Methotrexate monitoring: time for changes?

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Sep 4, 2002

Methotrexate monitoring: time for changes?

Could monitoring for methotrexate liver toxicity be reduced without

increasing the risk to patients? Less frequent monitoring would reduce

healthcare costs, and the proposal is both " reasonable and responsible, " say

a group of doctors at the Hospital for Special Surgery in New York.

At present, patients with rheumatoid arthritis being treated with

methotrexate are expected to have liver function tests (LFTs) every 4 to 8

weeks. But this monitoring could be relaxed to every 3 to 4 months in

patients on a stable dose of methotrexate and without an increased risk of

liver problems, say Drs Yusuf Yazici, Doruk Erkan, and Paget. In an

editorial in the August issue of The Journal of Rheumatology [1], they

report " impressive safety data " from a cohort of 182 patients and say this

" new and compelling information " calls for a revision of current monitoring

guidelines.

However, Dr Kremer (Albany Medical School, New York), who was

instrumental in drawing up the guidelines, disagrees. In a related editorial

in the same journal [2], Kremer says the current guidelines (published by

the American College of Rheumatology in 1994 [3]) have " served patients and

their physicians well " and there is little sense in altering them without

rigorous data and " credible new evidence of an alternative strategy. " He

suggests that the retrospective chart review offered by Yazici and

colleagues provides neither.

" Impressive safety data " from 182 patients

Yazici et al report data on 182 patients taking methotrexate for RA followed

over a period of 14 years, during which they underwent a total of 2791 LFT

assessments, at an estimated cost of $156 000. The LFT assessment includes

measurement of aspartate aminotransferase (AST), alanine aminotransferase

(ALT) and albumin. In addition, most rheumatologists also monitor at

intervals for complete blood count, platelets, and creatinine, they comment.

The majority of their patients (152/182, 83.5%) never had an abnormal result

on the liver function tests (from a total of 2007 LFTs). Of the 30 patients

(16.5%) who had at least 1 abnormal LFT result (from 784 tests), 22 patients

(73.3%) continued treatment and subsequent LFT results were within normal

limits. Of the remaining 8 patients, 2 stopped therapy; 3 temporarily

discontinued but then restarted and showed normal LFT results; and 1 patient

was discovered to have abnormal LFT results even before starting on

methotrexate and so continued taking it. Only 2 patients had liver biopsies,

and both showed normal histology.

Hypoalbuminemia was seen in 22 patients. All continued on the drug, and 8

patients had albumin levels returned to normal; in the other 14, the

decreased albumin levels had been noted even before methotrexate was began

and there was no clinically significant change during therapy.

In addition, leukopenia was seen in 3 patients, but only 1 discontinued

therapy. The other 2 continued, and subsequent white blood cell counts were

within normal limits.

" In our cohort, methotrexate seems to have very few clinically significant

side effects, " the authors comment. One factor may be the frequent use of

folic acid supplementation, they suggest. Discontinuation was mostly due to

ineffectiveness rather than adverse effects, in contrast to previous

reports. However, the mean dose used (13 mg methotrexate weekly) was

" relatively low, " comments Kremer, which may account for this observation.

Yazici et al claim their data " provides further evidence that methotrexate

may not be as hepatotoxic in patients with RA as formerly assumed. " The

profile of the typical RA patient using methotrexate has changed since the

guidelines were drawn up, they note. When the drug was first introduced for

the treatment of RA, it was reserved for patients who had " climbed the RA

treatment pyramid " and so were likely to have complications from both the

disease and the cumulative use of multiple toxic medications. But now

methotrexate is used earlier in the course of the disease, when patients are

younger and relatively healthier and so may be better able to tolerate

possible side effects, they suggest.

Relaxation of monitoring from 6 to 8 weeks to 3 to 4 months

Yazici et al concede that their small sample of patients represents only a

fraction of the estimated 250 000 patients presently using methotrexate in

the US. However, on the basis of a " responsible interpretation of our data, "

they suggest a new algorithm for monitoring for methotrexate liver toxicity.

When patients start therapy, LFT should be checked in 6 to 8 weeks, as per

the current guidelines. But if the result is within the normal range, then

for a patient taking a stable dose of methotrexate without an increased risk

of liver problems (ie, older age, alcohol dependence, or multiple concurrent

medical problems, especially diabetes, psoriasis, and hepatitis) further

monitoring can be relaxed to every 3 to 4 months, they suggest. If the dose

of methotrexate is adjusted, monitoring should return to 6 to 8 weeks until

a maintenance dose is reached.

However, if there are any clinic signs and symptoms of liver problems

(nausea, vomiting, right upper quadrant abdominal pain, icterus), then LFT

should be repeated immediately, and if abnormal, methotrexate should be

stopped and the cause defined.

" Not yet time to change the guidelines "

No, says the accompanying editorial in the same issue of the journal; it's

" not yet time to change the guidelines for monitoring methotrexate liver

toxicity: they have served us well. " They have served us so well, Kremer

argues, that " the infrequency of clinically significant liver damage in the

very large number of patients with RA receiving the drug around the world "

has allowed methotrexate hepatotoxicity to evolve from a primary concern

limiting drug use into a secondary concern. " It would therefore be ironic if

the reason for the drastic decrease in methotrexate-induced liver toxicity

became the driving force behind a movement to relax the vigilance with which

hepatic enzymes and serum albumin are monitored. "

Reducing the frequency of monitoring would miss liver enzyme elevations into

the abnormal range, Kremer points out. Blood sampling at intervals of 90

days would actually miss 68% of all elevations on AST, he notes, compared

with samples obtained every 45 or 60 days, which would miss 17% or 41%

respectively. Any alternative strategy for assessing the " very real

potential " for liver damage with methotrexate should be based on " credible

new evidence . . . with actual descriptions of liver histology obtained at

the time of biopsy, rather than only blood tests with no indication of the

relevance to the actual outcome of concern. "

Zosia Chustecka

Cited sources

1. Yazici Y, Erkan D, Paget SA. Monitoring methotrexate hepatic toxicity in

rheumatoid arthritis: is it time to update the guidelines? J Rheumatol 2002

Aug; 29(8):1586-9.

2. Kremer JM. Not yet time to change the guidelines for monitoring

methotrexate liver toxicity: they have served us well. J Rheumatol 2002 Aug;

29(8):1590-2.

3. Kremer JM, Alarcon GS, Lightfoot RW Jr, et al. Methotrexate for

rheumatoid arthritis. Suggested guidelines for monitoring liver toxicity.

American College of Rheumatology. Arthritis Rheum 1994 Mar; 37(3):316-28.