Background:Methotrexate (MTX) is the most effective and commonly used
disease-modifying anti-rheumatic drug in the management of juvenile idiopathic
arthritis. Several patients develop side effects, which may lead to low quality
of life and non-compliance to MTX. To reduce MTX-induced side effects, folic
acid supplementation is prescribed by most rheumatologists. Even after that,
some patients have symptoms while receiving MTX. Objectives: To assess
the efficacy of folinic acid in comparison to folic acid for reducing the side
effects of MTX in JIA patients. Material and methods: In this
prospective observational study, newly diagnosed cases of JIA who would be
getting MTX were included by purposive sampling. Data were collected using a predesigned questionnaire. Among 40 patients, 20
received folinic acid (Group A), and 20 received folic acid (Group B).
Disease activity levels were assessed by JADAS-27 (Juvenile Arthritis Disease
Activity Score). Contents from the MISS (MTX Intolerance severity score)
questionnaire were used to assess the side effects. All patients were evaluated
at baseline, 6th, and 12th weeks. Results: There were significant
differences in the frequency of MTX-related adverse events between folinic acid
(Group A) and folic acid (Group B). Group A patients only had nausea (10% and
15% in the 6th &12th week
respectively) and vomiting (5% at both follow-ups). On the other hand, in
addition to nausea (70% and 95% in the 6th &12th week) and vomiting (20% and 90% in the 6th
& 12th week), folic acid group patients had restlessness, crying, and
irritability. Self-discontinuation of MTX was present in the folic acid group (5% & 10% in the 6th & 12th week).
Improvement of disease activity was more in the folinic acid group.
References
[1]
Ravelli, A. and Martini, A. (2007) Juvenile Idiopathic Arthritis. The Lancet, 369, 767-778. https://doi.org/10.1016/S0140-6736(07)60363-8
Giannini, E.H., Brewer, E.J., Kuzmina, N., Shaikov, A., Newman, A.J., Cassidy, J.T. et al., (1992) Resistant Juvenile Rheumatoid Arthritis—Results of the U.S.A.-U.S.S.R. Double-Blind, Placebo-Controlled Trial. The New English Journal of Medicine, 326, 1043-1049. https://doi.org/10.1056/NEJM199204163261602
[4]
Islam, M.I., Hossain, M. and Rahman, S.A. (2008) Performance of the Preliminary Definition of Improvement in Juvenile Idiopathic Arthritis Patients Treated with Methotrexate: Experience from Bangladesh. International Journal of Rheumatic Diseases, 11, 241-245. https://doi.org/10.1111/j.1756-185X.2008.00372.x
[5]
Jolivet, J., Cowan, K.H., Curt, G.A., Clendeninn, N.J. and Chabner, B.A. (1983) The Pharmacology and Clinical Use of Methotrexate. The New England Journal of Medicine, 309, 1094-1104. https://doi.org/10.1056/NEJM198311033091805
[6]
Ravelli, A., Migliavacca, D., Viola, S., Ruperto, N., Pistorio, A. and Martini, A. (1999) Efficacy of Folinic Arid in Reducing Methotrexate Toxicity in Juvenile Idiopathic Arthritis. Clinical and Experimental Rheumatology, 17, 625-627.
[7]
Shea, B., Swinden, M.V., Ghogomu, E.T., Ortiz, Z., Katchamart, W., Rader, T., Bombardier, C., Wells, G.A. and Tugwell, P. (2014) Folic Acid and Folinic Acid for Reducing Side Effects in Patients Receiving Methotrexate for Rheumatoid Arthritis. The Journal of Rheumatology, 41, 1049-1060.
https://doi.org/10.3899/jrheum.130738
[8]
Goldman, I.D. and Matherly, L.H. (1987) Biochemical Factors in the Selectivity of Leucovorin Rescue: Selective Inhibition of Leucovorin Reactivation of Dihydrofolate Reductase and Leucovorin Utilization in Purine and Pyrimidine Biosynthesis by Methotrexate and Dihydrofolate Polyglutamates. NCI Monographs, 5, 17-26.
[9]
Van der Meer, A., Wulffraat, N.M., Prakken, B.J., Gijsbers, B., Rademaker, C.M.A. and Sinnema, G. (2007) Psychological Side Effects of MTX Treatment in Juvenile Idiopathic Arthritis: A Pilot Study. Clinical and Experimental Rheumatology, 25, 480-485.
