Update on vasculitis: an overview and dermatological clues for clinical and histopathological diagnosis - part I<sup>,</sup>

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

doi:10.1016/j.abd.2020.01.003

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

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

Gabriela Franco S. Trés

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

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

Roberta Fachini Jardim Criado

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

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

Mirian Nacagami Sotto

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

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

Paulo Ricardo Criado

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

Postgraduate Program, Faculdade de Medicina do ABC, Santo André, SP, Brazil

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

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

Author's contributions

Thâmara Cristiane Alves Batista Morita: Elaboration and writing of the manuscript; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; 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 the propaedeutic and/or therapeutic conduct of the 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.

Mirian Nacagami Sotto: Critical review 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; obtaining, analysis, and interpretation of the data; effective participation in research orientation; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.

Conflicts of interest

None declared.

Group	Nomenclature	Definitions	Main characteristics
Large vessels vasculitides	Takayasu arteritis	Arteritis, often granulomatous, predominantly affecting the aorta and/or its major branches. Onset usually in patients younger than 50 years.	Although any size can be affected, they involve large arteries more often than other vasculitides. Large arteries are the aorta and its major branches.
Large vessels vasculitides	Giant Cell Arteritis (GCA)	Arteritis, often granulomatous, usually affecting the aorta and/or its major branches, with a predilection for the branches of the carotid and vertebral arteries. It frequently involves the temporal artery. Onset usually in patients older than 50 years and often associated with polymyalgia rheumatica.
Medium vessels vasculitides	Polyarteritis Nodosa (PAN)	Necrotizing arteritis of medium or small vessels without glomerulonephritis or vasculitis in arterioles, capillaries, or venules, and not associated with Antineutrophil Cytoplasmic Antibodies (ANCA).	Vasculitides predominantly affecting medium arteries defined as the main visceral arteries and their initial branches. Arteries of any size may be affected. Inflammatory aneurisms and stenosis are common.
Medium vessels vasculitides	Kawasaki disease	Arteritis associated with the mucocutaneous lymph node syndrome and predominantly affecting medium and small arteries. Coronary arteries are often involved. Usually occurs in infants and young children.
ANCA-Associated Vasculitides (AAV)	Microscopic Polyangiitis (MPA)	Necrotizing vasculitis with few or no immune deposits, predominantly affecting small vessels (i.e., capillaries, venules, or arterioles). Necrotizing arteritis involving small and medium arteries may be present. Necrotizing glomerulonephritis is very common. Pulmonary capillaritis often occurs.	Necrotizing vasculitis with few or no immune deposits (pauci-immune), predominantly affecting small vessels (i.e. capillaries, venules, arterioles, and small arteries), associated with Myeloperoxidase (MPO) ANCA or Proteinase 3 (PR3) ANCA. Not all patients have ANCA positivity.
