Silymarin (Livergol®) Decreases Disease Activity Score in Patients with Rheumatoid Arthritis: A Non-randomized Single-arm Clinical Trial
Rheumatoid arthritis (RA) is a chronic autoimmune disease, which can lead to joint destruction and disability. Pannus formation due to chronic synovitis is the hallmark of RA. Oxidative stress as a consequence of immune cell activation and disease-modifying anti-rheumatic drugs can prevent inflammation and tissue destruction. Silymarin, an antioxidant extract from Silybum marianum, has been traditionally used for the treatment of liver diseases for decades. In the present non-randomized single-arm clinical trial (NRSACT) study we evaluated the effects of silymarin tablet (Livergol®) on inflammatory markers in stable RA patients. Disease activity score (DAS-28) was measured before and after adding silymarin to standard drug regimen used for controlling inflammation in RA patients. Silymarin significantly reduced the DAS28 related symptoms in 44 RA patients after 90 days (3.02±0.98 versus 2.3±0.74, p<0.001). The exact mechanism of therapeutic effects of silymarin in RA patients is not clear but it could be as the results of its anti-inflammatory and anti-oxidative properties. Conducting the study on larger number of patients and also measuring cytokines levels including TNF-α and IL-1β may clarify the underlying mechanisms of the anti-inflammatory effects of silymarin in RA patients.
1. Firestein GS. Evolving concepts of rheumatoid arthritis. Nature 2003;423(6937):356-61.
2. Alamanos Y, Drosos AA. Epidemiology of adult rheumatoid arthritis. Autoimmunity reviews 2005;4(3):130-6.
3. Tubach F, Ravaud P, Martin‐Mola E, Awada H, Bellamy N, Bombardier C, et al. Minimum clinically important improvement and patient acceptable symptom state in pain and function in rheumatoid arthritis, ankylosing spondylitis, chronic back pain, hand osteoarthritis, and hip and knee osteoarthritis: results from a prospective multinational study. Arthritis care & research 2012;64(11):1699-707.
4. Darlington LG, Stone TW. Antioxidants and fatty acids in the amelioration of rheumatoid arthritis and related disorders. British Journal of Nutrition 2001;85(03):251-69.
5. Cordain L, Toohey L, Smith M, Hickey M. Modulation of immune function by dietary lectins in rheumatoid arthritis. British Journal of Nutrition 2000;83(3):207-17.
6. McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. New England Journal of Medicine 2011;365(23):2205-19.
7. Van de Sande M, de Hair M, Van der Leij C, Klarenbeek P, Bos W, Smith M, et al. Different stages of rheumatoid arthritis: features of the synovium in the preclinical phase. Annals of the rheumatic diseases 2011;7(5):772-7.
8. Kokkonen H, Mullazehi M, Berglin E, Hallmans G, Wadell G, Ronnelid J, et al. Antibodies of IgG, IgA and IgM isotypes against cyclic citrullinated peptide precede the development of rheumatoid arthritis. Arthritis Res Ther 2011;13(1):R13.
9. Tian J, Chen J-w, Gao J-s, Li L, Xie X. Resveratrol inhibits TNF-α-induced IL-1β, MMP-3 production in human rheumatoid arthritis fibroblast-like synoviocytes via modulation of PI3kinase/Akt pathway. Rheumatology international 2013;33(7):1829-35.
10. Shen S, Guo J, Luo Y, Zhang W, Cui Y, Wang Q, et al. Functional proteomics revealed IL-1b amplifies TNF downstream protein signals in human synoviocytes in a TNF-independent manner. Proteomics 2014;51:1b.
11. Omair M, Akhavan P, Keystone E, Xiong J, Boire G, Pope J, et al. AB0768 Relationship between das28 1.2 and sdai50 responses in rheumatoid arthritis. Annals of the Rheumatic Diseases. 2013;72(Suppl 3):A1024-A.
12. Katayama K, Okubo T, Sato T, Ito H, Fukai R, Baba H. Inhibition of radiographic joint damage in rheumatoid arthritis patients in DAS28 remission using single-or combined with methotrexate non biological disease-modifying antirheumatic drug therapy in routine clinical practice. Modern Rheumatology 2015;25(1):50-5.
