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Systemic Sclerosis

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The Microbiome in Rheumatic Diseases and Infection

Abstract

Systemic sclerosis (SSc) is a rare systemic autoimmune connective tissue disease with clinical and laboratory features of inflammation, vasculopathy, and fibrosis of the skin and visceral organs. The role of the microbiota is an area that is largely unexplored in SSc. An overview is given of the studies that investigated the composition of the microbiome in the gastrointestinal tract and the skin. Furthermore, hypotheses that may strengthen the rationale for further investigation of the microbiome in SSc are discussed. There is tentative evidence that alterations in the microbiome can be associated with SSc. However, more research is needed to establish if these altered populations are the cause or the result of the disease. The fact that SSc affects the skin, lungs, and gastrointestinal tract, which are prominent locations of the microbiome, makes it both more challenging and interesting to explore the role of microorganisms in the disease process.

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Abbreviations

B. burgdorferi :

Borrelia burgdorferi

CMV:

Cytomegalovirus

DcSSc:

Diffuse cutaneous systemic sclerosis

EC:

Endothelial cells

F. prausnitzii :

Faecalibacterium prausnitzii

GvHD:

Graft versus host disease

HBV:

Hepatitis B virus

LcSSc:

Limited cutaneous systemic sclerosis

SIBO:

Small intestinal bacterial overgrowth

SSc:

Systemic sclerosis

References

  1. LeRoy EC, Medsger TA Jr. Criteria for the classification of early systemic sclerosis. J Rheumatol. 2001;28(7):1573–6.

    PubMed  CAS  Google Scholar 

  2. van den Hoogen F, Khanna D, Fransen J, et al. 2013 classification criteria for systemic sclerosis: an American college of rheumatology/European league against rheumatism collaborative initiative. Ann Rheum Dis. 2013;72(11):1747–55. https://doi.org/10.1136/annrheumdis-2013-204424.

    Article  PubMed  Google Scholar 

  3. Black CM. Scleroderma–clinical aspects. J Intern Med. 1993;234(2):115–8.

    Article  PubMed  CAS  Google Scholar 

  4. Steen VD. Clinical manifestations of systemic sclerosis. Semin Cutan Med Surg. 1998;17(1):48–54.

    Article  PubMed  CAS  Google Scholar 

  5. Ferri C, Sebastiani M, Lo Monaco A, et al. Systemic sclerosis evolution of disease pathomorphosis and survival. Our experience on Italian patients’ population and review of the literature. Autoimmun Rev. 2014;13(10):1026–34. https://doi.org/10.1016/j.autrev.2014.08.029.

    Article  PubMed  Google Scholar 

  6. Gabrielli A, Avvedimento EV, Krieg T. Scleroderma. N Engl J Med. 2009;360(19):1989–2003. https://doi.org/10.1056/NEJMra0806188.

    Article  PubMed  CAS  Google Scholar 

  7. Ioannidis JP, Vlachoyiannopoulos PG, Haidich AB, et al. Mortality in systemic sclerosis: an international meta-analysis of individual patient data. Am J Med. 2005;118(1):2–10. https://doi.org/10.1016/j.amjmed.2004.04.031.

    Article  PubMed  Google Scholar 

  8. Allanore Y, Simms R, Distler O, et al. Systemic sclerosis. Nat Rev Dis Primers. 2015;1:15002. https://doi.org/10.1038/nrdp.2015.2.

    Article  PubMed  Google Scholar 

  9. Jimenez SA. Role of endothelial to mesenchymal transition in the pathogenesis of the vascular alterations in systemic sclerosis. ISRN Rheumatol. 2013;2013:835948. https://doi.org/10.1155/2013/835948.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Pattanaik D, Brown M, Postlethwaite BC, et al. Pathogenesis of systemic sclerosis. Front Immunol. 2015;6:272. https://doi.org/10.3389/fimmu.2015.00272.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Feghali-Bostwick C, Medsger TA Jr, Wright TM. Analysis of systemic sclerosis in twins reveals low concordance for disease and high concordance for the presence of antinuclear antibodies. Arthritis Rheum. 2003;48(7):1956–63. https://doi.org/10.1002/art.11173.

    Article  PubMed  Google Scholar 

  12. Nietert PJ, Silver RM. Systemic sclerosis: environmental and occupational risk factors. Curr Opin Rheumatol. 2000;12(6):520–6.