	Granulomatosis with polyangiitis^a a New nomenclature: DADA2, Deficiency of Adenosine Deaminase type 2; DIRA, Deficiency of Interleukin-1 Receptor Antagonist; DVT, Deep Venous Thromboembolism; FMF, Familial Mediterranean Fever; HIDS, Hyper IgD with periodic fever Syndrome; PAPA, Pyogenic Arthritis, Pyoderma gangrenosum, and Acne; TRAPS, TNF Receptor-Associated Periodic Syndrome. (GPA) formerly known as Wegener's granulomatosis	Necrotizing granulomatous inflammation usually involving the upper and lower respiratory tract, and necrotizing vasculitis affecting predominantly small to medium vessels (e.g., capillaries, venules, arterioles, arteries and veins). Necrotizing glomerulonephritis is common.
	Eosinophilic Granulomatosis with Polyangiitis^a a New nomenclature: DADA2, Deficiency of Adenosine Deaminase type 2; DIRA, Deficiency of Interleukin-1 Receptor Antagonist; DVT, Deep Venous Thromboembolism; FMF, Familial Mediterranean Fever; HIDS, Hyper IgD with periodic fever Syndrome; PAPA, Pyogenic Arthritis, Pyoderma gangrenosum, and Acne; TRAPS, TNF Receptor-Associated Periodic Syndrome. (GEPA) formerly known as Churg-Strauss syndrome	Eosinophil-rich and necrotizing granulomatous inflammation often involving the respiratory tract, and necrotizing vasculitis predominantly affecting small to medium vessels and associated with asthma and eosinophilia. ANCA is more frequent when glomerulonephritis is present.
Immune complex vasculitides	Anti-Glomerular Basement Membrane (Ant-GBM) disease^a a New nomenclature: DADA2, Deficiency of Adenosine Deaminase type 2; DIRA, Deficiency of Interleukin-1 Receptor Antagonist; DVT, Deep Venous Thromboembolism; FMF, Familial Mediterranean Fever; HIDS, Hyper IgD with periodic fever Syndrome; PAPA, Pyogenic Arthritis, Pyoderma gangrenosum, and Acne; TRAPS, TNF Receptor-Associated Periodic Syndrome. formerly known as Goodpasture syndrome	Vasculitis affecting glomerular capillaries, pulmonary capillaries, or both, with GBM deposition of anti-GBM autoantibodies. Lung involvement causes pulmonary hemorrhage, and renal involvement causes glomerulonephritis with necrosis and crescents.	Vasculitis with moderate to marked vessel wall deposits of immunoglobulin and/or complement components predominantly affecting small vessels. Glomerulonephritis is frequent.
	Cryoglobulinemic vasculitis	Vasculitis with cryoglobulin immune deposits affecting small vessels (predominantly capillaries, venules, or arterioles) and associated with serum cryoglobulins. Skin, glomeruli, and peripheral nerves are often involved.
	IgA vasculitis^a a New nomenclature: DADA2, Deficiency of Adenosine Deaminase type 2; DIRA, Deficiency of Interleukin-1 Receptor Antagonist; DVT, Deep Venous Thromboembolism; FMF, Familial Mediterranean Fever; HIDS, Hyper IgD with periodic fever Syndrome; PAPA, Pyogenic Arthritis, Pyoderma gangrenosum, and Acne; TRAPS, TNF Receptor-Associated Periodic Syndrome. (formerly known as Henoch-Schonlein purpura)	Vasculitis, with IgA1-dominant immune deposits, affecting small vessels (predominantly capillaries, venules, or arterioles). Often involves skin and gastrointestinal tract, and frequently causes arthritis. Glomerulonephritis indistinguishable from IgA nephropathy may occur.
	Hypocomplementemic urticarial vasculitis (Anti-C1q vasculitis)	Vasculitis accompanied by urticaria and hypocomplementemia affecting small vessels (i.e., capillaries, venules, or arterioles), and associated with anti-C1q antibodies. Glomerulonephritis, arthritis, obstructive pulmonary disease, and ocular inflammation is common.
Variable Vessels Vasculitides (VVV)	Behçet's Disease (BD)	Vasculitis occurring in patients with BD that can affect arteries or veins. It is characterized by recurrent oral and/or genital aphthous ulcers accompanied by cutaneous, ocular, articular, gastrointestinal, and/or central nervous system inflammatory lesions. Small vessel vasculitis, thromboangiitis, thrombosis, arteritis, and arterial aneurysms may occur.	Vasculitis that can affect vessels of any size (small, medium, and large) and type (arteries, veins, and capillaries) with no predilection.
Variable Vessels Vasculitides (VVV)	Cogan's syndrome	Vasculitis occurring in patients with Cogan's syndrome. Cogan's syndrome characterized by ocular inflammatory lesions, including interstitial keratitis, uveitis, and episcleritis, and inner ear disease, including sensorineural hearing loss and vestibular dysfunction. Vasculitic manifestations may include arteritis (affecting small, medium, or large arteries), aortitis, aortic aneurysms, and aortic and mitral valvulitis
