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Published in: American Journal of Clinical Dermatology 3/2013

01-06-2013 | Evidence-Based Review Article

The Effect of Folate Supplementation on Methotrexate Efficacy and Toxicity in Psoriasis Patients and Folic Acid Use by Dermatologists in the USA

Authors: Amir Al-Dabagh, Scott A. Davis, Megan A. Kinney, Karen Huang, Steven R. Feldman

Published in: American Journal of Clinical Dermatology | Issue 3/2013

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Abstract

Background

Methotrexate (MTX) is an effective treatment for psoriasis but its use is limited by its toxicity. Folate supplementation can be used to reduce the adverse effects of MTX, though this may impact efficacy. The frequency of folic acid supplementation is not well characterized.

Purpose

The objective of this study was to review the literature involving the use of folate in patients (in particular those with psoriasis) treated with MTX and analyze trends in folic acid use.

Methods

We searched PubMed from 1 May 1989 through 1 April 2012 using the terms ‘folic acid,’ ‘folinic acid,’ ‘folate,’ ‘supplementation,’ and ‘methotrexate.’ We also used the National Ambulatory Medical Care Survey (NAMCS) database to collect data regarding trends in MTX use and folic acid supplementation by physicians in the USA from 1993 through 2009. We assessed data including the number of MTX visits, rate of folic acid use, diagnoses, physician specialty, and demographics of patients. We used linear regression to analyze the change in folic acid use over time.

Results

Twenty-six published trials were included addressing folic acid supplementation with MTX. The majority found a benefit to folic acid supplementation, but there were only seven studies in psoriasis. Dermatologists were among the highest prescribers of MTX, and psoriasis was commonly treated with MTX. Folic acid supplementation significantly increased over this time period (p < 0.0001). However, dermatologists ranked lowest for their folate use, co-prescribing folate to only 9.1 % of MTX-treated patients.

Limitations

In contrast to rheumatoid arthritis, there is a scarcity of literature describing the effect of folate on MTX toxicity and efficacy in psoriasis patients. NAMCS data only included outpatient visits to non-federally employed physicians, and there is the possibility of healthcare providers not documenting over-the-counter folic acid usage. Lastly, doses of MTX and folic acid were not recorded in the database.

