Volume : 10, Issue : 01, January – 2023

Title:

46.METHOTREXATE INDUCED FOLATE DEFICIENCY IN PATIENTS WITH RHEUMATOID ARTHRITIS: A REVIEW

Authors :

Dr Santhosh Uttangi , J.S Venkatesh , Rajasree Reghunath, Reshma Roy, Ranjini T P, Pooja S Raj

Abstract :

Objectives: The folate antagonist methotrexate (MTX) has become established as the most commonly used disease-modifying anti-rheumatic drug (DMARD) in the treatment of rheumatoid arthritis (RA), but it is frequently discontinued due to adverse effects. The negative effects are thought to be mediated by folate antagonism. In this paper, we summarise the current data on the use of folates as a supplement to MTX in RA for the prevention of adverse effects and as a potential modulator of cardiovascular risk, and we propose guidelines for standard practise. Methods:A Medline search was conducted using the terms’methotrexate,’ ‘folic acid,’ ‘folinic acid,’ ‘folate,’ and ‘homocysteine’. The literature on the use of folates as a supplement to MTX in the treatment of RA was reviewed, and other papers referred to as references were investigated. Results: Supplemental folates, such as folic and folinic acid, have been shown to improve MTX adherence by lowering the incidence of liver function test abnormalities and gastrointestinal intolerance. Folate supplements do not appear to reduce the effectiveness of MTX in the treatment of RA. Furthermore, supplemental folic acid reduces the increase in plasma homocysteine caused by MTX use. This may reduce the risk of cardiovascular disease, which is over-represented in RA patients and for which hyperhomocysteinaemia is now recognised as an independent risk factor. Conclusions: We propose that all patients receiving MTX for the treatment of RA be given folic acid supplements on a regular basis. We recommend a practical dosing schedule of 5 mg of oral folic acid given the morning after MTX administration.
Key words: Methotrexate, Folic acid, Folinic acid, Homocysteine.

Cite This Article:

Please cite this article in press Santhosh Uttangi et al, Methotrexate Induced Folate Deficiency In Patients With Rheumatoid Artritis: A Review., Indo Am. J. P. Sci, 2023; 10 (01).

Number of Downloads : 10

References:

