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112097 small-vessel vasculitis

Medical Progress and treatment. Small-vessel vasculitis is defined asvasculitis that affects vessels smaller than arteries,such as arterioles, venules, and capillaries. Importantcategories of the disease are listed in Table 1. It is important to note that small-vessel vasculitis some-times, but not always, also affects arteries, and thus the vascular distribution overlaps with that of the HARLES JENNETTE, M.D., AND RONALD J. FALK, M.D.
medium-sized-vessel and large-vessel vasculitides(Fig. 1).
ASCULITIS is inflammation of vessel walls.
It has many causes, although they result in Two paths of investigation, which eventually inter- only a few histologic patterns of vascular in- sected, led to our current understanding of small- flammation. Vessels of any type in any organ can be vessel vasculitis. One focused on necrotizing arteri- affected, a fact that results in a wide variety of signs tis, and the other on purpura.
and symptoms. These protean clinical manifesta- Discovery and Categorization of Necrotizing Arteritis
tions, combined with the etiologic nonspecificity ofthe histologic lesions, complicate the diagnosis of Kussmaul and Maier published the first definitive specific forms of vasculitis. This is problematic be- report of a patient with necrotizing arteritis in cause different vasculitides with indistinguishable 1866. They described a patient with fever, anorexia, clinical presentations have very different prognoses muscle weakness, paresthesias, myalgias, abdominal and treatments. For example, a patient with purpura, pain, and oliguria who was found to have nodular nephritis, and abdominal pain caused by Henoch– inflammatory lesions in medium-sized and small ar- Schönlein purpura usually has a good prognosis and teries throughout the body. They called this condi- needs only supportive care, whereas a patient with tion periarteritis nodosa, which evolved into the purpura, nephritis, and abdominal pain caused by more pathologically correct name polyarteritis no- microscopic polyangiitis is likely to go on to life- dosa. For more than 50 years (and unfortunately threatening organ failure if not treated promptly and even today in some settings), any patient with nec- rotizing arteritis was given a diagnosis of polyarteri- In recent years there has been substantial progress in identifying the attributes of specific types of vas- By the 1950s, many investigators had realized that culitis that allow accurate diagnosis. One approach there were a number of clinically and pathologically to classifying noninfectious vasculitides categorizes distinct forms of arteritis and that arteritis often oc- them, in part, on the basis of the predominant type curred as a component of a vasculitis in which many of vessel affected (Tables 1 and 2 and Fig. 1).1 There if not most of the involved vessels were smaller than is, however, substantial overlap among different vas- arteries (e.g., dermal venules, mucosal arterioles, culitides, and the type of vessel involved is merely glomerular capillaries, and pulmonary alveolar capil- one of many features that must be determined be- laries). Zeek et al. called this form of vasculitis fore a diagnosis can be rendered.
with small-vessel involvement "hypersensitivity angi- This review will focus on noninfectious necrotiz- itis," whereas Davson et al. and Godman and ing small-vessel vasculitis, beginning with a history Churg referred to it as the "microscopic form of of the discovery of the major categories of the dis- periarteritis." In 1994, the term "microscopic poly- ease and concluding with a review of its diagnosis angiitis" was advocated by an international consen-sus conference on vasculitis nomenclature,1 and itwill be used in this review. "Microscopic polyangi-itis" is preferable as a name to "microscopic polyar-teritis," because many patients with this type of vas-culitis have disease confined to arterioles, venules,and capillaries and thus have no arteritis.
From the Departments of Pathology and Laboratory Medicine (J.C.J.) and Medicine (R.J.F.), University of North Carolina at Chapel Hill, Chapel Also by the 1950s, two variants of vasculitis with Hill. Address reprint requests to Dr. Jennette at CB#7525, Department of associated necrotizing granulomatous inflammation Pathology and Laboratory Medicine, University of North Carolina, Chapel had been recognized — i.e., Wegener's granuloma- Hill, NC 27599-7525.
