Section A -

Vasculitides Volker Nickeleit, M.D. J. Charles Jennette, M.D.

1) Infectious versus Noninfectious Vasculitis Vasculitis is inflammation of blood vessels, and thus can affect any tissue and organ. Accurate diagnosis of vasculitis is based on correlation of the pathologic features with clinical, serologic, microbiologic and immunopathologic data. An infectious etiology always should be considered and excluded before considering a noninfectious vasculitis because of the important therapeutic implications of this differential diagnostic issue. Direct Infection of Vessels Bacterial vasculitis ( e.g., Neisserial) Mycobacterial vasculitis (e.g., Tuberculous) Spirochetal vasculitis (e.g., Syphilitic) Rickettsial vasculitis (e.g., Rocky Mountain Spotted Fever) Fungal vasculitis (e.g., Aspergillosis) Viral vasculitis (e.g., Herpes zoster)) Immunologic Injury Immune Complex Mediated Vasculitis Henoch-Schönlein purpura Cryoglobulinemic vasculitis Lupus vasculitis Rheumatoid vasculitis Serum sickness vasculitis Infection-induced immune complex vasculitis (e.g. by Hep B & C virus) Some drug-induced vasculitis (e.g. sulfonamide-induced vasculitis) Some paraneoplastic vasculitis Behçet's disease (?) Polyarteritis nodosa (?) Direct Antibody Attack Mediated Vasculitis Goodpasture's syndrome (mediated by anti-GBM antibodies) Kawasaki disease (?) (possibly mediated by anti-endothelial antibodies) Anti-neutrophil Cytoplasmic Autoantibody (ANCA) Mediated Vasculitis Wegener's granulomatosis Microscopic polyangiitis Churg-Strauss syndrome Some drug-induced vasculitis (e.g. thiouracil-induced vasculitis) Cell Mediated Vasculitis Allograft cellular vascular rejection Giant cell arteritis (?) Takayasu arteritis (?) The categorization system for noninfectious vasculitis that will be used in this syllabus is that proposed by the Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitis (Jennette JC, Falk RJ, Andrassy Ket al: Nomenclature of systemic vasculitides: The proposal of an international consensus conference. Arthritis Rheum 1994; 37:187-192): LARGE VESSEL VASCULITIS1 Giant cell (temporal) arteritis Granulomatous arteritis of the aorta and its major branches, with a predilection for the extracranial branches of the carotid artery. Often involves the temporal artery. Usually occurs in patients older than 50 and often is associated with polymyalgia rheumatica. Takayasu arteritis Granulomatous inflammation of the aorta and its major branches. Usually occurs in patients younger than 50. MEDIUM-SIZED VESSEL VASCULITIS1 Polyarteritis nodosa Necrotizing inflammation of medium-sized or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries or venules. Kawasaki disease Arteritis involving large, medium-sized and small arteries, and associated with mucocutaneous lymph node syndrome. Coronary arteries are often involved. Aorta and veins may be involved. Usually occurs in children. SMALL VESSEL VASCULITIS1 Wegener's granulomatosis Granulomatous inflammation involving the respiratory tract, and necrotizing vasculitis affecting small to medium-sized vessels, e.g. capillaries, venules, arterioles, and arteries. Necrotizing glomerulonephritis is common. Churg-Strauss syndrome Eosinophil-rich and granulomatous inflammation involving the respiratory tract and necrotizing vasculitis affecting small to medium-sized vessels, and associated with asthma and blood eosinophilia Microscopic polyangiitis (microscopic polyarteritis) Necrotizing vasculitis with few or no immune deposits affecting small vessels, i.e. capillaries, venules, or arterioles. Necrotizing arteritis involving small and medium-sized arteries may be present. Necrotizing glomerulonephritis is very common. Pulmonary capillaritis often occurs. Henoch-Schönlein purpura Vasculitis with IgA-dominant immune deposits affecting small vessels, i.e. capillaries, venules, or arterioles. Typically involves skin, gut and glomeruli, and is associated with arthralgias or arthritis. Essential cryoglobulinemic vasculitis Vasculitis with cryoglobulin immune deposits affecting small vessels, i.e. capillaries, venules, or arterioles, and associated with cryoglobulins in serum. Skin and glomeruli are often involved. Cutaneous leukocytoclastic angiitis Isolated cutaneous leukocytoclastic angiitis without systemic vasculitis or glomerulonephritis. 