Update on PML and PML-IRIS Occurring in Multiple Sclerosis Patients Treated With Natalizumab

Abstract

The use of natalizumab to treat multiple sclerosis (MS) has been associated with the development of progressive multifocal leukoencephalopathy (PML), with 242 PML cases reported as of May 3, 2012. Fortunately, rapid withdrawal of the drug and administration of plasma exchange has allowed survival in many of these patients, but a new problem, immune reconstitution inflammatory syndrome (IRIS), has emerged after drug withdrawal. This report provides an update on PML in natalizumab-treated patients and reviews what is currently known about PML-IRIS in this setting; autopsy findings from a well-studied patient are illustrated. This patient with relapsing-remitting MS had been treated for 4 years with natalizumab, with discontinuation of drug after diagnosis of PML by cerebrospinal fluid polymerase chain reaction testing. Disease was manifested by severe paraparesis and expressive aphasia, which progressed before and after the diagnosis of PML. Immune reconstitution inflammatory syndrome was diagnosed, comfort care was instituted, but demise did not occur until 9 months later. Autopsy showed ongoing severe PML-IRIS, with massive cavitary brain lesions containing abundant perivascular and parenchymal CD8-positive T-cell infiltrates. Bone marrow and spleen, but not brain, contained monoclonal T-cell populations by polymerase chain reaction-based gene rearrangement studies, indicating overstimulation of peripheral T cells; T-cell lymphoma was not identified by morphological or immunohistochemical criteria.

Neurological safety of fingolimod: An updated review

“…The use of NTZ to treat MS has been associated with the development of PML, but a new problem – IRIS – has emerged after cessation of NTZ (PML‐related IRIS [PML‐IRIS]) 74, 75. Clinical presentation is characterized by rapid worsening of previous neurological deficits as a result of an overwhelming immune response to JCV antigen, which leads to massive destruction of virus‐infected and non‐infected neuronal and glial tissues 76.…”

“…Autopsy showed massive cavitary lesions containing abundant perivascular and parenchymal CD8‐positive T‐cell infiltrates, and numerous macrophages within lesions 75, 80. Plasma cells are also prominent as compared with typical MS lesions.…”

“…PML‐IRIS itself causes significant morbidity and mortality, and is fatal in almost one‐third of patients 75. The outcome of PML‐IRIS was studied separately for patients before and after withdrawal/removal of NTZ.…”

Monoclonal Antibody for Multiple Sclerosis Treatment

“…После завершения лечения возможно наблюдать выраженную активацию заболевания, в основе чего лежит развитие иммунного воспалительного синдрома (IRIS) -наблюдается у ⅓ пациентов [5][6][7][8]. Единственным лечением IRIS является проведение гормональной пульс-терапии [9].…”

“…Это привело к тому, что в дальнейших исследова-ниях с препаратом алемтузумаб участвовали только пациенты с РРС. В последующем высокая эффективность лечения пациентов с РРС алемтузумабом была проде-монстрирована в трех крупных исследованиях -II фаза СAMMS223 и два исследования III фазы (CARE-MS I и CARE-MS II) [7,[9][10][11][12][13][14]. Во всех трех исследованиях алемту-зумаб сравнивали с ИФНβ-1а.…”