Immunological biomarkers identifying natalizumab-treated multiple sclerosis patients at risk of progressive multifocal leukoencephalopathy

Serana, Federico; Chiarini, Marco; Sottini, Alessandra; Bertoli, Diego; Giustini, Viviana; Tessitore, Marion Vaglio; Caimi, Luigi; Capra, Ruggero

doi:10.1016/j.jneuroim.2014.10.011

Cited by 6 publications

(7 citation statements)

References 68 publications

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“…29 A marker of risk for PML is anti-JCV antibody level in serum/plasma. 30,31 A PML risk stratification guideline, based on anti-JCV antibodies in multiple sclerosis (MS) patients receiving natalizumab has been proposed. 17 Additional risk factors in MS, include prior use of immunosuppressants, underlying hematologic malignancy, and long duration of treatment with natalizumab.…”

Section: 0 Discussionmentioning

confidence: 99%

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Detection of cases of progressive multifocal leukoencephalopathy associated with new biologicals and targeted cancer therapies from the FDA’s adverse event reporting system

Raisch

Rafi

Chen

et al. 2016

Expert Opinion on Drug Safety

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Objective To identify and summarize FDA’s Adverse Event Reporting System (FAERS) cases of progressive multifocal leukoencephalopathy (PML) associated with biological and targeted cancer therapies (BTCT) that were approved between 2009 and 2015. Methods FAERS was searched using each BTCT name as primary or secondary suspect drug and the adverse reaction of PML. Among BTCTs with >2 case reports of PML, proportional reporting ratios (PRR) and 95% confidence intervals (CI) were calculated. Results Among 49 new BTCTs, 82 cases of PML were found for 16 drugs. Significant PRR signals were found among 7 (14.6%) BTCTs including: brentuximab (24.5, CI:14.8–40.6), ofatumumab (16.3, CI:9.6–27.4), alemtuzumab (9.9, CI:6.0–16.4), obinutuzumab (7.4, CI:2.4–22.8), ibrutinib (5.6 CI:3.0–10.5), belimumab (4.5 CI:2.3–9.0), and idelalisib (4.1, CI:1.3–12.6). Among the 82 cases among BTCTs with significant signals, confirmation of the diagnosis of PML using objective criteria was found in 56% of the cases. A limitation of FAERS data is that missing data are common. Conclusions When using BTCTs, clinicians and patients consider the risk of PML versus the therapeutic benefit, particularly when used in combination with other drugs which may cause PML, such as rituximab. It is important to recognize that PML may occur in some conditions, such as chronic lymphocytic leukemia, regardless of drug therapy.

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Section: 0 Discussionmentioning

confidence: 99%

“…17 Additional risk factors in MS, include prior use of immunosuppressants, underlying hematologic malignancy, and long duration of treatment with natalizumab. 31 JCV antibody testing among rheumatoid arthritis patients receiving biologics, however is not recommended due to the much lower risk of PML in these patients. 32 …”

Section: 0 Discussionmentioning

confidence: 99%

Detection of cases of progressive multifocal leukoencephalopathy associated with new biologicals and targeted cancer therapies from the FDA’s adverse event reporting system

Raisch

Rafi

Chen

et al. 2016

Expert Opinion on Drug Safety

View full text Add to dashboard Cite

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“…B cell subtype analysis can also be highly relevant in the search for new markers for progressive multifocal leukoencephalopathy (PML) in natalizumab-treated patients, as B cells were described as potential carriers of the John Cunningham (JC) virus into the CNS ( 134 ). Other research is focused on finding risk factors for the development of PML during natalizumab treatment ( 112 , 130 , 135 , 136 ).…”

Section: Effects Of Treatment On B Cell Subtype Distributionmentioning

confidence: 99%

B Cells Are Multifunctional Players in Multiple Sclerosis Pathogenesis: Insights from Therapeutic Interventions

et al. 2015

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Multiple sclerosis (MS) is a severe disease of the central nervous system (CNS) characterized by autoimmune inflammation and neurodegeneration. Historically, damage to the CNS was thought to be mediated predominantly by activated pro-inflammatory T cells. B cell involvement in the pathogenesis of MS was solely attributed to autoantibody production. The first clues for the involvement of antibody-independent B cell functions in MS pathology came from positive results in clinical trials of the B cell-depleting treatment rituximab in patients with relapsing-remitting (RR) MS. The survival of antibody-secreting plasma cells and decrease in T cell numbers indicated the importance of other B cell functions in MS such as antigen presentation, costimulation, and cytokine production. Rituximab provided us with an example of how clinical trials can lead to new research opportunities concerning B cell biology. Moreover, analysis of the antibody-independent B cell functions in MS has gained interest since these trials. Limited information is present on the effects of current immunomodulatory therapies on B cell functions, although effects of both first-line (interferon, glatiramer acetate, dimethyl fumarate, and teriflunomide), second-line (fingolimod, natalizumab), and even third-line (monoclonal antibody therapies) treatments on B cell subtype distribution, expression of functional surface markers, and secretion of different cytokines by B cells have been studied to some extent. In this review, we summarize the effects of different MS-related treatments on B cell functions that have been described up to now in order to find new research opportunities and contribute to the understanding of the pathogenesis of MS.

