Folic Acid and Folinic Acid for Reducing Side Effects in Patients Receiving Methotrexate for Rheumatoid Arthritis (Review)

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

Ortiz Z, Shea B, Suarez-Almazor ME, Moher D, Wells GA, Tugwell P

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 1999, Issue 4 http://www.thecochranelibrary.com

Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. TABLE OF CONTENTS HEADER...... 1 ABSTRACT ...... 1 PLAINLANGUAGESUMMARY ...... 2 BACKGROUND ...... 2 OBJECTIVES ...... 3 METHODS ...... 3 RESULTS...... 4 DISCUSSION ...... 5 AUTHORS’CONCLUSIONS ...... 6 ACKNOWLEDGEMENTS ...... 6 REFERENCES ...... 7 CHARACTERISTICSOFSTUDIES ...... 9 DATAANDANALYSES...... 15 WHAT’SNEW...... 17 HISTORY...... 17 DECLARATIONSOFINTEREST ...... 17 SOURCESOFSUPPORT ...... 17 INDEXTERMS ...... 17

Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis (Review) i Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. [Intervention Review] Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis

Zulma Ortiz1, Beverley Shea2, Maria E Suarez-Almazor3, David Moher4, George A Wells5, Peter Tugwell6

1Epidemiological Research Center, National Academy of Medicine, Buenos Aires, Argentina. 2Institute of Population Health, University of Ottawa, Ottawa, Canada. 3General Internal Medicine, Ambulatory Treatment and Emergency Care, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas, USA. 4Chalmers Research Group, Children’s Hospital of Eastern Ontario Research Institute, Ottawa, Canada. 5Cardiovascular Research Reference Centre, University of Ottawa Heart Institute, Ottawa, Canada. 6Centre for Global Health, Institute of Population Health, University of Ottawa, Ottawa, Canada

Contact address: Zulma Ortiz, Epidemiological Research Center, National Academy of Medicine, Conde 718 10 H, Pacheco de Melo 3081, Buenos Aires, Federal Capital, 1425, Argentina. [email protected]. [email protected].

Editorial group: Cochrane Musculoskeletal Group. Publication status and date: Edited (no change to conclusions), published in Issue 1, 2009. Review content assessed as up-to-date: 13 July 1999.

Citation: 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.

ABSTRACT

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.

Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis (Review) 1 Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 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

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.

BACKGROUND studies, showing short-term clinical improvement in 48% to 90% of RA patients (Tugwell 1987, Tugwell 1989), and from 10% Methotrexate (MTX) is classified pharmacologically as an an- to 70% in placebo-controlled studies (Williams 1985, Weinblatt timetabolite due to its antagonistic effect on folic acid metabolism. 1985, Thompson 1984, Anderson 1985). Two meta-analyses Although its mechanism of action is uncertain, it has become (Tugwell 1987, Felson 1990) estimate that a third of the patients the second line drug of choice for many rheumatologists (Kremer show a major improvement. Felson also compared the benefit- 1995). The evidence for its efficacy at least over the short term toxicity trade offs of various second-line drugs and ranked MTX is well documented. MTX has proven efficacious in observational

Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis (Review) 2 Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. ahead of azathioprine, sulfasalazine, gold salts and penicillamine Types of studies (Felson 1992). However, toxicity does prevent many patients from All Double-blind, randomized, placebo-controlled clinical trials obtaining benefit from the drug. It has been reported that mild toxicity occurs in about 60% of patients, and roughly 7% to 30% of patients discontinue MTX therapy within the first year of treat- Types of participants ment due to toxicity (Schnabel 1994, Kremer 1992). Patients older than 18 years, who fulfilled the American Rheuma- Dose and length of exposure both influence toxicity from MTX tism Association’s criteria for RA (Arnett 1988) (Wallace 1995). Other predisposing factors include folate deficiency, advanced age, cumulative dose, renal insufficiency and con- Types of interventions comitant use of other antifolates (Jackson 1984). Depleted intra- cellular folate levels have been documented in hepatocytes and Treatment with low doses of MTX (<20 mg / week) concurrently peripheral blood lymphocytes of MTX treated patients (Stenger with folate supplementation 1992, Morgan 1991, Kremer 1986, Leeb 1995, Morgan 1987, Stewart 1991). Folate deficiency occurs frequently in patients with Types of outcome measures RA, and folate stores are further decreased in patients with RA who receive MTX (Leeb 1995). Results reported on at least one of the two main areas of concern regarding gastro intestinal toxicity and/or haematologic side ef- Gastrointestinal and haematologic side effects have been related to fects, and the beneficial effects of MTX. folate deficiency. Therefore, it could be expected that folate supplementation would be useful in reducing side effects associated with low dosage MTX therapy. There has been concern neverthe- Search methods for identification of studies less that folates may reduce the benefit seen with MTX, if the antirheumatic effects are also mediated through folate antagonism. It To identify trials of supplementation with folic acid or folinic acid has been suggested that since the mechanism of action of MTX in during MTX therapy for RA, we performed MEDLINE searches, RA is not known, the beneficial effect of folate supplementation from January 1966 to June 1999. We also searched the Controlled could be a result of the relative reduction of the dose of MTX Clinical Trials Register (CCTR) Issue 2, 1999 and the Cochrane (Stenger 1992). Several open prospective studies and RCTs have Musculoskeletal Group’s specialized register. We used the strategy been conducted to determine if folate supplementation, with folic developed by the Cochrane Collaboration as well as the search acid or folinic acid, has a beneficial effect in reducing the fre- adopted and modified for the Cochrane Musculoskeletal Group quency and severity of MTX side effects, with minimum inhibi- (Dickersin 1994). tion of therapeutic benefit. These studies have produced varying This computer search was complemented by the following hand estimates of the reduction in adverse effects, ranging from 0% to searches: (i) bibliographic references, (ii) current contents from 50%. Clinicians and patients need to have a “best-estimate” to June to December 1996, (iii) abstracts of the following rheumatol- make informed decisions on whether to use folate supplementa- ogy meetings from 1993 to 1996: American College of Rheuma- tion; therefore, a meta-analysis was undertaken using the approach tology, International League Against Rheumatism, British College recommended by the Cochrane Collaboration. of Rheumatologist, Canadian College of Rheumatologist, and Eu- ropean League Against Rheumatism, (iv) all issues of four journals; Journal of Rheumatology, Arthritis & Rheumatism, Clinical and Experimental Rheumatology, and British Journal of Rheumatol- OBJECTIVES ogy from January 1992 to April 1996. To determine the efficacy of folic acid and folinic acid to reduce All languages were included. gastrointestinal and haematologic side effects of low-dose of MTX Principal investigators were contacted, to seek unpublished liter- in patients with RA . ature.

Todetermine if folate supplementation alters the efﬁcacy of MTX. Data collection and analysis Data extraction METHODS Data were independently extracted by two observers (BS, ZO) and cross-checked. Folate supplementation was considered as - “the administration of folic or folinic acid in any dose, and at any time Criteria for considering studies for this review with respect to MTX”. The following gastrointestinal effects were combined because of lack of consistency in the reporting and to

Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis (Review) 3 Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. obtain sufficient events for analysis: stomatitis, abdominal com- RESULTS plaints, anorexia, nausea, vomiting, dyspepsia diarrhea, and con- stipation. Liver enzymes levels were analysed both independently as well as by including them with the other gastrointestinal effects. Description of studies The following haematologic side effects were included: cytopenia, macrocytosis, and pancytopenia. See: Characteristics of included studies; Characteristics of excluded To assess changes in disease activity, the following measurements studies. were considered a priori: swollen joint count, tender joint counts, A total of 12 trials were obtained. From the electronic search we ob- pain, disability score, grip strength, patient’s global assessment and tained seven (Buckley 1990, Hanrahan 1988, Joyce 1991, Morgan physician’s global assessment. Most trials reported swollen and ten- 1990, Morgan 1994, Shiroky 1993, Weinblatt 1993), from the der joint counts, or indices, and patient global assessments. These hand search two additional RCTs identified as abstracts from dif- were the outcomes finally included for the MTX efficacy analysis. ferent meetings, and two from hand searching bibliographic refer- Joint counts included the number of swollen and tender joints if ences. Seven RCTs met the eligibility criteria. The other six (two reported. Alternatively, when the number of involved joints was abstracts and four articles) were excluded: two abstracts were pub- not reported, indices (e.g. Ritchie index) were included. Data on lished as full length publications, one trial was not double-blind, pain, disability and physician global assessments were not con- one was uncontrolled and two did not include the outcomes of sistently reported across trials and were therefore not pooled for interest. One RCT evaluated two different doses of folic acid and summary estimates. was considered as two separate trials for this meta-analysis. Statistical analysis: All of the RCTs included in the analysis assessed haematologic Since folic and folinic acid do not appear to act at the same point side effects with a complete blood cell count including platelet on the folate pathway, they were analyzed separately. For side ef- count. Some trials also included mean corpuscular volume. Five of fects, the overall treatment effect across trials was calculated using a 7 trials reported the results as “there was no statistically significant fixed effect model [Peto model (Petitti 1994)]. The trials included difference in the frequency of haematologic side effects between in this review used different indices to evaluate changes in disease folate group and placebo group.” Hence, they did not report the activity. For instance, different total numbers of joints were con- number of patients with haematologic side effects, mean values, or sidered and global assessments were measured with various scales. measures of variance; they could not be included in the analysis. To enhance comparability across trials all the disease activity out- Overall, the included trials reported 307 patients, of which 147 come variables (joint counts and patient global assessments) were were treated with folinic (80 patients) or folic acid (67 patients). compared using standardized mean differences between treatment (folic or folinic acid) and placebo groups. The standardized mean differences were based on end-of-trial results. When appropriate, Risk of bias in included studies the standardized mean differences were pooled by applying the inverse of the variance of each trial as a weight. Additional data The quality of the randomized controlled trials (RCTs) was as- was obtained from the authors for one of the studies. Another sessed by two observers (BS, ZO) using a validated scale (Jadad study did not report any measures of dispersion. The end-of-trial 1996). This scale consists of three items pertaining to descriptions variance for this study was estimated using the mean coefficient of randomization, double-blinding, dropouts and withdrawals as of variation of the other trials weighted by the sample size of each described in the report of a RCT. The scale ranges from zero to five study. The pooled estimates were calculated using Revman 3.0. (two points each for randomization and double-blinding, and one The analysis was conducted separately for folic and folinic acid, point for withdrawals), with higher scores indicating superior re- high vs. low dose. porting. Interobserver agreement was measured using kappa [val- Sensitivity analysis using the median quality score (3.5) as a cut- ues between 0.60-0.80 indicate substantial strength of agreement, off value to define lower and higher quality was performed. A higher than 0.81 is almost perfect (Landis 1977)]. dose of 5 mg/wk was selected as the cut off value to compare high The median quality score of the included trials was 3.5, the in- vs low doses. Heterogeneity of the trials was measured using a terobserver agreement measured with kappa was equal to 0.81. standard chi square test on N degrees of freedom, where N equals Discussion resolved disagreements. the number of trials contributing data minus one. We also assessed the existence of publication bias using the inverted funnel plot technique. Effects of interventions When all of the included trials were pooled, there was no statis- We looked at the costs per month of folic acid and folinic acid tically significant heterogeneity (chi-square= 6.38). A significant in four different countries: Argentina, Canada, United States, and reduction in the odds of gastrointestinal side effects of 79% [OR= United Kingdom. 0.21 (95% CI 0.10 to 0.44) p< 0.0001] was observed. With folinic

Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis (Review) 4 Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. acid, a clinically but non-significant reduction of 43% was found DISCUSSION [OR = 0.57 (95% CI 0.28 to 1.15 p=0.12)]. The purpose of this study was to conduct a systematic review of Sensitivity analyses evaluating the quality of the trials showed a folate supplementation of low dose MTX therapy in patients with significant reduction of 70% [OR = 0.30 (95% CI 0.16 to 0.55), RA. Only those studies contributing high quality evidence (RCTs) p< 0.0001] for the RCTs with the highest quality, and a non were reviewed. The results clearly support the protective effect of significant reduction of 43% [OR = 0.57 (95% CI 0.22 to 1.50), folate supplementation in reducing MTX mucosal and GI side p= 0.24] for the RCTs with lower scores. effects. Although haematologic side effects could not be analyzed, Subgroup analyses using different doses showed that for a dose of five trials reported no significant differences between RA patients folic acid or folinic acid 5 mg/wk or less, there was a significant who received folate supplementation or placebo. The incidence reduction of GI side effects of 80% [OR= 0.20 (95% CI 0.08 to of clinically important cytopenia in RA patients treated with low- 0.48) p< 0.0001]. With a dose higher than 5 mg / wk the reduction, dose MTX is less than one percent (Canadian Pharmaceuticals although clinically important was not statistically significant [OR= Association 1996), and the size of a trial required to detect any dif- 0.55 (95% CI 0.24 to 1.29) p= 0.17]. In the trial by Buckley ferences would be enormous. Three studies reported the number 1990 patients received folinic acid at a dose equivalent in mg to of patients with increased levels of liver enzymes. Overall only 5 their MTX dose. The mean MTX dose was 9.9 mg/wk (5-15 mg/ patients had high levels and no patient developed clinically signif- wk) suggesting that most patients were in the high dose range for icant liver disease; however, the duration of MTX administration folinic acid. Since the side effects were not reported separately for was too short to draw meaningful conclusions. The pooled results patients above and below 5 mg/wk, we analyzed this trial both as a of the meta-analysis did not change with the inclusion or exclu- high dose and a low dose study. The overall results did not change sion of these patients. Subgroup analysis suggested lower rates of substantially. mucosal and GI side effects in: (i) patients receiving folic acid The standardized mean differences in disease activity between compared with those on folinic acid, (ii) patients on lower doses placebo or folate supplementation were analyzed. Three trials of folic/folinic acid, and (iii) the larger studies. However, sample started supplementation at the onset of MTX therapy, so the ex- size may be a confounding variable since only one study in the pected result assuming no effects on MTX efficacy would be an folinic acid group entered more than 40 patients per group. The improvement in disease activity parameters. The other trials added results of sensitivity analyses of the quality scores are interesting folate supplementation to established MTX regimens so marked wherein the benefit was greater for trials with higher quality. Sev- differences in disease activity during the duration of the trial would eral authors (Dijkmans 1995, Borigini 1995, Furst 1994) have not be expected. The results were analyzed separately for folic and reported that the inverse is usually true, with lower quality studies folinic acid high and low doses, since the potential detrimental showing greater benefits suggesting biases from poor design. The effect of folate supplementation has only been reported for high finding of a trend in the opposite direction in this meta-analysis is dosages of folinic acid. No significant differences were observed reassuring and indicates the likely validity of the reduction of side between placebo and folic or folinic acid at low dosages. For a high effects from folate co-administration. dose of folinic acid, an increase in the number of tender joints was observed (standardized mean difference 0.61). This was not A concern with meta-analysis is the potential existence of pub- observed for the number of swollen joints or patient global assess- lication bias. It is possible that some trials have been completed ment. that found no benefit of folate supplementation as evidenced by The Funnel plot analysis suggested the existence of publication the funnel plot results. It is difficult to be more definitive about bias. Readers should interpret this statement cautiously as there publication bias in this review but it is unlikely that we would be were only seven trials included in the meta-analysis. unaware of negative studies of sufficient size to eliminate the ben- Costs efit seen in this meta-analysis. There would need to be 30 trials of Costs of folic and folinic acid were converted to 1996 American a sample size of 40 patients showing no effect (OR = 1) included dollars for the following countries: Argentina, Canada, the United in this analysis to reduce the size of the benefit to above 0.80 (less States and the United Kingdom (UK). The cost of folic acid is than 20% reduction in adverse effects). lower than folinic acid in all countries. In Canada the cost for folic Two studies have suggested that high dose folinic acid supplemen- acid is $0.006 for each 5 mg tablet and approximately $3.60 for tation may reduce the beneficial effects of MTX on RA. The first each 5mg tablet of folinic acid resulting in a 600 fold increase in one is not a double blind RCT and was therefore not included in costs. In the United Kingdom the price for 5 mg is $0.5, with a our meta-analysis. Timing of administration of folinic acid and price ratio folinic/folic of 11. In the United States the costs for 5 MTX, as well as the folinic acid to MTX ratio may alter the effi- mg of folic acid is $0.01 and for 5 mg folinic acid approximately cacy of MTX. There are no indications so far that folic acid may $1.50 with a folinic/folic ratio of 150. In Argentina 5 mg of folic alter the efficacy of MTX, despite a folic acid to MTX ratio in acid cost $0.25 vs. $2.5 for folinic acid resulting in a ratio of 10. some trials higher than the folinic acid to MTX ratio used in the study by Joyce et al., which suggested a decrease in MTX efficacy.

Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis (Review) 5 Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. We did not find any major differences in disease activity changes be considered. between placebo and folic acid at low or high dosages. No statistical differences were observed for low dose folinic acid. For higher dosages a difference was observed for number of tender joints, A major problem in synthesising evidence is the lack of uniformity but not other variables. These results were mostly driven by the in outcome measures. In 1994, during the Conference on Out- study by Joyce et al., and in our view are still non-conclusive. Our come Measures in Rheumatoid Arthritis Clinical Trials (OMER- results support the protective effects of folate supplementation in ACT), determined that a core set of toxicity measures needed to reducing mucosal and GI side effects of MTX in RA patients. be established for antirheumatic drugs. This set will allow to com- Low doses appear adequate in view of the statistical significance, pare data across all trials, with accurate meta-analyses of toxic- the higher quality, and the larger sample sizes in the trials evalu- ity (Brooks 1995). Published Guidelines also urge investigators to ating lower dosages. This is consistent with the recommendations provide simple tabulation of the incidence of adverse events per by some authors (Weinblatt 1993, Morgan 1993, Shiroky 1993, patient, even where indices are used, to allow the reader to un- Drummond 1995). Deciding which of the two forms of folate derstand how the index was computed and the extend to which supplementation should be recommended is more difficult. Ex- more patients had single or multiple adverse experiences. We also perts have differing recommendations, often acknowledging that encourage investigators to describe fully the numbers and flow of there is insufficient evidence for advising the use of one compound patients by treatment groups throughout the trial, and to clearly over the other (Schnabel 1994, Salach 1994, Dijkmans 1995, Bo- report the reasons for dropouts for each group. This meta-analysis rigini 1995, Furst 1994, Weinblatt 1993). There is no evidence to was hampered by lack of uniformity in the way these items were date of a significant difference between folic or folinic acid. The reported. results in this meta-analysis were less impressive for folinic acid, In summary, low doses of folic acid supplementation a 80% re- but 4 of the five studies had small sample sizes; the larger study duction of mucosal and GI side effects. The results of our review by Shiroky did show a benefit. Furthermore, the folinic acid trials do not suggest any clear advantages with higher dosages of folic showed statistically significant heterogeneity, which could be re- acid or with the use of folinic acid, since for folinic acid to be con- lated to the different duration and drug regimes of the trials. This sidered more cost-effective it must be found to be more effective heterogeneity decreases the robustness of the findings for folinic than folinic acid at reducing MTX side effects. acid. No direct head-to-head comparison of the two formulations has been published.

