Methotrexate-Associated Hepatotoxicity Risk Differs Between Psoriasis, PsA, and RA Patients

Jeff Craven

February 26, 2021

Patients taking methotrexate for psoriasis or psoriatic arthritis (PsA) were at a higher risk of developing liver disease than were patients with rheumatoid arthritis (RA) on methotrexate, in a large population-based study published in the Journal of the American Academy of Dermatology.

"These findings suggest that conservative liver monitoring is warranted in patients receiving methotrexate for psoriatic disease," particularly psoriasis, the investigators concluded.

Dr Joel Gelfand

Joel M. Gelfand, MD, professor of dermatology at the University of Pennsylvania, Philadelphia, and colleagues performed a population-based cohort study of patients in Denmark in a hospital clinic with psoriasis, PsA, or RA who received methotrexate between 1997 and 2015; they compared rates of mild liver disease, moderate to severe liver disease, cirrhosis, and cirrhosis-related hospitalization between the groups.

In total, 5,687 patients with psoriasis, 6,520 patients with PsA, and 28,030 patients with RA met inclusion criteria: receiving one or more methotrexate prescriptions or having been dispensed methotrexate at the hospital clinic during the study period. Patients with RA tended to be older (mean, 59.7 years) and the group consisted of more women (71.6%) than the psoriasis patients (47.7 years; 45.3% women) or PsA patients (50.7 years; 57.3% women). In the groups, 17.9% to 23.5% had a history of smoking, and 2.8% to 7.4% had a history of alcohol abuse; the rates of diabetes were between 7.0% and 8.3%, and hyperlipidemia or statin use between 13.6% and 16.4%.

The average weekly methotrexate dose was similar in the three patient groups (a mean of 19.2-19.9 mg). However, the duration of methotrexate use among patients with RA was longer (a mean of 72.1 weeks) compared with the PsA (56.3 weeks) and psoriasis (43.0 weeks) groups. In addition, 50% of the patients in the RA group discontinued treatment after 80 months, 50% in the PsA group discontinued after 54 months, and 50% of patients with psoriasis discontinued after 26 months.

Patients with RA also had a higher cumulative methotrexate dose (a mean of 4.0 g) compared with PsA (3.0 g) and psoriasis (2.1) groups.

When the researchers looked at the incidence rate (IR) for the different categories of liver disease, they found the following differences:

  • Mild liver disease: The IR per 1,000 person-years for patients with psoriasis was 4.22 per 1,000 person-years (95% confidence interval, 3.61-4.91), compared with 2.39 per 1,000 person-years (95% CI, 1.95-2.91) for patients with PsA, and 1.39 per 1,000 person-years (95% CI, 1.25-1.55) for patients with RA.

  • Moderate to severe liver disease:The IR for patients with psoriasis was 0.98 per 1,000 person years (95% CI, 0.70-1.33), compared with 0.51 (95% CI, 0.32-0.77) for patients with PsA, and 0.46 (95% CI, 0.37-0.55) for patients with RA.

  • Cirrhosis: The IR for patients with psoriasis was 1.89 per 1,000 person years (95% CI, 1.49-2.37), compared with 0.84 (95% CI, 0.59-1.16) for patients with PsA, and 0.42 (95% CI, 0.34-0.51) for patients with RA.

  • Cirrhosis-related hospitalization: This was the least common outcome, with an IR per 1,000 person years of 0.73 (95% CI, 0.49-1.05) for patients with psoriasis, 0.32 (95% CI, 0.18-0.54) for patients with PsA, and 0.22 (95% CI, 0.17-0.29) for patients with RA.

When results were adjusted with Cox regression analyses, the psoriasis group had a significantly increased risk compared with the RA group with regard to mild liver disease (hazard ratio, 2.22; 95% CI, 1.81-2.72), moderate to-severe liver disease (HR, 1.56; 95% CI, 1.05-2.31), cirrhosis (HR, 3.38; 95% CI, 2.44-4.68), and cirrhosis-related hospitalization (HR, 2.25; 95% CI, 1.37-3.69). Compared with patients with RA, patients with PsA had a significantly increased risk of mild liver disease (HR, 1.27; 95% CI, 1.01-1.60) and cirrhosis (HR, 1.63; 95% CI, 1.10-2.42), but not moderate to severe liver disease or hospitalizations related to cirrhosis.

The researchers noted it is unclear why there was a difference in risk between the three groups of patients.

"While such differences in hepatotoxicity risk were previously attributed to differences in rates of alcoholism, obesity, diabetes, and other comorbidities between the disease populations, our study finds that the underlying disease influences liver disease risk independent of age, sex, smoking, alcohol use, diabetes, hyperlipidemia, overall comorbidity, and weekly methotrexate dose," wrote Dr. Gelfand and colleagues.

As far as they know, their study " is one of the first and largest population-based studies to directly compare" liver disease in these three groups of patients on methotrexate, they wrote, noting that earlier studies were smaller and frequently used indirect hepatic injury measures.

Limitations of the study included the inability to account for disease severity as well as the potential for disease misclassification, surveillance bias, and confounding by unmeasured variables such as body mass index. Further, the results do not show whether "liver disease is attributed to methotrexate use, the underlying disease, or a combination of both," the researchers noted.

Four authors report relationships in the form of consultancies, continuing medical information payments, deputy editor positions, fellowship support, individual or spousal honoraria, patents, research grants, and/or speaker positions with various pharmaceutical companies, medical journals, societies, and other organizations; two authors had no disclosures. There was no funding source.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

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