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Endocrine disorders associated with hepatitis C virus chronic infection

  • Michele ColaciEmail author
  • Lorenzo Malatino
  • Alessandro Antonelli
  • Poupak Fallahi
  • Dilia Giuggioli
  • Clodoveo Ferri
Article

Abstract

The term “HCV syndrome” encompasses several organ- and systemic pathophysiological states, which often recognize autoimmunity or neoplastic evolution in their pathophysiology, as well as chronic HCV infection as trigger. The clinical features of HCV patients are heterogenous, and may include endocrine or metabolic disorders, namely autoimmune thyroiditis, type 2 diabetes mellitus, and erectile/sexual dysfunctions. In this review, we summarize current knowledge on the endocrine/metabolic diseases associated with chronic HCV infection, focusing on the main concepts emerged in the recent literature in this field. The application of this knowledge in everyday clinical practice may be relevant, in order to reinforce a holistic vision of the patient with chronic HCV infection, stimulating in turn a multi-disciplinary approach, thus increasing the probability of early diagnosis, more effective treatments, and a better prognostic outcome.

Keywords

Hepatitis C HCV Diabetes Thyroiditis Hypothyroidism Erectile dysfunction 

Notes

Compliance with ethical standards

Conflict of interests

Michele Colaci, Lorenzo Malatino, Alessandro Antonelli, Poupak Fallahi, Dilia Giuggioli, and Clodoveo Ferri declare no conflict of interests.

