Circulating Mir-140 and leptin improve the accuracy of the differential diagnosis between psoriatic arthritis and rheumatoid arthritis: a case-control study

  • Sara Cheleschi
    Reprint requests: Sara Cheleschi, Department of Medicine, Surgery and Neuroscience, Rheumatology Unit, University of Siena, Policlinico Le Scotte, Viale Bracci 1, 53100 Siena, Italy.
    Rheumatology Unit, Department of Medicine, Surgery and Neuroscience, Azienda Ospedaliera Universitaria Senese, Viale Bracci 1, Siena, Italy
    Search for articles by this author
  • Sara Tenti
    Rheumatology Unit, Department of Medicine, Surgery and Neuroscience, Azienda Ospedaliera Universitaria Senese, Viale Bracci 1, Siena, Italy
    Search for articles by this author
  • Author Footnotes
    # These Authors contributed equally to the manuscript.
    Giorgio Bedogni
    # These Authors contributed equally to the manuscript.
    Data Science, Qeios, London, UK
    Search for articles by this author
  • Author Footnotes
    # These Authors contributed equally to the manuscript.
    Antonella Fioravanti
    # These Authors contributed equally to the manuscript.
    Rheumatology Unit, Department of Medicine, Surgery and Neuroscience, Azienda Ospedaliera Universitaria Senese, Viale Bracci 1, Siena, Italy
    Search for articles by this author
  • Author Footnotes
    # These Authors contributed equally to the manuscript.
Published:August 08, 2021DOI:
      The differential diagnosis of psoriatic arthritis (PsA) and rheumatoid arthritis (RA) is difficult because of the lack of diagnostic clinical signs and reliable biomarkers. This study investigated microRNAs (miRNA) and adipokines as potential additional markers to discriminate PsA from RA. The expression profile of miRNA (miR-21, miR-140, miR-146a, miR-155, miR-181b, miR-223, miR-let-7e) and inflammatory cytokines (IL-1β, IL-6, IL-17a, IL-23a, TNF-α) from peripheral blood mononuclear cells of PsA and RA patients compared to healthy controls (HC) were evaluated by real-time PCR, and serum adipokines (adiponectin, chemerin, leptin, resistin, visfatin) and cytokines by ELISA assay. Univariable binary logistic regression was used to find the association between PsA and potential predictors. The gene expression of miRNA and cytokines and the serum levels of adipokines were found significantly different in PsA and RA patients compared to HC, as well as in PsA versus RA. MiR-140 gene expression resulted up-regulated in PsA patients and reduced in RA in comparison to HC, and, for the first time, significantly higher in PsA compared with RA. Serum levels of IL-23a and leptin were significantly increased in PsA and RA populations than in HC, as well as in PsA versus RA. Furthermore, circulating TNF-α was up-regulated in PsA and RA in comparison to controls, while resulted higher in RA than in PsA. Univariable binary logistic regression analysis found the above-mentioned markers associated to PsA versus RA. Our results first demonstrated an increased expression of circulating miR-140 and serum leptin in PsA patients compared to RA, which were identified as potential additional biomarkers to discriminate PsA from RA. Since the differential diagnosis of PsA and RA poses challenges in clinical practice, our data may help to enhance the diagnostic performance of PsA in daily practice.


      To read this article in full you will need to make a payment


        • Coates LC
        • Helliwell PS.
        Psoriatic arthritis: state of the art review.
        Clin Med (Lond). 2017; 17: 65-70
        • Rida MA
        • Chandran V.
        Challenges in the clinical diagnosis of psoriatic arthritis.
        Clin Immunol. 2020; 214108390
        • Aletaha D
        • Smolen JS.
        Diagnosis and management of rheumatoid arthritis: a review.
        JAMA. 2018; 320: 1360-1372
        • Alivernini S
        • Bruno D
        • Tolusso B
        • et al.
        Differential synovial tissue biomarkers among psoriatic arthritis and rheumatoid factor/anti-citrulline antibody-negative rheumatoid arthritis.
