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Three Part Question

In [children with juvenile idiopathic arthritis] does [folate supplementation] counteract [the adverse side effects and/or effect the efficacy of methotrexate]?

Clinical Scenario

A 7 year old girl with sero-negative polyarticular juvenile idiopathic arthritis (JIA) has recently commenced weekly methotrexate (MTX). Within six months she develops painful apthous ulcerations, alopecia, and generalised gastrointestinal upset. Her hepatic transaminases (AST/ALT) are now raised. Her parents are obviously distressed and have read on the internet about the role of folate supplementation in counteracting the adverse side effects of MTX. They have also read however, that this beneficial effect may be at the expense of the efficacy of MTX. They ask you, the prescribing physician, if this additional medication is warranted, and if so in what form?

Search Strategy

Primary source: Medline via Pubmed
Secondary source: Cochrane Library
Pubmed:search terms "methotrexate" or "methotrexate efficacy" or " methotrexate toxicity", or " methotrexate side effects" and "juvenile arthritis" and "folinic acid supplementation" or "folic acid supplementation". Limits: all child: 0–18 years.

Search Outcome

Cochrane - nil relevant
Pubmed - 9 relevant

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Modesto et al, 1996	3 patients 2 SoJIA 1 Poly JIA Previous side effects Folinic acid (100%) MTX dose 4 hours after	Case series (level 4)	Resolution of side effects Disease flare	Gastrointestinal side effects Resolved in patients 1 and 2 Rash resolved patient 3 Flare of disease in all 3	Evidence very poor Folinic acid only
Ravelli et al, 1999	43 patients Ages 1.2–16 years Duration of JIA 0.5–8 years All previous toxic episode Folinic acid (25%–50%) MTX dose 24 hours after	Non-randomised retrospective case series (level 4)	Improvement of toxic episodes	Hepatic and gastrointestinal toxicity episodes reduced Mean 2.30 (CI 95% –2.21 to 11.23) to mean 0.32 (CI 95% –0.76 to 2.02) Mean 1.09 (CI 95% –2.29 to 6.57) to mean 029 (CI 95% –0.62 to 1.76)	Small numbers No control
			Episodes of disease flare	Mean 0.30 (CI 95% –0.57 to 1.74) to mean 0.36 (CI 95% –0.84 to 2.25) p value ns
			Clinical remission	Mean 0.17 (CI 95% –0.53 to 1.53) to mean 0.19 (CI 95% –0.65 to 1.39) p value ns
Hunt et al, 1997,	18 patients On MTX 6/12 or more Placebo versus 1 mg/kg/day folic acid	Randomised double blind crossover trial, 1 week washout (level 1b)	Disease flare (worsening of 2/5 clinical variables) Hepatic toxicity (AST/ALT levels)	No significant change in either treatment group No abnormal ASDT/ALT	Figures for baseline variables not given Study period very short.

Comment(s)

