S Chan1, E Kingwell, J Oger, E Yoshida, H Tremlett. 1. Faculty of Medicine, School of Population and Public Health, University of British Columbia, Vancouver, Canada.
Abstract
BACKGROUND: Post-marketing studies and case reports have linked beta-interferon (IFNβ) treatment with liver enzyme abnormalities and liver injuries in patients with multiple sclerosis (MS). Few predictors of risk exist. OBJECTIVE: We investigated the effect of IFNβ and other patient characteristics on levels of the liver enzyme, alanine aminotransferase (ALT). METHOD: Repeated ALT test results were reviewed retrospectively for 1064 MS patients prescribed an IFNβ as their first immunomodulatory drug. Liver enzyme abnormality was defined as an ALT elevation twice the upper limit of normal (≥ 2 ULN). The Generalized Estimating Equation (GEE) was used to analyze the effect of age (≤ 35, >35-40, >40-45, >45 years), gender, disease duration, IFNβ product, and duration of treatment (≤ 5, >5-15, >15-40, >40 months) on de novo liver enzyme abnormality. RESULTS: Over a mean treatment period of 38.7 months (SD=34.9), 12.4% (95/766) of MS patients developed de novo liver enzyme abnormality. Multivariable GEE results showed a dose frequency response effect of IFNβs on liver enzyme abnormality: OR=3.8(95% CI: 1.6-9.2) for IFNβ-1a 44 µg SC, and OR=3.4 (95% CI: 1.5-7.9) for IFNβ-1b 250 µg SC compared with the lower frequency IFNβ-1a 30 µg IM. Younger age (≤ 40 years), male gender, and ≤ 15 months of IFNβ exposure were also independent predictors. CONCLUSION: A dose frequency response effect was observed, with high-frequency IFNβs having the greatest risk. The first 15 months of treatment, men, and younger patients were also associated with elevated risk. Regular ALT monitoring in MS patients appears prudent; long-term consequences of ALT elevations should be further investigated.
BACKGROUND: Post-marketing studies and case reports have linked beta-interferon (IFNβ) treatment with liver enzyme abnormalities and liver injuries in patients with multiple sclerosis (MS). Few predictors of risk exist. OBJECTIVE: We investigated the effect of IFNβ and other patient characteristics on levels of the liver enzyme, alanine aminotransferase (ALT). METHOD: Repeated ALT test results were reviewed retrospectively for 1064 MSpatients prescribed an IFNβ as their first immunomodulatory drug. Liver enzyme abnormality was defined as an ALT elevation twice the upper limit of normal (≥ 2 ULN). The Generalized Estimating Equation (GEE) was used to analyze the effect of age (≤ 35, >35-40, >40-45, >45 years), gender, disease duration, IFNβ product, and duration of treatment (≤ 5, >5-15, >15-40, >40 months) on de novo liver enzyme abnormality. RESULTS: Over a mean treatment period of 38.7 months (SD=34.9), 12.4% (95/766) of MSpatients developed de novo liver enzyme abnormality. Multivariable GEE results showed a dose frequency response effect of IFNβs on liver enzyme abnormality: OR=3.8(95% CI: 1.6-9.2) for IFNβ-1a 44 µg SC, and OR=3.4 (95% CI: 1.5-7.9) for IFNβ-1b 250 µg SC compared with the lower frequency IFNβ-1a 30 µg IM. Younger age (≤ 40 years), male gender, and ≤ 15 months of IFNβ exposure were also independent predictors. CONCLUSION: A dose frequency response effect was observed, with high-frequency IFNβs having the greatest risk. The first 15 months of treatment, men, and younger patients were also associated with elevated risk. Regular ALT monitoring in MSpatients appears prudent; long-term consequences of ALT elevations should be further investigated.
Authors: Kaarina Kowalec; Galen E B Wright; Britt I Drögemöller; Folefac Aminkeng; Amit P Bhavsar; Elaine Kingwell; Eric M Yoshida; Anthony Traboulsee; Ruth Ann Marrie; Marcelo Kremenchutzky; Trudy L Campbell; Pierre Duquette; Naga Chalasani; Mia Wadelius; Pär Hallberg; Zongqi Xia; Philip L De Jager; Joshua C Denny; Mary F Davis; Colin J D Ross; Helen Tremlett; Bruce C Carleton Journal: Nat Genet Date: 2018-07-16 Impact factor: 38.330
Authors: Robert J Fontana; Paul Hayashi; Herbert L Bonkovsky; David E Kleiner; Sweta Kochhar; Jiezhun Gu; Marwan Ghabril Journal: Dig Dis Sci Date: 2013-02-02 Impact factor: 3.487