This is not the most recent version of the article. View current version (31 MAY 2013)

Intervention Review

Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis

  1. Zulma Ortiz1,*,
  2. Beverley Shea2,
  3. Maria E Suarez-Almazor3,
  4. David Moher4,
  5. George A Wells5,
  6. Peter Tugwell6

Editorial Group: Cochrane Musculoskeletal Group

Published Online: 25 OCT 1999

Assessed as up-to-date: 13 JUL 1999

DOI: 10.1002/14651858.CD000951


How to Cite

Ortiz Z, Shea B, Suarez-Almazor ME, Moher D, Wells GA, Tugwell P. Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. Cochrane Database of Systematic Reviews 1999, Issue 4. Art. No.: CD000951. DOI: 10.1002/14651858.CD000951.

Author Information

  1. 1

    National Academy of Medicine, Epidemiological Research Center, Buenos Aires, Federal Capital, Argentina

  2. 2

    University of Ottawa, Institute of Population Health, Ottawa, Ontario, Canada

  3. 3

    The University of Texas, M.D. Anderson Cancer Center, General Internal Medicine, Ambulatory Treatment and Emergency Care, Houston, Texas, USA

  4. 4

    Chalmers Research Group, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada

  5. 5

    University of Ottawa Heart Institute, Cardiovascular Research Reference Centre, Ottawa, Ontario, Canada

  6. 6

    University of Ottawa, Centre for Global Health, Institute of Population Health, Ottawa, Ontario, Canada

*Zulma Ortiz, Epidemiological Research Center, National Academy of Medicine, Conde 718 10 H, Pacheco de Melo 3081, Buenos Aires, Federal Capital, 1425, Argentina. zortiz@arnet.com.ar. zuortiz2001@yahoo.com.ar.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 25 OCT 1999

SEARCH

This is not the most recent version of the article. View current version (31 MAY 2013)

 

Abstract

  1. Top of page
  2. Abstract
  3. Plain language summary
  4. 摘要

Background

Methotrexate (MTX) is classified pharmacologically as an antimetabolite due to its antagonistic effect on folic acid metabolism. Although its mechanism of action is uncertain, it has become the second line drug of choice for many rheumatologists

Objectives

To assess the effects of folic acid and folinic acid in reducing the mucosal and gastrointestinal (GI) and haematologic side effects of low-dose of Methotrexate (MTX) in patients with Rheumatoid Arthritis (RA) and to determine whether or not folate supplementation alters MTX efficacy.

Search methods

We searched the Cochrane Controlled Clinical Trial's Register (CCTR), the Cochrane Musculoskeletal Group Specialized Register and MEDLINE up to and including June 1999, using the search strategy developed by the Cochrane Collaboration (Dickersin 1994).

We also handsearched the following: (i) bibliographic references; (ii) current contents of the last 6 months; (iii) abstracts of the rheumatology meetings; and (iv) all issues of four journals; Journal of Rheumatology, Arthritis & Rheumatism, Clinical and Experimental Rheumatology, and British Journal of Rheumatology.

All languages were included. Principal investigators were also contacted in order to look for unpublished literature.

Selection criteria

We selected all double-blind, randomized, placebo-controlled, clinical trials (RCTs), in which adult RA patients were treated with a low dose of MTX (<20 mg / week) concurrently with folate supplementation.

Data collection and analysis

Two observers extracted the data and assessed the quality of the trials. (BS, Z0) The overall treatment effect across trials was calculated using a fixed effect model. Disease activity was evaluated using standardized mean differences to ensure comparability across outcome measures. Results are presented with 95% Confidence Intervals (95% CI). Subgroup analyses were conducted evaluating different doses and sensitivity analysis looking at the quality of the trials. Publication bias was assessed with an inverted funnel plot technique. Heterogeneity of the trials was measured using a standard chi square test. Costs per month in different countries were compared.

Main results

Of the 12 trials retrieved, 7 met the inclusion criteria. The total sample included 307 patients, of which 147 were treated with folate supplementation, 80 patients with folinic acid and 67 patients with folic acid. A 79% reduction in mucosal and GI side effects was observed for folic acid [OR = 0.21 (95% CI 0.10 to 0.44)]. For folinic acid, a clinically but non-statistically significant reduction of 43% was found [OR = 0.57 (95% CI 0.28 to 1.15)]. No major differences were observed between low and high doses of folic or folinic acid. Haematologic side effects could not be analyzed, since details of each haematologic side effect by patients were not provided. No consistent differences in disease activity parameters were observed when comparing placebo and folic or folinic acid at low or high doses, although patients on high dose folinic acid had an increase in the number of tender joints, but not swollen joints. Large differences in costs across countries were found, but folinic acid was more expensive in all.

