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Background Although the concept that an initial course of immune-suppression facilitates subsequent immune-modulation (such as Th1 to Th2 deviation) is attractive for several autoimmune diseases, such a mechanism for serial-combination therapy has never been formally demonstrated. Recently, brief mitoxantrone induction-chemotherapy followed by immune-modulation with glatiramer acetate (GA) was significantly more effective at reducing multiple sclerosis disease activity than with GA alone. Objective To examine whether the benefit of initial immune suppression with mitoxantrone before GA treatment is associated with more efficient immune modulation. Methods IgG1/IgG4 GA-reactive antibody profiles, previously established as markers of GA-induced Th2 immune-deviation, were prospectively measured in vivo in patients treated with GA alone or with mitoxantrone induction therapy followed by GA. Results Significant and sustained increase in IgG4 antibodies (and the anticipated reversal of the IgG1/IgG4 ratio) was seen in patients treated with GA alone. Combination therapy resulted in lesser IgG4 induction (and no reversal of IgG1/IgG4 ratio). Thus, the enhanced efficacy of mitoxantrone--GA combination regimen was associated with decreased, rather than increased, efficiency of shifting the GA-reactive IgG1/IgG4 antibody profile. Conclusion These results provide important insights into mechanisms of combination therapy and therapeutic strategies for autoimmune diseases. [ABSTRACT FROM AUTHOR]

Background There is no specific serum-based biomarker for the diagnosis or prognosis of relapsing-remitting multiple sclerosis (RRMS). Objective We investigated whether levels of IgM antibodies to Glc(a1,4)Glc(a) (GAGA4) or to a panel of four glucose-based glycans could differentiate MS from other neurological diseases (OND) or predict risk of early relapse following first presentation (FP) of RRMS. Methods Retrospective analysis of 440 sera samples of three cohorts: A) FP-RRMS (n = 44), OND (n = 44); B) FP-RRMS (n = 167), OND (n = 85); and C) FP (n = 100). Anti-GAGA4 IgM levels were measured by enzyme immunoassay in cohort-A and cohort-B. Cohort-C IgM antibodies to glucose-based glycan panel were measured by immunofluorescence. Results FP-RRMS had higher levels of anti-GAGA4 IgM than OND patients (cohort-A, P = 0.01; cohort-B, P = 0.0001). Sensitivity and specificity were 27% and 97% for cohort-A; and 26% and 90% for cohort-B, respectively. In cohort-C, 58 patients experienced early relapse (<24 months), 31 had late relapse (≥24 months), and 11 did not experience second attack during follow-up. Kaplan-Meier curves demonstrated decrease in time to next relapse for patients positive for the antibody panel (P = 0.02, log rank). Conclusions Serum anti-GAGA4 IgM discerns FP-RRMS patients from OND patients. Higher levels of serum anti-α-glucose IgM in FP patients predict imminent early relapse. [ABSTRACT FROM AUTHOR]

Background Early intervention with an effective disease-modifying drug (DMD) offers the best chance of limiting the inflammatory process that contributes to irreversible axonal damage correlating with disability in multiple sclerosis (MS). It is equally important to ascertain fairly quickly whether patients are responding positively to the choice of therapy to allow time for either a treatment modification or a switch in treatment, a process we termed "treatment optimization". Various treatment optimization recommendations (TOR) have been proposed to help decide when a patient taking an MS DMD might be showing a sub-optimal response. We have applied the clinical scheme proposed by the Canadian TOR to the patients involved in the Prevention of Relapses and disability by Interferon Subcutaneously in MS 4-year (PRISMS-4) study, who received interferon 3-1 a treatment for 4 years, with the TOR applied retrospectively at year 1. Objective The aim of this investigation was to examine whether these TOR were able to predict which patients would go on to develop disease breakthrough (defined as any relapses or disease progression), indicative of a sub-optimal response over the ensuing 3 years of study and therefore might have benefited from a change in treatment. Results We found 39% of patients receiving therapy experienced either a medium or high level of concern of breakthrough after a year of treatment, and 89% of these patients went on to develop further breakthrough over years 2-4. Although 67% of the 61% of patients having no or low-level concern after a year of treatment also experienced further disease breakthrough, it was significantly less than the medium or high group. Conclusion This study shows that the Canadian TOR may be an important tool for early treatment optimization. [ABSTRACT FROM AUTHOR]