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“…However, this three-stage risk stratification algorithm does not allow for a precise prediction of PML risk in individual patients [4,9]. Moreover, its usefulness for risk stratification was regarded to be limited because of the imbalance between the high percentage of patients that are seropositive for JCV, and the rare occurrence of PML [10]. To improve the safety and efficacy of NTZ, and to guide individually tailored clinical decisions, immunological markers such as CD49d, CD11a, and CD62L expression on leukocytes, lipid-specific oligoclonal immunoglobulin M bands in cerebrospinal fluid, the intrathecal immunoglobulin G index, JCV-specific activated T effector memory cells, and genetic screening approaches have been proposed [9–13].…”

Section: Introductionmentioning

confidence: 99%

“…Due to the lack of available data in patients with ≥ 6 years of treatment exposure, the PML risk estimate is limited beyond 6 years of treatment [6]. Though, despite advances in risk stratification, the PML incidence in NTZ-treated patients with RRMS has not declined over the last few years [10,20]. This might be due to the fact that patients’ and physicians’ subjective risk estimations and acceptance differ from the objective PML risk, and that factors other than the real PML risk according to the common used PML stratification algorithm decide on continuation or cessation of NTZ therapy.…”

Section: Introductionmentioning

confidence: 99%

Is the risk of progressive multifocal leukoencephalopathy the real reason for natalizumab discontinuation in patients with multiple sclerosis?

et al. 2017

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BackgroundProgressive multifocal leukoencephalopathy (PML) is one of the major risks of natalizumab therapy. Despite introduction of the currently employed PML risk stratification algorithm, the incidence of natalizumab-associated PML cases is not decreasing.ObjectivesWe addressed the following questions: How do natalizumab-treated multiple sclerosis patients and their treating physicians assess and deal with PML risk? Is PML risk the real reason for natalizumab discontinuation?Methods699 natalizumab-treated multiple sclerosis patients and 99 physicians were included in this prospective observational study. Questionnaires were completed at 5 different time points. Patients were stratified into 5 subgroups according to the presence of PML risk factors (prior immunosuppression, anti-JCV antibody status, treatment duration). Patients with prior immunosuppression (n = 30, treated by n = 7 physicians) were excluded from analyses, because patient numbers were too small. Patients’ anti-JCV antibody index was not considered because data recruitment ended in 2014. Using Bayesian network and regression analysis, we examined the relationship between different patient- and physician-related factors and patients’ discontinuation of natalizumab.ResultsPatients of all subgroups and physicians assessed the PML risk as low. Overall patient adherence to natalizumab was high (87%). Only 13% of patients discontinued therapy. Natalizumab treatment cessation was associated with different patient- and physician-related factors (physicians’ assessment of general PML risk, number of treated patients per year, natalizumab treatment duration, relapses during the course of study) upon which only physicians’ judgment on treatment continuation, patients’ perception of personal PML risk, and JCV seroconversion showed significant relationships.ConclusionAccording to the currently employed risk stratification algorithm, the objective PML risk probably doesn’t play a dominant role in a patients’ decision to continue or stop natalizumab treatment. The decision-making process is rather guided by subjective views and experiences of patients and treating neurologists. Treating physicians should consider this discrepancy in their advice to improve the risk-benefit-ratio for the individual patient.

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Immunological biomarkers identifying natalizumab-treated multiple sclerosis patients at risk of progressive multifocal leukoencephalopathy

Cited by 6 publications

References 68 publications

Detection of cases of progressive multifocal leukoencephalopathy associated with new biologicals and targeted cancer therapies from the FDA’s adverse event reporting system

Detection of cases of progressive multifocal leukoencephalopathy associated with new biologicals and targeted cancer therapies from the FDA’s adverse event reporting system

B Cells Are Multifunctional Players in Multiple Sclerosis Pathogenesis: Insights from Therapeutic Interventions

Is the risk of progressive multifocal leukoencephalopathy the real reason for natalizumab discontinuation in patients with multiple sclerosis?

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