Continuing Progress in Vasculitis Research. Abstracts of the 17th International Vasculitis & ANCA WorkshopLondon, April 19-22, 2015: Abstracts.

Abstracts Nephron 2015;129(suppl 2):45–249 DOI: 10.1159/000381121

Published online: April 15, 2015

O1

O2

Genome-Wide Association Study Identifies Novel Genetic Susceptibility Loci in Takayasu’s Arteritis

CECR1 p.Gly47Arg Mutations Are Not

Increased in Frequency in Turkish Behçet’s Disease Patients Compared with Healthy Controls

Paul Renauer1, Güher Saruhan-Direskeneli2, Patrick Coit1, Adam Adler3, Deborah Cunninghame-Graham4, Timothy Vyse4, Jonathan Wren3, Peter Merkel (on behalf of VCRC)5, Haner Direskeneli (on behalf of TTSG)6, Amr Sawalha1

Burak Erer1, Elaine F. Remmers2, Masaki Takeuchi2, Duran Ustek3, Ilknur Tugal Tutkun1, Emire Seyahi1, Yilmaz Ozyazgan4, Ahmet Gül1, Michael J. Ombrello5, Daniel L. Kastner2

1

1

Objective: Takayasu’s arteritis is a rare large vessel vasculitis with incompletely understood etiology. We performed the first genome-wide association study (GWAS) in Takayasu’s arteritis. Methods: Two independent Takayasu’s arteritis cohorts from Turkey and North America were included in our study. The Turkish cohort consisted of 559 patients and 489 controls, and the North American cohort consisted of 134 European-derived patients and 1,047 controls. Genotyping was performed using the Omni1-Quad and Omni2.5 genotyping arrays. Genotyping data were subjected to rigorous quality control measures and subsequently analyzed to discover genetic susceptibility loci for Takayasu’s arteritis. Results: We identified genetic susceptibility loci for Takayasu’s arteritis with a genome-wide level of significance in IL6 (rs2069837, OR = 2.07, P = 6.70×10–9), RPS9/LILRB3 (rs11666543, OR = 1.65, P = 2.34×10–8), and an intergenic locus on chromosome 21q22 (rs2836878, OR = 1.79, P = 3.62×10–10). The genetic susceptibility locus in RPS9/LILRB3 is located within the leukocyte receptor complex (LRC) gene cluster on chromosome 19q13.4, and the disease risk variant in this locus correlates with reduced expression of multiple genes including the inhibitory leukocyte immunoglobulin-like receptor gene LILRB3 (P = 2.29×10– 8). In addition, we identified candidate susceptibility genes with suggestive levels of association (P 0.05; MPO: p > 0.05), seen

O4

DNA Methylation Differences at Gene Regulatory Elements are Associated with Disease Susceptibility in a Rat Model of Crescentic Glomerulonephritis Thomas Oates1, Richard Hull1, Michael Mueller2, Charles Pusey2, H. Terence Cook2, Enrico Petretto1 1

MRC Clinical Sciences Centre, London, UK, 2Imperial College London, London, UK

Objectives: Epigenetic mechanisms, including DNA cytosine methylation and histone modifications, cause stable changes in gene expression independently of the underlying DNA sequence. These mechanisms facilitate phenotypic diversity in distinct cell types. Recent evidence has demonstrated the importance of epigenetic modifications in immune cell phenotypes and autoimmune diseases such as vasculitis. The Wistar-Kyoto (WKY) rat is susceptible to crescentic glomerulonephritis (CRGN), whilst the Lewis (LEW) rat is resistant. Previous work has implicated macrophages in CRGN and defined some of the genetic determinants underlying CRGN susceptibility. In this study, we investigated DNA methylation in WKY and LEW rat macrophages in order to

MPOmRNA

R

A

A

R

Fig. 1. (for Abstract O3).

46

Nephron 2015;129(suppl 2):45–249 DOI: 10.1159/000381121

Abstracts

A

A

R

R

A

R Downloaded by: NYU Medical Center Library 128.122.253.212 - 4/28/2015 11:51:34 AM

Number of positive cell in 104 cells

Number of positive cell in 104 cells

PR3mRNA

find cytosine bases that are differentially methylated between the two rat strains and hence may participate in disease pathogenesis. Methods: Using macrophages from WKY and LEW animals, we assessed DNA methylation by whole-genome bisulfite sequencing (WGBS), and gene expression by Affymetrix microarrays and then investigated the relationship between cytosine methylation and gene expression. Bioinformatic analysis of WGBS, histone and transcription factor binding site data was used to explore the interaction of methylation and gene regulatory sequences. Results: Our combined 1.6 billion sequencing reads allowed us to assay methylation of 14.5 million cytosine bases in the rat genome. We were able to identify 13,553 differentially methylated cytosine (dmCpGs) bases between WKY and LEW (Fisher’s exact test; false discovery rate 50 erythrocytes/hpf), proteinuria (1.8 g/d), ESR 44 (ref < 21), CRP 18 (ref < 1) and MPO-antibodies. A renal biopsy showed pauciimmune glomerulonephritis with 50% crescents. A diagnosis of MPA was made. CYC iv pulses and prednisone (PRED) were given. Mycophenolate mofetil (MMF) was used as maintenance after 3 months due to Azathioprine intolerance. At 8 month follow-up CRP was 2 RU of in vitro PR3-ANCA (figure 1) or an ANCA titre ≥ 1:80 showed lower disease-free survival. A lower percentage of CD27+ memory B-cells (14.25% vs 7.72%) and CD24hiCD27+ regulatory B-cells (6.58% vs 3.36%), was observed in patients prior to relapse. However, no differences in disease-free survival were seen with percentages. When analysing the absolute numbers of B-cell subsets patients with lower numbers of CD27+ memory B-cells or CD24hiCD27+ B-cells were shown to be more prone to relapse. Conclusions: This study shows promising factors to assist in the prediction of relapse in GPA patients, most notably in vitro ANCA production and the number of CD27+ memory B-cells. Finding a better predictive factor for relapse in GPA would allow for timely intervention and possibly prevention of relapse. Further follow-up of this patient cohort is ongoing and expected to strengthen these data.

Abstracts

Downloaded by: NYU Medical Center Library 128.122.253.212 - 4/28/2015 11:51:34 AM

P18

100

Disease free survival

sured by Euroimmun direct ELISA and MCPR3–2 capture ELISA, with rise defined as a doubling in value within six months, with absolute increase ≥40 U or ≥0.40 O.D., respectively, if previously negative. Starting from the date of complete remission in 93 patients with positive PR3-ANCA at baseline, levels were analyzed using proportional hazards regression. Results: A rise in PR3-ANCA was identified in 58/93 subjects (62.4%) by direct ELISA, and 59/93 (63.4%) by capture ELISA. Disease relapse occurred in 55/93 (59.1%) subjects, with 33/55 (60.0%) occurring after a rise in PR3-ANCA by direct ELISA and 29/55 (52.7%) after a rise by capture ELISA. A rise by direct ELISA was predictive of any relapse (p = 0.006, HR 2.19) and severe relapses (p < 0.001, HR 3.92); a rise by capture ELISA was not predictive (p = 0.41, p = 0.108, respectively). In patients with baseline renal involvement, severe relapses were predicted by direct (p = 0.004, HR 6.62) but not capture ELISA (p = 0.115). Relapses involving renal manifestations were predicted by a rise using both direct ELISA (p = 0.005, HR 7.21) and capture ELISA (p = 0.006, HR 5.18). Similarly, for relapses involving capillaritis, a rise by direct ELISA (p = 0.001, HR 7.00) or capture ELISA (p = 0.002, HR 4.32) was predictive. Both assays predicted severe relapse in the rituximab group (direct: p = 0.012, HR 4.81; capture: p = 0.035, HR 3.13); neither was predictive in the cyclophosphamide group (p = 0.090, p = 0.981, respectively). Conclusions: Among patients with severe AAV who achieve complete remission, a rise in PR3-ANCA measured by direct ELISA or capture ELISA is a significant predictor of disease relapse, particularly with renal manifestations or capillaritis. These findings suggest that serial measurement of PR3-ANCA may be a valuable adjunct to clinical data during remission in this subset of AAV patients, with consideration given to the ELISA assay, disease phenotype, and treatment regimen in each case.

P19

P20

Impact of Cardiac Magnetic Resonance Imaging on Eosinophilic Granulomatosis with Polyangiitis Outcomes: A Long-Term Retrospective Study of 42 Patients

Remaining Anti-Neutrophil Cytoplasm Antibody Positive at Switch to Maintenance Therapy Is Associated with an Increased Risk of Relapse: Observation from the Long Term Follow Up of the CYCLOPS and IMPROVE Trials

Bertrand Dunogué1, Benjamin Terrier1, Pascal Cohen1, Julien Marmurzstejn2, Denis Duboc2, Olivier Vignaux3, Loïc Guillevin1 1

Hôpital Cochin, Department of Internal Medicine, Paris, France, 2Hôpital Cochin, Department of Cardiology, Paris, France, 3Hôpital Cochin, Department of Radiology, Paris, France

Matthew Morgan1, Matthew Szeto1, Jennifer Marsh1, Michael Walsh2, David Jayne3, Kerstin Westman4, Niels Rasmussen5, Thomas Hiemstra3, Oliver Flossmann6, Annelies Berden7, Peter Höglund8, Daina Selga9, Lorraine Harper1 1

Continuing Progress in Vasculitis Research

Introduction: Relapse of disease is frequent in anti-neutrophil cytoplasm antibody (ANCA) associated vasculitis (AAV). It is unclear whether changing from induction to maintenance therapy while patients have circulating ANCA increases the risk of relapse. We examined the association between ANCA status at the time maintenance therapy was started in two randomised controlled trials. Methods: ANCA positive patients in two trials, CYCLOPS and IMPROVE were switched from cyclophosphamide to either azathioprine or mycophenolate mofetil (MMF) after 3 to 6 months on the basis of having achieved clinical remission. We classified patients as being either ANCA positive or ANCA negative at the time they started maintenance therapy. We compared ANCA positive to ANCA negative patients in terms of time to first relapse. Results: 252 patients were included. 102 (40%) experienced at least one relapse during the follow up period. At time of switch from induction to maintenance therapy, 111 were ANCA positive, of whom 55 (50%) relapsed, compared to 141 patients who were ANCA negative of whom 47 (33%) relapsed. In multivariable time-to-event analysis a reduced risk of relapse was associated with having become ANCA negative at the time of switching to maintenance therapy (Hazard ratio 0.63 (95% confidence interval 0.42–0.95); p = 0.026). In addition initial PR3-ANCA, younger age, lower serum creatinine, pulsed cyclophosphamide for remission induction and mycophenolate mofetil for remission maintenance were all associated with an increased risk of relapse. Conclusion: Remaining ANCA positive at switch to maintenance is associated with an increased risk of relapse.


115


Objectives: To determine the diagnostic and prognostic significance of myocardial late gadolinium enhancement (LGE) lesions detected by cardiac magnetic resonance imaging (CMRI) in patients with Eosinophilic granulomatosis with polyangiitis (EGPA) presenting with or without signs of cardiomyopathy. Method: A retrospective analysis concerning a monocentric cohort of 42 EGPA patients having undergone systematic CMRI screening, regardless of signs of cardiomyopathy. Results: Characteristics of the 42 patients were: 25/42 male (59.5%); mean age at diagnosis of 46.5 years; 11/42 (26.2%) ANCA-positive; median duration of EGPA before first CMRI screening of 0.42 years. Seventeen patients (40.5%), 15 (88.2%) of whom were ANCA-negative, were diagnosed with cardiomyopathy, independently of CMRI findings. CMRI revealed myocardial LGE in 14/17 (82.4%) patients with cardiomyopathy vs. 11/25 (44%) without cardiomyopathy (p = 0.024). Using myocardial LGE as the sole diagnostic criterion, CMRI sensitivity and specificity for diagnosing cardiomyopathy were estimated at 82.4% (95% CI: 0.59–0.93) and 56% (95% CI: 0.37–0.73) respectively. Among patients without cardiomyopathy, no differences were found between those with or without CMRI anomalies concerning subsequent EGPA cardiac manifestations and outcomes. Among patients with cardiomyopathy who underwent additional CMRI during follow-up (median follow-up: 4.6 years), 7/15 patients’ CMRI-detected cardiac lesions had regressed under maintenance therapy, while those of 8/15 patients worsened or stabilized despite treatment. A significantly higher number of subsequent cardiac events occurred in patients whose CMRI did not improve during follow-up (5/8 (62.5%) vs. 0/7 (0%), p = 0.026). Conclusion: CMRI is a sensitive method for detecting potential cardiomyopathic lesions in EGPA but lacks specificity, and thus should not be used alone for diagnosing EGPA cardiomyopathy. In patients with no other signs of cardiomyopathy, CMRIdetected anomalies do not seem to adversely affect prognosis or outcome. For patients with cardiomyopathy, CMRI reassessment, when showing improvement of LGE lesions, seems promising in determining patients with a more favourable cardiac outcome.

University of Birmingham, Birmingham, UK, 2McMaster University, Hamilton, Canada, 3University of Cambridge, Cambridge, UK, 4Lund University, Lund, Sweden, 5Statens Seruminstitut, Copenhagen, Denmark, 6Royal Berkshire Hospital, Reading, UK, 7Leiden University Medical Center, Leiden, The Netherlands, 8Skane University Hospital, Lund, Sweden, 9Skane University Hospital, Göteborg, Sweden

Rona Smith1, Federico Alberici1,2, Kenneth Smith1,2, David Jayne1 1

Department of renal medicine, University of Cambridge, UK, 2Cambridge Institute for Medical Research, University of Cambridge, UK

% CD27– IgD+ naïve cells

Objectives: Rituximab is a remission induction agent in ANCA associated vasculitis (AAV), but little is known about potential predictors of response in this patient population. Data from patients with rheumatoid arthritis suggests incomplete B cell depletion is a predictor of poor response to rituximab1. This, together with extended B and T lymphocyte phenotyping is a potential method of identifying response and relapse biomarkers to guide rituximab treatment in AAV. Methods: Thirty patients with AAV were recruited at the time of relapse and treated with rituximab. Blood samples were obtained and surface phenotyping was performed on extracted peripheral blood mononuclear cells (PBMC) at the time of relapse and again 4 months later. Detailed parallel clinical data was also collected. Results: Median age was 66 years (range 20–84), and 23/30 (77%) had a diagnosis of granulomatosis with polyangiitis (GPA). Median prior disease duration was 150 months (5–750) and cumulative cyclophosphamide exposure was 6.8 g (0–150). Although markedly lower than at baseline, all patients had detectable B cells at 4 months (median CD19 count at 4 months was 0.0012 x 109/L (range 0.000371–0.003652 x 109/L)). There was no association between absolute B cell number at four months and response (p = 0.7057). However, poor responders to rituximab (non-responders and early relapsers (patients who relapsed within 6 months of last dose of rituximab) (n = 6)), had a lower proportion of naive B cells (CD27–IgD+) (p = 0.0320) and a tendency for a greater proportion of memory B cells (CD27 + IgD -) (p = 0.0568) at baseline (figure 1).

a

100 80 60 40 20 0

Good

Poor Response

References 1 2

Dass S, Rawstron AC, Vital EM, et al: High sensitive B cell analysis predicts response to rituximab in rheumatoid arthritis. Arthritis Rheum. 2008;58:2993–2999. Venhoff N, Niessen L, Kreuzaler M, et al: Reconstitution of the peripheral B lymphocyte compartment in patients with ANCA associated vasculitides treated with rituximab for relapsing or refractory disease. Autoimmunity 2014;47:401–408.

P22

The Association Between ANCA Antibodies and Thyroid Disease Is Independent of ANCA-Associated Vasculitis Fiona Pearce1, Richard A Watts2, Peter Lanyon1 1Nottingham 2Norwich

University Hospitals Trust, Nottingham, UK, Medical School, University of East Anglia, Suffolk,

UK

Objectives: Anti-thyroid drugs (e.g. propylthiouracil and carbimazole) have been causally implicated in the development of AAV in case reports and case series. Thyroid disease has also been associated with AAV in the absence of drug exposure, with one

b

80 60 40 20 0

Good

Poor Response

Fig. 1. Association of B cell subsets and response to rituximab A Proportion of naïve CD19 B cells at baseline in good and poor responders to rituximab therapy (p = 0.0320; unpaired T test). B Proportion of memory CD19 B cells at baseline in good and poor responders to rituximab therapy (p = 0.0568). Poor responders include nonresponders and those who relapsed within 6 months of rituximab therapy (n = 6) (for Abstract P21).

116


Abstracts


B Cell Subsets Associated with Poor Response to Rituximab in ANCA Associated Vasculitis

Conclusions: Repopulation with predominantly memory B cells following rituximab in AAV2 is predictive of relapse, but this has not been considered as a pre-emptive predictor of response prior to rituximab induction. In this cohort of relapsing AAV patients, there was an association with a lower proportion of naïve B cells, and a tendency for a higher proportion of memory B cells at baseline in poor responders. Such an observation is biologically plausible as memory B cells appear to be more resistant to depletion following rituximab therapy than naïve B cells, and the memory subset is also likely to contain the expanded autoantigen-specific clones that drive relapse. Validation of such an approach is required, but the ability to pre-emptively identify individuals that are likely to respond poorly to rituximab is desirable for personalised treatment.

% CD27+ IgD– memory B cells

P21

Table 1. (for Abstract P23)

Antigens

GCA

GPA

KIDS

PAN

GW182 ELASTASE GE-1 EEA1 LAMP2 GRASP1

138 (67–197) 67 (44–112) 76 (36–120) 126 (91–143) 317 (126–571) 101 (65–117)

152 (58–186) 80 (56–98) 72 (44–115) 102 (68–189) 129 (85–247) 119 (89–146)

299 (104–553) 191 (135–239) 80 (50–109) 48 (42–70) 74 (51–92) 76 (43–134) 85 (77–105) 102 (95–163) 130 (87–176) 1217 (198–1729) 112 (94–135) 141 (131–169)

TAK

p value

275 (368–219) 86 (73–129) 98 (64–154) 163 (62–193) 143 (76–396) 127 (92–295)

0.0146 0.1245 0.4780 0.1765 0.0078 0.1052

Performance of new markers among different types of vasculitis (median, IQR).


P23

LAMP-2 A Biomarker for Active Polyarteritis Nodosa? Cristina Moran Toro, Aurore Fifi-Mah, Roolan Tabassum, Marvin Fritzler University of Calgary, Calgary, Alberta, Canada

Background and objectives: Polyarteritis nodosa (PAN) is a systemic necrotizing vasculopathy typically affecting medium-sized arteries with occasional involvement of small muscular arteries. Unlike other vasculitides (e.g. Microscopic polyarteritis, granulomatosis with polyangiitis (GPA) and eosinophilic granulomatosis with polyangiitis (EGPA), PAN is not associated with anti-neutrophil cytoplasmic antibodies (ANCA) and outside an elevated ESR, does not have a specific biomarker identified for its diagnosis. We report serological profiles of 5 patients presenting with biopsy proven PAN. Methods: Five cases of biopsy-proven PAN, meeting the American College of Rheumatology (ACR) criteria for PAN, were diagnosed between Jan 2010 and April 2012 in the Rheumatology clinic database at the University of Calgary, Canada. Laboratory tests, therapeutic regimens and clinical correlations were studied retrospectively. Serum analysis included ANCA as detected by chemiluminescence (Bio Flash, INOVA Diagnostics, San Diego, CA) and atypical ANCAs including anti-LAMP-2 (lysosome associated membrane protein), were detected by addressable laser bead immunoassay. We used non-parametric analysis (Kruskal Wallis) to compare medians and IQR (Inter Quartile Range) between groups. Results: 3/5 (60%) of the PAN had a high titer anti-LAMP2. By comparison, the frequency of anti-LAMP-2 in 14 giant cell arteritis sera was 0.0%, in 23 granulomatosis with polyangiitis was 0.0%, and in 11 Takayasu arteritis, 18% of patients. Of the 3 PAN patients with high titer anti-LAMP2, the titres correlated with disease activity. Out of these 3 patients, 2 patients LAMP-2 titres decreased after initiation of immunosuppressive therapy. The two patients with low LAMP-2 titres had inactive disease or a milder form of the disease. The median anti-LAMP2 titer in the PAN group was 1217 (198–1729) which was higher than the other vasculitides (129–317), p = 0.0078.


117


study reporting thyroid disease in 20% of 158 AAV cases, compared to 7% of controls. As part of an institutional AAV audit we assessed whether ANCA positivity alone, in the absence of AAV, is associated with thyroid disease. Methods: All positive MPO or PR3 ANCA (Orgentec Diagnostika ELISA) at a single UK centre between March 2006 and June 2013 were identified. Documented presence or absence of thyroid disease was established from clinic letters (PMH and/or Medication history) and the centre’s electronic alert system for thyroid disease. The final diagnosis following ANCA testing was recorded. Analysis used Fisher’s exact test for 2×2 tables. Results: Amongst 685 patients with a positive MPO or PR3 ANCA, the overall prevalence of thyroid disease was 14.2%, compared to UK population estimates of 2–3%. No patients were taking propylthiouracil or carbimazole at the time of testing. Thyroid disease was significantly more prevalent in those with MPO antibodies (22.2%) compared to PR3 antibodies (9.6%), p = 0.0017. Amongst MPO positive patients, the prevalence of thyroid disease was significantly higher in those without AAV (30.2%) compared to those with AAV (12.0%), p = 0.0229. Amongst PR3 positive patients there was no significant difference in the prevalence of thyroid disease according to whether there was a diagnosis of AAV or not (p = 0.4037), although the overall prevalence in this group (9.6%) was still higher than the background population. Conclusion: ANCA antibodies (particularly MPO), rather than ANCA vasculitis alone, are associated with thyroid disease. There are two potential explanations. ANCA production and AAV might cluster within the spectrum of autoimmune conditions associated with thyroid disease. If so, this association appears stronger than in the diseases more usually associated e.g. RA and SLE, where the prevalence of thyroid disease is estimated at 9.8% and 6.1% respectively. Alternatively, ANCA could be a risk factor for the development of thyroid disease. This association is also clinically important, as it provides an alternative explanation for MPO/ PR3 ANCA in people without clinical evidence of vasculitis, particularly as some of the symptoms of thyroid disease (e.g. fever, weight loss) can mimic those of vasculitis.

P24

Association of Inflammatrory Bowel Disease with Anti-PR3 and MPO Antibodies Natalia Rodriguez1,2, Pablo Lopez1,2, Natalia Garcia1,2, Celia Buzzi1,2, Mauricio Carbia1,2, Raquel Balleste1,2 1Hospital

De Clinicas „Dr. Manuel Quintela’, Montevideo, Uruguay, 2Sociedad Uruguaya De Patologia Clinica (Supac), Montevideo, Uruguay

Objectives: Determine the PR3 and MPO ANCA frequency in IBD patients with IIF ANCA positive sera. Method: Study population: Serum samples ANCA positive arrived from patients derived of gastroenterologist or with IBD clinical data, from March 2002 to December 2008. The patients were classified according to the clinical data in four groups: a) UC, b) CD, c) IBDu d) Other intestinal disorders (OID). The ANCA test was an ‘in-house’ Indirect Immunofluorescence method assessed in the Laboratory-Immunology Unit from ‘Dr.Manuel Quintela’ Hospital. All ANCA positive samples were next analyzed seeking PR3 and MPO ANCA using an ELISA kit (Quanta lite, INOVA Diagnostics). We revised the anti MPO and PR3 ANCA positive patient medical records to gather clinical and histological information. Results: 174 serum samples were included, corresponding to 56 patients. The patient distribution was: UC 22, CD 5, IBDu 2, OID 15, 12 no clinical data. The female/male ratio was 1.8:1. The mean age was 44.6 years. 21 patients had P-ANCA, 24 X-ANCA and 11 C-ANCA patterns. 9 from 56 (16.1%) patients were antiPR3 ANCA (4/9 with P-ANCA, 4/9 C-ANCA and 1/9 X-ANCA patterns) while nobody was anti-MPO ANCA. From the 9 patients, 6 (66.7%) had UC, 2 (22.2%) IBDu and 1 (11.1%) OID. All of them had normal renal function and urine examination, and absent reno-pulmonar syndrome presentation). 1 IBDu patient had a ‘pancolitis’ histological data. Conclusions: We found more P and X than C-ANCA pattern in IBD patients. Our 16.1% PR3 ANCA frequency in adults IBD patients is higher than other reports but similar to Van Biervliet et al. report in a children cohort. 8/9 patients had PR3-ANCA ‘strong positive’ results. The medical record data of the PR3 ANCA positive patients reduce the probability of an AAV diagnosis. The IBD+PR3 ANCA association was found mainly in UC patients according with international reports. PR3 ANCA could be used to distinguish UC from other IBD patients.

118


P25

Unique Technology for the Simultaneous Screening and Confirmation of Autoantibodies in Emergency Situations of Rapidly Progressive Glomerulonephritis Mandy Sowa1, Barbara Trezzi2, Valentina Somma1, Rico Hiemann3, Dirk Roggenbuck1,3, Antonella Radice4 1

Research and Development Department, GA Generic Assays GmbH, Dahlewitz/Berlin, Germany, 2Department of Nephrology and Immunology, San Carlo Borromeo Hospital, Milan, Italy, 3Faculty of Science, Brandenburg Technical University Cottbus-Senftenberg, Senftenberg, Germany, 4Microbiology Institute, Autoimmunity Unit, San Carlo Borromeo Hospital, Milan, Italy

Background: Rapidly progressive glomerulonephritis (RPGN) is clinically characterized by a rapid loss of renal function. RPGN is mainly caused by anti-glomerular basement membrane (GBM) antibody-mediated, immune-complex or anti-neutrophil cytoplasmic antibody (ANCA)-associated diseases. Detection of the specifically associated autoantibodies (anti-GBM, anti-dsDNA, ANCA) allows early diagnosis and appropriate treatment starting, in order to avoid progression to end stage renal disease. Objectives: The novel CytoBead® technology combines autoantibody analysis by cell-based screening with corresponding confirmation by multiplex microbead technology using indirect immunofluorescence (IIF) in one reaction environment. The CytoBead® RPGN assay employs as autoantigenic substrates for autoantibody detection GBM as well as dsDNA, coated on microbeads, for the diagnosis of Goodpastures’syndrome/antiGBM disease (GPS) and systemic lupus erythematodes (SLE) nephritis, respectively. Additionally, ethanol fixed granulocytes as well as proteinase 3 (PR3) and myeloperoxidase (MPO) coated microbeads are provided as targets by the assay for the simultaneous determination of vasculitis specific autoantibodies (i.e. ANCA), detectable in RPGN patients. Method: This IIF assay can be analyzed with a standard fluorescence microscope for semi-quantitative and with the Aklides® system for quantitative interpretation with lot specific standard curves. The specially designed microscopic glass slide consists of triple parted reaction compartments with ethanol fixed granulocytes in the middle compartment, PR3 and MPO coated microbeads in the right compartment and GBM and dsDNA coated microbeads in the left one. Results: Results of 293 tested human sera (40 Granulomatosis with Polyangiitis [GPA], 38 Microscopic Polyangiitis [MPA], 10 ANCA associated vasculitis [AAV], 2 Eosinophilic granulomatosis with polyangiitis [EGPA], 48 SLE, 43 GPS, 55 negative human sera [NHS], 57 infectious diseases [INF]) were generated by automated read-out processed tests with Aklides® system in 60 seconds per sample and showed good agreement with manually obtained cell and microbead based data. The automated read-out provides quantitative results in international units (IU/ml) for antibodies to PR3, MPO and in units (U/ml) for dsDNA and GBM. Diagnostic sensitivity and specificity were carried out by receiver operating characteristic (ROC) and revealed 85.4% and 97.6% for PR3 microbeads, 73.5% and 95.5% for MPO micro-

Abstracts


Conclusion: Our studies, suggests that anti-LAMP-2 is a promising novel biomarker for PAN, a condition that otherwise had no previously documented biomarkers. Molecular biomarkers have changed our understanding of ANCA associated vasculitis and other disease entities. The role of anti-LAMP-2 in the pathogenesis and clinical phenotype of vasculitis needs further investigation, particularly given the evidence that autoantibodies to LAMP-2 may represent a distinct marker of PAN with high disease activity. This report is leading the way for further testing of antiLAMP-2 in a larger multi-center cohort of patient with PAN.

beads, 88.4% and 96.8% for GBM microbeads and 83.3% and 94.7% for dsDNA microbeads, respectively. Conclusions: The CytoBead® technology provides a unique combination of screening and confirmatory RPGN-specific autoantibody testing. CytoBead® RPGN assay is a very promising alternative to classical time-consuming single parameter testing and, therefore, can be used for emergency situations.

P27

Approach to Laboratory Diagnostics of Anti-Neutrophil Cytoplasmic Antibodies (ANCA) Associated Vasculitis (AAV) in Italian Clinical Laboratories Antonella Radice, Barbara Trezzi San Carlo Borromeo Hospital, Milan, Italy

P26

Classical and Alternative Pathway in ANCA-Associated Vasculitis Marcin Okroj1,2, Lisa Holm3, Sandra Lilliebladh3, Sophie Ohlsson3, Anna M Blom1, Thomas Hellmark3 1

Department of Laboratory Medicine, Malmö, Sweden, Region Skåne, Laboratory Medicine, Malmö, Sweden, 3 Department of Clinical Sciences, Lund, Sweden 2

Objectives: The alternative pathway of the complement sys-

tem has in experimental and clinical observations been suggested to play a role in the pathogenesis of ANCA associated vasculitis (AAV), but the role of the classical pathway has not been as evident. Our aim with this study was to investigate if there is a difference in levels of C3bBbP (alternative pathway convertase), sTCC (soluble terminal complement complexes composed of C5b-9) and C4d (resulting from the classical/lectin complement pathway activation) between AAV patients and healthy controls (HCs). We also wanted to see if there is any difference between patients with active disease and patients in remission. Method: 77 plasma samples from 30 patients with Granulomatosis with polyangiitis or Microscopic polyangiitis and 13 plasma samples from healthy controls were collected. C4d, C3bBbP and sTCC-levels were measured using ELISA-based methods. Results: Levels of TCC and C4d in plasma were significantly higher in patients compared to HCs (p ≤ 0.001), but here was no difference between patients in remission and active disease. C3bBbP levels were significantly higher in patients with active disease compared to patients in remission and HCs (p = 0.0042). Conclusion: Our results indicate that the classical pathway is activated in patients during both remission and active disease while the alternative pathway is involved only in active disease. This gives insight into the role of the various pathways of complement in AAV.