13. Ohtsubo H, Ohkura S, Akimoto M, Arishima Y, Sunahara N, Izumihara T, et al. An investigation of the correlation between blood concentration of mizoribine and its efficacy in treatment of rheumatoid arthritis based on indices of drug survival and improvement in DAS28-CRP. Modern rheumatology 2012;22(6):837-43.
14. Bensen WG, Bensen W, Deamude M, Mech C, Bensen R, Lau AN, et al., editors. Validation of Snapshot, a Rheumatoid Arthritis Assessment Tool, Against CDAI, DAS28 (ESR), and DAS28 (CRP) in Canadian Patients with Rheumatoid Arthritis. ARTHRITIS & RHEUMATOLOGY; 2014: WILEY-BLACKWELL 111 RIVER ST, HOBOKEN 07030-5774, NJ USA.
15. Singh JA, Furst DE, Bharat A, Curtis JR, Kavanaugh AF, Kremer JM, et al. 2012 Update of the 2008 American College of Rheumatology recommendations for the use of disease modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis care & research. 2012;64(5):625-39.
16. Moreland LW, O'Dell JR, Paulus HE, Curtis JR, Bathon JM, St Clair EW, et al. A randomized comparative effectiveness study of oral triple therapy versus etanercept plus methotrexate in early aggressive rheumatoid arthritis: the treatment of Early Aggressive Rheumatoid Arthritis Trial. Arthritis & Rheumatism. 2012;64(9):2824-35.
17. Świerkot J, Ślęzak R, Karpiński P, Pawłowska J, Noga L, Szechiński J, et al. Associations between single-nucleotide polymorphisms of RFC-1, GGH, MTHFR, TYMS, and TCII genes and the efficacy and toxicity of methotrexate treatment in patients with rheumatoid arthritis. POLSKIE ARCHIWUM MEDYCYNY WEWNETRZNEJ-POLISH ARCHIVES OF INTERNAL MEDICINE. 2015;125(3):152-61.
18. Verschueren P, De Cock D, Corluy L, Joos R, Langenaken C, Taelman V, et al. Methotrexate in combination with other DMARDs is not superior to methotrexate alone for remission induction with moderate-to-high-dose glucocorticoid bridging in early rheumatoid arthritis after 16 weeks of treatment: the CareRA trial. Annals of the rheumatic diseases 2015;74(1):27-34.
19. Conaghan PG. A turbulent decade for NSAIDs: update on current concepts of classification, epidemiology, comparative efficacy, and toxicity. Rheumatology international 2012;32(6):1491-502.
20. Agarwal SK. Core management principles in rheumatoid arthritis to help guide managed care professionals. Journal of Managed Care Pharmacy 2011;17(9):S3.
21. Khanna D, Sethi G, Ahn KS, Pandey MK, Kunnumakkara AB, Sung B, et al. Natural products as a gold mine for arthritis treatment. Current Opinion in Pharmacology2007;7(3):344-51.
22. Shakibaei M, John T, Schulze-Tanzil G, Lehmann I, Mobasheri A. Suppression of NF-κB activation by curcumin leads to inhibition of expression of cyclo-oxygenase-2 and matrix metalloproteinase-9 in human articular chondrocytes: implications for the treatment of osteoarthritis. Biochemical pharmacology 2007;73(9):1434-45.
23. Gupta O, Sing S, Bani S, Sharma N, Malhotra S, Gupta B, et al. Anti-inflammatory and anti-arthritic activities of silymarin acting through inhibition of 5-lipoxygenase. Phytomedicine 2000;7(1):21-4.
24. Fried MW, Navarro VJ, Afdhal N, Belle SH, Wahed AS, Hawke RL, et al. Effect of silymarin (milk thistle) on liver disease in patients with chronic hepatitis C unsuccessfully treated with interferon therapy: a randomized controlled trial. Jama 2012;308(3):74-82.
25. Ross SM. Milk thistle (Silybum marianum): an ancient botanical medicine for modern times. Holistic nursing practice 2008;22(5):299-300.
