Autoimmune hepatitis, daclizumab and MS

In response to several posts concerning the press release about autoimmune hepatitis as a complication of daclizumab treatment: Med Page Today 

"We must be careful not to throw the baby out with the bathwater. All DMTs have tolerance and safety issues. I agree serious or life threatening adverse events are worrying but we need to know how common they are, if they are predictable, can they be detected early and are they treatable. This knowledge then needs to balanced against how effective the drug is controlling MS disease activity. For Daclizumab we don't have this information; this is why there is a large ongoing phase 3 trial running. Another issue is ascribing a serious adverse event to a drug when it could have occurred by chance or is associated with MS rather than the drug treatment. Autoimmune hepatitis is just such an adverse event. I have personally seen two cases that occurred in MSers on interferon beta. In both cases they were considered by the hepatologist to be unrelated to the treatment. If you delve into the literature you will see that glatiramer acetate, interferon beta, steroids and natalizumab have all been associated with autoimmune hepatitis. In fact, MS itself seems to be associated with the disease."

"One swallow doesn't make a summer!"

"Daclizumab looks very promising ; it has a significant impact on disease progression, which is out of proportion to its apparent effect on relapse reduction. The drug boosts natural killer cells or NK cells, which are the cells that are know to fight viral infections. Could Daclizumab be the elusive anti-viral agent we are looking for? If yes, we need to be careful about prejudging something without all the information at hand." 

"We have just completed a meta-analysis, which we are about to submit to a journal, that shows MSers, and their first-degree, relatives are at increased risk of developing autoimmune thyroiditis and ulcerative colitis. It seems as if autoimmunity is a state that may be related to MS. Therefore these events could still have occurred by chance."

"I am still raw by the failure of cladribine. Cladribine is a very, very, effective drug that has failed due to a perceived excess risk of secondary malignancies and persistent lymphopaenia. The regulators wanted data that another phase 3 trial would be unlikely to deliver, i.e. long-term safety. I am hoping someone will resuscitate the cladribine programme; MSers deserve it."

"What the 'natalizumab and PML', and 'alemtuzumab and ITP (immune thrombocytopaenia)' stories have taught me is that MSers are comfortable with known risks. Knowledge is power is allows you to make informed decisions about the future. Please don't judge a promising emerging therapy on hearsay and a single journalists opinion. We need to give daclizumab, and all other emerging DMTs, a chance. Each trial is an experiment and until the experiment is over we need to reserve judgement. While  the trial or experiment is running the Data and Safety Monitoring Committee are responsible for making sure MSers in the trial are safe and that the benefits of continuing the trial outweigh the risks. This happens to be the case for daclizumab."

"Please note I have conflicts of interests."

References of interest

Subramaniam et al. Glatiramer acetate induced hepatotoxicity. Curr Drug Saf. 2012 Apr;7(2):186-8.

Arruti et al. Autoimmune hepatitis in a patient with multiple sclerosis under treatment with glatiramer acetate. Rev Neurol. 2012 Aug 1;55(3):190-2.

Deltenre et al. Acute hepatitis induced by glatiramer acetate. BMJ Case Rep. 2009;2009.

Neumann et al. Glatiramer acetate induced acute exacerbation of autoimmune hepatitis in a patient with multiple sclerosis. J Neurol. 2007 Jun;254(6):816-7.

Ramos-Casals et al. Autoimmune diseases induced by biological agents: a double-edged sword? Autoimmun Rev. 2010 Jan;9(3):188-93.

Burdick et al. Type I IFNs and their role in the development of autoimmune diseases. Expert Opin Drug Saf. 2009 Jul;8(4):459-72.

Takahashi et al. Development of autoimmune hepatitis type 1 after pulsed methylprednisolone therapy for multiple sclerosis: a case report. World J Gastroenterol. 2008 Sep 21;14(35):5474-7.
von Kalckreuth et al. Unmasking autoimmune hepatitis under immunomodulatory treatment of multiple sclerosis--not only beta interferon. Am J Gastroenterol. 2008 Aug;103(8):2147-8;

Ferrò et al. A case of multiple sclerosis with atypical onset associated with autoimmune hepatitis and silent coeliac disease. Neurol Sci. 2008 Feb;29(1):29-31.

Pulicken et al. Unmasking of autoimmune hepatitis in a patient with MS following interferon beta therapy. Neurology. 2006 Jun 27;66(12):1954-5.

de Seze et al. Autoimmune hepatitis and multiple sclerosis: a coincidental association? Mult Scler. 2005 Dec;11(6):691-3.

Martínez-Lapiscina et al. Natalizumab-induced autoimmune hepatitis in a patient with multiple sclerosis. Mult Scler 1352458512463485, first published on October 15, 2012 as doi:10.1177/1352458512463485


CoI: Multiple, I sit on the steering committee for the Select and Selection Daclizumab trials and the Royal London Hospital is participating in the phase 3 trial.

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