**3. Results**

#### *3.1. Baseline Characteristics*

From a total of 19,298,735 individuals between 1 January 2003 and 31 December 2015, 11,223,475 patients without HBV infection and baseline rheumatic diseases were identified; 104,281 patients with HCV infection and 11,119,194 patients without HCV infection were eligible for the study. Of all, 3 cohorts including HCV-treated (*n* = 6919), HCV-untreated (*n* = 27,676) and HCV-uninfected (*n* = 27,676) cohorts were enrolled (Figure 1). The 3 cohorts were matched with the propensity scores (1:4:4), did not differ in demographic factors, residency, CCI score and index year, which were the covariates in the models to calculate propensity scores, although baseline comorbidities were not similar (Table 1). Compared with HCV-untreated cohorts, the HCV-treated cohort had higher rates of baseline cirrhosis, comparable rates of COPD, but lower rates of other comorbidities. Compared with the HCV-uninfected cohort, the HCV-treated cohort had higher rates of most comorbidities including cirrhosis, comparable rates of DM and cardiovascular events, but lower rates of dyslipidemia and stroke. Compared with the HCV-uninfected cohort, the HCV-untreated cohort had higher rates of all baseline comorbidities except stroke. To lineate the HCVassociated complications, we compared the baseline factors between the HCV-infected cohort, which was a combination of the HCV-treated and HCV-untreated cohorts, and HCVuninfected cohort. The HCV-infected cohort had higher rates of all baseline comorbidities except indifferent rates of dyslipidemia and lower rates of stroke than the HCV-uninfected cohort (Supplementary Figure S2).

**Table 1.** Baseline characteristics of the 3 HCV cohorts of TNHIRD.



**Table 1.** *Cont*.

TNHIRD: Taiwan National Health Insurance Research Database; HCV: hepatitis C virus; CCI: Charlson Comorbidity Index; COPD: Chronic obstructive pulmonary disease; ESRD: end-stage renal disease; DM: diabetes mellitus; NAFLD: nonalcoholic fatty liver disease; ALD: alcoholic liver disease.

**Figure 1.** Flow chart of TNHIRD study subjects selection. TNHIRD: Taiwan National Health Insurance Research Database; HCV: hepatitis C virus; Peg-IFN: pegylated interferon; PS: propensity score.

#### *3.2. Cumulative Incidences and Associated Factors of Rheumatic Diseases*

The HCV-treated, -untreated, and -uninfected cohorts were followed up until 2015 or death, with the longest observation of 11 years. Rheumatic diseases occurred cumulatively at 11 years in 14.95%, 14.999%, and 9.535% of the HCV-treated, -untreated, and -uninfected cohorts, respectively (Figure 2, Table 2). The HCV-uninfected cohort had the lowest cumulative incidence of rheumatic diseases among the 3 cohorts. However, no difference of cumulative incidences of rheumatic diseases was identified between the HCV-treated and HCV-untreated cohorts. The multivariate analysis of the 3 cohorts showed, compared with the HCV-uninfected cohort, that both the HCV-treated and HCV-untreated cohorts had higher hazard ratios (HRs) to develop rheumatic disease. In addition, female sex, baseline age ≥ 49 years, CCI score ≥ 1, baseline COPD and dyslipidemia were associated with increased HRs of rheumatic diseases, while baseline liver cirrhosis, ESRD and DM were associated with decreased HRs of rheumatic diseases (Supplementary Figure S2). Given that HCV-treated and HCV-untreated cohorts yielded similar HRs to develop rheumatic diseases, we thus combined HCV-treated and HCV-untreated cohorts to form the HCVinfected cohort as mentioned above and compared the HCV-infected cohort with the HCVuninfected cohort to view the impact of HCV infection on the development of rheumatic diseases. In addition to sex, age, CCI score, baseline COPD, dyslipidemia, cirrhosis, ESRD and DM, HCV infection was significantly associated with the development of rheumatic diseases, with a HR of 1.649 (Figure 3).

**Table 2.** Comparison of the cumulative incidences of rheumatic diseases among (1) HCV-treated, (2) HCV-untreated and (3) HCV-uninfected cohorts.


CI: confidence interval.

*3.3. Cumulative Incidences of Mortality.*

Of the 3 cohorts, the HCV-untreated cohort had the highest cumulative incidence (29.163%) of overall mortality at 11 years (*p* < 0.0001). The HCV-treated and HCV-uninfected cohorts yielded indifferent mortality rates (*p* = 0.1796) (Table 3).

**Figure 2.** Cumulative incidences of rheumatic diseases among the 3 TNHIRD cohorts including HCV-treated, HCVuntreated and HCV-uninfected cohorts. TNHIRD: Taiwan National Health Insurance Research Database; HCV: hepatitis C virus.


**Figure 3.** Forrest plot of factors associated with incident rheumatic diseases in the 2 TNHIRD cohorts: HCV-positive (untreated) and HCV-negative (combination of treated and uninfected) cohorts. TNHIRD: Taiwan National Health Insurance Research Database; HR: hazards ratio; LCL: lower confidence interval limit; HCL: higher confidence interval limit; HCV: hepatitis C virus; CCI: Charlson Comorbidity Index score; COPD: Chronic obstructive pulmonary disease; ESRD: end-stage renal disease; DM: diabetes mellitus; NAFLD: Nonalcoholic fatty liver disease; ALD: alcoholic liver disease.

**Table 3.** Comparison of the cumulative incidences of overall mortality among(1) HCV-treated, (2) HCV-untreated and (3) HCV-uninfected cohorts.


CI: confidence interval.
