EDITORIAL - Monitoring MTX liver toxicity in RA: is it time to update the guidelines?

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Journal of Rheumatology

August 2002

Editorial

Monitoring Methotrexate Hepatic Toxicity in Rheumatoid Arthritis: Is It Time

to Update the Guidelines?

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YUSUF YAZICI, MD;

DORUK ERKAN, MD;

STEPHEN A. PAGET, MD,

The Hospital for Special Surgery,

Weill Medical College of Cornell University,

New York, New York, USA.

Address reprint requests to Dr. Yazici, the Hospital for Special Surgery,

535 East 70th Street, New York, NY 10021.

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Methotrexate (MTX) is the most commonly prescribed disease modifying

antirheumatic drug (DMARD) for the treatment of rheumatoid arthritis (RA)1.

It is one of many medications not developed specifically for rheumatology

but found to be useful in the treatment of RA. Rheumatologists have

benefited from the experience following use of this drug by other

subspecialties.

MTX was initially developed as an antimetabolite that was first used

successfully in the treatment of leukemia and other malignancies2. This was

followed by its use in organ transplantation and psoriasis3,4. Data from

these disparate disease populations were employed in defining the monitoring

algorithms in patients with RA.

In 1994, the American College of Rheumatology (ACR) published guidelines for

monitoring the development of hepatic toxicity related to MTX5. These

recommendations include measurement of aspartate aminotransferase (AST),

alanine aminotransferase (ALT), and albumin, collectively referred to as

liver function tests (LFT), every 4-8 weeks. Evaluations of the complete

blood count (CBC), platelets, and creatinine would also be performed at

baseline and most rheumatologists repeat these at intervals.

The necessity and cost effectiveness of routine monitoring of all patients

with RA receiving second-line agents for the development of hepatotoxicity

has been questioned6, and this led us to look at the issue of the potential

benefit to modifying the protocol.

We decided to review our experience at the Hospital for Special Surgery

(HSS), New York City, regarding MTX use in RA7. The ACR guidelines are

widely accepted for general use among our rheumatologists and have been

employed in our monitoring of MTX treatment. Our goal was to assess the

utility of these guidelines for detecting MTX toxicity and the possibility

that a change in this strategy could result in lower health care costs

without increased risk to patients.

The HSS RA Registry and Repository contains data on 562 patients meeting the

1987 revised RA criteria8. We identified 222 patients who had previously

taken or were currently taking MTX for their RA. Data from 40 patients were

not available.

In our review of 182 patients (155 women, mean age 59.7 years, white 111,

Hispanic 38, black 20, Asian 13) a total of 2791 LFT were performed, with 94

abnormal results. One hundred fifty-two patients (83.5%) with 2007 LFT

evaluations had no abnormal results, compared with 30 patients (16.5%) who

had at least one abnormal LFT in 784 tests. There was no statistically

significant difference in patients who did and did not have LFT

abnormalities with respect to age, sex, mean disease duration, current or

prior DMARD use, or the frequency of blood test monitoring.

Twenty-two of the 30 patients (73.3%) with at least one LFT abnormality

(highest AST 103 u/dl) continued treatment despite the elevation without

further evaluation or change in therapy, and subsequent guideline directed

LFT assessments were within normal limits. Two patients immediately

discontinued MTX therapy following a single elevation in AST (within 2 times

the upper limit of normal). Three patients with LFT abnormalities

temporarily discontinued MTX (one patient with a history of alcohol

dependence, one during total hip replacement, and one during concurrent

antibiotic treatment). Upon resuming their previous MTX dose, LFT had

returned to within normal limits in all 3 patients. A single patient with

abnormal LFT was found to have similar abnormalities before the initiation

of MTX; no change in MTX therapy or LFT was noted. Two other patients with

abnormal LFT underwent 3 liver biopsies. The patient with 2 biopsies had had

2 consecutively elevated results (4 times the upper limit of normal), and

both biopsies showed normal histology. The other patient underwent a liver

biopsy as a result of an alkaline phosphatase finding greater than twice the

upper limit of normal; this biopsy was also normal, but the patient did not

restart MTX therapy.

