An Bras Dermatol. 2020;95(4):493---507 Anais Brasileiros de Dermatologia www.anaisdedermatologia.org.br REVIEW Update on vasculitis: overview and relevant dermatological aspects for the clinical and ଝ,ଝଝ histopathological diagnosis --- Part II a,∗ b Thâmara Cristiane Alves Batista Morita , Paulo Ricardo Criado , b a a Roberta Fachini Jardim Criado , Gabriela Franco S. Trés , Mirian Nacagami Sotto a Department of Dermatology, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil b Dermatology Discipline, Faculdade de Medicina do ABC, Santo André, SP, Brazil Received 8 December 2019; accepted 28 April 2020 Available online 24 May 2020 Abstract Vasculitis is a group of several clinical conditions in which the main histopathological KEYWORDS finding is fibrinoid necrosis in the walls of blood vessels. This article assesses the main derma- Anti-neutrophil tological aspects relevant to the clinical and laboratory diagnosis of small- and medium-vessel cytoplasmic cutaneous and systemic vasculitis syndromes. The most important aspects of treatment are also antibodies; discussed. Churg-Strauss © 2020 Sociedade Brasileira de Dermatologia. Published by Elsevier Espana,˜ S.L.U. This is an syndrome; open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Henoch-Schönlein purple; Leukocytoclastic cutaneous vasculitis; Systemic vasculitis; Vasculitis; Vasculitis associated with lupus of the central nervous system ଝ How to cite this article: Morita TCAB, Criado PR, Criado RFJ, Trés GFS, Sotto MN. Update on vasculitis: overview and relevant dermato- logical aspects for the clinical and histopathological diagnosis --- Part II. An Bras Dermatol. 2020;95:493---507. ଝଝ Study conducted at the Department of Dermatology, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil. ∗ Corresponding author. E-mail: [email protected] (T.C. Morita). https://doi.org/10.1016/j.abd.2020.04.004 0365-0596/© 2020 Sociedade Brasileira de Dermatologia. Published by Elsevier Espana,˜ S.L.U. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). 494 Morita TCAB et al. Clinical spectrum of vasculitis cases. In general, systemic symptoms such as fever, malaise, weight loss, and arthralgia may be observed in all cutaneous 7 --- 9 vasculitis syndromes. In daily clinical practice, dermatologists are often asked to The classic histological findings of single-organ CSVV assess two groups of patients: those who present with small include a predominantly neutrophilic infiltrate affect- vessel vasculitis, and those who present with cutaneous ing post-capillary venules, fibrinoid deposits, endothelial arteritis (involvement of medium-caliber vessels). In light edema, and extravasation of red blood cells. A mixed inflam- of this scenario, the dermatological manifestations should matory infiltrate can be observed, particularly in older be characterized at the time of the initial presentation, and 1,3 lesions. It is important to note that this histological pat- the findings of an adequate biopsy (one that represents all tern is not exclusive to any particular disease. Infections, affected skin layers) should be taken into account in order insect bites, pyoderma gangrenosum, and even biopsies to reach an adequate diagnosis. The moment when the test obtained from the bottom of chronic ulcers may exhibit the is performed is also crucial, as it can be non-diagnostic when 2 findings of leukocytoclastic vasculitis. Whenever possible, performed too early or too late. A recent lesion, within a second biopsy should be performed for DIF, whose find- 24---48 h of onset, is the most suitable for a histopathological ings reveal predominantly complement (C3), IgM, and fibrin assessment. Lesions older than 48 h can present, regardless deposits. Again, these findings are typical, but not specific, of the underlying vasculitis, a lymphocyte-rich infiltrate. of any single-organ CSVV. Thus, the clinical---pathological The assessment of additional data, such as those provided correlation is mandatory before a definitive diagnosis is by direct immunofluorescence (DIF), as well as the status of established.4 the anti-neutrophil cytoplasmic antibody (ANCA), will fur- ther narrow the differential diagnoses. DIF biopsy should be performed on a lesion within 8---24 h of onset. Other- Localized cutaneous vasculitis: erythema elevatum wise, leukocytes degrade the immune complexes, leading 1 --- 4 diutinum and facial granuloma to a false negative result. Erythema elevatum diutinum (EED) and granuloma faciale Cutaneous single organ small vessel vasculitis (GF) are forms of localized chronic cutaneous vasculitis that affect small-caliber dermal vessels. In EED, the lesions Cutaneous single organ small vessel vasculitis is a syndrome appear as