Metabolomic Analysis May Predict Methotrexate Response in Rheumatoid Arthritis

Rheumatoid arthritis. General practitioner examining a patient’s hand for signs of rheumatoid arthritis. This condition is caused by the immune system attacking the body’s own tissues, causing progressive joint and cartilage destruction. As the cartilage is worn away, new bone grows as part of the repair process. This causes stiffness and deformity of the fingers. Treatment is with anti-inflammatory drugs and physiotherapy.
Researchers evaluated the clinical response of methotrexate in rheumatoid arthritis using plasma metabolomics profiling.

Pretreatment plasma metabolomic profiling can potentially identify clinical biomarkers of methotrexate response among patients with rheumatoid arthritis (RA), according to study results published in Seminars in Arthritis and Rheumatism.

Researchers conducted a 16-week, open-label study that included 20 patients (median age 53 years; 70% women) with RA who initiated methotrexate therapy.

Plasma samples were collected prior to the initial dose, and participants received either 15 mg/week of oral or subcutaneous methotrexate as well as 1 mg/day of oral folic acid. Methotrexate dose was increased to 20 mg/week, as tolerated, in those who did not reach clinical remission by 8 weeks.

Metabolomic profiling included 648 total metabolites. The Disease Activity Score in 28 Joints (DAS28-ESR) was used to define clinical response to methotrexate, with a clinically meaningful reduction threshold defined as more than 1.2.

Pretreatment plasma metabolomic profiling revealed statistically significant differences in 19 metabolites (P <.05) between participants with RA based on 16-week methotrexate response. The Spearman correlation between pretreatment plasma metabolite levels and change in DAS28-ESR identified 3 of the metabolites to be significantly associated with methotrexate response (P <.05).

Patients who responded well to methotrexate showed lower metabolite levels, but these levels were not intercorrelated. Using receiver operating characteristic analysis, the researchers identified a high degree of discrimination between responders and non-responders by pretreatment plasma levels of the following metabolites: nornicotine (area under the curve [AUC]=0.8384; P =.0001), N-methylisoleucine (AUC=0.8182; P =.0025), 2,3-dihydroxybutanoic acid (AUC=0.8182; P =.0004), and a combination biomarker panel score (AUC=0.9798; P <.0001).

Limitations of this study include a small sample size and a large number of variables.

The study authors concluded that these results provide “preliminary evidence of the ability to use metabolomic analysis as a discovery tool in the identification of predictive biomarkers of therapeutic success of [methotrexate] in RA.”


Medcalf MR, Bantis LE, Shi P, et al. Plasma metabolomic profiling as a tool to identify predictive biomarkers of methotrexate efficacy in rheumatoid arthritis. Sem Arthritis Rheum. Published online June 28, 2022. doi:​​10.1016/j.semarthrit.2022.152056