Background: ANCA detection is fundamental to the diagnosis of AAV. In the latest years the demand for autoantibodytesting has increased and highly performing new assays/technologies, as well as testing-strategies, have been developed. Aim: this survey was part of a project encouraged by the ‘European Autoimmunity Standardisation Initiative’ (E.A.S.I., www. easi-network.com), with the financial support of Phadia-Thermofisher Italia, aimed to photograph and compare the daily practice in the European countries, in order to favour discussion about the possible changes in the current guidelines. Method:

• a questionnaire with 59 multiple choice questions was sent to 500 laboratory managers and/or leaders for the area of autoimmunity Table 1. (for Abstract P27) a

Samples/week processed by each lab 50

5.8% 33.4% 26.7% 20.9% 8.1%

b

ANCA-testing strategies (new patients)

%

Screening by IFT + PR3/MPO confirmation of the +ve samples

41.4

Screening by IFT + PR3 or MPO confirmation of the +ve samples, according with the pattern

8.6

IFT + PR3 and MPO-ANCA on all samples

25.9

PR3 + MPO-ANCA (no IFT)

13.8

PR3 + MPO-ANCA + IFT confirmation of the +ve

1.7

Others

8.6


ANCA-testing strategies (follow-up)

%

ANCA-IFT without titer ANCA-IFT with titer PR3-ANCA or MPO-ANCA qualitative PR3-ANCA or MPO-ANCA quantitative

50.0 20.0 ≈5 >80


119


c Some labs use combining IFT and Ag-specific assay

120


P28

PR3-ANCA in GPA Partially Inhibit and Sometimes Stimulate PR3 Activity, But Do Not Predict Relapse or Disease Progression Lisa Hinkofer1, Amber Hummel2, John Stone3, Gary Hoffman4, Peter Merkel5, Robert Spiera6, William St. Clair7, Joseph McCune8, John Davis9,10, Ulrich Specks2, Dieter Jenne1,11 1

Comprehensive Pneumology Center, Institute of Lung Biology and Disease (iLBD), Helmholtz Zentrum München, Munich, Germany, 2Thoracic Diseases Research Unit, Division of Pulmonary and Critical Care Medicine, Mayo Clinic and Foundation, Rochester, USA, 3Massachusetts General Hospital, Boston, USA, 4Center for Vasculitis Care and Research, Cleveland Clinic, Cleveland, USA, 5Vasculitis Center, Division of Rheumatology and the Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, USA, 6Hospital for Special Surgery, New York, USA, 7Duke University Medical Center, Division of Rheumatology and Immunology, Durham, USA, 8University of Michigan, Ann Arbor, USA, 9Genentech, One DNA Way, South San Francisco, USA, 10University of California San Francisco, San Francisco, USA, 11Max-Planck-Institute of Neurobiology, Planegg-Martinsried, Germany

Objectives: Anti-neutrophil cytoplasmic antibodies (ANCA), directed against proteinase 3 (PR3) are believed to be implicated in the pathogenesis of granulomatosis with polyangiitis (GPA). It was repeatedly suggested that disease activity of GPA is more closely related to the appearance of PR3-inhibiting ANCA, than to an increase of total ANCA in general. Previous studies on a limited number of patient samples, however, lead to inconclusive results. To give a final judgment on the issue of whether specific PR3-ANCA subsets and particularly those inhibiting PR3 activity are associated with relapses, specific organ involvement and overall disease activity, we developed a new ultrasensitive assay to quantify the inhibitory capacity of PR3-ANCA. Method: The challenges of quantifying the levels of inhibitory PR3-ANCA are on one hand the high abundance of natural α1PI in serum, which immediately inhibits PR3, on the other hand the very low amounts of total PR3-specific ANCA in the small volumes of routine clinical samples. Protein G coated dynabeads were found to be best suited to obtain a completely α1PI-free IgG solution. Recent progress in the development of highly sensitive extended peptide substrates for PR3 and of optimized fluorophorequencher pairs additionally permitted us to establish such a highly sensitive method. Results: A large collection of samples from the Wegener Granulomatosis Etanercept Trial (WGET) was screened with this new method for the occurrence of ANCA with inhibitory potential. In these patient samples we not only detected ANCA with inhibitory capacity, but also ANCA with enhancing effects on the activity of PR3. However, no correlation of the activity modulating ANCA with disease activity, severity or disease progression was discernable. Epitope mapping revealed a binding of the activity modulating ANCA to the active site surface of PR3. As these ANCA were still able to bind to PR3 with an occupied active site

Abstracts


• provided for ongoing re-direction of the questionnaires according to the organizational changes, and a final check to prevent multiple responses from the same center and improve the accuracy of the extracted data • aims and objectives introduced by e-mail, together with the link to immediately start compilation • the questionnaire could be suspended anytime, automatically saved and re-opened to fill-in the remaining questions. After completion recipients were re-addressed to www.gruppofirma. com • statistical evaluation by using the online software Survey Monkey (www.surveymonkey.com) Results: Most laboratories performing diagnostics of autoimmune diseases belong to public certified structures and are of large dimension (60% >1.000.000 test/yr), confirming the consolidation process implemented in recent years and still ongoing. Weekly ANCA requests are shown in table 1a. • ANCA detected by IFT in 83.5%, always using commercial substrates (38°C, fatigue

Cardiovascular

Carotidynia, extremity hypoperfusion/ threatened limb, chest pain new hypertension, new vascular insufficiency

Laboratory

ESR, CRP, Hemoglobin

Renal

Rise in blood pressure

Vascular items

New bruits, new loss of pulse, new diminished pulse, BP inequality, pulse inequality, claudication

Ocular

Temporary vision loss, blurred vision, retinal vasculitis, new permanent visual loss

Gastrointestinal

Abdominal pain (vasculitic)

Nervous system

Transient ischemic episodes, syncope, stroke, new/worsened headache, hemiparesis, paraparesis

Musculoskeletal

Arthralgia, myalgia

Imaging

CT-angiography, PET-CT, MR-angiography, ultrasound

Patient-reported outcomes

General health-related outcome measure, SF-36, patient pain assessment, patient global assessment, fatigue

Physician-based assessments

Physician global assessment, relapse, vasculitis damage index, increase in glucocorticoids, change in immunosuppressive, DEI-Tak



121


Table 1. Items accepted commonly for both giant cell arteritis and Takayasu’s arteritis (for Abstract P30)

122


P31

Damage Assessment in Takayasu’s Arteritis Antoine Sreih1, Tanaz Kermani2, David Cuthbertson3, Simon Carette4, Gary Hoffman5, Nader Khalidi6, Curry Koening7, Carol Langford5, Carol McAlear1, Paul Monach8, Larry Moreland9, Philip Seo10, Steven Ytterberg11, Kenneth Warrington11, Peter Merkel1 1

Penn Vasculitis Center, Division of Rheumatology, The University of Pennsylvania, Philadelphia, PA, USA, 2 Division of Rheumatology, University of California Los Angeles, Los Angeles, CA, USA, 3Department of Biostatistics, University of South Florida, Tampa, FL, USA, 4Division of Rheumatology, Mount Sinai Hospital, Torronto, ON, Canada, 5Center for Vasculitis Care and Research, Cleveland Clinic, Cleveland, OH, USA, 6 Division of Rheumatology, Saint Joseph’s Healthcare, McMaster University, Hamilton, ON, Canada, 7Division of Rheumatology, University of Utah, Salt Lake City, UT, USA, 8The vasculitis center, Section of Rheumatology and the Clinical Epidemiology Clinic, Boston University, Boston, MA, USA, 9Division of Rheumatology, University of Pittsburgh, Pittsburgh, PA, USA, 10Division of Rheumatology, Johns Hopkins University, Baltimore, MD, USA, 11Division of Rheumatology, Mayo Clinic College of Medicine, Rochester, MN, USA

Objectives: This study aimed to describe disease-related damage in Takayasu’s arteritis (TAK) and evaluate damage assessment tools using data from a large longitudinal cohort. Methods: Patients with TAK enrolled in a prospective, multicenter, longitudinal study were included. Subjects were assessed through a standardized protocol. Measures of disease damage included the Vasculitis Damage Index (VDI) and the Large-Vessel Vasculitis Index of Damage (LVVID); LVVID was developed specifically for large-vessel vasculitis and only records items present for at least 3 months. Patients with a diagnosis of TAK made ≤180 days prior to study entry were also compared to patients with a diagnosis of TAK made >180 days. Results: The study included 178 patients with TAK: 167 women (94%), 150 Caucasians (84%), mean age at diagnosis 33.7±13.2 years, median (25th, 75th quartiles) time from diagnosis to entry in the cohort 2.9 (0.6, 6.7) years. At entry into the cohort, the mean VDI score was 2.6±1.8 and the mean LVVID score was 3.2±2.6. At least 1 damage item was measured by VDI in 158 (88%) patients and by LVVID in 158 (88%) patients. Organ systems affected by damage are outlined in the table. 39/178 patients had a diagnosis of TAK made ≤180 days prior to study entry. 34/39 (87%) diagnosed ≤180 days prior to study entry had at least 1 item on VDI and a mean VDI = 2.2±1.4, compared to 123/139 (88%) with duration >180 days, (P = 0.8) and a mean VDI = 2.7±1.9, (P = 0.08). Similarly, 32/39 (82%) patients ≤180 days from diagnosis had at least 1 damage item on LVVID and a mean LVVID = 2.6±2.2 compared to 125/139 (90%) enrolled >180 days from diagnosis, (P = 0.81) and a mean LVVID = 3.4±2.8, (P = 0.06). Conclusions: Damage from vasculitis is present in the majority (>80%) of patients with TAK even within 6 months of diagnosis. The cardiac, vascular, and ‘other’ sections in the VDI and

Abstracts


to systemically arrive at consensus expert opinion and identify candidate outcomes for assessment of disease activity in LVV. Methods: The Delphi survey was sent to 317 experts in LVV from different specialties. The first round included 99 items on a 5-point scale aiming to cover potential disease manifestations. Items accepted or rejected by >70% of voters are not advanced to the subsequent second and third rounds. An additional 7 items suggested in the first round by the investigators were voted on in the last 2 rounds. Results: 107 experts from 23 countries completed the survey. Experts represented multiple relevant medical specialties, including rheumatology, internal medicine, cardiology, neurology, immunology, vascular surgery, nephrology, ophthalmology and radiology. Fifty-seven of the items in 12 categories were accepted for both giant-cell arteritis (GCA) and Takayasu’s arteritis (TAK). These commonly accepted items covered a wide range of manifestations including constitutional, vascular/cardiovascular, and neurological items (table). The main differences in items endorsed for use for TAK and GCA were for weight loss, scalp tenderness and necrosis, morning stiffness, vision loss, scotoma, diplopia and halo sign by ultrasound which were only accepted for GCA and dizziness and conventional angiogram that were only accepted for TAK. Respiratory findings were excluded for both diseases as well as some neurological and gastrointestinal assessments. 63% of experts voted to have a common approach for both TAK and GCA but to also develop additional disease-specific instruments for each disease; 25% felt the two diseases were unsuitable for common outcome measures. Conclusion: This exercise points out similarities and differences in experts’ perspectives for assessing clinical activity in TAK and GCA. The final analysis of the Delphi will produce a consensus-driven set of outcomes to test prospectively with the long-term goal of developing a core set of validated outcomes for LVV.

Table 1. Major organ systems damage in 178 patients with TAK as captured by the VDI and the LVVID (for Abstract P31)

VDI (by organ system)

Mean number of items (mean ± SD**)

N* (%)

LVVID (by organ system)

Mean number of items (mean ± SD**)

N (%)

Cardiac Peripheral Musculoskeletal Ocular ENT Gastrointestinal Neuropsychiatric Endocrine Hematology/Oncology Pulmonary Renal Other

0.5±0.7 1.7±1.3 0.1±0.3 0.4±0.2 0±0.1 0±0.2 0.1±0.3 0±0.2 0±0 0±0.2 0±0.1 0.1±0.2

70 (39%) 137 (77%) 14 (8%) 9 (5%) 2 (1%) 3 (2%) 13 (7%) 5 (3%) 0 (0%) 4 (2%) 1 (1%) 11 (6%)

Cardiac Peripheral Musculoskeletal Ocular ENT Gastrointestinal Neuropsychiatric Endocrine Hematology/Oncology Pulmonary Renal Other Weight gain Damage requiring surgical intervention

0.65±0.85 2.1±1.7 0.1±0.3 0.1±0.3 0±0.1 0±0.1 0.1±0.3 0±0.2 0±0.1

80 (45%) 147 (83%) 13 (7%) 8 (5%) 1 (1%) 1 (1%) 17 (10%) 6 (3%) 5 (3%) NA NA 58 (32%) 35 (20%)

0.4±0.7

25 (14%)

*N = number with at least 1 item captured in that category; **Mean (±SD) = score for the entire cohort of patients with Takayasu’s arteritis. NA = Not applicable due to no items in this organ system appear in LVVID.

P32

Early Halo Sign Features on Ultrasound Examination of Treated Patients with Giant Cell Arteritis Ana Serafim, Surjeet Singh, Jennifer Piper, Andrew Hutchings, Mike Bradburn, Cristina Ponte, Bhaskar Dasgupta, Wolfgang Schmidt, Eugene McNally, Andreas Diamantopoulos, Raashid Luqmani 1 University of Oxford, Oxford, UK, 2University of Oxford, Oxford, UK, 3University of Oxford, Oxford, UK, 4London School of Hygiene and Tropical Medicine, London, UK, 5 University of Sheffield, Sheffield, UK, 6University of Oxford, Oxford, UK, 7Department of Rheumatology, Southend University Hospital, Essex, UK, 8Department of Rheumatology, Berlin-Buch, Berlin, Germany, 9University of Oxford, Oxford, UK, 10Department of Rheumatology, Hospital of Southern Norway,, Kristiansand, Norway, 11 University of Oxford, Oxford, UK

Background: TheTABUL study (Temporal Artery Biopsy Vs Ultrasound in diagnosis of Giant Cell Arteritis) compared temporal artery ultrasound with biopsy for diagnosing GCA. All pa-


tients with newly suspected GCA underwent a single ultrasound scan of temporal and axillary arteries, followed by a biopsy of the symptomatic temporal artery within 7 days of starting steroids. To determine the potential role of ultrasound as a biomarker in GCA, we measured differences in the size of the halo around the arteries with different duration of steroid therapy; furthermore we correlated halo size with ischaemic symptoms of GCA. Methods: We included 415 cases with suspected GCA. We analysed data from 301/415 patients with clinically defined definite or probable GCA at baseline. Using the IBM SPSS Statistics package v20, we performed a cross-sectional analysis with linear and logistic regression models to determine the relationship between halo size and days of steroid treatment and also with ischaemic symptoms of GCA (jaw and tongue claudication, amaurosis fugax and reduced, lost or double vision). Results: We studied 214 women and 87 men (mean [sd] age 72.6±9.3 and 71.6±9.6 years respectively) from 20 different recruitment centres. Fifty percent were scanned on or before day 2 of steroid treatment. Forty three per cent (131 patients) had a halo in one or more temporal segments, 48.5% (146 patients) had bilateral temporal artery halos and 12.6% (38 patients) had axillary involvement. The linear regression model showed a consistently smaller halo size over the 7 days of steroid treatment (p < 0.005) for temporal arteries. The likelihood of finding a halo diminished with time, until day 4 of steroid treatment (p < 0.005. At least one ischaemic symptom was present in 42% of the patients: jaw claudication in 48.2% (146 patients), reduced or lost vision in 36.6% (111 patients), double vision in 8.6% (26 patients), and tongue claudication in 6.6% (20 patients) and amaurosis fugax in 4% (12 patients). Jaw claudication occurred more frequently in patients with a halo (p < 0.05). Temporal artery symptoms correlated with ipsilateral ultrasound findings (p < 0.05).


123


LVVID capture most of the damage in TAK. LVVID appears to document more details of damage than VDI. Revision of the VDI or adoption of the LVVID, along with data-driven approaches to item weighting, may improve damage assessment in TAK.

Conclusions: In newly diagnosed GCA, ultrasound halo size decreases rapidly with steroid treatment and correlates with the presence of ischaemic symptoms, supporting its early use as a diagnostic and potentially prognostic marker. In future we will be exploring the potential value of change in halo size in individual patients over time to determine its value in monitoring response to treatment.

P34

A Comparison of Color Doppler Ultrasonography and Magnetic Resonance Angiography in Patients with Systemic Large Vessel Vasculitis Andreas P Diamantopoulos1,2, Julia Geiger3, Frode Lohne4, Geirmund Myklebust1, Wolfgang A Schmidt5 1

P33

Serum Markers Associated with Disease Activity in Giant Cell Arteritis and Polymyalgia Rheumatica Niels van der Geest, Wayel Abdulahad, Bram Rutgers, Gerda Horst, Johan Bijzet, Suzanne Arends, Mirjam Roffel, Mieke Boots, Elisabeth Brouwer

Department of Rheumatology, Hospital of Southern Norway Trust Kristiansand, Kristiansand, Norway, 2 Department of Rheumatology, Haugesund Sanitetsforenings Rheumatism Hospital AS, Haugesund, Norway, 3Department of Radiology, University Children’s Hospital,, Zurich, Switzerland, 4Departement of Radiology, Hospital of Southern Norway Trust Kristiansand, Kristiansand, Norway, 5Medical Center for Rheumatology Berlin-Buch, Immanuel Krankenhaus,, Berlin, Germany

UMCG, Groningen, Tokelau

124



Left common temporal Left parietal temporal Left frontal temporal Right common temporal Right parietal temporal Right frontal temporal Left carotid Right carotid Left subclavian Right subclavian Left vertebral Right vertebral Left axillary Right axillary Thoracic aorta

CDUS vasculitis only

Vasculitis MRA vasculitis in both modalities only

5 6 3 0 4 0 9 7 10 6 1 2 11 14 2

0 0 3 0 0 4 0 1 1 0 0 0 0 0 0

Abstracts

2 2 3 5 4 4 0 0 3 2 0 0 1 1 0 Downloaded by: NYU Medical Center Library 128.122.253.212 - 4/28/2015 11:51:34 AM

Objectives: Besides careful examination of clinical signs and symptoms, the assessment of disease activity in GCA and PMR patients typically relies on measurement of the erythrocyte sedimentation rate (ESR) and serum levels of C-reactive protein (CRP). Both the ESR and CRP are included in the 2012 Provisional Classification Criteria for Polymyalgia Rheumatica. These markers, however do not discriminate between active GCA/PMR and infections. Also, CRP and ESR are not elevated in a minority of GCA and PMR patients. Thus, there is a need for better markers of disease in both these patient groups. In the present study we sought to identify serum immune markers that are modulated in patients with giant cell arteritis (GCA) and those with polymyalgia rheumatica (PMR). Methods: Twenty-six markers, which are related to immune cells that may be involved in GCA and PMR, were determined by ELISA and multiplex assay in serum of 24 newly-diagnosed, untreated GCA/PMR patients, 14 corticosteroid treated GCA/PMR patients in remission and 13 healthy controls. Receiver operating characteristic (ROC) analysis with area under the curve (AUC) and Spearman’s correlation coefficients were performed. Results: Serum BAFF, CXCL9 and IL-6 were increased in both newly-diagnosed GCA and PMR patients. Serum CCL2, CCL11, IL-10 and sIL-2R were modulated in GCA patients only, and CXCL10 in PMR patients only. BAFF, CXCL9 and IL-6 accurately distinguished newly-diagnosed GCA and PMR patients from healthy controls, as shown by AUCs >0.80. Upon corticosteroid-induced remission, serum BAFF and IL-6 decreased significantly in both GCA and PMR patients, whereas CXCL9 remained high. Serum BAFF and IL-6 correlated strongly with the ESR and CRP in GCA and PMR patients. Conclusions: This is the first study to compare serum levels of 26 immune markers in GCA and PMR patients to those in healthy controls. Three serum markers (i.e. BAFF, CXCL9 and IL-6) were increased in both newly-diagnosed GCA and PMR patients. Moreover, these markers discriminated well between patients and healthy controls. Serum BAFF and IL-6, but not CXCL9, were attenuated upon corticosteroid-induced remission and showed the strongest association with disease activity in both GCA and PMR patients. It remains to be established if these markers discriminate between active disease and infections.

Objectives: Color Doppler ultrasound (CDUS) and Magnetic resonance angiography (MRA) have been used in the diagnostics of large vessel vasculitis (LVV) i.e. giant cell arteritis (GCA) and Takayasu arteritis (TA). No studies exist which compare the diagnostic accuracy of CDUS and MRA of LVV in the supra-aortic large vessels. Thus, the aim of this study is to perform a comparison between the CDUS and MRA of temporal arteries and supra-aortic large vessels in LVV patients. Method: MUSES (Magnetic resonance angiography vs Ultrasonography in Systemic large vEssel vasculitis, Clinical Trials. gov NCT02042092) is a prospective cross-sectional study. Patients diagnosed with LVV by ultrasound, MRA or Computed Tomography Angiography were identified and included in MUSES at the Department of Rheumatology Kristiansand between January and August 2014. One ultrasonographer experienced in the use of

vascular ultrasound (APD) examined and recruited the LVV patients. MRA imaging was performed within 0 to 5 days after the ultrasound evaluation. The common temporal, parietal and frontal branches, carotid, subclavian, vertebral, axillary arteries, and thoracic aorta were evaluated. Films/images of every CDUS and MRA evaluations were recorded. The recorded data were surveyed by two experts, one on vascular ultrasound (WAS) and one on MR imaging (FL). Both experts were blinded to clinical and laboratory data and were unaware of distribution and size of the vasculitis lesions. The experts applied a dichotomous score (vasculitis: yes/no) in every evaluated vessel. The identification of vasculitis in any vessel represented an independent result. Results: Twenty patients were recruited [(9 males, 11 females, median age 65 (32–78)]. Nineteen patients were diagnosed with GCA and one with TA. Seven patients had new onset LVV and 13 had long-lasting [(mean disease duration 3.3 years, 95% CI 1.95–4.67)]. Median time from CDUS to MRA examination was 2 days (IRQ 3). Median CRP was 5 mg/l (1–133) and ESR 25 mm/ hr (4–112). In two patients, no vasculitis changes were observed in any vessel either on CDUS or MRA. In the remaining 18 patients, CDUS revealed vasculitis in all patients while MRA was positive in 11 patients. The temporal artery branches and the supraaortic vessels in which CDUS, MRA or both modalities were positive, are presented in table 1.

Conclusions: In this study, CDUS seems to be more sensitive to detect vasculitis changes in the large vessels and cranial arteries than MRA, indicating that ultrasound should be used as a first line evaluation in all patients suspected to have LVV.

P35

Novel MRI-Based Longitudinal Scoring of Arterial Involvement in Large-Vessel Vasculitis Enrico Tombett1,2, Ahmad Zia2, Allan Kiprianos1, Ben Ariff1,2, Justin C Mason1,2 College London, London, UK, 2Imperial NHS Trust, London, UK

1Imperial

Objectives: Prevention of arterial progression is a hard therapeutic goal in large-vessel vasculitis (LVV). Moreover, lack of validated outcome measures for LVV limits the feasibility of clinical trials. Although distinguishing disease activity from damage in Takayasu arteritis (TA) is difficult, current proposed damage indices lack imaging data. The only validated quantitative methods for arterial damage are NASCET and ECST, both designed for


Score of stenotic disease Stenosis 0–50% Stenosis 50–70% Stenoses 70–99% Functional occlusion

1 2 3 4

Length: 3–10 cm >10 cm

0 extra point +1 extra point +2 extra points +3 extra points

Score of aneurysmal disease Dilatation 0–50% Dilatation 50–100% Dilatation >100% or requiring procedures

1 2 3

Length: 10 cm

0 extra point +1 extra point +2 extra points +3 extra points

Core set of arteries to be evaluated 1) Ascending aorta 2) Aortic arch 3) Thoracic aorta 4) Abdominal aorta 5) Brachiocephalic artery 6) Right subclavian artery 7) Right axillary artery 8) Right vertebral artery 9) Right common carotid artery 10) Left subclavian artery Total score (0–133)1: _________

11) Left axillary artery 12) Left vertebral artery 13) Left common carotid artery 14) Coeliac artery 15) Superior mesenteric artery 16) Right renal artery 17) Left renal artery 18) Right common iliac artery 19) Left common iliac artery



125


1 In case of stenotic and aneurysmal disease in different segments of the same artery, record the highest score according to either the stenosis or the dilatation (1 to 4), and consider the length according to the sum of the length of the restrictive and dilative disease.

carotid atherosclerosis. Starting with these scoring systems, we sought to develop a widely applicable magnetic resonance (MR)based system for scoring large artery injury in TA and large vesselgiant cell arteritis (LV-GCA). Method: Initially, NASCET was selected as it only requires intraluminal data which are: i) more readily accessible in routine clinical practice, ii) require less acquisition time than arterial wall sequences, iii) more directly describe the haemodynamic derangement in LVV, in which wall thickening may occur in the absence of demonstrable luminal changes. NASCET was modified to account for LVV intrinsic characteristics by: i) defining a core set of arteries to be evaluated, with the final score determined by summing individual artery scores, ii) the reference diameter was measured for every artery in a plane judged ‘uninvolved’; iii) including the length of the stenotic segment in the algorithm, iv) aneurysmal disease were scored similarly to stenotic disease, based on the percent diameter dilatation and the length of the involved segment (table 1). A cohort of 60 patients with TA and LV-GCA was selected, and those with vascular progression identified. Scans are analysed cross-sectionally and longitudinally by two independent observers. The κ-inter-observer variability and the sensitivity of the score in distinguishing patients with stable or progressive vascular involvement is evaluated. Results: To date, we have evaluated 14 scans from 7 LVV patients and scoring of the remaining images will be concluded in 3 months. If this scoring method proves reproducible and sensitive to evolution of arterial injury over time, it will represent an important measure for new clinical trials in LVV. Moreover, it could be used for quantifying vascular disease burden, as a basis for improving damage assessment in TA (currently based on clinical evaluation), and for monitoring disease course over time. Conclusions: Outcome measurement and assessment of vascular involvement in LVV should include imaging-based scores. We are developing a new system for quantifying vascular injury in TA and LV-GCA.

P37

A Very High Prevalance of Avascular Necrosis in Turkish Patients with Granulomatosis with Polyangiitis (Wegener’s): Preliminary Results from a Single Centre Sevil Kamali, Bahtiyar Toz, Burak Erer, Nilüfer Alpay Kanitez, Bahar Artım Esen, Murat Inanç, Lale Öcal, Ahmet Gül

Prognosis Value of Geriatric Assessment Scales in Older Adult with New Onset ANCA-Associated Vasculitis: A Pilot Retrospective Study Josephine Thomazeau, Christelle Volteau, Laure de Decker, Fadi Fakhouri, Christian Agard, Marie Lino, Julie Graveleau, Mohamed Hamidou, Antoine Néel CHU, NANTES, France

Objective: 1) To assess the prognostic value of comorbidities, frailty and dependency as measures by dedicated geriatric scales, in older adults with ANCA-associated vasculitis. 2) To identify factor that predict functional decline in Instrumental Activities of Daily Living. Methods: Retrospective single center study of patients diagnosed with ANCA associated vasculitis after 65 y between 2000 and 2013. Comorbidities, frailty and dependency were measured


Background: Avascular necrosis (AVN) in ANCA associated vasculitides (AAV) is a rare finding of damage that has not been investigated in detail in terms of risk factors. Aim: To investigate the prevalance of AVN risk factors in patients with AAV. Methods: AAV cohort diagnosed according to CHCC, presented with ≥1 organ involvement, being followed-up and treated ≥6 months after diagnosis were included into the study. All symptomatic AVN was demonstrated by MRI. Demographic and clinical data including pre-defined AVN risk factors such as high BMI (≥25), hyperlipidemia, diabetes, smoking status, alcohol intake and cumulative glucocorticoid (GC) exposure were noted into a protocol. Initial BVAS and cumulative VDI were calculated in the majority of cohort. The patients were stratified in accordance to the presence of AVN (AVN+/AVN-). Demographics and AVN risk factors were compared between the groups by using Mann Whitney U test. Results: The study group consisted of 129 AAV (16 e-GPA, 28 MPA, 85 GPA) patients (63 female) with the mean age at diag-

Abstracts


Division of Rheumatology Istanbul School of Medicine, Istanbul University,, Istanbul, Turkey

P36

126

using the Charlson Index, the CSHA Clinical Frailty Scale (CFS) and the Instrumental Activities of Daily Living 4 items (IADL4). These score were evaluated at 3 time points: 1 year prior to AAV diagnosis (baseline), at AAV diagnosis and 1 year after AAV diagnosis. Multivariate analysis was performed using Cox model. Results: Fourty four patients were analysed, including 33 with MPA and 11 with GPA. Mean age was 76 years. Mean eGFR was 49 ml/min/1.73 m2. Seventy percent of patients were treated with corticosteroids plus cyclophosphamide. Overall, a significant improvement of CFS and IADL were seen between disease onset and year 1 after the diagnosis. In multivariate analysis mortality was higher in patient with PR3 ANCA (HR = 4.2), palliative care (HR:3.5) and worse baseline IADL4 (HR:1.84). Relapse-free survival was longer in patients with worse baseline CFS score (HR = 0.41) and those with MPA (HR = 0.25). IALD was the only factor that predicted infection-free survival (HR = 1.95). Predictive factor of functional decline at 1 year were PR3 ANCA (HR = 85), Charlson comorbidity Index (3.2) and IADL4 at time of diagnosis (HR = 3.9). Conclusion: Geriatric assessment scales appear to have high prognostic value in older adults with AAV. These simple tools can be better predictors of outcome than age or some usual biological parameters such as eGFR. Multicenter prospective studies are needed to confirm our results. These tools may help identify at risk patients who may require more intensive supportive care.

(for Abstract P37) AVN+ Age at diagnosis Follow-up time (mo) Sex (F/M) BMI ≥25 (%) Diabetes Hypercholesterolemia (LDL >160 mg/dl) (%) Smoking (%) Dose of cumulative GC (g) Venous thrombosis (%) VDI score

AVN–

p

43±13 94±46 5/13 55 11

44±16 54±44 58/53 30 17

NS 0.001 0.05 0.03 NS

16 7 17±8 11 3.1±1.4 (16/18)

9 33 10±8 7 2.35±2 (98/111)

NS NS 0.002 NS NS

nosis 44±15 and mean follow-up time 60±46.7 (6–182) (med 48). Eighteen of 129 (14%) AAV patients developed AVN (2 MPA, 16 GPA). AVN was observed in knee (2), shoulder (1), hip (14) and ankle (1) and bilateral in 66%. Comparison of the AVN risk factors in AAV patients was shown in table. Conclusion: A very high prevalence of AVN was found in our GPA cohort, which is quite higher than the previously reported frequencies (2 were also followed prospectively via compression ultrasonography. Results: The cohort had an average age of 54.4±16.7 years, was 54% female, 85% white, and 54% PR3-ANCA. Ten of 48 patients (20.8%) were positive for anti-Plg at initial screening during a time of active disease; 7 of 10 were MPO-ANCA. Paired active and remission samples were available for 28 patients and in this sub-group of patients, anti-Plg were significantly increased during active disease compared to remission (p = 0.00004) in both patients with PR3-ANCA (p = 0.0005) and patients with MPO-ANCA (p = 0.04). Of patients who were positive for anti-Plg, 8 of 10 (80%) had an elevated D-dimer and 3 of 10 (30%) patients also had an elevated hsCRP value. Six of 48 (12.5%) patients have experienced a VTE since enrollment. One patient was positive for antiPlg prior to the VTE; the other 5 patients demonstrated elevations in anti-Plg surrounding the time of the VTE but remained within the normal reference range. Conclusions: We confirm that anti-plasminogen antibodies, when present in patients with AAV, correlate with disease activity. Additional data are needed to determine if circulating anti-Plg represent an increased risk factor for thrombosis via their documented ability to retard fibrin clot dissolution in vitro. Since plasminogen is a key protein in the fibrinolytic pathway, prospective screening of patients with AAV for anti-Plg could lead to early intervention with decreased morbidity and mortality from thromboembolic events.

P66

Anti-Plasminogen Antibodies in Patients with ANCA-Associated Vasculitis Are Elevated During Active Disease and Prior to Venous Thromboembolic Events Carmen Mendoza, Elizabeth J. Brant, Leslie Stewart, Anne B. Froment, Candace Henderson, Yichun Hu, Susan L. Hogan, Vimal K. Derebail, Patrick H. Nachman, Donna O’Dell Bunch University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Objectives: Patients with ANCA-associated vasculitis (AAV) are at increased risk for venous thromboembolic events (VTE), especially when disease is active. Circulating anti-plasminogen antibodies have been described in patients with AAV, shown to retard fibrin clot dissolution in vitro and correlate with both systemic and renal disease activity [Bautz et al, JASN 19:2421, 2008; Berden et al, JASN 21:2169, 2010; Hao et al, Rheumatology 53:300, 2014]. Our aim was to prospectively assess the impact of anti-plasminogen antibodies upon VTE in patients with AAV. Methods: Forty-eight patients presenting with active AAV who were not on anti-coagulant therapy were screened for D-dimer


Cytokine Profiles of B Cells Conditioned to Produce IL-10 in ANCA Associated Vasculitis Patients and Controls, and their Functional Immune Effects Sarah Katrina Todd1, Scott R. Henderson1, Ruth J. Pepper1, Juliana Draibe1,2, Alan D. Salama1 1

University College London, London, UK, 2Bellvitge Univeristy Hospital, Barcelona, Spain

Objectives: B cells contribute to the pathogenesis of ANCAassociated vasculitis (AAV) but a subset, characterised by IL-10 production, can act to limit inflammation. Conditions promoting B cell IL-10 production can also result in secretion of pro-inflammatory cytokines such as TNFα. Therefore, the overall B cell cytokine balance is likely to be important in determining functional effects of B cell subsets. We assessed the cytokine profile of B cells induced to produce IL-10 and tested the effects of cell supernatants on T cell activation in vitro. Methods: Peripheral blood mononuclear cells from AAV patients (n = 17) and healthy controls (n = 8) were cultured for 48 hours with no stimulus, CpG (TLR9 ligand) alone or CpG plus CD154 (for maximal B cell induction). Supernatant and cell cytokine production was assessed by flow cytometry, cytometric bead


143


P65

CPG alone

CPG and CD154

IL-17A IL-2 IL-9 ,)1ǅ 71)į IL-6 ,/Ǆ 7*)Ǆ IL-10

a

CD3 alone no supernatant 105

Supernatant anti-IL-10

Supernatant isotype

1.42

24.2

14.3

3.60

16.1

5.56

47.9

26.5

74.2

7.89

71.2

7.12

IFN-ǅ

104 103 102 101 100

100 101 102 103 104 105 100 101 102 103 104 105 100 101 102 103 104 105

Frequency of TNF-įSRVLWLYH T cells (%)

TNF-į

b

TNF-į

100 80

TNF-į

p = 0.0136*

60

n.s.

40 20 0

CD3 alone

Sup anti-IL-10

Sup isotype

array and ELISA (for IL-12p70, IFNγ, IL-17A, IL-2, IL-10, IL-9, IL-22, IL-6, IL-13, IL-4, IL-5, IL-1β, TNFα, TGFβ and IL-35). Pooled supernatants were then added to healthy control CD3+ CD25– T cells activated by plate bound anti-CD3 (n = 4). Supernatants were pre-incubated with anti-IL-10 monoclonal antibody, or isotype control, and intracellular staining of T cells conducted for IFNγ and TNF-α. Results: TGFβ, IL-10, IL1-β, IL-6 and IFN-γ were the main cytokines detected in the cell supernatants following maximal B cell stimulation (figure 1a); TGFβ and IL-10 are archetypal immunoregulatory cytokines, whilst IL-1β and IL-6 have recently been shown to be involved in maintenance of B regulatory cells (Bregs) in vivo (Rosser et al). Levels of IL-9, TNFα, IL-2 and IL-17 were low; however, intracellular TNFα was globally expressed in all B

144


cell subsets. IL-4, IL-5, IL-12 p70, IL-13, IL-22 and IL-35 were beneath the limit of detection. Profiles were comparable in AAV patients and healthy controls, confirming that Bregs are functionally comparable (Lepse et al; Todd et al). Pooled supernatants inhibited T cell TNFα production in vitro but had no significant effect on IFNγ (figure 1b). The inhibitory effect was not significantly different in supernatants pre-incubated with anti-IL-10 monoclonal antibody, relative to isotype. Conclusion: These results show that conditions promoting B cell IL-10 production in vitro stimulate release of additional antiinflammatory cytokines. The lack of effect of supernatants preincubated with anti-IL-10 highlights the importance of other cytokines in limiting Th1 differentiation. Candidates include TGFβ, IL1-β, IL-6 and IFN-γ itself.

Abstracts


Fig. 1. (for Abstract P66).

P67

P68

Immunometabolism in ANCA Vasculitis

In vitro Culture Method for the Study of Circulating ANCA-Reactive B Cell

Trinity College Dublin, Dublin, Ireland

Plinio Hurtado1, Ernesto Hurtado-Perez2, Jodie Nitsche1, Chen Au Peh1 1

Anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis (AAV) is an autoimmune condition characterised by inflammation of the microvasculature. In its most severe form it manifests with rapidly progressive glomerulonephritis and vasculitis of the respiratory tract. The Warburg effect (switch from oxidative phosphorylation to glycolysis for the production of energy, in the presence of oxygen) was first noted in cancer cells but has recently been described in pro-inflammatory immune cells. The aim of this study is to investigate if this metabolic switch to aerobic glycolysis occurs in the pathophysiology of AAV by studying both patient samples and experimental models of vasculitis. Methods: Peripheral blood mononuclear cells (PBMCs) were obtained from AAV patients (active disease and remission) and age-matched healthy donors. Cellular metabolism was measured by Seahorse extracellular flux analysis. Glucose uptake was analysed using 2NBDG (a fluorescently-labelled deoxyglucose analogue) and flow cytometry. Cell populations were identified by cell surface marker expression. Mitochondrial content of cells was quantified by a combination of flow cytometry and PCR-based assays. The experimental autoimmune vasculitis (EAV) WKY rat model was used to examine immune cell metabolism in vivo. Results: We have optimised the quantification of metabolism in PBMCs by Seahorse extracellular flux analysis. Data from the analyses of patient samples show that oxygen consumption is decreased in PBMCs from patients with active disease compared to those in remission, and also to healthy controls. Conversely, we have detected increased glycolysis in cells from patients with active disease. These data support our hypothesis that peripheral immune cells undergo a metabolic shift in vasculitis. We have also developed a method for the isolation of leukocytes (CD45+ cells) from the kidneys of rodents and have successfully quantified oxidative phosphorylation and glycolysis in these cells. In these studies, leukocytes isolated from the kidneys of EAV animals were found to preferentially use glycolysis with a concomitant reduction in oxygen consumption compared to nonimmunised animals. Conclusions: We have optimised methods to allow us to investigate immune cell metabolism both in cells from patients with ANCA vasculitis and in experimental models of this disease. Using these state of the art technologies we have found that peripheral immune cells from patients with active disease display a metabolic switch to aerobic glycolysis and that a similar metabolic profile is seen in immune cells infiltrating to the kidneys in a rodent model of AAV. Objective:


2

The Royal Adelaide Hospital, Adelaide, Australia, University of Adelaide, Adelaide, Australia

Background: Understanding the origin and characteristic of circulating ANCA-reactive B cells, known to be present in patients with ANCA-associated vasculitis could provide vital information into the genesis of ANCA not only in patients but in normal individuals where circulating ANCA autoreactive IgG and IgM has also been reported. However, the low numbers in which these cells exist and the limited capacity they have to expand in vitro has restricted their study. Method and Results: In order to overcome such limitations, we have designed a PBMC culture system in which B cells are preferentially expanded and differentiated into antibody producing cells. The method is based in the combination of molecules known to play a central role in B cell biology such as CD40/ CD40L, BAFF and IL-21 molecules. The high efficiency of the system allows the production of antibodies in the quantities (mgs) required to use convectional clinical laboratory tests for their characterisations. The system allows the study of the specificity of B cell subpopulations as well as isolated antigen specific B cells such as ANCA-reactive B cells. Conclusions: Here we show the unique opportunities this culture method provides for the understanding the mechanisms leading to the production of ANCA in health and disease.