Conclusion

Dermatologists were the least likely specialists to supplement MTX with folic acid. The evidence for supplementation of folic acid is mixed. The literature confirms a reduction in the adverse effects of MTX but less strongly that there may be a reduction in efficacy too. Keeping in mind the potential for folate to reduce MTX efficacy, folic acid supplementation should be considered in MTX-treated patients.
Literature
1.
go back to reference Morgan S, Alarcon GS, Krumdieck CL. Folic acid supplementation during methotrexate therapy: it makes sense. J Rheumatol. 1993;20(6):929–30.PubMed Morgan S, Alarcon GS, Krumdieck CL. Folic acid supplementation during methotrexate therapy: it makes sense. J Rheumatol. 1993;20(6):929–30.PubMed
2.
go back to reference Morgan SL, Oster RA, Lee JY, et al. The effect of folic acid and folinic acid supplements on purine metabolism in methotrexate-treated rheumatoid arthritis. Arthritis Rheum. 2004;50(10):3104–11.PubMedCrossRef Morgan SL, Oster RA, Lee JY, et al. The effect of folic acid and folinic acid supplements on purine metabolism in methotrexate-treated rheumatoid arthritis. Arthritis Rheum. 2004;50(10):3104–11.PubMedCrossRef
3.
go back to reference Morgan SL, Baggott JE, Vaughn 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(1):9–18.PubMedCrossRef Morgan SL, Baggott JE, Vaughn 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(1):9–18.PubMedCrossRef
4.
go back to reference Morgan SL, Baggott JE, Vaughn WH, et al. Supplementation with folic acid during methotrexate therapy for rheumatoid arthritis: a double-blind, placebo-controlled trial. Ann Intern Med. 1994;121(11):833–41.PubMedCrossRef Morgan SL, Baggott JE, Vaughn WH, et al. Supplementation with folic acid during methotrexate therapy for rheumatoid arthritis: a double-blind, placebo-controlled trial. Ann Intern Med. 1994;121(11):833–41.PubMedCrossRef
5.
go back to reference Morgan SL, Baggott JE, Lee JY, et al. Folic acid supplementation prevents deficient blood folate levels and hyperhomocysteinemia during longterm, low dose methotrexate therapy for rheumatoid arthritis: implications for cardiovascular disease prevention. J Rheumatol. 1998;25(3):441–6.PubMed Morgan SL, Baggott JE, Lee JY, et al. Folic acid supplementation prevents deficient blood folate levels and hyperhomocysteinemia during longterm, low dose methotrexate therapy for rheumatoid arthritis: implications for cardiovascular disease prevention. J Rheumatol. 1998;25(3):441–6.PubMed
6.
go back to reference Masuria BL, Mittal A, Gupta LK, et al. Methotrexate: side effects and the role of folic acid supplementation in psoriasis: a study. Indian J Dermatol Venereol Leprol. 1997;63(4):219–22.PubMed Masuria BL, Mittal A, Gupta LK, et al. Methotrexate: side effects and the role of folic acid supplementation in psoriasis: a study. Indian J Dermatol Venereol Leprol. 1997;63(4):219–22.PubMed
7.
go back to reference Huemer M, Fodinger M, Huemer C, et al. Hyperhomocysteinemia in children with juvenile idiopathic arthritis is not influenced by methotrexate treatment and folic acid supplementation: a pilot study. Clin Exp Rheumatol. 2003;21(2):249–55.PubMed Huemer M, Fodinger M, Huemer C, et al. Hyperhomocysteinemia in children with juvenile idiopathic arthritis is not influenced by methotrexate treatment and folic acid supplementation: a pilot study. Clin Exp Rheumatol. 2003;21(2):249–55.PubMed
8.
go back to reference Strober BE, Menon K. Folate supplementation during methotrexate therapy for patients with psoriasis. J Am Acad Dermatol. 2005;53(4):652–9.PubMedCrossRef Strober BE, Menon K. Folate supplementation during methotrexate therapy for patients with psoriasis. J Am Acad Dermatol. 2005;53(4):652–9.PubMedCrossRef
9.
go back to reference Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 4. Guidelines of care for the management and treatment of psoriasis with traditional systemic agents. J Am Acad Dermatol. 2009;61(3):451–85.PubMedCrossRef Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 4. Guidelines of care for the management and treatment of psoriasis with traditional systemic agents. J Am Acad Dermatol. 2009;61(3):451–85.PubMedCrossRef
