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Methotrexate is prescribed to at least 500,000 patients with rheumatoid arthritis (RA) worldwide; the best route of administration, however, is not clear.To compare the efficacy and safety of subcutaneous versus oral administration of methotrexate for the treatment of patients with active RA.This multicenter, phase IV, randomized, doubleblind, controlled trial took place at 29 centers in Germany from 20 November 2003 to 28 July 2005.Patients aged 18-75 years were eligible for enrollment if they presented with active RA, defined as a Disease Activity Score in 28 joints (DDAS28) ≥4, and had never been treated with methotrexate. Patients were excluded from enrollment if they had any of the following conditions: severe, acute, or chronic infectious diseases; known clinically relevant pulmonary disease; history of severe liver disease or elevated serum transaminase levels; and ulcers of the oral cavity or the gastrointestinal tract in the 6 months before enrollment. Additional exclusion criteria included treatment with biologic agents before or during the study and DMARD treatment during and less than 2 weeks before enrollment. Participants were randomly assigned to receive either 15 mg of subcutaneous methotrexate plus 2 placebo tablets or 15 mg of oral methotrexate (2 × 7.5 mg tablets) plus 1 syringe containing placebo, to be taken once week over study period f months. Patients who received oral methotrexate and showed no response at week 16 were assigned to receive treatment subcutaneously for the remaining 8 weeks.The primary outcome measure was the American College of Rheumatology criteria for 20% improvement (ACR20) at 24 weeks. Secondary outcome measures included the occurrence of adverse events, the number of swollen joints, the number of tender joints, and the DAS28.In total, 384 patients were enrolled and randomly allocated to receive methotrexate treatment via subcutaneous (n = 194) or oral (n = 190) administration. Of these patients, 188 in the subcutaneous group and 187 in the oral group were included in the clinical efficacy analysis, and 193 and 188 patients, respectively, were included in the safety analysis. The treatment groups were demographically similar (median age 59 years, ∼775% female), with no differences in clinical characteristics at enrollment (the majority presented with very early RA). At week 24, a significantly higher percentage of patients in the subcutaneous group achieved an ACR20 response than in the oral group (78% versus 70%, P <0.05). Of the patients switched to subcutaneous methotrexate at week 16 after failing to show a response to oral methotrexate, 30% subsequently achieved an ACR20 response. At 24 weeks, patients receiving subcutaneous methotrexate had a lower number of swollen joints, tender joints, and a lower median DAS28 than those receiving oral methotrexate. The rates of adverse events were similar for both groups.Subcutaneous administration of methotrexate showed superior efficacy, with no increase in adverse events when compared with oral administration.