TOPLINE: 

Ultrasonography-guided synovial biopsy in patients with refractory rheumatoid arthritis (RA) found a pauci‑immune fibroid pathotype and higher opioid use in the noninflammatory subtype, as well as a lymphomyeloid pathotype with elevated inflammatory markers in the persistent inflammatory subtype.

METHODOLOGY:

• Researchers conducted a prospective observational study to characterize the synovial pathology of two clinical phenotypes of refractory RA.
• They included adults with active RA who underwent synovial biopsy at two Italian centers between January 2020 and November 2024. Nonrefractory RA was defined as no exposure to biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs).
• Refractory RA was defined as an inadequate response to one or more b/tsDMARDs. The noninflammatory phenotype required a Physician Global Assessment (PhGA) score ≤ 20/100 mm or C-reactive protein (CRP) levels ≤ 5 mg/L, whereas the persistent inflammatory phenotype required a PhGA score and CRP levels above these thresholds.
• The final analysis included 43 patients with persistent inflammatory refractory RA, 21 with noninflammatory refractory RA, and 29 with nonrefractory RA; median ages ranged from 59 to 61 years, and women comprised 63.0%-77.3% of the cohort across groups.
• Pathologists used the Krenn Synovitis Score (KSS) and immunohistochemistry to classify synovial tissue as lymphomyeloid, diffuse myeloid, or pauci‑immune fibroid pathotypes.

TAKEAWAY:

• Patients with noninflammatory refractory RA had a lower median KSS (4 vs 6; P = .012), a 1.6-fold higher relative risk for pauci-immune fibroid synovitis (P = .006), and fewer lymphoid aggregates (P < .001) than those with persistent inflammatory refractory RA.
• Most patients with the persistent inflammatory phenotype had lymphomyeloid (53%) or diffuse myeloid (33%) pathotypes, with significantly higher CRP levels and erythrocyte sedimentation rates than those with noninflammatory refractory or nonrefractory RA.
• Patients with noninflammatory phenotype had similar composite disease activity scores as those with persistent inflammatory phenotype, with fewer swollen joints (P = .029), yet they had higher opioid use (P = .014) and worse physical function among all subgroups.
• The ultrasonography-guided synovial biopsy procedure was safe and well tolerated; only 6% of patients experienced adverse events including mild bleeding, mild swelling, and flushing.

IN PRACTICE:

“Routine incorporation of ultrasound-guided synovial biopsy with validated histopathological scoring into the clinical work-up of refractory RA could enable the identification of inflammatory versus noninflammatory pathotypes at the point of care, thereby facilitating a truly mechanistic, precision-based selection of immunomodulatory or nonimmunological interventions for each individual patient,” the authors wrote.

SOURCE:

This study was led by Alessandro Giollo, MD, PhD, University of Padova in Padova, Italy. It was published online on August 22, 2025, in Annals of the Rheumatic Diseases.

LIMITATIONS:

PhGA and CRP may not capture the full spectrum of disease activity. The study cohort lacked ethnic diversity. Some experts might classify patients with refractory RA as nonresponders rather than truly refractory.

DISCLOSURES:

This study was partially supported by local funds from the University of Ferrara, Ferrara, Italy. The authors declared having no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.