1 Large artery refers to the aorta and the largest branches directed toward major body regions (e.g., to the extremities and the head and neck); medium-sized artery refers to the main visceral arteries (e.g. renal, hepatic, coronary and mesenteric arteries), and small artery refers to the distal arterial radicals that connect with arterioles (e.g., renal arcuate and interlobular arteries). ALGORITHM FOR THE DIAGNOSIS OF NONINFECTIOUS SYSTEMIC VASCULITIS Diagram depicting the predominant distribution of renal vascular involvement by a variety of vasculitides. 2) Large Vessel Vasculitides (Chronic Granulomatous Arteritis) The large vessel vasculitides affect the aorta and its major branches. The two major vasculitides that involve these vessels are Takayasu arteritis and giant cell arteritis. Both of these vasculitides are characterized histologically by chronic granulomatous inflammation. Takayasu Arteritis Takayasu arteritis is granulomatous inflammation of the aorta and its major branches that almost always occurs in patients younger than 50 years old. The pulmonary trunk also may be involved. Takayasu arteritis involves primarily the aorta and large elastic arteries. Histologically, the earliest vascular changes are focal inflammation and necrosis of the media of involved arteries, with later extension of the inflammation into the adventitia and intima. The inflammatory cell infiltrates are composed predominantly of lymphocytes and mononuclear phagocytes, with admixed eosinophils, neutrophils and plasma cells. Multinucleated giant cells are often, but not always, present. In advanced stages of the disease, the mural injury is characterized by dense fibrosis without inflammatory cells. The most common gross changes of Takayasu arteritis are mural thickening and lumenal narrowing, but aneurysm formation may occur as well. Approximate frequency of arterial involvement is subclavian artery 85% of patients, renal artery 60%, carotid artery 45%, vertebral artery 20%, iliac artery 15%, innominate artery 15% and pulmonary artery 15%. Giant Cell Arteritis (formerly Temporal Arteritis) Giant cell arteritis is a granulomatous arteritis of the aorta and its major branches, with a predilection for the extracranial branches of the carotid artery. It usually occurs in patients older than 50, and often is associated with polymyalgia rheumatica. Giant cell arteritis is the most common form of vasculitis in older patients. Pulmonary arteries are involved in 5%-10% of patients. The granulomatous arteritis of giant cell arteritis has a predilection for the aorta and its major branches, especially the extracranial branches of the carotid artery. The lesions typically are segmental. Histologically, the lesions are characterized by a panarteritis, which begins in the media but extends to involve the intima and adventitia. The typical inflammatory infiltrate consists primarily of mononuclear leukocytes, with lymphocytes and macrophages predominating. Multinucleated giant cells are frequently but not always present. Although focal fibrinoid necrosis may occur, when extensive, it should raise the possibility of another type of systemic arteritis, such as Wegener's granulomatosis or polyarteritis with temporal artery involvement. Granulomatous inflammation with giant cells may be centered on the internal and less often external elastic lamina, which typically shows fragmentation. A temporal artery biopsy often is obtained for diagnosing giant cell arteritis. In patients with signs and symptoms of giant cell arteritis, temporal artery biopsy often is diagnostic even when there is no clinical evidence of temporal artery involvement. Because of the segmental nature of vascular involvement, for adequate sensitivity a 3 cm or more segment of artery should be obtained for examination. After 1 week of corticosteroid treatment, the diagnostic yield of temporal artery biopsies declines. 