Ludwig Kappos

Diagnostic criteria for multiple sclerosis: 2010 Revisions to the McDonald criteria

New evidence and consensus has led to further revision of the McDonald Criteria for diagnosis of multiple sclerosis. The use of imaging for demonstration of dissemination of central nervous system lesions in space and time has been simplified, and in some circumstances dissemination in space and time can be established by a single scan. These revisions simplify the Criteria, preserve their diagnostic sensitivity and specificity, address their applicability across populations, and may allow earlier diagnosis and more uniform and widespread use. Ann Neurol 2011

A Placebo-Controlled Trial of Oral Fingolimod in Relapsing Multiple Sclerosis

BACKGROUND Oral fingolimod, a sphingosine-1-phosphate-receptor modulator that prevents the egress of lymphocytes from lymph nodes, significantly improved relapse rates and end points measured on magnetic resonance imaging (MRI), as compared with either placebo or intramuscular interferon beta-1a, in phase 2 and 3 studies of multiple sclerosis. METHODS In our 24-month, double-blind, randomized study, we enrolled patients who had relapsing-remitting multiple sclerosis, were 18 to 55 years of age, had a score of 0 to 5.5 on the Expanded Disability Status Scale (which ranges from 0 to 10, with higher scores indicating greater disability), and had had one or more relapses in the previous year or two or more in the previous 2 years. Patients received oral fingolimod at a dose of 0.5 mg or 1.25 mg daily or placebo. End points included the annualized relapse rate (the primary end point) and the time to disability progression (a secondary end point). RESULTS A total of 1033 of the 1272 patients (81.2%) completed the study. The annualized relapse rate was 0.18 with 0.5 mg of fingolimod, 0.16 with 1.25 mg of fingolimod, and 0.40 with placebo (P<0.001 for either dose vs. placebo). Fingolimod at doses of 0.5 mg and 1.25 mg significantly reduced the risk of disability progression over the 24-month period (hazard ratio, 0.70 and 0.68, respectively; P=0.02 vs. placebo, for both comparisons). The cumulative probability of disability progression (confirmed after 3 months) was 17.7% with 0.5 mg of fingolimod, 16.6% with 1.25 mg of fingolimod, and 24.1% with placebo. Both fingolimod doses were superior to placebo with regard to MRI-related measures (number of new or enlarged lesions on T(2)-weighted images, gadolinium-enhancing lesions, and brain-volume loss; P<0.001 for all comparisons at 24 months). Causes of study discontinuation and adverse events related to fingolimod included bradycardia and atrioventricular conduction block at the time of fingolimod initiation, macular edema, elevated liver-enzyme levels, and mild hypertension. CONCLUSIONS As compared with placebo, both doses of oral fingolimod improved the relapse rate, the risk of disability progression, and end points on MRI. These benefits will need to be weighed against possible long-term risks. (ClinicalTrials.gov number, NCT00289978.)

Oral Fingolimod or Intramuscular Interferon for Relapsing Multiple Sclerosis

BACKGROUND Fingolimod (FTY720), a sphingosine-1-phosphate-receptor modulator that prevents lymphocyte egress from lymph nodes, showed clinical efficacy and improvement on imaging in a phase 2 study involving patients with multiple sclerosis. METHODS In this 12-month, double-blind, double-dummy study, we randomly assigned 1292 patients with relapsing-remitting multiple sclerosis who had a recent history of at least one relapse to receive either oral fingolimod at a daily dose of either 1.25 or 0.5 mg or intramuscular interferon beta-1a (an established therapy for multiple sclerosis) at a weekly dose of 30 microg. The primary end point was the annualized relapse rate. Key secondary end points were the number of new or enlarged lesions on T(2)-weighted magnetic resonance imaging (MRI) scans at 12 months and progression of disability that was sustained for at least 3 months. RESULTS A total of 1153 patients (89%) completed the study. The annualized relapse rate was significantly lower in both groups receiving fingolimod--0.20 (95% confidence interval [CI], 0.16 to 0.26) in the 1.25-mg group and 0.16 (95% CI, 0.12 to 0.21) in the 0.5-mg group--than in the interferon group (0.33; 95% CI, 0.26 to 0.42; P<0.001 for both comparisons). MRI findings supported the primary results. No significant differences were seen among the study groups with respect to progression of disability. Two fatal infections occurred in the group that received the 1.25-mg dose of fingolimod: disseminated primary varicella zoster and herpes simplex encephalitis. Other adverse events among patients receiving fingolimod were nonfatal herpesvirus infections, bradycardia and atrioventricular block, hypertension, macular edema, skin cancer, and elevated liver-enzyme levels. CONCLUSIONS This trial showed the superior efficacy of oral fingolimod with respect to relapse rates and MRI outcomes in patients with multiple sclerosis, as compared with intramuscular interferon beta-1a. Longer studies are needed to assess the safety and efficacy of treatment beyond 1 year. (ClinicalTrials.gov number, NCT00340834.)

