Skip to main content
SpringerLink
Log in

Systemic Sclerosis in the Elderly

  • Chapter
  • First Online:
Rheumatic Disease in Geriatrics

  • 534 Accesses

Abstract

Systemic sclerosis (SSc) is a rare autoimmune disease that occurs in women six times more than in men usually at the fourth to fifth decade of life. Late onset SSc (LOSSc) is usually defined as an onset beyond 60 years of age. The most common presentation of LOSSc is limited disease, anti-centromere positive, with less digital ulcers (DU) than expected, but tendency to cardiac involvement including high rate of primary and mixed pulmonary hypertension (PHT). Elderly age at onset portends a poor prognosis in SSc, and high mortality, yet it seems that the standardized mortality ratio (SMR) is higher in younger SSc patients. Treatment is very similar to the general population of SSc patients with special attention to comorbidities as hypertension, cardiac involvement, osteoporosis and depression. High rate of malignancies in LOSSc warrants meticulous workup including tumor markers serial testing.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 69.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 89.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Denton CP. Systemic sclerosis: from pathogenesis to targeted therapy. Clin Exp Rheumatol. 2015;33(4 Suppl 92):S3–7.

    PubMed  Google Scholar 

  2. Burbelo PD, Gordon SM, Waldman M, Edison JD, Little DJ, Stitt RS, et al. Autoantibodies are present before the clinical diagnosis of systemic sclerosis. PLoS One. 2019;14(3):e0214202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Galluccio F, Matucci-Cerinic M. Registry evaluation of digital ulcers in systemic sclerosis. Int J Rheumatol. 2010;2010:363679.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Matucci-Cerinic M, Krieg T, Guillevin L, Schwierin B, Rosenberg D, Cornelisse P, et al. Elucidating the burden of recurrent and chronic digital ulcers in systemic sclerosis: long-term results from the DUO Registry. Ann Rheum Dis. 2016;75(10):1770–6.

    Article  CAS  PubMed  Google Scholar 

  5. Tyndall AJ, Bannert B, Vonk M, Airo P, Cozzi F, Carreira PE, 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.

    Article  PubMed  Google Scholar 

  6. Walker UA, Tyndall A, Czirjak L, Denton C, Farge-Bancel D, Kowal-Bielecka O, et al. Clinical risk assessment of organ manifestations in systemic sclerosis: a report from the EULAR Scleroderma Trials And Research group database. Ann Rheum Dis. 2007;66(6):754–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Pokeerbux MR, Giovannelli J, Dauchet L, Mouthon L, Agard C, Lega JC, et al. Survival and prognosis factors in systemic sclerosis: data of a French multicenter cohort, systematic review, and meta-analysis of the literature. Arthritis Res Ther. 2019;21(1):86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Elhai M, Meune C, Boubaya M, Avouac J, Hachulla E, Balbir-Gurman A, et al. Mapping and predicting mortality from systemic sclerosis. Ann Rheum Dis. 2017;76(11):1897–905.

    Article  PubMed  Google Scholar 

  9. Benan M, Hande I, Gul O. The natural course of progressive systemic sclerosis patients with interstitial lung involvement. Clin Rheumatol. 2007;26(3):349–54.

    Article  PubMed  Google Scholar 

  10. Clements P, Lachenbruch P, Furst D, Paulus H. The course of skin involvement in systemic sclerosis over three years in a trial of chlorambucil versus placebo. Arthritis Rheum. 1993;36(11):1575–9.

    Article  CAS  PubMed  Google Scholar 

  11. Achille A, Journeau L, Espitia O, Connault J, Espitia-Thibault A, Durant C, et al. Late-onset systemic sclerosis: a retrospective study of 27 patients diagnosed after the age of 70. Ann Dermatol Venereol. 2018;145(3):166–72.

    Article  CAS  PubMed  Google Scholar 

  12. Alba MA, Velasco C, Simeon CP, Fonollosa V, Trapiella L, Egurbide MV, et al. Early-versus late-onset systemic sclerosis: differences in clinical presentation and outcome in 1037 patients. Medicine (Baltimore). 2014;93(2):73–81.

    Article  CAS  Google Scholar 

  13. Carreira PE, Carmona L, Joven BE, Loza E, Andreu JL, Riemekasten G, et al. Differences associated with age at onset in early systemic sclerosis patients: a report from the EULAR Scleroderma Trials and Research Group (EUSTAR) database. Scand J Rheumatol. 2019;48(1):42–51.

