I just learned about a major improvement in the treatment of relapsing Multiple Sclerosis.

 

Multiple Sclerosis is caused by immune cells that for some reason attack the myelin coating of our nerve cells in the brain and spinal cord. When the myelin is damaged nerve impulses that require communication between parts of our nervous system become disrupted. 

“A generation ago, after 15 years of relapsing MS 50 percent of people required a cane and had developed progressive MS leading to a wheel chair.  It was thought that T lymphocytes were necessary and sufficient to cause the disease.  All you needed were T cells.”  Hauser.

In the 1990s Steven Hauser, a UCSF neurologist and his team were studying the pathology of multiple sclerosis in a mouse model—and they detected antibodies “tightly bound” to proteins in damaged myelin. These were the same antibodies found in samples of spinal fluid from patients, and were widely used as biomarkers for MS although not considered to have a role in disease mechanisms.

The team also discovered that MS could be induced in healthy animals by transferring these antibodies and B-cells, as well as T-cells. This showed that these antibodies, which not many people seemed to care much about, were actually partners in crime — alongside T-cells — in causing MS.

“This was a paradigm change for the field,”  

We currently believe that autoimmune B cells cross the blood-brain barrier and undergo stimulation, antigen-driven affinity maturation and clonal expansion within the supportive CNS environment. These highly restricted populations of clonally expanded B cells and plasma cells can be detected in MS lesions, in cerebrospinal fluid, and also in peripheral blood.

Hauser got permission to use rituximab an antibody that is infused and that destroys B cells, but he was told by the NIH that the science lacks biological probability.  

In phase II trials in relapsing MS, monoclonal antibodies that target circulating CD20-positive B lymphocytes dramatically reduced disease activity. These beneficial effects occurred within weeks of treatment, indicating that a direct effect on B cells--and likely not on putative autoantibodies--was responsible. The discovery that depletion of B cells has an impact on MS biology enabled a paradigm shift in treatment.

in a February 15, 2024 NEJM editorial Hauser updated his understanding


"Multiple sclerosis has two principal forms. Relapsing multiple sclerosis is characterized by recurrent attacks, initially with remissions but over time leading to lasting disability. In progressive multiple sclerosis, continuous worsening that leads to a wheelchair- or bed-bound state is typical. Progressive multiple sclerosis usually develops after a period of relapsing disease or, less commonly, is present from onset. Relapsing multiple sclerosis is primarily a disorder of the adaptive immune system (B and T lymphocytes) that is orchestrated by circulating B lymphocytes that traffic into the central nervous system. Progression, by contrast, is mediated by both the adaptive and innate immune systems — B and T cells, as well as resident microglia and macrophages — that are located behind an intact blood–brain barrier, impermeable to most systemically administered drugs.  
he then said the results from drugs that block CD40 were confusing.  and an earlier trial of an inhibitor of a different costimulatory molecule (CTLA4) showed no effect on relapsing multiple sclerosis, blocking of B-cell activity with atacicept, a decoy receptor for the B-cell survivor factors APRIL paradoxically worsened multiple sclerosis.
and he concluded that the depletion of circulating B cells with the use of anti-CD20 monoclonal antibodies6,7 has become a mainstay of treatment in multiple sclerosis. Their rapid onset of effect has indicated that B-cell antigen presentation8 and cytokine secretion,3 rather than antibody production, are likely to be responsible for their benefit — a situation that emphasizes the central role of B-cell antigen presentation to T cells and the effects on B-cell cytokines as mediators of tissue damage. Highly effective therapies against relapsing multiple sclerosis, with the anti-CD20 agents or the α4β1 integrin inhibitor natalizumab,9 have shown that when relapses are prevented, a progression independent of disease activity is uncovered; this progression was previously obscured by fluctuating neurologic findings that were due to relapses and partial remissions. Thus, progression is present in most, if not all, patients with multiple sclerosis, regardless of where they are in the disease continuum. In addition to marked effects against relapses, B-cell–based therapies provide partial benefits against progression,10 a finding that suggests that removal of B cells may also reduce microglial activation and neurodegeneration, components of the pathologic features of progressive multiple sclerosis.
The striking clinical benefits and safety profile of the available high-efficacy therapies for relapsing multiple sclerosis create a high bar for any new treatment.  the paramount need is for more effective therapy against progression."

Rituximab is an antibody to CD 20, a protein present on the surface of B cells.  It is chimeric—part human, part mouse, and some people develop antibodies to it.  When they are activated B cells become plasma cells.  They start producing large volumes of antibodies and plasma cells do not have CD 20 on their surface. 