3) Medium-sized Vessel Vasculitis (Necrotizing Arteritis) Medium-sized vessel vasculitides are characterized by predominant involvement of main visceral arteries, such as the coronary, hepatic, renal, and mesenteric arteries and their branches. Pulmonary arteries are rarely involved. These same vessels, however, also can be involved with large vessel vasculitides and small vessel vasculitides. Polyarteritis Nodosa Polyarteritis nodosa necrotizing arteritis in medium-sized or small arteries such as the coronary, hepatic, renal, and mesenteric arteries, and their major intraparenchymal radicals. The term polyarteritis nodosa has been used quite variably over the years, with some definitions allowing involvement of vessels smaller than arteries. According to the Chapel Hill nomenclature system the name polyarteritis nodosa is confined to necrotizing arteritis that affects arteries but does not involve vessels smaller than arteries. Microscopic polyangiitis (or less appropriately microscopic polyarteritis) is the diagnostic term for necrotizing vasculitis without immune deposits that affects vessels smaller than arteries, i.e. arterioles, venules and capillaries, with or without small and medium-sized artery involvement. Microscopic polyangiitis frequently involves the lungs, whereas polyarteritis nodosa rarely involves the lungs, and when it does, it usually affects the bronchial arteries. The light microscopic lesions of polyarteritis nodosa are mural fibrinoid necrosis and accompanying inflammation, which initially has predominantly neutrophils and sometimes eosinophils, but later has predominantly mononuclear leukocytes. The segmental inflammation and necrosis in artery walls may produce an aneurysm (actually a pseudoaneurysm), which causes the grossly visible arterial nodules that prompted the term "nodosa". The injured vessels often undergo fibrosis. Kawasaki Disease Kawasaki disease is an acute febrile illness of childhood associated with mucocutaneous lymph node syndrome that has arteritis involving large, medium-sized and small arteries. Coronary arteries are often affected. I am not aware of pulmonary involvement by Kawasaki disease other than the induction of pulmonary congestion secondary to heart failure. The vasculitic lesions of Kawasaki disease involve predominantly small and medium-sized arteries, especially the coronary arteries. The histologic lesions are characterized by segmental mural necrosis with infiltration by neutrophils or mononuclear leukocytes, with the latter predominating in older lesions. All layer of the arteries are involved, including the intima, which may become markedly thickened resulting in lumenal narrowing. Areas of necrosis occur but typically contain more numerous leukocytes and more leukocyte debris than the areas of fibrinoid necrosis seen with polyarteritis nodosa and the ANCA-associated vasculitides. Aneurysms are most common in the coronary arteries but they also occur in other arteries. 4) Small Vessel Vasculitis (Necrotizing Polyangiitis) Small vessel vasculitides have a predilection for capillaries, venules and arterioles, although some of them may affect arteries. Small vessel vasculitides are the vasculitides that most often affect the lungs, usually by causing capillaritis, and sometimes accompanied by necrotizing granulomatous inflammation with some variants (i.e., Wegener's granulomatosis, Churg-Strauss syndrome). Behcet's disease and necrotizing sarcoid vasculitis also can affect arteries and other small vessels in the lungs. Anti-GBM small vessel vasculitis and ANCA-small vessel vasculitis often affect the lungs, whereas immune complex small vessel vasculitis less frequently involve the lungs (lupus vasculitis>cryoglobulinemic vasculitis>Henoch-Schönlein purpura). Henoch-Schönlein Purpura Henoch-Schönlein purpura is a vasculitis characterized by IgA-dominant