1997, Massachusetts Medical Society.
tosis and Churg–Strauss syndrome. Wegener's gran-  November 20, 1997 Downloaded from www.nejm.org at HELLENIC SOCIETY OF ENDOCRINOL on December 23, 2004 . Copyright 1997 Massachusetts Medical Society. All rights reserved. TABLE 1. MAJOR CATEGORIES
TABLE 2. NAMES AND DEFINITIONS OF VASCULITIS ADOPTED
OF NONINFECTIOUS VASCULITIS.* BY THE CHAPEL HILL CONSENSUS CONFERENCE ON THE NOMENCLATURE OF SYSTEMIC VASCULITIS.* Large-vessel vasculitisGiant-cell arteritisTakayasu's arteritis Giant-cell (temporal) arteritis Granulomatous arteritis of the aorta and Polyarteritis nodosa its major branches, with a predilection Kawasaki's disease for the extracranial branches of the ca- Primary granulomatous central nervous system rotid artery. Often involves the temporal artery. Usually occurs in patients more than 50 years old and is often associated Small-vessel vasculitis with polymyalgia rheumatica. ANCA-associated small-vessel vasculitis Takayasu's arteritis Granulomatous inflammation of the aorta Microscopic polyangiitis and its major branches. Usually occurs Wegener's granulomatosis in patients younger than 50. Churg–Strauss syndromeDrug-induced ANCA-associated vasculitis Immune-complex small-vessel vasculitis Polyarteritis nodosa Necrotizing inflammation of medium- sized or small arteries without glomeru- lonephritis or vasculitis in arterioles, Rheumatoid vasculitis capillaries, or venules.
Sjögren's syndrome vasculitis Kawasaki's disease Arteritis involving large, medium-sized, Hypocomplementemic urticarial vasculitis and small arteries and associated with Behçet's disease mucocutaneous lymph node syndrome. Goodpasture's syndrome Coronary arteries are often involved. Aorta and veins may be involved. Usual- Drug-induced immune-complex vasculitis ly occurs in children. Infection-induced immune-complex vasculitis Paraneoplastic small-vessel vasculitis Lymphoproliferative neoplasm-induced vasculitisMyeloproliferative neoplasm-induced vasculitis Granulomatous inflammation involving the respiratory tract and necrotizing Inflammatory bowel disease vasculitis vasculitis affecting small-to-medium-sized vessels (e.g., capillaries, venules, *Vascular inflammation is categorized as either in- arterioles, and arteries). Necrotizing glo- fectious vasculitis, which is caused by the direct in- merulonephritis is common. vasion of vessel walls by pathogens (e.g., rickettsial Eosinophil-rich and granulomatous in- organisms in Rocky Mountain spotted fever), or flammation involving the respiratory noninfectious vasculitis, which is not caused by the tract and necrotizing vasculitis affecting direct invasion of vessel walls by pathogens (al- small-to-medium-sized vessels and asso- though infections can indirectly induce noninfec- ciated with asthma and eosinophilia.
tious vasculitis — e.g., by generating pathogenic im- Necrotizing vasculitis with few or no im- mune complexes). ANCA denotes antineutrophil mune deposits affecting small vessels (capillaries, venules, or arterioles). Nec-rotizing arteritis involving small and medium-sized arteries may be present. Necrotizing glomerulonephritis is very common. Pulmonary capillaritis often occurs. ulomatosis was initially reported by Klinger in 19318 Vasculitis with IgA-dominant immune de- and later described in more detail by Wegener.9 The posits affecting small vessels (capillaries, venules, or arterioles). Typically involves definitive description was provided in 1954 by God- skin, gut, and glomeruli and is associated man and Churg, who identified a triad of features: with arthralgias or arthritis. systemic necrotizing "angiitis," necrotizing inflam- Essential cryoglobulinemic Vasculitis with cryoglobulin immune de- posits affecting small vessels (capillaries, mation of the respiratory tract, and necrotizing glo- venules, or arterioles) and associated merulonephritis.7 Subsequently, patients with limit- with cryoglobulins in serum. Skin and ed expressions of the disease were recognized — for glomeruli are often involved. Cutaneous leukocytoclastic Isolated cutaneous leukocytoclastic angii- example, patients with no glomerulonephritis.10 tis without systemic vasculitis or glo- Churg and Strauss, in 1951, described 13 patients who had asthma, eosinophilia, granulomatous in- *This table is adapted with modifications from Jennette et al.,1 with the flammation, necrotizing systemic vasculitis, and nec- permission of the publisher. "Large vessel" refers to the aorta and the larg- rotizing glomerulonephritis.11 This disease is now est arterial branches directed toward major body regions (e.g., to the ex- called Churg–Strauss syndrome.
