Over time, neurologists who specialize in multiple sclerosis (MS) have tended to tolerate less and less disease activity before they consider changing their patients’ therapies. “The concept that’s starting to emerge in the MS field is that of striving for no detectable disease activity,” said Jeffrey A. Cohen, MD, Director of Experimental Therapeutics at the Cleveland Clinic Mellen MS Center.
Neurologists generally understand a disease activity–free state to mean an absence of MRI activity, relapses, and progression of disability. “With some of the more highly effective therapies, we’re also looking for remission of fatigue and depression complaints,” said Timothy Vollmer, MD, Professor of Neurology and Director of Clinical Research at the University of Colorado School of Medicine.
Why Is Tolerance for Disease Activity Decreasing?
One reason that the treating-to-target or “zero tolerance” approach to MS disease activity is gaining acceptance is that “we’re realizing that almost any ongoing disease activity has some potential ramifications, in terms of causing additional tissue damage,” said Dr. Cohen. The emergence of an increasing number of new and more effective disease-modifying therapies also has decreased tolerance for disease activity.
Some new therapies are more potent than the established drugs, but they also raise concerns about patient safety. For example, natalizumab increases the risk of progressive multifocal leukoencephalopathy in patients who have John Cunningham virus (JCV). The JCV antibody assay, however “increases the potential for using natalizumab,” and thus broadens neurologists’ therapeutic options, said Fred Lublin, MD, Saunders Family Professor of Neurology at the Icahn School of Medicine at Mount Sinai in New York City.
“Increasingly, we strive for a completely stable disease if we can attain it with reasonable safety and tolerability,” said Dr. Cohen. “Because none of our assessment tools is 100% sensitive, repeated re-evaluation of individual patients over time is needed. In addition, no particular treatment is going to work for all patients.”
How Should Neurologists Respond to Disease Activity?
The zero-tolerance approach would prompt a neurologist to consider changing therapies if the patient showed any signs of disease activity. But, because of a lack of data, the neurologist could not be sure that the patient would improve after switching to the new drug. Switch studies have all shown benefits, “but they’ve not been properly designed,” said Dr. Lublin.
“To answer the question in a scientific fashion, you’d have to take individuals who meet your definition of an inadequate response and randomize them to one of two other therapies. And then you could say whether switching them to therapy A is better than switching to therapy B,” he continued. “If you say to someone, ‘Well, we don’t think you’re doing so well, so we’re going to try you on this therapy or keep you on your same therapy,’ that’s not a real scientifically valid study design.
“When you take people who meet a definition of inadequate response, you’ve already got a biased population,” Dr. Lublin explained. “When you switch them to something else, just by regression to the mean, they tend to do better. And that’s why switch studies are challenged and, if not designed properly, don’t answer the question,” Dr. Lublin observed. Remission and Improvement May Be Possible for Some Patients The complete suppression of disease activity remains an elusive goal. “The problem with zero tolerance is that we don’t have any zero-activity drugs,” said Dr. Lublin. “Even with a therapy as good as natalizumab, 63% of individuals will fail that definition [ie, a disease activity–free state] over two years.
“However, we’ve seen zero activity with every drug we have out there in some people,” added Dr. Lublin. “So, for some people, it’s achievable ... for some people, it may not be achievable.”
Full disease remission is not possible in patients with high levels of disability, but it may be possible in patients with early-onset MS. A disease activity–free state appears to be achievable in at least some patients who are JCV antibody negative (ie, approximately 45% of the overall patient population) and are in the earlier relapsing-remitting phase of the disease, said Dr. Vollmer.
“On natalizumab and, we think, also on rituxumab, and probably on alemtuzumab, … in that patient population, a majority of patients … will not only have cessation of disease activity, they’ll actually get better over time,” he added. “About 30% continue to have relapses and will continue to develop ongoing disability.” Symptom stability or improvement may also be achievable in some patients with newer drugs such as fingolimod and dimethyl fumarate, “but we just haven’t treated enough patients and haven’t had them out long enough to be sure yet,” said Dr. Vollmer.