Advertisement

Skin Involvement

  • Angelo Valerio MarzanoEmail author
  • Simona Tavecchio
  • Emilio Berti
Chapter
Part of the Rare Diseases of the Immune System book series (RDIS)

Abstract

Cutaneous lesions may be the clinical expression of inflammatory disorders predominantly affecting skin blood vessels, but may also be part of systemic vasculitis. In particular, skin involvement occurs frequently in the context of the antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis, which are characterized by inflammatory cell infiltration of the small and medium-sized vessel wall. ANCA-associated vasculitis are rare and systemic diseases, which can be classified based on different distribution of vascular inflammation and the presence or absence of granulomatosis and asthma. Despite their diversities, ANCA-associated vasculitis, namely granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis and microscopic polyangiitis, can all present with a broad variety of cutaneous manifestations, which can appear during the course of these conditions or even as first sign of disease. Among the skin manifestations, palpable purpura represents the most common vasculitis-related lesion, but the cutaneous picture of ANCA-associated vasculitis is typically polymorphic including also papules, nodules, urticarial lesions, livedo, pustules, blisters, and necrotic ulcers. Due to this polymorphism, the diagnosis of skin involvement in ANCA-associated vasculitis is very challenging and must be supported by medical history, physical examination, histology of skin specimens, and ANCA serology. In this chapter, we focus on the cutaneous manifestations that can develop in the context of ANCA-associated vasculitis, describing clinical features, histopathological aspects, and direct immunofluorescence findings for each of these entities. Moreover, we address the differential diagnosis with different dermatological conditions and report the main therapeutic approaches.

Keywords

Anti-neutrophil cytoplasmic antibodies Vasculitis Skin Granulomatosis with polyangiitis Eosinophilic granulomatosis with polyangiitis Microscopic polyangiitis 

