Systemic involvement |
Hematologic conditions |
Symptoms and physical exam: lymph node palpation, liver and spleen palpation. |
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. |
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.
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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. |
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. |
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.
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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.
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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. |
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.
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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.
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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.
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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.
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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. |