Downloaded from http://ard.bmj.com/ on July 8, 2015 - Published by group.bmj.com
ARD Online First, published on July 25, 2014 as 10.1136/annrheumdis-2014-205389 Clinical and epidemiological research
EXTENDED REPORT
Association between tobacco smoking and response to tumour necrosis factor α inhibitor treatment in psoriatic arthritis: results from the DANBIO registry Pil Højgaard,1,2 Bente Glintborg,1,3,4 Merete Lund Hetland,3,4,5 Torben Højland Hansen,6 Philip Rask Lage-Hansen,7 Martin H Petersen,8 Mette Holland-Fischer,9 Christine Nilsson,10 Anne Gitte Loft,11 Bjarne Nesgaard Andersen,12 Thomas Adelsten,13 Jørgen Jensen,14 Emina Omerovic,3 Regitse Christensen,1 Ulrik Tarp,15 René Østgård,16 Lene Dreyer1,4 Handling editor Tore K Kvien For numbered affiliations see end of article. Correspondence to Dr Bente Glintborg, Copenhagen Centre for Arthritis Research, Centre for Rheumatology and Spine Diseases, Copenhagen University Hospital Glostrup, Copenhagen, Denmark; [email protected] Bente Glintborg and Pil Højgaard share first co-authorship. Received 11 February 2014 Revised 8 May 2014 Accepted 11 July 2014
To cite: Højgaard P, Glintborg B, Hetland ML, et al. Ann Rheum Dis Published Online First: [please include Day Month Year] doi:10.1136/ annrheumdis-2014-205389
ABSTRACT Objectives To investigate the association between tobacco smoking and disease activity, treatment adherence and treatment responses among patients with psoriatic arthritis (PsA) initiating the first tumour necrosis factor α inhibitor therapy (TNFi) in routine care. Methods Observational cohort study based on the Danish nationwide DANBIO registry. Kaplan–Meier plots, logistic and Cox regression analyses by smoking status (current/previous/never smoker) were calculated for treatment adherence, ACR20/50/70-responses and EULAR-good-response. Additional stratified analyses were performed according to gender and TNFi-subtype (adalimumab/etanercept/infliximab). Results Among 1388 PsA patients included in the study, 1148 (83%) had known smoking status (33% current, 41% never and 26% previous smokers). Median follow-up time was 1.22 years (IQR 0.44–2.96). At baseline, current smokers had lower Body Mass Index (27 kg/m2 (23–30)/28 kg/m2 (24–31)) (median (IQR)), shorter disease duration (3 years (1–8)/5 years (2–10)), lower swollen joint count (2 (0–5)/3 (1–6)), higher visualanalogue-scale (VAS) patient global (72 mm (54–87)/ 68 mm (50–80)), VAS fatigue (72 mm (51–86)/63 mm (40–77)) and Health Assessment Questionnaire (HAQ) score (1.1 (0.7 to 1.5)/1.0 (0.5 to 1.5)) than never smokers (all p10% in any of the analyses (data not shown). Baseline VAS scores, CRP, BMI, tender joint count, HAQ, and DAS28 were considered intermediate variables between tobacco smoking and outcomes, and were hence excluded from multivariate analyses. Additional stratified Kaplan–Meier plots, and multivariate Cox and logistic regression analyses according to (1) gender and (2) TNFi type were performed. In the subanalysis of time to discontinuation due to adverse events, discontinuations due to ineffectiveness were treated as censored observations and vice versa.
RESULTS A total of 1388 bDMARD-naive patients initiating treatment with adalimumab, etanercept or infliximab as the first TNFi were included (table 1). Among 1148 patients (83%) with known smoking status, 33% were current, 41% never and 26% previous smokers. Patients with missing smoking information had lower BMI, younger age, longer disease duration, higher CRP, higher SJC, lower VAS global and fatigue scores, compared to patients with available smoking information (table 1). Thirty-four percent of women and 31% of men with known smoking status were current smokers. At baseline, current smokers had shorter disease duration, lower BMI, higher HAQ, higher VAS fatigue and VAS global compared to previous and never smokers (table 1). Previous smokers were older than current and never smokers. The reasons for stopping TNFi treatment were independent of smoking status (table 1). Male current smokers had higher HAQ (1 (0.6–1.4) vs 0.8 (0.4–1.3), (median (IQR)), p=0.03) and shorter disease duration (3 years (1–10) vs 6 years (2–13), p=0.03) than male never smokers, whereas VAS scores, DAS28 and BMI were similar (all p>0.05). Female current smokers had lower BMI (25 kg/m2 (23–29) vs 28 kg/m2 (24–32), p=0.001), Højgaard P, et al. Ann Rheum Dis 2014;0:1–7. doi:10.1136/annrheumdis-2014-205389
Downloaded from http://ard.bmj.com/ on July 8, 2015 - Published by group.bmj.com
Clinical and epidemiological research Table 1
Baseline demographics, disease activity and reasons for terminating TNFi treatment according to smoking status at the baseline visit Smoking status
Number, n (%) Age, years Disease duration, years Women, n (%) Body Mass Index, kg/m2 TNFi drug type, n (%) Adalimumab Etanercept Infliximab TNFi start year, n (%) 2000–2003 2004–2007 2008–2011 Methotrexate use, n (%) CRP, mg/L Tender joint count (0–28) Swollen joint count (0–28) HAQ DAS28 Patient’s global (0–100), mm Pain (0–100), mm Fatigue (0–100), mm Doctor’s global (0–100), mm Stop reason, n (%)‡ Lack of efficacy Adverse events Other Unknown
Current
Never
Previous
p Value*
p Value†
Smoking status unknown
380 (33) 47 (38–55) 3 (1–8) 197 (48) 27 (23–30)
466 (41) 47 (37–56) 5 (2–10) 204 (44) 28 (24–31)
302 52 4 156 28
0.9 10% and was not included in the multivariate analysis. Baseline distribution of covariates according to TNFi drug type (adalimumab/infliximab/etanercept). Current smokers: 34%/37%/27%. Males: 50%/55%/47%. Age, median (IQR): 48 (38–56) years/48 (39–56) years/48 (39–56) years. Disease duration, median (IQR): 4 (1–9) years/4 (2–12) years/4 (1–10) years. HR, hazard ratio; TNFi, tumour necrosis factor alpha inhibitor.