immune deposits in small vessels, i.e. capillaries, venules, or arterioles. It most often affects the skin, gut and glomeruli, and is associated with arthralgias or arthritis. The lungs are rarely affected. In fact, in a patient with a clinical diagnosis of Henoch-Schönlein purpura, lung involvement should raise the possibility of another small vessel vasculitis, especially microscopic polyangiitis or another variant of ANCA small vessel vasculitis. The characteristic although not specific acute histologic lesion is a leukocytoclastic angiitis affecting postcapillary venules, capillaries and arterioles. This is characterized by focal necrosis of vessel walls as well as necrosis of infiltrating neutrophils, which results in accumulation of conspicuous leukocytoclastic debris at the sites of injury. IgA-dominant immune complexes can be demonstrated by immunohistology in injured as well as uninjured vessels, including pulmonary capillaries. The lesion in the kidney is identical to IgA nephropathy. Cryoglobulinemic Vasculitis Patients with cryoglobulinemic vasculitis have cryoglobulinemia and deposits of cryoglobulins in small vessels, i.e. capillaries, venules, or arterioles. Skin and glomeruli are often involved. Lungs are rarely involved with overt hemorrhagic capillaritis, however, nonspecific pulmonary symptoms and many patients have radiographic evidence for alveolar septal thickening. Hepatitis C virus infection often is present. Affected vessels have segmental necrosis and neutrophilic infiltration with leukocytoclasia. This leukocytoclastic angiitis is similar to that seen in other small vessel vasculitides, such as Henoch-Schönlein purpura, microscopic polyangiitis and Wegener's granulomatosis. The most specific histologic finding is the presence of "hyaline thrombi", which are aggregates of cryoglobulins within vessel lumens. Immunofluorescence microscopy demonstrates granular deposits of immunoglobulins and complement in vessel walls, and sometimes aggregates of cryoglobulins and complement in lumens. Anti-GBM Disease Anti-GBM disease is essentially a small vessel vasculitis that affects the glomerular capillaries and pulmonary alveolar capillaries. It may occur as a isolated glomerulonephritis, just as IgA nephropathy is conceptually a form of isolated Henoch-Schönlein purpura, and pauci-immune crescentic glomerulonephritis is an isolated form of ANCA-small vessel vasculitis. The acute pulmonary lesion is characterized by pulmonary hemorrhage, often with no discernable capillaritis. However, occasional patients have overt capillaritis. The presence of overt capillaritis in a patient with anti-GBM disease should raise the possibility of concurrent ANCA disease. The glomerular lesion of anti-GBM disease is characterized by segmental to global glomerular necrosis with crescent formation in over 90% of patients. The light microscopic lesion cannot be accurately distinguished from ANCA-glomerulonephritis. Immunohistology demonstrates intense linear GBM staining for predominantly IgG along with more granular and discontinuous staining for C3. About a quarter to a third of patients with anti-GBM disease also have ANCA. Microscopic Polyangiitis Microscopic polyangiitis is necrotizing vasculitis with few or no immune deposits affecting small vessels, i.e. capillaries, venules, or arterioles. Pulmonary involvement is frequent. Necrotizing arteritis occurs in some but not all patients. Approximately 80% of MPA patients have ANCA, usually P-ANCA (MPO-ANCA). Microscopic polyangiitis shares many clinical, pathologic, serologic and probably pathogenetic features with Wegener's granulomatosis and Churg-Strauss syndrome. The acute vascular lesions are characterized by segmental fibrinoid necrosis, and mural and perivascular neutrophilic infiltration with leukocytoclasia. Eosinophils may be numerous. Thrombosis may complicate the lesions. Older lesions have predominantly mononuclear leukocytes and undergo fibrosis. Necrotizing glomerulonephritis and necrotizing alveolar capillaritis