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Creating a care-effective cost-effective strategy for methotrexate liver toxicity monitoring in rheumatoid arthritiscomment on the article by kremer et al.

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Number 2, February 1995, pp 297-300
0 1995, American College of Rheumatology
Creating a care-effective cost-effective strategy for
methotrexate liver toxicity monitoring in rheumatoid
arthritis: comment on the article by Kremer et a1
To the Editor:
We are concerned about the recommendations made
by the Subcommittee on Hepatic Toxicity and Methotrexate, Committee on Health Care Research, Council on Research, American College of Rheumatology (ACR) regarding
methotrexate (MTX) monitoring guidelines (Kremer JM,
Alarc6n GS, Lightfoot RW Jr, Willkens RF, Furst DE,
Williams HJ, Dent PB, Weinblatt ME: Methotrexate for
rheumatoid arthritis: suggested guidelines for monitoring
liver toxicity. Arthritis Rheum 37:31&328, 1994). As a
subcommittee for the ACR, these guidelines are going to be
viewed as the de facto standard of monitoring by practitioners and healthcare regulatory agencies. We would like to
address the following points:
1. It is emphasized that aspartate aminotransferase
(AST) elevation is a predictor of clinical liver disease and
that a liver biopsy be performed if 5 of 9 or 6 of 12 AST
values are above the normal range. The study referenced as
supporting this approach (Kremer JM, Lee RG, Tolman KG:
Liver histology in rheumatoid arthritis patients receiving
long-term methotrexate therapy: a prospective study with
baseline and sequential biopsy samples. Arthritis Rheum
32: 121-127, 1989) showed no significant correlation between
the number of AST elevations and hepatic histologic changes
for the study as a whole or during weeks 0 through 29 of
MTX treatment, but did show a correlation during weeks
29-53. If there is no correlation for the study as a whole,
what is the rationale for analyzing at these intervals? What
about after week 53? The correlation during weeks 29-53
was between AST elevations and histologic deterioration,
not fibrosis. The authors themselves considered these
changes to be clinically insignificant.
2. The values in Table 7 of that paper review the
costs per case of clinically significant liver disease (CSLD)
identified. The cost analysis implies that liver function test
(LFT) screening, i.e., AST, alanine aminotransferase
(ALT), and albumin at 48-week intervals, reduces the cost
per case found from $100,000 to $20,000 if the incidence of
CSLD is 1.0% (100 biopsies necessary to find 1 case), and
reduces the cost per case found from $1,000,000 to $200,000
if the incidence of CSLD is 0.1% (1,000 biopsies necessary to
find 1 case), based on 5 years of MTX treatment. However,
the cost of LFT blood monitoring is not factored into the
cost analysis. At our institution, a biochemical screen is the
most cost-effective way to measure AST and albumin levels
($62). Even at their minimal recommended frequency (9
times per year), the costs of including LFT screening are
nearly $300,000 at a 1.O% incidence and $3,000,000 at a 0.1%
incidence, thus reversing the fiscal benefit of LFT screening.
In addition, if one includes the costs of measuring ALT
levels, which are clearly stated to correlate with nothing and
are not included on our biochemical screen, the costs rise an
additional 50%.
Most rheumatologists are convinced that the frequency of clinically significant liver disease in RA, even with
long-term MTX use, is quite low, and the need for liver
biopsy is rare. An algorithmic approach to liver biopsy is
certainly warranted; however, we are not convinced that the
current recommendations are either cost effective or more
advantageous to the patient than judicious screening prior to
MTX institution, less frequent laboratory monitoring, and
appropriate clinical care.
Eric D. Newman, MD
Thomas M. Harrington, MD
James L. Pemquet, MD
Duane E. Davis, MD
Dennis Torretti, MD
Geisinger Clinic
D a n d l e , PA
To the Editor:
We thank Dr. Newman and colleagues for their
thoughtful letter. They raise several issues which we would
like to address. First, although they have correctly summarized our earlier study of liver biopsies (l), we have continued to collect data for an additional 6 years on this cohort of
patients. A preliminary analysis has been published in abstract form (2), and a final description of this cohort has been
submitted for publication (3). An analysis of 451 biopsies
from 3 prospectively followed cohorts, including the one previously published (1-3), was presented at the Annual Scientific
Meeting of the ACR in Minneapolis last October, and published in abstract form in Arthritis and Rheumatism (4).
All the data establish and confirm a significant statistical relationship between AST values and hepatic histologic
grade. The changes observed in all of these biopsies are
generally not considered to be clinically significant. It should
again be stated that it was our practice to adjust the weekly
MTX dose whenever elevations in AST occurred, in blood
testing performed at intervals of every 4-6 weeks, and we
feel that this is the reason we have not seen any fibrosis or
clinically significant liver disease.
Dr. Newman and colleagues also question the cost
effectiveness of LFT screening and use Table 7 from our
article to establish a case for the fiscal waste associated with
this testing. They suggest that blood should be obtained less
frequently and that clinicians should use ‘‘appropriate clinical care.” It may appear after a superficial consideration of
their calculations, that they make some sense. Why spend
$3,000,000 to find liver disease if its prevalence is only 0.1%?
They have, however, missed the point that it is precisely
because of the liver monitoring recommendations that we
would anticipate the real incidence of this serious potential
toxicity to be so low. That is, with appropriate monitoring,
hepatic toxicity from MTX will be avoided because the
weekly dose of MTX can be adjusted downwards for elevations in AST or decreases in serum albumin detected with
laboratory monitoring at the suggested intervals. An analysis
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