Q: What is the most effective treatment strategy for reducing active symptoms and delaying disability in patients with MS?

Although there have not been head-to-head comparisons of ocrelizumab (B-cell depletion), natalizumab (T-cell traffic blocking), or alemtuzumab (anti-CD52) with fingolimod or dimethyl fumarate, I think that most of us agree, and the literature strongly suggests, that the former drugs are most effective and should be used as a first line. Specifically, early B-cell depletion appears to have a major effect on stopping the inflammatory process associated with early MS, and may be the most effective drugs for stopping flare-ups with minimal side effects. Alemtuzumab is similarly a highly effective way of stopping relapses, but there is the issue of drug-induced autoimmunity. Approximately 35% of patients develop autoimmune thyroid disease, 1% to 2% of patients develop idiopathic thrombocytopenic purpura, and there have been a few reported cases of Goodpasture syndrome. This suggests that ocrelizumab may be the most cost-effective in terms of therapeutic index. Still, those 2 drugs are clearly the most effective. An additional issue with natalizumab is progressive multifocal leukoencephalopathy, with approximately half of the patients being positive for the JC virus. Also, some patients will have a flare-up when they discontinue taking natalizumab. However, while the most effective method of stopping the disease may be with ocrelizumab and alemtuzumab, the major question is whether these drugs stop the disease from entering the progressive phase later on. We do not know the answer to that question.

Despite some thoughts on platform therapies that I have expressed previously, and that most people do not need these kinds of aggressive treatments, I think that alemtuzumab is a unique kind of medicine because it does 2 things at once. The drug is immunosuppressive, for at least the first 2 years or longer, but it is also immune-reconstitutive, meaning that it does not affect the bone marrow directly, and it recruits more regulatory populations into the blood and into the immune system after several years. There are issues with the drugs, particularly as they affect the thyroid, and the autoimmune problems in the early return of B cells, but when you examine the evidence, you can superimpose the relapse-free 5-year data of alemtuzumab upon that of autologous bone marrow transplants, (There were a number of meta-analyses published last year, including 1 in JAMA Neurology [formerly Archives of Neurology] and 1 in Neurology.) Dr Hafler had mentioned that, throughout the world, alemtuzumab can be used as a first-line agent; however, in this country we are not allowed to use it until the patient “fails” 2 other therapies. There are individuals I see clinically and I would like to start them on a drug such as alemtuzumab. Alemtuzumab, unlike ocrelizumab or natalizumab, provides 55% relapse-free activity at 7 years, without re-treatment. This would be my approach to aggressive therapy, currently limited by our ability to get it through the insurers, the payers.

That remains an open question and an area of active debate. There is no question that currently available therapies are beneficial, but in what order or sequence they should be used and which therapy should be used first remain a major challenge. In general, many clinicians have used, at least up until recently, a so-called step-wise approach where the clinician might start with a platform therapy such as a self-injectable interferon or glatiramer acetate, see how the patient does, and then escalate to a more effective therapy if there is breakthrough disease. More recently, there has been emphasis on considering the use of the more highly effective therapies earlier in the disease, even as a first-line therapy, for the reason that more successful suppression of all or the vast majority of inflammatory activity right from the beginning might translate into better intermediate and long-term success. The outcomes we are really looking for are prevention or delay of transition from relapsing MS to a more disabling progressive form of the disease. And there are some data now suggesting that, perhaps, highly effective early therapy may be more likely to achieve that. Some studies now are starting to directly address that issue.