Neurology -- Correspondence for Durelli et al., 57 (8) 1363-1370

Correspondence published:

Liver and thyroid function and autoimmunity during interferon-ß1b treatment for MS: Helen Tremlett (15 March 2002)

Liver and thyroid function and autoimmunity during interferon-ß1b treatment for MS 15 March 2002

Helen Tremlett
Vancouver Hospital and Health Sciences Centre
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Re: Liver and thyroid function and autoimmunity during interferon-ß1b treatment for MS

tremlett{at}interchange.ubc.ca Helen Tremlett

I was interested to read the findings of Durelli et. al.[1] regarding raised liver enzymes associated with beta-interferon-1b treatment. I find their conclusion that ‘there is no need for repeated assessment of (liver function) in MS patients treated with IFN-beta’ disturbingly hasty given the evidence. Firstly their study only focuses on one of the beta- interferons – Betaferon (IFNB-1b). The incidence of raised liver enzymes found during the clinical trials of Betaferon, Avonex (beta interferon-1a) and Rebif (beta-interferon-1a) varies considerably. Their conclusion therefore is only applicable to Betaferon and cannot automatically be extended to the other interferons without further studies. Secondly their study followed only 156 RRMS patients over 2 years, totaling 312 patient years. Assuming no background incidence of the adverse event in this population, at best they have a 95% chance of finding an adverse event with an incidence of 1 in 104. [2] To put this into perspective, the FDA has stated that withdrawal of a drug should occur if the incidence of severe liver injury is 1 in 10,000 or greater, unless the drug treats a ‘lethal disease.’ [3] To detect such an incidence, at least 30,000 treated patient-years are required in order to have a 95% chance of detection. [2] Drug-induced liver hepatotoxicty is the single most common reason for withdrawal or limited clinical use of a drug. [3] The reaction is typically idiosyncratic and only noted after the drug is licensed and utilized in a larger population than clinical trials allow. One example is Troglitazone, licensed in 1997 for type II diabetes mellitus. Despite 2510 patients being treated and raised liver enzymes reported in pre- marketing clinical trials, the drug was not withdrawn until 13 years later when it was found to cause life-threatening acute liver failure. [4]
There is one published report of fulminant liver failure requiring liver transplant associated with beta-interferon-1a for MS. [5] Until more experience is gained with the interferons in MS it appears unwise to advocate the cessation of repeated assessment of liver function tests.
Further post-marketing studies such as the one carried out by Durelli et al are vital to elucidate such information which otherwise could take considerably longer to surface through the spontaneous adverse-drug reaction reporting schemes established in most countries world-wide.
As an aside issue, I was somewhat surprised to find no reference to a paper [6] by the same authors, containing largely the same dataset from the same group of MS patients published only a few months earlier in a different journal.
References
1. Durelli L, Ferrero B, Oggero A, et al: Liver and thyroid function and autoimmunity during interferon-beta 1b treatment for Multiple Sclerosis. Neurology 2001; 57: 1363-1370.
2. Lewis JA: Post-marketing surveillance - how many patients? Trends in Pharmacological Sciences 1981; 2: 93-94.
3. PHRMA/FDA/AASLD: Drug-induced hepatotoxicity White Paper Post marketing Considerations 2000. http:www//fda.gov/cder/livertox/postmarket.pdf.
4. Liver Enzyme Monitoring in Patients Treated With Troglitazone; David J. Graham, MD, MPH; Carol R. Drinkard, MPH, PhD; Deborah Shatin, PhD; Yi Tsong, PhD; Margaret J. Burgess; Jama; Vol. 286 No. 7,August 15, 2001)
5.Yoshida EM, Rasmussen SL, Steinbrecher UP, et al: Fulminant liver failure during interferon beta treatment of Multiple Sclerosis. Neurology 2001; 56: 1416.
6.Durelli L, Ferrero B, Oggero A, et al: Thyroid Function and Autoimmunity during Interferon beta-1b Treatment: A Multi-center Prospective Study. Journal of Clinical Endocrinology and Metabolism 2001; 86: 3525-3532.