Risk of natalizumab-associated PML in patients with MS is reduced with extended interval dosing

Ryerson, Lana Zhovtis; Foley, John; Chang, Ih; Kister, Ilya; Cutter, Gary; Metzger, Ryan R.; Goldberg, Judith D.; Li, Xiaochun; Riddle, Evan L.; Smirnakis, Karen; Kasliwal, Rachna; Ren, Zheng; Hotermans, Christophe; Ho, Pei-Ran; Campbell, Nolan

doi:10.1212/wnl.0000000000008243

Cited by 139 publications

(127 citation statements)

References 18 publications

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“…19 This has particularly been driven by the risk of progressive multifocal leukoencephalopathy (PML), a serious complication of natalizumab therapy in patients previously exposed to JC virus. 25 Retrospective studies of off-label treatment with EID have shown maintained efficacy 26,27 and reduced PML risk 28 compared with standard interval dosing. However, these studies are limited by possible selection bias due to nonrandomized design, and the efficacy and safety of EID is not fully known.…”

Section: Discussionmentioning

confidence: 99%

Wearing-off at the end of natalizumab dosing intervals is associated with low receptor occupancy

Bringeland

Blaser

Myhr

et al. 2020

Neurol Neuroimmunol Neuroinflamm

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ObjectiveWe aimed to investigate whether wearing-off symptoms at the end of the natalizumab dosing interval were associated with clinical and demographic patient characteristics or natalizumab receptor occupancy (RO) on leukocytes.MethodsIn this cross-sectional study of 40 patients with relapsing-remitting MS (RRMS) receiving natalizumab at the Department of Neurology, Haukeland University Hospital, we recorded clinical and demographic data including age, body mass index (BMI), working status, smoking habits, disease characteristics, treatment duration, vitamin D levels, and wearing-off symptoms. We quantified neurofilament light chain in serum and measured natalizumab RO in leukocyte subtypes by high-parameter mass cytometry. Associations with wearing-off symptoms were analyzed.ResultsEight (20.0%) patients who reported regular occurrence of wearing-off symptoms, 9 (22.5%) who sometimes had wearing-off symptoms, and 23 (57.5%) who did not have wearing-off symptoms were evaluated. Patients who regularly had wearing-off symptoms had lower natalizumab RO than patients who reported having such symptoms sometimes or never. The former group also had higher BMI and higher frequency of sick leave. High BMI was associated with low RO. No other demographic or disease characteristics were associated with the phenomenon.ConclusionsLow RO may explain the wearing-off phenomenon observed in some patients with RRMS treated with natalizumab, and high BMI may be the underlying cause.

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Section: Discussionmentioning

confidence: 99%

Wearing-off at the end of natalizumab dosing intervals is associated with low receptor occupancy

Bringeland

Blaser

Myhr

et al. 2020

Neurol Neuroimmunol Neuroinflamm

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“…B-cell depletion frequently lasts much longer than the scheduled dosing interval, and extended-interval dosing should be considered, especially in patients who are B cell depleted (as measured by CD19/CD20 lymphocyte counts) at the time of the next scheduled dose or those with low levels of immunoglobulin G. Extended-interval dosing is already widely used in patients treated with natalizumab because of observational data showing a reduced risk of progressive multifocal leukoencephalopathy. 10 Whether this approach reduces the risk of other infections is unknown, but should be considered during the COVID-19 pandemic to reduce hospital visits.…”

Section: Disease-modifying Therapiesmentioning

confidence: 99%

Treating multiple sclerosis and neuromyelitis optica spectrum disorder during the COVID-19 pandemic

et al. 2020

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The emergence of novel coronavirus 2019 (COVID-19) 1 and the subsequent pandemic present a unique challenge to neurologists managing patients with multiple sclerosis (MS) and related neuroinflammatory disorders, such as neuromyelitis spectrum disorder (NMOSD). National professional bodies (e.g., Italian Society of Neurology and Association of British Neurologists) and patient organizations (e.g., National MS Society, MS International Federation, UK MS Society, and MS Australia) have responded rapidly by issuing guidelines for the COVID-19 pandemic, primarily focused on MS disease-modifying therapies (DMTs). In this commentary, we highlight the implications of COVID-19 for people with MS and related disorders, including the risk of respiratory infections, general health advice, and recommendations (from consensus-based guidelines) for immunotherapies, relapse management, and service delivery during the COVID-19 pandemic. Risk of respiratory infectionsWhether people with MS and NMOSD are at an increased risk of COVID-19 infection or at a higher risk of more severe infection is unknown. There are no data available on whether the rate of mild, self-limiting respiratory infections that do not require a medical encounter is increased in people with MS. However, there is increased infection-related health care utilization across all age groups in people with MS compared with the general population. 2 These infections include pneumonia 2,3 (particularly in people with bulbar weakness resulting in aspiration and impaired pulmonary function due to severe quadriparesis) and influenza, 3 but not upper respiratory tract infections. 2 Older age, male sex, worse physical disability, and lower socioeconomic status are associated with increased hospitalization rates in MS. 3 People with MS have a higher risk of intensive care unit admission with infections and higher 1-year mortality after admission than the general population. 4 In addition to the higher background risk of infection-related health care utilization, people with MS treated with the secondgeneration DMTs are exposed to a further increased risk of infections. 5 These factors should be considered when counseling individuals about the risks of COVID-19 infection. General health advicePeople with MS and related disorders should follow World Health Organization (WHO) and national or local health authority guidance on preventive measures to reduce transmission of COVID-19 in the general population. These include social distancing, frequent hand washing with soap and water or an alcohol-based hand rub, and respiratory hygiene. Advice from the WHO is updated regularly (who.int/emergencies/diseases/novel-coronavirus-2019).

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“…Immunization with live but attenuated vaccines (MMR, VZV live vaccine, yellow fever), in contrast, should be completed at least 4 weeks prior to treatment initiation, Recently, the natalizumab product information has been updated [14], to include data suggestive of a lower risk of PML in patients treated with extended interval dosing (EID) [90]. However, it remains to be demonstrated that EID of natalizumab yields the same degree of efficacy if close clinical and MRI monitoring is performed [91].…”

Section: Vaccination Responsesmentioning

confidence: 99%

Effects of disease-modifying therapy on peripheral leukocytes in patients with multiple sclerosis

et al. 2020

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Modern disease-modifying therapies (DMTs) in multiple sclerosis (MS) have variable modes of action and selectively suppress or modulate the immune system. In this review, we summarize the predicted and intended as well as unwanted adverse effects on leukocytes in peripheral blood as a result of treatment with DMTs for MS. We link changes in laboratory tests to the possible therapeutic risks that include secondary autoimmunity, infections, and impaired response to vaccinations. Profound knowledge of the intended effects on leukocyte counts, in particular lymphocytes, explained by the mode of action, and adverse effects which may require additional laboratory and clinical vigilance or even drug discontinuation, is needed when prescribing DMTs to treat patients with MS.

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Risk of natalizumab-associated PML in patients with MS is reduced with extended interval dosing

Cited by 139 publications

References 18 publications

Wearing-off at the end of natalizumab dosing intervals is associated with low receptor occupancy

Wearing-off at the end of natalizumab dosing intervals is associated with low receptor occupancy

Treating multiple sclerosis and neuromyelitis optica spectrum disorder during the COVID-19 pandemic

Effects of disease-modifying therapy on peripheral leukocytes in patients with multiple sclerosis

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