In men, previous smokers tended to have higher EULAR-good-response and ACR20 response rates than current smokers, and lower rates compared to never smokers (univariate logistic regression analyses, data not shown) (figure 2).
DISCUSSION In this observational study of 1388 PsA patients initiating their first treatment with a TNFi, one-third of patients were current smokers. Current smokers had higher HAQ and patient VAS scores, but shorter disease duration than never smokers upon initiation of treatment. Current smokers had reduced response rates, most pronounced in male smokers where the EULAR-good-response and ACR20 response rates were nearly halved compared to male never smokers. For previous smokers, the effect of smoking on drug adherence diminished with time and was equivalent to never smokers ∼4 years after smoking cessation. The impact of smoking on disease activity and functional status is well described in RA17–19 but scarcely investigated in PsA. A cross-sectional study among 283 patients with PsA reported that current smokers had higher HAQ.9 It has been suggested that smoking alters illness behaviour and causes a more severe perception of musculoskeletal pain.19 This may lead to higher DAS28 scores among current smokers compared to non-smokers with a similar inflammatory activity.22 Thus, perhaps the DAS28 score should be interpreted with more caution among smokers. This may be especially relevant in patients with PsA, in whom the validity of the DAS28 measure is debated.33 34 We found shorter disease duration among current compared to never smokers upon start of TNFi, which may indicate a more aggressive disease course among smokers.18 However, objective markers of disease activity (CRP and SJC) were independent of smoking status. One may hypothesise that a worse Højgaard P, et al. Ann Rheum Dis 2014;0:1–7. doi:10.1136/annrheumdis-2014-205389
disease perception or a poorer general health condition among current smokers contributed to earlier TNFi treatment. Alternatively, sDMARD therapy may be less effective in smokers.19 The differences in baseline disease activity and demographics according to smoking status might explain, at least in part, why current smokers had poorer treatment response and treatment adherence in univariate but not multivariate analyses. However, in multivariate subanalyses, smoking was associated with poorer treatment response in men and poorer treatment adherence among patients treated with etanercept or infliximab. The nonrandomised study design implies that these findings must be interpreted with caution due to the risk of residual confounding or uneven distribution of baseline demographics. Two previous studies have described the impact of smoking on TNFi treatment response in PsA. An observational study of 440 patients found current smoking to be associated with shorter 3-year TNFi drug survival.12 A single-centre study of 78 TNFi-treated PsA patients reported smokers to have poorer treatment response and lower drug retention rates after 6 months’ treatment in univariate analyses.10 Further studies are needed to confirm the relationship between smoking and treatment outcome in PsA. In RA, several studies have reported poorer TNFi adherence and treatment response among smokers.6 20–23 It has been suggested that smoking causes higher levels of TNF-α and other inflammatory markers,22 35 36 altered bioavailability of antirheumatic drugs, cutaneous vasoconstriction and slower absorption from subcutaneous injection, or increased basal metabolic rate.20 37 38 Few studies analysed the impact of smoking according to type of TNFi, and found that smoking mainly affected infliximab treatment.6 22 This might be explained by differences in drug metabolism or formation of antichimeric antibodies.22 39 5
Downloaded from http://ard.bmj.com/ on July 8, 2015 - Published by group.bmj.com
Clinical and epidemiological research
Figure 2 Treatment response rates after 6 months treatment according to smoking status overall and stratified according to gender. p Values are current vs never smokers (Mann–Whitney). (A) EULAR-good-response rates. (B) ACR20 response rates. (C) ACR50 response rates. (D) ACR70 response rates. Y-axis: percentage of patients achieving response.
We found that previous smokers who had stopped smoking more than ∼4 years ago had nearly same drug adherence rates as never smokers. This may illustrate a gradual normalisation of pathological processes and smoking-related behaviour, and is noticeable, as tobacco smoking is a potentially modifiable lifestyle factor. Studies in RA have found previous smoking to have no21 or an intermediate17 impact on the effect of TNFi compared to never smoking, though the influence of the time since smoking cessation was not investigated. The strengths of this study are the high external validity for routine care due to inclusion of an unselected nationwide population of patients with PsA and the long follow-up time. Our study also has limitations. Smoking status was retrieved cross-sectionally although smoking status might alter later on.21 An obvious misclassification occurs when previous smokers resume smoking during follow-up. However, the exclusion of previous smokers from all main analyses made this bias less important. Furthermore, we had no valid data on the number of package years and thus the potential dose-response relationship between smoking and outcome could not be investigated. In Denmark, heavy smokers are more often men.40 41 One might assume that the stronger impact of smoking among male patients is associated with greater exposure to tobacco. Smoking may be linked to comorbid disease, depression, socioeconomic and lifestyle factors, which all potentially affect baseline disease activity and treatment outcome.17 22 Psoriatic manifestations in, for example, skin and nails may influence the decision on when to start TNFi treatment and the evaluation of treatment effect. However, these data are not included in DANBIO, and this might have affected our results, as smoking is suspected to increase the severity of skin psoriasis and to decrease the effect of TNFi on psoriatic skin lesions.42–44 In conclusion, we found current smoking to have a negative impact on treatment duration and clinical response in TNFi 6
