John Cunningham virus conversion in relation to natalizumab concentration in multiple sclerosis patients.

BACKGROUND AND PURPOSE: Infection with the John Cunningham virus (JCV) is required for the development of progressive multifocal leukoencephalopathy, the feared complication of natalizumab treatment in multiple sclerosis patients. The JCV seroconversion rate seems higher in natalizumab treated patients than in the normal population, with an unknown cause. METHODS: Natalizumab concentration was correlated to JCV antibody status and seroconversion in a large cohort of multiple sclerosis patients. RESULTS: One hundred and thirty-five patients were included. No correlation was found between natalizumab concentration and JCV status, JCV seroconversion or JCV index. CONCLUSIONS: Higher natalizumab concentrations do not explain the increased JCV seroconversion rate in natalizumab treated patients.

High cumulative JC virus seroconversion rate during long-term use of natalizumab.

BACKGROUND AND PURPOSE: John Cunningham virus (JCV) seropositivity is a risk factor for the development of natalizumab-associated progressive multifocal leukoencephalopathy (PML) in multiple sclerosis (MS) patients. When JCV seronegative patients seroconvert, their risk of developing PML increases. Limited longitudinal data exist about the seroconversion rate amongst natalizumab-treated relapsing-remitting MS (RRMS) patients. Our objective was to evaluate the seroconversion rate in a large Dutch cohort of natalizumab-treated RRMS patients. Seroconversion was defined as at least two consecutive seropositive serum samples (or cessation of therapy after a single seropositive sample because of seropositivity) after initial seronegative testing. METHODS AND RESULTS: In our study of 179 patients for whom longitudinal blood samples were available over a long period (median 4.2 years), anti-JCV antibody indices were measured in 933 available samples. Eighty-six patients (48.0%) tested seronegative initially. Of these 86 seronegative patients, 23 patients (26.7%) seroconverted during follow-up. The annualized seroconversion rate was 7.1%. Seroconversion occurred between 9 and 90 months (median 43 months) of treatment. The rate of seroconversion was independent of follow-up duration. No significant increase was seen in the anti-JCV antibody index in the non-converting patients during the follow-up. CONCLUSION: The annualized seroconversion rate of 7.1% in patients using natalizumab, cumulatively leading to more than 25% of seronegative patients becoming seropositive in 4 years, is of clinical relevance and should be taken into account in the risk assessment when considering the start of natalizumab therapy.

Application of serum natalizumab levels during plasma exchange in MS patients with progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) is a severe complication of natalizumab treatment. Restoring immune function by plasmapheresis/immunoadsorption (PLEX/IA) is important for the outcome of PML. We report on four multiple sclerosis (MS) patients whom developed PML during natalizumab treatment, in whom we measured serum natalizumab concentrations before and during PLEX. Depending on the serum natalizumab concentration at the time of PML diagnosis, the number of PLEX treatments necessary to reach subtherapeutic serum natalizumab concentrations is variable. Measuring serum natalizumab concentrations before and during PLEX is helpful to determine the optimum number of PLEX treatments in individual MS patients with PML.

Influence of personalized extended interval dosing on the natalizumab wearing-off effect - a sub-study of the NEXT-MS trial.

BACKGROUND AND OBJECTIVES: Wearing-off symptoms during natalizumab treatment in multiple sclerosis are characterized by an increase of MS-related symptoms prior to natalizumab administration. The influence of extended interval dosing (EID) on wearing-off symptoms are important to consider, as this might cause hesitancy in initiating or continuing EID. METHODS: Participants of the NEXT-MS trial, in which treatment intervals are adjusted based on drug concentrations, were divided into two groups: an extended group containing participants with at least one week of additional interval extension, and a group with a fixed interval during the trial (range 4-7 weeks). Changes in the occurrence, frequency, onset, and severity of wearing-off symptoms were evaluated. RESULTS: 255 participants were included (extended group n = 171, fixed group n = 84). The odds on occurrence of wearing-off symptoms in the extended group did not increase after extending the treatment interval. Additional analyses for frequency, onset, and severity of wearing-off symptoms showed no changes over time. Mean decrease in natalizumab drug concentration did not influence the frequency of wearing-off symptoms. DISCUSSION: Wearing-off symptoms were not reinforced by further extending the natalizumab interval. Wearing-off symptoms might increase in a minority of patients after EID, although our data support the view that wearing-off symptoms appear to be unrelated to the decrease in natalizumab trough drug concentrations.

