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Home , Giant cell arteritis, Kawasaki disease, Systemic disease

Clinical AND Health Affairs

A Primer on

BY KENNETH J. WARRINGTON, M.D., AND ERIC L. MATTESON, M.D., M.P.H.

Vasculitides are rare but serious conditions involving of the body’s blood vessels that can lead to organ damage and myriad complications. This article describes the various forms of vasculitis and their incidence, and discusses diagnosis and treatment of patients with the more common forms.

asculitis refers to a heterogenous occasionally, they can be limited to a single The incidence of ANCA-associated vascu- group of conditions characterized by organ. Cutaneous vasculitis, testicular vas- litis is approximately 10 to 20 persons per Vinflammation of walls, culitis and primary million per year, with granulomatosis with which results in vascular damage. Because vasculitis are examples of single-organ polyangiitis being more common than inflammation can affect vessels of any size vasculitides. Vasculitis may develop in the and eosinophilic in any location, vasculitides have varying context of an underlying autoimmune dis- granulomatosis with polyangiitis. clinical presentations. ease such as systemic erythematosus Vasculitides are generally classified and rheumatoid as well as with Etiology based on the predominant type of vessel malignancy, or use. In the majority of cases, the cause of (large, medium or small) involved. Giant (Table).1 vasculitis is unknown. The prevailing cell and Takayasu’s arteritis are hypothesis is that vasculitis is initiated by both large-vessel vasculitides that affect Incidence an environmental agent in a genetically the and its primary and second- In general, vasculitis is rare and therefore predisposed individual. Genetic polymor- ary branches. and can be difficult to recognize clinically. The phisms in the human leukocyte Kawasaki predominantly involve incidence of specific vasculitic disorders (HLA) genes and polymorphisms in genes medium-sized arteries. The most com- varies according to patient age, race and encoding and other immuno- mon forms of small-vessel vasculitis are geographic location. For example, giant regulatory proteins have been associated granulomatosis with polyangiitis (formerly cell arteritis affects people older than 50 with an increased risk of several types of Wegener’s granulomatosis), microscopic years of age and is most common among vasculitis.2 polyangiitis, and eosinophilic granuloma- people of Northern European descent. It In certain forms of vasculitis, investiga- tosis with polyangiitis (formerly Churg- is one of the most common forms of vas- tors have identified probable etiologies. Strauss ). The latter three condi- culitis in adults, with an average annual About one-third of polyarteritis nodosa tions are often collectively referred to as incidence of about 19 cases per 100,000 cases are caused by chronic B the anti-neutrophil cytoplasmic persons 50 years of age and older. Con- infection, while hepatitis C can trigger (ANCA)-associated vasculitides. Other versely, Takayasu arteritis generally occurs cryoglobulinemic vasculitis. Neoplasms, less common forms of small-vessel vasculi- in individuals younger than 40 years of age particularly hematologic malignancies, can tis include cryoglobulinemic vasculitis and and is more common among Asians. In the also cause vasculitis. Drug-induced vas- Henoch-Schönlein . Some forms United States, its annual incidence is about culitis can occur with such as of such as Behçet’s dis- 2.6 per million population. Polyarteritis , hydralazine, propylthiouracil ease can affect vessels of any size and type nodosa affects about five to 10 individuals and allopurinol. (arteries, veins and capillaries). per million per year, and it is becoming Typically, vasculitides are systemic dis- even less common in countries with a de- eases with multi-organ involvement; but creasing prevalence of hepatitis B infection.

