COPENHAGEN—At the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), Sten Fredrikson, MD, Professor of Neurology at the Department of Clinical Neuroscience at the Karolinska Institute in Stockholm, summarized the arguments for and against early MS treatment.
“As it turns out, MS is really a moving target,” he said. “It’s not the same thing now as [it was] 20 or 30 years ago.” Prof. Fredrikson pointed to recent updates to MS diagnostic criteria that allow for immediate diagnosis if the first MRI shows dissemination in space (DIS) and dissemination in time (DIT). “When we talk about early MS, it has probably been ongoing for quite a long time, not only in clinically isolated syndrome (CIS), but also before that, without any clinical symptoms,” he explained. This new diagnostic classification is called radiologically isolated syndrome (RIS).
The Arguments for Early Treatment
A comparison of the 2010 diagnostic criteria with the 2005 criteria showed that 30% of CIS patients can now be diagnosed as having MS after a single MRI. The significance of altering these diagnostic margins is not only that it moves up the diagnostic timeline for individual patients, but that it also reclassifies into a treatment category a large percentage of patients who previously would not have been treated. “The time to diagnosis differed significantly between the 2005 and 2010 criteria, so the conclusion will be that the CIS group will probably be reduced after the introduction of the new MS criteria, and we will have more relapsing-remitting cases,” Prof. Fredrikson explained.
The main presenting complaint for patients referred for an MRI that identifies RIS is headache, he reported. “About two-thirds of the patients with RIS show radiologic progression over the next five years, and about one-third develop neurologic symptoms,” said Prof. Fredrikson.
“The question that we come back to is, of course, should RIS also be treated?” Prof. Fredrikson looked at the current understanding of MS pathogenesis, according to which, inflammation appears to be dominant in early phases of the disease, while degeneration dominates in later, progressive disease. “The drugs we have are anti-inflammatory, which means [that] these drugs are most effective during the anti-inflammatory phase,” he said. The rationale for early treatment (ie, at the point of CIS or RIS) is the prevention of irreversible axonal damage that leads to later disability. Cognitive effects resulting from early gray matter changes also may be averted.
One of the interesting arguments for early treatment in MS comes from a knowledge base borrowed from hypertension studies, Prof. Fredrikson explained, where it has been established that the number of patients with mildly elevated blood pressure who need to be treated to prevent one stroke is 118. In studies of CIS, numbers needed to treat are reported in the BENEFIT and CHAMPS trials as six and seven patients, respectively. “This [result] speaks in favor of the treatments that we can offer the patients having clinical effect,” said Prof. Fredrikson.
Questions of long-term efficacy are beginning to be answered, he said, pointing to recent studies by Trojano et al and Tedeholm et al that indicate a longer time to progression, as well as a study by Goodin et al that showed improved long-term survival with earlier intervention.
The Arguments Against Early Treatment
Still, Prof. Fredrikson said, there are a number of arguments against early treatment, the most significant of which is the potential for misdiagnosis. “Everyone who has been working with the disease for some years has seen so-called typical CIS that has been caused by other reasons,” he explained, emphasizing that it is important when managing patients with CIS to exclude other pathologies. “One way of doing that is by looking for the red flags described by Miller et al,” he said.
Data from the BENEFIT trial show that 85% of CIS patients will develop MS within two years based on MRI findings. Long-term data are not yet available on CIS patients, but benign MS appears to be a rare phenomenon, said Prof. Fredrikson. Therefore, 15 to 20 years of disease-modifying therapy in these few patients may entail more risks than benefits.
Patient Selection Is Key
Prof. Fredrikson offered practical recommendations for early treatment approaches. Initiation of therapy is appropriate for patients whose symptoms have no explanation other than MS, and for CIS with demyelination, he said, noting that the decision to treat or not to treat is less clear in CIS with MRI not showing DIT and DIS. In these cases, he recommended repeating the MRI in three to six months, but noted that starting therapy is also an option. Finally, for patients with RIS who have clinical symptoms with no better explanation, the notion of treatment is more controversial. “There are no studies or evidence to indicate how to handle these patients,” concluded Prof. Fredrikson, suggesting that waiting three to six months before repeating the MRI to decide on treatment is the most reasonable approach.