2022, Volume 16, Issue 9
Engineering >> 2022, Volume 16, Issue 9 doi: 10.1016/j.eng.2021.04.014
The Correlation Between Decreased Ornithine Level and Alleviation of Rheumatoid Arthritis Patients Assessed by a Randomized, Placebo-Controlled, Double-Blind Clinical Trial of Sinomenine
a Department of Rheumatology, The Southwest Hospital of Army Military Medical University, Chongqing 400038, China
b State Key Laboratory of Dampness Syndrome Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510000, China
c State Key Laboratory of Quality Research in Chinese Medicine & Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology,
Macao 999078, China
d People’s Hospital of Changshou Chongqing, Chongqing 401220, China
e Traditional Chinese Medicine Hospital Dianjiang Chongqing, Chongqing 408300, China
f Medical Management Center, World Federation of Chinese Medicine Societies, Beijing 100101, China
# These authors contributed equally to this work.
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Abstract
Sinomenine (SIN) is commonly used as part of rheumatoid arthritis (RA) therapy in China, but there is still no published evidence of the efficacy of SIN monotherapy. This work investigates the efficacy and safety of SIN in treating RA patients and analyzes the correlation between ornithine level and the alleviation of disease activity in RA patients. In this 24 week, randomized, placebo-controlled, double-blind clinical trial, people with mild to moderate RA were randomly assigned (1:1:1, stratified by hospital) to receive SIN (120 mg, twice daily), methotrexate (MTX) (10 mg per week), or SIN + MTX therapy. The primary outcome was the proportion of patients who achieved a 50% improvement in the American College of Rheumatology (ACR) criteria at week 24 and who showed improvement according to the clinical disease activity index (CDAI). In this prospective subgroup analysis, we also assessed whether the 24 week alterations of disease activity in the treatment group were significantly correlated to the levels of blood ornithine. Of the 135 enrolled participants, 38, 39, and 36 patients were treated with SIN, MTX, and SIN + MTX, respectively. In the SIN-treated group, 52.63% of patients achieved ACR50 after 24 weeks of treatment, which was comparable to the results in the MTX-treated and SIN + MTX-treated groups. Hepatic and gastrointestinal disorders were the main adverse events; however, the ratio of patients suffering from hepatic disorder in the SIN group (1/38) was much lower than that in the MTX (10/39) and SIN + MTX (8/36) groups. A total of 221 serum samples were collected at the four follow-up time points in the three treatments, and the levels of ornithine, citrulline, and arginine were obtained through ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF/MS). The serum ornithine level decreased after the 24 week treatment along with a decrease in disease activity, and may reflect therapeutic responses with a sensitivity value of 80%. In conclusion, SIN revealed a comparable efficacy to MTX for treating RA patients, but with fewer side effects. In addition, the serum ornithine level was found for the first time to have a close correlation with the alleviation of RA, which shows the value of this measure as an assessment indicator of drugs in treating RA.
Keywords
Rheumatoid arthritis ; Sinomenine ; Efficacy ; Safety ; Inflammatory biomarker
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References
[ 1 ] Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet 2016;388 (10055):2023–38. link1
[ 2 ] Sparks JA. Rheumatoid arthritis. Ann Intern Med 2019;170(1):ITC1–16. link1
[ 3 ] Van Vollenhoven R. Treat-to-target in rheumatoid arthritis—are we there yet? Nat Rev Rheumatol 2019;15(3):180–6. link1
[ 4 ] Conigliaro P, Triggianese P, de Martino E, Fonti GL, Chimenti MS, Sunzini F, et al. Challenges in the treatment of rheumatoid arthritis. Autoimmun Rev 2019;18(7):706–13. link1
[ 5 ] Yu C, Li M, Duan X, Fang Y, Li Q, Wu R, et al.; the co-authors of CREDIT. Chinese registry of rheumatoid arthritis (CREDIT): I. introduction and prevalence of remission in Chinese patients with rheumatoid arthritis. Clin Exp Rheumatol 2018;36(5):836–40. link1
[ 6 ] Gavigan K, Nowell WB, Serna MS, Stark JL, Yassine M, Curtis JR. Barriers to treatment optimization and achievement of patients’ goals: perspectives from people living with rheumatoid arthritis enrolled in the ArthritisPower registry. Arthritis Res Ther 2020;22(1):4. link1
