Cutaneous manifestations of anti-neutrophil cytoplasmic antibody associated vasculitis

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a distinct group of systemic vasculitis with severe multi-organ involvement. It includes three types: granulomatosis with polyangiitis (GPA), eosinophilic granulomatosis with polyangiitis (EGPA), and microscopic polyangiitis (MPA). Cutaneous manifestations are present at the time of presentation in around 35% of cases and are more frequently encountered in EGPA than in GPA or MPA. They can also occur during the course of the disease or mark a disease relapse. They can be classified into specific or non-specific according to the presence or absence of vasculitis, whether or not associated with granuloma, in skin biopsies. The most common presentation of vasculitic skin lesions in AAV is palpable purpura. Other manifestations include hemorrhagic blisters, tender subcutaneous nodules, livedo reticularis/racemosa, painful ulcers that may mimic pyoderma gangrenosum (PG), and digital gangrenes. A wide range of non-specific cutaneous manifestations can occur in association with AAV including urticarial rash, prurigo, sterile pustules, and oral lesions. The presence of cutaneous lesions is usually associated with severe organ involvement and systemic manifestations. Since skin lesions in AAV can occur in other types of vasculitis and in other disorders, attributing them to AAV requires meticulous clinical, laboratory, and serological correlation. Awareness of cutaneous lesions of AAV is important for all physicians working in the field of systemic vasculitis as a skin biopsy may provide an easy clue to diagnose AAV in such cases. Page 2 of Abdel-Halim et al. Vessel Plus 2022;6:8 https://dx.doi.org/10.20517/2574-1209.2021.40 14


INTRODUCTION
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a clinically distinct group of severe multi-organ vasculitis involving small/medium-sized vessels with subsequent tissue damage. Vessels involved are mainly capillaries, arterioles, and venules but small/medium-sized arteries and veins may also be involved. According to clinical features and presence or absence of asthma and/or granulomatosis, this group includes three diseases: granulomatosis with polyangiitis (GPA), eosinophilic granulomatosis with polyangiitis (EGPA), and microscopic polyangiitis (MPA) [1] .
As in many other systemic disorders, cutaneous involvement is commonly encountered in AAV and may be the first presenting sign of the disease. Variable incidences among different reports are noted. According to recently published data from a large international multi-center study, cutaneous manifestations at time of presentation were present in 35% of AAV cases and were found to be more frequently encountered in EGPA (47%) when compared to GPA and MPA (34% and 28%, respectively) [2] . Other studies reported skin manifestations occurring during the course of the disease in 47% of GPA cases, 44% of MPA cases, and 40% of EGPA cases [3][4][5] . Skin lesions can also mark a disease relapse [6] .
The spectrum of skin lesions in AAV is wide and more than 50% of cases will have more than one type of skin lesions at a certain time [2,6] . Accordingly, knowledge of such lesions and collaboration with dermatologists is important for physicians providing care for systemic vasculitis patients.
Being an easily accessible organ for biopsy, the presence of skin lesions may provide an easy way to confirm the presence of vasculitis by routine histopathological and immunofluorescence studies. This can be further substantiated by clinical examination and laboratory investigations including ANCA testing.

