Natalizumab in multiple sclerosis: protecting patients from viral disease PML
02.07.2012 11:42
The drug Natalizumab has been considered a major advance in the treatment of relapsing-remitting multiple sclerosis since its introduction in Europe about six years ago. However, in patients who have certain risk factors, prolonged treatment with the monoclonal antibody can cause a serious viral illness, progressive multifocal leukoencephalopathy (PML), to occur as a side effect. This was confirmed in a recent analysis of clinical trials and a Swedish registry. At the same time, a new information sheet for patients was published in Germany.
“After two years of therapy with natalizumab - after a thorough risk-benefit assessment between patient and doctor and detailed information - the patient's written consent should be renewed. At this point, an alternative therapy must be sought in the risk groups,” recommends Professor Ralf Gold, MS expert from Bochum and board member of the German Society for Neurology (DGN). The DGN, the Multiple Sclerosis Disease-Related Competence Network (KKNMS) and the German Multiple Sclerosis Society (DMSG) have already pointed this out in the past. The current results, recently published in the New England Journal of Medicine, underline these precautionary measures. The relevant patient information sheet on long-term therapy with natalizumab is updated and available on the KKNMS website.
Rare but serious brain infection
Progressive multifocal leukoencephalopathy is a severe demyelinating disease of the central nervous system caused by the JC virus (JCV). It is the most feared complication of natalizumab therapy, as the disease is fatal or causes severe disability in 20 percent of these patients. The JCV is a human polyomavirus 2; JC stands for the initials of the index patient, John Cunningham, in whom the virus was first described as the cause of his illness. 60 percent of people are naturally infected with the virus. However, it only becomes pathogenic when it passes from the blood and peripheral organs into the central nervous system. The risk of disease is generally low: by the end of the study period, 212 cases (as of May 2012: 242) out of a total of 99,571 patients worldwide who had been treated with natalizumab were confirmed. The researchers calculated an incidence of 2.1 diseases per 1000 patients, but this increased approximately fivefold to 11.1 JCV diseases per patient in patients with positive JC antibody detection, previous immunosuppressive therapy and treatment with natalizumab for longer than two years 1000 increases.
Individual risk assessment
Conversely, the risk of the viral disease appears to be significantly lower in people who do not have JC antibodies. “According to current knowledge, the risk of JCV antibody-negative patients developing PML while taking natalizumab is close to zero (0.09 cases per 1000 patients). However, if the patients are JCV-positive, have received previous immunosuppressive therapy and have been treated for more than two years, the risk even increases to 1: 90,” says Professor Gold. Therefore, various options are being researched to identify early on those MS patients who are at increased risk of PML. The determination of JCV serology is an important option and is currently offered free of charge by a European central laboratory. The JCV antibody status can be tested through a simple blood test and helps to assess the individual risk of developing PML and to detect other subgroups.
“In addition, risk monitoring strategies for seropositive patients should be defined and optimized,” is the recommendation of Professor Heinz Wiendl, director of the Clinic for Inflammatory Diseases of the Nervous System and Neuro-Oncology at the Westphalian Wilhelms University of Münster and spokesman for the board of the KKNMS. Treatment with natalizumab is carried out under neurological control. If PML is suspected, an MRI, blood tests and usually a cerebrospinal fluid examination are ordered immediately. Natalizumab therapy is stopped until PML is ruled out.
First available monoclonal antibody for the treatment of MS
Natalizumab is approved for the treatment of relapsing-remitting multiple sclerosis in patients who do not respond to conventional therapy. The monoclonal antibody is directed against the adhesion molecule VLA-4 and reduces the passage of lymphocytes across the blood-brain barrier. This therapy often results in a significant reduction in relapse events and stabilization, and in some cases even an improvement in the degree of disability. Natalizumab is administered as a monthly infusion and is generally very well tolerated. It is one of the most effective medications for MS. However, the risk of developing PML during therapy led to the drug being withdrawn from the market in the USA in 2004 shortly after its introduction. In 2006, Natalizumab again received a strict, narrow approval. In the same year, natalizumab was also introduced in Europe with corresponding warnings.
In order to ensure standards in therapy with natalizumab, the KKNMS published a quality manual for doctors last year in close cooperation with DGN, DMSG and the neurological professional associations BDN and BVDN. It can be ordered through the KKNMS office.
service
Patient information sheet can be downloaded at www.competencenetz-multiplesklerose.de/de/eskalationstherapie/natalizumab