multiple sclerosis

Multiple sclerosis: stem cell therapy and its role in remyelination

Virginia Thornley, M.D., Neurologist

February 25, 2018

Stem cell research is a fast-growing arm of science. Multiple sclerosis is an autoimmune disease where the central nervous system is attacked as foreign. Clinical symptoms depend on the area involved, primarily in the white matter. Scientific research is being more and more directed towards agents and treatment modalities that differ from today’s immunomodulating agents given the potentially devastating side effects of the more efficacious medications. The heavy hitters tend to be more serious adverse effects.

How stem cell administration works

Umbilical cord mesenchymal stem cells may play a significant role in tissue repair and immunomodulatory processes that are important in multiple sclerosis. Stem cells divide into different types of cells which give rise to different tissues. They hold a wealth of potential in repairing damaged tissue as that found in multiple sclerosis. In one study, the mesenchymal stem cells from the umbilical cord were found with low immunogenicity. They can inhibit the multiplication of killer cells, T lymphocytes, and B lymphocytes and can inhibit the maturation of dendritic cells. Mesenchymal stem cells migrate to the site of injury and proliferate to repair damaged tissue.

Different stem cells that can be used in multiple sclerosis

Other types of stem cells are derived from hematopoeitic, embryonic, neural, spermatogonic, adipose, endometrial, Wharton jelly surrounding the umbilical cord and pluripotent-induced stem cells.

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Stem cell administration in 2 patients and reduction of abnormal MRI abnormalities

In one study, 2 patients were treated with stem cells. Clinical symptoms were reduced in the 1st patient, they were followed 8 years and found without adverse effects. The 2nd patient progressed and the timing of stem cell administration was shortened resulting in the reduction of symptoms. The number of abnormal foci seen in the MRI of the brain was less suggesting remyelination of damaged tissue within the brain. During illness, the body increases the immunogenicity with amplification of inhibitory co-stimulatory signals. With stem cell administration, this process reduces these destructive immune processes. Umbilical cord mesenchymal cells were found to inhibit IL-17c, HLA-DRB1, and IL-2 thereby protecting against an autoimmune response. The mechanism of action by which the stem cells work favors a remyelination repairing the damaged area(1).

Stem cell research in a study of 20 patients and reduction in disability

In another larger study of 20 patients, mesenchymal stem cell neural progenitor was applied. Results showed 70% had improved muscle strength and 50% improved in bladder symptoms. Improved EDSS (Expanded Disability Status Scale) was noted in 40% of patients, there were some minor adverse effects (2).

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Larger clinical randomized case control trials are needed.

References
  1. Meng, et al, “Umbilical cord mesenchymal stem cell transplantation in the treatment of multiple sclerosis,” American Journal of Translational Research, 2018, 10(1): 212-223.
  2. Harris, et al, “Phase I trial of intrathecal mesenchymal stem cell-derived neural progenitors in progressive multiple sclerosis,” EBioMedicine, 2018, Feb., pii.S2352-3964 (18)30051-3 (Epub ahead of print)
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multiple sclerosis

A summary and comparison of the different immunomodulating agents used in multiple sclerosis

Virginia Thornley, M.D., Neurologist

February 17, 2018

Introduction

Research on multiple sclerosis occurs at a dizzying rate. Because there are many newer agents on the market, the treatment options may be confusing for both the patient and even for neurologists wading through a large morass of novel therapeutic options. This seeks to compare and summarize the most current immunomodulating agents in a quick and concise way based on the package inserts, original drug websites and clinical trials performed. It reviews the most common and most striking potential serious side effects, the annual relapse rate reductions and effects on brain MRI lesions (abnormalities in the brain). Some agents were tested against placebo (placebo is an agent with no medicine in it used in comparison studies) others were against older immunomodulatory agents which were previously the gold standard. Currently, there are no head to head clinical trials comparing each immunmodulating agent against each other.  They are listed according to efficacy based on a reduction in annual relapse rate, although some authorities might prefer to compare the effect on MRI lesion burdens. Of note, the most efficacious agents also have some of the most potentially devastating side effects, including cancer and progressive multifocal leukoencephalopathy (PML) which is an irreversible destructive process affecting white matter in the brain occurring in the immunosuppressed state. Consult your neurologist.