THE CLINICOPATHOLOGIC SPECTRUM OF CUTANEOUS LESIONS IN AAV
Understanding the underlying histopathological changes is important to appreciate the wide spectrum of skin lesions encountered in AAV. Accordingly, skin manifestations in AAV can be classified as specific or non-specific. The term specific does not mean lesions that occur exclusively in AAV, but rather skin lesions that show histopathological evidence of vasculitis with or without granulomas when biopsied. They can still be encountered in other systemic disorders or other forms of vasculitis. On the other hand, non-specific skin lesions do not show histopathological features of vasculitis or granuloma. They may show features reflecting the various morphologies of these lesions or just show non-specific perivascular lymphocytic infiltrates [7] . In either case, attributing skin lesions to AAV needs careful clinical, laboratory, and serological correlations and exclusion of all other possible causes of similar lesions or their mimics.
In all three types of AAV, cutaneous vasculitis presents as leukocytoclastic vasculitis with fibrinoid necrosis of vessel walls (usually involving small dermal vessels and less commonly medium-sized subcutaneous ones), perivascular infiltrates (mainly composed of neutrophils), endothelial cell swelling, red cell extravasation, neutrophil fragmentation, and neutrophil dust [8] [ Figure 1]. Vasculitis with granulomatosis (perivascular collections of epithelioid histiocytes and/or giant cells-perivascular granulomatosis) is a rare finding in skin lesions of GPA and EGPA [9] . The term vasculitis with granulomatosis is better used to describe such finding than granulomatous vasculitis since the term granulomatous vasculitis usually implies the presence of granulomas inside the vessel walls as in giant cell vasculitis and Takayasu's arteritis, which is not the case in GPA and EGPA [10][11][12] . Direct immunofluorescence (DIF) will show immunoglobulin (usually IgM) and complement C3 deposition around the walls of blood vessels in 70% and 50% of cases of GPA and EGPA, respectively [8,13] . DIF is usually negative in MPA apart from possible few deposits of IgM and C3 [4,14] .
Granulomas which are extravascular in nature (usually necrobiotic palisading or necrotizing granulomas surrounding foci of collagen necrobiosis or necrosis) such as those encountered in internal organs in GPA and EGPA cases can be seen in skin lesions of these patients. They usually occur in association with vasculitic changes [8] . The necrobiotic/necrotic zones may be large and geographic in appearance [ Figure 2]. A special type of granulomatous reaction known as palisaded neutrophilic and granulomatous dermatitis (PNGD) (sometimes referred to as Winkelmann's granuloma, Churg-Strauss granuloma, or interstitial granulomatous dermatitis) can develop in association with AAV [15,16] . It is characterized histopathologically by various changes according to their age. Early lesions show intense neutrophil infiltrates, karyorrhectic debris, and frank leukocytoclastic vasculitis, whereas late lesions show necrobiotic collagen changes, palisades of histiocytes, and small granulomas eventually associated with areas of fibrosis [17] [ Figure 3].
In addition, skin lesions in EGPA characteristically show large amount of eosinophils in the infiltrate surrounding the inflamed blood vessels, in the dermis (tissue eosinophilia), and in the context of the granulomas admixed with histiocytes and multi-nucleated giant cells [8,13] [ Figure 4]. Such finding explains the pruritus frequently expressed by these patients.

Common clinical presentations of vasculitic skin lesions in AAV
AAV mainly involves small dermal vessels, hence the clinical presentation is predominantly that of palpable purpura/petechia usually involving the lower limbs [8,18] [ Figure 5]. This was reported in 15% of cases of AAV [2] . When deep subcutaneous vessels are involved, patients present with livedo reticularis/racemosa, papules, or nodules on purpuric background, as well as tender subcutaneous nodules [19] . Severe cases may show widespread extension, hemorrhagic blisters, and painful ulcerations secondary to skin necrosis [6,7] [ Figures 6 and 7]. Splinter hemorrhages have also been reported [2] . In GPA and EGPA, vasculitic lesions may involve the face and scalp [5,8,20] [ Figure 8].
Vasculitic lesions in AAV typically follow a chronic relapsing course with recurrent attacks lasting for weeks to months that generally improve with treatment directed to the associated deep organ in focus.

Rare or unusual clinical presentations of vasculitic skin lesions in AAV
GPA patients may develop pyoderma gangrenosum (PG)-like ulcers characterized by being large, intensely painful with undermined edges [8,21,22] . Several pediatric cases of GPA have been reported with PG-like ulcers mainly presenting on the face as the initial presenting manifestation of the disease. This can even precede the classic systemic symptoms [23][24][25][26][27] [ Figure 9]. Localized variants of GPA may present with long standing recalcitrant ulcerative skin lesions mainly localized to the face and upper respiratory tract mucosa [28,29] .     Other rare vasculitic cutaneous manifestations of GPA include digital or penile ulceration and gangrene [8,21] . McKenney and Siegel [30] described another rare example of cutaneous pathology in GPA. They presented a case with large tender indurated subcutaneous violaceous skin lesion that was initially thought to be a hematoma. The diagnosis was only established following a skin biopsy which revealed perivascular infiltrates and necrotizing granulomas involving small vessels in the subcutaneous septa [30] .
Erythema elevatum diutinum-like nodules and plaques mainly involving the extensor aspects of the limbs with symmetric distribution have been described early in the course of MPA [31] . Digital ischemia and gangrene can also rarely develop in MPA [4] .

Clinical presentation of PNGD which can develop with AAV
The classic clinical presentation of PNGD is erythematous or flesh-colored papules which may develop central umbilication or crustations. They usually take a symmetrical distribution on the extremities, mainly involving elbows and knees and but frequently other sites [15,32] [ Figure 10].

