Patient-reported outcomes as early warning signs of flare following drug cessation in rheumatoid arthritis

Abstract

Objectives: Drug withdrawal in rheumatoid arthritis (RA) in remission can reduce toxicity, but with the risk of flare which requires close monitoring. We explored the potential of patient-reported outcomes (PROs) for flare detection among RA patients in sustained remission after conventional synthetic disease-modifying antirheumatic drug (csDMARD) cessation.

Methods: Four PROs (Factors that Limit sustAined Remission in rhEumatoid arthritis (FLARE-RA), EuroQol-5 Dimensions (EQ5D), Routine Assessment of Patient Index Data-3 (RAPID-3) and RA Flare Questionnaire (RA-FQ)) were captured at baseline and at sequential visits until time-of-flare or end of 6-month follow-up as part of the BIO-FLARE prospective cohort study. Flare was defined as any of (i) Disease Activity Score 28 (DAS28)-C reactive protein (CRP) ≥3.2 at any visit, (ii) DAS28-CRP≥2.4 on two visits within 2 weeks or (iii) resuming DMARD and/or steroid therapy despite DAS28-CRP<2.4. Cox regression models with time-varying covariates were fitted to evaluate associations between PRO changes and likelihood of flare. Receiver-operating characteristic (ROC) curves enabled discriminatory changes in each PRO to be compared as a means of identifying flare.

Results: 58/121 (47.9%) participants (70.1% females, mean age 64.8 years) experienced a flare. A 1-point change in each PRO score was strongly associated with flare development in the multivariate Cox regression model (p<0.001 in each case). ROC curve analysis confirmed that monitoring adverse changes in PROs from baseline offered robust discriminatory utility for identifying flare occurrence. This was most evident for RA-FQ and FLARE-RA (both areas under the curves 0.90, 95% CI 0.84 to 0.96; p=0.001); for example, an RA-FQ increment of ≥5.5 from baseline identified objective flare with positive and negative predictive values of 80% and 91%, respectively.

Conclusions: Our data support the potential value of remote PRO monitoring of RA patients in drug-free remission to identify flare occurrence.

Keywords: Autoimmune Diseases; Patient Reported Outcome Measures; Rheumatoid Arthritis.

Figure 1. Receiver operating characteristic curves for change in patient-reported outcome scores from baseline to point-of-flare. Area under curve and 95% CI have been presented for each patient-reported outcome. EQ5D Index scores were inverted (negative values rendered positive) for purposes of plot generation only, to allow representation on the same axis. EQ5D, EuroQol-5 Dimensions; FLARE-RA, Factors that Limit sustAined Remission in rhEumatoid arthritis; RA-FQ, Rheumatoid Arthritis Flare Questionnaire; RAPID-3, Routine Assessment of Patient Index Data-3.

Figure 2. Longitudinal trends in patient-reported outcomes for flare (A) and remission (B) groups prior to the last clinical visit. Red lines show the fitted trends by loess regression, grey shading shows 95% CIs. The last clinical visit was defined as the point-of-flare for the flare group and the end of follow-up for the remission group. EQ5D, EuroQol-5 Dimensions; FLARE-RA, Factors that Limit sustAined Remission in rhEumatoid arthritis; RA-FQ, Rheumatoid Arthritis Flare Questionnaire; RAPID3, Routine Assessment of Patient Index Data-3.