While 3 patients experienced leukopenia during MTX treatment (lowest

2300/mm3), only in one did this lead to discontinuation. The other 2 did not

change their MTX dose and subsequent white blood cell evaluations were

within normal limits.

Twenty-two patients had hypoalbuminemia during their MTX treatment (lowest

3.4 g/dl). Fourteen of these had had decreased albumin levels before MTX

therapy and no clinically significant change while taking MTX. The remaining

8 patients had subsequently normal albumin levels without change in their

MTX regimens.

One hundred twenty-eight patients (70.3%) continued taking MTX at the time

of our analysis. Their mean MTX dose was 13.0 ± 5.5 mg/wk, with average

duration of treatment of 37.9 ± 30.0 months. A total of 54 patients

permanently discontinued MTX. Mean maximal MTX dose among these patients was

11.5 ± 3.7 mg/wk, with an average duration of treatment 19.4 ± 17.9 months.

Other DMARD used by patients with no LFT abnormalities were

hydroxychloroquine (n = 44), etanercept (n = 12), azathioprine (n = 8),

leflunomide (n = 6), intramuscular (IM) gold (n = 4), sulfasalazine (n = 3),

and penicillamine (n = 1). Among patients with LFT abnormalities, the other

DMARD utilized were hydroxychloroquine (n = 5), azathioprine (n = 3),

etanercept (n = 1), and IM gold (n = 1). Discontinuations of MTX were due

to: inadequate response (n = 23); disease improvement (n = 3);

gastrointestinal (n = 6), dermatologic (n = 5), pulmonary (n = 3) side

effects; a new diagnosis of cancer (n = 3 breast, lung, and squamous

epiglottis cancer); high LFT (n = 2); monocytosis (n = 1) or leukopenia (n =

1); increased intake of ethanol (n = 1); and hepatitis A (n = 1). Five

patients wished to discontinue treatment and did not specify a reason.

These impressive safety data led us to review the literature from which the

original guidelines were drawn. During our review, we noticed some numerical

discrepancies in the number of patients whose LFT data were used to develop

the current guidelines. We were able to determine that the guidelines were

actually based on 446 instead of 700 patients, of which 383 are in published

studies9-19 (Table 1). Eight of the 11 cohort studies were continuations of

3 separate investigations that had been reported previously. Individual

subjects were counted multiple times as different patients, once for each

separate publication. Thus, it is likely that the recommendations are based

on a database with information gathered from a population in which many of

the subjects have been included more than once, and this limits the power

and generalizability of the data.

MTX has a well defined toxicity profile, and physicians monitor patients for

gastrointestinal, hepatic and pulmonary toxicity, bone marrow suppression,

and stomatitis. Hepatic toxicity has been noted in psoriasis patients using

MTX for some time, and guidelines for monitoring hepatic toxicity have been

published20.

Since its initial use in the treatment of RA, the demographic and baseline

profiles of those patients for whom MTX was prescribed have changed.

Initially, MTX was reserved for patients who had climbed the RA treatment

pyramid. These patients likely manifested complications due to both RA and

the cumulative use of multiple toxic medications, as well as having other

unrelated comorbidities that come with increasing age. More and more, MTX

has been used earlier in the course of the disease. Patients are relatively

healthier early in their disease and may be better able to tolerate possible

side effects21.

We believe the original cohort that was studied and that formed the basis

for the current recommendations may not reflect the current group of

patients using MTX. These guidelines were drawn from a cohort of RA patients

who averaged more than 10 years of disease before they were enrolled in MTX

trials, and failed multiple other DMARD before participating in RA trials.

Patients with RA seen over the last decade might not meet the inclusion

criteria that would lead to their enrollment in the DMARD clinical trials

that generated the data used for the current guideline. This provides

further evidence about the limitations in the use of data gathered solely

from clinical trials22. Also, as with many guidelines, they signify a " best

fit " based upon available data, often represent compromises, and demand

updating when new data are available.

