Prioritizing Phenotypes Over Escalation
“Management of RA, and D2T RA patients in particular, requires a holistic approach, always,” Jaap M. van Laar stated. A new diagnostic algorithm for difficult-to-treat rheumatoid arthritis (D2T RA) prioritizes patient phenotyping over immediate treatment escalation, according to Bryant R. England, MD, PhD, of the University of Nebraska Medical Center. Presented at Perspectives in Rheumatic Diseases (PRD) 2026, the strategy aims to distinguish inflammatory symptoms from noninflammatory ones to avoid unnecessary medication adjustments.
The Three-Step Decision Pathway
The algorithm simplifies the management of D2T RA—an umbrella term for persistent symptoms after multiple trials of standard therapies—into three distinct decision points. The primary goal is to isolate the underlying driver of a patient’s complaints. By carefully phenotyping the patient, clinicians can identify whether functional decline, fatigue, or chronic pain stems from active joint disease or unrelated comorbidities.
This approach builds upon the EULAR D2T RA recommendations published in 2022. While the EULAR framework is comprehensive, England’s model focuses specifically on segregating inflammatory drivers from noninflammatory causes, such as cardiovascular disease, or spinal issues.
Evaluating Potential Symptom Origins
Patients often present with a broad list of concerns, leaving the physician to determine the cause. Based on literature reviews, England noted that the widely accepted prevalence rate for D2T RA sits near 12%, whereas specific studies report estimates ranging from 5% to 25%. This variance likely stems from how different clinicians account for noninflammatory contributors to a patient’s health status.
In clinical practice, the algorithm requires an initial assessment of disease activity. If laboratory tests and physical exams show no evidence of systemic inflammation, the physician investigates potential comorbidities. England uses a shorthand for quickly organizing the possibilities: the thumb represents cardiovascular health, while the four fingers account for cancer, respiratory disease, infection, and osteoporosis, respectively.
Alignment with Holistic Standards
The focus on noninflammatory factors is gaining traction among specialists. Commenting on the algorithm, Jaap M. van Laar, MD, PhD, a professor of rheumatology and clinical immunology at the University Medical Center in Utrecht, Netherlands, observed that it mirrors his personal clinical strategy. Having served as the senior author for both the 2022 EULAR guidelines and a 2025 review article, van Laar pointed out that many individuals experience prolonged distress because physicians mistakenly escalate antirheumatic drugs instead of addressing prevalent conditions like fibromyalgia and obesity. He expressed approval that the medical community is increasingly prioritizing this distinction between inflammatory and noninflammatory symptom sources.
Criteria Define Difficult-To-Treat Rheumatoid Arthritis
What criteria define difficult-to-treat rheumatoid arthritis?
Three specific conditions establish the EULAR definition of D2T RA per the 2022 guidelines: lack of response to a minimum of two biologic or targeted synthetic DMARDs; ongoing evidence of active and advancing RA; and continuing symptoms that either the patient or the physician finds concerning.
How does the algorithm handle patients who lack systemic inflammation?
If evaluation shows no active inflammation, the algorithm directs the clinician away from escalating RA therapies. Instead, it prompts an investigation into noninflammatory causes, such as concomitant spinal disease, osteoarthritis, or other comorbidities that may be driving the patient’s reported pain and fatigue.
Why is distinguishing between phenotypes important?
Phenotyping allows clinicians to more clearly consider the sources of symptoms. By identifying that a patient’s symptoms are noninflammatory, a physician can provide more effective, targeted care rather than continuing to cycle through ineffective biologic treatments.
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