LYON, FRANCE—Among patients with multiple sclerosis (MS) who are treated with natalizumab, those of North African origin may be more likely to test positive for John Cunningham virus (JCV) than patients of European origin, according to research presented at the 28th Congress of the European Committee for Treatment and Research in MS (ECTRIMS). No previous research has linked ethnicity and risk of JCV, according to Patrick Vermersch, MD, a coauthor of the study. Increasing antibody titers have been identified as a risk factor for progressive multifocal leukoencephalopathy (PML).
Using multivariate analysis, Dr. Vermersch, Assistant Dean of Research at the University of Lille Medical School in France, and colleagues found that age at serology and length of exposure to natalizumab at serology also were significantly linked to the presence of anti-JCV antibodies. Patients older than 36.5 and those exposed to natalizumab for 24.5 months or more were more likely to have anti-JCV antibodies than were younger patients or those with shorter duration of treatment.
Using a validated enzyme-linked immunosorbent assay (ELISA), the researchers analyzed sera of 361 patients with MS who were receiving natalizumab. The mean duration of participants’ exposure to natalizumab was 27.27 months. Approximately 15% of patients had used immunosuppressants previously. More than half (51%) of participants tested positive for JCV.
New Assay May Improve Detection of JCV Antibodies
Gen-2, a new generation of the ELISA test, has improved signal resolution and appears to detect JCV antibodies with greater sensitivity than Gen-1, said Dr. Vermersch. He and his colleagues measured the seroprevalence of anti-JCV antibodies twice in the same patient cohort—once using the original assay, and again one year later with the new assay.
The Gen-1 test resulted in a seroprevalence of approximately 46%, and the Gen-2 test yielded a seroprevalence of nearly 61%. The proportion of patients converting from a negative result in the first test to a positive result in the second test was 29.1%, an “unexpectedly high rate,” said Dr. Vermersch. The false negative rates were 2.5% and 2.7%for STRATA and STRATIFY-1, respectively.
Most Patients With PML Have Anti-JCV Antibodies
The new test could soon improve neurologists’ ability to identify patients with MS who are at risk for PML. Of 91 patients with MS and PML who were treated with natalizumab, 89 (98%) tested anti-JCV positive at all time points in which samples were available for testing.
Patients who test positive for anti-JCV antibodies six months before being diagnosed with PML are considered anti-JCV antibody positive, said Dr. Vermersch. One patient was considered anti-JCV antibody negative because he or she tested anti-JCV antibody negative nine months before PML diagnosis and no additional pre-PML samples were available.
Another patient tested anti-JCV antibody negative 15 months before PML diagnosis and antibody positive two months before PML diagnosis. This patient’s time of seroconversion is unknown, so his or her anti-JCV antibody status six months before PML diagnosis cannot be known with certainty.
Early Diagnosis of PML Could Improve Patient Outcomes
The overall risk of PML is 2.71 for 1,000 patients with MS. Of 285 reported cases of natalizumab-associated PML, 62 patients died, yielding a mortality rate of 22%. The median time to death is 2.2 months. A total of 140 surviving patients with PML were followed up as of last year. A minority of these patients had mild disability, but approximately 40% were severely disabled, and approximately half had moderate disability.
JCV exposure, natalizumab treatment for more than two years, and receiving an immunosuppressant before receiving natalizumab have been documented as risk factors for developing PML, noted Dr. Vermersch. Patients with all three risk factors have an approximately 1% risk of developing PML.
Younger age at PML diagnosis, lower MS-related disability before PML diagnosis, and a shorter time from first symptoms to PML diagnosis appear to be associated with improved survival, said Dr. Vermersch. Gender, previous use of immunosuppressants, MS duration, natalizumab exposure at PML diagnosis, JCV DNA load in CSF at PML diagnosis, and gadolinium enhancement on MRI at time of diagnosis do not appear to affect survival.
“We are now able to detect PML very early—maybe even in presymptomatic cases … and we have quite good clinical outcomes in these patients,” said Dr. Vermersch. “A shorter time from first symptoms of PML to diagnosis is critical” because, in a 2011 study, the time from symptom onset to PML diagnosis was 10 days shorter for nonfatal cases of PML than for fatal cases of PML, he added. Localized PML extension on MRI at diagnosis is equally important, and neurologists should exercise good clinical vigilance with patients to improve outcomes, concluded Dr. Vermersch.