P69

Synthetic Immunoglobulin Selected from Clone Library for MPO-ANCA-Related Vasculitis Yosuke Kameoka1, Fukuko Kishi1, Yoshio Yamakawa1, Rora Nagasawa1, Setsuko Ikeda1, Minako Koura2, Junichiro Matsuda2, Toshinori Nakayama3, Kazuo Suzuki3 1 A-CLIP Institute, Chiba, Japan, 2National Institute of Biomedical Innovations, Osaka, Japan, 3Chiba University Graduate School of Medicine, Chiba, Japan

Objective: Treatment of intravenous IgG (IVIg) for vasculitis is effective in the induction therapy (Ito-Ihara T, et al. Nephron Clin Pract. 2005; 102:c35-c42). However, IVIg has some problems such as limitation of materials, concern about infection of unknown agents. Accordingly, we established a library of clones consisting of clones having synthetic hScFv of IgG in MHLW project in Japan. We must select a few clones from all clones in the library for drug innovation. Methods: We purified recombinant protein of human single chain of Fv region (hScFv) from E. coli expressing genes in clones grouped in 4 trees in the library we established.


145


Paul O’Hara, Emma Connolly, Vincent O’Reilly, Tee Sui Wu, Alice Coughlan, Mark Little, Fionnuala Hickey

P70

New Application of Easy-Rapid Detection of ANCA Epitope Antibodies for MPO-ANCA Associated with Vasculitis Yosuke Kameoka, Fukuko Kishi, Yoshio Yamakawa, Rora Nagasawa, Setsuko Ikeda, Hisae Onodera, Yukiko Okada, Kazuo Suzuki A-CLIP Institute, Chiba, Japan

Background: Based on the study for risk epitope analysis of disease severity (Suzuki K, et. al. Microbiol Immunol. 2007;51:1215–20), detection kit for MPO (myeloperoxidase)-ANCA epitopes is developing. Already, we developed a kit to detect ANCA antibodies by introducing the immuno-chromatography, which recognize their target antigens easily and quickly, for use in bed-side. Method: Large scale of whole molecule and fragments of the heavy chain of human MPO were produced and purified using recombinant techniques (K. Tomizawa et al,. J Clin Immunol 1998;18: 142–152). These proteins were applied to immuno-chromato membrane. Results: H-4 fragment of MPO showed the highest risk epitope for disease severity compared to the other part of MPO molecule. H-4 fragment was introduced to immuno-chromato membrane for a new kit. This kit detected anti-MPO antibody with risk eptope for 15 to 30 min. Conclusion: Already, we developed a kit to detect ANCA antibodies by introducing the immuno-chromatography, which recognize their target antigens easily and quickly, for use in bedside. The other epitope fragments of MPO molecules are also developing for antigen set of anti-epitope analysis of ANCA antibodies.

146


P71

The Activity of AAV and IL-6, IL-17, sIL-2R, Tregs cells Yoshikazu Fuse Kamagaya General Hospital, Kamagaya City, Japan

Objectives: Though the activity of antineutrophic cytoplasmic autoamtibody (ANCA)-associated vasculitides (AAVs) is generally related with the titer of antineutrophil cytoplasmic autoantibodies (ANCAs), ANCA titer does not reflect the vasculitides activity in some cases. We experienced such two phases in one patient and have considered the relation between vasculitides activity and cytokines. Method and Results: A 70-years-old woman began to take hemodialysis for the unknown reason thirty-three years ago and has continued it until now. In Day 540 she coughed up blood and was found MPO-ANCA 50 EU (20≥). She spontaneously recovered from hemoptysis without any treatments. In those days soluble IL-2R (sIL-2R) was 4420U/ml. MPO-ANCA titers rised to 216 EU without any symptoms in Day945. Thereafter MPO-ANCA titer gradually diminished without any treatments (fig. 1). About Day 2047 she felt fatigue and dizziness. At that time C-reactive protein (CRP) elevated to 14.6 mg/dl (0.30≧), MPO-ANCA titers 120 EU. Predonisolone (PSL) 10 mg was started and her condition was improved. In Day 2316 sIL-2R decreased to 1570 U/ml. In Day 2445 she burst out hemoptysis again and CRP elevated to 18.6 mg/dl, MPO-ANCA titers 115EU, IL-1β was 18 pg/ml (10≥), IL-6 99.0 pg/ml (4.0≥), TNFα 24.1 pg/ml (0.6~2.8), IL-17 31.2 pg/ ml (31.2≥). PSL was increased to 25 mg/day. AZA and CPA was also given. Then ANCA titer and CRP, sIL-2R value decreased. Conclusion: IL1β, TNFα, especially IL6 are involved in the production of CRP. We have considered the change of CRP as the one of IL-6. Her anemia remarkably improved through the effect of hepcidin related to IL-6 after the administration of steroid. IL-6 is involved in the transform from naïve CD4+ T cells to Th17 cells producing IL-17. It‘s estimated that the transformation from regulatory T cells (Tregs) to Th17 cells and the production of ANCA was promoted under high IL-6 value, but they were depressed under low IL-6 value without and with the administration of steroid. Though Tregs might be active when sIL-2R value was high, ANCA titer had increased. We’ve thought this might be because the transformation from Tregs to Th17 cells were promoted by high IL-6 value under a relatively large amount of steroid was greater than the depression by the active Tregs. When both sIL-2 and IL-6 diminished, the production of ANCA might be depressed by the effect of the decrease of IL-6.

Abstracts


Results: Effective hScFv was isolated from clones with chromatography steps following Ni-resin, DEAEsepharoseFF, and Sephacryl S-100. It was evaluated in histological observations of spleen, kidney and lung of SCG/Kj mouse, which is a model for MPO-ANCA-related vasculitis (Tomizawa K, et al. Rheumatology. 2010;49:1245–56). Then, we found decrease of crescent formation in glomeruli, urinary scores, and WBC and lymphocytes in peripheral blood. When biomarkers was examined MPO-ANCA, anti-Moesin, IL-6sR, TNF-α, G-CSF, PDGF-bb decreased by the treatment. Conclusion: Recovery of crescent formation in glomeruli, urinary scores, biomarkers shows it is effective in a model mice for vasculitis. This study is supported by a grant of JST A-STEP (AS2524128Q).

25

PSL mg/day 10

5

10

10

5

25

2.5

216 213 211 206

4420 4330

178

142

109

50

12.5

10 7.5

5

AZA 50 mg/day CPA 50 mg/day

191 187

sIL-2

10

15

Hemoptysis

ANCA(EU)

165 164

CRP 3160

15

17.5

TNFįIL-ǄIL-17

Hemoptysis

20

25 20 15

5

2.5

mg/dl

20

61

36

5

149 141 137

65.1

152 150

99

138

sIL-2 55.6 128 53.1 122 2580 120 120 51.4 118 115 49.6 114115 49.4 50.1 111010 113 111 45.6 105 103 106 99 96 61.7 85 1570 76 70 70 67.7 67 29.4 62 59 IL-6 55 22.1 20.8 19.4 35 33 33 27 23 12 18 14.6 14.2 1210101010

ANCA (U/ml)

1030

6.6 5.6

1 350 503 545 566 610 692 757 847 931 1,009 1,086 1,156 1,233 1,289 1,373 1,471 1,543 1,634 1,726 1,803 1,880 1,992 2,047 2,087 2,129 2,187 2,248 2,290 2,318 2,367 2,392 2,441 2,451 2,462 2,474 2,483 2,495 2,509 2,523 2,539 2,560 2,584 2,644 2,670 2,703

0 Days


Circulating IgA Class Anti-PR3 Antibodies in Relation to Organ Involvement and Disease Activity in PR3-ANCA Associated Vasculitis Aladdin Mohammad1, Jörgen Wieslander2, Mårten Segelmark3 1

Lund University, Lund, Sweden, 2Eurodiagnostica AB, Malmö, Sweden, 3Linköping Univeristy, Linköping, Sweden

Objectives: IgG autoantibodies against MPO and PR3 are common in MPA and GPA, but the prevalence and clinical significance of IgA autoantibodies with such specificity is largely unknown. Methods: Serum sampled at time of diagnosis from patients with AAV were re-analyzed for the presence of IgA-ANCA. All samples were tested in both direct and capture ELISA for IgAPR3-ANCA and IgA-MPO-ANCA. >+3SD from mean of healthy controls was considered as positive. Results were correlated with clinical data at time of diagnosis.


Results: The four IgA-ANCA assays yielded positive results in approximately half of the 94 patients tested. There was a correlation with serotype, but IgA-MPO ANCA was positive in 31 and 33% in IgG-PR3 positive patients and IgA-PR3 in 29 and 40% of the IgG-MPO-ANCA positive patients. There was no significant correlation between IgA-MPO ANCA and IgA-PR3 ANCA assays. We found no correlation between presence for IgA-ANCA and organ manifestation. There as a weak correlation between IgAPR3 ANCA and inflammation markers such as CRP and white blood cell count, highest for direct ELISA IgA-PR3 ANCA (r = 0.25 and r = 0.33), no such correlation existed for IgA-MPO-ANCA. Conclusion: It is common with IgA-ANCA in patients with MPA and GPA, indicating a polyclonal response to ANCA antigens. We were not able to reveal any clinical important correlations with baseline clinical data.


147


P72


Age median (IQR)

Creatinine median (IQR)

IgA-PR3 direct

IgA-PR3 capture

IgA-MPO direct

IgA-MPO capture

42 (19/23) 52 (30/22) 94 (49/45)

72 (62–79) 70 (59–78) 70 (60–79)

334 (154–604) 222 (79–362) 260 (103–461)

17 (40%) 33 (63%) 50 (53%)

12 (29%) 46 (88%) 58 (62%)

29 (69%) 16 (31%) 45 (48%)

32 (76%) 17 (33%) 49 (52%)

P73

IgA Anti-MPO Antibodies in Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss) Esha Oommen1, Amber Hummel2, Simon Carette3, David Cuthbertson4, Gary Hoffman5, Nader Khalidi6, Curry Koenig7, Carol Langford5, Carol McAlear8, Kathleen Maksimowicz-McKinnon9, Antoine Sreih8, Peter Merkel8, Larry Moreland10, Christian Pagnoux3, Philip Seo11, Stephen Ytterberg2, Paul Monach1 1

Boston University, Boston, Massachusetts, USA, Mayo Clinic, Minneapolis, Minnesota, USA, 3Mount Sinai Hospital, Toronto, Ontario, Canada, 4University of Southern Florida, Tampa, Florida, USA, 5Cleveland Clinic Foundation, Cleveland, Ohio, USA, 6McMaster University, Hamilton, Ontario, Canada, 7University of Utah, Salt Lake City, Utah, USA, 8University of Pennsylvania, Philadelphia, Pennsylvania, USA, 9Henry Ford Health System, Detroit, Michigan, USA, 10University of Pittsburgh, Pittsburgh, Pennsylvania, USA, 11Johns Hopkins University, Baltimore, Maryland, USA 2

Objective: To determine the prevalence of anti-myeloperoxidase (MPO) antibodies of IgA isotype in patients with eosinophilic granulomatosis with polyangiitis (EGPA), and the association of the IgA antibodies to IgG anti-MPO and disease activity. Methods: Serum samples from patients with EGPA followed in a multicentered longitudinal cohort were tested by ELISA for the presence of IgA anti-MPO antibodies using a modified conventional assay for IgG anti-MPO. 1–2 samples per patient (300 sera from 168 patients) were tested, one sample during active EGPA and one during remission, if possible. Proportions of IgA anti-MPO positive samples were compared between 87 healthy controls and: 1) all patients with EGPA, 2) samples from periods of active EGPA, 3) samples from periods of relatively high activity, and 4) high activity off treatment. Clinical manifestations were compared between IgA-positive and IgA-negative patients. Results: The ELISA showed low background readings in controls and high readings in some EGPA samples, and was therefore interpretable. IgA anti-MPO was detected in 11 of 168 (7%) patients with EGPA (12 of 300 serum samples) compared to 1 of 87 (1%) healthy controls (p = 0.067). All but one (11 of 12) samples testing positive for IgA anti-MPO also tested positive for IgG anti-MPO. In contrast, 90 of 101 samples tested positive for IgG

148


anti-MPO but negative for IgA. Samples taken during active EGPA were positive for IgA anti-MPO in 6 of 64 cases (9%, p = 0.042). Among samples taken during relatively high disease activity (physician global assessment > 3 on a scale of 0–10), 5 of 40 were positive (13%, p = 0.012). Among the samples reflecting high activity, only two were taken from untreated patients, but both were positive for both IgA and IgG anti-MPO. No significant differences (P > 0.108) in the rates of historical ENT, pulmonary, or skin involvement were detected between the IgA anti-MPO positive and negative patients. Conclusions: Although IgA anti-MPO is detectable in some patients with EGPA and may be detectable more frequently during active disease, its presence seems unlikely to assist with diagnosis or determination of disease activity above what is obtained from conventional IgG anti-MPO. Further study of more untreated patients with active disease is indicated to determine whether IgA anti-MPO has potential clinical utility.

P74

Erythrocyturia During Follow-Up in ANCA Associated Renal Vasculitis: Relation with Renal Disease Activity and Renal Outcome? Stephanie Middelkoop, Anoek de Joode, Jan Stephan Sanders, Coen Stegeman University Medical Center Groningen, Department of Internal Medicine, Division of Nephrology, Groningen, The Netherlands

Background: renal involvement with necrotizing glomerulonephritis is common in ANCA-associated small vessel vasculitis (AAV) with glomerular haematuria, red blood cell casts, proteinuria and a variable degree of (severe) renal failure. During treatment and follow-up remission of renal vasculitis is defined as stabilization in serum creatinine, while controversy exists regarding the importance of persistence of erythrocyturia and proteinuria in patients with AAV. Objective: to describe the course of erythrocyturia, proteinuria and renal function after diagnosis and induction/maintenance therapy and its possible predictive value of long term renal function. Methods: we analysed 96 consecutive patients newly diagnosed, between January 2000 and December 2007, with systemic AAV with renal involvement (PR3-ANCA n = 56/MPO-ANCA n = 37/HNE n = 1/none n = 2). Patients were followed for at least

Abstracts


MPO-ANCA+ PR3-ANCA+ All patients

N (M/F)

18 months. Primary outcome was the course of erythrocyturia during treatment. Secondary outcomes were renal function (serumcreatinine), proteinuria (protein/creatinine ratio in 24 h urine collection), and change in renal function during follow-up. Time moments of remission for erythrocyturia (< 5 erythrocytes/hpf for 3 consecutive months), stable creatinine (lowest serum creatinine value, combined with a clinical stable patient), and the ratio of proteinuria and creatinine (lowest value during follow-up) were defined. The course of these three parameters were analysed and time moments of remission between creatinine and erythrocyturia as well as protein/creatinine ratio were compared. Results: After 3, 6 and 12 months of follow-up erythrocyturia had disappeared in 53%, 72% and 92%, respectively, creatinine was stable in 57%, 84% and 94%, respectively, and the proteinuria was stable at its lowest value in 21%, 35% and 74%, respectively. Erythrocyturia disappeared at 3 months (median, IQR 1.3–4.8), stabilisation of the renal function occurred after 3 months (IQR 2–4), and proteinuria ratio was lowest at 8.5 months (IQR 3–12). The mean difference between disappearance of erythrocyturia and stabilization of renal function was 0.04 (SD 2.79) months. On average, renal function stabilized 6.1 (SD 4.93) months prior to proteinuria. No correlation existed between persistence of erythrocyturia for more than 6 or 12 months and changes of renal function at 18 and 60 months follow-up. Conclusions: Erythrocyturia persists long after diagnosis and disappears usually at the same moment as stabilisation of the kidney function occurs. Erythrocyturia is probably a sensitive marker presence or absence of inflammatory disease activity and damage/repair, while microscopic injury as indicated by proteinuria persists for a longer time. Proteinuria is, therefore, not a marker for renal disease remission.

admitted to ICU due to cardiogenic pulmonary oedema (myocardial infarction, arrhythmias, high BP). Multivariate analysis suggested that predictors for ICU admission included respiratory failure at admission (OR 9.3, p < 0.05), high activity of vasculitis (BVAS ≥12) (OR 6.5, p < 0.05), dialysis (OR 2.7, p < 0.05) and kidney disease (serum creatinine >200 mmol/l) (OR 2.1, p < 0.05). Nineteen (41.3%) patients died in ICU from secondary pulmonary infection (n = 9), respiratory failure associated with lung vasculitis (n = 6), major pulmonary bleeding (n = 3) or pulmonary oedema (n = 1). Predictors of death were mechanical ventilation (OR 12.2, p < 0.05), hemotransfusion (OR 8.3, p < 0.05), severe vasculitis damage (VDI ≥5) (OR 6.7, p < 0.05) and secondary infections (OR 4.3, p < 0.05). Conclusions: In our retrospective study almost every fifth patient with GPA required an ICU admission that was associated with very poor outcome. Predictors of ICU transfer or death in emergency department patients included severe respiratory failure, kidney disease, high activity of GPA, severity of irreversible vasculitis damage and secondary infection. Lung disease due to GPA and/or infection was one of the major causes for ICU admission.

P76

From Polyuria to Renal Mass: A Unique Presentation of GPA Paraskevi Kazakou, Frédéric Vandergheynst, Bruno Couturier, Daniel Van Gansbeke, Sandrine Rorive, Nicolas Dumarey, Agnes Burniat

P75

Pulmonary Causes for ICU Admissions in Granulomatosis with Polyangiitis Pavel Novikov, Sergey Moiseev, Yuriy Sorokin, Nikolay Bulanov Sechenov First Moscow State Medical University, Moscow, Russia

Objectives: To evaluate the occurrence, predictors, outcomes and pulmonary causes for ICU admissions in a cohort of granulomatosis with polyangiitis (GPA) patients. Methods: We evaluated ICU admissions in a cohort of 242 GPA patients during average follow-up of 3.6 years (total 865 patients-years). Diagnosis of GPA complied to ACR criteria and CHCC-2012 definition in all patients and was confirmed histologically in 78.1% of patients. ANCA were found in 82.6% of patients. Results: There were 48 ICU admissions in 46 (19.0%) patients who required respiratory support. Direct pulmonary causes for ICU admissions included hemorrhagic alveolitis (n = 8), pulmonary hemorrhage (n = 6), pneumonia (n = 20) and pneumothorax (n = 2). All these patients presented with severe respiratory failure requiring noninvasive respiratory support or intubation with mechanical ventilation (n = 16). The other 12 patients were


Objective: We report the first association of central diabetes insipidus (DI) and renal inflammatory pseudotumor in the setting of Granulomatosis with Polyangiitis (GPA). Introduction: Classical renal involvement in GPA consists in segmental necrotizing glomerulonephritis sometimes leading to rapidly progressive renal failure. The presence of a granulomatous renal inflammatory pseudotumor (IPT) is rare, only 16 cases have been reported (table 1). Pituitary involvement is another rare complication of the disease with only 23 previous case reports. When it occurs, the most common clinical presentation is DI that usually follows rather than precedes lung and kidney involvement. Method: A 23-year-old woman initially presented with polydipsia and polyuria. The diagnosis of central DI was established by a water restriction test and a treatment with intranasal desmopressin was started. Magnetic resonance imaging of the pituitary gland showed thickening of the pituitary stalk and loss of the hyperintense signal of the posterior pituitary on T1-weighted images. Circulating levels of anterior pituitary hormones were within normal limits. Chest X-ray was unremarkable. A 18F-FDGPET/CT revealed a tumor-like lesion in the right kidney which was confirmed by a renal contrast-enhanced ultrasonography (CEUS). Results: As PET/CT also showed an increased FDG uptake of the maxillary sinus, GPA was suspected. Biology confirmed the presence of anti-MPO ANCA but sinus biopsy did not revealed


149


Erasme University Hospital – Université Libre de Bruxelles, Brussels, Belgium

Table 1. Characteristics of published case report of GPA-associated renal inflammatory pseudotumors (for Abstract P76)

Year

Patient

ANCA/IF

ENT lesions

Pulmonary involvement

Nervous system involvement

Other

Urinalysis

Renal Glomerulonephrites

Granulomas

Fibrosis

Multiple mass lesions

Nephrectomy

Maguire

1978

27y/F

Not applicable

x

x

no

no

NM

x

x

no

no

partial

Thomas

1983

51y/F

Not applicable

x

no

no

papilledema

normal

x

x

x

no

total

ANCA/ELISA

Author

Histopathology

Schapira

1986

45y/M

NM

x

x

no

no

proteinuria

x

x

no

no

partial

Schlydlowsky

1992

47y/M

positive (no details)

no

x

no

arthralgias

NM

x

x

no

no

total

Boubenider

1994

45y/F

cytoplasmic

no

no

no

purpura

proteinuria hematuria cylindruria

x

x

x

no

total

Smith

1993

52y/F

NM

x

no

no

episcleritis

NM

x

x

no

no

total

Verswijvel

2000

25y/M

cytoplasmic

PR3

x

no

no

no

microscopic hematuria

x

NM

NM

no

no

Fairbanks

2000

68y/M

perinuclear (1/20)

NM

x

no

no

no

NM

x

x

no

yes

total

Ruiz Carazo

2001

29y/M

cytoplasmic

NM

no

no

no

scleritis

x

x

x

yes

nephrectomy

Kapoor

2002

22y/M

cytoplasmic

PR3

no

no

no

no

hematuria proteinuria

x

no

no

yes

no

Leung

2004

66y/M

perinuclear

MPO

x

no

no

no

normal

no

x

x

yes

no (involvement of both kidneys)

Krambeck

2005

61y/M

negative

x

yes

no

no

normal

no

x

x

no

partial

Vandergheynst

2006

32y/M

cytoplasmic

PR3

x

no

mononeuritis multiplex

colitis, arthralgias

proteinuria

x

x

x

no

partial

Roussou

2008

72y/M

perinuclear

NM

x

no

no

normal

x

x

no

yes

total

Dufour

2012

70y/M

perinuclear

MPO

x

x

mononeuritis multiplex

no

NM

x

x

no

no

total

Dufour

2012

67y/M

cytoplasmic

PR3

no

x

meningitis

arthralgia

22y/F

perinuclear

MPO

x

no

diabetes insipidus

Present case

PR3

NM

NM

NM

NM

no

no

normal

x

x

no

yes

no

ENT = Ear, nose and throat; NM = not mentioned.

150


Conclusions: GPA should be considered in the differential diagnosis of central DI on the one hand and of renal mass-lesions on the other hand. Furthermore, the case reported here is unique in many aspects. It is the first case of GPA combining initially a central DI and subsequently bilateral renal IPT. These pseudotumoral lesions have exceptionally been described by PET/CT and never by CEUS. Finally whereas most of the cases of GPA-associated renal IPT have been treated by surgery or less frequently by classical medical treatment (cyclophosphamide and steroids), our patient experienced rapid and complete renal response to rituximab.

Abstracts


typical granulomatous inflammation. Urinalysis strikingly showed neither proteinuria nor hematuria. Glomerular filtration rate was normal. Ultrasound control performed 6 months later showed that the renal mass had doubled in size (4.3 cm) and also the apparition of new lesions in the left kidney. This was confirmed by PET/CT. Histopathological examination of the renal biopsy specimen revealed granulomatous inflammation with multinucleated giant cells, vasculitis and fibrinoid necrosis, consistent with the diagnosis of GPA-associated renal IPT. BVAS-WG was 5.Treatment with prednisolone and rituximab was started, resulting 6 weeks later in complete remission (BVAS-WG = 0), in particular complete regression of renal tumors. Unfortunately, DI persisted (considered as damage)

Orbital Involvement of Granulomatosis with Polyangiitis: Clinical, Imaging and Histological Features Lee Teak Tan1,2, Hazlita Isa1,5, Indran Davagnanam2,6, Oren Tomkins-Netzer1, Norshamsiah Md Din1,5, Simon R.J. Taylor1,4, David H. Verity1, Geoffrey E. Rose1, Philip J. Luthert1, Charles D. Pusey3, Sue Lightman1,2 1

UCL Institute of Ophthalmology, London, UK, 2Moorfields Eye Hospital, London, UK, 3Multidisciplinary Vasculitis Clinic, Hammersmith Hospital, London, UK, 4Division of Immunology & Inflammation, Imperial College, London, UK, 5 Department of Ophthalmology, University Kebangsaan Malaysia, Kuala Lumpur, Malaysia, 6Brain Repair & Rehabilitation Unit, Institute of Neurology, London, UK

Objectives: Granulomatosis with polyangiitis (GPA), previously Wegener’s granulomatosis, requires prompt diagnosis and systemic review to exclude life-threatening disease. Early diagnosis of orbital GPA may, however, be difficult as anti-neutrophil cytoplasmic antibody (ANCA) and anti-PR3 antibody screening can be negative at presentation and orbital biopsies taken for diagnosis may not show the classic features of GPA. This study was designed to compare GPA with other causes of orbital inflammation to identify the presenting clinical, imaging and histological features most likely to predict GPA and its systemic spread. Methods: This is a retrospective non-interventional comparative case series. Two hundred and forty-seven patients who had undergone orbital biopsies for clinical presentations with orbital inflammation were identified from the Institute of Ophthalmology pathology database, for which imaging was available in 165 (67%). Patients were divided into GPA and non-GPA groups based on their final clinical diagnosis. Clinical, imaging and histological features of these two groups were compared to determine those predictive of GPA. Results: Thirty-seven (15%) patients had a final diagnosis of GPA. The 37 GPA patients (male:female ratio 15:22) presented with orbital disease at a median age of 51 years (range 14–87). Features highly suggestive of GPA were sinonasal symptoms, sinonasal changes or paranasal bone erosion on imaging (p < 0.001 respectively). Bony erosion was independent of ANCA status or systemic involvement. The subgroup presenting with lacrimal gland enlargement were younger, with a median age of 30 years (range 14–57) and lacked sinonasal symptoms at presentation. Histologically, GPA showed more inflammatory activity. Necrosis and vasculitis were independently associated with the diagnosis of GPA (p = 0.02, OR = 0.12). IL17 (p = 0.002), IL-23 (p < 0.001) and BAFF-R (p = 0.008) were seen significantly more in orbital GP compared to other causes of orbital inflammatory diseases. Twenty two percent (8/37) patients with GPA had evidence of systemic involvement at presentation and no patient presenting with solely orbital GPA developed later systemic disease over a median follow-up of 2.7 years. Conclusions: A high index of suspicion should be maintained for GPA where a patient presents with an orbital mass and sinonasal symptoms, or where imaging shows sinonasal involve-


ment or paranasal bone erosion, even in the younger age group. The presence of necrosis, vasculitis and increased inflammatory activity on histology may play a role in diagnosis of the disease. No patient with solely orbital GPA involvement at presentation developed systemic disease, suggesting that orbital GPA can remain localised in the long-term.

P78

Association of Physical Trauma and Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis Activity: A Report of Two Cases Jack Samways1, Nina Brown2, Michael Venning2 1

Manchester Medical School, University of Manchester, Manchester, UK, 2Renal Unit, Manchester Royal Infirmary, Manchester, UK

Objectives: The current understanding of the aetiology and pathogenesis of anti-neutrophilic cytoplasmic antibody (ANCA) associated vasculitis (AAV) is incomplete and many questions relating to triggers of disease activity remain unanswered. Past studies have demonstrated that the development or relapse of AAV may be associated with infection. Similarly, trauma has been shown to activate innate immunity and create a systemic inflammatory response syndrome (SIRS)-like state. Examples of trauma inducing other autoimmune conditions such as Systemic Lupus Erythematosus and relapsing polychondritis have already been demonstrated. Based on the existing evidence that trauma induces SIRS by similar mechanisms to infection, and the likely association between infection and AAV activity, this case series hypothesises that trauma may also trigger AAV activity. Method: Two patients’ cases were reported based on retrospective reviews of their clinical notes, serology results, radiological imaging and histopathological reports. Further detail and informed consent was gained via interviewing the patients. Patient 1 was a 50 year old male who was diagnosed with a relapse of his Granulomatosis with Polyangiitis (GPA) involving his optic nerve and upper respiratory tract days after a blunt trauma to the head which resulted in comminuted fractures of the right frontal bone in 2006. Patient 2 was a 45 year old male who presented with 2 months of persistent epistaxis on a background of systemic symptoms (lethargy, unintentional weight loss and night sweats) which started after a bicycle accident in which he sustained facial/nasal trauma and a deep laceration to his lateral thigh in 2007. ENT examination revealed a granulomatous lesion in the left septum and left anterior turbinate and the diagnosis of ENT limited GPA was made following serum studies and review of the histology of the lesion. Results: Both patients showed changes suggestive of active GPA histologically and serologically (raised ANCA titres and positive PR3 assays) within days of their respective traumas. Conclusions: In these cases it appears that tissue trauma may act as a trigger for disease activity in GPA. One possible mechanism, previously postulated for the formation of extravascular granulomas is the accumulation of neutrophils in the extravascular


151


P77

tissue susceptible to ANCA activation in patient capable of producing these antibodies. Further neutrophil recruitment and activation could result in necrotising inflammation. This mechanism could possibly explain the link between trauma and vasculitis. Given the lack of reported cases, further investigation is required to enhance the validity of these findings, and the possible underlying pathogenic mechanisms.

P80

Analysis of Microscopic Polyangiitis Patients (MPA) Presenting with Pulmonary Fibrosis (PF) as Single Manifestation Versus Those with More Widespread Disease Luis Felipe Flores-Suárez, Natllely Ruiz, Lina María Saldarriaga-Rivera, Lya Pensado Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico

P79

Clinical Features of Patients with ANCA Vasculitis Affecting the Lungs Anna Conterato, Taylor Lincoln, Caroline Poulton, Susan Hogan, JulieAnne McGregor, William Pendergraft, Ronald Falk, Patrick Nachman, Ashley Henderson University of North Carolina Chapel Hill, Chapel Hill, North Carolina, USA

Objectives: To describe specifics in lung function characteristics ANCA associated vasculitis (AAV). Methods: Patients with AAV from the University of North Carolina’s Glomerular Disease Collaborative Network (GDCN) inception cohort who had lung involvement and were evaluated by a pulmonologist were included. Demographic and clinical data, as well as pulmonary function test (PFT) results were collected and analyzed. Results: PFTs were reported on 28 patients (47% male, 82% Caucasian, 57% PR3-ANCA positive, 54% with a smoking history) within a median of 1 year (IQR 3.2 years) following diagnosis. Predominant pattern was obstructive (N = 12): n = 1 mild (forced expiratory volume [FEV1] ≥ 81%), n = 5 moderate (FEV1 51–80%), n = 5 severe (FEV1 31–50%), and n = 1 very severe (FEV1 ≤30%) disease. Restriction (N = 8) was observed in n = 2 mild (forced vital capacity [FVC] 65–79%), n = 5 moderate (FVC 50–64%), and n = 1 severe disease (FVC < 49%). Normal spirometry n = 8. Patients whose initial pulmonary involvement included cavities and/or nodules at initial presentation did not have PFT differences from those that did not (table 1). Conclusions: Pulmonary involvement in AAV exhibited an obstructive pattern of pulmonary function, although restrictive and normal spirometric patterns were also observed as was reduction in Carbon Monoxide Diffusing Capacity (DLCO). In this small sample there is no difference in lung function characteristics between those with and without cavities/nodules at presentation. Future research should include reasons for delay in obtaining objective PTF data, characterization following alveolar hemorrhage, concomitant illness, and degree to which inhaled tobacco accelerates vasculitic pulmonary damage.

Introduction: PF can complicate MPA. Some patients present it initially. We found that PF decreases survival in MPA (ACR Meeting 2014). A majority had PF prior to other disease manifestations. Objective: We sought differences in patients presenting with respiratory symptoms as sole manifestation for ≥12 months (‘limited’), compared to those with multisystemic disease (‘generalised’). Methods: Retrospective analysis of MPA patients from a single, referral respiratory centre (January 2003-December 2014), defined according to CHCC 2012. Clinical charts were reviewed, and data regarding demographics, relevant history, clinical and paraclinical data, disease activity (BVAS) and damage (VDI), at time of first symptom attributable to the disease, time of diagnosis, and at last follow-up visit, were obtained. Statistical analysis: univariate to establish proportions, medians and means differences; bivariate for group comparisons; Student’s t test for continuous variables and X2 test for categorical variables. Kaplan-Meier and logrank test for survival analysis. Significance: p≤0.05. Results: 41 patients, 26 women, 15 men; 25 (11 women, 14 men) were studied for only respiratory symptoms present for at least ≥12 months. Of the 18 patients with PF (6 women, 12 men), 14 were diagnosed as having idiopathic pulmonary fibrosis, ultimately related to MPA, 3 developed it after, and 1 presented it concurrently with other MPA symptoms. By definition no abnormal renal findings were found in those with ‘limited’ disease. Other differences between groups presenting with ‘limited’ vs ‘generalised’ disease: gender (females presented with ‘generalised’ disease in 93.8% vs. males 6.2%, p-0.002), nasal bleeding (18.8% ‘generalised’ vs. 0% ‘limited’, p-0.05), dyspnoea (56.3% ‘generalised’ vs 96% ‘limited’, p-0.003), and at follow-up: peripheral neuropathy (39.4% ‘generalised’ vs 0% ‘limited’, p-0.037). At time of last evaluation, no difference in survival was observed according to mode of onset as categorised. Conclusions: Although an important number of our MPA patients presented with ≥12 months of symptoms restricted to the respiratory system, -the majority already having PF-, the impact of this mode of presentation seems at the moment, negligible. The influence of treating these cases with standard therapy once MPA diagnosis is established, -something done in our practice-, must be analysed.

