Effectivity and Safety Profile of Metformin as an Adjuvant Immunomodulator in Psoriasis: A Literature Review

Authors

  • Jessica Tjia Third Year Medical Student, Faculty of Medicine, Hasanuddin University, Makassar, 90245, Indonesia
  • Eugenia Agnes Rombelayuk Third Year Medical Student, Faculty of Medicine, Hasanuddin University, Makassar, 90245, Indonesia
  • Muh. Iqra Romadhan Third Year Medical Student, Faculty of Medicine, Hasanuddin University, Makassar, 90245, Indonesia

DOI:

https://doi.org/10.32734/sumej.v8i2.18218

Keywords:

immunomodulator, metformin, psoriasis, safety

Abstract

Background: Psoriasis is a chronic inflammatory skin disorder associated with an increased risk of comorbidities and reduced quality of life. Metformin, a first-line therapy for type 2 diabetes mellitus (T2DM), has been investigated for its potential as an adjuvant therapy for psoriasis. Objective: This literature review aims to explore the molecular mechanisms by which metformin exerts immunomodulatory effects and assess clinical studies that evaluate its efficacy and safety profile. Methods: A literature search was conducted in PubMed, MDPI, Epistemonikos, ScienceDirect, and Wiley Online Library, with the keywords: metformin AND psoriasis AND immunomodulator AND safety. Results: Qualitative synthesis revealed that metformin exhibits anti-inflammatory, anti-proliferative, and pro-apoptotic effects through induction of G0/G1 cycle arrest and  inhibition of mechanistic target of rapamycin (mTOR), nuclear factor-kappa B (NF-κB), and Raf/MEK/extracellular signal-regulated kinase (Raf/MEK/ERK) pathways. These mechanisms correlate with improvements in psoriasis severity indices, including Psoriasis Area Severity Index (PASI), Erythema, Scaling, and Induration (ESI), and Physician Global Assessment (PGA) scores (p < 0.05. A rare case of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome has been reported. Conclusion: Metformin demonstrates potential as an adjuvant immunomodulatory treatment for psoriasis. However, a rare adverse effect highlights the need for careful patient selection and evaluation.

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References

Armstrong AW, Read C. Pathophysiology, clinical presentation, and treatment of psoriasis: a review. JAMA. 2020;323(19):1945–60. Available from: https://doi.org/10.1001/jama.2020.4006.

Rendon A, Schakel K. Psoriasis pathogenesis and treatment. Int J Mol Sci. 2019;20(6):1475. Available from: https://doi.org/10.3390/ijms20061475.

Takeshita J, Grewal S, Langan SM, Mehta NN, Ogdie A, Van Voorhees AS, et al. Psoriasis and comorbid diseases: epidemiology. J Am Acad Dermatol. 2017;76(3):377–90. Available from: https://doi.org/10.1016/j.jaad.2016.07.064.

Parisi R, Iskandar IYK, Kontopantelis E, Augustin M, Griffiths CEM, Ashcroft DM. National, regional, and worldwide epidemiology of psoriasis: systematic analysis and modelling study. BMJ. 2020;369:m1590. Available from: https://doi.org/10.1136/bmj.m1590.

World Health Organization. Global report on psoriasis [Internet]. Geneva: WHO; 2016 [cited 2024 Mar 9]. Available from: https://www.who.int/publications/i/item/9789241565189.

Nitiyoso N. Pilihan pengobatan sistemik pada psoriasis. Cermin Dunia Kedokteran. 2022;49(3):164–9. Available from: https://doi.org/10.55175/cdk.v49i3.213.

Armstrong AW, Puig L, Joshi A, Kircik L, Menter A. Comparison of biologics and oral treatments for plaque psoriasis: a meta-analysis. JAMA Dermatol. 2020;156(3):258–69. Available from: https://doi.org/10.1001/jamadermatol.2019.4029.

