Progressive multifocal leukoencephalopathy (PML) was reported to have developed in three patients treated with natalizumab. We conducted an evaluation to determine whether PML had developed in any other treated patients.
We invited patients who had participated in clinical trials in which they received recent or long-term treatment with natalizumab for multiple sclerosis, Crohn's disease, or rheumatoid arthritis to participate. The clinical history, physical examination, brain magnetic resonance imaging (MRI), and testing of cerebrospinal fluid for JC virus DNA were used by an expert panel to evaluate patients for PML. We estimated the risk of PML in patients who completed at least a clinical examination for PML or had an MRI.
Of 3417 patients who had recently received natalizumab while participating in clinical trials, 3116 (91 percent) who were exposed to a mean of 17.9 monthly doses underwent evaluation for PML. Of these, 44 patients were referred to the expert panel because of clinical findings of possible PML, abnormalities on MRI, or a high plasma viral load of JC virus. No patient had detectable JC virus DNA in the cerebrospinal fluid. PML was ruled out in 43 of the 44 patients, but it could not be ruled out in one patient who had multiple sclerosis and progression of neurologic disease because data on cerebrospinal fluid testing and follow-up MRI were not available. Only the three previously reported cases of PML were confirmed (1.0 per 1000 treated patients; 95 percent confidence interval, 0.2 to 2.8 per 1000).
A detailed review of possible cases of PML in patients exposed to natalizumab found no new cases and suggested a risk of PML of roughly 1 in 1000 patients treated with natalizumab for a mean of 17.9 months. The risk associated with longer treatment is not known.
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"Natalizumab, a humanized anti-α4-integrin monoclonal antibody, is effective in the treatment of moderately to severely active CD patients, but it is not approved in Europe because it has been associated with an increased risk of multifocal leukoencephalopathy (one case/10,000 patients).64,65 Vedolizumab is a humanized immunoglobulin G1 mAb against α4β7 integrin that has been shown to be superior to placebo in inducing and maintaining clinical and endoscopic remission in UC patients.66 "
[Show abstract][Hide abstract] ABSTRACT: Dovepress 359 R E v i E w open access to scientific and medical research Open Access Full Text Article http://dx.doi.org/10.2147/CEG.S45297 Abstract: Infliximab (IFX) is an effective treatment for inducing and maintaining response in Crohn's disease and ulcerative colitis patients. Some patients present lack of response or loss of response to IFX during maintenance therapy. Empirical management with combination therapy with an immunomodulator, IFX dose escalation, or switching IFX for another antitumor necrosis factor-α drug, mainly adalimumab, is common in clinical practice. Selecting the best choice with the help of serum drug concentrations and trough IFX antibody concentrations could be a very interesting approach. In addition to surgery, a broad spectrum of new drugs has been tested and could expand treatment options in the near future.
"No patient had detectable JCV DNA in cerebrospinal fluid. PML was ruled out in 43 of the 44 patients, but could not be ruled out in one patient because cerebrospinal fluid and follow-up MRI were not available.42 No new PML cases were identified in this study, suggesting a risk of PML of roughly one in 1,000 patients treated with natalizumab for a mean of 17.9 months. "
[Show abstract][Hide abstract] ABSTRACT: Natalizumab was the first monoclonal antibody to be approved for the treatment of relapsing-remitting multiple sclerosis (RRMS) based on its short-term efficacy and overall tolerability. However, the incidence of treatment-associated progressive multifocal leukoencephalopathy (PML), an infection of the brain caused by the John Cunningham virus, jeopardized this efficacious treatment from the beginning. Eight years after licensing of natalizumab, long-term studies confirm the considerable and sustained efficacy of natalizumab, although the PML complication still threatens one of the most successful treatments available for RRMS. During these years, considerable progress has been made in identification of risk factors that allow more effective management of PML risk. In addition, long-term studies to define better when to start or stop treatment and to optimize treatment strategies after cessation of natalizumab are ongoing, and hopefully will improve management and will allow natalizumab to remain as a valuable therapeutic option for patients with highly active RRMS.
"They have proven to be efficacious in reducing relapse frequency and disability progression in the short term. NTZ, a novel drug approved in Europe as second line therapy, exerts a robust anti-inflammatory activity in RRMS, but is associated with an increased risk of progressive multifocal leukoencephalopathy (PML) [1-8] which limits its prolonged use in the majority of cases. However, NTZ cessation is followed by a reactivation of disease activity  and no established guidelines exist on patient risk stratification and management. "
[Show abstract][Hide abstract] ABSTRACT: De-escalating natalizumab (NTZ) to interferon beta 1b (IFN B 1B) is a possible treatment option in multiple sclerosis (MS) patients interrupting NTZ because of increased risk of progressive multifocal leukoencephalopathy (PML). The aim of this study was to evaluate satisfaction and adherence to treatment, behavioral and fatigue changes in patients switched to IFN B 1B compared to continued NTZ treatment.
A 1 year, prospective, randomized, rater-blinded, parallel-group study. Nineteen relapsing remitting (RR) MS patients, randomly assigned to undergo either NTZ (n = 10) or IFN B 1B (n = 9) treatment, who had previously received NTZ for at least 12 months with disease stability and fearing or at risk for PML were included. Patients underwent behavioral and treatment assessments at baseline, after 24-week and 1 year follow-up. Behavioral assessment included measures of cognition, fatigue and quality of life. Treatment assessment included measures of satisfaction, persistence and adherence to treatment. Clinical-radiological disease activity and safety were also assessed.
Baseline characteristics of patients were similar between groups except for Euro Quality Visual Analogue Scale, being higher in the NTZ group (p = 0.04). Within-group comparisons at the three time points, as well as interaction analysis of treatment effect over time did not show any statistically significant differences in behavioral or treatment assessments, but a coherent trend favoring NTZ over IFN B 1B.
De-escalating NTZ to IFN B 1B is feasible and associated with overall good patient related outcome and persistently stable behavioral measures.