Risk of Natalizumab-Associated Progressive Multifocal Leukoencephalopathy

Bloomgren, Gary; Richman, Sandra; Hotermans, Christophe; Subramanyan, Meena; Goelz, Susan; Natarajam, Amy; Lee, Sophia; Plavina, Tatiana; Scanlon, James; Sandrock, Alfred; Bozic, Carmen

doi:10.1097/01.sa.0000422027.26626.8d

Cited by 81 publications

(135 citation statements)

References 2 publications

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“…44 This disease has been observed in 2 of 1000 patients with multiple sclerosis after therapy with the antibody natalizumab. 45 PML was also observed during therapy with natalizumab in some patients with CD. 46…”

Section: Substancesmentioning

confidence: 96%

Emerging oral targeted therapies in inflammatory bowel diseases: opportunities and challenges

Vetter

Neurath

2017

Therap Adv Gastroenterol

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To improve quality of life and prevent long-term risks in patients with inflammatory bowel diseases (IBDs: Crohn's disease, ulcerative colitis), it is essential to suppress inflammatory activity adequately. However, corticosteroids are only suitable for therapy of acute flares and the evidence for positive effects of immunosuppressive substances like azathioprine or 6-mercapropurine is mainly limited to maintenance of remission. In addition, only subgroups of patients benefit from biologicals targeting tumour necrosis factor α or α4β7 integrins. In summary, until now the disease activity is not sufficiently controlled in a relevant fraction of the patients with IBD. Thus, there is an urge for the development of new substances in the therapy of ulcerative colitis and Crohn's disease. Fortunately, new oral and parenteral substances are in the pipeline. This review will focus on oral substances, which have already passed phase II studies successfully at this stage. In this article, we summarize data regarding AJM300, phosphatidylcholine (LT-02), mongersen, ozanimod, filgotinib and tofacitinib. AJM300 and ozanimod were tested in patients with ulcerative colitis and target lymphocyte trafficking through inhibition of the α subunit of integrin, respectively binding to the sphingosine-1-phosphate receptor (subtypes 1 and 5) on lymphocytes. Mongersen was utilized in patients with Crohn's disease and accelerates the degradation of SMAD7 mRNA, which consequently strengthens the mainly anti-inflammatory signalling pathway of transforming growth factor β1. Various Janus kinase (JAK) inhibitors were developed, which inhibit the intracellular signalling pathway of cytokines. For example, the JAK1 blocker filgotinib was tested in Crohn's disease, whereas the JAK1/3 inhibitor tofacitinib was tested in clinical trials for both Crohn's disease and ulcerative colitis. A different therapeutic approach is the substitution of phosphatidylcholine (LT-02), which might recover the colonic mucus. Taken together, clinical trials with these new agents have opened avenues for further clinical studies and it can be expected that at least some of these agents will be finally approved for clinical therapy.

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Section: Substancesmentioning

confidence: 96%

Emerging oral targeted therapies in inflammatory bowel diseases: opportunities and challenges

Vetter

Neurath

2017

Therap Adv Gastroenterol

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“…Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection caused by the JC virus (JCV), and it currently represents a significant concern for multiple sclerosis (MS) patients taking potent immunomodulatory disease-modifying therapies (DMTs). The JCV antibody index is the current standard for assessing risk, with antibody titers greater than 1.5 associated with elevated risk, 1,2 but its reliability is compromised by false-negatives. 3 While it is not yet possible to accurately predict which patients will develop PML, age has emerged as a significant risk factor.…”

Section: Introductionmentioning

confidence: 99%

Aging and lymphocyte changes by immunomodulatory therapies impact PML risk in multiple sclerosis patients

Mills

Mao-Draayer

2018

Mult Scler

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New potent immunomodulatory therapies for multiple sclerosis (MS) are associated with increased risk for progressive multifocal leukoencephalopathy (PML). It is unclear why a subset of treated patients develops PML, but patient age has emerged as an important risk factor. PML is caused by the JC virus and aging is associated with immune senescence, which increases susceptibility to infection. With the goal of improving PML risk stratification, we here describe the lymphocyte changes that occur with disease-modifying therapies (DMTs) associated with high or moderate risk toward PML in MS patients, how these changes compare to immune aging, and which measures best correlate with risk. We reviewed studies examining how these therapies alter patient immune profiles, which revealed the induction of changes to lymphocyte number and/or function that resemble immunosenescence. Therefore, the immunosuppressive activity of these MS DMTs may be enhanced in the context of an immune system that is already exhibiting features of senescence.

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“…1 Unfortunately, the risk of progressive multifocal leukoencephalopathy (PML), an opportunistic brain infection caused by the John Cunningham (JC) virus, complicates the long-term use of natalizumab in JC virus–positive patients. 2 Because of the risk of PML, patients often switch to an alternative disease-modifying therapy like fingolimod, a sphingosine 1-phosphatereceptor modulator. Natalizumab limits lymphocyte transport over the blood–brain barrier, whereas fingolimod prevents recirculation of lymphocytes from the lymph nodes.…”

Section: Introductionmentioning

confidence: 99%

Switching natalizumab to fingolimod within 6 weeks reduces recurrence of disease activity in MS patients

et al. 2017

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Background:Natalizumab is an effective treatment in relapsing-remitting multiple sclerosis (MS). Mainly because of the risk of progressive multifocal leukoencephalopathy (PML), a substantial proportion of John Cunningham (JC) virus–positive patients switch to fingolimod. Previous reports show a clear benefit when the duration of a washout (WO) period of natalizumab is 0–3 months in comparison to longer WO periods. However, there is no consensus regarding the optimal duration of a WO period under 3 months.Objective:We compared MS disease activity after different WO periods. In addition, we investigated several factors that possibly influence recurrence of disease activity, including serum natalizumab concentration and lymphocyte counts.Methods:From a prospective observational cohort study of natalizumab-treated patients, we selected 52 patients who switched to fingolimod. We divided the patients in three groups (<6 weeks, 6–8 weeks, >8 weeks WO). Serum natalizumab concentration and lymphocyte count were assessed during and after natalizumab treatment.Results:Patients with a WO period of >8 weeks had a significant higher recurrence of disease activity (odds ratio, 6.8; 95% confidence interval, 1.4–32.8) compared to patients with a WO period of <6 weeks. Serum natalizumab concentration and lymphocyte count did not predict recurrence of disease activity.Interpretation:A short WO period decreases the risk of recurrence of disease activity. The possible impact of a short WO period on the risk of carry-over PML in JC virus–positive patients remains uncertain.

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Risk of Natalizumab-Associated Progressive Multifocal Leukoencephalopathy

Cited by 81 publications

References 2 publications

Emerging oral targeted therapies in inflammatory bowel diseases: opportunities and challenges

Emerging oral targeted therapies in inflammatory bowel diseases: opportunities and challenges

Aging and lymphocyte changes by immunomodulatory therapies impact PML risk in multiple sclerosis patients

Switching natalizumab to fingolimod within 6 weeks reduces recurrence of disease activity in MS patients

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