    Article  PubMed  CAS  Google Scholar 

  13. Rubio-Rivas M, Moreno R, Corbella X. Occupational and environmental scleroderma. Systematic review and meta-analysis. Clin Rheumatol. 2017;36(3):569–82. https://doi.org/10.1007/s10067-016-3533-1.

    Article  PubMed  Google Scholar 

  14. Arnson Y, Amital H, Guiducci S, et al. The role of infections in the immunopathogenesis of systemic sclerosis–evidence from serological studies. Ann N Y Acad Sci. 2009;1173:627–32. https://doi.org/10.1111/j.1749-6632.2009.04808.x.

    Article  PubMed  CAS  Google Scholar 

  15. Grossman C, Dovrish Z, Shoenfeld Y, et al. Do infections facilitate the emergence of systemic sclerosis? Autoimmun Rev. 2011;10(5):244–7. https://doi.org/10.1016/j.autrev.2010.09.010.

    Article  PubMed  Google Scholar 

  16. Radic M, Martinovic Kaliterna D, Radic J. Infectious disease as aetiological factor in the pathogenesis of systemic sclerosis. Neth J Med. 2010;68(11):348–53.

    PubMed  CAS  Google Scholar 

  17. Dolcino M, Puccetti A, Barbieri A, et al. Infections and autoimmunity: role of human cytomegalovirus in autoimmune endothelial cell damage. Lupus. 2015;24(4–5):419–32. https://doi.org/10.1177/0961203314558677.

    Article  PubMed  CAS  Google Scholar 

  18. Muryoi T, Kasturi KN, Kafina MJ, et al. Antitopoisomerase I monoclonal autoantibodies from scleroderma patients and tight skin mouse interact with similar epitopes. J Exp Med. 1992;175(4):1103–9.

    Article  PubMed  CAS  Google Scholar 

  19. Randone SB, Guiducci S, Cerinic MM. Systemic sclerosis and infections. Autoimmun Rev. 2008;8(1):36–40. https://doi.org/10.1016/j.autrev.2008.07.022.

    Article  PubMed  Google Scholar 

  20. Heijnen T, Wilmer A, Blockmans D. Outcome of patients with systemic diseases admitted to the medical intensive care unit of a tertiary referral hospital: a single-centre retrospective study. Scand J Rheumatol. 2016;45(2):146–50. https://doi.org/10.3109/03009742.2015.1067329.

    Article  PubMed  CAS  Google Scholar 

  21. Woytala PJ, Morgiel E, Łuczak A, et al. The safety of intravenous cyclophosphamide in the treatment of rheumatic diseases. Adv Clin Exp Med. 2016;25(3):479–84. https://doi.org/10.17219/acem/28736.

    Article  PubMed  Google Scholar 

  22. Foocharoen C, Siriphannon Y, Mahakkanukrauh A, et al. A incidence rate and causes of infection in Thai systemic sclerosis patient. Int J Rheum Dis. 2012;15(3):277–83. https://doi.org/10.1111/j.1756-185X.2012.01728.x.

    Article  PubMed  Google Scholar 

  23. Tyndall AJ, Bannert B, Vonk M, et al. Causes and risk factors for death in systemic sclerosis: a study from the EULAR scleroderma trials and research (EUSTAR) database. Ann Rheum Dis. 2010;69(10):1809–15. https://doi.org/10.1136/ard.2009.114264.

    Article  PubMed  Google Scholar 

  24. Steen V, Denton CP, Pope JE, et al. Digital ulcers: overt vascular disease in systemic sclerosis. Rheumatology (Oxford). 2009;48(Suppl 3):iii19–24. https://doi.org/10.1093/rheumatology/kep105.

    Article  Google Scholar 

  25. Korn JH, Mayes M, Matcci Cerinic M, et al. Digital ulcers in systemic sclerosis: prevention by treatment with bosentan, an oral endothelin receptor antagonist. Arthritis Rheum. 2004;50(12):3985–93. https://doi.org/10.1002/art.20676.

    Article  PubMed  CAS  Google Scholar 

  26. Giuggioli D, Manfredi A, Colaci M, et al. Scleroderma digital ulcers complicated by infection with fecal pathogens. Arthritis Care Res. 2012;64(2):295–7. https://doi.org/10.1002/acr.20673.