Clinical presentation of non-specific skin lesions in AAV
Many non-specific skin lesions can occur in AAV patients. Non-specific maculopapular rash is the second most frequently encountered skin manifestation in AAV occurring in 8% of cases [2] . In GPA, non-specific oral lesions develop in 10%-60% of patients and may be the presenting sign of the disease in 5% of cases [33,34] . They take the form of oral erosions or ulcers [3] [ Figure 11], strawberry gingivitis with exophytic hyperplasia, and mucosal petechial spots and erythematous granular appearance (with or without loss of alveolar bone and loosening of teeth) [33][34][35] . Other non-specific lesions in GPA include skin ulcers (with no pathological evidence of vasculitis or granulomas) [7] , erythema nodosum-like lesions [24] , xanthelasmas [3] , sterile pustules [7] , acneiform lesions [36] , and chronic eyelid edema and infiltration [37] . EGPA patients commonly develop urticarial-like, angioedema-like, erythema multiforme-like, and chronic itchy lichenified prurigo nodularis-like lesions, as well as sterile pustules [19,38] . Allergic manifestations such as pruritus are also frequently observed in EGPA [2,39] . Cases of EGPA presenting with Well's syndrome (eosinophilic panniculitis)-like picture have been reported [40] . Urticarial lesions may also develop with MPA [4] . Table 1 represents a summary of the clinicopathological spectrum of cutaneous lesions in AAV.

CUTANEOUS LESIONS IN RELATION TO DIFFERENT TYPES OF AAV AND DIFFERENT TYPES OF ANCA
Certain skin lesions were noticed to develop more frequently in certain types of AAV. For example, livedo reticularis/racemosa and segmentary edema develop significantly more frequently in MPA. Non-specific manifestations such as pruritus, urticaria, and maculopapular rash are more likely encountered in EGPA. Urticaria is uncommon in GPA and MPA. Painful skin lesions and skin ulcers occur more significantly in GPA and EGPA when compared to MPA [2,39] . Oral ulcers are also more frequently associated with GPA as compared to EGPA and MPA [39] . PG-like lesions and palpebral xanthomas can only occur in GPA [39] .
Cutaneous lesions were found to be the presenting manifestation of AAV in patients with positive cytoplasmic/anti-PR3ANCA or in ANCA-negative patients when compared to patients with positive perinuclear/anti-MPO ANCA. The same was observed as regards the development of the typical vasculitic skin lesions of purpura/petechiae and splinter hemorrhages. Coinciding with their significantly higher occurrence in MPA, livedo reticularis/racemosa were reported more often in patients with positive perinuclear/anti-MPO ANCA than in those without. Non-specific manifestations such as pruritus and urticaria were more frequently encountered in ANCA-negative patients. The presence of multiple types of cutaneous manifestations was most frequently reported in patients who were ANCA-negative [2] .

CUTANEOUS LESIONS IN RELATION TO SPECIFIC ORGAN INVOLVEMENT AND SEVERITY OF SYSTEMIC MANIFESTATIONS OF AAV
GPA patients with skin lesions were more prone to have pulmonary, renal, neurologic, musculoskeletal, and gastrointestinal involvement and more severe manifestations [2,39] . Similarly, EGPA patients with skin lesions were more likely to suffer from renal, neurologic, musculoskeletal, and gastrointestinal involvement. They also had more severe manifestations [2,39] . In a recent study, purpura in patients with EGPA was associated with increased C-reactive protein, interleukin 5, and Birmingham Vasculitis Activity Scores [41] . Cutaneous lesions in patients with MPA were usually associated with arthralgia and ophthalmologic involvement [4] , and these patients suffered more from neurologic and musculoskeletal manifestations and were less likely to have pulmonary or renal involvement [2] . No difference in the severity of the systemic manifestations of MPA was found between patients with or without cutaneous disease [2,39] . Cutaneous manifestations were associated with poorer relapse-free and overall survival in GPA when compared to EGPA and MPA [39] .

