Gender Differences in the Treatment Effect of Methotrexate Among RA Patients

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A new study evaluated gender differences in physical functioning, sexual dysfunction, depression, fatigue, pain, and loneliness among RA patients using and not using methotrexate.

A new study found significant gender differences in physical functioning, sexual dysfunction, depression, and fatigue at the time of enrollment among patients with rheumatoid arthritis (RA) using and not using methotrexate.1

“The results revealed better physical function at the time of diagnosis and a higher loneliness score in [methotrexate] users compared to [methotrexate] non-users in general,” wrote investigators, led by Laila T. Bay, from Odense University Hospital in Denmark.

Methotrexate may be the first choice of treatment for RA according to Danish and international guidelines, but gender differences have yet to be assessed.2 Thus, investigators conducted a cross-sectional study to assess gender differences and gender-specific associations regarding sexual functioning, loneliness, depression, fatigue, and physical function in RA patients who use or do not use methotrexate.1

The team recruited patients, aged ≥ 18 years with an RA diagnosis, from the outpatient rheumatology department at Danish University Hospital by distributing an electronic joint survey to 380 patients between April – September 2018. Participants were included if they could speak and understand Danish.

Investigators collected data until October 2018. In the survey, participants self-reported age, gender, co-living status, employment status, education, daily smoking, weekly alcohol consumption, height, weight, body mass index (BMI), and comorbidity. Participants also completed the sexual functioning questionnaire (CSFQ), the University of California Los Angeles loneliness scale, Beck’s depression inventory, the Bristol rheumatoid arthritis fatigue numerical rating scale (BRAF NRS), and the Health Assessment Questionnaire (HAQ).

The team also leveraged clinical and paraclinical data from medical records at the participant’s diagnosis and 1 year later. Data collected included treatment with methotrexate or other synthetic and biologic disease-modifying antirheumatic drug 1 year after diagnosis, seropositivity with IgM-RF and anti-CCP-status, number of tender joints, number of swollen joints, Disease Activity Score, Charlson’s Comorbidity Index, Patient Global Assessment (PtGA), Physician Global Assessment, and Health Assessment Questionnaire assessing fatigue and pain.

In total, 286 patients were included in the study, with most women (n = 217). Participants had a mean age of 45 years at the time of the diagnosis, and after the survey, a mean age of 56.6 years. The mean disease duration lasted 12.1 years.

In total, 67.8% of patients used methotrexate (women: 60.2%). In contrast, 93 participants did not use methotrexate (women: 57.2%). Most patients (73%) received > 12 years of education, half (50.1%) were unemployed, and one-fourth (24.1%) lived by themselves.

Investigators found several significant gender differences after adjusting for age, education, employment, and cohabitation status. For instance, women had significantly greater mean scores in the HAQ score at diagnosis (mean difference, 0.4; confidence interval [CI], 0.2 – 0.7). At the time of enrollment, women had greater scores than men in HAQ (mean difference, 0.4; CI, 0.2 – 0.5), fatigue (8.8; CI, 2.4 – 15.3), PtGA (7.4, CI, 0.8 – 14.0), BDI (2.8, CI, 1.0 – 4.5), BRAF NRS severity (1.0, CI, 0.3 – 1.6), and BRAF NRS effect (1.1, CI, 0.4 – 1.7).

However, women had significantly lower mean CSFQ scores than men (mean difference, -12.2; CI, -14.8 to – 9.5).

The team found patients using methotrexate had a significantly greater score on the UCLA Loneliness Scale than non-users (mean difference, 4.15; CI, 1.5 – 6.9).

Compared to women who were not using methotrexate, women methotrexate users had increased scores in mean HAQ score (mean difference, 0.4; CI 0.2 to 0.6), fatigue (11.2; CI, 4.0 to 18.4), pain (8.7; CI, 1.4 to 16.0), PtGA (9.2; CI, 1.5 – 17.0), BRAF-NRS severity (1.1; CI, 0.3 to 1.8). BRAF-NRS effect (1.1; CI, 0.3 – 1.9). Women methotrexate users had a reduced CSFQ score (-13.3; CI, -16.3 to -10.3).

Investigators observed a significant difference in the CSFQ mean score for both female and male non-users, which demonstrates increased sexual dysfunction in women (-9.2; CI, -15.0 to -3.5).

When comparing male users and non-users, as well as female users and non-users, the team saw no differences in mean age, the proportion of seropositivity, or mean DAS-28 CRP. Additionally, male and female users (9.5 vs 12.9) had a lower mean disease duration than non-users (9.8 vs 18.2). There were also gender differences between the HAQ score at the time of diagnosis for male users and non-users (0.7 vs 0.4) and female users and non-users (1.0 vs 1.6).

Male users and non-users had significant differences than female users and non-users in the UCLA Loneliness mean score (36.2 vs. 32.8 and 39.0 vs. 35.0), the CSFQ mean score (49.1 vs. 46.7 and 36.4 vs. 37.4), and the BDI mean score (7.0 vs. 5.6 and 10.5 vs. 8.9).

“The low number of male participants makes it difficult to reach firm conclusions on gender differences, and consequently, caution is needed in group comparisons,” investigators wrote. “However, the study’s female-to-male ratio reflects the clinical population of RA patients (one male to four females).”


  1. Bay LT, Nielsen DS, Flurey C, et al. Associations of gender with sexual functioning, loneliness, depression, fatigue and physical function amongst patients suffering from rheumatoid arthritis with a particular focus on methotrexate usage. Rheumatol Int. Published online March 14, 2024. doi:10.1007/s00296-024-05555-y
  2. Smolen JS, Breedveld FC, Burmester GR, Bykerk V, Dougados M, Emery P, et al. Treating Rheumatoid Arthritis to Target: 2014 Update of The Recommendations of An International Task Force. Ann Rheum Dis. 2014. 75(1):3–15.