Liver histology in patients receiving low dose pulse methotrexate for the treatment of rheumatoid arthritis.

217

Objective. To determine the long-term efficacy and safety of low-dose methotrexate (MTX) in rheumatoid arthritis (RA).Method&. Eighty-four-month open prospective trial at a single academic rheumatology center.Results. Twenty-six patients were enrolled in a prospective study of the long-term efficacy of MTX in RA; a significant improvement had been demonstrated after 36 months of therapy. Twelve patients remained in the study at the 84-month visit; the mean weekly dosage of MTX was 10.2 mg. A significant improvement was still noted at 84 months in the number of painful joints, number of swollen joints, joint pain index, joint swelling index, and physician and patient global assessments. A 50% improvement in the joint pain index and joint swelling index was observed in more than 80% of the 12

Section: Discussionsupporting

confidence: 71%

Long‐Term Prospective Study of Methotrexate in the Treatment of Rheumatoid Arthritis

Weinblatt

Weissman

Holdsworth

et al. 1992

217

“…A low albumin level early in the course of therapy in this data set is therefore more likely to reflect the severity of the chronic inflammatory state, rather than liver disease. A decrease in serum albumin from the normal range to <3.3 g/dl in clinically improved patients taking MTX is more likely to signal the presence of underlying liver disease (45,49,56). In the study by Walker et a1 (56), albumin values were measured in 17 of 24 patients within 1 year of the diagnosis of CSLD.…”

Section: Resultsmentioning

confidence: 99%

Methotrexate for Rheumatoid Arthritis

Kremer

Alarcón

Lightfoot

et al. 1994

536

Methotrexate (MTX) has become an important drug in the treatment of rheumatoid arthritis (RA). The American College of Rheumatology convened a committee to assess the risks of development of clinically significant liver disease (CSLD) during MTX treatment, to evaluate the risk and role of surveillance liver biopsies, and to provide recommendations about monitoring patients for liver toxicity. The committee recommends obtaining liver blood tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, albumin, bilirubin), hepatitis B and C serologic studies, and other standard tests including complete blood cell count and serum creatinine tests prior to starting treatment with MTX. A pretreatment liver biopsy should be considered only for patients with a history of prior excessive alcohol consumption, persistently abnormal baseline AST values, or chronic hepatitis B or C infection. At intervals of every 4–8 weeks the AST, ALT, and albumin levels should be monitored. Routine surveillance liver biopsies are not recommended for RA patients receiving traditional doses of MTX. However, a biopsy should be performed if a patient develops persistent abnormalities on liver blood tests. These are defined as elevations (above the upper limit of laboratory normal) in the AST in 5 of 9 determinations within a given 12‐month interval (6 of 12 if tests are performed monthly) or a decrease in serum albumin below the normal range. The recommendations for monitoring and selection of patients for liver biopsy identify patients at potential risk for CSLD, and thus significantly reduce the number of patients who would be exposed to this procedure. Close monitoring is essential to reduce the risk of unrecognized serious liver disease. These recommendations should be revised as necessary to reflect new and compelling information.

“…The potential for toxic effects involving the pulmonary (11-15) and hepatic (16)(17)(18)(19) systems have been documented. Risk factors for the development of hepatotoxicity have been well defined in patients with psoriatic arthritis (16,2&22); these factors include a history of alcohol abuse, obesity, and advanced age at the time of initiation of MTX therapy.…”

mentioning

confidence: 99%

“…Although the incidence of cirrhosis in patients receiving MTX for psoriatic arthritis is high (16,(20)(21)(22), the frequency of serious hepatotoxicity occurring in patients receiving the drug for treatment of RA is quite low (16)(17)(18)(19)(23)(24)(25)(26). In an earlier study using light microscopy (LM) to examine liver biopsy samples, however, we observed the beginnings of fibrotic changes in samples from 56% of the RA patients who had taken MTX for a mean period of 53 months (23).…”

mentioning

confidence: 99%

Electron microscopic analysis of sequential liver biopsy samples from patients with rheumatoid arthritis. Correlation with light microscopic findings

Kremer

Kaye

1989

We used electron microscopy (EM) to analyze 52 biopsy samples from 22 patients who were receiving long-term weekly oral doses of methotrexate (MTX) for the treatment of rheumatoid arthritis. Forty-eight biopsy samples were obtained after 2-6 years of continuous treatment, and 4 samples were obtained before treatment was begun. Specimens were graded for neutral fat, secondary and tertiary Iysosomes, and smooth endoplasmic reticulum (SER) in hepatocytes, and for collagen in the perisinusoidal space (Disse's space). We examined the correlations between the EM findings and the light microscopic (LM) findings in the same biopsy specimens, and between the EM findings and the results of simultaneous monthly measures of aspartate transaminase, alkaline phosphatase, bilirubin, and albumin levels, as well as history of alcohol consumption before MTX treatment and monthly assessments of clinical status during the course of treatment. The presence of collagen was minimally increased in these sequential biopsy samples, whereas fat, lysosomes, and SER were decreased. The SER decrease was statistically significant. EM findings of collagen in the space of Disse did not correlate with early fibrotic changes observed with LM. Thus, after as long as 6 years of weekly oral treatment with MTX, hepatic ultrastructural changes are minimal and are not clinically significant. The use of EM for sequential biopsy studies allows the quantitation of long-term hepatic changes that may be more limited than the impression gained after LM analysis.Methotrexate (MTX) is an effective agent in the treatment of refractory rheumatoid arthritis (RA) (1-lo), but there are concerns about its long-term use. The potential for toxic effects involving the pulmonary (11-15) and hepatic (16-19) systems have been documented. Risk factors for the development of hepatotoxicity have been well defined in patients with psoriatic arthritis (16,2&22); these factors include a history of alcohol abuse, obesity, and advanced age at the time of initiation of MTX therapy.We have previously examined multiple variables that assess the progression of hepatic abnormalities in liver biopsy specimens from patients with RA who have been taking MTX, and we have found similar risk factors in this population (23). Although the incidence of cirrhosis in patients receiving MTX for psoriatic arthritis is high (16,(20)(21)(22), the frequency of serious hepatotoxicity occurring in patients receiving the drug for treatment of RA is quite low (16)(17)(18)(19)(23)(24)(25)(26). In an earlier study using light microscopy (LM) to examine liver biopsy samples, however, we observed the beginnings of fibrotic changes in samples from 56% of the RA patients who had taken MTX for a mean period of 53 months (23).To determine whether the changes that are detectable by electron microscopy (EM) are more sensitive indicators of the beginning of hepatic abnormalities in RA patients, we examined sequential liver biopsy specimens (obtained annually during treatment) with both LM and EM. Preliminary result...