Disease Modifying Therapies in Multiple Sclerosis: Background for General Readers

Multiple sclerosis (MS) is a presumed autoimmune condition of demyelination and often inflammation of the central nervous system. Its evolution is very variable; some patients suffer episodes lasting weeks to months with complete or near complete recovery in between, and the periods between episodes may span months to decades (relapsing remitting MS). Other patients accumulate progressive disability as a result of or between episodes (secondary progressive MS). Still other patients, around 10% in total, do not suffer episodes but instead undergo a gradually progressive course with variable rapidity, but usually noticeable over the course of months to years (primary progressive MS). Patients with MS can evolve from one category to another; some in fact at a certain point remain clinically stable indefinitely.

For many decades, its immune basis has prompted trials of various immunomodulatory agents to try and reverse or at least arrest the progression of multiple sclerosis. Some have been shown not to work, e.g corticosteroids, immunoglobulin. Some work but have largely been overtaken by newer, more expensive, therapies. For example, azathioprine is a traditional commonly used immunosuppressant and in a Cochrane review was found to reduce relapses by around 20% each year for three years of therapy, and to reduce disease progression in secondary progressive disease by 44% (though with wide confidence intervals of 7-64%). There were the expected side effects but no increased risk of malignancy. However it remains possible that there could be a cumulative risk of malignancy for treatment durations above ten years. In the 1990s, beta-interferon became widely used but was never compared directly with azathioprine. With the 21st century came the introduction of “biological therapies”, typically monoclonal antibodies against specific immune system antigen targets. There has also been a reintroduction of non-biological therapies originally used to treat haematological malignancy or to prevent organ transplant rejection.

These new therapies, called disease modifying therapies, as opposed to symptomatic treatments or short courses of steroids for relapses, are now conceptually, though not biochemically or mechanistically, divided into two groups: those better tolerated or with fewer risks of causing malignancy or infections but less effective, and those with more risk of cancer and serious infection, including reactivation of the JC virus to cause fatal progressive multifocal leukoencephalopathy, but with greater efficacy.

The former group includes beta-interferons, glatirimer acetate and fingolimod. Fingolimod is an agent derived, like ciclosporin, from fungal toxins that parasitise insects and has the convenience of oral administration, but is now not routinely recommended because of severe relapses on withdrawal, and cardiac and infection risks.  The latter group includes the biological agents natalizumab (which targets a cell adhesion molecule on lymphocytes), rituximab and ocrelizumab (which target CD20 to deplete B-cells) and alemtuzimab (which targets CD52 expressed on more mature B and T cells) and the oral non-biological anti-tumour agent cladribine which blocks deoxycytidine kinase and thus interferes with DNA synthesis. Another  non biological oral agent, dimethyl fumarate, acts as an immunomodulatory rather than immunosuppressive agent and sits somewhere between the two groups, having oral administration convenience and better efficacy than the first group, but also possessing the increased PML and Fanconi renal syndrome risk of the second group.

Recent studies indicate that higher strength DMTs may slow disability progression in secondary progressive MS, as well as reduce the number of relapses. There have also been trials in primary progressive MS but these, most notably using rituximab, were not clearly positive. For a study looking at ocrelizumab on primary progressive MS, see the accompanying Journal Club review.

 

Cost of Disease Modifying Therapies

The disease modifying therapies are extremely expensive and, given MS is unfortunately not a rare disease, have a significant impact upon the health economy.

For example, in relation to the accompanying paper review of ocrelizumab for primary progressive MS, this drug is not really expensive compared to similar medications, having a list price of £4790 per 300 mg vial, with four infusions a year. There are many further costs associated with imaging, screening, monitoring and admission for infusions.

Normally, cost effectiveness is justified at around £35,000 per Quality of Life Adjusted Year (QUALY). This means the cost would be justified at £35,000 a year if each year it gave patients 100% quality of life who would otherwise die or have zero quality of life. Clearly ocrelizumab does not do that; it appears to preserve at least 0.5 or 1 out of 10 on a disability scale in 6% of patients on an ongoing basis, giving a quality of life per patient benefit of very roughly 0.6% and a QUALY estimate of over £3 million. Of course, there are other considerations such as wider health economy costs of disability, the fact that some patients might have been prevented from deteriorating by more than 1 point on the EDSS, and the potential costs of monitoring for and treating cancer and PML complications in a relatively young patient population even after treatment is stopped. Note that there was actually no significant difference in this study in the SF 36, with both groups remaining surprisingly little changed after about 2 years, which probably fits with the 0.6% mean improvement figure calculated above.

If the NHS, or the health economies of other countries, do not consider a tighter subset of primary progressive patients who might respond better, it is difficult to balance this with other medical, or indeed social care, conditions that require resourcing.

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1 Response to Disease Modifying Therapies in Multiple Sclerosis: Background for General Readers

  1. Pingback: Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis | Neurology Online Journal Club

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