Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis.

BACKGROUND: There are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll-like receptor 4 and can cross the blood-brain barrier, with potential salutary effects in progressive multiple sclerosis. METHODS: We enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (≤100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal-appearing brain tissue, the thickness of the retinal nerve-fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis. RESULTS: Of 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was -0.0010 per year with ibudilast and -0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P=0.04), which represents approximately 2.5 ml less brain-tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression. CONCLUSIONS: In a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression. (Funded by the National Institute of Neurological Disorders and Stroke and others; NN102/SPRINT-MS ClinicalTrials.gov number, NCT01982942 .).

Immediate transient thrombocytopenia at the time of alemtuzumab infusion in multiple sclerosis.

BACKGROUND: Alemtuzumab is a monoclonal antibody approved for relapsing-remitting multiple sclerosis (RRMS). Although Immune thrombocytopenia (ITP) has been reported as a secondary autoimmune phenomenon following alemtuzumab infusion, immediate thrombocytopenia during the infusion has not been reported. OBJECTIVE: We report transient, reversible, self-limiting acute-onset thrombocytopenia during the first course with alemtuzumab. RESULTS AND CONCLUSION: In total, 3 of 22 paitents developed mild self-limited bruising associated with a drop in platelet count from their baseline during the intial 5-day course of alemtuzumab. Upon chart review, all 22 patients who received alemtuzumab developed an immediate mostly asymptomatic drop in platelet count which returned to normal within 2 months post-infusion.

Subcutaneous administration of alemtuzumab in patients with highly active multiple sclerosis.

Alemtuzumab is an anti-CD52 monoclonal antibody with remarkable efficacy in relapsing multiple sclerosis (MS). In clinical trials and off-label use in MS, alemtuzumab has been administered intravenously (IV). Alemtuzumab is approved for chronic lymphoid leukemia as IV. Oncology guidelines recommend alemtuzumab subcutaneous (SC) over IV. There is no report of alemtuzumab SC in MS. We report two patients with highly active relapsing MS who were treated with SC alemtuzumab, had significant improvement and tolerated SC alemtuzumab well without the typical infusion-associated adverse events. SC alemtuzumab in MS warrants further studies as this may enhance patient convenience and minimize infusion-associated adverse events.

Disease correlates of rim lesions on quantitative susceptibility mapping in multiple sclerosis.

Quantitative susceptibility mapping (QSM), an imaging technique sensitive to brain iron, has been used to detect paramagnetic rims of iron-laden active microglia and macrophages in a subset of multiple sclerosis (MS) lesions, known as rim+ lesions, that are consistent with chronic active lesions. Because of the potential impact of rim+ lesions on disease progression and tissue damage, investigating their influence on disability and neurodegeneration is critical to establish the impact of these lesions on the disease course. This study aimed to explore the relationship between chronic active rim+ lesions, identified as having a hyperintense rim on QSM, and both clinical disability and imaging measures of neurodegeneration in patients with MS. The patient cohort was composed of 159 relapsing-remitting multiple sclerosis patients. The Expanded Disability Status Scale (EDSS) and Brief International Cognitive Assessment for Multiple Sclerosis, which includes both the Symbol Digit Modalities Test and California Verbal Learning Test-II, were used to assess clinical disability. Cortical thickness and thalamic volume were evaluated as imaging measures of neurodegeneration. A total of 4469 MS lesions were identified, of which 171 QSM rim+ (3.8%) lesions were identified among 57 patients (35.8%). In a multivariate regression model, as the overall total lesion burden increased, patients with at least one rim+ lesion on QSM performed worse on both physical disability and cognitive assessments, specifically the Symbol Digit Modalities Test (p = 0.010), California Verbal Learning Test-II (p = 0.030), and EDSS (p = 0.001). In a separate univariate regression model, controlling for age (p < 0.001) and having at least one rim+ lesion was related to more cortical thinning (p = 0.03) in younger patients (< 45 years). Lower thalamic volume was associated with older patients (p = 0.038) and larger total lesion burden (p < 0.001); however, the association did not remain significant with rim+ lesions (p = 0.10). Our findings demonstrate a novel observation that chronic active lesions, as identified on QSM, modify the impact of lesion burden on clinical disability in MS patients. These results support further exploration of rim+ lesions for therapeutic targeting in MS to reduce disability and subsequent neurodegeneration.

