Antineutrophil cytoplasmic antibodies (ANCA) are group of autoantibodies that target the cytoplasm of the neutrophils. As a result, neutrophils attack the small blood vessels in the body causing inflammation and vasculitis. ANCA-associated vasculitis can involve any organs in the body. Skin and mucosal involvement, known as cutaneous vasculitides, are commonly seen and can present as the initial manifestation of the disease. Understanding the complicated clinical picture of the skin lesions variants will result in the early diagnosis and treatment of ANCA-associated vasculitis (Chen, 2013; Marzano et al., 2017). In this review article, we have focused on the different cutaneous manifestations presenting in ANCA-associated small-vessel vasculitis.
Granulomatosis With Polyangiitis
The triad of pathological features associated with granulomatosis with polyangiitis (GPA), formerly known as Wegener's granulomatosis, include necrotizing granlomatous inflammation of the upper and lower respiratory system, systemic necrotizing vasculitis, and necrotizing glomerulonephritis. The pathogenesis has been associated with the presence of ANCA directed against proteinase-3 and often correlates with activity of the disease (Marzano et al., 2017; Wojciechowska et al., 2016). GPA affects men and women equally and can occur at any age but is more common in ages between 45 and 60 years (Marzano et al., 2017). The spectrum and severity of the disease is varied, ranging from limited disease involving only one site to systemic vasculitis. In 80%–95% of the cases, otorhinolaryngological manifestations, particularly sinus involvement, are reported to be the first presenting features of GPA (Wojciechowska et al., 2016). The lungs are often involved, but renal involvement may be lacking early in the course of the disease. Kidney involvement usually presents as focal segmental necrotizing glomerulonephritis, which can rapidly result in renal failure (Marzano et al., 2017). Prognosis is poor if left untreated with a mortality rate of 80% in 1 year. The relapse rate is high and occurs in up to 50% of patients within 5 years (Carlson & Chen, 2006). Ocular and central nervous system involvement occurs from primary vasculitis or from spread of the granulomatous inflammation from the nearby structures such as nasopharynx or sinuses. Patients with GPA more typically have evidence of destruction of the dorsal nasal cartilage resulting in the characteristic saddle nose deformity (Figure 1). Retro-orbital pseudotumor is another unique manifestation in GPA that can present with periorbital swelling, proptosis, and vision disturbances. Peripheral nervous system involvement can present as a mononeuritis multiplex or polyneuritis. The most common cardiac features are coronary arteritis and pericarditis. Gastrointestinal and urogenital systems are less frequently affected (Groh et al., 2015; Marzano et al., 2017). In the past, cyclophosphamide and corticosteroids were the mainstay of therapy for multisystem GPA. However, rituximab has been shown to be more effective in the last decade (Groh et al., 2015).
Cutaneous involvement in GPA presents in around 60% of patients and rarely is the initial presentation of the disease. The extremities are the most common site of involvement, followed by the face and scalp. The most observed skin lesion is palpable purpura (Figure 2), but the cutaneous presentation can be polymorphic. Other skin manifestations are papules, papulonecrotic lesions, subcutaneous nodules, splinter hemorrhages, pyoderma gangrenosum (PG), livedo reticularis, and vesiculobullous lesions (Marzano et al., 2017; Xu et al., 2009). In most cases, the histopathological pattern of GPA in purpuric papules (Figure 2) is similar to leukocytoclastic vasculitis, which often correlates with active and generalized disease. Its hallmark is characterized by fibrinoid necrosis of the dermal and subcutaneous small vessel wall surrounded by a granuloma or granulomatous inflammation (Atzeni et al., 2006; Groh et al., 2015). Severe skin involvement with diffused pattern is not common but has been reported in a few cases (Dinić et al., 2013).
Papulonecrotic lesions on the extensor surfaces of the limbs, especially over the elbows, have been reported and can be mistaken for rheumatoid arthritis nodules. The nodules tend to ulcerate and are usually mobile (Stone & Nousari, 2001; Xu et al., 2009). PG, which presents as a painful, necrotic ulcer with violaceous, undermined borders, can also occur in GPA (Boudny et al., 2008). PG is characterized histopathologically by a palisaded granuloma surrounding a large area of a geographic necrosis, with prominent dermal neutrophilic infiltrate and abscess formation (Chen, 2013).