Single Organ Vasculitides (SOV)	Cutaneous leukocytoclastic angiitis	Cutaneous small vessel vasculitis	Vasculitis in arteries or veins of any size in a single organ that has no features that indicate that it is a limited expression of a systemic vasculitis. The involved organ and vessel type should be included in the name (e.g., cutaneous small vessel vasculitis, testicular arteritis, central nervous system vasculitis). Vasculitis distribution may be unifocal or multifocal (diffuse) within an organ. Some patients originally diagnosed as having a single-organ vasculitis will develop additional disease manifestations that warrant redefining the case as one of the systemic vasculitides (e.g., cutaneous arteritis later becoming systemic PAN, etc.)
	Cutaneous arteritis	E.g. formerly cutaneous PAN.
	Cutaneous arteritis	Macular arteritis, also called lymphocytic thrombophilic arteritis.
	Primary central nervous system (CNS) vasculitis	The diagnosis of primary CNS vasculitis requires determining that CNS vasculitis is not a component of a systemic vasculitis (e.g., GCA, BD, MPA, GPA, EGPA), caused by infection (e.g., syphilis), or associated with a systemic disease (e.g., lupus, sarcoidosis).
	Isolated aortitis	Isolated idiopathic (thoracic and/or abdominal) aortitis.
	Others	Isolated idiopathic (thoracic and/or abdominal) aortitis.
Vasculitides associated with systemic disease	Lupus vasculitis	Secondary vasculitis due to systemic lupus erythematous.	Vasculitis that is associated with or that may be secondary to a systemic disease. The name should have a prefix term specifying the systemic disease (e.g., rheumatoid vasculitis, lupus vasculitis, etc.).
	Rheumatoid vasculitis	Secondary vasculitis due to rheumatoid arthritis.
	Sarcoid vasculitis	Secondary vasculitis due to systemic sarcoidosis.
	Relapsing polychondritis vasculitis	Secondary vasculitis due to multi-organ relapsing polychondritis.
	Others	Example, vasculitis cases reports as a manifestation of monogenic or polygenic autoinflammatory syndromes: multifactorial and polygenic autoinflammatory Behçet's syndrome (small vessel - skin, retina; medium vessel/artery - DVT, dural sinus, intracranial, pulmonary artery; large vessel); FMF (small vessel IgA vasculitis; medium vessel - PAN); CAPS (small vessels - skin, testes, kidney; rare case reports); HIDS (small vessels - skin); TRAPS (small vessels - skin); PAPA syndrome (medium vessel - cerebral artery vasculopathy\vasculitis); DIRA (CNS-vasculitis\vasculopathy), Blau syndrome (small vessel - retina; skin large vessel vasculitis); DADA2 (systemic inflammation, mild immune deficiency, and vasculopathy manifested as recurrent stroke or PAN).
Vasculitides associated with probable etiology	Hepatitis C virus associated cryoglobulinemic vasculitis	E.g., hepatitis C virus-associated cryoglobulinemic small vessel vasculitis.	Vasculitis that is associated with a probable specific etiology. The name (diagnosis) should have a prefix term specifying the association (e.g., hydralazine-associated microscopic polyangiitis, HBV-associated vasculitis, HCV-associated cryoglobulinemic vasculitis, etc.).
	Hepatitis B virus-associated vasculitis	E.g., hepatitis B virus-associated PAN.
	Syphilis-associated vasculitis	Secondary vasculitis due to syphilis.
	Drug-associated immune complex vasculitis	E.g., serum sickness-associated immune complex vasculitis due drugs.
	Drug-associated ANCA-positive vasculitis	E.g., hydralazine-associated microscopic polyangiitis, propylthiouracil-ANCA-associated vasculitis.
	Cancer-associated vasculitis	Hematologic and solid organ neoplasms, as well as clonal B cell lymphoproliferative disorders and myelodysplastic syndrome can be associated with and may cause vasculitis.
	Others	Small-vessel vasculitis due bowel inflammatory disease.

