Simultaneous Use of Immunoglobulin with Natalizumab Attenuates the JCV Stratify Index Elevation- a 2 Year Analysis

Background: The incidence of progressive multifocal leukoencephalopathy (PML) in multiple sclerosis (MS) increases exponentially with prolonged Natalizumab (NTZ) use. JCV Stratify (Stratify) is a sensitive test, but lacks specificity to help determine NTZ course of action.¹ Use of immunoglobulin (IgG) in MS treatment is controversial. 'Off-label' IgG use is limited to those patients who are steroid non-responders, refractory to steroids because of prolonged use, or in whom steroids are contraindicated.

Objectives: To assess whether combined use of IgG with NTZ alters Stratify index.

Methods: Subjects included MS patients (N=35) enrolled in the Touch Program and treated with NTZ for 2 years. They were divided into 2 groups: IgG plus NTZ (n=20) and NTZ alone (n=15). NTZ was dosed at 300 mg. IV q 28 days, and those receiving IgG dosed at 40 gm. q month. In addition to Touch Program parameters, patients were evaluated with monthly blood testing, monthly neurologic exams, and annual MRI scans. JCV DNA PCR probes in whole blood and urine, as well as Stratify testing were performed at baseline and every 6 months. Neutralizing antibodies (NABs) to NTZ were obtained at time of MS exacerbation.

Results: Initial Stratify indices ranged from 0.19-4.0. Expanded Disability Status Scale (EDSS) scores ranged from 2.0-8.0. Attempts were made to match Stratify indices with those receiving and not receiving IgG. No patients developed PML. There was no correlation between Stratify and DNA PCR probe determination in whole blood and urine over the two year interval. Stratify indices were greater than 1.5 in 60% (n=12) of the IgG/NTZ group and 40% (n=6) in the NTZ group. Patients in the NTZ group continued to display elevated (above baseline) Stratify indices. However, in the IgG/NTZ there was a decline in the Stratify index initially at month 6 for 20% (N=4) of patients and continued to decline for the duration of the study for 80% (N=16) of patients. Those patients not receiving IgG continued to display Stratify indices that were elevated above initial baseline readings. Six MS patients (17%) remained Stratify negative throughout the study. Over the 2 year interval, 50% (n=10) in the IgG/NTZ group and 40% (N=6) in the NTZ group had improved EDSS scores. Two MS patients had exacerbations, one treated with methylprednisolone and the other with repository corticotropin. MRI data revealed an increase in T2 burden in both.

Conclusions: The immunomodulatory effect of IgG is reflected in the disparities of Stratify index in those taking IgG/NTZ therapy versus NTZ alone. The study continues to emphasize that Stratify is sensitive but not specific in determining NTZ use. Furthermore, the study also suggests that the concomitant use of IgG with NTZ lessens elevations in Stratify index and may attenuate development of PML.

¹Bailey RO, Garcia MV, Sprague CG. Stratify JCV Antibody ELISA Test: Who Gets What? Issues of Sensitivity Versus Specificity. International J. of MS Care. 18:(Suppl. 1), p. 17, 2016.