Table 3 Predicting adverse events at 1 and 2 years Extended report Predictor Number of patients Female gender n (%) Age diagnosis (years) Age MTX onset (years) Symptom duration prior to MTX (months) RF positive (yes/no) ARA criteria (yes/no) SJC TJC 28 SJC 28 TJC Baseline CRP* Baseline DAS28* Baseline HAQ SE positive (yes/no){ Steroids (yes/no) 1 year Adverse event 34 (11) 27 (79) 58.4 (44.5–64.4) 58.8 (45.6–64.7) 8.76 (4–18.95) 11 (32) 16 (47) 4 (2–10) 9 (2–15) 3 (2–8) 6 (3–9) 8 (2–17) 3.8 (3.3–5.1) 1.625 (0.875–2) 19 (68) 5 (15) Still on 231 (75) 147 (64) 59.3 (48.3–69) 60 (50.8–69.8) 6.27 (3.75–12.68) 94 (41) 121 (52) 4 (1–11) 5 (1–15) 4 (1–9) 3 (0–10) 13 (5–26) 3.9 (3.0–4.8) 1 (0.5–1.625) 126 (64) 39 (17) p Value Adverse event Still on p Value 0.07 0.25 0.29 0.21 0.31 0.56 0.83 0.06 0.99 0.05 0.04 0.65 0.02 0.71 0.75 2 years 46 (15) 35 (76) 59 (45.1–65.6) 59 (45.8–68.0) 6.97 (4.01–16.79) 15 (44) 20 (44) 4 (2–9) 8 (3–16) 3 (1–7) 6 (2–11) 7 (2–17) 3.6 (3.3–4.9) 1.25 (0.875–2) 25 (63) 9 (20) 188 (61) 117 (62) 58.7 (46.9–69.5) 59.4 (49.1–70.5) 6.09 (3.56–14.59) 87 (46) 101 (54) 5 (1–11) 5 (1–13) 4 (1–9) 4 (0–10) 13 (5–26) 4.0 (3.0–4.8) 1 (0.5–1.625) 99 (63) 18 (10) 0.08 0.56 0.6 0.33 0.2 0.2 0.43 0.08 0.4 0.09 0.01 0.86 0.1 0.91 0.06 ARA, American Rheumatism Association; CRP, C-reactive protein; DAS, disease activity score (using 28 joint counts); HAQ, Health Assessment Questionnaire; MTX, methotrexate; RF, rheumatoid factor; SE, shared epitope; SJC, swollen joint count; TJC, tender joint count. This table illustrates clinical variables in those stopping for adverse events and those remaining on treatment at 1 and 2 years. Results are expressed as median (IQR) unless stated. *293 patients had baseline CRP available and, therefore, could have DAS28 results calculated. {260 patients had DNA samples and were successfully genotyped for SE. within 3 months of drug start) was relatively small this analysis provides additional evidence that MTX is effective and generally well tolerated in an unselected IP cohort, with 75% of patients remaining on monotherapy at 1 year and 61% at 2 years. Within this cohort, standard clinical and laboratory variables collected at first visit were poorly predictive of treatment outcome. Interestingly, the most strongly associated predictor of MTX inefficacy at both 1 and 2 years was possession of the SE, whereas other variables, such as CRP, DAS28 and HAQ, did not appear to be associated with inefficacy. The majority of patients stopping for adverse events did so within the first 12 months, within this group higher HAQ score, higher TJC and lower CRP were associated with stopping treatment for adverse events. However, for neither outcome were these variables, even when used in combination, sufficiently pre- dictive of outcome to be of clinical use. Studies suggest that high levels of inflammation (as measured by erythrocyte sedimentation rate, CRP or joint counts) predict a poor prognosis in terms of radiological damage.13 Our results suggest that disease activity does not influence treatment response in either direction. It could be hypothesised that the patients with the least active disease will do better because of their better underlying natural history or conversely those who have the most active disease have the greatest potential for showing a response. Increased disability, as measured by the HAQ score, was predictive for stopping treatment for adverse events, although not for inefficacy. The explanation for this finding is unclear. In other studies,7 higher levels of disability (as measured by the Steinbrocker functional class) were associated with a poorer response to treatment, which may be explained on the basis that chronic severe disease is less responsive to treatment, The association in the current study seen with adverse events may be explained by a high HAQ score being a marker for other psychosocial factors that may increase adverse events such as depression or altered illness beliefs. Previous studies have shown that the HAQ score, although accepted as one of the gold standard measures of disability in RA, is also associated with pain,14 depression and disease activity.15 In a meta-analysis, Anderson et al7 found that female patients had a poorer response to treatment. Although within the NOAR cohort, female patients were more likely to stop treatment for adverse events, the difference was not statistically significant. Other studies9 suggest that male patients are more likely to respond to MTX, although whether this relates to gender differences in MTX clearance or other factors remains unclear. Interestingly, the strongest factor demonstrated was the association between being positive for the HLA DRB1 SE and stopping MTX for inefficacy. Small numbers limited the ability to be able to detect a dose effect, or the relative importance of different SE alleles. No association was observed between stopping MTX for adverse events and SE status. Other studies support a link between SE and MTX efficacy; O’Dell et al16 found that patients who were SE positive were less likely to respond to MTX monotherapy compared with combination Table 4 Predicting adverse events Predictor HAQ score 1 year Unadjusted OR (95% CI) 1.84 (1.12 to 3.01) Adjusted OR p Value (95% CI) 0.02 1.87 (1.11 to 3.15) p Value 0.02 2 years Unadjusted OR (95% CI) 1.47 (0.94 to 2.29) Adjusted OR p Value (95% CI) 0.09 1.42 (0.89 to 2.26) p Value 0.14 HAQ, Health Assessment Questionnaire. This table illustrates OR of stopping methotrexate for adverse events—OR displayed as unadjusted and adjusted for age, gender, symptom duration and steroid use at baseline. 60 Ann Rheum Dis 2009;68:57–62. doi:10.1136/ard.2008.088237