Methotrexate was first developed in 1940s by Yellapragada Subbarao. In 1947, Dr. Sydney Faber & colleagues found that Methotrexate could induce remission in children with leukemias. In 1953, it was approved by FDA as an oncology drug. It was later studied for non-cancer indications including psoriasis & rheumatoid arthritis.
Attention was first drawn to Methotrexate related liver side effects in the late 1960s, when isolated cases of Methotrexate induced liver toxicity in psoriasis patients were reported. Studies conducted to look into this matter showed that psoriasis patients on Methotrexate indeed have varying degrees of liver fibrosis.
The next logical step from the scientific community was to confirm whether Methotrexate was responsible for the liver fibrosis. Liver fibrosis can be only be confirmed by a liver biopsy. Hence, studies were conducted with a liver biopsy before & after starting Methotrexate to confirm the cause & effect relationship. A few facts emerged from these studies – 1) many psoriasis patients (as many as 50%) had liver fibrosis even before starting Methotrexate; alcohol being the main causative factor. 2) methotrexate was given on a daily basis in those days & this was found to increase the chances of liver toxicity four fold as compared to weekly doses. 3) Risk factors contributing to liver toxicity were identified as alcohol consumption, diabetes, obesity & preexisting liver disease. 4) No consensus was reached regarding Methotrexate as the cause of liver fibrosis since different studies came up with contrasting results.
Similar studies were conducted in Rheumatoid arthritis (RA) patients. These studies revealed that- 1) Liver fibrosis (baseline biopsies) is much less common in RA patients as compared to those with psoriasis. 2) Liver toxicity with Methotrexate is much less common in RA as compared to psoriasis. 3) Folate & hydroxychloroquine reduce the risk of Methotrexate induced liver side effects. 4) A few studies showed that Methotrexate induced liver fibrosis/ cirrhosis occurred only in the presence of other risk factors mentioned above. Alcohol was the main risk factor.
Thus, these studies added three main safety features to Methotrexate therapy: Weekly doses (in contrast to daily Methotrexate in the past), folate supplementation & avoiding alcohol. They also cleared the air about severe liver toxicity with Methotrexate.
Pincus & colleagues studied 248 RA patients treated with Methotrexate over 13 years. This amounted to 1007 person years (Person years is the product of the number of years times the number of members. 1007 would mean approximately 100 patients taking methotrextae for 10 years.) of Methotrexate exposure. The incidence of severe liver enzyme abnormalities was only 0.9 per 100 years. A similar study by Kramer & colleagues showed that severe ALT elevation was found in 6% & did not require withdrawal of Methotrexate. Paget & colleagues found a rate of 3.4% abnormal liver function tests in 182 patients. Salliot C & colleagues studied 88 available studies of Methotrexate in RA & concluded that transient elevation of liver enzymes with Methotrexate is seen in about 20.2% patients. This number definitely looks bigger but it is worthwhile to note that folate was not given to patients in many of the included studies.
Walker A M & colleagues also studied methotrexate liver toxicity & found that severe liver toxicity is rare. The study concluded that on an average, one case of serious liver disease is seen per 1000 patients treated for 5 years.
The incidence of liver enzyme abnormalities observed with methotrexate are much lower than that listed for Rofecoxib, celecoxib & other NSAIDs. Pincus & colleagues thus concluded that low dose weekly Methotrexate with folate supplementation is safe (probably even safer than the NSAIDs). In fact, the side effects of untreated RA are substantially greater than the observed side effects of Methotrexate.
Thus, Methotrexate does have the potential to affect the liver; however, with weekly doses, folate supplementation the risk is substantially reduced. Regular clinical monitoring, & that of liver enzyme make it a safe drug to use. Side effects of untreated RA are many times bigger that the liver toxicity risk associated with Methotrexate.
· Y Yazici, T Sokka, H Kautiainen, C Swearingen, I Kulman, T Pincus Long term safety of methotrexate in routine clinical Care : discontinuation is unusual and rarely the result of laboratory abnormalities. Annals of Rheumatic Disease 2005;64:207-211
· Yazici Y, Erkan D, Paget SA. Monitoring methotrexate hepatic toxicity in rheumatoid arthritis: is it time to update the guidelines? Journal of Rheumatol 2002;29:1586–9.
· Bridges SL, Alarcon GS, Koopman WJ. Methotrexate-induced liver abnormalities in rheumatoid arthritis. Journal of Rheumatol 1989;16:1180–3.
· Shergy WJ, Polisson RP, Caldwell DS, Rice JR, Pisetsky DS, Allen NB. Methotrexate-associated hepatotoxicity: retrospective analysis of 210 patients with rheumatoid arthritis. American Journal of Medicine 1988;85:771–4.
· Cartwright VW, Michaud K, Choi HK, Wolfe F. Methotrexate, laboratory testing and risk of serious illness: analyses in 20 000 patients. Arthritis Rheumatism 2003;48:S428.
· C Salliot, D Van der Heijde Long-term safety of methotrexate monotherapy in patients with rheumatoid arthritis: a systematic literature research Annals Rheumatic Diseases 2009;68:1100-1104
· Walker Am, Funch D, Dreyer NA et al. Determinants of serious liver disease among patients receiving low-dose methotrexate for Rheumatoid Arthritis. Arthritis Rheumatism 1987; 36:186-95.