Skip to main content
Top
Published in: European Journal of Medical Research 1/2023

Open Access 01-12-2023 | Rheumatoid Arthritis | Research

Effects of metformin therapy on HMGB1 levels in rheumatoid arthritis patients

Authors: Lihua Zhang, Yuqing Zhou, Shengzhi Jiang, Yubei Fan, Jierou Huang, Bin Xiao, Hui Rao, Lingyun Huang

Published in: European Journal of Medical Research | Issue 1/2023

Login to get access

Abstract

Objective

The traditional treatment of rheumatoid arthritis (RA) has some side effects. We aimed to explore the effect of metformin treatment on the expression of HMGB1, cytokines, T cell subtypes and the clinical outcomes in RA patients.

Methods

The present prospective cohort study recruited 124 RA patients (metformin group) who were treated with metformin and conventional therapy (methotrexate, hydroxychloroquine sulfate and sulfasalazine) and 98 RA patients (conventional therapy group) who were only treated with conventional therapy. All subjects were admitted from December 2018 to December 2021 and continuous medication for 90 days. The serum high mobility group box 1 (HMGB1), tumor necrosis factor α (TNF-α), interleukin (IL)-6, IL-1β and C-reactive protein (CRP) levels were measured by enzyme-linked immunosorbent assay (ELISA). Flow cytometric were used to analyze the expression of CD4+ and CD8+. Demographic and clinical statistics including age, body mass index (BMI), sex, course of disease, erythrocyte sedimentation rate (ESR), rheumatoid factor (RF), visual analogue score (VAS)and disease activity score (DAS)-28 were collected.

Results

The serum levels of HMGB1, CRP, IL-6, CD4+ expression and CD4+/CD8+ ratio were significantly increased in patients with DAS-28 score ≥ 2.6. The serum HMGB1 and cytokines levels of metformin group declined more quickly during the study time. Pearson’s analysis supported that a positive correlation existed between the HMGB1 and IL-6, TNF-α, CRP, CD4+, CD4+/CD8+ ratio, and VAS scores. HMGB1 could be a potential diagnostic biomarker for RA patients in active phase. Serum HMGB1 (95% CI 1.133–1.397, P < 0.001) was a factor associated with active RA.