High work absence around time of diagnosis of multiple sclerosis is associated with fatigue and relapse rate.

BACKGROUND: Multiple sclerosis (MS) is associated with high rates of disability pension and work absence. Little is known about work absence in early MS. The objectives of this study were (1) to assess the prevalence of work absence shortly after MS diagnosis, (2) to explore health-related quality of life (HRQoL) and disease impact in relation to work absence and (3) to investigate demographic and clinical factors that may be associated with high work absence. METHODS: Patients with relapsing remitting (RRMS) or primary progressive MS (PPMS) were included shortly after MS diagnosis. We collected data on work absence due to MS in the year prior to inclusion, disability (Expanded Disability Status Scale), relapse rate, fatigue (Neurological Fatigue Index), health-related quality of life (HRQoL, 36-Item Short Form Survey) and disease impact (Multiple Sclerosis Impact Scale). For analysis, patients were divided in 2 groups: low work absence (<1 month) and high work absence (≥1 month). Data was analyzed using backward logistic regression techniques. RESULTS: In total, 90 MS patients participated (80 RRMS, 10 PPMS, mean age = 39.3 years, median disease duration since diagnosis = 0.5 year). Work absence in the year prior to inclusion was reported by 66 patients (73.3%). High work absence of ≥ 1 month was reported by 41 patients (45.6%). Disability, gender, age, disease duration and education did not differ between groups. Patients with high work absence reported a lower HRQoL and higher disease impact compared to patients with low work absence. Backward regression analysis showed that high work absence is associated with being single/not married, fatigue and relapses. The strongest association was found for fatigue (highest fatigue vs. lowest fatigue level: OR total group = 7.8, RRMS = 15.8). In RRMS patients the second-strongest association was relapse rate (≥2 relapses in the past year vs. no relapses: OR 11.1). CONCLUSION: Prevalence of work absence is high in early MS. Patients with high work absence report a lower HRQoL and a higher disease impact. High work absence is associated with being single/not married, fatigue and relapses. Interventions aimed at fatigue and prevention of relapses may help maintain employment in early MS.

PML-IRIS during Fingolimod Diagnosed after Natalizumab Discontinuation.

Background. Natalizumab treatment is frequently discontinued and replaced by alternative medication in multiple sclerosis (MS) patients having a high risk of progressive multifocal leukoencephalopathy (PML). Case Presentation. We report a PML case that was missed on magnetic resonance imaging (MRI) at the time Natalizumab treatment was discontinued. The patient subsequently developed a PML-immune reconstitution inflammatory syndrome after the initiation of Fingolimod treatment, suggesting that immune reconstitution may occur even during Fingolimod induced lymphopenia. Conclusion. This report highlights the need for strict drug surveillance using MRI of Natalizumab-associated MS patients at the time of drug discontinuation and beyond. This is important with respect to pharmacovigilance purposes not only for Natalizumab, but also for alternative drugs used after Natalizumab discontinuation.

Spontaneous MxA mRNA level predicts relapses in patients with recently diagnosed MS.

OBJECTIVE: To determine if myxovirus resistance protein A (MxA) mRNA is related to clinical disease activity in multiple sclerosis (MS). METHODS: Baseline MxA mRNA levels were measured in a prospective cohort of 116 untreated patients with early MS and were related to clinical relapses and MRI at baseline and at follow-up. RESULTS: Low levels of MxA mRNA were associated with the occurrence of relapses (p = 0.002) and contrast-enhancing lesions (CELs) on baseline MRI (p = 0.045). In addition, high baseline MxA mRNA levels were related to a longer time to a first new relapse (hazard ratio [HR] 0.59; 95% confidence interval [CI] 0.35-1.00; p = 0.044). Adding the absence of CELs to high MxA mRNA, the predictive value increased (HR 0.35; 95% CI 0.17-0.74; p = 0.006), clearly showing a cumulative value for combining both factors. CONCLUSIONS: MxA mRNA is related to clinical exacerbations, the number of CELs on MRI, and is indicative for the time to a subsequent relapse. If confirmed, MxA mRNA has potential as a biomarker for clinical disease activity in MS.