Methods: Patients with early rheumatoid arthritis (ERA) initiating methotrexate therapy were included from the Canadian Early Arthritis Cohort (CATCH), a multicenter, prospective cohort study of patients with ERA. In CATCH patients are treated at the discretion of the rheumatologist and followed every 3 months over the first year according to a standardized protocol. For this study, all patients had an age >16 years, a diagnosis of RA by 2010 criteria, symptom duration < 1 year, used MTX within 3 months of study entry and were MTX-naive or minimally exposed to MTX. We compared the survival between sc and oral administration over the first year. Treatment failure was defined as either a change in route of MTX or addition/switch of any DMARDs other than glucocorticoids. A Cox-Proportional Hazards model was used to adjust for important potential confounders: age, gender, comorbidities, smoking, education, symptom duration, serological status, erosions, baseline DAS28, functional status (HAQ-DI), mean starting dose of MTX (over first 3 months of treatment) and other concurrent DMARDs or corticosteroids.

Results: 674 patients were included (418 oral MTX, 256 sc MTX); mean age 53, 72% female, mean symptom duration 5.2 months, mean baseline DAS-28 5.5. Patients treated with sc MTX were less likely to receive other DMARDs (56% vs. 71%, p<0.01), and had a higher mean starting dose of MTX (23 mg vs. 17 mg, p<0.01). Other characteristics were similar between groups. Unadjusted Kaplan-Meier curves showed significantly improved survival with sc MTX (figure 1, log-rank p<0.001). After adjusting for confounders the association remained significant (Hazard ratio (HR) for treatment failure: 0.58 (95%CI: 0.37-0.92, p=0.02). Older age (HR: 0.98 (95%CI: 0.97-0.99) per year of age) and the use of other DMARDs in combination (HR: 0.53 (0.35-0.81)) were also associated with improved survival. The starting dose of MTX (HR: 0.98 (0.94-1.02)) and all other covariates demonstrated no significant association. Conclusion: Subcutaneous MTX is associated with improved survival over oral MTX for initial treatment in patients with early rheumatoid arthritis. This is not a randomized trial so other confounding could have occurred.