10.
go back to reference van Ede AE, Laan RF, Blom HJ, et al. Homocysteine and folate status in methotrexate-treated patients with rheumatoid arthritis. Rheumatology (Oxford). 2002;41(6):658–65.CrossRef van Ede AE, Laan RF, Blom HJ, et al. Homocysteine and folate status in methotrexate-treated patients with rheumatoid arthritis. Rheumatology (Oxford). 2002;41(6):658–65.CrossRef
11.
go back to reference Hornung N, Ellingsen T, Stengaard-Pedersen K, et al. Folate, homocysteine, and cobalamin status in patients with rheumatoid arthritis treated with methotrexate, and the effect of low dose folic acid supplement. J Rheumatol. 2004;31(12):2374–81.PubMed Hornung N, Ellingsen T, Stengaard-Pedersen K, et al. Folate, homocysteine, and cobalamin status in patients with rheumatoid arthritis treated with methotrexate, and the effect of low dose folic acid supplement. J Rheumatol. 2004;31(12):2374–81.PubMed
12.
go back to reference Chladek J, Simkova M, Vaneckova J, et al. The effect of folic acid supplementation on the pharmacokinetics and pharmacodynamics of oral methotrexate during the remission–induction period of treatment for moderate-to-severe plaque psoriasis. Eur J Clin Pharmacol. 2008;64(4):347–55.PubMedCrossRef Chladek J, Simkova M, Vaneckova J, et al. The effect of folic acid supplementation on the pharmacokinetics and pharmacodynamics of oral methotrexate during the remission–induction period of treatment for moderate-to-severe plaque psoriasis. Eur J Clin Pharmacol. 2008;64(4):347–55.PubMedCrossRef
13.
go back to reference Clare G, Colley S, Kennett R, et al. Reversible optic neuropathy associated with low-dose methotrexate therapy. J Neuroophthalmol. 2005;25(2):109–12.PubMedCrossRef Clare G, Colley S, Kennett R, et al. Reversible optic neuropathy associated with low-dose methotrexate therapy. J Neuroophthalmol. 2005;25(2):109–12.PubMedCrossRef
14.
go back to reference Len C, Hilario MO, Kawakami E, et al. Gastroduodenal lesions in children with juvenile rheumatoid arthritis. Hepatogastroenterology. 1999;46(26):991–6.PubMed Len C, Hilario MO, Kawakami E, et al. Gastroduodenal lesions in children with juvenile rheumatoid arthritis. Hepatogastroenterology. 1999;46(26):991–6.PubMed
15.
go back to reference Prey S, Paul C. Effect of folic or folinic acid supplementation on methotrexate-associated safety and efficacy in inflammatory disease: a systematic review. Br J Dermatol. 2009;160(3):622–8.PubMedCrossRef Prey S, Paul C. Effect of folic or folinic acid supplementation on methotrexate-associated safety and efficacy in inflammatory disease: a systematic review. Br J Dermatol. 2009;160(3):622–8.PubMedCrossRef
16.
go back to reference Guzzo C. Folic acid supplementation with methotrexate therapy: what benefit if any? J Am Acad Dermatol. 1994;31(4):689.PubMedCrossRef Guzzo C. Folic acid supplementation with methotrexate therapy: what benefit if any? J Am Acad Dermatol. 1994;31(4):689.PubMedCrossRef
17.
go back to reference Shiroky JB. The use of folates concomitantly with low-dose pulse methotrexate. Rheum Dis Clin North Am. 1997;23(4):969–80.PubMedCrossRef Shiroky JB. The use of folates concomitantly with low-dose pulse methotrexate. Rheum Dis Clin North Am. 1997;23(4):969–80.PubMedCrossRef
18.
go back to reference Gisondi P, Fantuzzi F, Malerba M, et al. Folic acid in general medicine and dermatology. J Dermatolog Treat. 2007;18(3):138–46.PubMedCrossRef Gisondi P, Fantuzzi F, Malerba M, et al. Folic acid in general medicine and dermatology. J Dermatolog Treat. 2007;18(3):138–46.PubMedCrossRef
19.
go back to reference Hughes R, Harries M, Chalmers RJ, et al. Folic acid supplementation and methotrexate therapy for psoriasis. J Am Acad Dermatol. 2006;55(2):366–7.PubMedCrossRef Hughes R, Harries M, Chalmers RJ, et al. Folic acid supplementation and methotrexate therapy for psoriasis. J Am Acad Dermatol. 2006;55(2):366–7.PubMedCrossRef
20.
