Extended report treatment within the ﬁrst 6 months of symptoms (adj_MDIC –0.10, 95% CI –0.19 to –0.02). Furthermore, a signiﬁcant ben- eﬁt from each additional month of the continuation of the ﬁrst treatment past 6 months was found (adj_MDIC –0.004, 95% CI –0.01 to –0.0004). DISCUSSION The results of this analysis have three important clinical mes- sages. The ﬁrst is that the beneﬁts of early DMARD/S treat- ment in patients with IP are still apparent after 10 years of follow-up. Even in the unadjusted analysis, those who started their ﬁrst DMARD/S within 6 months of symptom onset had no overall deterioration in HAQ, whereas those who started treatment later experienced deterioration. When adjusted for baseline disease severity and subsequent treatment decisions, those treated early experienced a non-signiﬁcant improve- ment in change in function compared with those judged by their clinicians not to require DMARD/S at all (adj_MDIC in HAQ –0.24, 95% CI –0.58 to 0.09); and a signiﬁcant beneﬁt from each additional month of treatment within 6 months of the onset of symptoms (adj_MDIC –0.10, 95% CI –0.19 to –0.02). This provides still further evidence of a ‘window of opportunity’ for optimal beneﬁt from the introduction of DMARD/S and that early referral to a rheumatologist is justiﬁed.23 We have previously reported the beneﬁt of early treatment with respect to physical function at 5 years in the NOAR cohort.9 In that analysis we used the propensity score method to adjust for baseline disease activity and thus confounding by indication. This showed the beneﬁt of early treatment regard- less of subsequent treatment duration. In this new analysis we test the hypothesis that the time receiving ﬁrst treatment is also an important prognostic indicator. We found that patients who discontinued their ﬁrst DMARD/S within 6 months experienced a signiﬁcant deterioration in long-term functional ability, irre- spective of subsequent treatment decisions (adj_MDIC in HAQ 0.28, 95% CI 0.04 to 0.52). This has important implications for the future treatment of patients with IP. For example, presently in the UK, anti-tumour necrosis factor treatment is only recom- mended for patients for whom two or more DMARD/S have failed.24 Our results suggest that patients who fail to respond to, or cannot tolerate, their ﬁrst DMARD/S are likely to have a poor long-term outcome and that it may be appropriate to con- sider more aggressive treatment at this stage rather than wait for another DMARD/S to fail. The third clinical message is that the total duration of DMARD/S over the ﬁrst 10 years of disease has an important impact on functional outcome. Patients who received a total duration of treatment >8 years experienced an improvement in function compared with those never treated (adj_MDIC in HAQ –0.37; 95% CI –0.77 to 0.04). Other studies have also shown that the beneﬁt of early treatment is not sustained unless that treatment is continued. For example, a randomised controlled trial in the Netherlands found clinical and radiological beneﬁt at 12 months in those randomised to early aggressive treatment compared with the pyramid approach.25 However, in the 5-year follow-up of this cohort these differences did not persist.26 As the treatment strategies were not continued during follow-up, the authors conclude that early aggressive treatment should be continued into the long term. Inevitably, a 10-year follow-up study reﬂects the changing prescribing practice over the period of follow-up. Patients in this study were recruited in the early 1990s when SSZ mono- therapy was the usual ﬁrst DMARD. However, even though the 694 treatment strategies in the 1990s were less aggressive than those used today, we were still able to show a beneﬁt of early and sustained treatment. It is likely that the beneﬁt will be greater with the use of MTX and combination therapy much earlier in the disease course. Until recently there were relatively few treatment options for patient with IP and RA and treatment goals were less ambitious than they are now. Therefore clinicians continued to prescribe a treatment even if there was only minor improvement so long as no adverse events were seen. Many studies looked at drug survival rates as an outcome in itself,27–29 rather than the sub- sequent consequences of treatment persistence on patient out- comes, as we have done here. The current strategy of targeting remission or low-disease activity results in the faster changing of DMARDs and so shortening of times on any particular treat- ment. Thus, the association between the time receiving the ﬁrst treatment and functional disability may be stronger in patients presenting now. A pooled analysis of MTX and anti-anti-tumour necrosis factor clinical trials of patients with early RA found that disease activity at baseline and particularly at 3 months (ie, early treatment response) was signiﬁcantly related to disease activity after 1 year.30 We would have liked to have explored the conse- quences of treatment strategies on radiological progression. We have previously shown that treating patients within 6 months of IP symptom onset has a beneﬁcial effect on radiological pro- gression10 at 5 years. However x-ray examinations were not undertaken on all subjects at the tenth assessment, therefore radiological progression by 10 years’ follow-up could not be analysed. Our study has a number of strengths and weaknesses. It uses a primary care-based inception cohort of patients followed up systematically over a 10-year period. Patients were recruited with IP rather than RA. We have therefore been able to include patients who do not satisfy the ACR criteria for RA at baseline but do satisfy them subsequently. The results should therefore have good generalisability. Some rheumatologists might con- sider the inclusion of subjects with RA, IP, psoriatic arthritis or postviral arthritis as patients with different disease course and treatment strategies. However, the marginal structural models approach adjusts for the differences in disease severity and treat- ment over time which might be seen in the different conditions. Furthermore, the restriction in the analysis in table 4 to those 497 patients (77% of those who had 10 year follow-up) who cumulatively satisﬁed the ACR criteria for RA, produced results similar to that for the whole IP cohort. Adjusting for a series of treatment decisions and ﬂuctuating disease activity over 10 years is complex, particularly as patients were seen at predeﬁned time intervals and not speciﬁcally at the time of ﬂares or treatment change. A variety of methods have been suggested including propensity scores,31 as we have used previously.9 10 In this study, we used marginal structural mod- els as they are the only method which adjusts for time-varying confounders. This method has only been used previously once in RA research.8 There is a debate as to which variables should be included in the models.32 In accordance with the recommen- dations of Rubin33 and Robins et al34 we included variables even with weak effects on outcome (although strong associations with treatment) in order to minimise bias. Results from simula- tion experiments32 suggest that variables related to outcome but not to treatment should always be included as they decrease the variance of estimates without increasing bias. However, the pos- sibility of residual confounding remains owing to unmeasured variables that are associated either with treatment decisions or with outcome. While we included variables that cover the full Ann Rheum Dis 2010;69:689–695. doi:10.1136/ard.2009.108639