Effect of high dose intravenous ascorbic acid on the level of inflammation in patients with rheumatoid arthritis

DOI: 10.4236/mri.2012.12004   PDF   HTML     7,340 Downloads   16,807 Views   Citations


Rheumatoid arthritis (RA) is a major inflammatory joint disease that causes cartilage destruction, bone erosions, and joint destruction. Oxidative stress is elevated in RA patients implying reactive oxygen species (ROS) are possible mediators of tissue damage. ROS trigger a cascade of events through nuclear factors’ activation (NF-kappa B), which up-regulates gene expression of pro-inflammatory cytokines that mediate the immune responses causing inflammation. As ascorbic acid can reduce oxidative stress, decrease production of pro-inflammatory cytokines, and suppress the activation of NF-kappa B, we suggest that millimolar concentration of ascorbic acid may be useful in RA treatment. In our study we analyzed the effect of intravenous vitamin C (IVC) treatment on eleven subjects with RA. Our data suggest that IVC therapy with dosages of 7.5 g - 50 g can reduce inflammation. The level of inflammation as measured by C-reactive protein levels was decreased on average by 44%. Based on our pilot study, we hypothesize that IVC therapy can be a useful strategy in treating RA.

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Mikirova, N., Rogers, A., Casciari, J. and Taylor, P. (2012) Effect of high dose intravenous ascorbic acid on the level of inflammation in patients with rheumatoid arthritis. Modern Research in Inflammation, 1, 26-32. doi: 10.4236/mri.2012.12004.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Tyler, J.A. (1985) Articular cartilage cultured with catabolin (pig interleukin 1) synthesizes a decreased number of normal proteoglycan molecules. Biochemical Journal, 227, 869-878.
[2] Gaby, A.R. (1999) Alternative treatments for rheumatoid arthritis. Alternative Medicine Review, 4.
[3] Pattison, D.J., Harrison, R.A. and Symmons, D.P. (2004) The role of diet in susceptibility to rheumatoid arthritis: A systematic review. The Journal of Rheumatology, 31, 1310-1319.
[4] Edmonds, S., Winyard, P., Guo, R., Kidd, B., Merry, P., Langrish-Smith, A., Hansen, C., Ramm, S. and Blake, D.R. (1997) Putative analgesic activity of repeated oral doses of vitamin E in the treatment of rheumatoid arthritis. Results of a prospective placebo controlled double blind trial. Annals of the Rheumatic Diseases, 56, 649-655. doi:10.1136/ard.56.11.649
[5] Peretz, A., Siderova, V. and Neve, J. (2001) Selenium su- pplementation in rheumatoid arthritis investigated in a double-blind, placebo-controlled trial. Scandinavian Journal of Rheumatology, 30, 208-212. doi:10.1080/030097401316909549
[6] Remans, P.H.J., Sont, J.K., Wagenaar, L.W., Wouter- wesseling, W., Zuijderduin, W.M., Jongma, A., Breedveld, F.C. and van Laar, J.M. (2004) Nutrient supplementation with polyunsaturated fatty acids and micronutriens in rheumatoid arthritis: Clinical and biochemical effects. European Journal of Clinical Nutrition, 58, 839-845. doi:10.1038/sj.ejcn.1601883
[7] Bae, S., Jung, W., Lee, E., Yu, R. and Sung, M. (2009) Effects of antioxidant supplements intervention on the level of plasma inflammatory molecules and disease se- verity of rheumatoid arthritis patients. Journal of the Ame- rican College of Nutrition, 28, 56-62.
[8] Lipsky, P.E. (2000) Rheumatoid arthritis. In: Braunwald, E., Fauci, A.S., Kasper, D.L., Hauser, S.L., Longo, D.L. and Jameson, J.L., Eds., Harrison’s Principles of Internal Medicine, McGraw Hill, New York, 1928-1936.