    Article  CAS  PubMed  Google Scholar 

  14. Czirjak L, Nagy Z, Szegedi G. Systemic sclerosis in the elderly. Clin Rheumatol. 1992;11(4):483–5.

    Article  CAS  PubMed  Google Scholar 

  15. Derk CT, Artlett CM, Jimenez SA. Morbidity and mortality of patients diagnosed with systemic sclerosis after the age of 75: a nested case-control study. Clin Rheumatol. 2006;25(6):831–4.

    Article  PubMed  Google Scholar 

  16. Hugle T, Schuetz P, Daikeler T, Tyndall A, Matucci-Cerinic M, Walker UA, et al. Late-onset systemic sclerosis--a systematic survey of the EULAR scleroderma trials and research group database. Rheumatology (Oxford). 2011;50(1):161–5.

    Article  Google Scholar 

  17. Luís M, Costa F, Carmo A, Ferreira J, Santiago T, Cunha R, et al. SAT0501 early versus late-onset systemic sclerosis: are there clinical and immunological differences? Ann Rheum Dis. 2018;77(Suppl 2):1106–7.

    Google Scholar 

  18. Manno RL, Wigley FM, Gelber AC, Hummers LK. Late-age onset systemic sclerosis. J Rheumatol. 2011;38(7):1317–25.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Perez-Bocanegra C, Solans-Laque R, Simeon-Aznar CP, Campillo M, Fonollosa-Pla V, Vilardell-Tarres M. Age-related survival and clinical features in systemic sclerosis patients older or younger than 65 at diagnosis. Rheumatology (Oxford). 2010;49(6):1112–7.

    Article  Google Scholar 

  20. Wangkaew S, Phiriyakrit P, Sawangduan V, Prasertwittayakij N, Euathrongchit J. Differences in clinical presentation and incidence of cardiopulmonary involvement in late-onset versus early-onset systemic sclerosis: inception cohort study. Int J Rheum Dis. 2018;21(5):1082–92.

    Article  PubMed  Google Scholar 

  21. Amoda O, Ravat V, Datta S, Saroha B, Patel RS. Trends in demographics, hospitalization outcomes, comorbidities, and mortality risk among systemic sclerosis patients. Cureus. 2018;10(5):e2628.

    PubMed  PubMed Central  Google Scholar 

  22. Butt SA, Jeppesen JL, Fuchs C, Mogensen M, Engelhart M, Torp-Pedersen C, et al. Trends in incidence, mortality, and causes of death associated with systemic sclerosis in Denmark between 1995 and 2015: a nationwide cohort study. BMC Rheumatol. 2018;2:36.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Wooten M. Systemic sclerosis and malignancy: a review of the literature. South Med J. 2008;101(1):59–62.

    Article  PubMed  Google Scholar 

  24. Shah AA, Hummers LK, Casciola-Rosen L, Visvanathan K, Rosen A, Wigley FM. Examination of autoantibody status and clinical features associated with cancer risk and cancer-associated scleroderma. Arthritis Rheumatol. 2015;67(4):1053–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Shah AA, Xu G, Rosen A, Hummers LK, Wigley FM, Elledge SJ, et al. Brief report: anti-RNPC-3 antibodies as a marker of cancer-associated scleroderma. Arthritis Rheumatol. 2017;69(6):1306–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Barbosa NS, Wetter DA, Wieland CN, Shenoy NK, Markovic SN, Thanarajasingam U. Scleroderma induced by pembrolizumab: a case series. Mayo Clin Proc. 2017;92(7):1158–63.

    Article  PubMed  Google Scholar 

  27. Ling SM, Wigley FM. Raynaud’s phenomenon in older adults: diagnostic considerations and management. Drugs Aging. 1999;15(3):183–95.

    Article  CAS  PubMed  Google Scholar 

  28. Corzo P, Pros A, Martinez-Llorens J, Molina L, Ling SF, Balcells E. Isolated DLco/VA reduction in systemic sclerosis patients: a new patient subset? Clin Rheumatol. 2018;37(12):3365–71.

    Article  PubMed  Google Scholar 

  29. De Luca G, Bosello SL, Berardi G, Rucco M, Canestrari G, Correra M, et al. Tumour-associated antigens in systemic sclerosis patients with interstitial lung disease: association with lung involvement and cancer risk. Rheumatology. 2015;54(11):1991–9.

    Article  PubMed  CAS  Google Scholar 

  30. Parrado RH, Lemus HN, Coral-Alvarado PX, Quintana LG. Gastric antral vascular ectasia in systemic sclerosis: current concepts. Int J Rheumatol. 2015;2015:762546.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Ingraham KM, O’Brien MS, Shenin M, Derk CT, Steen VD. Gastric antral vascular ectasia in systemic sclerosis: demographics and disease predictors. J Rheumatol. 2010;37(3):603–7.

