Neurology -- Correspondence for Tremlett et al., 62 (4) 628-631

Correspondence published:

Liver injury associated with the ß-interferons for MS: A comparison between the three products: Eliot M. Wallack, Robert Callon, M.D. (13 April 2004)

Liver injury associated with the ß-interferons for MS: A comparison between the three products: Gordon S Francis, Neil Kaplowitz, Enrica Alteri (13 April 2004)

Reply to Wallack et al and Francis et al: Helen L Tremlett, Eric M. Yoshida and Joel Oger (13 April 2004)

Liver injury associated with the ß-interferons for MS: A comparison between the three products 13 April 2004

Eliot M. Wallack,
JWM Neurology
1400 N. Ritter Ave., #120, Indianapolis, IN 46219,
Robert Callon, M.D.
Send Correspondence to journal:
Re: Liver injury associated with the ß-interferons for MS: A comparison between the three products

elwallack{at}att.net Eliot M. Wallack, et al.

Hepatotoxicity has been associated with all forms of interferon beta. [1] Autoimmune hepatitis (AIH), another hepatic complication of IFN (beta)-1a treatment for MS, has been reported. [2] We present an unusual case.
A 52-year-old woman with a 10-year history of MS was initially treated with glatiramer acetate from 1997 to 1999. In January 2000, IFN beta-1a (Avonex) was started after relapsing symptoms occurred and new MRI lesions appeared. In December 2002, she developed painless jaundice, a cholecystectomy was performed, and her jaundice resolved. Avonex was continued. Hepatic function tests were normal in February 2003. IFN beta-1a (Rebif) was instituted in early May 2003 because of worsening gait and progressive MRI changes. The patient received 8.8 mcg sc (20% of target dose) every other day for only six doses until she noted increasing fatigue and jaundice. There was no history of acetaminophen, ethanol or nefazodone use. Physical examination revealed marked jaundice. Laboratory tests showed increased hepatic enzymes and total bilirubin of 28.6 mgm/dl (0.2-1.3 mgm/dl). Hepatitis panel and thyroid function tests were normal.
ANA screen was positive in a 1:320 homogenous pattern. Anti-smooth antibodies were positive at 1:40 titer. A CT of the abdomen revealed no biliary obstruction. Prednisone 20 mgm/day was administered. Over the next several months there was a dramatic decrease in jaundice and bilirubin levels, and by March 2004 the total bilirubin was 0.8 mgm/dl.
Autoimmune complications have been reported in MS patients treated with interferon alpha and interferon beta after several months. [2,3,4] The etiology of this immunologic complication is unclear but may involve disruption of vital intracellular functions, induction of antibody cytotoxicity, or mitochondrial injury. [5]
A previous case of AIH has been reported after a cumulative dose of 215 mcg of IFN (beta)-1a, however this patient had taken nefazodone. [4] Another patient on IFN (beta)-1a developed AIH after 24 months. [2] The patient reported here had signs and symptoms of hepatic dysfunction after only 51 mcg of Rebif had been administered in just six doses. At the onset of treatment with IFN (beta)-1a, patients with MS should be informed about possible hepatic complications of their medication since our patient developed signs and symptoms two weeks before her first recommended blood test at one month.
References
1. Tremlett, H., Yoshida, E., Oger, J. Liver injury associated with the beta-interferons for MS. Neurology 2004; 62:628-631.
2. Duchini A. Autoimmune hepatitis and interferon beta-1a for multiple sclerosis. AM J Gastroenterol 2002; 97:767-768.
3. Durelli L, Bongioanni MR, Ferrero B, et al. Interferon treatment for multiple sclerosis: Autoimmune complications may be fatal. Neurology 1998; 50:570-571.
4. Yoshida EM, Rasmussen SL, Steinbrecher SL, et al. Fulminant liver failure during interferon beta treatment for multiple sclerosis. Neurology 2001; 56:1416.
5. Lee WM. Drug-Induced Hepatotoxicity. New England Journal of Medicine 2003; 474-485.

Liver injury associated with the ß-interferons for MS: A comparison between the three products 13 April 2004

Gordon S Francis,
Serono, Inc.
1 Technology Place, Rockland, MA 02370,
Neil Kaplowitz, Enrica Alteri
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Re: Liver injury associated with the ß-interferons for MS: A comparison between the three products

gordon.francis{at}serono.com Gordon S Francis, et al.

