Advertisement

Vascular Behçet’s syndrome: an update

  • Giacomo Emmi
  • Alessandra Bettiol
  • Elena Silvestri
  • Gerardo Di Scala
  • Matteo Becatti
  • Claudia Fiorillo
  • Domenico Prisco
IM - REVIEW
Part of the following topical collections:
  1. Behcet disease

Abstract

Behçet’s syndrome (BS) is a complex vasculitis, characterised by peculiar histological, pathogenetic and clinical features. Superficial venous thrombosis (SVT) and deep vein thrombosis (DVT) are the most frequent vascular involvements, affecting altogether 15–40% of BS patients. Atypical thrombosis is also an important clinical feature of BS, involving the vascular districts of the inferior and superior vena cava, suprahepatic veins with Budd–Chiari syndrome, portal vein, cerebral sinuses and right ventricle. On the other hand, arterial involvement, although affecting only 3–5% of patients, represents a unique feature of BS, with aneurysms potentially affecting peripheral, visceral and pulmonary arteries. Vascular events in BS are promoted by inflammation, with neutrophils playing a key role in the pathogenesis of thrombotic events; in turn, coagulative components such as fibrinogen, thrombin, factor Xa and factor VIIa amplify the inflammatory cascade. Understanding the contribution of inflammatory and coagulation components in the pathogenesis of BS vascular events is crucial to define the most effective therapeutic strategy. Control of vascular thrombosis is achieved with immunosuppressants drugs rather than anticoagulants. In particular, use of azathioprine and cyclosporine in association with low-dose corticosteroids should be considered in DVT and SVT cases, while treatment with cyclophosphamide together with anti-TNF-α agents can be effectively used in arterial involvement. More recently, the anti-TNF-α drugs have also been reported as a valid alternative for the treatment also of venous events, especially DVT. An exception to the use of anticoagulant in BS could be represented by cerebral veins thrombosis. In this review, we will depict the main characteristics of the vascular involvement in BS, briefly describing histological and pathogenetic features, while focusing on the clinical and therapeutical approaches of the vascular manifestations of BS.

Keywords

Behçet’s syndrome Angio-Behçet Vascular Behçet Thrombosis Anti-TNFα Adalimumab 

Notes

Acknowledgements

This study was not funded. The authors wish to thank Stefano Salvati and Javier Hernández Plasencia for their help in preparing Fig. 2.

Compliance with ethical standards

Conflict of interest

The author declares that they have no conflict of interest.

Statement of human and animal rights

This study does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

Informed consent is not applicable to this study (review).

Supplementary material

11739_2018_1991_MOESM1_ESM.docx (75 kb)
Supplementary material 1 (DOCX 74 kb)