Placebo-controlled multicentre randomised trial of interferon β-1b in treatment of secondary progressive multiple sclerosis

Summary Background The beneficial effects of interferon β have only been shown for patients in the relapsing-remitting phase of multiple sclerosis (MS). The role of interferon β in the treatment of patients who are in the secondary progressive phase of the disease (SP-MS), and for whom no effective drug treatment is available, has not been assessed. Methods In this multicentre, double-masked, randomised, placebo-controlled trial, outpatients with SP-MS having scores of 3·0–6·5 on the Expanded Disability Status Scale (EDSS) received either 8 million IU interferon β-1b every other day subcutaneously, or placebo, for up to 3 years. The primary outcome was the time to confirmed progression in disability as measured by a 1·0 point increase on the EDSS, sustained for at least 3 months, or a 0·5 point increase if the baseline EDSS was 6·0 or 6·5. A prospectively planned interim analysis of safety and efficacy of the intention-to-treat population was done after all patients had been in the study for at least 2 years. Findings 358 patients with SP-MS were allocated placebo and 360 were allocated interferon β-1b; 57 patients (31 placebo, 26 interferon β-1b) were lost to follow-up. There was a highly significant difference in time to confirmed progression of disability in favour of interferon β-1b (p=0·0008). Interferon β-1b delayed progression for 9–12 months in a study period of 2–3 years. The odds ratio for confirmed progression was 0·65 (95% Cl 0·52–0·83). This beneficial effect was seen in patients with superimposed relapses and in patients who had only progressive deterioration without relapses. Positive results were also obtained regarding time to becoming wheelchair-bound, relapse rate and severity, number of steroid treatments and hospital admissions, as well as on magnetic resonance imaging variables. The drug was safe and side effects were in line with previous experience with interferon β-1b. The study was stopped after the interim results gave clear evidence of efficacy. Interpretation Treatment with interferon β-1b delays sustained neurological deterioration in patients with SP-MS. Interferon β-1b is the first treatment to show a therapeutic effect in patients with SP-MS.

Defining the clinical course of multiple sclerosis The 2013 revisions

Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) are important for communication, prognostication, design and recruitment of clinical trials, and treatment decision-making. Standardized descriptions published in 1996 based on a survey of international MS experts provided purely clinical phenotypes based on data and consensus at that time, but imaging and biological correlates were lacking. Increased understanding of MS and its pathology, coupled with general concern that the original descriptors may not adequately reflect more recently identified clinical aspects of the disease, prompted a re-examination of MS disease phenotypes by the International Advisory Committee on Clinical Trials of MS. While imaging and biological markers that might provide objective criteria for separating clinical phenotypes are lacking, we propose refined descriptors that include consideration of disease activity (based on clinical relapse rate and imaging findings) and disease progression. Strategies for future research to better define phenotypes are also outlined.

Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci

We report the results of a meta-analysis of genome-wide association scans for multiple sclerosis (MS) susceptibility that includes 2,624 subjects with MS and 7,220 control subjects. Replication in an independent set of 2,215 subjects with MS and 2,116 control subjects validates new MS susceptibility loci at TNFRSF1A (combined P = 1.59 × 10−11), IRF8 (P = 3.73 × 10−9) and CD6 (P = 3.79 × 10−9). TNFRSF1A harbors two independent susceptibility alleles: rs1800693 is a common variant with modest effect (odds ratio = 1.2), whereas rs4149584 is a nonsynonymous coding polymorphism of low frequency but with stronger effect (allele frequency = 0.02; odds ratio = 1.6). We also report that the susceptibility allele near IRF8, which encodes a transcription factor known to function in type I interferon signaling, is associated with higher mRNA expression of interferon-response pathway genes in subjects with MS.

