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Pharmacological induction of interferon type I activity following treatment with rituximab determines clinical response in rheumatoid arthritis
  1. Saskia Vosslamber1,
  2. Hennie G Raterman2,
  3. Tineke C T M van der Pouw Kraan3,
  4. Marco W J Schreurs1,
  5. B Mary E von Blomberg1,
  6. Michael T Nurmohamed4,
  7. Willem F Lems2,4,
  8. Ben A C Dijkmans2,4,
  9. Alexandre E Voskuyl2,
  10. Cornelis L Verweij1,2
  1. 1Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
  2. 2Department of Rheumatology, VU University Medical Center, Amsterdam, The Netherlands
  3. 3Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands
  4. 4Department of Rheumatology, Reade/Jan van Breemen Research Institute, Amsterdam, The Netherlands
  1. Correspondence to Cornelis L Verweij, VU University Medical Center, Inflammatory Disease Profiling, CCA260, PO Box 7057, 1007MB Amsterdam, The Netherlands; c.verweij{at}vumc.nlSV and HGR contributed equally to this work

Abstract

Objective Despite the fact that rituximab depletes B cells in all treated patients with RA, not all patients show a favourable clinical response. The goal of this study was to provide insight into pharmacological changes in peripheral blood that are associated with clinical response to rituximab.

Methods Gene expression profiling was performed on peripheral blood RNA of 13 patients with RA (test group) using Illumina HumanHT beadchip microarrays. An independent group of nine patients was used for validation using TaqMan quantitative PCR. Clinical responder status was determined after 6 months using change in 28-joint Disease Activity Score (ΔDAS28) and European League Against Rheumatism (EULAR) response criteria. Significance analysis of microarrays and ontology analysis were used for data analysis and interpretation.

Results Pharmacogenomic analyses demonstrated marked interindividual differences in the pharmacological responses at 3 and 6 months after start of treatment with rituximab. Interestingly, only differences in the regulation of type I interferon (IFN)-response genes after 3 months correlated with the ΔDAS28 response. Good responders (∆DAS>1.2; n=7) exhibited a selective increase in the expression of type I IFN-response genes, whereas this activity was unchanged or hardly changed in non-responders (∆DAS<1.2; n=6) (p=0.0040 at a cut-off of 1.1-fold induction). Similar results were obtained using EULAR response criteria. These results were validated in an independent cohort of nine patients (five non-responders and four responders, p=0.0317).

Conclusions A good clinical response to rituximab in RA is associated with a selective drug-induced increase in type I IFN-response activity in patients with RA. This finding may provide insight in the biological mechanism underlying the therapeutic response to rituximab.

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Footnotes

  • SV and HGR contributed equally to this work

  • Funding This study was partly supported by grants from the European Community's FP6 funding (AUTOCURE), MS-Research (grant no. 04-549 MS) and the Centre for Medical Systems Biology (CMSB, a centre of excellence from The Netherlands Genomics Initiative).

  • Competing interests MTN has received research and speaking fees from Roche. WFL is member of advisory board van Roche, Abbott and Shering Plough (MSD). BACD received speaking fees from Pfizer and Abbott. CLV is an inventor on a patent application on the predictive value of IFN type I response activity for the clinical outcome of B cell depletion treatment. SV, HGR, TCTMvdPK, MWJS, BMEvB and AEV have no competing interests to declare.

  • Ethics approval This study was conducted with the approval of the local medical ethics committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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