Skip to main content

Advertisement

SpringerLink
Log in

Vascular complications in systemic sclerosis: a prospective cohort study

  • Original Article
  • Published:
Clinical Rheumatology Aims and scope Submit manuscript

Abstract

Two major complications in scleroderma patients that cause substantial morbidity and mortality are ischemic digital lesions (DL) and pulmonary hypertension (PH). The clinician’s ability to predict which patients will develop these complications is imperfect. We conducted a prospective observational cohort study of 300 patients with scleroderma who were followed for at least a 5-year period. At baseline, patients lacked evidence of PH and were without a current DL. At each 6-month visit, the patient was examined for signs/symptoms of PH and/or a DL. The primary outcomes were (1) PH defined as a mean pulmonary artery pressure ≥ 25 mmHg by right heart catheterization and (2) ≥ 1 DL defined as new onset of severe vascular compromise. Thirty patients (10%) developed PH (11 group 1/PAH, 4 group II, 15 group III) and 69 developed DL. The average time from enrollment until diagnosis of PH was 3.2 ± 2 years. In multivariable analyses, patients who developed PH were more likely to have diffuse disease (HR 3.2, p = 0.004), a forced vital capacity (FVC)/diffusing capacity of the lungs for carbon monoxide (DLCO) ratio > 1.6 (HR 1.7, p = 0.008), and elevated RVSP (HR = 1.07, p = 0.007). Patients who developed PAH were more likely to have a FVC/DLCO ratio > 1.6 (HR = 5.8, p = 0.014), and patients who developed group III PH were less likely to have an elevated FVC (HR = 0.92, p = 0.001). Patients were more likely to develop a DL if they had a history of prior DL (HR = 7.0, p < 0.001), or were men (HR = 2.3, p = 0.007). In a prevalent cohort of scleroderma patients, individuals who develop PH or DL have simple to measure clinical features that can predict these complications years before they occur.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Hachulla E, Gressin V, Guillevin L, Carpentier P, Diot E, Sibilia J et al (2009) Early detection of pulmonary arterial hypertension in systemic sclerosis: a French nationwide prospective multicenter study. Arthritis Rheumatol 52:3792–3800

    Article  Google Scholar 

  2. Mukerjee D, St George D, Coleiro B, Knight C, Denton CP, Davar J, Black CM, Coghlan JG (2003) Prevalence and outcome in systemic sclerosis associated pulmonary arterial hypertension: application of a registry approach. Ann Rheum Dis 62:1088–1093

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Steen VD, Medsger TA (2007) Changes in causes of death in systemic sclerosis, 1972–2002. Ann Rheum Dis 66:940–944

    Article  PubMed  PubMed Central  Google Scholar 

  4. Wigley FM, Wise RA, Miller R, Needleman BW, Spence RJ (1992) Anticentromere antibody as a predictor of digital ischemic loss in patients with systemic sclerosis. Arthritis Rheumatol 35:688–693

    Article  CAS  Google Scholar 

  5. Hachulla E, Clerson P, Launay D, Lambert M, Morell-Dubois S, Queyrel V, Hatron PY (2007) Natural history of ischemic digital ulcers in systemic sclerosis: single-center retrospective longitudinal study. J Rheumatol 34:2423–2430

    PubMed  Google Scholar 

  6. Lefevre G, Dauchet L, Hachulla E, Montani D, Sobanski V, Lambert M et al (2013) Survival and prognostic factors in systemic sclerosis-associated pulmonary hypertension: a systematic review and meta-analysis. Arthritis Rheum 65:2412–2423

    Article  PubMed  Google Scholar 

  7. Walker UA, Tyndall A, Czirjak L, Denton C, Farge-Bancel D, Kowal-Bielecka O, Muller-Ladner U, Bocelli-Tyndall C, Matucci-Cerinic M, EUSTAR Co-authors (2007) Clinical risk assessment of organ manifestations in systemic sclerosis: a report from the EULAR scleroderma trials and research group database. Ann Rheum Dis 66:754–763

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Steen V, Denton CP, Pope JE, Matucci-Cerinic M (2009) Digital ulcers: overt vascular disease in systemic sclerosis. Rheumatology (Oxford) 48:19–24

    Article  Google Scholar 

  9. Nihtyanova SI, Brough GM, Black CM, Denton CP (2008) Clinical burden of digital vasculopathy in limited and diffuse cutaneous systemic sclerosis. Ann Rheum Dis 67:120–123