tremities and the head and neck). "Medium-sized vessel" refers to the mainvisceral arteries and their branches. "Small vessel" refers to arterioles, In their landmark 1954 article,7 Godman and venules, and capillaries, although arteries, especially small arteries, may be Churg concluded that Wegener's granulomatosis, included in this category of vasculitis. Note that all three categories affect Churg–Strauss syndrome, and the "microscopic form arteries, but only small-vessel vasculitis has a predilection for vessels smallerthan arteries.
of periarteritis" (microscopic polyangiitis) are closely †These vasculitides are associated with antineutrophil cytoplasmic auto- related and distinct from polyarteritis nodosa. As antibodies (ANCA).
Downloaded from www.nejm.org at HELLENIC SOCIETY OF ENDOCRINOL on December 23, 2004 . Copyright 1997 Massachusetts Medical Society. All rights reserved. Small-Vessel Vasculitis (e.g., microscopic polyangiitis, Wegener's granulomatosis) (e.g., polyarteritis nodosa, Kawasaki's disease) Large-Vessel Vasculitis (e.g., giant-cell arteritis, Takayasu's arteritis) Goodpasture's syndrome Isolated cutaneous LCA Henoch–Schönlein purpura and cryoglobulinemic vasculitis Microscopic polyangiitis, Wegener's granulomatosis, and Churg–Strauss syndrome Figure 1. Preferred Sites of Vascular Involvement by Selected Vasculitides.
The widths of the trapezoids indicate the frequencies of involvement of various portions of the vasculature. LCA denotes leukocy-toclastic angiitis.
will be discussed later, this conclusion is supported noninfectious purpura.13 He noted that noninfec- by recent immunologic observations.
tious purpura had a predilection for the lower ex- Pathological evaluation of patients with arterial tremities, was characterized by recurrent groups of inflammation demonstrated that histologically indis- lesions, and could be associated with systemic dis- tinguishable necrotizing arteritis (Fig. 2) is shared ease. Over the next century, Schönlein,14 Henoch,15,16 by a variety of vasculitides, including polyarteritis Osler,17,18 and others elucidated a broad spectrum of nodosa, Kawasaki's disease, microscopic polyangiitis, signs and symptoms that were associated with pur- Wegener's granulomatosis, and Churg–Strauss syn- pura, and thus with small-vessel vasculitis, including drome. However, whereas medium-sized-vessel vas- arthritis, peripheral neuropathy, abdominal pain, pul- culitis, such as polyarteritis nodosa and Kawasaki's monary hemorrhage, epistaxis, iritis, and nephritis.
disease, involves predominantly if not exclusively ar- Osler recognized that these clinical manifestations teries, small-vessel vasculitis, such as microscopic were caused by necrotizing inflammation in small polyangiitis and Wegener's granulomatosis, may or may not include arteritis but virtually always affects In 1919, Goodpasture reported a patient with vessels smaller than arteries (Fig. 1). By the 1980s, pulmonary hemorrhage and rapidly progressive glo- this concept of "small-vessel vasculitides" that are merulonephritis who had vasculitis affecting small distinct from vasculitides affecting predominantly splenic arteries, arterioles in the gut, pulmonary cap- medium-sized and large arteries was well estab- illaries, and glomerular capillaries.19 This pulmo- nary–renal vasculitic syndrome is now recognized tobe a manifestation of multiple pathogenetically dis- Historical Description of the Manifestations of Venulitis
tinct forms of small-vessel vasculitis. The designation "Goodpasture's syndrome" now is usually restricted Purpura (Fig. 3) was the first manifestation of vas- to patients with vascular injury caused by antibodies culitis in vessels smaller than arteries to be extensive- to glomerular basement membrane,20 even though ly investigated. In 1808, Willan clearly distinguished most patients with pulmonary–renal vasculitic syn- purpura caused by systemic febrile infections from drome have some other small-vessel vasculitis21,22  November 20, 1997 Downloaded from www.nejm.org at HELLENIC SOCIETY OF ENDOCRINOL on December 23, 2004 . Copyright 1997 Massachusetts Medical Society. All rights reserved.