Methotrexate, a dihydrofolate reductase (DHR) inhibitor, is now the leading disease modifying antirheumatic drug (DMARD) used in the management of juvenile idiopathic arthritis. In a double blind, randomised controlled multicentre study, MTX was found to be efficacious in 63% (n = 127) of patients with resistant JIA, and it is now the standard first line agent in those with polyarticular disease(Giannini). Adverse reactions are generally mild and transient and it is generally well tolerated, much more so than in the adult population in whom approximately 30% will discontinue the drug one year after therapy is initiated(Alarcon). Estimates for common toxicities range from 5% to 21%, with nausea (21%), vomiting (11%), mouth sores (10%), loss of appetite (7.5%), cited most commonly and hair loss (5%), malaise (5%), elevated liver function tests (5%), and leucopenia (5%) less commonly(Ruperto). Toxicity has been suggested to be a result of an induced state of folate depletion(Morgan). The addition of folate has therefore been suggested to counteract the signs of toxicity, either as folic acid or the reduced form folinic acid which is able to function in biosynthetic pathways independent of DHR. Meta-analysis of seven trials assessing the benefits of folic and folate supplementation in rheumatoid arthritis (RA), clearly show a reduction in gastrointestinal and mucosal side effects(Ortiz). A randomised controlled study directly comparing folic acid to folinic acid in RA, showed no beneficial difference between the two forms of supplementation(Van Ede). Nevertheless, there is no consensus practise for folate supplementation in RA. The concern is that folate supplementation may have a detrimental effect on the therapeutic benefit of MTX. Folinic acid has been associated with a reduction in the effectiveness of MTX, thought to possibly be explained by competition between folinic acid and MTX for binding to cellular transport molecules(Joyce, Endresen). The same concerns exist for the paediatric population and where compliance is often an issue, any additional medication can be a great burden to the patient and family involved. With the exception of a small case series (three patients) examining weekly folinic acid, neither folic acid or folinic acid have shown any reduction in the benefit of methotrexate administration in JIA(Modesto). This effect however may have been as a result of a dosage effect. The folinic acid was administered at an equivalent dose to the methotrexate which is the dose required to reverse haematological toxicity. In terms of reducing MTX toxicity, there may be evidence for weekly folinic acid at 25–50% of the MTX dose in diminishing hepatic and gastrointestinal related toxicities(Ravelli). The mean number of episodes per patient-year of hepatotoxicity and gastrointestinal toxicity decreased significantly after the start of folinic acid supplementation. Folinic acid was also reported to have a favourable response in the small case series above(Modesto). As there was no reports of any MTX toxicity (hepatotoxicity measured only) in the study examining folic acid versus placebo, it is difficult to make any conclusion whether folic acid has any effect, beneficial or not(Hunt). The evidence for weekly folinic acid for diminishing MTX related toxicities is weak (grade 4) and limited. All three studies only address hepatic and gastrointestinal toxicity and no reference is made to other common toxicities such as mucositis. Despite the widespread and variable practise of prescribing folate supplementation to prevent or counteract MTX toxicity in JIA, to date there have been no trials comparing the efficacy of folic acid and folinic acid directly. No conclusions can be made regarding the effect of folate supplementation on methotrexate's efficacy in JIA. The effectiveness, form, and dosage of folate supplementation for treating or preventing MTX related toxicities, and whether it has any effect detrimental or not on methotrexate's efficacy, needs therefore to be urgently determined in a prospective, randomised, double blinded, placebo controlled trial.

References

1. 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 blinded placebo-controlled trial. The Pediatric Rheumatology Collaborative Study Group and The Cooperative Children's Study Group. N Engl J Med 1992;326:1043–9.
2. Alarcon GS, Tracy IC, Blackburn WD Jr. Methotrexate in rheumatoid arthritis. Toxic effects as the major factor in limiting long-term treatment. Arthritis Rheum 1989;32:671–6.
3. Ruperto N, Murray K. Gerloni V. et al. A randomised trial of parental methotrexate comparing an intermediate dose with a higher dose in children with juvenile idiopathic arthritis who failed to respond to standard doses of methotrexate. Arthritis Rheum 2004;50:2191–201.
4. Morgan SL, Baggott JE. Vaughan WH. et al. The effect of folic acid supplementation on the toxicity of low-dose methotrexate in patients with rheumatoid arthritis. Arthritis Rheum 1990;33:9–18.
5. Ortiz Z, Shea B, Suarez-Almazor ME. et al. The efficacy of folic acid and folinic acid in reducing methotrexate gastrointestinal toxicity in rheumatoid arthritis. A metaanalysis of randomised controlled trials. J Rheumatol 1998;25:36–43.
6. Van Ede AE, Laan RF, Rood MJ. et al. Effect of folic acid or folinic acid supplementation on the toxicity and efficacy of methotrexate in rheumatoid arthritis: a forty-eight week, multicenter, randomised, double blinded, placebo-controlled study. Arthritis Rheum 2001;44:1515–24.
7. Joyce DA, Will RK. Hoffman DM. et al. Exacerbation of rheumatoid arthritis in patients treated with methotrexate after administration of folinic acid. Ann Rheum Dis 1991;50:913–14.
8. Endresen GK, Husby G. Folate supplementation during methotrexate treatment of patients with rheumatoid arthritis. An update and proposals for guidelines. Scand J Rheum 2001;30:129–34.
9. Modesto C, Castro L. Folinic acid supplementation in patients with juvenile rheumatoid arthritis treated with methotrexate. J Rheumatol 1996;23:403–4.
10. Ravelli A, Migliavacca D, Viola S. et al. Efficacy of folinic acid in reducing methotrexate toxicity in juvenile idiopathic arthritis. Clin Exp Rheumatol 1999;17:625–7.
11. Hunt PG, Rose CD, McIlvain-Simpson. et al. The effects of daily intake of folic acid on the efficacy of methotrexate therapy in children with juvenile rheumatoid arthritis. A controlled study. J Rheumatol 1997;24:2230–2.