Hans-Peter Hartung

Recommended diagnostic criteria for multiple sclerosis: Guidelines from the International Panel on the Diagnosis of Multiple Sclerosis

The International Panel on MS Diagnosis presents revised diagnostic criteria for multiple sclerosis (MS). The focus remains on the objective demonstration of dissemination of lesions in both time and space. Magnetic resonance imaging is integrated with clinical and other paraclinical diagnostic methods. The revised criteria facilitate the diagnosis of MS in patients with a variety of presentations, including “monosymptomatic” disease suggestive of MS, disease with a typical relapsing‐remitting course, and disease with insidious progression, without clear attacks and remissions. Previously used terms such as “clinically definite” and “probable MS” are no longer recommended. The outcome of a diagnostic evaluation is either MS, “possible MS” (for those at risk for MS, but for whom diagnostic evaluation is equivocal), or “not MS.”

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.)

Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study

BACKGROUND Interferon beta reduces activity in multiple sclerosis as measured clinically and by magnetic resonance imaging (MRI). We assessed the effect of interferon beta-1a on the occurrence of relapses in patients after first presentation with neurological events, who are at high risk of conversion to clinically definite multiple sclerosis. METHODS Eligible patients had had a first episode of neurological dysfunction suggesting multiple sclerosis within the previous 3 months and had strongly suggestive brain MRI findings. Patients were randomly assigned interferon beta-1a 22 microg or placebo subcutaneously once weekly for 2 years. Neurological and clinical assessments were done every 6 months and brain MRI every 12 months. Analyses excluded one patient assigned placebo who received no study injections. FINDINGS 241 (78%) of 308 randomised patients received study treatment for 2 years; 278 (90%) remained in the study until termination. 57 (85%) of 67 who stopped therapy did so after conversion to clinically definite multiple sclerosis. Fewer patients developed clinically definite multiple sclerosis in the interferon group than in the placebo group (52/154 [34%] vs 69/154 [45%]; p=0.047). The time at which 30% of patients had converted to clinically definite multiple sclerosis was 569 days in the interferon group and 252 in the placebo group (p=0.034). The annual relapse rates were 0.33 and 0.43 (p=0.045). The number of new T2-weighted MRI lesions and the increase in lesion burden were significantly lower with active treatment. INTERPRETATION Interferon beta-1a treatment at an early stage of multiple sclerosis had significant positive effects on clinical and MRI outcomes.

Chemotherapy-induced peripheral neuropathy

Abstract The induction of peripheral neuropathy is a common factor in limiting therapy with chemotherapeutic drugs. Little is known about the mechanisms responsible for the development of neuropathy. Depending on the substance used, a pure sensory and painful neuropathy (with cisplatin, oxaliplatin, carboplatin) or a mixed sensorimotor neuropathy with or without involvement of the autonomic nervous system (with vincristine, taxol, suramin) can ensue. Neurotoxicity depends on the total cumulative dose and the type of drug used. In individual cases neuropathy can evolve even after a single drug application. A general predisposition for developing a chemotherapy-induced neuropathy has been observed in nerves previously damaged by diabetes mellitus, alcohol or inherited neuropathy. The recovery from symptoms is often incomplete and a long period of regeneration is required to restore function. Up to now, no drug is available to reliably prevent or cure chemotherapy-induced neuropathy.

Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial

BACKGROUND Treatment options for patients with secondary progressive multiple sclerosis are few. Encouraging results in open-label studies prompted this randomised trial of mitoxantrone in such patients. METHODS 194 patients with worsening relapsing-remitting or secondary progressive multiple sclerosis were assigned placebo or mitoxantrone (5 mg/m(2) [exploratory group] or 12 mg/m(2) intravenously) every 3 months for 24 months. Clinical assessments were made every 3 months for 24 months. The primary endpoint was a multivariate analysis of five clinical measures. Analyses of mitoxantrone 12 mg/m(2) versus placebo were based on patients who received at least one dose and returned for at least one assessment of efficacy. FINDINGS Of 194 patients enrolled, 188 were able to be assessed at 24 months. There were no drug-related serious adverse events or evidence of clinically significant cardiac dysfunction. At 24 months, the mitoxantrone group experienced benefits compared with the placebo group for the primary outcome (difference 0.30 [95% CI 0.17-0.44]; p<0.0001) and the preplanned univariate analyses of those measures: change in expanded disability status scale (0.24 [0.04-0.44]; p=0.0194), change in ambulation index (0.21 [0.02-0.40]; p=0.0306), adjusted total number of treated relapses (0.38 [0.18-0.59]; p=0.0002), time to first treated relapse (0.44 [0.20-0.69]; p=0.0004), and change in standardised neurological status (0.23 [0.03-0.43]; p=0.0268). INTERPRETATION Mitoxantrone 12 mg/m(2) was generally well tolerated and reduced progression of disability and clinical exacerbations. Further studies are needed to identify the patients with these forms of multiple sclerosis who are most likely to respond to therapy, the best treatment protocols, and the frequency of long-term drug-related side-effects.

Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial.

BACKGROUND The anti-CD52 monoclonal antibody alemtuzumab reduces disease activity in previously untreated patients with relapsing-remitting multiple sclerosis. We aimed to assess efficacy and safety of alemtuzumab compared with interferon beta 1a in patients who have relapsed despite first-line treatment. METHODS In our 2 year, rater-masked, randomised controlled phase 3 trial, we enrolled adults aged 18-55 years with relapsing-remitting multiple sclerosis and at least one relapse on interferon beta or glatiramer. Eligible participants were randomly allocated in a 1:2:2 ratio by an interactive voice response system, stratified by site, to receive subcutaneous interferon beta 1a 44 μg, intravenous alemtuzumab 12 mg per day, or intravenous alemtuzumab 24 mg per day. Interferon beta 1a was given three-times per week and alemtuzumab was given once per day for 5 days at baseline and for 3 days at 12 months. The 24 mg per day group was discontinued to aid recruitment, but data are included for safety assessments. Coprimary endpoints were relapse rate and time to 6 month sustained accumulation of disability, comparing alemtuzumab 12 mg and interferon beta 1a in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00548405. FINDINGS 202 (87%) of 231 patients randomly allocated interferon beta 1a and 426 (98%) of 436 patients randomly allocated alemtuzumab 12 mg were included in the primary analyses. 104 (51%) patients in the interferon beta 1a group relapsed (201 events) compared with 147 (35%) patients in the alemtuzumab group (236 events; rate ratio 0·51 [95% CI 0·39-0·65]; p<0·0001), corresponding to a 49·4% improvement with alemtuzumab. 94 (47%) patients in the interferon beta 1a group were relapse-free at 2 years compared with 278 (65%) patients in the alemtuzumab group (p<0·0001). 40 (20%) patients in the interferon beta 1a group had sustained accumulation of disability compared with 54 (13%) in the alemtuzumab group (hazard ratio 0·58 [95% CI 0·38-0·87]; p=0·008), corresponding to a 42% improvement in the alemtuzumab group. For 435 patients allocated alemtuzumab 12 mg, 393 (90%) had infusion-associated reactions, 334 (77%) had infections (compared with 134 [66%] of 202 patients in the interferon beta 1a group) that were mostly mild-moderate with none fatal, 69 (16%) had thyroid disorders, and three (1%) had immune thrombocytopenia. INTERPRETATION For patients with first-line treatment-refractory relapsing-remitting multiple sclerosis, alemtuzumab could be used to reduce relapse rates and sustained accumulation of disability. Suitable risk management strategies allow for early identification of alemtuzumabs main adverse effect of secondary autoimmunity. FUNDING Genzyme (Sanofi) and Bayer Schering Pharma.

Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial

BACKGROUND The anti-CD52 monoclonal antibody alemtuzumab reduced disease activity in a phase 2 trial of previously untreated patients with relapsing-remitting multiple sclerosis. We aimed to assess efficacy and safety of first-line alemtuzumab compared with interferon beta 1a in a phase 3 trial. METHODS In our 2 year, rater-masked, randomised controlled phase 3 trial, we enrolled adults aged 18-50 years with previously untreated relapsing-remitting multiple sclerosis. Eligible participants were randomly allocated in a 2:1 ratio by an interactive voice response system, stratified by site, to receive intravenous alemtuzumab 12 mg per day or subcutaneous interferon beta 1a 44 μg. Interferon beta 1a was given three-times per week and alemtuzumab was given once per day for 5 days at baseline and once per day for 3 days at 12 months. Coprimary endpoints were relapse rate and time to 6 month sustained accumulation of disability in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00530348. FINDINGS 187 (96%) of 195 patients randomly allocated interferon beta 1a and 376 (97%) of 386 patients randomly allocated alemtuzumab were included in the primary analyses. 75 (40%) patients in the interferon beta 1a group relapsed (122 events) compared with 82 (22%) patients in the alemtuzumab group (119 events; rate ratio 0·45 [95% CI 0·32-0·63]; p<0.0001), corresponding to a 54·9% improvement with alemtuzumab. Based on Kaplan-Meier estimates, 59% of patients in the interferon beta 1a group were relapse-free at 2 years compared with 78% of patients in the alemtuzumab group (p<0·0001). 20 (11%) of patients in the interferon beta 1a group had sustained accumulation of disability compared with 30 (8%) in the alemtuzumab group (hazard ratio 0·70 [95% CI 0·40-1·23]; p=0·22). 338 (90%) of patients in the alemtuzumab group had infusion-associated reactions; 12 (3%) of which were regarded as serious. Infections, predominantly of mild or moderate severity, occurred in 253 (67%) patients treated with alemtuzumab versus 85 (45%) patients treated with interferon beta 1a. 62 (16%) patients treated with alemtuzumab had herpes infections (predominantly cutaneous) compared with three (2%) patients treated with interferon beta 1a. By 24 months, 68 (18%) patients in the alemtuzumab group had thyroid-associated adverse events compared with 12 (6%) in the interferon beta 1a group, and three (1%) had immune thrombocytopenia compared with none in the interferon beta 1a group. Two patients in the alemtuzumab group developed thyroid papillary carcinoma. INTERPRETATION Alemtuzumabs consistent safety profile and benefit in terms of reductions of relapse support its use for patients with previously untreated relapsing-remitting multiple sclerosis; however, benefit in terms of disability endpoints noted in previous trials was not observed here. FUNDING Genzyme (Sanofi) and Bayer Schering Pharma.