26. Khan N, Monagas M, Urpi-sarda M, Llorach R, Andres-Lacueva C. Contribution of Bioactive Foods and Their Emerging Role in Immunomodulation, Inflammation, and Arthritis. Bioactive Food as Dietary Interventions for Arthritis and Related Inflammatory Diseases 2012:43-65.
27. Girish C, Pradhan S. Hepatoprotective activities of picroliv, curcumin, and ellagic acid compared to silymarin on carbon-tetrachloride-induced liver toxicity in mice. Journal of pharmacology & pharmacotherapeutics 2012;3(2):149.
28. Longmore B. Herbal treatment for arthritis pain. Australian Pharmacist 2013;32(3):56.
29. Kang JS, Jeon YJ, Park S-K, Yang K-H, Kim HM. Protection against lipopolysaccharide-induced sepsis and inhibition of interleukin-1β and prostaglandin E2 synthesis by silymarin. Biochemical pharmacology 2004;67(1):175-81.
30. Tamayo C, Diamond S. Review of clinical trials evaluating safety and efficacy of milk thistle (Silybum marianum [L.] Gaertn.). Integrative cancer therapies 2007;6(2):146-57.
31. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis & Rheumatism 2010;62(9):2569-81.
32. Smolen J, Aletaha D. The assessment of disease activity in rheumatoid arthritis. Clinical and experimental rheumatology 2009;28(3 Suppl 59):S18-27.
33. Furst D, Ulrich R, Varkey-Altamirano C. Nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, nonopioid analgesics, and drugs used in gout. Basic and clinical pharmacology. 2001;11:621-42.
34. Theander E, Horrobin DF, Jacobsson LT, Manthorpe R. Gammalinolenic acid treatment of fatigue associated with primary Sjögren's syndrome. Scandinavian journal of rheumatology 2002;31(2):72-9.
35. Furse R. Oral Administration of Gamma Linoleic Acid, an Unsaturated Fatty Acid with..., Modulates Interleukin-1beta Production by Human Monocytes. Journal of Clinical Immunology 2002;22(2):83-91.
36. Fiebich B, Heinrich M, Hiller K, Kammerer N. Inhibition of TNF-α synthesis in LPS-stimulated primary human monocytes by Harpagophytum extract SteiHap 69. Phytomedicine 2001;8(1):28-30.
37. Singh S. Comparative evaluation of antiinflammatory potential of fixed oil of different species of Ocimum and its possible mechanism of action. Indian journal of experimental biology 1998;36(10):1028-31.
38. Vane J. The fight against rheumatism: from willow bark to COX-1 sparing drugs. Journal of physiology and pharmacology 2000;1(4):51-7.
39. Chrubasik S, Künzel O, Thanner J, Conradt C, Black A. A 1-year follow-up after a pilot study with Doloteffin® for low back pain. Phytomedicine 2005;12(1):1-9.
40. Chrubasik S, Model A, Black A, Pollak S. A randomized double‐blind pilot study comparing Doloteffin® and Vioxx® in the treatment of low back pain. Rheumatology 2003;42(1):141-8.
41. Naderi M, Oliazadeh N, Jamshidi A, Ahmadi Ashtiani H, Jafarzadeh M, Taheri Boroujerdi M. A key to thousand unlock: Comprehensive review of herbal medicine (Silymarin) and Introducing of Silybum> marianum. Tehran: Noavar. 2007.
42. Abascal K, Yarnell E. The many faces of Silybum marianum (milk thistle): part 2-clinical uses, safety, and types of preparations. Alternative & Complementary Therapies 2003;9(5):251-6.
43. Saller R, Meier R, Brignoli R. The use of silymarin in the treatment of liver diseases. Drugs 2001;61(14):2035-63.
44. Saliou C, Valacchi G, Rimbach G. Assessing bioflavonoids as regulators of NF-κB activity and inflammatory gene expression in mammalian cells. Methods in enzymology 2001;335:380-7.
45. Yoo HG, Jung SN, Hwang YS, Park JS, Kim MH, Jeong M, et al. Involvement of NF-κB and caspases in silibinin-induced apoptosis of endothelial cells. International journal of molecular medicine 2004;13(1):81-6.
|Issue||Vol 16, No 2 (2017)|
|Disease activity score DAS 28 Rheumatoid arthritis Silymarin|
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