References

  1. 1.
    Cornec D, Cornec-Le Gall E, Fervenza FC, Specks U. ANCA-associated vasculitis—clinical utility of using ANCA specificity to classify patients. Nat Rev Rheumatol. 2016;12(10):570–9.CrossRefGoogle Scholar
  2. 2.
    Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of vasculitides. Arthritis Rheum. 2013;65(1):1–11.CrossRefGoogle Scholar
  3. 3.
    Csernok E, Moosig F. Current and emerging techniques for ANCA detection in vasculitis. Nat Rev Rheumatol. 2014;10(8):494–501.CrossRefGoogle Scholar
  4. 4.
    Damoiseaux J, Csernok E, Rasmussen N, et al. Detection of antineutrophil cytoplasmic antibodies (ANCAs): a multicentre European Vasculitis Study Group (EUVAS) evaluation of the value of indirect immunofluorescence (IIF) versus antigen-specific immunoassays. Ann Rheum Dis. 2016;76(4):647–53.CrossRefGoogle Scholar
  5. 5.
    Jennette JC, Falk RJ. Pathogenesis of antineutrophil cytoplasmic autoantibody-mediated disease. Nat Rev Rheumatol. 2014;10(8):463–73.CrossRefGoogle Scholar
  6. 6.
    Watts RA, Mahr A, Mohammad AJ, Gatenby P, Basu N, Flores-Suarez LF. Classification, epidemiology and clinical subgrouping of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Nephrol Dial Transplant. 2015;30(Suppl 1):i14–22.CrossRefGoogle Scholar
  7. 7.
    Frumholtz L, Laurent-Roussel S, Aumaître O, et al. Clinical and pathological significance of cutaneous manifestations in ANCA-associated vasculitides. Autoimmun Rev. 2017;16:1138–46.CrossRefGoogle Scholar
  8. 8.
    Carlson JA, Chen KR. Cutaneous vasculitis update: small vessel neutrophilic vasculitis syndromes. Am J Dermatopathol. 2006;28(6):486–506.CrossRefGoogle Scholar
  9. 9.
    Guillevin L, Pagnoux C, Seror R, et al. The five factor score revisited: assessment of prognoses of systemic necrotizing vasculitides based on the French Vasculitis Study Group (FVSG) cohort. Medicine (Baltimore). 2011;90:19–27.CrossRefGoogle Scholar
  10. 10.
    Mohammad AJ, Jacobsson LT, Westman KW, Sturfelt G, Segelmark M. Incidence and survival rates in Wegener’s granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome and polyarteritis nodosa. Rheumatology (Oxford). 2009;48(12):1560–5.CrossRefGoogle Scholar
  11. 11.
    Comarmond C, Cacoub P. Granulomatosis with polyangiitis (Wegener): clinical aspects and treatment. Autoimmun Rev. 2014;13(11):1121–5.CrossRefGoogle Scholar
  12. 12.
    Calatroni M, Oliva E, Gianfreda D, et al. ANCA-associated vasculitis in childhood: recent advances. Ital J Pediatr. 2017;43(1):46.CrossRefGoogle Scholar
  13. 13.
    Iudici M, Pagnoux C, Quartier P, et al. Childhood-versus adult-onset ANCA-associated vasculitides: a nested, matched case-control study from the French Vasculitis Study Group Registry. Autoimmun Rev. 2018;17(2):108–14.CrossRefGoogle Scholar
  14. 14.
    Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med. 1992;116(6):488–98.CrossRefGoogle Scholar
  15. 15.
    Trimarchi M, Sinico RA, Teggi R, Bussi M, Specks U, Meroni PL. Otorhinolaryngological manifestations in granulomatosis with polyangiitis (Wegener’s). Autoimmun Rev. 2013;12(4):501–5.CrossRefGoogle Scholar
  16. 16.
    Chang DY, Wu LH, Liu G, Chen M, Kallenberg CG, Zhao MH. Re-evaluation of the histopathologic classification of ANCA-associated glomerulonephritis: a study of 121 patients in a single center. Nephrol Dial Transplant. 2012;27(6):2343–9.CrossRefGoogle Scholar
  17. 17.
    Mukhtyar C, Flossmann O, Hellmich B, et al. Outcomes from studies of antineutrophil cytoplasm antibody associated vasculitis: a systematic review by the European league against rheumatism systemic vasculitis task force. Ann Rheum Dis. 2008;67(7):1004–10.CrossRefGoogle Scholar
  18. 18.
