Use of methotrexate in juvenile idiopathic arthritis

[Guest guest]

Use of methotrexate in juvenile idiopathic arthritis

http://adc.bmj.com/cgi/content/full/88/3/197

Archives of Disease in Childhood 2003;88:197-200

© 2003 BMJ Publishing Group & Royal College of Paediatrics and Child Health

A V Ramanan1, P Whitworth2 and E M Baildam1

1 Department of Paediatric Rheumatology, Royal Manchester Children's

Hospitals, town Road, Manchester, UK

2 Department of Paediatric Rheumatology, Birmingham Children's Hospital,

Birmingham, UK

Correspondence to:

Dr A V Ramanan, 508, 77 Elm Street, Toronto, Canada M5G 1H4;

avramanan@...

Accepted for publication 27 August 2002

The aim of modern treatment for juvenile idiopathic arthritis (JIA) is for

rapid induction of disease control to prevent joint damage, to maximise

physical function, and to achieve a normal lifestyle for our patients.

Weekly methotrexate (MTX) is an established treatment in paediatric

rheumatology, with its efficacy shown by a randomised controlled trial in

children with severe JIA and borne out in many years of subsequent clinical

use.1 JIA is one of the most common chronic disorders in childhood, with a

UK incidence of 1/10 000 and a prevalence of 1/1000.2 There has been too

little awareness of the major role played by modern treatment regimes in JIA

where MTX has transformed the outlook for most children with severe disease

There is clinical experience and data from adult studies of early arthritis

to suggest that there may be a window of opportunity whereby early

aggressive intervention may buy long term disease suppression. Thus the

concept of a therapeutic pyramid, with gradual addition of more active

treatments, has been reversed. Treatment regimes are individualised

depending on the subtype of JIA and according to individual response, to

achieve maximum regression of disease.

In polyarticular JIA, MTX is the mainstay of treatment and is used as a

first line agent, either alone or with initial pulses of methylprednisolone

and/or multiple intra-articular steroid injections to achieve rapid disease

control. The use of etanercept, either instead of, or in addition to MTX has

added another step in improving the lot of the most severely affected

patients.3-5 However, etanercept is a new drug and hence deserves the usual

cautions for use in children, whereas MTX now has a 16 year track record of

safe and effective use in JIA.6

MTX is also used in other rheumatic diseases such as juvenile

dermatomyositis, localised scleroderma, sarcoidosis, Wegener's

granulomatosis, and some cases of systemic lupus erythematosus.7 There are

no controlled trials of the use of MTX in these rarer disorders but

experience in treating JIA successfully has encouraged the same treatment

principles to be tried.