    Article  PubMed  Google Scholar 

  32. Hachulla AL, Launay D, Gaxotte V, de Groote P, Lamblin N, Devos P, et al. Cardiac magnetic resonance imaging in systemic sclerosis: a cross-sectional observational study of 52 patients. Ann Rheum Dis. 2009;68(12):1878–84.

    Article  PubMed  Google Scholar 

  33. Mavrogeni SI, Schwitter J, Gargani L, Pepe A, Monti L, Allanore Y, et al. Cardiovascular magnetic resonance in systemic sclerosis: “pearls and pitfalls”. Semin Arthritis Rheum. 2017;47(1):79–85.

    Article  PubMed  Google Scholar 

  34. Zeineddine N, Khoury LE, Mosak J. Systemic sclerosis and malignancy: a review of current data. J Clin Med Res. 2016;8(9):625–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Bellando-Randone S, Tartarelli L, Cavigli E, Tofani L, Bruni C, Lepri G, et al. 18F-fluorodeoxyglucose positron-emission tomography/CT and lung involvement in systemic sclerosis. Ann Rheum Dis. 2019;78(4):577–8.

    Article  CAS  PubMed  Google Scholar 

  36. Sheikhbahaei S, Marcus CV, Fragomeni RS, Rowe SP, Javadi MS, Solnes LB. Whole-body (18)F-FDG PET and (18)F-FDG PET/CT in patients with suspected paraneoplastic syndrome: a systematic review and meta-analysis of diagnostic accuracy. J Nucl Med. 2017;58(7):1031–6.

    Article  CAS  PubMed  Google Scholar 

  37. Kowal-Bielecka O, Fransen J, Avouac J, Becker M, Kulak A, Allanore Y, et al. Update of EULAR recommendations for the treatment of systemic sclerosis. Ann Rheum Dis. 2017;76(8):1327–39.

    Article  PubMed  Google Scholar 

  38. Sullivan KM, Majhail NS, Bredeson C, Carpenter PA, Chatterjee S, Crofford LJ, et al. Systemic sclerosis as an indication for autologous hematopoietic cell transplantation: position statement from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2018;24(10):1961–4.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Christmann RB, Wells AU, Capelozzi VL, Silver RM. Gastroesophageal reflux incites interstitial lung disease in systemic sclerosis: clinical, radiologic, histopathologic, and treatment evidence. Semin Arthritis Rheum. 2010;40(3):241–9.

    Article  PubMed  Google Scholar 

  40. Giordano N, Puccetti L, Papakostas P, Di Pietra N, Bruni F, Pasqui AL, et al. Bosentan treatment for Raynauds phenomenon and skin fibrosis in patients with Systemic Sclerosis and pulmonary arterial hypertension: an open-label, observational, retrospective study. Int J Immunopathol Pharmacol. 2010;23(4):1185–94.

    Article  CAS  PubMed  Google Scholar 

  41. Vilela VS, da Silva BRA, da Costa CH, Lopes AJ, Levy RA, Rufino R. Effects of treatment with rituximab on microcirculation in patients with long-term systemic sclerosis. BMC Res Notes. 2018;11(1):874.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Tashkin DP, Roth MD, Clements PJ, Furst DE, Khanna D, Kleerup EC, et al. Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial. Lancet Respir Med. 2016;4(9):708–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Daoussis D, Melissaropoulos K, Sakellaropoulos G, Antonopoulos I, Markatseli TE, Simopoulou T, et al. A multicenter, open-label, comparative study of B-cell depletion therapy with Rituximab for systemic sclerosis-associated interstitial lung disease. Semin Arthritis Rheum. 2017;46(5):625–31.

    Article  CAS  PubMed  Google Scholar 

  44. Ebata S, Yoshizaki A, Fukasawa T, Miura S, Takahashi T, Sumida H, et al. Rituximab therapy is more effective than cyclophosphamide therapy for Japanese patients with anti-topoisomerase I-positive systemic sclerosis-associated interstitial lung disease. J Dermatol. 2019;46(11):1006–13.

    Article  CAS  PubMed  Google Scholar 

  45. Elhai M, Boubaya M, Distler O, Smith V, Matucci-Cerinic M, Alegre Sancho JJ, et al. Outcomes of patients with systemic sclerosis treated with rituximab in contemporary practice: a prospective cohort study. Ann Rheum Dis. 2019;78(7):979–87.