[9] Shingu, M., Nagai, Y., Isayama, T., Naono, T., Nobunaga, M. and Nagai, Y. (1993) The effects of cytokines on metalloproteinase inhibitors (TIMP) and collagenase production by human chondrocytes and TIMP production by synovial cells and endothelial cells. Clinical & Experimental Immunology, 94, 145-149. doi:10.1111/j.1365-2249.1993.tb05992.x
[10] Feldmann, M., Brennan, F.M. and Maini, R.N. (1996) Role of cytokines in rheumatoid arthritis. Annual Review of Immunology, 14, 397-440. doi:10.1146/annurev.immunol.14.1.397
[11] Gowen, M., Wood, D.D., Ihrie, E.J., Meats, J.E. and Russell, R.G. (1984) Stimulation by human interleukin 1 of cartilage breakdown and production of collagenase and proteoglycanase by human chondrocytes but not by human osteoblasts in vitro. Biochimica et Biophysica Acta, 797, 186-193. doi:10.1016/0304-4165(84)90121-1
[12] Kevorkian, L., Young, D.A., Darrah, C., Donell, S.T., Shepstone, L., Porter, S., Brockappa Bank, S.M., Edwards, D.R., Parker, A.E. and Clark, I.M. (2004) Expression profiling of metalloproteinases and their inhibitors in cartilage. Arthritis & Rheumatism, 50, 131-141. doi:10.1002/art.11433
[13] Martel-Pelletier, J. (1998) Pathophysiology of osteoar- thritis. Osteoarthritis and Cartilage, 6, 374-376. doi:10.1053/joca.1998.0140
[14] Sarban, S., Kocyigit, A., Yazar, M. and Isikan, U.E. (2005) Plasma total antioxidant capacity, lipid peroxidation, and erythrocyte antioxidant enzyme activities in patients with rheumatoid arthritis and osteoarthritis. Clinical Biochemistry, 38, 981-986. doi:10.1016/j.clinbiochem.2005.08.003
[15] Kamanli, A., Naziroglu, M., Aydilek, N. and Hacievliyagil, C. (2004) Plasma lipid peroxidation and antioxidant levels in patients with rheumatoid arthritis. Cell Biochemistry and Function, 22, 53-57. doi:10.1002/cbf.1055
[16] Gambhir, J.K., Lali, P. and Jain, A.K. (1997) Correlation between blood antioxidant levels and lipid peroxidation in rheumatoid arthritis. Clinical Biochemistry, 30, 351-355. doi:10.1016/S0009-9120(96)00007-0
[17] Halliwell, B., Hoult, J.R. and Blake, D.R. (1988) Oxidants, inflammation, and anti-inflammatory drugs. FASEB Journal, 2, 2867-2873.
[18] Blake, D.R., Merry, P., Unsworth, J., Kidd, B.L., Outhwaite, J.M., Ballard, R., Morris, C.J., Gray, L. and Lunec J. (1989) Hypoxid-reperfusion injury in the inflamed human joint. The Lancet, 1, 289-293. doi:10.1016/S0140-6736(89)91305-6
[19] Bubici, C., Papa, S., Pham, C.G., Zazzeroni, F. and Franzoso G. (2006) The NF-kappa B-mediated control of ROS and JNK signaling. Histology and Histopathology, 21, 69-80.
[20] Siebenlist, U., Franzoso, G. and Brown, K. (1994) Structure, regulation and function of NF-kappa B. Annual Review of Cell Biology, 10, 405-455. doi:10.1146/annurev.cb.10.110194.002201
[21] Barnes, P.J. and Karin, M. (1997) Nuclear factor-kappa B: A pivotal transcription factor in chronic inflammatory diseases. The New England Journal of Medicine, 336, 1066-1071. doi:10.1056/NEJM199704103361506
[22] Kumar, A., Takada, Y., Boriek, A.M. and Aggarwal, B.B. (2004) Nuclear factor-kappa B: Its role in health and disease. Journal of Molecular Medicine, 82, 434-448. doi:10.1007/s00109-004-0555-y
[23] Simmonds, E. and Foxwell, B.M. (2008) Signaling, inflammation and arthritis NF-kappa B and its relevance to arthritis and inflammation. Rheumatology, 47, 584-590.
