Incidence and Risk Factors of Hepatic Fibrosis in Psoriatic Patients Receiving Methotrexate with Concomitant Acitretin Therapy and Methotrexate Monotherapy

Abstract

Background

The use of methotrexate-acitretin (MTX-ACI) combination therapy in treating psoriasis has been limited due to concerns related to hepatic fibrosis. However, in vitro evidence revealed a protective effect of acitretin in methotrexate (MTX)-induced liver fibrosis.

Objective

This study aimed to compare the real-life incidence of hepatic fibrosis in patients with psoriasis receiving MTX-ACI and MTX monotherapy and to investigate factors associated with hepatic fibrosis in MTX-exposed patients.

Methods

A retrospective cohort study was conducted based on a real-life registry containing data on patients with psoriasis who were administered MTX-ACI or MTX between 2008 and 2019 and underwent transient elastography according to cumulative MTX dose of 1.0–1.5 g and/or 3.5–4.0 g. Time-to-event analysis was performed to determine the cumulative incidence, incidence rate, and factors potentially affecting the occurrence of hepatic fibrosis.

Results

Of the 160 patients, 32 (20%) were treated with MTX-ACI, and 128 (80%) with MTX alone. Four patients (12.5%) in MTX-ACI group and 21 (16.4%) in MTX group developed hepatic fibrosis (p = 0.59). There was no statistically significant difference in cumulative incidence (16% in MTX-ACI vs 17% in MTX, p = 0.89) and incidence rate (37 cases per 1000 person-year in MTX-ACI vs 23 cases per 1000 person-year in MTX; hazard ratio [HR] = 1.07; p = 0.90) of hepatic fibrosis between the two groups. Diabetes and obesity were identified as significant factors associated with hepatic fibrosis (adjusted HR = 2.40, 95% confidence interval [CI]: 1.05–5.51; p = 0.04 and adjusted HR = 3.28, 95% CI: 1.18–9.16; p = 0.02, respectively) regardless of the cumulative MTX dose.

Conclusion

The incidence of hepatic fibrosis in a real-life clinical situation, determined by transient elastography in patients with psoriasis receiving MTX-ACI, was not increased compared to those receiving MTX monotherapy. Type 2 diabetes mellitus and obesity were identified as risk factors of hepatic fibrosis; hence, patients with these factors receiving long-term MTX therapy should be regularly monitored for this particular event.

Keywords:

• cirrhosis
• combination therapy
• drug
• liver fibrosis
• liver injury
• non-alcoholic steatohepatitis

Acknowledgments

We acknowledge the assistance of Dr Kunlawat Thadanipon from the Section of Clinical Epidemiology and Biostatistics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, in the advisement of statistical analysis.

Abbreviations

ACI, acitretin; CI, confidence interval; MTX, methotrexate; MTX-ACI, methotrexate-acitretin; NAFLD, non-alcoholic fatty liver disease; PASI, Psoriasis Area and Severity Index; HR, hazard ratio; TE, transient elastography; T2DM, type 2 diabetes mellitus.

Data Sharing Statement

All datasets are available from the corresponding author on reasonable request.

Ethics Approval and Consent to Participate

The study was approved by the Ramathibodi Hospital Review Board for Ethics in Human Research (MURA2019/889) and was performed in accordance with the Helsinki Declaration adopted in 1964. The informed consent to review medical records was exempted by the ethics committee, and data were anonymized prior to analysis.

Disclosure

The authors report no conflicts of interest in this work.

Additional information

Funding

The authors received no financial support for this research.