go back to reference Hoekstra M, van de Laar MA, Bernelot Moens HJ, et al. Longterm observational study of methotrexate use in a Dutch cohort of 1022 patients with rheumatoid arthritis. J Rheumatol. 2003;30(11):2325–9.PubMed Hoekstra M, van de Laar MA, Bernelot Moens HJ, et al. Longterm observational study of methotrexate use in a Dutch cohort of 1022 patients with rheumatoid arthritis. J Rheumatol. 2003;30(11):2325–9.PubMed
21.
go back to reference Hoekstra M, van Ede AE, Haagsma CJ, et al. Factors associated with toxicity, final dose, and efficacy of methotrexate in patients with rheumatoid arthritis. Ann Rheum Dis. 2003;62(5):423–6.PubMedCrossRef Hoekstra M, van Ede AE, Haagsma CJ, et al. Factors associated with toxicity, final dose, and efficacy of methotrexate in patients with rheumatoid arthritis. Ann Rheum Dis. 2003;62(5):423–6.PubMedCrossRef
22.
go back to reference Niehues T, Horneff G, Michels H, et al. Evidence-based use of methotrexate in children with rheumatic diseases: a consensus statement of the Working Groups Pediatric Rheumatology Germany (AGKJR) and Pediatric Rheumatology Austria. Rheumatol Int. 2005;25(3):169–78.PubMedCrossRef Niehues T, Horneff G, Michels H, et al. Evidence-based use of methotrexate in children with rheumatic diseases: a consensus statement of the Working Groups Pediatric Rheumatology Germany (AGKJR) and Pediatric Rheumatology Austria. Rheumatol Int. 2005;25(3):169–78.PubMedCrossRef
23.
go back to reference Strand V, Morgan SL, Baggott JE, et al. Folic acid supplementation and methotrexate efficacy: comment on articles by Schiff, Emery et al, and others. Arthritis Rheum. 2000;43(11):2615–6.PubMedCrossRef Strand V, Morgan SL, Baggott JE, et al. Folic acid supplementation and methotrexate efficacy: comment on articles by Schiff, Emery et al, and others. Arthritis Rheum. 2000;43(11):2615–6.PubMedCrossRef
24.
go back to reference Bressolle F, Kinowski JM, Morel J, et al. Folic acid alters methotrexate availability in patients with rheumatoid arthritis. J Rheumatol. 2000;27(9):2110–4.PubMed Bressolle F, Kinowski JM, Morel J, et al. Folic acid alters methotrexate availability in patients with rheumatoid arthritis. J Rheumatol. 2000;27(9):2110–4.PubMed
25.
go back to reference Franks P, Clancy CM, Nutting PA. Defining primary care: empirical analysis of the National Ambulatory Medical Care Survey. Med Care. 1997;35(7):655–68.PubMedCrossRef Franks P, Clancy CM, Nutting PA. Defining primary care: empirical analysis of the National Ambulatory Medical Care Survey. Med Care. 1997;35(7):655–68.PubMedCrossRef
26.
go back to reference Binns HJ, Lanier D, Pace WD, et al. Describing primary care encounters: the Primary Care Network Survey and the National Ambulatory Medical Care Survey. Ann Fam Med. 2007;5(1):39–47.PubMedCrossRef Binns HJ, Lanier D, Pace WD, et al. Describing primary care encounters: the Primary Care Network Survey and the National Ambulatory Medical Care Survey. Ann Fam Med. 2007;5(1):39–47.PubMedCrossRef
27.
go back to reference Kirby B, Lyon CC, Griffiths CE, et al. The use of folic acid supplementation in psoriasis patients receiving methotrexate: a survey in the United Kingdom. Clin Exp Dermatol. 2000;25(4):265–8.PubMedCrossRef Kirby B, Lyon CC, Griffiths CE, et al. The use of folic acid supplementation in psoriasis patients receiving methotrexate: a survey in the United Kingdom. Clin Exp Dermatol. 2000;25(4):265–8.PubMedCrossRef
28.
go back to reference Duhra P. Treatment of gastrointestinal symptoms associated with methotrexate therapy for psoriasis. J Am Acad Dermatol. 1993;28(3):466–9.PubMedCrossRef Duhra P. Treatment of gastrointestinal symptoms associated with methotrexate therapy for psoriasis. J Am Acad Dermatol. 1993;28(3):466–9.PubMedCrossRef
29.
go back to reference Griffith SM, Fisher J, Clarke S, et al. Do patients with rheumatoid arthritis established on methotrexate and folic acid 5 mg daily need to continue folic acid supplements long term? Rheumatology (Oxford). 2000;39(10):1102–9. Griffith SM, Fisher J, Clarke S, et al. Do patients with rheumatoid arthritis established on methotrexate and folic acid 5 mg daily need to continue folic acid supplements long term? Rheumatology (Oxford). 2000;39(10):1102–9.