Oral lesions are rare in GPA and have been reported in 6%–13% of patients. These usually occur in advanced stages of the disease and present as nonspecific erosive ulcers and nodules on the tongue, palate, buccal mucosa, posterior pharynx, tonsils, and gums. The most characteristic oral lesion is hyperplastic gingivitis, which usually involves erythema and petechiae of the upper anterior gingivae. This lesion is known as strawberry gingivitis and is reportedly pathognomonic for GPA (Figure 3). Advanced disease might affect the underlying bone by causing osteomyelitis and necrosis, resulting in loss of teeth (Marzano et al., 2017; Sung et al., 2015). Rarely does strawberry gingivitis present as the initial manifestation of GPA (Hanisch et al., 2016; Siar et al., 2011). Facial plaques have been reported without other systemic involvement, resulting in bony disruption and palatal bone perforation (Figure 4; Marzano et al., 2011).
Penile GPA is rare and can present as an ulceration with PG-like appearance. Few case reports have reported penile involvement as an initial presentation of GPA. In most of these cases, GPA progresses to a more severe disease with other organ involvement months later (Bories et al., 2007).
Digital ulceration and gangrene are rare (Figure 5), resulting from destruction of medium-sized vessels along with in situ thrombosis (Lau et al., 2017; Pokharel et al., 2018).
Data on disease course suggest that the cutaneous features of GPA can relapse episodically lasting for weeks to months. The usual treatment for systemic disease resolves the cutaneous manifestations (Marzano et al., 2017).
The most recent criteria for the classification of eosinophilic GPA (EGPA), previously known as Churg–Strauss syndrome, is described by the Chapel Hill Consensus Conference Nomenclature, which defined EGPA as “eosinophil-rich and granulomatous inflammation involving the respiratory tract, necrotizing vasculitis affecting small- to medium-sized vessels, associated with asthma and eosinophilia” (Marzano et al., 2017; Vaglio et al., 2013; Yann Nguyen & Semin, 2018). EGPA can affect all ages but is rare in children. It mostly affects adults between the ages of 30 and 60 years, with the mean age of 46 years at the time of diagnosis. There is no significant gender difference (Bosco et al., 2011; Gioffredi et al., 2014; Marzano et al., 2017; Yann Nguyen & Semin, 2018). Blood eosinophils and serum Immunoglobulin E are markedly elevated in EGPA. ANCA, predominately with perinuclear immunofluorescence staining, associated with antimyeloperoxidase antibodies is found in 30%–40% of patients with EGPA (Bosco et al., 2011; Ishibashi et al., 2015; Vaglio et al., 2013). Vasculitic and eosinophilic symptoms are two major clinical presentations that can be seen in EGPA.
Presence of ANCA positivity in EGPA is usually associated with vasculitic symptoms such as peripheral neuropathy and glomerulonephritis, whereas ANCA-negative patients have a higher incidence of cardiac, lung, gastrointestinal, and skin involvement (Ishibashi et al., 2015; Vaglio et al., 2013).
EGPA usually develops in three phases: (a) a prodromal phase characterized by severe asthma that may precede systemic disease manifestations for many years, (b) eosinophillic phase characterized by peripheral blood eosinophilia, and (c) vasculitic phase that appears as an eosinophil-rich small-vessel vasculitis and is usually associated with tissue necrosis and granuloma formation (Bosco et al., 2011; Vaglio et al., 2013).
Asthma is the major characteristic feature affecting over 90% of patients, often years before the multisystem involvement. The overlap between severe asthma and mild EGPA symptoms can make the diagnosis challenging in the initial phase of the disease (Kawakami et al., 2005; Marzano et al., 2017; Yann Nguyen & Semin, 2018). Allergic rhinitis, sinusitis, and nasal polyposis are also common initial features that usually present before the vasculitis occur. Peripheral neuropathies, particularly mononeuritis multiplex, frequently occur, but central nervous system involvement is rare and can present as cerebral vasculitis. Gastrointestinal and cardiac involvements are seen mostly in ANCA-negative patients with EGPA and often associated with a worse prognosis. Renal and ophthalmologic involvement can also occur (Bosco et al., 2011; Marzano et al., 2017; Yann Nguyen & Semin, 2018).