Conclusion

The serum HMGB1 levels were significantly increased in RA patients in active phase. The serum levels of HMGB1 and inflammatory factors and VAS scores were decreased gradually with metformin treatment. HMGB1 might act as a novel therapeutic target for RA.
Literature
1.
go back to reference Guo Q, Wang Y, Xu D, Nossent J, Pavlos NJ, Xu J. Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies. Bone Res. 2018;6(1):1–14.CrossRef Guo Q, Wang Y, Xu D, Nossent J, Pavlos NJ, Xu J. Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies. Bone Res. 2018;6(1):1–14.CrossRef
2.
go back to reference Aletaha D, Smolen JS. Diagnosis and management of rheumatoid arthritis: a review. JAMA. 2018;320(13):1360–72.PubMedCrossRef Aletaha D, Smolen JS. Diagnosis and management of rheumatoid arthritis: a review. JAMA. 2018;320(13):1360–72.PubMedCrossRef
4.
go back to reference Hazes JM, Dijkmans BA, Vandenbroucke JP, De Vries RR, Cats A. Lifestyle and the risk of rheumatoid arthritis: cigarette smoking and alcohol consumption. Ann Rheum Dis. 1990;49(12):980–2.PubMedPubMedCentralCrossRef Hazes JM, Dijkmans BA, Vandenbroucke JP, De Vries RR, Cats A. Lifestyle and the risk of rheumatoid arthritis: cigarette smoking and alcohol consumption. Ann Rheum Dis. 1990;49(12):980–2.PubMedPubMedCentralCrossRef
6.
go back to reference Frisell T, Saevarsdottir S, Askling J. Family history of rheumatoid arthritis: an old concept with new developments. Nat Rev Rheumatol. 2016;12(6):335–43.PubMedCrossRef Frisell T, Saevarsdottir S, Askling J. Family history of rheumatoid arthritis: an old concept with new developments. Nat Rev Rheumatol. 2016;12(6):335–43.PubMedCrossRef
7.
go back to reference Oliver JE, Silman AJ. Risk factors for the development of rheumatoid arthritis. Scand J Rheumatol. 2006;35(3):169–74.PubMedCrossRef Oliver JE, Silman AJ. Risk factors for the development of rheumatoid arthritis. Scand J Rheumatol. 2006;35(3):169–74.PubMedCrossRef
8.
go back to reference Nell VPK, Machold KP, Eberl G, Stamm TA, Uffmann M, Smolen JS. Benefit of very early referral and very early therapy with disease-modifying anti-rheumatic drugs in patients with early rheumatoid arthritis. Rheumatology. 2004;43(7):906–14.PubMedCrossRef Nell VPK, Machold KP, Eberl G, Stamm TA, Uffmann M, Smolen JS. Benefit of very early referral and very early therapy with disease-modifying anti-rheumatic drugs in patients with early rheumatoid arthritis. Rheumatology. 2004;43(7):906–14.PubMedCrossRef
9.
go back to reference Benjamin O, Bansal P, Goyal A, Lappin SL. Disease modifying anti-rheumatic drugs (DMARD). 2018. Benjamin O, Bansal P, Goyal A, Lappin SL. Disease modifying anti-rheumatic drugs (DMARD). 2018.
10.
go back to reference Grove ML, Hassell AB, Hay EM, Shadforth MF. Adverse reactions to disease-modifying anti-rheumatic drugs in clinical practice. QJM. 2001;94(6):309–19.PubMedCrossRef Grove ML, Hassell AB, Hay EM, Shadforth MF. Adverse reactions to disease-modifying anti-rheumatic drugs in clinical practice. QJM. 2001;94(6):309–19.PubMedCrossRef
11.
go back to reference Wang W, Zhou H, Liu L. Side effects of methotrexate therapy for rheumatoid arthritis: a systematic review. Eur J Med Chem. 2018;158:502–16.PubMedCrossRef Wang W, Zhou H, Liu L. Side effects of methotrexate therapy for rheumatoid arthritis: a systematic review. Eur J Med Chem. 2018;158:502–16.PubMedCrossRef
12.
13.
go back to reference Matsuoka Y, Morimoto S, Fujishiro M, Hayakawa K, Kataoka Y, Suzuki S, Ikeda K, Takamori K, Yamaji K, Tamura N. Metformin repositioning in rheumatoid arthritis. Clin Exp Rheumatol. 2020;39:763–8.PubMedCrossRef Matsuoka Y, Morimoto S, Fujishiro M, Hayakawa K, Kataoka Y, Suzuki S, Ikeda K, Takamori K, Yamaji K, Tamura N. Metformin repositioning in rheumatoid arthritis. Clin Exp Rheumatol. 2020;39:763–8.PubMedCrossRef
14.
go back to reference Salvatore T, Pafundi PC, Galiero R, Gjeloshi K, Masini F, Acierno C, Di Martino A, Albanese G, Alfano M, Rinaldi L. Metformin: a potential therapeutic tool for rheumatologists. Pharmaceuticals. 2020;13(9):234.PubMedPubMedCentralCrossRef Salvatore T, Pafundi PC, Galiero R, Gjeloshi K, Masini F, Acierno C, Di Martino A, Albanese G, Alfano M, Rinaldi L. Metformin: a potential therapeutic tool for rheumatologists. Pharmaceuticals. 2020;13(9):234.PubMedPubMedCentralCrossRef
