Predicting drug-free remission in rheumatoid arthritis: A prospective interventional cohort study

Abstract

Background: Many patients with rheumatoid arthritis (RA) achieve disease remission with modern treatment strategies. However, having achieved this state, there are no tests that predict when withdrawal of therapy will result in drug-free remission rather than flare. We aimed to identify predictors of drug-free remission in RA.

Methods: The Biomarkers of Remission in Rheumatoid Arthritis (BioRRA) Study was a unique, prospective, interventional cohort study of complete and abrupt cessation of conventional synthetic disease-modifying anti-rheumatic drugs (DMARDs). Patients with RA of at least 12 months duration and in clinical and ultrasound remission discontinued DMARDs and were monitored for six months. The primary outcome was time-to-flare, defined as disease activity score in 28 joints with C-reactive protein (DAS28-CRP) ≥ 2.4. Baseline clinical and ultrasound measures, circulating inflammatory biomarkers, 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 respectively.

Results: 23/44 (52%) eligible patients experienced an arthritis flare after a median (IQR) of 48 (31.5-86.5) days following DMARD cessation. A composite score incorporating five baseline variables (three transcripts [FAM102B, ENSG00000228010, ENSG00000227070], one cytokine [interleukin-27], one clinical [Boolean remission]) differentiated future flare from drug-free remission with an area under the ROC curve of 0.96 (95% CI 0.91-1.00), sensitivity 0.91 (0.78-1.00) and specificity 0.95 (0.84-1.00).

Conclusion: We provide proof-of-concept evidence for predictors of drug-free remission in RA. If validated, these biomarkers could help to personalize immunosuppressant withdrawal: a therapy paradigm shift with ensuing patient and economic benefits.

Keywords: Biomarker; CD4(+) T cell; Cessation; Disease-modifying anti-rheumatic drug; Drug-free remission; Rheumatoid arthritis.

Fig. 1

Study design and recruitment. 78 patients attended a baseline visit, of whom 44 stopped disease-modifying anti-rheumatic drug (DMARD) therapy. Patients then attended routine study visits at 1, 3 and 6 months following DMARD cessation, with additional unscheduled visits at the request of the patient in the event of suspected arthritis flare. Flare was confirmed if disease activity score in 28 joints with CRP (DAS28-CRP) ≥ 2.4, at which point the patient exited the study to restart DMARD therapy via their referring rheumatology team. Patients who maintained drug-free remission at 6 months remained without DMARDs and exited the study. PD: power Doppler.

Fig. 2

Kaplan-Meier plot showing maintenance of drug-free remission following disease-modifying anti-rheumatic drug (DMARD) cessation. Shaded area depicts the 95% confidence interval.

Fig. 3

Prediction of flare/remission using the composite biomarker score. (A): Receiver-operating characteristic curve for prediction of flare by the composite biomarker. The threshold for a positive versus negative test (39.65) is shown by the cross. (B): Kaplan-Meier plot of maintenance of drug-free remission stratified by positive (red) or negative (blue) baseline composite biomarker score. A significant difference in drug-free remission between the strata was observed (log-rank test). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)