Background and objectives Diagnosis of multiple sclerosis (MS) requires exclusion of diseases that could better explain the clinical and paraclinical findings. A systematic process for exclusion of alternative diagnoses has not been defined. An International Panel of MS experts developed consensus perspectives on MS differential diagnosis. Methods Using available literature and consensus, we developed guidelines for MS differential diagnosis, focusing on exclusion of potential MS mimics, diagnosis of common initial isolated clinical syndromes, and differentiating between MS and non-MS idiopathic inflammatory demyelinating diseases. Results We present recommendations for 1) clinical and paraclinical red flags suggesting alternative diagnoses to MS; 2) more precise definition of "clinically isolated syndromes" (CIS), often the first presentations of MS or its alternatives; 3) algorithms for diagnosis of three common CISs related to MS in the optic nerves, brainstem, and spinal cord; and 4) a classification scheme and diagnosis criteria for idiopathic inflammatory demyelinating disorders of the central nervous system. Conclusions Differential diagnosis leading to MS or alternatives is complex and a strong evidence base is lacking. Consensus-determined guidelines provide a practical path for diagnosis and will be useful for the non-MS specialist neurologist. Recommendations are made for future research to validate and support these guidelines. Guidance on the differential diagnosis process when MS is under consideration will enhance diagnostic accuracy and precision. [ABSTRACT FROM AUTHOR]

Forty relapsing multiple sclerosis patients with 1-15 gadolinium (Gd)-enhancing lesions on screening brain magnetic resonance imaging (MRI) and Expanded Disability Status Scale (EDSS) scores 0-6.5 were randomized to receive short-term induction therapy with mitoxantrone (three monthly 12 mg/m² infusions) followed by 12 months of daily glatiramer acetate (GA) therapy 20 mg/day subcutaneously for a total of 15 months (M-GA, n = 21) or daily GA 20 mg/day for 15 months (GA, n = 19). MRI scans were performed at months 6, 9, 12 and 15. The primary measure of outcome was the incidence of adverse events; secondary measures included number of Gd-enhanced lesions, confirmed relapses and EDSS changes. Except age, baseline demographic characteristics were well matched in both treatment arms. Both treatments were safe and well tolerated. M-GA induction produced an 89% greater reduction (relative risk (RR) = 0.11, 95% confidence interval (CI): 0.04-0.36, p = 0.0001) in the number of Gd-enhancing lesions at months 6 and 9 and a 70% reduction (RR = 0.30, 95% Ch 0.11-0.86, p = 0.0147) at months 12 and 15 versus GA alone. Mean relapse rates were 0.16 and 0.32 in the M-GA and GA groups, respectively. Short-term immunosuppression with mitoxantrone followed by daily GA for up to 15 months was found to be safe and effective, with an early and sustained decrease in MRI disease activity. [ABSTRACT FROM AUTHOR]

