Background: Despite the growing number of available drugs for Rheumatoid Arthritis (RA) and the significant improvement in disease management, there is still a significant proportion of RA patients with failure to multiple therapeutic lines. These cases are defined by the EULAR criteria as Difficult-to-Treat RA (D2T-RA). The EULAR D2T-RA definition is based on 3 criteria: failure to 2 or more b/tsDMARDs with different mechanism of action, persistence of signs of active/progressive disease despite treatments, and clinician or patients’ perception of a “problematic” management. Regarding RA outcomes gender differences have been reported, due to physiological differences but also differences in subjective assessment of patient reported outcomes (PROMs). Moreover, real world data comparing associated factors to D2T-RA between genders is scarce.

Objectives: To compare D2R-RA associated fatigue in a real-life cohort of patients, by gender.

Methods: We retrospectively collected data of 205 patients with RA fulfilling the ACR/EULAR 2010 classification criteria, treated with biological and targeted synthetic disease modifying anti-rheumatic drugs (b/tsDMARDs) at an outpatient rheumatology clinic. We included and followed-up patients between July 2018 and September 2024. The main outcome was development of D2T-RA. As covariates we collected: demographic, clinical, serological data. Independent variable was fatigue, assessed by the Bristol Rheumatoid Arthritis Fatigue Multidimensional Questionnaire (BRAF-MDQ) including physical, living, cognitive and emotional dimensions. We compared male and female patients fulfilling the D2T-RA criteria using univariate and multivariate logistic regressions to determine the impact of fatigue on the main outcome, adjusted by confounders. Results were expressed as Odds ratio (OR) with their corresponding 95% confidence interval (CI).

Results: From 205 included patients (33% males, 67% females), a total of 54 (26.3%) patients were found D2T-RA, comprising of 35 women (65%) and 19 men (35%). Mean age was 57.92±11.78 years with no significant differences for age at baseline. Regarding comorbidities, 36% had hypertension, 44% dyslipidemia, 25% obesity and 11% diabetes, without differences between genders. Regarding cardiovascular events, a total of 11.3% patients had it, being higher for males (20% vs 8%, p=0.02). The univariate analysis for D2R-RA in female gender is shown in Table 1. The multivariate analysis confirmed the correlation of emotional fatigue with D2T-RA outcome (OR 1.29, 95% CI 1.13-1.48; p < 0.001) in females. For males, the univariate analysis for D2T-RA is also detailed in Table 1. The multivariate analysis for male gender found that physical fatigue (OR 1.13, 95% CI 1.01-1.26; p = 0.03) and obesity (OR 8.29, 95% CI 1.07-64.2; p=0.04) were associated with development of D2T-RA.

Conclusion: Our findings revealed distinct gender-specific patterns associated with D2T-RA. In females, emotional fatigue (e.g., feelings of discouragement or being downcast) emerged as an independent factor linked to D2T-RA, but in male patients, physical fatigue (e.g., low physical energy) was a significant factor associated with the development of D2T-RA, regardless other factors. Additionally, our results indicate that obesity played a contributing role in male patients, highlighting the importance of this comorbidity. Further personalized characterization is warranted to better approach to D2T-RA, particularly to understand the contribution of comorbidities and PROMs.

REFERENCES: NIL.

Acknowledgements: NIL.

Disclosure of Interests: None declared.

© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.