Prospective analysis of liver biopsies before and after methotrexate therapy in rheumatoid patients

The significance of hepatic changes in methotrexate-treated RA patients is unclear at this time.³⁶ In our group of RA patients, there was a slight increase in the incidence of triaditis and fat during methotrexate therapy. Disease duration ≥ 10 years was associated with increased hepatic triaditis before treatment. Age > 50 years was associated with increased hepatic fat before and after treatment. It appears that patients' ages and duration of underlying RA account for some changes, independent of methotrexate therapy. Several of our patients changed from higher to lower histologic grade or had an apparent decrease in fibrosis, fat, or triaditis on the pathologists' reports and the blind readings of the repeat biopsies. This may be explained by sampling error. More importantly, some of these changes may not be of clinical significance. One report of methotrexate-induced cirrhosis in patients with psoriasis demonstrated that in all but one of 14 patients who continued receiving methotrexate the cirrhosis decreased or did not progress.⁴⁷ This may also be true of the hepatic fibrosis seen in RA after methotrexate treatment.^64,65. In this study, there did not appear to be changes seen on pretreatment liver biopsy that were predictive of subsequent fibrosis or cirrhosis. Our data indicate that pretreatment biopsy is unwarranted in a population similar to ours. However, our practice has been to try to avoid methotrexate in patients with diabetes, prior liver disease, alcoholism, or obesity because of previous reports suggesting that these patients are at increased risk for the development of cirrhosis.²⁹ Only the above-mentioned patient, eventually diagnosed as having cirrhosis, might have been handled differently. Including this study, none of the approximately 700 RA patients in the literature having liver biopsies after methotrexate therapy have developed cirrhosis consequent to its use. Most of these had received a total dose of approximately 1,500 mg in small weekly doses, and alcohol was prohibited. Below this cumulative dose the risk of clinically significant liver damage in carefully selected patients is very low. In view of this experience, the recommendation that RA patients have liver biopsies after 1,500 mg of methotrexate⁶⁸ (a holdover from the psoriasis literature) may be too conservative in low-risk RA patients, provided methotrexate is administered weekly and alcohol is prohibited. Recognizing that the absolute need for biopsy is unproven, a more realistic milestone for those choosing biopsy might be after each 2,000 to 2,500 mg. Until more data are available this will need to be a decision arrived at by the physician and patient. Obviously, a longer period of observation will be needed to confirm these conclusions regarding the hepatic abnormalities in RA patients following methotrexate treatment. This is particularly true of the portal fibrosis or portal tract expansion seen in these biopsies even before methotrexate treatment, because the natural history of these changes is not clear. It is important to emphasize that our data do not exclude the possibility that at higher cumulative doses or after longer duration of therapy, clinically significant liver problems may become manifest in these patients. More data are desperately needed from RA patients treated with > 5 g of methotrexate and should be available within the next few years. However, the results of this study are encouraging and suggest that cautious optimism is in order regarding the short- and intermediateterm hepatic effects of this drug in RA patients failing or intolerant of more conventional therapy.