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Research Article

Statins Impair Antitumor Effects of Rituximab by Inducing Conformational Changes of CD20

  • Magdalena Winiarska,

    Affiliations: Department of Immunology, Center of Biostructure Research, the Medical University of Warsaw, Warsaw, Poland, Department of Laboratory Diagnostics and Clinical Immunology, the Medical University of Warsaw, Warsaw, Poland

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  • Jacek Bil,

    Affiliation: Department of Immunology, Center of Biostructure Research, the Medical University of Warsaw, Warsaw, Poland

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  • Ewa Wilczek,

    Affiliation: Department of Pathology, Center of Biostructure Research, the Medical University of Warsaw, Warsaw, Poland

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  • Grzegorz M Wilczynski,

    Affiliation: Laboratory of Molecular and Systemic Neuromorphology, Nencki Institute of Experimental Biology, Warsaw, Poland

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  • Malgorzata Lekka,

    Affiliation: Department of Applied Spectroscopy, The Henryk Niewodniczanski Institute of Nuclear Physics, Krakow, Poland

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  • Patrick J Engelberts,

    Affiliation: Genmab, Utrecht, The Netherlands

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  • Wendy J. M Mackus,

    Affiliation: Genmab, Utrecht, The Netherlands

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  • Elzbieta Gorska,

    Affiliation: Department of Laboratory Diagnostics and Clinical Immunology, the Medical University of Warsaw, Warsaw, Poland

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  • Lukasz Bojarski,

    Affiliation: Laboratory of Neurodegeneration, International Institute of Molecular and Cell Biology, Warsaw, Poland

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  • Tomasz Stoklosa,

    Affiliation: Department of Immunology, Center of Biostructure Research, the Medical University of Warsaw, Warsaw, Poland

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  • Dominika Nowis,

    Affiliation: Department of Immunology, Center of Biostructure Research, the Medical University of Warsaw, Warsaw, Poland

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  • Zuzanna Kurzaj,

    Affiliation: Department of Immunology, Center of Biostructure Research, the Medical University of Warsaw, Warsaw, Poland

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  • Marcin Makowski,

    Affiliation: Department of Immunology, Center of Biostructure Research, the Medical University of Warsaw, Warsaw, Poland

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  • Eliza Glodkowska,

    Affiliation: Department of Immunology, Center of Biostructure Research, the Medical University of Warsaw, Warsaw, Poland

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  • Tadeusz Issat,

    Affiliation: Department of Immunology, Center of Biostructure Research, the Medical University of Warsaw, Warsaw, Poland

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  • Piotr Mrowka,

    Affiliation: Department of Immunology, Center of Biostructure Research, the Medical University of Warsaw, Warsaw, Poland

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  • Witold Lasek,

    Affiliation: Department of Immunology, Center of Biostructure Research, the Medical University of Warsaw, Warsaw, Poland

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  • Anna Dabrowska-Iwanicka,

    Affiliation: Department of Lymphoproliferative Disease, Maria Sklodowska-Curie Memorial Cancer Center, Institute of Oncology, Warsaw, Poland

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  • Grzegorz W Basak,

    Affiliation: Department of Hematology, Oncology and Internal Diseases, the Medical University of Warsaw, Warsaw, Poland

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  • Maria Wasik,

    Affiliation: Department of Laboratory Diagnostics and Clinical Immunology, the Medical University of Warsaw, Warsaw, Poland

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  • Krzysztof Warzocha,

    Affiliation: Institute of Hematology and Transfusion Medicine, Warsaw, Poland

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  • Maciej Sinski,

    Affiliation: Department of Internal Diseases, Hypertension and Vascular Disease, the Medical University of Warsaw, Warsaw, Poland

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  • Zbigniew Gaciong,

    Affiliation: Department of Internal Diseases, Hypertension and Vascular Disease, the Medical University of Warsaw, Warsaw, Poland

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  • Marek Jakobisiak,

    Affiliation: Department of Immunology, Center of Biostructure Research, the Medical University of Warsaw, Warsaw, Poland

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  • Paul W. H. I Parren,

    Affiliation: Genmab, Utrecht, The Netherlands

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  • Jakub Golab mail

    To whom correspondence should be addressed. E-mail: jgolab@ib.amwaw.edu.pl

    Affiliation: Department of Immunology, Center of Biostructure Research, the Medical University of Warsaw, Warsaw, Poland

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  • Published: March 25, 2008
  • DOI: 10.1371/journal.pmed.0050064

Reader Comments (1)

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Cholesterol-lowering treatments do not impair the B-cell depletion obtained with rituximab in the context of autoimmune diseases

Posted by plosmedicine on 31 Mar 2009 at 00:33 GMT

Author: Laurent Chiche
Position: No occupation was given
Institution: Hôpital de la Conception
E-mail: Laurent.Chiche@mail.ap-hm.fr
Additional Authors: Julien Mancini, MD; Rodolphe Jean, MD; Jean-Robert Harlé, MD; Jean-Marc Durand, MD; Françoise Dignat-George, MD; Corinne Brunet, MD
Submitted Date: December 15, 2008
Published Date: December 18, 2008
This comment was originally posted as a “Reader Response” on the publication date indicated above. All Reader Responses are now available as comments.

