Update on vasculitis: overview and relevant dermatological aspects for the clinical and histopathological diagnosis - Part II<sup>,</sup>

Morita, Thâmara Cristiane Alves Batista; Criado, Paulo Ricardo; Criado, Roberta Fachini Jardim; Trés, Gabriela Franco S.; Sotto, Mirian Nacagami

doi:10.1016/j.abd.2020.04.004

Thâmara Cristiane Alves Batista Morita ^** Corresponding author. E-mail:thamaramorita@usp.br (T.C. Morita).

Department of Dermatology, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil

http://orcid.org/0000-0002-7248-1742

Paulo Ricardo Criado

Dermatology Discipline, Faculdade de Medicina do ABC, Santo André, SP, Brazil

http://orcid.org/0000-0001-9785-6099

Roberta Fachini Jardim Criado

Dermatology Discipline, Faculdade de Medicina do ABC, Santo André, SP, Brazil

http://orcid.org/0000-0003-2482-3047

Gabriela Franco S. Trés

Department of Dermatology, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil

http://orcid.org/0000-0003-0053-438X

Mirian Nacagami Sotto

Department of Dermatology, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil

http://orcid.org/0000-0001-6380-7192

* Corresponding author. E-mail:thamaramorita@usp.br (T.C. Morita).

Authors' contributions

Thâmara Cristiane Alves Batista Morita: Elaboration and writing of the manuscript.

Paulo Ricardo Criado: Approval of the final version of the manuscript; conception and planning of the study; elaboration and writing of the manuscript; effective participation in research orientation; intellectual participation in propaedeutic and/or therapeutic conduct of studied cases; critical review of the literature; critical review of the manuscript.

Roberta Fachini Jardim Criado: Approval of the final version of the manuscript; conception and planning of the study, elaboration and writing of the manuscript; effective participation in research orientation; critical review of the literature; critical review of the manuscript.

Gabriela Franco S. Trés: Approval of the final version of the manuscript; elaboration and writing of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of studied cases; critical review of the literature; critical review of the manuscript.

Mirian Nacagami Sotto: Approval of the final version of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of studied cases; critical review of the manuscript.

Conflicts of interest

None declared.

Organ/system findings	Granulomatosis with polyangiitis (GPA)	Eosinophilic granulomatosis with polyangiitis (EGPA)	Microscopic polyangiitis (MPA)
Cutaneous signs and symptoms	(10-50%) Palpable purpura, subcutaneous nodules, papules, vesicles, blisters, necrotic-ulcerative lesions, livedo reticularis/racemosa; pyoderma gangrenous-like ulcers. Ulceration and gangrene of the fingers or penis are rarely observed.	(40-50%) Subcutaneous nodules, purpura, livedo reticularis/racemosa, vesicles, aseptic pustules, hives, necrosis - ulcerative and maculopapular rash mimicking erythema multiforme with target lesions on the limbs, particularly on the palmar regions.	(30-60%) Palpable purpura, livedo reticularis/racemosa, nodules, hives lesions, skin ulcers with necrosis, blisters, erythema elevatum diutinum-like plaques. The limbs are most commonly affected and the lesions usually appear in an early stage of MPA. No relationship between any type of skin rash and incidence of renal and/or pulmonary involvement has been demonstrated.
Oral mucosa	(10-60%) Non-specific erosive/ulcerative oral lesions; strawberry gingivitis.	-	-
Upper and lower airways	(70-100%) Sinusitis with purulent or bloody discharge; ulceration of the nasal mucosa and palate; saddle nose deformity, perforation of the septum.	The prodromal or allergic phase is characterized by the occurrence of asthma (in approximately 95% of cases). Nasal polyposis, allergic rhinosinusitis, epistaxis.	Pulmonary involvement is frequent and can be observed in up to 90% of patients. The classic pulmonary manifestation is diffuse alveolar hemorrhage due to pulmonary capillaritis.
Kidney and urogenital tract	(40-100% of cases) Usually with a characteristic histopathology of pauci-immune focal necrotizing glomerulonephritis with crescents formation associated with extracapillary proliferation, which in turn can cause a wide range of clinical features, from urinary abnormalities to rapidly progressive renal failure. The severity of renal involvement remains the main prognostic factor for renal function, as well as for survival. Prostatitis, orchitis, epididymitis, ureteral stenosis.	In 25% of patients the most typical condition is a pauci-immune glomerulonephritis with crescents formation.	Renal involvement is present in almost 100% of patients and is characterized by rapidly progressive glomerulonephritis with a histological pattern of pauci-immune necrotizing glomerulonephritis with crescents formation.
Gastrointestinal system	Ulcerative lesions, intestinal perforation.	Eosinophilic gastroenteritis.	-
Peripheral nervous system	Multiplex mononeuritis, sensory-motor neuropathy.	Peripheral neuropathy.	Peripheral neuropathy.
Ophthalmologic involvement	Episcleritis, scleritis, corneal ulceration, retinal vasculitis, retro-orbital granulomatous pseudotumor, or dacryoadenitis.	-	-
Histopathological findings	Leukocytoclastic vasculitis with fibrinoid necrosis and neutrophilic infiltration of small dermal vessels; granulomatous inflammation around the vessels; nonspecific perivascular lymphocytic infiltration.	Leukocytoclastic vasculitis with fibrinoid necrosis and granulomatous inflammation involving venules; neutrophil-rich inflammatory infiltrate. Tissue eosinophilia.	Leukocytoclastic vasculitis with fibrinoid necrosis and neutrophilic infiltration of small dermal vessels; nonspecific perivascular infiltrate. A lymphocytic infiltration can be observed; cutaneous nodules often indicate vasculitis involving vessels in the deep dermis or subcutaneous tissue.
Deposits in direct immunofluorescence of the skin	IgM and/or C3 deposits around small dermal vessels in almost 70% of cases.	IgM and/or C3 deposits around small dermal vessels in over 50% of cases.	Usually negative; eventually IgM and/or C3 deposits are observed around small vessels.

