 81 Skold M, 3 Skovsted T, 82 Sohrabian A, 22 Sokka T, 6 Sokka T, 45 Stache V, 9 Staelens F, 14 Stawiarz L, 64 Stengaard-Pedersen K, 85 Stern A, 58 Stevens R, 12 Stevens R, 67 Stevens R, 68 Stubelius A, 17 Stubelius A, 28 Stubelius A, 53 Sun M, 21 Sundbaum JK, 29 Sundberg E, 81 Sundelin B, 95 Sundman-Engberg B, 14 Sundström B, 71 Sundström C, 83 Sunkari VG, 56 Svärd A, 26 Svanberg A, 37 Sveälv BG, 12 Svensson B, 75 Svenungsson E, 7 Svenungsson E, 10 Svenungsson E, 86 Svenungsson E, 89 Svenungsson E, 90 Svenungsson E, 91 Svenungsson E, 92 Svenungsson E, 94 Svenungsson E, 95 Svenungsson E, 95 Syvänen A-C, 92 Täng MS, 12 Taimen K, 51 Taliju¯niene· I, 85 Tandre K, 88 Tandre K, 92 Tarasova N, 55 Tarp U, 27 Taylor P, 59 Tengvall S, 58 Theander E, 83 Theander E, 87 Thormann A, 27 Toes REM, 21 Tollefsrud I, 78 Tomson T, 94 Torp-Pedersen S, 15 Torstenson T, 42 Troelsen LN, 81 Troldborg A, 89 Trouw LA, 21 Truedsson L, 22 Truedsson L, 9 Trygg J, 95 Turesson C, 11 Turesson C , 22 Turesson C, 23 Turesson C, 25

Turesson C, 48 Turesson C, 51 Turesson C, 64 Uchtenhagen H, 58 Uhlig T, 30 Ulus Y, 33 Ulus Y, 66 van Bui Hansen MN, 29 van Vollenhoven R, 2 van Vollenhoven R, 13 van Vollenhoven R, 16 van Vollenhoven R, 18 van Vollenhoven R, 19 van Vollenhoven R, 20 van Vollenhoven R, 30 van Vollenhoven R, 34 van Vollenhoven R, 39 van Vollenhoven R, 59 van Vollenhoven R, 61 van Vollenhoven RF, 15 Vasaitis L, 37 Vasaitis L, 83 Vasaitis L, 87 Venalis A, 44 Venalis A, 85 Venalis A, 93 Venalis P, 9 Venalis P, 40 Venalis P, 86 Venalis P, 93 Verheul MK, 21 Vikerfors A, 89 Vikman I, 29 Vivar N, 34 Vivar N, 55 Wållberg-Jonsson S, 71 Wållberg-Jonsson S, 76 Wähämaa H, 21 Wähämaa H, 55 Wadstrom H, 63 Wahlström J, 93 Wahren-Herlenius M, 87 Wallace DJ, 61 Wallerstedt SM, 42 Warrington K, 51 Weihe JP, 73 Weihe P, 46 Weitoft T, 25 Weitoft T, 53 Wetterö J, 81 Wheelock C, 95 Wiberg K, 43 Wick C, 41 Wikberg J, 25 Wirestam L, 81 Wolk A, 18 Wollenhaupt J, 12 Wollenhaupt J, 68 Xiao H, 41 Ytterberg J, 3 Ytterberg J, 55 Zablockis R, 44 Zepa J, 65 Zepa J, 71 Zepa L, 65 Zerr P, 41 Zheng X, 56 Zickert A, 10 Zickert A, 86 Zickert A, 95 Zong M, 41

Abstracts of the 11th European Congress on Epileptology, 29 June - 3 July, 2014, Stockholm, Sweden.

Abstracts for the Scandinavian Physiological Society's Annual Meeting, 22-24 August, 2014, Stockholm, Sweden.

Abstracts of the Eighteenth International Congress of Parkinson's Disease and Movement Disorders, June 8-12, 2014, Stockholm, Sweden.

Prostate cancer screening: highlights from the 29th European association of urology congress stockholm, sweden, april 11-15, 2014.

Abstracts from the 2014 ISDE World Congress, September 22-24, 2014, Vancouver, Canada.

Abstracts of the 28th EFI European Immunogenetics and Histocompatibility Conference, June 25th–28th, 2014, Stockholm, Sweden.

Abstracts of the AAGBI Annual Congress, 17-19 September 2014, Harrogate, UK.

[35th Congress of the European Society for Clinical Nutrition and Metabolism (ESPEN) 2013 - Congress report].

Hot line II: Stockholm, 5 September 2005.

Abstracts of the Lupus 2014: new targets, new approaches Congress, September 18-20, 2014, Quebec City, Canada.

Multimodality imaging: bird's eye view from The European Society of Cardiology Congress 2014 Barcelona, August 30-September 3, 2014.

Report on the 9th EONS Congress, Istanbul, Turkey, 18-19 September 2014: nursing highlights.

Abstracts of the XV World Congress on Cancers of the Skin, 3-6 September 2014. Edinburgh, Scotland.

Abstracts of the 22nd Congress of the European Sleep Research Society, 16-20 September, 2014, Tallinn, Estonia.

Proceedings of the 21st European Pediatric Rheumatology (PReS) Congress.

Evolution of Minimum Mortality Temperature in Stockholm, Sweden, 1901-2009.

Abstracts of the XVIII International Congress of Neuropathology, Rio de Janeiro, Brazil, September 14 to 18, 2014.

Ageing and heart failure: what's new?: Stockholm, 5 September 2005.

Acute myocardial infarction: update 2005: Stockholm, 4 September 2005.

Abstracts of the 16th Asia Pacific League of Associations for Rheumatology Congress, 31 March-4 April 2014, Cebu City, Philippines.

[Abstracts of the 24th German Skin Cancer Congress and ADO Annual Meeting, 11-13 September, 2014, Frankfurt, Germany].

Editor's perspectives--September 2014.

Women at heart: Stockholm, 4-7 September 2005.

thrombosis: Stockholm, 6 September 2005.