Figure 2. Necrotizing Arteritis in a Small Epineural Artery in a
Nerve-Biopsy Specimen from a Patient with Microscopic Poly-
angiitis.
The muscularis is completely destroyed by fibrinoid necrosisthat extends into the perivascular tissue. (Hematoxylin andeosin, 300.) Figure 4. Leukocytoclastic Angiitis in a Skin-Biopsy Specimen
from a Patient with Purpura.
There is extensive karyorrhexis of the vascular and perivascularleukocytes (leukocytoclasia). (Hematoxylin and eosin, 500.) and the vasculitis in Goodpasture's patient was prob-ably not caused by these antibodies.23 By the 1950s, the histologic features of necrotiz- ing vasculitis in venules and other small vessels hadbeen well described, including the conspicuous leu-kocytoclasia, which prompted the etiologically non-specific pathological term "leukocytoclastic angii-tis"24,25 (Fig. 4). The similarity of this pattern ofinjury to the Arthus reaction, as well as an associa-tion between some cases of necrotizing vasculitisand exposure to drugs and foreign proteins, led tothe contention that some if not most necrotizingvasculitides were hypersensitivity diseases.5,6,12,18,24-28 The ability to identify pathogenic antibodies in tissue and serum by immunofluorescence microsco- Figure 3. Purpura on the Lower Leg of a Patient Found to Have
py led to discoveries that allowed the categorization Leukocytoclastic Angiitis in a Skin-Biopsy Specimen.
of certain small-vessel vasculitides — for example, There are also several darker areas of necrosis. (Photograph recognition of antibodies to glomerular basement kindly provided by Robert A. Briggaman.) membrane as the cause of some cases of pulmonary–renal vasculitic syndrome29-31; the identification of asubgroup of patients with purpura, arthralgias, andglomerulonephritis caused by the deposition ofcryoglobulin32; the identification of vascular IgA de- Downloaded from www.nejm.org at HELLENIC SOCIETY OF ENDOCRINOL on December 23, 2004 . Copyright 1997 Massachusetts Medical Society. All rights reserved. posits as a marker for Henoch–Schönlein purpura33; patients with typical Wegener's granulomatosis or and the detection of pathogen-derived antigens and microscopic polyangiitis have negative assays for cognate antibodies in the vessels of patients with ANCA; thus, ANCA negativity does not completely small-vessel vasculitis that is associated with infections rule out these diseases. In addition, the specificity of such as hepatitis B.34 These and other observations ANCA positivity is not absolute; thus, a positive re- supported the concept of an immune-complex patho- sult is not diagnostic for an ANCA-associated vascu- genesis for at least some forms of small-vessel vasculi- litis, especially if the result of an indirect immuno- tis; however, evaluation of a wide range of vasculitides fluorescence assay has not been confirmed by a more failed to document a high frequency of vascular im- specific immunochemical assay for PR3-ANCA or mune complexes in many important categories, in- cluding Wegener's granulomatosis, microscopic poly- The addition of serologic tests for ANCA to the angiitis, and Churg–Strauss syndrome.21,35,36 This diagnostic armamentarium provided a positive mark- absence or paucity of vascular immune deposits dis- er for certain types of pauci-immune small-vessel vas- tinguished the "pauci-immune" vasculitides from the culitis. Testing for ANCA, along with other immu- immune-complex vasculitides, but categorization nopathologic markers such as vascular IgA deposits based on negative data was unsettling. This problem and serum cryoglobulins, facilitates the diagnostic was resolved, in part, with the discovery of antineu- categorization of small-vessel vasculitis (Table 3).
trophil cytoplasmic autoantibodies (ANCA).