References

  1. 1.
    Silvestri E, Emmi G, Prisco D (2013) Vascular Behçet’s disease: new insights in the management of thrombosis. Expert Rev Cardiovasc Ther 11:1583–1585.  https://doi.org/10.1586/14779072.2013.836449 CrossRefPubMedGoogle Scholar
  2. 2.
    Yazici H, Ugurlu S, Seyahi E (2012) Behçet syndrome: is it one condition? Clin Rev Allergy Immunol 43:275–280.  https://doi.org/10.1007/s12016-012-8319-x CrossRefPubMedGoogle Scholar
  3. 3.
    International Team for the Revision of the International Criteria for Behçet’s Disease (ITR-ICBD) F, Assaad-Khalil S, Calamia KT et al (2014) The International Criteria for Behçet’s Disease (ICBD): a collaborative study of 27 countries on the sensitivity and specificity of the new criteria. J Eur Acad Dermatol Venereol 28:338–347.  https://doi.org/10.1111/jdv.12107 CrossRefGoogle Scholar
  4. 4.
    Jennette JC, Falk RJ, Bacon PA et al (2013) 2012 revised international chapel hill consensus conference nomenclature of vasculitides. Arthritis Rheum 65:1–11.  https://doi.org/10.1002/art.37715 CrossRefPubMedGoogle Scholar
  5. 5.
    McDonald DR, Lee C, Fowler RA, Abuhaleeqa K (2007) Behcet’s disease. CMAJ 176:1273–1274.  https://doi.org/10.1503/cmaj.061136 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Boyd SR, Young S, Lightman S (2001) Immunopathology of the noninfectious posterior and intermediate uveitides. Surv Ophthalmol 46:209–233CrossRefGoogle Scholar
  7. 7.
    Hirohata S, Kikuchi H (2009) Histopathology of the ruptured pulmonary artery aneurysm in a patient with Behçet’s disease. Clin Exp Rheumatol 27:S91–S95PubMedGoogle Scholar
  8. 8.
    Ergun T, Gürbüz O, Harvell J et al (1998) The histopathology of pathergy: a chronologic study of skin hyperreactivity in Behçet’s disease. Int J Dermatol 37:929–933CrossRefGoogle Scholar
  9. 9.
    Verity DH, Wallace GR, Vaughan RW, Stanford MR (2003) Behçet’s disease: from Hippocrates to the third millennium. Br J Ophthalmol 87:1175–1183CrossRefGoogle Scholar
  10. 10.
    Emmi G, Silvestri E, Squatrito D et al (2014) Behçet’s syndrome pathophysiology and potential therapeutic targets. Intern Emerg Med 9:257–265.  https://doi.org/10.1007/s11739-013-1036-5 CrossRefPubMedGoogle Scholar
  11. 11.
    Consolandi C, Turroni S, Emmi G et al (2015) Behçet’s syndrome patients exhibit specific microbiome signature. Autoimmun Rev 14:269–276.  https://doi.org/10.1016/j.autrev.2014.11.009 CrossRefPubMedGoogle Scholar
  12. 12.
    Aldinucci A, Bonechi E, Biagioli T et al (2018) CSF/serum matrix metallopeptidase-9 ratio discriminates neuro Behçet from multiple sclerosis. Ann Clin Transl Neurol 5:493–498.  https://doi.org/10.1002/acn3.538 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Emmi G, Silvestri E, Della Bella C et al (2016) Cytotoxic Th1 and Th17 cells infiltrate the intestinal mucosa of Behcet patients and exhibit high levels of TNF-α in early phases of the disease. Medicine 95:e5516.  https://doi.org/10.1097/MD.0000000000005516 (Baltimore) CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Aksu K, Donmez A, Keser G (2012) Inflammation-induced thrombosis: mechanisms, disease associations and management. Curr Pharm Des 18:1478–1493CrossRefGoogle Scholar
  15. 15.
    Emmi G, Silvestri E, Squatrito D et al (2015) Thrombosis in vasculitis: from pathogenesis to treatment. Thromb J 13:15.  https://doi.org/10.1186/s12959-015-0047-z CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Matsumura N, Mizushima Y (1975) Leucocyte movement and colchicine treatment in Behcet’s disease. Lancet 2:813 (London, England) CrossRefGoogle Scholar