Cavities/nodules No cavities/nodules

152

N

FVC (L)

FVC (%)

FEV1 (L)

FEV1 (%)

FEV1:FVC (%)

DLCO (%)

17 11

3.2 3.0

75.6 75.0

2.2 2.1

66.6 69.9

68.8 73.7

64.0 60.3


Abstracts


Table 1. Mean PFTs of AAV patients with initial pulmonary involvement with and without cavities/nodules (for Abstract P79)

P81

P82

Pachymeningitis (PM) in Granulomatosis with Polyangiitis (GPA)

Differential Diagnosis of a Large Nasopalatine Fistula

Luis Felipe Flores-Suárez, Violeta Higuera, Natllely Ruiz

Nina Tello-Winniczuk, Ricardo Vásquez-Colón, Gabriel Tona, Miriam Lara, Natllely Ruiz, Luis Felipe Flores-Suárez

Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico

Objective: To describe the characteristics of patients with granulomatosis with polyangiitis (GPA) and pachymeningitis (PM) seen in a non-neurological, referral respiratory centre. Methods: Demographic, clinical, serological and neuroimaging characteristics of patients with neurological symptoms attributable to PM are described. Patients were classified according to the ACR 1990 criteria and the Chapel Hill Consensus Conference 2012 Nomenclature. Activity was determined with BVAS-GW, chronicity by VDI. ANCA were detected by IIF and antigen specific ELISA against PR-3 and MPO. Gadolinium-enhanced brain magnetic resonance imaging was done in all patients; the presence of diffuse or focal meningeal enhancement was necessary for PM diagnosis. Results: From June 2003 to September 2014, 10 patients (mean age 42.9±17.1 years) were diagnosed with PM (6 women, 4 men, all IIF-ANCA positive, ranging from 1:40 to 1:320, with 6 PR3-ANCA, 1 MPO-ANCA positive; 4 with generalised and 6 with localised disease at time of PM symptoms) with the following manifestations: chronic headache (n = 9), intracranial hypertension (n = 5), multiple cranial nerve palsies (n = 5), seizures (n = 2), cavernous sinus syndrome (n = 2), meningism (n = 1) and cerebellar syndrome (n = 1). The mean time between the first symptom of GPA and PM was 76.9±71.8 months, median of 64.5 months (5– 252). Neuroimaging: dural thickening in 8 and leptomeningeal enhancement in 2. Three had abnormal lumbar puncture (high pressure or pleocytosis). Infections were thoroughly discarded. At time of PM diagnosis, mean BVAS-GW of 4.3±3.3 and mean VDI of 2.6±1.43 (mostly due to ENT damage). Treatment: all received prednisone at 1 mg/kg, 5 received IV-cyclophosphamide, 3 methotrexate (from 25–30 mg/week), 1 continued with azathioprine, but at higher dose (up to 150 mg qd) and 1 rituximab (2 gr total), due to poor response to IV-CYC. Addtionally, this patient required a lumboperitoneal shunt, with good results. Improvement was observed in 6/10 cases, 1 continued with chronic cephalalgia, 1 went on to complete blindness due to bilateral optic nerve compression and 2 were lost to follow-up. Conclusion: In this series, the largest known from our geographical region, GPA patients present with PM late in their disease course. As they mostly had prior ENT activity and damage, the presence of chronic, -irrespective of its intensity-, and/or persistent headache should lead to suspect PM. Treatment is difficult and remains non-standardised, with variable response. PM poses an important challenge to physicians dealing with this complication.


Objective: To describe a difficult case of nasoplatine fistula and discuss the differential diagnosis. Method and Results: A 44 years-old male with a history of cocaine abuse for 4 years presented with a 3 year history of nasal obstruction, purulent discharge, and nasal deformity. He had fever, 30 lb. weight loss, night sweats and intermitent dysphonia. On physical exam opaque tympanii, saddle nose deformity and an extense hard palate perforation at the midline with necrotic borders were found. He had normochromic normocytic anaemia, leukocytosis, thrombocytosis and elevated acute phase reactants. P-ANCA 1:20 and PR-3-ANCA 185 U/mL were found. CT-scan: extensive facial bone necrosis, unified nasal cavity with absence of nasal septum and paranasal sinus destruction. He developed pneumonia and on chest imaging bilateral pulmonary cavitated nodules were detected. A pulmonary biopsy demonstrated granulomatous vasculitis. A nasopharyngeal biopsy disclosed leukocytoclastic vasculitis with necrotic foci and well defined granulomas. Immunohistochemistry discarded neoplasia. The diagnosis of granulomatosis with polyangiitis (GPA) was established and he was started on prednisone (1 mg/kg) and 4 IV-cyclophosphamide pulses (15 mg/ kg). Remission was achieved with resolution of lung lesions and no further palatine destruction. While awaiting outpatient consult his wife reported us his sudden, overnight death at home without prior complaints. No necropsy was performed. Conclusion: The differential diagnosis of a nasopalatine ulcer includes destructive midline lesions such as those induced by cocaine, natural killer lymphomas and some other neoplasias. All these ailments may present with positive ANCA, usually with an atypical pattern. In cases of cocaine abuse, up to 57% of patients may also present with positive PR3-ANCA, but HNE (human neutrophil elastase)-ANCA point to cocaine-induced midline destructive lesions, and other antigenic specificities can be present too. Histopathology remains the mainstay for a definitive diagnosis. In our case, the lung nodules, a single positive ANCA specificity and biopsy proven vasculitis supported GPA diagnosis, coupled with a favourable therapeutic response.

P83

Atypical Pulmonary Manifestations of Granulomatosis with Polyangiitis (GPA) Nina Tello-Winniczuk, Natllely Ruiz, Luis Felipe Flores-Suárez

Introduction: The most frequent thoracic manifestations in GPA are nodules, pleuritis, alveolar haemorrhage and interstitial lung disease. We present two cases with atypical manifestations.



153



P84

Effect of Smoking on Manifestations of MPO-ANCA Associated Vasculitis Takahiro Nunokawa, Yuji Inagaki, Kengo Murata, Naoto Yokogawa, Kota Shimada, Shoji Sugii Tokyo Metropolitan Tama Medical Center, Tokyo, Japan

Objectives: The aim of this study is to investigate the influence of smoking on manifestations of MPO-ANCA associated vasculitis (MPO-AAV), especially lung involvement. Method: This retrospective study focused on consecutive patients in whom MPO-AAV was diagnosed between 2003 and 2014 at Tokyo Metropolitan Tama Medical Center. We investigated their clinical and radiological profile by reviewing the medical records. Results: A total of 148 patients with MPO-AAV were seen at the hospital in this period. Thirteen patients were excluded from the study because their smoking status was unavailable. There were 12 current smokers, 41 past smokers and 82 never smokers. Ever smokers exhibited interstitial pneumonia more frequently than never smokers (74% vs 46%, P = 0.002%). Of 80 patients with interstitial pneumonia, 11 ever smokers showed combined pulmo-

154


nary fibrosis and emphysema (CPFE), whereas no never smokers showed CPFE. Conclusions: Smoking is a risk of development of interstitial pneumonia and CPFE in patients with MPO-AAV.

P85

Treatment Outcome of Vasculitic Neuropathy – A Single Centre Experience Thomas Daikeler, Antje Bischof University Hospital Basel, Basel, Switzerland

Objectives: Vasculitides of the peripheral nervous system are rare. Diagnosis may be challenging and outcome is uncertain. New treatments are available, influencing the disease outcome. We here describe the outcome of peripheral vasculitic neuropathy for different vasculitic disease entities and treatments in a single centre patient series. Methods: We identified all patients with suspicion of vasculitic peripheral neuropathy from our interdisciplinary Vasculitis Clinic register at the University Hospital Basel diagnosed between 2001 and 2014. Detailed clinical records were available for 22 patients including neuropathology and neurophysiology findings, if performed, as well as treatment data. Follow-up data could be obtained for all patients. Outcome was measured by improvement of paralysis and/or pain and relapse rate. Results: 18 patients had systemic vasculitis and four patients had vasculitis confined to the peripheral nervous system. ANCAassociated vasculitis, primary Sjoegren syndrome and non-systemic vasculitic neuropathy were the most frequent entities (see table). All patients were treated with high dose corticosteroids initially and for relapse. For induction therapy, ten patients received cyclophosphamide, four patients methotrexate or azathioprine resp. and six patients rituximab, in one patient combined with methotrexate. In one patient infection-triggered vasculitis resolved with adequate treatment of infection. One patient relapsed after cyclophosphamide and remitted with rituximab. One patient presenting with a severe neuropathy received rituximab and two doses of cyclophosphamide, and has been stable on rituximab maintenance therapy. All ten patients receiving rituximab remained stable. All three patients treated with methotrexate had no improvement of neuropathy symptoms, irrespective of disease entity. All patients with AAV improved whether receiving cyclophosphamide or rituximab. Overall relapse rate for neuropathy was 32%. Neurological outcome was good in 73% of the patients. No patient died during the follow-up period. Conclusions: Peripheral nerve vasculitides occurred in our centre most often as ANCA-associated vasculitis, primary Sjoegren syndrome and non-systemic vasculitic neuropathy. Most patients required induction therapy with cyclophosphamide or rituximab. After treatment the majority of patients recovered. Rituximab was effective for induction therapy in most patients and for maintenance therapy in all ten patients. Interestingly, one patient relapsing after cyclophosphamide induction became stable with rituximab therapy. In addition to cyclophosphamide, rituximab may be an effective treatment in patients with vasculitic peripheral neuropathy. The

Abstracts


Method and Results: Case 1. 44 years-old male with history of severe scleritis which led to enucleation (and histological disease confirmation), deafness, headache, weight loss, dysgeusia, hyposmia, oral ulcers, arthritis, purpura and subcutaneous nodules. The diagnostic work-up detected multiple lung nodules. Serology: C-ANCA 1:40, PR3-ANCA 83 U/mL. He was started on high-dose prednisone (PDN) and IV-cyclophosphamide (IV-CYC); however, after 3 pulses, new purpura and progression of pulmonary nodules led to rituximab treatment (2 gr total). Two months later, while on azathioprine, he presented low-grade fever and symptoms of an upper respiratory tract infection. He started oral antibiotics. During follow-up, lung imaging (HRCT) showed a left lung ruptured nodule opened to pleura. Surgical drainage was performed. Cultures were negative, biopsy of the ruptured nodule confirmed GPA. Case 2. 44 years-old male with dysphonia, haemoptysis, fever, night sweats and 30-lb weight loss. He recalled prior history of left recurrent otitis with secondary facial nerve palsy, which required surgical management and high-dose PDN. Sent to our centre after detection of a pulmonary mass in X-rays, the chest CT reported this lesion involved and destroyed the right upper lobe, infiltrated pleura and soft tissues of the thoracic cage. Bronchoscopy and CT-guided biopsies were non-diagnostic; cultures were negative. Suspecting lung cancer, right superior lobectomy was performed. The findings were GPA-diagnostic. PR3-ANCA: >200 U/mL, The patient is currently under induction to remission therapy with IV-CYC and highdose PDN with favourable response. Discussion: Pulmonary nodules are present in 60–93% of patients. These are multiple and bilateral in 70% with random distribution, and may be the single manifestation in ~23% of patients. Tendency to cavitation increases with size, being greater when >20 mm in diameter. On the other hand, we are not aware of patients with a solitary nodule destroying the parenchyma and eroding the soft tissues of the thorax, which led to considering cancer as first likely diagnosis.

Table1. Clinicopathological features, therapy and treatment outcome of vasculitic neuropathy (for Abstract P85) Patient

Age at onset of vasculitis

Age at onset of VN

Sex Entity

Neuropathy FU time Induction type (mo) therapy

Maintenance therapy

Pain

Initial muscle strength

Pain improved at FU

Muscle strength at FU

AAV 1 2 3 4 5

67 65 65 44 65

74 65 65 44 65

m m m f f

AAV, Overlap GPA GPA GPA GPA

n.a. MM MM MM MM

108 122 9 7 136

CYC CYC, IVIG** RTX RTX, CYC** AZA

n y n y y

4-5 0 2 2 4

n.a. y n.a. y n

5 2 4 n.a. 5

6 7 8

62 78 60

62 78 60

f m f

MPA MPA MPA

MM AS AS

24 32 11

CYC, RTX* CYC RTX

MTX MMF RTX RTX AZA, MMF, MTX*, CYC, RTX RTX MMF RTX

y y y

3 3-4 3

n y y

5 5 3-4

NSVN 9 10 11 12

25 68 63 70

25 70 63 70

f f m f

NSVN NSVN NSVN NSVN

MM AS MM AS

113 164 9 15

AZA, CYC* CYC CYC MTX

MMF*, RTX AZA RTX MTX

y y y y

2-3 n.a. 0 n.a.

y y y n

2-3 n.a. 0 n.a.

PSS 13 14 15 16 17

71 52 69 46 69

61 51 69 52 74

f m f f f

PSS PSS PSS PSS PSS, low grade NHL

AS AS AS AS SP

144 76 9 59 17

MTX none, CYC* MTX, RTX* PLQ, RTX* AZA

MTX* None*** RTX RTX RTX

y y y n n

n.a. 0 n.a. 4-5 4

n y y n.a. n

n.a. 1 n.a. 4 5

RA 18 19

62 38

86 48

f f

RA RA

MM MM

7 70

MTX MTX CYC, PLX** MTX, TNFa

y n

0 0

n.a. n.a.

0 3

Others 20 21 22

58 48 35

66 48 35

f m m

CREST Syndrom PAN, acute Hep B EGPA

AS AS SP

33 97 142

RTX Entecavir CYC

y n y

3 1 3

y n.a. y

5 4 5

refused further therapy Entecavir AZA

VN = Vasculitic neuropathy; f = female; m = male; CREST = Calcinosis cutis- Raynaud phenomenon-Esophageal dysmotility-Sclerodactyly-Teleangiectasia-syndrome; EGPA = eosinophilic granulomatous polyangiitis; GPA = granulomatous polyangiitis; Hep B = Hepatitis B; MPA = microscopic polyangiitis; NHL = non-Hodgkin-lymphoma; NSVN = nonsystemic vasculitic neuropathy; PAN = panarteritis nodosa; PSS = primary Sjoegren Syndrome; RA = rheumatoid arthritis; AS = asymmetrical neuropathy; MM = multiple mononeuropathy; SP = symmetrical polyneuropathy; AZA = azathioprine; CYC = cyclophosphamide; IVIG = intravenous immunoglobulins; MMF = mycophenolate mofetile; MTX = methotrexate; PLQ = plaquenile; RTX = rituximab; TNFa = tumor necrosis factor alpha-inhibitor; y = yes; n = no; n.a. = not applicable. * For relapsing activity, ** for persistent activity, *** developed carcinoma; ****muscle strength = Medical Research Council grading system.

P86

ANCA-Associated Lung Fibrosis in Southern Spain Carlos Romero-Gómez, Josefa A. Aguilar-García, Ana M. Escribano-Dueñas, Fátima Fernández-Del Alamo, Maria Dolores Garcia-De Lucas, Rafael Cotos-Canca, Maria Dolores Martin-Escalante Hospital Costa del Sol, Marbella, Málaga, Spain

Last years several small series described patients with pulmonary fibrosis (PF) associated with ANCA vasculitis (VANCA). We have observed how PF is common presentation of VANCA.


From 1994 to 2004, 23 patients were diagnosed of microscopic poliangiitis (MPA). Only 5 had haemoptysis (21.7%), while 8 presented PF (34.7%). All this eight patients had ANCA-MPO, average 167 U/mL (45–327), 7 women (88%), the mean age were 72.8 years (46–81). It coincided PF with vasculitis in 7 (85%), only one patient (12%) had symptoms of PF before other symptoms of vasculitis, preceded by 24 months. The most common radiological pattern was UIP in 5/7, compared with a case NSIP and 2 with COP. In 63% had honeycombing, 88% bronchiectasis, 50% septal thickening, 25% ground glass, 25% consolidation, and 12% pleural thickening. Regarding pulmonary symptoms, none patients had hemoptysis, 2 patients had dyspnea at diagnosis (25%), the most common symptom cough 50%. In all patients crackles were presents. Symptoms of Systemic Vasculitis: fever 88%, weight loss 75%, peripheral neuropathy 50%, arthralgia 38%, cutaneous vasculitis 38%. Only two patients had altered sediment and proteinuria (25%), with normal renal function being in all patients. In 2 patients with rheumatoid factor, none had antinuclear antibodies. Only one patient lung biopsy was performed.


155


study is hampered by its small sample size and its heterogeneity. Prospective data from larger multicenter cohorts are needed to more precisely identify prevalence, pattern of nerve involvement and response to therapy in patients with peripheral nerve vasculitis.

Patients were treated with cyclophosphamide (3), methotrexate (2), only prednisone (2), and rituximab (1). All patients had clinical improvement, showing a progression of PF in one patient (with methotrexate and she died at 4 month), stabilizing lung function in 2 patients and improvement in 4 (57%). The patients was follow up on average 31 months (4–81), having presented recurrence of symptoms in 4 patients (50%). Conclusions: The clinical presentation of VANCA in our environment often presents with interstitial lung disease, being more frequent than haemoptysis and renal involvement. In some patients can be considered as a limited form of the disease.

P87

Pulmonary Involvement in ANCA-Associated Vasculitis – A Preliminary Report Aladdin Mohammad1,2, Judith Babar3, Kristian Mortensen3, Rona Smith1, Rachel Jones1, Daiki Nakagomi1, Pasupathy Sivasothy4, David Jayne1 1

Vasculitis and Lupus clinic, Addenbrooke’s Hospital, Cambridge, UK, 2Department of Clinical Sciences, Rheumatology, Lund University, Lund, Sweden, 3 Department of Radiology, Addenbrookes’s Hospital, Cambridge, UK, 4Department of Respiratory medicine, Addenbrooke’s Hospital, Cambridge, UK

Objectives: To study the clinical characteristics and outcome of patients with ANCA-associated vasculitis (AAV: granulomatosis with polyangiitis, GPA and microscopic polyangiitis, MPA) with chronic irreversible pulmonary involvement (PI, fibrosis and bronchiectasis) Methods: Patients with GPA and MPA treated followed at a University vasculitis clinic. All patients with diagnosis of GPA and MPA, based on clinical and histopathology findings, were included, and were stratified by proteinase 3 (PR3)-ANCA and myeloperoxidase (MPO)-ANCA serology. Pulmonary involvement (PI)

is defined as the presence of pulmonary fibrosis (PF) and/or bronchiectasis (not including pulmonary hemorrhage or nodular parenchymal disease) confirmed by computed tomography of the chest (CT-chest), at any time during the disease course. Patients were followed from AAV diagnosis to either death or June 1, 2014. Results: 260 patients (133 women) with GPA (n = 122) and MPA (n = 138) were included. CT-chest was available for 145 patients. 22/145 (15%) were found to have pulmonary involvement (PI) of which 16 (11%) had pulmonary fibrosis. Among patients with PI, 9 were PR3-ANCA positive and 13 MPO-ANCA positive (p = 0.251). Among patients with pulmonary fibrosis (PF), 5/16 (31%) were PR3-ANCA + compared to 11 (69%) were MPO-ANCA+ (p = 0.077). Patients with PI were older at diagnosis (66.2±10.0 years) compared to those without PI (59.3±16.5 years), p = 0.007. At diagnosis of AAV, there were no differences in inflammatory activity (table) or prevalence of extra-pulmonary organ involvement (data not shown). The mean time from diagnosis to end stage renal disease (ESRD) was 68.4 months (±46.9). The corresponding time to death was 77.4 months (±43.0). Among patients with PI, 1 (5%) developed ESRD compared to 37 (16%) of those without PI (p = 0.217). Among patients with PI, 3 (14%) died during followup compared to 50 (21%) of patients without PI (p = 0.582). For the whole cohort, survival was better among PR3-ANCA positive patients (p = 0.023). Conclusions: In this preliminary report, differences in serology, demographics and outcome were indicated for patients with AAV and pulmonary involvement compared to those without PI. The differences did, however, not reach statistical significance, possibly due to relatively few events. Studies of larger cohorts are warranted.

Table 1. Pulmonary involvement (PI) in patients with ANCA-associated vasculitis (for Abstract P87)

Age at diagnosis, mean ± SD Sex, female, n (%) Creatinine at diagnosis, median (IQR) CRP at diagnosis Creatinine last assessment GFR 500 μmol/l in only 38%); alveolar hemorrhage in 41%, most frequently associated with rapidly progressive renal failure, and requiring mechanical ventilation in one third of patients; uncontrolled vasculitis in 26%; extensive and severe multiple mononeuropathy in 18%, most frequently with acute onset and severe motor weakness; extensive skin necrosis in 4%. Median number of PE was 7 (1–12) during a median duration of 11 days (1–43). Side effects attributable to PE were: anemia (45%), venous thrombosis (8%), thrombocytopenia (8%), catheter-related infection (6%), bleeding (6%), arrhythmia (6%), and cardiovascular event (2%). PE were associated with corticosteroids in all cases (median dose 60 mg/day), with pulses of methylprednisolone in 76%, cyclophosphamide 82%, rituximab in 19%. Dialysis was required at last follow-up in 20% of patients with renal involvement, compared to 33% initially. In multiple mononeuropathy, severe motor sequelae were noted in 15%, compared to 55% initally. After a median follow-up of 17 months, 15 (12%) deaths were noted, among which 5 (4%) during the first 3 months. Conclusions: This study illustrates indications of PE for the treatment of primary necrotizing vasculitides, and shows that renal failure with serum creatinin level >500 μmol/l represents only 30% of indications of PE. Majority of patients exhibited significant side effects attributable to PE. Non validated indications need to be evaluated in prospective and controlled studies.

P93

The Role of Hydroxychloroquine in ANCA Positive and Negative Vasculitis Alina Casian, Shirish Sangle, David D’Cruz The Louise Coote Lupus Unit, London, UK

Objectives: To assess retrospectively the therapeutic efficacy and safety of hydroxychloroquine (HCQ) in patients with systemic vasculitis. Methods: Patients were identified by searching our departmental vasculitis database including 248 patients in total and electronic clinical records. Twenty-five patients received hydroxychloroquine along with corticosteroids and immunosuppressants. We assessed the effect of hydroxychloroquine on clinical symptoms and the median dose of corticosteroids required. Results: Twenty five patients with various vasculitides were treated with hydroxychloroquine (median dose 200 mg OD): 6 patients with Henoch Schonlein purpura (HSP), 6 urticarial vasculitis, 5 with ANCA+ vasculitis (AAV) (3 PR3-ANCA, 2 MPO-ANCA), 1 Eosinophilic Granulomatosis with Polyangiitis (EGPA), 2 Takayasu arteritis, 2 Behcet’s disease, 1 adult Still’s disease (AOSD), 1 relapsing polychondritis, 1 polyarteritis nodosa (PAN). The female: male ratio was 20:5. Median age was 53 years. The median duration of HCQ treatment was 3 years. Sixteen patients experienced a reduction in arthralgia, skin rashes improved in 8 patients and completely resolved in a further 4. Eight patients were able to reduce corticosteroid doses (from 9


159


three years (20% vs. 38%, p = 0.19). Subgroup analysis revealed a significant reduction in the number of patients reaching the primary endpoint among anti-Proteinase3 (PR3)-positive patients following PE (6% vs. 44%, p = 0.01). Furthermore, a greater improvement in renal function after three years was observed amongst surviving PE-treated patients not on dialysis (ΔeGFR 27.7 vs. 16.5 ml/min, p = 0.027).The PE-treated anti-PR3 positive patients had less relapses by three years (31% vs. 72%, p = 0.022) compared to patients not receiving PE. This was also observed after one year although not significant (6% vs. 32%, p = 0.07). There was no difference in types and doses of induction immunosuppressive therapy, but more patients in the PE group received Azathioprine (AZA) and less received Mycofenolate mofetil (MMF) as maintenance therapy compared to patients in the nonPE group. Conclusion: This study suggests that addition of PE to standard induction treatment with cyclophosphamide and glucocorticoids to patients with renal PR3-AAV should be evaluated as a way to improve long term outcome.


P94

Patient No.

Diagnosis

Nil

8

3 Behcet, 2 HSP, 1 AAV, 1 PAN, 1 urticarial vasculitis

Methotrexate + Prednisolone

5

2 HSP, 1 AAV, 1 AOSD, 1 polychondritis

Azathioprine + Prednisolone

3

1 HSP, 1 AAV, 1 urticarial vasculitis

Mycophenolate mofetil + Prednisolone

2

1 urticarial vasculitis, 1 EGPA

Mycophenolate mofetil

2

1 AAV, 1 Takayasu

Methotrexate

2

Urticarial vasculitis

Azathioprine

1

Takayasu

Prednisolone

1

AAV

Mepacrine

1

HSP

mg to 6 mg) and 3 could discontinue corticosteroids. Four patients developed fewer vasculitic relapses, 6 felt less fatigued, 2 patients no longer experienced abdominal pain and diarrhoea, 2 improved their mood and ability to think clearly. The 6 patients with ANCA associated vasculitis experienced improvement in arthralgia, reduced their prednisolone doses by a third, had fewer relapses and felt less tired. One patient developed asymptomatic QT prolongation on ECG and subsequently stopped the hydroxychloroquine, with no other adverse events reported. Conclusions: All 25 patients reported symptomatic benefits associated with hydroxychloroquine treatment, especially improvement in joint pains, fatigue, rash. Vasculitic relapses were less frequent, with a reduction in corticosteroid doses. Hydroxychloroquine was generally well tolerated.

160


The Influence of the Immunosuppressive Therapy on the Cardiac Function in Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss) Patients Wojciech Szczeklik1, Tomasz Miszalski- Jamka2,3, Barbara Sokolowska1, Krzysztof Karwat4, Karol Miszalski- Jamka5, Przemyslaw Jazwiec6, Lukasz Malek7, Hussein Al-Khalidi8, Jeanette Shulz- Menger9,10, Sophie Mavrogeni11, Alfred Mahr12, Wojciech Mazur13, Dean J. Kereiakes13, Jacek Musial1 1

Jagiellonian University Medical College, Deparment of Allergy and Immunology, Krakow, Poland, 2Department of Radiology and Imaging Diagnostics, John Paul II Hospital, Krakow, Poland, 3Center for Heart Disease, Clinical Military Hospital, Wrocław, Wroclaw, Poland, 4Department of Coronary Disease and Heart Failure, John Paul II Hospital, Krakow, Poland, 5Department of Cardiology, Congenital Heart Disease and Electrotherapy, Silesian Medical University, Silesian Center for Heart Disease, Zabrze, Poland, 6Department of Clinical Radiology and Imaging Diagnostics, Clinical Military Hospital, Wroclaw, Poland, 7 Department of Interventional Cardiology and Angiology, Institute of Cardiology, Warsaw, Poland, 8Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, USA, 9Charite University Medicine Berlin, Experimental and Clinical Research Center, Berlin, Germany, 10Department of Cardiology and Nephrology, HELIOS Klinikum Berlin-Buch, Berlin, Germany, 11Onassis Cardiac Surgery Center, Athens, Greece, 12Department of Internal Medicine, Hospital Saint-Louis, University Paris Diderot, Paris, France, 13The Christ Hospital Heart and Vascular Center/The Lindner Center for Research and Education, Cincinnati, USA

Introduction: Cardiac involvement remains the major predictor of mortality in eosinophilic granulomatosis with polyangiitis (EGPA) (Churg-Strauss syndrome). The efficacy of immunosuppression to limit cardiac involvement in EGPA remains unknown. Objectives: To assess the impact of non-steroid immunosuppression added to glucocorticoids on the cardiac involvement in EGPA. Methods: 65 patients with EGPA treated in years 1990–2013 were identified in the Jagiellonian University Medical College Vasculitis Registry (Kraków, Poland). Out of this group 51 patients with available data from the time of diagnosis, including: transthoracic echocardiography (TTE), complete clinical and laboratory data, and no severe valve dysfunction nor contraindication for the cardiac magnetic resonance (CMR) were enrolled to the study. The study follow-up visit was performed in disease remission and cardiac involvement was assessed with CMR in 4 tertiary centers. Main measured CMR outcomes, were: left ventricular (LV) ejection fraction (EF), and myocardial damage detected by the presence of late gadolinium enhancement (LGE). LVEF values

Abstracts


Additional immunosuppressive therapy

assessed by the CMR in follow-up were compared to those from TTE examination at the time of diagnosis. Statistical analysis was performed, comparing the CMR findings and clinical outcomes between two groups of patients – those that at the time of diagnosis were treated with additional immunosuppression (other than corticosteroids) n = 18 and those that were treated with corticosteroids alone (n = 33). Results: At diagnosis, 15 (29%) patients presented heart failure and 13 had LVEF 1 year. She has returned to work and maintains remission. Discussion: Laringotracheobronchial stenosis develops in 50% of PR patients. Often, infectious symptoms may be confused

Abstracts


P97

Impact of Pulmonary Rehabilitation in Extensive Laringotracheobronchial Stenosis in Relapsing Polychondritis (RP)

P99

B-Cells Recovery After Induction Therapy with Rituximab in a Cohort of AAV Patients Gina Gregorini1, Chiara Salviani1, Elisa Delbarba1, Guido Jeannin1, Antonio Regazzoli2, Giovanni Cancarini1 1

UO Nefrologia e Dialisi, Spedali Civili di Brescia, Brescia, Italy, 2Laboratorio Chimica-Clinica, Spedali Civili Brescia, Brescia, Italy

Objectives: Proposals of maintenance therapy with Rituximab are based on the assumption that time to B-cell recovery after Rituximab is usually 6–12 months and that there are no substantial differences among patients. The aims of our study were: 1 to evaluate the time to B-cells redetection and reconstitution after induction therapy with Rituximab; 2 to identify factors associated with differences in time of B-cell return among patients.

We examined only data obtained after the first Rituximab induction treatment. Methods: We retrospectively evaluated time to redetection (10–69/mm3) and reconstitution (>69/mm3) (as defined by Specks and coll.) of B-cells from patients receiving for the first time Rituximab for remission induction either at onset of disease or at relapse. Patients received Rituximab as 4 weekly infusions of 375 mg/m2 or 2 infusions of 1 g two weeks apart. All patients received glucocorticoids; plasma-exchange was added when indicated. Once remission was achieved, patients were maintained on low dose glucocorticoids (=500 mmol/L: group 1 and 90%. Treatment – in place of cyclophosphamide and plasma exchange, she was given methylprednisolone 250 mg IV Q6 hours x 9.5 days, Rituximab 1000 mg IV on days 0, 9 and 49, the 1st dose of Eculizumab 900 mg IV was given 8 hours after Ritux #1.She received a total of 3 doses of Eculizumab; #2 on day 7 and #3 on day 14. Bld draws were limited. Aminocaproic acid 1000 mg IV/hr was given on days 1–5. EPO 40 K units SC x 4 doses, and Venofer 1000 mg IV were given to stimulate erythropoiesis. Results: Clinical course: her pulmonary function remained precarious, but did not progress. Her hematocrit held at 17.4%. On day 5 her oxygenation improved. Her anemia improved to 23.8%/ Hgb 7.7 at discharge. Her last dose of anti-C5 was on day 14. Daily cyclophosphamide 100 mg was added on day 18. She was discharged on day 19. Between day 18 and day 49 her Cr rose from 1.04 to 3.03. ANCA level remained high at 1511 units. Her B cells remained 0. Conclusion: The patient was treated for 3 weeks with Rituximab, Eculizumab and steroids, during which time her lungs improved, her Cr remained stable and anemia started to improve, but her ANCA remained high. After finishing Eculizumab, her renal function deteriorated despite cyclphosphamide, continued B cell depletion and continued high dose steroids, but is holding at 2.23. The findings suggest that Eculizumab (antiC5) was highly effective in blocking active vasculitis, but that active vasculitis returned rapidly when Eculizumab was discontinued.

P106

Efficacy of Anakinra as First Line Therapy in Behçet’s Uveitis Giacomo Emmi1, Elena Silvestri1, Danilo Squatrito1, Daniela Bacherini2, Lorenzo Vannozzi2, Lorenzo Emmi3, Domenico Prisco1,3 1

Eculizumab – Anti-C5 Monoclonal Antibody: Use in the Treatment of Life Threatening ANCA Associated Vasculitis with Pulmonary Hemorrhage and Profound Anemia John Niles, Karen Laliberte, Katherine Cosgrove, Robert Makar Massachusetts General Hospital, Boston, Massachusetts, USA

Objectives: We report the first case of active vasculitis treated with Eculizumab (anti-C5 monoclonal antibody). Animal models show the importance of C5 in the development of ANCA injury. We describe the results using anti-C5 to treat a patient with

166


Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy, Florence, Italy, 2 Department of Translational Surgery and Medicine, Eye Clinic, University of Florence, Florence, Italy, Florence, Italy, 3 Interdisciplinary Internal Medicine, Center for Autoimmune Systemic Diseases, Behçet Center and Lupus Clinic, AOU Careggi, Florence, Italy, Florence, Italy

Objective: Behçet’s disease is a systemic vasculitis, and uveitis represents one of the most important organ involvement, with high rate of recurrence, resulting in partial or total blindness sometimes despite an appropriate approach. Treatments for ocular involvement in Behçet vary from local ones to systemic traditional immunosuppressants or biological agents such as anti-TNFα and IFNα. Recently growing descriptions have suggested in clinical practice a possible role also for anti-IL1 drugs (anakinra and canakinumab) in refractory Behçet’s uveitis.

Abstracts


P105

a

Fig. 1. Ocular involvement before and after 6 months of anakinra treatment: a) Color fundus photograph showing optic disc swelling, peripapillary retinal edema and hemorrhages in papillitis; b) Optical Coherence Tomography (OCT) demonstrating serous fo-

Methods: We describe the case of a 41 year-old gentleman, diagnosed as BD due to mucocutaneous, articular and severe ocular involvement; he had also a past medical history of abdominal pain with diarrhea and recurrent fever, spontaneously resolved 1 year after onset of symptoms. The patient, previously treated with low doses of corticosteroids, colchicine and eye drops, has recently developed a progressive visual reduction in the right eye due to acute papillitis, with a best corrected visual acuity of 20/400. After intravenous corticosteroids, then orally tapered, a maintenance therapy with anakinra 100 mg/day was started, without evidence of adverse events. Results: Anakinra allowed a rapid resolution of the ocular manifestations. Indeed further ophthalmological evaluations performed every two months, have shown after a 6 months follow-up, the resolution of the papillitis, the increase in BCVA to 20/25 and the stability of the ocular inflammatory disease (figure 1). Conclusion: In literature there are no evidences regarding the usefulness of anti-IL1 agents as first line therapy for ocular involvement in Behçet disease. In the present case, after 6 months follow-up, the patient no longer experienced ocular symptoms. Our first description of anakinra efficacy as first line treatment in Behçet’s uveitis could be important, in the light of anakinra good safety profile, especially in those patients requiring a rapid and persistent therapeutic response, but who present some contraindications to anti-TNFα treatment.

b

c

veal and interpapillomacular retinal neuroepithelial detachment; c) Color fundus photograph confirming complete resolution of the

papillitis after 6 months of therapy with anakinra (for Abstract P106).