DIAGNOSIS AND TREATMENT OF SMALL-
In 1982, Davies and his associates reported hav- The first step in diagnosis is to recognize that ing detected antibodies that reacted with neutrophil small-vessel vasculitis is present, and the second, cytoplasm in eight patients with pauci-immune nec- more difficult step is to determine the specific type rotizing glomerulonephritis and small-vessel vasculi- of the disease. The signs and symptoms of small-ves- tis.37 Two years later, Hall et al. confirmed this sel vasculitis are extremely varied, and many are observation in four patients with small-vessel vascu- shared by all small-vessel vasculitides. Diagnosis re- litis.38 These first two articles on ANCA did not re- quires assessment of both the presence of prerequi- ceive much attention, but a 1985 article by van der site features and, just as important, the absence of Woude and his collaborators generated substantial incompatible features (Table 3). Accurate diagnosis interest by suggesting that detection of ANCA was is important, because the prognosis and appropriate a useful diagnostic and prognostic marker for Weg- treatment are different for different types of small- ener's granulomatosis.39 Subsequent studies revealed vessel vasculitis.
that ANCA are closely associated with three majorcategories of small-vessel vasculitis: Wegener's gran- General Signs and Symptoms of Small-Vessel Vasculitis
ulomatosis, microscopic polyangiitis, and Churg– Constitutional signs and symptoms, such as fever, Strauss syndrome40-42 — the same three diseases that myalgias, arthralgias, and malaise, often accompany Godman and Churg had concluded were related in small-vessel vasculitis. Many patients describe a "flu- their 1954 publication.7 like" syndrome early in the course of their disease.
ANCA are specific for antigens in neutrophil Arthralgias are migratory and affect both small and granules and monocyte lysosomes. They can be de- large joints, with evidence of synovitis in 10 to 20 tected with indirect immunofluorescence microsco- percent of patients. Vessels in the skin, respiratory py by using alcohol-fixed neutrophils as substrate.
tract, kidneys, gut, peripheral nerves, and skeletal This produces two major staining patterns: cytoplas- muscle are often involved, but the frequencies vary mic ANCA and perinuclear ANCA. Specific immu- among categories of small-vessel vasculitis (Table 4).
nochemical assays demonstrate two major antigen For example, Wegener's granulomatosis and micro- specificities in patients with vasculitis: antimyeloper- scopic polyangiitis are more likely to cause pulmo- oxidase (MPO-ANCA)43 and antiproteinase 3 (PR3- nary–renal syndrome, whereas cryoglobulinemic vas- ANCA).44-47 In patients with vasculitis, approximate- culitis and Henoch–Schönlein purpura are more ly 90 percent of cytoplasmic ANCA are PR3-ANCA likely to cause dermal–renal syndrome.
and approximately 90 percent of perinuclear ANCA The most common cutaneous lesion is leukocyto- are MPO-ANCA. Either ANCA specificity may oc- clastic angiitis (Fig. 4), which typically causes pur- cur in a patient with any type of ANCA-associated pura, sometimes with slight focal necrosis and ulcer- small-vessel vasculitis; however, most patients with ation, that preferentially affects the lower extremities Wegener's granulomatosis have PR3-ANCA (cyto- (Fig. 3).27,66 Necrotizing arteritis in small dermal and plasmic ANCA), whereas most patients with micro- subcutaneous arteries causes erythematous tender scopic polyangiitis or Churg–Strauss syndrome have nodules, focal necrosis, ulceration, and livedo retic- MPO-ANCA (perinuclear ANCA).41-43 It is very im- ularis. Patients with Wegener's granulomatosis and portant to realize that approximately 10 percent of Churg–Strauss syndrome may also have cutaneous  November 20, 1997 Downloaded from www.nejm.org at HELLENIC SOCIETY OF ENDOCRINOL on December 23, 2004 . Copyright 1997 Massachusetts Medical Society. All rights reserved. TABLE 3. DIFFERENTIAL DIAGNOSTIC FEATURES OF SEVERAL FORMS
OF SMALL-VESSEL VASCULITIS.