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Complications and Clinical TABLE Manifestations 1 The clinical manifestations and complica- Nomenclature for Vasculitides tions of vasculitis are varied and depend Large-vessel vasculitis on the vascular bed that is involved by the • Takayasu arteritis inflammatory process: • arteritis In , the lumen may • Medium-vessel vasculitis become occluded through intimal • Polyarteritis nodosa hyperplasia, causing end-organ isch- • emia. Since the extracranial arteries are Small-vessel vasculitis typically involved, patients often pres- • Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis ent with and tender- • Microscopic polyangiitis ness. Patients frequently complain of • Granulomatosis with polyangiitis (Wegener’s) symptoms of • Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) including pain and stiffness in the neck • SVV • Anti–glomerular basement membrane disease and proximal extremities. The serious • Cryoglobulinemic vasculitis clinical consequences that may ensue • IgA vasculitis (Henoch-Schönlein) include jaw , vision loss • Hypocomplementemic urticarial vasculitis (anti-C1q vasculitis) caused by ischemic , Variable-vessel vasculitis cerebrovascular ischemic events and • Behçet’s disease claudication. In the aorta, damage • Cogan’s syndrome to the vessel wall may lead to progres- Single-organ vasculitis sive dilatation, formation and • Cutaneous leukocytoclastic angiitis life-threatening events such as aortic • Cutaneous arteritis dissection.3 • Primary central nervous system vasculitis • The inflammatory vasculopathy in • Isolated Others Takayasu arteritis may lead to complica- • tions such as cerebrovascular events, Vasculitis associated with systemic disease limb claudication, renovascular hyper- • Lupus vasculitis Rheumatoid vasculitis tension and aneurysm formation. Less • • Sarcoid vasculitis often, it involves the , • Others causing ischemic disease and Vasculitis associated with probable etiology pulmonary . Patients often • Hepatitis C-associated cryoglobulinemic vasculitis require surgical revascularization to re- • Hepatitis B-associated vasculitis store vascular patency. • Syphilis-associated aortitis • Polyarteritis nodosa is characterized by • Drug-associated immune complex vasculitis necrotizing inflammation of muscular • ANCA-associated vasculitis arteries, which often produces microan- • Cancer-associated vasculitis Others eurysms of the visceral arteries. Patients • typically present with constitutional SOURCE symptoms and evidence of multi-organ dysfunction. Neurologic manifestations 1. Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised International Chapel Hill Consensus Conference such as mononeuritis multiplex, cutane- Nomenclature of Vasculitides. Arthritis Rheum. 2013;65(1):1-11. ous lesions (eg, skin ulcerations) and gastrointestinal complications such as mesenteric , bowel • Because the various forms of ANCA- • Clinical manifestations of granulo- or hemorrhage are characteristic. Renal associated vasculitis primarily involve matosis with polyangiitis may include involvement often leads to arterial hy- small vessels such as arterioles, venules sinusitis, otitis, pulmonary nodules pertension and ischemic nephropathy and capillaries, the main target organs and alveolar hemorrhage. The major- with renal failure. Peripheral arterial are the and kidneys, ity of patients will develop glomeru- occlusions can result in ischemia and where extensive capillary networks are lonephritis, which can lead to rapidly of the digits.4 present. progressive renal failure. Other disease manifestations may include ocular

