What We Know Today: Multiple Sclerosis

There has been a veritable explosion in our understanding of the pathophysiology of multiple sclerosis (MS). That understanding correlates with experimental work that has also identified novel treatment innovations. In the time between the earliest effective therapy of beta-interferon and today’s agents, further decreasing the frequency of relapses has become a reality. This month’s Top Paper¹ is a succinct summary of these efforts and inroads.

Here are 5 key take-away messages:

1. One way to categorize the ever-increasing therapeutic armamentarium utilized to treat MS is to divide the agents into the era in which they were discovered.

• Era 1 (1993-2003): The treatments of this era—methyprenisolone, interferon, and glatiramer acetate—represented the first time we could treat MS with measurable success. The latter 2 agents led to slightly greater than 30% reductions in annual relapse rates. 

• Era 2 (2003-2009): Therapeutic advances included natalizumab and fingolimod.

• Era 3 (2009-present): We are now in the era of biological agents and “small molecules.” 

2. We now have an idea of efficacy comparing agents across therapeutic eras. The most effective agent is natalizumab, but other agents that are considered “highly effective” include fingolimod (an oral agent) and dimethyl fumarate. Moderately effective therapies include beta-interferon, glatiramer acetate, and teriflunomide.

3. Since agents come from disparate categories, their differences can be very important. For example, glatiramer acetate is favored in pregnancy. Natalizumab can cause progressive mutifocal leukoencephalopathy. Fingolimod can lead to disseminated zoster and should not be used in patients with conduction system disease. A newer agent, alemtuzumab, is a CD52 antibody that can cause severe autoimmunity including idiopathic thrombocytopenic purpura. Note: Side effects for each therapy can be different as well.

4. Work has been directed at biomarkers reflecting MS activity. The severity and activity of MS today is calculated by the number and frequency of relapses and the number of white matter plaques on an MRI. Some day we may be better equipped and possess serum and cerebrospinal markers that are far more sensitive in uncovering even smoldering MS activity.

5. All the efforts to find therapeutic success against MS have taught us valuable facts about the disease itself. For example, success treating rheumatoid arthritis and inflammatory bowel disease with tumor necrosis factor-blocking agents led to trials in MS; however, these agents did not work. But rituxamab, a CD20 antibody, has been beneficial in MS. And, as previously mentioned, alemtuzumab also substantially decreases relapse rates.² As a correlate of its success, we have acquired insights into lymphocytes and MS disease mechanisms.

We still have not conquered MS and surely do not completely understand its pathophysiology. But we are learning. Newer understanding of gray matter atrophy and the risk of later and slower cognitive decline that may not be a result of acute inflammation have expanded our appreciation of the complexity of MS. The progress over 3 relatively recent eras provides optimism for future novel successes. Stay tuned: The landscape for battling MS is changing rapidly.

Gregory W. Rutecki, MD, is a physician at the National Consult Service at the Cleveland Clinic. He is also a member of the editorial board of Consultant. Dr Rutecki reports that he has no relevant financial relationships to disclose.

References:

1.Ransohoff RM, Hafler DA, Lucchinetti CF. Multiple sclerosis—a quiet revolution. Nat Rev Neurol. 2015;11(3):134-142.

2.Willis MD, Robertson NP. Alemtuzumab for the treatment of multiple sclerosis. Ther Clin Risk Manag. 2015;11:525-534.