  17. 17.
    Kawakami T, Ohashi S, Kawa Y et al (2004) Elevated serum granulocyte colony-stimulating factor levels in patients with active phase of sweet syndrome and patients with active behcet disease: implication in neutrophil apoptosis dysfunction. Arch Dermatol 140:570–574.  https://doi.org/10.1001/archderm.140.5.570 CrossRefPubMedGoogle Scholar
  18. 18.
    Erkan F, Gül A, Tasali E (2001) Pulmonary manifestations of Behçet’s disease. Thorax 56:572–578CrossRefGoogle Scholar
  19. 19.
    Mantovani A, Cassatella MA, Costantini C, Jaillon S (2011) Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol 11:519–531.  https://doi.org/10.1038/nri3024 CrossRefPubMedGoogle Scholar
  20. 20.
    Becatti M, Emmi G, Silvestri E et al (2016) Neutrophil activation promotes fibrinogen oxidation and thrombus formation in Behçet disease. Circulation 133:302–311.  https://doi.org/10.1161/CIRCULATIONAHA.115.017738 CrossRefPubMedGoogle Scholar
  21. 21.
    Nasr H, Scriven JM (2015) Superficial thrombophlebitis (superficial venous thrombosis). BMJ 350:h2039.  https://doi.org/10.1136/bmj.h2039 CrossRefPubMedGoogle Scholar
  22. 22.
    Sarr SA, Fall PD, Mboup MC et al (2015) Superior vena cava syndrome revealing a Behçet’s disease. Thromb J 13:7.  https://doi.org/10.1186/s12959-015-0039-z CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Lakhanpal S, Tani K, Lie JT et al (1985) Pathologic features of Behçet’s syndrome: a review of Japanese autopsy registry data. Hum Pathol 16:790–795CrossRefGoogle Scholar
  24. 24.
    Hamuryudan V, Er T, Seyahi E et al (2004) Pulmonary artery aneurysms in Behçet syndrome. Am J Med 117:867–870.  https://doi.org/10.1016/j.amjmed.2004.05.027 CrossRefPubMedGoogle Scholar
  25. 25.
    Saadoun D, Wechsler B, Desseaux K et al (2010) Mortality in Behçet’s disease. Arthritis Rheum 62:2806–2812.  https://doi.org/10.1002/art.27568 CrossRefPubMedGoogle Scholar
  26. 26.
    Hughes JP, Stovin PG (1959) Segmental pulmonary artery aneurysms with peripheral venous thrombosis. Br J Dis Chest 53:19–27CrossRefGoogle Scholar
  27. 27.
    Khalid U, Saleem T (2011) Hughes–Stovin syndrome. Orphanet J Rare Dis 6:15.  https://doi.org/10.1186/1750-1172-6-15 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Hatemi G, Christensen R, Bang D et al (2018) 2018 update of the EULAR recommendations for the management of Behçet’s syndrome. Ann Rheum Dis 77:808–818.  https://doi.org/10.1136/annrheumdis-2018-213225 CrossRefPubMedGoogle Scholar
  29. 29.
    Vitale A, Rigante D, Lopalco G et al (2016) New therapeutic solutions for Behçet’s syndrome. Expert Opin Investig Drugs 25:827–840.  https://doi.org/10.1080/13543784.2016.1181751 CrossRefPubMedGoogle Scholar
  30. 30.
    Ahn JK, Lee YS, Jeon CH et al (2008) Treatment of venous thrombosis associated with Behcet’s disease: immunosuppressive therapy alone versus immunosuppressive therapy plus anticoagulation. Clin Rheumatol 27:201–205.  https://doi.org/10.1007/s10067-007-0685-z CrossRefPubMedGoogle Scholar
  31. 31.
    Alibaz-Oner F, Karadeniz A, Ylmaz S et al (2015) Behçet disease with vascular involvement. Medicine 94:e494.  https://doi.org/10.1097/MD.0000000000000494 (Baltimore) CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Desbois AC, Wechsler B, Resche-Rigon M et al (2012) Immunosuppressants reduce venous thrombosis relapse in Behçet’s disease. Arthritis Rheum 64:2753–2760.  https://doi.org/10.1002/art.34450 CrossRefPubMedGoogle Scholar
  33. 33.
