VOL. 14 No. 3 - 2007 SMALL VESSEL VASCULITIS REVISTA COLOMBIANA DE REUMATOLOGÍA VOL. 14 No. 3, Septiembre 2007, pp. 187-205 © 2007, Asociación Colombiana de Reumatología ARTÍCULO DE REVISIÓN Small vessel vasculitis History, classification, etiology, histopathology, clinic, diagnosis and treatment Antonio Iglesias Gamarra1, Eric L. Matteson2, José Félix Restrepo3 Summary Resumen Small-vessel vasculitis is a convenient descriptor El término vasculitis de pequeños vasos descri- for a wide range of diseases characterized by vascular be a un grupo de enfermedades caracterizadas por inflammation of the venules, capillaries, and/or inflamación de vénulas, capilares y/o arteriolas con arterioles with pleomorphic clinical manifestations. manifestaciones clínicas pleomórficas. El fenotipo clí- The classical clinical phenotype is leukocytoclastic vas- nico clásico es la vasculitis leucocitoclástica con púr- culitis with palpable purpura, but manifestations vary pura palpable, pero con manifestaciones que varían widely depending upon the organs involved. His- ampliamente dependiendo del órgano comprometido. topathologic examination in leukocytoclastic vasculi- La histología en la vasculitis leucocitoclástica revela tis reveals angiocentric segmental inflammation, una inflamación segmentaria angiocéntrica, necrosis fibrinoid necrosis, and a neutrophilic infiltrate around fibrinoide e infiltrado neutrofílico alrededor de los the blood vessel walls with erythrocyte extravasation. vasos sanguíneos, con extravasación de eritrocitos. The etiology of small-vessel vasculitis is unknown in La etiología de las vasculitis de pequeños vasos es many cases, but in others, drugs, post viral syndromes, desconocida, en muchos casos, pero en otros se ha malignancy, primary vasculitis such as microscopic pol- asociado con drogas, síndromes post virales, neo- yarteritis, and connective tissue disorders are associ- plasias, vasculitis primarias como la poliarteritis mi- ated. The diagnosis of small-vessel vasculitis relies croscópica, y enfermedades del tejido conjuntivo. El on a thorough history and physical examination, as well diagnóstico de las vasculitis de pequeños vasos se as relevant antibody testing including antinuclear an- basa en la historia clínica y el examen físico, así como tibody and antineutrophil cytoplasmic antibody, hepa- con estudio de anticuerpos como los anticuerpos titis B and C serologies, assessment of complement, antinucleares y los anticuerpos contra el citoplasma immunoglobulins, blood count, serum creatinine, liver de los neutrófilos, serología de hepatitis B y C, de- function tests, urinalysis, radiographic imaging, and terminación de inmunoglobulinas, complemento, biopsy. The treatment is based primarily on corticos- creatinina sérica, función renal, urianálisis, estudios teroid and immunosuppressive agents. de imágenes y biopsia. El tratamiento se basa prima- riamente en el uso de corticosteroides e inmuno- Key words: vasculitis, small vessel vasculitis, supresores. leukocytoclastic vasculitis, linphomonocitic vascu- litis, ANCA associated vasculitis. Palabras clave: vasculitis, vasculitis de peque- ños vasos, vasculitis leucocitoclástica, vasculitis linfomonocítica, vasculitis asociada a ANCA. 1 Profesor Titular de Medicina Interna y Reumatología. Universidad Na- cional de Colombia. 2 Division of Rheumatology, Mayo Clinic College of Medicine. 3 Profesor Titular de Medicina Interna y Reumatología. Universidad Na- Recibido: junio 29/2007 cional de Colombia. Aceptado: agosto 30/2007 187 IGLESIAS GAMARRA A. & Cols. Rev.Colomb.Reumatol. Introduction taining the sample. These variables affect and aid verification of the diagnosis. A positive biopsy sup- The systemic inflammatory vascular diseases are ports the diagnosis, while a negative one does not a heterogeneous group of conditions whose com- necessarily exclude it. This may be the case, for ex- mon feature is that of vessel inflammation. This vas- ample, when vasculitis affects an organ or append- culitis is characterized by fibrinoid necrosis, age which is poorly amenable to biopsy or biopsy thrombosis, and sometimes a granulomatous reac- of apparently involved tissue demonstrates a non- tion1. Vascular damage may occur in venules, capil- inflammatory vasculopathy1,2. laries, and arterioles, causing local and systemic Small vessel vasculitis with cutaneous involve- clinical manifestations, depending on the organs in- ment does not constitute a subgroup of either pri- volved. Vessels of any type in any organ can be af- mary or secondary vasculitis. Rather, it can be fected, a fact that result in a wide variety of sign and associated with a number of comorbidities, further symptoms. The clinical picture of small vessel vas- complicating diagnosis and, hence, treatment