Benefits, Risks of Immunomodulatory MS Drugs Assessed

Immunomodulatory drugs for multiple sclerosis (MS) control autoimmune damage to the central nervous system (CNS) by reducing immune cell numbers, altering their function, or blocking their access to the brain and spinal cord, but they do not to halt disease progression entirely, so developing drugs that protect patients from neurodegeneration or that regenerate damaged nerves is crucial — especially for those with late-stage progressive MS.

Oxford researchers Calliope Dendrou, PhD, and Lars Fugger (pictured), MD, PhD, reached this conclusion in a review article that appeared in last month’s issue of Current Opinion in Immunology, which focused on the theme of autoimmunity.

“This review gives a completely updated account of the therapeutic opportunities in MS,” Fugger, the chair of neuroimmunology in the department of clinical neurosciences of Oxford University Hospitals at the University of Oxford told MD Magazine. “In the last 20 years, we have progressed from using only one [class of] drugs — steroids — to using a variety of drugs that target different parts of the immune system.”

“The new drugs have also shown that MS is not only a T-cell driven disease but definitely also a B-cell driven disease,” he added.

Older, first-line immunomodulators, including the injectables glatiramer acetate (Copaxone) and interferon-β (Avonex, Betaseron, Plegridy, Rebif), are believed to work by affecting T-cells. Moderately effective and relatively safe, they decrease relapses by approximately 30% and remain cost-effective for 5 years or more. However, they do not work in all patients with relapsing-remitting MS (RRMS), and resistance to them may develop in those who respond to them initially.

Fugger’s team also assessed several other treatments, such as Cladribine, which inhibits DNA synthesis and although highly effective may cause opportunistic infections; Dimethyl fumarate (DMF) which appears to exert its immunomodulatory effects by changing the activation of dendritic cells, differentiation of T_H cells, and induction of regulatory B cells (its anti-oxidative effects may exert neuroprotection as well), but may cause lymphopenia; and Teriflunomide, which blocks the proliferation of activated T cells, and although effective, is also teratogenic and toxic.

Second-line agents are appropriate for patients who do not respond to first-line agents, those who have 2 or more disabling relapses annually, or those with progressive MS with relapses or with active disease shown by magnetic resonance imaging. According to the review, mitoxantrone (Novantrone), a cytotoxic immunosuppressant used for secondary progressive MS, is moderately effective in treating MS but can be cardiotoxic and cause leukemia with long-term use.

Some of the other second-line agents examined were Natalizumab (Tysabri), which reduces the yearly relapse rate by nearly 70% but may cause progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection that destroys oligodendrocytes in the CNS; Fingolimod (Gilenya), the only oral second-line agent, which is highly effective in treating MS but may result in PML, other infections, and cardiac arrhythmias; and alemtuzumab (Lemtrada), which results in the depletion of a large percentage of T and B cells, including pathogenic ones, and causes secondary immune disorders such as autoimmune thyroid disease to develop in 30% to 40% of patients treated with it.

“The neurodegenerative phase of the disease is the next big challenge,” Fugger said. “We are just beginning to understand the basis for this neurodegeneration. With time, this new understanding will lead to new drugs that, when given with immunomodulatory drugs, will lead to a much better life for MS patients.”

The review appeared in the September 16, 2017, issue of Current Opinion in Immunology.