[24] Fujisawa, K., Aono, H., Hasunuma, T., Yamamoto, K., Mita, S. and Nishioka, K. (1996) Activation of transcription factor NF-kappa B in human synovial cells in response to tumor necrosis factor alpha. Arthritis & Rheumatism, 39, 197-203. doi:10.1002/art.1780390205
[25] Roshak, A.K., Jackson, J.R., McGough, K., Chabot-Fletcher, M., Mochan, E. and Marshall, L.A. (1996) Manipulation of distinct NF-kappa B proteins alters interleukin-1beta- induced human rheumatoid synovial fibroblast prostaglandin E2 formation. The Journal of Biological Chemistry, 271, 31496-31501. doi:10.1074/jbc.271.49.31496
[26] Yamasaki, S., Kawakami, A., Nakashima, T., et al. (2001) Importance of NF-kappa B in rheumatoid synovial tissues: In situ NF-kappa B expression and in vitro study using cultured synovial cells. Annals of the Rheumatic Diseases, 60, 678-84. doi:10.1136/ard.60.7.678
[27] Carlsen, H., Moskaug, J.O., Fromm, S.H. and Blomhoff, R. (2002) In vivo imaging of NF-kappa B activity. The Journal of Immunology, 168, 1441-1446.
[28] Sioud, M., Mellbye, O. and Forre, O. (1998) Analysis of the NF-kappa B p65 subunit, Fas antigen, Fas ligand and Bcl-2-related proteins in the synovium of RA and polyarticular JRA. Clinical and Experimental Rheumatology, 16, 125-134.
[29] Marok, R., Winyard, P.G., Coumbe, A. et al. (1996) Activation of the transcription factor nuclear factor-kappaB in human inflamed synovial tissue. Arthritis & Rheumatism, 39, 583-591. doi:10.1002/art.1780390407
[30] Handel, M.L., McMorrow, L.B. and Gravallese, E.M. (1995) Nuclear factor-kappa B in rheumatoid synovium. Localization of p50 and p65. Arthritis & Rheumatism, 38, 1762-1770. doi:10.1002/art.1780381209
[31] Benito, M.J., Murphy, E., Murphy, E.P., van den Berg, W.B., FitzGerald, O. and Bresnihan, B. (2004) Increased synovial tissue NF-kappa B1 expression at sites adjacent to the cartilage-pannus junction in rheumatoid arthritis. Arthritis & Rheumatism, 50, 1781-1787. doi:10.1002/art.20260
[32] Danning, C.L., Illei, G.G., Hitchon, C., Greer, M.R., Boumpas, D.T. and McInnes, I.B. (2000) Macrophage- derived cytokine and nuclear factor kappa B p65 expression in synovial membrane and skin of patients with psoriatic arthritis. Arthritis & Rheumatism. 43, 1244-1256. doi:10.1002/1529-0131(200006)43:6<1244::AID-ANR7>3.0.CO;2-2
[33] Tsao, P.W., Suzuki, T., Totsuka, R., et al. (1997) The effect of dexamethasone on the expression of activated NF-kappa B in adjuvant arthritis. Clinical Immunology and Immunopathology, 83, 173-178. doi:10.1006/clin.1997.4333
[34] Han, Z., Boyle, D.L., Manning, A.M. and Firestein, G.S. (1998) AP-1 and NF-kappa B regulation in rheumatoid arthritis and murine collagen-induced arthritis. Autoimmunity, 28, 197-208. doi:10.3109/08916939808995367
[35] Wehling, N., Palmer, G.D., Pilapil, C., Liu, F., Wells, J.W., Müller, P.E., Evans, C.H. and Porter, R.M. (2009) Interleukin-1beta and tumor necrosis factor alpha inhibit chondrogenesis by human mesenchymal stem cells through NF-kappa B-dependent pathways. Arthritis & Rheuma- tism, 60, 801-812. doi:10.1002/art.24352
[36] Li, X.L. and Makarov, S.S. (2006) An essential role of NF-κB in the “tumor-like” phenotype of arthritic synoviocytes. Proceedings of the National Academy of Sciences, 103, 17432-17437. doi:10.1073/pnas.0607939103
[37] Yamasaki, S., Nakashima, T., Kawakami, A., Miyashita, T., Tanaka, F., Ida, H., Migita, K., Origuchi, T. and Eguchi, K. (2004) Cytokines regulate fibroblast-like synovial cell differentiation to adipocyte-like cells. Rheumatology, 43, 448-452.
