MULTIPLE SCLEROSIS – THE YEAR IN REVIEW
The year 2019 saw some important developments in how MS is treated, with increasing use of more effective medications, a number of new therapies in development, and a few cautionary tales about drug safety.
Older MS therapies, such as Copaxone and the interferons, have been declining in recent years due to the unpopularity of frequent injections and the availability of more effective oral or infusion medications. People often prefer starting treatment with an oral drug that can be taken daily, such as Aubagio or Tecfidera. Many have now been taking these therapies for over a decade and have generally done well. A 10-year analysis reported this year that most people on Tecfidera remained free of relapses and had no worsening of their disability (Gold and colleagues. ECTRIMS 2019; abstract P1397).
An increasingly popular therapy is Mavenclad, an oral drug that is taken just 8-10 days a year. The therapy has been in use in a number of countries (including Canada) for a couple of years and received FDA approval in March 2019. Two other MS medications also got the green light from the FDA: Mayzent and Vumerity (neither is available in Canada yet). Mayzent is a second-generation version of Gilenya and is noteworthy as the first treatment to be successful in a phase III trial of people with secondary-progressive MS. The dose of the drug is slowly increased at the beginning (called titration) so the first dose doesn’t have to be taken in a clinic. Vumerity is a second-generation version of Tecfidera that aims to cause less stomach upset.
Four other MS medications are in late-stage development and are expected to be released soon. Ozanimod and ponesimod are the same category of drug as Gilenya (and Mayzent). Ofatumumab is in the same class as Ocrevus but it given as a once-monthly injection. Initial results were presented this year and showed that ofatumumab was more effective than Aubagio (Hauser and colleagues. ECTRIMS 2019; abstract 336). Evobrutinib is a novel therapy that switches off immune cells that contribute to MS inflammation in the brain. The oral therapy has completed a phase II trial (Montalban and colleagues. N Engl J Med 2019;380:2406-2417) and has now entered phase III testing.
Drug safety is always a concern, especially with increasing use of medications that have potent, sustained effects on the immune system. A watershed event of this year was the report of a case of PML (progressive multifocal leukoencephalopathy), a potentially fatal brain infection, in a person during treatment with Ocrevus. PML is caused by a virus (the John Cunningham [JC] virus). It normally lies dormant in most people, hiding out in places such as the kidneys, tonsils and immune cells (B cells) and escaping detection by the immune system. But if the immune surveillance is impaired, the virus can flare up and cause an infection. The risk of PML is considered to be very low when people are treated with a medication that targets B cells (one of the virus’ hiding places). The one PML case thus far to be directly attributed to Ocrevus is the exception that proves the rule.
That case led to two important discussions this year about MS and its treatment. The PML case occurred in a man who started treatment with Ocrevus when he was 76 years old. It isn’t clear why he started treatment so late or why he was given such a potent drug. His immune system was showing signs of age-related decline (called immune senescence) before treatment. So it sounded a note of caution about using potent immune-suppressing drugs in older people.
This led to a second discussion: is there an age at which the potential benefits of an MS drug are outweighed by the potential harms? MS becomes less inflammatory (fewer relapses and MRI lesions) over time and there is evidence to suggest that MS medications become less effective as a person ages (Weideman and colleagues. Front Neurol 2017;8:577). Meanwhile, aging makes a person more susceptible to risk because the immune response is less robust, the person may have other medical conditions and may be taking other medications. So the benefits are decreasing while the potential harms are increasing. This issue is still a hot topic of debate but it’s likely that we’ll see doctors considering stopping treatment once a person has reached age 60 or 65 (Salavisa and colleagues. ECTRIMS 2019; abstract P703).
2019 also saw the first full year of legalized cannabis in Canada. While many people with MS now use cannabis for symptoms such as muscle stiffness, sleep difficulties or pain, a few worrisome problems have emerged.
A high-profile effect has been the increasing number of regular cannabis users showing up at Emergency rooms with uncontrollable vomiting, a condition that is now being called cannabinoid hyperemesis syndrome (CHS). In severe cases, chronic vomiting can cause dehydration, electrolyte abnormalities and kidney failure. People at risk are those who use cannabis on a daily basis. Since cannabis is often used to relieve nausea, it’s likely a dose-related effect, with lower doses reducing nausea/vomiting signals in the brain and higher cumulative doses triggering nausea/vomiting signals in the gut. Anti-nausea drugs offer little relief. Symptoms can be relieved with a hot bath or shower – which can worsen MS symptoms. Unfortunately, symptoms can often persist for months after stopping cannabis. (For Health Canada’s summary of cannabis and CHS go to www.canada.ca/content/dam/hc-sc/documents/services/drugs-medication/cannabis/information-medical-practitioners/information-health-care-professionals-cannabis-cannabinoids-eng.pdf).
There are also more common concerns. Cannabis may increase the risk of falls since it can cause balance problems and dizziness, so caution is advised. Many people with MS also suffer from cognitive difficulties and regular cannabis use can make them worse (Feinstein and colleagues. ECTRIMS 2019; abstract P542). Cognition appears to return to normal after a month of being weed-free. The cognitive test that doctors typically use is called the SDMT, which may well come to stand for: Sorry Dude, Marijuana’s Taboo.
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