As powerful new drugs enter the market for the treatment of multiple sclerosis, methods are emerging for stratifying patients’ risk of progressive multifocal leukoencephalopathy.
Researchers are looking to immunosuppressive history and specific biomarkers to detect progressive multifocal leukoencephalopathy (PML) in its early stages. Also, they are gaining a better understanding of PML’s pathogenesis. At the joint meeting of the European and Americas Committees for Treatment and Research in Multiple Sclerosis in Boston, researchers will discuss each of these areas.
PML risk stratification
Two recently developed methods for determining a patient’s risk for PML while taking natalizumab – an anti–JC virus antibody index greater than 0.9 and a finding of less than 21.6% of CD4-positive T cells with l-selectin (CD62L) – may be best used for risk stratification when patients’ previous immunosuppressive drug use is known, according to research that Dr. Heinz Wiendl of the University of Münster in Germany will present Sept. 11. He and his colleagues’ analysis of nearly 2,000 natalizumab-treated MS patients found a statistical correlation between the anti-JCV antibody index and CD62L that existed only in patients who had previously been on immunosuppression. In addition, there was a stronger correlation between CD62L values and treatment duration in patients with previous immunosuppression, "suggesting CD62L as a first biological marker explaining why [previously immunosuppressed] patients are at higher risk to develop PML over time," the investigators wrote in their abstract.
Diagnosing PML regardless of etiology
A hypointense T2* band at the gray-white junction with variable thickness that at least partially encompasses the characteristic PML lesion sign of asymmetric hyperintensities on T2*-weight imaging may be helpful in detecting PML irrespective of the underlying etiology, according to new research from the National Institute of Neurological Disorders and Stroke that will be presented during the same session on Sept. 11. Dr. Varun Sethi and his colleagues at NINDS used a 3-T scanner to evaluate nine PML patients, including four with natalizumab-treated MS, two with lymphoma, one with idiopathic low CD4 T-cell count, and two with HIV infection. The band was never seen in association with preexisting MS lesions and had a tendency to spread over time in the five patients who had an additional scan 1-7 months after the first scan.
Insight into JC virus reactivation
On Sept. 11, Dr. Spyridon Chalkias of Beth Israel Deaconess Medical Center, Boston, will describe a study he led that provides further insight into how JC virus is reactivated in patients taking natalizumab, which has a mechanism of action that prevents trafficking of leukocytes out of the bloodstream. Dr. Chalkias and his colleagues found that JCV-seropositive patients taking natalizumab could be clinically asymptomatic and free of radiographic findings of PML despite evidence of JCV reactivation in the cerebrospinal fluid or in specific leukocyte populations. The researchers enrolled 43 JCV-seropositive MS patients, including 32 on natalizumab monotherapy for greater than 18 months, 6 on interferon beta-1a monotherapy for greater than 36 months, and 5 untreated controls. Of 27 natalizumab-treated patients who were asymptomatic and MRI-negative for PML, 2 had JCV DNA detected in their cerebrospinal fluid. Overall, the investigators found JCV DNA in the blood of 12 (28%) of the 43 patients. The two natalizumab-treated patients with JCV DNA in CSF did not have JCV DNA in blood or urine; however, the investigators detected JCV-specific CD4-positive T cells ex vivo more frequently in natalizumab-treated patients who were viremic, and in vitro stimulation led to more frequent detection of JCV-specific CD4-positive T cells than of CD8-positive T cells, indicating that "viremia might trigger a JCV-specific CD4-positive mediated response."
PML after natalizumab switchover to fingolimod
An analysis of a Novartis safety reporting database for fingolimod points to no new risk for PML that can be attributed to the drug, although 11 new cases have been reported in patients who switched from natalizumab to fingolimod. The study, to be presented by Dr. Norman Putzki of Novartis on Sept. 12, is based on 135,800 patient-years of fingolimod exposure in MS patients through February 2014. About 15%-20% of patients in the database had previously been on natalizumab. The 11 natalizumab-associated PML cases have been reported following 4 years’ mean duration of natalizumab use, and in all cases the onset of PML was either confirmed prior to the switch (in retrospect) or occurred within 6 months after the switch to fingolimod. In one additional case, a patient who had not been exposed to natalizumab was reported to have PML after 7 months of fingolimod treatment based on the results of a low JCV copy number in cerebrospinal fluid, but it was later determined that the patient’s clinical features and MRI evolution were consistent with neuromyelitis optica.