    Article  Google Scholar 

  27. Andreasson K, Alrawi Z, Persson A, et al. Intestinal dysbiosis is common in systemic sclerosis and associated with gastrointestinal and extraintestinal features of disease. Arthritis Res Ther. 2016;18(1):278. https://doi.org/10.1186/s13075-016-1182-z.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Suau A, Bonnet R, Sutren M, et al. Direct analysis of genes encoding 16S rRNA from complex communities reveals many novel molecular species within the human gut. Appl Environ Microbiol. 1999;65(11):4799–807.

    PubMed  PubMed Central  CAS  Google Scholar 

  29. Swidsinski A, Loening-Baucke V, Vaneechoutte M, et al. Active Crohn’s disease and ulcerative colitis can be specifically diagnosed and monitored based on the biostructure of the fecal flora. Inflamm Bowel Dis. 2008;14(2):147–61. https://doi.org/10.1002/ibd.20330.

    Article  PubMed  Google Scholar 

  30. Miquel S, Martin R, Rossi O, et al. Faecalibacterium prausnitzii and human intestinal health. Curr Opin Microbiol. 2013;16(3):255–61. https://doi.org/10.1016/j.mib.2013.06.003.

    Article  PubMed  CAS  Google Scholar 

  31. Sokol H, Pigneur B, Watterlot L, et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci U S A. 2008;105(43):16731–6. https://doi.org/10.1073/pnas.0804812105.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Volkmann ER, Hoffman-Vold A, Chang Y, et al. Systemic sclerosis is associated with specific alterations in gastrointestinal microbiota in two independent cohorts. BMJ Open Gastroenterol. 2017;4(1):e000134.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Patrone V, Puglisi E, Cardinali M, et al. Gut microbiota profile in systemic sclerosis patients with and without clinical evidence of gastrointestinal involvement. Sci Rep. 2017;7(1):14874.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Wang W, Chen L, Zhou R, et al. Increased proportions of Bifidobacterium and the Lactobacillus group and loss of butyrate-producing bacteria in inflammatory bowel disease. J Clin Microbiol. 2014;52(2):398–406. https://doi.org/10.1128/jcm.01500-13.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Willing BP, Dicksved J, Halfvarson J, et al. A pyrosequencing study in twins shows that gastrointestinal microbial profiles vary with inflammatory bowel disease phenotypes. Gastroenterology. 2010;139(6):1844–1854.e1841. https://doi.org/10.1053/j.gastro.2010.08.049.

    Article  PubMed  Google Scholar 

  36. Sartor RB. Therapeutic manipulation of the enteric microflora in inflammatory bowel diseases: antibiotics, probiotics, and prebiotics. Gastroenterology. 2004;126(6):1620–33.

    Article  PubMed  Google Scholar 

  37. Di Cerbo A, Palmieri B, Aponte M, et al. Mechanisms and therapeutic effectiveness of lactobacilli. J Clin Pathol. 2015;69(3):187–203. https://doi.org/10.1136/jclinpath-2015-202976.

    Article  PubMed  Google Scholar 

  38. Martinez RC, Bedani R, Saad SM. Scientific evidence for health effects attributed to the consumption of probiotics and prebiotics: an update for current perspectives and future challenges. Br J Nutr. 2015;114(12):1993–2015. https://doi.org/10.1017/s0007114515003864.

    Article  CAS  PubMed  Google Scholar 

  39. Marie I, Leroi AM, Gourcerol G, et al. Fructose malabsorption in systemic sclerosis. Medicine (Baltimore). 2015;94(39):e1601.

    Article  CAS  Google Scholar 

  40. Volkmann ER, Chang YL, Barroso N, et al. Association of systemic sclerosis with a unique colonic microbial consortium. Arthritis Rheumatol. 2016;68(6):1483–92. https://doi.org/10.1002/art.39572.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Alekseyenko AV, Perez-Perez GI, De Souza A, et al. Community differentiation of the cutaneous microbiota in psoriasis. Microbiome. 2013;1(1):31. https://doi.org/10.1186/2049-2618-1-31.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Fahlen A, Engstrand L, Baker BS, et al. Comparison of bacterial microbiota in skin biopsies from normal and psoriatic skin. Arch Dermatol Res. 2012;304(1):15–22. https://doi.org/10.1007/s00403-011-1189-x.

    Article  PubMed  CAS  Google Scholar 

  43. Arron ST, Dimon MT, Li Z, et al. High Rhodotorula sequences in skin transcriptome of patients with diffuse systemic sclerosis. J Invest Dermatol. 2014;134(8):2138–45. https://doi.org/10.1038/jid.2014.127.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Gyger G, Baron M. Systemic sclerosis: gastrointestinal disease and its management. Rheum Dis Clin North Am. 2015;41(3):459–73. https://doi.org/10.1016/j.rdc.2015.04.007.

