effects of ocrelizumab on b-cell tolerance defect in relapsing multiple sclerosis

Conditions: Multiple Sclerosis, Relapsing-Remitting

Summary: b-cells have an important role in the pathogenesis of multiple sclerosis (ms). ocrelizumab, a medication that targets b-cells have been found to be highly effective in stopping the disease activity in relapsing-remitting ms. the efficacy of ocrelizumab might be related to the specific pattern of b-cell tolerance defect in patients with ms and the potential of its normalization with treatment with ocrelizumab. by analyzing the reactivity of recombinant antibodies expressed from single b-cells, the investigators' collaborators have demonstrated that the pattern of b-cell tolerance defect is different in people with ms who only display an impaired removal of developing autoreactive b-cells in the periphery while central b-cell tolerance in the bone marrow is functional in most patients. in contrast, patients with rheumatoid arthritis (ra), type-1 diabetes (t1d) or sjögren's syndrome (ss) show defective central and peripheral b-cell tolerance checkpoints. as a consequence, while anti-b-cell therapy does not correct defective early b-cell tolerance checkpoints in t1d and only temporarily slows down autoimmune processes before newly generated autoreactive b-cells likely induce patient relapse, the investigators postulate that the efficacy of ocrelizumab in ms may be linked to normal central b-cell tolerance and the production of a normal b-cell and t-cell compartment after ocrelizumab therapy. in an open-label study, 10 patients with relapsing ms will be treated with two courses of ocrelizumab and will be followed clinically and radiologically for at least two and a half years. assessment of t and b-cell phenotypes and function at baseline and 18-24 months post-b-cell depletion will be the primary outcome of the study.


Eligibility criteria:
inclusion criteria: * diagnosis of relapsing remitting multiple sclerosis (rrms) based on revised mcdonald criteria * at least one gd-enhancing lesions on the brain or spinal cord mri done in the prior three months or at least one new t2/flair lesion on the brain or spinal cord mri done in the prior three months (compared to a prior mri performed within 18 months of the most recent mri) * naïve to disease modifying therapy (dmt) or at least off these dmts (natalizumab, fingolimod, dmf) for three months or on an injectable dmt (interferons or glatiramer acetate) * expanded disability status scale (edss) score at the time of screening =\<3 * negative urine or serum pregnancy test must be available for premenopausal women and for women \<12 months after the onset of menopause unless these women have undergone surgical sterilization * women of childbearing potential must agree to remain abstinent (refrain from heterosexual intercourse) or use one method of contraception with a failure rate of \<1% per year or a barrier method supplemented with spermicide. contraception must continue for the duration of study treatment and for at least 24 weeks after the last dose of study treatment exclusion criteria: * contraindication to treatment with an anti- cluster of differentiation antigen 20 (cd20) antibodies, including being seropositive for hbsag * active hepatitis b virus infection * ever received b-cell depleting antibodies (rituximab, ocrelizumab, ofatumumab), alemtuzumab, daclizumab, mitoxantrone or hematopoietic stem-cell transplant * pregnant or lactating women * hypersensitivity to ocrelizumab * treatment with steroids in the past 30 days