Date Published: May 23, 2018
Publisher: Public Library of Science
Author(s): Marjan Ghiti Moghadam, Femke B. G. Lamers-Karnebeek, Harald E. Vonkeman, Peter M. ten Klooster, Janneke Tekstra, Annemarie M. Schilder, Henk Visser, Eric H. Sasso, David Chernoff, Willem F. Lems, Dirk-Jan van Schaardenburg, Robert Landewe, Hein J. Bernelot Moens, Timothy R. D. J. Radstake, Piet L. C. M. van Riel, Mart A. F. J. van de Laar, Tim L. Jansen, Bryant England.
Successfully stopping or reducing treatment for patients with rheumatoid arthritis (RA) in low disease activity (LDA) may improve cost-effectiveness of care. We evaluated the multi-biomarker disease activity (MBDA) score as a predictor of disease relapse after discontinuation of TNF inhibitor (TNFi) treatment.
439 RA patients who were randomized to stop TNFi treatment in the POET study were analyzed post-hoc. Three indicators of disease relapse were assessed over 12 months: 1) restarting TNFi treatment, 2) escalation of any DMARD therapy and 3) physician-reported flare. MBDA score was assessed at baseline. Associations between MBDA score and disease relapse were examined using univariate analysis and multivariate logistic regression.
At baseline, 50.1%, 35.3% and 14.6% of patients had low (<30), moderate (30−44) or high (>44) MBDA scores. Within 12 months, 49.9% of patients had restarted TNFi medication, 59.0% had escalation of any DMARD and 57.2% had ≥1 physician-reported flare. MBDA score was associated with each indicator of relapse. At least one indicator of relapse was observed in 59.5%, 68.4% and 81.3% of patients with low, moderate or high MBDA scores, respectively (P = 0.004). Adjusted for baseline DAS28-ESR, disease duration, BMI and erosions, high MBDA scores were associated with increased risk for restarting TNFi treatment (OR = 1.85, 95% CI 1.00–3.40), DMARD escalation (OR = 1.99, 95% CI 1.01–3.94) and physician-reported flare (OR = 2.00, 95% 1.06–3.77).
For RA patients with stable LDA who stopped TNFi, a high baseline MBDA score was independently predictive of disease relapse within 12 months. The MBDA score may be useful for identifying patients at risk of relapse after TNFi discontinuation.
Rheumatoid arthritis (RA) is a chronic inflammatory disease that can cause joint damage and physical disability . Early detection of RA and the availability of biologic agents have markedly improved outcomes in these patients . Many studies have shown that the use of combinations of conventional synthetic DMARDs (csDMARDs) and biological DMARDs (bDMARDS) such as tumor necrosis factor inhibitors (TNFi) is effective for reaching and maintaining a state of low disease activity (LDA) or remission [3–5]. Once LDA or remission has been reached, patients often continue their combination therapy indefinitely. This practice may lead to overtreatment, as recent studies suggest that in some RA patients the more expensive TNFi can be tapered or stopped [6,7]. However, before implementing this therapeutic strategy in routine care, a validated predictor of disease relapse would be desirable .
Our analyses of the POET study show that, for RA patients in remission or stable LDA, a high MBDA score at the time of TNFi discontinuation was significantly associated with disease relapse during the next 12 months. Over 80% of patients with a high baseline MBDA score relapsed according to at least one of the three criteria we used. This rate of relapse was substantially higher for patients with low or moderate MBDA scores, suggesting that patients with low clinical disease activity and high MBDA scores may have inflammation that is partly or entirely subclinical. Several other studies have found the MBDA score to be frequently elevated when conventional clinical measures indicate remission or LDA [19,20,22,23]. Moreover, such patients were at increased risk for progressive joint damage [19,20,22]. Consequently, discontinuation of TNFi treatment in POET may have allowed a resurgence of residual inflammation and subsequent clinical relapse . Our finding that the MBDA score was a predictor of relapse independently of DAS28-ESR suggests that it may be a clinically useful tool for identifying patients who are at increased risk of unsuccessful TNFi discontinuation.