New concepts in the immunopathogenesis of multiple sclerosis.

Multiple sclerosis (MS) is a commonly occurring inflammatory and demyelinating neurological disease. It has been considered to be an autoimmune disorder mediated by CD4+ type 1 T helper cells, but recent studies have challenged this idea by indicating a role for other immune cells. So, T- and B-cell responses in the brain of patients with MS involve the clonal expansion of lymphocytes and the antigen-driven maturation of the B-cell receptors, indicating that the immune response in MS engages a broad range of immune cells that target a limited number of brain antigens. At variance with the classical view, axons are not spared during the inflammatory process. Indeed, axonal damage determines clinical outcome to a large extent. Studies of the mechanisms of axonal damage and neurodegeneration in MS are in their infancy. Here, we summarize recent advances in our understanding of the pathogenesis of MS, and conclude with an outlook on how to capitalize on this knowledge to develop new therapeutic approaches.

Natalizumab treatment for multiple sclerosis: updated recommendations for patient selection and monitoring.

Natalizumab, a highly specific α4-integrin antagonist, is approved for treatment of patients with active relapsing-remitting multiple sclerosis (RRMS). It is generally recommended for individuals who have not responded to a currently available first-line disease-modifying therapy or who have very active disease. The expected benefits of natalizumab treatment have to be weighed against risks, especially the rare but serious adverse event of progressive multifocal leukoencephalopathy. In this Review, we revisit and update previous recommendations on natalizumab for treatment of patients with RRMS, based on additional long-term follow-up of clinical studies and post-marketing observations, including appropriate patient selection and management recommendations.

Intravenous immune globulin (10% caprylate-chromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomised placebo-controlled trial

BACKGROUND Short-term studies suggest that intravenous immunoglobulin might reduce disability caused by chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) but long-term effects have not been shown. We aimed to establish whether 10% caprylate-chromatography purified immune globulin intravenous (IGIV-C) has short-term and long-term benefit in patients with CIDP. METHODS 117 patients with CIDP who met specific neurophysiological inflammatory neuropathy cause and treatment (INCAT) criteria participated in a randomised, double-blind, placebo-controlled, response-conditional crossover trial. IGIV-C (Gamunex) or placebo was given every 3 weeks for up to 24 weeks in an initial treatment period, and patients who did not show an improvement in INCAT disability score of 1 point or more received the alternate treatment in a crossover period. The primary outcome was the percentage of patients who had maintained an improvement from baseline in adjusted INCAT disability score of 1 point or more through to week 24. Patients who showed an improvement and completed 24 weeks of treatment were eligible to be randomly re-assigned in a blinded 24-week extension phase. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00220740. FINDINGS During the first period, 32 of 59 (54%) patients treated with IGIV-C and 12 of 58 (21%) patients who received placebo had an improvement in adjusted INCAT disability score that was maintained through to week 24 (treatment difference 33.5%, 95% CI 15.4-51.7; p=0.0002). Improvements from baseline to endpoint were also recorded for grip strength in the dominant hand (treatment difference 10.9 kPa, 4.6-17.2; p=0.0008) and the non-dominant hand (8.6 kPa, 2.6-14.6; p=0.005). Results were similar during the crossover period. During the extension phase, participants who continued to receive IGIV-C had a longer time to relapse than did patients treated with placebo (p=0.011). The incidence of serious adverse events per infusion was 0.8% (9/1096) with IGIV-C versus 1.9% (11/575) with placebo. The most common adverse events with IGIV-C were headache, pyrexia, and hypertension. INTERPRETATION This study, the largest reported trial of any CIDP treatment, shows the short-term and long-term efficacy and safety of IGIV-C and supports use of IGIV-C as a therapy for CIDP.