        Arthritis Res Ther. 2019; 21: 116
        • Souto-Carneiro M
        • Tóth L
        • Behnisch R
        • et al.
        Differences in the serum metabolome and lipidome identify potential biomarkers for seronegative rheumatoid arthritis versus psoriatic arthritis.
        Ann Rheum Dis. 2020; 79: 499-506
        • Lu TX
        • MicroRNA Rothenberg ME.
        J Allergy Clin Immunol. 2018; 141: 1202-1207
        • De Palma A
        • Cheleschi S
        • Pascarelli NA
        • Tenti S
        • Galeazzi M
        • Fioravanti A.
        Do MicroRNAs have a key epigenetic role in osteoarthritis and in mechanotransduction?.
        Clin Exp Rheumatol. 2017; 35: 518-526
        • Ciancio G
        • Ferracin M
        • Saccenti E
        • et al.
        Characterisation of peripheral blood mononuclear cell microRNA in early onset psoriatic arthritis.
        Clin Exp Rheumatol. 2017; 35: 113-121
        • Pelosi A
        • Lunardi C
        • Fiore PF
        • et al.
        MicroRNA expression profiling in psoriatic arthritis.
        Biomed Res Int. 2018; 20187305380
        • Treiber T
        • Treiber N
        • Meister G.
        Regulation of microRNA biogenesis and its crosstalk with other cellular pathways.
        Nat Rev Mol Cell Biol. 2019; 20 (Erratum in: Nat Rev Mol Cell Biol. 2018;19(12):808. Nat Rev Mol Cell Biol. 2019;20(5):321): 5-20
        • Martínez-Hernández R
        • Fuente H
        • Lamana A
        • et al.
        Utility of circulating serum miRNA profiles to evaluate the potential risk and severity of immune-mediated inflammatory disorders.
        J Autoimmun. 2020; 102472
        • Chen XM
        • Zhao Y
        • Wu XD
        • et al.
        Novel findings from determination of common expressed plasma exosomal microRNAs in patients with psoriatic arthritis, psoriasis vulgaris, rheumatoid arthritis, and gouty arthritis.
        Discov Med. 2019; 28: 47-68
        • Lin SH
        • Ho JC
        • Li SC
        • Chen JF
        • Hsiao CC
        • Lee CH.
        MiR-146a-5p expression in peripheral CD14⁺ monocytes from patients with psoriatic arthritis induces osteoclast activation, bone resorption, and correlates with clinical response.
        J Clin Med. 2019; 8 (pii: E110)
        • Wade SM
        • McGarry T
        • Wade SC
        • Fearon U
        • Veale DJ.
        Serum microRNA signature as a diagnostic and therapeutic marker in patients with psoriatic arthritis.
        J Rheumatol. 2020; 47: 1760-1767
      1. Pasquali L, Svedbom A, Srivastava A, et al. Circulating microRNAs in extracellular vesicles as potential biomarkers for psoriatic arthritis in patients with psoriasis. 2020;34:1248-56. doi:10.1111/jdv.16203.

        • Mookherjee N
        • El-Gabalawy HS.
        High degree of correlation between whole blood and PBMC expression levels of miR-155 and miR-146a in healthy controls and rheumatoid arthritis patients.
        J Immunol Methods. 2013; (106-10): 400-401
        • Filková M
        • Aradi B
        • Senolt L
        • et al.
        Association of circulating miR-223 and miR-16 with disease activity in patients with early rheumatoid arthritis.
        Ann Rheum Dis. 2014; 73: 1898-1904
        • Dunaeva M
        • Blom J
        • Thurlings R
        • Pruijn GJM.
        Circulating serum miR-223-3p and miR-16-5p as possible biomarkers of early rheumatoid arthritis.
        Clin Exp Immunol. 2018; 193: 376-385
        • Liu Y
        • Han Y
        • Qu H
        • Fang J
        • Ye M
        • Yin W
        Correlation of microRNA expression profile with clinical response to tumor necrosis factor inhibitor in treating rheumatoid arthritis patients: a prospective cohort study.