    Stone JH. Wegener’s Granulomatosis Etanercept Trial Research G. Limited versus severe Wegener’s granulomatosis: baseline data on patients in the Wegener’s granulomatosis etanercept trial. Arthritis Rheum. 2003;48(8):2299–309.CrossRefGoogle Scholar
  19. 19.
    Luqmani R, Suppiah R, Edwards CJ, et al. Mortality in Wegener’s granulomatosis: a bimodal pattern. Rheumatology (Oxford). 2011;50(4):697–702.CrossRefGoogle Scholar
  20. 20.
    Marzano AV, Vezzoli P, Berti E. Skin involvement in cutaneous and systemic vasculitis. Autoimmun Rev. 2013;12(4):467–76.CrossRefGoogle Scholar
  21. 21.
    Patten SF, Tomecki KJ. Wegener’s granulomatosis: cutaneous and oral mucosal disease. J Am Acad Dermatol. 1993;28(5 Pt 1):710–8.CrossRefGoogle Scholar
  22. 22.
    Tashtoush B, Memarpour R, Johnston Y, Ramirez J. Large pyoderma gangrenosum-like ulcers: a rare presentation of granulomatosis with polyangiitis. Case Rep Rheumatol. 2014;2014:850364.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Feighery C, Conlon N, Abuzakouk M. Skin ulcer presentation of Wegener’s granulomatosis. BMJ Case Rep. 2010;2010:bcr0420102908.CrossRefGoogle Scholar
  24. 24.
    Holle JU, Gross WL, Holl-Ulrich K, et al. Prospective long-term follow-up of patients with localised Wegener’s granulomatosis: does it occur as persistent disease stage? Ann Rheum Dis. 2010;69(11):1934–9.CrossRefGoogle Scholar
  25. 25.
    Marzano AV, Balice Y, Papini M, Testa R, Berti E, Crosti C. Localized Wegener’s granulomatosis. J Eur Acad Dermatol Venereol. 2011;25(12):1466–70.CrossRefGoogle Scholar
  26. 26.
    Ruokonen H, Helve T, Arola J, Hietanen J, Lindqvist C. Hagstrom. Strawberry-like gingivitis being the first sign of Wegener’s granulomatosis. Eur J Intern Med. 2009;20(6):651–3.CrossRefGoogle Scholar
  27. 27.
    Stewart C, Cohen D, Bhattacharyya I, et al. Oral manifestations of Wegener’s granulomatosis: a report of three cases and a literature review. J Am Dent Assoc. 2007;138(3):338–48. quiz396,398CrossRefGoogle Scholar
  28. 28.
    Marzano AV, Balice Y, Tavecchio S, Desimine C, Colombo A, Berti E. Granulomatous vasculitis. G Ital Dermatol Venereol. 2015;150(2):193–202.PubMedGoogle Scholar
  29. 29.
    Ozen S, Pistorio A, Iusan SM, et al. EULAR/PRINTO/PRES criteria for Henoch-Schönlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: final classification criteria. Ann Rheum Dis. 2010;69(5):798–806.CrossRefGoogle Scholar
  30. 30.
    Gajic-Veljic M, Nikolic M, Peco-Antic A, Bogdanovic R, Andrejevic S, Bonaci-Nikolic B. Granulomatosis with polyangiitis (Wegener’s granulomatosis) in children: report of three cases with cutaneous manifestations and literature review. Pediatr Dermatol. 2013;30(4):e37–42.CrossRefGoogle Scholar
  31. 31.
    Decleva I, Marzano AV, Barbareschi M, Berti E. Cutaneous manifestations in systemic vasculitis. Clin Rev Allergy Immunol. 1997;15(1):5–20.CrossRefGoogle Scholar
  32. 32.
    Mouthon L, Dunogue B, Guillevin L. Diagnosis and classification of eosinophilic granulomatosis with polyangiitis (formerly named Churg-Strauss syndrome). J Autoimmun. 2014;48–49:99–103.CrossRefGoogle Scholar
  33. 33.
    Gioffredi A, Maritati F, Oliva E, Buzio C. Eosinophilic granulomatosis with polyangiitis: an overview. Front Immunol. 2014;5:549.CrossRefGoogle Scholar
  34. 34.
    Sinico RA, Di Toma L, Maggiore U, et al. Renal involvement in Churg-Strauss syndrome. Am J Kidney Dis. 2006;47(5):770–9.CrossRefGoogle Scholar
  35. 35.
    Comarmond C, Pagnoux C, Khellaf M, et al. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): clinical characteristics and long-term follow-up of the 383 patients enrolled in the French Vasculitis Study Group cohort. Arthritis Rheum. 2013;65(1):270–81.CrossRefGoogle Scholar
  36. 36.
    Sable-Fourtassou R, Cohen P, Mahr A, et al. Antineutrophil cytoplasmic antibodies and the Churg-Strauss syndrome. Ann Intern Med. 2005;143(9):632–8.CrossRefGoogle Scholar
