RESEARCH - Incidence of liver enzyme elevations and liver biopsy abnormalities during MTX treatment of RA

[Guest guest]

ACR/ARHP 2008 Scientfic Meeting

Session: RA: Treatment and Pharmacosurveillance

Monday, Oct 27, 2008, 9:00 AM - 6:00 PM

Presentation: 1051 - Incidence of Liver Enzyme Elevations and Liver

Biopsy Abnormalities During Methotrexate Treatment in Rheumatoid

Arthritis: a Systematic Review of the Literature

Author(s): Visser, Désirée van der Heijde. Leiden University

Medical Center, Leiden, Netherlands

Abstract:

Purpose:

To perform a systematic review of the available literature on

methotrexate (MTX) associated liver toxicity in patients with

rheumatoid arthritis (RA), as part of an evidence-based approach for

generating recommendations on managing MTX, including the need for a

liver biopsy (LB), in case of elevated liver enzymes (LE).

Methods:

A systematic literature search for studies evaluating the management

of MTX or LB in case of elevated LE in RA was performed in Medline,

Embase, Cochrane and ACR/EULAR abstracts. Identified references were

screened using predefined in/exclusion criteria. Included articles

were systematically reviewed and the quality was appraised according

to the Oxford Levels of Evidence. Cumulative incidences of at least

one abnormal LE test during the use of MTX were pooled across the

studies. The percentage of patients who discontinued permanently,

adjusted the dose of MTX, or continued MTX unchanged after an abnormal

LE test were pooled. Pooled prevalences of fibrosis and cirrhosis in

pre-MTX and post-MTX biopsies were calculated. In patients with

multiple biopsies, progression from a normal biopsy to

fibrosis/cirrhosis was assessed.

Results:

Of 426 identified references, 46 articles were included in the

systematic review, resulting in level 2a to 2b evidence on

hepatotoxicity. Pooled data of 2062 RA patients after a mean of 3.3

years on MTX (cumulative dose 1900 mg), showed a cumulative incidence

of abnormal LE of 49% above the upper limit of normal (ULN) and 17%

above 2-3 times the ULN. MTX was continued without a dose change in

71% of the patients with elevated LE, the dosis was adjusted or paused

in 22% and permanently discontinued in 7%. However, the frequency of

spontaneous normalization was insufficiently reported. Lack of folic

acid and obesity were found as predictors for elevated LE. Pooled

cumulative incidences of mild fibrosis, severe fibrosis and cirrhosis

in monitoring biopsies in 1113 RA patients after a mean of 4.1 years

on MTX (cumulative dose 2200 mg), were 15.3%, 1.3% and 0.5%,

respectively. However, pooled results of pre-MTX biopsies already

showed a prevalence of 9.1% mild fibrosis and 0.3% cirrhosis. In

serial biopsies in 689 patients, progression from a normal biopsy to

(mild) fibrosis was seen in 6.2%, while no progression to cirrhosis

was observed. High age, alcohol, disease duration, obesity and

cumulative MTX dose are reported as risk factors for LB abnormalities.

Furthermore, the percentage of elevated aspartate aminotransferase

(AST) has been found to correlate with liver fibrosis/cirrhosis.

Conclusions:

The available evidence suggests that LE elevation during MTX use in RA

is frequent but often transient, that multiple rather than single

abnormal LE tests correlate with LB abnormalities and that MTX-induced

fibrosis/cirrhosis is rare. This evidence was used by a broad panel of

rheumatologists to formulate recommendations on managing MTX and LB in

case of abnormal LE tests.

http://www.abstractsonline.com/plan/start.aspx?mkey={5880E483-F47E-4EFF-A557-2EF\

143592815}

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