Autoimmune hepatitis as an adverse effect of long-term methotrexate therapy.

Methotrexate (MTX) is one of the most commonly used medicines in the treatment of psoriatic arthritis. The drug can produce steatosis and cirrhosis. Autoimmune hepatitis is a rare and serious adverse effect. We describe the case of a 53-year-old woman who developed autoimmune hepatitis after a long-term use of MTX for psoriatic arthritis. Hepatitis was completely resolved 4 months after stopping this drug. The pathophysiologic mechanisms of a drug-induced autoimmunity are unclear and complex. This report confirms the need to monitor liver enzymes carefully in patients using long-term treatment with MTX for psoriasis or rheumatoid arthritis.

Introduction

Methotrexate (MTX) is a folic acid antagonist with antiproliferative and antiinflammatory properties. It is one of the most commonly used medicines in the treatment of rheumatoid arthritis or psoriatic arthritis.[12] Potential liver toxicity of MTX is characterized by hepatic fibrosis. Autoimmune hepatitis is a rare and serious adverse-effect. It is idiosyncratic and is classified as type B adverse drug reaction.[3] We report the case of an adult woman with psoriatic arthritis who developed acute severe hepatitis following long-term treatment with MTX.

Case Report

A 53-year-old woman was diagnosed with psoriatic arthritis in the year 2000. She received 15 mg MTX weekly, with a satisfactory clinical response. The periodic biological monitoring of liver enzymes: Alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), gamma-glutamyl transpeptidase (gamma-GT) performed every 6 months did not reveal any abnormalities. MTX was stopped in the year 2005 due to remission of the disease. In 2009, it was reintroduced at a dose of 15 mg/week due to decompensation of the disease. Monitoring of liver enzymes performed every 6 months showed an elevation <2 times the normal levels on average of ASAT and ALAT since 2010. Assessing the risk-benefit ratio and given the severe decompensation of the disease, MTX was continued. In May 2013, patient presented with jaundice following the development of asthenia and weight loss. Laboratory investigation showed the following results: Prothrombin time (71%), ASAT 580 U/L, ALAT 620 U/L, serum gamma-GT 146 IU/L, serum alkaline phosphatase 170 IU/L and total serum bilirubin 12 mg/dl. Antimitochondrial antibodies (titer >1/40) and antinuclear antibodies (titer of 1/640) were detected in serum. Serum gamma-globulin was 16.9 g/L, serum albumin was 34.9 g/L and IgG was 16.6 g/L. Routine laboratory investigations for infection with hepatitis A, B, and C viruses and serology for cytomegalovirus and Epstein-Barr virus were negative. Abdominal ultrasound detected no anomalies. Patient denied ingestion of any herbal medicines or drugs other than MTX.

Methotrexate was stopped, and therapy with oral methylprednisolone (80 mg/day) was initiated. A significant improvement in the following parameters was observed a week later: Prothrombin time (88%), ASAT 270 U/L, ALAT 340 U/L, S. gamma-GT 122 IU/L, and S. alkaline phosphatase 173 IU/L. After 4 months, all laboratory parameters had normalized, and serum was negative for antimitochondrial and antinuclear antibodies. Methylprednisolone was gradually withdrawn after 5 months of treatment.

Discussion

Patients taking MTX are more likely to discontinue therapy because of adverse drug effects rather than because of lack of efficacy. Adverse effects of MTX are, usually, mild and self-limiting, but may include serious adverse drug reactions such as hematopoietic suppression, pulmonary, and hepatotoxicity.[4]

Hepatic fibrosis is a usual adverse reaction reported with long-term use of MTX therapy in psoriatic patients. However, severe hepatic damage may occur unexpectedly.[2]

Causality assessment of the adverse drug event (ADE) was carried out using WHO-UMC criteria,[5] Naranjo's Scale,[6] and Roussel Uclaf Causality Assessment Method (RUCAM) scale.[7] In this case, patient improved on withdrawal of the drug, and there were no other confounding factors that could have caused this adverse effect. Hence, the ADE was probably caused by MTX (WHO-UMC criteria: Probable; Naranjo's Score: 7, probable; and RUCAM scale: 5).

In addition, sufficient and continuous exposure to the drug, lack of previous evidence of autoimmune disease and complete resolution of the condition within 4 months of discontinuation of the suspected drug confirmed the diagnostic criteria of drug-induced autoimmunity.[3]

The first case of autoimmune hepatitis associated with MTX was described in 2011 in a 57-year-old man after 11 years of treatment with MTX. The case was confirmed by liver biopsy. A complete normalization of laboratory parameters was obtained 5 months after stopping this drug.[8] To the best of our knowledge, this is the second case of autoimmune hepatitis reported with MTX.

The pathophysiologic mechanisms of drug-induced autoimmunity are unclear and complex. Production of autoantibodies may result from a loss of tolerance to self-antigens. This drug reaction may involve genetic, epigenetic and environmental factors.[8] It, usually, occurs at higher doses and also positively correlates with the cumulative dose of drugs.[38] Other risk factors for the development of elevated liver enzymes and changes in liver biopsy include obesity, higher alcohol intake prior to commencement of MTX and persistent hepatitis B or C infection.[4] In the present case, patient was obese with a body mass index of 30.

Appearance of autoantibodies and transitory autoimmune disease associated with infliximab in a patient with psoriatic arthritis has also been documented and the preexistent serological signs of autoimmunity are believed to be a risk factor for the development of similar autoimmune reactions.[9]

Conclusion

This report confirms the need to monitor liver enzymes carefully in patients with psoriatic arthritis using long-term treatment with MTX. Clinicians must collaborate with the pharmacovigilance center to detect and notify serious adverse effects of MTX. Further research is needed to identify the exact mechanism and establish, if possible, primary means of prevention of this serious adverse effect.