Repost: Use of Methotrexate in Children

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Use of Methotrexate in Children

Murray H. Passo, MD, Children's Hospital Medical Center, Cincinnati,

Ohio

Philip J. Hashkes, MD, MSc, Sieff Hospital, Safed, Israel

SUMMARY POINTS: Methotrexate has emerged as the drug of choice for

treating JRA. Methotrexate may also be an effective steroid-sparing

therapy for battling other childhood rheumatic diseases. Although a

specialist should implement methotrexate therapy, the primary care

physician may need to monitor for drug toxicity and

be responsible for administering methotrexate.

Methotrexate has emerged as one of the most important medications used

to treat rheumatic diseases in children. It is the drug of choice for

treating juvenile rheumatoid arthritis (JRA) that is unresponsive to

nonsteroidal anti-inflammatory drug (NSAID) therapy. In addition, it

serves as a steroid-sparing agent for many other inflammatory diseases.

Additional uses for methotrexate are being investigated because of its

efficacy, its excellent risk-to-benefit ratio, and because it does not

cause permanent sterility or significant oncogenesis.

Methotrexate use in the treatment of childhood rheumatic diseases has

been reviewed in several comprehensive articles (1-3). Cronstein and

Merrill recently reviewed methotrexate's mechanisms of action in the

Bulletin on the Rheumatic Diseases, including its capacity to inhibit

transmethylation reactions and promote adenosine release.

USE IN CHILDHOOD RHEUMATIC DISEASES

Juvenile Rheumatoid Arthritis. Low-dose methotrexate was the only

second-line drug found to be effective in the treatment of JRA in a

double-blind, placebo-controlled study (5). An estimated 25,000 children

in the United States, or 39% of patients with JRA, are currently taking

methotrexate (6). Although the definitions of response and remission

differ among studies, 33% to 100% of patients were found to respond to

methotrexate, and 5% to 45% achieved remission (1).

There are no predictors to indicate whether an individual patient will

respond to methotrexate therapy.Some investigators have suggested that

patients with systemic-onset JRA are less responsive than those with

pauci- or polyarticular onset, whereas others have demonstrated

excellent results with systemic-onset disease (1). Occasionally,

patients who are not responsive to conventional dosages of methotrexate

(10 to 15 mg/m2 per week) may respond to dosages as high as 30 mg/m2 per

week (1 mg/kg) (7). Doses above 15 mg/m2 should be given parenterally

due to decreased oral bioavailability at higher doses (1,8). Dosage

starts at 10 mg/m2 and may be increased by 2.5 mg every 4 to 6 weeks as

necessary to maximize clinical response.

The average wholesale price for methotrexate in pill form is

approximately $85 per month. The average wholesale price for one month

of intramuscular injections is $20. Both of these prices are based on an

assumed dosage of 15 mg/m2 per week.

It is unclear whether methotrexate can modify the course of JRA. Many

clinicians think that fewer patients have needed joint replacement

surgery or achieved poor functional outcomes since methotrexate use

became widespread in the early 1990s. However, formal outcome studies

have yet to be conducted. In the only published report to investigate

the effect of methotrexate on the radiographic progression of disease in

the affected wrists of children with JRA, no progression of erosions or

joint narrowing was demonstrated in 11 of 17 responders to therapy (9).

Another unanswered question is how long to continue methotrexate after

remission is achieved. In a recent study, 13 of 25 patients (52%) who

discontinued methotrexate after remission experienced flares after a

mean of 11 months (10). Patients younger than 4.5 years at the time of

diagnosis were at higher risk for disease flare. Other predictors,

including the length of remission before methotrexate was discontinued,

or whether the drug was stopped gradually or abruptly, were not

associated with increased risk. However, more than 80% of these patients

responded well to a second course of methotrexate therapy. Therefore, an

attempt to discontinue methotrexate after remission can probably be

made, although the optimal time has not yet been determined and

retreatment may be necessary.

Inflammatory Ocular Disease. Inflammatory ocular complications can occur

in several rheumatic diseases in children, particularly in JRA and the

spondylarthropathies. Methotrexate has been used to treat several ocular

diseases in adult patients (11). Wallace et al employed subcutaneous

dosages of 0.5 to 1 mg/kg per week in children with JRA-associated

iridocyclitis (1). Five of the 6 patients responded. More studies must

be conducted in this area to evaluate the efficacy of methotrexate and

the dosage necessary to suppress the ocular inflammation.

