Natalizumab Withdrawal Poses Risk for New T2 Lesions in Patients With MS

Discontinuing the use of natalizumab may increase the number and size of T2 brain lesions in patients with multiple sclerosis (MS), according to a study in the online September 13 Neurology.

Machteld Vellinga, MD, a neurologist at the VU University Medical Center in Amsterdam, and colleagues retrospectively reviewed the annualized number of new and enlarging T2 lesions before and after treatment with natalizumab in 21 patients (12 men, 9 women; mean age, 39.8; mean disease duration, 5.8 years) who participated in two pivotal phase III clinical trials. One group of participants received natalizumab infusions for two months, while the other received natalizumab infusions for approximately three years. In patients who received natalizumab for two months, the median annualized number of new and enlarging T2 lesions increased from 2.24 pretreatment to 10.37 posttreatment. In the group treated with natalizumab for three years, T2 lesions increased from 3.47 pretreatment to 4.81 posttreatment. According to the authors, this is the first time such a rebound effect has been observed in patients treated with natalizumab. This finding may be important, because accumulation of T2 lesions has been associated with progression of brain atrophy and disability, noted Dr. Vellinga.

Approved by the FDA in November 2004, natalizumab was withdrawn in February 2005 due to three cases of progressive multifocal leukoencephalopathy. After further evaluation and institution of a risk management plan, natalizumab was reapproved in June 2006 for the monotherapy treatment of relapsing forms of MS in patients who cannot tolerate or have not responded to other treatments. Guidelines for the safe use of natalizumab have recently been published.

Richard Ransohoff, MD, Director of the Neuroinflammation Research Center at the Cleveland Clinic, and author of the natalizumab guidelines, commented, “This small study is potentially important but a very preliminary finding. A similar ‘rebound’ phenomenon has been observed in the mouse model of MS, but the pathogenic mechanism is uncertain. There is a large database of patients who have taken natalizumab that will allow for further investigation. In time, this observation will be either strengthened or falsified. Based on this study, I would not change the guidelines for the use of natalizumab, which is indicated for patients who require second-stage treatment for aggressive MS. However, I would introduce the subject to patients at the time the medication is discussed and make time for any questions.”

Dr. Vellinga agreed, “For now, our observations do not change the way we use natalizumab in our center. Given the small sample size, our results do not give rise to practical recommendations for patients and physicians.

“I recommend that further research be conducted to explore and quantify the suggested rebound effect on T2 lesional activity in larger patient groups,” Dr. Vellinga concluded. “In addition, it would be important to establish whether this rebound effect occurs not only in T2 lesional activity but in relapse frequency and disability progression as well.”

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