References

  1. 1.
    Ferri C, Antonelli A, Mascia MT, Sebastiani M, Fallahi P, Ferrari D, et al. HCV-related autoimmune and neoplastic disorders: the HCV syndrome. Dig Liver Dis. 2007;39(Suppl 1):S13–21.CrossRefGoogle Scholar
  2. 2.
    Ferri C, Sebastiani M, Giuggioli D, Colaci M, Fallahi P, Piluso A, et al. Hepatitis C virus syndrome: a constellation of organ- and non-organ specific autoimmune disorders, B-cell non-Hodgkin's lymphoma, and cancer. World J Hepatol. 2015 Mar 27;7(3):327–43.CrossRefGoogle Scholar
  3. 3.
    Ferrari SM, Fallahi P, Mancusi C, Colaci M, Manfredi A, Ferri C, et al. HCV-related autoimmune disorders in HCV chronic infection. Clin Ter. 2013;164(4):e305–12.PubMedGoogle Scholar
  4. 4.
    Antonelli A, Ferri C, Ferrari SM, Colaci M, Sansonno D, Fallahi P. Endocrine manifestations of hepatitis C virus infection. Nat Clin Pract Endocrinol Metab. 2009;5:26–34.CrossRefGoogle Scholar
  5. 5.
    Shen Y, Wang XL, Xie JP, Shao JG, Lu YH, Zhang S, et al. Thyroid disturbance in patients with chronic hepatitis C infection: a systematic review and meta-analysis. J Gastrointestin Liver Dis. 2016;25:227–34.PubMedGoogle Scholar
  6. 6.
    Desbois AC, Cacoub P. Diabetes mellitus, insulin resistance and hepatitis C virus infection: a contemporary review. World J Gastroenterol. 2017 Mar 7;23(9):1697–711.CrossRefGoogle Scholar
  7. 7.
    Gentile I, Fusco F, Buonomo AR, Scotto R, Zappulo E, Pinchera B, et al. Prevalence and risk factors of erectile dysfunction in patients with hepatitis B virus or hepatitis C virus or chronic liver disease: results from a prospective study. Sex Health 2018;in press.Google Scholar
  8. 8.
    Ferri C, Monti M, La Civita L, Longombardo G, Greco F, Pasero G, et al. Infection of peripheral blood mononuclear cells by hepatitis C virus in mixed cryoglobulinemia. Blood. 1993 Dec 15;82(12):3701–4.PubMedGoogle Scholar
  9. 9.
    Antonelli A, Ferrari SM, Corrado A, Di Domenicantonio A, Fallahi P. Autoimmune thyroid disorders. Autoimmun Rev. 2015;14:174–80.CrossRefGoogle Scholar
  10. 10.
    Di Domenicantonio A, Politti U, Marchi S, De Bortoli N, Giuggioli D, Antonelli A, et al. A review on thyroid autoimmune disorders and HCV chronic infection. Clin Ter. 2014;165:e376–81.PubMedGoogle Scholar
  11. 11.
    Antonelli A, Ferri C, Pampana A, Fallahi P, Nesti C, Pasquini M, et al. Thyroid disorders in chronic hepatitis C. Am J Med. 2004;117:10–3.CrossRefGoogle Scholar
  12. 12.
    Giordano TP, Henderson L, Landgren O, Chiao EY, Kramer JR, El-Serag H, et al. Risk of non-Hodgkin lymphoma and lymphoproliferative precursor diseases in US veterans with hepatitis C virus. JAMA. 2007;297:2010–7.CrossRefGoogle Scholar
  13. 13.
    Antonelli A, Ferri C, Fallahi P, Giuggioli D, Nesti C, Longombardo G, et al. Thyroid involvement in patients with overt HCV-related mixed cryoglobulinemia. QJM. 2004;97:499–506.CrossRefGoogle Scholar
  14. 14.
    Ferri C, Colaci M, Fallahi P, Ferrari SM, Antonelli A, Giuggioli D. Thyroid involvement in hepatitis C virus-infected patients with/without mixed cryoglobulinemia. Front Endocrinol. 2017;8:159.CrossRefGoogle Scholar
  15. 15.
    Wang P, Jing Z, Liu C, Xu M, Wang P, Wang X, et al. Hepatitis C virus infection and risk of thyroid cancer: a systematic review and meta-analysis. Arab J Gastroenterol. 2017;18:1–5.CrossRefGoogle Scholar
  16. 16.
    Akeno N, Blackard JT, Tomer Y. HCV E2 protein binds directly to thyroid cells and induces IL-8 production: a new mechanism for HCV induced thyroid autoimmunity. J Autoimmun. 2008;31:339–44.CrossRefGoogle Scholar
  17. 17.
    Zignego AL, Gragnani L, Piluso A, Sebastiani M, Giuggioli D, Fallahi P, et al. Virus-driven autoimmunity and lymphoproliferation: the example of HCV infection. Expert Rev Clin Immunol. 2015;11:15–31.CrossRefGoogle Scholar
  18. 18.
