Background/Purpose: Patients with rheumatic diseases (RD) are typically treated with conventional and /or biologic disease modifying anti-rheumatic drugs (DMARD’s) including tumor necrosis factor inhibitors (TNFi).  Prior to biologic initiation subjects are typically screened for latent tuberculous infection (LTBI) with tuberculin skin test (TST) or Quantiferon-Gold in Tube (QFN) assay (Cellestis) and chest x-ray (CXR).  If positive, such patients are treated with Isoniazid (INH) for 9 months in addition to their standard therapy. Since both INH and DMARDs may be individually hepatoxic, there is a concern for enhanced liver toxicity when those are combined. We investigated the incidence of liver toxicity upon combination of traditional and/ or biologic DMARDs with INH in pts with RD.

Methods: One hundred and eighty patients with RD and a positive TST (≥5 mm induration) and/or QFN result, from a single institution were evaluated. Liver function tests (LFTs) including aspartate (AST), alanine aminotransferase (ALT), alkaline phosphatase (AP), and total bilirubin (TB) were tested at baseline and every 8-12 weeks while on therapy. Subjects’ serial LFTs over 6 months prior to INH initiation were used as controls for incident liver toxicity while on therapy. Results were expressed as –fold increases from upper limit of normal (x-fold ULN).

Results: Average duration of INH therapy was 8.8± 3.2 months. 180 patients underwent a mean of 4.2 tests while on INH; 177 baseline samples were collected, followed by 580 additional samples during INH treatment. The latter were compared to 259 samples serially collected from the respective subjects within 6 months prior to INH therapy (table). Patients received 1.85±0.83 DMARDs, 88% of which was methotrexate at a dose of 19.2±2.6 mg. One hundred forty seven (82%) subjects were on concomitant TNFi. 171/177 (96.6%) baseline AST, and 164/177 (92.6%) baseline ALT tests were normal (table); Any AST or ALT elevations above the ULN occurred in 13.5% and 10.8% of tests while on INH compared to 6.5% and 3.8% respectively prior to INH (p=0.004 and p=0.001 respectively). However, AST or ALT elevations ≥2-fold ULN occurred in 2.2% and 1.5% of tests on INH compared to 0.4% and 0.4% (respective p-values of 0.2 and 0.29). In 6 out of 180 pts (3.3%) INH was thought to be responsible for elevation of LFT’s therefore necessitating withdrawal of the drug.  None of the pts developed significant adverse events and LFT’s normalized after INH was discontinued.   

Conclusion: Despite the heightened concern for significant hepatoxicity, the combination of traditional and/ or biologic DMARDs with INH is clinically well tolerated; the incidence of significant LFT elevations is uncommon in compliant and regularly monitored patients.