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High-quality evidence suggests that methotrexate and other conventional nonbiologic DMARDs are effective in many patients with rheumatoid arthritis. Initial therapy for rheumatoid arthritis should be a conventional nonbiologic DMARD unless these are contraindicated. If a patient has had an inadequate response to methotrexate with or without other nonbiologic DMARDs during an initial three-month trial, then biologic therapy can be considered. Exceptions include patients with high disease activity AND poor prognostic features (functional limitations, disease outside the joints, seropositivity, or bony damage), where biologic therapy may be appropriate first-line treatment.