MONTREAL—Treating patients with multiple sclerosis (MS) who have breakthrough disease activity despite the use of disease-modifying drug therapy requires identification of suboptimal responders, a monitoring strategy, and consideration of largely unproven treatment approaches, said Richard A. Rudick, MD, at the 2008 World Congress on Treatment and Research in Multiple Sclerosis.
“A large proportion of patients with relapsing-remitting MS will show signs of disease activity within one to two years,” said Dr. Rudick. “This is not necessarily a poor response to therapy; this is expected.”
In published phase III trials, 62% to 75% of patients with relapsing-remitting MS had one or more relapses within two years while on disease-modifying drug therapy, about one fourth had a sustained increase in Expanded Disability Status Scale score, about one fourth had one or more gadolinium (Gd)-enhancing lesions, and more than half had one or more new T2 lesions.
Identifying nonresponders, therefore, is the first consideration in managing true breakthrough disease, said Dr. Rudick, Director of the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic. Patient self-report and the physician’s global impression of change are usually the initial approaches, although the validity of these approaches has not been studied.
Relapses do not appear to be a reliable marker for response to a disease-modifying drug, according to Dr. Rudick. In placebo-controlled clinical studies, many patients who remain on placebo will have fewer relapses in year 2 than in year 1—a regression to the mean phenomenon. Reliance on relapse data—especially from studies in which patients are crossed over from placebo to treatment after a length of time—to justify a switch of therapy is therefore misleading, said Dr. Rudick, who is also Vice Chairman of Research and Development in the Neurological Institute at Cleveland Clinic and Professor of Medicine in the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University.
“MRI findings are considerably more promising,” he said. Several studies suggest that Gd-enhancing lesions or T2 lesions developing while on treatment are reliable indicators of suboptimal response or nonresponse to interferon treatment.
Dr. Rudick cited a study in which 383 patients with clinically isolated syndrome underwent MRI scans every six months for up to 18 months. Among patients treated with interferon beta-1a, those who developed at least one Gd-enhancing lesion, or two or more T2 lesions, at six months had nearly four times the risk of converting to clinically definite MS within 30 months (hazard ratio, 3.94), compared with treated patients who had no Gd-enhancing lesions and/or less than two T2 lesions at six months.
MRI activity “appears to be a marker at six months that identifies progression over the subsequent 18 months and is predominantly seen in the treated groups, so this appears to be a treatment response marker,” said Dr. Rudick. “We may not need to wait for one or two years.” The same predictor has not been studied in groups treated with glatiramer acetate, he noted.
At this point, there is no reliable biomarker for response or nonresponse to interferon or glatiramer acetate. However, “multiple studies by groups worldwide have documented a blunted or absent biologic and clinical response to interferon in patients with high titer neutralizing antibodies,” he said.
Managing patients with breakthrough disease starts with a monitoring strategy, asserted Dr. Rudick. “I see patients semiannually for a history and physical. I do an annual MRI scan, and I always consider the possibility of noncompliance. Patients don’t volunteer that they’re not taking their medication,” he said.
Next, he recommends deciding how much disease activity is tolerable. “I believe this has to be individualized,” he said. “In many patients, an occasional relapse is not only anticipated, but it may be okay. You need to consider how well the individual patient recovers from relapses.”
More aggressive management would be warranted in those patients who recover poorly from relapses. “For patients on interferon, I check neutralizing antibodies if I’m in doubt, and some argue that all patients on interferon should have antibodies tested,” he said.
For patients with unacceptable levels of disease activity, clinicians should consider changing therapy “probably earlier rather than later,” Dr. Rudick advised. Switching between interferon products and glatiramer acetate is a common practice for patients with breakthrough disease, but there are no randomized controlled trials to support this practice. Regression to the mean will drive the appearance of switching toward benefit. Dr. Rudick recommended that treatment should only be switched when a patient develops neutralizing antibodies while on interferon, in which case the patient should be switched to glatiramer acetate.