30.
go back to reference Salim A, Tan E, Ilchyshyn A, et al. Folic acid supplementation during treatment of psoriasis with methotrexate: a randomized, double-blind, placebo-controlled trial. Br J Dermatol. 2006;154(6):1169–74.PubMedCrossRef Salim A, Tan E, Ilchyshyn A, et al. Folic acid supplementation during treatment of psoriasis with methotrexate: a randomized, double-blind, placebo-controlled trial. Br J Dermatol. 2006;154(6):1169–74.PubMedCrossRef
31.
go back to reference Roenigk HH Jr, Fowler-Bergfeld W, Curtis GH. Methotrexate for psoriasis in weekly oral doses. Arch Dermatol. 1969;99(1):86–93.PubMedCrossRef Roenigk HH Jr, Fowler-Bergfeld W, Curtis GH. Methotrexate for psoriasis in weekly oral doses. Arch Dermatol. 1969;99(1):86–93.PubMedCrossRef
32.
go back to reference Ive FA, De Saram CF. Methotrexate and the citrovorum factor in the treatment of psoriasis. Trans St Johns Hosp Dermatol Soc. 1970;56(1):45–7.PubMed Ive FA, De Saram CF. Methotrexate and the citrovorum factor in the treatment of psoriasis. Trans St Johns Hosp Dermatol Soc. 1970;56(1):45–7.PubMed
33.
go back to reference Hills RJ, Ive FA. Folinic acid rescue used routinely in psoriatic patients with known methotrexate “sensitivity”. Acta Derm Venereol. 1992;72(6):438–40.PubMed Hills RJ, Ive FA. Folinic acid rescue used routinely in psoriatic patients with known methotrexate “sensitivity”. Acta Derm Venereol. 1992;72(6):438–40.PubMed
34.
go back to reference Campalani E, Arenas M, Marinaki AM, et al. Polymorphisms in folate, pyrimidine, and purine metabolism are associated with efficacy and toxicity of methotrexate in psoriasis. J Invest Dermatol. 2007;127(8):1860–7.PubMedCrossRef Campalani E, Arenas M, Marinaki AM, et al. Polymorphisms in folate, pyrimidine, and purine metabolism are associated with efficacy and toxicity of methotrexate in psoriasis. J Invest Dermatol. 2007;127(8):1860–7.PubMedCrossRef
35.
go back to reference Leeb BF, Witzmann G, Ogris E, et al. Folic acid and cyanocobalamin levels in serum and erythrocytes during low-dose methotrexate therapy of rheumatoid arthritis and psoriatic arthritis patients. Clin Exp Rheumatol. 1995;13(4):459–63.PubMed Leeb BF, Witzmann G, Ogris E, et al. Folic acid and cyanocobalamin levels in serum and erythrocytes during low-dose methotrexate therapy of rheumatoid arthritis and psoriatic arthritis patients. Clin Exp Rheumatol. 1995;13(4):459–63.PubMed
36.
go back to reference Harris RP, Helfand M, Woolf SH, et al. Current methods of the US Preventive Services Task Force: a review of the process. Am J Prev Med. 2001;20(3 Suppl.):21–35.PubMedCrossRef Harris RP, Helfand M, Woolf SH, et al. Current methods of the US Preventive Services Task Force: a review of the process. Am J Prev Med. 2001;20(3 Suppl.):21–35.PubMedCrossRef
37.
go back to reference 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 randomized controlled trials. J Rheumatol. 1998;25(1):36–43.PubMed 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 randomized controlled trials. J Rheumatol. 1998;25(1):36–43.PubMed
38.
go back to reference Visser K, van der Heijde DM. Risk and management of liver toxicity during methotrexate treatment in rheumatoid and psoriatic arthritis: a systematic review of the literature. Clin Exp Rheumatol. 2009;27(6):1017–25.PubMed Visser K, van der Heijde DM. Risk and management of liver toxicity during methotrexate treatment in rheumatoid and psoriatic arthritis: a systematic review of the literature. Clin Exp Rheumatol. 2009;27(6):1017–25.PubMed
Metadata
Title
The Effect of Folate Supplementation on Methotrexate Efficacy and Toxicity in Psoriasis Patients and Folic Acid Use by Dermatologists in the USA
Authors
Amir Al-Dabagh
Scott A. Davis
Megan A. Kinney
Karen Huang
Steven R. Feldman
Publication date
01-06-2013
Publisher
Springer International Publishing AG
Published in
American Journal of Clinical Dermatology / Issue 3/2013
Print ISSN: 1175-0561
Electronic ISSN: 1179-1888
DOI
https://doi.org/10.1007/s40257-013-0017-9

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