Abstracts & Commentary
Sources: Berger T, et al. Antimyelin antibodies as a predictor of clinically definite multiple sclerosis after a first demyelinating event. N Engl J Med. 2003;349:139-145; Wandinger KP, et al. TNF-related apoptosis inducing ligand (TRAIL) as a potential response marker for interferon-beta treatment in multiple sclerosis. Lancet. 2003;361:2036-2043.
Berger and colleagues studied 103 patients presenting with a clinically isolated demyelinating syndrome, positive findings on brain MRI, and positive oligoclonal bands in the CSF. Baseline serum samples were collected to test for antimyelin oligodendrocyte glycoprotein (MOG) and antimyelin basic protein (MBP) antibodies (Abs). Brain lesions on MRI were quantified. Patients were treated with 3-5 days of IV methylprednisolone, 1000 mg/d, and then monitored every 3 months for clinical relapse or disease progression for at least 12 months. Berger et al found that only 9 of the 39 antibody seronegative patients (23%) had a relapse, with a mean time of 45.1 ± 13.7 months. In contrast, 21 of 22 patients (95%) with antibodies against both MOG and MBP had a relapse within a mean of 7.5 ± 4.4 months (P < .001). The adjusted hazard ratio for the development of clinically definite MS was 76.5 (95% confidence interval, 20.6 to 284.6) for seropositive patients compared to seronegative patients. The conventional markers of disease activity, including brain MRI T2 lesions and gadolinium positive lesions on T1 and elevated CSF IgG index, were also highest in the seropositive patients.
Wandinger and associates examined the gene expression of TRAIL, which is typically upregulated with exposure to interferon-beta, in the peripheral blood lymphocytes of 82 multiple sclerosis patients. In a group of 62 patients, 20 were classified as first-year responders since they did not have relapses on treatment with interferon-beta; 19 were first-year nonresponders; 23 developed neutralizing antibodies to interferon-beta. A second group with MRI characterization consisted of 11 patients on interferon-beta and 9 untreated patients. Concentration of soluble TRAIL were also measured by ELISA in serum before and after treatment in 49 patients (29 responders, 20 nonresponders). Patients responding to interferon-beta could be distinguished from nonresponders by the early and sustained induction of TRAIL (P < .0001). After the development of neutralizing antibodies, the initial upregulation of TRAIL was subsequently abrogated. Raised serum levels of soluble TRAIL before treatment allowed prediction of the treatment response in the first year.
Commentary
Clinicians commonly encounter patients presenting with clinically isolated syndromes as a first demyelinating event. Several previous studies have shown that baseline disease activity on brain MRI and elevated IgG parameters in the CSF are reliable prognostic indicators for future disease activity of multiple sclerosis. Berger et al state that the presence of both anti-MBP and anti-MOG Abs are also a sensitive predictor for future conversion to "clinically definite" multiple sclerosis. Several criticisms must be leveled, however, with the methodological design of this study. The whole basis of the assay, a Western immunoblot method for MBP and MOG, is a subjective, qualitative interpretation of a "positive" result. A straight serum dilution was used rather than normalizing for a specific amount of serum IgG, which can lead to a higher incidence of nonspecific positives. Further, no controls were incorporated in the immunoassay for nonrelevant antigens (such as tetanus toxoid) that would be measuring the degree of IgG background activity. For unclear reasons, Berger et al excluded 9 patients in their study with CSF who were negative for oligoclonal bands, since it is particularly in that clinical subset that a sensitive prognostic marker would be desirable. Given the apparent sensitivity of this serum assay as an indicator of future disease activity, it is surprising that previous studies on disease pathogenesis in multiple sclerosis have failed to show a clear role for B-cell and T-cell responses against those myelin antigens, and therapeutic attempts at plasmapheresis have been unremarkable.
Given the widespread use of interferon-beta and sometimes variable response to treatment, this study by Wandinger et al may provide a helpful marker of disease response to drug therapy. TRAIL, which is selectively upregulated by interferon-beta, but not other type-I interferons, has potent anti-inflammatory properties at the T-cell level. Only those patients who had a defined induction of TRAIL gene expression appeared to derive the clinical benefit of interferon-beta. This assay might help guide the use of immunomodulatory therapy in multiple sclerosis. — Brian R. Apatoff, MD, PhD, Associate Professor of Neurology, New York Presbyterian Hospital-Cornell Campus, Assistant Editor, Neurology Alert.
Berger and colleagues studied 103 patients presenting with a clinically isolated demyelinating syndrome, positive findings on brain MRI, and positive oligoclonal bands in the CSF.
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