17.
go back to reference Xue J, Li X, Liu P, Li K, Sha L, Yang X, Zhu L, Wang Z, Dong Y, Zhang L. Inulin and metformin ameliorate polycystic ovary syndrome via anti-inflammation and modulating gut microbiota in mice. Endocr J. 2019;66(10):859–70.PubMedCrossRef Xue J, Li X, Liu P, Li K, Sha L, Yang X, Zhu L, Wang Z, Dong Y, Zhang L. Inulin and metformin ameliorate polycystic ovary syndrome via anti-inflammation and modulating gut microbiota in mice. Endocr J. 2019;66(10):859–70.PubMedCrossRef
18.
go back to reference Yan N, Wang L, Li Y, Wang T, Yang L, Yan R, Wang H, Jia S. Metformin intervention ameliorates AS in ApoE-/- mice through restoring gut dysbiosis and anti-inflammation. PLoS ONE. 2021;16(7): e0254321.PubMedPubMedCentralCrossRef Yan N, Wang L, Li Y, Wang T, Yang L, Yan R, Wang H, Jia S. Metformin intervention ameliorates AS in ApoE-/- mice through restoring gut dysbiosis and anti-inflammation. PLoS ONE. 2021;16(7): e0254321.PubMedPubMedCentralCrossRef
19.
go back to reference Fan K-J, Wu J, Wang Q-S, Xu B-X, Zhao F-T, Wang T-Y. Metformin inhibits inflammation and bone destruction in collagen-induced arthritis in rats. Ann Transl Med. 2020;8(23):1565.PubMedPubMedCentralCrossRef Fan K-J, Wu J, Wang Q-S, Xu B-X, Zhao F-T, Wang T-Y. Metformin inhibits inflammation and bone destruction in collagen-induced arthritis in rats. Ann Transl Med. 2020;8(23):1565.PubMedPubMedCentralCrossRef
21.
go back to reference Deng M, Scott MJ, Fan J, Billiar TR. Location is the key to function: HMGB1 in sepsis and trauma-induced inflammation. J Leukoc Biol. 2019;106(1):161–9.PubMedCrossRef Deng M, Scott MJ, Fan J, Billiar TR. Location is the key to function: HMGB1 in sepsis and trauma-induced inflammation. J Leukoc Biol. 2019;106(1):161–9.PubMedCrossRef
22.
go back to reference Zhang T, Sun L, Wang T, Liu C, Zhang H, Zhang C, Yu L. Gestational exposure to PM2.5 leads to cognitive dysfunction in mice offspring via promoting HMGB1-NLRP3 axis mediated hippocampal inflammation. Ecotoxicol Environ Safety. 2021;223:112617.PubMedCrossRef Zhang T, Sun L, Wang T, Liu C, Zhang H, Zhang C, Yu L. Gestational exposure to PM2.5 leads to cognitive dysfunction in mice offspring via promoting HMGB1-NLRP3 axis mediated hippocampal inflammation. Ecotoxicol Environ Safety. 2021;223:112617.PubMedCrossRef
23.
go back to reference Zhao H, Gu Y, Chen H. Propofol ameliorates endotoxin-induced myocardial cell injury by inhibiting inflammation and apoptosis via the PPARγ/HMGB1/NLRP3 axis. Mol Med Rep. 2021;23(3):1–1. Zhao H, Gu Y, Chen H. Propofol ameliorates endotoxin-induced myocardial cell injury by inhibiting inflammation and apoptosis via the PPARγ/HMGB1/NLRP3 axis. Mol Med Rep. 2021;23(3):1–1.
24.
go back to reference Cecchinato V, D’Agostino G, Raeli L, Nerviani A, Schiraldi M, Danelon G, Manzo A, Thelen M, Ciurea A, Bianchi ME. Redox-mediated mechanisms fuel monocyte responses to CXCL12/HMGB1 in active rheumatoid arthritis. Front Immunol. 2018;9:2118.PubMedPubMedCentralCrossRef Cecchinato V, D’Agostino G, Raeli L, Nerviani A, Schiraldi M, Danelon G, Manzo A, Thelen M, Ciurea A, Bianchi ME. Redox-mediated mechanisms fuel monocyte responses to CXCL12/HMGB1 in active rheumatoid arthritis. Front Immunol. 2018;9:2118.PubMedPubMedCentralCrossRef
25.
go back to reference Lu X, Gong S, Wang X, Hu N, Pu D, Zhang J, Wang Y, Luo J, An Q, Ju B. Celastrol exerts cardioprotective effect in rheumatoid arthritis by inhibiting TLR2/HMGB1 signaling pathway-mediated autophagy. Int Arch Allergy Immunol. 2021;182(12):1245–54.PubMedCrossRef Lu X, Gong S, Wang X, Hu N, Pu D, Zhang J, Wang Y, Luo J, An Q, Ju B. Celastrol exerts cardioprotective effect in rheumatoid arthritis by inhibiting TLR2/HMGB1 signaling pathway-mediated autophagy. Int Arch Allergy Immunol. 2021;182(12):1245–54.PubMedCrossRef
26.