    Blackard JT, Kong L, Huber AK, Tomer Y. Hepatitis C virus infection of a thyroid cell line: implications for pathogenesis of HCV and thyroiditis. Thyroid. 2012;23:863–70.CrossRefGoogle Scholar
  19. 19.
    Fallahi P, Ferrari SM, Giuggioli D, Sebastiani M, Colaci M, Ferri C, et al. Chemokines in the pathogenesis and as Therapeutical markers and targets of HCV chronic infection and HCV extrahepatic manifestations. Curr Drug Targets. 2017;18(7):786–93.CrossRefGoogle Scholar
  20. 20.
    Fallahi P, Ferri C, Ferrari SM, Corrado A, Sansonno D, Antonelli A. Cytokines and HCV-related disorders. Clin Dev Immunol. 2012;2012:468107.CrossRefGoogle Scholar
  21. 21.
    Antonelli A, Ferri C, Ferrari SM, De Marco S, Di Domenicantonio A, Centanni M, et al. Interleukin-1β, C-x-C motif ligand 10, and interferon-gamma serum levels in mixed cryoglobulinemia with or without autoimmune thyroiditis. J Interf Cytokine Res. 2010;30:835–42.CrossRefGoogle Scholar
  22. 22.
    Antonelli A, Fallahi P, Ferrari SM, Colaci M, Giuggioli D, Saraceno G, et al. Increased CXCL9 serum levels in hepatitis C-related mixed cryoglobulinemia, with autoimmune thyroiditis, associated with high levels of CXCL10. J Interf Cytokine Res. 2013;33:739–45.10.CrossRefGoogle Scholar
  23. 23.
    Antonelli A, Fallahi P, Ferrari SM, Sebastiani M, Manfredi A, Mazzi V, et al. Circulating CXCL11 and CXCL10 are increased in hepatitis C-associated cryoglobulinemia in the presence of autoimmune thyroiditis. Mod Rheumatol. 2012;22:659–67.CrossRefGoogle Scholar
  24. 24.
    Antonelli A, Ferri C, Ferrari SM, Di Domenicantonio A, Ferrari P, Pupilli C, et al. The presence of autoimmune thyroiditis in mixed cryoglobulinemia patients is associated with high levels of circulating interleukin-6, but not of tumor necrosis factor-alpha. Clin Exp Rheumatol. 2011;29(1 Suppl 64):S17–22.PubMedGoogle Scholar
  25. 25.
    Antonelli A, Ferrari SM, Frascerra S, Galetta F, Franzoni F, Corrado A, et al. Circulating chemokine (CXC motif) ligand (CXCL)9 is increased in aggressive chronic autoimmune thyroiditis, in association with CXCL10. Cytokine. 2011 Aug;55(2):288–93.CrossRefGoogle Scholar
  26. 26.
    Fallahi P, Ferrari SM, Politti U, Giuggioli D, Ferri C, Antonelli A. Autoimmune and neoplastic thyroid diseases associated with hepatitis C chronic infection. Int J Endocrinol. 2014;2014:935131.CrossRefGoogle Scholar
  27. 27.
    Antonelli A, Ferri C, Ferrari SM, Colaci M, Fallahi P. Immunopathogenesis of HCV-related endocrine manifestations in chronic hepatitis and mixed cryoglobulinemia. Autoimmun Rev. 2008;8:18–23.CrossRefGoogle Scholar
  28. 28.
    Antonelli A, Ferri C, Fallahi P. Thyroid cancer in patients with hepatitis C infection. JAMA. 1999 May 5;281(17):1588.CrossRefGoogle Scholar
  29. 29.
    Montella M, Crispo A, de Bellis G, Izzo F, Frigeri F, Ronga D, et al. HCV and cancer: a case-control study in a high-endemic area. Liver. 2001 Oct;21(5):335–41.CrossRefGoogle Scholar
  30. 30.
    Fiore E, Rago T, Latrofa F, Provenzale MA, Piaggi P, Delitala A, et al. Hashimoto’s thyroiditis is associated with papillary thyroid carcinoma: role of TSH and treatment with L-thyroxine. Endocr Relat Cancer. 2011;18:429–37.CrossRefGoogle Scholar
  31. 31.
    Ferri C, Ramos-Casals M, Zignego AL, Arcaini L, Roccatello D, Antonelli A, et al. ISG-EHCV coauthors. International diagnostic guidelines for patients with HCV-related extrahepatic manifestations. A multidisciplinary expert statement. Autoimmun Rev. 2016 Dec;15(12):1145–60.CrossRefGoogle Scholar
  32. 32.
    White DL, Ratziu V, El-Serag HB. Hepatitis C infection and risk of diabetes: a systematic review and meta-analysis. J Hepatol. 2008;49(5):831–44.CrossRefGoogle Scholar
  33. 33.
    Fabiani S, Fallahi P, Ferrari SM, Miccoli M, Antonelli A. Hepatitis C virus infection and development of type 2 diabetes mellitus: Systematic review and meta-analysis of the literature. Rev Endocr Metab Disord. 2018;in press.Google Scholar