P107

Withdrawn as requested by the authors

P108

Abdominal Visceral Adipose Tissue Measured by DXA as a Novel Surrogate Marker of Cardiovascular Risk in Primary Necrotizing Vasculitides (OSTEOVAS study) Bertrand Dunogué, Karine Briot, Sami Kolta, Alexis Régent, Pascal Cohen, Alice Berezne, Xavier Puéchal, Claire Le Jeunne, Luc Mouthon, Christian Roux, Loic Guillevin, Benjamin Terrier

Objectives: Studies have shown a strong prevalence of cardiovascular events among patients with primary necrotizing vasculitides. Recent studies indicate that visceral adipose tissue (VAT) is highly associated with insulin resistance and cardiovascular events. Dual energy X-ray absorptiometry (DXA) is a vali-



167


Cochin Hospital, Paris, France

sequelae and comorbidities have now become a major concern. Studies assessing the prevalence of osteoporosis, fractures and their determinants, in these patients are lacking. We aimed to assess the prevalence of osteoporosis and fractures in patients with vasculitides and to identify variables associated with their presence. Methods: Patients with AAV and PAN seen in our department were prospectively included in an ongoing cross-sectional study assessing bone complications and other sequelae (OSTEOVAS cohort). Lumbar spine and hip bone mineral density (BMD) and body composition (lean and fat masses) were measured by Dual X-ray Absorptiometry (DXA). Vertebral fractures were assessed using the Vertebral Fracture Assessment (VFA) measured by DXA. Demographic, clinical and biological, and treatment characteristics were assessed. Univariate and multivariate analyses were performed to assess associations between the presence of bone involvement and disease-related factors. Results: Sixty-five patients were analyzed (38 females and 27 males, mean age 50±18 years, with a mean disease duration of 85±79 months). Diagnoses were granulomatosis with polyangiitis in 33 patients, microscopic polyangiitis in 6, eosinophilic GPA in 18, and PAN in 8. The median daily dose of glucorticoids was 5 mg/ day (0–80), and 23/65 (35%) received bisphosphonates at the time of assessment. Osteoporosis was observed in 17 patients (26%) and vertebral fractures in 9 patients (14%). Overall, osteoporosis and/or vertebral fractures were observed in 22 patients (34%). Variables significantly associated with the presence of osteoporosis or vertebral fractures in multivariate analysis were an increased Vasculitis Damage Index [OR 1.80 (1.23–2.64); p = 0.002] and decreased grip strength [OR 5.56 (1.33–25), p = 0.019]. Among patients older than 40 years, the 10-year probability of major osteoporotic fracture was 10.2±8.4% using the FRAX. Using multiple linear regression analysis, FRAX was independently associated with VDI (p = 0.03), cardiovascular Framingham risk score (p = 0.006), and appendicular lean mass (p = 0.004). Conclusions: Osteoporosis and vertebral fractures are observed in one third of patients with primary necrotizing vasculitides. Decrease in muscular function assessed by grip strength is strongly associated with bone complications. Bone complications assessment and muscular function should be assessed and managed in clinical practice in patients with primary necrotizing vasculitides.

P109

P110

High Prevalence of Osteoporosis and Fractures Is Associated with Decreased Muscular Strengh in Primary Necrotizing Vasculitides (OSTEOVAS Study)

Late Onset Neutropenia After Rituximab in ANCA-Associated Vasculitis

Bertrand Dunogue, Karine Briot, Alexis Régent, Pascal Cohen, Alice Berezne, Xavier Puéchal, Claire Le Jeunne, Luc Mouthon, Christian Roux, Loic Guillevin, Benjamin Terrier

1

Cochin Hospital, Paris, France

Objectives: Overall survival of primary necrotizing vasculitides, including ANCA-associated vasculitis (AAV) and polyarteritis nodosa (PAN), has greatly improved over the last 50 years. Because of a longer survival and prolonged treatment, long-term

168


Ann Knight1, Ola Börjesson2, Annette Bruchfeld3, Iva Gunnarsson2 Inst of Medical Sciences, Dpt of Rheumatology, Uppsala University, Uppsala, Sweden, 2Dpt of Medicine, Unit of Rheumatology, karolinska University Hospital, Stockholm, Sweden, 3Dpt of Renal Medicine, Clintec, Karolinska Institute, Stockholm, Sweden

Background: Rituximab (RTX) is increasingly used in antineutrophil cytoplasmatic antibody (ANCA) associated vasculitis (AAV). Late onset neutropenia (LON) has been observed following RTX therapy in rheumatoid arthritis, systemic lupus erythema-

Abstracts


dated technique able to accurately determine cross-sectionally the mass of discreet fat deposits. We aimed to assess the relevance of abdominal adipose tissue measurement as potential surrogate markers for cardiovascular risk in patients with primary necrotizing vasculitides. Methods: Patients with ANCA-associated vasculitides (AAN) and polyarteritis nodosa (PAN) seen in our department were prospectively included in an ongoing cross-sectional study assessing cardio-vascular complications and other sequelae (OSTEOVAS cohort). Alongside the evaluation of usual clinical and extra-clinical features associated with increased cardiovascular risk, DXA was performed to evaluate body composition and abdominal adipose tissue (subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT). Results: Sixty-five patients were analyzed (38 females, mean age 50±18 years, mean disease duration of 85±79 months). Diagnoses were granulomatosis with polyangiitis (GPA) in 33 patients, microscopic polyangiitis in 6, eosinophilic GPA in 18, and PAN in 8. Five (7.7%) patients had developed cardiovascular complications. The median daily dose of corticosteroid was 5 mg/day (0– 80). High cardiovascular risk defined by the NCEP-ATPIII was found in 11 (16.9%) patients. Using univariate analysis, cumulated dose of corticosteroids (p = 0.038), Vascular Damage Index (VDI) (p = 0.008), and VAT/SAT ratio (p = 0.009) were significantly associated with high cardiovascular risk. Using multivariate analysis, VAT/SAT ratio remained independently associated with highrisk status [OR 1.07 (1.03–1.12), p = 0.004]. VAT/SAT ratio was also independently correlated with an increased Framingham cardiovascular risk score (p < 0.01). Among factors correlated with a higher VAT/SAT ratio, we identified male gender (p < 0.0001), age (r=+0.31, p = 0.014), cumulated corticosteroid dose (r=+0.26, p = 0.048), VDI score (r=+0.26, p = 0.04), Body Mass Index (r=+0.35, p = 0.006), waist circumference (r=+0.56, p < 0.0001), and elevated troponin levels at time of assessment (r=+0.36, p = 0.007). Conclusions: This is the first study showing a significant association between a high VAT/SAT ratio assessed by DXA and cardiovascular risk in patients with primary necrotizing vasculitides. Abdominal adipose tissue seems to be an accurate and independent surrogate marker of cardiovascular risk in these patients.

tosus and granulomatosis with polyangiitis (GPA) but data on microscopic polyangiitis (MPA) is not at hand. Neutropenia is associated with an increased infection risk but studies on the prevalence and consequences of LON in AAV are lacking. Methods: 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 the Karolinska University Hospital, Stockholm and Uppsala University Hospital, Uppsala. The patient charts were retrospectively reviewed for the occurrence of LON as well as for information on disease extent, previous and concomitant medication, immunoglobulin levels etc. For inclusion in the study, a minimum follow-up time of 6 months after latest RTX was required. LON was defined as a neutrophil count < 1.5 10E9 with onset >one month after treatment. Results: Seven of the total 59 patients (11.9%) developed LON after a median time of 13 months since first rituximab dose. Of the seven LON patients, 5/47 (10.6%) had a diagnosis of GPA and 2/12 (16.7%) of MPA. A majority of patients were given RTX as second line treatment. The most common dose regimen for RTX was 1000 mg administered twice two weeks apart. Three of the patients developed LON after the first RTX treatment and four had received repeated courses. Five of the patients developed infectious symptoms; 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. Six of seven LON patients had previously been treated with CYC. One patient had ongoing CYC treatment, and three had treatment with azathioprine or mykofenolatmofetil at the time of LON. Previous treatment with anti-TNFs was more common in the LON group. Conclusion: LON is a potentially severe but not uncommon side-effect of RTX treatment in AAV. Repeated RTX courses did not increase the risk of LON. The patients who developed LON did not differ from the non-LON patients in respect to previous or ongoing treatment with DMARDs with the exception of previous anti-TNF treatment. LON in AAV carries the risk of serious infections and increased surveillance for LON in AAV patients treated with RTX is recommended.

P111

Symptomatic and Asymptomatic Venous Thromboembolic Events in ANCA-Associated Vasculitides Egor Makarov1, Sergey Moiseev1,2, Leonid Strizhakov2, Pavel Novikov2 1

Lomonov State University, Moscow, Russia, 2Sechenov First Moscow State Medical University, Moscow, Russia

Objectives: To evaluate the prevalence of symptomatic and asymptomatic VTE and other veins thrombosis in a cohort of AAV patients. Methods: We retrospectively studied the health records of 367 patients with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA) that complied with CHCC2012 definitions. The classic risk factors of thrombosis were evaluated in patients with a history of symptomatic DVT, PE or other veins thrombosis. We also studied the occurrence of asymptomatic DVT in patients with AAV using compression US. Results: There were 30 (8.4%) cases of VTE and other veins thrombosis in our cohort of AAV patients (table 1). The frequency of VTE in EGPA was higher (10.1%) than in GPA (8.2%) and MPA (6.7%) probably due to thrombogenic effect of eosinophilia. The majority of patients with thrombotic complications were relatively young, developed VTE during first year after diagnosis and had no other known risk factors for thromboembolic events. Moreover, compression US showed asymptomatic DVT in 4 (9.5%) of 42 patients with AAV. Conclusions: Patients with AAV have a high risk of VTE and other veins thrombosis. Active disease apparently predisposes to thrombotic events as the majority of patients developed VTE within the first year after diagnosis. In a pilot study we also showed high prevalence of asymptomatic DVT in AAV patients. These data may justify wider screening for DVT in AAV though obviously we need more data.

Table 1. Characteristic of patients with VTE events (for Abstract P111)

VTE, n (%) Males, n Median age, y (range) Traditional VTE risk factors* VTE events: DVT DVT + PE Other vein thrombosis** Time to VTE after diagnosis First 6 months First 12 months Death from any cause Death from PE

GPA (n = 243)

MPA (n = 45)

EGPA (n = 69)

Total (n = 357)

20 (8.2) 11 51 (25–78) 5 14 12 2 8

3 (6.7) 2 49 (46–64) 1 2 2 0 1

7 (10.1) 3 53 (30–65) 2 5 5 0 2

30 (8.4) 16 52 (25–78) 8 21 19 2 11

5/16 8/16 2 0

3/3 3/3 0 0

2/5 3/5 0 0

10/24 13/24 2 0



169


* Metabolic syndrome, type 2 diabetes melitus, multiple IV injections, chronic venous insufficiency; ** orbital vein (2), jugular vein (1), renal vein (1), testicular vein (1), superficial veins (6).

P112

P113

Quo Vadis: Are Infections During Induction of Remission in ANCA Associated Vasculitis Related to Cyclophosphamide or Glucocorticoids Exposure?

An Audit on the Prevention of Long-Term Complications in Patients with an ANCA-Associated Vasculitis

Elizabeth

Krarup2,

Martin

Egfjord1

1

Rigshospitalet, Copenhagen, Denmark, 2Herlev hospital, Copenhagen, Denmark

Objectives: In ANCA Associated Vasculitis (AAV), infections during induction treatment are closely correlated to mortality and morbidity. Among patients in the EUVAS trials, infections were the direct cause of mortality in 50% of cases while active vasculitis only accounted for 14% (Little et al.).The severe infections mainly occur during the first 3 months when prednisolone (CS) dose is high and cyclophosphamide (CYC) is administered, however it is still discussed, which of these two agents accounts for the highest risk of becoming infected. In Pexivas RCT a reduced CS dose arm will answer if there is CS relation, furthermore B. Brezina –Cambridge presented at EUVAS meeting in Paris June 2014 results of infection independence to CYC exposure. Methods: At Rigshospitalet between 2000 and 2010 induction treatment consisted of standard CS 1 mg/kg tapered to 20 mg at 3 months and 5 mg at 6 months + low dose of CYC (100 mg/ day in pts < 65 years and 50 mg/day in pts > 65 years) combined with Plasma Exchange (PLEX) in 106 pts. Since 2005 all pts received PCP prophylaxis. Azathioprine or Mycophenolate Mofetil was given for maintenance of remission after 4 months. Results: 132 pts were admitted and 115 followed for a mean of 5.7 years (range 0.2–12.3; 676 pt years), 79 pts < 65 years and 100 mg CYC/day and 37 pts > 65 years and on CYC 50 mg/day. 53 pts (46%) had 78 episodes of infections, 43 admission demanding during the follow up. 34 of these episodes (44%) occurred during induction treatment, 6 in patients on CYC50 mg/day. Only 2 patients died of infection during CYC treatment (2%), all during the initial month, 1 of septicaemia and 1 of UTI (all on HD) and were on CYC 100 mg/day, both had leucopenia which occurred in 23 (19%) pts. Most common was pneumonia (39%) followed by UTI (15%) whereas only 13% had septicaemia (77% during induction treatment). The most common microbial agent was herpes zoster (8%). Only 2 of our pts had CMV and 1 pt PCP, all before 2005. No difference in infections dependent on ± PLEX was observed (45/51) Conclusions: Thus our cohort, which has been treated with a relatively low dose CYC-regime combined with standard CS and PLEX exhibited lower infection morbidity and mortality rates, when compared to the elsewhere reported results.

170


Mir Naushad Amin1, Sahena Haque2, Michael Venning3, Nina Brown3 1

University of Manchester, Manchester, UK, 2University Hospital of South Manchester, Manchester, UK, 3Central Manchester University Hospital, Manchester, UK

Objective: The aim for this audit was to assess whether patients were receiving the correct adjuvant treatment and counselling in order to protect them against the long term complications of ANCA-associated vasculitis and the side effects from treatment. Methods: Patients under the Rheumatology or Renal team from the University Hospital of South Manchester (UHSM), with a diagnosis of an AAV, were identified by the North West Renal Vasculitis Team. Audit standards were set using 2008 EULAR recommendations and BSR/BHPR guidelines for management of patients with vasculitis, therefore patients diagnosed before the publication of the 2008 EULAR recommendations (April 2008) were excluded from this audit. Standards were set at 100% unless stated otherwise. Data was collected retrospectively from patient’s medical records, and electronic secondary care records. Results: We were able to identify a total of 48 patients with AAV under the care of UHSM, of which 22 patients were diagnosed after April 2008, comprising of 12 male and 10 female patients, with ages ranging from 23 to 70 years of age. Of these patients, 25% were assessed for their risk of tuberculosis prior to treatment and 77.2% and 72.7%, were given the influenza and pneumococcal vaccines respectively. Only 4.76% of patients had a full cardiovascular risk assessment in the 12 months prior to this audit. This comprised of monitoring the patients’ blood pressure (95.24%), weight (90.48%), cholesterol (80.95%) and HbA1c/ fasting glucose levels (76.19%) and counselling patients about smoking cessation (0% documented) and exercise (23.81% documented). From the patients treated with intravenous cyclophosphamide, 87.5% received Mesna, 91.6% were monitored for bladder cancer with a urinalysis in the 12 months prior to this audit and 40% of women were documented to have been advised to have cervical smears. 37.5% of these patients were informed about the risk of infertility; however, no male patients had a documented offer of sperm banking. Conclusions: Although these patients were receiving adequate treatment for their AAV, optimal preventative management for the complications of disease and treatment were not uniformly applied. The majority of patients were receiving the correct interventions; however there is room for improvement with regards to counselling these patients about possible risks associated with treatment of the disease, such as infertility and encouraging uptake of protective measures.

Abstracts


Wladimir

Szpirt1,

P114

P115

Risk of Cancer Is Increased in Norwegian Patients with Biopsy-Proven ANCAAssociated Glomerulonephritis 1988–2012

Decreased Risk of Bladder and Haematological Malignancies in ANCA-Associated Vasculitis in Relation to Novel Therapy Regimens

1

Department of Medicine, Haukeland University Hospital, Bergen, Norway, 2Cancer Registry of Norway, Oslo, Norway, 3Department of Nephrology, St Olavs Hospital, Trondheim, Norway

Objectives: Several studies have shown an increased risk cancer in patients with ANCA associated vasculitis (AAV). Few studies have specifically investigated risk of cancer in patients with AAV having biopsy proven ANCA associated glomerulonephritis (AAGN). Methods: Patients diagnosed with pauci-immune crecentic glomerulonephritis, most of whom also having a positive ANCA test, registered in the Norwegian Kidney Biopsy Registry (NKBR) 1988–2012 were included. Using the unique 11-digit Norwegian personal identification number, the study cohort was linked to the Cancer Registry of Norway and standardized incidence ratios (SIR´s) were calculated for all-type cancer and site-specific cancers. Patients with cancer prior to AAGN were excluded. The observation period was time from diagnostic kidney biopsy to death or end of year 2012. Results: We included 485 patients in the analyses (523 patients with AAGN were identified in NKBR, but 38 were excluded because of cancer prior to AAGN diagnosis). Mean age in the study population was 58 years (SD 17 years) and 267 (55%) were males. Mean duration of follow-up was 7.2 years (SD 6 and range 0.0–24.3 years). During follow-up 63 cancers (all-sites) were diagnosed and the expected number was 41.0, giving a SIR of 1.5, 95% CI 1.2–2.0. Risk of the following site specific cancers were increased; Skin (non-melanoma) SIR 5.5 95% CI 3.1–9.6, Leukemia SIR 5.0 95% CI 2.2–11.1, Prostate SIR 2.3 95% CI 1.1–4.6 and Lung SIR 2.3 95% CI 1.2–4.2. Conclusions: Risk of cancer is significantly increased in Norwegian patients with AAGN. However, a SIR of 1.5 is lower than in most previous studies addressing risk of cancer in patients with AAV. A particularly high risk of non-melanoma skin cancer (SIR 5.5) and leukemia (SIR 5.0) was found, this is in accordance with previous studies. Somewhat surprisingly, risk of cancer in the bladder/urinary tract was not significantly increased. In the present study-cohort, many patients have been treated with traditional high dose cyclophosphamide (CYC) regimens but a substantial fraction of patients has received CYC sparing regimens (substitution of CYC with azathioprine after remission and/ or iv pulse instead of po CYC). We plan to also investigate the importance of CYC regiment for risk of cancer in AAGN patients.


Chinar Rahmattulla1, Annelies Berden1, Sophie- Charlotte Wakker1, Marlies Reinders1, E. Christiaan Hagen2, Ron Wolterbeek1, Jan Bruijn1, Ingeborg Bajema1 1

Leiden University Medical Center, Leiden, The Netherlands, 2Meander Medical Center Amersfoort, Amersfoort, The Netherlands

Objective: The introduction of immunosuppressive therapy has dramatically improved the prognosis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). As a result, attention has shifted to long-term complications in patients. In this study, we investigated the incidence of malignancies in a well-defined AAV population. Additionally, we investigated the effect of therapy on malignancy incidence. Methods: We included patients with histopathologicallyproven AAV, diagnosed between 1991 and 2013 at a large university hospital. Malignancy incidence was assessed with the Dutch National Pathology Database. We used the Netherlands Cancer Registry incidence rates for comparing the malignancy incidence in our AAV cohort to that of the general Dutch population. Results: Thirty-six of 138 patients with AAV developed a total of 85 malignancies during a mean follow-up of 9.7 years. The malignancy risk was 2.21 (95% CI: 1.64–2.92) fold higher than that of the general population. Non-melanoma skin cancers occurred most frequently (standardized incidence ratio: 4.23, 95% CI: 2.76–6.19). The incidences of other reported malignancies were not significantly increased. Malignancy risk was associated with the duration of cyclophosphamide therapy. Interestingly, malignancy risk was not increased in patients that received cyclophosphamide for less than 1 year. Conclusion: Patients with AAV have a higher risk of malignancies than the general population, but this risk is accounted for solely by non-melanoma skin cancers. Over the years, the risk of other malignancies – specifically bladder and haematological malignancies – has decreased in patients with AAV. This finding reflects ongoing efforts to reduce cyclophosphamide exposure by developing new therapy regimens.


171


Rune Bjørneklett1, Sanjeevan Sriskandarajah1, Bjørn Møller2, Tor Åge Myklebust2, Knut Aasarød3

P116

P117

Two Case Reports of Progressive Multifocal Leukoencephalopathy (PML) in Granulomatous Polyangiitis (GPA) Treated with Rituximab

Unusually High Rate of Idiosyncratic Drug Reaction to Azathioprine Among ANCA-Associated Vasculitis Patients in Adelaide, Australia

Paul Brunetta1, Carmen Martin2, Patricia B. Lehane2, Nicole Mairon3

Chen Au Peh

1

2

Background: Two cases involving patients with granulomatous polyangiitis (GPA) who developed progressive multifocal leukoencephalopathy (PML) were spontaneously reported into the company global safety database. To our knowledge, these are the first reports of confirmed PML in GPA patients treated with rituximab. PML is a frequently fatal demyelinating disease of the central nervous system (CNS) that results from lytic infection of glial cells caused by the John Cunningham polyomavirus (JCV). Immunosuppression is a common risk factor, due to either human immunodeficiency virus (HIV) infection, malignancy or immunosuppressive therapies. Rituximab in combination with glucocorticoids is indicated for the induction of remission in adult patients with severe, active GPA and microscopic polyangiitis (MPA). Case Reports: The first patient was a 70-year-old woman with a history of immunoglobulin deficiency, breast cancer, diabetes mellitus and vasculitis with chronic stage III renal insufficiency. She had no history of HIV infection, bone marrow or solid organ transplant, opportunistic infections or CNS disease. Prior treatments included cyclophosphamide, epirubicin, fluorouracil, prednisolone and methotrexate. Concurrent treatment included azathioprine. Two months after the last infusion of rituximab, the patient presented with forgetfulness, difficulty in finding words and walking. Some of these symptoms were reported as present prior to rituximab treatment. A brain MRI revealed white matter lesions, and JCV was identified in cerebrospinal fluid (CSF). The patient discontinued azathioprine, received immune apharesis, and was treated with cidofovir, mirtazapine and mefloquine. The second patient was a 62-year-old man with an 8-year history of GPA. He had received prior treatment with cyclophosphamide, azathioprine and high-dose glucocorticoids and was HIV negative without other known immunodeficiencies. The patient received rituximab over 2 years. About four months after the last dose, the patient developed severe headache, memory difficulties, slight confusion and speech impairment. Two brain MRIs showed alterations characteristic of PML, and JCV was detected in the CSF. He was treated with mefloquine, cytarabine and mirtazapine. At the time of reporting, the condition of both patients had improved. Discussion: Overall, the number of patients with GPA or MPA treated with rituximab is estimated to be 32,000 to 40,000. PML remains very rare in this population, which is frequently pretreated with immunosuppressives, such as cyclophosphamide, known to independently confer a risk of PML. Multiple risk factors for this rare event make attribution to any single factor challenging. Continued awareness of PML and vigilant reporting remain important priorities to assess its prevalence and outcome.

172


Royal Adelaide Hospital, Adelaide, Australia, University of Adelaide, Adelaide, Australia

Background: Azathioprine is commonly used as maintenance therapy in patients with ANCA-associated vasculitis (AAV). Methods and Results: Among 44 patients who were diagnosed with AAV between 2008–2014 in one centre in Adelaide, 9 had to cease Azathioprine due to severe idiosyncratic drug reaction (20%). Typically, this occurred 12 to 16 days after commencing Azathioprine. This rate of idiosyncratic reaction is unusually high compared to what had been reported in the literature. The adverse reactions included high fever, severe skin eruption, arthritis and interstitial nephritis. High CRP was a uniform laboratory finding. The median age of these 44 patients was 67 years. 24/44 had PR3+ve AAV; 20/44 had MPO+ve AAV. Among those who experienced idiosyncratic reactions, no apparent association was found with ANCA subtype, gender or age. Discussion: Thiopurine S-methyltransferase (TPMT) polymorphism is currently being typed to see if it might explain this unusually high rate of idiosyncratic reaction.

P118

Strongyloides Stercolaris Infection Associated with Eosinophilic Granulomatosis with Polyangiitis: A Case Report Paula Mendoza, Vanesa Antoñana, Raquel Rodil, Maria Areses, Manuel Gonzalez, Carlos Perez Complejo Hospitalario de Navarra, Pamplona, Navarra, Spain

Objectives: Strongyloides stercolaris infection is endemic in tropical and subtropical regions. Manifestations of infection can range from asymptomatic eosinophilia in the immunocompetent host to disseminated disease with septic shock in the immunocompromised host. We report a case of Strongyloides stercolaris infection with eosinophilic pleural effusion who developed a few months later eosinophilic granulomatosis with polyangiitis (EGPA). Method: We have retrospectively reviewed the clinical, laboratory, and histological data of this case. Results: In 2012, a 52-year old-man living in Paraguay, was diagnosed of posible cerebral vasculitis based on fever, acute ataxia and loss of conciousness. Magnetic resonante Imaging revelaed multiple bilateral, periventricular hyperintense lesions on T2weighted images. The results of cerebrospinal fluid (CSF) analysis were normal. Blood, urine, stool, and CSF cultures were negative

Abstracts


Genentech, Inc., South San Francisco, California, USA, 2 Roche Products Ltd., Welwyn Garden City, England, UK, 3 F. Hoffmann-La Roche Ltd., Basel, Switzerland

1

for organisms. He was treated with antibiotics and corticosteroids and then azathioprine, with complete resolution of his symptoms. He presented an acute hepatitis secondary to azathioprine. He had a past history of asthma, arthralgias, abdominal pain, and nasal polyposis. Autoimmune analyses were negative, for many years. In 2013, he was admitted to our hospital with a 4-week history of fever, abdominal pain, arthralgias and pain on the left side of the thorax. The blood analysis showed leukocytosis with eosinophilia. An increase of C reactive protein and erythrocyte sedimentation rate, were observed. No circulating immune complexes, cryoglobulins, antinuclear antibodies, rheumatoid factor, or antineutrophil cytoplasmic antibodies were detected. A thoraco-abdominal scanner was performed showing left pleural effusion, and a jejunal thickening. An enteroscopy was carried out showing a few eosinophils in jejunum, without histologic evidence of vasculitis. Stool analysis and serology were negative to parasite. The results of the thoracocentesis revealed hemorrhagic pleural fluid, containing high rate of eosinophils. Nor tumor cells neither microbiological agent were found. Nasal polyp biopsy specimens showed an eosinophilic infiltrate without signs of vasculitis. He underwent a surgical thoracoscopy and the pleura biopsy showed an eosinophilic infiltrate and PAS-positive forms, suggesting the diagnosis of Strongyloides stercoralis infection. After initial Ivermectin treatment, there was clinical improvement with persistent eosinophilia. A few months later, the patient was studied in another hospital, and he had a cutaneous rash. A cutaneous biopsy was done and showed evidence of eosinophilic vasculitis. The patient was diagnosed with EGPA and treated with corticosteroids and cyclophosphamide, with improvement of the symptoms and signs. Conclusions: We suggest that Strongyloides stercolaris infection may have played a role in triggering EGPA in this patient.

Grampian region of Scotland with radiologic evidence of large vessel vasculitis. Following retrospective record review, cases were selected based on fulfilment of the CHCC 2012 GCA definition and a first line prescription of GC and MMF combination therapy. Baseline and follow-up characteristics were collated and summarised using descriptive statistics. Results: Seven patients were identified: 2 male, mean (SD) age at diagnosis 67 (4.8) years and mean disease duration 27.6 (12.6) months. At diagnosis, the mean CRP was 72.8 (49.2) mg/l and positron emission tomography–computed tomography (PET CT) confirmed evidence of active large vessel vasculitis in all patients. Following 6 weeks of therapy, there was a dramatic reduction in the mean CRP level to 10.3 (10.56) mg/l, a response which was maintained at one year (mean CRP level of 8.4 (6.7) mg/l). Similarly, Prednisolone usage decreased from a mean dose of 54.3 (9.7) mg at diagnosis to 7.5 (2.0) mg at one year follow up. The mean cumulative GC dose at one year was 5.9 (1.7) g. Throughout follow up, only one patient experienced a relapse which responded to an increment in the MMF dose. MMF was switched to Mycophenolic acid in one patient due to diarrhoea, but was otherwise well tolerated, with no reported severe adverse effects. At last follow-up, all patients remained well on MMF (or derivative) and were asymptomatic on Prednisolone ≤7.5 mg. Conclusions: MMF appears to be a safe and effective steroid sparing immunosuppressant in patients with LV-GCA, allowing a rapid taper of GC.

P120

Long-Term Outcomes of Takayasu’s Arteritis Patients with Renal Artery Involvement Corisande Baldwin1, Aladdin Mohammad2,3, David Jayne3 1

Mycophenolate Mofetil: A Useful Tool in the Management of Large Vessel Giant Cell Arteritis? Dospinescu1,

Paula Dana Lars Erwig3, Neil Basu3

Kidder2,

Nicholas

Fluck2,

1

Department of Rheumatology, NHS Grampian, Aberdeen, UK, 2Department of Renal Medicine, NHS Grampian, Aberdeen, UK, 3Musculoskeletal Collaboration, School of Medicine and Dentistry, University of Aberdeen, Aberdeen, UK

Objectives: Large vessel involvement in giant cell arteritis (LV-GCA) represents a challenging disease subset characterised by high glucocorticosteroid (GC) requirements and poor outcomes. Although recommended, the evidence base which underpins the prescription of adjuvant GC sparing therapies such as Azathioprine and Methotrexate is weak and for Mycophenolate mofetil (MMF) surprisingly absent. To our knowledge, we describe the first case-series of MMF use in LV-GCA. Method: Departmental databases identified all LV-GCA patients diagnosed between January 2008 and January 2014 in the


University of British Columbia, Vancouver, British Columbia, Canada, 2Lund University, Lund, Sweden, 3 Addenbrooke’s Hospital, Cambridge, UK

Background: Takayasu’s Arteritis (TAK) is a chronic granulomatous inflammatory large vessel vasculitis involving the aorta and its branches. TAK incidence is 2.6/million annually. Prevalence is higher in Asian and Indian populations. TAK predominantly affects woman under 40 years of age. Renal artery involvement (RAI) in TAK is a poor prognostic factor. However, long-term outcomes of TAK patients with RAI have not been reported. Methods: We performed a retrospective chart review of 50 patients. TAK diagnosis was based on the presence of constitutional symptoms, elevated inflammatory markers, and vascular abnormalities on angiography. RAI was identified based on conventional angiography, CTA or MRA. Patient demographics and presenting symptoms, signs, co-morbidities, blood pressure, medications and laboratory values were collated. Disease activity was assessed using the Indian Takayasu Clinical Activity Score 2010 (ITAS2010). Irreversible organ damage was assessed using the vasculitis damage index (VDI). Worsening renal function was defined as a drop in eGFR > 20%. Results: Sixteen of 50 (32%) TAK patients were identified to have RAI. Fifteen (94%) were female, 13 (81%) were white. Mean age at presentation was 32 years (9–68). Fourteen (88%) met the


173


P119


Age at diagnosis (years) Presenting symptoms

63

Patient 2 63

Myalgia, arthritis, limb claudication, absent radial pulse, blood pressure (BP) difference

Polymyalgia rheumatica, sweats, fatigue, weight loss, headache, jaw claudication

Duration of presenting symptoms (months)

12

4

CRP at diagnosis (mg/l)

88

Baseline Prednisolone dose (mg)

Patient 3

Patient 4

76

Limb claudication, absent upper limb pulse

65

Patient 5 66

Polymyalgia rheumatica, general malaise, reduced appetite, weight loss, limb claudication, BP difference

Patient 6 65

Fever, fatigue, drenching sweats, Raynaud’s phenomenon, shoulder girdle myalgia, BP difference

Fever, night sweats, reduced appetite, weight loss, Raynaud’s phenomenon, arthralgia

Patient 7 71

Raynaud’s phenomenon, pulmonary oedema, goitre

6

16

6

6

4

123

17

4

88

132

58

40

60

60

40

60

60

60

CRP at 1 year (mg/l)

10

22

11

4

4

4

4

Prednisolone dose at 1 year (mg)

10

05.júl

5

5

05.júl

10

5

Total follow-up duration (months)

50

30

27

14

32

28

12

Prednisolone dose (mg)at last follow-up

5

2

5

5

7

4

05.júl

12 м/с, n (%)

122±18 78±12 44±12 –26±21 10±8 140±18 7.9±1.8 11 (22.4)* 0

126±17 81±9 45±12 –21±22 11±8 141±16 7.5±1.3 1 (4.0) 0



213


BP = Blood pressure. * p < 0.05 compared to control group.

Results: The median SDMA levels in patients with active disease at entry (>0.971 μmol/l) was significantly higher in older patients (p < 0.001) who had more cardiovascular disease (18.4% vs 2.6%, p = 0.025), more chronic kidney disease (p < 0.01) and shorter follow up days alive (1630±1269 vs 2166±975). Only SDMA levels were significantly higher in serum samples from active disease vs remission (p = 0.001) and in patients with MPO ANCA (p = 0.026). In a multivariate analysis there was no association between ADMA/SDMA levels and CVE at 5 year followup. Higher SDMA levels (>mean of 0.971 μmol/l) predicted worse outcome for the composite endpoint of death and ESRD at 5 year follow-up, independent of entry creatinine level. Conclusions: SDMA/ADMA levels were not predictive of CVE at 5 year follow-up. However, the, overall CVE rate was low in the present cohort of AASV. Interestingly, entry SDMA and not ADMA levels were significantly associated with poorer survival (death/ESRD), independent of entry creatinine levels. This novel finding in a large and uniformly treated group of AASV patients indicates a different mechanism or endothelial response in AASV. This should be further explored in a larger cohort of AASV patients with a higher CVE rate and/or a longer follow up. Moreover, these findings should be correlated to other markers of vascular damage.

having an ANCA rise during remission were included. Differences in time to relapse since the ANCA rise were assessed using a cox regression model. Results: Sixty patients with an ANCA rise were included, of whom 36 patients relapsed. Three risk factors were significantly and independently associated with a relapse at the time of the ANCA rise: induction regimen lacking cyclophosphamide or rituximab (HR3.48 [95% CI 1.60–7.59]), an ANCA rise during the fall season (HR4.37 [95% CI 1.60–11.90]) and an extended ANCA rise (HR3.57 [95% CI 1.50–8.48]). Current immunosuppressive therapy and antibiotic maintenance therapy did not protect the patient for a relapse (p = 0.542 and 0.922, respectively). Conclusion: ANCA rises occurring during the fall season are more frequently followed by a relapse than ANCA rises occurring during other seasons. Whether insufficient vitamin D levels or (viral) respiratory tract infections are responsible for this phenomenon should be further studied.

