The brain antigen-specific B cell response correlates with glatiramer acetate responsiveness in relapsing-remitting multiple sclerosis patients.

B cells have only recently begun to attract attention in the immunopathology of multiple sclerosis (MS). Suitable markers for the prediction of treatment success with immunomodulatory drugs are still missing. Here we evaluated the B cell response to brain antigens in n = 34 relapsing-remitting MS (RRMS) patients treated with glatiramer acetate (GA) using the enzyme-linked immunospot technique (ELISPOT). Our data demonstrate that patients can be subdivided into responders that show brain-specific B cell reactivity in the blood and patients without this reactivity. Only in patients that classified as B cell responders, there was a significant positive correlation between treatment duration and the time since last relapse in our study. This correlation was GA-specific because it was absent in a control group that consisted of interferon-ß (IFN-ß)-treated RRMS patients (n = 23). These data suggest that GA has an effect on brain-reactive B cells in a subset of patients and that only this subset benefits from treatment. The detection of brain-reactive B cells is likely to be a suitable tool to identify drug responders.

Identification of a B cell-dependent subpopulation of multiple sclerosis by measurements of brain-reactive B cells in the blood.

B cells are increasingly coming into play in the pathogenesis of multiple sclerosis (MS). Here, we screened peripheral blood mononuclear cells (PBMC) from patients with clinically isolated syndrome (CIS), MS, other non-inflammatory neurological, inflammatory neurological or autoimmune diseases, and healthy donors for their B cell reactivity to CNS antigen using the enzyme-linked immunospot technique (ELISPOT) after 96 h of polyclonal stimulation. Our data show that nine of 15 patients with CIS (60.0%) and 53 of 67 patients with definite MS (79.1%) displayed CNS-reactive B cells, compared to none of the control donors. The presence of CNS-reactive B cells in the blood of the majority of patients with MS or at risk to develop MS along with their absence in control subjects suggests that they might be indicative of a B cell-dependent subpopulation of the disease.

Effects of pioglitazone on diffusion tensor imaging indices in multiple sclerosis patients.

Pioglitazone is an FDA-approved peroxisome proliferator activated receptor gamma (PPARgamma) agonist. We tested the hypothesis that treatment with pioglitazone reduces new lesion development in patients with RRMS. Twenty-two patients were treated with pioglitazone or placebo and monitored by diffusion tensor imaging (DTI) at baseline and after 12 months. A negative correlation was found between the 1-year change in relative anisotropy (RA) and fluid attenuated inversion recovery (FLAIR) lesion burden in the pioglitazone group. Regions of interest (ROIs) having high ADC and low RA values at baseline had a significantly higher chance to develop into lesions in the placebo group than similar ROIs in the pioglitazone group. These findings suggest that baseline DTI parameters can provide a prognostic surrogate marker for lesions, and that pioglitazone can reduce conversion of normal appearing white matter to lesions.

A pilot test of pioglitazone as an add-on in patients with relapsing remitting multiple sclerosis.

The peroxisome proliferator-activated receptor gamma agonist pioglitazone is FDA-approved for treatment of type-2 diabetes due to insulin sensitizing effects. However pioglitazone has anti-inflammatory and neuroprotective effects, reduces glial and T-cell activation, and reduces signs in an animal model of multiple sclerosis (MS). We tested the effects of daily treatment with pioglitazone in a small cohort of relapsing remitting MS patients. RRMS patients taking IFNbeta-1alpha and having an EDSS score <6.5 were randomized to treatment with pioglitazone (30 mg daily, p.o.) or placebo and monitored clinically and by MRI for 1 year. Primary outcomes were safety and tolerability, secondary outcomes included changes in neurological outcome, lesion burden, and gray matter volume. After 1 year 11 patients in the pioglitazone arm and 10 in the placebo arm completed the trial. Pioglitazone was well tolerated with a similar incidence of non-serious adverse events in placebo and treatment groups. After 1 year there were no significant differences in clinical symptoms as assessed by EDSS; however MRI showed a significant reduction in gray matter atrophy, and a trend for reduced lesion burden in the treatment group. These results show that pioglitazone was well tolerated in RRMS patients with indications of beneficial effects, warranting further trials to establish clinical efficacy.

Effect of pioglitazone treatment on behavioral symptoms in autistic children.

INTRODUCTION: Autism is complex neuro-developmental disorder which has a symptomatic diagnosis in patients characterized by disorders in language/communication, behavior, and social interactions. The exact causes for autism are largely unknown, but is has been speculated that immune and inflammatory responses, particularly those of Th2 type, may be involved. Thiazolidinediones (TZDs) are agonists of the peroxisome proliferator activated receptor gamma (PPARgamma), a nuclear hormone receptor which modulates insulin sensitivity, and have been shown to induce apoptosis in activated T-lymphocytes and exert anti-inflammatory effects in glial cells. The TZD pioglitazone (Actos) is an FDA-approved PPARgamma agonist used to treat type 2 diabetes, with a good safety profile, currently being tested in clinical trials of other neurological diseases including AD and MS. We therefore tested the safety and therapeutic potential of oral pioglitazone in a small cohort of children with diagnosed autism. CASE DESCRIPTION: The rationale and risks of taking pioglitazone were explained to the parents, consent was obtained, and treatment was initiated at either 30 or 60 mg per day p.o. A total of 25 children (average age 7.9 +/- 0.7 year old) were enrolled. Safety was assessed by measurements of metabolic profiles and blood pressure; effects on behavioral symptoms were assessed by the Aberrant Behavior Checklist (ABC), which measures hyperactivity, inappropriate speech, irritability, lethargy, and stereotypy, done at baseline and after 3-4 months of treatment. DISCUSSION AND EVALUATION: In a small cohort of autistic children, daily treatment with 30 or 60 mg p.o. pioglitazone for 3-4 months induced apparent clinical improvement without adverse events. There were no adverse effects noted and behavioral measurements revealed a significant decrease in 4 out of 5 subcategories (irritability, lethargy, stereotypy, and hyperactivity). Improved behaviors were inversely correlated with patient age, indicating stronger effects on the younger patients. CONCLUSION: Pioglitazone should be considered for further testing of therapeutic potential in autistic patients.