**1. Introduction**

Hepatitis C virus (HCV) is a human pathogen responsible for acute and chronic liver disease that infects an estimated 150 million individuals worldwide [1]. In addition to hepatic complications including cirrhosis and hepatocellular carcinoma, HCV may cause many extrahepatic complications such as diabetes mellitus (DM), hypolipidemia,

**Citation:** Cheng, J.-S.; Lin, Y.-S.; Hu, J.-H.; Chang, M.-Y.; Ku, H.-P.; Chien, R.-N.; Chang, M.-L. Impact of Interferon-Based Therapy on Hepatitis C-Associated Rheumatic Diseases: A Nationwide Population-Based Cohort Study. *J. Clin. Med.* **2021**, *10*, 817. https:// doi.org/10.3390/jcm10040817

Academic Editors: Maria Carla Liberto and Nadia Marascio

Received: 12 January 2021 Accepted: 12 February 2021 Published: 17 February 2021

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cardiovascular events [1], and rheumatic diseases [2]. HCV is both hepatotropic and lymphotropic [3]. HCV lymphotropism represents the most important step in the pathogenesis of virus-related immunological diseases [4], especially rheumatic diseases. Rheumatologic extrahepatic manifestations are observed in 2% to 38% of HCV-infected patients [5], and this variability is attributed to the various geographic region and design of the studies [6–8]. Moreover, HCV antibodies were found in 18.5% among patients admitted to the rheumatology ward [9], being higher than the estimated global prevalence (2.2–2.8%) of HCV infection [10]. The Hispanoamerican Study Group of Autoimmune Manifestations associated with Hepatitis C Virus (HISPAMEC) Registry showed that the systemic autoimmune diseases most associated with chronic HCV infection were Sjogren syndrome (SS), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) [11]. Specifically, the co-prevalence of HCV and SS ranged from 49% [12] to 80% [13], HCV infection was found in 13% of a large series of Spanish patients with SS [14], and sicca symptoms were reported in 11% of French HCV patients [15]. HCV infection was also associated with increased RA risks [16,17], and the pooled prevalence of RA was 4.5% (0.6–25.7%) of chronic HCVinfected patients in East Asia [2]. Moreover, the prevalence of HCV infection among SLE patients was found to be 10% [18].

The combination of pegylated interferon (Peg-IFN) and ribavirin has provided a "cure" for a considerable proportion of patients with chronic hepatitis C infection (CHC), particularly in patients with a favorable interferon λ 3 (IFNL3) genotype [1]. These cure rates were further improved by replacing interferon-based therapy with potent, directacting antiviral agents (DAAs) [1], and the sustained virological response rate (SVR) to DAA in HCV-infected patients is approaching 100% [19]. However, some HCV-associated complications such as cardiometabolic and oncogenic events cannot be reversed, even after viral clearance [1,20,21]. Whether the HCV-associated risk of rheumatic diseases can be attenuated after the completion of anti-HCV therapy thus is still a crucial issue of public health in the era of DAA to eradicate HCV infection but remains elusive.

Accordingly, we conducted a nationwide population-based cohort study in Taiwan, where HCV infection is rampant [22]. The impacts of HCV infection and anti-HCV therapy on the risk of rheumatic diseases were investigated by comparing the cumulative incidences of rheumatic diseases and of the overall mortalities among HCV-infected subjects with and without anti-HCV therapy and the subjects without HCV infection, based on data from the Taiwan National Health Insurance Research Database (TNHIRD). This database provides medical information of the nationwide population, which comprises 26,573,661 individuals.