Background Recently, a clinical classification system was described to determine whether symptoms and signs of patients presenting with a first episode suggestive of multiple sclerosis (MS) indicate the presence of monofocal or multifocal disease. Objectives To evaluate the value of this new classification system by comparing the results with those of simultaneously obtained magnetic resonance imaging (MRI) scans. Methods The 487 patients, randomised in the BENEFIT study, were centrally assessed using the new system and classified as monofocal or multifocal, based on clinical information by two neurologists masked for the MRI results. MRI analyses were performed by expert readers masked for the clinical classification. Results Patients classified as multifocal had more T2 hyperintense (median: 21 versus 15.5) and more T1 hypo-intense lesions (median: 2 versus 1) than those classified as monofocal. Patients classified at the local site as having evidence of a single clinical lesion, but reclassified centrally as having a clinical multifocal central nervous system presentation, had more T2 lesions than monofocal patients. In addition, patients with a multifocal presentation more often fulfilled the MRI criteria for dissemination in space, as incorporated in the International Panel (IP) diagnostic criteria for MS. Conclusion These data provide justification for the recently proposed clinical classification system to be used in patients who present with a first episode suggestive of MS, in that ‘multifocal’, based on symptoms and signs, is associated with more lesions on MRI. [ABSTRACT FROM AUTHOR]

Background: Once weekly interferon β-1a for multiple sclerosis (OWIMS) demonstrated modest, but significant, magnetic resonance imaging (MRI) benefit of once-weekly (qw) interferon (IFN) β-1a at 48 weeks, but no significant effect on relapses. Objective: An OWIMS extension permitted assessment of longer-term efficacy/safety of qw IFN β-1a in relapsing-remitting multiple sclerosis (RRMS). Methods: Placebo patients were rerandomized to IFN β-1a, 22 or 44 mcg qw, for two additional 48-week intervals. Primary outcome was MRI lesion activity. Relapse rate and other MRI measures were secondary outcomes. Results: After three years, median (mean) T2 lesion count/patient/scan was 1.3 (2.6) for 44 mcg, 1.7 (3.3) for 22 mcg, 1.7 (3.4) for placebo/22 mcg, 2.0 (3.6) for placebo/44 mcg (all differences not significant). Annualized relapse rates were lowest for 44 mcg (0.77) versus other groups (0.83-0.86, not significant). Persistent neutralizing antibodies did not affect relapse rates, but MRI active lesions were increased in antibody-positive patients receiving 44 mcg compared to antibody negative patients. Conclusions: In RRMS, once weekly IFN β-1a, particularly 44 mcg, can induce a significant MRI, but not relapse, effect, compared with placebo. No significant dose effect was seen. In contrast to the significant effect observed with three-times-weekly dosing of subcutaneous IFN β-1a compared with placebo, this study confirms the lack of meaningful clinical benefit with once-weekly dosing. [ABSTRACT FROM AUTHOR]

Objective: To provide recommendations on the use of disease-modifying agents in the management of multiple sclerosis (MS) and to ensure that treatment will be available to those patients who may benefit. Methods: An initial draft of the consensus statement was prepared by the Steering Committee and amended in the light of written comments from a group of MS specialists. At a subsequent workshop, the wording of the consensus statement was discussed, modified if necessary, and the participants indicated their level of support using an electronic voting system. A new draft of the statement was then sent to a much larger group of international opinion leaders in MS for further comment. Results: A number of statements were agreed, which outline the criteria for consideration of disease-modifying therapy for MS and recommendations for treatment. Each statement was accepted completely, or with only minor reservations by 95% or more of those present at the workshop. Conclusions: Periodic reviews and modifications to the statement will be required, as new approaches to the treatment of MS and other therapeutic agents become available. [ABSTRACT FROM AUTHOR]

An abstract of the article "Validation of anti-GAGA4 IgM antibodies for predicting the development of relapsing-remitting MS after the first neurological event," by M. S. Freedman, J. Laks, N. Dotan, R. T. Altstock, A. Dukler and C. Sindic is presented.

The article offers a look whether autoantibodies that bind properly folded oligodendrocyte glycoprotein (MOG) are present in the serum and central nervous system (CNS) parenchyma of patients with multiple sclerosis (MS)and controls. Results showed that autoantibodies recognizing MOG are rarely present in the serum of patients with MS. Collectively, the data also demonstrated that autoantibodies recognizing folded MOG are present in the CNS parenchyma of patients.