MTX is not only the DMARD most commonly used to treat RA, but is also the

first prescribed, and the most common DMARD used alone or in combination

treatments by most rheumatologists1. In our cohort, MTX seems to have very

few clinically significant side effects. In contrast to previous

publications5, discontinuation of MTX was mostly due to ineffectiveness

rather than adverse effects. This provides further evidence that MTX may not

be as hepatotoxic in patients with RA as formerly assumed. The frequent use

of folic acid supplementation may be one of the factors contributing to the

low incidence of side effects in this cohort, as noted23. The 5 year

cumulative incidence of cirrhosis in RA patients treated with MTX has been

calculated to be 1/100024. Cirrhosis risk was increased in patients with

psoriasis, diabetes, or alcohol use. It can be argued that the numbers of

our patients were not high enough to yield one occurrence of cirrhosis;

however, neither were the number of patients used in the guidelines. Both

cohorts combined may not be sufficient to include one episode of cirrhosis

of the liver. Our data reflect the experience of a single, urban, tertiary

care center, thus potentially influencing the generalizability of our

findings. Although we are also limited by the retrospective nature of our

data, we believe and the authors of the current recommendations have noted

that a prospective analysis of the question is not feasible due to the

population size required, a low incidence of toxicity with MTX, and ethical

considerations.

Our data do not provide an answer for the best frequency for LFT monitoring.

One way to determine this would be to prospectively follow cohorts getting

LFT evaluations at differing frequencies and to assess the safety of each

different time interval protocol.

We suggest the following algorithm based on a responsible interpretation of

our data. At initiation of MTX therapy, LFT should be checked in 6-8 weeks,

per the current guidelines. If these are normal and the patient is taking a

stable dose of MTX, then patients with no increased risk for liver problems

(older age, alcohol dependence, multiple concurrent medical problems,

especially diabetes, psoriasis, hepatitis) may be followed every 3-4 months.

In case of a dose change, LFT should be monitored again every 6-8 weeks

until a maintenance dose is reached. If any clinical signs or symptoms of

liver problems are encountered (nausea, vomiting, right upper quadrant

abdominal pain, icterus), then LFT should be repeated immediately and if

abnormal, MTX should be stopped and the cause defined.

This small sample of patients, representing a fraction of the 250,000

patients presently using MTX in the USA, had 2791 LFT assessments over 14

years, at an estimated cost of $156,000 (utilizing the current direct

charges at our institution for the tests recommended by the current

guidelines). Consequently, less frequent liver function testing would

decrease the cost of MTX monitoring, and would likely not place the patient

at any increased danger of toxicity.

In view of our safety data, consideration for revision of the current MTX

monitoring guidelines seems appropriate to reflect " new and compelling

information " as suggested by the authors of the original recommendations5

and others25,26. Based on longterm experience, less frequent monitoring,

especially in patients without risk factors for liver disease, is both

reasonable and responsible.

REFERENCES

1. Mikuls TR, O'Dell J. The changing face of rheumatoid arthritis therapy:

results of serial surveys. Arthritis Rheum 2000;43:464-7. [MEDLINE]

2. Farber S, Diamond LK, Mercer RD, Sylvester RF, Wolf VA. Temporary

remission in acute leukemia in children produced by folic acid antagonist

4-amethopteroylglutamicacid (aminopterin). New Engl J Med 1948;238:787-93.

3. Tobias H, Auerbach R. Hepatotoxicity of long-term methotrexate therapy

for psoriasis. Arch Intern Med 1973;132:391-6.

4. Palmer HM. Hepatotoxicity of methotrexate in the treatment of psoriasis.

Practitioner 1973;211:324-8.

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

rheumatoid arthritis: Suggested guidelines for monitoring liver toxicity.

Arthritis Rheum 1994;37:316-28. [MEDLINE]

6. Dieppe P. Evidence-based medicine or medicines-based evidence? Ann Rheum

Dis 1998;57:385-6. [MEDLINE]

7. Yazici Y, Erkan D, Tai K, Paget SA. Monitoring for methotrexate hepatic

toxicity in RA patients: Is it time to update the guidelines? [abstract].

Ann Rheum Dis 2000;7:154.

8. Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism

Association 1987 revised criteria for the classification of rheumatoid

arthritis. Arthritis Rheum 1988;31:315-24. [MEDLINE]

9. Weinblatt ME, Coblyn JS, Fox DA, et al. Efficacy of low-dose methotrexate

in rheumatoid arthritis. N Engl J Med 1985; 312:818-22. [MEDLINE]

10. HJ, Willkens RF, son CO Jr, et al. Comparison of low-dose

oral pulse methotrexate and placebo in the treatment of rheumatoid

arthritis. A controlled clinical trial. Arthritis Rheum 1985;28:721-30.

[MEDLINE]

11. Weinblatt ME, Kaplan H, Germain BF, et al. Low-dose methotrexate

compared with auranofin in adult rheumatoid arthritis. A thirty-six-week,

double blind trial. Arthritis Rheum 1990; 33:330-8. [MEDLINE]

12. Kremer JM, Lee JK. The safety and efficacy of the use of methotrexate in

long-term therapy for rheumatoid arthritis. Arthritis Rheum 1986;29:822-31.

[MEDLINE]

13. Kremer JM, Lee JK. A long-term prospective study of the use of

methotrexate in rheumatoid arthritis. Update after a mean of fifty-three

months. Arthritis Rheum 1988;31:577-84. [MEDLINE]

14. Kremer JM, Phelps CT. Long-term prospective study of the use of

methotrexate in the treatment of rheumatoid arthritis. Update after a mean

of 90 months. Arthritis Rheum 1992;35:138-45. [MEDLINE]

15. Weinblatt ME, Kaplan H, Germain BF, et al. Methotrexate in rheumatoid

arthritis: effects on disease activity in a multicenter prospective study. J

Rheumatol 1991;18:334-8. [MEDLINE]

16. Weinblatt ME, Trentham DE, Fraser PA, et al. Long-term prospective trial

of low-dose methotrexate in rheumatoid arthritis. Arthritis Rheum

1988;31:167-75. [MEDLINE]

17. Weinblatt ME, Weissman BN, Holdsworth DE, et al. Long-term prospective

study of methotrexate in the treatment of rheumatoid arthritis. 84-month

update. Arthritis Rheum 1992;35:129-37. [MEDLINE]

18. Furst DE, son N, Clute L, Koehnke R, Burmeister LF, Kohler JA.

Adverse experience with methotrexate during 176 weeks of a longterm

prospective trial in patients with rheumatoid arthritis. J Rheumatol

1990;17:1628-35. [MEDLINE]

19. Furst DE, Koehnke R, Burmeister LF, Kohler J, Cargill I. Increasing

methotrexate effect with increasing dose in the treatment of resistant

rheumatoid arthritis. J Rheumatol 1989;16:313-20. [MEDLINE]

20. Roenigk HH Jr, Auerbach R, Maibach HI, Weinstein GD. Methotrexate in

psoriasis: revised guidelines. J Am Acad Dermatol 1988;19:145-56. [MEDLINE]

21. Emery P, Salmon M. Early rheumatoid arthritis: time to aim for

remission? Ann Rheum Dis 1995;54:944-7. [MEDLINE]

22. Pincus T. Rheumatoid arthritis: disappointing long-term outcomes despite

successful short-term clinical trials. J Clin Epidemiol 1988;41:1037-41.

[MEDLINE]

23. Kremer JM. Safety, efficacy, and mortality in a long-term cohort of

patients with rheumatoid arthritis taking methotrexate: followup after a

mean of 13.3 years. Arthritis Rheum 1997;40:984-5. [MEDLINE]

24. AM, Funch D, Dreyer NA, et al. Determinants of serious liver

disease among patients receiving low-dose methotrexate for rheumatoid

arthritis. Arthritis Rheum 1993;36:329-35. [MEDLINE]

25. Fries JF, Ramey RD, Singh G. Suggested guidelines for monitoring liver

toxicity in rheumatoid arthritis patients treated with methotrexate: comment

on article by Kremer et al [letter]. Arthritis Rheum 1994;37:1829-30.

[MEDLINE]

26. Newman ED, Harrington TM, Perruquet JL, DE, Torretti D. Creating a

care-effective cost-effective strategy for methotrexate liver toxicity

monitoring in rheumatoid arthritis: comment on article by Kremer et al

[letter]. Arthritis Rheum 1995;38:297. [MEDLINE]

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