MECHANISM OF ACTION

MTX is a folate analogue with an amino group (NH2), methyl group (CH3), and

a fully oxidised pteridine ring, rendering the molecule inactive as a

cofactor.8 MTX binds dihydrofolate reductase (DHFR) with high affinity. It

may also inhibit thymidylate synthase and interferes with the metabolic

transfer of single carbon units in methylation reaction, especially those

involved in synthesis of thymidylate and purine deoxynucleosides, which are

essential components of DNA.9

Once administered, MTX is delivered to cells in the same way as the

parenteral folates; 3-12% is hydroxylated in the liver and circulates as

7-OH MTX.10 Intracellular MTX and 7-hydroxy-MTX (7-OH-MTX) are metabolised

to polyglutamtes (MTX-glu) in the same manner as naturally occurring

folates.11

MTX may also interfere with de novo purine biosynthesis by inhibition of

5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase, an

enzyme in the purine biosynthetic pathway. Because there is a latent period

of weeks before the MTX effects are appreciated in children with JIA, it may

be that the intracellular MTX-glu derivatives are the true active

anti-inflammatory agents.12

MTX-glu binds DHFR and has fairly high affinity for enzymes that require

folate cofactor, including thymidylate synthetase (TS) and AICAR

transformylase. The inhibition of TS, induced by MTX, interferes with DNA

synthesis in actively dividing cells, and the increase of AICAR enzyme

system, which plays a key part in the purine metabolism of the cell, leads

to enhanced release of adenosine into the blood.13-15

Although the primary mechanism of action of MTX in JIA, or adult RA is not

clearly known, recent reviews suggest that the anti-inflammatory effects of

MTX seem to be related to the extracellular adenosine release and its

interaction with specific cell surface receptors.12,16

EFFICACY OF MTX FOR JIA

The short to medium term efficacy of MTX in children with JIA is now well

established. A recent review by the Cochrane Database of Systematic Reviews

only identified two controlled clinical trials from the literature. The

study by Giannini et al forms the basis of the current use of MTX in

paediatric rheumatological practice.1 This was a six month randomised,

double blind controlled multicentre study of 127 children with resistant

juvenile rheumatoid arthritis (JRA) (mean age 10.1 years, mean disease

duration 5.1 years); 63% of the group, treated with 10 mg/m2 of MTX,

improved compared with only 32% of those treated with 5 mg/m2, and 36% of

the placebo group. The assessment of efficacy was based on a composite of

clinical and laboratory parameters and subjective scores. Global assessment

was by physician and parent but did not include any functional assessment or

radiographic examinations.

A more recent randomised, controlled, double blind crossover, multicentre

study by Woo et al looked at the effectiveness and safety of orally

administered MTX in extended oligoarticular and systemic arthritis.17 This

study used a MTX dose of 15-20 mg/m2. A significant improvement occurred in

three of the five core variables (ESR, physician's and parent's global

assessment of disease activity) for the extended oligoarthritis group.

Neither trial included functional outcomes as there were no validated

outcome tools at the time.

The role of MTX in systemic onset JIA is still unclear. Woo et al showed

significant improvement in only two of the five core variables (physician's

and parent's global assessment of disease activity).17 The systemic feature

score was not significantly different between MTX and the placebo group in

their study.

Early treatment with MTX, before the appearance of radiographic changes, may

influence the outcome in children with systemic onset JIA.18 MTX may also

slow the radiographic progression of disease in JIA, especially if commenced

early in the disease course, although the data are not conclusive and most

studies were uncontrolled.19,20

PRACTICAL ISSUES

Dose and route of administration

In general, for children with JIA, MTX therapy is started at a dose of 10-15

mg/m2/week or 0.3-0.6 mg/kg/week. However, children seem to tolerate much

higher doses than adults and some series describe using up to 20-25

mg/m2/week in children with refractory disease, with relative safety in the

short term.6,7 At doses more than 15 mg/m2/week the parenteral route may be

better because of the decreased oral bioavailability of the drug at high

doses. It has been shown that subcutaneous administration of MTX has a

10-12% increased absorption compared with oral preparations.21

At the standard dose regime, 60-75% of patients with JIA benefit

significantly from MTX therapy, with the maximum therapeutic effect usually

becoming apparent 4-6 months after the beginning of treatment.

The issue of whether MTX acts in a dose dependent manner in JIA is still

unclear. A recent multinational, randomised controlled study coordinated by

the Paediatric Rheumatology International Trials Organization (PRINTO)

compared higher dose (30 mg/m2/week) MTX with medium dose (15 mg/m2/week) in

children with polyarticular JIA who failed to improve significantly on the

conventional dose regimen (8-12.5 mg/m2). There was a high rate of response

to the conventional dose, with 72% improving significantly, and there was a

significant improvement in the non-responders when the dose was increased to

15 mg/m2. However, there was no added benefit of the 30 mg/m2 dose over the

15 mg/m2 dose.22

Oral treatment is satisfactory in most patients as a single weekly dose.

Occasionally the liquid preparation is needed, but there are issues around

handling a liquid cytotoxic in the community where instructions for handling

of spillage and disposal of empty containers need to be clear. Subcutaneous

MTX may be required and provided in prefilled syringes to the home, for self

administration. The time of adolescence can add compliance difficulties.

The education and organisation of parents, children, and health

professionals is essential to facilitate adherence, optimise efficacy, and

monitor MTX safety. The reasons for using MTX, potential side effects, and

the justification for monitoring, along with the precautions and safety

mechanisms to deal with problem all form part of informed consent. The

concerns of parents and children regarding efficacy and long term side

effects are usually reassured by the lack of evidence for long term

complications, with reversibility on cessation of treatment or dosage

reduction of the short term side effects. Drug interactions are rarely

significant at the low doses used in rheumatology, and non-steroidal

anti-inflammatory drugs (NSAIDs) can be safely used together with MTX.

Guidelines on immunisation in the immunocompromised child should be

followed. In particular, the use of live attenuated vaccines should be

avoided and use of live polio vaccines in family members avoided. Children

who are varicella zoster non-immune may be at risk of severe chickenpox

infection and may require zoster immune globulin if in close contact, or

treatment with oral or intravenous acyclovir if they acquire an infection

with the virus.