Pediatric-onset multiple sclerosis in African-American black and European-origin white patients.

Pediatric-onset multiple sclerosis is now recognized, but the association with ethnicity has not been well studied. In a retrospective review at a major teaching facility, 46 pediatric-onset multiple sclerosis patients were identified; of these, 24 were African-American black and 19 were European-origin white. Both groups were similar in mean age at onset (black, 13.6 +/- 3.36 years; white, 13.68 +/- 3.42 years) and total duration of follow-up (black, 42.7 +/- 43.5 months; white, 38.2 +/- 35.3 months), with no significant difference in time to onset of disease-modifying therapy (black, 11.2 +/- 4.7 months; white, 12.4 +/- 5.1 months). The percentage of females was higher in the black than in the white group (83% vs 47%; P = 0.014). The annualized relapse rate was significantly higher in the black than in the white group (1.80 +/- 1.14 vs 1.13 +/- 0.50; P < 0.001). These findings are consistent with data suggesting a more aggressive disease phenotype among African-American blacks with adult-onset multiple sclerosis. Larger multicenter studies are warranted to confirm the findings.

Induction of disease remission with one cycle of alemtuzumab in relapsing-remitting MS.

OBJECTIVE: To investigate a single-course treatment with alemtuzumab in patients with relapsing-remitting multiple sclerosis. METHODS: We performed a retrospective chart review of all patients diagnosed with RRMS who were treated with alemtuzumab at our MS center and who had at least 12 month follow-up since the first dose. Data on radiological and clinical relapse were collected for the 2 years prior to patients' first dose of alemtuzumab and were tracked until the time of analysis. RESULTS: In the 2 years prior to first dose of alemtuzumab, 82.8% of the 29 patients had a new lesion on MRI and/or a clinical relapse, with an ARR of 0.67. In the mean 24.7 month follow-up after the first dose of alemtuzumab, 17.2% of patients displayed new disease activity and the ARR was 0.08. 4 out of 5 patients who relapsed did so within 12 month post-first infusion and received a second dose. Of the 24 patients who did not relapse, 8 received a second dose at 1 year and 16 did not. 5 out of all 29 patients developed thyroid disorder. CONCLUSIONS: Given that 96% of patients who did not relapse in the first 12 months following the initial dose of alemtuzumab remained relapse-free regardless of receiving a second course of drug, our data suggests that induction of disease remission for some patients might occur following just one dose of alemtuzumab. With further study, these data could support modification of the current therapy regimen.

Differential Impact of Multiple Sclerosis on Cortical and Deep Gray Matter Structures in African Americans and Caucasian Americans.

BACKGROUND: African Americans with multiple sclerosis (AAwMS) have different disease phenotypes when compared to Caucasians Americans with MS (CAwMS). The pathologic basis of this difference in disease presentation is unknown. METHODS: Fifty-Four AAwMS and 54 CAwMS were appropriately matched for age, gender, treatment duration, and disease duration. FreeSurfer was used to segment brain white matter and gray matter from T1 images and compute thalamic volume. Regional cortical thickness was calculated using QDEC. RESULTS: The 2 matched cohorts differed in disability, with AAwMS demonstrating significantly higher EDSS scores (2.3±2.2 vs. 1.3±1.5, P < .009), yet the 2 populations had similar T2 hyperintense lesion volumes (P = .35). AAwMS had a significantly lower total global cortical thickness when compared to CAwMS (P = .03). Controlling for EDSS, AAwMS showed multiple cortical regions to be significantly thinner than CAwMS; these included areas within the temporal, parietal and occipital lobes, as well as the precentral and postcentral gyrus. Middletemporal cortex was most affected in AAwMS in the left hemisphere (P = .009), while the superiortemporal cortex was most affected in the right hemisphere (P = .0001). In contrast, thalamic volume was significantly reduced in CAwMS when compared to AAwMS (P = .01). In both groups, worse disability was associated with lower total thalamic volume percentage. CONCLUSION: AAwMS and CAwMS patients differ with regard to global and regional cortical thickness and thalamic volume. This diverging pattern of gray matter volumetrics among otherwise matched patients suggests that racial-specific disease differences may exist.

A study of patients with aggressive multiple sclerosis at disease onset.