    Article  CAS  PubMed  Google Scholar 

  46. Jordan S, Distler JH, Maurer B, Huscher D, van Laar JM, Allanore Y, et al. Effects and safety of rituximab in systemic sclerosis: an analysis from the European Scleroderma Trial and Research (EUSTAR) group. Ann Rheum Dis. 2015;74(6):1188–94.

    Article  CAS  PubMed  Google Scholar 

  47. Saunders P, Tsipouri V, Keir GJ, Ashby D, Flather MD, Parfrey H, et al. Rituximab versus cyclophosphamide for the treatment of connective tissue disease-associated interstitial lung disease (RECITAL): study protocol for a randomised controlled trial. Trials. 2017;18(1):275.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Smith V, Piette Y, van Praet JT, Decuman S, Deschepper E, Elewaut D, et al. Two-year results of an open pilot study of a 2-treatment course with rituximab in patients with early systemic sclerosis with diffuse skin involvement. J Rheumatol. 2013;40(1):52–7.

    Article  CAS  PubMed  Google Scholar 

  49. Smith V, Van Praet JT, Vandooren B, Van der Cruyssen B, Naeyaert JM, Decuman S, et al. Rituximab in diffuse cutaneous systemic sclerosis: an open-label clinical and histopathological study. Ann Rheum Dis. 2010;69(1):193–7.

    Article  CAS  PubMed  Google Scholar 

  50. Thiebaut M, Launay D, Riviere S, Mahevas T, Bellakhal S, Hachulla E, et al. Efficacy and safety of rituximab in systemic sclerosis: French retrospective study and literature review. Autoimmun Rev. 2018;17(6):582–7.

    Article  CAS  PubMed  Google Scholar 

  51. Levy Y, Amital H, Langevitz P, Nacci F, Righi A, Conforti L, et al. Intravenous immunoglobulin modulates cutaneous involvement and reduces skin fibrosis in systemic sclerosis: an open-label study. Arthritis Rheum. 2004;50(3):1005–7.

    Article  PubMed  CAS  Google Scholar 

  52. Levy Y, Sherer Y, Langevitz P, Lorber M, Rotman P, Fabrizzi F, et al. Skin score decrease in systemic sclerosis patients treated with intravenous immunoglobulin--a preliminary report. Clin Rheumatol. 2000;19(3):207–11.

    Article  CAS  PubMed  Google Scholar 

  53. Nacci F, Righi A, Conforti ML, Miniati I, Fiori G, Martinovic D, et al. Intravenous immunoglobulins improve the function and ameliorate joint involvement in systemic sclerosis: a pilot study. Ann Rheum Dis. 2007;66(7):977–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Takehara K, Ihn H, Sato S. A randomized, double-blind, placebo-controlled trial: intravenous immunoglobulin treatment in patients with diffuse cutaneous systemic sclerosis. Clin Exp Rheumatol. 2013;31(2 Suppl 76):151–6.

    PubMed  Google Scholar 

  55. Goh NS, Desai SR, Veeraraghavan S, Hansell DM, Copley SJ, Maher TM, et al. Interstitial lung disease in systemic sclerosis: a simple staging system. Am J Respir Crit Care Med. 2008;177(11):1248–54.

    Article  PubMed  Google Scholar 

  56. Moazedi-Fuerst FC, Kielhauser SM, Brickmann K, Hermann J, Lutfi A, Meilinger M, et al. Rituximab for systemic sclerosis: arrest of pulmonary disease progression in five cases. Results of a lower dosage and shorter interval regimen. Scand J Rheumatol. 2014;43(3):257–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Sari A, Guven D, Armagan B, Erden A, Kalyoncu U, Karadag O, et al. Rituximab experience in patients with long-standing systemic sclerosis-associated interstitial lung disease: a series of 14 patients. J Clin Rheumatol. 2017;23(8):411–5.

    Article  PubMed  Google Scholar 

  58. Narvaez J, LLuch J, Alegre Sancho JJ, Molina-Molina M, Nolla JM, Castellvi I. Effectiveness and safety of tocilizumab for the treatment of refractory systemic sclerosis associated interstitial lung disease: a case series. Ann Rheum Dis. 2018;78(11):e123.

    Article  PubMed  CAS  Google Scholar 

  59. Khanna D, Denton CP, Lin CJF, van Laar JM, Frech TM, Anderson ME, et al. Safety and efficacy of subcutaneous tocilizumab in systemic sclerosis: results from the open-label period of a phase II randomised controlled trial (faSScinate). Ann Rheum Dis. 2018;77(2):212–20.

