Front Immunol: Association between interferon therapy and autoimmune disease risk in patients with chronic hepatitis C

Background: Hepatitis C virus (HCV) is a causative agent of hepatitis that was previously known as non-A and non-B hepatitis
.
In 2015, more than 71 million people worldwide were chronically infected with the hepatitis C virus
.
According to the Taiwan National Health Insurance Research Database (NHIRD), as of 2015, there were 400,000 carriers of
the hepatitis C virus in Taiwan.
Hepatitis C virus infection predisposes patients to hepatocellular carcinoma, liver failure, and cirrhosis
.

Chronic hepatitis C virus infection can trigger an immune response
in the host.
Thus, hepatitis C virus infection is associated with many extrahepatic diseases, such as type 2 mixed cryoglobulinemia and B-cell lymphoma
.
Agnello et al.
identified at least 36 manifestations of extrahepatic disorders, mainly autoimmune diseases such as Sjogren's syndrome, systemic lupus erythematosus, autoimmune hemolytic anemia, antiphospholipid syndrome, autoimmune hemolytic anemia, Behcet's syndrome, autoimmune thyroiditis, and dermatomyositis, which have been reported to be associated with
hepatitis C virus infection.
Sayiner et al.
also reported that 2% to 38% of patients with hepatitis C virus infection have rheumatic features and are associated with many autoimmune rheumatic diseases, such as rheumatoid arthritis (RA).

Type I interferon (IFN) is a cytokine with a variety of effects, such as inducing inhibition of cell growth, regulation of apoptosis, and cellular autonomic antiviral resistance
.
In addition, type I interferons can modulate the function of immune effectors and serve as signals
that connect native immune responses and acquired immune responses.
Since the 80s of the 20th century, interferon-A has been the cornerstone of
antiviral treatment for hepatitis C virus infection.
After completion of antiviral therapy, pegylated interferons can significantly increase sustained virologic response
.
Although direct-acting antivirals are now becoming a popular and successful treatment option, the effects of interferon-based therapy (IBT) still need to be studied
.
The reported incidence of interferon-related autoimmunity ranged
from 4% to 19%.
In addition, autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis, polymyositis, psoriasis arthropathy, sarcoidosis, autoimmune hemolysis, autoimmune thyroid disease, and immune thrombocytopenia may occur
during interferon-a therapy.
Few studies have evaluated the effect of IBT on the risk of autoimmune disease (ADS) in people with hepatitis C, and it is not possible to conduct randomised clinical trials to understand the effects of
IBT.

Objective: We used claim data from NHIRD to examine the association
between IBT and ADS risk of hepatitis C virus infection.

Methods: This retrospective cohort study identified patients diagnosed with hepatitis C virus infection from the National Medical Insurance Research Center
of Taiwan between January 1, 2006 and December 31, 2015.
There were 1 6 cases of hepatitis C virus infection and 0 2 9 cases of IBT in group 1, and 141 2 14 cases
of hepatitis C virus infection who did not receive IBT.
Both groups of participants were followed to assess the development of
ADS.
The risk ratio (HR) is calculated using the COX proportional hazards regression model, which adjusts
for potential confounders.

Results: The median follow-up period for IBT users and non-IBT users was 4.
53 years and 3.
34 years
, respectively.
There was no significant difference
in the risk of global ADS (adjusted HR [AHR]: 0.
96, 95% confidence interval [CI]: 0.
81 to 1.
14) or systemic ADS (AHR: 0.
88, 95% CI: 0.
71 to 1.
10) during the study period.
However, there was a slight increase in the risk of organ-specific advertising among IBT users (incidence ratio: 1.
33, 95% confidence interval, CI: 1.
02 to 1.
72).

In addition, analysis of AD subgroups showed a significantly increased
risk of Graves' disease (AHR: 6.
06, 95% CI: 1.
27-28.
8) and Hashimoto's thyroiditis (AHR: 1.
49, 95% CI: 1.
01-2.
21) in IBT users.

Table 1 Risk incidence ratio and risk rate
of ADS in IBT group and non-IBT group.

Table 2 Risk incidence ratio and risk rate of ADS subgroup in IBT group and non-IBT group

Table 3 Risk incidence ratio and hazard ratio
of systemic ADS in IBT group and non-IBT group.

Fig.
1 Cumulative incidence of organ-specific autoimmune diseases (A) Graves disease (B) Hashimoto's thyroiditis
.

Conclusion: In patients with hepatitis C virus infection, the use of IBT increases the risk of
autoimmune thyroid diseases (Hashimoto's thyroiditis and Graves' disease) more easily than not using IBT.

Chou SM, Yeh HJ, Lin TM, et al.
Association of interferon-based therapy with risk of autoimmune diseases in patients with chronic hepatitis C virus infection: A population-based Taiwanese cohort study.
Front Immunol 2022; 13