The Journal of Rheumatology 2002; 29:8 1590 Methotrexate (MTX) use in patients with psoriasis may be associated with considerable hepatotoxicity 1-3 . Liver biop- sies were therefore recommended after a patient had achieved a mean cumulative dose of MTX of 1.5 g, and then again after each additional 1 g 4 . Testing of liver transami- nase enzyme levels was thought to be of no value in predicting the development of clinically significant liver disease (CSLD) 4 . Because of the reports of liver disease associated with the use of MTX in psoriatic patients, rheumatologists recog- nized the need to assess hepatic safety in patients taking MTX for the treatment of rheumatoid arthritis (RA). With the more widespread use of MTX in the 1980s, the issue of determining the hepatic safety profile of the drug in this group of patients came into sharp focus. The early prospective studies of MTX in patients with RA confirmed that its use was accompanied by some increase in hepatic transaminase enzymes 5 . The implications of these abnormalities were unclear until prospective studies could be performed in which frequent monitoring of the enzyme abnormalities could be correlated with actual biopsy samples of hepatic tissue. When this was done, it became possible to examine the relationship between the abnormalities of blood testing of transaminase enzymes and serum albumin with the actual evaluation of changes of hepatic architecture. With the analysis of liver blood tests and liver biopsy tissue obtained, certain clinically useful relationships emerged. Contrary to the doctrine that hepatic changes in patients with psoriatic arthritis could not be predicted by abnormalities in liver enzymes 1-4 , it became apparent that there was indeed a significant correlation between hepatic aspartate aminotransferase (AST) and progression of histo- logic deterioration in patients with RA receiving chronic weekly MTX 6 . The disparity between the seemingly conflicting data in patients with psoriasis and RA was resolved when the methodology of blood sampling was examined more closely. The psoriatic patients had blood sampling for determination of enzyme levels on the day of the biopsy 1-3 , while the patients with RA underwent frequent and regular blood monitoring at regular intervals between liver biopsies 6 . Examination of the results of sequential liver biopsies in patients with RA who were managed to keep the hepatic AST and serum albumin within the normal range while avoiding all alcohol actually revealed some improvement in hepatic histology over prolonged periods of MTX expo- sure 7,8 . It therefore became apparent that liver toxicity was not necessarily an inevitable outcome of longterm MTX treatment 9 . The pattern of increase of transaminase enzymes, which actually correlated with hepatic damage seen at the time of liver biopsy, was of interest. Any elevation of serum AST into the abnormal range was predictive of hepatic histologic deterioration 6 . This made sense considering that the mean value of AST in patients with RA taking MTX more than doubles from baseline values, even while remaining in the normal range 10 (Figure 1). This observation, along with the consideration that the laboratory defined upper limit of normal is 2 standard deviations from the norm, lends further credibility to the finding that any increase in AST values into the abnormal range may be associated with liver damage, and led to the recommendations in the American College of Rheumatology guidelines published in 1994, which indicate that the MTX dose should be adjusted to keep the transaminase enzyme values within the upper limit of normal 11 . The utility of these recommendations has been validated by others 12 , and they have generally served us well. MTX hepatotoxicity has evolved from a primary concern limiting drug use into a secondary concern because of the infrequency of CSLD in the very large number of patients with RA receiving the drug around the world. It would therefore be ironic if the reason for the drastic decrease in MTX induced liver toxicity became the driving Editorial Not Yet Time to Change the Guidelines for Monitoring Methotrexate Liver Toxicity: They Have Served Us Well See Monitoring for MTX hepatic toxicity in RA: Is it time to update the guidelines? page 1586 Personal non-commercial use only. The Journal of Rheumatology Copyright © 2002. All rights reserved. www.jrheum.org Downloaded on June 29, 2021 from