Given both the efficacy of folic acid in reducing MTX side ef- AUTHORS’ CONCLUSIONS fects and its comparatively low costs, the use of low-dose folic acid is likely to be a cost-effective therapy. However, it is unclear Implications for practice whether folinic acid would be cost-effective, given its higher cost. Our results support the protective effects of low doses of folate For folinic acid to be considered cost-effective it must be found supplementation in reducing mucosal and GI side effects of MTX more effective than folic acid at reducing MTX gastrointestinal in RA patients. side effects. Thus, it is desirable that any future trial comparing folic acid to folinic acid includes a cost-effectiveness evaluation. Implications for research The cost ratio of folinic relative to folic acid varies across countries, so the additional benefit in reducing side effects needed to A multicentre RCT comparing both folate compounds and in- make folinic acid cost-effective will vary across countries as has cluding an economic analysis may be necessary to adequately as- been demonstrated for sess potential differences between both drugs. other rheumatologic drugs such as non-steroidal anti-inflamma- tory drugs (Drummond 1995). ACKNOWLEDGEMENTS It is unclear whether all patients on MTX, or only those with side effects, should receive folate supplementation. This systematic re- We would like to acknowledge Drs. S Morgan and G. Alarcón for view cannot address this issue. At face value, it may be proposed providing additional data needed to perform the meta-analysis. that only patients with clear side effects will benefit from supple- We are also thankful to Drs. G. Alarcón and J. Shiroky for their mentation. Yet, the effects of folic or folinic acid on the develop- comments in relation to the initial draft of the review. We would ment of liver disease are unknown. It has been suggested that sup- also like to thank the editors of the Cochrane Musculoskeletal plementation may have a protective effect on the development of Group and the facilitators of the rheumatoid arthritis subgroup liver disease, in which case universal administration could perhaps for their comments on this review.

Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis (Review) 6 Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. REFERENCES

References to studies included in this review Dose Methotrexate Therapy for Rheumatoid Arthritis: Implications for Cardiovascular Disease Prevention. J Buckley 1990 {published data only} Rheumatol 1998;25:441–446. Buckley L, Vacek P,Cooper S. Administration of folinic acid Stewart 1991 {published data only} after low dose methotrexate in patients with rheumatoid Stewart K. , Mackenzie A., Clough J., Wilke W. Folate arthritis. J Rheumatol 1990;17:1158–61. supplementation in methotrexate-treated rheumatoid Hanrahan 1988 {published data only} arthritis patients. Semin Arthritis Rheum 1991;20(5): Hanrahan P, Russell A. Concurrent use of folic acid and 332–338. methotrexate in rheumatoid arthritis. J Rheumatol 1988;15: Tishler 1988 {published data only} 1078–80. Tishler M, Caspi D, Fishel B, Yaron M. The effects Joyce 1991 {published data only} of leucovorin (folinic acid) on methotrexate therapy in Joyce D, Will D, Hoffman D, Laing B, Blackbourn S. rheumatoid arthritis patients. Arthritis Rheum 1988;31(7): Exacerbation of rheumatoid arthritis in patients treated 906–08. with methotrexate after administration of folinic acid. Ann Weinblatt 1992 {published data only} Rheum Dis 1991;50:913–4. Weinblatt M. , Maier A., Coblyn J. Low dose leucovorin Morgan 1990 {published data only} plus methotrexate (MTX) in rheumatoid arthritis (RA): an Morgan SL, Baggott J, Vaughn W, Young P, Austin J, eight week placebo controlled randomized trial. [Abstract]. Krumdieck C, Alarcon S. G. The effect of folic acid Arthritis Rheum 1992, (suppl):S340. supplementation on the toxicity of low-dose methotrexate in patients with rheumatoid arthritis. Arthritis Rheum 1990; Additional references 33(1):9–18. Anderson 1985 Morgan 1994 {published data only} Andersen P. , West S., O’Dell J., et al. Weekly pulse Morgan S, Baggot J, Vaughn W, et al.Supplementation methotrexate in rheumatoid arthritis. Clinical and with folic acid during methotrexate therapy for rheumatoid immunologic effects in a randomized, double-blind study. arthritis. A double-blind, placebo controlled trial. Ann Int Ann Int Med 1985;103:489–96. Med 1994;121(11):833–41. Arnett 1988 Shiroky 1993 {published data only} Arnett F. , Edworthy S., Bloch D., et al. The American Shiroky J, Neville C, Esdaile J, et al.Low dose methotrexate Rheumatism Association 1987 revised criteria for the with leucovorin (folinic acid) in the management of classification of rheumatoid arthritis. Arthritis Rheum 1988; rheumatoid arthritis. Results of a randomized, double- 31:315–324. blind, placebo controlled trial. Arthritis Rheum 1993;36(3): 795–803. Brooks 1995 Brooks P. , Day R. Toxicity of antirheumatic drugs. J Weinblatt 1993 {published data only} Rheumatol 1995;22(5):998–990. Weinblatt M, Maier A, Coblyn J. Low dose leucovorin does not interfere with the efficacy of methotrexate in Detsky 1992 rheumatoid arthritis: an 8 weeks randomized placebo Detsky A. , Naylor D., O’Rourke K., McGeer A., L’Abbé controlled trial. J Rheumatol 1993;20:950–2. K. Incorporating variations in the quality of individual randomized trials into meta-analysis. J Clin Epidemiol 1992; References to studies excluded from this review 45(3):255–265. Andersen 1997 {published data only} Dickersin 1994 Andersen LS, Hansen EL, Knusdsen JB, Wester JU, Hansen Dickersin K. , Scherer R., Lefebvre C. Identifying relevant GVO, Hansen TM. Propectively Measured Red Cell Folate studies for systematic reviews. BMJ 1994;309:1286–91. Levels in Methotrexate Treated Patients with Rheumatoid Dijkmans 1995 Arthritis: Relation to Withdrawal and Side Effects. J of Dijkmans B. Folate supplementation and methotrexate. BJ Rheum 1997;24(5):830–837. Rheumatol 1995;34:1172–74. Canadian Group 1992 {unpublished data only} Drummond 1995 The Canadian Leucovorin Study Group. Low dose Drummond M. , Bosi Ferraz M., Mason J. Assessing the methotrexate with leucovorin in the management of cost effectiveness of NSAID: an international perspective. J rheumatoid arthritis. [Abstract]. Arthritis Rheum 1992; Rheumatol 1995;22(7):1408–1414. (suppl);39. Felson 1990 Morgan 1998 {published data only} Felson D. , Anderson J., Meenan R. The comparative Morgan SL, Baggott JE, Lee JY, Alarcon GS. Folic Acid efficacy and toxicity of second-line drugs in rheumatoid Supplementation Prevents Deficient Blood Folate Levels arthritis. Results of two meta-analyses. Arthritis Rheum and Hyperhomocysteinemia During Longterm, Low 1990;33(10):1449–1461.

Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis (Review) 7 Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Felson 1992 Morgan 1991 Felson D. , Anderson J., Meenan R.: Use of short-term Morgan S. , Baggot J., Refsum H, Ueland P. Homocysteine efficacy/toxicity tradeoffs to select second-line drugs in levels in patients with rheumatoid arthritis treated with low- rheumatoid arthritis: A meta-analysis of published clinical dose methotrexate. Clin Pharmacol Therapeutics 1991;50: trials. Arthritis Rheum 1992;35:1117–1125. 547–56. Furst 1994 Morgan 1993 Furst D. , Clements P. Pharmacological approaches. Morgan S. , Alarcón G., Krumdieck C. Folic acid SAARDs- II. In: Klippel JH, Dieppe PA, eds Rheumatology. supplementation during methotrexate therapy: it makes St. Louis: C.V. Mosby, 1994:13. 13.1–8. sense [Editorial]. J Rheumatol 1993;20(6):929–930. Petitti 1994 Hine 1990 Petitti D. Meta-analysis, decision analysis, and cost- Hine R. , Alarcon G., Koopman W., et al. Serum folates effectiveness analysis: methods for quantitative synthesis in (FA) levels of rheumatoid arthritis (RA) patients treated medicine. 90–114. with methotrexate (MTX) or other disease-modifying antirheumatic drugs (DMARDs) [Abstract]. Arthritis Salach 1994 Rheum 1990;33:S60. Salach R. , Cash J. Methotrexate: The emerging drug of choice for serious rheumatoid arthritis. Clin Therapeutics Jackson 1984 1994;16(6):912–922. Jackson R. Biological effects of folic acid antagonists with Schnabel 1994 antineoplastic activity. Pharmacol Ther 1984;25:61–82. Schnabel A. , Gross Wl. Low-dose methotrexate in Jadad 1996 rheumatic diseases: efficacy, side effects and risk factors for Jadad A. , Moore A., Carrol D., et al. Assessing the side effects. Semin Arthritis Rheum 1994;23:310–27. quality of reports of randomized clinical trials: is blinding Shiroky 1997 necessary?. Controlled Clinical Trials 1996;17:1–12. Shiroky JB. The use of folates concomitantly with low-dose Jenicek 1989 pulse methotrexate. Rheum Dis Clin North Am. 1997;23 Jenicek M. Meta-analysis in medicine. Where we are and (4):969–980. where we want to go. J Clin Epidemiol 1989;42(1):35–44. Stenger 1992 Stenger A. , Houtman P., Bruyn G. Does folate Kremer 1986 supplementation make sense in patients with rheumatoid Kremer J. , Galivan J., Streckfuss A., Kamen B. Methotrexate arthritis treated with methotrexate?. Ann Rheum Dis 1992; metabolism analysis in blood and liver of rheumatoid 51:1019–20. arthritis patients. Association with hepatic folate deficiency and formation of polyglutamates. Arthritis Rheum 1986;29: Thompson 1984 832–34. Thompson R. , Watts C., Edelman J., et al. A controlled two-centre trial of parenteral methotrexate therapy for Kremer 1995 refractory rheumatoid arthritis. J Rheumatol 1984;11: Kremer J. The changing face of therapy for rheumatoid 760–63. arthritis. Rheum Dis Clin N Am 1995 (August);21(3): Tugwell 1987 845–52. Tugwell P. , Bennett K., Gent M. Methotrexate in Landis 1977 rheumatoid arthritis. Ann Int Med 1987;107:358–366. Landis R. , Koch G. The measurement of observer Tugwell 1989 agreement for categorical data. Biometrics 1977;33: Tugwell P. , Bennett K., Gent M. Methotrexate in 159–174. rheumatoid arthritis. Feedback on American College of Moher 1995 Physicians guidelines. Ann Int Med 1989;110:581–583. Moher D. , Jadad A., Nichol G., Penman M., Tugwell P., van Ede 1998 Walsh S. Assessing the quality of randomized controlled van Ede AE, Laan RFJ<, Blom HJ, De Abreu RA, van trials: an annotated bibliography of scales and checklists. de Putte, LBA. Methotrexate in rheumatoid arthritis: an Controlled Clin Trials 1995;16:62–73. update with focus on mechanisms involved in toxicity. Moher 1996 Semin Arthritis Rheum. 1998;27(5):277–292. Moher D. , Jadad A., Tugwell P. Assessing the quality of Wallace 1995 randomized controlled trials. Current issues and future Wallace C. , Sherry D. A practical to avoidance of directions. Intl J of Technology Assessment in Health Care methotrexate toxicity.[Editorial]. J Rheumatol 1995; 22 (6); 1996;12(2):195–208. 1009-1012. Morgan 1987 Weinblatt 1985 Morgan S. , Baggot J. Altz-Smith M. Folate status of Weinblatt M. , Coblyn J., Fox D., et al. Efficacy of low- rheumatoid arthritis patients receiving long-term, low-dose dose methotrexate in rheumatoid arthritis. N Engl J Med methotrexate therapy. Arthritis Rheum 1987;30:1348–56. 1985;312:818–22.

Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis (Review) 8 Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Williams 1985 Williams H. , Wilkens R., Samuelson C., et al. Comparison of low-dose oral pulse methotrexate and placebo in the treatment of rheumatoid arthritis. A controlled clinical trial. Arthritis Rheum 1985;28:721–730. ∗ Indicates the major publication for the study

Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis (Review) 9 Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. CHARACTERISTICSOFSTUDIES

Characteristics of included studies [ordered by study ID]

Buckley 1990

Methods Randomized controlled , double-blind, clinical trial . A crossover study design.

Participants Twenty patients, 7 males and 13 females, with RA, older than 18 years, treated with low dose of MTX (less than 20 mg/week), were included into a 48-week trial

Interventions Patients were randomized to receive either folinic acid or placebo weekly for 24 weeks, then they were crossed over to receive the alternate treatment. The dose of FNA was about equal to the dose of MTX, between 5 and 15 mg/week. The mean dose of MTX was 9.9 mg/ week

Outcomes The reduction of MTX toxicity (gastrointestinal and haematologic side effects) and the reduction of MTX efﬁcacy (joint count, 50’walk time, grip strength, rheumatoid factor, ESR, patient and physician assessment, a questionnaire asking patient to self rate fatigue and pain on a scale from 0-3, and to report the duration of morning stiffness)

Notes Quality score= 4

Risk of bias

Item Authors’ judgement Description

Allocation concealment? Yes A - Adequate

Hanrahan 1988

Methods Randomized controlled , double-blind, clinical trial . A crossover study design.

Participants Thirteen patients, 7 males and 6 females, with RA, older than 18 years, treated with low dose of MTX (less than 20 mg/week), were included into a 8-week trial

Interventions Patients were randomized to receive either FNA or placebo weekly for 4 weeks, then they were crossed over to receive the alternate treatment. The dose of FNA was 20 mg/week. The mean dose of MTX was 18.5 (5-25) mg/ week

Outcomes The reduction of MTX GI side effects

Notes Quality score= 2

Risk of bias

Item Authors’ judgement Description

Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis (Review) 10 Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Hanrahan 1988 (Continued)

Allocation concealment? Yes A - Adequate

Joyce 1991

Methods Randomized controlled , double-blind, clinical trial. A parallel study design.