        J Clin Lab Anal. 2019; 33: e22953
        • Neumann E
        • Junker S
        • Schett G
        • Frommer K
        • Müller-Ladner U.
        Adipokines in bone disease.
        Nat Rev Rheumatol. 2016; 12: 296-302
        • Carrión M
        • Frommer KW
        • Pérez-García S
        • Müller-Ladner U
        • Gomariz RP
        • Neumann E.
        The adipokine network in rheumatic joint diseases.
        Int J Mol Sci. 2019; 20 (pii: E4091)
        • Cantarini L
        • Simonini G
        • Fioravanti A
        • et al.
        Circulating levels of the adipokines vaspin and omentin in patients with juvenile idiopathic arthritis, and relation to disease activity.
        Clin Exp Rheumatol. 2011; 29: 1044-1048
        • Fioravanti A
        • Simonini G
        • Cantarini L
        • et al.
        Circulating levels of the adipocytokines vaspin and omentin in patients with Kawasaki disease.
        Rheumatol Int. 2012; 32: 1481-1482
        • Tenti S
        • Palmitesta P
        • Giordano N
        • Galeazzi M
        • Fioravanti A
        Increased serum leptin and visfatin levels in patients with diffuse idiopathic skeletal hyperostosis: a comparative study.
        Scand J Rheumatol. 2017; 46: 156-158
        • Fioravanti A
        • Cheleschi S
        • De Palma A
        • et al.
        Can adipokines serum levels be used as biomarkers of hand osteoarthritis?.
        Biomarkers. 2018; 23: 265-270
        • Fioravanti A
        • Tenti S
        • Bacarelli MR
        • et al.
        Tocilizumab modulates serum levels of adiponectin and chemerin in patients with rheumatoid arthritis: potential cardiovascular protective role of IL-6 inhibition.
        Clin Exp Rheumatol. 2019; 37: 293-300
        • Lee YH
        • Bae SC.
        Circulating leptin level in rheumatoid arthritis and its correlation with disease activity: a meta-analysis.
        Z Rheumatol. 2016; 75: 1021-1027
        • Cao H
        • Lin J
        • Chen W
        • Xu G
        • Sun C
        Baseline adiponectin and leptin levels in predicting an increased risk of disease activity in rheumatoid arthritis: a meta-analysis and systematic review.
        Autoimmunity. 2016; 49: 547-553
        • Lee YH
        • Bae SC.
        Circulating adiponectin and visfatin levels in rheumatoid arthritis and their correlation with disease activity: a meta-analysis.
        Int J Rheum Dis. 2018; 21: 664-672
        • Tolusso B
        • Gigante MR
        • Alivernini S
        • et al.
        Chemerin and PEDF are metaflammation-related biomarkers of disease activity and obesity in rheumatoid arthritis.
        Front Med (Lausanne). 2018; 5: 207
        • MᵃᶜDonald IJ
        • Liu SC
        • Huang CC
        • Kuo SJ
        • Tsai CH
        • Tang CH.
        Associations between adipokines in arthritic disease and implications for obesity.
        Int J Mol Sci. 2019; 20: 1505
        • Xue Y
        • Jiang L
        • Cheng Q
        • et al.
        Adipokines in psoriatic arthritis patients: the correlations with osteoclast precursors and bone erosions.
        PLoS One. 2012; 7: e46740
        • Eder L
        • Jayakar J
        • Pollock R
        • et al.
        Serum adipokines in patients with psoriatic arthritis and psoriasis alone and their correlation with disease activity.
        Ann Rheum Dis. 2013; 72: 1956-1961
        • Dikbas O
        • Tosun M
        • Bes C
        • Tonuk SB
        • Aksehirli OY
        • Soy M.
        Serum levels of visfatin, resistin and adiponectin in patients with psoriatic arthritis and associations with disease severity.
        Int J Rheum Dis. 2016; 19: 672-677
        • Feld J
        • Nissan S
        • Eder L
        • et al.
        Increased prevalence of metabolic syndrome and adipocytokine levels in a psoriatic arthritis cohort.