[10]
Fischer, E.A., Hetland, M.L. and Krabbe, S. (2020) Folinic Acid Alleviates Side Effects of Methotrexate in Arthritis Patients with Side Effects Despite Folic Acid Supplementation: An Observational Cohort Study. Rheumatology, 59, 3566-3568.
https://doi.org/10.1093/rheumatology/keaa277
[11]
Bulatović, M., Heijstek, M.W., Verkaaik, M., van Dijkhuizen, E.H., Armbrust, W., Hoppenreijs, E.P., Kamphuis, S., Kuis, W., Egberts, T.C., Sinnema, G., Rademaker, C.M. and Wulffraat, N.M. (2011) High Prevalence of Methotrexate Intolerance in Juvenile Idiopathic Arthritis: Development and Validation of a Methotrexate Intolerance Severity Score. Arthritis and Rheumatism, 63, 2007-2013.
https://doi.org/10.1002/art.30367
[12]
Mcerlane, F., Beresford, M.W., Baildam, E.M., Chieng, S.A., Davidson, J.E., Foster, H.E., Gardner-Medwin, J., Lunt, M., Wedderburn, L.R., Thomson, W. and Hyrich, K.L. (2013) Validity of a Three-Variable Juvenile Arthritis Disease Activity Score in Children with New-Onset Juvenile Idiopathic Arthritis. Annals of the Rheumatic Diseases, 72, 1983-1988. https://doi.org/10.1136/annrheumdis-2012-202031
[13]
Manfredi, A., Sebastiani, M., Iannone, F., Gremese, E., Bortoluzzi, A., Favalli, E., Gorla, R., Salaffi, F., Fusaro, E., Foti, R., Cantarini, L., Caporali, R., Cauli, A., Alivernini, S., Cantatore, F.P., Carletto, A., Conti, F., D’Angelo1, S., Epis, O., Ramonda R, Marchesoni A., Ferraccioli. G. and Lapadula, G. (2019) Factors Predicting Early Discontinuation of Methotrexate as a First-Line Treatment for Rheumatoid Arthritis in Italy: Results from the GISEA Registry. Indian Journal of Rheumatology, 14, 271-276. https://doi.org/10.4103/injr.injr_60_19
[14]
Wu, J.F., Yang, Y.H., Wang, L.C., Lee, J.H., Shen, E.Y. and Chiang, B.L. (2007) Comparative Usefulness of C-Reactive Protein and Erythrocyte Sedimentation Rate in Juvenile Rheumatoid Arthritis. Clinical and Experimental Rheumatology, 25, 782-785.
[15]
van Ede, A.E., Laan, R.F., Rood, M.J., Huizinga, T.W., van de Laar, M.A., van Denderen, C.J., Westgeest, T.A., Romme, T.C., de Rooij, D.J., Jacobs, M.J., de Boo, T.M., van der Wilt, G.J., Severens, J.L., Hartman, M., Krabbe, P.F., Dijkmans, B.A., Breedveld, F.C. and van de Putte, L.B. (2001) 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 & Rheumatology, 44, 1515-1224.
https://doi.org/10.1002/1529-0131(200107)44:7<1515::AID-ART273>3.0.CO;2-7
[16]
Hanrahan, P.S. and Russell, A.S. (1988) Concurrent Use of Folinic Acid and Methotrexate in Rheumatoid Arthritis. The Journal of Rheumatology, 15, 1078-1080.
[17]
Tishler, M., Csapi, D., Fishel, B. and Yaron, M. (1988) The Effects of Leucovorin (Folinic Acid) on Methotrexate Therapy in Rheumatoid Arthritis Patients. Arthritis & Rheumatology, 31, 906-908. https://doi.org/10.1002/art.1780310712
[18]
Buckley, L.M., Vacek, P.M. and Cooper, S.M. (1990) Administration of Folinic Acid after Low Dose Methotrexate in Patients with Rheumatoid Arthritis. The Journal of Rheumatology, 17, 1158-1161.
[19]
Joyece, D.A., Will, R.K., Hoffman, D.M., Laing, B. and Blackburn, S.J. (1991) Exacerbation of Rheumatoid Arthritis in Patients Treated with Methotrexate after Administration of Folinic Acid. Annals of Rheumatic Diseases, 50, 913-914.
https://doi.org/10.1136/ard.50.12.913
[20]
Shiroky, J.B., Neville, C., Esdaile, J.M., et al. (1993) Low-Dose Methotrexate with Leucovorin (Folinic Acid) in the Management of Rheumatoid Arthritis. Arthritis & Rheumatology, 36, 795-803. https://doi.org/10.1002/art.1780360609
[21]
Islam, M.I., Sonia, S.P., Haque, M., Laila, K., Talukder, M.K., Islam, M.M. and Rahman, S.A. (2022) Disease Activity States of Juvenile Idiopathic Arthritis in a Referral Centre in Bangladesh: Disease Activity States of JIA Patients. Bangladesh Medical Research Council Bulletin, 48, 41-47.
https://doi.org/10.3329/bmrcb.v48i1.60659