Cutaneous involvement occurs in 40%–70% of patients with EGPA. Palpable purpura is the most frequent manifestation and is typically located on the lower extremities. Other hemorrhagic lesions such as petechiae, ecchymosis, and bullous lesions are less frequent (Bosco et al., 2011; Marzano et al., 2017; Yann Nguyen & Semin, 2018). Cutaneous and subcutaneous nodules are seen in 30% of the cases and are often distributed bilaterally and localized on the legs, scalp, fingers, and extensor surfaces of the elbows. Necrotic ulcerative changes may occur in both papular and nodular lesions (Atzeni et al., 2006; Marzano et al., 2013, 2017; Xu et al., 2009; Yann Nguyen & Semin, 2018). Other cutaneous manifestations include urticaria, erythema multiforme, papulonecrotic lesions, livedo reticularis (Figure 6), Raynaud's phenomenon, digital gangrene, aseptic pustules, cutaneous and nail fold infarctions, deep pannicular vasculitis, and facial edema (Atzeni et al., 2006; Bosco et al., 2011; Ishibashi et al., 2015; Yann Nguyen & Semin, 2018). Papulonecrotic lesions resemble those seen in GPA, but the presence of eosinophils differentiates these two (Xu et al., 2009). Urticarial vasculitis is distinguished from common urticaria by duration lasting more than 24 hours, more burning rather than pruritic sensation, and prominent postinflammatory hyperpigmentation (Marzano et al., 2013).
Skin biopsy shows a leukocytoclastic vasculitis involving small vessels. It is characterized by necrotizing vasculitis with fibrinoid necrosis and eosinophilic infiltration of the vessel walls. Extravascular granuloma with eosinophilic core of necrosis is also seen, which is typical but nonspecific for EGPA (Bosco et al., 2011; Marzano et al., 2017; Vaglio et al., 2013). In almost 50% of the patients, the direct immunofluorescence of the skin lesions can recognize the presence of the IgM and C3 deposits in blood vessel walls (Marzano et al., 2017). The treatment of the cutaneous manifestations of EGPA is as same as the treatment of the systemic disease and usually responds well to immunomodulatory medications (Marzano et al., 2013).
Microscopic polyangiitis (MPA) involves men more than women, usually of middle age (Kallenberg, 2014; Villiger & Guillevin, 2010). ANCA is positive in 50%–75% of the cases and more frequently directed against myeloperoxidase than proteinase-3 (Kallenberg, 2014; Marzano et al., 2017).
MPA may initially present with constitutional symptoms. Myalgia and arthralgia can occur, which can be mistaken with polymyalgia rheumatica. The most involved organs are the lungs and kidneys. Focal, segmental, rapidly progressive necrotizing glomerulonephritis is the most common renal involvement. Diffuse alveolar hemorrhage is the classical lung involvement in 30% of the patients and can be severe with frank robust bleeding or mild hemoptysis. Interstitial pneumonia and lung fibrosis are less frequent. Pulmonary–renal syndrome is a serious condition in MPA that can lead to hospitalization in the intensive care unit. Peripheral neuropathy such as mononeuritis multiplex, gastrointestinal symptoms, ophthalmologic, and less-frequent cardiac involvement can be observed during the course of MPA (Villiger & Guillevin, 2010).
Skin lesions are seen in 30%–60% of patients, and they can be the initial presentation in 15%–30% of cases (Marzano et al., 2017). Similar to GPA and EPGA, the most common cutaneous manifestation is palpable purpura (30, 60%), mostly seen in the lower extremities followed by livedo. The other skin presentations include nodules, urticaria, ulcers, necrotic lesions, sublingual hemorrhages, vesicles, bullae, palmar erythema, facial edema, erythema elevatum diutinum, and PG-like lesions (Carlson & Chen, 2006; Kluger et al., 2008; Marzano et al., 2017; Villiger & Guillevin, 2010). Erythema elevatum diutinum, which is characterized by red or purple papules, plaques, or nodules, on the extensor aspect of the limbs can also present in MPA (Marzano et al., 2017). Leukocytoclastic vasculitis is also seen in the biopsy and is characterized by fibrinoid necrosis and neutrophilic infiltration of the small vessels (Kluger et al., 2008; Marzano et al., 2017; Villiger & Guillevin, 2010).