        J Clin Rheumatol. 2018; 24: 302-307
        • Caso F
        • Postiglione L
        • Covelli B
        • et al.
        Pro-inflammatory adipokine profile in psoriatic arthritis: results from a cross-sectional study comparing PsA subset with evident cutaneous involvement and subset "sine psoriasis".
        Clin Rheumatol. 2019; 38: 2547-2552
        • Toussirot E
        • Aubin F
        • Desmarets M
        • et al.
        Visceral adiposity in patients with psoriatic arthritis and psoriasis alone and its relationship with metabolic and cardiovascular risk.
        Rheumatology (Oxford). 2020; : keaa720
        • Taylor W
        • Gladman D
        • Helliwell P
        • et al.
        Classification criteria for psoriatic arthritis: development of new criteria from a large international study.
        Arthritis Rheum. 2006; 54: 2665-2673
        • Aletaha D
        • Neogi T
        • Silman AJ
        • Funovits J
        • Felson DT
        • Bingham 3rd, CO
        2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative.
        Arthritis Rheum. 2010; 62: 2569-2581
        • Lohman TG
        • Roche AF
        • Martorell R.
        Anthropometric standardization reference manual.
        Human Kinetics Books, Champaign, Illinois1991
        • Health National Institutes of
        Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults. the evidence report. national institutes of health.
        Obes Res. 1998; 6: 51S-209S
      2. Executive summary of the third report of the national cholesterol education program (NCEP) (2001) Expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 285:2486–97.

        • Bruce B
        • Fries JF.
        The Stanford Health Assessment Questionnaire: dimensions and practical applications.
        Health Qual Life Outcomes. 2003; 1: 20
        • Prevoo MLL
        • van Riel PLCM
        • van T'hof MA
        • et al.
        Validity and reliability of joint indices. a longitudinal study in patients with recent onset rheumatoid arthritis.
        Br J Rheumatol. 1993; 32: 589-594
        • Acosta Felquer ML
        • Ferreyra Garrott L
        • Marin J
        • et al.
        Remission criteria and activity indices in psoriatic arthritis.
        Clin Rheumatol. 2014; 33: 1323-1330
        • Fredriksson T
        • Pettersson U
        Severe psoriasis – oral therapy with a new retinoid.
        Dermatologica. 1978; 157 (Feldman SR, Krueger GG. Psoriasis assessment tools in clinical trials. Ann Rheum Dis 2005; 64:65–73): 238-244
        • Morozzi G
        • Bellisai F
        • Fioravanti A
        • Galeazzi M.
        Absence of anti-cyclic citrullinated peptide antibodies in erosive osteoarthritis: further serological evidence of the disease as a subset of osteoarthritis.
        Ann Rheum Dis. 2005; 64: 1095-1096
        • Fioravanti A
        • Tenti S
        • McAllister M
        • et al.
        Exploring the Involvement of NLRP3 and IL-1β in Osteoarthritis of the hand: results from a pilot study.
        Mediators Inflamm. 2019; 20192363460
        • Cheleschi S
        • Barbarino M
        • Gallo I
        • et al.
        Hydrostatic pressure regulates oxidative stress through microRNA in human osteoarthritic chondrocytes.
        Int J Mol Sci. 2020; 21: 3653
        • Ramakers C
        • Ruijter JM
        • Deprez RH
        • Moorman AF.
        Assumption-free analysis of quantitative real-timepolymerase chain reaction (PCR) data.
        Neurosci Lett. 2003; 339: 62-66
        • Harris T
        • Hardin JW.
        Exact Wilcoxon signed-rank and Wilcoxon Mann–Whitney ranksum tests.
        Stata J. 2013; 13: 337-343
        • Steyerberg EW.
        Clinical prediction models.
        Springer International, Cham, Switzerland2019
        • Royston P
        • Sauerbrei W.
        Multivariable model-building: a pragmatic approach to regression analysis based on fractional polynomials for modelling continuous variables.
        John Wiley, Chichester2008
        • Royston P
        • Sauerbrei W.
        Two techniques for investigating interactions between treatment and continuous covariates in clinical trials.
