Extended report Can clinical factors at presentation be used to predict outcome of treatment with methotrexate in patients with early inflammatory polyarthritis? S L Hider, A J Silman, W Thomson, M Lunt, D Bunn, D P M Symmons arc Epidemiology Unit, University of Manchester, UK Correspondence to: Deborah P M Symmons, arc Epidemiology Unit, Stopford Building, University of Manchester, Oxford Road, Manchester M13 9PT UK; Deborah.symmons@ manchester.ac.uk Accepted 8 February 2008 Published Online First 21 February 2008 ABSTRACT Purpose: Methotrexate (MTX) is the first choice conventional disease-modifying antirheumatic drug (DMARD) for rheumatoid arthritis. It is not universally effective, however; although to date it is not possible to predict with any accuracy which patients will respond to treatment. The aim of this analysis was to examine whether clinical and genetic variables could be used to predict response to MTX. Methods: Patients recruited to the Norfolk Arthritis Register (NOAR), a primary care based inception cohort of patients with inflammatory polyarthritis, were eligible for this analysis if they were commenced on MTX as their first DMARD within 3 months of their baseline visit and had at least 2 years of follow-up data. Outcome on MTX was defined as: (1) stopped for adverse events; (2) stopped for inefficacy or second DMARD added; (3) stopped for other reasons; or (4) remained on MTX monotherapy. Multiple logistic regression was used to establish which variables (including demographics, dis- ease activity and Health Assessment Questionnaire score) predicted stopping monotherapy for inefficacy or adverse event (with those remaining on treatment taken as the referent category). The area under the Receiver Operating Characteristic curves (AUC ROC), were used to determine how accurate the model was at predicting outcome. Results: 309 patients were included in this analysis. At 1 year (2 years), 34 (46) patients had stopped for adverse events and 25 (49) had either stopped monotherapy for inefficacy or had a second DMARD added. 231 (188) patients remained on MTX mono- therapy. The strongest predictor of inefficacy at both time points was shared epitope positivity: odds ratios (OR) 5.8 (95% confidence intervals (CI) 1.3 to 25.6) at 1 year, OR 3.0 (95% CI 1.3 to 7.3) at 2 years. High Health Assessment Questionnaire score (OR 1.84 95% CI 1.12 to 3.01) and female gender (OR 2.2, 95% CI 0.92 to 5.28) were associated with adverse events on MTX at 1 year. However, even the most optimal combinations of the factors analysed were only weakly predictive of treatment outcome: AUC ROC for adverse events 0.68 (95% CI 0.58 to 0.78) and for inefficacy AUC ROC 0.71 (95% CI 0.6 to 0.81). Conclusions: Within this cohort, routine clinical and laboratory factors were poor at predicting outcome of treatment with MTX. Given the major therapeutic advantage to be derived from accurate prediction of treatment outcome, further studies will need to investigate novel biological and other markers. This paper is freely available online under the BMJ Journals unlocked scheme, see http:// ard.bmj.com/info/unlocked.dtl Methotrexate (MTX) is the key conventional disease-modifying antirheumatic drug (DMARD) treatment for rheumatoid arthritis (RA) as it is Ann Rheum Dis 2009;68:57–62. doi:10.1136/ard.2008.088237 cheap, effective and can be prescribed as mono- therapy or in combination with other agents, including biologicals. Studies suggest it is now the first DMARD of choice for RA worldwide.1 Recent studies have done much to confirm its clinical efficacy with ACR50 responses between 46% and 65%.2 3 In addition, patients remain on MTX significantly longer than other conventional DMARDs.4 5 MTX is, however, not universally effective, and a significant proportion of patients stop treatment because of inefficacy or adverse events. There are, however, few data as to the possibility of being able to predict patients’ response to treatment. As patients usually have to fail treatment with MTX prior to the prescription of biologicals it would be particularly useful to be able to predict treatment outcome, in that patients unlikely to respond to treatment could be fast-tracked to drugs from which they would be more likely to derive benefit. Although outcome studies have identified RA- related factors (eg, high erythrocyte sedimentation rate/C-reactive protein (CRP), rheumatoid factor, shared epitope (SE) positivity and extra-articular disease) to be associated with an adverse prognosis in RA in terms of radiographic damage or disability,6 to date few studies have examined the effect of such factors on treatment outcome. Anderson et al7 identified disease duration as the strongest predictor of treatment response in a meta-analysis of 1435 patients, with patients with longer disease duration at the start of treatment being less likely to respond to MTX. Other factors suggested to be associated with poorer response include previous DMARD use7 8 and poor functional status.7 Clearly these factors may be, in part, confounded by disease duration, in that patients with a longer duration of disease will usually have been exposed to more drugs and have had longer to accrue physical disability. Similarly, failure with other DMARDs might indicate drug-resistant disease, or disease less likely to respond to treatment. Studies examining disease activity as a predictor of MTX response are inconsistent, with some studies suggesting that patients with low disease activity are less likely to respond to treatment.7 8 However, in a study published by Hoekstra et al,9 patients with low disease activity at baseline were more likely to respond to treatment with MTX. In part, these differences may reflect the different definitions of disease activity used, in that some studies used inflammatory markers as a marker of disease activity,8 whereas others used composite measures such as the disease activity score.9 57