The article on liver injury with IFN beta in MS by Tremlett et al [1] prompts four comments:
Firstly, Tremlett ranks IFN potency by MIU based on product monographs. Each product is tested on different assay systems rendering such comparisons invalid. Direct comparative data indicates that IFN beta-1a is approximately 9-fold more biopotent than IFN beta-1b. [2] A more accurate ranking by potency would be IFN beta-1a sc 44mcg tiw, IFN beta-1b sc 8 MIU (or 250mcg) on alternate days, IFN beta-1a sc 22mcg tiw and finally IFN beta-1a im 30mcg qw.
Secondly, the authors cite mortality in 10-15% with ALT >3 ULN and Tbili >1.6 ULN. However, the mortality associated with ‘Hy’s Rule’ rather refers to patients with jaundice (generally Tbili >3) and ALT > 3ULN. [3] Thus one, and possibly two (of 835 patients) had this combination while no cases were seen in 1995 patients exposed to IFN beta- 1a at various doses in clinical trials, [4] making the risk very low, though not absent.
Thirdly, the rate of ALT increase in PRISMS is cited as 19.6% and 27.2% and the authors imply this is lower than their values due to “vague reporting style” in clinical trials. The comparison is not relevant because the values in PRISMS refer to ALT elevation considered as adverse events by the physician, not to patients with laboratory evidence of ALT elevation, as per Tremlett. Because ALT elevations are predominantly mild, they are often not considered as clinically relevant, nor reported as adverse events. Rates of laboratory detected ALT elevations higher than those found by Tremlett have been reported, including the fact that most are mild and self-limited. [4] This suggests that the level of ascertainment in the Tremlett series was less thorough, presumably due to the retrospective nature of the study, than in prospective, controlled clinical study data in which placebo comparative results are also provided.
Finally, with respect to the suggestion that acetaminophen might increase liver dysfunction in patients receiving IFN therapy, concomitant use of IFN and acetaminophen in over 700 patients was associated with reduced, not increased, risk of ALT elevation compared to patients receiving IFN alone. [4] The brief report by Tremlett otherwise confirms previous reports on the high prevalence, but relatively low impact, of liver dysfunction with IFN therapy in MS. The suggested guidance regarding testing of liver function forms part of IFN product package inserts worldwide. It is important to understand however, as noted by Tremlett, that such monitoring may not prevent the rare occurrence of severe symptomatic cases. [5]
References
1) Tremlett HL, Yoshida EM, Oger J. Liver injury associated with the b-interferons for MS. Neurology 2004;62:628-631,
2) Antonetti F, Finocchiaro O, Mascia M, Terlizzese MG, Jaber A. A comparision of the biologic activity of two recombinant IFN-b preparations used in the treatment of relapsing-remitting Multiple Sclerosis. J Interferon Cytokine Res 2002; 22:1181-1184.
3) Zimmerman HJ, Drug-Induced liver disease. In Hepatotoxicity, 2nd Ed. Philadelphia: Lippincott, Williams & Wilkins, 1999:427-456
4) Francis G, Grumser Y, Alteri E. Hepatic reactions during treatment of multiple sclerosis with interferon beta 1a: Incidence and clinical significance. Drug Saf 2003; 26:815-827.
5) Kaplowitz, N. Drug-Induced Liver Disorders. Implications for drug development and regulation. Drug Safety 2001;24:483-490

Reply to Wallack et al and Francis et al 13 April 2004

Helen L Tremlett,
University of British Columbia
Medicine (Neurology) (rm S159), VHHSC,2211 Wesbrook Mall, University of British Columbia, Vancouver,
Eric M. Yoshida and Joel Oger
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Re: Reply to Wallack et al and Francis et al

tremlett{at}interchange.ubc.ca Helen L Tremlett, et al.