Randomized Trial of Oral Teriflunomide for Relapsing Multiple Sclerosis

BACKGROUND Teriflunomide is a new oral disease-modifying therapy for relapsing forms of multiple sclerosis. METHODS We concluded a randomized trial involving 1088 patients with multiple sclerosis, 18 to 55 years of age, with a score of 0 to 5.5 on the Expanded Disability Status Scale and at least one relapse in the previous year or at least two relapses in the previous 2 years. Patients were randomly assigned (in a 1:1:1 ratio) to placebo, 7 mg of teriflunomide, or 14 mg of teriflunomide once daily for 108 weeks. The primary end point was the annualized relapse rate, and the key secondary end point was confirmed progression of disability for at least 12 weeks. RESULTS Teriflunomide reduced the annualized relapse rate (0.54 for placebo vs. 0.37 for teriflunomide at either 7 or 14 mg), with relative risk reductions of 31.2% and 31.5%, respectively (P<0.001 for both comparisons with placebo). The proportion of patients with confirmed disability progression was 27.3% with placebo, 21.7% with teriflunomide at 7 mg (P=0.08), and 20.2% with teriflunomide at 14 mg (P=0.03). Both teriflunomide doses were superior to placebo on a range of end points measured by magnetic resonance imaging (MRI). Diarrhea, nausea, and hair thinning were more common with teriflunomide than with placebo. The incidence of elevated alanine aminotransferase levels (≥1 times the upper limit of the normal range) was higher with teriflunomide at 7 mg and 14 mg (54.0% and 57.3%, respectively) than with placebo (35.9%); the incidence of levels that were at least 3 times the upper limit of the normal range was similar in the lower- and higher-dose teriflunomide groups and the placebo group (6.3%, 6.7%, and 6.7%, respectively). Serious infections were reported in 1.6%, 2.5%, and 2.2% of patients in the three groups, respectively. No deaths occurred. CONCLUSIONS Teriflunomide significantly reduced relapse rates, disability progression (at the higher dose), and MRI evidence of disease activity, as compared with placebo. (Funded by Sanofi-Aventis; TEMSO ClinicalTrials.gov number, NCT00134563.).

Induction of a non-encephalitogenic type 2 T helper-cell autoimmune response in multiple sclerosis after administration of an altered peptide ligand in a placebo- controlled, randomized phase II trial

In this ‘double-blind’, randomized, placebo-controlled phase II trial, we compared an altered peptide ligand of myelin basic protein with placebo, evaluating their safety and influence on magnetic resonance imaging in relapsing–remitting multiple sclerosis. A safety board suspended the trial because of hypersensitivity reactions in 9% of the patients. There were no increases in either clinical relapses or in new enhancing lesions in any patient, even those with hypersensitivity reactions. Secondary analysis of those patients completing the study showed that the volume and number of enhancing lesions were reduced at a dose of 5 mg. There was also a regulatory type 2 T helper-cell response to altered peptide ligand that cross-reacted with the native peptide.

Predictive value of gadolinium-enhanced magnetic resonance imaging for relapse rate and changes in disability or impairment in multiple sclerosis: a meta-analysis

BACKGROUND Reliable prognostic factors are lacking for multiple sclerosis (MS). Gadolinium enhancement in magnetic resonance imaging (MRI) of the brain detects with high sensitivity disturbance of the blood-brain barrier, an early event in the development of inflammatory lesions in MS. To investigate the prognostic value of gadolinium-enhanced MRI, we did a meta-analysis of longitudinal MRI studies. METHODS From the members of MAGNIMS (European Magnetic Resonance Network in Multiple Sclerosis) and additional centres in the USA, we collected data from five natural-course studies and four placebo groups of clinical trials completed between 1992 and 1995. We included a total of 307 patients, 237 with relapsing disease course and 70 with secondary progressive disease course. We investigated by regression analysis the relation between initial count of gadolinium-enhancing lesions and subsequent worsening of disability or impairment as measured by the expanded disability status scale (EDSS) and relapse rate. FINDINGS The relapse rate in the first year was predicted with moderate ability by the mean number of gadolinium-enhancing lesions in monthly scans during the first 6 months (relative risk per five lesions 1.13, p=0.023). The predictive value of the number of gadolinium-enhancing lesions in one baseline scan was less strong. The best predictor for relapse rate was the variation (SD) of lesion counts in the first six monthly scans which allowed an estimate of relapse in the first year (relative risk 1.2, p=0.020) and in the second year (risk ratio=1.59, p=0.010). Neither the initial scan nor monthly scans over six months were predictive of change in the EDSS in the subsequent 12 months or 24 months. The mean of gadolinium-enhancing-lesion counts in the first six monthly scans was weakly predictive of EDSS change after 1 year (odds ratio=1.34, p=0.082) and 2 years (odds ratio=1.65, p=0.049). INTERPRETATION Although disturbance of the blood-brain barrier as shown by gadolinium enhancement in MRI is a predictor of the occurrence of relapses, it is not a strong predictor of the development of cumulative impairment or disability. This discrepancy supports the idea that variant pathogenetic mechanisms are operative in the occurrence of relapses and in the development of long-term disability in MS.

Differential diagnosis of suspected multiple sclerosis: a consensus approach

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.