Efficacy and Safety of Subcutaneous Methotrexate Compared to Oral Methotrexate Administration in Patients with Active Rheumatoid Arthritis: an Open Level Randomized Clinical Trial

Background: Methotrexate (MTX) is the corner stone in management of rheumatoid arthritis (RA), but its limited use as oral formulation is frequently due to gastrointestinal intolerance, variable absorption and bioavailability. Subcutaneous (SC) MTX may offer better efficacy and tolerability. Objective: To compare the efficacy and safety of subcutaneous (SC) injection versus oral methotrexate (MTX) in patients suffering from active rheumatoid arthritis (RA). Methods: This open labeled randomized clinical trial was conducted on 84 patients at the department of rheumatology in Bangladesh medical university (BMU) during the period of January 2013 to October 2014. In phase 1, MTX was given 10 mg orally, weekly and the dose of MTX was increased to 15 mg/week after four weeks. All patients were followed up for 8 weeks from enrollment. In phase 2, patients were randomized in two groups. One group received 20 mg MTX subcutaneously weekly (n=40) and the other group received the same dose of MTX orally (n=44). After another 8 weeks the dose of MTX was increased to 25 mg/week. Final follow up was given at 16 weeks after randomization. ACR20, ACR50 and ACR70 response criteria was used to see the efficacy of MTX. Safety and adverse events were also recorded. Results: At the end of phase 1, ACR 20 response was observed in 20% patients and a significant improvement was noticed across multiple disease activity parameters (p < 0.05) after 8 weeks. After phase 2 follow up(16 weeks), ACR 20 & ACR 50 response were 100% & 45% , respectively in subcutaneous group and 95.5% and 29.5%, respectively, in oral group, difference was statistically significant (P value of 0.172 & 0.143). None of the patient achieved ACR70 response. The measures of disease activity (except swollen joint count) like tender joint counts, pain VAS, patient and physician global scores, HAQ, ESR, and DAS28 were significantly improved in the SC group (p < 0.05). Gastrointestinal upset were more in oral group like nausea occurred in 65% (SC) vs. 87% (oral), anorexia in 45% vs. 73%, and dizziness in 43% vs. 82% (p < 0.01). One patient discontinued oral MTX due to intolerance. Conclusion: Subcutaneous route was safe and effective than oral methotrexate. Subcutaneous MTX may be a preferable option in patients with inadequate response or intolerance to oral MTX in patient with active RA. Bangladesh Medical Res Counc Bull 2026;52(1): 40-49