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inflammation (scleritis, proptosis), Laboratory findings suggestive of vas- lung nodules, alveolar infiltrates/hemor- cutaneous vasculitis and mononeuritis culitis may include normocytic anemia, rhage, organ infarcts). Vascular imaging multiplex.5 thrombocytosis, and elevated erythrocyte such as magnetic resonance • Rapidly progressive glomerulonephritis sedimentation rate (ESR) and C-reactive (MRA) or computed tomography angi- and alveolar hemorrhage are the most protein (CRP). Unfortunately, these tests ography (CTA) is particularly useful for common clinical manifestations of mi- are not specific and may be abnormal be- noninvasive imaging of medium-sized and croscopic polyangiitis, which clinically cause of myriad inflammatory, infectious large arteries. Vessel wall , contrast can be very similar to granulomatosis or neoplastic disease entities. Typically, enhancement and/or wall thickening are with polyangiitis.6 ESR and CRP are markedly elevated in characteristic findings of large-vessel • Eosinophilic granulomatosis with poly- vasculitis; however, not all patients with vasculitis. In addition, MRA or CTA may angiitis has three main disease features: vasculitis mount an inflammatory re- reveal luminal changes such as long ta- and , eosino- sponse—especially those with single-organ pered arterial stenoses of the aortic arch philic infiltrative disease and systemic vasculitis. branches or .9 Conventional small-vessel vasculitis. It often involves There are no specific laboratory bio- arteriography is rarely used but may be the lungs, peripheral nerves and skin markers for large-vessel and medium- necessary to evaluate for microaneurysms but less frequently the heart and gas- sized-vessel vasculitides. The major forms in the renal and mesenteric circulation if trointestinal tract. However, cardiac of small-vessel vasculitis are associated polyarteritis nodosa is suspected. In some involvement can be a significant cause with the presence of anti-neutrophil cy- patients with suspected large-vessel vascu- of morbidity and mortality.7 toplasmic . Most patients with litis, positron emission tomography (PET) • In cryoglobulinemic vasculitis, cryo- granulomatosis with polyangiitis have imaging may be required to evaluate for globulin immune deposits in small ves- antibodies to proteinase-3 (with cytoplas- fluorodeoxyglucose (FDG) uptake in the sels typically lead to cutaneous vasculi- mic staining on immunofluorescence, aorta and major branches. Although costly, tis, glomerulonephritis and peripheral c-ANCA) while patients with microscopic PET imaging is an attractive diagnostic neuropathy. polyangiitis and eosinophilic granuloma- tool for patients with a cryptic constitu- tosis with polyangiitis often have antibod- tional syndrome, as it can help distinguish Diagnosis ies directed against myeloperoxidase (with between a vasculitic process and an occult Vasculitis should be suspected in patients perinuclear staining on immunofluores- malignancy or infection. Other diagnostic with an unexplained systemic consti- cence, p-ANCA). Although ANCA testing studies may be necessary depending on tutional syndrome (, chills, night is helpful in diagnosing small-vessel vas- the patient’s clinical presentation. For ex- sweats, unexplained weight loss) and/or culitis, physicians should be aware that a ample, nerve conduction studies should be evidence of a multi-organ disorder. The subset of patients can be ANCA-negative. done if the clinician suspects mononeuritis diagnosis of vasculitis requires a careful Patients with suspected small-vessel multiplex caused by the vasculitis. integration of clinical, laboratory, imaging vasculitis should also be tested for cryo- Whenever clinically feasible, a diag- and histopathologic findings. Moreover, it globulins, as these conditions can trigger nosis of vasculitis should be made by is essential that conditions mimicking vas- cryoglobulinemic vasculitis. histopathologic examination of a culitis (eg, infection) are considered in the Laboratory testing is also necessary to specimen from an affected vessel or organ. and excluded before evaluate the extent of organ involvement, For example, histopathologic examination initiating treatment. Whenever vasculitis is and all patients should have renal and liver of a superficial temporal artery biopsy suspected, patients should undergo a com- function tests. When indicated, autoim- specimen is the “gold-standard” diagnostic prehensive multisystem clinical evaluation, mune serologies such as rheumatoid fac- modality for giant cell arteritis. In patients with particular attention to the vascular tor and antinuclear antibodies should be with suspected small-vessel vasculitis, bi- examination. checked to evaluate for possible underly- opsy of involved , such as skin, nerve, The American College of ing systemic rheumatic disease. Vasculitis lung or kidney, is generally necessary to has established classification criteria for can be associated with viral (eg, confirm the diagnosis. In cases where most forms of vasculitis.8 Although these hepatitis B, hepatitis C), and, therefore, cli- surgical intervention is required, resected were not designed as diagnostic criteria, nicians should order serologic testing for specimens (eg, from the small intestine) they can be useful to clinicians.8 The defi- these possible causes. may demonstrate histopathologic evidence nitions developed by the 2012 Chapel Hill Imaging is often essential for diagnos- of vasculitis. Consensus Conference on the Nomencla- ing a patient with suspected vasculitis. The ture of Vasculitides are also helpful.1 type of imaging study will vary according Treatment to the clinical presentation and form of Treatment of vasculitis needs to be care- vasculitis. Cross-sectional imaging may fully tailored according to the type of suggest internal organ involvement (eg, vasculitis, extent of organ involvement and

