Anti–JC virus antibody levels in serum or plasma further define risk of natalizumab‐associated progressive multifocal leukoencephalopathy

Abstract

ObjectiveThe increased risk of progressive multifocal leukoencephalopathy (PML) with natalizumab treatment is associated with the presence of anti–JC virus (JCV) antibodies. We analyzed whether anti-JCV antibody levels, measured as index, may further define PML risk in seropositive patients.MethodsThe association between serum or plasma anti-JCV antibody levels and PML risk was examined in anti-JCV antibody–positive multiple sclerosis (MS) patients from natalizumab clinical studies and postmarketing sources. For PML and non-PML patients, the probabilities of having an index below and above a range of anti-JCV antibody index thresholds were calculated using all available data and applied to the PML risk stratification algorithm. Longitudinal stability of anti-JCV antibody index was also evaluated.ResultsAnti-JCV antibody index data were available for serum/plasma samples collected >6 months prior to PML diagnosis from 71 natalizumab-treated PML patients and 2,522 non-PML anti-JCV antibody–positive patients. In patients with no prior immunosuppressant use, anti-JCV antibody index distribution was significantly higher in PML patients than in non-PML patients (p < 0.0001). Among patients who were anti-JCV antibody negative at baseline in the AFFIRM and STRATIFY-1 trials, 97% remained consistently negative or below an index threshold of 1.5 over 18 months. Retrospective analyses of pre-PML samples collected longitudinally from PML patients displayed sustained higher anti-JCV antibody index over time.InterpretationAnti-JCV antibody levels in serum/plasma, measured as index, may differentiate PML risk in anti-JCV antibody–positive MS patients with no prior immunosuppressant use. Continued evaluation of anti-JCV antibody index and PML risk is warranted. Ann Neurol 2014;76:802–812

Guidelines for the use of magnetic resonance imaging in diagnosing and monitoring the treatment of multiple sclerosis: recommendations of the Swedish Multiple Sclerosis Association and the Swedish Neuroradiological Society

“…There is no available study data on which to reliably base recommendations regarding frequency of MRI monitoring in this case. Depending on the estimation of the PML risk in the individual patient, performing MRI every 3–6 months is a practical approach 38. For additional MRI follow‐ups specifically for PML monitoring, a reduced protocol can be used.…”

Advances in and Algorithms for the Treatment of Relapsing-Remitting Multiple Sclerosis

“…Modified according to [107]. *According to Plavina et al antibody indices may accurately predict PML risk in natalizumab [65]. The index is increasingly used for stratification, but should be used with caution until validated in independent samples.…”

“…Even for some time after the cessation of natalizumab, a certain risk of PML remains and pharmacovigilance should be continued [63,64]. There are increasing efforts to further refine PML risk stratification, especially for patients that convert to anti-JCV antibody positive status while on natalizumab, using antibody indices in serum and cerebrospinal fluid, as well as other approaches [65][66][67][68].…”

“…Risk stratification includes previous use of immunosuppressants, the duration of natalizumab treatment, and (especially important for treatment decisions) JCV status (positive or negative for JCV-specific IgG). Recently, this has been refined by introduction of JCV index, and the JCV index is used by more and more centers [65,87]. Thistogether with an intensified MRI regimen-could open up treatment options, especially for JCV-positive patients.…”

Use of Natalizumab in Patients with Multiple Sclerosis: 2015 Update

“…The results of a quantitative analysis of risk by anti-JCV antibody index are shown in Table 1. 24 Note that there is a false-negative rate of approximately 2.0% to 2.5% per year, and seroconversion occurs in approximately 2% to 8% of natalizumab-treated patients per year. 20,21 It is also important to note that there can be fluctuation in the JCV index at lower levels.…”