    Emmi G, Vitale A, Silvestri E et al (2018) Adalimumab-based treatment versus DMARDs for venous thrombosis in Behçet syndrome. A retrospective study of 70 patients with vascular involvement. Arthritis Rheumatol 70:1500–1507.  https://doi.org/10.1002/art.40531 CrossRefPubMedGoogle Scholar
  34. 34.
    Hamzaoui A, Fatima J, Thouraya BS et al (2014) Vena cava thrombosis in Behçet’s disease. Anadolu Kardiyol Derg 14:292–293.  https://doi.org/10.5152/akd.2014.5042 CrossRefPubMedGoogle Scholar
  35. 35.
    Seyahi E, Caglar E, Ugurlu S et al (2015) An outcome survey of 43 patients with Budd–Chiari syndrome due to Behçet’s syndrome followed up at a single, dedicated center. Semin Arthritis Rheum 44:602–609.  https://doi.org/10.1016/j.semarthrit.2014.10.014 CrossRefPubMedGoogle Scholar
  36. 36.
    Seyahi E, Hamuryudan V, Hatemi G et al (2007) Infliximab in the treatment of hepatic vein thrombosis (Budd–Chiari syndrome) in three patients with Behcet’s syndrome. Rheumatology 46:1213–1214.  https://doi.org/10.1093/rheumatology/kem103 (Oxford) CrossRefPubMedGoogle Scholar
  37. 37.
    Ben Ghorbel I, Belfeki N, Houman MH (2016) Intracardiac thrombus in Behçet’s disease. Reumatismo 68:148–153.  https://doi.org/10.4081/reumatismo.2016.887 CrossRefPubMedGoogle Scholar
  38. 38.
    Wang H, Guo X, Tian Z et al (2016) Intracardiac thrombus in patients with Behcet’s disease: clinical correlates, imaging features, and outcome: a retrospective, single-center experience. Clin Rheumatol 35:2501–2507.  https://doi.org/10.1007/s10067-015-3161-1 CrossRefPubMedGoogle Scholar
  39. 39.
    Prisco D, Silvestri E, Di Scala G, Emmi G (2018) Behçet’s disease as a cause of cerebral sinus vein thrombosis: an emerging role. Rheumatology.  https://doi.org/10.1093/rheumatology/key279 (Oxford) CrossRefPubMedGoogle Scholar
  40. 40.
    Uluduz D, Midi I, Duman T et al (2018) Behçet’s disease as a causative factor of cerebral venous sinus thrombosis: subgroup analysis of data from the VENOST study. Rheumatology 55:464.  https://doi.org/10.1093/rheumatology/key153 (Oxford) CrossRefGoogle Scholar
  41. 41.
    Saadoun D, Wechsler B, Resche-Rigon M et al (2009) Cerebral venous thrombosis in Behçet’s disease. Arthritis Rheum 61:518–526.  https://doi.org/10.1002/art.24393 CrossRefPubMedGoogle Scholar
  42. 42.
    Shi J, Huang X, Li G et al (2018) Cerebral venous sinus thrombosis in Behçet’s disease: a retrospective case-control study. Clin Rheumatol 37:51–57.  https://doi.org/10.1007/s10067-017-3718-2 CrossRefPubMedGoogle Scholar
  43. 43.
    Seyahi E, Melikoglu M, Akman C et al (2012) Pulmonary artery involvement and associated lung disease in Behçet disease: a series of 47 patients. Medicine 91:35–48.  https://doi.org/10.1097/MD.0b013e318242ff37 (Baltimore) CrossRefPubMedGoogle Scholar
  44. 44.
    Zhang X, Dai H, Ma Z et al (2015) Pulmonary involvement in patients with Behçet’s disease: report of 15 cases. Clin Respir J 9:414–422.  https://doi.org/10.1111/crj.12153 CrossRefPubMedGoogle Scholar
  45. 45.
    Rossi GM, Emmi G, Vaglio A (2018) Hemoptysis in Behçet’s syndrome: from bedside to bench? Intern Emerg Med 13:467–469.  https://doi.org/10.1007/s11739-018-1863-5 CrossRefGoogle Scholar
  46. 46.
    Voiriot G, Parrot A, Antoine M et al (2018) Transcatheter embolotherapy of pulmonary artery aneurysms as emergency treatment of hemoptysis in Behcet patients: experience of a referral center and a review of the literature. Intern Emerg Med 13:491–500.  https://doi.org/10.1007/s11739-018-1817-y CrossRefPubMedGoogle Scholar