1990 American College of Rheumatology (ACR) Classification criteria for adult PAN	Polyarteritis nodosa is diagnosed if at least three of these ten criteria are present. The presence of three or more criteria correlates with a sensitivity of 82.2% and a specificity of 86.6%.	1. Weight loss > 4 kg;
		2. Livedo reticularis;
		3. Testicular pain or tenderness (usually unilateral, secondary to vasculitis of the testicular artery, requiring emergency treatment due to the risk of irreversible ischemia);
		4. Myalgia, weakness or tenderness in the legs;
		5. Mononeuropathy or polyneuropathy;
		6. Diastolic BP > 90 mmHg;
		7. Elevated urea > 40 mg/dL or creatinine > 1.5 mg/dL, except for dehydration or obstruction;
		8. Presence of hepatitis B surface antigen or antibody in serum;
		9. Arteriogram showing aneurysms or visceral artery occlusions, except for arteriosclerosis, fibromuscular dysplasia, or other non-inflammatory causes;
		10. Small or medium artery biopsy containing PMN.
European League Against Rheumatism (EULAR) Classification criteria childhood PAN	A systemic illness accompanied by either a biopsy showing small and mid-size artery necrotizing vasculitis or angiographic abnormalities (aneurysms or occlusions) (mandatory criteria) (should include conventional angiography if magnetic resonance angiography is negative), plus at least two of the following seven criteria:	1. Skin involvement (livedo reticularis, tender subcutaneous nodules, other vasculitic lesions);
		2. Myalgia or muscle tenderness;
		3. Systemic hypertension, relative to childhood normative data;
		4. Mononeuropathy or polyneuropathy;
		5. Abnormal urine analysis and/or impaired renal function (glomerular filtration rate < 50% of normal for age);
		6. Testicular pain or tenderness;
		7. Signs or symptoms suggesting vasculitis of any other major organ system (gastrointestinal, cardiac, pulmonary, or central nervous system).