treatment of PsA, most pronounced in men and among patients treated with infliximab and etanercept. The effects seemed partially reversible, which stresses the importance of smoking cessation programmes for these patients. Clinicians should beware that current smokers potentially have higher HAQ and VAS scores compared with non-smokers, and this might affect the clinical evaluation of this patient group. Author affiliations 1 Department of Rheumatology, Gentofte Hospital, Copenhagen, Denmark 2 Department of Rheumatology, Frederiksberg Hospital, Copenhagen, Denmark 3 Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Copenhagen University Hospital Glostrup, Denmark 4 The Danish Rheumatologic Database (DANBIO), Copenhagen University Hospital Glostrup, Denmark 5 Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark 6 Department of Rheumatology, Holbæk Hospital, Holbæk, Denmark 7 Department of Rheumatology, Esbjerg Hospital, Esbjerg, Denmark 8 Department of Rheumatology, Svendborg Hospital, Svendborg, Denmark 9 Department of Rheumatology, Aalborg University Hospital, Aalborg,Denmark 10 Department of Rheumatology, Odense University Hospital, Odense, Denmark 11 Department of Rheumatology, Vejle Sygehus, Sygehus Lillebælt, Vejle, Denmark 12 Department of Infectious Diseases and Rheumatology, Rigshospitalet, Copenhagen, Denmark 13 Department of Rheumatology, Helsingør and Hillerød Hospital, Hillerød, Denmark 14 Department of Rheumatology, Køge Hospital, Køge, Denmark 15 Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark 16 Department of Rheumatology, Silkeborg Hospital, Denmark Acknowledgement Thanks to all the departments of rheumatology in Denmark for reporting to the DANBIO registry. Contributors All authors have contributed to acquisition of data, revised the article for important intellectual content and given approval of this version of the article to be published. PH, BG and LD have given substantial contributions to the study design, interpretation of data and formation of the article content. PH has been responsible for the collection and analyses of data. Competing interests MH-F: UCB, MSD, Roche: Consulting fees, speaking fees, honoraria. AGL: Abbvie: Advisory board, Wyeth: Investigator. Provenance and peer review Not commissioned; externally peer reviewed. Højgaard P, et al. Ann Rheum Dis 2014;0:1–7. doi:10.1136/annrheumdis-2014-205389
Downloaded from http://ard.bmj.com/ on July 8, 2015 - Published by group.bmj.com
Clinical and epidemiological research REFERENCES 1
2 3
4
5
6
7 8
9
10
11 12
13
14
15
16
17
18
19
20
21
Kavanaugh A, McInnes I, Mease P, et al. Golimumab, a new human tumor necrosis factor alpha antibody, administered every four weeks as a subcutaneous injection in psoriatic arthritis: twenty-four-week efficacy and safety results of a randomized, placebo-controlled study. Arthritis Rheum 2009;60:976–86. Mease PJ, Kivitz AJ, Burch FX, et al. Etanercept treatment of psoriatic arthritis: safety, efficacy, and effect on disease progression. Arthritis Rheum 2004;50:2264–72. Glintborg B, Ostergaard M, Dreyer L, et al. Treatment response, drug survival, and predictors thereof in 764 patients with psoriatic arthritis treated with anti-tumor necrosis factor alpha therapy: results from the nationwide Danish DANBIO registry. Arthritis Rheum 2011;63:382–90. Saad AA, Symmons DP, Noyce PR, et al. Risks and benefits of tumor necrosis factor-alpha inhibitors in the management of psoriatic arthritis: systematic review and metaanalysis of randomized controlled trials. J Rheumatol 2008;35:883–90. Ash Z, Gaujoux-Viala C, Gossec L, et al. A systematic literature review of drug therapies for the treatment of psoriatic arthritis: current evidence and meta-analysis informing the EULAR recommendations for the management of psoriatic arthritis. Ann Rheum Dis 2012;71:319–26. Hyrich KL, Watson KD, Silman AJ, et al. Predictors of response to anti-TNF-alpha therapy among patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register. Rheumatology (Oxford) 2006;45:1558–65. Li W, Han J, Qureshi AA. Smoking and risk of incident psoriatic arthritis in US women. Ann Rheum Dis 2012;71:804–8. Eder L, Shanmugarajah S, Thavaneswaran A, et al. The association between smoking and the development of psoriatic arthritis among psoriasis patients. Ann Rheum Dis 2012;71:219–24. Haroon M, Petty-Saphon N, Gallagher P, et al. Clinical and patient-reported outcome measures as predictors of poor functional outcome in psoriatic arthritis [Abstract]. Ann Rheum Dis 2013;72(Suppl3):682. Miller S, Bawa S. The effect of smoking on treatment response and drug survival in psoriatic arthritis patients treated with their first anti-TNFa drug: a single-centre restrospective analysis [Abstract]. Ann Rheum Dis 2013;72(Suppl3):686. Haddad A, Thavaneswaran A, Ruiz Arruza R, et al. Psoriatic arthritis on TNF blockers [Abstract]. Ann Rheum Dis 2013;72(Suppl3):675. Fagerli KM, Lie E, van der Heijde D, et al. The role of methotrexate co-medication in TNF-inhibitor treatment in patients with psoriatic arthritis: results from 440 patients included in the NOR-DMARD study. Ann Rheum Dis 2014;73:132–7. Tillett W, Jadon D, Shaddick G, et al. Smoking and delay to diagnosis are associated with poorer functional outcome in psoriatic arthritis. Ann Rheum Dis 2013;72:1358–61. Chung HY, Machado P, van der Heijde D, et al. Smokers in early axial spondyloarthritis have earlier disease onset, more disease activity, inflammation and damage, and poorer function and health-related quality of life: results from the DESIR cohort. Ann Rheum Dis 2012;71:809–16. Mattey DL, Dawson SR, Healey EL, et al. Relationship between smoking and patient-reported measures of disease outcome in ankylosing spondylitis. J Rheumatol 2011;38:2608–15. Poddubnyy D, Haibel H, Listing J, et al. Cigarette smoking has a dose-dependent impact on progression of structural damage in the spine in patients with axial spondyloarthritis: results from the GErman SPondyloarthritis Inception Cohort (GESPIC). Ann Rheum Dis 2013;72:1430–2. Manfredsdottir VF, Vikingsdottir T, Jonsson T, et al. The effects of tobacco smoking and rheumatoid factor seropositivity on disease activity and joint damage in early rheumatoid arthritis. Rheumatology (Oxford) 2006;45:734–40. Papadopoulos NG, Alamanos Y, Voulgari PV, et al. Does cigarette smoking influence disease expression, activity and severity in early rheumatoid arthritis patients? Clin Exp Rheumatol 2005;23:861–6. Westhoff G, Rau R, Zink A. Rheumatoid arthritis patients who smoke have a higher need for DMARDs and feel worse, but they do not have more joint damage than non-smokers of the same serological group. Rheumatology (Oxford) 2008;47:849–54. Abhishek A, Butt S, Gadsby K, et al. Anti-TNF-alpha agents are less effective for the treatment of rheumatoid arthritis in current smokers. J Clin Rheumatol 2010;16:15–8. Saevarsdottir S, Wedren S, Seddighzadeh M, et al. Patients with early rheumatoid arthritis who smoke are less likely to respond to treatment with methotrexate and tumor necrosis factor inhibitors: observations from the Epidemiological Investigation of Rheumatoid Arthritis and the Swedish Rheumatology Register cohorts. Arthritis Rheum 2011;63:26–36.
