Light and electron microscopic analysis of sequential liver biopsy samples from rheumatoid arthritis patients receiving long-term methotrexate therapy. Followup over long treatment intervals and correlation with clinical and laboratory variables

Arthritis Rheum. 1995 Sep;38(9):1194-203. doi: 10.1002/art.1780380904.


Objective: To describe liver histopathologic features and ultrastructural changes in a prospectively studied cohort of rheumatoid arthritis (RA) patients receiving long-term methotrexate (MTX) therapy, and to seek correlations between these changes and simultaneously measured laboratory indices of liver function.

Methods: This was a long-term, prospective, open observational study. Twenty-seven outpatients with RA who began therapy with MTX and continued treatment for extended periods underwent baseline and followup liver biopsies. One hundred seventy liver biopsy specimens were analyzed by light microscopy (LM) and assessed according to a modified Roenigk score and a newly devised numerical grading system. Ninety-three biopsy specimens were also analyzed by electron microscopy (EM). Blood samples were obtained at 4-6-week intervals for determination of bilirubin, alkaline phosphatase, aspartate aminotransferase (AST), and albumin levels, and the weekly dosage of MTX was adjusted if there were abnormalities in the AST or albumin level. A mean of 6.3 liver biopsies per patient were obtained over a mean followup period of 8.2 years (range 2-13 years).

Results: The modified Roenigk score was significantly different from baseline at year 3, when it increased from a mean of 1.8 to 2.3 (P = 0.05) and at year 6, when it increased to 2.4 (P = 0.04), but this was not considered clinically meaningful. No other significant changes from baseline were observed by either LM grading system. No significant progression was observed by EM over the course of the investigation. Increases in serial measurements of AST correlated with both the modified Roenigk score (r = 0.21, P = 0.016) and the numerical rating score (r = 0.19, P = 0.027).

Conclusion: Patients with RA who are receiving weekly single-dose oral MTX therapy exhibit little deterioration in hepatic architecture by LM or EM when the dosage of the drug is adjusted for abnormalities in AST and serum albumin, monitored at frequent intervals.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antirheumatic Agents / administration & dosage
  • Antirheumatic Agents / therapeutic use*
  • Arthritis, Rheumatoid / drug therapy*
  • Arthritis, Rheumatoid / pathology*
  • Arthritis, Rheumatoid / physiopathology
  • Aspartate Aminotransferases / blood
  • Biopsy
  • Cohort Studies
  • Female
  • Humans
  • Liver / pathology*
  • Male
  • Methotrexate / administration & dosage
  • Methotrexate / therapeutic use*
  • Microscopy, Electron
  • Middle Aged
  • Regression Analysis
  • Serum Albumin / analysis
  • Time Factors


  • Antirheumatic Agents
  • Serum Albumin
  • Aspartate Aminotransferases
  • Methotrexate