Carmen Bozic

Anti‐John Cunnigham virus antibody prevalence in multiple sclerosis patients: Baseline results of STRATIFY‐1

A study was undertaken to define the prevalence of anti‐JC virus (JCV) antibodies in multiple sclerosis (MS) patients and to evaluate the analytical false‐negative rate of a 2‐step anti‐JC virus antibody assay.

Outcome and survival of asymptomatic PML in natalizumab‐treated MS patients

As of 3 September 2013, 399 cases of natalizumab‐associated progressive multifocal leukoencephalopathy (PML) were confirmed in multiple sclerosis (MS) patients. We evaluated outcomes of natalizumab‐treated MS patients who were asymptomatic at PML diagnosis.

Anti‐JC virus (JCV) antibody prevalence in the JCV Epidemiology in MS (JEMS) trial

Progressive multifocal leukoencephalopathy (PML) is caused by reactivation of JC virus (JCV) infection due to combined host and viral factors. Anti‐JCV antibodies provide a means to assess JCV exposure and stratify PML risk. The reported seroprevalence of anti‐JCV antibodies varies from 39% to 91% depending on assay methodology and population studied. A two‐step anti‐JCV antibody assay (STRATIFY JCV™; Focus Diagnostics, Cypress, CA, USA) detected anti‐JCV antibodies in approximately 55% of multiple sclerosis (MS) patients. This study describes the prevalence of anti‐JCV antibodies in a large, multinational MS population.

Natalizumab and central nervous system lymphoma: No clear association†

Schweikert et al report a single case of primary central nervous system lymphoma (PCNSL) in a multiple sclerosis (MS) patient who received 21 infusions of natalizumab. Details from the Schweikert et al case, as well as data from preclinical studies, controlled clinical trials, and postmarketing surveillance, suggest that this case of PCNSL is not causally related to natalizumab therapy. There was an absence of Epstein-Barr virus (EBV) staining by in situ hybridization of the PCNSL in the case reported by Schweikert et al. Studies indicate that latent EBV infection is strongly implicated in the oncogenesis of immunosuppression-related lymphoproliferative disease. EBV genomic material is identified in tissue from 90% of immunocompromised patients with PCNSL, and is usually seen in the setting of patients with human immunodeficiency virus-acquired immunodeficiency syndrome, or in patients receiving immunosuppressant drugs for organ transplantation or autoimmune disease. Hence, the absence of EBV is evidence against an immunosuppression-related lymphoproliferative disease in this patient. Data from preclinical and clinical studies, as well as postmarketing experience, show no signal for PCNSL related to natalizumab therapy. In natalizumab preclinical toxicology studies, there was no evidence of immunosuppression-related lymphoproliferative disease at any dose in nonhuman primates, including doses 10 greater than the therapeutic dose. In the natalizumab phase 3 clinical studies, one Crohn’s disease (CD) patient developed a peripheral nodal B-cell lymphoma following 6 doses of natalizumab. This CD patient had multiple risk factors (including concurrent treatment with long-standing immunosuppressive therapies and a 1-year history of lymphadenopathy prior to the start of natalizumab therapy), and the lymphoma was considered unlikely to be related to natalizumab. In the cumulative clinical trial experience, no other cases of lymphoma, including PCNSL, have been reported in 4,400 natalizumabtreated patients, comprising 7500 person-years of natalizumab exposure. In postmarketing experience, there have been no EBV-positive lymphomas or lymphomas suggestive of immunosuppression-related lymphoproliferative disease. As of the end of June 2009, 2 cases of PCNSL have been reported in approximately 56,500 patients, comprising approximately 63,900 person-years of natalizumab exposure, which is consistent with the expected background rate in the general US population. One of the 2 cases is the case reported by Schweikert et al; we were informed of this case over a year ago and reported it to regulatory authorities at that time. The other case occurred in a 44-year-old woman who was diagnosed with PCNSL after approximately 3 infusions of natalizumab. Histologic type and EBV staining results were not available for this case; however, the patient’s brief exposure to natalizumab makes it unlikely that the lymphoma was related to the drug. Indeed, it is possible that this patient had PCNSL even prior to initiating natalizumab therapy. Diagnostic uncertainty may occur between early PCNSL and MS, with neurologic manifestations presenting years before the diagnosis of PCNSL. Natalizumab has demonstrated compelling efficacy in the treatment of MS and continues to be an important treatment option for many patients. In the pivotal phase 3 study, natalizumab reduced the annualized relapse rate by 68% and the cumulative probability of sustained progression of disability by 42% to 54% over 2 years compared with placebo. Furthermore, natalizumab has shown efficacy in a broad range of outcomes, including significant improvements in visual function and health-related quality of life. More recently published data indicate that a higher proportion of patients treated with natalizumab are free of both clinical and radiological evidence of disease activity compared with placebotreated patients (37% vs 7%). Data regarding the risks of natalizumab are important to physicians and patients who need to make informed benefit-risk decisions. However, risk should be systematically investigated in carefully conducted and rigorous postmarketing programs. To that end, natalizumab remains one of the most extensively monitored drugs to date for the treatment of neurological disease, and the risk-management program is one of the most rigorous ever designed. We closely monitor the safety of natalizumab and are in immediate contact with regulators regarding any adverse events that may signal a potential safety issue. In this context, based on available data, we believe at this time that there is no evidence that natalizumab is causally associated with the development of PCNSL.