Højgaard P, et al. Ann Rheum Dis 2014;0:1–7. doi:10.1136/annrheumdis-2014-205389
22
23
24
25
26
27 28
29 30
31
32
33 34
35
36
37
38 39
40
41 42
43 44
Mattey DL, Brownfield A, Dawes PT. Relationship between pack-year history of smoking and response to tumor necrosis factor antagonists in patients with rheumatoid arthritis. J Rheumatol 2009;36:1180–7. Soderlin MK, Petersson IF, Geborek P. The effect of smoking on response and drug survival in rheumatoid arthritis patients treated with their first anti-TNF drug. Scand J Rheumatol 2012;41:1–9. Glintborg B, Ostergaard M, Krogh NS, et al. Clinical response, drug survival, and predictors thereof among 548 patients with psoriatic arthritis who switched tumor necrosis factor alpha inhibitor therapy: results from the Danish Nationwide DANBIO Registry. Arthritis Rheum 2013;65:1213–23. Hetland ML, Unkerskov J, Ravn T, et al. Routine database registration of biological therapy increases the reporting of adverse events twentyfold in clinical practice. First results from the Danish Database (DANBIO). Scand J Rheumatol 2005;34:40–4. Hetland ML, Lindegaard HM, Hansen A, et al. Do changes in prescription practice in patients with rheumatoid arthritis treated with biological agents affect treatment response and adherence to therapy? Results from the nationwide Danish DANBIO Registry. Ann Rheum Dis 2008;67:1023–6. Hetland ML. DANBIO--powerful research database and electronic patient record. Rheumatology (Oxford) 2011;50:69–77. Schefte DB, Hetland ML. An open-source, self-explanatory touch screen in routine care. Validity of filling in the Bath measures on Ankylosing Spondylitis Disease Activity Index, Function Index, the Health Assessment Questionnaire and Visual Analogue Scales in comparison with paper versions. Rheumatology (Oxford) 2010;49:99–104. Fries JF, Spitz P, Kraines RG, et al. Measurement of patient outcome in arthritis. Arthritis Rheum 1980;23:137–45. Prevoo ML, van‘t Hof MA, Kuper HH, et al. Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 1995;38:44–8. Felson DT, Anderson JJ, Boers M, et al. American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 1995;38:727–35. van Gestel AM, Prevoo ML, van’t Hof MA, et al. Development and validation of the European League Against Rheumatism response criteria for rheumatoid arthritis. Comparison with the preliminary American College of Rheumatology and the World Health Organization/International League Against Rheumatism Criteria. Arthritis Rheum 1996;39:34–40. Ritchlin CT, Kavanaugh A, Gladman DD, et al. Treatment recommendations for psoriatic arthritis. Ann Rheum Dis 2009;68:1387–94. Leeb BF, Andel I, Sautner J, et al. The Disease Activity Score in 28 joints in rheumatoid arthritis and psoriatic arthritis patients. Arthritis Rheum 2007;57:256–60. Glossop JR, Dawes PT, Mattey DL. Association between cigarette smoking and release of tumour necrosis factor alpha and its soluble receptors by peripheral blood mononuclear cells in patients with rheumatoid arthritis. Rheumatology (Oxford) 2006;45:1223–9. Park SJ, Shin JI. The effect of smoking on response and drug survival in rheumatoid arthritis patients treated with their first anti-TNF drug: comments on the article by Soderlin et al. Scand J Rheumatol 2012;41:411–2. Metsios GS, Stavropoulos-Kalinoglou A, Nevill AM, et al. Cigarette smoking significantly increases basal metabolic rate in patients with rheumatoid arthritis. Ann Rheum Dis 2008;67:70–3. Zevin S, Benowitz NL. Drug interactions with tobacco smoking. An update. Clin Pharmacokinet 1999;36:425–38. Bendtzen K, Geborek P, Svenson M, et al. Individualized monitoring of drug bioavailability and immunogenicity in rheumatoid arthritis patients treated with the tumor necrosis factor alpha inhibitor infliximab. Arthritis Rheum 2006;54:3782–9. Danskernes rygevaner 2012. Tabelrapport for hele befolkningen. Danish Health and Medicines Authority. http://sundhedsstyrelsen.dk/~/media/ 29DD77B5D497489F99D75F1AC757862E.ashx. 2012. (GENERIC) Berner O, Etwil P, Graversen T, et al. 50 års oversigten. Danmarks statistik. 2001. http://www.dst.dk/pukora/epub/upload/3189/halvtres.pdf Di Lernia V, Ricci C, Lallas A, et al. Clinical predictors of non-response to any tumor necrosis factor (TNF) blockers: a retrospective study. J Dermatolog Treat 2014;25:73–4. Attwa E, Swelam E. Relationship between smoking-induced oxidative stress and the clinical severity of psoriasis. J Eur Acad Dermatol Venereol 2011;25:782–7. Emre S, Metin A, Demirseren DD, et al. The relationship between oxidative stress, smoking and the clinical severity of psoriasis. J Eur Acad Dermatol Venereol 2013;27:e370–5.
7
Downloaded from http://ard.bmj.com/ on July 8, 2015 - Published by group.bmj.com
Association between tobacco smoking and response to tumour necrosis factor α inhibitor treatment in psoriatic arthritis: results from the DANBIO registry Pil Højgaard, Bente Glintborg, Merete Lund Hetland, Torben Højland Hansen, Philip Rask Lage-Hansen, Martin H Petersen, Mette Holland-Fischer, Christine Nilsson, Anne Gitte Loft, Bjarne Nesgaard Andersen, Thomas Adelsten, Jørgen Jensen, Emina Omerovic, Regitse Christensen, Ulrik Tarp, René Østgård and Lene Dreyer Ann Rheum Dis published online July 25, 2014
Updated information and services can be found at: http://ard.bmj.com/content/early/2014/07/25/annrheumdis-2014-2053 89
These include:
References Email alerting service
Topic Collections
This article cites 42 articles, 20 of which you can access for free at: http://ard.bmj.com/content/early/2014/07/25/annrheumdis-2014-2053 89#BIBL Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article.
