Methotrexate is a multi-acting systemic antipsoriatic drug which simultaneously inhibits purine and pyrimidine synthesis, nitric oxide production and the transcription factor nuclear-factor kappa B (NFĸB) which is an inducible transcription factor for the production of pro-inflammatory cytokines and chemokines.¹ In a recently published population study conducted in Denmark, psoriasis (PsO) or psoriatic arthritis (PsA) patients who have received methotrexate were found to be at a significantly higher risk of developing mild liver disease and cirrhosis when compared to those with rheumatoid arthritis (RA).² To address this increased risk of hepatic injury, conservative monitoring of liver function in psoriatic patients receiving methotrexate is recommended.²

PsO and PsA are known to be associated with metabolic comorbidities. Patients with PsO or PsA are two- to three-fold more prone to develop non-alcoholic fatty liver disease (NAFLD) and cirrhosis, as compared to individuals with RA.³ Between 1997 and 2015, a population-based cohort study was conducted in Denmark to determine the incidence rate (IR) of liver diseases among patients with PsO (n=5,687), PsA (n=6,520) or RA (n=28,030) receiving methotrexate.² At baseline, the prevalence of smoking history (17.9%-23.5%), alcohol abuse (2.8%-7.4%), diabetes mellitus (7.0%-8.3%), and hyperlipidemia or statin use (13.6%-16.4%) were comparable across three groups. Each of the three groups received similar dose of methotrexate, ranging from 19.2mg to 19.9mg per week. Outcome measurements were mild liver disease, moderate-to-severe liver disease, cirrhosis and cirrhosis-associated hospitalization. ²

Overall, methotrexate was less tolerated by patients with PsO or PsA as compared to those with RA.² Where methotrexate treatment was tolerated and maintained in >50% RA patients for 80 months, the treatment was only maintained in >50% of PsO and PsA patients for 26 and 54 months, respectively.² In this connection, the RA group had received a mean of 4.0g cumulative dose of methotrexate as compared to 2.1g in the PsO group and 3.0g in the PsA group. ²

Over the treatment course of methotrexate, the IRs of mild liver disease, moderate to severe liver disease, liver cirrhosis, and cirrhosis-related hospitalization were highest among patients with PsO followed by PsA.² Compared to patients with RA, those diagnosed with PsO or PsA were at significantly higher risk of developing mild liver disease (HR=1.27; 95% CI: 1.01-1.60) and cirrhosis (HR=1.63; 95% CI: 1.10-2.42).² Mild liver disease was observed at 4.22, 2.39 and 1.39 per 1,000 person-years for PsO, PsA and RA groups, respectively.² Moderate to severe liver disease was most frequent among those with PsO with a rate of 0.98, 0.51 and 0.46 per 1,000 person-years for PsO, PsA, and RA groups, respectively.² Notably, the PsO group was at more than three-fold increased risk for developing cirrhosis (IR=1.89; 95% CI: 1.49-2.37) and cirrhosis-related hospitalization (IR=0.73; 95% CI: 0.49-1.05).²

As the first study to provide direct epidemiological evidence linking hepatic injury with methotrexate treatment in psoriatic treatment that is independent of age, sex, comorbidities, smoking history, and alcohol use, Prof. Joel Gelfand, Department of Dermatology of the University of Pennsylvania Perelman School of Medicine, concluded that “more conservative monitoring should be considered in patients receiving methotrexate for psoriatic disease, particularly in PsO patients”.