Participants Twenty-seven patients, (13/14 placebo/control respectively) with RA, older than 18 years, treated with low dose of MTX (less than 20 mg/week), were included into a 12 week trial. The mean age was 59.8 and 62.8 years for the folinic acid and placebo group respectively

Interventions Patients were randomized to receive either FNA or placebo weekly for 12 weeks. The dose of FNA was 15 mg/week. The mean dose of MTX was 7.9 mg/week (7.3-8.5 mg/week)

Outcomes The reduction of MTX toxicity (gastrointestinal and haematologic side effects) and the reduction of MTX efﬁcacy (Ritchie index, joint pain (VAS), patient global assessment, and the duration of morning stiffness)

Notes Quality score= 3

Risk of bias

Item Authors’ judgement Description

Allocation concealment? Yes A - Adequate

Morgan 1990

Methods Randomized controlled, double-blind, clinical trial. A parallel study design.

Participants Thirty-two patients (16/16 placebo/control respectively) with RA, older than 18 years, treated with low dose of MTX (less than 20mg/week), were included into a 24-week trial. Six males, 26 females, with a mean age of 52.0 and 50.9 years for the folic acid and placebo group respectively

Interventions Patients were randomized to receive either FA 1mg/d or placebo for 24 weeks. The median dose of MTX was 7.5 mg/week (2.5-15 mg/week)

Outcomes The reduction of MTX toxicity (gastrointestinal and haematologic side effects) and the reduction of MTX efﬁcacy (swelling joint count, tenderness joint count, joint swellin index, joint tenderness index, joint pain (VAS), patient global assessment of disease activity, the duration of morning stiffness, grip strength

Notes Quality core=3

Risk of bias

Item Authors’ judgement Description

Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis (Review) 11 Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Morgan 1990 (Continued)

Allocation concealment? Yes A - Adequate

Morgan 1994

Methods Randomized controlled double-blind, clinical trial. A parallel study design.

Participants Seventy-nine, 20 males and 59 females, with RA older than 18 years, treated with low dose of MTX (less than 20 mg/week), were included into a 48 week-trial. The mean age was 54.4 years for the FA and 52.2 for the placebo group

Interventions Patients were randomized to receive either FA or placebo weekly for 48 weeks. The dose of FA was 5 mg/ week or 27.5 mg/week. The mean dose of MTX was 9.16 mg/week. Three groups were compared low dose (5 mg/w), high dose (27.5) or placebo. [25, 26 and 28 patients respectively]

Outcomes The reduction of MTX GI and haematological side effects.

Notes Quality score=5

Risk of bias

Item Authors’ judgement Description

Allocation concealment? Unclear D - Not used

Shiroky 1993

Methods Randomized controlled , double-blind, clinical trial. A parallel study design.

Participants Ninety-two patients (48/44 placebo/control respectively) with RA, older than 18 years, treated with low dose of MTX (less than 20 mg/week), were included into a 52-week trial. Thirty males, 62 females, with a mean age of 53.1 and 53.4 years for the FNA and placebo group respectively

Interventions Patients were randomized to receive either FNA 2.5-5mg/d or placebo for 52 weeks. The mean dose of MTX was 13.6 mg/week (2.5- 30 mg/week)

Outcomes The reduction of MTX toxicity (gastrointestinal and haematologic side effects) and the reduction of MTX efﬁcacy (swelling joint count, tenderness joint count, patient global assessment, physician assessment of disease activity, the duration of morning stiffness, grip strength, 50 foot walking time, morning stiffness and HAQ)

Notes Quality score= 5

Risk of bias

Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis (Review) 12 Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Shiroky 1993 (Continued)

Item Authors’ judgement Description

Allocation concealment? Yes A - Adequate

Weinblatt 1993

Methods Randomized controlled , double-blind, clinical trial. A parallel design

Participants Sixteen (8/8 placebo/control respectively) with RA, older than 18 years, treated with low dose of MTX (less than 20 mg/week), were included into a 8-week trial. Six males, 10 females. The mean age was 55.9 for the MTX group and 62.3 for the placebo group

Interventions Patients were randomized to receive either FNA 1 mg/d or placebo for 8 weeks. The mean dose of MTX was 13.6 mg/week (2.5-20 mg/week)

Notes Quality score= 3

Risk of bias

Item Authors’ judgement Description

Allocation concealment? Yes A - Adequate

FA= folic acid RA= rheumatoid arthritis FNA= folinic acid HAQ = Health Assessment Questionnaire

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Andersen 1997 Does not include outcomes of interest

Canadian Group 1992 Abstract published a full paper

Morgan 1998 Does not include outcomes of interest

Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis (Review) 13 Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. (Continued)

Stewart 1991 Uncontrolled clinical trial

Tishler 1988 Unblinded clinical trial

Weinblatt 1992 This study was published after its presentation on ACR ’92 meeting

Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis (Review) 14 Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. DATA AND ANALYSES

Comparison 1. Folic Acid vs. Placebo