P191

Validation of the ‘Combined Burden of Events’ Score Quantifying Adverse Events and Mortality in ANCA Vasculitis in an Inception Cohort from the Southeastern United States

P190

Fernanada Schober1, Mona Shaban1, Caroline Poulton1, William Pendergraft III1, Yichun Hu1, Patrick Nachman1, Ronald Falk1, Mark Little2, Susan Hogan1, Lorraine Harper3, JulieAnne McGregor1

Risk Factors for a Relapse at a Rise of Anti-Neutrophil Cytoplasmic Antibodies in Vasculitis Patients with Renal Involvement Michael Kemna1,2, Jan Damoiseaux3, Pieter van Paassen1, Jan Willem Cohen Tervaert0

1

University of North Carolina, Chapel Hill, NC, USA, Centre for Nephrology, University College London, Royal Free Campus, London, UK, 3Department of Renal Immunobiology, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK

2

1

Cardiovascular Research Institute Maastricht (CARIM), Maastricht, The Netherlands, 2Department of Internal Medicine, Clinical and Experimental Immunology, Maastricht University Medical Center, Maastricht, The Netherlands, 3Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht, The Netherlands, 4 Sint Franciscus Gasthuis, Rotterdam, The Netherlands

Objective: The use of an ANCA rise to guide therapy in patients with ANCA-associated vasculitis (AAV) is controversial. The objective of this study is to identify patient characteristics at the time of an ANCA rise associated with a relapse. Methods: All patients between January 2000 and November 2011 with a diagnosis of AAV and previous renal involvement

Objectives: To evaluate how the ‘combined burden of events’ CBOE score (Little et al, ARD 2009) predicted 1-year mortality in the Glomerular Disease Collaborative Network (GDCN) inception cohort of patients with ANCA vasculitis. Methods: CBOE results in 341 patients who died within or had at least 12 months of follow-up from the GDCN were compared to 524 EUVAS patients. Adverse events were weighted by severity and summed to an overall CBOE score. Cox proportional hazards models were used.

214

HR (95% CI), p value

EUVAS: controlling for eGFR

GDCN: univariate associations

GDCN: controlling for eGFR

Leukopenia score Infection score CBOE score eGFR

1.2 (1.1, 1.2), 50%. Thus, the destructive lesion of the upper way respiratory tract was proved to be IgG4-related. The PRED dose was increased to 0.6 mg/kg, the patient was given a full dose of CYC p.o. One month later there was no disease progression. If the treatment proves ineffective we will consider therapy with rituximab. Conclusions: IgG4-related paranasal sinus destructive lesion is possible in the setting of localized GPA and has a significant impact on the course of the disease and efficacy of treatment. Whether we should consider this lesion to be an independent nosological form (i.e. IgG4-related disease) is an open question. We suggest that IgG4-positive plasma-cells might be merely a marker of a GPA subtype, characterized by the development of the progressing destructive lesion, refractory to standard treatment, which may require therapy with rituximab.

es in the right temporal lobe and in the pontine area. Brain noncontract MRA revealed no changes. He worsened with dizziness, somnolence, vomiting and low-grade-fever in 2012, 2-fold CRP elevation was found. MRI showed progression of the cerebral small multiple hemorrhages and ischemic infarcts. Infectious, inherited, demyelinating, connective tissue diseases, antiphospholipid, paraneoplastic syndromes and coagulopathy were excluded, CSF was normal, low-grade fever and 2–3-fold CRP persisted. 16 mg of dexamethasone per day improved all the symptoms but was tapered off in two months. Along 2013–2014 the patient had several recurrent episodes of deterioration after a long alcohol abuse and another episode of closed head injury followed by multiplying of the hemorrhagic and ischemic brain lesions. A large temporal intracerebral hemorrhage occurred in the beginning of the 2014 while taking hot bath; transtentorial herniation required a surgical brain decompression. Brain and meninges biopsy revealed granulomatous destructive angiitis with diffuse and local vessel betaamyloid deposits in the meninges and brain tissue. ABRA was diagnosed and treatment with three PRED 1500 mg IV pulses followed by 75 mg orally and CYC 1400 mg IV every four weeks began. In two weeks temperature and CPR level came to normal, MRI showed no new lesions in two months. Facial nerve paralysis is a rare form of the disease onset. Granulomatous destructive angiitis accompanied by amyloid deposits, presence of multiple hemorrhagic and ischemic strokes, cognitive impairment, epilepsy in middle age are the main features of the disease. Conclusions: ABRA is a potentially well treatable condition and is more susceptible to treatment with glucocorticosteroids and cytostatic agents then other forms of PACNS. Performing biopsy is crucial either in diagnosing of PACNS or deciding on antithrombotic treatment since antiplatelet and anticoagulant agents are undesirable in patients with amyloid angiopathy due to a high risk of hemorrhagic strokes.

P233

Facial Nerve Paralysis as Initial Manifestation of Amyloid Beta Related Angiitis of CNS

P234

Kirill Fedorov1, Timofey Sergienko2, Sergey Golubev3, Elena Atyasova4, Natalia Nazarova2, Sergey Moiseev1, Pavel Novikov1

Natalia Nazarova1, Kirill Fedorov2, Svetlana Gebert1, Sergey Moiseev2, Pavel Novikov2

First Moscow State Medical University, Moscow, Russia, 2First Clinical Hospital, Moscow, Russia, 3Moscow International Patomorphology Laboratory «LABORATOIRES DE GENIE», Moscow, Russia, 4Medical center «Petrovskie vorota», Moscow, Russia

Objectives: To our knowledge facial nerve paralysis is a rare manifestation of primary angiitis of nervous system (PACNS) including amyloid-beta related angiitis (ABRA). Methods: Description of the clinical, radiological and histological findings. Results: A 28 years old male developed peripheral right facial nerve paralysis in 2011, brain MRI was negative, the patient recovered completely in three weeks. A diffuse headache, diplopia and gate disturbance appeared soon after a mild closed head injury the same year. MRI showed multiple subcortical small hemorrhag-

238


1

First Clinical Hospital, Moscow, Russia, 2Sechenov First Moscow State Medical University, Moscow, Russia

Objective: To our knowledge herpes simplex virus (HSV) is an extremely rare cause of cerebral vasculitis. Methods: Clinical case – description of the clinical, radiological and laboratory findings. Results: A 34-year-old female with a history of recurrent headache, smoking, oral contraception and prior spontaneous abortion presented to ICU in June 2013 with a severe headache, vomiting, depressed consciousness and left sided focal deficit. Brain CT showed two ischemic lesions in subcortical nucleus of the right hemisphere. MRI revealed multiple cortical and subcortical strokes in the frontal, temporal, occipital and hippocampal regions of the right hemisphere. Digital subtraction angiography on admission showed no stenosis of the cerebral arteries. WBC count was increased, serum protein C level was slightly reduced.

Abstracts


1Sechenov

Stroke Related to Herpes Simplex VirusAssociated Vasculitis of Cerebral Arteries

Cerebrospinal fluid (CSF) was normal. Extended examination excluded SLE and antiphospholipid syndrome. MTHFR, PAI 1 and ACE genes showed heterozygote mutations. The patient was treated with LMWH for 14 days, dexamethasone 16 mg for 7 days, aspirin and statin. She recovered well within two weeks to a mild hemiparesis. In July 2013 noncontrast brain MRA showed absence of the blood flow in the right anterior and middle cerebral arteries which was confirmed by digital subtraction angiography. Brain and neck MRI revealed thickening and contrast enhancement of the right internal carotid and the proximal part of the middle cerebral arteries walls confirming CNS vasculitis. There was four-fold increase in plasma anti-HSV IgM while CSF PCR was positive for HSV DNA. Intravenous acyclovir 20 mg/kg was started. Within two weeks HSV was eliminated from CSF but MRA showed no improvement. Oral prednisolone 30 mg daily and rivaroxaban 20 mg were administered. In August 2013 a CTA and MRA imaging revealed complete cerebral arteries recanalization with a slight residual extra- and intracerebral arteries narrowing. Prednisolone was tapered off. In September 2014 she was symptom free. There are only few reports of cerebral vasculitis related to HSV infection. Occlusion of the intracranial arteries was not evident at presentation but developed later, apparently due to the untreated HSV infection. Acyclovir administration leaded to elimination of HSV from CSF but recanalization of the cerebral arteries was achieved after steroid treatment only. Conclusion: HSV should be considered as a potential etiology of the CNS vasculitis. MRI showing the inflammation of the vessel wall in conjunction with CSF PCR for viral DNA should be performed for the evaluation of unexplained stroke.

Results: Case 1 is a 17 years old boy presented with tachpnea in infancy and had cold induced acral necrosis of fingers, toes and ear. His skin biopsy revealed small vessel vasculitis characterized by inflammatory infiltrate composed of neutrophils with karyorrhexis and and ectatic vessels with fibrin thrombi inside the lumen and on the wall, staining positive for fibrinogen and C3. He had also features of interstitial lung disease on respiratory function test and thorax tomography. His mutation analysis revealed a previously described mutation. Case 2 is a 14 years old girl presented with joint contracture, gangrene of fingers, toes and recurrent sinusitis. She also had a cellulitis like rash and a superficial punch biopsy demonstrated thickened vessel walls. Because of high transaminase levels, a liver biopsy was done revealing interphase hepatitis and fibrosis. Case 3 is a 17 years old boy presented with neurodevelopmental delay and spasticity and brain BT has showed basal ganglia calcification. He also had cold induced ischemic acral lesions, reflecting an ischemic vasculopathy. Mutation analysis of case 2 and 3 revealed a novel compound heterozygous mutation of V155E/L170Q. Conclusion: These three cases widens genetic and clinical features of SAVI syndrome. Besides the vascular ischemic lesions, a cranial involvement resembling Aicardi Goutiers syndrome is a new feature of SAVI syndrome.

P236

Recurrence of Anti-GBM Antibody Disease (Goodpasture’s Syndrome) 14 Years After Renal Transplantation. Holger Hägele1, Simon Rau1, Antje Habicht3, Manuel Carranza2, Michael Fischereder1, Ulf Schönermarck1

STING-Associated Vasculopathy with Onset In Infancy: New Clinical Findings and Mutation in Three Turkish Children Fehime Kara Eroglu1, Ihsan Gursel2, Mayda Gursel3, Ali Duzova1, Adriana A. Jesus4, Raphaela Goldbach- Mansky4, Seza Ozen1 1

Hacettepe University, Faculty of Medicine, Ankara, Turkey, 2 Bilkent University, Department Molecular Biology and Genetics, Ankara, Turkey, 3METU University, Department of Molecular Biology and Genetics, Ankara, Turkey, 4National Institude of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Turkey

Objective: STING-associated vasculopathy with onset in infancy (SAVI) is a recently identified autoinflammatory disease caused by gain-of-function mutations in TMEM173. This syndrome is a new interferonopathy characterized by neonatal-onset systemic inflammation with a severe cutaneous vasculopathy leading to extensive tissue loss and interstitial lung disease. Patients: We clinically evaluated three patients with acral necrosis and systemic inflammation from three unrelated nonconsangineous Turkish families. Genetic analysis of TMEM173 was performed by direct sequencing.


1Nephrologisches

Zentrum, Medizinische Klinik IV, University Hospital Munich, Ludwig-Maximilians-University, Munich, Germany, 2Departmentof Pathology, LudwigMaximilians-University, Munich, Germany, 3Transplant Centre, University Hospital Munich, Ludwig-MaximiliansUniversity, Munich, Germany

Objectives: After kidney transplantation recurrence of antiGBM disease is rare and usually occurring within the first years after transplantation. Method: We describe a patient with late recurrence of antiGBM disease and will review the available literature. Case Report: We report the case of a 41-year old male with recurrent anti-GBM antibody disease 14 years after successful cadaveric renal transplantation. The patient presented with rapidly worsening general condition, hemoptysis and acute renal failure (creatinine 5.6 mg/dl). Biopsy of the renal allograft showed extracapillary proliferative glomerulonephritis with crescents. Despite immediate and extensive treatment with plasma exchange, steroids, cyclophosphamide and rituximab kidney transplant function did not recover and the patient remained on chronic hemodialysis. Conclusions: Recurrence of anti-GBM disease more than ten years after successful transplantation is extremely uncommon and possible reasons will be discussed.


239


P235

P237

Cerebrovascular and Peripheral Vascular Involvement in Kimura’s Disease Navjot Dhindsa University of Manitoba, Winnipeg, Manitoba, Canada

Background: Kimura’s disease (KD) is a chronic inflammatory condition characterized by painless subcutaneous masses that uniformly involve regional lymph nodes and often salivary glands. KD has predilection for the head and neck region and predominantly affects young Asian men. It is characteristically associated with eosinophilia and elevated serum IgE levels. Etiology is not known. Infections, allergic reaction and immune mechanisms are postulated. Renal disease is a recognized systemic manifestation. Raynaud’s phenomenon has been reported with KD. Case reports of thromboangiitis obliterans and stroke with internal carotid occlusion have been reported in patients with KD. Case Reports: We describe a case of established Kimura’s disease who presented with left sided facial droop and limb weakness. He was also noted to have absent left upper extremity distal pulses. Investigations revealed multivessel cerebral occlusion as well occluded left radial and ulnar arteries. This is the first reported case of intracerebral and peripheral vascular involvement with Kimura’s disease. Discussion: Literature review and association of vasculitis versus vasculopathy in Kimura’s disease and therapeutic decision dilemmas in this poorly understood condition is presented.

cles of bortezomib induced partial clinical remission with marked clinical improvement, including renal function (creatinine 100 μmol/L) and reduction in plasma exchange frequency to 1 session every 10 weeks at 22 months follow-up. Conclusions: Bortezomib is an effective agent for the treatment of the plasma cell neoplasm multiple myeloma. Based on increasing evidence that long-lived CD-20-negative plasma cells are implicated in the pathogenesis of autoimmune disease as the main producer of antibodies, bortezomib has been used successfully in non-malignant antibody-mediated disease as a long-lived plasma cell depleting agent. Good results have been reported in preclinical models, a limited number of case reports and a case series of 8 refractory systemic lupus erythematosus patients. We present a case of bortezomib treatment in IgA vasculitis, a small vessel vasculitis caused by IgA-1-containing immune complex deposition. Because of the high prevalence of peripheral neuropathy, a serious, dose-dependent but generally transient side effect associated with the use of bortezomib, the drug cannot be suggested as an initial therapy in non-malignant diseases, but should be considered in severe and refractory cases of IgA vasculitis and other autoimmune diseases.

P239

The Occurence of Lupus Nephritis in a 64 Year Old Female >10 Years After Presenting with Anti-PR3 ANCA Positive Granulomatous Polyangiitis (GPA) John McLaren1, Stewart Fleming2, David Walker1, Annette Alfonzo1 1

Successful Outcome Using Bortezomib in Adult Refractory IGA Vasculitis (HenochSchönlein Purpura): A Case Report Els Van de Perre, Lisa C. Willcocks, David R.W. Jayne Addenbrooke’s Hospital, Cambridge University Hospitals, Cambridge, UK

Background: Proteasome inhibition is a potential treatment for autoantibody-associated autoimmunity. Methods: We describe a patient with adult refractory IgA vasculitis (Henoch-Schönlein purpura), successfully treated with the proteasome inhibitor bortezomib. Case Report: A 49-year old Caucasian female was diagnosed with severe progressive IgA vasculitis, comprising renal insufficiency (creatinine 130 μmol/L), severe polyarthritis, painful vasculitic rash, gastrointestinal symptoms and fatigue, causing severe morbidity and incapacity. She was resistant or intolerant to a variety of therapeutic options, including oral and intravenous corticosteroids, high dose intravenous immunoglobulin, rituximab, intravenous cyclophosphamide, mycophenolate mofetil, tacrolimus, alemtuzumab, infliximab, leflunomide, thalidomide, dapsone, methotrexate and tonsillectomy. The sole therapeutic regimen capable of providing some clinical improvement was plasma exchange, which had been performed for more than 2 years with an ultimate frequency of 2 sessions weekly. Treatment with 4 cy-

240


NHS Fife, Fife, UK, 2University of Dundee, Dundee, UK

Case Report: Case presentation – A 51 y female with longstanding chronic sinusitis developed deafness in 2001. Bilateral grommets inserted in 2003. Developed an acutely painful red right eye in 2003 and was diagnosed with peripheral ulcerative keratitis. Investigations: Anti-PR3 ANCA > 100. ANA and anti-dsDNA negative. Renal function normal (Creat 70 umol/L). Urine dip blood ++, prot +. CT chest and sinuses normal. Managed with iv pulse methylprednisolone followed by high dose oral prednisolone and oral ciclosporin reducing to zero over 12 months. Discharged without a formal diagnosis. She re-presented in 2012 aged 62 to ENT surgeons with a 2–3 year history of nasal bridge collapse and ongoing nasal crusting and stuffiness. No other features of systemic vasculitis. Investigations: Anti-PR3 ANCA > 100. Urine dip blood +, prot -. Creat 72 umol/L, eGFR > 60 mL/min. Nasal swab Staphylococcus aureus colonisation. CXR normal. CT sinuses opacification left maxillary sinus. No bony destruction. GPA was diagnosed. Managed with mupirocin nasal ointment, saline and bicarbonate nasal douches. Reconstructive nasal surgery performed. Urinalysis in 2013 showed blood ++, prot +. Creat 63 umol/L, eGFR >60 mL/min. Repeat urine dip in 2014 sowed blood +++, prot ++. Urine ACR 26 mg/mmol, urine alb 368 mg/L. Creat 77 eGFR > 60. Anti-PR3 ANCA 79, c-ANCA positive. Results: Renal biopsy contained 9 glomeruli of which 3 were hyalinised. One glomerulus showed a proliferative necrotising lesion and a cellular crescent. The remaining glomeruli showed mild

Abstracts


P238

P240

Retinal Vasculitis: Is It Associated with Systemic Vasculitis? Patricia Fanlo Mateo1, Teresa Carrasquer Pirla1, Susana Clemos Matamoros1, Laureano Menendez Ozcoidi1, Henar Heras Mulero2, Iñaki Elejalde Guerra1, Iñaki Liberal Iriarte2 1

Internal Medicine, Complejo Hospitalario de Navarra, Pamplona, Navarra, Spain, 2Ophthalmology Department, Complejo Hospitalario de Navarra, Pamplona, Navarra, Spain

Objectives: To determine the association of systemic vasculitis with retinal vasculitis. Method: A retrospective chart review was performed of patients diagnosed of retinal vasculitis (RV) at Multidisciplinary Uveitis Unit in Pamplona between 2010 and 2014. Retinal vasculitis was identified by the presence of perivascular exudates, intraretinal hemorrhage or cotton wool spots as seen on clinical ocular examination and by vascular occlusion or leakage as identified by fluorecein angiogram. We documented age, gender, association with uveitis, type of uveitis, causes and ANCA levels. Result: We identified 21 patients with evidence for RV. 12 (58%) were male and mean age was 44.19 years. RV was associated with uveitis in 20 patients (95%).Panuveitis were diagnosed in 10 patients (50%), anterior uveitis in 7 patients (35%) and posterior uveitis in 3 patients (15%).19 patients (90%) had a recognizable entity. 13 patients had an autoimmune disease (61%), 5 patients had an infectious cause (24%) and 1 patient had an ophthalmologic syndrome. ANCA antibodies were negative in all patients. We did´nt find any systemic vasculitis but 3 patients had Behçet disease, 2 patients had SLE and 2 patients had sarcoidosis. Conclusions: Systemic vasculitis is often mistakenly assumed to be a frequent cause of RV.


P241

Could Blastocystis Hominis Induce IgA Vasculitis? Patricia Fanlo Mateo1, Teresa Carrasquer Pirla1, Susana Clemos Matamoros1, Laureano Menendez Ozcoidi1, Rosa Guarch Troyas2, Fermin Jimenez Bermejo1 1

Internal Medicine, Complejo Hospitalario de Navarra, Pamplona, Navarra., Spain, 2Anatomopathology Department, Complejo Hospitalario de Navarra, Pamplona, Navarra, Spain

Objectives: Blastocystis hominis is unicellular organism found commonly in the intestinal tract of humans and frequently causes gastrointestinal symptoms in immunocompromised patients. It is controversial its pathogenicity in healthy people. IgA vasculitis is frequently preceded by an upper respiratory illness. An infection can be pathogenesis of the vasculitis, The exposure to the antigen of the infection may trigger the immunological cascade for the disease development. We describe the second case in the literature of Ig A vasculitis associated to Blastocystis hominis. Method: Review the medical history and current literature. Case Report: A 56 years-old man with no relevant past medical history was admitted in Internal Medicine Department because of continuous and severe abdominal pain localized in right flank and generalized bilateral symmetric arthralgias. He denied fever, vomits and diarrhea. During his hospitalization, purpuric skin lesions in lower extremities, arms and buttocks appeared. Laboratory test detected leucocytosis with elevated acute phase reactants, proteinuria (275 mg/L) and hematuria with normal renal function. Abdominal ultrasonography, abdominal CT and abdominal angioCT were normal. Anti-nuclear antibodies and anti-neutrophil cytoplasmic antibodies were negative. Skin biopsy showed a leukocytoclastic vasculitis. Increased serum IgA levels were detected in blood analysis. Our patient fulfilled three criteria (palpable purpura, abdominal pain and leukocytoclastic vasculitis) of the American College of Rheumatology. So we made a diagnosis of IgA vasculitis (Henoch-Schönlein). The study was completed with colonoscopy that showed erythematous areas in mucosa of colon and ileum. Blastocystic Hominis was isolated in stool culture sensitive to metronidazole. The treatment given consisted of intravenous methylprednisolone 70 mg/day (dose 1 mg/kg/day) and metronidazole 1.5 g during 10 days with complete remission of symptoms. Conclusions: This case supports the hypothesis that an intestinal parasite such as Blastocystis hominis could be the trigger of Ig A vasculitis.


241


mesangial hypercellularity. There was no significant interstitial nephritis or tubulitis. Immunofluorescence staining revealed bright granular fluorescence for IgA, IgG, IgM, C3 and C1q mostly within mesangial regions. The features were strongly suggestive of lupus nephritis. Subsequently additional serology was performed and the patient was found to be ANA positive 1:80 homogeneous and anti-dsDNA positive 36 (0–20). ENAs were negative and C3 and C4 were normal. Anti-PR3 remained positive at 85. The patient is being considered for immunosuppression with oral prednisolone and mycophenolate mofetil. Conclusions: The occurrence of lupus nephritis in a patient with anti-PR3 ANCA positive GPA is extremely rare. We were only able to find reference to 8 cases of SLE associated with antiPR3 ANCA alluded to in one publication by Hervier B et al (Rheumatol Int 2012;32:3285–90) with details of only 1 case by Cavagna L et al (Scand J Rheumatol 2007;36:74–6) which did not include data on renal histology.

P242

P243

Cutaneous Vasculitis Secondary to Brucellosis: A Report of two Cases.

IgA Multiple Myeloma Following Recurrent Adult Henoch Shönlein Purpura: A Case Report

Complejo Hospitalario de Navarra, Pamplona, Navarra, Spain

Objectives: Brucellosis is a zoonosis transmitted to humans from infected animal. Cutaneous lesions are an unusual manifestation of brucellosis. We described two cases of leucocytoclastic vasculitis as the initial presentation of acute brucellosis. Method: We identified two patients with acute brucellosis and cutaneous lesions, which met the criteria for leucocytoclastic vasculitis. Retrospectively, clinical, laboratory and histological data were analysed. Case Reports:

Case 1. A 31-year-old man who had previously been in good health was admitted to our hospital because a 2-week history of cutaneous lesions and arthralgia involving the knees and ankles. Physical examination revealed an erythematous papulopustular rash on the forearms, lower back and legs. Mild synovitis of the knees and ankles was observed. Laboratory evaluation revealed and erythrocyte sedimentation of 67. The results of the remainder of the routine laboratory tests were within the normal range. Blood cultures were sterile. A Brucella serum agglutination test of 1/160 was detected. The Rose Bengal test was positive and the antibrucella Coombs test titre was 1/2560. On careful questioning, it was revealed that he had eaten fresh goat’s cheese. A skin biopsy specimen showed evidence of leucocytoclastic vasculitis. Direct immunofluorescence showed perivascular deposits of IgA and IgG. After treatment with doxycycline and rifampicin, clinical symptoms resolved. Case 2. A previously healthy 41-year-old man was hospitalized with a 2-week histoy of arthralgia, malaise, fever, and sore throat. On admission, his temperature was 39ºC; he had symmetrical synovitis of the elbows and knees joints. A purpuric rash was observed on the distant parts of the lower extremities. Laboratory evaluation revealed an increase of erythrocyte sedimentation rate and C reactive protein. The results of the remainder of the routine laboratory tests were within the normal range. Blood cultures were sterile. A Brucella serum agglutination test of 1/80 was detected. The Rose Bengal test and the antibrucella Coombs test were positive. A skin biopsy specimen showed evidence of leucocytoclastic vasculitis. Direct immunofluorescence studies were negative. He was treated with doxycycline, rifampicin, with complete resolution of the clinical manifestations. Conclusions: Leucocytoclastic vasculitis manifesting as papulopustular cutaneous lesions or a purpuric rash may be the initial presentation of acute brucellosis. Unless brucellosis is excluded as a cause, these patients may receive inappropriate therapy.

242


Teresa Carrasquer, Susana Clemos, Uxoa Gutierrez, Patricia Garcia, Victoria Duro, Carlos Perez Complejo Hospitalario de Navarra, Pamplona, Navarra, Spain

Objectives: Henoch-Shönlein purpura (HSP), also called IgA vasculitis is the most common vasculitis syndrome of chlilhood. Although cases are well described in adults, HSP is much more frequent in children. The occurrence of neoplasia and HSP is rare and poorly understood in adults. The majority of patients developed HSP within 1 month of cancer diagnosis or detection of matastases. We report the unusual case of a 52-year-old man with a 11-year history of recurrent HSP as early manifestation of IgA multiple myeloma. Method: We have retrospectively reviewed the clinical, laboratory, and histological data of this case. Case Report: A 42-year-old man was admitted to the hospital in July 1998 with a 2-day history of fever, malaise, headache, irritability, arthalgia, abdominal pain, and a nonpruritic purpuric rash. At admission, his temperature was 36.8ºC, and his blood pressure was 110/70 mm Hg. He had a purpuric rash on the skin of the buttocks and lower extremities, abdominal pain, and bloody stools. A symmetric synovitis of the knees and ankles was present. Laboratory tests showed an increase serum IgA level. No circulating immune complexes, cryoglobulins, antinuclear antibodies, rheumatic factor, or antineutrophil cytoplasmic antibodies were detected. Bacterial serology revealed negative findings. Colonic endoscopy showed petechiae and erosions of the mucosa. A skin biopsy specimen showed leukocytoclastic vasculitis, with positive Immunofluorescence for cutaneous IgA deposits. Over the following 11 years, he had experienced all these features during several similar episodes that persisted for 7–10 days and then recurred every 6–9 months, with complete recovery between episodes and no residual damage. Because of the relapsing course of the HSP in this patient and the patient’s lack of response to corticosteroids, the patient was treated during the relapsing episodes with IV immunoglobulin (total dose, 2 g/Kg), with good control during several months. Ten years after initial presentation the patient was diagnosed with IgA multiple myeloma with poor response to specific treatment. The patient died after an intestinal perforation and sepsis cause by Stenotrophomona maltophilia. Conclusions: Clinicians should suspect a malignancy in men older than 40 years of age who develop a recurrent HSP in the absence of a precipitating factor.

Abstracts


Elisa Huarte, Amaya Villanueva, Manuel Gonzalez, Amaia Redondo, Pablo Gonzalez, Carlos Perez

P244

P245

Renal Involvement in Levamisole Contaminated Cocaine Associated Vasculitis/Vasculopathy

Human Leucocyte Antigen Class II Genes Association Analysis in a Large Cohort of Chinese Patients with Anti-Glomerular Basement Membrane Disease

Navjot Dhindsa1, Aurore Fifi-Mah2 1 2

University of Manitoba, Winnipeg, Manitoba, Canada, University of Calgary, Calgary, Alberta, Canada

Xie Lijun1,2, Cui Zhao1, Tian Xueyuan3, Hu Shuiyi1, Liao Yunhua2, Zhao Minghui1 1

Introduction: Levamisole contaminated cocaine associated

vasculitis/vasculopathy (LCCAV) is being increasingly recognized and reported. Skin involvement with sparing of viscera is the usual and only manifestation. We report two cases of biopsy proven membranous nephropathy complicating vasculitis in heavy cocaine users. Objective: Recognition and understanding of LCCAV is still evolving. The disease spectrum needs further characterization. We aim to add to the available literature available on clinical features, laboratory markers, treatment, and outcome of LCCAV. Case Reports: See table 1. Discussion: Case one presented with classical levamisole associated skin involvement, ANCA and lupus inhibitor positivity. He developed membranous nephropathy 12 months after his initial diagnosis in setting of ongoing cocaine use. Cocaine cessation and immunosuppression with corticosteroids and tacrolimus resulted in improvement of renal disease. Case 2 presented with pulmonary renal syndrome with predominant membranous nephropathy, positive ANCA in setting of regular cocaine use. Both patients had positive urine results for levamisole at one time during disease course. The two cases demonstrate a broader and more severe disease spectrum then what is ascribed to levamisole/cocaine. While case 1 presented with classical levamisole associated skin manifestation, the second case did not have skin disease despite positive urine for levamisole. The role of either agent alone as well as combined effect in pathogenesis of kidney disease is not understood. Genetic susceptibility in disease causation and spectrum needs to be studied.

Renal Division, Peking University First Hospital, Beijing, China, 2Renal Division, Department of Medicine, First Affiliated Hospital of Guangxi Medical University, Nanning, China, 3Peking-Tsinghua Center for Life Sciences, Beijing, China

Objectives: Anti-glomerular basement membrane (antiGBM) disease is a severe autoimmune disease with strong HLA association, in particular DRB1*1501 allele. However, DRB1*1501 presented strong linkage disequilibrium (LD) with other alleles and variability was reported between Caucasian and Chinese. We tried to further investigate the HLA genetic basis of anti-GBM disease in Chinese population. Method: We investigated the association between HLA class II genes and anti-GBM disease in a large cohort of 140 Chinese patients and 599 race and geography matched healthy controls. Single-nucleotide polymorphisms (SNPs), alleles and haplotypes were screened and analyzed. Associations were calculated by chisquare test; the threshold for significance was adjusted for multiple comparisons with the Bonferroni method. Results: We confirmed previous studies thatDRB1*1501 (OR = 4.55, P = 5.66×10–28) and DQB1*0602 (OR = 3.34, P = 2.03×10–17) were susceptible alleles.DQA1*0502 (OR = 30.69, P = 7.00×10–7) was a novel susceptible allele. In addition, a novel SNP rs41541412 (C/G) withinDQA1 was associated with the onset of the disease. The risk genotype (rs41541412:G) (OR = 30.69, P = 6.987×10–7), which is located on DQA1*0502, results in the


#

ANCA

APLA/ LuI

Leucopenia/ neutropenia

Skin disease

Renal disease

Other organ

1

pANCA/MPO

Yes

Yes

Diffuse purpura

Membranous nephropathy

Arthritis

2

pANCA/MPO

No

No

No

Membranous nephropathy Focal segmental GN

Pulmonary vasculitis

HLA-allele

Allele frequency in cases (n = 140 × 2)

Allele frequency in controls (n = 599 × 2)

OR

p value

DRB1*1501 DQB1*0602 DQA1*0502 DQB1*0303 DRB1*0901

0.4384 0.3840 0.025547 0.0471 0.0652

0.1469 0.1544 0.0008347 0.1444 0.1494

4.55 3.34 30.69 0.29 0.39

5.66×10–28 2.03×10–17 7.00×10–7 8.58×10–6 1.61×10–4



243


Table 1. Association results for HLA alleles in Chinese anti-GBM disease (p < 3.55 × 10–4) (for Abstract P245)

78th amino acid on DQ α chain changing from proline to arginine. Both DQB1*0303 (OR = 0.29, P = 8.58×10–6) and DRB1*0901 (OR = 0.39, P = 1.61×10–4) were firstly identified as protective alleles.HaplotypeDRB1*1501-DQB1*0602 was positively associated with the onset of the disease (haplo.score = 8.84, P = 9.70×10– 19 ), while haplotypeDRB1*0901-DQB1*0303 was protective (haplo.score = –4.31, P = 1.60×10–5). In patients with anti-GBM disease, DRB1*0803 was a risk marker for hemoptysis (P = 0.005); DQB1*0302 was a protective marker for kidney injury (P = 0.006). Conclusions: We conclude that besides DRB1*1501 andDQB1*0602, HLA-DQA1*0502 and its SNP rs41541412(G) are novel genetic markers for anti-GBM disease susceptibility, while DQB1*0303 and DRB1*0901 are protective, at least in Chinese population.

DQB1*02 were found to be distinctly associated with GPA. AA genotype of rs 4553808 was significantly associated with AAV. It was present at higher frequency in MPA patients compared to PR3 patients. AG (rs 231775), GG (rs 2488457), GA (rs 3087243), AA (rs 1217412) genotypes were present at higher frequency in MPA patients compared to GPA patients. Conclusion: There was a shared genetic association of DRB1*03:01, DQB1*03:02, AA (rs 4553808) in GPA and MPA patients in north Indian population and DRB1*13, DQB1*02 were distinctly associated with GPA. Two SNPs each in CTLA-4 and PTPN22 gene showed higher frequency of specific genotypes in MPA patients.

P247

Shared and Distinct Genetic Associations in two Subtypes of ANCA Associated Vasulitides Ranjana W. Minz, Jagdeep Singh, Navchetan Kaur, Shashi Anand, Lekha Rani, Dheeraj Gupta, Naresh K. Panda, Aman Sharma Post Graduate institute of Medical Education and Research, Chandigarh, India

Objective: Heritable factors contribute immensely to the etiology of many autoimmune diseases that are mostly multifactorial. Anti neutrophil cytoplasmic antibody (ANCA) associated vasculitides (AAV) is one such disorder that comprises of two main subtypes viz. granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). These two subtypes are marked by autoantigen specific ANCA i.e. proteinase 3 (PR3) ANCA in GPA and myeloperoxidase (MPO) ANCA in MPA. Owing to the autoimmune diathesis, the immune response genes may be the major predisposing factors for AAV. This study was planned to elucidate the association of DRB1, DQB1 loci and cytotoxic T lymphocyte antigen -4 (CTLA-4) and protein tyrosine phosphatase nonreceptor 22 (PTPN22) gene with AAV and its subtypes in north Indian population. Methods: 120 patients and 120 healthy, age and sex matched controls were enrolled in the study from same ethnicity. ANCA were detected by indirect immunofluorescence and cANCA and pANCA were ascribed accordingly. ELISAs for PR3 and MPO were done for patients’ categorization. Medium resolution typing was done for DRB1 and DQB1 loci by PCR-SSP method. 5 SNPs in CTLA-4 gene and 3 SNPs in PTPN22 gene were genotyped by melt curve analysis using simple probes. Statistical analysis was done by SPSS. Results: Out of 120, 45 patients had MPA and 75 had GPA. DRB1*03:01 and DQB1*03:02 were found to be significantly associated with AAV. DRB1*14 and DQB1*05 were found to be the protective factors for AAV in the population. The susceptibility haplotype of HLA was found to be DRB1*03:01-DRB3*01:07DQB1*02:01. In the two subtypes, the susceptibility alleles were found at higher frequency in GPA patients and protecting alleles were found at higher frequency in MPA patients. DRB1*13 and

244


DNA Methylation Analysis of the Temporal Artery Microenvironment in Giant Cell Arteritis Patrick Coit, Lindsey De Lott, Bin Nan, Victor Elner, Amr Sawalha University of Michigan, Ann Arbor, MI, USA

Objective: To elucidate the inflammatory response in giant cell arteritis (GCA) by characterizing the DNA methylation pattern within the temporal artery microenvironment. Methods: Twelve patients with non-equivocal histological evidence for GCA and twelve age, sex, and ethnicity matched controls with normal biopsies were studied. DNA was extracted from the affected portions of temporal artery tissue in GCA patients and from histologically-confirmed normal arteries in controls. Genome-wide DNA methylation status was evaluated using the Illumina Infinium HumanMethylation 450 BeadChip Array. Differentially methylated loci between affected and unaffected arterial tissues were identified, and subsequent bioinformatic analysis performed. Immunohistochemistry was used to examine tissue expression patterns in temporal artery biopsies. Results: We identified 1555 hypomethylated CpG sites (853 genes) in affected temporal artery tissue from GCA patients compared to normal controls. Gene ontology enrichment analysis of hypomethylated genes revealed significant representation in T cell activation and differentiation pathways, including both TH1 and TH17 gene signatures. Our DNA methylation data suggest a role for increased activity of the calcineurin/NFAT signaling pathway in GCA, confirmed by immunohistochemistry showing increased protein expression of NFAT1, IL-21, IL-21R, and CD40L in GCA affected arteries. Further, proinflammatory genes such as TNF, LTA, LTB, CCR7, RUNX3, CD6, IL2, IL6, NLRP1, IL1B, IL18, IL21, IL23R, and IFNG were all hypomethylated in the cellular milieu of GCA arteries. Conclusion: We comprehensively characterized the inflammatory response in GCA affected arteries using ‘epigenetic immunophenotyping’, and identified novel potential therapeutic targets in this form of large vessel vasculitis.