Small vessels vasculitides	Neutrophilic	Immune-complex mediated (DIF positive)	Cutaneous leukocytoclastic angiitis (or hypersensitivity vasculitis, leukocytoclastic cutaneous vasculitis or small vessel cutaneous vasculitis)
			IgA vasculitis
			Acute infantile hemorrhagic edema
			Urticarial vasculitis
			Chronic localized fibrosing vasculitis: erythema elevatum diutinum, granuloma faciale, inflammatory pseudo tumors
		Incidental vasculitis (DIF negative)	Sweet's syndrome and pustular vasculitis of the dorsa of the hands
	Eosinophilic	Eosinophilic vasculitis
	Eosinophilic	Recurrent cutaneous eosinophilic vasculitis
	Granulomatous	Postherpetic eruptions
	Granulomatous	Lymphomatoid granulomatosis
	Lymphocytic	Rickettsia and viral infections
		Lichenoid dermatosis, some cases, perniosis, pityriasis lichenoides, graft versus host disease
		T cell lymphomas: angiocentric T cell lymphoma, lymphomatoid papulosis
		Rare drug reactions and arthropod bites
Mixed, predominately small- and medium-vessels vasculitides	Neutrophilic	Immune-complex mediated (DIF positive)	Cryoglobulinemic vasculitis due hepatitis C virus or paraproteinemia
			Hypocomplementemic urticarial vasculitis syndrome
			Connective tissue disease vasculitis (e.g., lupus, rheumatoid arthritis, Sjogren's syndrome)
		ANCA-associated/pauci-immune (DIF negative)	Granulomatosis with polyangiitis
			Eosinophilic granulomatosis with polyangiitis
			Microscopic polyangiitis
			Drug-induced ANCA positive vasculitis
	Lymphocytic	Degos disease
		Rickettsia and viral infections
		Collagen tissue disease vasculitis (e.g., Sjogren's syndrome, lupus vasculitis)
		Behçet's disease
	Miscellaneous/other	Septic vasculitis
		Behçet's disease
Medium (to large) muscular vessels vasculitides	Neutrophilic	Polyarteritis nodosa and cutaneous arteritis
Medium (to large) muscular vessels vasculitides	Neutrophilic	Polyarteritis nodosa and cutaneous arteritis
		Nodular vasculitis (erythema induratum)
	Eosinophilic	Juvenile temporal arteritis
	Granulomatous	Giant cell arteritis
		Takayasu's arteritis
		Postherpetic eruptions
	Lymphocytic	Sneddon's syndrome
		Degos disease
		Buerger's disease (thromboangiitis obliterans)
		Superficial thrombophlebitis (Mondor's disease, sclerosing lymphangitis)
		Kawasaki disease
		Macular arteritis/lymphocytic thrombophilic arteritis

