Patients with difficult-to-treat rheumatoid arthritis may differ biologically and clinically depending on whether prior treatment “failure” reflects lack of efficacy or intolerance, according to a recent viewpoint.

Led by György Nagy, of the Department of Rheumatology and Immunology; Heart and Vascular Center; and Department of Genetics, Cell- and Immunobiology, of Semmelweis University, in Budapest, Hungary, the researchers reported that the European Alliance of Associations for Rheumatology (EULAR) definition for difficult-to-treat rheumatoid arthritis successfully established a unified framework for identifying a previously ill-defined patient population, but its real-world application exposes important methodological limitations. The definition identifies patients with persistent rheumatoid arthritis activity despite treatment escalation, and it groups biologically refractory disease together with a wide range of complex clinical situations.

A primary limitation arises from the first criterion, which requires treatment according to guideline-based recommendations and failure of 2 or more biological or targeted synthetic disease-modifying antirheumatic drugs with different mechanisms after inadequate response to conventional synthetic disease-modifying antirheumatic drugs. The researchers noted that the term “failure” is not explicitly defined, which means it could reflect lack of efficacy, intolerance, or both. These scenarios represent distinct clinical and biological profiles, and research cited in the article showed that differences between lack of efficacy and intolerance reflect fundamentally different underlying drivers within a broad, heterogeneous patient group. Suggested refinements include stratifying difficult-to-treat status according to inadequate efficacy, toxicity, or mixed patterns, particularly because many patients cycle through 4 or 5 targeted therapies over time.

The second criterion encompasses signs of active or progressive disease. Rapid radiographic progression is a validated marker of aggressive rheumatoid arthritis, but routine assessment requires serial imaging and structured scoring systems that are impractical in standard clinical settings. Measures of quality of life, while clinically relevant, are challenging to capture consistently because they rely on subjective reporting and are not routinely quantified with validated instruments.

The third criterion includes cases in which symptoms are perceived as problematic by the patient or the physician. “This criterion acknowledges that D2T RA is not solely a biological phenomenon of persistent inflammation but a complex interplay of patient experience and clinical considerations that make treatment decision-making more challenging,” the authors described. This encompasses pain, fatigue, comorbidity burdens, and psychosocial factors, yet it lacks objective measures for research settings.

In suggesting updates for the future, they concluded a "more ‘clinical-friendly’ version that is easier to implement in busy daily practice without sacrificing scientific rigor, and [that] suggest[s] means of stratifying D2T cohorts for more precise research investigation....would further empower rheumatologists to accurately identify, stratify and ultimately improve outcomes for patients living with the persistent and multifaceted challenges of D2T RA, ensuring that the right patient receives the right treatment for the right reason."

GN reported receiving consulting fees, lecture honoraria, and conference support from multiple pharmaceutical companies and serves on the European Alliance of Associations for Rheumatology congress committee. MHB stated that her institution received consultancy fees and research funding without personal compensation, and she is a National Institute for Health Research Senior Investigator. She noted the views expressed are her own.

Source: RMD Open