MTX is not licensed in the UK for use in JIA, other connective tissue

diseases, and vasculitis, but this is not an uncommon situation with drug

treatments in children.

Folic acid supplementation

Although it is standard practice by most paediatric rheumatologists to use

folic acid or folinic acid along with MTX, there is little consensus on the

regime and even less evidence supporting the use of folate supplementation

in children with JIA on MTX. A recent multicentre randomised, double blind

placebo controlled study on the effect of folate supplementation in adult

rheumatoid arthritis shows that it reduced the incidence of increased liver

enzyme levels during MTX therapy and as a consequence, MTX was discontinued

less frequently.23 However, this study showed that folate supplementation

had no effect on the incidence, severity, and duration of other adverse

effects, including gastrointestinal and mucosal side effects.

One approach to folate supplementation is to prescribe 1 mg tablets of folic

acid daily, for all children begun on oral or subcutaneous MTX. Other

combinations used include: (1) not giving folate at all unless the patient

develops side effects such as oral ulcers; (2) skipping folic acid on the

day before and/or after MTX administration; and (3) giving 2.5-5.0 mg of

folic acid once a week two days after MTX administration. There are no

clinical trials in childhood to support either regime, and the least

frequent dosing is often used for reasons of patient compliance. Children

are more likely than adults to have an adequate intake of folic acid in

their diet, through enriched foods such as breakfast cereals or vitamin

supplements.

When to discontinue MTX

The question of when, how, and by what criteria to attempt withdrawal of MTX

therapy in JIA is still more a clinical art than a science. " Remission " is a

controversial concept in JIA. The criteria for " remission " or " relapse " have

never been operationally defined and then prospectively tested in JIA. In

literature on JIA, the cited criteria for remission are often subjective and

have not included long term physical and functional outcomes. MTX withdrawal

may result in disease flare in more than 50% of patients as shown by Ravelli

et al, a feature also noted by others.24,25 The ease with which remission is

achieved when MTX is re-established is still unclear. Reported rates of

" remission " in JIA treated with MTX vary from 6.9 to 45%; the average

duration of MTX treatment until " remission " is around one year at a weekly

dose of 10-15 mg/m.26

Side effects

Nausea is infrequent and may be lessened by the use of folic acid, splitting

the dose over 12-24 hours, parenteral dosing, or the use of antiemetics such

as ondansetron. Consideration needs to be given to the psychological support

of children/young persons on MTX, in whom habitual nausea may sometimes

occur. Table 1 shows the reported list of adverse events seen in children

treated with MTX from various trials.

Although in vitro studies have shown that MTX has mutagenic and carcinogenic

potential, in vivo studies in animal models have failed to show any

carcinogenicity. To date, there are only five case reports of lymphoma seen

in children treated with MTX.27 Long term prospective studies with

appropriate controls are needed to define the risk of malignancies in MTX

treated children.

High doses of MTX as used in cancer chemotherapy have been shown to be

teratogenic ( " fetal aminopterin syndrome " ).28 The effect of low dose weekly

MTX on fetal development is not clear. Based on case reports from the 1950s,

the suggested critical dose by one report is >10 mg weekly.29,30 The 6-8

week period of gestation is thought to be the critical period according to

some reports.30 On current evidence, the best practice would be to counsel

all youngsters of child bearing age to practice effective contraception

during the course of treatment. They often confuse the reduction in

fertility which occurs while taking the drug with a safe contraceptive

alternative and this needs to specifically addressed in all cases. Other

lifestyle issues include advice to limit the use of alcohol while on MTX in

order to minimise the risk of liver enzyme disturbance.

Monitoring MTX

Table 2 lists the baseline information to be obtained before commencing MTX.

Full blood count and liver function monitoring is required fortnightly until

a stable dose is achieved. Thereafter monthly monitoring for six months,

increasing to six weekly is the usual practise. Urea and electrolytes and

creatinine should be checked six monthly. The responsibility for initiating

this monitoring rests with the initiating centre but can be shared with

their district consultants or general practitioners with appropriate shared

care guidelines. The use of parent/patient held shared care monitoring

booklets can prove invaluable in this situation.

Children generally tolerate MTX well. Haematological abnormalities are rare.