  47. 47.
    Hamuryudan V, Seyahi E, Ugurlu S et al (2015) Pulmonary artery involvement in Behçet׳s syndrome: effects of anti-Tnf treatment. Semin Arthritis Rheum 45:369–373.  https://doi.org/10.1016/j.semarthrit.2015.06.008 CrossRefPubMedGoogle Scholar
  48. 48.
    Hamuryudan V, Yurdakul S, Moral F et al (1994) Pulmonary arterial aneurysms in Behçet’s syndrome: a report of 24 cases. Rheumatology 33:48–51.  https://doi.org/10.1093/rheumatology/33.1.48 CrossRefGoogle Scholar
  49. 49.
    Uzun O, Erkan L, Akpolat I et al (2008) Pulmonary involvement in Behçet’s disease. Respiration 75:310–321.  https://doi.org/10.1159/000101954 CrossRefPubMedGoogle Scholar
  50. 50.
    Balcioglu O, Ertugay S, Bozkaya H et al (2015) Endovascular repair and adjunctive immunosuppressive therapy of aortic involvement in Behçet’s disease. Eur J Vasc Endovasc Surg 50:593–598.  https://doi.org/10.1016/j.ejvs.2015.07.011 CrossRefPubMedGoogle Scholar
  51. 51.
    Kwon Koo B, Shim W-H, Yoon Y-S et al (2003) Endovascular therapy combined with immunosuppressive treatment for pseudoaneurysms in patients with Behçet’s disease. J Endovasc Ther 10:75–80.  https://doi.org/10.1177/152660280301000116 CrossRefPubMedGoogle Scholar
  52. 52.
    Seyahi E (2016) Behçet’s disease: how to diagnose and treat vascular involvement. Best Pract Res Clin Rheumatol 30:279–295.  https://doi.org/10.1016/j.berh.2016.08.002 CrossRefPubMedGoogle Scholar
  53. 53.
    Vitale A, Emmi G, Lopalco G et al (2017) Adalimumab effectiveness in Behçet’s disease: short and long-term data from a multicenter retrospective observational study. Clin Rheumatol 36:451–455.  https://doi.org/10.1007/s10067-016-3417-4 CrossRefPubMedGoogle Scholar
  54. 54.
    Fabiani C, Vitale A, Rigante D et al (2018) Predictors of sustained clinical response in patients with Behçet’s disease-related uveitis treated with infliximab and adalimumab. Clin Rheumatol 37:1715–1720.  https://doi.org/10.1007/s10067-018-4092-4 CrossRefPubMedGoogle Scholar
  55. 55.
    Fabiani C, Sota J, Vitale A et al (2018) Cumulative retention rate of adalimumab in patients with Behçet’s disease-related uveitis: a 4-year follow-up study. Br J Ophthalmol 102:637–641.  https://doi.org/10.1136/bjophthalmol-2017-310733 CrossRefPubMedGoogle Scholar
  56. 56.
    Fabiani C, Vitale A, Emmi G et al (2017) Efficacy and safety of adalimumab in Behçet’s disease-related uveitis: a multicenter retrospective observational study. Clin Rheumatol 36:183–189.  https://doi.org/10.1007/s10067-016-3480-x CrossRefPubMedGoogle Scholar
  57. 57.
    Lopalco G, Emmi G, Gentileschi S et al (2017) Certolizumab Pegol treatment in Behcet’s disease with different organ involvement: a multicenter retrospective observational study. Mod Rheumatol 27:1031–1035.  https://doi.org/10.1080/14397595.2017.1285857 CrossRefPubMedGoogle Scholar
  58. 58.
    Vitale A, Emmi G, Lopalco G et al (2018) Correction to: long-term efficacy and safety of golimumab in the treatment of multirefractory Behçet’s disease. Clin Rheumatol 5:123.  https://doi.org/10.1007/s10067-018-4302-0 CrossRefGoogle Scholar

Copyright information

© Società Italiana di Medicina Interna 2018

Authors and Affiliations

  1. 1.Department of Experimental and Clinical MedicineUniversity of FirenzeFirenzeItaly
  2. 2.Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA)University of FirenzeFirenzeItaly
  3. 3.Department of Experimental and Clinical Biomedical Sciences “Mario Serio”University of FirenzeFirenzeItaly

Personalised recommendations