Lee HJ, Kim M. Challenges and future trends in the treatment of psoriasis. Int J Mol Sci. 2023;24(17):13313. Available from: https://doi.org/10.3390/ijms241713313.

Kalb RE, Fiorentino DF, Lebwohl MG, Toole J, Poulin Y, Cohen AD, et al. Risk of serious infection with biologic and systemic treatment of psoriasis: results from the Psoriasis Longitudinal Assessment and Registry (PSOLAR). JAMA Dermatol. 2015;151(9):961–9. Available from: https://doi.org/10.1001/jamadermatol.2015.0718.

Abramczyk R, Plaszczyca K, Chmielik E, Szmigielska I, Wojtowicz-Prus P, Wcislo-Dziadecka D. Diabetes and psoriasis: different sides of the same prism. Diabetes Metab Syndr Obes. 2020;13:3571–7. Available from: https://doi.org/10.2147/dmso.s273147.

Brazzelli V, Maffioli P, Bolcato V, Ciolfi C, D'Angelo A, Tinelli C, et al. Psoriasis and diabetes, a dangerous association: evaluation of insulin resistance, lipid abnormalities, and cardiovascular risk biomarkers. Front Med (Lausanne). 2021 Mar 23;8:605691. Available from: https://doi.org/10.3389/fmed.2021.605691.

Lonnberg AS, Skov L, Skytthe A, Kyvik KO, Pedersen OB, Thomsen SF. Association of psoriasis with the risk for type 2 diabetes mellitus and obesity. JAMA Dermatol. 2016 Jul 1;152(7):761–7. Available from: https://doi.org/10.1001/jamadermatol.2015.6262.

Oglesby W, Kara AM, Granados H, Cervantes JL. Metformin in tuberculosis: beyond control of hyperglycemia. Infection. 2019 Oct;47(5):697–702. Available from: https://doi.org/10.1007/s15010-019-01322-5.

Malaekeh-Nikouei A, Shokri Naei S, Karbasforoushan S, Bahari H, Rahimi VB, Heidari R, et al. Metformin beyond an anti-diabetic agent: a comprehensive and mechanistic review on its effects against natural and biochemical toxins. Biomed Pharmacother. 2023 Sep;65:115263. Available from: https://doi.org/10.1016/j.biopha.2023.115263.

Bost F, Rena G, Viollet B. Metformin: beyond diabetes. Front Endocrinol (Lausanne). 2019 Dec 6;10:851. Available from: https://doi.org/10.3389/fendo.2019.00851.

Tam HTX, Thuy LND, Vinh NM, et al. The combined use of metformin and methotrexate in psoriasis patients with metabolic syndrome. Dermatol Res Pract. 2022;2022:9838867. Available from: https://doi.org/10.1155/2022/9838867.

El-Gharabawy RM, Ahmed AS, Al-Najjar AH. Mechanism of action and effect of immune-modulating agents in the treatment of psoriasis. Biomed Pharmacother. 2017;85:141–7. Available from: https://doi.org/10.1016/j.biopha.2016.11.105.

Singh S, Bhansali A. Randomized placebo control study of metformin in psoriasis patients with metabolic syndrome (systemic treatment cohort). Indian J Endocrinol Metab. 2017;21:581–7. Available from: https://doi.org/10.4103/ijem.ijem_46_17.

Singh S, Bhansali A. Randomized placebo control study of insulin sensitizers (metformin and pioglitazone) in psoriasis patients with metabolic syndrome (topical treatment cohort). BMC Dermatol. 2016;16:12. Available from: https://doi.org/10.1186/s12895-016-0049-y.

Su YJ, Chen TH, Hsu CY, Chiu WT, Lin YS, Chi CC. Safety of metformin in psoriasis patients with diabetes mellitus: a 17-year population-based real-world cohort study. J Clin Endocrinol Metab. 2019 Aug;104(8):3279–86. Available from: https://doi.org/10.1210/jc.2018-02526.

