Dose Effect Relationship of Methotrexate and Hepatic Fibrosis in Patients With Inflammatory Bowel Disease

Inflammatory bowel disease is a chronic, relapsing and remitting, inflammatory disorder of the GI tract. The mainstay of medical therapy is comprised of 5-aminosalicylates, corticosteroids, immunomodulators such as mercaptopurine and MTX, and biologics such as infliximab and adalimumab.

Mercaptopurine historically had been the immunomodulator of choice for disease maintenance and as an adjuvant to biologic therapy to prevent antibody formation.

However in 2008 the FDA communicated an increase incidence of a lethal blood cancer, hepatosplenic T-cell lymphoma, in adolescent males taking mercaptopurine along with Infliximab. In addition there is a known four-fold increase in the risk of lymphoma in patients treated with mercaptopurine while the risk is not significantly increased with MTX use. Due to these reasons there has been a shift amongst pediatric gastroenterologists to starting children with newly diagnosed IBD on MTX as a first line immunomodulator and/or as an adjuvant to biologic therapy. Given the chronic nature of this disease, children are more likely to be on long term MTX therapy. There is paucity of data for evaluation and monitoring of hepatic fibrosis associated with prolonged methotrexate usage in patients with IBD. The influence of co-morbid factors like obesity, alcohol intake and smoking are also not well understood. The primary purpose of this pilot study is to assess for hepatic fibrosis using shear wave elastography in patients on methotrexate in relation to the cumulative dose they have received. .

MTX is a folic acid antagonist, which has been used as a mainstay of therapy in other chronic inflammatory diseases such as rheumatoid arthritis and psoriatic arthritis. Known side effects from the medication are nausea, leukopenia and hepatotoxicity. In addition, patients with refractory psoriasis on MTX therapy are reported to develop hepatic fibrosis in a cumulative dose dependent fashion. Currently the gold standard of assessment is a liver biopsy, as serological biomarkers have proven to correlate poorly in early stages of fibrosis. Liver biopsy is not only an invasive test but could lead to serious complications such as pneumothorax and intra-peritoneal bleeding.

As standard of care our pediatric patients with IBD on MTX therapy are screened quarterly with serological biomarkers such as complete blood counts, albumin and liver function tests to evaluate for these side effects. As previously stated, the dilemma arises in that the derangement of these lab tests poorly correlate with early stages of fibrosis and it is likely that by the time they are elevated the patient already has experienced irreversible liver damage. In fact in an adult study by Te et al in 2000 reported that patients with IBD on MTX show poor correlation of liver function tests and histological findings on liver biopsy. Therefore they concluded that following the same surveillance guidelines in IBD patients on MTX as those with psoriasis on MTX is not warranted as risks of the procedure outweigh the benefits of biopsy. Pediatric patients with a lifelong diagnosis of IBD and a life expectancy of 80 years can reach a considerably higher cumulative MTX dose over their lifetime and may need non-invasive monitoring for liver damage and fibrosis.