Intercurrent infections may cause transient dips in white cell count and/or

neutrophils. Transient elevations of liver function enzymes, often with

concurrent infections, usually settle without any action. A small percentage

of children/young people develop persistent or frequently raised liver

function tests. This is often a dose dependent phenomenon. Current

guidelines allow the transaminases to be raised up to twice the upper limit

of normal. If transaminitis persists or increases further, MTX is

discontinued for two doses or the dose reduced, after which the liver

enzymes are rechecked. If levels have returned to normal, MTX can be

recommenced at the current dose; if further elevations occur, the MTX dose

should then be reduced by 20%. Although these precautions are taken there is

still little evidence of significant long term toxicity or liver damage

caused by MTX.

Monitoring guidelines

AST (or ALT) >2 times above upper level of the normal range

Full blood count

Platelets <150 x 109/l

White cell count <3.5 x 109/l

Neutrophils <1.5 x 109/l

Rash or severe oral ulcers, new or increasing dyspnoea or cough

Action: For any of the above, withhold dose and discuss with paediatric

rheumatologist.

REFERENCES

Giannini EH, Brewer EJ, Kuzmina N, et al. Methotrexate in resistant juvenile

rheumatoid arthritis. Results of the U.S.A.-U.S.S.R. double-blind,

placebo-controlled trial. The Pediatric Rheumatology Collaborative Study

Group and The ative Children's Study Group. N Engl J Med

1992;326:1043-9.[Abstract]

Symmons DP, M, Osborne J, et al. Pediatric rheumatology in the United

Kingdom: data from the British Pediatric Rheumatology Group National

Diagnostic Register. J Rheumatol 1996;23:1975-80.[Medline]

Lovell DJ, Giannini EH, Reiff A, et al. Etanercept in children with

polyarticular juvenile rheumatoid arthritis. Pediatric Rheumatology

Collaborative Study Group. N Engl J Med 2000;342:763-9.[Abstract/Free Full

Text]

Schmeling H, Mathony K, V, et al. A combination of etanercept and

methotrexate for the treatment of refractory juvenile idiopathic arthritis:

a pilot study. Ann Rheum Dis 2001;60:410-12.[Abstract/Free Full Text]

Weinblatt ME, Kremer JM, Bankhurst AD, et al. A trial of etanercept, a

recombinant tumor necrosis factor receptor:Fc fusion protein, in patients

with rheumatoid arthritis receiving methotrexate. N Engl J Med

1999;340:253-9.[Abstract/Free Full Text]

Truckenbrodt H, Hafner R. Methotrexate therapy in juvenile rheumatoid

arthritis: a retrospective study. Arthritis Rheum 1986;29:801-7.[Medline]

Wallace CA, Bleyer WA, Sherry DD, et al. Toxicity and serum levels of

methotrexate in children with juvenile rheumatoid arthritis. Arthritis Rheum

1989;32:677-81.[Medline]

Seeger D, Cosalich DDB, JM, et al. Analogs of pteroglutamic acid II,

4-aminoderivatives. J Am Chem Soc 1949;71:1297-301.

Kremer JM. The mechanism of action of methotrexate in rheumatoid arthritis:

the search continues. J Rheumatol 1994;21:1-5.[Medline]

Sonneveld P, Schultz FW, Nooter K, et al. Pharmacokinetics of methotrexate

and 7-hydroxy-methotrexate in plasma and bone marrow of children receiving

low-dose oral methotrexate. Cancer Chemother Pharmacol

1986;18:111-16.[Medline]

Baugh CM, Krumdieck CL, Nair MG. Polygammaglutamyl metabolites of

methotrexate. Biochem Biophys Res Commun 1973;52:27-34.[CrossRef][Medline]

Cutolo M, Sulli A, Pizzorni C, et al. Anti-inflammatory mechanisms of

methotrexate in rheumatoid arthritis. Ann Rheum Dis 2001;60:729-35.[Free

Full Text]

Cronstein BN, Eberle MA, Gruber HE, et al. Methotrexate inhibits neutrophil

function by stimulating adenosine release from connective tissue cells. Proc

Natl Acad Sci U S A 1991;88:2441-5.[Abstract/Free Full Text]

Baggott JE, SL, Ha TS, et al. Antifolates in rheumatoid arthritis: a

hypothetical mechanism of action. Clin Exp Rheumatol 1993;11(suppl

8):S101-5.[Medline]

Gruber HE, Hoffer ME, McAllister DR, et al. Increased adenosine

concentration in blood from ischemic myocardium by AICA riboside. Effects on

flow, granulocytes, and injury. Circulation 1989;80:1400-11.[Abstract/Free

Full Text]

Kremer JM. Possible mechanisms of action of methotrexate in patients with

rheumatoid arthritis. Br J Rheumatol 1995;34(suppl 2):26-9.[Medline]

