Prevalence and Risk Factors Associated With Non-Alcoholic Steatohepatitis in Patients With Rheumatoid Arthritis on Hydroxychloroquine: A Population-Based Study

Introduction: In recent times, newer drugs have been developed to slow down the progression of Rheumatoid arthritis (RA), one of which is called hydroxychloroquine (HCQ). Though HCQ has been shown to be associated with slowly progressive transaminitis, evidence correlating HCQ as an independent factor to the development of Non-alcoholic fatty liver leading to Non-alcoholic steatohepatitis (NASH) is lacking. Hence, we decided to carry out a study with the aim of assessing the prevalence as well as risk factors of NASH in RA patients on HCQ. Methods: A Multicenter and research platform database of more than 360 hospitals from 26 different healthcare systems across the United States from 1999 to September 2022 was utilized to construct this study. Adult patients with rheumatoid arthritis were included. Pregnant individuals were excluded from the analysis. The risk of NASH was calculated using a multivariate regression analysis to account for potential confounders including smoking history, male gender, individuals with dyslipidemia, hypertension, type 2 diabetes mellitus, obesity, and those who have been using hydroxychloroquine. A 2-sided P value < 0.05 was considered as statistically significant, and all statistical analyses. Results: 79,428,638 individuals were screened in the database and 619,350 were selected in the final analysis after accounting for inclusion and exclusion criteria. The baseline characteristics of patients with NASH and control is seen in Table 1. Using a multivariate regression analysis, risk of developing NASH was calculated in smokers (OR: 1.24; 95% CI: 1.14-1.36), male (OR: 0.88; 95% CI: 0.81-0.96), individuals with dyslipidemia (OR: 1.34; 95% CI: 1.21-1.47), hypertension (OR: 1.11; 95% CI: 1.00-1.27), type 2 diabetes mellitus (OR: 3.24; 95% CI: 2.98-3.54), obesity (OR: 3.59; 95% CI: 3.31-3.89), and individuals who have been using hydroxychloroquine (OR: 1.79; 95% CI: 1.65-1.94) ( (Figure 1). Conclusion: In our study, RA patients on HCQ have increased prevalence and odds of developing NASH. The odds remained significantly elevated after controlling for common risk factors for NASH. We believe this correlation stems from the ability of HCQ to alter molecular pathways causing increased hepatic lipogenesis, decreased hepatic fat secretion which ultimately leads to mitochondrial damage and liver fibrosis. We recommended that clinicians be familiar with this association as it will be crucial in preventing advanced liver disease with appropriate screening guidelines. Table 1. - Baseline characteristics of patients with NASH and control NASH (%) Control (%) Smoker 660 (21.42) 97,550 (15.82) Male 700 (22.72) 159,850 (25.93) Hyperlipidemia 2,420 (78.57) 333,610 (54.13) Hypertension 2,580 (83.76) 388,480 (63.03) T2DM 1,990 (64.61) 161,370 (26.18) Obesity 2,040 (66.23) 155,730 (25.26) Hydroxychloroquine 870 (28.24) 109,900 (17.83) Total 3,080 616,270 Abbreviations: NASH, non-alcoholic steatohepatitis; T2DM, type 2 diabetes mellitus. Figure 1.: Forest plot for risk of developing NASH compared to control. Abbreviations: NASH, non-alcoholic steatohepatitis; T2DM, type 2 diabetes mellitus.