Effects of Methotrexate on Serum Drug Levels, Clinical Response in TNFi-Treated RA

Concomitant methotrexate use was associated with longer TNFi survival.

Concomitant methotrexate (MTX) treatment significantly maintains tumor necrosis factor inhibitor (TNFi) serum levels in patients with rheumatoid arthritis (RA), according to a recent study published in Clinical Rheumatology.

In this study, researchers reviewed baseline and 1-year data from patients in the RA-Paz study cohort to measure the following outcomes: the effect of concomitant use of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) on serum drug levels in patients receiving adalimumab or infliximab treatment for 1 year, the association between the use and type of concomitant csDMARDs, including the clinical response achieved after the first year of TNFi treatment, and the dose-dependent effect of methotrexate on the first two outcomes.  

The researchers collected the following data from 92 study participants: age, sex, body mass index, disease characteristics, and treatment. Disease activity was measured using the 28-joint Disease Activity Score (DAS28) at baseline, 6 months, and 12 months. The DAS28 was also used to calculate clinical improvement according to European League Against Rheumatism (EULAR) measurement standards. Serum drug and anti-drug antibodies levels were measured in 92 samples.

For statistical analysis, the participants were divided into groups based on concomitant csDMARD use.. The first group received TNFi monotherapy, the second group received TNFi plus concomitant oral MTX, and the third group received TNFi plus concomitant csDMARDs other than MTX, including leflunomide, sulfasalazine, and hydroxychloroquine at baseline. The second group also included patients receiving TNFi, MTX, and other concomitant csDMARDs.

Sensitivity analyses were performed to determine a dose-dependent effect of MTX on the outcomes being evaluated. To measure this, participants receiving TNFi plus MTX were further classified into 2 groups according to median dose received: MTX at <15 mg per week and MTX dose ≥15 mg per week.

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For each group, percentages of patients with drug levels in serum were determined. Logistic regression models were used to measure the relationship between the concomitant use of csDMARDs along with serum drug levels and clinical response, which were reported as an odds ratio (OR). Kaplan-Meier curves explained treatment survival for each group and the log-rank test was performed to compare treatment survival across the groups.

The authors found that the probability of maintaining serum TNFi levels was 2-fold in patients with MTX compared with those without MTX (OR, 2.3; P =.06) and 5-fold in patients receiving the highest MTX dose compared with patients not receiving MTX (OR, 4.9; P =.02). Overall, most patients (81%) who achieved adequate EULAR responses were treated with TNFi plus MTX. The reported probability of achieving this response was highest in the TNFi plus MTX group (OR, 3.4; P =.03).

The authors note that the main limitation of their findings was the low number of participants in the study. As a result, adjustments for possible confounders were not feasible. The authors recommended that to confirm these results, “further long-term studies including broader cohorts and also including patients in treatment with other TNFi are warranted.”

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Martínez-Feito A, Plasencia-Rodríguez C, Navarro-Compán V, et al. The effect of methotrexate versus other disease-modifying anti-rheumatic drugs on serum drug levels and clinical response in patients with rheumatoid arthritis treated with tumor necrosis factor inhibitors [published online November 6, 2018]. Clin Rheum. doi:10.1007/s10067-018-4355-0