Correspondence
Anti–Glomerular Basement Membrane Disease after Alemtuzumab
N Engl J Med 2008; 359:768-769August 14, 2008
- Article
To the Editor:
Alemtuzumab (Campath-1H) is a humanized anti-CD52 monoclonal antibody, the administration of which causes profound B- and T-lymphocyte depletion. It is licensed for use in the treatment of chronic lymphocytic leukemia, and it is increasingly used in the treatment of autoimmune diseases (particularly multiple sclerosis) and as an induction agent in renal transplantation. Although alemtuzumab is a potent immunosuppressant, several groups have described the paradoxical occurrence of autoimmune disease after its use, including thyroid disease and cytopenias. We describe two patients in whom anti–glomerular basement membrane disease developed after treatment with alemtuzumab.
Patient 1 was a 40-year-old white woman with relapsing–remitting multiple sclerosis who received a total dose of 100 mg of alemtuzumab. Nine months after treatment, she received the diagnosis of acute renal failure secondary to anti–glomerular basement membrane disease (Table 1Table 1
Characteristics of the Patients.). Patient 2 was a 43-year-old white man with a refractory antineutrophil cytoplasmic antibody–associated vasculitis who was subsequently treated with a total dose of 788 mg of alemtuzumab. Ten months later, he was found to have acute renal failure with elevated titers of anti–glomerular basement membrane antibodies and renal-biopsy findings that were consistent with anti–glomerular basement membrane disease (Table 1 and Figure 1Figure 1
Photomicrograph of a Renal-Biopsy Specimen from Patient 2, Showing Crescentic Glomerulonephritis.). Despite appropriate treatment, both patients became dialysis-dependent and eventually underwent renal transplantation, with no recurrence of anti–glomerular basement membrane disease. At the time of presentation with anti–glomerular basement membrane disease, the levels of CD4+ T cells were reduced in both patients, whereas the levels of CD19+ B cells were within the normal range (Table 1). Both patients also carried the anti–glomerular basement membrane susceptibility allele HLA-DRB1-15.The anti-CD52 antibody alemtuzumab causes rapid and prolonged lymphocyte depletion; the levels of CD4+ T cells may remain depressed for many years, but the data show that it is not the depletion of CD4+ regulatory T cells by alemtuzumab that induces autoimmunity.1,2 After the administration of alemtuzumab, B-cell recovery tends to precede T-cell recovery2 (Table 1), and the number of B cells may exceed baseline values in some patients.2 The autoimmune diseases observed after the administration of alemtuzumab are predominantly antibody-mediated, and they respond to B-cell depletion.3 Autoreactive B cells can function without T-cell help4; thus, the emergence of autoreactive B cells during the reconsititution of lymphocytes may cause autoimmunity after treatment with alemtuzumab.
Menna R. Clatworthy, M.B., Ch.B., Ph.D.
University of Cambridge, Cambridge CB2 2XY, United Kingdom
mrc38@cam.ac. uk Elizabeth F. Wallin, M.B., B.Chir.
David R. Jayne, M.D.
Addenbrooke's Hospital, Cambridge CB2 2QQ, United KingdomDr. Jayne reports receiving consulting fees from Genzyme. No other potential conflict of interest relevant to this letter was reported.
4 References1
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Cox AL ,Thompson SA ,Jones JL , et al. Lymphocyte homeostasis following therapeutic lymphocyte depletion in multiple sclerosis. Eur J Immunol 2005;35:3332-3342
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Clatworthy MR ,Jayne DR . Acquired hemophilia in association with ANCA-associated vasculitis: response to rituximab. Am J Kidney Dis 2006;47:680-682
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Groom JR ,Fletcher CA ,Walters SN , et al. BAFF and MyD88 signals promote a lupuslike disease independent of T cells. J Exp Med 2007;204:1959-1971
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Eric T. Boder, Wei Jiang. (2011) Engineering Antibodies for Cancer Therapy. Annual Review of Chemical and Biomolecular Engineering 2:1, 53-75
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D Sean Riminton, Hans-Peter Hartung, Stephen W Reddel. (2011) Managing the risks of immunosuppression. Current Opinion in Neurology 24:3, 217-223
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Gavin Giovannoni. (2011) Promising Emerging Therapies for Multiple Sclerosis. Neurologic Clinics 29:2, 435-448
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Philippa Peto, Alan D Salama. (2011) Update on antiglomerular basement membrane disease. Current Opinion in Rheumatology 23:1, 32-37
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Anthony Weetman. (2009) Immune reconstitution syndrome and the thyroid. Best Practice & Research Clinical Endocrinology & Metabolism 23:6, 693-702
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Maddalena Marasà, Jeffrey B. Kopp. (2009) Monoclonal antibodies for podocytopathies: rationale and clinical responses. Nature Reviews Nephrology 5:6, 337-348
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C. Warnke, B.C. Kieseier, U. Zettl, H-P. Hartung. (2009) Alemtuzumab als neue Therapieoption der Multiplen Sklerose. Der Nervenarzt 80:4, 468-474
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Joseph R. Berger, Sidney Houff. (2009) Opportunistic infections and other risks with newer multiple sclerosis therapies. Annals of Neurology 65:4, 367-377
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(2009) Current awareness: Pharmacoepidemiology and drug safety. Pharmacoepidemiology and Drug Safety 18:1, i-xiv
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(2008) More on Anti–Glomerular Basement Membrane Disease after Alemtuzumab. New England Journal of Medicine 359:23, 2501-2502
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