        Stata J. 2009; 9: 230-251
        • Weisberg S.
        Applied linear regression.
        Wiley, Hoboken2014
        • Vander Cruyssen B
        • Hoffman IE
        • Zmierczak H
        • et al.
        Anti-citrullinated peptide antibodies may occur in patients with psoriatic arthritis.
        Ann Rheum Dis. 2005; 64: 1145-1149
        • Merola JF
        • Espinoza LR
        • Fleischmann R.
        Distinguishing rheumatoid arthritis from psoriatic arthritis.
        RMD Open. 2018; 4e000656
        • Jang DI
        • Lee AH
        • Shin HY
        • et al.
        The role of tumor necrosis factor alpha (TNF-α) in autoimmune disease and current TNF-α inhibitors in therapeutics.
        Int J Mol Sci. 2021; 22: 2719
        • Mohanakrishnan R
        • Beier S
        • Deodhar A.
        IL-23 inhibition for the treatment of psoriatic arthritis.
        Expert Opin Biol Ther. 2021; (Epub ahead of print)
        • Su LC
        • Huang AF
        • Jia H
        • Liu Y
        • Xu WD.
        Role of microRNA-155 in rheumatoid arthritis.
        Int J Rheum Dis. 2017; 20: 1631-1637
        • Bae SC
        • Lee YH.
        MiR-146a levels in rheumatoid arthritis and their correlation with disease activity: a meta-analysis.
        Int J Rheum Dis. 2018; 21 (P): 1335-1342
        • Evangelatos G
        • Fragoulis GE
        • Koulouri V
        • Lambrou GI.
        MicroRNAs in rheumatoid arthritis: From pathogenesis to clinical impact.
        Autoimmun Rev. 2019; 18102391
        • Sekar D.
        Implications of microRNA 21 and its involvement in the treatment of different type of arthritis.
        Mol Cell Biochem. 2020;
        • Rezaeepoor M
        • Pourjafar M
        • Tahamoli-Roudsari A
        • Basiri Z
        • Hajilooi M
        • Solgi G.
        Altered expression of microRNAs may predict therapeutic response in rheumatoid arthritis patients.
        Int Immunopharmacol. 2020; 83106404
        • Taha M
        • Shaker OG
        • Abdelsalam E
        • Taha N.
        Serum a proliferation-inducing ligand and MicroRNA-223 are associated with rheumatoid arthritis: diagnostic and prognostic implications.
        Mol Med. 2020; 26: 92
        • Ormseth MJ
        • Solus JF
        • Sheng Q
        • et al.
        Development and validation of a microRNA panel to differentiate between patients with rheumatoid arthritis or systemic lupus erythematosus and controls.
        J Rheumatol. 2020; 47: 188-196
        • Yuan Y
        • Shen Y
        • Xue L
        • Fan H.
        miR-140 suppresses tumor growth and metastasis of non-small cell lung cancer by targeting insulin-like growth factor 1 receptor.
        PLoS One. 2013; 8: e73604
        • Ntoumou E
        • Tzetis M
        • Braoudaki M
        • et al.
        Serum microRNA array analysis identifies miR-140-3p, miR-33b-3p and miR-671-3p as potential osteoarthritis biomarkers involved in metabolic processes.
        Clin Epigenetics. 2017; 9: 127
        • Cheleschi S
        • Giordano N
        • Volpi N
        • et al.
        A Complex Relationship between visfatin and resistin and microRNA: an in vitro study on human chondrocyte cultures.
        Int J Mol Sci. 2018; 19: 3909
        • Peng JS
        • Chen SY
        • Wu CL
        • et al.
        Amelioration of experimental autoimmune arthritis through targeting of synovial fibroblasts by intraarticular delivery of microRNAs 140-3p and 140-5p.
        Arthritis Rheumatol. 2016; 68: 370-381
        • Niederer F
        • Ospelt C
        • Brentano F
        • et al.
        SIRT1 overexpression in the rheumatoid arthritis synovium contributes to proinflammatory cytokine production and apoptosis resistance.