  37. 37.
    Greco A, Rizzo MI, De Virgilio A, et al. Churg-Strauss syndrome. Autoimmun Rev. 2015;14(4):341–8.CrossRefGoogle Scholar
  38. 38.
    Greco A, De Virgilio A, Rizzo MI, et al. Microscopic polyangiitis: advances in diagnostic and therapeutic approaches. Autoimmun Rev. 2015;14(9):837–44.CrossRefGoogle Scholar
  39. 39.
    Mohammad AJ, Jacobsson LT, Mahr AD, Sturfelt G, Segelmark M. Prevalence of Wegener’s granulomatosis, microscopic polyangiitis, polyarteritis nodosa and Churg-Strauss syndrome within a defined population in southern Sweden. Rheumatology (Oxford). 2007;46(8):1329–37.CrossRefGoogle Scholar
  40. 40.
    Guillevin L, Durand-Gasselin B, Cevallos R, et al. Microscopic polyangiitis: clinical and laboratory findings in eighty-five patients. Arthritis Rheum. 1999;42(3):421–30.CrossRefGoogle Scholar
  41. 41.
    Niles JL, Bottinger EP, Saurina GR, et al. The syndrome of lung hemorrhage and nephritis is usually an ANCA-associated condition. Arch Intern Med. 1996;156(4):440–5.CrossRefGoogle Scholar
  42. 42.
    Savage CO, Winearls CG, Evans DJ, Rees AJ, Lockwood CM. Microscopic polyarteritis: presentation, pathology and prognosis. Q J Med. 1985;56(220):467–83.Google Scholar
  43. 43.
    Lhote F, Cohen P, Guillevin L. Polyarteritis nodosa, microscopi polyangiitis and Churg-Strauss syndrome. Lupus. 1998;7(4):238–58.CrossRefGoogle Scholar
  44. 44.
    Kluger N, Pagnoux C, Guillevin L, Frances C. French Vasculitis Study G. Comparison of cutaneous manifestations in systemic polyarteritis nodosa and microscopic polyangiitis. Br J Dermatol. 2008;159(3):615–20.CrossRefGoogle Scholar
  45. 45.
    Kawakami T, Soma Y, Saito C, et al. Cutaneous manifestations in patients with microscopic polyangiitis: two case reports and a minireview. Acta Derm Venereol. 2006;86(2):144–7.PubMedGoogle Scholar
  46. 46.
    Niiyama S, Amoh Y, Tomita M, Katsuoka K. Dermatological manifestations associated with microscopic polyangiitis. Rheumatol Int. 2008;28(6):593–5.CrossRefGoogle Scholar
  47. 47.
    Wallach D, Vignon-Pennamen MD. From acute febrile neutrophilic dermatosis to neutrophilic disease: forty years of clinical research. J Am Acad Dermatol. 2006;55(6):1066–71.CrossRefGoogle Scholar
  48. 48.
    Marzano AV, Menicanti C, Crosti C, Trevisan V. Neutrophilic dermatoses and inflammatory bowel diseases. G Ital Dermatol Venereol. 2013;148(2):185–96.PubMedGoogle Scholar
  49. 49.
    Seishima M, Oyama Z, Oda M. Skin eruptions associated with microscopic polyangiitis. Eur J Dermatol. 2004;14(4):255–8.PubMedGoogle Scholar
  50. 50.
    Chen KR. Skin involvement in ANCA-associated vasculitis. Clin Exp Nephrol. 2013;17(5):676–82.CrossRefGoogle Scholar
  51. 51.
    Ishibashi M, Kawahara Y, Chen KR. Spectrum of cutaneous vasculitis in eosinophilic granulomatosis with polyangiitis (Churg- Strauss): a case series. Am J Dermatopathol. 2015;37(3):214–21.CrossRefGoogle Scholar
  52. 52.
    Carlson JA. The histological assessment of cutaneous vasculitis. Histopathology. 2010;56(1):3–23.CrossRefGoogle Scholar
  53. 53.
    Rachapalli SM, Kiely PD. Cocaine-induced midline destructive lesions mimicking ENT-limited Wegener’s granulomatosis. Scand J Rheumatol. 2008;37(6):477–80.CrossRefGoogle Scholar
  54. 54.
    Marzano AV, Ishak RS, Saibeni S, Crosti C, Meroni PL, Cugno M. Autoinflammatory skin disorders in inflammatory bowel diseases, pyoderma gangrenosum and Sweet’s syndrome: a comprehensive review and disease classification criteria. Clin Rev Allergy Immunol. 2013;45(2):202–10.CrossRefGoogle Scholar
  55. 55.
    Marzano AV, Cugno M, Trevisan V, et al. Role of inflammatory cells, cytokines and matrix metalloproteinases in neutrophil-mediated skin diseases. Clin Exp Immunol. 2010;162(1):100–7.CrossRefGoogle Scholar
  56. 56.
