Natalizumab treatment for multiple sclerosis: updates and considerations for safer treatment in JCV positive patients

Abstract

Natalizumab is currently one of the best options for treatment of patients with Multiple Sclerosis who have failed traditional prior therapies. However, prolonged use, prior immunosuppressive therapy and anti-JCV antibody status have been associated with increased risk of developing progressive multifocal leukoencephalopathy (PML). The evaluation of these conditions has been used to estimate risks of PML in these patients, and distinct (sometimes extreme) approaches are used to avoid the PML onset. At this time, the biggest issue facing the use of Natalizumab is how to get a balance between the risks and the benefits of the treatment. Hence, strategies for monitor JCV-positive patients undergoing Natalizumab treatment are deeply necessary. To illustrate it, we monitored JCV/DNA in blood and urine of a patient receiving Natalizumab for 12 months. We also bring to discussion the effectiveness of the current methods used for risk evaluation, and the real implications of viral reactivation.Keywords: multiple sclerosis, Natalizumab, JCV, risk factors, progressive multifocal leucoencephalopaty, viruria. RESUMO Natalizumabe é atualmente uma das melhores opções para o tratamento de pacientes com Esclerose Múltipla que não respondem aos tratamentos tradicionais. No entanto, o seu uso prolongado, o uso de terapia imunossupressora prévia e o status sorológico antivírus JC têm sido associados com o risco aumentado de desenvolvimento de Leucoencefalopatia Multifocal Progressiva (LEMP). A avaliação destas condições tem sido utilizada para estimar os riscos do desenvolvimento de LEMP nestes pacientes, e abordagens distintas (por vezes extremas) são empregadas para evitar o aparecimento dessa patologia. Atualmente, o grande desafio está em obter um equilíbrio entre os riscos e os benefícios do tratamento com Natalizumabe. Assim, é crucial desenvolver estratégias para monitorar pacientes portadores do vírus JC sob tratamento com Natalizumabe. A título de ilustração, pesquisamos o vírus no sangue e na urina de um paciente sob tratamento durante 12 meses. Também discutimos a eficácia dos métodos atualmente utilizados para avaliação de riscos e as implicações reais de reativação viral.Palavras-chave: esclerose múltipla, Natalizumabe, vírus JC, leucoencefalopatia multifocal progressiva, viruria. Natalizumab (Tysabri), used for treatment of relapsingremitting multiple sclerosis (MS), is a monoclonal antibody directed to the a4b1 integrin, a subunit of an adhesion molecule expressed on the surface of T lymphocytes. The antibodies act by blocking the migration of T Lymphocytes from blood to the CNS through the blood brain barrier (BBB) and attenuate the inflammatory effects 1 . The AFFIRM study showed that monotherapy with Natalizumab (NTZ) for 2 years decreased the relapse rate by 68% and the disability progression rate by 42% compared with placebo 2 . NTZ is well tolerated and the overall incidence of serious adverse events is low. Although the efficacy of NTZ is up to

Natalizumab treatment for multiple sclerosis

“…Despite the presence of rearranged forms of JCV virus in urine, there was no viremia or concomitant increased viral load after a 12 months treatment with Natalizumab 1 . These findings of Nali et al 1 seem to reinforce the new management algorithm proposed by Sørensen 3 , where JCV positivity may point out to another therapy. This conduct is discussed by Nali et al 1 , on considering the risks of drug holiday after 12 months of Natalizumab treatment.…”

“…This issue brings an interesting research on the controversial risk of progressive multifocal leukoencephalopathy (PML) in multiple sclerosis patients treated with Natalizumab. Nali et al 1 present a brief review on the PML of patients submitted to Natalizumab treatment for relapsing-remitting multiple sclerosis and describe the results of virus load and JVC/DNA positivity in urine and blood, of a patient, after a 12 months' follow-up.…”

Hands on Alemtuzumab-experience from clinical practice: whom and how to treat

“…Additionally the relative and absolute contraindications should be carefully assessed to choose the most suitable drug. For example, patients with positive anti-JCV status represent high-risk group for PML development on longterm Natalizumab treatment [43]. For female patients in child-bearing age, Alemtuzumab can be the choice, but the it should be planned 4 months after the last infusion [44].…”

Melanoma complicating treatment with natalizumab for multiple sclerosis: A report from the Southern Network on Adverse Reactions (SONAR)

“…VCAM‐1 is expressed on surfaces of vascular endothelial cells in brain and spinal cord blood vessels 1. Blocking α 4 integrins reduces further brain inflammation¸ apparently accounting for the drug's effectiveness for MS 2, 3, 4, 5. Natalizumab also inhibits expression of alpha4 integrin, which has been shown to prevent melanoma metastasis but also may promote melanoma invasion 3.…”

“…Blocking α 4 integrins reduces further brain inflammation¸ apparently accounting for the drug's effectiveness for MS 2, 3, 4, 5. Natalizumab also inhibits expression of alpha4 integrin, which has been shown to prevent melanoma metastasis but also may promote melanoma invasion 3. The most serious complication of natalizumab is progressive multifocal leukoencephalopathy (PML), an adverse drug reaction (ADR) confirmed to have been reported in 714 patients through March 6, 2017, and a risk estimate of 4.2/1000 patients (95% confidence interval, 3.89‐4.52) 5.…”