1arc Epidemiology Unit, Stopford Building, The University of Manchester, Manchester, UK 2Norfolk Arthritis Register, Norfolk and Norwich University Hospital, Norwich, UK Correspondence to Professor Deborah Symmons, arc Epidemiology Unit, The University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK; Deborah.Symmons@ manchester.ac.uk Accepted 3 October 2009 Published Online First 26 October 2009 Ann Rheum Dis 2010;69:689–695. doi:10.1136/ard.2009.108639 Extended report Early treatment with, and time receiving, ﬁrst disease-modifying antirheumatic drug predicts long-term function in patients with inﬂammatory polyarthritis Tracey M Farragher,1 Mark Lunt,1 Bo Fu,1 Diane Bunn,2 Deborah P M Symmons1 ABSTRACT Objectives To investigate the inﬂuence of early disease- modifying antirheumatic drug (DMARD) treatment on long-term functional outcome in patients with recent- onset inﬂammatory polyarthritis (IP), and the impact of the duration of ﬁrst and subsequent DMARD treatment. Methods 642 subjects from a primary care registry of patients with new-onset IP, recruited 1990–4, were followed up for 10 years. Mean change in Health Assessment Questionnaire (HAQ) scores between baseline and 10 years were compared by time to, and time receiving, ﬁrst DMARD treatment and total time receiving treatment, using linear regression. Adjustment for time-dependent confounders and censoring was performed using marginal structural weights. Results When adjusted for baseline and subsequent disease severity, those treated early (<6 months from symptom onset) experienced a non-signiﬁcant improvement in function compared with those never treated (adjusted mean difference in change (adj_MDIC) in HAQ –0.24; 95% CI –0.58 to 0.09); and a signiﬁcant beneﬁt for each additional month of treatment within 6 months of the onset of symptoms (adj_MDIC –0.10; 95% CI –0.19 to –0.02). Patients who discontinued their ﬁrst DMARD within 6 months experienced a signiﬁcant deterioration in long-term function (adj_MDIC in HAQ 0.28; 95% CI 0.04 to 0.52), while those who continued their ﬁrst treatment for > 3 years experienced an improvement (adj_MDIC in HAQ –0.37; 95% CI –0.77 to 0.04). Conclusions The importance of time to, and response to, ﬁrst DMARD treatment and total duration of DMARD treatment in modifying the 10-year function in patients with IP has been demonstrated. INTRODUCTION A recent systematic review reported that clinical trials have shown the beneﬁt of disease-modifying antirheumatic drugs (DMARDs) and steroids (DMARD/S) in reducing functional disability and disease activity in patients with rheumatoid arthritis (RA).1 As highlighted by subsequent commentaries on this review,2–5 clinical trials have limitations as most are of short duration (generally ≤3 years) and have narrow patient selection criteria. Longitudinal observational studies (LOS) provide an opportunity to examine the inﬂuence of treatment on long-term outcome and are often more generalisable than clin- ical trials.6 However, the effect of treatment is con- founded in LOS as those treated most intensively are likely to have the most severe disease.7 A number of long-term LOS have examined the inﬂuence of DMARDs on outcome in patients with inﬂammatory polyarthritis (IP) and its subset RA while adjusting for ‘confounding by indication’.8–10 Choi et al reported a beneﬁt on mortality in 1240 patients with RA treated with methotrexate (MTX),8 while we have previously shown that treating patients with IP with DMARD/S, within 6 months of symptom onset, has a beneﬁcial effect on functional disability9 and radiological progression10 at 5 years. Our analyses adjusted for the decision to prescribe the ﬁrst DMARD but not for subsequent treatment decisions. Over time, particularly in the long-term, potential confounders will alter, both as a result of the natural course of the disease and also in response to treatment. Therefore, to assess the impact of treatment over the long term, adjustment for these time-dependent confounders is required. In addition to the inﬂuence of the timing of the ﬁrst treatment, time receiving the ﬁrst treatment and total duration of treatment may also contrib- ute to subsequent long-term outcome. A Swedish trial of 245 patients with recent-onset RA found that those who received their ﬁrst DMARD treatment for <2 years had lower response and remission rates than those who continued with treatment.11 Analysis of 2888 patients with established RA from the ARAMIS database, found that the consistent use of a DMARD (measured as the proportion of visits at which a patient was taking at least one DMARD) was associ- ated with improved functional outcome.12 Our study was conducted in an inception cohort of patients with IP followed up for 10 years with regular assessment of disease activity, physi- cal function and treatment. We have adjusted for potential time-dependent confounders over the length of the follow-up. We aimed to investigate whether the beneﬁt of early DMARD treatment on functional outcome continues in the long term and to examine the impact of the duration of ﬁrst and subsequent DMARD treatment. PATIENTS AND METHODS Patients Patients were recruited from the Norfolk Arthritis Register (NOAR), a primary care-based incep- tion cohort of subjects with recent-onset IP. As described in detail elsewhere,13 NOAR aims to recruit all adults aged ≥16 years, who have swell- ing of at least two joints persisting for at least 4 weeks and whose symptom onset was after 1 January 1990. The catchment area is the former 689