A team of neurologists have proposed a new algorithm to help clinicians determine which patients with relapsing forms of multiple sclerosis (MS) may be suitable for first-line treatment with natalizumab (Nicholas JA, et al. Ther Adv Chronic Dis. 2014;5:62-68).
Natalizumab is associated with an increased risk for progressive multifocal leukoencephalopathy (PML), a rare infection in the brain. However, that risk is very small in patients with low levels of antibodies to the JC virus (JCV), the pathogen responsible for PML, and the clinical effectiveness of natalizumab outweighs its risks in many of those patients, according to the investigators.
Jacqueline A. Nicholas, MD, MPH, Assistant Professor of Neurology, Division of Neuroimmunology, Ohio State University, Columbus, and her colleagues suggest that patients with newly diagnosed relapsing-remitting MS (RRMS) who are JCV-antibody–negative, or have not received immunosuppression and have a JCV antibody index of ≤1.5, are potential candidates for natalizumab treatment.
Dr Nicholas and colleagues caution against the use of antibody titer to determine the exact risk of a patient for PML; however, they believe they are on safe ground with these general proposed guidelines.
“This is the algorithm I have used to care for multiple sclerosis patients at the Ohio State University Multiple Sclerosis Center,” Dr Nicholas told Value-Based Care in Neurology. “It has been well-received by patients and by my colleagues.” At the same time, she noted, “we are absolutely monitoring patients’ outcomes and adverse events as this is the standard of care. I may report on this at a later date.”
Dr Nicholas and colleagues are making the pitch for more first-line use of natalizumab, as a result of the impressive results of the clinical trials AFFIRM (Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis) and SENTINEL (Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing-Remitting Multiple Sclerosis).
For example, patients in the AFFIRM trial who were treatment-naïve (ie, received natalizumab as first-line therapy) and had highly active RRMS had a 64% drop in 24-week sustained disability progression at 2 years, as was shown in a 2009 study. And a post hoc analysis of the AFFIRM results showed that 64% of patients receiving natalizumab were without clinical disease activity throughout the 2 years of the study, while 58% were free of radiographic disease activity, and 37% had neither clinical nor radiographic disease activity.
In addition, results of a more recent study confirm that natalizumab may be particularly effective as first-line therapy and also suggest that aggressive phenotypes of MS in African Americans respond well to the medication.
However, PML can occur in patients with MS who are being treated with natalizumab, possibly because of reduced immune surveillance in the brain that, in turn, allows previously quiescent viruses to multiply.
As of February 4, 2014—the latest data that are available according to the manufacturer of the drug—437 patients with MS from around the world who are receiving natalizumab had contracted PML. The overall natalizumab-associated PML incidence was 3.5/1000 people, and the mortality rate was 23% (https://medinfo.biogenidec.com).
The New Proposed Guidelines
Because of the strong efficacy data, Dr Nicholas’s group posited that natalizumab “should be considered in patients with aggressive MS disease courses at least for the first 12-24 months regardless of JCV serum antibody status.”
For other patients, the treatment decision depends on the JCV-antibody status. The investigators suggest that:
- JCV-antibody–negative patients who have a <1/10,000 risk for developing PML may be considered for first-line natalizumab
- JCV-antibody–positive patients who have had immunosuppression events should not receive first-line natalizumab
- JCV-antibody–positive patients who have not had immunosuppression and have a JCV antibody index of up to 15—which is associated with a 1:10,000 risk for PML in the first 24 months of treatment, and up to 1.3:1000 at 49 to 72 months of treatment—are potential candidates for first-line natalizumab; these patients should undergo a limited cerebral magnetic resonance imaging to monitor for PML lesions every 3 to 4 months, and their JCV antibody index should be remeasured every 3 to 6 months
- JCV-antibody–positive individuals who have not had immunosuppression events and have a JCV antibody index of more than 1.5 should be considered for 12 to 24 months of first-line natalizumab only if they have aggressive MS; the PML risk with a JCV antibody index of more than 1.5 is 1:1000 for the first 24 months, 8.1:1000 from 25 to 48 months, and 8.5:1000 for months 49 to 72.