Articles on similar topics can be found in the following collections Degenerative joint disease (4255) Musculoskeletal syndromes (4547) Epidemiology (1267)
Notes
To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions To order reprints go to: http://journals.bmj.com/cgi/reprintform To subscribe to BMJ go to: http://group.bmj.com/subscribe/
ARD Online First, published on July 25, 2014 as 10.1136/annrheumdis-2014-205389 Clinical and epidemiological research
EXTENDED REPORT
Association between tobacco smoking and response to tumour necrosis factor α inhibitor treatment in psoriatic arthritis: results from the DANBIO registry Pil Højgaard,1,2 Bente Glintborg,1,3,4 Merete Lund Hetland,3,4,5 Torben Højland Hansen,6 Philip Rask Lage-Hansen,7 Martin H Petersen,8 Mette Holland-Fischer,9 Christine Nilsson,10 Anne Gitte Loft,11 Bjarne Nesgaard Andersen,12 Thomas Adelsten,13 Jørgen Jensen,14 Emina Omerovic,3 Regitse Christensen,1 Ulrik Tarp,15 René Østgård,16 Lene Dreyer1,4 Handling editor Tore K Kvien For numbered affiliations see end of article. Correspondence to Dr Bente Glintborg, Copenhagen Centre for Arthritis Research, Centre for Rheumatology and Spine Diseases, Copenhagen University Hospital Glostrup, Copenhagen, Denmark; [email protected] Bente Glintborg and Pil Højgaard share first co-authorship. Received 11 February 2014 Revised 8 May 2014 Accepted 11 July 2014
To cite: Højgaard P, Glintborg B, Hetland ML, et al. Ann Rheum Dis Published Online First: [please include Day Month Year] doi:10.1136/ annrheumdis-2014-205389
ABSTRACT Objectives To investigate the association between tobacco smoking and disease activity, treatment adherence and treatment responses among patients with psoriatic arthritis (PsA) initiating the first tumour necrosis factor α inhibitor therapy (TNFi) in routine care. Methods Observational cohort study based on the Danish nationwide DANBIO registry. Kaplan–Meier plots, logistic and Cox regression analyses by smoking status (current/previous/never smoker) were calculated for treatment adherence, ACR20/50/70-responses and EULAR-good-response. Additional stratified analyses were performed according to gender and TNFi-subtype (adalimumab/etanercept/infliximab). Results Among 1388 PsA patients included in the study, 1148 (83%) had known smoking status (33% current, 41% never and 26% previous smokers). Median follow-up time was 1.22 years (IQR 0.44–2.96). At baseline, current smokers had lower Body Mass Index (27 kg/m2 (23–30)/28 kg/m2 (24–31)) (median (IQR)), shorter disease duration (3 years (1–8)/5 years (2–10)), lower swollen joint count (2 (0–5)/3 (1–6)), higher visualanalogue-scale (VAS) patient global (72 mm (54–87)/ 68 mm (50–80)), VAS fatigue (72 mm (51–86)/63 mm (40–77)) and Health Assessment Questionnaire (HAQ) score (1.1 (0.7 to 1.5)/1.0 (0.5 to 1.5)) than never smokers (all p10% in any of the analyses (data not shown). Baseline VAS scores, CRP, BMI, tender joint count, HAQ, and DAS28 were considered intermediate variables between tobacco smoking and outcomes, and were hence excluded from multivariate analyses. Additional stratified Kaplan–Meier plots, and multivariate Cox and logistic regression analyses according to (1) gender and (2) TNFi type were performed. In the subanalysis of time to discontinuation due to adverse events, discontinuations due to ineffectiveness were treated as censored observations and vice versa.
RESULTS A total of 1388 bDMARD-naive patients initiating treatment with adalimumab, etanercept or infliximab as the first TNFi were included (table 1). Among 1148 patients (83%) with known smoking status, 33% were current, 41% never and 26% previous smokers. Patients with missing smoking information had lower BMI, younger age, longer disease duration, higher CRP, higher SJC, lower VAS global and fatigue scores, compared to patients with available smoking information (table 1). Thirty-four percent of women and 31% of men with known smoking status were current smokers. At baseline, current smokers had shorter disease duration, lower BMI, higher HAQ, higher VAS fatigue and VAS global compared to previous and never smokers (table 1). Previous smokers were older than current and never smokers. The reasons for stopping TNFi treatment were independent of smoking status (table 1). Male current smokers had higher HAQ (1 (0.6–1.4) vs 0.8 (0.4–1.3), (median (IQR)), p=0.03) and shorter disease duration (3 years (1–10) vs 6 years (2–13), p=0.03) than male never smokers, whereas VAS scores, DAS28 and BMI were similar (all p>0.05). Female current smokers had lower BMI (25 kg/m2 (23–29) vs 28 kg/m2 (24–32), p=0.001), Højgaard P, et al. Ann Rheum Dis 2014;0:1–7. doi:10.1136/annrheumdis-2014-205389
Downloaded from http://ard.bmj.com/ on July 8, 2015 - Published by group.bmj.com
Clinical and epidemiological research Table 1
Baseline demographics, disease activity and reasons for terminating TNFi treatment according to smoking status at the baseline visit Smoking status
Number, n (%) Age, years Disease duration, years Women, n (%) Body Mass Index, kg/m2 TNFi drug type, n (%) Adalimumab Etanercept Infliximab TNFi start year, n (%) 2000–2003 2004–2007 2008–2011 Methotrexate use, n (%) CRP, mg/L Tender joint count (0–28) Swollen joint count (0–28) HAQ DAS28 Patient’s global (0–100), mm Pain (0–100), mm Fatigue (0–100), mm Doctor’s global (0–100), mm Stop reason, n (%)‡ Lack of efficacy Adverse events Other Unknown
Current
Never
Previous
p Value*
p Value†
Smoking status unknown
380 (33) 47 (38–55) 3 (1–8) 197 (48) 27 (23–30)
466 (41) 47 (37–56) 5 (2–10) 204 (44) 28 (24–31)
302 52 4 156 28
0.9 10% and was not included in the multivariate analysis. Baseline distribution of covariates according to TNFi drug type (adalimumab/infliximab/etanercept). Current smokers: 34%/37%/27%. Males: 50%/55%/47%. Age, median (IQR): 48 (38–56) years/48 (39–56) years/48 (39–56) years. Disease duration, median (IQR): 4 (1–9) years/4 (2–12) years/4 (1–10) years. HR, hazard ratio; TNFi, tumour necrosis factor alpha inhibitor.