Systemic involvement	Hematologic conditions	Symptoms and physical exam: lymph node palpation, liver and spleen palpation.
	Hematologic conditions	Laboratorial tests: total blood count cells, serum protein electrophoresis test, lactate dehydrogenase.
	Cardiovascular system	Symptoms and physical exam: auscultation of the heart, arterial blood pressure in both arms, assessment of the arterial pulse characteristics in carotid, radial, brachial, femoral, popliteal, posterior tibial, and dorsalis pedis pulses should be routinely examined bilaterally to ascertain any differences in the pulse amplitude, contour, and upstroke.
	Cardiovascular system	Laboratorial tests and other exams: arterial doppler ultrasound evaluation if abnormal pulses are present or if systemic Polyarteritis Nodosa (PAN) is suspected - in this particular situation aorta and renal arteries should be evaluated). Doppler echocardiography study when it appears that be a septic vasculitis case (intermittent or recurrent fever, weight loss, complement protein system lower levels). In medium-vessel (arteritis) or large-vessel vasculitis angiotomography or magnetic resonance angiography studies can be useful. Sometimes the 18F-fluorodeoxyglucose Positron Emission Tomography (PET) can be added to investigation of medium and large vessel vasculitis. Deep, large vessels can be examined by Computed Tomography (CT) or Magnetic Resonance Image (MRI), while ultrasound is the method of choice for the evaluation of superficial vessels (such as temporal, carotid, and axillary arteries). PET is very sensitive in detecting large vessel inflammation, but it does not delineate the vessel wall.¹¹11 Muratore F, Pipitone N, Salvarani C, Schmidt WA. Imaging of vasculitis: state of the art. Best Pract Res Clin Rheumatol. 2016;30:688-706.
	Kidneys and genitourinary system	Symptoms and physical exam: periorbital, sacral, lower-extremities edema, muscle tenderness, ascites, hypertension. Dilated neck vein, weight loss, orthostatic hypotension and tachycardia (acute prerenal kidney injury). Testicular pain, suggestive of PAN.
	Kidneys and genitourinary system	Laboratorial tests and other exams: serum blood urea nitrogen and creatinine, creatinine clearance, urinalysis (urine density, proteinuria, hematuria, cylindruria) and/or 24 h urine protein test if proteinuria is present. Urine culture test.
	Liver function and gastrointestinal system	Symptoms and physical exam: jaundice, oral ulcerations, gingival hyperplasia, dyspepsia, vomiting, diarrhea, abdominal pain, hematochezia or melena, gastroduodenal ulcers, peritonitis, bowel perforation. These symptoms and signs suggest gastrointestinal vasculitis that can occurs in the setting of PAN, Microscopic Polyangiitis (MPA), Granulomatosis with Polyangiitis (GPA), Eosinophilic Granulomatosis with Polyangiitis (EGPA), lupus enteritis and rheumatoid arthritis- associated vasculitis. Recurrent right quadrant pain gallbladder vasculitis as single Organ Vasculitis of the Skin (SOV) or systemic vasculitis.
	Liver function and gastrointestinal system	Laboratorial tests and other exams: alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, and alkaline phosphatase, bilirubin levels, serum albumin level, prothrombin time. Fecal occult blood test is relevant to investigation for IgA-vasculitis and bowel neoplasia associated vasculitis. Colonoscopy and/or upper gastrointestinal endoscopy in suspect of active gastrointestinal vasculitis or screening for neoplasia.
	Central and peripheral nervous system [both immune-mediated changes and ischemia of the vascular wall- the hallmark of vasculitis, are the main causes of Central Nervous System (CNS) and Peripheral Nervous System (PNS) symptoms].¹⁷17 Takatu CM, Heringer APR, Aoki V, Valente NYS, de Faria Sanchez PC, de Carvalho JF, et al. Clinicopathologic correlation of 282 leukocytoclastic vasculitis cases in a tertiary hospital: a focus on direct immunofluorescence findings at the blood vessel wall. Immunol Res. 2017;65:395-401.	Symptoms and physical exam: depression, anxiety. Migraine localized in the temporal area, accompanied by fever, malaise, myalgia, muscle weakness and anorexia, with swollen and sensitive temporal artery during palpation (often in Takayasu arteritis). Unilateral or bilateral loss of vision due to ischemic optic neuropathy (Takayasu arteritis). Aphasia, hemiplegia, visual disturbance (blurred vision and hemianopia), seizures, transverse myelitis and subarachnoid hemorrhage typically in patients with PAN. Mononeuritis multiplex or distal symmetrical sensorimotor polyneuropathy Takayasu arteritis (15%), ANCA-positive Vasculitis (AAV) (60% in EGPA, 10-22% in MPA), systemic PAN (65%), cutaneous arteritis (former cutaneous PAN, 20%) and Sjogren syndrome (30% of patients suffering of distal symmetric sensory or sensorimotor polyneuropathy and mononeuritis multiplex).¹²12 Bougea A, Anagnostou E, Spandideas N, Triantafyllou N, Kararizou E. An update of neurological manifestations of vasculitides and connective tissue diseases: a literature review. Einstein (Sao Paulo). 2015;13:627-35. In Systemic Lupus Erythematous (SLE) can be observed two types of lesions and signs in CNS: (i) non-thrombotic disease (psychoses, seizures, headaches, cognitive dysfunction and chorea) or (ii) thrombotic disease (stroke or recurrent transient ischemic attacks) and PNS involvement (10%) as trigeminal neuropathy, distal symmetric sensory or sensorimotor polyneuropathy.¹²12 Bougea A, Anagnostou E, Spandideas N, Triantafyllou N, Kararizou E. An update of neurological manifestations of vasculitides and connective tissue diseases: a literature review. Einstein (Sao Paulo). 2015;13:627-35.
