Effects of Ocrelizumab on B-cell Tolerance Defect in Relapsing Multiple Sclerosis
Effects of Ocrelizumab on B-cell Tolerance Defect in Relapsing Multiple Sclerosis
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.
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