In men, previous smokers tended to have higher EULAR-good-response and ACR20 response rates than current smokers, and lower rates compared to never smokers (univariate logistic regression analyses, data not shown) (figure 2).
DISCUSSION In this observational study of 1388 PsA patients initiating their first treatment with a TNFi, one-third of patients were current smokers. Current smokers had higher HAQ and patient VAS scores, but shorter disease duration than never smokers upon initiation of treatment. Current smokers had reduced response rates, most pronounced in male smokers where the EULAR-good-response and ACR20 response rates were nearly halved compared to male never smokers. For previous smokers, the effect of smoking on drug adherence diminished with time and was equivalent to never smokers ∼4 years after smoking cessation. The impact of smoking on disease activity and functional status is well described in RA17–19 but scarcely investigated in PsA. A cross-sectional study among 283 patients with PsA reported that current smokers had higher HAQ.9 It has been suggested that smoking alters illness behaviour and causes a more severe perception of musculoskeletal pain.19 This may lead to higher DAS28 scores among current smokers compared to non-smokers with a similar inflammatory activity.22 Thus, perhaps the DAS28 score should be interpreted with more caution among smokers. This may be especially relevant in patients with PsA, in whom the validity of the DAS28 measure is debated.33 34 We found shorter disease duration among current compared to never smokers upon start of TNFi, which may indicate a more aggressive disease course among smokers.18 However, objective markers of disease activity (CRP and SJC) were independent of smoking status. One may hypothesise that a worse Højgaard P, et al. Ann Rheum Dis 2014;0:1–7. doi:10.1136/annrheumdis-2014-205389
disease perception or a poorer general health condition among current smokers contributed to earlier TNFi treatment. Alternatively, sDMARD therapy may be less effective in smokers.19 The differences in baseline disease activity and demographics according to smoking status might explain, at least in part, why current smokers had poorer treatment response and treatment adherence in univariate but not multivariate analyses. However, in multivariate subanalyses, smoking was associated with poorer treatment response in men and poorer treatment adherence among patients treated with etanercept or infliximab. The nonrandomised study design implies that these findings must be interpreted with caution due to the risk of residual confounding or uneven distribution of baseline demographics. Two previous studies have described the impact of smoking on TNFi treatment response in PsA. An observational study of 440 patients found current smoking to be associated with shorter 3-year TNFi drug survival.12 A single-centre study of 78 TNFi-treated PsA patients reported smokers to have poorer treatment response and lower drug retention rates after 6 months’ treatment in univariate analyses.10 Further studies are needed to confirm the relationship between smoking and treatment outcome in PsA. In RA, several studies have reported poorer TNFi adherence and treatment response among smokers.6 20–23 It has been suggested that smoking causes higher levels of TNF-α and other inflammatory markers,22 35 36 altered bioavailability of antirheumatic drugs, cutaneous vasoconstriction and slower absorption from subcutaneous injection, or increased basal metabolic rate.20 37 38 Few studies analysed the impact of smoking according to type of TNFi, and found that smoking mainly affected infliximab treatment.6 22 This might be explained by differences in drug metabolism or formation of antichimeric antibodies.22 39 5
Downloaded from http://ard.bmj.com/ on July 8, 2015 - Published by group.bmj.com
Clinical and epidemiological research
Figure 2 Treatment response rates after 6 months treatment according to smoking status overall and stratified according to gender. p Values are current vs never smokers (Mann–Whitney). (A) EULAR-good-response rates. (B) ACR20 response rates. (C) ACR50 response rates. (D) ACR70 response rates. Y-axis: percentage of patients achieving response.
We found that previous smokers who had stopped smoking more than ∼4 years ago had nearly same drug adherence rates as never smokers. This may illustrate a gradual normalisation of pathological processes and smoking-related behaviour, and is noticeable, as tobacco smoking is a potentially modifiable lifestyle factor. Studies in RA have found previous smoking to have no21 or an intermediate17 impact on the effect of TNFi compared to never smoking, though the influence of the time since smoking cessation was not investigated. The strengths of this study are the high external validity for routine care due to inclusion of an unselected nationwide population of patients with PsA and the long follow-up time. Our study also has limitations. Smoking status was retrieved cross-sectionally although smoking status might alter later on.21 An obvious misclassification occurs when previous smokers resume smoking during follow-up. However, the exclusion of previous smokers from all main analyses made this bias less important. Furthermore, we had no valid data on the number of package years and thus the potential dose-response relationship between smoking and outcome could not be investigated. In Denmark, heavy smokers are more often men.40 41 One might assume that the stronger impact of smoking among male patients is associated with greater exposure to tobacco. Smoking may be linked to comorbid disease, depression, socioeconomic and lifestyle factors, which all potentially affect baseline disease activity and treatment outcome.17 22 Psoriatic manifestations in, for example, skin and nails may influence the decision on when to start TNFi treatment and the evaluation of treatment effect. However, these data are not included in DANBIO, and this might have affected our results, as smoking is suspected to increase the severity of skin psoriasis and to decrease the effect of TNFi on psoriatic skin lesions.42–44 In conclusion, we found current smoking to have a negative impact on treatment duration and clinical response in TNFi 6