Ba W, Xu Y, Yin G, Yang J, Wang R, Chi S, et al. Metformin inhibits pro-inflammatory responses via targeting nuclear factor-kB in HaCaT cells. Cell Biochem Funct. 2019 Jan;37(1):4–10. Available from: https://doi.org/10.1002/cbf.3367.

Liu Y, Yang F, Ma W, Sun Q. Metformin inhibits proliferation and proinflammatory cytokines of human keratinocytes in vitro via mTOR-signaling pathway. Pharm Biol. 2016 Jul;54(7):1173–8. Available from: https://doi.org/10.3109/13880209.2015.1057652.

Wu J, Xiao S, Ren J, Zhang D. A unified mitochondria mechanistic target of rapamycin acyl-coenzyme A dehydrogenase 10 signal relay modulation for metformin growth inhibition in human immortalized keratinocytes cells. J Cell Biochem. 2019 Feb;120(2):1773–82. Available from: https://doi.org/10.1002/jcb.27481.

Wang X, Li R, Zhao X, Yu X, Sun Q. Metformin promotes HaCaT cell apoptosis through generation of reactive oxygen species via Raf-1-ERK1/2-Nrf2 inactivation. Inflammation. 2018 Jun;41:948–58. Available from: https://doi.org/10.1007/s10753-018-0749-z.

Matsuda-Taniguchi T, Takemura M, Nakahara T, Hashimoto-Hachiya A, Takai-Yumine A, Furue M, et al. The antidiabetic agent metformin inhibits IL-23 production in murine bone-marrow-derived dendritic cells. J Clin Med. 2021 Nov 29;10(23):5610. Available from: https://doi.org/10.3390/jcm10235610.

Tashiro T, Sawada Y. Psoriasis and systemic inflammatory disorders. Int J Mol Sci. 2022 Apr 18;23(8):4457. Available from: https://doi.org/10.3390/ijms23084457.

Patrick MT, Stuart PE, Zhang H, Zhao Q, Yin X, He K, et al. Causal relationship and shared genetic loci between psoriasis and type 2 diabetes through trans-disease meta-analysis. J Invest Dermatol. 2021 Jun;141(6):1493–502. Available from: https://doi.org/10.1016/j.jid.2020.11.025.

Brazzelli V, Maffioli P, Bolcato V, Ciolfi C, D'Angelo A, Tinelli C, et al. Psoriasis and diabetes, a dangerous association: evaluation of insulin resistance, lipid abnormalities, and cardiovascular risk biomarkers. Front Med (Lausanne). 2021 Mar 23;8:605691. Available from: https://doi.org/10.3389/fmed.2021.605691.

Sluczanowska-Glabowska S, Staniszewska M, Marchlewicz M, Duchnik E, Luczkowska K, Safranow K, et al. Adiponectin, leptin and resistin in patients with psoriasis. J Clin Med. 2023 Jan 13;12(2):663. Available from: https://doi.org/10.3390/jcm12020663.

Kielbowski K, Bakinowska E, Ostrowski P, Pala B, Gromowska E, Gurazda K, et al. The role of adipokines in the pathogenesis of psoriasis. Int J Mol Sci. 2023 Mar 28;24(7):6390. Available from: https://doi.org/10.3390/ijms24076390.

Guo Z, Yang Y, Liao Y, Shi Y, Zhang LJ. Emerging roles of adipose tissue in the pathogenesis of psoriasis and atopic dermatitis in obesity. JID Innov. 2022 Jan 1;2(1):100064. Available from: https://doi.org/10.1016/j.xjidi.2021.100064.

Woo YR, Cho DH, Park HJ. Molecular mechanisms and management of a cutaneous inflammatory disorder: psoriasis. Int J Mol Sci. 2017 Dec 11;18(12):2684. Available from: https://doi.org/10.3390/ijms18122684.

