Monday, 25 September 2017

#NeuroSpeak: treating MS in patients with PML

Teriflunomide is the drug of choice for treating MS in patients recovering from PML. #NeuroSpeak #CharcotProject

Summary: This post summarises the scientific principles for treating multiple sclerosis in patients who have PML as a complication of natalizumab treatment. I make the case for using DMTs that are not immunosuppressive and highlight the antiviral effects of Teriflunomide that make it the DMT of choice. 

At the grand round at Imperial College on Friday, a case of natalizumab-associated PML was presented. The patient had developed IRIS and was deteriorating. The question was posed about MS rebound contributing to some of the later deterioration in functioning and how to treat MS in this situation. 

It is clear that you cannot use an MS DMT that causes immunosuppression, particularly one that targets T-cells, in this situation. Patients with PML need their CD8+ cytotoxic T-cell to recover from PML. In my opinion, this only leaves 4 drugs that have a suitable profile:

(1) Interferon-beta: IFNbeta is not immunosuppressive and has many activities that are anti-viral. However, a lot of people who are on natalizumab may have failed IFNbeta in the past. IFNbeta has also been shown not to be that effective in preventing MS rebound post-natalizumab. 

(2) Glatiramer acetate: GA is not immunosuppressive, is only moderately effective in treating MS, is not effective in preventing MS rebound post-natalizumab and has a delayed onset of action. Therefore, it would not be the ideal agent to prevent MS rebound post-alemtuzumab in a patient with PML.

(3) Teriflunomide: Teri is not immunosuppressive as defined by the regulators, it has a complex mode of action that includes general anti-viral activity. Interestingly, leflunomide, a prodrug that is converted into teriflunomide, has been shown to have antiviral effects against BK virus (see below), that is very closely related to JCV, the cause of PML. In addition, there is some emerging evidence that Teri may cross the blood-brain barrier and hence may be able to inhibit JCV with the CNS. At the last AAN there was a poster of a switch study showing that Teri, post-natalizumab, was able to hold back rebound MS disease activity in the majority of patients and overall these patients did well.

(4) Daclizumab: Dac is not immunosuppressive, as defined by regulators, and only drops CD8 cell numbers by ~10%. Therefore, antiviral responses, for example against JCV should be intact. Dac also expands the NK, or natural killer, cell population that have anti-viral effects. We are in the process of doing a switch study to assess the effectiveness of Dac post-natalizumab to see how effective it is in preventing post-natalizumab rebound. Daclizumab also has a rapid-onset of action making which makes it an ideal agent post-natalizumab. However, as Dac reduces IL2 signalling in activated T-cells it may blunt effector T cell responses, i.e. reduce their reactivity, which makes me concerned about using it in patients with active JCV infection and PML. 

My recommendation, therefore, to the team looking after this patient particular patient was to use high dose Leflunomide (40mg per day) until JCV was not detectable in her CSF and then to switch her to Teriflunomide 14mg per day. The choice of Leflunomide dose is based on that used to treat BK-virus associated nephropathy. In my opinion, the team looking after this patient have little to lose; her JCV viral load in the spinal fluid was dropping so the IRIS (immune reconstitution syndrome) was at least taking care of the JC virus. However, she needs something to take care of MS without impacting on her immune system and at the same time assisting with the treatment of her PML.


With regard to Teriflunomide, there is an increasing number of reports of how well pwMS are doing on teriflunomide long-term. Teriflunomide is the only DMT that works significantly better second, or third, line than it does as a first-line treatment (see figure below). I have hypothesised that these observations may be due to teriflunomide's mode of action as an anti-viral agent. Professor Julian Gold and I are in the process of exploring this hypothesis under the umbrella of the Charcot Project. We will let you know as soon as we have data available.  




Josephson et al. Treatment of renal allograft polyoma BK virus infection with leflunomide. Transplantation. 2006 Mar 15;81(5):704-10.



BACKGROUND: Polyoma BK virus produces an aggressively destructive nephropathy in approximately 3% to 8% of renal allografts, is associated with graft loss within one year in 35% to 67% of those infected and there is no therapy of proven efficacy. Leflunomide is an immune suppressive drug with anti viral activity in vitro and in animals.

METHODS: We treated twenty-six patients with biopsy proven NK virus nephropathy (BKN) with either leflunomide alone (n=17) or leflunomide plus a course of cidofovir (n=9) and followed them for six to forty months. Leflunomide was dosed to a targeted blood level of active metabolite, A77 1726, of 50 microg/ml to 100 microg/ml (150 microM to 300 microM). Response to treatment was gauged by serial determinations of viral load in blood and urine (PCR), serum creatinine, and repeat allograft biopsy.

RESULTS: In the 22 patients consistently sustaining the targeted blood levels of active drug, blood and urine viral load levels uniformly decreased over time (P<.001). Mean serum creatinine levels stabilized over the first six months of treatment, and with 12 months or more of follow-up in 16 patients the mean serum creatinine has not changed significantly from base line. Four patients who did not consistently have blood levels of active drug (A77 1726) above 40 microg/ml did not clear the virus until these levels were attained or cidofovir was added.

CONCLUSIONS: Leflunomide inhibits Polyoma virus replication in vitro and closely monitored leflunomide therapy with specifically targeted blood levels appears to be a safe and effective treatment for Polyoma BK nephropathy.

Morita et al. Successful low-dose leflunomide treatment for ganciclovir-resistant cytomegalovirus infection with high-level antigenemia in a kidney transplant: A case report and literature review. J Clin Virol. 2016 Sep;82:133-8. doi: 10.1016/j.jcv.2016.07.015.

Ganciclovir-resistant cytomegalovirus infection is sometimes life-threatening for organ transplant recipients. Foscarnet is an alternative, although it may potentially worsen the preexistent impaired renal function. Here we report the case of a successful low-dose leflunomidetreatment in a kidney transplant recipient with very high viral replication, who underwent kidney transplantation 10 years before. Administering 10mg leflunomide daily for 5 months without a loading dose completely cleared the ganciclovir-resistant cytomegalovirus strains.


CoI: multiple

5 comments:

  1. How long does it take to clear PML after natalizumab? Does the IRIS eventually resolve?

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    1. I am aware of one case who still had JCV-detectable in the CSF ~9 months after onset. I suspect the ability to clear virus will depend on how big the viral load is, the extent of the PML and whether or not the virus can mutate and develop escape variants. The problem we have is that IRIS (immune response to the virus) overlaps with MS rebound. You need the IRIS to recover from PML, but you don't need the MS rebound.

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  2. Hi, I just wanted to ask about your statement: " Interestingly, leflunomide, a prodrug that is converted into teriflunomide, has been shown to have antiviral effects against BK virus (see below), that is very closely related to JCV, the cause of MS." I thought that you hypothesized that the EBV (Epstein Barr Virus) was the cause of MS. I am now confused with the statement that JCV is the CAUSE of MS. Please clarify. Thank you very much. As usual, your blog is so informative and I look forward to reading daily!

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  3. So maybe worth going for Teriflunomide following breakthrough activity with Copaxone, rather than taking the risk of more serious infections etc with Natalizumab and Alemtuzimab? Or wait patiently for Ocrelizumab to be available or wait even longer for Cladribine? Feeling rather overwhelmed with so much info and nervous about possible further damage whilst waiting for Ocrelizumab. Reading this post is making me seriously consider Teriflunomide.

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