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Background: Methotrexate (MTX) is the first-choice treatment for rheumatoid arthritis (RA), but the exact prevalence rates and predictors of important adverse events (AEs) associated with MTX treatment are less well investigated.
Objectives: To determine the prevalence of MTX AEs (gastrointestinal (GI), mucocutaneous, neurological, haematological, pulmonary, and liver enzymes elevation), and to identify baseline demographic, clinical and drug related predictors of liver and GI AEs.
Methods: The Rheumatoid Arthritis Medication Study (RAMS) is a UK multi-centre prospective cohort study of patients with RA commencing MTX for the first time. Relevant demographic, medication, clinical and disease related data, and blood samples were collected from patients at baseline. Data on MTX therapy and occurrence of AEs were reported at six and twelve month follow-ups, and include recorded laboratory values of alanine transaminase (ALT) enzyme.
The prevalence rates of AEs were calculated based on the number of patients who reported the AE at either 6 or 12 month follow-up visits. The association between candidate baseline predictors and occurrence of GI or liver AEs was assessed using multivariable logistic regression.
Results: In total, 2089 participants were included (mean age=58.4±13.5 years; 1390 [66.5%] women). Of those, 1816 and 1584 completed their visits at 6 and 12 months, respectively.
The frequency of abnormal ALT values (>1xULN) was 10.8% (183/1685) and 11.6% (170/1461) at 6 and 12 month follow-up visits, and 15.5% (286/1845) for either visits. The number of patients who reported GI AEs was 777 (40.6%) within 1 year of follow-up. The prevalence of mucocutaneous, neurological, haematological and pulmonary AEs were 441 (23.1%), 487 (25.5%), 116 (6.1%), and 406 (21.3%), respectively.
Male sex, having high ALT at baseline and a history of diabetes were all associated with increased risk of ALT elevation during the study period (
Baseline predictors of elevated alanine transaminase (ALT) and gastrointestinal (GI) adverse events
| Variable | Elevated ALT | GI adverse events |
|---|---|---|
| Adjusted Odds Ratio (95% CI) | ||
| Age (years) | 1.00 (0.99, 1.01) | 0.99 (0.98, 1.00) |
| Male sex | 1.39 (1.02, 1.90) | 0.53 (0.42, 0.67) |
| Drink alcohol | 1.23 (0.88, 1.73) | 1.09 (0.86, 1.37) |
| Current or past smoking | 1.10 (0.80, 1.49) | 1.10 (0.88, 1.37) |
| BMI (kg/m 2 ) | 1.01 (0.98, 1.03) | 1.02 (1.00, 1.03) |
| Symptoms duration (months) | 1.00 (1.00, 1.00) | 1.00 (1.00, 1.00) |
| RF positivity | 0.81 (0.60, 1.10) | 0.93 (0.75, 1.16) |
| DAS28-CRP | 0.97 (0.87, 1.08) | 1.13 (1.04, 1.23) |
| ALT at baseline (IU) | 1.03 (1.02, 1.04) | – |
| History of diabetes | 1.94 (1.22, 3.08) | 0.91 (0.62, 1.34) |
| History of liver disease | 1.73 (0.43, 6.95) | – |
| History of renal disease | 1.29 (0.42, 3.96) | 1.13 (0.50, 2.52) |
| MTX starting dose (mg/week) | 1.03 (0.98, 1.08) | 1.03 (0.99, 1.06) |
Conclusion: GI events were the most commonly reported AEs among patients with RA in the first year of MTX treatment, followed by neurological, mucocutaneous and pulmonary AEs. Identifying predictors of AEs may help to optimise drug therapy in RA by tailoring the dosing strategy or frequency of monitoring. This may lead to increased adherence and consequently improved effectiveness.
Disclosure of Interests: Ahmad Sherbini: None declared, James Gwinnutt Grant/research support from: BMS, Kimme Hyrich Grant/research support from: Pfizer, UCB, BMS, Speakers bureau: Abbvie, Suzanne Verstappen Grant/research support from: BMS, Consultant of: Celltrion, Speakers bureau: Pfizer