Many of these skin manifestations and their clinicohistopathologic features are similar to polyarteritis nodosa, which is a medium-vessel vasculitis. The occasional presence of dermal venulitis is only seen in MPA and not in polyarteritis nodosa (Chen, 2013; Kluger et al., 2008). In MPA, skin lesions are usually associated with ophthalmologic involvement and peripheral neuropathy (Kluger et al., 2008; Villiger & Guillevin, 2010).
Dermatologic manifestations are very common in ANCA-associated vasculitis. Skin lesions can be the initial presentation or as part of systemic ANCA-associated vasculitis. Most of the cases with initial cutaneous manifestations will proceed to more severe vasculitis with multiple-organ involvement months later. Because undiagnosed ANCA-associated vasculitis is correlated with a high mortality risk, detecting the skin lesions early in the disease course can result in timely diagnosis. Starting early treatment is significantly associated with reduced mortality rate and results in remission induction. As a result, vasculitis should be suspected in any patient with new and unusual skin lesions described in this article.
The role of nurses in detecting skin lesions in different inpatient and outpatient settings is well known. Registered nurses observe and evaluate their patients' skin every day in inpatient units so they can help with the early detection of skin lesions. Reporting such findings can be a great asset to the physicians for early diagnosis and further evaluation. In addition, the role of the dermatology nurses is to recognize symptoms of ANCA-associated vasculitis. Being familiar with vasculitis-related skin lesions, obtaining a history of the patient's skin condition, and asking about other systemic symptoms is the key for suspecting vasculitis. Early identification of the vasculitis symptoms by the dermatology nurses promotes better patient outcomes.
We thank Dr. Karina Torralba for her critical comments and assistance in preparing the article. We also appreciate the American College of Rheumatology for giving us permission to use their images for this educational article.
Atzeni F., Carrabba M., Davin J. C., Francès C., Ferri C., Guillevin L., Jorizzo J. L., Mascia M. T., Patel M. J., Pagnoux C., Vulpio L., Sarzi-Puttini P. (2006). Skin manifestations in vasculitis and erythema nodosum. Clinical and Experimental Rheumatology
, 24(1, Suppl. 40), S60–S66.
Bories N., Becuwe C., Marcilly M. C., Wolf F., Balme B., Thomas L. (2007). Glans penis ulceration revealing Wegener's granulomatosis. Dermatology
, 214(2), 187–189.
Bosco L., Peroni A., Schena D., Colato C., Girolomoni G. (2011). Cutaneous manifestations of Churg–Strauss syndrome: Report of two cases and review of the literature. Clinical Rheumatology
, 30(4), 573–580.
Boudny C., Nievergelt H., Braathen L. R., Simon D. (2008). Wegener's granulomatosis presenting as pyoderma gangrenosum. Journal der Deutschen Dermatologischen Gesellschaft
, 6(6), 477–479.
Carlson J. A., Chen K. R. (2006). Cutaneous vasculitis update: Small vessel neutrophilic vasculitis syndromes. The American Journal of Dermatopathology
, 28(6), 486–506.
Chen K. R. (2013). Skin involvement in ANCA-associated vasculitis. Clinical and Experimental Nephrology
, 17(5), 676–682.
Dinić M. Z., Sekulović L. K., Zolotarevski L., Zecević R. D. (2013). Fulminant Wegener's granulomatosis: A case report. Vojnosanitetski Pregled
, 70(9), 887–890.
Gioffredi A., Maritati F., Oliva E., Buzio C. (2014). Eosinophilic granulomatosis with polyangiitis: An overview. Frontiers in Immunology
, 5, 549.
Groh M., Pagnoux C., Baldini C., Bel E., Bottero P., Cottin V., Dalhoff K., Dunogué B., Gross W., Holle J., Humbert M., Jayne D., Jennette J. C., Lazor R., Mahr A., Merkel P. A., Mouthon L., Sinico R. A., Specks U., Guillevin L. (2015). Eosinophilic granulomatosis with polyangiitis (Churg–Strauss) (EGPA) consensus task force recommendations for evaluation and management. European Journal of Internal Medicine
, 26(7), 545–553.