    Article  PubMed  CAS  Google Scholar 

  10. Allanore Y, Denton CP, Krieg T, Cornelisse P, Rosenberg D, Schwierin B, Matucci-Cerinic M, DUO Investigators (2016) Clinical characteristics and predictors of gangrene in patients with systemic sclerosis and digital ulcers in the Digital Ulcer Outcome Registry: a prospective, observational cohort. Ann Rheum Dis 75:1736–1740

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Nihtyanova SI, Schreiber BE, Ong VH, Rosenberg D, Moinzadeh P, Coghlan JG, Wells AU, Denton CP (2014) Prediction of pulmonary complications and long-term survival in systemic sclerosis. Arthritis Rheumatol 66:1625–1635

    Article  PubMed  Google Scholar 

  12. Cappelli L, Wigley FM (2015) Management of Raynaud phenomenon and digital ulcers in scleroderma. Rheum Dis Clin N Am 41:419–438

    Article  Google Scholar 

  13. Highland KB (2014) Recent advances in scleroderma-associated pulmonary hypertension. Curr Opin Rheumatol 26:637–645

    Article  PubMed  CAS  Google Scholar 

  14. Hughes M, Ong VH, Anderson ME, Hall F, Moinzadeh P, Griffiths B, Baildam E, Denton CP, Herrick AL (2015) Consensus best practice pathway of the UK scleroderma study group: digital vasculopathy in systemic sclerosis. Rheumatology (Oxford) 54:2015–2024

    Article  CAS  Google Scholar 

  15. Le Pavec J, Humbert M, Mouthon L, Hassoun PM (2010) Systemic sclerosis-associated pulmonary arterial hypertension. Am J Respir Crit Care Med 181:1285–1293

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Allanore Y, Borderie D, Avouac J, Zerkak D, Meune C, Hachulla E, Mouthon L, Guillevin L, Meyer O, Ekindjian OG, Weber S, Kahan A (2008) High N-terminal pro-brain natriuretic peptide levels and low diffusing capacity for carbon monoxide as independent predictors of the occurrence of precapillary pulmonary arterial hypertension in patients with systemic sclerosis. Arthritis Rheumatol 58:284–291

    Article  CAS  Google Scholar 

  17. Hsu VM, Chung L, Hummers LK, Wigley F, Simms R, Bolster M, Silver R, Fischer A, Hinchcliff ME, Varga J, Goldberg AZ, Derk CT, Schiopu E, Khanna D, Shapiro LS, Domsic RT, Medsger T, Mayes MD, Furst D, Csuka ME, Molitor JA, Alkassab F, Steen VD (2014) Development of pulmonary hypertension in a high-risk population with systemic sclerosis in the Pulmonary Hypertension Assessmentand Recognition of Outcomes in Scleroderma (PHAROS) cohort study. Semin Arthritis Rheum 44:55–62

    Article  PubMed  Google Scholar 

  18. Shah AA, Chung SE, Wigley FM, Wise RA, Hummers LK (2013) Changes in estimated right ventricular systolic pressure predict mortality and pulmonary hypertension in a cohort of scleroderma patients. Ann Rheum Dis 72:1136–1140

    Article  PubMed  Google Scholar 

  19. Meune C, Avouac J, Airo P, Beretta L, Dieude P, Wahbi K et al (2011) Prediction of pulmonary hypertension related to systemic sclerosis by an index based on simple clinical observations. Arthritis Rheum 63:2790–2796

    Article  PubMed  Google Scholar 

  20. Avouac J, Meune C, Ruiz B, Couraud PO, Uzan G, Boileau C, Kahan A, Chiocchia G, Allanore Y (2012) Angiogenic biomarkers predict the occurrence of digital ulcers in systemic sclerosis. Ann Rheum Dis 71:394–399

    Article  PubMed  CAS  Google Scholar 

  21. Elhai M, Avouac J, Walker UA, Matucci-Cerinic M, Riemekasten G, Airo P et al (2016) A gender gap in primary and secondary heart dysfunctions in systemic sclerosis: a EUSTAR prospective study. Ann Rheum Dis 75:163–169

    Article  PubMed  Google Scholar 

  22. Silva I, Teixeira A, Oliveira J, Almeida I, Almeida R, Aguas A et al (2015) Endothelial dysfunction and nailfold videocapillaroscopy pattern as predictors of digital ulcers in systemic sclerosis: a cohort study and review of the literature. Clin Rev Allergy Immunol 49:240–252

    Article  PubMed  CAS  Google Scholar 

  23. Herrick AL, Heaney M, Hollis S, Jayson MI (1994) Anticardiolipin, anticentromere and anti-Scl-70 antibodies in patients with systemic sclerosis and severe digital ischaemia. Ann Rheum Dis 53:540–542

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. McMahan ZH, Wigley FM, Casciola-Rosen L (2016) Increased risk of digital vascular events in scleroderma patients who have both anti-centromere and anti-interferon-inducible protein 16 antibodies. Arthritis Care Res 69:922–926

    Article  CAS  Google Scholar 

  25. LeRoy EC, Medsger TA Jr (2001) Criteria for the classification of early systemic sclerosis. J Rheumatol 28:1573–1576

    PubMed  CAS  Google Scholar 

  26. van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, Matucci-Cerinic M, Naden RP, Medsger TA Jr, Carreira PE, Riemekasten G, Clements PJ, Denton CP, Distler O, Allanore Y, Furst DE, Gabrielli A, Mayes MD, van Laar JM, Seibold JR, Czirjak L, Steen VD, Inanc M, Kowal-Bielecka O, Müller-Ladner U, Valentini G, Veale DJ, Vonk MC, Walker UA, Chung L, Collier DH, Csuka ME, Fessler BJ, Guiducci S, Herrick A, Hsu VM, Jimenez S, Kahaleh B, Merkel PA, Sierakowski S, Silver RM, Simms RW, Varga J, Pope JE (2013) 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative. Arthritis Rheum 65:2737–2747

    Article  PubMed  PubMed Central  Google Scholar 

  27. Medsger TA Jr, Bombardieri S, Czirjak L, Scorza R, Della Rossa A, Bencivelli W (2003) Assessment of disease severity and prognosis. Clin Exp Rheumatol 21:S42–S46

    PubMed  Google Scholar 

  28. Hankinson JL, Odencrantz JR, Fedan KB (1999) Spirometric reference values from a sample of the general U.S. population. Am J Respir Crit Care Med 159:179–187

    Article  PubMed  CAS  Google Scholar 

  29. Knudson RJ, Kaltenborn WT, Knudson DE, Burrows B (1987) The single-breath carbon monoxide diffusing capacity. Reference equations derived from a healthy nonsmoking population and effects of hematocrit. Am Rev Respir Dis 135:805–811

    Article  PubMed  CAS  Google Scholar 

  30. Hoeper MM, Bogaard HJ, Condliffe R, Frantz R, Khanna D, Kurzyna M, Langleben D, Manes A, Satoh T, Torres F, Wilkins MR, Badesch DB (2013) Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol 62:D42–D50

    Article  PubMed  Google Scholar 

  31. Badesch DB, Champion HC, Sanchez MA, Hoeper MM, Loyd JE, Manes A et al (2009) Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol 54:S55–S66

    Article  PubMed  Google Scholar 

  32. Steen VD (2005) Autoantibodies in systemic sclerosis. Semin Arthritis Rheum 35:35–42

    Article  PubMed  CAS  Google Scholar 

  33. Meyer O, De Chaisemartin L, Nicaise-Roland P, Cabane J, Tubach F, Dieude P et al (2010) Anti-RNA polymerase III antibody prevalence and associated clinical manifestations in a large series of French patients with systemic sclerosis: a cross-sectional study. J Rheumatol 37:125–130

    Article  PubMed  CAS  Google Scholar 

  34. Graf SW, Hakendorf P, Lester S, Patterson K, Walker JG, Smith MD et al (2012) South Australian scleroderma register: autoantibodies as predictive biomarkers of phenotype and outcome. Int J Rheum Dis 15:102–109

    Article  PubMed  Google Scholar 

  35. Motegi S, Toki S, Yamada K, Uchiyama A, Ishikawa O (2015) Demographic and clinical features of systemic sclerosis patients with anti-RNA polymerase III antibodies. J Dermatol 42:189–192

    Article  PubMed  CAS  Google Scholar 

  36. Hoffmann-Vold AM, Midtvedt O, Tennoe AH, Garen T, Lund MB, Aalokken TM et al (2017) Cardiopulmonary disease development in anti-RNA polymerase III-positive systemic sclerosis: comparative analyses from an unselected, prospective patient cohort. J Rheumatol 44:459–465

    Article  PubMed  CAS  Google Scholar 

  37. Chung L, Fairchild RM, Furst DE, Li S, Alkassab F, Bolster MB et al (2016) Utility of B-type natriuretic peptides in the assessment of patients with systemic sclerosis-associated pulmonary hypertension in the PHAROS registry. Clin Exp Rheumatol 106:106–113

    Google Scholar 

  38. Allanore Y, Borderie D, Meune C, Cabanes L, Weber S, Ekindjian OG et al (2003) N-terminal pro-brain natriuretic peptide as a diagnostic marker of early pulmonary artery hypertension in patients with systemic sclerosis and effects of calcium-channel blockers. Arthritis Rheumatol 48:3505–3508

    Article  CAS  Google Scholar 

  39. Impens AJ, Wangkaew S, Seibold JR (2008) The 6-minute walk test in scleroderma—how measuring everything measures nothing [Editorial]. Rheumatology (Oxford) 47:v68–v69

    Article  Google Scholar 

  40. Sunderkotter C, Herrgott I, Bruckner C, Moinzadeh P, Pfeiffer C, Gerb J et al (2009) Comparison of patients with and without digital ulcers in systemic sclerosis: detection of possible risk factors. B J Dermatol 160:835–843

    Article  CAS  Google Scholar 

  41. Khimdas S, Harding S, Bonner A, Zummer B, Baron M, Pope J, Canadian Scleroderma Research Group (2011) Associations with digital ulcers in a large cohort of systemic sclerosis: results from the Canadian Scleroderma Research Group registry. Arthritis Care Res 63:142–149

    Article  Google Scholar 

  42. D'Agostino RB Sr, Vasan RS, Pencina MJ, Wolf PA, Cobain M, Massaro JM, Kannel WB (2008) General cardiovascular risk profile for use in primary care: the Framingham Heart Study. Circulation 117:743–753

    Article  PubMed  Google Scholar 

  43. Charchar FJ, Bloomer LD, Barnes TA, Cowley MJ, Nelson CP, Wang Y et al (2012) Inheritance of coronary artery disease in men: an analysis of the role of the Y chromosome. Lancet 379:915–922

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Coghlan JG, Wolg M, Distler O, Denton C, Doelberg M, Harutyunova S et al (2018) Incidence of pulmonary hypertension and determining factors in patients with systemic sclerosis. Eur Respir J 51:1701197

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Adrianne Woods and Margaret Sampedro for their assistance in database querying, quality control, and aliquoting of biospecimens for this study.

Funding

Research reported in this publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Number T32AR048522. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. C.M. is a Jerome L. Greene Foundation Scholar and the Foundation has provided support for his work. This work was also supported by NIH grants 5K23AR52742-5 from NIAMS and P50-HL084946-01 from NHLBI. This work was also supported by the Scleroderma Research Foundation, Martha McCrory professorship, The John Staurulakis Endowed Scholar in Rheumatology (LKH), and Chresanthe Staurulakis Memorial Fund for Scleroderma Research.

Author information

Authors and Affiliations

  1. Division of Rheumatology, Johns Hopkins University School of Medicine, 5200 Eastern Ave, MFL Bldg, Center Tower, Suite 4100, Baltimore, MD, 21224, USA

    Christopher A. Mecoli, Ami A. Shah, Fredrick M. Wigley & Laura K. Hummers

  2. Division of Rheumatology, Department of Medicine, University of California, San Francisco, CA, USA

    Francesco Boin

Authors
  1. Christopher A. Mecoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ami A. Shah
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Francesco Boin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fredrick M. Wigley
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Laura K. Hummers
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Laura K. Hummers.

Ethics declarations

The Johns Hopkins University Institutional Review Board approved of this study (NA_00001412).

Disclosures

None.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mecoli, C.A., Shah, A.A., Boin, F. et al. Vascular complications in systemic sclerosis: a prospective cohort study. Clin Rheumatol 37, 2429–2437 (2018). https://doi.org/10.1007/s10067-018-4148-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10067-018-4148-5

Keywords

Search

Navigation