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For the last 15 years, progressive multifocal leukoencephalopathy (PML) has attracted a lot of attention from the multiple sclerosis (MS) community.

As , chief of the multiple sclerosis division in the University of Pennsylvania's Perelman School of Medicine in Philadelphia, pointed out, it's not MS per se that puts a patient at risk for PML, the rare but often fatal inflammatory viral disease -- characterized by progressive damage or inflammation of the white matter of the brain.

"For many years before we had any specific treatments for MS, we used a wide variety of drugs that immune-suppressed people," said Joseph Berger. "Although they weren't used widely in great numbers, they were still used, and we never had a case of PML reported as associated with MS, despite the fact that we gave people cyclophosphamide and azathioprine, and large doses of steroids, and a large variety of other drugs when they had aggressive disease that, in theory, would have put them at risk for developing PML."

Instead, in MS, PML has been associated with a few disease-modifying drugs, the first being natalizumab (Tysabri).

Natalizumab was approved for treatment for MS in 2004 on the basis of results from the AFFIRM and SENTINEL TRIALS. Not long after, reports appeared and ) of PML in two patients who had been treated with natalizumab.

According to the National Multiple Sclerosis Society, while the vast majority of PML cases in MS involve patients taking natalizumab, cases of PML have since been reported in individuals treated with other agents including dimethyl fumarate (Tecfidera) and fingolimod (Gilenya).

In a 2017 , Berger divided MS disease-modifying therapies into three classes, depending on the degree of PML risk:

• Class I – high potential risk of PML
• Class II – low potential risk of PML
• Class III – no or very low potential risk of PML

As he put it in his article, "natalizumab occupied a place of its own with respect to PML risk," and was the only drug he assigned to class I.

PML is caused by activation of the JC (John Cunningham) virus that, , is eventually acquired by more than 70% of the population. It remains suppressed and nonpathogenic in patients with intact immune function. Yet, Berger points out, "even in the context of people who are immune suppressed, it collectively remains a rare disease."

"That rarity, we believe, is a consequence of the fact that there are multiple high barriers to the development of the disease," he said. "One of these is a viral barrier so that the virus has to mutate in order to grow effectively in the brain. The second is that the immunity response has to be blunted in some way, and then there are a number of other host factors that are likely contributors. And it appears a drug like natalizumab" -- an integrin inhibitor that reduces cellular adhesion needed for certain immune cells to function properly -- "blows through all three barriers to some degree."

Considering the risks involved with natalizumab (from 0.1% to 1% incidence rate for PML), risk mitigation strategies are needed. As , a patient's risk of developing PML is higher if that patient has been infected by the JC virus, has taken natalizumab for a prolonged period of time (especially beyond 2 years), and was previously treated (before natalizumab) with an immunosuppressant.

"So you don't start the drug in someone who is antibody positive, unless it is absolutely needed," said Berger. "And in that context, stop the drug after 12 to 18 months, because there have been very few cases where the disease has developed in a patient in less than 12 months."

Researchers have toyed with as a means of reducing PML risk while maintaining the drug's efficacy. The drug's manufacturer Biogen is now conducting to assess the effectiveness and safety of extended interval dosing of natalizumab.

As for the , "there is no risk mitigation strategy right now," said Berger, who added that the risk with fingolimod is "very low" (about one case per 18,000 patients).

On the other hand, he said, there is a risk mitigation strategy for dimethyl fumarate or DMF (one in 50,000 incident cases).

Several cases of PML have occurred in patients treated with DMF who have had sustained lymphopenia (more than 6 months). "With individuals who have a lymphocyte count less than 500 mm³, we discontinue the drug and find another one," Berger said.

With regard to the other disease-modifying therapies, such as alemtuzumab (Lemtrada), rituximab (Rituximab), mitoxantrone, teriflunomide (Aubagio), and daclizumab (Zinbryta, now withdrawn), they are currently classified as class III agents. "Whether PML will be observed with other [disease-modifying therapies] in use for MS ... remains uncertain," wrote Berger in his article.

PML is a rare opportunistic infection caused by a slow replicating virus, said DO, of Johns Hopkins Hospital in Baltimore. "So it takes time for PML to come out, and so even though with the approval of a therapy, you may not see a PML signal up front, you have to be very cautious in saying this drug will not cause PML or some other opportunistic infections down the road, because we've learned with some therapies that are FDA approved that that is what happened."

"We talk a lot about the safety of these medications, including PML, with our patients, but I would say it's still an exceedingly rare infection," said Newsome. "What I try to tell people is that MS is a bad disease, and untreated or inadequately treated MS is a risk in and of itself. And, in my view, it is a greater risk than developing PML, especially in the context of some of the risk mitigation strategies that we can employ with some of the medications we have."

For patients who develop PML, is a cure possible? Current treatment involves withdrawal of the offending drug and restoring immune function, typically with plasmapheresis. But the latter often leads to so-called immune reconstitution inflammatory syndrome or IRIS, which can be as devastating in the brain as the PML.

Berger said the "greatest buzz" concerns two forms of therapy that were recently the subjects of reports in the New England Journal of Medicine.

In one, researchers from the University of Texas MD Anderson Cancer Center, found that three patients with PML saw their .

In the other, researchers at the National Institutes of Health found that five of eight patients with PML who were experienced clinical improvement or stabilization.

However, all those patients had conditions other than MS that led to PML development.

The lead author of the pembrolizumab study noted that patients with underlying autoimmune diseases were not considered for this study; participants were immunocompromised from their primary diseases, not from drugs they were receiving.

"Checkpoint inhibitors could possibly potentiate autoimmune responses," , of the National Institute of Neurological Disorders and Stroke, told 乌鸦传媒. "For MS or any central nervous system autoimmune disease we did not feel comfortable treating with a drug like this where it could exacerbate the underlying disease."

Consequently, PD-1/PD-L1 inhibitors wouldn't be suitable for PML stemming from MS drug therapy. Instead, she said, "I think the thing that is going to be most helpful is going to be developing improved biomarkers of the PML infection."

Berger noted that Spanish researchers have proposed that one such marker -- lipid-specific IgM bands in spinal fluid -- .

"It is believed to be high sensitivity and appears to be independent of JC virus serology," said Berger. "The problem is that it is non-specific and non-validated, and you have to do it in spinal fluid and [it] has a complex methodology, so it's not widely used."

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