THU0561 PREDICTING LIVER TOXICITY CAUSED BY CONVENTIONAL SYNTHETIC DISEASE-MODIFYING ANTIRHEUMATIC DRUGS
Authors: L. Kuusalo, M. Venäläinen, S. Saranpää, H. Kirjala, L. Elo, L. Pirilä
Journal: Annals of the Rheumatic Diseases (2020)

Background: Routine laboratory testing is recommended for early identification of toxicity during conventional synthetic disease modifying antirheumatic drug (csDMARD) treatment. Based on expert consensus, testing is recommended every 2–4 weeks for the first 3 moths and quarterly thereafter (1). Objectives: In addition to evaluating the incidence of alanine transaminase (ALT) elevations in rheumatoid arthritis (RA) patients initiated on 1–2 csDMARDs, we aimed to distinguish patterns in ALT levels to develop a model for identifying patients at high risk for liver toxicity. Methods: We identified RA patients who were initiated a new csDMARD course at the rheumatology clinic of Turku University Hospital in 2013–2019. Baseline and follow-up safety monitoring results were drawn from the electronic health record (EHR) data. Data on diagnoses and csDMARD initiation/cessation dates were manually confirmed from the EHR. As the primary endpoint, we used ALT-elevations of more than twice the upper limit of reference range (women ≥ 70 U/l, men ≥ 100 U/l) within 6 months after treatment initiation. Intergroup differences were tested using Mann-Whitney test for continuous variables and the chi-square test or Fisher’s exact test (n&lt;5) for categorical variables. Associations between different characteristics and the primary endpoint were tested using Cox proportional hazards regression. Results: We identified 2851 RA patients of whom 1017 initiated a new csDMARD course requiring laboratory monitoring. Of these, 860 patients (58.9 years, 68% women, 65% seropositive) were included in the analyses after excluding patients with missing laboratory results (n=148) or elevated ALT at baseline (n=9). Of the 860 patients, 220 initiated two csDMARDs simultaneously [99% sulfasalazine (SSZ) and methotrexate (MTX)]. Primary endpoint was reached in 55 of 860 (6.4%) patients, including 10 who initiated two csDMARDS. Of these 55 patients, primary endpoint was reached in 40 of 55 (73%) patients during first three follow-up tests. In 31 of 55 (56%) patients, including 3 initiators of 2 csDMARDs, elevated ALT led to csDMARD cessation during the first 6 months. In Cox proportional hazards model with age, sex, seropositivity, baseline ALT, and csDMARDs as the explanatory variables, only baseline ALT level [hazard ratio 1.56 per 1 SD increase, 95% confidence interval (CI) 1.30–1.88, p&lt;0.001] was associated with incident ALT-elevations. Survival according to normalized baseline ALT is shown in Figure, where normalized ALT value of 1.0 refers to the upper limit of reference range (women 35 U/l, men 50 U/l). Table. Multivariable Cox proportional hazards model including the results of the first follow-up laboratory test. Only values before occurrence of primary endpoint were used (n=843). Characteristic Hazard ratio (95% CI ) P Value Age (per year ) 1.00 (0.98-1.02) 0.78 Sex (male ) 0.50 (0.21-1.15) 0.10 Seronegativity 0.88 (0.44-1.75) 0.71 Baseline ALT* 1.72 (1.32-2.25) &lt;0.001 ALT / t (per 1 SD increase / 30 days ) § 1.33 (1.17-1.52) &lt;0.001 Methotrexate 0.58 (0.22-1.52) 0.27 Sulfasalazine 0.95 (0.38-2.35) 0.91 Azathioprine 2.30 (0.48-11.13) 0.30 Leflunomide 1.08 (0.23-5.16) 0.92 *Normalized ALT according to sex-specific reference range; § Rate of change from baseline to 1 st follow-up test Conclusion: Most incident ALT elevations can be predicted before the first csDMARD dose. Patients with elevated ALT at baseline or a rising trend at first follow-up are at high risk for liver toxicity and benefit from frequent testing. References: [1]Saag KG et al. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum 2008;59:762-84. Disclosure of Interests: Laura Kuusalo Consultant of: Gilead, Pfizer Finland, Speakers bureau: Abbvie, Orion, Pfizer Finland, Novartis, Sanofi, Mikko Venäläinen: None declared, Sofia Saranpää: None declared, Heidi Kirjala: None declared, Laura Elo: None declared, Laura Pirilä Consultant of: Novartis, MSD Finland, Roche, Bristol-Myers-Squibb, Pfizer Finland, Sanofi, Abbvie, Eli Lilly Finland, UCB Pharma, Janssen-Cilag, Mylan, Sandoz, Boerhinger-Ingelheim, Paid instructor for: Boehringer-Ingelheim, MSD Finland, Speakers bureau: Boehringer-Ingelheim, Pfizer Finland