Use of Whole-Blood Transcriptomic Profiling to Highlight Several Pathophysiologic Pathways Associated With Response to Rituximab in Patients With Rheumatoid Arthritis: Data From a Randomized, Controlled, Open-Label Trial

Authors

  • Jérémie Sellam,

    1. Hôpital Saint-Antoine, AP-HP, DHU i2B, and Université Pierre et Marie Curie Paris 6, Paris, France
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    • Drs. Sellam and Marion-Thore contributed equally to this work.

    • Dr. Sellam has received consulting fees, speaking fees, and/or honoraria from Roche France (less than $10,000).

    • Drs. Sellam, Sibilia, Tebib, Le Loët, Combe, Dougados, and Mariette have received honoraria from Roche for serving on the scientific committee of the SMART study (less than $10,000 each).

  • Sandrine Marion-Thore,

    1. INSERM U987, Laboratoire d'Excellence INFLAMEX, and Université Versailles Saint Quentin, Versailles, France, and Université de Limoges, Limoges, France
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    • Drs. Sellam and Marion-Thore contributed equally to this work.

  • Florent Dumont,

    1. Institut Cochin, Université Paris Descartes, and INSERM U1016, Paris, France
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  • Sébastien Jacques,

    1. Institut Cochin, Université Paris Descartes, and INSERM U1016, Paris, France
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  • Henri-Jean Garchon,

    1. INSERM U987, Laboratoire d'Excellence INFLAMEX, and Université Versailles Saint Quentin, Versailles, France and UFR des Sciences de la Santé, Versailles Saint Quentin en Yvelines Université, Montigny-Le-Bretonneux, France
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  • Stéphanie Rouanet,

    1. Roche, Neuilly/Seine, France
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  • Yassine Taoufik,

    1. Université Paris-Sud 11 and Hôpitaux Universitaires Paris-Sud, AP-HP, Le Kremlin Bicêtre, France
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  • Houria Hendel-Chavez,

    1. Université Paris-Sud 11 and Hôpitaux Universitaires Paris-Sud, AP-HP, Le Kremlin Bicêtre, France
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  • Jean Sibilia,

    1. EA 3432, Hôpitaux Universitaires de Strasbourg, and Université de Strasbourg, Strasbourg, France
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    • Drs. Sellam, Sibilia, Tebib, Le Loët, Combe, Dougados, and Mariette have received honoraria from Roche for serving on the scientific committee of the SMART study (less than $10,000 each).

    • Dr. Sibilia has received consulting fees and/or speaking fees from AbbVie, Roche, Pfizer, Merck, UCB, Novartis, Bristol-Myers Squibb, and Actelion (less than $10,000 each).

  • Jacques Tebib,

    1. Centre Hospitalier Lyon-Sud, Pierre-Bénite, France
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    • Drs. Sellam, Sibilia, Tebib, Le Loët, Combe, Dougados, and Mariette have received honoraria from Roche for serving on the scientific committee of the SMART study (less than $10,000 each).

  • Xavier Le Loët,

    1. Centre Hospitalier Universitaire de Rouen and INSERM U905, Rouen, France
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    • Drs. Sellam, Sibilia, Tebib, Le Loët, Combe, Dougados, and Mariette have received honoraria from Roche for serving on the scientific committee of the SMART study (less than $10,000 each).

  • Bernard Combe,

    1. Lapeyronie University Hospital, Université Montpellier I, and UMR 5535, Montpellier, France
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    • Drs. Sellam, Sibilia, Tebib, Le Loët, Combe, Dougados, and Mariette have received honoraria from Roche for serving on the scientific committee of the SMART study (less than $10,000 each).

  • Maxime Dougados,

    1. Université Paris Descartes, UPRES-EA 4058, and Hôpital Cochin, AP-HP, Paris, France
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    • Drs. Sellam, Sibilia, Tebib, Le Loët, Combe, Dougados, and Mariette have received honoraria from Roche for serving on the scientific committee of the SMART study (less than $10,000 each).

  • Xavier Mariette,

    Corresponding author
    1. Université Paris-Sud 11, Hôpitaux Universitaires Paris-Sud, AP-HP, and INSERM U1012, Le Kremlin Bicêtre, France
    • Service de Rhumatologie, Hôpital de Bicêtre, 78 Rue du Général Leclerc, 94275 Le Kremlin Bicêtre, France (e-mail: xavier.mariette@bct.aphp.fr); or to INSERM U987, Université Versailles Saint Quentin, 2 Avenue de la source de la Bièvre, 78180 Montigny-Le-Bretonneux, France. E-mail: gilles.chiocchia@inserm.fr

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    • Drs. Sellam, Sibilia, Tebib, Le Loët, Combe, Dougados, and Mariette have received honoraria from Roche for serving on the scientific committee of the SMART study (less than $10,000 each).

    • Drs. Mariette and Chiocchia contributed equally to this work.

    • Dr. Mariette has received consulting fees, speaking fees, and/or honoraria from Roche (less than $10,000).

  • Gilles Chiocchia

    Corresponding author
    1. INSERM U987, Laboratoire d'Excellence INFLAMEX, and Université Versailles Saint Quentin, Versailles, France and UFR des Sciences de la Santé, Versailles Saint Quentin en Yvelines Université, Montigny-Le-Bretonneux, France
    • Service de Rhumatologie, Hôpital de Bicêtre, 78 Rue du Général Leclerc, 94275 Le Kremlin Bicêtre, France (e-mail: xavier.mariette@bct.aphp.fr); or to INSERM U987, Université Versailles Saint Quentin, 2 Avenue de la source de la Bièvre, 78180 Montigny-Le-Bretonneux, France. E-mail: gilles.chiocchia@inserm.fr

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    • Drs. Mariette and Chiocchia contributed equally to this work.

    • Dr. Chiocchia received a grant from Roche to conduct this transcriptomic study.


Abstract

Objective

To identify a molecular signature that could be predictive of the clinical response to rituximab (RTX) and elucidate the transcriptomic changes after RTX therapy in patients with rheumatoid arthritis (RA), with the use of whole-blood transcriptomic profiling.

Methods

A microarray assay of the whole human genome was performed using RNA from peripheral blood samples obtained before the first cycle of RTX from 68 patients with RA in the SMART study. The transcriptomic profile was also assessed 24 weeks after the first administration of RTX (among 24 nonresponders and 44 responders, according to the European League Against Rheumatism response criteria at week 24). Ingenuity Interactive Pathways Analysis was used to identify molecular pathways that were modified by RTX therapy according to the clinical response. Quantitative polymerase chain reaction was performed to confirm the microarray results.

Results

In total, 198 genes showed significant baseline differential expression between patient groups according to their subsequent response to RTX (good or moderate responder versus nonresponder). This molecular signature could be reduced to 143 genes, which allowed for correctly classifying 89% of the patients by their EULAR response status at week 24, with 93% identification of responders and 100% identification of nonresponders. The signature for response featured up-regulation of inflammatory genes centered on NF-κB, including IL33 and STAT5A, and down-regulation of the interferon pathway. As expected, at week 24 post–RTX therapy, genes involved in the development and functions of B cells were the genes most strongly down-regulated, without any difference between the 2 groups.

Conclusion

Whole-blood transcriptomic analyses may accurately identify patients with RA who will not respond to RTX therapy. These findings could open new perspectives on the clinical management of RA.

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