1. Cronstein BN. Molecular therapeutics. Methotrexate and its mechanism of action. Arthritis Rheum 1996;39:1951–60.
2. Gubner R, August S, Ginsberg V. Therapeutic suppression of tissue reactivity. II. Effect of aminopterin in rheumatoid arthritis and psoriasis. Am J Med Sci 1951;221:176–82.
3. 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;33:9–18.
4. Hoffmeister R. Methotrexate in rheumatoid arthritis. Arthritis Rheum 1972;15:114.
5. Felson DT, Anderson JJ, Meenan RF. Use of short-term efficacy/toxicity tradeoffs to select second-line drugs in rheumatoid arthritis.A meta analysis of published clinical trials. Arthritis Rheum1992;35:1117–25. [0:13 pm, 18/01/2023] Ranjini TP: 6. Genestier L, Paillot R, Quemeneur L, Izeradjene K, Revillard JP. Mechanisms of action of methotrexate. Immunopharmacology
2000;47:247–57.
7. Cronstein BN, Eberle MA, Gruber HE, Levin RI. Methotrexate inhibits neutrophil function by stimulating adenosine release from connective tissue cells. Proc Natl Acad Sci USA 1991;88:2441–5.
8. 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.
9. Ortiz Z, Shea B, Suarez-Almazor ME, Moher D, Wells GA, Tugwell P. The efficacy of folic acid and folinic acid in reducing methotrexate gastrointestinal toxicity in rheumatoid arthritis. A meta analysis of randomized controlled trials. J Rheumatol 1998;25:36–43.
10. 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;121:833–41.
11. Weinblatt ME, Fraser P. Elevated mean corpuscular volume as a predictor of hematologic toxicity due to methotrexate therapy.Arthritis Rheum 1989;32:1592–6.
12. 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 2000;39:1102–9.
13. Stewart KA, Mackenzie AH, Clough JD, Wilke WS. Folate supplementation in methotrexate-treated rheumatoid arthritispatients. Semin Arthritis Rheum 1991;20:332–8.
14. National Guidelines for the Monitoring of Second Line Drugs.London: British Society for Rheumatology, 2000.
15. Guidelines for monitoring drug therapy in rheumatoid arthritis. American College of Rheumatology Ad Hoc Committee on Clinical Guidelines. Arthritis Rheum 1996;39:723–31.
16. 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.
17. Suzuki Y, Uehara R, Tajima C et al. Elevation of serum hepatic
aminotransferases during treatment of rheumatoid arthritis with lowdose methotrexate. Risk factors and response to folic acid. Scand J Rheumatol 1999;28:273–81.
18. van Ede AE, Laan RF, Blom HJ et al. The C677T mutation in the methylenetetrahydrofolate reductase gene: a genetic risk factor for methotrexate-related elevation of liver enzymes in rheumatoid arthritis patients. Arthritis Rheum 2001;44:2525–30.
19. Morgan SL, Baggott JE, Alarcon GS, Koopman WJ. Folic acid and folinic acid supplementation during low-dose methotrexate therapy for rheumatoid arthritis: comment on the article by van Ede et al. Arthritis Rheum 2002;46:1413–4.
20. Strand V, Cohen S, Schiff M et al. Treatment of active rheumatoid arthritis with leflunomide compared with placebo and methotrexate. Leflunomide Rheumatoid Arthritis Investigators Group. Arch Intern Med 1999;159:2542–50.
21. Emery P, Breedveld FC, Lemmel EM et al. A comparison of the efficacy and safety of leflunomide and methotrexate for the treatment of rheumatoid arthritis. Rheumatology 2000;39:655–65.
22. Strand V, Morgan SL, Baggott JE, Alarcon GS. Folic acid supplementation and methotrexate efficacy: comment on articles by Schiff, Emery et al., and others. Arthritis Rheum 2000;43:2615–6.
23. Joyce DA, Will RK, Hoffman DM, Laing B, Blackbourn SJ. Exacerbation of rheumatoid arthritis in patients treated with methotrexate after administration of folinic acid. Ann Rheum Dis
1991;50:913–4.
24. Endresen GK, Husby G. Folate supplementation during methotrexate treatment of patients with rheumatoid arthritis. An update and proposals for guidelines. Scand J Rheumatol 2001;30:129–34.
25. Kitas GD, Erb N. Tackling ischaemic heart disease in rheumatoid arthritis. Rheumatology 2003;42:607–13.
26. Van Doornum S, McColl G, Wicks IP. Accelerated atherosclerosis:an extraarticular feature of rheumatoid arthritis? Arthritis Rheum 2002;46:862–73.
27. Banks M, Flint J. Rheumatoid arthritis is an independent risk factor or ischaemic heart disease. Arthritis Rheum 2000;43(Suppl.):S385.
28. Symmons DP, Jones MA, Scott DL, Prior P. Longterm mortality outcome in patients with rheumatoid arthritis: early presenters continue to do well. J Rheumatol 1998;25:1072–7.
29. Duell PB, Malinow MR. Homocyst[e]ine: an important risk factor for atherosclerotic vascular disease. Curr Opin Lipidol 1997;8:28–34.
30. van Ede AE, Laan RF, Blom HJ et al. Homocysteine and folate status in methotrexate-treated patients with rheumatoid arthritis.Rheumatology 2002;41:658–65.
31. Morgan SL, Baggott JE, Lee JY, Alarcon GS. 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;25:441–6.
32. Slot O. Changes in plasma homocysteine in arthritis patients starting treatment with low-dose methotrexate subsequently supplemented with folic acid. Scand J Rheumatol 2001;30:305–7.
33. Haagsma CJ, Blom HJ, van Riel PL et al. Influence of sulphasalazine, methotrexate, and the combination of both on plasma homocysteine concentrations in patients with rheumatoid arthritis. Ann Rheum Dis 1999;58:79–84.
34. Jensen OK, Rasmussen C, Mollerup F et al. Hyperhomocysteinemia in rheumatoid arthritis: influence of methotrexate treatment and folic acid supplementation. J Rheumatol 2002;29:1615–8.
35. Vermeulen EG, Stehouwer CD, Twisk JW et al. Effect of homocysteine-lowering treatment with folic acid plus vitamin B6 on progression of subclinical atherosclerosis: a randomised, placebocontrolled trial. Lancet 2000;355:517–22.
36. Landewe RB, van den Borne BE, Breedveld FC, Dijkmans BA. Methotrexate effects in patients with rheumatoid arthritis with cardiovascular comorbidity. Lancet 2000;355:1616–7.
37. Choi HK, Hernan MA, Seeger JD, Robins JM, Wolfe F. Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. Lancet 2002;359:1173–7.
38. Choi HK, Hernan MA, Seeger JD, Robins JM, Wolfe F.Methotrexate treatment and mortality in rheumatoid arthritis.Lancet 2002;360:1097–8.
39. British National Formulary, Vol. 44. London: British Medical Association and the Royal Pharmaceutical Society of Great Britain,2002.