		Laboratorial tests and other exams: the diagnosis of polyneuropathy is based on clinical and electrophysiologic studies, but precise histology, immunohistochemistry and morphometric studies of the peripheral nerve biopsy may be decisive to make diagnosis.
	Upper and lower respiratory system	Symptoms and physical exam: hemoptysis, shortness of breath, hoarseness, cough, wheezing, eye or ear symptoms, sinusitis (suggestive of AAV). Two kinds of lung involvement can be seen, (i) one with acute or subacute presentation, and with capillaritis as the pathogenic mechanism, giving rise to the syndrome of diffuse alveolar hemorrhage. It can be part of any of the AAV and manifest itself with dyspnea, cough, and hemoptysis; (ii) the other, more chronic and often asymptomatic, mainly seen in GPA, and often with accompanying otorhinolaryngological involvement, or signs of activity in other organs, is the development of lung nodules, which clinically represent granulomas. Hemoptysis (the most feared symptom and sign of lung hemorrhage) occurs in over half of patients with GPA and a third of patients with MPA.
	Upper and lower respiratory system	Laboratorial tests and other exams: the sensitivity of conventional chest X Rays in patients with suspicion of lung hemorrhage is high, but its specificity is very low.¹¹11 Muratore F, Pipitone N, Salvarani C, Schmidt WA. Imaging of vasculitis: state of the art. Best Pract Res Clin Rheumatol. 2016;30:688-706. High-resolution CT is a better imaging tool, disclosing typical patterns such as focal or diffuse infiltrates with ground-glass opacities or alveolar occupation.¹¹11 Muratore F, Pipitone N, Salvarani C, Schmidt WA. Imaging of vasculitis: state of the art. Best Pract Res Clin Rheumatol. 2016;30:688-706.
	Other organs and organic systems	Symptoms and physical exam: fever, nasal crusting, hearing loss (especially in AAV), uveitis (hypocomplementemic urticarial vasculitis syndrome), arthritis (connective tissue diseases), myalgia with or without consequent severe limitation in movements (connective tissue diseases, AAV, PAN). Symptoms of connective tissue diseases should be noted, such as dry eyes or mouth, photosensitivity and/or facial cutaneous eruption, oral lesions or genital lesions (aphthous stomatitis, ulcers), or muscle weakness. Past medical history, including hospitalizations, underlying diseases/disorders (including febrile diseases), pre-immunization signs and symptoms including identification of indicators for, or the absence of, a history of allergy to vaccines, vaccine components or any medications; food allergy; allergic rhinitis; atopic eczema; asthma, autoimmune diseases.¹⁰10 Zanoni G, Girolomoni G, Bonetto C, Trotta F, Häusermann P, Opri R, et al. Single organ cutaneous vasculitis: case definition & guidelines for data collection, analysis, and presentation of immunization safety data. Vaccine. 2016;34:6561-71.
	Other organs and organic systems	Laboratorial tests and other exams: marked elevation of erythrocyte sedimentation rate and c-reactive protein, while muscle enzymes were generally normal (PAN). Electromyography and/or MRI in suspect of myositis. Muscle biopsies, mostly revealing a histological pattern compatible with PAN, presenting with necrotizing arteritis, leukocytoclastic angiitis, fibrinoid necrosis of small and medium arteries and leukocyte infiltration of the vessel walls or perivasculitis in systemic PAN. Complement serum protein consumption is suggestive of systemic vasculitis as connective autoimmune tissue diseases (SLE, rheumatoid arthritis, Sjögren syndrome), cryoglobulinemic vasculitis, malignancy-associated vasculitis and septic vasculitis.
Etiologic associated factors	Drugs, non-prescribed medicines and immunizations	Several medications, as penicillin and derivates, sulfonamides, quinolones, hydantoins, insulin, tamoxifen, oral contraceptives, phenothiazines, allopurinol, thiazides, retinoids, radiocontrast agents and anti-influenza vaccine. Chemical substances (e.g., insecticides and petroleum products) and foods (e.g., milk proteins and gluten) can also cause a vasculitis. Many illicit drugs can cause vasculitis, with the best evidence being that for the sympathomimetic drugs. Vitamins and nutritional supplements have also been reported to cause vasculitis. Drug-Induced Vasculitis (DIV) is a diagnosis of exclusion, as there are no laboratory studies diagnostic for DIV. Although eosinophilia is common in systemic DIV (79%), it is present in only 22% of DIV limited to the skin.¹³13 Fiorentino DF. Cutaneous vasculitis. J Am Acad Dermatol. 2003;48:311-44. Drug-induced AAV may be associated with: propylthiouracil, hydralazine, minocycline, anti-TNF alfa agents, acitretin, allopurinol, methimazole, and other.
