A multi-parameter response prediction model for rituximab in rheumatoid arthritis

• Published in: Joint, bone, spine : revue du rhumatisme bone, spine : revue du rhumatisme, 2018-03, Vol.85 (2), p.219-226
• Main Authors: de Jong, Tamarah D, Sellam, Jérémie, Agca, Rabia, Vosslamber, Saskia, Witte, Birgit I, Tsang-A-Sjoe, Michel, Mantel, Elise, Bijlsma, Johannes W, Voskuyl, Alexandre E, Nurmohamed, Mike T, Verweij, Cornelis L, Mariette, Xavier
• Format: Article
• Language: English
• Subjects: Age Factors; Aged; Antirheumatic Agents - therapeutic use; Arthritis, Rheumatoid - diagnosis; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - genetics; Cohort Studies; Female; France; Humans; Interferon-alpha - genetics; Internal Medicine; Life Sciences; Logistic Models; Male; Middle Aged; Molecular Targeted Therapy; Multivariate Analysis; Prediction; Predictive Value of Tests; Rheumatoid arthritis; Rheumatology; Risk Assessment; Rituximab; Rituximab - therapeutic use; Severity of Illness Index; Sex Factors; Treatment Outcome; Type I interferon
• ISSN: 1297-319X; 1778-7254
• DOI: 10.1016/j.jbspin.2017.02.015

Abstract Objectives To validate the IFN response gene (IRG) set for the prediction of non-response to rituximab in rheumatoid arthritis (RA) and assess the predictive performance upon combination of this gene set with clinical parameters. Methods In two independent cohorts of 93 (cohort I) and 133 (cohort II) rituximab-starting RA patients, baseline peripheral blood expression of eight IRGs was determined, and averaged into an IFN score. Predictive performance of IFN score and clinical parameters was assessed by logistic regression. A multivariate prediction model was developed using a forward stepwise selection procedure. Patients with a decrease in disease activity score (ΔDAS28) ≥ 1.8 after 6 months of therapy were considered responders. Results The mean IFN score was higher in non-responders compared to responders in both cohorts, but this difference was most pronounced in patients who did not use prednisone, as described before. Univariate analysis in cohort I showed that baseline DAS28, IFN score, DMARD use and negativity for IgM-RF and/or ACPA were associated with rituximab non-response. The multivariate model consisted of DAS28, IFN score and DMARD use, which showed an area under the curve (AUC) of 0.82. In cohort II, this model revealed a comparable AUC in PREDN-negative patients (0.78), but AUC in PREDN-positive patients was significantly lower (0.63), which seemed due to effect modification of the IFN score by prednisone. Conclusions Combination of predictive parameters provided a promising model for the prediction of non-response to rituximab, with possibilities for optimization via definition of the exact interfering effect of prednisone on IFN score. Trial registration (Cohort II, SMART trial) NCT01126541 , registered 18 May 2010.