Progressive Multifocal Leukoencephalopathy (PML)
PML is a rare brain disease caused by infection by, or re-activation of the John Cunningham virus (JC virus). PML can cause severe disability or death. PML is known as an opportunistic infection, which is an infection that is caused by pathogens that usually do not cause illness in people with healthy immune systems. People with weakened immune systems and those with autoimmune diseases such as multiple sclerosis, lupus and rheumatoid arthritis who are treated with certain types of disease-modifying therapies are at higher risk for PML. Disease-modifying therapies alter how the immune system functions, including its ability to effectively fight infections. As a result, people who take these therapies are at higher risk for JC virus infection or re-activation. To date, occurrences of PML have been reported in individuals with MS treated with natalizumab (Tysabri®), dimethyl fumarate (Tecfidera™), fingolimod (Gilenya®) and ocrelizumab (Ocrevus™).
Symptoms of PML may include:
· Loss of coordination, clumsiness
· Loss of language ability (aphasia)
· Memory loss
· Vision problems
· Weakness of the legs and arms that gets worse
There is no cure for PML. Treatment includes immediate termination of current medication. In some cases treatment may include treatment with antiretroviral medication or other experimental approaches. Blood plasma exchange may be used to remove any remaining medication from the body for those who have received natalizumab (Tysabri).
In 2005, three cases of PML were reported in patients enrolled in clinical trials for Tysabri. There were two deaths: one in a person with MS who was also taking Avonex, and one in a person with Crohn’s disease who was also taking immunosuppressants. Additional cases of PML were reported in people outside of clinical trials who were not taking another disease-modifying medication at the same time. In total, 134,600 individuals worldwide have received Tysabri and a reported 541 cases of PML (Biogen, 2015).
There are three factors known to increase the risk of PML in people treated with Tysabri: the presence of anti-JCV antibodies (indicates prior infection with JC Virus), longer treatment duration (especially beyond 24 months) and prior treatment with an immunosuppressant, which appear to be independent of Tysabri treatment duration. People who have all three risk factors have the highest risk of PML. The risks and benefits of continuing Tysabri therapy should be carefully considered in these people. Health Canada’s product monograph provides detailed monitoring practices related to PML. For additional information or support with treatment of Biogen ONETM program at 1-855-MSONE-00 or 1-855-676-6300.
Dimethyl fumarate (Tecfidera)
Two cases of PML have been reported in individuals treated with Tecfidera. Both cases exhibited severely reduced blood cell counts – known as lymphopenia, a known adverse effect of this treatment. Health Canada has updated the product monograph for Tecfidera to include monitoring practices for PML. For additional information or support with treatment of Biogen ONETM program at 1-855-MSONE-00 or 1-855-676-6300.
In 2012 a case of PML was reported in a patient who was taking
Gilenya, who had previously been treated with natalizumab
(Tysabri). Novartis noted that the PML was likely associated
with previous treatment with Tysabri. In 2015, three cases of
PML were reported in individuals treated with Gilenya who had
not been previously treated with Tysabri.
Novartis has informed regulatory authorities of these cases, and is investigating whether treatment with Gilenya contributed to the development of PML. Novartis has stated that they will continue to explore all potential factors that may contribute to the risk of PML for patients on Gilenya. No changes to patient management or routine monitoring with Gilenya treatment are recommended beyond the guidance in the Gilenya Product Monograph at this time. For additional information or support with treatment of Gilenya please contact Gilenya® Go Program: 1-855-PILL-4MS (1-855-745-5467).
A carry-over case of progressive multifocal leukoencephalopathy
(PML) in a multiple sclerosis patient on a compassionate use
program was reported. The patient was anti-JCV
antibody-positive with a high JCV index (4.1) and was
previously treated with natalizumab for 3.5 years (36
infusions; last infusion in February 2017). The patient then
received one dose of OCREVUS in April 2017. The case was
reported as a carry-over from natalizumab by the treating
physician and was also reported as unrelated to OCREVUS by the
Another carry-over case of progressive multifocal leukoencephalopathy (PML) in a multiple sclerosis patient was reported in April 2018. The patient had increasingly worsening neurological symptoms and MRI changes prior to discontinuing treatment with fingolimod in December 2017. The patient switched to ocrelizumab in March 2018. The case was reported as a carry-over from fingolimod by the treating physician. All cases of serious adverse effects are reported to Health Canada’s Post-Market Surveillance Program.