Predictors of drug-free remission in rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is a common autoimmune disease characterised by joint inflammation and systemic manifestations. Remission is achievable with disease-modifying anti-rheumatic drugs (DMARDs) prescribed in modern treat-to-target strategies, albeit with potential side effects, and inconvenient and expensive safety monitoring. Half of patients can maintain remission following DMARD cessation, though this cannot be reliably predicted. Clinicians and patients thus face a dilemma – when is it appropriate to stop DMARDs in RA remission? In this Thesis, I explore biomarkers of drug-free remission in RA in the setting of a prospective interventional cohort study of conventional synthetic DMARD (csDMARD) cessation. Method Patients with established RA satisfying clinical and ultrasound remission criteria discontinued all csDMARDs and were monitored for six months. The primary outcome was time-to-flare, defined as DAS28-CRP (disease activity score in 28 joints with C-reactive protein) ≥ 2.4. Baseline clinical and ultrasound measures, circulating cytokines, and peripheral CD4+ T cell gene expression were assessed for their ability to predict time-to-flare and flare/remission status by Cox regression and receiver-operating characteristic (ROC) analysis. Results 23/44 (52%) eligible patients experienced an arthritis flare at a median (IQR) of 48 (31.5 – 86.5) days following csDMARD cessation. A composite score incorporating five baseline variables (three genes, one cytokine, one clinical, no ultrasound) differentiated future flare and drug-free remission with an area under the ROC curve of 0.96 (95% CI 0.92-1.00), sensitivity 0.91 (0.78 – 1.00) and specificity 0.95 (0.84 – 1.00). Longitudinal analysis identified increased concentrations of circulating pro-inflammatory cytokines, and upregulation of proliferative genes by CD4+ T cells at the onset of flare. Conclusions This study provides proof-of-concept evidence for the existence of biomarkers of drug-free remission in RA, and offers insights to the pathophysiology of arthritis flare. If validated, these biomarkers may help guide csDMARD withdrawal, with consequent minimisation of medication side effects and healthcare costs.