deci- culitis is also dependent on the extent of vascular sions. As an example, patients with small vessel dis- bed involvement, delay in diagnosis, and treatment1. ease may have hepatitis B or C, with or without These heterogeneous clinical manifestations, com- cryoglobulinemia. bined with the etiologic non specificity of the histo- logic lesions, complicate the diagnosis of specific The discovery that autoantibodies against cyto- form of vasculitis. plasmic antigens of neutrophils (anti-neutrophil cytoplasmic antibodies (ANCA)) are closely asso- Recognition of these features of vasculitis and ciated with vasculitic disorders has improved diag- evaluation with selected laboratory and other clini- nosis of patients with clinically suspected vasculitis cal tests and histologic evaluation of biopsy speci- and/or glomerulonephritis (GN). Like the introduc- mens generally permits a specific diagnosis, which tion of ANA serology for systemic lupus erytema- directs the evaluation of activity, extent, and dam- tosus, introduction of ANCA testing for vasculitis age, and guides treatment. However, signs and has revealed myriad clinicopathological presenta- symptoms of various forms of vasculitis are over- tions beyond the previously recognized patterns of lapping, and diagnostic precision is often hampered systemic disease3. As a clinicopathological proc- by the lack of diagnosis-specific histologic findings. ess, vasculitis occurs both as a primary process or This creates a clinical dilemma, because the treat- idiopathic vasculitis and as a secondary feature of ment and prognosis of specific forms of vasculitis other diseases secondary vasculitis such as colla- varies. For example, a patient with cutaneous leuko- gen vascular diseases, infectious disorders, malig- cytoclastic vasculitis with abdominal and renal nancy and adverse drugs reaction. involvement may have disease due to classic pol- The vasculitic syndromes share a common his- yarteritis nodosa (PAN) or to microscopic polyan- topathological substrate inflammation within blood giitis, or Henoch-Schönlein purpura. Indeed, there vessels resulting in vascular obstruction with tissue are few clinical conditions which cause as much ischemia and infarction. Focal necrotizing lesions are confusion and consternation among clinicians and the common vascular pathology that characterizes patients alike as do the protean presentations and the ANCA-associated disorders: Wegener’s granu- 1,2 management of vasculitis . lomatosis (WG), microscopic polyangiitis (MPA) and The gold standard for a diagnosis of vasculitis is Churg-Strauss syndrome (CSS). These lesions can histologic confirmation on biopsy, as few forms of affect many types of vessel and lead to a variety of vasculitis have a pathognomonic laboratory or symptoms and signs. Immunohistology shows little imaging finding. Interpretation of the biopsy sam- deposition of immune reactants, a feature which dis- ple is dependent on a number of variables, includ- tinguishes lesions due to ANCA-associated vasculi- ing the interest and experience of the pathologist, tis (AAV) from those of antiglomerular basement tissue selection and quantity, and the amount of time membrane disease, IgA nephropathy, and lupus which has occurred between diseases onset and ob- nephritis3. 188 VOL. 14 No. 3 - 2007 SMALL VESSEL VASCULITIS ANCA were first described in 1982 by Davies introduced in 1808 was expanded on by Bauer in and his associates as a cause of diffuse granular cy- 182421, 22. A unifying concept of purpura and its rela- toplasmic inmuno-fluorescence staining (C-ANCA) tionship to leukocytoclastic vasculitis was put forward on ethanol-fixed neutrophils in association with by Zeek et al. in 1948 and 1952, who called this form glomerulonephritis, vasculitis and Wegener’s granu- of vasculitis with small vessel involvement hypersen- lomatosis4. Two years later, Hall et al. confirmed this sitivity angitis23, 24. Davson et al. and Godman et al. observation in four patients with small-vessel vas- referred to it as microscopic polyangiitis, a concept culitis5. Van der Woude et al.6 in 1985 generated sub- adopted by the Chapel Hill international consensus con- stantial interest by suggesting that detection of ANCA ference in 1994, at which time several forms of small was a useful diagnostic and prognostic marker for vessel vasculitis were more clearly defined15, 25, 26. Wegener´s granulomatosis. Subsequent work by Van This progress was the direct result of William’s early der Woude et al. Falk et al. and others demonstrated work. He clearly distinguished purpura caused by that ANCA are closely associated with three major systemic febrile infections from non infectious pur- categories of small-vessel vasculitis: Wegener´s pura20, 21, 27.