Leflunomide-Associated Progressive Multifocal Leukoencephalopathy

Rahmlow, Megan; Shuster, Elizabeth A.; Dominik, Jacob; Deen, H. Gordon; Dickson, Dennis W.; Aksamit, Allen J.; Robles, Hector A.; Freeman, William D.

doi:10.1001/archneur.65.11.1538

Cited by 54 publications

(31 citation statements)

References 4 publications

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“…The much more serious and rare opportunistic infection PML, caused by reactivation of the JC virus, occurred in a patient who also received cancer chemotherapy. PML has also been reported in patients with autoimmune diseases other than RA, who had received other immunosuppressive therapies with or without rituximab 27,28 . The effect of rituximab treatment in relation to PML remains unclear, although patients with systemic lupus erythematosus (SLE) may be predisposed to PML and in 2 cases of patients with SLE who were treated with rituximab, PML was reported 29 .…”

Section: Discussionmentioning

confidence: 94%

Longterm Safety of Patients Receiving Rituximab in Rheumatoid Arthritis Clinical Trials

Vollenhoven¹,

Emery²,

Bingham³

et al. 2010

J Rheumatol

275

202

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Objective.To evaluate the longterm safety of rituximab in clinical trials in patients with rheumatoid arthritis (RA).Methods.Pooled analysis of safety data, including adverse events (AE) and infections, from patients treated with rituximab in combination with methotrexate in a global clinical trial program.Results.A total of 2578 patients with RA received at least 1 course of rituximab. Safety analyses were based on 5013 patient-years of rituximab exposure. The most frequent AE was infusion-related reactions (25% of patients during the first infusion of Course 1). Less than 1% of infusion-related reactions were considered serious. Rates of AE and serious AE (SAE; 17.85 events/100 patient-yrs, 95% CI 16.72, 19.06) were stable following each course. The overall serious infection rate was 4.31/100 patient-years (95% CI 3.77, 4.92). Infections and serious infections over time remained stable across 5 courses at 4–6 events/100 patient-years. Compared with other patients with RA and with the general US population, there was no increased risk of malignancy.Conclusion.In this longterm safety update in RA clinical trial patients, rituximab remained well tolerated over multiple courses. SAE and infections remained stable over time and by treatment course.

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Section: Discussionmentioning

confidence: 94%

Longterm Safety of Patients Receiving Rituximab in Rheumatoid Arthritis Clinical Trials

Vollenhoven¹,

Emery²,

Bingham³

et al. 2010

J Rheumatol

275

202

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“…The most common cause of PML is associated with human immunodeficiency virus (HIV) and AIDS (10,23). However, in recent years PML has been reported in patients receiving immunosuppressive therapies for autoimmune diseases such as Crohn's disease (44), multiple sclerosis (MS) (24,26,28,47), systemic lupus erythematosus (5,33), and rheumatoid arthritis (5,19,37). The prognosis of PML is bleak, as the disease progresses rapidly and usually proves fatal within 1 year of the onset of symptoms.…”

