Introducing Polyrefractory RA: A New Frontier in Difficult-to-Treat RA Save

At a EULAR 2025 session titled “What makes ‘Difficult-to-treat RA’ so difficult to treat? And what can we do?”, Drs. Paula David and Dennis McGonagle introduced the emerging concept of polyrefractory rheumatoid arthritis (RA), a term now being used to describe a subset of patients who have failed to respond to five or more biologic or targeted synthetic DMARDs. This new classification, derived from recent multinational registry data, represents a significant step in refining our understanding and management of the most treatment-resistant forms of RA.

Polyrefractory RA appears to affect nearly one in five patients within the broader difficult-to-treat RA (D2T-RA) category. These individuals are often younger, female, and seropositive. Yet demographic features tell only part of the story. The key insight is that not all treatment resistance in RA is inflammatory in origin, and this has major implications for care.

During the session, the speakers described two distinct clinical patterns: one group with persistently high disease activity and objective signs of inflammation despite trying multiple mechanisms of action, and another group with low inflammatory markers but ongoing fatigue, pain, and disability. The latter group often carries comorbid conditions such as fibromyalgia, obesity, or depression and may show signs of central sensitization. This dichotomy between inflammatory and non-inflammatory polyrefractory RA remains largely overlooked in routine practice.

Dr. McGonagle framed this complexity within an immunological continuum that positions RA between classic autoimmunity and autoinflammatory disease. He proposed that some polyrefractory cases may involve cryptic autoinflammatory drivers, such as IL-1 or IL-23 dysregulation or innate immune activation, that evade standard DMARD targeting. Identifying these endotypes could open the door to more precise diagnostic and therapeutic strategies.

Dr. David illustrated this possibility with a striking real-world case of a patient with long-standing, treatment-resistant RA who experienced a dramatic clinical response to CAR-T cell therapy. Though still investigational in rheumatology, this case underscores how much remains unknown about the underlying biology of polyrefractoriness—and how rethinking mechanisms may help us move beyond reflexive DMARD switching.

The session echoed many of the priorities outlined in the 2021 EULAR recommendations and research agenda for difficult-to-treat RA, which call for distinguishing inflammatory from non-inflammatory disease drivers, improving shared decision-making, and reducing reliance on empiric escalation of immunosuppression. Importantly, EULAR advocates for trials that stratify D2T-RA by underlying biology and include integrated non-pharmacologic interventions.

Polyrefractory RA is a heterogeneous condition; roughly half of patients remain driven by inflammation, while the other half experience persistent symptoms driven by non-inflammatory mechanisms. This has significant implications for both care and research. Clinical practice should shift from reflexive DMARD swapping toward precision phenotyping and holistic management strategies.

Future research should prioritize distinguishing refractory phenotypes in trials and develop integrated care models spanning pharmacologic and non-pharmacologic domains. Polyrefractory RA is not just more of the same; it is a frontier that demands nuanced, interdisciplinary care.