Woo P, Southwood TR, Prieur AM, et al. Randomized, placebo-controlled,

crossover trial of low-dose oral methotrexate in children with extended

oligoarticular or systemic arthritis. Arthritis Rheum

2000;43:1849-57.[CrossRef][Medline]

Ravelli A, Ramenghi B, Di Fuccia G, et al. Factors associated with response

to methotrexate in systemic-onset juvenile chronic arthritis. Acta Paediatr

1994;83:428-32.[Medline]

Harel L, Wagner-Weiner L, Poznanski AK, et al. Effects of methotrexate on

radiologic progression in juvenile rheumatoid arthritis. Arthritis Rheum

1993;36:1370-4.[Medline]

Ravelli A, Viola S, Ramenghi B, et al. Radiologic progression in patients

with juvenile chronic arthritis treated with methotrexate. J Pediatr

1998;133:262-5.[CrossRef][Medline]

Jundt JW, Browne BA, Fiocco GP, et al. A comparison of low dose methotrexate

bioavailability: oral solution, oral tablet, subcutaneous and intramuscular

dosing. J Rheumatol 1993;20:1845-9.[Medline]

Ruperto N, Murray KJ, Gerloni V, et al. For the Paediatric Rheumatology

International Trials Organisation (PRINTO). A randomized trial of

methotrexate in medium versus higher doses in children with juvenile

idiopathic arthritis who failed on standard dose. Ann Rheum Dis 2002;61:60.

van Ede AE, Laan RF, Rood MJ, et al. Effect of folic or folinic acid

supplementation on the toxicity and efficacy of methotrexate in rheumatoid

arthritis: a forty-eight week, multicenter, randomized, double-blind,

placebo-controlled study. Arthritis Rheum

2001;44:1515-24.[CrossRef][Medline]

Ravelli A, Viola S, Ramenghi B, et al. Evaluation of response to

methotrexate by a functional index in juvenile chronic arthritis. Clin

Rheumatol 1995;14:322-6.[CrossRef][Medline]

Gottlieb BS, Keenan GF, Lu T, et al. Discontinuation of methotrexate

treatment in juvenile rheumatoid arthritis. Pediatrics

1997;100:994-7.[Abstract/Free Full Text]

Ravelli A, i A. Methotrexate in juvenile idiopathic arthritis: answers

and questions. J Rheumatol 2000;27:1830-3.[Medline]

Cleary AG, McDowell H, Sills JA. Polyarticular juvenile idiopathic arthritis

treated with methotrexate complicated by the development of non-Hodgkin's

lymphoma. Arch Dis Child 2002;86:47-9.[Free Full Text]

Milunsky A, Graef JW, Gaynor MF Jr. Methotrexate-induced congenital

malformations. J Pediatr 1968;72:790-5.[CrossRef][Medline]

Ostensen M, Hartmann H, Salvesen K. Low dose weekly methotrexate in early

pregnancy. A case series and review of the literature. J Rheumatol

2000;27:1872-5.[Medline]

Feldkamp M, Carey JC. Clinical teratology counseling and consultation case

report: low dose methotrexate exposure in the early weeks of pregnancy.

Teratology 1993;47:533-9.[CrossRef][Medline]

Speckmaier M, Findeisen J, Woo P, et al. Low-dose methotrexate in systemic

onset juvenile chronic arthritis. Clin Exp Rheumatol 1989;7:647-50.[Medline]

Rose CD, Singsen BH, Eichenfield AH, et al. Safety and efficacy of

methotrexate therapy for juvenile rheumatoid arthritis. J Pediatr

1990;117:653-9.[CrossRef][Medline]

Halle F, Prieur AM. Evaluation of methotrexate in the treatment of juvenile

chronic arthritis according to the subtype. Clin Exp Rheumatol

1991;9:297-302.[Medline]

Graham LD, Myones BL, Rivas-Chacon RF, et al. Morbidity associated with

long-term methotrexate therapy in juvenile rheumatoid arthritis. J Pediatr

1992;120:468-73.[CrossRef][Medline]

Huang JL. Methotrexate in the treatment of children with chronic

arthritis-long-term observations of efficacy and safety. Br J Clin Pract

1996;50:311-14.[Medline]

Singsen BH, Goldbach-Mansky R. Methotrexate in the treatment of juvenile

rheumatoid arthritis and other pediatric rheumatoid and nonrheumatic

disorders. Rheum Dis Clin North Am 1997;23:811-40.[CrossRef][Medline]