mentioning

confidence: 99%

Role of N-Linked Glycosylation of the 5-HT _2A Receptor in JC Virus Infection

Maginnis

Haley

Gee

et al. 2010

J Virol

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JC virus (JCV) is a human polyomavirus and the causative agent of the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML). JCV infection of host cells is dependent on interactionsThe initial interaction between virus and host occurs via molecular interactions of viral attachment proteins and receptors on host cells. Therefore, receptor recognition is a critical host cell determinant and may play a key regulatory role in viral pathogenesis. The polyomavirus JC virus (JCV) is a ubiquitous human pathogen (21,25,32) that is initially subclinical yet establishes a persistent infection in the kidney (11). In immunosuppressed individuals JCV can become reactivated, leading to infection in the central nervous system (CNS) (13)(14)(15)20), where the virus specifically targets glial cells, including astrocytes and the myelin-producing cells, oligodendrocytes (40,48). JCV infection and cytolytic destruction of oligodendroglia cause the fatal disease progressive multifocal leukoencephalopathy (PML) (1, 22). The most common cause of PML is associated with human immunodeficiency virus (HIV) and AIDS (10, 23). However, in recent years PML has been reported in patients receiving immunosuppressive therapies for autoimmune diseases such as Crohn's disease (44), multiple sclerosis (MS) (24,26,28,47), systemic lupus erythematosus (5, 33), and rheumatoid arthritis (5, 19, 37). The prognosis of PML is bleak, as the disease progresses rapidly and usually proves fatal within 1 year of the onset of symptoms. While current treatment options for PML are limited (23), recent studies suggest that mirtazapine, a serotonin receptor antagonist, may be capable of slowing the progression of PML (6,27,45,46). JCV has a nonenveloped, icosahedral capsid that encapsidates a circular double-stranded DNA (dsDNA) genome (39). JCV attachment to cells is mediated by an N-linked glycoprotein with either ␣(2,3)-or ␣(2,6)-linked sialic acid (16, 31), suggesting that N-linked glycosylation of cellular receptors is important for JCV infection. N-linked glycosylation is a posttranslational process by which oligosaccharides are added to asparagine residues, and this modification is important for protein processing, folding, expression, and function (43). Previous studies from our laboratory revealed that the JCV also requires the serotonin 5-hydroxytryptamine 2A receptor (5-HT 2A R) to mediate JCV infection (18,35,38), while others report that JCV infection can occur in the absence of 5-HT 2A R (7,8). 5-HT 2A R is a seven-transmembrane-spanning G-protein-coupled receptor that belongs to a large family of 5-HT serotonin receptors. 5-HT 2A R is abundantly expressed on cells in the brain (4), including glial cells (3), and in the kidney (4), which parallels the sites of JCV infection. N-linked glycosylation plays a key regulatory role in the function of serotonin receptors. Mutation of N-linked glycosylation sites in human 5-HT 3A R and 5-HT 5A R results in decreased expression at the plasma membrane, which is critical for receptor functio...

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“…However, leflunomide's safety profile is relevant for teriflunomide and some rare serious side effects have been observed with this predecessor drug, including 3 cases of PML (in > 2 million patient-years of leflunomide use). Two patients had previously been treated with other immunosuppressants [33,34], and there is limited information on the third [35]. A safety concern relevant for many young female patients with MS is the probable teratogenic potential of leflunomide and teriflunomide.…”

Section: Teriflunomidementioning

confidence: 99%

Advances in and Algorithms for the Treatment of Relapsing-Remitting Multiple Sclerosis

2016

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Treatment options in relapsing-remitting multiple sclerosis have increased considerably in recent years; currently, a dozen different preparations of diseasemodifying therapies are available and some more are expected to be marketed soon. For the treating neurologist this broad therapeutic repertoire not only greatly improves individualized management of the disease, but also makes choices more complex and difficult. A number of factors must be considered, including disease activity and severity, safety profile, and patient preference. We here discuss the currently existing options and suggest treatment algorithms for managing relapsing-remitting multiple sclerosis.

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Leflunomide-Associated Progressive Multifocal Leukoencephalopathy

Cited by 54 publications

References 4 publications

Longterm Safety of Patients Receiving Rituximab in Rheumatoid Arthritis Clinical Trials

Longterm Safety of Patients Receiving Rituximab in Rheumatoid Arthritis Clinical Trials

Role of N-Linked Glycosylation of the 5-HT _2A Receptor in JC Virus Infection

Advances in and Algorithms for the Treatment of Relapsing-Remitting Multiple Sclerosis

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Leflunomide-Associated Progressive Multifocal Leukoencephalopathy

Cited by 54 publications

References 4 publications

Longterm Safety of Patients Receiving Rituximab in Rheumatoid Arthritis Clinical Trials

Longterm Safety of Patients Receiving Rituximab in Rheumatoid Arthritis Clinical Trials

Role of N-Linked Glycosylation of the 5-HT 2A Receptor in JC Virus Infection

Advances in and Algorithms for the Treatment of Relapsing-Remitting Multiple Sclerosis

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Role of N-Linked Glycosylation of the 5-HT _2A Receptor in JC Virus Infection