Krueger JG, Eyerich K, Kuchroo VK, Ritchlin CT, Abreu MT, Elloso MM, et al. IL-23 past, present, and future: a roadmap to advancing IL-23 science and therapy. Front Immunol. 2024 Apr 15;15:1331217. Available from: https://doi.org/10.3389/fimmu.2024.1331217.

Liu T, Li S, Ying S, Tang S, Ding Y, Li Y, et al. The IL-23/IL-17 pathway in inflammatory skin diseases: from bench to bedside. Front Immunol. 2020 Nov 17;11:594735. Available from: https://doi.org/10.3389/fimmu.2020.594735.

Korman NJ. Management of psoriasis as a systemic disease: what is the evidence? Br J Dermatol. 2020 Apr 1;182(4):840–8. Available from: https://doi.org/10.1111/bjd.18245.

Ghoreschi K, Balato A, Enerback C, Sabat R. Therapeutics targeting the IL-23 and IL-17 pathway in psoriasis. Lancet. 2021 Feb 20;397(10275):754–66. Available from: https://doi.org/10.1016/S0140-6736(21)00184-7.

Sharbaji R, Siyah P. Targeting IL-23 with small molecule inhibitors: a new horizon in psoriasis therapy. Chemistry Select. 2025 Feb;10(8):e202406013. Available from: https://doi.org/10.1002/slct.202406013.

Bridgewood C, Fearnley GW, Berekmeri A, Laws P, Macleod T, Ponnambalam S, et al. IL-36y is a strong inducer of IL-23 in psoriatic cells and activates angiogenesis. Front Immunol. 2018 Feb 26;9:200. Available from: https://doi.org/10.3389/fimmu.2018.00200.

Iznardo H, Puig L. Exploring the role of IL-36 cytokines as a new target in psoriatic disease. Int J Mol Sci. 2021 Apr 21;22(9):4344. Available from: https://doi.org/10.3390/ijms22094344.

Li W, Jin K, Luo J, Xu W, Wu Y, Zhou J, et al. NF-kB and its crosstalk with endoplasmic reticulum stress in atherosclerosis. Front Cardiovasc Med. 2022 Sep 20;9:988266. Available from: https://doi.org/10.3389/fcvm.2022.988266.

Yuan ZC, Xu WD, Liu XY, Liu XY, Huang AF, Su LC. Biology of IL-36 signaling and its role in systemic inflammatory diseases. Front Immunol. 2019 Oct 31;10:2532. Available from: https://doi.org/10.3389/fimmu.2019.02532.

Buerger C. Epidermal mTORC1 signaling contributes to the pathogenesis of psoriasis and could serve as a therapeutic target. Front Immunol. 2018 Nov 30;9:2786. Available from: https://doi.org/10.3389/fimmu.2018.02786.

Ardestani A, Lupse B, Kido Y, Leibowitz G, Maedler K. mTORC1 signaling: a double-edged sword in diabetic B cells. Cell Metab. 2018 Feb 6;27(2):314–31. Available from: https://doi.org/10.1016/j.cmet.2017.11.004.

Chun Y, Kim J. AMPK–mTOR signaling and cellular adaptations in hypoxia. Int J Mol Sci. 2021 Sep 9;22(18):9765. Available from: https://doi.org/10.3390/ijms22189765.

Fakhrioliaei A, Tanhaei S, Pakmehr S, Noori Shakir M, Qasim MT, Hariri M, et al. Potential role of Nrf2, HER2, and ALDH in cancer stem cells: a narrative review. J Membr Biol. 2024 Apr;257(1):3–16. Available from: https://doi.org/10.1007/s00232-024-00307-2.

Wu PK, Becker A, Park JI. Growth inhibitory signaling of the Raf/MEK/ERK pathway. Int J Mol Sci. 2020 Jul 30;21(15):5436. Available from: https://doi.org/10.3390/ijms21155436.