        Ann Rheum Dis. 2011; 70: 1866-1873
        • Takata A
        • Otsuka M
        • Kojima K
        • et al.
        MicroRNA-22 and microRNA-140 suppress NF-κB activity by regulating the expression of NF-κB coactivators.
        Biochem Biophys Res Commun. 2011; 411: 826-831
        • Yang H
        • Fang F
        • Chang R
        • Yang L.
        MicroRNA-140-5p suppresses tumor growth and metastasis by targeting transforming growth factor β receptor 1 and fibroblast growth factor 9 in hepatocellular carcinoma.
        Hepatology. 2013; 58: 205-217
        • Hu Y
        • Li Y
        • Wu C
        • Zhou L
        • et al.
        MicroRNA-140-5p inhibits cell proliferation and invasion by regulating VEGFA/MMP2 signaling in glioma.
        Tumour Biol. 2017; 391010428317697558
        • Zhao RL
        • Zhang XM
        • Jia LN
        • et al.
        pNNS-conjugated chitosan mediated IGF-1 and miR-140 overexpression in articular chondrocytes improves cartilage repair.
        Biomed Res Int. 2019; 20192761241
        • Liu QQ
        • Ren K
        • Liu SH
        • Li WM
        • Huang CJ
        • Yang XH.
        MicroRNA-140-5p aggravates hypertension and oxidative stress of atherosclerosis via targeting Nrf2 and Sirt2.
        Int J Mol Med. 2019; 43: 839-849
        • Afonina IS
        • Van Nuffel E
        • Beyaert R.
        Immune responses and therapeutic options in psoriasis.
        Cell Mol Life Sci. 2021; (Epub ahead of print)
        • Honma M
        • Hayashi K.
        Psoriasis: recent progress in molecular-targeted therapies.
        J Dermatol. 2021; (Epub ahead of print)
        • Masalha M
        • Sidi Y
        • Avni D.
        The contribution of feedback loops between miRNAs, cytokines and growth factors to the pathogenesis of psoriasis.
        Exp Dermatol. 2018; 27: 603-610
        • Franco-Trepat E
        • Alonso-Pérez A
        • Guillán-Fresco M
        • et al.
        Visfatin as a therapeutic target for rheumatoid arthritis.
        Expert Opin Ther Targets. 2019; 23: 607-618
        • Mohammed Ali DM
        • Al-Fadhel SZ
        • Al-Ghuraibawi NHA
        • Al-Hakeim HK
        Serum chemerin and visfatin levels and their ratio as possible diagnostic parameters of rheumatoid arthritis.
        Reumatologia. 2020; 58: 67-75
        • Zhang Y
        • Peltonen M
        • Andersson-Assarsson JC
        • et al.
        Elevated adiponectin predicts the development of rheumatoid arthritis in subjects with obesity.
        Scand J Rheumatol. 2020; 49: 452-460
        • Mini-Review Toussirot E.
        The contribution of adipokines to joint inflammation in inflammatory rheumatic diseases.
        Front Endocrinol (Lausanne). 2020; 11606560
        • Szumilas K
        • Szumilas P
        • Słuczanowska-Głąbowska S
        • Zgutka K
        • Pawlik A.
        Role of adiponectin in the pathogenesis of rheumatoid arthritis.
        Int J Mol Sci. 2020; 21: 8265
        • Hwang J
        • Yoo JA
        • Yoon H
        • et al.
        The role of leptin in the association between obesity and psoriasis.
        Biomol Ther (Seoul). 2021; 29: 11-21
        • Mattioli B
        • Straface E
        • Quaranta MG
        • Giordani L
        • Viora M.
        Leptin promotes differentiation and survival of human dendritic cells and licenses them for Th1 priming.
        J Immunol. 2005; 174 (Erratum in: J Immunol. 2005;175(5):3446): 6820-6828
        • Xibillé-Friedmann DX
        • Ortiz-Panozo E
        • Bustos Rivera-Bahena C
        • et al.
        Leptin and adiponectin as predictors of disease activity in rheumatoid arthritis.
        Clin Exp Rheumatol. 2015; 33: 471-477