Patients with multiple sclerosis (MS) who receive natalizumab may have as much as a 10-fold greater risk of seroconversion to John Cunningham virus (JCV)-positive status, according to a study published online January 27 in Neurology Neuroimmunology & Neuroinflammation.
“An increase in the levels of anti-JCV antibodies could signify an increased risk of progressive multifocal leukoencephalopathy (PML),” said the study’s senior author, Heinz Wiendl, MD, Professor of Neurology at the University of Münster in Germany.
Dr. Wiendl and colleagues performed a longitudinal analysis of 525 German patients with MS and 711 French patients with MS, all of whom were treated with natalizumab, to assess whether the therapy influenced JCV seroconversion or JCV index value (ie, the level of anti-JCV antibody titers). An independent contractor processed and analyzed sera samples with the second-generation enzyme-linked immunosorbent assay kit STRATIFY JCV DxSelect.
Seroconversion and Increasing Index Value
Of the 525 German patients, 296 (56.4%) were JCV-negative throughout the observation period, and 171 were JCV-positive (32.6%). Forty-three patients changed from being JCV-negative to JCV-positive (8.2%), and 15 patients changed from being JCV-positive to JCV-negative (2.9%). When the authors used JCV serostatus to determine seroconversion, the longitudinal assessment started out with 339 initially JCV-negative patients. The serostatus of 43 of these initially JCV-negative patients changed to JCV-positive, which is a rate of 12.7% in 14.8 months (10.3% per year).
Of the 711 French patients, 243 initially were JCV-negative. The serostatus of 20 (8.2%) of these latter patients changed to JCV-positive in their first year of treatment, and 21 (8.6%) of the patients became JCV-positive in their second year of treatment. In all, the serostatus of 41 of 243 patients (16.9%) changed to JCV-positive in the first two years of natalizumab treatment (8.5% per year).
In addition, JCV index values changed in 525 patients during the observation period. The proportion of patients with an index value less than 0.4 was reduced by 20 patients (ie, from 65.1% to 61.3%), and the group of patients with low risk (ie, values between 0.4 and 0.9) was reduced by one patient to 7.8%. The patient groups with medium (ie, 0.9–1.5) and high risk (ie, greater than 1.5) increased by seven patients from 4.6% to 5.9% and by 14 patients from 22.3% to 25%, respectively.Furthermore, 161 of 201 JCV-positive patients (80%) had stable JCV index values over time. The remaining 40 patients (20%) had fluctuations of more than 30% in 14.8 months. Six of these patients (3%) had decreasing index values, and 34 (17%) had increasing index values (mean, 200.8%). Overall, the index value of all JCV-positive patients increased by an average of 15.9% in 14.8 months (12.9% per year).
Increased Index May Not Indicate Imminent PML
The high rate of seroconversion that the investigators observed “clearly supports the facilitation by treatment with natalizumab,” said Dr. Wiendl. “Our observed seroconversion of 8% to 10% per year and the rise in seroprevalence of 5% to 6% in 15 to 24 months is at least eight to 10 times as much as would be expected by age.” The study results imply that not every patient with MS is susceptible to JCV seroconversion by treatment, but natalizumab might facilitate seroconversion in patients who are susceptible.
No research has examined the influence of other MS treatments on JCV index values, and the investigators thus cannot be certain that natalizumab treatment caused the increase in index values observed in the study. But because there was no correlation between age and index value in JCV-positive patients, it is valid to speculate that natalizumab treatment induces rising JCV index values.
“If the hypothesis that treatment with natalizumab is associated with enhanced JCV seroconversion and higher index values is proven, it would also be important to determine whether cessation of natalizumab therapy (or perhaps prolonged infusion intervals) could lead to lower JCV index values as well,” Dr. Wiendl continued. The association “does not diminish [natalizumab’s] clinical efficacy, but calls for more elaborate strategies for PML risk stratification according to current scientific developments, also regarding patients with prior use of immunosuppressants, where the JCV index is not helpful.
“It is important that people with MS taking natalizumab speak with their doctor before making any changes to their treatment,” Dr. Wiendl added. “Still, this study shows anti-JCV antibodies may serve as a useful biomarker…. The results of this study underscore the need for frequent monitoring of anti-JCV antibodies in people who are being treated with natalizumab for MS.”
JCV serology, however, should not be the only PML risk biomarker to stratify patients treated with natalizumab, said Dr. Wiendl. Neurologists should explore and potentially apply additional biomarkers such as CD62L in peripheral blood or IgM bands in CSF. Together, all of these biomarkers may provide more accurate information about patients’ PML risk and help reduce the incidence of PML.