Targeting Mental Health, Pain-Related Illnesses May Improve Outcomes in Difficult to Treat RA

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The presence of mental health, pain-related illnesses, and metabolic diseases were significantly associated with the worsening of arthritis-related pain, severity, and disease activity.

In patients with difficult to treat (D2T) rheumatoid arthritis (RA), mental health, pain-related illnesses, and metabolic diseases may contribute to long-term adverse outcomes. Therefore, these should be targeted by the healthcare team to optimize the long-term disease course of this heterogeneous patient population, according to a study published in Rheumatic & Musculoskeletal Diseases.1

Although novel targeted therapies have greatly improved the outcome of patients with RA, there still remains a group of patients to whom targeted therapy has failed to adequately control disease activity. These patients are categorized as “difficult to treat.”2

“Representing a group of patients with unmet needs, D2T RA has been in the epicenter of RA clinical investigation during the last years,” wrote investigator George Bertsias, MD, PhD, associated with the Clinical Immunology and Allergy Department, School of Medicine, University of Crete, Greece, and colleagues.

To better understand the heterogeneity and factors related to long-term outcome, investigators recruited adult patients from a prospective, single-center cohort, the University of Crete Rheumatology Clinic Registry (UCRCR). D2T was defined using European Alliance of Associations for Rheumatology (EULAR) criteria, which included patients who have failed ≥2 more biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD) classes, or those who were currently receiving a second b/tsDMARDs but Disease Activity Score-28 erythrocyte sedimentation rate (DAS28-ESR) score was ≥3.2 in all measurements.

The cohort collects data on demographics, comorbidities, disease activity and characteristics, function, and quality of life at first b/tsDMARDs initiation followed by 3—6 months for the first 2 years and annually thereafter.

Latent-class trajectory analysis used longitudinal clustering of functional status, as determined by a modified Health Assessment Questionnaire (mHAQ), and disease activity, evaluated using the DAS28. Multiple linear mixed models were implemented to assess the impact of comorbidities and their clusters on the long-term outcome of D2T RA.

Of the 1264 patients with RA enrolled (81.2% female), 251 (19.9%) were categorized as D2T. Among the significant predictors of becoming D2T were younger age, an osteoarthritis or fibromyalgia diagnosis, failure to reduce DAS28-ESR within the first 6 months of treatment with a b/tsDMARD, and DAS28-ESR at first b/tsDMARD initiation.

Four groups of functional status were revealed through long-term follow-up (5872 total person-years): stable, mildly compromised mHAQ (18.2%, mean .41); gradual improvement (39.9%, 1.21—.87); and 2 groups with either slow deterioration or stable significant functional impairment (HAQ >1).

Additionally, 4 groups of disease activity evolution were identified: stable moderate disease activity (8.3%); gradual improvement from high to moderate disease activity (38%), and 2 groups with distinct but high disease activity throughout the follow-up period (total 53.6%).

The presence of “mental health and pain-related illnesses” and “metabolic diseases” were significantly associated with the worsening of mHAQ (P <.0001 for both) and DAS28 evolution (P <.0001 and P = .018, respectively).

The large cohort of patients in a real-world clinical setting, prospectively monitored by experienced rheumatologists using the same protocol, strengthened the findings. However, investigators noted the observational nature of the study design, which included incomplete follow-up records, patients lost to follow-up, and missing covariates, limited the results. To combat this, investigators decided to remove patients in whom missing data precluded their D2T classification.

“A group of patients with lower burden of ‘mental-health and pain-related illnesses’ as well as ‘metabolic diseases’ showed the most favorable outcome, underscoring the importance of targeting these common comorbid diseases together with RA inflammatory burden in order to improve the outcome of these patients,” investigators concluded. “Our results indicated that disease clusters which were identified as significantly different between trajectory-groups, were also significant predictors of DAS28 or HAQ scores.”


  1. Bertsias A, Flouri ID, Repa A, et al. Patterns of comorbidities differentially affect long-term functional evolution and disease activity in patients with 'difficult to treat' rheumatoid arthritis. RMD Open. 2024;10(1):e003808. Published 2024 Jan 19. doi:10.1136/rmdopen-2023-003808
  2. Tan Y, Buch MH. Difficult to treat' rheumatoid arthritis: Current position and considerations for next steps. RMD Open 2022;8:e002387. doi:10.1136/rmdopen-2022-002387