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Show ORIGINAL CONTRIBUTION Absence of Neuromyelitis Optica IgG Antibody in an Active Relapsing-Remitting Multiple Sclerosis Population Craig H. Smith, MD, Emmanuelle Waubant, MD, PhD, and Annette Langer-Gould, MD, PhD Background: Neuromyelitis optica (NMO, Devic disease) had been defined clinically until a novel autoantibody directed against the aquaporin-4 chan-nel (NMO IgG antibody) was identified. Although previous studies have demonstrated that the NMO IgG antibody is not present in patients with multiple sclerosis (MS), these studies may have been biased by the inclusion of patients with inactive MS. We resolved to test for NMO antibody in a population of patients with active relapsing-remitting (RR) MS. Methods: A total of 130 patients with RRMS pre-viously enrolled in phase I (n = 26) and phase II (n - 104) trials of rituximab therapy were tested for serum NMO IgG antibody at the Mayo Clinic Neuroimmunology Laboratory by indirect immuno-fluorescence on a substrate of mouse central nervous system tissue. Serum samples were obtained at baseline before initiation of therapy. All patients had experienced at least one relapse in the year before study entry and had not received treatment with immunomodulatory agents for at least 2 months. Results: None of the 130 patients with active RRMS tested positive for NMO IgG antibody. Conclusions: Our findings indicate that anti-aquaporin- 4 immunoreactivity is unlikely to play a role in the pathogenesis of RRMS and support the results of previous studies suggesting that that the NMO IgG antibody is specific for NMO. Similar studies in a larger cohort will be necessary to fortify our conclusions. (J Neuro-Ophthalmol 2009;29:104-106) Neuromyelitis optica (NMO, Devic syndrome) is an inflammatory demyelinating disease that Genentech Corporation (CHS), South San Francisco, California; Department of Neurology (EW), University of California, San Francisco, California; and Department of Neurology (AL-G), Stanford University, Palo Alto, California. Address correspondence to Craig H. Smith, MD, 1507 42nd Avenue, East Seattle, WA 98112; E-mail: nwmsdoc@cs.com predominantly affects the optic nerves and spinal cord (1-4). NMO is rare and is frequently misdiagnosed as multiple sclerosis (MS), although it differs from MS in prognosis and response to treatment (3,5-9). Its distinct neuropathologic features, radiologic pattern, and fulminant clinical course suggest that it is a distinct disease (4,10). Indeed, a novel auto-antibody directed against the aqua-porin- 4 channel (NMO IgG antibody) was recently identified as a potential NMO diagnostic test (10,11). Although previous studies have demonstrated a high specificity of the NMO IgG antibody for NMO, these studies may have been biased by the inclusion of patients with MS with inactive disease. If the presence of NMO IgG antibody were an epiphenomenon of central nervous system (CNS) inflammation, some individuals with active relapsing MS might also test positively for the antibody. To further validate the specificity of the NMO IgG antibody, we have tested for its presence in a cohort of 130 patients with active relapsing-remitting (RR) MS previ-ously enrolled in two clinical trials. We have also explored whether the clinical diagnosis of NMO is adequate in excluding such patients from clinical trials of RRMS. METHODS Sera from 130 patients with RRMS, as defined by MacDonald criteria 1-4 (12), who were previously enrolled in phase I (n = 26) (13) and phase II (n = 104) (14) clinical trials were retrospectively tested for NMO IgG antibody. These trials were designed to evaluate the safety and efficacy of the anti-CD20 antibody rituximab in treating patients with active RRMS. Serum samples were obtained before rituximab therapy was initiated. Patients had experienced at least one relapse in the year before study entry and had not received treatment with immunomodulatory agents such as interferon and glatiramer acetate for at least 2 months. Exclusion criteria included NMO defined solely by clinical judgment according to published criteria (15). NMO IgG antibody was assayed in a masked fashion at the Mayo Clinic Neuroimmunology Laboratory by indirect immunofluorescence on a substrate of mouse central nervous system tissue (11). 104 J Neuro-Ophthalmol, Vol. 29, No. 2, 2009 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Neuromyelitis Optica Antibody J Neuro-Ophthalmol, Vol. 29, No. 2, 2009 RESULTS Patient characteristics in phase I and phase II trials are provided in Table 1. Clinical characteristics of previous exacerbations were not available for review. None of the 130 patients with active RRMS tested positive for NMO IgG antibody. DISCUSSION We found that in two active RRMS populations previously enrolled in clinical trials, anti-aquaporin-4 immunoreactivity was undetectable in serum. It is thus unlikely that this antibody plays a role in the pathogenesis of RRMS or is an epiphenomenon of MS disease activity. Multiple independent investigations have shown a wide range of sensitivity (58%-73%) but a high specificity (>90%) of the NMO IgG antibody for the diagnosis of NMO (2,15). Our results further confirm its high specificity and therefore support the notion that NMO is a distinct entity and suggest that relying on clinical judgment to exclude patients with NMO from RRMS clinical trials appears to be valid. The revised 2006 diagnostic criteria for NMO (15) remove the stipulation that NMO be limited to the optic nerves and spinal cord and emphasize NMO IgG seropos-itivity and the specificity of longitudinally extensive spinal cord lesions. Traditionally considered a severe variant of MS, NMO appears to be easily distinguishable when the defining criteria include the presence of this autoantibody. As disease-modifying treatments for NMO may be different from those for MS, early recognition of NMO is important for prevention of serious neurologic deficits (5-9). 105 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. J Neuro-Ophthalmol, Vol. 29, No. 2, 2009 Smith et al Confirming the differences between MS and NMO also has implications for designing and interpreting randomized controlled trials (15,16). This is the first report of an NMO IgG antibody assay in patients in an MS clinical trial. Considering that diagnosis of NMO is relatively infrequent (0.3%) in patients with clinically isolated syndromes suggestive of MS (17), we were unlikely to detect NMO antibody in our sample of only 130 patients. Our study thus has two main limitations. First, the small sample size decreases the chance of erroneous enrollment of NMO patients. Second, clinical characteristics of relapses were not available; thus, we are unable to comment on possible inclusion of opticospinal forms of MS. However, the Asians in our cohort represented less than 1% of the total population (Table 1). Larger, more well-defined RRMS cohorts will have to be studied before one can be more certain that NMO IgG is not an epiphenomenon of active demyelination. Acknowledgments Drs. Emmanuelle Waubant and Annette Langer- Gould had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. We thank Dr. Christopher Dant of Genentech for his assistance in the preparation of this article. REFERENCES Jacob A, Matiello M, Wingerchuk DM, et al. Neuromyelitis optica: changing concepts. J Neuroimmunol 2007;187:126-38. Jarius S, Franciotta D, Bergamaschi R, et al. NMO-IgG in the diagnosis of neuromyelitis optica. Neurology 2007;68:1076-7. 3. Matiello M, Jacob A, Wingerchuk DM, et al. Neuromyelitis optica. Curr Opin Neurol 2007;20:255-60. 4. Weinshenker BG, Wingerchuk DM. Neuromyelitis optica: clinical syndrome and the NMO-IgG autoantibody marker. Curr Top Microbiol Immunol 2008;318:343-56. 5. 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Neuromyelitis optica diagnosis in clinically isolated syndromes suggestive of multiple sclerosis. Neurology 2006;66:1568-70. 106 © 2009 Lippincott Williams & Wilkins Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. |