[38] Zvaifler, N.J., Tsai, V., Alsalameh, S., von Kempis, J., Firestein, G.S. and Lotz, M. (1997) NF-KB activation provides the potential link between inflammation and hyperplasia in the arthritic joint. American Journal of Pathology, 150, 1125-1138. doi:10.1073/pnas.95.23.13859
[39] Miagkov, A.V., Kovalenko, D.V., Borwn, C.E., Didsbury, J.R., Cogswell, J.P., Stimpson, S.A., Baldin, A.S. and Makarov SS. (1998) NF-KB activation provides the potential link between inflammation and hyperplasia in the arthritic joint. Proceedings of the National Academy of Sciences of the USA, 95, 13859-13864.
[40] Bendich, A. and Langseth, L. (1995) The health effects of vitamin C supplementation: A review. Journal of the American College of Nutrition, 14, 124.
[41] Cathcart, R. F. (1984) Vitamin C in the treatment of acquired immune deficiency syndrome (AIDS). Medical Hypotheses, 14, 423. doi:10.1016/0306-9877(84)90149-X
[42] Mikirova, N.A., Ichim, T.E. and Riordan, N.H. (2008) Anti-angiogenic effect of high doses of ascorbic acid. Journal of Translational Medicine, 6.
[43] Duconge, J., Miranda-Massari, J.R., Gonzalez, M.J., Jackson, J.A., Warnock, W. and Riordan, N.H. (2008) Pharmacokinetics of vitamin C: Insights into the oral and intravenous administration of ascorbate. Puerto Rico Health Sciences Journal, 27, 7-19.
[44] Duconge, J., Miranda-Massari, J.R., González, M.J., Taylor, P.R., Riordan, H.D., Riordan, N.H., Casciari, J.J. and Alliston, K. (2007) Vitamin C pharmacokinetics after continuous infusion in a patient with prostate cancer. The Annals of Pharmacotherary, 41, 1082-1083. doi:10.1345/aph.1H654
[45] Riordan, H.D., Casciari, J.J., González, M.J., Riordan, N.H., Miranda-Massari, J.R., Taylor, P. and Jackson, J.A. (2005) A pilot clinical study of continuous intravenous ascorbate in terminal cancer patients. Puerto Rico Health Sciences Journal, 24, 269-276.
[46] Riordan HD et al (1990) Case study: High-dose intravenous Vitamin C in the treatment of a patient with adenocarcinoma of the kidney. Journal of Orthomolecular Medicine, 13.
