Relapsing multiple sclerosis (MS) who are withdrawn from the monoclonal antibody natalizumab (Tysabri, Biogen-Idec) may experience a significant rebound increase in disease activity.

Researchers at the VU University Medical Center, in Amsterdam, the Netherlands, found patients with relapsing MS who stopped taking the drug developed 3 times as many brain lesions in the 15-month period after discontinuing natalizumab as they had before starting the medication.

Furthermore, with an observed 5-fold increase in brain lesions, this effect was most pronounced among individuals who took the drug for only a short time.

The study, which included 21 patients, came about because in 2005 natalizumab was withdrawn from the market and clinical trials put on hold after 3 patients in clinical studies developed progressive multifocal leukoencephalopathy (PML).

Following completion of a safety analysis of all patients treated with the drug, natalizumab was subsequently reintroduced in 2006, and clinical trials resumed under a Food and Drug Administration special restricted-distribution program with specific guidelines for use and monitoring of patients for signs of PML.

"All our patients had an MRI shortly after the drug was suspended, and our neuroradiologist noticed that in some patients a considerable number of new lesions developed during this 15-month interval. We decided to do a formal analysis to see whether this is actually the case," principal investigator Machteld Vellinga, MD, said in a statement from the American Academy of Neurology.

The study is published online September 12 in Neurology.

Rebound Effect

A total of 21 patients were included in the analysis — 9 women and 12 men, with a mean age of 39.8 years and mean disease duration of 5.8 years. All subjects were participants in the phase 3 program of 2 clinical trials — the Natalizumab Safety and Efficacy in Relapsing Remitting MS (AFFIRM) or the Safety and Efficacy of Natalizumab in Combination with Interferon beta-1a in Patients with Relapsing Remitting MS (SENTINEL).

Patients randomized to natalizumab had active treatment during the double-blind and extension phases of the study, with a median of 36 infusions. Those randomized to placebo received the drug only during the extension phase and received a median of 2 infusions.

To create the longest possible interval between pretreatment MRI scans, the earliest available brain MRI was chosen for each patient. A total of 42 pairs of scans were scored for new and enlarging T2 lesions.

According to the study, the median annualized number of active T2 lesions was increased in the postwithdrawal interval compared with the pretreatment interval. The researchers found no effect of age, sex, disease duration, MRI lesion load, or whether the subjects had been enrolled in either AFFIRM or SENTINEL trials.

Furthermore, the authors note, the increase in disease activity was much more pronounced in the placebo/natalizumab patients compared with the natalizumab/natalizumab subjects.

"Our data suggest a significant 'rebound' increase in the development of new and enlarging T2 lesions in patients with MS who discontinued natalizumab treatment, which appears to be driven by the patients with only short exposure to natalizumab," the investigators write.

Clinical Practice Remains The Same

It is not clear, said Dr. Vellinga, why discontinuation of the drug would lead to increased disease activity. However, she notes the finding of partial immunosuppression giving rise to extra disease activity has previously been observed in rats with an animal model of MS who were treated with low-dose cyclosporine A.

However, she added, further research needs to be done with larger numbers of patients before any recommendations can be made about the use of natalizumab.

"For now the recommendations remain the same — patients and their doctors should choose the most applicable treatment for them," she said.

Dr. Villenga declares no conflict of interest related to the study. Conflict-of-interest information for other authors is available in the paper.

Neurology. Published online September