**2. Methods**

#### *2.1. TNHIRD Samples and Measurements*

This population-based retrospective cohort study used nation-level data, including the National Health Insurance (NHI) administrative database, the Cancer Registry Database, and the Death Registry Database of Taiwan. The mandatory, single-payer NHI program provides comprehensive coverage including ambulatory care, hospital services, laboratory tests, and prescription drugs. Over 99% of the population is enrolled in the program and approximately 90% of the healthcare organizations are contracted with NHI Administration. Given that Taiwan is a hyperendemic area for hepatitis B virus (HBV) infection, which is highly oncogenic, causes many hepatic complications and prominently biases the phenotype of HCV infection [23], the subjects diagnosed with HBV infection in the observation period (2003–2015), or with any baseline rheumatic diseases including RA (International Classification of Disease, Ninth. Revision, Clinical Modification (ICD-9-CM) code (714)), ankylosing spondylitis (ICD-9-CM code (720)) [24], psoriatic arthopathy (ICD-9-CM code (696.0)), sicca syndrome (also called SS) (ICD-9-CM code (710.2)), systemic sclerosis (ICD-9-CM code (710.1)), SLE (ICD-9-CM code (710.0)), Behcet's syndrome (ICD-9-CM code (136.1)) [25], Raynaud's syndrome (ICD-9-CM code (443.0)), polyarteritis nodosa and allied conditions (ICD-9-CM code (446)) [26], and psoriasis (ICD-9-CM code (696.X)) [27] or

mortality occurred prior to 6 months after completing anti-HCV treatment (the baseline), when it is the time to ensure therapeutic response, were excluded.

The HCV-treated cohort included subjects who had a HCV RNA test and received ribavirin and pegylated interferon (Peg-IFN) in 2003–2015. Their first HCV test was assumed to be the index date of diagnosis. The baseline for the HCV-treated cohort was the date of 6 months after completing the combination therapy. Untreated HCV-infected patients were those who had been examined for HCV infection (HCV antibody or HCV RNA test) (their first HCV test was the index date), were diagnosed with HCV (The International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes: 070.41, 070.44, 070.51, 070.54, 070.70, 070.71, V02.62), were prescribed hepatoprotective agents (silymarin, liver hydrolysate, choline bitartrate, or ursodeoxycholic acid), but did not receive any anti-HCV therapy (ribavirin or peg-interferon). HCV-uninfected individuals were those who did not have a HCV diagnosis (ICD-9-CM) or tests for HCV infection, and received no hepatoprotective agents or anti-HCV therapy, and they were classified as being HCV-uninfected. The HCV-treated cohort was matched with untreated HCV-infected patients (HCV-untreated cohort) and with HCV-uninfected individuals (HCV-uninfected cohort) through a propensity score-matching method indicating the probability of receiving the combination therapy, estimated by using a logistic model. The covariates in the model included sex (male, female), age (20–39, 40–49, 50–59, ≥60), NHI registration location (city, township, rural area), Charlson Comorbidity Index (CCI) score (0, 1, ≥2), and year of the index date (2003–2006, 2007–2009, 2010–2012). This method was used to assure that the HCV-treated cohort and the selected counterparts were comparable in observed characteristics. The baselines for the HCV-untreated and HCV-uninfected cohorts were assigned according to the period from the index date to the baseline of their matched counterparts of the HCV-treated cohort, and subjects with rheumatic disease or mortality occurred before the baselines were not selected. The index date of the HCV-uninfected individuals was the date of one of their physician visits randomly selected from their claims database. The matching process for the 3 cohorts is shown in Supplementary Figure S1.

Outcomes were defined as the development of rheumatic diseases as mentioned above. Subjects were followed until the date of the event, death, or the end of follow-up (31 December 2015), whichever came first. Dates of death were adopted from the Death Registry database. For the HCV-treated group, only the rheumatic disease or mortality occurred 6 months after the complement of anti-HCV therapy (the baseline) were recorded.

#### *2.2. Statistical Analysis*

All statistical analyses were performed using the Statistical Analysis System (SAS version 9.4, SAS Institute Inc., Cary, NC, USA) software. Continuous variables were analyzed using a Student's *t*-test or analysis of variance, as appropriate, and categorical variables were analyzed using a Chi-square test or Fisher's exact test, as appropriate. Cumulative incidences of outcomes were estimated and compared by using the modified Kaplan–Meier method and the Gray method, with death being a competing risk event. Sub-distribution hazards models for competing risks, an extension of Cox proportional hazards models taking competing mortality into consideration, were used to estimate adjusted hazard ratio of developing rheumatic diseases, adjusting for age, sex, NHI registration location, the CCI score, year of the index date, and comorbid liver cirrhosis, chronic obstructive pulmonary disease (COPD), end-stage renal disease (ESRD), DM, hypertension, dyslipidemia, cardiovascular events (including percutaneous coronary intervention, coronary artery bypass graft, myocardial infarction, heart failure, cardiogenic shock, and peripheral vascular disease), stroke, nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), and autoimmune liver disease. Statistical significance was defined at the 5% level.

#### *2.3. Ethics Approval and Consent to Participate*

The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the local Institutional Review Board. The need for consent was waived because the national-level data used in this study were de-identified by encrypting personal identification information.