    Marzano AV, Fanoni D, Antiga E, et al. Expression of cytokines, chemokines and other effector molecules in two prototypic autoinflammatory skin diseases, pyoderma gangrenosum and Sweet’s syndrome. Clin Exp Immunol. 2014;178(1):48–56.CrossRefGoogle Scholar
  57. 57.
    Gastman B, Hashem AM, Djohan R, et al. Malignant pyoderma associated with granulomatosis with polyangiitis (Wegener granulomatosis) as a unique indication for facial vascularized composite Allotransplantation: part I. Plast Reconstr Surg. 2016;137(6):1007e–15e.CrossRefGoogle Scholar
  58. 58.
    Jeong HS, Layher H, Cao L, Vandergriff T, Dominguez AR. Pyoderma gangrenosum (PG) associated with levamisole adulterated cocaine: clinical, serologic, and histopathologic findings in a cohort of patients. J Am Acad Dermatol. 2016;74(5):892–8.CrossRefGoogle Scholar
  59. 59.
    Jimenez-Gallo D, Albarran-Planelles C, Linares-Barrios M, et al. Pyoderma gangrenosum and Wegener granulomatosis-like syndrome induced by cocaine. Clin Exp Dermatol. 2013;38(8):878–82.CrossRefGoogle Scholar
  60. 60.
    Saulsbury FT. Clinical update: Henoch-Schönlein purpura. Lancet. 2007;369(9566):976–8.CrossRefGoogle Scholar
  61. 61.
    Yates M, Watts RA, Bajema IM, et al. EULAR/ERA-EDTA recommendations for the management of ANCA associated vasculitis. Ann Rheum Dis. 2016;75(9):1583–94.CrossRefGoogle Scholar
  62. 62.
    Guillevin L, Cordier JF, Lhote F, et al. A prospective, multicenter, randomized trial comparing steroids and pulse cyclophosphamide versus steroids and oral cyclophosphamide in the treatment of generalized Wegener’s granulomatosis. Arthritis Rheum. 1997;40(12):2187–98.CrossRefGoogle Scholar
  63. 63.
    Jayne D, Rasmussen N, Andrassy K, et al. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med. 2003;349(1):36–44.CrossRefGoogle Scholar
  64. 64.
    Hogan SL, Falk RJ, Chin H, et al. Predictors of relapse and treatment resistance in antineutrophil cytoplasmic antibody-associated small-vessel vasculitis. Ann Intern Med. 2005;143(9):621–31.CrossRefGoogle Scholar
  65. 65.
    De Groot K, Rasmussen N, Bacon PA, et al. Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody associated vasculitis. Arthritis Rheum. 2005;52(8):2461–9.CrossRefGoogle Scholar
  66. 66.
    Wegener’s Granulomatosis Etanercept Trial Research G. Etanercept plus standard therapy for Wegener’s granulomatosis. N Engl J Med. 2005;352(4):351–61.CrossRefGoogle Scholar
  67. 67.
    Pagnoux C, Mahr A, Hamidou MA, et al. Azathioprine or methotrexate maintenance for ANCA-associated vasculitis. N Engl J Med. 2008;359(26):2790–803.CrossRefGoogle Scholar
  68. 68.
    de Groot K, Harper L, Jayne DR, et al. Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann Intern Med. 2009;150(10):670–80.CrossRefGoogle Scholar
  69. 69.
    Food and Drug Administration. (2011). http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm251946.htm. Accessed October 10 2014.
  70. 70.
    Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010;363(3):221–32.CrossRefGoogle Scholar
  71. 71.
    Specks U, Merkel PA, Seo P, et al. Efficacy of remission induction regimens for ANCA-associated vasculitis. N Engl J Med. 2013;369(5):417–27.CrossRefGoogle Scholar
  72. 72.
    Marzano AV, Raimondo MG, Berti E, Meroni PL, Ingegnoli F. Cutaneous Manifestations of ANCA-Associated Small Vessels Vasculitis. Clin Rev Allergy Immunol. 2017;53(3):428–38.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Angelo Valerio Marzano
    • 1
    • 2
    Email author
  • Simona Tavecchio
    • 1
    • 2
  • Emilio Berti
    • 1
    • 2
  1. 1.Dermatology UnitFondazione IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoMilanItaly
  2. 2.Department of Pathophysiology and TransplantationUniversità degli Studi di MilanoMilanItaly

Personalised recommendations