38 | MINNESOTA MEDICINE | MAY 2013 Clinical AND Health Affairs disease severity. Damage from vasculitis infection) are essential. In particular, pa- mon nature of vasculitic disorders and the can progress rapidly and may be irrevers- tients should receive prophylaxis against potential for devastating clinical complica- ible; therefore, patients with organ- or life- Pneumocystis jiroveci pneumonia. tions from these conditions, patients with threatening disease require prompt and Patients with nonsevere vasculitis and vasculitis should preferably be managed aggressive therapy. Initial treatment for a known trigger (eg, drug-induced cu- by rheumatologists with expertise in the patients with systemic vasculitis generally taneous vasculitis) may simply require field. MM includes high-dose (CS) discontinuation of the inciting agent. Kenneth Warrington and Eric Matteson and immunosuppressive medications. Patients with some types of single-organ are with the ’s Division of Corticosteroids, generally oral vasculitis (localized disease) may be cured Rheumatology in Rochester. at an initial daily dose of 1 mg/kg, are by surgical resection of the involved organ the gold standard treatment for giant cell (eg, cholecystectomy in a patient with vas- REFERENCES arteritis. Patients whose vision is threat- culitis limited to the ). In cases 1. Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised ened by ischemic optic neuropathy caused of vasculitis related to a viral etiology (eg, International Chapel Hill Consensus Conference by giant cell arteritis may benefit from hepatitis B-related polyarteritis nodosa), Nomenclature of Vasculitides. Arthritis Rheum. 2013;65(1):1-11. intravenous pulse methylprednisolone. anti-viral therapy should be given while 2. Warrington KJ, Matteson EL. Personalized medi- Corticosteroids should be tapered gradu- controlling the inflammatory process with cine for the vasculitis patient: hope for the future? International J Clinical Rheum. 2009;4:127-32. ally over many months, and patients may a limited course of CS. Paraneoplastic vas- 3. Salvarani C, Cantini F, Hunder GG. Polymyalgia require several years of treatment. For pa- culitis will generally remit only with treat- rheumatica and giant-cell arteritis. Lancet. tients with recurrent relapses of giant cell ment of the underlying malignancy. 2008;372(9634):234-45. 4. Guillevin L, Pagnoux C, Teixeira L. Polyarteritis arteritis and/or CS toxicity, use of metho- Patients with vasculitis should be re- Nodosa. In: Ball GV, Bridges SL, eds. Vasculitis. trexate may be considered.10 evaluated frequently, often by a multi- Second ed: Oxford; 2008:335-53. Takayasu arteritis is treated with CS and specialty team, and careful monitoring of 5. Gross W, Csernok E. Wegener’s granulomatosis:clinical and immunodiagnostic immunosuppressive agents such as metho- laboratory parameters is necessary. Most aspects. In: Ball GV, Bridges SL, eds. Vasculitis. Second trexate, azathioprine or mycophenolate forms of vasculitis are prone to relapse, ed: Oxford; 2008:403-13. 6. Guillevin L, Pagnoux C, Teixeira L. Microscopic mofetil. Tumor- factor inhibitors and therefore immunosuppressive therapy polyangiitis. In: Ball GV, Bridges SL, eds. Vasculitis. are often effective in cases of Takayasu needs to be adjusted according to the level Second ed: Oxford; 2008:355-64. arteritis that is refractory to conventional of disease activity. Over time, it can be 7. Keogh KA, Specks U. Churg-Strauss syndrome: update on clinical, laboratory and therapeu- immunosuppressive agents. challenging to distinguish recurrent dis- tic aspects. Vasc Diffuse Lung Dis. Idiopathic polyarteritis nodosa may ease activity (a flare) from damage caused 2006;23(1):3-12. 8. Hunder GG, Arend WP, Bloch DA, et al. The respond to CS alone; however, patients by vasculitis. Standardized assessment American College of Rheumatology 1990 criteria for with adverse prognostic indicators (eg, forms and disease activity indices (eg, the the classification of vasculitis. Introduction. Arthritis Rheum. 1990;33(8):1065-7. renal insufficiency or gastrointestinal, car- Birmingham Vasculitis Activity Scale) are 9. Kermani TA, Warrington KJ. Recent advances diac, or neurologic involvement) require helpful for the longitudinal care of patients in diagnostic strategies for giant cell arteritis. Curr CS combined with to with vasculitis. Because treatment-related Neurol Neurosci Rep. 2012;12(2):138-44. 10. Warrington KJ, Matteson EL. Management guide- induce disease remission. For most forms complications (eg, infection) can mimic lines and outcome measures in giant cell arteritis of severe small-vessel vasculitis, clinicians a vasculitis flare, the clinician must thor- (GCA). Clin Exp Rheum. 2007;25(6 Suppl 47):137-41. 11. Cartin-Ceba R, Fervenza FC, Specks U. Treatment must attempt to induce remission with oughly evaluate the patient before adjust- of antineutrophil cytoplasmic antibody-associated high-dose CS in combination with either ing therapy. vasculitis with rituximab. Curr Opin Rheumatol. cyclophosphamide or the B-cell-depleting 2012;24(1):15-23. monoclonal antibody rituximab. Plasma Conclusion exchange may be indicated in the context Vasculitides are a heterogenous group of of severe alveolar hemorrhage and/or rare conditions in which inflammation of rapidly progressive renal failure. Remis- blood vessel walls leads to vascular dam- sion maintenance is usually achieved with age and end-organ ischemia. Vasculitis methotrexate or azathioprine, or with re- may result in rapidly progressive multi-or- peated courses of rituximab.11 gan dysfunction and premature mortality. In most cases, the morbidity associated The clinical manifestations can be quite with therapy is significant and preventive varied, presenting a diagnostic challenge measures to attenuate risks associated for clinicians. The evaluation and manage- with corticosteroids (eg, ) and ment of patients with vasculitis requires a immunosuppressive agents (cytopenias, prompt and comprehensive multi-disci- plinary approach. Because of the uncom-

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