Background Methotrexate is the anchor drug used most widely as monotherapy or combination therapy with other DMARDS & biologics in treatment of RA. It is widely perceived by clinicians to have potentially dangerous adverse effects (AE). The present study was designed to assess safety of long term methotrexate in patients with RA on standard care in clinical practice.

Objectives To evaluate the safety of long term methorexate therapy in patients with RA

Methods RA patients on methotrexate therapy at recommended doses (15–25 mg per week) as monotherapy or in combination with other conventional dmards or biologics for over 4 years were enrolled between Jan 2016 to Dec 2016. Since the objective was to assess safety, those patients initiated on methotrexate 4 years ago but had discontinued due to adverse effects were also included. Patients were analysed with a questionnaire and review of past records from the clinic. The questionnaire included questions about duration and compliance of methotrexate therapy, any untoward effects that patient felt were due to methotrexate and direct questions related to known methotrexate side effects. Investigations were reviewed from past records.Data were presented by 1- year intervals starting from the time patient received first dose of methotrexate. Adverse events (AE), rate of discontinuation and abnormal laboratory results were analysed per 100 patient (pt.) years in 1 year intervals.

ResultsThe cumulative exposure to methotrexate was 926 patient years. Of 228 patients, 218 continued methotrexate through 4 years. Overall 10 patients discontinued methotrexate over 4 years, 5 due to GI intolerance and 1 due skin allergy in the first year. In subsequent years 2 patients were withdrawn due to chronic cough, 1 due to raised transaminases and 1 patient after severe infection and pancytopenia. Incidence of AEs, severe AEs, infections, laboratory abnormalities and discontinuations due to AE's declined during 4 years exposure. The most common AEs included nausea and dyspepsia (24.6/ 100 pt. years in first year with declining incidence through 4 years). The second most common AE reported was infections (7/100 pt. years). Most common infections were mild UTI & respiratory tract infections.14 patients initially asymptomatic or having mild nausea reported significantly increased nausea in year 4 and beyond, all responding to reduction of methotrexate dose. The incidence of severe AE that needed hospitalisation &/ or discontinuation of methotrexate was 2.6/100 pt. years in year 1 with declining events over time. The cumulative risk of serious AE over 4 years was 1.2/ 100 pt. years.

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Conclusions Methotexate therapy was well tolerated over 4 years treatment period with a good safety profile. Most of the AE's were mild to moderate severity not needing discontinuation of methotrexate. Study has limitations since it is retrospective observational study with small patient number from two outpatient rheumatology clinics. Some AE's may have been underestimated as patient compliance not ascertained and patients with AE's may have lost to follow up. Some effects may have been overestimated as precise causality is not proven. During the 4 years methotrexate treatment, no new safety concerns emerged.

Disclosure of Interest None declared