Case reports detailing unexpected adverse consequences of medications such as autoimmune hepatitis associated with beta-interferon by Drs. Wallack and Callon are of clinical importance. Such events may not occur within the context of a clinical trial due to limited time, patient numbers and patient selection or even in a limited post-marketing study such as ours [2] due to exposure time and numbers of treated cases. It is only when very large numbers of MS patients are treated with the licensed beta-interferons will cases such as this [1] be reported. Pooling of such cases is then vital to facilitate the identification of emerging patterns, such as a preponderance of females developing severe hepatic injury associated with beta-interferon treatment in MS. [3]
We encourage others to report such cases should they arise and also to complete an ‘adverse drug reaction report’ to the relevant National Health Authority. Most of these forms are available online, including in the US, [4] Canada [5] and the UK.[6]
We welcome the comments from Dr Francis, Dr Alteri (Serono; manufacturers of beta-interferon-1a (Rebif®) and Dr Kaplowitz. Answering each point raised in order:
1. Comparing the relative potency of the beta-interferons (IFNBs) is quite a challenge. Several different options were considered before the current methodology was decided upon. Using the ranking suggested by Francis et al does not change our results in that a dose-response effect is still observed.
2. Unfortunately, neither our post-marketing study [1] nor the pooled results from 1995 IFNB treated trial patients [2] will give a true indication of the risk of severe hepatotoxicity associated with the beta-interferons for MS. Even if the risk of serious hepatotoxicity is deemed as ‘fairly high,’ (ie 1/10,000 to 1/50,000), [6] at least 30,000 to 150,000 MS patients need to be exposed to IFNB AND every single case of serious hepatotoxicity reported before the true risk will be known (the ‘rule of 3’s). [7] Again, we encourage the reporting of such cases to the relevant National Health Authorities. Since submission and acceptance of our post-marketing study,[1] another alert warning health care professionals of hepatic injury associated with IFNB was issued by Health Canada [8] in conjunction with the Pharmaceutical Manufacturers of IFNB.
3. The ‘vague reporting style’ refers to this exact problem highlighted by Francis et al. It is unclear in the PRISMS clinical trial report [9] that the numbers of patients with elevated ALT were not ALL the patients who developed elevated ALT, rather only those who individual physicians flagged as having an adverse event. This is not a consistent, reproducible or acceptable way to report adverse drug reactions in clinical trials. Hence there is an apparent sharp increase in the proportion of IFNB-1a(sc 44mcg three times weekly) patients developing elevated ALT over a 2 year period - from 27.2% reported in PRISMS [9] to 67% reported in a part re-analysis of PRISMS/part pooling with other IFNB-1a clinical trials. [2]
4. We hypothesized that concomitant medication, particularly acetaminophen (paracetamol), known to cause hepatotoxicity and frequently recommended to MS patients as prophylaxis against the flu-like symptoms associated with IFNB treatment, might increase the risk of hepatoxocity. [1] Francis et al [2] were able to show that acetaminophen was not a risk factor in IFNB-treated patients developing an elevation in ALT (>ULN), although propionic acid derivatives (including ibuprofen) did increase the risk in both the placebo and IFNB groups. [2]
References
1. Tremlett HL, Yoshida E, Oger J. Liver injury associated with the IFNBs for MS: a comparison between IFNB-1b(sc), IFNB-1a (sc) and IFNB-1a (im); Neurology 2004;62(4):628-631.
2. Francis GS, Grumser Y, Alteri E, et al. Hepatic Reactions during treatment of Multiple Sclerosis with Interferon-beta-1a. Drug Safety 2003;26:815-27.
3. FDA Safety Information and Adverse Event Reporting Program: MedWatch FDA Form 3500 (expires 09/30/05) [on-line] Available at: http://www.fda.gov/medwatch/safety/3500.pdf Accessed March 23, 2004.
4. Health Canada: Canadian Adverse Drug Reaction Monitoring Program Form. [on-line] Available at: http://www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/adr_guideline_e.html Accessed March 23, 2004.
5. Committee on Safety of Medicines. The Yellow Card Scheme: How to report. Available at: http://medicines.mhra.gov.uk/aboutagency/regframework/csm/csmhome.htm Accessed March 23, 2004.
6. CDER-PHRMA-AASLD. Drug-induced hepatotoxicity White Paper Postmarketing Considerations 2000. http:www//fda.gov/cder/livertox/postmarket.pdf (Accessed 30th March 2004).
7. Lewis JA. Post-marketing surveillance - how many patients? Trends Pharmacol Sci 1981;2:93-94.
8. Gehshan A, Ruebig A, Salesse M. Important new safety information: Hepatic injury associated with beta-interferon treatment for Multiple Sclerosis. 2003. http://www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/beta-interferon_hpc_e.pdf (Accessed 30th March 2003)
9. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing-remitting Multiple Sclerosis. Lancet 1998;352:1498-1504.