  34. 34.
    Liang J, Lv C, Chen M, Xu M, Zhao C, Yang Y, Wang J, Zhu D, Gao J, Rong R, Zhu T, Yu M. Effects of preoperative hepatitis B virus infection, hepatitis C virus infection, and co-infection on the development of new-onset diabetes after kidney transplantation. J Diabetes. 2018;in press.Google Scholar
  35. 35.
    Choi HY, Kim Y, Cho H, Kim BH, Ki M. Risk of diabetes in viral hepatitis B or C patients compared to that in noninfected individuals in Korea, 2002-2013: a population-based cohort study. J Viral Hepat. 2018 Mar;25(3):272–80.CrossRefGoogle Scholar
  36. 36.
    Subramaniam S, Wong VW, Tse YK, Yip TC, Chan HL, Wong GL. Impact of diabetes mellitus and hepatitis B virus coinfection on patients with chronic hepatitis C: a territory-wide cohort study. J Gastroenterol Hepatol. 2018 Apr;33(4):934–41.CrossRefGoogle Scholar
  37. 37.
    Farshadpour F, Taherkhani R, Ravanbod MR, Eghbali SS. Prevalence and genotype distribution of hepatitis C virus infection among patients with type 2 diabetes mellitus. Med Princ Pract. 2018;27(4):308–16.CrossRefGoogle Scholar
  38. 38.
    Soverini V, Persico M, Bugianesi E, Forlani G, Salamone F, Masarone M, et al. HBV and HCV infection in type 2 diabetes mellitus: a survey in three diabetes units in different Italian areas. Acta Diabetol. 2011;48:337–43.CrossRefGoogle Scholar
  39. 39.
    Li X, Gao Y, Xu H, Hou J, Gao P. Diabetes mellitus is a significant risk factor for the development of liver cirrhosis in chronic hepatitis C patients, particularly for women. Sci Rep. 2017 Aug 22;7(1):9087.CrossRefGoogle Scholar
  40. 40.
    Cao LH, Lu FM, Lu XJ, Zhu LY. Study on the relationship between insulin growth factor 1 and liver fibrosis in patients with chronic hepatitis C with type 2 diabetes mellitus. J Cell Biochem. 2018;in press.Google Scholar
  41. 41.
    Bakulin IG, Sandler YG, Vinnitskaya EV, Keiyan VA, Rodionova SV, Rotin DL. Diabetes mellitus and nonalcoholic fatty liver disease: the verges of contingency. Ter Arkh. 2017;89:59–65.CrossRefGoogle Scholar
  42. 42.
    Hui JM, Sud A, Farrell GC, Bandara P, Byth K, Kench JG, et al. Insulin resistance is associated with chronic hepatitis C virus infection and fibrosis progression. Gastroenterology. 2003;125:1695–704.CrossRefGoogle Scholar
  43. 43.
    Paradis V, Perlemuter G, Bonvoust F, Dargere D, Parfait B, Vidaud M, et al. High glucose and hyperinsulinemia stimulate connective tissue growth factor expression: a potential mechanism involved in progression to fibrosis in nonalcoholic steatohepatitis. Hepatology (Baltimore, Md.). 2001;34:738–44.CrossRefGoogle Scholar
  44. 44.
    Kasai D, Adachi T, Deng L, Nagano-Fujii M, Sada K, Ikeda M, et al. HCV replication suppresses cellular glucose uptake through down-regulation of cell surface expression of glucose transporters. J Hepatol. 2009;50:883–94.CrossRefGoogle Scholar
  45. 45.
    Romero-Gómez M. Insulin resistance and hepatitis C. World J Gastroenterol. 2006;12:7075–80.CrossRefGoogle Scholar
  46. 46.
    Banerjee S, Saito K, Ait-Goughoulte M, Meyer K, Ray RB, Ray R. Hepatitis C virus core protein upregulates serine phosphorylation of insulin receptor substrate-1 and impairs the downstream akt/protein kinase B signaling pathway for insulin resistance. J Virol. 2008;82:2606–12.CrossRefGoogle Scholar
  47. 47.
    Knobler H, Zhornicky T, Sandler A, Haran N, Ashur Y, Schattner A. Tumor necrosis factor-alpha-induced insulin resistance may mediate the hepatitis C virus-diabetes association. Am J Gastroenterol. 2003;98(12):2751–6.PubMedGoogle Scholar
  48. 48.
    Mitsuyoshi H, Itoh Y, Sumida Y, Minami M, Yasui K, Nakashima T. Evidence of oxidative stress as a cofactor in the development of insulin resistance in patients with chronic hepatitis C. Hepatol Res. 2008;38(4):348–53.CrossRefGoogle Scholar