Hanisch M., Fröhlich L. F., Kleinheinz J. (2016). Gingival hyperplasia as first sign of recurrence of granulomatosis with polyangiitis (Wegener's granulomatosis): Case report and review of the literature. BMC Oral Health
, 17(1), 33.
Ishibashi M., Kawahara Y., Chen K. R. (2015). Spectrum of cutaneous vasculitis in eosinophilic granulomatosis with polyangiitis (Churg–Strauss): A case series. The American Journal of Dermatopathology
, 37(3), 214–221.
Kallenberg C. G. (2014). The diagnosis and classification of microscopic polyangiitis. Journal of Autoimmunity
, 48(49), 90–93.
Kawakami T., Soma Y., Kawasaki K., Kawase A., Mizoguchi M. (2005). Initial cutaneous manifestations consistent with mononeuropathy multiplex in Churg–Strauss syndrome. Archives of Dermatology
, 141(7), 873–878.
Kluger N., Pagnoux C., Guillevin L. (2008). Comparison of cutaneous manifestations in systemic polyarteritis nodosa and microscopic polyangiitis. British Journal of Dermatology
, 159(3), 615–620.
Lau R. A., Bains R., Suraweera D., Ma J., Heinze E. R., Wong A. L., Clements P. J. (2017). A rare case of digital ischemia and gangrene in ANCA-associated vasculitis with review of the literature. Case Reports in Rheumatology
, 2017, 2421760.
Marzano A. V., Balice Y., Papini M., Testa R., Berti E., Crosti C. (2011). Localized Wegener's granulomatosis. The Journal of the European Academy of Dermatology and Venereology
, 25(12), 1466–1470.
Marzano A. V., Raimondo M. G., Berti E., Meroni P. L., Ingegnoli F. (2017). Cutaneous manifestations of ANCA-associated small vessels vasculitis. Clinical Reviews in Allergy & Immunology
, 53, 428–438.
Marzano A. V., Vezzoli P., Berti E. (2013). Skin involvement in cutaneous and systemic vasculitis. Autoimmunity Reviews
, 12(4), 467–476.
Pokharel S., Singh S., Shaukat M. S. (2018). An unusual presentation of granulomatosis with polyangiitis (GPA). American Journal of Case Reports
, 19, 1071–1073.
Siar C. H., Yeo K. B., Nakano K., Nagatsuka H., Tsujigiwa H., Tomida M., Ng K. H., Kawakami T. (2011). Strawberry gingivitis as the first presenting sign of Wegener's granulomatosis: Report of a case. European Journal of Medical Research
, 16(7), 331–334.
Stone J. H., Nousari H. C. (2001). “Essential” cutaneous vasculitis: What every rheumatologist should know about vasculitis of the skin. Current Opinion in Rheumatology
, 13, 23–34.
Sung I. Y., Kim Y. M., Cho Y. C., Son J. H. (2015). Role of gingival manifestation in diagnosis of granulomatosis with polyangiitis (Wegener's granulomatosis). Journal of Periodontal & Implant Science
, 45(6), 247–251.
Vaglio A., Buzio C., Zwerina J. (2013). Eosinophilic granulomatosis with polyangiitis (Churg–Strauss): State of the art. Allergy
, 68(3), 261–273.
Villiger P. M., Guillevin L. (2010). Microscopic polyangiitis: Clinical presentation. Autoimmunity Reviews
, 9(12), 812–819.
Wojciechowska J., Krajewski W., Krajewski P., Kręcicki T. (2016). Granulomatosis with polyangiitis in otolaryngologist practice: A review of current knowledge. Clinical and Experimental Otorhinolaryngology
, 9(1), 8–13.
Xu L. Y., Esparza E. M., Anadkat M. J., Crone K. G., Brasington R. D. (2009). Cutaneous manifestations of vasculitis. Seminars in Arthritis and Rheumatism
, 38(5), 348–360.
Yann Nguyen Y., Semin L. (2018). Eosinophilic granulomatosis with polyangiitis (Churg–Strauss). American Journal of Respiratory and Critical Care Medicine
, 39(4), 471–481.