IMPORTANT DIFFERENTIAL DIAGNOSES OF CUTANEOUS LESIONS OF AAV
Since skin lesions of AAV are non-specific from the point of view that they can develop in other types of vasculitis and in other systemic disorders, careful evaluation of cases presenting with skin lesions is mandatory.
Palpable purpura/petechiae can be seen in all types of cutaneous vasculitis including allergic vasculitis (triggered by infections or drugs or occurring as an idiopathic disorder), Henoch-Schönlein purpura, and cutaneous vasculitis in collagen diseases. Proper history taking, clinical verification of visceral involvement, and laboratory and serological investigations can help to correctly diagnose such cases. The detection of IgA deposits by DIF is characteristic of Henoch-Schönlein purpura, which also presents with renal involvement,  creating possible clinical confusion with AAV [42] .
The presence of associated skin necrosis, ulceration, and gangrenes in the context of palpable purpuric lesions warrants exclusion of other conditions such as hepatitis C virus-induced vasculitis other causes of cryoglobulinemic vasculitis and vasculitis associated with underlying vasculopathic disorders such as protein C and S deficiency or factor V Leiden mutation [43] . Livedo reticularis/racemosa and skin nodules can also be a manifestation of polyarteritis nodosa [4] .
Localized cases of GPA involving mainly the face, nose, ears, and throat should be differentiated from levamisole induced vasculopathy associated with levamisole-adulterated cocaine abuse. History taking, skin biopsy findings, and negative ANCA can help in verifying this condition [44] .
PG-like lesions of GPA should be differentiated from classic PG. The presence of cytoplasmic/anti-PR3-ANCA, the involvement of internal organs (mainly the lungs), the presence of palisaded neutrophilic and granulomatous dermatitis, necrotizing vasculitis and basophilic collagen degeneration on skin biopsy, and not diffuse neutrophilic infiltrate helps in excluding classic PG in such cases [45] . Cultures to exclude infectious causes are also important in PG-like lesions or in cases presenting with ulcerated nodules/plaques that show granulomatous inflammation on biopsy. Finally, many types of cutaneous lymphomas can present as PG-like lesions [46] , and a skin biopsy will easily establish the diagnosis.
It is important also to remember that lesions of PNGD can occur in association with a wide range of systemic disorders other than AAV such as connective tissue disorders, arthritides, Behçet's disease, ulcerative colitis, lymphoproliferative disorders, and multiple sclerosis [15,47,48] . Careful clinical, laboratory, and serological assessment is important in such cases.
Finally, care should be given not to confuse vasculitic lesions of AAV with hemorrhagic or occlusive pseudovasculitis. Hemorrhagic pseudovasculitis presents with non-palpable petechiae, purpura, or ecchymoses as a result of vessel wall dysfunction that can occur in many conditions such as metabolic disorders, nutritional deficiencies, drug reactions, infections, thrombocytopenias, or simply with aging. Occlusive pseudovasculitis on the other hand presents with livedo, acral cyanosis, or digital necrosis/gangrene as a result of occlusion of vessel lumen by emboli, thrombi, or other materials. Examples of occlusive pseudovasculitis include essential cryoglobulinemia, purpura fulminans, coumadin necrosis, antiphospholipid syndrome, cardiac myxoma, calciphylaxis, cholesterol embolization, and radiation arteritis [49] . In all cases, a skin biopsy and laboratory investigations can easily verify such conditions.

MANAGEMENT OF CUTANEOUS LESIONS OF AAV
AAV patients presenting with skin manifestations should follow the same standard algorithms and guidelines of management used in patients without cutaneous manifestations. These include measures to induce remission of new-onset organ threatening (life threatening) or non-organ threatening disease, as well as measures to induce remissions of relapses and measures to maintain remissions [50] .
Although skin ulcers if present can become contaminated with different types of bacteria, routine administration of topical or systemic antibiotics is not encouraged, as it was not found to be associated with reduced bacterial colonization or better healing and can lead to emergence of resistant strains [51] . Systemic and non-topical antibiotics are recommended only in the presence of significant evidence of infection such as increasing pain, erythema in the surrounding skin, progressive increase in ulcer size, pus discharge, hotness, or edema [52] . Proper management of ulcers should also include removal of necrotic tissue by surgical or chemical debridement and the use of appropriate dressings such as hydrocolloid and hydrogel sheets which absorb fluids from the wound and keep it moist [53,54] . Pain relief measures should also be considered and tailored according to the needs of each patient in a way that improves his/her quality of life [55] .

CONCLUSION
Cutaneous manifestations are common in AAV. They may be the presenting manifestation of the disease, occur during its course, or mark a disease relapse. They may be specific or non-specific according to the presence or absence of vasculitis with or without granulomas in skin biopsies. They are usually associated with severe systemic manifestations and multiple organ involvement. Since such lesions can occur in other types of systemic vasculitis and in other disorders, linking them with AAV requires meticulous clinical, laboratory, and serological correlation.