treatment of PsA, most pronounced in men and among patients treated with infliximab and etanercept. The effects seemed partially reversible, which stresses the importance of smoking cessation programmes for these patients. Clinicians should beware that current smokers potentially have higher HAQ and VAS scores compared with non-smokers, and this might affect the clinical evaluation of this patient group. Author affiliations 1 Department of Rheumatology, Gentofte Hospital, Copenhagen, Denmark 2 Department of Rheumatology, Frederiksberg Hospital, Copenhagen, Denmark 3 Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Copenhagen University Hospital Glostrup, Denmark 4 The Danish Rheumatologic Database (DANBIO), Copenhagen University Hospital Glostrup, Denmark 5 Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark 6 Department of Rheumatology, Holbæk Hospital, Holbæk, Denmark 7 Department of Rheumatology, Esbjerg Hospital, Esbjerg, Denmark 8 Department of Rheumatology, Svendborg Hospital, Svendborg, Denmark 9 Department of Rheumatology, Aalborg University Hospital, Aalborg,Denmark 10 Department of Rheumatology, Odense University Hospital, Odense, Denmark 11 Department of Rheumatology, Vejle Sygehus, Sygehus Lillebælt, Vejle, Denmark 12 Department of Infectious Diseases and Rheumatology, Rigshospitalet, Copenhagen, Denmark 13 Department of Rheumatology, Helsingør and Hillerød Hospital, Hillerød, Denmark 14 Department of Rheumatology, Køge Hospital, Køge, Denmark 15 Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark 16 Department of Rheumatology, Silkeborg Hospital, Denmark Acknowledgement Thanks to all the departments of rheumatology in Denmark for reporting to the DANBIO registry. Contributors All authors have contributed to acquisition of data, revised the article for important intellectual content and given approval of this version of the article to be published. PH, BG and LD have given substantial contributions to the study design, interpretation of data and formation of the article content. PH has been responsible for the collection and analyses of data. Competing interests MH-F: UCB, MSD, Roche: Consulting fees, speaking fees, honoraria. AGL: Abbvie: Advisory board, Wyeth: Investigator. Provenance and peer review Not commissioned; externally peer reviewed. Højgaard P, et al. Ann Rheum Dis 2014;0:1–7. doi:10.1136/annrheumdis-2014-205389
Downloaded from http://ard.bmj.com/ on July 8, 2015 - Published by group.bmj.com
Clinical and epidemiological research REFERENCES 1
2 3
4
5
6
7 8
9
10
11 12
13
14
15
16
17
18
19
20
21
Kavanaugh A, McInnes I, Mease P, et al. Golimumab, a new human tumor necrosis factor alpha antibody, administered every four weeks as a subcutaneous injection in psoriatic arthritis: twenty-four-week efficacy and safety results of a randomized, placebo-controlled study. Arthritis Rheum 2009;60:976–86. Mease PJ, Kivitz AJ, Burch FX, et al. Etanercept treatment of psoriatic arthritis: safety, efficacy, and effect on disease progression. Arthritis Rheum 2004;50:2264–72. Glintborg B, Ostergaard M, Dreyer L, et al. Treatment response, drug survival, and predictors thereof in 764 patients with psoriatic arthritis treated with anti-tumor necrosis factor alpha therapy: results from the nationwide Danish DANBIO registry. Arthritis Rheum 2011;63:382–90. Saad AA, Symmons DP, Noyce PR, et al. Risks and benefits of tumor necrosis factor-alpha inhibitors in the management of psoriatic arthritis: systematic review and metaanalysis of randomized controlled trials. J Rheumatol 2008;35:883–90. Ash Z, Gaujoux-Viala C, Gossec L, et al. A systematic literature review of drug therapies for the treatment of psoriatic arthritis: current evidence and meta-analysis informing the EULAR recommendations for the management of psoriatic arthritis. Ann Rheum Dis 2012;71:319–26. Hyrich KL, Watson KD, Silman AJ, et al. Predictors of response to anti-TNF-alpha therapy among patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register. Rheumatology (Oxford) 2006;45:1558–65. Li W, Han J, Qureshi AA. Smoking and risk of incident psoriatic arthritis in US women. Ann Rheum Dis 2012;71:804–8. Eder L, Shanmugarajah S, Thavaneswaran A, et al. The association between smoking and the development of psoriatic arthritis among psoriasis patients. Ann Rheum Dis 2012;71:219–24. Haroon M, Petty-Saphon N, Gallagher P, et al. Clinical and patient-reported outcome measures as predictors of poor functional outcome in psoriatic arthritis [Abstract]. Ann Rheum Dis 2013;72(Suppl3):682. Miller S, Bawa S. The effect of smoking on treatment response and drug survival in psoriatic arthritis patients treated with their first anti-TNFa drug: a single-centre restrospective analysis [Abstract]. Ann Rheum Dis 2013;72(Suppl3):686. Haddad A, Thavaneswaran A, Ruiz Arruza R, et al. Psoriatic arthritis on TNF blockers [Abstract]. Ann Rheum Dis 2013;72(Suppl3):675. Fagerli KM, Lie E, van der Heijde D, et al. The role of methotrexate co-medication in TNF-inhibitor treatment in patients with psoriatic arthritis: results from 440 patients included in the NOR-DMARD study. Ann Rheum Dis 2014;73:132–7. Tillett W, Jadon D, Shaddick G, et al. Smoking and delay to diagnosis are associated with poorer functional outcome in psoriatic arthritis. Ann Rheum Dis 2013;72:1358–61. Chung HY, Machado P, van der Heijde D, et al. Smokers in early axial spondyloarthritis have earlier disease onset, more disease activity, inflammation and damage, and poorer function and health-related quality of life: results from the DESIR cohort. Ann Rheum Dis 2012;71:809–16. Mattey DL, Dawson SR, Healey EL, et al. Relationship between smoking and patient-reported measures of disease outcome in ankylosing spondylitis. J Rheumatol 2011;38:2608–15. Poddubnyy D, Haibel H, Listing J, et al. Cigarette smoking has a dose-dependent impact on progression of structural damage in the spine in patients with axial spondyloarthritis: results from the GErman SPondyloarthritis Inception Cohort (GESPIC). Ann Rheum Dis 2013;72:1430–2. Manfredsdottir VF, Vikingsdottir T, Jonsson T, et al. The effects of tobacco smoking and rheumatoid factor seropositivity on disease activity and joint damage in early rheumatoid arthritis. Rheumatology (Oxford) 2006;45:734–40. Papadopoulos NG, Alamanos Y, Voulgari PV, et al. Does cigarette smoking influence disease expression, activity and severity in early rheumatoid arthritis patients? Clin Exp Rheumatol 2005;23:861–6. Westhoff G, Rau R, Zink A. Rheumatoid arthritis patients who smoke have a higher need for DMARDs and feel worse, but they do not have more joint damage than non-smokers of the same serological group. Rheumatology (Oxford) 2008;47:849–54. Abhishek A, Butt S, Gadsby K, et al. Anti-TNF-alpha agents are less effective for the treatment of rheumatoid arthritis in current smokers. J Clin Rheumatol 2010;16:15–8. Saevarsdottir S, Wedren S, Seddighzadeh M, et al. Patients with early rheumatoid arthritis who smoke are less likely to respond to treatment with methotrexate and tumor necrosis factor inhibitors: observations from the Epidemiological Investigation of Rheumatoid Arthritis and the Swedish Rheumatology Register cohorts. Arthritis Rheum 2011;63:26–36.