Natalizumab Use in Patients With Crohnʼs Disease (CD) and Relapsing Multiple Sclerosis (MS): Updated Utilization and Safety Results: P-129

and complete data is available on 3 subjects who have completed the study. Their baseline PUCAI scores were 30, 35 and 50, which improved to 15, 0 and 40 respectively, at one month after FMT. All the subjects tolerated fecal enemas without leakage. One subject received only 6 oz enemas due to feeling of fullness. No serious adverse events were noted. Symptoms associated with FMT were mild (cramping, fullness, flatulence, bloating, diarrhea and nausea, which did not need treatment) to moderate (fever in one, which responded to antipyretic and anti-histaminic medications). These symptoms were self-limiting and lasted only for the duration of FMT treatment days. CONCLUSION(S): Fecal microbial transplantation as an enema is feasible, well tolerated and can be performed easily in children with UC with minimal training and support. Two of three subjects achieved clinical response by reduction in PUCAI of 15 points or more. One of them had complete resolution of disease activity. More data is anticipated for the Advances in IBD meeting in December. Larger prospective and controlled studies are needed to study clinical efficacy, endoscopic healing and the mechanism of action of FMT.

Reply: To PMID 19798640.

We thank Dr Bourdette and colleagues and Dr Focosi for their interesting comments regarding our article. Although we were concerned by the occurrence of a primary central nervous system lymphoma (PCNSL) in an otherwise healthy middle-aged multiple sclerosis patient treated with natalizumab, and considered it relevant to report to the medical community, we were surprised by the somewhat diverse echo it received in 4 editorials. We interpret these editorials, except one, as supporting our conclusion that a causal relationship between natalizumab treatment and the occurrence of PCNSL cannot be excluded. We thank Dr Bourdette and colleagues for emphasizing the fact that Epstein-Barr virus (EBV) positivity is not an absolute prerequisite for assuming a causative role of natalizumab in the pathogenesis of PCNSL. Although its absence may argue against the classical pathway of lymphomagenesis in immunocompromised patients by EBV, reduced central nervous system (CNS) immunosurveillance associated with long-lasting treatment with natalizumab may impact carcinogenesis and tumor equilibrium within the CNS. Currently, a causal relationship between natalizumab therapy and PCNSL has to rely on epidemiological and pharmacovigilance data. The second case of PCNSL in a patient treated with natalizumab, as disclosed by Bozic et al, increases the incidence to 3.5 in 100.000. We thank Dr Bourdette and colleagues for their epidemiological reassessment of the data, and agree entirely with their conclusion that this incidence is substantially higher than that observed in the general population. Dr Focosi addresses the heterogeneous pharmacokinetics of natalizumab. We agree that there are conflicting data on the variable half-time and biological longevity of natalizumab, and that this contributes to the difficulty in predicting drug-related side effects. In our patient, we did not measure the serum concentration of natalizumab at the time point of PCNSL diagnosis, which was 2 weeks after the last drug infusion. Nevertheless, based on the pivotal study by Khatri et al, we advocate plasmapheresis or immunoadsorption as a pivotal therapeutic step. This approach is now widely accepted as a method to accelerate the elimination of natalizumab, and is increasingly incorporated in guidelines for the management of natalizumab-associated complications.