Risk Factors for Difficult-to-Treat Rheumatoid Arthritis

Risk factors at rheumatoid arthritis onset, contributing factors, and the burden of disease were identified in patients with difficult-to-treat rheumatoid arthritis.

Several factors may predict the risk for developing difficult-to-treat (D2T) rheumatoid arthritis (RA), including limited therapeutic options because of adverse events or comorbidities, fibromyalgia, poor coping abilities, and low socioeconomic status. These factors may be used to provide individualized treatment, according to study results published in Rheumatology.

The European League Against Rheumatism definition of D2T RA includes persistent signs and/or symptoms despite a trial of 2 or more biologic or targeted synthetic disease-modifying antirheumatic drugs (DMARDs) with different mechanisms of action, signs suggestive of active/progressive disease, and management perceived as problematic by the rheumatologist and/or patient.

Because the treatment approach to patients with D2T RA is generally based on trial-and-error, the objective of the current study was to identify factors that may predict the development of D2T RA.

The study included patients with RA from the Department of Rheumatology & Clinical Immunology of University Medical Center Utrecht, enrolled from February 2019 to August 2020. The patients were classified as having D2T RA if all 3 criteria were fulfilled, whereas patients with RA who did not fulfill all criteria served as control patients.

Examinations that included questionnaires were used to collect data on patient and disease characteristics, potentially contributing factors, and burden of disease during an extensive study visit.

The study cohort included 52 patients (mean age, 60.2 years; 73% women) with D2T RA and 100 patients (mean age, 64.5 years; 72% women) with RA who served as a control group.

Lower socioeconomic status at onset of RA was associated with a 2-fold increased risk for D2T RA (odds ratio, 1.97; 95% CI, 1.08-3.61; P =.03).

Several contributing factors were significantly more common among patients with D2T RA, compared with control patients, including limited drug options because of adverse events (94% vs. 57%) or comorbidities (69% vs. 37%), a mismatch in the wish to intensify treatment strategies of patient and rheumatologists (37% vs. 6%), a diagnosis of fibromyalgia (38% vs. 9%), and poorer coping abilities (worse levels).

The burden of disease, including lower physical functioning and quality of life and worse levels of fatigue and pain, was statistically significantly higher in patients with D2T RA, compared with control patients.

Reflecting the heterogeneity in D2T disease state, 3 subgroups of D2T RA patients were identified: nonadherent dissatisfied patients, patients with pain syndromes and obesity, and patients with true refractory RA.

The main study limitation was the relatively small sample size, whereas the exclusion of patients who have not yet failed 2 or more DMARDs was another potential study limitation.

“The occurrence of factors contributing to the disease state, the burden of disease and the heterogeneity in D2T RA patients suggest that these factors should be identified in daily practice in order to tailor therapeutic strategies further to the individual patient,” wrote the researchers.

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Roodenrijs NMT, van der Goes MC, Welsing PMJ, et al. Difficult-to-treat rheumatoid arthritis: contributing factors and burden of disease Published online Jan 22, 2021. Rheumatology (Oxford). 2020 Dec 17:keaa860. doi: 10.1093/rheumatology/keaa860