Ngo V, Duennwald ML. Nrf2 and oxidative stress: a general overview of mechanisms and implications in human disease. Antioxidants (Basel). 2022 Nov 27;11(12):2345. Available from: https://doi.org/10.3390/antiox11122345.

Ezhilarasan D. Hepatotoxic potentials of methotrexate: understanding the possible toxicological molecular mechanisms. Toxicology. 2021 Jun 30;458:152840. Available from: https://doi.org/10.1016/j.tox.2021.152840.

Berkemeyer A, Wagner E, Hashmat S, Azzam RK. Methotrexate induced hepatotoxicity in metabolic dysfunction-associated steatotic liver disease. JPGN Rep. 2024 Nov;5(4):548-51. Available from: https://doi.org/10.1002/jpr3.12127.

Chung MM, Nicol CJ, Cheng YC, Lin KH, Chen YL, Pei D, et al. Metformin activation of AMPK suppresses AGE-induced inflammatory response in hNSCs. Exp Cell Res. 2017 Mar 1;352(1):75–83. Available from: https://doi.org/10.1016/j.yexcr.2017.01.017.

Wu CY, Shieh JJ, Shen JL, Liu YY, Chang YT, Chen YJ. Association between antidiabetic drugs and psoriasis risk in diabetic patients: results from a nationwide nested case-control study in Taiwan. J Am Acad Dermatol. 2015 Jan 1;72(1):123–30. Available from: https://doi.org/10.1016/j.jaad.2014.08.042.

Muraguchi T, Nanba D, Nishimura EK, Tashiro T. IGF-1R deficiency in human keratinocytes disrupts epidermal homeostasis and stem cell maintenance. J Dermatol Sci. 2019 May 1;94(2):298–305. Available from: https://doi.org/10.1016/j.jdermsci.2019.05.001.

Kiernan K, Alwarawrah Y, Nichols AG, Danzaki K, MacIver NJ. Insulin and IGF-1 have both overlapping and distinct effects on CD4+ T cell mitochondria, metabolism, and function. Sci Rep. 2024 Feb 21;14(1):4331. Available from: https://doi.org/10.1038/s41598-024-54836-w.

Malhotra B, Hiteshi P, Khalkho P, Malik R, Bhadada SK, Bhansali A, et al. Bladder cancer with pioglitazone: a case–control study. Diabetes Metab Syndr. 2022 Nov 1;16(11):102637. Available from: https://doi.org/10.1016/j.dsx.2022.102637.

Adil M, Khan RA, Ghosh P, Venkata SK, Kandhare AD, Sharma M. Pioglitazone and risk of bladder cancer in type 2 diabetes mellitus patients: a systematic literature review and meta-analysis of observational studies using real-world data. Clin Epidemiol Glob Health. 2018 Jun 1;6(2):61–8. Available from: https://doi.org/10.1016/j.cegh.2017.08.002.

Voore P, Odigwe C, Mirrakhimov AE, Rifai D, Iroegbu NA. DRESS syndrome following metformin administration: a case report and review of the literature. Am J Ther. 2016 Nov 1;23(6):e1970–3. Available from: https://doi.org/10.1097/MJT.0000000000000292.

Calle AM, Aguirre N, Ardila JC, Villa RC. DRESS syndrome: a literature review and treatment algorithm. World Allergy Organ J. 2023 Mar 1;16(3):100673. Available from: https://doi.org/10.1016/j.waojou.2022.100673.

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Published

2025-05-01

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1.
Tjia J, Rombelayuk EA, Romadhan MI. Effectivity and Safety Profile of Metformin as an Adjuvant Immunomodulator in Psoriasis: A Literature Review. Sumat. Med. J. [Internet]. 2025May1 [cited 2025Aug.4];8(2):116-28. Available from: https://idjpcr.usu.ac.id/smj/article/view/18218

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Vol. 8 No. 2 (2025): Sumatera Medical Journal (SUMEJ)

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Literature Review

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