OBJECTIVE: Identify aggressive onset multiple sclerosis (AOMS) and describe its clinical course. METHODS: AOMS patients were identified from a multiple sclerosis (MS) database based on a set of criteria. The subsequent clinical course of AOMS patients was then reviewed with the goal of potentially identifying the best approaches to manage these patients. RESULTS: Fifty-eight of 783 (7.4%) patients in the MS database met the criteria for AOMS, and 43 patients who had complete data for the duration of their follow-up were included in the subsequent analysis. The mean duration of the follow-up was 54 months. Thirty-five patients (81%) were started on a conventional first-line agent (injectable therapies for MS). Only two of these 35 patients (5.7%) had no evidence of disease activity. Twenty-two of 35 patients suffering from refractory disease were switched to a more aggressive treatment (natalizumab, rituximab, alemtuzumab, cyclophosphamide). Eight patients were started on aggressive treatment as their initial therapy, and seven of these eight (87.5%) patients showed no evidence of disease activity. CONCLUSION: With recognition of the crucial significance of early optimal treatment during the potential window of opportunity for best long-term outcomes, we describe AOMS within 1 year of disease onset and discuss possible treatment considerations for these patients.

Comparative efficacy of alemtuzumab and established treatment in the management of multiple sclerosis.

Alemtuzumab is the newest disease-modifying therapy approved for the treatment of relapsing multiple sclerosis. Alemtuzumab is an anti-CD52 targeted antibody that causes lysis of T and B lymphocytes, monocytes, natural killer cells, macrophages, and dendritic cells. Following its administration, a prolonged T-cell lymphopenia results with emergence of a reconstituted immune system that differs in its composition from that pretreatment. In clinical trials, alemtuzumab has shown impressive efficacy with regard to clinical and radiological outcomes in relapsing multiple sclerosis, along with sustained long-term beneficial effects, and it is attractive for its once-yearly administration. Despite this, the occurrence of serious secondary autoimmune disorders, infections, and a potential risk of malignancy necessitates a careful evaluation of risks versus benefits for an individual patient prior to its use. The requirement of patient commitment to the intense mandatory monitoring program is also a factor to be considered when incorporating alemtuzumab into the treatment regimen.

Review of daclizumab and its therapeutic potential in the treatment of relapsing-remitting multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. It can present in several forms, with the relapsing-remitting pattern being the most common. Since the approval of the first disease-modifying therapy and the initiation of appropriate treatments from the early stages of the disease, there seem to be positive impacts on the long-term outcomes and disability associated with MS. Currently, there are ten approved drugs for the treatment of MS, and several more are in various stages of development. These medications each have their unique profile in terms of efficacy, dose, routes of administration, tolerability, and adverse effects. Daclizumab is a humanized monoclonal antibody that is being explored for the treatment of MS. It is currently approved for use in allograft renal transplantation. Given its modulatory effects on the immune system, daclizumab's potential for use in MS was tested in extensive Phase II trials. With continued demonstration of its efficacy, it is currently in a Phase III trial for relapsing-remitting MS. While daclizumab has demonstrated beneficial effects in controlling disease activity in MS, there were also some safety and tolerability concerns that were raised. Further information from the ongoing Phase III trial, and from open-label studies, will shed light on the benefit and risk profile of this drug and its potential for use in MS.

Fingolimod and cardiac risk: latest findings and clinical implications.

Fingolimod is an oral medication approved for the treatment of relapsing multiple sclerosis (MS). It is unique compared with other approved disease-modifying therapies for MS in that it is the first oral agent and it has a novel mechanism of action. In clinical trials and postmarket use, it demonstrates clear therapeutic efficacy. However, it is associated with certain risks including cardiac concerns. The recent reports of cardiac events potentially associated with the drug prompted a regulatory agencies review of the use of fingolimod for MS in the USA and Europe. After completion of their review, the US Food and Drug Administration and the European Medicines Agency concluded that its benefits outweighed the risks. However, certain recommendations were made for appropriate patient selection for fingolimod and for more cautious first-dose monitoring. We review the use of fingolimod for MS in light of the recently reported potential cardiac risks. We conclude that with appropriate patient selection and careful monitoring, it appears to have a favorable benefits/risks profile and can be a valuable treatment option for relapsing MS. Continued postmarketing surveillance and data from the extension phase of its clinical trials will be very important in understanding the long-term efficacy and safety of fingolimod and to help determine its place in the treatment algorithm for multiple sclerosis.