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From the Neurology Section (O.S.), VA North Texas Health Care System, Medical Service, Dallas; Departments of Neurology (O.S., P.D.C., E.M.F., G.M.R., M.P.S., E.M.C., N.L.M.), Immunology (O.S., E.M.C., N.L.M.), Ophthalmology (E.M.F.), and Clinical Sciences (S.Z.), University of Texas Southwestern Medical Center at Dallas; Department of Neurology (O.S., G.v.G., S.C.), Heinrich Heine University Düsseldorf, Germany; Multiple Sclerosis Center at Texas Neurology (J.T.P.), Dallas; Departments of Clinical and Experimental Immunology (J.W.C.T.) and Neurology (M.D.B.), University Hospital Maastricht, The Netherlands; Department of Neuroinflammation (D.M., D.H.M.), Institute of Neurology, Queen Square, London, UK; Institute of Neuroradiology (E.W.R.), Department of Medical Radiology, University Hospital Basel, Switzerland; Biogen-Idec (R.K.), Cambridge, MA; Department of Neurology (B.H.), Klinikum Rechts der Isar, Technische Universität München, Germany; and Department of Neurology (M.K.R.), The Ohio State University Medical Center, Columbus.
Address correspondence and reprint requests to Dr. Olaf Stüve, Neurology Section, VA North Texas Health Care System, Medical Service, 4500 South Lancaster Rd., Dallas, TX 75216 olaf.stuve{at}utsouthwestern.edu
Objective: Natalizumab is a humanized recombinant monoclonal antibody against very late activation antigen-4 approved for the treatment of patients with multiple sclerosis (MS). A phase II study failed to demonstrate a difference between natalizumab treatment groups and the placebo group with regard to gadolinium enhancing lesions on MRI 3 months after discontinuation of therapy. The objective of this study was to assess clinical MS disease activity, surrogate disease markers on MRI, immunologic parameters in peripheral blood and CSF, as well as safety in patients with MS after discontinuation of natalizumab therapy.
Methods: This study is a longitudinal and serial cross-sectional assessment, in which 23 patients who were treated with natalizumab in the context of two phase III clinical trials were originally enrolled. A subgroup of patients was followed over 14 months. The annual relapse rate, neurologic disease progression assessed by the Expanded Disability Status Scale, disease surrogate markers on MRI, cellular and humoral immune markers in peripheral blood and CSF, and adverse events of the drug were monitored.
Results: With regard to clinical disease activity, neuroimaging, and immune responses, the majority of patients in our cohort were stable. Decreased lymphocyte cell numbers and altered cell ratios returned to normal 14 months after cessation of natalizumab. No infectious complications were observed.
Conclusion: This is the first long-term follow-up of patients who discontinued natalizumab. We did not observe a clinical, radiographic, or immunologic rebound phenomenon after discontinuation of natalizumab therapy.
Abbreviations: EDSS = Expanded Disability Status Scale; FDA = Food and Drug Administration; MS = multiple sclerosis; OCB = oligoclonal band; PML = progressive multifocal leukoencephalopathy; VLA-4 = very late activation antigen 4; WBC = white blood cell.
Supplemental data at www.neurology.org
Editorial, page 392
e-Pub ahead of print on November 5, 2008, at www.neurology.org.
*These authors contributed equally to this work.
Dr. Stüve was supported by a start-up grant from the Dallas VA Research Corporation, a New Investigator Award grant from VISN 17, Department of Veterans Affairs, a merit award from the Department of Veterans Affairs, research grants from National Multiple Sclerosis Society (NMSS; RG3427A8/T and RG2969B7/T), and a grant from the Viragh Foundation. Supported by grants (NS 37513 and NS 44250) from the NIH and NMSS grant RG 2969-B-7 to Dr. Racke. Drs. Hemmer and Cepok were supported by grants from the Deutsche Forschungsgemeinschaft (He 2386/4-2). Supported in part by the Adult AIDS Clinical Trials Group funded by the National Institute of Allergy and Infectious Diseases (AI 38858 and AI 27664). Dr. Monson was supported by a grant from the NIH (NS 40993).
Disclosure: The authors report no disclosures. While the AFFIRM monotherapy trial and the SENTINEL add-on trial with interferon beta-1a (Avonex) were sponsored by Biogen-Idec Inc. and Elan Corp., the manufacturers of natalizumab, the work presented in this study was not.
Received October 31, 2007. Accepted in final form June 9, 2008.
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