Højgaard P, et al. Ann Rheum Dis 2014;0:1–7. doi:10.1136/annrheumdis-2014-205389
22
23
24
25
26
27 28
29 30
31
32
33 34
35
36
37
38 39
40
41 42
43 44
Mattey DL, Brownfield A, Dawes PT. Relationship between pack-year history of smoking and response to tumor necrosis factor antagonists in patients with rheumatoid arthritis. J Rheumatol 2009;36:1180–7. Soderlin MK, Petersson IF, Geborek P. The effect of smoking on response and drug survival in rheumatoid arthritis patients treated with their first anti-TNF drug. Scand J Rheumatol 2012;41:1–9. Glintborg B, Ostergaard M, Krogh NS, et al. Clinical response, drug survival, and predictors thereof among 548 patients with psoriatic arthritis who switched tumor necrosis factor alpha inhibitor therapy: results from the Danish Nationwide DANBIO Registry. Arthritis Rheum 2013;65:1213–23. Hetland ML, Unkerskov J, Ravn T, et al. Routine database registration of biological therapy increases the reporting of adverse events twentyfold in clinical practice. First results from the Danish Database (DANBIO). Scand J Rheumatol 2005;34:40–4. Hetland ML, Lindegaard HM, Hansen A, et al. Do changes in prescription practice in patients with rheumatoid arthritis treated with biological agents affect treatment response and adherence to therapy? Results from the nationwide Danish DANBIO Registry. Ann Rheum Dis 2008;67:1023–6. Hetland ML. DANBIO--powerful research database and electronic patient record. Rheumatology (Oxford) 2011;50:69–77. Schefte DB, Hetland ML. An open-source, self-explanatory touch screen in routine care. Validity of filling in the Bath measures on Ankylosing Spondylitis Disease Activity Index, Function Index, the Health Assessment Questionnaire and Visual Analogue Scales in comparison with paper versions. Rheumatology (Oxford) 2010;49:99–104. Fries JF, Spitz P, Kraines RG, et al. Measurement of patient outcome in arthritis. Arthritis Rheum 1980;23:137–45. Prevoo ML, van‘t Hof MA, Kuper HH, et al. Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 1995;38:44–8. Felson DT, Anderson JJ, Boers M, et al. American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 1995;38:727–35. van Gestel AM, Prevoo ML, van’t Hof MA, et al. Development and validation of the European League Against Rheumatism response criteria for rheumatoid arthritis. Comparison with the preliminary American College of Rheumatology and the World Health Organization/International League Against Rheumatism Criteria. Arthritis Rheum 1996;39:34–40. Ritchlin CT, Kavanaugh A, Gladman DD, et al. Treatment recommendations for psoriatic arthritis. Ann Rheum Dis 2009;68:1387–94. Leeb BF, Andel I, Sautner J, et al. The Disease Activity Score in 28 joints in rheumatoid arthritis and psoriatic arthritis patients. Arthritis Rheum 2007;57:256–60. Glossop JR, Dawes PT, Mattey DL. Association between cigarette smoking and release of tumour necrosis factor alpha and its soluble receptors by peripheral blood mononuclear cells in patients with rheumatoid arthritis. Rheumatology (Oxford) 2006;45:1223–9. Park SJ, Shin JI. The effect of smoking on response and drug survival in rheumatoid arthritis patients treated with their first anti-TNF drug: comments on the article by Soderlin et al. Scand J Rheumatol 2012;41:411–2. Metsios GS, Stavropoulos-Kalinoglou A, Nevill AM, et al. Cigarette smoking significantly increases basal metabolic rate in patients with rheumatoid arthritis. Ann Rheum Dis 2008;67:70–3. Zevin S, Benowitz NL. Drug interactions with tobacco smoking. An update. Clin Pharmacokinet 1999;36:425–38. Bendtzen K, Geborek P, Svenson M, et al. Individualized monitoring of drug bioavailability and immunogenicity in rheumatoid arthritis patients treated with the tumor necrosis factor alpha inhibitor infliximab. Arthritis Rheum 2006;54:3782–9. Danskernes rygevaner 2012. Tabelrapport for hele befolkningen. Danish Health and Medicines Authority. http://sundhedsstyrelsen.dk/~/media/ 29DD77B5D497489F99D75F1AC757862E.ashx. 2012. (GENERIC) Berner O, Etwil P, Graversen T, et al. 50 års oversigten. Danmarks statistik. 2001. http://www.dst.dk/pukora/epub/upload/3189/halvtres.pdf Di Lernia V, Ricci C, Lallas A, et al. Clinical predictors of non-response to any tumor necrosis factor (TNF) blockers: a retrospective study. J Dermatolog Treat 2014;25:73–4. Attwa E, Swelam E. Relationship between smoking-induced oxidative stress and the clinical severity of psoriasis. J Eur Acad Dermatol Venereol 2011;25:782–7. Emre S, Metin A, Demirseren DD, et al. The relationship between oxidative stress, smoking and the clinical severity of psoriasis. J Eur Acad Dermatol Venereol 2013;27:e370–5.
7
Downloaded from http://ard.bmj.com/ on July 8, 2015 - Published by group.bmj.com
Association between tobacco smoking and response to tumour necrosis factor α inhibitor treatment in psoriatic arthritis: results from the DANBIO registry Pil Højgaard, Bente Glintborg, Merete Lund Hetland, Torben Højland Hansen, Philip Rask Lage-Hansen, Martin H Petersen, Mette Holland-Fischer, Christine Nilsson, Anne Gitte Loft, Bjarne Nesgaard Andersen, Thomas Adelsten, Jørgen Jensen, Emina Omerovic, Regitse Christensen, Ulrik Tarp, René Østgård and Lene Dreyer Ann Rheum Dis published online July 25, 2014
Updated information and services can be found at: http://ard.bmj.com/content/early/2014/07/25/annrheumdis-2014-2053 89
These include:
References Email alerting service
Topic Collections
This article cites 42 articles, 20 of which you can access for free at: http://ard.bmj.com/content/early/2014/07/25/annrheumdis-2014-2053 89#BIBL Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article.
Articles on similar topics can be found in the following collections Degenerative joint disease (4255) Musculoskeletal syndromes (4547) Epidemiology (1267)
Notes
To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions To order reprints go to: http://journals.bmj.com/cgi/reprintform To subscribe to BMJ go to: http://group.bmj.com/subscribe/