	Infections and parasitic infestations	Infections can cause lesions which both mimic vasculitis as well as those which represent either a septic or true reactive vasculitis. Infection can present in many ways, including septic vasculitis, upper respiratory tract flares of GPA, PAN, cryoglobulinemic vasculitis, urticarial vasculitis, IgA-vasculitis, and cutaneous small-vessel vasculitis (CSVV, a SOV).¹³13 Fiorentino DF. Cutaneous vasculitis. J Am Acad Dermatol. 2003;48:311-44. Common agents include bacteria, viruses, parasites, and fungi. Special mention should be given to the known association of hepatitis B virus with PAN and hepatitis C virus with mixed cryoglobulinemia.¹³13 Fiorentino DF. Cutaneous vasculitis. J Am Acad Dermatol. 2003;48:311-44. Other complementary exams should include an investigation for asymptomatic or oligosymptomatic infections and/or parasite infestations as anti-streptolysin O, tuberculosis (Mantoux test and/or QuantiFERON-TB Gold In-Tube assay), Parvovirus B19 (serology IgM and IgG), schistosomiasis (eggs in stool exam), toxocariasis (serology IgG, peripheral eosinophilia), strongyloidiasis (larvae in stool exam and serology) and syphilis (serology and/or immunohistochemistry in cutaneous biopsy). Others agents are reported in case reports or case series as, (i) Bacterial agents: Streptococcus (Streptococcus viridans; group A, C, and G streptococci), enterococci, Staphylococcus aureus, Mycobacterium leprae (Lucio's phenomenon in leprosy and vasculitis in erythema nodosum), Salmonella species, Borrelia burgdorferi, Pseudomonas aeruginosa, Legionella pneumophila; (ii) Parasites: Schistosoma haematobium, Onchocerca volvulus, Cysticercus, Loa loa; (iii) Viruses: HIV infection, herpes simplex 1 and 2, Cytomegalovirus, Epstein-Barr, Varicella-Zoster, Rubella, adenovirus, echovirus, coxsackievirus, parainfluenza, hepatitis A virus infections, and (iv) Fungi: Aspergillus spp., Fusarium spp., Coccidioides immitis.¹⁴14 Choucair J. Infectious causes of vasculitis in: updates in the diagnosis and treatment of vasculitis. InTech. 2013.
	Inflammatory systemic conditions (autoimmune diseases)	SLE, Sjögren's syndrome, rheumatoid arthritis, scleroderma, dermatomyositis, complement deficiency, alpha1 antitrypsin deficiency, inflammatory bowel disease, chronic active hepatitis, intestinal bypass surgery, primary biliary cirrhosis, relapsing polychondritis, and other.
	Neoplasia and paraneoplastic syndrome	Hematologic disorders constitute the most common group of malignancies associated with cutaneous vasculitis (lymphoma Hodgkin and non-Hodgkin, acute myelogenous leukemia, chronic lymphoid or lymphocytic leukemia, lymphoblastic leukemia, immunoblastic sarcoma, megakaryocytic leukemia malignant B-cell lymphoma, T-cell lymphoma, myelodysplastic syndrome, myelofibrosis) and less commonly the vasculitis related to solid organ tumors (colon carcinoma, renal carcinoma, colon adenocarcinoma, prostate carcinoma, lung carcinoma, lung squamous carcinoma, gastric tubular carcinoma, gastric adenocarcinoma, pancreatic carcinoma, breast carcinoma, ovarian cancer, pharyngeal carcinoma, vocal cord carcinoma, pelvic carcinoma, hepatocarcinoma, urinary bladder carcinoma).¹⁵15 Loricera J, Calvo-Río V, Ortiz-Sanjuán F, González-López MA, Fernández-Llaca H, Rueda-Gotor J, et al. The spectrum of paraneoplastic cutaneous vasculitis in a defined population. Medicine (Baltimore). 2013;92:331-43. Cutaneous paraneoplastic vasculitis is an entity not uncommonly encountered by clinicians. In these cases, the presence of cytopenia and immature cells may be red flags for the diagnosis of cancer. In patients with paraneoplastic cutaneous vasculitis, the prognosis depends on the underlying neoplasia.¹⁵15 Loricera J, Calvo-Río V, Ortiz-Sanjuán F, González-López MA, Fernández-Llaca H, Rueda-Gotor J, et al. The spectrum of paraneoplastic cutaneous vasculitis in a defined population. Medicine (Baltimore). 2013;92:331-43.
	Idiopathic	Despite the efforts of the clinicians on work-up for an etiology to cutaneous or systemic vasculitis, most of patients remain as undetermined etiology. Some authors refer an idiopathic origin for vasculitis in 45-50%¹⁶16 Tai YJ, Chong AH, Williams RA, Cumming S, Kelly RI. Retrospective analysis of adult patients with cutaneous leukocytoclastic vasculitis. Australas J Dermatol. 2006;47:92-6. to 69¹⁷17 Takatu CM, Heringer APR, Aoki V, Valente NYS, de Faria Sanchez PC, de Carvalho JF, et al. Clinicopathologic correlation of 282 leukocytoclastic vasculitis cases in a tertiary hospital: a focus on direct immunofluorescence findings at the blood vessel wall. Immunol Res. 2017;65:395-401.-79%¹⁸18 Arora A, Wetter DA, Gonzalez-Santiago TM, Davis MD, Lohse CM. Incidence of leukocytoclasic vasculitis 1996-2010: a population-based study in Olmsted County, Minnesota. Mayo Clin Proc. 2014;89:1515-24. of the patients suffering of CSVV. In both CSVV and IgA vasculitis, the most common etiologic association is idiopathic.

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

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