Abstracts


P246

P248

p = 0.0135 100

FCGR3B Copy Number Variations in

Eosinophilic Granulomatosis with Polyangiitis (EGPA) Alberici2,3,

80

Gioffredi3,

Francesco Federico Andrea Michele Reina1, Renato Sinico4, Antonella Radice5, Silvia Pizzolato6, Gina Gregorini7, Guido Jeannin7, Monica Boita8, Giuseppe Guida8, Alberto Pesci9, Federica Maritati3, Elena Oliva3, Alessia Adorni1, Tauro Maria Neri1, Davide Martorana1, Augusto Vaglio3

Frequency (%)

Bonatti1,

EGPA patients Controls

60 40

1

0


FCGR3B copies

Fig. 1. Genotype distribution of FCGR3B CNVs in EGPA pa-

tients and healthy controls (for Abstract P248).


FCGR3B

Objectives: To investigate whether Copy Number Varia-

tions (CNVs) of the FCGR3B gene are associated with susceptibility to Eosinophilic Granulomatosis with Polyangiitis (EGPA). Methods: One hundred and twenty-six patients with EGPA were studied. The cases were recruited from nine Northern Italian centres. In all cases, the diagnosis of EGPA had to fulfil the ACR1990 classification criteria for Churg-Strauss syndrome and the 2013 revised Chapel Hill Consensus conference nomenclature. A total of 249 age- and gender-matched healthy Caucasian subjects with no history of autoimmune diseases served as controls. FCGR3B gene CNVs from genomic DNA were assessed by quantitative real-time PCR, using a pre-designed Taqman® probe real-time, quantitative PCR assay (Hs04211858, FAM-MGB duallabelled probe); RNase P (4401631, VIC-TAMRA dual-labelled probe) was used as reference assay, performed in a single tube. All samples were tested in triplicate. The relative FCGR3B CN for each individual was calculated using the 2-ΔΔCt method, which compares the ΔCt (CtFCGR3B gene – CtReference) value of the test samples with CNV to the ΔCt of the reference sample. If the 95% confidence interval of the mean relative quantity was between 0.7 and 1.3 then the copy status was considered to be normal (two copies of the gene). Values less than 0.7 were considered as deletion (single copy of the gene) while values higher than 1.3 were considered duplication (1.3–1.7 three copies of the gene; 1.7–2.3 four copies of the gene). Differences in the frequency among groups were compared with Kruskal-Wallis test and Mann-Whitney Rank Sum test where appropriate. Results: As shown in figure 1, presence of one copy of the FCGR3B gene was associated with EGPA (p = 0.01352, OR 2.284, 95% CI 1.17–4.458). Moreover, a subgroup analysis revealed that

1

CN = 1 CN ≥ 2 P value OR Wald 95% CI

FCGR EGPA patients (n = 126)

3B Controls (n = 249)

20 (16%) 106 (84%) 0.01352 2.28401 1.17 >2.284> 4.458

19 (8%) 230 (92%)

CNVs = Copy number variations; EGPA = Eosinophilic Granulomatosis with Poliangiitis; OR = odds-ratio; 95% CI = 95% confidence interval.

the proportion of patients with 1 copy was higher in those with vasculitic manifestations of EGPA, namely purpura (p = 0.00887), renal involvement (p = 0.0084), and peripheral neuropathy (p = 0.0061). Notably, within patients with renal involvement, the highest prevalence of CNV = 1 was revealed in those with impaired renal function (p = 0.000936). The higher prevalence of CNV = 1 in patients with vasculitic manifestations was also in line with a higher prevalence of CNV = 1 in the group with positive ANCA (p = 0.0409). Conclusions: In this study, we observed that the presence of one FCGR3B copy number was significantly associated with EGPA, suggesting that FcgRIIIB deficiency may be a risk factor for EGPA in our population. Additionally, one FCGR3B copy seems to be associated with increased risk of developing vasculitic phenotype of EGPA.


245


Unit of Medical Genetics, University Hospital of Parma, Parma, Italy, 2Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge UK, Cambridge, UK, 3Nephrology Unit, University Hospital of Parma, Parma, Parma, Italy, 4Clinical Immunology Unit and Renal Unit, Azienda Ospedaliera Ospedale San Carlo Borromeo, Milano, Italy, 5Institute of Microbiology, Azienda Ospedaliera Ospedale San Carlo Borromeo, Milano, Italy, 6Pneumology Unit, Azienda Ospedaliera Ospedale San Carlo Borromeo, Milano, Italy, 7Nephrology Unit, Spedali Civili Brescia, Brescia, Italy, 8Dipartimento di Scienze Mediche, Università degli Studi di Torino, Torino, Italy, 9Dipartimento Cardio-Toraco-Vascolare, Clinica Pneumologica, Università degli Studi di Milano Bicocca, A.O. San Gerardo, Monza, Milano, Italy

P249

Polymorphisms in the MIF and PTX3 Genes are not Associated with Susceptibility to Disease and Relapse Risk in ANCA Associated Vasculitis Marten Wendt1, Aune Avik2, Ola Borjesson2, Karin Luttropp3, Louise Nordfors3, Iva Gunnarsson2, Annette Bruchfeld1 1

Department of Renal medicine, Karolinska University Hospital, CLINTEC, Karolinska Institutet, Stockholm, Sweden, 2Unit of Rheumatology, Karolinska University Hospital, Department of Medicine, Karolinska Institutet, Stockholm, Sweden, 3Dept of Molecular Medicine and Surgery, Div Neurogenetics, CMM, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

Results: Patients were followed for a mean of 109.3 months. During that time 111 patients relapsed (50.0%). 68.4% of the patients were MIF rs 755622 G/G, 27.1% G/C and 3.5% C/C. Two percent of the patients were homozygous for MIF CATT7 and 21.1% heterozygous. The frequencies of the CATT7 allele were 14.1% among AAV patients and 12.6% among controls (NS). 24.8% were homozygous for PTX3 rs 2305619 and rs 1840680 A/A genotypes, a similar rate to previously published controls. None of the investigated gene polymorphisms were associated with relapse. Conclusions: Whether MIF and PTX3 polymorphisms are associated with disease severity is unknown, but they do not appear to influence relapse risk or disease susceptibility in AAV.

P250

mi-RNA Profile of Active Vascular Behçet’s Patients

Objectives: Macrophage inhibitory factor (MIF) and pen-

Gaziantep University, Gaziantep, Turkey

Objectives: Behçet’s Disease (BD) is a systemic vasculitis that predominantly presented with oral aphtous ulcers and additionally at least two of the following findings like genital ulcers, eye involvement, skin lesions and pathergy reaction. Vascular involvement is devastating face of BD and thrombosis of the arterial and venous system and aneurismatic arterial disease is not rare. The flares are the typical nature of BD and the pathology of the disease is mostly constructed on vasculitis. However the satisfied mechanism of BD remains unknown. We herein tried to evaluate the micro RNA (miRNA) behavior in BD. Methods: Eighty-five BD patients were enrolled in to the study group, which were divided to 3 groups of 20–20 and 25 with active vascular disease, active mucocutaneous disease and patients with remission at least for the last 6 months, respectively. Addi-

Mucocutaneous active BDs


246


miR93–5p

25–3p

0.25

Abstracts


All active and vascular active BDs

20b–5p

9b–3p

93–5p

6–5p

06b–5p

9a–3p

26b–5p

451a

7–5p

0.25

0.50

miR106b–5p

0.50

Mucocutaneous active cases/control

miR17–5p

CNQR log2 based

1.00

miR451a

Active cases/control

1.00

CNQR log2 based

Ahmet Mesut Onat, Ozan Gerenli, Bunyamin Kisacik, Mustafa Ulasli, Gezmis Kimyon, Yavuz Pehlivan, Serdar Oztuzcu

miR26b–5p

traxin-3 (PTX3) are two pleiotropic proinflammatory molecules believed to be involved in the pathogenesis of many autoimmune conditions including anti-neutrophil cytoplasmic autoantibody (ANCA) associated vasculitis (AAV). Their corresponding genes exhibit polymorphisms associated with increased MIF and PTX3 levels. These polymorphisms have been linked to disease susceptibility and prognosis in other inflammatory conditions such as rheumatoid arthritis (MIF) and Aspergillosis (PTX3). We investigated whether MIF and PTX3 polymorphisms are important in AAV as well. Methods: We genotyped 222 prevalent AAV patients in the Stockholm area for the MIF rs 755622 G/C single nucleotide polymorphism (SNP) and the -794 (CATT)(5–8) (rs5844572) repeat as well as for the PTX3 rs 2305619 and rs 1840680 A/G SNPs. All patients received standard induction treatment with cyclophosphamide, rituximab or methotrexate in combination with glucocorticoids and were followed for at least 12 month. Patients who developed at least one major item on the BVAS and required renewed induction treatment were considered as relapsing. In addition 365 healthy controls were genotyped for -794 (CATT)(5–8).


Active vasculer BD

Active mucocutaneous BD

BD in remission

Healthy controls

32.60±4.57

32.60±6.36

35.72±9.21

32.20±1.71

4.30±2.71

4.25±3.31

4.68±3.21

CRP (mg/l)

29.35±36.47

22.53±21.38

4.92±3.11

3.1±1.8

ESR (mm/hour)

34.90±26.46

30.0±24.03

15.56±11.85

10.02±4.21

Age Disease duration (y)

tional 25 volunteers were the healthy controls and the 4 of the groups have no difference for the demographic statistics. The whole study population was male, due to difficulties of finding active women BD patients. Serum samples were analyzed for miRNA with PCR assay and the data were analyzed statistically. Active vascular patients had significantly higher CRP and ESR results than active mucocutaneous ones and they both had significantly higher levels than remission and healthy groups. Results: There was no difference for any miRNA between BD patients with remission and healthy controls. The comparison of active BD patients and healthy controls revealed lower levels of miR17-5p, miR-451A, miR-106b-5p, miR-16-5p, miR-19b-3p, miR26b-5p, miR-93-5p, miR-20b, miR-25-3p. However miR451A was found lower only in mucocutaneous group inspite of vasculars. Conclusions: The miRNA profile of active BD especially the vascular group was remarkable. These miRNAs were related mainly with T and B lymphocytes and especially with prolonged apoptosis. miRNA studies might be beneficial for detecting better targets for treating the disease in the future.

cluded in the meta-analysis. Pooled odds ratios were calculated for AAV, and for specific AAV subtypes were possible. Results: The literature search yielded 5,180 articles. Fiftythree articles investigating 55 genetic variants were included in this meta-analysis, 33 of which remained significantly associated with AAV after meta-analysis. These variants were in or near the following genes: alpha-1-antitrysin, CD226, CTLA-4, HLA B, HLA DPA1, HLA DPB1, HLA DPB2, HLA DQB1, HLA DRB1, HLA DRB3, HLA DRB4, HSD17B8, IRF5, LEPR, PTPN22, RING1/RXRB, RXRB, and TLR9. Moreover, we found different genetic associations for the different AAV subtypes. Conclusions: This meta-analysis identified 33 genetic variants associated with AAV, supporting a role for alpha-1-antitrypsin, the MHC system, and other inflammatory processes in the pathogenesis of AAV. Moreover, we showed genetic distinctions between the different AAV subtypes, supporting the concept that these subtypes may represent distinct autoimmune syndromes.

P252

Genetic Variants in ANCA-Associated Vasculitis: A Meta-Analysis

Early-Onset Polyarteritis Nodosa Associated with CECR1 Mutations in two Unrelated Spanish Patients

Chinar Rahmattulla1, Antien Mooyaart1, Daphne Van Hooven1, Jan Schoones1, Jan Bruijn1, Olaf Dekkers1, Ken Smith2, Paul Lyons2, Ingeborg Bajema1

Maria C Cid1, Sergio Prieto-González1, Georgina Espígol- Frigolé1, Marco A Alba1, José Hernández- Rodríguez1, Jordi Yagüe2, Juan I. Arostegui2

1Leiden

1Vasculitis

University Medical Center, Leiden, The Netherlands, 2University of Cambridge, Cambridge, UK

Objectives: Although the etiology of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is unknown, both genetic and environmental factors are considered to be involved in the pathogenesis of AAV. The aim of this metaanalysis is to determine the genetic variants that are most likely to be associated with AAV, and to investigate whether different subtypes within AAV have distinct genetic backgrounds. Methods: Studies that assessed the association between genes and AAV were searched in PubMed, Embase, and Web of Science. All genetic variants that were significantly associated with AAV at least once and investigated at least twice were in-


Research Unit, Department of Autoimmune Diseases. Hospital Clínic. UNiversity of Barcelona. IDIBAPS, Barcelona, Spain, 2Department of Immunology-CDB. Hospital Clínic, Barcelona, Spain

Objectives: Recessively-inherited loss-of-function mutations in the cat-eye chromosome region 1 (CECR1) gene encoding adenosine deaminase-2 (ADA-2) have been recently associated with an inflammatory vasculopathy fulfilling classification criteria for polyarteritis nodosa. Here we describe two ADA2 deficient patients from unrelated Spanish families. Case Reports: Case 1 (Male): Recurrent fevers were first detected at age 4. At age 7 livedoid skin lesions appeared and at age 8 he developed hypertension, abdominal pain, subarachnoid hem-


247


P251

p.His424Tyr/WT

p.Gly47Arg/WT

p.Arg92Gln/WT p.Thr557Arg/WT p.His424Tyr/p.Gly47Arg

a

p.Thr360Ala/p.Thr360Ala

p.Arg92Gln/WT p.Thr557Arg/WT

b


248


P253

The Relationship of ARMS2/HTRA1 Locus with Idiopathic Inflammatory Vasculitis Christopher Mecoli1, Flint Wang1, Christopher Pappas2, Peter Grayson3, David Cuthbertson4, Simon Carette5, Gary Hoffman6, Nader Khalidi7, Curry Koening2, Carol Langford6, Carol McAlear1, Paul Monach8, Larry Moreland9, Philip Seo10, Ulrich Specks11, Steven Ytterberg11, Rui Feng1, Gregory Hageman2, Peter Merkel1 1

University of Pennsylvania, Philadelphia, PA, USA, University of Utah School of Medicine, Salt Lake City, UT, USA, 3National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD, USA, 4University of South Florida, Tampa, FL, USA, 5University of Toronto, Toronto, Canada, 6Cleveland Clinic, Cleveland, OH, USA, 7 McMaster University, Ontario, Canada, 8Boston University School of Medicine, Boston, MA, USA, 9University of Pittsburgh, Pittsburgh, PA, USA, 10Johns Hopkins University, Baltimore, MD, USA, 11Mayo Clinic, Rochester, MN, USA 2

Objective: Patients with age-related macular degeneration (AMD), a leading cause of irreversible blindness, have a 10-fold increased prevalence of abdominal aortic aneurysms. Single nucleotide polymorphisms (SNPs) in a number of genes, including age-related macular susceptibility protein 2 (ARMS2) and HTRA Serine Peptidase 1 (HTRA1), are strongly associated with increased risk for developing AMD. These AMD-associated loci are also strongly associated with vasculopathies, including choroidal neovascularization, polypoidal choroidal vasculopathy, and retinal angiomatous proliferation in both Caucasians and Japanese. These finding raise intriguing possibilities of a potential association between vascular pathology and AMD-associated genes. This study tested the hypothesis that AMD-associated gene variants may also be involved in the development of vasculitis, especially the large-

Abstracts


orrhage and mononeuritis multiplex. An excellent recovery with high-dose prednisolone and methotrexate was observed, and the drugs were subsequently tapered and withdrawn after 2 years. At age 11 the livedoid skin lesions recurred and a skin biopsy revealed necrotizing arteritis. He developed a hemorrhagic brain infarction. He was initially treated with glucocorticoids. At that time, genetic studies detected the variant p.R92Q in the TNFRSF1A gene and the novel variant p.T557A in the NLRP3 gene. Both variants were also detected in his healthy father. Anakinra was started on the basis of these genetic results. Silent lacunar infarcts developed while on anakinra. After a new hemorrhagic brain infarct he was treated with methyl-prednisolone and IV cyclophosphamide. He died from massive brain infarction at age 13. ADA2 deficiency was genetically confirmed six years after his death (see genotypes at fig. 1a). Case 2 (Female): She developed recurrent fevers and livedoid skin lesions at age 10. At age 15 she developed disartria and mild left hemiparesis. At age 27 she developed hypertension, mononeuritis multiplex and skin ulcers. Skin biopsy showed arteritis. Angiography showed kidney infarcts and arterial stenoses and microaneurysms. MRIs showed kidney infarcts and small brain infarcts in the corpus callosum and pons. She was treated with high-dose prednisone subsequently tapered and IV cyclophosphamide pulses subsequently switched to azathioprine with good recovery. She had an uneventful pregnancy with term delivery of a healthy girl at age 34. She carried a novel CECR1 mutation in homozygosity (figure 1b). Conclusions: These families confirm the causal relationship between CECR1 mutations and an early-onset polyarteritis nodosa inherited as a recessive trait and expand the clinical diversity and severity associated to different genotypes. The role of the TNFRSF1A and NLRP3 variants in the severity of case 1 needs further investigations. Our findings support a previously suggested adverse impact of anti-IL-1 drugs in this disease. Supported by Ministerio de Economía y Competitividad (SAF 11/30073 and Instituto de Salud Carlos III (PIE 13/00033).

Type of vasculitis

Cases, n

MAF in controls

*MAF in cases

Additive OR (95% CI)

Additive p value

GPA MPA EGPA PAN All non-LVV TAK GCA All LVV (TAK+GCA) All 6 vasculitides

584 88 133 62 867 116 213 329 1196

0.21 0.21 0.21 0.21 0.21 0.21 0.21 0.21 0.21

0.23 0.28 0.20 0.21 0.23 0.25 0.25 0.25 0.23

1.11 (0.93–1.32) 1.46 (1.03–2.08) 0.92 (0.67–1.26) 0.99 (0.63–1.55) 1.10 (0.95–1.29) 1.26 (0.92–1.72) 1.43 (1.07–1.92) 1.30 (1.05–1.60) 1.15 (1.00–1.32)

0.2478 0.0390 0.6222 0.9522 0.2086 0.1461 0.0199 0.0177 0.0449

vessel vasculitides (LVV), giant cell arteritis (GCA), and Takayasu’s arteritis (TAK). Methods: A candidate gene study was performed to investigate the relationship between AMD-associated variants and vasculitis. We examined for an association of ARMS2/HTRA1 gene locus with six phenotypes of vasculitis: GCA, TAK, granulomatosis with polyangiitis (Wegener’s, GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (ChurgStrauss, EGPA), and polyarteritis nodosa (PAN). The study included samples from 1196 patients with vasculitis and 1248 healthy controls matched for age, sex, race, and ethnicity. Additive p-values were calculated for each subtype of vasculitis. Results: The main results of the study are reported in the table. The controls had a minor allele frequency of 21% for

rs10490924. Overall there was a significant association of all vasculitis types with rs10490924 (p = 0.0449). Large-vessel vasculitides were significantly associated with rs10490924 (p-value of 0.0177). The GCA and MPA groups were each independently associated with rs10490924 (p-values of 0.0199 and 0.039, respectively). Conclusion: This candidate gene study demonstrated a significant association between variants in ARMS2/HTRA1 and idiopathic forms of vasculitis, including large-vessel vasculitides. In addition, all of the entities associated with this locus occur in older populations, possibly suggesting an interaction with immunosenescence. While further validation is needed, this study suggests the possibility of a common pathogenesis between aortic pathology in AMD and large-vessel vasculitis.



249



Author Index Nephron 2015;129(suppl 2):250–256 DOI: 10.1159/000381123

Ashdown, S. 190 Atsumi, T. 197 Atyasova, E. 238 Audard, V. 129 Aumaitre, O. 55, 159 Avik, A. 140, 246 Aviña-Zubieta, A. 107 Aybar, L. 66 Aydin, S. 224 Aydin, S.Z. 121 Aydin-Tatli, I. 222 Ayhan, A.S. 76 Babar, J. 156 Bacherini, D. 166 Bacon, P.A. 94 Bähring, S. 89 Bailly, S. 159 Bajema, I. 54, 171, 213, 247 Balci, M.A. 187 Baldini, C. 158 Baldwin, C. 173 Balius, A. 218, 219 Balkarli, A. 58 Ball, M. 53 Ballarin, J. 218, 219 Balleste, R. 118 Barany, P. 110 Basu, N. 6, 55, 173, 177, 189 Batu, E.D. 59 Baud, V. 222 Baydar, D.E. 76 Beauvillain, C. 215 Becatti, M. 106 Bedi, R. 111 Behrens, T. 97 Bel, E. 158 Bello, M.D. 103 Benagiano, M. 221 Benarous, L. 188, 190 Bengoufa, D. 215 Benseler, S. 84, 105, 196 Benveniste, O. 226 Berden, A. 54, 115, 171 Berezne, A. 167, 168, 190, 226 Berger, C.T. 225 Bergmann, A. 48 Bermejo, F.J. 241 Berthier, S. 180 Bertram, A. 90

© 2015 S. Karger AG, Basel E-Mail [email protected] www.karger.com/nef

Bhangal, G. 49, 50 Bhavsar, S. 79 Bicakcigil, M. 105 Bigi, S. 105 Bigler, M. 225 Bijzet, J. 124, 141 Bilge, S.Y. 58 Bilgen, S.A. 76, 179, 195 Bilgin, E. 58 Birn, H. 158 Biscardi, S. 134 Bischof, A. 154, 192 Bjørneklett, R. 171, 186 Bjornsson, J. 62 Blanchard-Delaunay, C. 55 Blockmans, D. 194, 209, 234 Blom, A.M. 119 Boffa, J.-J. 80 Böhm, M. 196 Boita, M. 245 Boletis, J. 83, 164 Bonatti, F. 245 Bonnefoy, F. 204 Bontscho, J. 73 Boonen, A. 218 Boots, A.H. 51 Boots, M. 93, 124 Boralevi, F. 103 Borjesson, O. 246 Börjesson, O. 168 Bosdure, E. 103 Bosio, G. 178 Bossuyt, X. 209 Bottero, P. 158 Boulanger, C. 95 Bourgarit-Durand, A. 180 Boutin, T.H.D. 180 Bozcan, S. 47 Bradburn, M. 123 Brant, E. 46, 90, 143, 202 Brenchley, P. 138, 206 Brennan, C. 234 Bressollette, C. 137 Brézin, A. 222 Briot, K. 167, 168 Brix, S.R. 112 Brogan, P. 75, 196 Brom, R.R.H. 162 Broussard, C. 142, 222 Brouwer, E. 51, 93, 124, 162 Brown, N. 47, 128, 134, 138, 151, 170, 206, 233

Bruce, I. 134 Bruchfeld, A. 110, 168, 246 Bruchfeldt, A. 140 Bruijn, J. 54, 171, 247 Brunetta, P. 81, 97, 172 Brunner, J. 196 Bruschi, G. 106 Bucala, R. 203 Bucchia, M. 137 Bulanov, N. 149, 237 Bunch, D. 54, 66, 143, 202 Burgmann, H. 53 Burniat, A. 149 Burns, A. 86 Buzzi, C. 118 Cabane, J. 64 Cabral, D. 196 Cabre, C. 218, 219 Cacoub, P. 180 Cagatay, Y. 58 Cairns, T. 70, 108, 111 Calabrese, L. 234–236 Calayir, G.B. 187 Callery, E. 137 Campo, E. 82 Can, M. 105 Cancarini, G. 163, 232, 233 Candalh, C. 72 Carbia, M. 118 Carette, S. 79, 122, 148, 203, 229, 248 Carmona-Rivera, C. 89 Carol McAlear, 148 Carpenter, D. 127, 189, 192 Carranza, M. 239 Carrasquer, T. 236, 242 Cartin-Ceba, R. 96, 113, 130 Casian, A. 109, 159 Castelein, T. 234 Castro, J. 236 Cathébras, P. 180 Cefle, A. 58 Celestino, M. 161 Cerri, G. 178 Cetin, G.Y. 58 Chafey, P. 222 Chakrabarty, A. 82 Chakravarty, K.C. 18 Chalhoub, G. 180 Chang, D. 92, 197 Chang, S. 108


Aasarød, K. 171, 186 Abad, S. 70, 180 Abbate, R. 106 Abdulahad, W. 68, 93, 114, 124, 139–141, 162 Abe, M. 211 Adams, D. 226 Adler, A. 45 Adorni, A. 245 Agard, C. 126, 137 Aguilar-García, J.A. 155 Akdeniz, T. 105 Akdogan, A. 76, 179, 195 Akdogan, B. 76 Akpınar, I.N. 184 Aksentijevich, I. 23, 59 Aksu, K. 223 Al-Ali, S. 136 Al-Khalidi, H. 160 Alamo, F.F.-D. 155 Alba, M.A. 39, 88, 221, 247 Alberici, F. 116, 245 Aldag, B. 184, 231 Aldag, M. 231 Alexander, D. 189, 192 Alexander, S. 133 Alfonzo, A. 240 Alibaz-Oner, F. 58, 184, 220, 222, 223, 231 Allegri, F. 232 Amin, M.N. 170 Amoura, Z. 180, 226 Anand, S. 244 Andres, N. 161 Andrews, J. 164 Anema, J. 140, 141 Anndale, J. 165 Anton, J. 196 Antoñana, V. 172 Antonelou, M. 133 Arden, N. 63 Arends, S. 124 Areses, M. 172 Arfi, S. 132 Ariel, A. 204 Ariff, B. 125, 228 Arimura, Y. 131, 204, 212 Ariyasu, Y. 216 Armangaud, J.B. 103 Arnoux, A. 103 Arostegui, J.I. 247 Asare, A. 89

Cousins, C. 78 Couturier, B. 149 Cox, A. 65 Craven, A. 87, 88, 101, 103, 192 Créange, A. 226 Cronholm, P. 190 Crowson, C. 77, 94, 104 Csernok, E. 11 Cuffaro, S. 175 Culliford, D. 63 Culver, D. 235 Cunninghame-Graham, D. 45 Cuthbertson, D. 79, 122, 148, 203, 229 Dagli, M.N. 183 Daikeler, T. 154, 225 Dale, J. 48, 100, 135 Dalhoff, K. 158 Dallet-Choissy, S. 202 Dalmau, J. 105 Damoiseaux, J. 136, 214 Das, S. 66 Dasgupta, B. 63, 84, 123, 210 Dass, S. 66 Dauphin, C. 180 Davagnanam, I. 151 David Carmona, F. 3 David, J. 196 David, S. 180 Davis, J. 120 Dawson, J. 190 D’Cruz, D. 159 de Decker, L. 126 de Joode, A. 79 de Suremain, N. 134 Decaux, O. 55 Dechartres, A. 64 Degauque, N. 137 DeGroot, K. 213 Dekkers, O. 247 Delahousse, M. 129 Delaval, P. 80 Delbarba, E. 163, 232, 233 Deligny, C. 132 D’Elios, M.M. 221 Della Bella, C. 221 Deniz, R. 222 Denton, C.P. 18 Derebail, V.K. 143, 202 Desbuissons, G. 129 Deshpande, V. 106 Desmurs-Clavel, H. 55 Deterding, L. 72 Devauchelle-Pensec, V. 70 DeVellis, R. 189, 192 Devillers, H. 180 Dhaygude, A. 133, 137, 138, 219


Dhindsa, N. 240, 243 Dhote, R. 64, 180 Di Filippo, S. 103 Diamantopoulos, A. 84, 108, 123, 124, 181, 182, 210, 231 Diaz, M. 218, 219 Dib, H. 142 Dimonaco, S. 175 Din, N.M. 151 Ding, L. 81, 85, 97 Direskeneli, H. 45, 58, 121, 184, 220, 222, 223, 231 Dixon, W. 134 Djaffar, H. 134 Dobashi, H. 131 Dobson, L. 176 Dogan, I. 195 Dolezalova, P. 196 Donmez, I. 76 Donmez, S. 187 Dorman, A. 56 Dospinescu, P. 55, 173, 177 Doube, A. 177 Doucet, L. 129 Doyle, A.F. 133 Draak, T.H. 192 Draibe, J. 95, 100, 143, 165 Drayson, M. 136 Dropol, A. 84 Drosos, A. 83 Druce, K. 189 Duboc, D. 115 Dumarey, N. 149 Duna, G. 132, 185 Dunogue, B. 158, 168 Dunogué, B. 70, 115, 132, 167, 188, 190 Duro, V. 242 Durrbach, A. 129 Duzova, A. 239 Dyall, L. 135 Egfjord, M. 170 Ekstrand, A. 97 El-Benna, J. 72 Eleftheriou, D. 75, 196 Elejalde, I. 161 Elliott, L. 56 Elner, V. 244 Emery, P. 66, 164 Emin, A. 63 Emmi, G. 73, 106, 166, 179, 221 Emmi, L. 73, 106, 166, 221 Endo, A. 204 Endo, T. 216 Engel, A. 90 Englund, M. 77, 98, 130 Enomoto, Y. 104, 208


Epaulard, O. 180 Erdbruegger, U. 213 Erden, A. 179, 195 Erer, B. 45, 121, 126 Ergun, T. 184, 222, 231 Erhayiem, B. 176 Eriksson, P. 52, 138, 186 Erken, E. 58 Ernerudh, J. 138 Eroglu, F.K. 239 Ertenli, I. 76, 179, 195 Erwig, L. 55, 173, 177 Erzurum, S. 234 Esatoglu, N. 47 Escribano-Dueñas, A.M. 155 Esen, B.A. 126 Espígol-Frigolé, G. 39, 247 Eulenberg, C. 89, 91 Ezzeddine, R. 203 Faber, C.G. 192 Fain, O. 180 Fakhouri, F. 126, 137 Falk, R. 13, 26, 46, 60, 64, 66, 72, 82, 90, 152, 202, 214 Fan, J. 203 Fanlo, P. 236 Farr, A. 132, 185 Farrar, J. 190 Faye, A. 103 Fearon, U. 228 Fédérici, C. 142, 222 Fedorov, K. 237, 238 Feenstra, T. 53 Feighery, C. 56 Feng, R. 248 Fernandez, J. 235 Fernández-Juárez, G. 218, 219 Fervenza, F. 81, 96 Fifi-Mah, A. 117, 227, 243 Fiorillo, C. 106 Fischereder, M. 239 Fisher, V. 54 Fleming, J. 240 Flint, J. 136 Flint, S. 59 Flores-Suárez, L.F. 152, 153, 162 Flossman, O. 79, 115 Fluck, N. 55, 173, 177 Fomin, V. 176 Forrester-Barker, W. 84 Fortune, F. 34 Frachet, P. 95 Fragoulis, G. 164 Fraison, J.-B. 180 Frausova, D. 109

251


Chanouzas, D. 100, 135 Chao, N. 81 Charles, P. 70, 132 Chaudhry, A. 131 Chauveau, D. 159 Chávez-Rubio, A. 162 Chen, M. 57, 92, 157, 197, 198 Chen, N. 216 Chen, S.-F. 57, 157 Chen, Y.-X. 216 Cheriyan, J. 109 Chevailler, A. 215 Choi, H. 51, 101, 107 Choi, M. 91 Chou, J. 217 Choudat, D. 190 Chrysidis, S. 231 Cianchi, F. 221 Ciavatta, D. 46, 90 Cid, M.C. 39, 82, 221, 247 Cimaz, R. 196 Cinar, M. 58 Cisternas, M. 157 Ciucciarelli, L. 106, 221 Clarkson, M. 56, 75 Clary, G. 222 Clemos, S. 236, 242 Cobankara, V. 58 Cohen-Aubart, F. 226 Cohen, P. 55, 80, 115, 132, 167, 168, 180, 188, 190 Coit, P. 45, 244 Colby, K. 66 Coles, A. 65 Colic, A. 231 Collins, M.P. 16, 192 Collinson, N. 175, 188 Comarmond, C. 180 Conlon, P. 75 Connolly, E. 56, 145 Connolly, M. 93 Conterato, A. 152 Conway, R. 228 Cook, H.T. 46, 49, 70, 108, 199 Corbera-Bellalta, M. 39, 221 Cordier, J.-F. 158 Cornec, D. 70 Cornec-Le Gall, E. 70 Corral-Gudino, L. 210 Cortazar, F. 99 Cosgrove, K. 99, 166 Cosgun, B.N. 58 Costedoat-Chalumeau, N. 180, 190 Cotos-Canca, R. 155 Cottin, V. 158 Coudyzer, W. 234 Coughlan, A. 56, 145

Galempoix, J.-M. 180 Gallagher, P. 228 Gallerini, S. 73 Galmiche-Rolland, L. 129 Gansbeke, D.V. 149 Gao, Z. 89 Garandeau, C. 137 García-Martínez, A. 221 Garcia, N. 118 Garcia-Osuna, R. 218, 219 Garcia, P. 242 Garg, P. 176 Gatenby, P. 217 Gauthier, F. 202 Gebert, S. 238 Gebhart, D. 190 Geetha, D. 165 Geiger, J. 124, 181 Georget, E. 134 Geraldes, R. 88 Gérard, F. 70 Gerenli, O. 246 Geri, G. 55 Geryk, L. 189 Ghosh, A. 178 Gintoli, E. 207 Gioffredi, A. 245 Girard, C. 64 Gobert, P. 55 Göçerog˘lu, A. 54 Godeau, B. 180 Godmer, P. 55, 132, 137 Goldbach-Mansky, R. 239 Goldblatt, D. 136 Golubev, S. 238 Gommard-Menesson, E. 180 González-Fernandez, A. 210 González-Gay, M.A. 3 Gonzalez, M. 172, 242 Gonzalez, P. 242 González-Vázquez, E. 210 Gordins, P. 54 Górka, J. 193 Grassi, A. 221 Grau, J.M. 82, 221 Graveleau, J. 126, 137 Grayson, P. 79, 87–89, 103, 248 Greenwood, J. 176