 Ocrelizumab (Ocrevus) was approved by the FDA in 2017.  It is a fully humanized antibody to CD 20.  It destroys B cells that are moving about in the body.  They are damaged for several months after one treatment of ocrelizumab.  (ocrelizumab has a half life of 72 weeks).  Currently people with MS receive infusions of ocrelizumab 600mg twice a year.

According to drugs.com Ocrevus costs $16,974 for one 300mg/10mL dose “This works out to an annual cost of just over $65,000 per year, but most people do not pay this amount.”

We know the treatment substantially decreases the likelihood of a relapse but we don’t yet have long term observational studies.

https://multiplesclerosisnewstoday.com/2017/04/05/ucsf-neurologist-stephen-hauser-key-to-b-cell-role-in-multiple-sclerosis-ocrevus-development/

https://pubmed.ncbi.nlm.nih.gov/25480864/

addendum:

https://pmc.ncbi.nlm.nih.gov/articles/PMC7790722 

J Neuro. 2021 Jan 8;269(1):159–183.

Rituximab for the treatment of multiple sclerosis: a review

Clara Grazia Chisari et al. In recent decades, evidence suggesting the direct or indirect involvement of B cells on multiple sclerosis (MS) pathogenesis has accumulated. The increased data on the efficacy and safety of B-cell-depleting therapies has suggested adding these drugs as treatment options to the current armamentarium of disease modifying therapies (DMTs) for MS. Particularly, rituximab (RTX), a chimeric monoclonal antibody directed at CD20 positive B lymphocytes resulting in cell-mediated apoptosis, has been demonstrated to reduce inflammatory activity, incidence of relapses and new brain lesions on magnetic resonance imaging (MRI) in patients with relapsing–remitting MS (RRMS). Additional evidence also demonstrated that patients with progressive MS (PMS) may benefit from RTX, which also showed to be well tolerated, with acceptable safety risks and favorable cost-effectiveness profile.

Despite these encouraging results, RTX is currently approved for non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, several forms of vasculitis and rheumatoid arthritis, while it can only be administered off-label for MS treatment. Between Northern European countries exist different rules for using not licensed drug for treating MS. The Sweden MS register reports a high rate (53.5%) of off-label RTX prescriptions in relation to other annually started DMTs to treat MS patients, while Danish and Norwegian neurologists have to use other anti-CD20 drugs, as ocrelizumab, in most of the cases.  In this paper, we review the clinical efficacy, safety profile and cost effectiveness of RTX for the treatment of MS.

 Introduction

Multiple sclerosis (MS) has been historically considered as an autoimmune disease of the central nervous system (CNS) mediated by CD4+ T cells reactive to myelin antigens.  It has been demonstrated that B cells are present in MS lesions, meninges and cerebrospinal fluid (CSF) and can contribute to disease progression through several antibody-dependent and -independent mechanisms.  B cells produce antibodies after differentiating into plasma cells and can also stimulate T cells activity.

Meningeal-based ectopic B-cell follicles have been found adjacent to areas of focal cortical demyelination. B cells are able to migrate to the CNS In the meninges, these migrated B cells form ectopic B-cell follicular-like structures.  B cells are also able to induce antigen-specific T-cell expansion, memory formation and cytokine production, B cells from untreated MS patients (compared to healthy controls) have been demonstrated to secrete more pro-inflammatory interleukines-IL (such as IL-6) and less regulatory ones (such as IL-10)

Several B-cell-targeted therapies have been developed and they target the Fab (fragment antigen-binding antibody) domains of CD20+ or CD19+ B lymphocytes, selectively allowing the depletion of the circulating B-cell population, apart from the mature antibody-secreting plasma cells Anti-CD20 monoclonal antibodies currently in use for the treatment of MS are Rituximab (RTX), Ocrelizumab (OCR), Ofatumumab (OFA) and Ublituximab (UTX).

 Two randomized placebo-controlled phase 2 trials, the “Helping to Evaluate Rituxan in Relapsing–Remitting Multiple Sclerosis (HERMES)” and “A Study to Evaluate the Safety and Efficacy of Rituximab in Adults With Primary Progressive Multiple Sclerosis (OLYMPUS)”, have demonstrated the efficacy of RTX for the treatment of relapsing–remitting MS (RRMS) and primary progressive MS (PPMS), respectively.

In the last years, several observational studies confirmed the high efficacy, relatively benign safety/tolerance profile, low cost and convenient administration regimen contributing to make RTX an interesting option for MS treatment, attracting increasing attention as an escalation and first-line therapy.

 

 

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