Peripheral and central contributions to persistent pain in rheumatoid arthritis: an unbiased latent profile analysis identifies four mechanism-based phenotypes

Background Pain frequently persists in rheumatoid arthritis (RA), despite effective control of inflammation. The mechanisms driving this residual pain remain poorly characterised in individual patients. Methods In 172 patients with established RA and clinically relevant pain (mean NRS 6.5/10) and 80 pain free controls, we combined indicators of inflammatory disease (CRP, joint counts, power Doppler ultrasound), centrally mediated pain (Widespread Pain Index, painDETECT), psychological distress (PHQ ADS) and quantitative sensory testing (QST). Latent profile analysis was applied without predefined thresholds. Results Four phenotypes were identified: a peripheral, low-inflammation/low-central phenotype (38%); a predominantly inflammatory phenotype (7%); and moderate (43%) and severe (12%) centrally mediated phenotypes. Centrally mediated phenotypes reported the highest pain (NRS 8.2), worst disease impact and lowest employment. DAS28 CRP was similar in both the inflammatory and severe centrally mediated phenotypes but for different reasons, swollen joints and CRP versus tender joints , and did not distinguish them. Conditioned pain modulation was impaired relative to controls (p<0.001) and most reduced in the severe centrally mediated phenotype. Psychological distress was the strongest independent predictor of pain severity (model R squared=0.33), whereas inflammatory markers were not. Principal components analysis identified swollen joint count (loading 0.63) and the tender swollen joint difference (loading 0.60) as accessible clinical markers of the inflammatory and centrally mediated phenotypes respectively. Conclusions A data driven approach identified four mechanism-based pain phenotypes in RA. This framework moves pain assessment beyond inflammation alone and provides a basis for testing analgesic strategies to target the predominant pain mechanism in individual patients.