The prevalence of side effects on methotrexate and its associated risk factors in South African patients with rheumatoid arthritis

Abstract

Background Methotrexate (MTX) remains one of the anchor disease-modifying antirheumatic drugs (DMARDS) used to treat rheumatoid arthritis (RA). Methotrexate usage can be associated with a variety of side effects which range from mild to severe. This can lead to premature discontinuation or dose adjustments of a drug which is very efficacious in the treatment of RA. Objectives To document the prevalence and nature of MTX toxicities in patients with RA, in a South African population. We also tried to identify potential risk factors for developing these toxicities and determined whether MTX doses of more than 30mg a week as based on a clinician’s judgement are associated with an increased frequency of toxic events. Methods A retrospective chart review of 200 consecutive RA patients was carried out in the Department of Rheumatology at Charlotte Maxeke Johannesburg Academic Hospital. Information was captured from the files and patients were not clinically assessed. Patient characteristics were reviewed and recorded at three time intervals i.e. entry to the clinic, at the time toxicity developed and at the time of data collection. Data was expressed as mean, median or percentages as appropriate. Age and gender adjusted associations of recorded variables other than MTX with toxicity characteristics were determined in multivariable regression models. Those factors that were associated in age and sex adjusted models with toxicity were entered together with MTX variables in a single model with consideration of collinearity, interactions and cause-effect relations. Results Overall toxicity was recorded as 25% (60 toxic events in 50 patients). There were 9 patients who developed more than 1 adverse event. Leucopenia was most prevalent (9.5%), followed by a transaminitis (8.5%). Stomatitis (4.5%), nausea (3%) and anaemia (1.5%) accounted for the other toxic events. Leucopenia was associated with age at entry (OR 0.96, 95%CI: 0.91-0.99), concomitant sulphasalazine usage at entry or exit (OR 3.76, 95%CI: 1.08-13.09 and OR 2.8, 95%CI: 1.07-7.34 respectively) and the development of anaemia (OR 21.18, 95%CI: 1.83-245.7; p=0.01). Transaminitis was borderline associated with age at entry (OR 0.96, 95%CI: 0.91-1.0; p=0.06) and with the simultaneous development of nausea and stomatitis (OR 5.97, 95%CI: 1.01-35.29; p=0.04 and OR 6.32, 95%CI: 1.43-28.2; p=0.01 respectively). Alcohol usage was present in 4 patients who developed a transaminitis (OR 2.25, 95%CI: 0.66-7.69; p=0.2). Doses higher than 30mg/week were prescribed in 45 patients of which only 12 developed toxic events, 6 leucopenia (OR 1.68, 95%CI: 0.6-4.7; p=0.3), 5 transaminitis (OR 1.49, 95%CI: 0.5-4.43; p=0.5) and 1 nausea. Conclusions This study delineates the prevalence of toxicities on MTX in a predominantly Black, South African population. The most frequently occurring toxicity in our population was leucopenia. Most other studies in RA patients looking at MTX toxicity described transaminitis as the most prevalent toxic event. Doses of MTX higher than 30mg a week were not associated with an increased prevalence of toxicity. In patients with refractory disease, high doses of MTX comprise a potential alternative preceding the use of a biologic agent.