Juvenile Dermatomyositis. Patients with juvenile dermatomyositis are

highly responsive to glucocorticoid therapy; unfortunately, adverse

effects include profound growth retardation, osteoporosis, and

cataracts. In patients who require further anti-inflammatory treatment,

methotrexate can be a highly beneficial adjunct therapy and a

steroid-sparing agent. et al (12) reported good results in 12

patients who received methotrexate for at least 8 months; all regained

normal muscle strength. In 11 of the 12, the prednisone dosage was

tapered to < 5 mg/day. Active disease recurred in 5 patients in

remission when methotrexate was discontinued. Relapse is common and may

be inherently related to the nature of inflammatory disease and the

ameliorating, noncurative effects of methotrexate. (some snipped, on

other diseases treated by MTX)

ADVERSE EFFECTS In general, methotrexate is well tolerated in children.

Side effects are usually mild and transient. The most commonly noted

adverse effects are gastrointestinal - particularly nausea and vomiting

- on the day that methotrexate is taken. Oral mucosal ulcerations, which

may be painless or painful, are also seen frequently. These side effects

can be ameliorated by the use of folic acid at a dosage of 1 mg/day. A

recent controlled study demonstrated no decrease in the efficacy of

methotrexate when folic acid was used (17). Patients rarely may require

the addition of supplemental folinic acid (2.5 to 5 mg as a single dose)

following the methotrexate therapy on a weekly basis. Anecdotally, we

have not found diminished efficacy of

methotrexate with supplemental folinic acid. Other strategies for

reducing nausea include the administration of methotrexate at bedtime,

withholding one dose of NSAIDs around the time of methotrexate

administration, use of anti-emetics, and subcutaneous administration of

methotrexate. Fatigue and mood alterations may be noted on the day after

administration. We often advise patients to take weekly methotrexate

over the weekend so that school attendance and performance will not be

affected.

Transient liver biochemical abnormalities, mainly elevated serum

aminotransferase levels, are noted at least once during methotrexate

therapy in a majority of patients. Blood tests to monitor hepatotoxicity

should be obtained every 4 to 8 weeks, prior to methotrexate

administration, because aminotransferase abnormalities are more frequent

immediately following administration of the drug. These abnormalities

usually respond to temporary discontinuation of methotrexate or dose

modifications. Occasionally, discontinuing use of concurrent NSAIDs will

result in the resolution of liver biochemical abnormalities.

No cases of severe fibrosis or cirrhosis have been reported in children

with JRA taking methotrexate for as long as 10 years (18). However, only

51 liver biopsies have been reported in the literature (1,18). Until

more data is accumulated, it appears sensible to follow the guidelines

of the American College of Rheumatology in monitoring methotrexate

hepatotoxicity (19). Other side effects often seen in adults, such as

hematologic, infectious, and pulmonary toxicity, are rarely seen in

children (20). Accelerated nodulosis, which is frequently reported in

adults with rheumatoid arthritis taking methotrexate, has been reported

in 3 patients with JRA, two of whom had rheumatoid factor-positive

disease (21,22). Methotrexate is highly teratogenic; therefore,

counseling and management strategies (as discussed below) should be

implemented with adolescent girls who may be or may become sexually

active. From accumulated data, there does not appear to be a long-term

deleterious effect of methotrexate on gonadal function and

reproductivity. Although several cases of both Hodgkin's and

non-Hodgkin's lymphomas in patients receiving methotrexate have been

reported, most have been in adults. There is no evidence of an increased

risk of malignancies or causal effect in these patients. Many of the

lymphomas are associated with Epstein-Barr virus and may regress

spontaneously after discontinuing methotrexate. We recommend

discontinuing methotrexate in patients with active Epstein-Barr virus.

MANAGEMENT STRATEGIES Children and adolescents with rheumatic diseases

are typical of their peers in terms of experimentation with alcohol,

drugs, and sexual behaviors (23). However, adolescent patients taking

methotrexate must be cautioned against the use of alcohol. Despite

counseling, some patients will drink alcohol; methotrexate should

probably be withheld from patients deemed unreliable. Evaluation and

management of underlying psychosocial issues (eg, depression, substance

abuse, or maladjustment to chronic disease) should be considered. In

addition to being highly teratogenic, methotrexate can be an abortient.

Sexually active adolescent girls must use effective birth control. It is

important to review this issue with appropriate patients at each visit.

SUMMARY Methotrexate continues to be the safest and most efficacious

second-line drug for the treatment of JRA. In addition, it is useful in

other inflammatory conditions in children. Careful education is

necessary, particularly with regard to the importance of laboratory

tests and the avoidance of comorbidity such as pregnancy and

alcohol-induced liver injury. Health care providers should be

comfortable discussing these issues with children and adolescents.

Note: REFERENCES snipped for space