252

Gregersen, J.W. 158 Gregorini, G. 163, 232, 233, 245 Greiff, V. 225 Grenmyr, E. 54 Griffith, M. 108, 111 Grinyó, J.M. 165 Groh, M. 70, 158, 222 Groot, D. 162 Gross, W. 158, 201 Guarino, C. 202 Gudnason, V. 62 Guellec, D. 70 Guenno, G.L. 64, 159 Guerra, I.E. 241 Guida, G. 245 Guilevin, L. 222 Guillevin, L. 55, 64, 70, 72, 79, 80, 115, 132, 142, 158, 159, 167, 168, 180, 188, 190, 204, 226, 227 Gul, A. 45, 121, 126 Guleria, A. 94 Gunn, J. 196 Gunnarsson, I. 140, 168, 246 Gunnarsson, L. 199 Gupta, D. 244 Gursel, I. 239 Gursel, M. 239 Gutierrez, U. 242 Habicht, A. 239 Hachulla, E. 70 Hadden, R.D. 16, 192 Hałek, A. 193 Haes, P.D. 194 Hägele, H. 239 Hageman, G. 248 Hagen, C. 54, 171 Hajj-Ali, R. 234, 235, 236 Halac, M. 58 Halbwachs, L. 21 Hamidou, M. 80, 126, 137, 180 Hamilton, P. 134, 233 Hamilton. W. 63 Hammad, T. 234–236 Hamour, S. 86 Hamuryudan, V. 58, 194 Hancer, V. 105 Hanci, I. 184 Handa, T. 216 Hanrotel-Saliou, C. 80 Hansen, P.R. 231 Hanslik, T. 72 Hanzal, V. 62 Hao, J. 92, 197 Haque, S. 170 Harland, D. 108 Harper, L. 48, 100, 101, 113, 115, 135, 136, 165, 191, 214


Harris, S. 138, 206 Hart, S. 54 Haskard, D. 92 Häsler, R. 201 Hasselbacher, K. 141 Hatemi, G. 47, 194 Hatron, P.-Y. 159 Haubitz, M. 90 Haugeberg, G. 181, 182 Hawkins, C. 84 Hayakawa, S. 204 Hayem, G. 132 Hazirolan, T. 76 Hedström, A. 110 Heeringa, P. 51, 68, 114, 139, 140, 141 Heijl, C. 99 Hellmark, T. 119, 142, 199 Henderson, A. 152 Henderson, C. 46, 72, 90, 143, 202 Henderson, S.K. 143 Hensor, E. 82 Hernández-Rodríguez, J. 82, 221, 247 Herrera, A. 157 Herrmann, T. 207 Hess, C. 225 Hess, J. 72 Hessels, A. 100 Hetland, H. 181 Hewins, P. 191 Hickey, F. 56, 145, 206, 208 Hie, M. 180 Hiemann, R. 118 Hiemstra, T. 79, 115 Higuera, V. 153 Hilhorst, M. 136 Hill, N. 199 Hinkofer, L. 120 Hladio, M. 105 Hočevar, A. 226, 237 Hoffman, G. 79, 81, 85, 96, 113, 120, 122, 130, 148, 203, 229, 248 Hogan, J. 165 Hogan, S. 60, 64, 66, 82, 90, 100, 127, 143, 152, 189, 192, 202, 214 Höglund, P. 115 Holding, S. 54 Holdsworth, S.R. 8 Holl-Ulrich, K. 141, 201, 205 Holle, J. 158 Holm, L. 71, 119, 199 Holweg, C. 97 Homma, S. 131 Hong, Y. 75, 205 Hooven, D.V. 247 Horst, G. 93, 124

Horvath, R. 62 Hospers, G. 162 Hot, A. 180 Hruskova, Z. 53, 62, 71, 109, 165, 186 Hu, P. 50 Hu, Y. 60, 64, 66, 143, 202, 214 Huang, Y.-M. 57, 157 Huarte, E. 242 Hubalewska-Mazgaj, M. 200, 201 Hubsch, A. 109 Huitema, M. 139, 140 Hull, R. 46 Humbert, M. 158 Humbert, P. 180 Humbert, S. 180 Hummel, A. 113, 120, 148 Hurtado, P. 145 Hurtado-Perez, E. 145 Hutchings, A. 63, 84, 123, 210 Iesato, K. 211 Iinuma, C. 207 Ikeda, K. 211 Ikeda, S. 145, 146 Ikegaya, N. 204 Iking-Konert, C. 112 Ikle, D. 81, 85, 97 Imanaka-Yoshida, K. 104 Imbert, B. 80 Inagaki, Y. 154 Inanç, M. 126 Indrakanti, D. 96, 130 Iordache, L. 215 Iovesan, F. 175 Iriarte, I.L. 241 Isa, H. 151 Isaeva, E. 200 Ishizu, A. 197, 207 Isorna-Porto, M. 164 Ito, T. 211 Ivarsen, P. 158 Iwakiri, T. 217 Iwamoto, I. 211 Jade, J. 177 Jancova, E. 62 Jane, M. 101 Janigro, D. 234 Janneck, M. 112 Janocha, A. 234 Javaid, K. 192 Jayne, D. 33, 59, 65, 78, 79, 97, 98, 109, 110, 115, 116, 131, 156, 158, 165, 173, 186, 213, 240 Jazwiec, P. 160

Author Index


Freeley, S. 74 Fremeaux-Bacchi, V. 21 Fritzler, M. 117 Froment, A.B. 143, 202 Fujimoto, S. 131, 217 Fukuoka, T. 204 Fulladosa, X. 165, 218, 219 Furuta, S. 131, 211 Fuse, Y. 146 Fussner, L.A. 113

Kahn, J.-E. 64, 180, 226 Kain, R. 53 Kallankara, S. 54 Kallenberg, C. 81, 85, 89, 96, 113, 130, 140 Kalyoncu, U. 58, 59, 76, 179, 195 Kamali, S. 121, 126 Kameoka, Y. 145, 146 Kaname, S. 204, 212 Kang, Y. 127, 216 Kanitez, N.A. 121, 126 Kaplan, M. 89 Kara, M. 224 Karaaslan, Y. 58 Karadag, O. 58, 59, 76, 179, 195 Karadeniz, A. 58 Karam, C. 64 Karatay, E. 184 Karras, A. 55, 70, 72, 129, 159 Karube, M. 204 Karwat, K. 160 Kashiwakuma, D. 211 Kasifoglu, T. 58 Kastbom, A. 52, 71 Kastner, D.L. 45 Kaur, N. 244 Kawakami, A. 207 Kawashima, S. 204, 212 Kazakou, P. 149 Kelesoglu, A.B. 179 Kellom, K. 190 Kelly, Y. 75 Kemna, M. 214 Kennedy, C. 56, 86 Kereiakes, D.J. 160 Kermani, T. 122, 229

Kerstein, A. 141, 204, 205 Keser, G. 223 Kettritz, R. 48, 73, 89, 91 Khalidi, N. 79, 122, 148, 203, 229, 248 Khamis, R. 228 Khetrapal, C.L. 94 Khifer, C. 222 Khouatra, B. 80 Khouatra, C. 55 Kida, C. 204 Kidambi, A. 176 Kidder, D. 55, 173, 177 Kielstein, J. 213 Kilic, L. 76, 179, 195 Kilickap, S. 195 Kim, G. 132, 185 Kimyon, G. 58, 246 Kint, N. 194 Kiprianos, A. 92, 125, 228 Kiran, A. 63 Kiraz, S. 76, 179, 195 Kirsch, T. 90 Kisacik, B. 58, 246 Kishi, F. 145, 146 Kitagawa, K. 217 Kitamura, K. 217 Kitching, A.R. 8 Klaboch, J. 62 Klapa, S. 141 Klearman, M. 175, 188 Klein, N. 75 Knight, A. 168 Knoll, K. 212 Kobalava, Z. 213 Koca, S.S. 183, 224 Kodeda, M. 62 Koenig, C. 148 Koenig, K. 225 Koening, C. 79, 122, 203, 229, 248 Kojima, T. 67 Kolta, S. 167 Komagata, Y. 204, 212 Komatsu, S. 67 Koné-Paut, I. 103, 134, 180 Korkmaz, B. 202 Koster, M. 77, 94, 104 Kotzen, E. 66 Koura, M. 145 Kovrigina, A. 237 Krarup, E. 170 Krautwald, S. 48 Krebs, C. 112 Kristensen, T. 158 Kroesen, B.-J. 162 Krüger, S. 48, 73 Kuchai, R. 49 Kucukoglu, S. 185


Kulikova, M. 106 Kumar, D. 94 Kumar, S. 182 Kusunoki, Y. 197 Kuznetsova, E. 213 Kwame, I. 65 Kyndt, X. 80 Labarca, C. 77, 94 Laborde-Casterot, H. 190 Labrousse, F. 222 Lachmanova, J. 109 Lacruz, B. 161 Laliberte, K. 99, 166 Lambert, M. 80, 180 Lamprecht, P. 141, 204, 205 Land, J. 114, 141 Landis, J.R. 82 Landron, C. 180 Langford, C. 79, 81, 85, 89, 96, 113, 122, 130, 148, 203, 229, 248 Lanier, G. 190 Lanska, V. 62, 109 Lanyon, P. 61, 84, 116 Lara, M. 153 Lardinois, O. 72 Lascoux, C. 215 Laudien, M. 201 Launay, E. 103 LaValley, M. 189 Lavigne, C. 180 Lawrence, A. 182 Lazaro, E. 64 Lazor, R. 158 Lazzaroni, M.G. 178 Le Jeunne, C. 80, 222 Lee, S. 165 Lee Teak Tan, 151 Lefèvre, E. 129 Lehane, P.B. 172 Lehmann, T. 212 Leng, L. 203 Lerma-Márquez, J.L. 210 Lesavre, P. 21 Leské, C. 80 Levy, J. 71, 108 Lewis, M. 189 Li, R. 51 Li, Z. 157 Liapis, G. 83 Liferman, F. 80 Lightman, S. 49, 151, 220 Lightstone, L. 70 Lijun, X. 243 Lilliebladh, S. 119 Lim, N. 81, 89, 95, 97 Lincoln, T. 152 Lindland, A. 182 Linkermann, A. 48


Lino, M. 126, 137 Lintermans, L.L. 68, 139 Lionaki, S. 83, 164 Little, M. 56, 75, 86, 128, 145, 206, 208, 214 Liu, J. 199 Lo Gullo, A. 104 Lofek, S. 142, 222 Logan, S. 191 Lohne, F. 124, 181 Lopatina, I. 213 Lopatina, L. 200 Lopez, P. 118 Lott, L.D. 244 Loudon, K. 165 Lovric, S. 90 Lozano, E. 221 Lu, L. 51 Lu, N. 101, 107 Lucas, M.D.G.-D. 155 Luft, F. 89 Luna, G.D. 159 Lunt, M. 134 Luqmani, R. 29, 47, 60, 63, 78, 84, 87, 88, 101, 103, 123, 190, 192, 196, 210 Luster, A.D. 223 Luthert, P.J. 151 Luttropp, K. 246 Ly, K. 80, 222 Lyons, P. 59, 247 Ma, J. 213 Mackie, S. 82, 176 Magill, B. 47 Magliano, M. 84 Mahajan, V. 76, 106 Mahr, A. 42, 129, 134, 158, 160, 180, 189, 215 Mairon, N. 172 Maisonobe, T. 226 Makar, R. 166 Makarov, E. 169 Maki-Petaja, K. 109 Makol, A. 77, 94, 104 Maksimowicz-McKinnon, K. 148, 203 Maldini, C. 189 Malek, L. 160 Malmström, V. 140 Manenti, L. 207 Mankia, K. 196 Mansfield, N. 108 Marasca, R. 73 Marchand-Adam, S. 159, 202 Marchand, G. 180 Marco, H. 218, 219 Marconi, R. 73 Marie, I. 180 Maritati, F. 245

253


Jeannin, G. 163, 245 Jenne, D. 120, 202 Jennette, J.C. 26, 46, 158 Ješe, R. 226 Jesus, A.A. 239 Jeunne, C.L. 167, 168, 188, 190 Jick, S.S. 188 Jimenez, F. 236 Johansson, Å. 142 John, S. 225, 234–236 Jones, B. 46, 90 Jones, R. 156 Joode, A. 148 Jordan, J. 192 Joshi, L. 65, 220 Jouneau, S. 64 Jourde-Chiche, N. 159 Judge, A. 87, 88, 101 Jung, C. 212

254

Meshkov, A. 176 Messas, E. 180 Mesturoux, L. 222 Mezentseva, M. 200 Middelkoop, S. 148 Millet, A. 72, 204 Mills, J. 47 Milman, N. 190, 218 Miloslavsky, E. 51, 81, 85 Minghui, Z. 243 Minz, R.W. 244 Mirault, T. 180 Misra, D.P. 94, 182 Misra, R. 94, 182 Mistry, A. 60 Miszalski-Jamka, K. 160 Miszalski-Jamka, T. 160 Miyabe, C. 223 Miyabe, Y. 223 Miyoshi, A. 197 Mocek, J. 72, 204 Mohammad, A. 77, 78, 98, 99, 130, 147, 156, 173, 186 Moiseev, S. 149, 161, 169, 176, 200, 213, 229, 237, 238 Molina, J.-M. 215 Møller, B. 171 Molloy, E. 93, 228 Monach, P. 79, 81, 85, 89, 96, 113, 122, 130, 148, 203, 229, 248 Mondal, S. 178 Mooney, J. 209 Moorlag, H. 51 Mooyaart, C. 247 Moran, S. 56, 75, 86, 208 Moreland, L. 79, 122, 148, 229, 248 Morgan, A. 82, 176 Morgan, M. 48, 100, 113, 115, 128, 135, 136, 165, 191 Morlat, P. 180 Morreale, M. 70, 133 Mortensen, K. 156 Moss, P. 135 Mouthon, L. 55, 64, 72, 80, 132, 142, 158, 159, 167, 168, 188, 190, 204, 222, 226 Moutsopoulos, H. 83, 164 Mueller, A. 141, 204 Mueller, M. 46 Mukhin, N. 229 Mulero, H.H. 241 Müller, A. 201, 205 Muller, G. 180 Mumcu, G. 222 Muñoz-Elías, E.J. 139


Murakami, K. 204 Murata, K. 154 Murgia, G. 82 Murphy, A. 99 Murphy, C. 75, 93, 228 Musa, T. 176 Musiał, J. 160, 193 Muso, E. 216 Muthigi, A. 90 Myklebust, G. 124, 181, 182 Myklebust, T.A. 171 Naccache, J.-M. 72 Nachman, P. 13, 64, 66, 143, 152, 202, 214 Nag, A. 178 Nagasawa, R. 145, 146 Naisbett-Groet, B. 108 Najem, C. 235 Nakagomi, D. 78, 156, 211 Nakajima, H. 211 Nakayama, T. 145 Nakazawa, D. 197 Nan, B. 244 Nanthapisal, S. 75 Napalkov, P. 188 Nazarova, N. 238 Néel, A. 126, 137, 180 Néel, M. 137 Neill, L.O.’, 228 Neri, T.M. 245 Neumann, T. 212 Niles, J. 99, 166 Nilsson, J.-Å. 98 Nishio, S. 197 Nishioka, Y. 207 Nitsche, J. 145 Nordfors, L. 246 Noriega, M. 112 Nouri, M.N. 84 Novikov, P. 149, 161, 169, 176, 200, 213, 229, 237, 238 Nunokawa, T. 154 O’Neil, K. 196 Oates, T. 46 O’Brien, F. 206 Öcal, L. 121, 126 Oda, T. 67 O’Donoghue, J. 196 Oelzner, P. 212 O’Hara, P. 56, 145 Oharaseki, T. 104, 208 Ohlsson, S. 119, 142, 199 Ohno, N. 208 Okada, Y. 146 Okroj, M. 119 Oktay, V. 185

Olgun, D.C. 184 Oliva, E. 245 Oliveira, G. 60 Ombrello, M.J. 45 OMERACT Vasculitis Working Group, 121 Omma, A. 58 Omoyinmi, E. 75 Onat, A.M. 58, 246 O’Neill, L. 93, 196 Onodera, H. 146 Ooi, J.D. 8 Oomatia, A. 86 Oommen, E. 148 O’Reilly, V. 56, 145, 208 Ortmann, W. 97 Oshima, T. 67 Owczarczyk, K. 97 Owens, C. 99 Ozcoidi, L.M. 241 Ozen, G. 222 Özen, S. 59, 196, 239 Ozguler, Y. 47 Oziol, E. 180 Oztuzcu, S. 246 Ozyazgan, Y. 45 Paassen, P. 136, 214 Padalia, A. 202 Page, T. 199 Pagnoux, C. 55, 79, 80, 148, 158, 227 Paletta, D. 207 Palmisano, A. 179 Pamuk, O. 187 Pan, X.-X. 216 Panda, 244 Panzer, U. 73, 112 Papo, T. 64, 80 Pappas, C. 248 Parrinello, M. 215 Pay, S. 58 Pearce, F. 61, 103, 116 Pearlman, H. 133 Peck, J. 190 Peckham, D. 139 Pederzoli-Ribeil, M. 95 Peh, C.A. 145, 172 Pehlivan, Y. 58, 246 Pendergraft, W. 13, 46, 64, 66, 72, 90, 99, 100, 152, 214 Pensado, L. 152 Pepper, R.J. 95, 143 Peracha, J. 191 Péraldi, M.-N. 129 Perez, C. 161, 172, 242 Perez-Garrido, L. 210 Perkmann, T. 53 Perre, E.V. 240

Author Index


Marmurzstejn. J. 115 Marsh, J. 115 Martin, C. 172 Martin, D. 218, 219 Martin-Escalante, M.D. 155 Martín, J. 3 Martin, K. 72, 95, 204 Martin, N. 218, 219 Martorana, D. 245 Mason, A. 48, 113 Mason, J.C. 92, 125, 228 Masuda, E. 49 Matamoros, S.C. 241 Mateo, P.F. 241 Matsuda, J. 145 Matteson, E. 77, 94, 104, 121 Mattoo, H. 76, 106 Maurier, F. 55 Mavragani, C. 83 Mavrogeni, S. 160 Maya, J. 234 Mazur, W. 160 McAdoo, S. 49, 50, 71, 108, 111, 133, 220 McAlear, C. 79, 122, 190, 203, 229, 248 McCarthy, G. 93, 228 McClean, A. 48 McCormick, J. 93, 228 McCune, J. 120 McDaid, J. 49, 50 McDermott, M. 202 McDiarmid, A. 176 McDonald, B. 84 McGregor, J. 13, 64, 66, 82, 90, 100, 127, 152, 214 McLaren, J. 240 McNally, E. 123, 210 Mecoli, C. 248 Medjeral-Thomas, N. 49, 108, 220 Mehrabyan, A. 64 Meier, C.R. 188 Mekinian, A. 180 Melikoglu, M. 58 Mellotte, G. 56 Melo Gomes, S. 75 Mendoza, C. 66, 143, 202 Mendoza, P. 172 Menendez, L. 236 Mensikova, R. 62 Merkel, P. 45, 62, 77, 79, 81, 82, 85, 87–89, 95 96, 98, 103, 107, 110, 113, 120– 122, 130, 148, 190, 203, 218, 229, 248 Merkel, R.A. 158 Merkies, I.S. 192 Merlin, E. 103 Merrien, D. 80

Quemeneur, T. 55 Querin, H. 196 Quesada-Moreno, A. 210 Quincey, V. 177 Quintana, L.F. 218, 219 Radice, A. 118, 119, 245 Rahmattulla, C. 171, 247 Raimundo, K. 132, 185 Rami, A. 215 Randall, K. 217 Rani, L, 244 Rasmussen, N. 79, 97, 115, 131, 213 Rau, S. 239 Raugei, G. 73

Ravaud, P. 80 RAVE Investigators, 95 Rawat, A. 94 Rawstron, A.C. 66 Recher, M. 225 Redondo, A. 242 Rees, A. 1, 53 Regazzoli, A. 163 Régent, A. 142, 167, 168, 222 Regnard, D. 134 Regon, M.R. 180 Reina, M. 245 Reinders, M. 171 Remmers, E.F. 45 Renauer, P. 45 Renier, G. 215 Rhee, R. 82 Ribeil, J.-A. 204 Richter, A. 136 Rigolet, A. 226 Ripley, D. 176 Rivas-Lamazares, A. 210 Roberts, D. 109 Roblot, P. 80, 180 Robson, J. 60, 63, 87, 88, 101, 103, 190 Robson, M. 74 Roccabianca, A. 72 Rodil, R. 161, 172 Rodrigues, A. 88, 196 Rodriguez, N. 118 Roffel, M. 124 Roggenbuck, D. 118 Romero-Gómez, C. 155 Rondeau, E. 129 Roozendaal, C. 162 Rorive, S. 149 Rosa, J. 196 Rose, G.E. 151 Rossi, A. 73 Rossi, M. 178 Rotar, Z. 226, 237 Rouvet, C. 215 Roux, C. 167, 168 Rovin, B. 96, 130 Rowbottom, A. 137 Rowland, T. 54 Ruivard, M. 80 Ruiz, M. 157 Ruiz, N. 152, 153, 162 Russu, L. 200 Rüster, C. 212 Rutgers, A. 68, 114, 139, 140, 141 Rutgers, B. 93, 100, 124, 162 Ryan, M. 208 Saas, P. 95, 204 Sabitzki, R. 201


Sage, A. 189 Salama, A. V, 71, 86, 95, 100, 108, 143, 233 Salamon, R. 129 Saldarriaga-Rivera, L.S. 152 Salmela, A. 97 Salviani, C. 163, 232, 233 Sämann, A. 212 Samson, M. 72 Samways, J. 151 Sanak, M. 200, 201 Sanders, J.S. 79, 100, 148 Sandhu, G. 49, 220 Sandin, C. 52 Sangle, S. 159 Saraux, A. 70 Sarica, S. 6 Sarsour, K. 188 Saruhan-Direskeneli, G. 45, 220, 223 Sasaki, N. 207 Sathyanarayanan, S.K. 204 Sato, Y. 217 Saurina, A. 218, 219 Savinykh, N. 59 Sawalha, A. 45, 244 Sawyer, L. 108 Sayarlioglu, M. 58 Saygin, C. 47 Scarpini, C. 73 Scheidereit, C. 91 Schepis, D. 140 Scherbakova, V. 213 Schiavon, F. 175 Schinke, S. 201 Schleinitz, N. 64 Schmidt-Ullrich, R. 91 Schmidt, W. 123, 124, 181, 210 Schmitz, J. 66 Schneiter, S. 199 Schober, F. 214 Schönermarck, U. 239 Schoones, J. 247 Schreiber, A. 48, 73, 91 Schroder, C. 162 Schroeder, D. 113 Schwaeble, W. 74 Scott, D.G.I. 209 Sedova, L. 62 Seeliger, B. 87, 101, 196 Segelmark, M. 52, 71, 98, 99, 130, 138, 147, 165, 186 Selga, D. 115, 142 Sellier, P.-O. 215 Sengölge, G. 53 Seo, P. 79, 81, 85, 89, 96, 113, 122, 130, 148, 203, 229, 248 Sequiera, R. 86


Serafim, A. 123, 210 Sergienko, T. 238 Sève, P. 180 Seyahi, E. 45, 58, 184, 185 Shaban, M. 214 Sharma, A. 244 Shea, J. 190 Sheikh, S. 84 Shevtsova, T. 229 Shida, H. 197 Shimada, K. 154 Shimizu, H. 204 Shinkawa, K. 216 Shuiyi, H. 243 Shulz-Menger, J. 160 Sibilia, J. 180 Silva, F. 113, 157 Silvestri, E. 73, 106, 166, 221 Singh, J. 244 Singh, S. 84, 123, 210 Singhal, A. 235 Sinha, D. 178 Sinico, R. 158, 245 Sivasothy, P. 156 Skattum, L. 199 Skogh, T. 52, 71 S.Lightman, D. 37 Smail, A. 80 Smith, K. 59, 116, 247 Smith, R. 98, 110, 116, 156 Smitienko, I. 161, 176, 229 Snanoudj, R. 129 Snyder, M. 113 Söderberg, D. 138 Sokolowska, B. 160 Solanki, K. 177 Somarakis, G. 83 Somma, V. 118 Sommarin, Y. 54, 71 Sorokin, Y. 149 Sowa, M. 118 Specks, U. 51, 81, 85, 89, 95, 96, 97, 113, 120, 130, 158, 203, 248 Spiera, R. 81, 85, 89, 96, 113, 120, 130 Springer, J. 235 Squatrito, D. 106, 166, 221 Sreih, A. 122, 148, 203, 229 Sriskandarajah, S. 171 St. Claire, E.W. 81, 85, 89, 96, 113, 120, 130 Stahl, R.A.K. 112 Stål, P. 110 Standing, A. 75 Stanway, J. 233 Starmer, J. 90 Stegeman, C. 68, 79, 100, 114, 139–141, 148 Stewart, L. 143, 202

255


Perrin, F. 137 Perrodeau, E. 80 Perruche, S. 204 Pertuiset, E. 80 Perugino, C. 60 Pesci, A. 245 Petersen, A.H. 51 Petretto, E. 46 Petrushkin, H. 34 Pettersson, A. 142, 199 Phippard, D. 85, 97 Pieri, L. 73 Pillai, S. 76, 106 Pino-Montes, J.D. 210 Piper, J. 123, 210 Piram, M. 103, 134, 180 Pirla, T.C. 241 Pizzolato, S. 245 Planas, E. 39, 221 Plein, S. 176 Polat, N.G. 121 Poli, C. 215 Polok, K. 193 Ponge, T. 137 Ponte, C. 88, 123, 192, 196, 210 Popat, R. 74 Poulton, C. 46, 60, 64, 66, 82, 152, 202, 214 Poulton, C.J. 100 Poveda, R. 165 Praga, M. 218, 219 Prieto-González, S. 88, 221, 247 Prisco, D. 73, 106, 166, 221 Puéchal, X. 55, 72, 79, 80, 132, 159, 167, 168, 180, 188, 190 Pusey, C. V, 46, 49, 50, 65, 68, 70, 71, 108, 111, 133, 151, 199, 208, 220 Puvenna, V. 234

Tabassum, R. 117 Tak, Q. 219 Takahashi, K. 104, 208 Takahashi, R. 184 Takeuchi, M. 45 Tam, F. 49, 50, 68, 208 Tamas, N. 142 Tamby, M. 142, 222 Tanna, A. 49, 50, 68, 71, 108, 133, 220 Tarzi, R. 49, 70, 108, 111, 133, 199, 220 Tascilar, K. 47, 194 Taskiran, E.Z. 59 Tatsumi, K. 211 Taulera, O. 215 Tavee, J. 235 Taylor, S. 151, 220 Tchao, N. 85, 89, 95–97, 113, 130 Tellier, S. 103 Tello-Winniczuk, N. 153 Tepper, S. 234–236 Terrades-García, N. 39 Terrades, N. 221 Terrier, B. 55, 64, 72, 80, 115, 132, 159, 167, 168, 188, 190, 204, 226 Tervaert, J.W.C. 97, 136, 214 Tesar, V. 53, 62, 71, 109, 165, 186 Tessoulin, B. 137 Thieblemont, N. 204 Thomazeau, J. 126 Thompson, B. 53

256

Thorpe, C. 127, 189 Thorpe, J. 127 Tincani, A. 178 Tiple, A. 159 Todd, S.K. 143 Tomaru, U. 197, 207 Tomasson, G. 62, 77, 107, 130, 190 Tombetti, E. 92, 125, 228 Tomiyasu, T. 67 Tomkins-Netzer, O. 151 Tomšič, M. 226, 237 Tona, G. 153 Toniati, P. 178 Tooth, D. 128 Toppmöller, T. 212 Toptas, T. 231 Toro, C.M. 117 Torras, J. 165 Toz, B. 121, 126 Trezzi, B. 118, 119 Troitskaya, E. 213 Troyas, R.G. 241 Tsushima, K. 211 Tuckwell, K. 175, 188 Tugwell, P. 218 Tulunay-Virlan, A. 222 Ture-Ozdemir, F. 222 Turesson, C. 77 Turner-Stokes, T. 70 Tutkun, I.T. 45 Twilt, M. 84, 105 Tyrrell, P. 84 Tzioufas, A. 83, 164 Uchino, K. 234–236 Ugurlu, S. 47, 58, 184, 185, 194 Ulasli, M. 246 Unal, A.U. 222 Unizony, S. 51, 85, 101, 107, 223 Urban, M.L. 73, 179, 207 Ustek, D. 45 Uzunaslan, D. 47 Vaglio, A. 73, 158, 179, 207, 245 van der Geest, N. 93, 124 van Timmeren, M.M. 51 Vandenhende, M.A. 180 Vandergheynst, F. 149 Vanderschueren, S. 209 Vannozzi, L. 166 Vannucchi, A.M. 73 Varron, L. 180 Vasculitis Research Unit – Hospital Clínic Members 82 Vásquez-Colón, R. 153


Vatankulu, B. 58 Veale, D. 93, 228 Venetsanopoulou, A. 164 Venning, M. 47, 128, 134, 138, 151, 170, 206, 233 Verity, D.H. 151 Verstockt, B. 209 Viallard, J.-F. 80 Vidal, E. 222 Vignaux, O. 115 Villanueva, A. 242 Villar, I. 82 Villarreal, M. 81, 85 Vital, E.M. 66, 164 Vlahogiannopoulos, P. 164 Volteau, C. 126 Vrancken, A.F. 192 Vyse, T. 45 Wada, T. 217 Wade, S. 93 Waki, M. 207 Wakker, S.-C. 171 Walker, D. 240 Wallace, Z. 60, 76, 101, 106 Walls, C. 55 Walsh, M. 115 Wang, C. 92, 197, 198 Wang, F. 248 Wang, H. 57, 65, 92, 157, 198 Wang, Q. 51 Wang, S.-X. 157 Warrington, K. 77, 79, 94, 104, 122, 229 Watts, R.A. 61, 87, 88, 103, 116, 209 Wawrzycka-Adamczyk, K. 196, 201 Wawrzycka, K. 200 Wechsler, M.E. 158 Weiner, M. 71, 186 Weksler, B. 142 Wendt, M. 246 Weppner, G. 141 Westman, K. 31, 79, 98, 99, 115, 213 Westra, J. 51 White, D. 177 Wiech, T. 112 Wieslander, J. 54, 71, 147 Wilde, B. 136 Wilkinson, I. 109 Wilkinson, N. 196 Willard, B. 236 Willcocks, L. 65, 240 Wilson, J.C. 188 Witko-Sarsat, V. 72, 95, 204, 222 Witzke, O. 136 Wolf, G. 212

Wolfe, K. 84 Wolterbeek, R. 171 Wong, L. 56 Woollad, K. 199 Wren, J. 45 Wu, T.S. 145 Włudarczyk, A. 193 Xin, W. 213 Xu, J. 216 Xu, L. 89 Xueyuan, T. 243 Yagüe, J, 247 Yamada, A. 204 Yamada, M. 67 Yamagata, M. 211 Yamaguchi, M. 207 Yamaguchi, R. 216 Yamakawa, Y. 145, 146 Yang, J. 46, 90 Yanikkaya-Demirel, G. 105 Yavuz, S. 105 Yazici, A. 58 Yazici, H. 58, 184, 185 Yentur, S.P. 220, 223 Yiannakis, C. 136 Yigit, Z. 185 Yildiz, F. 58 Yilmaz, M. 224 Yilmaz, S. 58 Yin, M. 95 Yokogawa, N. 154 Yokouchi, Y. 104, 208 Yolbas, S. 183, 224 Yonemoto, S. 216 Yoshida, M. 67, 197 Yoshikawa, N. 67 Yoshiki, T. 207 Ytterberg, S. 79, 89, 122, 130, 148, 203, 229, 248 Yu, F. 157 Yuan, J. 51 Yunhua, L. 243 Yusof, M.Y.M. 66, 164 Zamboch, K. 62 Zandi, M,, 65 Zhabina, E. 161 Zhang, W. 216 Zhang, Y. 62, 107 Zhao, C. 243 Zhao, M.-H. 57, 92, 157, 197, 198 Zia, A. 125

Author Index


Stillman, M. 234–236 Stone, J. 51, 60, 76, 81, 85, 89, 95–97, 101, 106, 107, 113, 120, 130, 175, 188, 223 Strizhakov, L. 169, 213 Strle, K. 223 Subra, J.-F. 80 Sudo, Y. 67 Sugii, S. 154 Sugiyama, T. 211 Sungher, D. 108 Suppiah, R. 87, 88, 103 Surmiak, M. 200, 201 Suzuki, H. 216 Suzuki, K. 145, 146 Svärd, A. 71 Svojanovsky, J. 62 Swoboda, P. 176 Szczeklik, W. 160, 193 Szeki, I. 233 Szeto, M. 115 Sznajd, J. 78, 87, 101, 196 Szpirt, W. 170

Continuing Progress in Vasculitis Research. Abstracts of the 17th International Vasculitis & ANCA WorkshopLondon, April 19-22, 2015: Abstracts.

Proteinase 3-ANCA Vasculitis versus Myeloperoxidase-ANCA Vasculitis.

ANCA Glomerulonephritis and Vasculitis.

Anca-associated vasculitis.

10th international scientific conference of the international occupational hygiene association, london april 25-30, 2015: program abstracts.

Updates in ANCA-associated vasculitis.

Treatment of ANCA-associated vasculitis.

Classification of ANCA-associated vasculitis.

The immunopathology of ANCA-associated vasculitis.

Abstracts of the Safe States 2015 Annual Meeting, April 29th–May 1st, 2015, Atlanta, GA.

Erratum: Oral & Poster Abstracts from the 2016 International Massage Therapy Research Conference.

Biological drugs in ANCA-associated vasculitis.

Prion 2015 poster abstracts.

Residents' corner February 2015. DeRmpath & Clinic--Leukocytoclastic vasculitis.

Recent pathogenetic advances in ANCA-associated vasculitis.

Biologic therapy in ANCA-negative vasculitis.

Neutrophil Extracellular Traps in ANCA-Associated Vasculitis.

2015 IHDM Abstracts.

43rd European Mathematical Genetics Meeting (EMGM) 2015. April 16-17, 2015, Brest, France: Abstracts.

2015 RIV Abstracts.

Prion 2015 oral abstracts.

Abstracts & Extracts.

Antineutrophil cytoplasmic antibodies (ANCA) and vasculitis.

Induction regimens for ANCA-Associated Vasculitis.