    Article  PubMed  Google Scholar 

  45. Tauber M, Avouac J, Benahmed A, et al. Prevalence and predictors of small intestinal bacterial overgrowth in systemic sclerosis patients with gastrointestinal symptoms. Clin Exp Rheumatol. 2014;32(6 Suppl 86):S-82–7.

    Google Scholar 

  46. Grace E, Shaw C, Whelan K, et al. Review article: small intestinal bacterial overgrowth–prevalence, clinical features, current and developing diagnostic tests, and treatment. Aliment Pharmacol Ther. 2013;38(7):674–88. https://doi.org/10.1111/apt.12456.

    Article  PubMed  CAS  Google Scholar 

  47. Marie I, Ducrotte P, Denis P, et al. Small intestinal bacterial overgrowth in systemic sclerosis. Rheumatology (Oxford). 2009;48(10):1314–9. https://doi.org/10.1093/rheumatology/kep226.

    Article  Google Scholar 

  48. Parodi A, Sessarego M, Greco A, et al. Small intestinal bacterial overgrowth in patients suffering from scleroderma: clinical effectiveness of its eradication. Am J Gastroenterol. 2008;103(5):1257–62. https://doi.org/10.1111/j.1572-0241.2007.01758.x.

    Article  PubMed  Google Scholar 

  49. Ebert EC. Gastric and enteric involvement in progressive systemic sclerosis. J Clin Gastroenterol. 2008;42(1):5–12. https://doi.org/10.1097/MCG.0b013e318042d625.

    Article  PubMed  Google Scholar 

  50. Fiorucci S, Distrutti E, Bassotti G, et al. Effect of erythromycin administration on upper gastrointestinal motility in scleroderma patients. Scand J Gastroenterol. 1994;29(9):807–13.

    Article  PubMed  CAS  Google Scholar 

  51. Asama T, Kimura Y, Kono T, et al. Effects of heat-killed Lactobacillus kunkeei YB38 on human intestinal environment and bowel movement: a pilot study. Benef Microbes. 2016;7(3):337–44. https://doi.org/10.3920/bm2015.0132.

    Article  PubMed  CAS  Google Scholar 

  52. Attaluri A, Jackson M, Valestin J, et al. Methanogenic flora is associated with altered colonic transit but not stool characteristics in constipation without IBS. Am J Gastroenterol. 2010;105(6):1407–11. https://doi.org/10.1038/ajg.2009.655.

    Article  PubMed  Google Scholar 

  53. Parthasarathy G, Chen J, Chen X, et al. Relationship between microbiota of the colonic mucosa vs feces and symptoms, colonic transit, and methane production in female patients with chronic constipation. Gastroenterology. 2016;150(2):367–379.e361. https://doi.org/10.1053/j.gastro.2015.10.005.

    Article  PubMed  Google Scholar 

  54. Taur Y, Jenq RR, Perales MA, et al. The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation. Blood. 2014;124(7):1174–82. https://doi.org/10.1182/blood-2014-02-554725.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Wang W, Xu S, Ren Z, et al. Gut microbiota and allogeneic transplantation. J Transl Med. 2015;13:275. https://doi.org/10.1186/s12967-015-0640-8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Whangbo J, Ritz J, Bhatt A. Antibiotic-mediated modification of the intestinal microbiome in allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2017;52(2):183–90. https://doi.org/10.1038/bmt.2016.206.

    Article  PubMed  CAS  Google Scholar 

  57. Bujor AM, Haines P, Padilla C, et al. Ciprofloxacin has antifibrotic effects in scleroderma fibroblasts via downregulation of Dnmt1 and upregulation of Fli1. Int J Mol Med. 2012;30(6):1473–80. https://doi.org/10.3892/ijmm.2012.1150.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Mayes MD, O’Donnell D, Rothfield NF, et al. Minocycline is not effective in systemic sclerosis: results of an open-label multicenter trial. Arthritis Rheum. 2004;50(2):553–7. https://doi.org/10.1002/art.20036.

    Article  PubMed  CAS  Google Scholar 

  59. Frech TM, Khanna D, Maranian P, et al. Probiotics for the treatment of systemic sclerosis-associated gastrointestinal bloating/distention. Clin Exp Rheumatol. 2011;29(2 Suppl 65):S22–5.