are common lesions in patients with microscopic polyangiitis. The necrotiing glomerulonephritis of microscopic polyangiitis is indistinguishable from the necrotizing glomerulonephritis of Wegener's granulomatosis, Churg-Strauss syndrome, and isolated pauci-immune crescentic glomerulonephritis. Immunohistology demonstrates an absence or paucity of immunoglobulin deposition, which distinguishes the vascular inflammation of microscopic polyangiitis from immune complex and anti-glomerular basement membrane (anti-GBM) antibody-mediated disease. Wegener's Granulomatosis Wegener's granulomatosis is characterized by necrotizing granulomatous inflammation, often involving the upper or lower respiratory tract, and frequently accompanied by necrotizing vasculitis affecting small to medium-sized vessels, such as capillaries, venules, arterioles, and arteries. Necrotizing glomerulonephritis is common. Approximately 90% of patients with active systemic disease have ANCA, usually C-ANCA (PR3-ANCA). Necrotizing granulomatous inflammation is the constant feature of Wegener's granulomatosis, and is observed most often in the upper and lower respiratory tract, but occasionally in other tissues, such as the orbit, skin and kidneys. The lesions consist of loosely arranged mononuclear and polymorphonuclear leukocytes with scattered multinucleated giant cells. In the lungs and elsewhere, the differential diagnosis includes necrotizing sarcoid granulomatosis with vasculitis. In the lungs, the poorly defined entity known as bronchocentric granulomatosis must also be considered if no vasculitis is identified. Bronchocentric granulomatosis probably is not a specific disease but rather a common end point that can be caused by multiple persistent inflammatory infectious and noninfectious stimuli in pulmonary airways. The vasculitis in the lungs and elsewhere can involve arteries, arterioles, veins, venules and capillaries, and can be granulomatous or nongranulomatous. The latter is histologically identical to other types of necrotizing vasculitis, such as microscopic polyangiitis (microscopic polyarteritis). The glomerulonephritis of Wegener's granulomatosis is a pauci-immune necrotizing and crescentic glomerulonephritis that is pathologically indistinguishable from the glomerulonephritis of microscopic polyangiitis. Churg-Strauss Syndrome Churg-Strauss syndrome is characterized by eosinophil-rich and granulomatous inflammation involving the respiratory tract and necrotizing vasculitis affecting small to medium-sized vessels that is associated with asthma and blood eosinophilia. The vasculitis of Churg-Strauss syndrome is histologically very similar to that of Wegener's granulomatosis and microscopic polyangiitis; however, there is a tendency for more eosinophils among the infiltrating leukocytes. The vasculitis of Churg-Strauss syndrome can affect many organ systems, with the lungs, heart, peripheral nervous system, skin, gut and kidneys being the most frequent targets. A pauci-immune focal necrotizing glomerulonephritis may occur, but this is usually less severe than the glomerulonephritis in Wegener's granulomatosis or microscopic polyangiitis. The necrotizing granulomatous inflammation of Churg-Strauss syndrome resembles that of Wegener's granulomatosis, but tends to have more eosinophils. Table: Approximate frequency of ANCA with specificity for proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA) in patients with active untreated renal-limited pauci-immune crescentic glomerulonephritis, microscopic polyangiitis, Wegener's granulomatosis, and Churg-Strauss syndrome.   