go back to reference Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham Iii CO, Birnbaum NS, Burmester GR, Bykerk VP, Cohen MD. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European league against rheumatism collaborative initiative. Arthritis Rheum. 2010;62(9):2569–81.PubMedCrossRef Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham Iii CO, Birnbaum NS, Burmester GR, Bykerk VP, Cohen MD. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European league against rheumatism collaborative initiative. Arthritis Rheum. 2010;62(9):2569–81.PubMedCrossRef
27.
go back to reference Ganji A, Farahani I, Khansarinejad B, Ghazavi A, Mosayebi G. Increased expression of CD8 marker on T-cells in COVID-19 patients. Blood Cells Mol Dis. 2020;83: 102437.PubMedPubMedCentralCrossRef Ganji A, Farahani I, Khansarinejad B, Ghazavi A, Mosayebi G. Increased expression of CD8 marker on T-cells in COVID-19 patients. Blood Cells Mol Dis. 2020;83: 102437.PubMedPubMedCentralCrossRef
28.
go back to reference Aly SS, Fayed HM, Ismail AM, Abdel Hakeem GL. Assessment of peripheral blood lymphocyte subsets in children with iron deficiency anemia. BMC Pediatr. 2018;18(1):1–6.CrossRef Aly SS, Fayed HM, Ismail AM, Abdel Hakeem GL. Assessment of peripheral blood lymphocyte subsets in children with iron deficiency anemia. BMC Pediatr. 2018;18(1):1–6.CrossRef
29.
go back to reference Otón T, Carmona L. The epidemiology of established rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2019;33(5): 101477.PubMedCrossRef Otón T, Carmona L. The epidemiology of established rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2019;33(5): 101477.PubMedCrossRef
30.
go back to reference Kim J-W, Choe J-Y, Park S-H. Metformin and its therapeutic applications in autoimmune inflammatory rheumatic disease. Korean J Intern Med. 2022;37(1):13.PubMedCrossRef Kim J-W, Choe J-Y, Park S-H. Metformin and its therapeutic applications in autoimmune inflammatory rheumatic disease. Korean J Intern Med. 2022;37(1):13.PubMedCrossRef
31.
go back to reference Han Y, Yuan F, Deng C, He F, Zhang Y, Shen H, Chen Z, Qian L. Metformin decreases LPS-induced inflammatory response in rabbit annulus fibrosus stem/progenitor cells by blocking HMGB1 release. Aging (Albany NY). 2019;11(22):10252.PubMedCrossRef Han Y, Yuan F, Deng C, He F, Zhang Y, Shen H, Chen Z, Qian L. Metformin decreases LPS-induced inflammatory response in rabbit annulus fibrosus stem/progenitor cells by blocking HMGB1 release. Aging (Albany NY). 2019;11(22):10252.PubMedCrossRef
33.
go back to reference Zhang X, Zhang X, Zhuang L, Xu C, Li T, Zhang G, Liu Y. Decreased regulatory T-cell frequency and interleukin-35 levels in patients with rheumatoid arthritis. Exp Ther Med. 2018;16(6):5366–72.PubMedPubMedCentral Zhang X, Zhang X, Zhuang L, Xu C, Li T, Zhang G, Liu Y. Decreased regulatory T-cell frequency and interleukin-35 levels in patients with rheumatoid arthritis. Exp Ther Med. 2018;16(6):5366–72.PubMedPubMedCentral
34.
go back to reference Jafari-Nakhjavani MR, Ghorbanihaghjo A, Bagherzadeh-Nobari B, Malek-Mahdavi A, Rashtchizadeh N. Serum YKL-40 levels and disease characteristics in patients with rheumatoid arthritis. Caspian J Intern Med. 2019;10(1):92.PubMedPubMedCentral Jafari-Nakhjavani MR, Ghorbanihaghjo A, Bagherzadeh-Nobari B, Malek-Mahdavi A, Rashtchizadeh N. Serum YKL-40 levels and disease characteristics in patients with rheumatoid arthritis. Caspian J Intern Med. 2019;10(1):92.PubMedPubMedCentral
35.
go back to reference Soleimani N, Hosseinzadeh M, Habibagahi Z. Value of serum glucose-6-phosphate isomerase in patients with rheumatoid arthritis and correlation with disease activity: a case–control study. J Educ Health Promot. 2019;8:125.PubMedPubMedCentral Soleimani N, Hosseinzadeh M, Habibagahi Z. Value of serum glucose-6-phosphate isomerase in patients with rheumatoid arthritis and correlation with disease activity: a case–control study. J Educ Health Promot. 2019;8:125.PubMedPubMedCentral
36.
go back to reference Wang R, Wang P. HMGB1 promotes myocardial ischemic injury and regulates the proportion of CD4+, CD8+ T cells and Th17 cells in spleen through TLR4. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2018;34(9):794–9.PubMed Wang R, Wang P. HMGB1 promotes myocardial ischemic injury and regulates the proportion of CD4+, CD8+ T cells and Th17 cells in spleen through TLR4. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2018;34(9):794–9.PubMed