    Article  CAS  PubMed  Google Scholar 

  60. Spiera R, Hummers L, Chung L, Frech T, Domsic R, Hsu V, et al. OP0006 Safety and efficacy of lenabasum (JBT-101) in diffuse cutaneous systemic sclerosis subjects treated for one year in an open-label extension of trial jbt101-ssc-001. Ann Rheum Dis. 2018;77(Suppl 2):52.

    Google Scholar 

  61. Distler O, Highland KB, Gahlemann M, Azuma A, Fischer A, Mayes MD, et al. Nintedanib for systemic sclerosis-associated interstitial lung disease. N Engl J Med. 2019;380(26):2518–28.

    Article  CAS  PubMed  Google Scholar 

  62. Hughes M, Ong VH, Anderson ME, Hall F, Moinzadeh P, Griffiths B, et al. Consensus best practice pathway of the UK Scleroderma Study Group: digital vasculopathy in systemic sclerosis. Rheumatology (Oxford). 2015;54(11):2015–24.

    Article  CAS  Google Scholar 

  63. Wigley FM, Wise RA, Seibold JR, McCloskey DA, Kujala G, Medsger TA Jr, et al. Intravenous iloprost infusion in patients with Raynaud phenomenon secondary to systemic sclerosis. A multicenter, placebo-controlled, double-blind study. Ann Intern Med. 1994;120(3):199–206.

    Article  CAS  PubMed  Google Scholar 

  64. Mirasoglu B, Bagli BS, Aktas S. Hyperbaric oxygen therapy for chronic ulcers in systemic sclerosis - case series. Int J Dermatol. 2017;56(6):636–40.

    Article  CAS  PubMed  Google Scholar 

  65. Klinger JR, Elliott CG, Levine DJ, Bossone E, Duvall L, Fagan K, et al. Therapy for pulmonary arterial hypertension in adults: update of the CHEST guideline and expert panel report. Chest. 2019;155(3):565–86.

    Article  PubMed  Google Scholar 

  66. Distler O, Pope J, Denton C, Allanore Y, Matucci-Cerinic M, de Oliveira PJ, et al. RISE-SSc: riociguat in diffuse cutaneous systemic sclerosis. Respir Med. 2017;122(Suppl 1):S14–S7.

    Article  PubMed  Google Scholar 

  67. Humbert M, Coghlan JG, Ghofrani HA, Grimminger F, He JG, Riemekasten G, et al. Riociguat for the treatment of pulmonary arterial hypertension associated with connective tissue disease: results from PATENT-1 and PATENT-2. Ann Rheum Dis. 2017;76(2):422–6.

    Article  CAS  PubMed  Google Scholar 

  68. Nagaraja V, Spino C, Bush E, Tsou PS, Domsic RT, Lafyatis R, et al. A multicenter randomized, double-blind, placebo-controlled pilot study to assess the efficacy and safety of riociguat in systemic sclerosis-associated digital ulcers. Arthritis Res Ther. 2019;21(1):202.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Shreiner AB, Murray C, Denton C, Khanna D. Gastrointestinal manifestations of systemic sclerosis. J Scleroderma Relat Disord. 2016;1(3):247–56.

    Article  PubMed  Google Scholar 

  70. Parodi A, Sessarego M, Greco A, Bazzica M, Filaci G, Setti M, et al. Small intestinal bacterial overgrowth in patients suffering from scleroderma: clinical effectiveness of its eradication. Am J Gastroenterol. 2008;103(5):1257–62.

    Article  PubMed  Google Scholar 

  71. Raja J, Nihtyanova SI, Murray CD, Denton CP, Ong VH. Sustained benefit from intravenous immunoglobulin therapy for gastrointestinal involvement in systemic sclerosis. Rheumatology (Oxford). 2016;55(1):115–9.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Rheumatology Unit, Bnai Zion Medical Center, Haifa, Israel

    Doron Rimar

Authors
  1. Doron Rimar
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Rheumatology Unit, Bnai Zion Medical Center, Haifa, Israel

    Gleb Slobodin

  2. Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel

    Yehuda Shoenfeld

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Rimar, D. (2020). Systemic Sclerosis in the Elderly. In: Slobodin, G., Shoenfeld, Y. (eds) Rheumatic Disease in Geriatrics . Springer, Cham. https://doi.org/10.1007/978-3-030-44234-7_16

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-44234-7_16

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-44233-0

  • Online ISBN: 978-3-030-44234-7

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation