Skip to main content

Advertisement

Log in

Combination therapy with Bosentan and Sildenafil improves Raynaud’s phenomenon and fosters the recovery of microvascular involvement in systemic sclerosis

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

Abstract

The aim of this study was to evaluate in systemic sclerosis (SSc) retrospectively the effect of Bosentan and Sildenafil and their combination on Raynaud’s phenomenon (RP), function, and capillaroscopic patterns. One hundred and twenty-three SSc patients (mean age ± sd, 57.69 ± 14.07 years) were retrospectively evaluated and divided into two groups according to American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification score: group 1 score < 10, group 2 score > 10. Each group was divided into three subgroups according to treatment: Bosentan, Sildenafil, and Bosentan + Sildenafil. Nailfold videocapillaroscopy (NVC), Scleroderma Health Assessment Questionnaire (SHAQ) and Raynaud Condition Score (RCS) were performed at baseline and after 3 and 6 months. In Bosentan (29 patients: 12, group 1; 17, group 2), NVC changed significantly in both groups, after 3 and 6 months (p = 0.00439, group 1; p = 0.00035, group 2). In group 1, the “active” and the “late” patterns reduced, and the “aspecific” increased. In group 2, there was a reduction of late patterns, a worsening of SHAQ (p < 0.005) and an improvement of RCS (p = 0.00014). In Sildenafil (63 patients: 35, group 1; 28, group 2), after 3 months, NVC patterns changed significantly in both groups(p = 0.042 group 1, p = 0.00089 group 2). In group 1, the late and early patterns increased, and the aspecific decreased. In group 2, a significant change of NVC pattern was observed also after 6 months (p = 0.00089): the late pattern increased while the active one reduced. After 6 months, SHAQ was significantly reduced in group 1 (p = 0.00027) and in group 2 (p = 0.0043). RCS improved in both groups (p = 0.0042, group 1; p = 0.0016, group 2). Combination therapy (Bosentan + Sildenafil) (31 patients: 14, group 1; 17, group 2) induced significant changes on NVC only in group 1 after 3 (p = 0.00256) and 6 months (p = 0.000349) with a reduction of the late and active patterns and an increase of the early pattern. In both groups, after 6 months, SHAQ (p < 0.05, group 1; p = 0.00049, group 2) and RCS significantly reduced (group 1, p = 0.00024; group 2, p = 0.0021). Patients treated with Bosentan + Sildenafil show a significant improvement of RCS and NVC. This combination therapy may exert a vascular activity achieving an amelioration of the structure of microvasculature in SSc.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Matucci-Cerinic M, Kahaleh B, Wigley FM (2013) Review: evidence that systemic sclerosis is a vascular disease. Arthritis Rheum 65(8):1953–62

    Article  PubMed  CAS  Google Scholar 

  2. Avouac J, Fransen J, Walker UA, Riccieri V, Smith V, Muller C et al (2011) EUSTAR group preliminary criteria for the very early diagnosis of systemic sclerosis: results of a Delphi consensus study from EULAR scleroderma trials and research group. Ann Rheum Dis 70(3):476–81

    Article  PubMed  CAS  Google Scholar 

  3. Kowal-Bielecka O, Landewé R, Avouac J, Chwiesko S, Miniati I, Czirjak L et al (2009) EULAR recommendations for the treatment of systemic sclerosis: a report from the EULAR scleroderma trials and research group (EUSTAR). Ann Rheum Dis 68(5):620–8

    Article  PubMed  CAS  Google Scholar 

  4. MatucciCerinic M, Kahaleh MB (2002) Beauty and the beast. The nitric oxide paradox in systemic sclerosis. Rheumatology (Oxford) 41:843–7

    Article  CAS  Google Scholar 

  5. Roustit M, Blaise S, Allanore Y et al (2013) Phosphodiesterase-5 inhibitors for the treatment of secondary Raynaud’s phenomenon: systematic review and meta-analysis of randomised trials. Ann Rheum Dis 72:1696–1699

    Article  PubMed  CAS  Google Scholar 

  6. Fries R, Shariat K, von Wilmowsky H et al (2005) Sildenafil in the treatment of Raynaud’s phenomenon resistant to vasodilatory therapy. Circulation 112:2980–5

    PubMed  CAS  Google Scholar 

  7. Brueckner CS, Becker MO, Kroencke T, Huscher D, Scherer HU, Worm M, Burmester G, Riemekasten G (2010) Effect of sildenafil on digital ulcers in systemic sclerosis: analysis from a single centre pilot study. Ann Rheum Dis 69(8):1475–8

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  8. Abraham D, Distler O (2007) How does endothelial cell injury start? The role of endothelin in systemic sclerosis. Arthritis Res Ther 9(Suppl 2):S2

    Article  PubMed  PubMed Central  Google Scholar 

  9. Denton CP, Pope JE, Peter HH, Gabrielli A, Boonstra A, van den Hoogen FH, TRacleer Use in PAH associated with Scleroderma and Connective Tissue Diseases (TRUST) Investigators et al (2008) Long-term effects of bosentan on quality of life, survival, safety and tolerability in pulmonary arterial hypertension related to connective tissue diseases. Ann Rheum Dis 67(9):1222–8

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  10. Korn J, Mayes M, Matucci-Cerinic M et al (2004) Digital ulcers in systemic sclerosis: prevention by treatment with Bosentan, an oral endothelin receptor antagonist. Arthritis Rheum 50:3985–93

    Article  PubMed  CAS  Google Scholar 

  11. Matucci-Cerinic M, Denton C, Furst D et al (2011) Bosentan treatment of digital ulcers related to systemic sclerosis: results from the RAPIDS-2 randomized, double-blind, placebo-controlled trial. Ann Rheum Dis 70:32–8

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  12. Cutolo M, Ruaro B, Pizzorni C, Ravera F, Smith V, Zampogna G, Paolino S, Seriolo B, Cimmino M, Sulli A (2014) Longterm treatment with endothelin receptor antagonist bosentan and iloprost improves fingertip blood perfusion in systemic sclerosis. J Rheumatol 41(5):881–6

    Article  PubMed  CAS  Google Scholar 

  13. Guiducci S, Bellando-Randone S, Bruni C et al (2012) Bosentan fosters microvascular de-remodelling in systemic sclerosis. Clin Rheumatol 31:1723–1725

    Article  PubMed  CAS  Google Scholar 

  14. Cutolo M, Zampogna G, Vremis L et al (2013) Longterm effects of endothelin receptor antagonism on microvascular damage evaluated by nailfold capillaroscopic analysis in systemic sclerosis. J Rheumatology 40:40–45

    Article  CAS  Google Scholar 

  15. Van den Hoogen F, Khanna D, Fransen J et al (2013) 2013 classification criteria for systemic sclerosis: an American college of rheumatology/European league against rheumatism collaborative initiative. Ann Rheum Dis 72(11):1747–55

    Article  PubMed  Google Scholar 

  16. Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee (1980) Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum 23:581–590

    Article  Google Scholar 

  17. Valentini G, Cuomo G, Abignano G et al (2011) Early systemic sclerosis: assessment of clinical and pre-clinical organ involvement in patients with different disease features. Rheumatology (Oxford) 50:317–23

    Article  Google Scholar 

  18. Cutolo M, Pizzorini C, Meroni M et al (2010) The role of nailfold videocapillaroscopy in Raynaud’s phenomenon monitoring and early diagnosis of systemic sclerosis. Reumatismo 62:237–47

    PubMed  CAS  Google Scholar 

  19. Matucci-Cerinic M, Bellando-Randone S, Lepri G, Bruni C, Guiducci S (2013) Very early versus early disease: the evolving definition of the many faces of systemic sclerosis. Ann Rheum Dis 72:319–21

    Article  PubMed  Google Scholar 

  20. Minier T, Guiducci S, Bellando-Randone S, Bruni C, Lepri G, Czirják L et al (2014) Preliminary analysis of the very early diagnosis of systemic sclerosis (VEDOSS) EUSTAR multicentre study: evidence for puffy fingers as a pivotal sign for suspicion of systemic sclerosis. Ann Rheum Dis 73(12):2087–93

    Article  PubMed  Google Scholar 

  21. Korn JH, Mayes M, MatucciCerinic M et al (2004) Digital ulcers in systemic sclerosis: prevention by treatment with bosentan, an oral endothelin receptor antagonist. Arthritis Rheum 50:3985–93

    Article  PubMed  CAS  Google Scholar 

  22. Matucci-Cerinic M, Denton CP, Furst DE, Mayes MD, Hsu VM, Carpentier P et al (2011) Bosentan treatment of digital ulcers related to systemic sclerosis: results from the RAPIDS-2 randomized, double-blind, placebo-controlled trial. Ann Rheum Dis 70:32–8

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  23. Moinzadeh P, Hunzelmann N, Krieg T (2011) Combination therapy with an endothelin-1 receptor antagonist (bosentan) and a phosphodiesterase V inhibitor (sildenafil) for the management of severe digital ulcerations in systemic sclerosis. J Am Acad Dermatol 65:e102–4

    Article  PubMed  Google Scholar 

  24. Catarsi E, Doveri M, Tavoni A (2013) Bosentan and sildenafil: successful treatment in a sclerodermic patient with refractory ulcers. Reumatismo 65(2):79–81

    Article  PubMed  CAS  Google Scholar 

  25. Cappelli S, Bellando-Randone S, Guiducci S, Matucci-Cerinic M (2014) Is immunosuppressive therapy the anchor treatment to achieve remission in systemic sclerosis? Rheumatology (Oxford) 53(6):975–87

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to S. Bellando-Randone or G. Lepri.

Ethics declarations

None.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bellando-Randone, S., Lepri, G., Bruni, C. et al. Combination therapy with Bosentan and Sildenafil improves Raynaud’s phenomenon and fosters the recovery of microvascular involvement in systemic sclerosis. Clin Rheumatol 35, 127–132 (2016). https://doi.org/10.1007/s10067-015-3119-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10067-015-3119-3

Keywords

Navigation