Abstract
To investigate associations between isoniazid for latent tuberculosis and risk of severe hepatitis, affecting patients with rheumatoid arthritis or ankylosing spondylitis whose treatment includes tumor necrosis factor inhibitors. Our self-controlled case series study analyzed Taiwan’s National Health Insurance Database from 2003 to 2015 to identify RA or AS patients, aged ≥ 20 years, receiving TNF inhibitors and a 9-month single isoniazid treatment. The outcome of interest was hospitalization due to severe hepatitis. We defined risk periods by isoniazid exposure (days): 1–28, 29–56, 57–84, 85–168, 169–252, and 253–280. To compare risk of severe hepatitis in exposed and non-exposed periods, we performed conditional Poisson regressions to generate incidence rate ratios (IRR) and 95% confidence intervals, with adjustment of patients’ baseline covariates including age, sex, HBV, HCV and related medication. Of 54,267 RA patients and 137,889 AS patients identified between 2000 and 2015, 11,221 (20.7%) RA and 4,208 (3.1%) AS patients underwent TNFi therapy, with 722 (5%) receiving isoniazid for latent tuberculosis. We identified 31 incident cases (4.3%) of hospitalization due to severe hepatitis. Of these hospitalization events, 5 occurred in the exposed periods, 25 occurred in the INH unexposed periods, and 1 occurred in the pre-exposure period. Compared with non-exposure, the risk of severe hepatitis was higher in exposed periods (incidence rate ratio [IRR]: 5.1, 95% CI: 1.57–16.55), especially 57–84 days (IRR: 17.29, 95% CI: 3.11–96.25) and 85–168 days (IRR:10.55, 95% CI: 1.90–58.51). The INH related fatal hepatotoxicity was not identified in our study. Our findings suggest an association between risk of severe hepatitis and exposure to isoniazid in patients with RA or AS under TNFi therapy, particularly within the exposed period 57–168 days. A close monitoring of liver function is mandatory to minimize the risk, especially within the first 6 months after initiation of 9 months isoniazid.
Highlights
Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) are chronic inflammatory rheumatic diseases involving peripheral joints and the axial skeleton
We identified a total of 54,267 patients with RA and 137,889 patients with AS between 2000 and 2015, of which 11,221 (20.7%) RA patients and 4,208 (3.1%) AS patients initiated Tumor necrosis factor inhibitors (TNFi) therapy
We identified 6 patients (19.35%) with hepatitis B virus (HBV) and 5 (16.13%) with hepatitis C virus (HCV)
Summary
Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) are chronic inflammatory rheumatic diseases involving peripheral joints and the axial skeleton. Tumor necrosis factor inhibitors (TNFi) are the first class of biological DMARDs (bDMARDs) used in treating RA and AS, their anti-inflammatory effect mainly resulting from the binding of cytokines in order to block TNF-mediated s ignaling[4]. Both randomized controlled trials (RCTs) and real-world s tudies[5,6] have implicated tumor necrosis factor inhibitors (TNFis) as increasing the risk of tuberculosis (TB), in patients with a pre-existing latent. The RMP recommends that isoniazid treatment for latent TB infection (LTBI) should be given one month before TNFi therapy. A self-controlled design was implemented to eliminate time-constant confounders
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