[47] Ichim, T.E., Minev, B., Braciak, T., Luna, B., Hunninghake, R., Mikirova, N.A., Jackson, J.A., Gonzalez, M.J., Miranda-Massari, J.R., Alexandrescu, D.T., Dasanu, C., Bogin, V., Ancans, J., Stevens R.B., Markosian, B., Koropatnick, J., Chen, C.-S., and Riordan, N.H. (2011) Intravenous ascorbic acid to prevent and treat cancer-associated sepsis? Journal of Translational Medicine, 9, 25. doi:10.1186/1479-5876-9-25
[48] Mikirova, N., Casciari, J., Rogers, A. and Taylor, P. (2012) Effect of high-dose intravenous vitamin C on inflammation in cancer patients. Journal of translational medicine, 10, 189. doi:10.1186/1479-5876-10-189
[49] Ford, E.S., Liu, S., Mannino, D.M., Giles, W.H. and Smith, S.J. (2003) C-reactive protein concentration and concentrations of blood vitamins, carotenoids, and selenium among United States adults. European Journal of Clinical Nutrition, 57, 1157-1163. doi:10.1038/sj.ejcn.1601667
[50] H?rtel, C., Strunk, T., Bucsky, P. and Schultz, C. (2004) Effects of vitamin C on intracytoplasmic cytokine production in human whole blood monocytes and lymphocytes. Cytokine, 27, 101-106. doi:10.1016/j.cyto.2004.02.004
[51] Caecamo, J.M., Borquez-Ojeda, O. and Golde, D.W. (2002) Vitamin C inhibites macrophage-colony-stimulating fac- tor-induced signaling pathways. Blood, 99, 3205-3212. doi:10.1182/blood.V99.9.3205
[52] Bowie, A.G. and O’Neill, L.A.J. (2000) Vitamin C inhibits NF-kappa B activation by TNF via the activation of p38 mitogen-activated protein kinase1. The Journal of Immunology, 165, 7180-7188.
[53] Munoz, E., Blazquez, M.V., Ortiz, C., Gomez-Diaz, C. and Navas, P. (1997) Role of ascorbate in the activation of NF-kappa B by tumor necrosis factor-a in T-cells. Biochemical Journal, 325, 23.
[54] Harakeh, S., Jariwalla. R. J. (1997). NF-kappa B-inde- pendent suppression of HIV expression by ascorbic acid. AIDS Research and Human Retroviruses, 13, 235. doi:10.1089/aid.1997.13.235
[55] Bowie, A.G., Carcamo, J.M., Pedraza, A., Borquez-Qjeda, O. and Golde, D.W. (2002) Vitamin C suppresses TNFa- induced NFκB activation by inhibiting IκBα phosphorilation. Biochemistry, 41, 12995-13002. doi:10.1021/bi0263210
[56] Halliwell, B. and Gutteridge, J.M. (1999) Free Radicals in Biology and Medicine, Oxford University Press, New York.
[57] Calder, P.C., Albers, R., Antoine, J.M., et al. (2009) Inflammatory disease processes and interactions with nutrition. British Journal of Nutrition, 101, S1-S45.
[58] Boyera, N., Galey, I. and Bernard, B.A. (1998) Effect of vitamin C and its derivatives on collagen synthesis and cross-linking by normal human fibroblasts. International Journal of Cosmetic Science, 20, 151-158.
[59] Franceschi, R.T., Iyer, B.S. and Cui, Y.L. (1994) Effects of ascorbic acid on collagen matrix formation and osteoblast differentiation in murine MC3T3-E1 cells. Journal of Bone and Mineral Research, 9, 843-854.
[60] Abrams E, Sandsont J. (1964) Effect of ascorbic acid on rheumatoid synovial fluid. Annals of the Rheumatic Diseases, 23, 295. doi:10.1161/01.CIR.0000125690.80303.A8
[61] Riordan, H.D., Casciari, J.J., González, M.J., Riordan, N.H., Miranda-Massari, J.R., Taylor, P. and Jackson, J.A. (2005) A pilot clinical study of continuous intravenous ascorbate in terminal cancer patients. Puerto Rico Health Sciences Journal, 24, 269-276.
[62] Ridker, P.M. and Cook, N. (2004) Clinical usefulness of very high and very low levels of C-reactive protein across the full range of Framingham Risk Scores. Circulation, 109, 1955-1959.
[63] Goodson, N.J., Symmons, D.P., Scott, D.G., Bunn, D., Lunt, M. and Silman, A.J. (2005) Baseline levels of C-reactive protein and prediction of death from cardiovascular disease in patients with inflammatory polyarthritis: A ten-year follow up study of a primary care-based inception cohort. Arthritis & Rheumatism, 52, 2293-2299. doi:10.1002/art.21204

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