  49. 49.
    Bose SK, Shrivastava S, Meyer K, Ray RB, Ray R. Hepatitis C virus activates the mTOR/S6K1 signaling pathway in inhibiting IRS-1 function for insulin resistance. J Virol. 2012;86(11):6315–22.CrossRefGoogle Scholar
  50. 50.
    Singhal A, Agrawal A, Ling J. Regulation of insulin resistance and type II diabetes by hepatitis C virus infection: a driver function of circulating miRNAs. J Cell Mol Med. 2018 Apr;22(4):2071–85.CrossRefGoogle Scholar
  51. 51.
    Huang YW, Yang SS, Fu SC, Wang TC, Hsu CK, Chen DS, et al. Increased risk of cirrhosis and its decompensation in chronic hepatitis C patients with new-onset diabetes: a nationwide cohort study. Hepatology. 2014;60:807–14.CrossRefGoogle Scholar
  52. 52.
    Elkrief L, Chouinard P, Bendersky N, Hajage D, Larroque B, Babany G, et al. Diabetes mellitus is an independent prognostic factor for major liver-related outcomes in patients with cirrhosis and chronic hepatitis C. Hepatology. 2014;60:823–31.CrossRefGoogle Scholar
  53. 53.
    Lai SW, Chen PC, Liao KF, Muo CH, Lin CC, Sung FC. Risk of hepatocellular carcinoma in diabetic patients and risk reduction associated with anti-diabetic therapy: a population-based cohort study. Am J Gastroenterol. 2012;107:46–52.CrossRefGoogle Scholar
  54. 54.
    Nkontchou G, Cosson E, Aout M, Mahmoudi A, Bourcier V, Charif I, et al. Impact of metformin on the prognosis of cirrhosis induced by viral hepatitis C in diabetic patients. J Clin Endocrinol Metab. 2011;96:2601–8.CrossRefGoogle Scholar
  55. 55.
    Delgado-Borrego A, Jordan SH, Negre B, Healey D, Lin W, Kamegaya Y. Reduction of insulin resistance with effective clearance of hepatitis C infection: results from the HALT-C trial. Clin Gastroenterol Hepatol. 2010;8(5):458–62.CrossRefGoogle Scholar
  56. 56.
    Aghemo A, Prati GM, Rumi MG, Soffredini R, D’Ambrosio R, Orsi E. Sustained virological response prevents the development of insulin resistance in patients with chronic hepatitis C. Hepatology. 2012;56(5):1681–7.CrossRefGoogle Scholar
  57. 57.
    Pavone P, Tieghi T, d’Ettorre G, Lichtner M, Marocco R, Mezzaroma I. Rapid decline of fasting glucose in HCV diabetic patients treated with direct-acting antiviral agents. Clin Microbiol Infect. 2016;22(5):462 e1–3.CrossRefGoogle Scholar
  58. 58.
    Fabrizio C, Procopio A, Scudeller L, Dell’Acqua R, Bruno G, Milano E. HCV and diabetes: towards a ‘sustained’ glycaemic improvement after treatment with DAAs? Clin Microbiol Infect. 2017;23(5):342–3.CrossRefGoogle Scholar
  59. 59.
    Ciancio A, Bosio R, Bo S, Pellegrini M, Sacco M, Vogliotti E, et al. Significant improvement of glycemic control in diabetic patients with HCV infection responding to direct-acting antiviral agents. J Med Virol. 2018 Feb;90(2):320–7.CrossRefGoogle Scholar
  60. 60.
    Drazilova S, Gazda J, Janicko M, Jarcuska P. Chronic hepatitis C association with diabetes mellitus and cardiovascular risk in the era of DAA therapy. Can J Gastroenterol Hepatol. 2018 Aug 13;2018:6150861.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Gastaldi G, Goossens N, Clément S, Negro F. Current level of evidence on causal association between hepatitis C virus and type 2 diabetes: a review. J Adv Res. 2017 Mar;8(2):149–59.CrossRefGoogle Scholar
  62. 62.
    Cacoub P, Desbois AC, Comarmond C, Saadoun D. Impact of sustained virological response on the extrahepatic manifestations of chronic hepatitis C: a meta-analysis. Gut. 2018;67(11):2025–34.CrossRefGoogle Scholar
  63. 63.
    Akbar DH, Siddique AM, Ahmed MM. Prevalence of Type-2 diabetes in patients with hepatitis C and B virus infection in Jeddah, Saudi Arabia. Med Princ Pract. 2002 Apr-Jun;11(2):82–5.CrossRefGoogle Scholar
  64. 64.
