Patients with PsA More Likely to Experience Side Effects of Methotrexate

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"This risk-to-benefit profile has a different connotation for patients because, although a therapy may improve certain aspects of their disease, it may also have a substantial impact on their quality of life.”

When compared with patients with rheumatoid arthritis (RA), patients with psoriatic arthritis (PsA) were more likely to experience treatment-related side effects. This difference was particularly more pronounced in patients receiving methotrexate (MTX) versus tumor necrosis factor inhibitors (TNFi), according to a study published in Open Rheumatology.1

“Treatment burden is a complex construct that… reflects the patient's experience with the medication and, particularly, any challenging experiences,” investigators explained. “When prescribing a new therapy, physicians are taught to discuss the risks and benefits of that drug. However, this risk-to-benefit profile has a different connotation for patients because, although a therapy may improve certain aspects of their disease, it may also add a new symptom that can have a substantial impact on their quality of life.”

Data from the FORWARD databank (The National Databank for Rheumatic Diseases) between January 2000 and January 2019 were used to compare patients with PsA and RA in this retrospective cohort analysis. Eligible patients had either self-reported or physician-confirmed diagnosis and completed 1 or more questionnaires before initiating and within 12 months after initiation of either MTX or a TNFi. Questions included the type of medication, severity of side effects (mild, moderate, and severe), any hospitalization due to side effects, lost time from work, and the start date and duration of side effects. Other data collected were any concomitant medications, length of medication exposure, and reasons for discontinuation.

The primary outcome was determining the prevalence of side effects with either medication during the first year of treatment initiation. Secondary outcomes analyzed the prevalence of symptoms potentially related to treatment burden and patient-reported outcomes. A multivariate logistic regression analysis evaluated the association between PsA and RA and reported side effects.

Ultimately, 116 patients with PsA and 4247 patients with RA received MTX, and 124 patients with PsA and 4361 patients with RA were in the TNFi cohort. Of the patients in the MTX group, 44.8% of those with PsA experienced side effects compared with 29.4% of patients with RA. The proportions of patients reporting TNFi-related side effects was comparable between both PsA and RA groups (24.2% and 22.8%, respectively).

Patients with PsA initiating MTX were more likely to experience nausea (28.4% vs 17.4%), numbness or tingling (49.1% vs 36.5%), depression (32.8% vs 20.1%), abdominal pain (21.6% vs 13.8%), vomiting (10.3% vs 3.5%), and tinnitus (27.6% vs 22.1%), when compared with patients with RA receiving MTX. These patients were also more likely to experience side effects when compared with either group initiating a TNFi.

The use of a large patient registry, which included data on symptoms, side effects, patient characteristics, outcomes, and disease confirmation strengthened the study. Additionally, observer bias was reduced due to data being captured prospectively. However, the databank did not contain physician measures of disease activity. The observational nature of the study was limiting due to possible unmeasured cofounders, selection bias, recall bias, confounding by indication, and order effect. Lastly, certain subgroups contained few observations, which hindered the ability to detect differences between groups.

“Although it is one of the most commonly used therapies in the treatment of PsA and RA, patients with PsA and RA discontinue MTX because of poor tolerability,” investigators concluded. “Future studies are needed to further characterize the patient experience with respect to treatment burden, and a more thorough examination of side effects critical to patient outcomes should be considered for measurement in clinical trials.”


Ogdie A, Maksabedian Hernandez EJ, Shaw Y, Stolshek B, Michaud K. Side Effects of Methotrexate and Tumor Necrosis Factor Inhibitors: Differences in Tolerability Among Patients With Psoriatic Arthritis and Rheumatoid Arthritis [published online ahead of print, 2022 Aug 15]. ACR Open Rheumatol. 2022;10.1002/acr2.11467. doi:10.1002/acr2.11467