37.
go back to reference Xin K, Sun J, Liu P, Ge J, Leng C, Pang F. Expression and significance of HMGB1 in patients with sepsis and effects on prognosis. All Life. 2020;13(1):164–70.CrossRef Xin K, Sun J, Liu P, Ge J, Leng C, Pang F. Expression and significance of HMGB1 in patients with sepsis and effects on prognosis. All Life. 2020;13(1):164–70.CrossRef
38.
go back to reference Amini M, Pakdaman A, Shapoori S, Mosayebi G. High mobility group box-1 (HMGB1) protein as a biomarker for acute cholecystitis. Rep Biochem Mol Biol. 2019;7(2):204.PubMedPubMedCentral Amini M, Pakdaman A, Shapoori S, Mosayebi G. High mobility group box-1 (HMGB1) protein as a biomarker for acute cholecystitis. Rep Biochem Mol Biol. 2019;7(2):204.PubMedPubMedCentral
39.
go back to reference Chen L, Long X, Xu Q, Tan J, Wang G, Cao Y, Wei J, Luo H, Zhu H, Huang L. Elevated serum levels of S100A8/A9 and HMGB1 at hospital admission are correlated with inferior clinical outcomes in COVID-19 patients. Cell Mol Immunol. 2020;17(9):992–4.PubMedCrossRef Chen L, Long X, Xu Q, Tan J, Wang G, Cao Y, Wei J, Luo H, Zhu H, Huang L. Elevated serum levels of S100A8/A9 and HMGB1 at hospital admission are correlated with inferior clinical outcomes in COVID-19 patients. Cell Mol Immunol. 2020;17(9):992–4.PubMedCrossRef
40.
go back to reference Gao N, Yan C, Zhang G. Changes of serum procalcitonin (PCT), C-reactive protein (CRP), interleukin-17 (IL-17), interleukin-6 (IL-6), high mobility group protein-B1 (HMGB1) and D-dimer in patients with severe acute pancreatitis treated with continuous renal replacement therapy (CRRT) and its clinical significance. Med Sci Monit. 2018;24:5881.PubMedPubMedCentralCrossRef Gao N, Yan C, Zhang G. Changes of serum procalcitonin (PCT), C-reactive protein (CRP), interleukin-17 (IL-17), interleukin-6 (IL-6), high mobility group protein-B1 (HMGB1) and D-dimer in patients with severe acute pancreatitis treated with continuous renal replacement therapy (CRRT) and its clinical significance. Med Sci Monit. 2018;24:5881.PubMedPubMedCentralCrossRef
41.
go back to reference Kaur I, Behl T, Bungau S, Kumar A, Mehta V, Setia D, Uddin MS, Zengin G, Aleya L, Arora S. Exploring the therapeutic promise of targeting HMGB1 in rheumatoid arthritis. Life Sci. 2020;258: 118164.PubMedCrossRef Kaur I, Behl T, Bungau S, Kumar A, Mehta V, Setia D, Uddin MS, Zengin G, Aleya L, Arora S. Exploring the therapeutic promise of targeting HMGB1 in rheumatoid arthritis. Life Sci. 2020;258: 118164.PubMedCrossRef
42.
go back to reference Pullerits R, Urbonaviciute V, Voll RE, Forsblad-D’Elia H, Carlsten H. Serum levels of HMGB1 in postmenopausal patients with rheumatoid arthritis: associations with proinflammatory cytokines, acute-phase reactants, and clinical disease characteristics. J Rheumatol. 2011;38(7):1523–5.PubMedCrossRef Pullerits R, Urbonaviciute V, Voll RE, Forsblad-D’Elia H, Carlsten H. Serum levels of HMGB1 in postmenopausal patients with rheumatoid arthritis: associations with proinflammatory cytokines, acute-phase reactants, and clinical disease characteristics. J Rheumatol. 2011;38(7):1523–5.PubMedCrossRef
43.
go back to reference Ozturk A, Bilgetekin YG, Atilla HA, Emlek M, Ersan O, Çetin E, Yalcindag A. High mobility group box-1 in patients with bacterial septic arthritis of the knee: a controlled prospective study. Erciyes Med J. 2020;42(4):463–8. Ozturk A, Bilgetekin YG, Atilla HA, Emlek M, Ersan O, Çetin E, Yalcindag A. High mobility group box-1 in patients with bacterial septic arthritis of the knee: a controlled prospective study. Erciyes Med J. 2020;42(4):463–8.
Metadata
Title
Effects of metformin therapy on HMGB1 levels in rheumatoid arthritis patients
Authors
Lihua Zhang
Yuqing Zhou
Shengzhi Jiang
Yubei Fan
Jierou Huang
Bin Xiao
Hui Rao
Lingyun Huang
Publication date
01-12-2023
Publisher
BioMed Central
Published in
European Journal of Medical Research / Issue 1/2023
Electronic ISSN: 2047-783X
DOI
https://doi.org/10.1186/s40001-023-01476-x

Other articles of this Issue 1/2023

European Journal of Medical Research 1/2023 Go to the issue