Michael Racke

Factors that influence adherence with disease-modifying therapy in MS

BackgroundThe complexity and cost of injection treatment can represent a formidable challenge for patients affected by a chronic illness, particularly those whose treatment is primarily preventative and only modestly effective on the more conspicuous symptomatic aspects of the disease process. The aim of this investigation was to identify which factors most influenced nonadherent behavior with the available diseasemodifying injection therapies for multiple sclerosis (MS).MethodsA multicenter, observational (threewave) study using surveys was developed and administered to patients with MS through the World Wide Web. Healthcare providers at 17 neurology clinics recruited patients for the study.ResultsA total of 798 patients responded to the baseline wave of the study (708 responded to all three waves). The nonadherence rates for all patients (missing one or more injections) across these waves remained relatively stable at 39 %, 37 %, and 36 %, respectively. The most common reason participants listed for missing injections was that they simply forgot to administer the medication (58 %). Other factors including injection-site reactions, quality of life, patients’ perceptions on the injectable medications, hope, depression, and support were also assessed in relation to adherence.ConclusionsThis study characterizes factors that are associated with failure to fully adhere with disease modifying injection therapy for MS and underscores the principles associated with optimizing adherence and its implications for effective treatment of the disease process in MS.

Design, rationale, and baseline characteristics of the randomized double-blind phase II clinical trial of ibudilast in progressive multiple sclerosis

BACKGROUND Primary and secondary progressive multiple sclerosis (MS), collectively called progressive multiple sclerosis (PMS), is characterized by gradual progression of disability. The current anti-inflammatory treatments for MS have little or no efficacy in PMS in the absence of obvious active inflammation. Optimal biomarkers for phase II PMS trials is unknown. Ibudilast is an inhibitor of macrophage migration inhibitor factor and phosphodiesterases-4 and -10 and exhibits possible neuroprotective properties. The goals of SPRINT-MS study are to evaluate the safety and efficacy of ibudilast in PMS and to directly compare several imaging metrics for utility in PMS trials. METHODS SPRINT-MS is a randomized, placebo-controlled, phase II trial of ibudilast in patients with PMS. Eligible subjects were randomized 1:1 to receive either ibudilast (100mg/day) or placebo for 96weeks. Imaging is conducted every 24weeks for whole brain atrophy, magnetization transfer ratio, diffusion tensor imaging, cortical brain atrophy, and retinal nerve fiber layer thickness. Clinical outcomes include neurologic disability and patient reported quality of life. Safety assessments include laboratory testing, electrocardiography, and suicidality screening. RESULTS A total of 331 subjects were enrolled, of which 255 were randomized onto active study treatment. Randomized subjects were 53.7% female and mean age 55.7 (SD 7.3) years. The last subject is projected to complete the study in May 2017. CONCLUSION SPRINT-MS is designed to evaluate the safety and efficacy of ibudilast as a treatment for PMS while simultaneously validating five different imaging biomarkers as outcome metrics for use in future phase II proof-of-concept PMS trials.

Critical contribution from antigen presenting cells for encephalitogenic T cells

umbelliferone (4-MU), that prevents development of EAE. We found that treatment with 4-MU significantly decreases the incidence (13/21 vs. 28/30 in untreated animals), delays the onset (24.9 ± 1.5 days post immunization vs. 13.3 ± 0.6 days) and reduces the severity (average score of 1.5 ± 0.1 vs. 2.8 ± 0.2, peak score of 1.9 ± 0.1 vs. 3.6 ± 0.2) of EAE. In addition, 4-MU treatment substantially reduces clinical deficits in already established EAE (average score of 1.9 ± 0.2 vs. 2.8 ± 0.1, peak score of 2.6 ± 0.2 vs. 3.7 ± 0.2). Using multi-parameter flow cytometry, we further analyzed the immunological mechanism of this therapeutic effect. We found that 4-MU treatment skews the immune response towards an antiinflammatory profile, characterized by an increase in the number of FoxP3 regulatory T-cells. Together, our data provides the therapeutic profile and immunological mechanism of 4-MU treatment in EAE. Considering that 4-MU is already an approved drug currently used in people throughout Europe and Asia, we therefore propose that 4-MU has great promise for the treatment of MS.

Differentially expressed microRNAs in multiple sclerosis patients alter regulatory T cells

expression of Ly6C and Ly6G, very important in infectious, autoimmune and tumor models. The present work will further characterize the potential role of miR-223 in the EAE model and MS. First we found an upregulation of miR-233 in the Peripheral Blood Mononuclear Cell (PBMC) of 20 MS samples vs. 20 controls (fold change over controls 1.64 ± 1.25 vs. 1.20 ± 0.95, P = 0.018). This result was confirmed in a different cohort of subjects, including 15 untreated MS subjects (population from Italy: 11 RRMS, 4 PPMS) and 12 healthy controls. In this cohort, miR-233 was upregulated in MS vs. control subjects (fold change over controls 0.81 ± 0.65 vs. 0.40 ± 0.26, P = 0.010). We also performed several active EAE experiments in miR-223 knockout (miR-223 KO) mice and littermate control mice. MiR-223 KO mice developed a significantly less severe disease (P b 0.0001 by two-way ANOVA) with a significantly higher percentage of PMN-MDSC (CD11b/Ly6G positive cells) and MO-MDSC (CD11b/Ly6C positive cells) in the spleens and spinal cords compared to control mice. We found also that MO-MDSC from miR-223 KO mice had greater immune-suppressive effects on CD4 T cell proliferation than controls in antigen T cell stimulatory conditions. It is established that MO-MDSCs inhibit CD4 and CD8 T cell proliferation mostly via ARG1 action. ARG1 was promptly upregulated in MO-MDSC from miR-223 KO cells corresponding to their high immunosuppressive function. These results demonstrate altered levels of miR 223 in the PBMC of MS patients and suggest that miR-223 plays a role in EAE. This may lead to the identification of new disease biomarkers of therapeutic targets.