Clinical severity	Findings	Therapeutic approach
Mild vasculitis limited to the skin	Persistent or recurrent vasculitis and/or symptomatic diseases (burning or pruritus)	Dapsone or colchicine (useful for mild disease, IgAV, UV or Behçet's disease; both drugs have better therapeutic effects after two to four weeks);
		Dapsone 25-50 mg/day orally at the beginning of treatment. After a complete blood count and liver function laboratory evaluation with normal results, the dosage may be increased to 100-200 mg/day;
		Colchicine: 0.5 mg, two to three times daily, orally;
		Other agents: pentoxifylline 400 mg, three times daily (Behçet's disease or mild cutaneous arteritis).
Moderate to severe cutaneous vasculitis	Extensive skin involvement, persistent vasculitis, recurrent vasculitis with ulcers, nodules or recalcitrant symptoms	Methotrexate, azathioprine, and/or prednisone (cutaneous arteritis, mild vasculitis limited to the skin, rheumatoid vasculitis, lupus vasculitis);
		Methotrexate: 5-20 mg/week;
		Azathioprine (AZA; PNS involvement, renal involvement): TPMT (levels); TPMT < 5, not recommended; TPMT 5-13.7 U (AZA 0.5 mg/kg/day); TPMT 13.7-19 U (AZA 1.5 mg/kg/day); TPMT > 19 U (AZA 2.5 mg/kg/day).
		Prednisone: 1-1.5 mg/kg/day orally;
		Hydroxychloroquine: 400 mg/day orally;
		Cyclosporine 2.5-5.0 mg/kg/day orally;
		Cyclophosphamide (extensive skin and ulcerative vasculitis or PNS involvement, or renal involvement): 100 mg/day to 2000 mg/day, orally.
Systemic vasculitis	Potentially fatal disease or permanent organ damage, serum creatinine levels >150 µmoL/L (severe if >500 µmoL/L)	Prednisone ± cyclophosphamide or azathioprine or cyclosporine or mofetil mycophenolate (AAV, PAN, severe IgAV, lupus vasculitis, large vessel vasculitis);
		Methylprednisolone (intravenous) 1000 mg/day for three consecutive days, then prednisone 1.0-1.5 mg/kg/day orally;
		Mofetil mycophenolate: 2000 mg/day (HUV, AAV).

[1] * Corresponding author. E-mail:thamaramorita@usp.br (T.C. Morita).

Skin involvement	Absent: no skin lesions;
	Moderate: skin lesions located on (a) buttocks and lower limbs and (b) on the trunk or upper limbs;
	Severe: cutaneous lesions located on (a) the gluteal area and lower limbs, (b) trunk and (c) upper limbs.
Abdominal involvement	Absent: no symptoms, no findings;
	Mild: mild abdominal pain (induced by physical examination);
	Moderate: moderate abdominal pain (transient complaints referred by the patient);
	Severe: severe abdominal pain and/or melena and/or hematemesis and/or intussusception.
Joint involvement	Absent: no symptoms, no findings;
	Mild: symptoms or findings of joint involvement, without functional abnormalities;
	Moderate: symptoms and findings of joint involvement that cause moderate functional impairment (e.g., claudication);
	Severe: symptoms and findings that cause moderate functional loss (e.g., inability to walk).
Renal involvement	Absent: normal urinary sediment exam.
	Mild: pathological hematuria, normal proteinuria (negative dipstick or [+]).
	Moderate: pathological hematuria, mild to moderate proteinuria (dipstick + to [++]).
	Severe: pathological hematuria, severe proteinuria (dipstick ≥[+++]).

Compatible clinical findings	Subcutaneous nodules, livedo, purpura or ulcers.
Histopathological findings	Fibrinoid necrotizing vasculitis of small and medium caliber arteries.
Exclusion manifestation	Fever (≥38 ºC, ≥2 weeks)
	Weight loss (≥6 kg in 6 months);
	Arterial hypertension;
	Rapidly progressive renal failure, renal infarction;
	Cerebral hemorrhage, cerebral infarction;
	Myocardial infarction, ischemic heart disease, pericarditis, heart failure;
	Pleuritis;
	Intestinal bleeding, intestinal infarction;
	Peripheral neuropathy outside the affected skin region;
	Arthralgia/arthritis or myalgia/myositis outside the affected skin region;
	Abnormal arteriography (multiple microaneurysms, stenosis, and obliteration).

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