Authors' conclusions

The results support the protective effect of folate supplementation in reducing MTX side effects related to the oral and GI systems. We could not determine if folic was different from folinic acid. Therefore, for folinic acid to be considered cost-effective it must be found more effective than folic acid at reducing MTX side effects.

 

Plain language summary

  1. Top of page
  2. Abstract
  3. Plain language summary
  4. 摘要

Folic acid and folinic acid for reducing side effects in patients taking methotrexate for rheumatoid arthritis

This review included 7 trials of 307 patients, of which 147 were treated with folate supplementation, 80 patients with folinic acid and 67 patients with folic acid. A 79% reduction in mucosal and gastrointestinal (GI) side effects was observed for folic acid. For folinic acid, a clinically but non-statistically significant reduction of 43% was found. No major differences were observed between low and high doses of folic or folinic acid. Not enough information on blood disorder side effects was available to perform an analysis. No consistent differences in disease activity measures were observed when comparing patients taking placebo or folic or folinic acid at low or high doses, although patients on high dose folinic acid had an increase in the number of tender joints, but not swollen joints. Large differences in costs across countries were found, but folinic acid was more expensive in all.

The results support the protective effect of folate supplementation in reducing methotrexate (MTX) side effects related to the oral and GI systems. We could not determine if folic was different from folinic acid. Therefore, for folinic acid to be considered cost-effective it must be found more effective than folic acid at reducing MTX side effects.

 

摘要

  1. Top of page
  2. Abstract
  3. Plain language summary
  4. 摘要

背景

葉酸及folinic acid減少類風濕性關節炎患者使用Methotrexate (MTX)時的副作用

Methotrexate (MTX)為拮抗葉酸的抗代謝(antimetabolite)藥物,是許多風濕科醫師廣泛使用於治療免疫疾病的第二線藥物首選。

目標

評估葉酸及folinic acid對減少類風濕性關節炎患者使用低劑量Methotrexate (MTX)時的黏膜、胃腸、及血液副作用,及合併葉酸使用是否減少MTX的療效。

搜尋策略

搜尋包括Cochrane Controlled Clinical Trial's Register (CCTR), the Cochrane Musculoskeletal Group Specialized Register and MEDLINE (直到1999年6月),同時手動搜尋文章之參考文獻,風濕病會議摘要,及四個雜誌(Journal of Rheumatology, Arthritis & Rheumatism, Clinical and Experimental Rheumatology, and British Journal of Rheumatology)。並諮詢主要研究者以搜尋未發表之文獻。

選擇標準

研究所有包含低劑量Methotrexate (MTX < 20 mg/week)同時合併葉酸使用的隨機雙盲安慰劑對照試驗。

資料收集與分析

2個評論者分別評估試驗品質跟擷取數據,意見不一致者由兩者之共識決定,並使用固定效果模式計算治療效果。疾病活性以標準化差異評估,以保持結果評估的可比較性。次群分析藥物劑量的影響,敏感度分析評估研究品質對結果的影響。出版偏差以倒轉漏斗圖(inverted funnel plot)作為評估。異質性由卡方檢定評估。也比較不同國家每月使用的費用。

主要結論

12個摘錄研究中7篇符合選入條件。總共有307例病患包含於分析中,其中folate 147例及folinic acid 80例、葉酸67例。其中folic acid減少79% 的黏膜及胃腸副作用 [OR .21 (95% CI 0.10 to 0.44)]。Folinic acid臨床減少43% ,但統計上無顯著差異 [OR = 0.57 (95% CI 0.28 to 1.15)]。高劑量及低劑量folic或folinic acid並無重大差異。血液副作用因資料不足無法分析。比較安慰劑與高或低劑量folic或folinic acid時,疾病活性並無一致顯著差異;雖然高劑量folinic acid增加疼痛關節數,但並未增加腫脹關節數目。不同國家的每月使用費用差別極大,但皆以folinic acid較貴。

作者結論

根據上述之研究發現補充folate的確有降低因使用MTX所造成之口腔及胃腸道副作用。但無法區分folic與folinic acid的差異。

翻譯人

本摘要由林口長庚醫院余光輝翻譯。

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

無總結