 

Older immunomodulating agents

Avonex, Betaseron, Copaxone, Rebif

Mechanism of action: immunomodulation

Efficacy is about 23-25% all very similar

Side effects: flu-like symptoms, transaminitis

Pros: least amount of significant side effect

Cons: least efficacious

 

Newer agents

Aubagio (teriflunomide)

Mechanism of action: reduces B and T cell lymphocyte proliferation, inhibits DHODH required for rapidly dividing cells, exact mechanism is unknown

Efficacy: 30% relative risk reduction in TEMSO trial, 36% ARR (annualized relapse rate)reduction in TOWER trial

57% relapse-free after 108 weeks

Side effects: hepatotoxicity (can cause liver problems), teratogenesis (can affect fetus), bone marrow suppression, hypersensitivity

Pros: efficacious compared to older agents, to date still no reports of PML post-market

Cons: very little

 

Plegridy (peginterferon beta-1a)

Mechanism of action: reduces antigen presentation and proliferation, alters cytokine and matrix metalloproteinase

It is delivered by pegylation, where the medicine is bound to a glycol such that there is reduced renal clearance. Thus, delivery is long spanning 2 weeks.

Efficacy: 36% reduction in ARR

38% reduction in disability progression

Side effects: flu-like symptoms, seizures, suicidal ideations, anaphylaxis, congestive heart failure, autoimmune disorder, abnormal liver enzymes

Pros: efficacious

Cons: very little

 

Ocrevus (ocrelizumab)

Mechanism of action: Ab that target cells with B lymphocytes, Ag CD20 this results in less Ab-dependent cytolysis and complement-mediated lysis

Efficacy:  47% ARR reduction compared with Rebif in RRMS (relapsing-remitting multiple sclerosis)

24% less likely to have a disability in PPMS (primary progressive multiple sclerosis)

Side effects: infusion reactions, hepatitis B reactivation, you cannot receive live vaccine, possible breast cancer

Pros: efficacious

Cons: concern for progressive multifocal leukoencephalopathy found in 1 patient post-marketing, possible breast cancer

 

Tecfidera (dimethyl fumarate)

Mechanism of action: nicotinic receptor agonist, mechanism is unknown

Efficacy:  49% ARR reduction in the DEFINE and CONFIRM clinical trials

38% delay in disability progression compared with placebo

85% reduction in new MRI lesions

Side effects: anaphylaxis, lymphopenia, abnormal liver enzymes, liver injury

Pros: oral, efficacious

Cons: PML found in 1 patient during the clinical trial, few more cases found post-marketing

 

Lemtrada (alemtuzamab)

Mechanism of action: binds to CD52 and depletes T and B cells

Efficacy: 49% less relapses compared with Rebif

65% relapse-free compared to 47% in patients with Rebif

Side effects: joint pain, infections, autoimmune diseases, lymphomas, breast cancer, skin cancer, thyroid cancer and lymphoproliferative cancer, infusion reactions

Pros: efficacious

Cons: Can cause serious autoimmune diseases, lymphomas, breast cancer, skin cancer, thyroid cancer and lymphoproliferative cancer, infusion reactions
Gilenya (fingolimod)

Mechanism of action: immunomodulation, works on the sphingosine 1-receptor modulator

Efficacy: 52% reduction in ARR compared with Avonex

82% reduced disability progression

38% reduction in T2 lesions

60% reduced T1 gad + lesions

Side effects: most common are headache, transaminitis, bradycardia (low heart rate), PML, heart block, PRES or posterior reversible encephalopathy syndrome (reversible damage to the posterior portion of the brain), basal cell carcinoma, teratogenicity

Pros: very efficacious compared to older agents

Cons: some of the worst side effects include PML, PRES, macular edema (swelling of the optic disc)

 

Tysabri (novantrone)

Mechanism of action: blocks alpha-4 integrin, an adhesion molecule on vascular endothelium, reduces activation of autoimmune cells

Efficacy: 67% reduction in ARR compared with placebo

85% reduction in new MRI lesions

Side effects: PML, herpes simplex virus, infections, abnormal liver enzymes, bradycardia, heart block

Pros: efficacious

Cons: risk of PML, bradycardia, heart block

 

In summary, the least efficacious medications are the most benign in terms of side effect profile, while the strongest immunomodulators have the more devastating potential side effects. While clinical trials reflect beneficial conclusions, attention must still be directed towards potential side effects occurring over a prolonged time which may not be reflected in clinical trials which usually involve a timeframe of a few years and do not span over decades. The real test is in the post-marketing groups.  Speak to your neurologist. See package insert for more complete information of side effects.

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