Rituximab is a chimeric anti-CD20 monoclonal antibody (mAb) widely used in the treatment of both B-cell malignancies and autoimmune disorders such as rheumatoid arthritis [1], systemic lupus erythematosus and autoimmune cytopenias [2]. Recently, Winiarska et al. [3] showed that statins could impair the tumoral B-cell depletion obtained by Rituximab, because a cholesterol-dependent change in the conformation of surface CD20 was responsible for a loss of CD20 binding in vitro. We aimed to compare rituximab-induced B-cell depletion in patients with or without cholesterol-lowering treatments.

We retrospectively assessed the rate and time to complete B-cell depletion (les than 0,5%) and reconstitution (greater than/equal to 0,5% of total lymphocyte count) in consecutive patients receiving rituximab without concomitant chemotherapy at our institution during a 6-year period (2002-2008). We included all the patients (n=39) who had at least 3 blood B-lymphocyte counts (using FITC-conjugated mouse anti-human CD19 mAb, clone J4-119, Beckman Coulter) before and/or after rituximab initiation. Rituximab was used for various autoimmune diseases in 36 patients and hemopathy without associated chemotherapy in 3 patients. In all these patients but one, rituximab was administered in four weekly infusions of 375 mg/m2. We then identified and compared two groups of 13 and 26 patients respectively with and without long-term cholesterol-lowering treatment (181 blood lymphocyte counts were available for these patients). In the group with cholesterol-lowering drugs, patients were receiving statins (n=9), fibrates (n=2), ezetimibe (n=2) and tocopherol (n=1). The two group were comparable for age, sex ratio, triglyceridemia, underlying disease indicating rituximab therapy (autoimmune versus hemopathy) and associated specific treatments (corticosteroids, immunosuppressive drugs or both) except for cholesterolemia. Autoimmune diseases were mainly represented by autoimmune cytopenias (n=15), acquired hemophilia and thrombotic microangiopathies (n=10) and connective tissue diseases (n=8). Both the rate (84 vs 96%) and time (13 +/- 6 vs 20 +/- 8 days, mean±SD) to complete B-cell depletion were not different in both groups, respectively patients with and without cholesterol-lowering drugs. Moreover, the time to B-cell reconstitution (analysis available for 30 out of 39 patients with similar repartition between compared groups) was comparable in the two groups (308 +/- 144 vs 275 +/- 43 days, mean±SD).

In this single-center retrospective case series of patients receiving rituximab therapy mainly in the context of autoimmune diseases, the long-term prescription of cholesterol-lowering treatments did not influence the rate and time to B- cell depletion neither its reconstitution. Our study aims to assess the effect of cholesterol-lowering treatments on B-cell depletion induced by rituximab regardless other B-cell depleting drugs. So that, patients receiving chemotherapy in association with rituximab were excluded, explaining why most patients have autoimmune disease as well as the limited number of patients in our cohort. Our results and the existence of case report confirming the clinical efficiency of rituximab in patients on cholesterol-lowering treatments [4] invite to consider the results of Winiarska et al. [3] with caution in a clinical setting. Regarding the importance of cardiovascular complications among patients with chronic inflammatory diseases [5], prospective studies are needed to definitely establish whether or not cholesterol-lowering treatments should be removed from the treatment of patients with autoimmune diseases who are required to undergo CD20-specific therapy.

References

[1] Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close DR et al : Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med. 2004 ; 350:2572-2581
[2] Edwards JC, Cambridge G: B-cell targeting in rheumatoid arthritis and other autoimmune diseases. Nat Rev Immunol. 2006; 6:394-403
[3] Winiarska M, Bil J, Wilczek E, Wilczynski GM, Lekka M, Engelberts PJ et al. : Statins impair antitumor effects of rituximab by inducing conformational changes of CD20. PLoS Med. 2008: 5:e64
[4] Gallon L, Chhabra D : Anti-CD20 monoclonal antibody (rituximab) for the treatment of recurrent idiopathic membranous nephropathy in a renal transplant patient.
Am J Transplant. 2006; 6: 3017-3021
[5] Sherer Y, Shoenfeld Y. Mechanisms of disease: atherosclerosis in autoimmune diseases. Nat Clin Pract Rheumatol. 2006; 2:99-106

No competing interests declared.