    PubMed  Google Scholar 

  60. Rieder F. The gut microbiome in intestinal fibrosis: environmental protector or provocateur? Sci Transl Med. 2013;5(190):190ps110. https://doi.org/10.1126/scitranslmed.3004731.

    Article  CAS  Google Scholar 

  61. Sakamoto N, Kakugawa T, Hara A, et al. Association of elevated alpha-defensin levels with interstitial pneumonia in patients with systemic sclerosis. Respir Res. 2015;16:148. https://doi.org/10.1186/s12931-015-0308-1.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. van Bon L, Affandi AJ, Broen J, et al. Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis. New Engl J Med. 2013;370(5):433–43. https://doi.org/10.1056/NEJMoa1114576.

    Article  PubMed  CAS  Google Scholar 

  63. Espinoza-Leon F, Hassanhi-Hassanhi M, Arocha-Sandoval F, et al. Absence of Borrelia burgdorferi antibodies in the sera of Venezuelan patients with localized scleroderma (morphea). Invest Clin. 2006;47(3):283–8.

    PubMed  Google Scholar 

  64. Goodlad JR, Davidson MM, Gordon P, et al. Morphoea and Borrelia burgdorferi: results from the Scottish highlands in the context of the world literature. Mol Pathol. 2002;55(6):374–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Prinz JC, Kutasi Z, Weisenseel P, et al. “Borrelia-associated early-onset morphea”: a particular type of scleroderma in childhood and adolescence with high titer antinuclear antibodies? Results of a cohort analysis and presentation of three cases. J Am Acad Dermatol. 2009;60(2):248–55. https://doi.org/10.1016/j.jaad.2008.09.023.

    Article  PubMed  Google Scholar 

  66. Weide B, Walz T, Garbe C. Is morphoea caused by Borrelia burgdorferi? A review. Br J Dermatol. 2000;142(4):636–44.

    Article  PubMed  CAS  Google Scholar 

  67. Bowler PG, Duerden BI, Armstrong DG. Wound microbiology and associated approaches to wound management. Clin Microbiol Rev. 2001;14(2):244–69. https://doi.org/10.1128/cmr.14.2.244-269.2001.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Dagenais M, MacDonald D, Baron M, et al. The Canadian systemic sclerosis oral health study IV: oral radiographic manifestations in systemic sclerosis compared with the general population. Oral Surg Oral Med Oral Pathol Oral Radiol. 2015;120(2):104–11. https://doi.org/10.1016/j.oooo.2015.03.002.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Gonzales TS, Coleman GC. Periodontal manifestations of collagen vascular disorders. Periodontol. 1999;21:94–105.

    Article  CAS  Google Scholar 

  70. Baron M, Hudson M, Dagenais M, et al. Relationship between disease characteristics and oral radiologic findings in systemic sclerosis: results from a Canadian oral health study. Arthritis Care Res. 2016;68(5):673–80. https://doi.org/10.1002/acr.22739.

    Article  Google Scholar 

  71. Slocum C, Kramer C, Genco CA. Immune dysregulation mediated by the oral microbiome: potential link to chronic inflammation and atherosclerosis. J Intern Med. 2016;280(1):114–28. https://doi.org/10.1111/joim.12476.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Rheumatology and Clinical Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands

    Julia Spierings, Femke C. van Rhijn-Brouwer & Jacob M. van Laar

  2. Department of Nephrology and Hypertension, University Medical Centre Utrecht, Utrecht, The Netherlands

    Femke C. van Rhijn-Brouwer

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  1. Julia Spierings
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  2. Femke C. van Rhijn-Brouwer
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  3. Jacob M. van Laar
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Correspondence to Jacob M. van Laar .

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Editors and Affiliations

  1. Faculty of Medicine, Cairo University, Cairo, Egypt

    Gaafar Ragab

  2. University of Alabama, Birmingham, Alabama, USA

    T. Prescott Atkinson

  3. University of Alabama, Birmingham, Alabama, USA

    Matthew L. Stoll

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Spierings, J., van Rhijn-Brouwer, F.C., van Laar, J.M. (2018). Systemic Sclerosis. In: Ragab, G., Atkinson, T., Stoll, M. (eds) The Microbiome in Rheumatic Diseases and Infection. Springer, Cham. https://doi.org/10.1007/978-3-319-79026-8_24

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