Finally! a definition for difficult-to-treat rheumatoid arthritis

A recent study published in the Annals of Rheumatic Diseases has proposed European League Against Rheumatism (EULAR) definition for difficult-to-treat RA, which could be beneficial in clinical practice, clinical trials, and future research. The 3 criteria proposed by the EULAR task force members for defining difficult-to-treat RA are as follows:

(1) Treatment according to the EULAR recommendation and failure of ≥2 biological disease-modifying antirheumatic drugs (DMARDs)/targeted synthetic DMARDs (with different mechanisms of action) after failing conventional synthetic DMARD therapy (unless contraindicated).

(2) Presence of at least one of the following: at least moderate disease activity; signs and/or symptoms suggestive of active disease; inability to taper glucocorticoid treatment; rapid radiographic progression; RA symptoms that are causing a reduction in quality of life.

 (3) The management of signs and/or symptoms is perceived as problematic by the rheumatologist and/or the patient

Different factors serve as key determinants of the persistence of signs and symptoms in RA. Poor understanding of the properties, mechanisms, and biological correlation of these factors makes the clinical decision on management often challenging. Difficult-to-treat RA is defined as the persistence of signs and or symptoms suggestive of the inflammatory disease activity, despite previous treatment with csDMARD, and at least two bDMARDs.

In routine follow-up, the signs and symptoms are evaluated, disease activity is graded, and anti-inflammatory medication is matched to the level of disease activity.

If the disease activity remains too high, the therapy is changed, and the effect on signs and symptoms is re-evaluated. However, in difficult-to-treat RA, various factors preclude this cycle of management, making the treatment highly challenging.

Although the overall prevalence of difficult-to-treat RA is unclear, it is estimated to be 3-10% of all RA patients. Due to a lack of understanding of contributing components of difficult-to-treat RA, therapy stages and decisions for each individual patient are carried out through trial and error.

The long-term persistence of signs and/or symptoms directly impairs the social life, workability, and quality of life of the affected subjects, until an effective treatment regimen or approach is identified.

Since there is a subset of individuals who continue to show signs and symptoms of active illness, despite using multiple conventional synthetic and biological DMARDs, a patient-centric approach is highly warranted to confer tailored treatment by considering multiple contributory factors.

The adoption of the current definition in routine practice will help rheumatologists for robust and coherent identification of patients with difficult-to-treat RA. Moreover, in the research field, the proposed definition may assist researchers in classifying a group of similar patients.



Nagy G, Roodenrijs NMT, Welsing PMJ, et al. EULAR definition of difficult-to-treat rheumatoid arthritis. Ann Rheum Dis. 2021;80:31–35.