well-defined papules, plaques or nodules, with an characterized by clinical and histological manifestations of erythematous to brownish color, smooth surface, and rela- cutaneous small vessel vasculitis (CSVV) without involve- tively symmetrical distribution, with a chronic course and ment of vessels of any other organ, which can be confirmed lasting around five to ten years. They occur preferably on by anamnesis, physical examination, and specialized labo- the extensor surfaces of the limbs, a highly characteristic 5 ratory tests. Most cases manifest as palpable purpura or topography, especially on the skin over the joints. Rarely, erythematous macules. However, hives, hemorrhagic vesi- EED can present as widespread papules on the upper and 2,3 cles, and shallow ulcers may be observed (Fig. 1). Half of lower limbs, verrucous eruptions, or extensive nodular and the patients present lesions exclusively on the lower limbs; fibrotic lesions on the palms and soles. Lesions may dis- however, the upper limbs, trunk, and gluteal region may also appear spontaneously, without leaving scars, but atrophic 6 be involved. The disease is usually mild and self-limiting, hyper- or hypopigmented areas can be observed. This vas- with a good prognosis. Many patients with single-organ CSVV culitis most commonly affects female patients in any age experience a single episode, which usually resolves within group, although it is more frequently observed between the 10---12 a few weeks. Recurrences are observed in about 10---25% of fourth and sixth decades of life. While the pathophysiology of EED is not fully understood, it is believed that skin lesions are caused by the deposition of immune complexes in small dermal vessels, which results in complement fixation and subsequent inflammation. Sev- eral publications relate EED to hematological abnormalities, particularly monoclonal gammopathies due to IgA; infec- tions, by the human immunodeficiency virus (HIV), hepatitis C (HCV), hepatitis B (HBV), or tuberculosis; autoimmune diseases, such as rheumatoid arthritis, recurrent polychon- dritis, and inflammatory bowel disease; and solid lung or 13 breast tumors. IgA-class ANCA may be a relevant marker of the disease. Immunoelectrophoresis should be used to 11,12 investigate possible associated gammopathies. EED can progress with ophthalmologic alterations, including nodular 14 scleritis, panuveitis, and peripheral keratitis. GF has a predilection for middle-aged individuals, espe- Figure 1 Cutaneous small vessel vasculitis limited to the skin: cially males, and is characterized by the appearance of (a) palpable purpura and necrotic ulcers in the lower limbs; (b) purplish to brownish, asymptomatic or slightly pruritic necrosis of endothelial cells from superficial papillary dermis papules, plaques, or nodules, usually located on the face. with fibrin deposition, neutrophil infiltration, and leukocytocla- It has a smooth surface and can enhance the follicular sia. ostia. Eosinophilic angiocentric fibrosis is a variant that Update on vasculitis 495 affects the nasal mucosa, and rarely coexists with facial skin The clinical suspicion of UV occurs in cases of urticar- lesions. Extrafacial involvement is exceptional, but it can be ial lesions with an atypical presentation and suggestive observed in photoexposed areas or in the genitalia. Although laboratory tests, such as the following: high erythrocyte usually refractory to treatment and showing rare sponta- sedimentation rate (ESR), observed in 42.6% of patients; neous resolution, GF has not been associated with systemic positivity for antinuclear antibodies (ANA), in 33.4% of diseases. Its differential diagnoses include sarcoidosis, lym- patients; low levels of C3, C4, and CH50, in approximately phomas and cutaneous pseudolymphomas, discoid lupus, one-third of patients, especially in the most severe forms leprosy, granulomatous rosacea, and Jessner lymphocytic of the disease; and, the presence of suppressed anti-C1q 15,16 infiltrate. and/or C1q antibodies in 55% of patients with hypocom- EED and GF are fibrous vasculitis without signs of gran- plementemic urticarial vasculitis syndrome. However, the ulomatous reaction. The appearance of old lesions is of diagnosis must be confirmed through a skin biopsy. Low 11 ‘‘onion skin’’ concentric fibrosis around the vessels. His- levels of C1q can also be found in SLE (61%), rheuma- tologically, in GF there is a dense, superficial, and deep toid arthritis (20%), scleroderma (15%), Sjögren’s syndrome dermal polymorphic inflammatory infiltrate, mostly perivas- (15%), mixed connective tissue disease (15%), and chronic 15,19,23 cular. Characteristically, an infiltrate composed of all types infection by HCV