Long-term safety of combination treatment with methotrexate and tumor necrosis factor (TNF)-α antagonists versus TNF-α antagonists alone in psoriatic patients.

Methotrexate, a folic acid analog, is the conventional systemic anti-psoriatic agent most commonly chosen for combination with biologics in the treatment of psoriasis. Real-world long-term safety data of this combination versus biologic treatment alone in dermatological practice are sparse. Here, we present results of a comparative retrospective study of laboratory dynamics and adverse events in psoriatic patients receiving a tumor necrosis factor (TNF)-α antagonist (adalimumab or etanercept) with and without concomitant methotrexate (176 treatment courses, mean duration of 629 days). Co-treatment with methotrexate significantly (P < 0.05) correlated with a decrease of leukocyte, neutrophil and erythrocyte counts and an increase of glutamate pyruvate transaminase (GPT) (Pearson correlation, n > 148). The relative risk for a Common Terminology Criteria for Adverse Events (CTCAE) grade 1-2 laboratory adverse event was significantly elevated to 1.11 for anemia and 1.16 for a GPT increase if the patients received concomitant methotrexate at the time the laboratory test was performed. Combination treatment was given for equal or more than 30% of the time (MTX≥30% ) during 12% of the treatment courses. During these treatment courses, dynamics of leukocyte (-8.1%), neutrophil (-8.1%), erythrocyte (-3.2%) counts and GPT (+16.9%) from baseline to average under treatment were significantly more pronounced. CTCAE grade 3-4 laboratory adverse events occurred in 9.5% and 5.2% of treatment courses with and without MTX≥30% , respectively (p = 0.70), and affected transaminases in 90% of the cases. Methotrexate was discontinued due to CTCAE grade 3-4 laboratory adverse events in 4.25% of the treatment courses with MTX of 30% or more. Elevated baseline γ-glutamyl transferase levels significantly predicted the occurrence of CTCAE grade 3-4 laboratory adverse events and should trigger investigations for pre-existing liver disease or alcohol abuse. In conclusion, our comparative data supplement previous short-term studies and support a tolerable long-term safety profile of the combination treatment. However, given the additional toxicities and low evidence for benefits, alternative options such as biologic monotherapy or switching to a different biologic should be considered in a dermatological setting.