[ 7 ] Crowson CS, Rahman MU, Matteson EL. Which measure of inflammation to use? A comparison of erythrocyte sedimentation rate and C-reactive protein measurements from randomized clinical trials of golimumab in rheumatoid arthritis. J Rheumatol 2009;36(8):1606–10. link1
[ 8 ] Huang RY, Pan HD, Wu JQ, Zhou H, Li ZG, Qiu P, et al. Comparison of combination therapy with methotrexate and sinomenine or leflunomide for active rheumatoid arthritis: a randomized controlled clinical trial. Phytomedicine 2019;57:403–10. link1
[ 9 ] Chen XM, Huang RY, Huang QC, Chu YL, Yan JY. Systemic review and metaanalysis of the clinical efficacy and adverse effects of Zhengqing Fengtongning combined with methotrexate in rheumatoid arthritis. Evid Based Complement Alternat Med 2015;2015:910376. link1
[10] Chandrasekharan UM, Wang Z, Wu Y, Tang WHW, Hazen SL, Wang S, et al. Elevated levels of plasma symmetric dimethylarginine and increased arginase activity as potential indicators of cardiovascular comorbidity in rheumatoid arthritis. Arthritis Res Ther 2018;20(1):123. link1
[11] Huffman KM, Jessee R, Andonian B, Davis BN, Narowski R, Huebner JL, et al. Molecular alterations in skeletal muscle in rheumatoid arthritis are related to disease activity, physical inactivity, and disability. Arthritis Res Ther 2017;19 (1):12. link1
[12] Abdelkarem HM, Fadda LH, El-Sayed EM, Radwan OK. Potential role of Larginine and vitamin E against bone loss induced by nano-zinc oxide in rats. J Diet Suppl 2018;15(3):300–10. link1
[13] Hu Y, Li B, Wen L, He K. Study on the anti-endotoxin effect of sinomenine using an Agilent genome array. QJM 2018;111(3):171–8. link1
[14] Van der Linden MP, Knevel R, Huizinga TW, van der Helm-van Mil AH. Classification of rheumatoid arthritis: comparison of the 1987 American College of Rheumatology criteria and the 2010 American College of Rheumatology/European League Against Rheumatism criteria. Arthritis Rheum 2011;63(1):37–42. link1
[15] Bian X, Li N, Tan B, Sun B, Guo MQ, Huang G, et al. Polarity-tuning derivatization-LC-MS approach for probing global carboxyl-containing metabolites in colorectal cancer. Anal Chem 2018;90(19):11210–5. link1
[16] 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 Rheum 2010;62(9):2569–81. link1
[17] Aletaha D, Smolen J. The Simplified Disease Activity Index (SDAI) and the Clinical Disease Activity Index (CDAI): a review of their usefulness and validity in rheumatoid arthritis. Clin Exp Rheumatol 2005;23(5 Suppl 39):S100–8. link1
[18] Trang LE, Fürst P, Odeback AC, Lövgren O. Plasma amino acids in rheumatoid arthritis. Scand J Rheumatol 1985;14(4):393–402. link1
[19] Partsch G, Tausch G, Eberl R. Plasma amino acid level in rheumatoid arthritis and ankylosing spondylitis and its variation during age. Z Rheumatol 1978;37 (3–4):105–11. link1
[20] Mäntyselkä P, Ali-Sisto T, Kautiainen H, Niskanen L, Viinamäki H, Velagapudi V, et al. The association between musculoskeletal pain and circulating ornithine: a population-based study. Pain Med 2017;18(6):1145–51. link1
[21] Marini JC, Didelija IC, Castillo L, Lee B. Plasma arginine and ornithine are the main citrulline precursors in mice infused with arginine-free diets. J Nutr 2010;140(8):1432–7. link1
[22] Senft AW. Studies in arginine metabolism by schistosomes. II. Arginine depletion in mammals and snails infected with S. mansoni or S. hematobium. Comp Biochem Physiol 1967;21(2):299–306. link1
[23] Curran AM, Naik P, Giles JT, Darrah E. PAD enzymes in rheumatoid arthritis: pathogenic effectors and autoimmune targets. Nat Rev Rheumatol 2020;16 (6):301–15. link1
[24] Schellekens GA, de Jong BA, van den Hoogen FH, van de Putte LB, van Venrooij WJ. Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies. J Clin Invest 1998;101 (1):273–81. link1
[25] Yoshida M, Tsuji M, Kurosaka D, Kurosaka D, Yasuda J, Ito Y, et al. Autoimmunity to citrullinated type II collagen in rheumatoid arthritis. Mod Rheumatol 2006;16(5):276–81. link1
[26] McNearney T, Speegle D, Lawand N, Lisse J, Westlund KN. Excitatory amino acid profiles of synovial fluid from patients with arthritis. J Rheumatol 2000;27 (3):739–45. link1
[27] McNearney T, Baethge BA, Cao S, Alam R, Lisse JR, Westlund KN. Excitatory amino acids, TNF-a, and chemokine levels in synovial fluids of patients with active arthropathies. Clin Exp Immunol 2004;137(3):621–7. link1
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