A third case of progressive multifocal leukoencephalopathy ( PML ) has been reported in a patient with rheumatoid arthritis treated with Rituxan ( Rituximab; MabThera ). This occurred in a 73-year old woman with a diagnosis of seronegative rheumatoid arthritis of 3 years. Concomitant and/or prior treatments for rheumatoid arthritis included Leflunomide ( Arava ), Hydroxychloroquine ( Plaquenil ), and Prednisone. Other medical history included hypertension, hypothyroidism, osteoporosis, recurrent bronchitis and a cerebrovascular accident. In February 2009, she received one course of Rituxan ( 1000 mg given two weeks apart ). She developed dysesthesias and ataxia 4 to 6 months following treatment with Rituxan. PML was diagnosed based on clinical symptoms, MRI findings, and detection of JC viral DNA in the CSF by PCR.

This is the first case of progressive multifocal leukoencephalopathy in a patient with rheumatoid arthritis treated with Rituximab who has not previously received treatment with a TNF antagonist. PML has been reported in patients with rheumatoid arthritis, including those treated with other immunosuppressive medications in the absence of Rituxan.

Previously, 2 fatal cases of confirmed progressive multifocal leukoencephalopathy have been reported in patients with rheumatoid arthritis treated with Rituximab. These cases involved a 51 year-old woman and a 73 year-old woman with possible risk factors for the development of PML, including oropharyngeal malignancy treated with chemotherapy and radiation therapy and/or long standing lymphopenia prior to and during Rituximab treatment.

The overall reporting incidence of progressive multifocal leukoencephalopathy in patients with rheumatoid arthritis receiving Rituximab is rare ( 3 reports in approximately 100,000 rheumatoid arthritis patients that have been exposed ). However, the information to date suggests that patients with rheumathoid arthritis who receive Rituximab have an increased risk of PML.

Physicians should consider PML in any patient being treated with Rituxan who presents with new onset neurologic manifestations. Consultation with a neurologist, brain MRI, and lumbar puncture should be considered as clinically indicated. In patients who develop progressive multifocal leukoencephalopathy, Rituximab should be discontinued.

Progressive multifocal leukoencephalopathy is a rare, progressive, demyelinating disease of the central nervous system that usually leads to death or severe disability. PML is caused by activation of the JC virus. JC virus resides in latent form in 40-80% of healthy adults. The factors leading to activation of the latent infection are not fully understood.
Progressive multifocal leukoencephalopathy has been reported in HIV-positive patients, immunosuppressed cancer patients, transplantation patients and patients with autoimmune diseases. There are no known interventions that can reliably prevent or adequately treat PML.

Rituxan in combination with Methotrexate is indicated to reduce signs and symptoms and slow the progression of structural damage in adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies.
Rituxan is also indicated for the treatment of patients with relapsed or refractory, low-grade or follicular, CD20-positive, B-cell, non-Hodgkin’s lymphoma ( NHL ) as a single agent, and for the treatment of previously untreated follicular, CD20-positive, B-cell NHL in combination with CVP ( Cyclophosphamide, Vincristine and Prednisone ) chemotherapy.
Rituxan is indicated for the treatment of non-progressing ( including stable disease ), low-grade, CD20-positive, B-cell NHL, as a single agent, after first-line treatment with CVP chemotherapy.
Rituxan is also indicated for previously untreated diffuse large B-cell, CD20-positive, NHL in combination with CHOP ( Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone ) or other anthracycline-based chemotherapy regimens.

Rituximab has been associated with fatal infusion reactions, tumor lysis syndrome, severe mucocutaneous reactions and progressive multifocal leukoencephalopathy.
Hepatitis B reactivation and cardiac arrhythmias and angina have also been observed. Patients should be closely observed for signs of infection if biologic agents and/or DMARDs other than Methotrexate are used concomitantly. Common adverse reactions include hypertension, nausea, upper respiratory tract infection, arthralgia, pruritus, and pyrexia.

Souce: FDA: 2009

XagenaMedicine2009


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