Background/Purpose

Elevated type I IFN response gene (IRG) expression has been described to be clinically relevant in predicting the non-response to rituximab in rheumatoid arthritis (RA) patients. Interference between glucocorticoids (GCs) and type I IFN signaling has been demonstrated in vitro. Since the use and dose of oral GCs is highly variable among patients prior to the start of treatment with rituximab, we aimed to determine what the effect of GC usage is on the IRG expression in relation to the clinical response to rituximab.

Methods

The study was performed in two independent cohorts of established RA patients (n=32 and n=182) and a third cohort of 40 established RA patients that were candidates for rituximab therapy, recruited from the VU University medical center and the Jan van Breemen Institute | Reade in Amsterdam. All patients fulfilled the revised American College of Rheumatology (ACR) 1987 criteria for the diagnosis of RA. In all patients, peripheral blood gene expression of 8 IRGs was determined by microarray or multiplex quantitative (q)PCR and an IFN-score was calculated. GC use consisted of oral prednisone in doses varying from 2.5-10mg/day in 19%, 29% and 70% of the patients in the three cohorts, respectively. The clinical response to rituximab was determined after 6 months of therapy based on the change in 28 joints Disease Activity Score (DDAS28); patients with DDAS28>1.2 were considered responders. The IFN score was tested for its predictive value using Receiver Operating Characteristics (ROC) curve analysis in the patients who started with rituximab (n=40).

Results

In all three cohorts, we consistently observed suppression of the IFN-score in patients using prednisone (PREDN⁺) compared to patients that were not using prednisone (PREDN^–). No clinical differences were observed between PREDN^– and PREDN⁺ patients. The suppression of IFN-score appeared to be dose-dependent as it was most pronounced in the highest dose range (>10mg/day). In the rituximab cohort, separate ROC analysis on PREDN^– patients alone revealed improved prediction of non-response to rituximab by baseline IFN-score with an AUC of 0.969 compared to 0.848 when analyzed in all patients, whereas prednisone use itself had no predictive value in this cohort. Using a subgroup-specific cutoff of the IFN-score in the PREDN^– and PREDN⁺ groups the sensitivity increased from 41% in all patients up to 88% in the PREDN^– group, combined with a specificity of 100%.

Conclusion

Prednisone use in RA patients causes suppression of IRG expression. Rituximab response prediction based on the IFN-score at baseline could be considerably improved when prednisone use is taken into account.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/improvement-of-rituximab-response-prediction-in-rheumatoid-arthritis-via-correction-for-prednisone-related-suppression-of-type-i-interferon-response-gene-expression/