    Kabbaj N, Errabih I, Guédira M, El Atmani H, Benabed K, Al Hamany Z, et al. Hepatitis C and diabetes mellitus: effect of diabetes on the course of the liver disease. Ann Endocrinol. 2006 Jun;67(3):233–7.CrossRefGoogle Scholar
  65. 65.
    Antonelli A, Ferri C, Fallahi P, Sebastiani M, Nesti C, Barani L, et al. Type 2 diabetes in hepatitis C-related mixed cryoglobulinaemia patients. Rheumatology (Oxford). 2004 Feb;43(2):238–40.CrossRefGoogle Scholar
  66. 66.
    Hunter SS, Gadallah A, Azawi MK, Doss W. Erectile dysfunction in patients with chronic hepatitis C virus infection. Arab J Gastroenterol. 2014 Mar;15(1):16–20.CrossRefGoogle Scholar
  67. 67.
    Abdelhamid AA, Sherief MH, Nemr NA, Hassoba HM, El-Sakka AI. Homocysteine, insulin-like growth factor one and oestrogen levels in patients with erectile dysfunction-associated chronic hepatitis C virus infection. Andrologia. 2018 Jul;31:e13116.CrossRefGoogle Scholar
  68. 68.
    Wang FP, Zhang PA, Yang XY. Relationship between sex hormones and RIG-I signaling in peripheral blood mononuclear cells of patients infected with hepatitis C virus. Exp Ther Med. 2017 Sep;14(3):2728–32.CrossRefGoogle Scholar
  69. 69.
    White DL, Tavakoli-Tabasi S, Kuzniarek J, Pascua R, Ramsey DJ, EI-Serag HB. Higher serum testosterone is associated with increased risk of advanced hepatitis C-related liver disease in males. Hepatology. 2012;55:759–68.CrossRefGoogle Scholar
  70. 70.
    Magri A, Barbaglia MN, Foglia CZ, Boccato E, Burlone ME, Cole S, et al. 17,β-estradiol inhibits hepatitis C virus mainly by interference with the release phase of its life cycle. Liver Int. 2017 May;37(5):669–77.CrossRefGoogle Scholar
  71. 71.
    Ahmed NH, El-Abaseri TB, El-Sayed HF, El-Serafi TI. Female sex hormones pattern and its relation to disease severity and treatment in pre- and postmenopausal patients with chronic hepatitis C virus (genotype 4) infection. Int J Chronic Dis. 2015;2015:927974.PubMedPubMedCentralGoogle Scholar
  72. 72.
    Soykan A, Boztaş H, Idilman R, Ozel ET, Tüzün AE, Ozden A, et al. Sexual dysfunctions in HCV patients and its correlations with psychological and biological variables. Int J Impot Res. 2005 Mar-Apr;17(2):175–9.CrossRefGoogle Scholar
  73. 73.
    Karaivazoglou K, Tsermpini EE, Assimakopoulos K, Triantos C. Sexual functioning in patients with chronic hepatitis C: a systematic review. Eur J Gastroenterol Hepatol. 2017 Nov;29(11):1197–205.CrossRefGoogle Scholar
  74. 74.
    Durazzo M, Premoli A, Di Bisceglie C, Bertagna A, Faga E, Biroli G, et al. Alterations of seminal and hormonal parameters: an extrahepatic manifestation of HCV infection? World J Gastroenterol. 2006 May 21;12(19):3073–6.CrossRefGoogle Scholar
  75. 75.
    Hofny ER, Ali ME, Taha EA, Nafeh HM, Sayed DS, Abdel-Azeem HG, et al. Semen and hormonal parameters in men with chronic hepatitis C infection. Fertil Steril. 2011 Jun 30;95(8):2557–9.CrossRefGoogle Scholar
  76. 76.
    Hussein TM, Elneily D, Eid AA, Abou-ElKhier H. Assessment of antisperm antibodies in a sample of Egyptian patients with hepatitis C virus infection. Andrologia. 2017 Jun;49(5).CrossRefGoogle Scholar
  77. 77.
    Benvenga S, Guarneri F. Molecular mimicry and autoimmune thyroid disease. Rev Endocr Metab Disord. 2016 Dec;17(4):485–98.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Michele Colaci
    • 1
    Email author
  • Lorenzo Malatino
    • 1
  • Alessandro Antonelli
    • 2
  • Poupak Fallahi
    • 2
  • Dilia Giuggioli
    • 3
  • Clodoveo Ferri
    • 3
  1. 1.Internal Medicine Unit, Cannizzaro Hospital, Department of Clinical and Experimental MedicineUniversity of CataniaCataniaItaly
  2. 2.Department of Clinical and Experimental MedicineUniversity of PisaPisaItaly
  3. 3.Rheumatology Unit, Azienda Ospedaliero-Universitaria di ModenaUniversity of Modena and Reggio EmiliaModenaItaly

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