Renal-limited pauci-immune crescentic glomerulonephritis Microscopic polyangiitis Wegener's granulomatosis Churg-Strauss syndrome PR3-ANCA 20% 40% 75% 10% MPO-ANCA 60% 50% 20% 60% Negative 20% 10% 5% 30% Table: Predictive Value of Combined IFA & EIA ANCA Testing. Data derived from an analysis of 2,315 patients, with ANCA assay sensitivity 81% and specificity 96%. Data derived from Lim LCL, Taylor III JG, Schmitz JL, et al. Diagnostic usefulness of antineutrophil cytoplasmic autoantibody serology: comparative evaluation of commercial indirect fluorescent antibody kits and enzyme immunoassay kits. Am J Clin Pathol 1999; 111:363-69. Adult with: Prevalence (Pre-test Likelihood) PPV(Post-test Likelihood) NPV (Post-test Unlikelihood) RPGN 47% 95% 85% Hematuria, Proteinuria, Cr >3mg/dl 21% 84% 95% Hematuria, Proteinuria, Cr 1.5-3mg/dl 7% 60% 99% Hematuria, Proteinuria, Cr <1.5mg/dl 2% 29% 100% Table: Differential Diagnostic Features of Several Forms of Small Vessel Vasculitis (SVV). (From: Jennette JC, Falk RJ: Small Vessel Vasculitis. N Engl J Med 1997; 337:1512-23)   Henoch Schönlein Purpura Cryoglobulinemic Vasculitis Microscopic Polyangiitis Wegener's Granulomatosis Churg-Strauss Syndrome SVV Signs & Symptoms * + + + + + IgA-Dominant Immune Deposits + o o o o Cryoglobulins in Blood & Vessels o + o o o ANCA in Blood o o + + + Necrotizing Granulomas o o o + + Asthma & Eosinophilia o o o o + * All of these small vessel vasculitides can manifest any or all of the shared features of small vessel vasculitides, such as purpura, nephritis, abdominal pain, peripheral neuropathy, myalgias and arthralgias. Each is distinguished by the presence and just as importantly the absence of certain specific features. Table: Approximate* Frequency of Organ System Manifestations in Several Forms of Small Vessel Vasculitis. (From Jennette JC, Falk RJ: Small Vessel Vasculitis. N Engl J Med 1997; 337:1512-23)   Henoch-Schönlein Purpura Cryoglobulinemic Vasculitis Microscopic Polyangiitis Wegener's Granulomatosis Churg-Strauss Syndrome Pulmonary <5% <5% 50% 90% 70% Cutaneous 90% 90% 40% 40% 60% Renal 50% 55% 90% 80% 45% Ear, nose and throat <5% <5% 35% 90% 50% Musculoskeletal 75% 70% 60% 60% 50% Neurologic 10% 40% 30% 50% 70% Gastrointestinal 60% 30% 50% 50% 50% Selected References (Section A) Gaudin PB, Askin FB, Falk RJ, Jennette JC: The pathologic spectrum of pulmonary lesions in patients with anti-neutrophil cytoplasmic antibodies specific for anti-proteinase 3 and anti-myeloperoxidase. Am J Clin Path 1995; 104:7-16 Jennings CA, King TE Jr., Tuder R, Cherniack RM, Schwarz MI. Diffuse alveolar hemorrhage with underlying isolated, pauciimmune pulmonary capillaritis. American Journal of Respiratory and Critical Care Medicine. 155(3): 1101-9, 1997. Jennette JC, Falk RJ: Anti-neutrophil cytoplasmic autoantibodies: Discovery, specificity, disease associations and pathogenic potential. Adv Pathol Lab Med 8:363, 1995 Jennette JC, Rosen S: Vasculitis, in Anderson 's Pathology, 10th ed, Damjanov I, Linder J (eds), Mosby, Philadelphia , 1996, Chapter 47B, 1397-1445 Jennette JC, Falk RJ: Small Vessel Vasculitis. N Engl J Med 1997; 337:1512-23 Jennette JC: Renal Involvement in Systemic Vasculitis in Heptinstall's Pathology of the Kidney, 5th Edition, Jennette JC, Olson JL, Schwartz MM, Silva FG (eds), Lippincott-Raven, Philadelphia, 1998, chapter 23, 1059-1096 Jennette JC, Falk RJ: Renal Involvement in Systemic Vasculitis in Greenberg A, Cheung AK, Coffman TM, Falk RJ, Jennette JC (eds), National Kidney Foundation Nephrology Primer, 2nd Edition, Academic Press, San Diego, 1998, Chapter 27, 200-7 Jennette JC: ANCA Pauci-immune Glomerulonephritis and Vasculitis and Other Forms of Vasculitis in Non-Neoplastic Renal Disease in D'Agati V, Jennette JC, Silva FG, American Registry of Pathology, Washington, D.C., 2004, Chapter 15, in press Kallenberg CGM, Brouwer E, Weening JJ, Cohen Tervaert JWC. Anti-neutrophil cytoplasmic antibodies: Current diagnostic and pathophysiologic potential. Kidney Int 46:1-15, 1994 Katzenstein ALA , Askin FB, Bennington JL (consulting editor). Surgical pathology of non-neoplastic lung disease. Philadelphia: Saunders, 1990. Lim LCL, Taylor III JG, Schmitz JL, Folds JD, Wilkman AS, Falk RJ, Jennette JC: Diagnostic usefulness of antineutrophil cytoplasmic autoantibody serology: comparative evaluation of commercial indirect fluorescent antibody kits and enzyme immunoassay kits. Am J Clin Pathol 111:363-369, 1999