Strategies to counteract side effects of new MS therapies

The drawback in the new immunotherapies in multiple sclerosis (MS) include severe infections that can be fatal. For example, treatment with natalizumab, which reduces the immune surveillance of the brain, can lead to the development of progressive multifocal leukoencephalopathy (PML), a typically fatal form of viral encephalitis.

Prof. Ralf Gold (RUB Clinic for Neurology, St. Josef Hospital) and Dr. Werner Wenning (Ortenau Clinic, Offenburg-Gengebach) employed plasmapheresis to eliminate the active pharmaceutical agent and thus clear the virus from the brain. A report on their successful method of treatment has been published in the current edition of the New England Journal of Medicine.

Suppressing the destructive impact of leukocytes in MS

Natalizumab is a monoclonal antibody that has been approved for the treatment of severe RR MS (relapse remitting MS) in the EU since 2006. The antibody attaches to specific structures on the surface of white blood cells thus reducing their ability to attach to and pass through vascular wall into the inflamed tissue. The active agent thus suppresses the destructive effects of leukocytes that attack the myelin sheath, the insulating layer of nerve fibres. Leukocytes theoretically attack and destroy destructive foreign substances such as viruses or bacteria, thus the drawback of this medication is a decrease in the immune defense of the brain.

Unfulfilled hope: monotherapy is also not harmless

Clinical studies with Natalizumab led to progressive multifocal leukoencephalopathy (PML) in two MS patients. This severe brain infection is triggered by the JC virus found in about 80% of all adults. Normally the immune system does however control the virus. Less experienced physicians can easily mistake PML symptoms with an acute attack of MS. Prof. Gold explained that both study patients had also been administered the immune activating drug Interferon Beta, thus the hope that the monotherapy was relatively harmless had been realistic. Moreover, when the drug was approved at the beginning of summer 2006, the manufacturing company BiogenIdec had offered country-specific intensive preparatory seminars covering almost all precautionary and therapeutic measures. In July 2008, PML was diagnosed almost simultaneously in a German and Swedish MS patient, after 14 and 16 months of Natalizumab treatment respectively.

Treatment in Offenburg, supervision in Bochum

The strategies of treating the infection are the topic of the two studies that were simultaneously submitted for publication by the German and Swedish authors. The German patient was treated by Dr. Werner Wenning in Offenburg, and the therapy supervised by Prof. Gold in Bochum.

Plasmapheresis eliminates the active agent natalizumab

The treatment was targeted at re-establishing the patients own immune system to enable it to eliminate the JC virus. The physicians thus had to remove the active agent Natalizumab from the patient's body. Natalizumab circulates within the body for a very long time, taking an average half–life of 16 days (before the concentration is reduced by about 50%). The researchers in Bochum and Offenburg thus decided to perform Plasmapheresis. Subsequent measurements showed that the drug plasma level had dropped from 10,8 µg/ml to below 0,25 µg/ml within a week. In parallel a temporary improvement of the symptoms was observed. A secondary deterioration developed 4 weeks later, with increased motor deficits as well as clouding of consciousness. In this phase of the immune reconstruction inflammatory syndrome (IRIS), immune cells (cytotoxic lymphocytes) eliminate the virus in the brain. This leads to the destruction of the infected oligodendrocytes, supporting cells in the brain responsible for the insulation of the nerve cell connections. The patient required 4 weeks of intensive care, including artificial respiration and tube feeding, before he could be transferred for follow-up rehabilitation. The therapeutic measures have been described and discussed in detail in the manuscript.

Neurologist must know how to handle new side effects

Prof. Gold pointed out that new MS drugs unfortunately also have new side effects that can sometimes be fatal. Currently Natalizumab is the focal point of interest throughout the world, but that other new drugs, such as Alemtuzumab or anti-CD20 antibodies may soon follow. It is thus important that the neurologists are extremely well-informed about complications and the treatment thereof. In future, “therapeutic navigation” through modern immune therapies with escalation and de-escalation cycles according to the activity of the disease may be possible.

Title

Werner Wenning, Aiden Aghikia, Jörg Laubenberger, David B. Clifford, Peter F. Behrens, Andrew Chan, Ralf Gold: Treatment of Progressive Multifocal Leukoencephalopathy Associated with Natalizumab. In: N Engl J Med 361;11, 10.9.2009

Linker RA, Kieseier BC, Gold R. Identification and development of new therapeutics for multiple sclerosis. Trends Pharmacol Sci 2008; 29: 558-565

Further Information

Prof. Ralf Gold, Neurological Clinic at the Ruhr-University Bochum in St. Josef-Hospital, Gudrunstraße 56, 44791 Bochum, Tel.: 0234/509-2410, Fax: 0234/509-2414, E-Mail: ralf.gold@rub.de