Signs and symptoms of small-vessel IgA-dominant immune deposits Cryoglobulins in blood and vessels Necrotizing granulomas Asthma and eosinophilia *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 arthral-gias. Each is distinguished by the presence and, just as important, the absence of certain specific fea-tures. ANCA denotes antineutrophil cytoplasmic autoantibodies.
TABLE 4. APPROXIMATE FREQUENCY OF ORGAN-SYSTEM MANIFESTATIONS IN SEVERAL
FORMS OF SMALL-VESSEL VASCULITIS.* ORGAN SYSTEM
Ear, nose, and throat *Approximate frequencies are estimated from data in previous reports.49-65 nodules caused by granulomatous inflammation.
blood. Ischemic ulceration in the gut causes not Urticaria can be a manifestation of small-vessel vas- only abdominal pain but also blood in the stool. In- culitis, especially when there is immune-complex tussusception and perforation of the gut and pancre- deposition with extensive complement activation.
atitis are serious complications.
Unlike nonvasculitic allergic urticaria, vasculitic ur- Respiratory tract disease is frequent in ANCA- ticaria lasts for more than a day, may evolve into pur- associated small-vessel vasculitis and in Goodpas- puric lesions, and may be accompanied by hypocom- ture's syndrome but is rare in immune-complex small- vessel vasculitis, such as Henoch–Schönlein purpura Peripheral neuropathy, especially mononeuritis and cryoglobulinemic vasculitis (Table 4). Inflamma- multiplex, is the most common neurologic manifes- tion of the upper respiratory tract is frequent in tation.68,69 This is caused by inflammation of small small-vessel vasculitis associated with ANCA. Pulmo- epineural arteries and arterioles, resulting in neural nary manifestations range from fleeting focal infil- ischemia. Both sensory and motor fibers are in- trates to massive pulmonary hemorrhage and he- volved. Central nervous system disease usually re- moptysis caused by hemorrhagic alveolar capillaritis sults from involvement of the meningeal vessel.
(Fig. 5), the most life-threatening feature of small- Necrotizing inflammation in small arteries, arteri- vessel vasculitis. Granulomatous pulmonary inflam- oles, and venules in skeletal muscle and viscera caus- mation of Wegener's granulomatosis and Churg– es pain and elevations of tissue enzymes in the Strauss syndrome cause nodular and occasionally Downloaded from www.nejm.org at HELLENIC SOCIETY OF ENDOCRINOL on December 23, 2004 . Copyright 1997 Massachusetts Medical Society. All rights reserved.

itive and negative. Laboratory assessment for ANCA,antinuclear antibodies, complement, cryoglobulins,fecal blood, antibodies to hepatitis B and C, rheu-matoid factor, azotemia, hematuria, and proteinuriais useful. Chest and sinus radiographs and computedtomographic scans may reveal occult respiratory tractdisease. Nerve-conduction studies can document pe-ripheral neuropathy. Evidence of conditions that areknown to cause vasculitis, such as drug hypersensi-tivity, infection, rheumatoid arthritis, systemic lupuserythematosus, cancer, and inflammatory bowel dis-ease, should be sought. Pathological examination ofinvolved tissue, such as skin, muscle, nerve, lung, orkidney, may document small-vessel vasculitis. Immu-nohistologic evaluation may yield more specific in- Figure 5. Pulmonary Hemorrhagic Alveolar Capillaritis in a Pa-
tient with ANCA-Associated Small-Vessel Vasculitis in Whom
formation, such as the presence of IgA-dominant Severe Hemoptysis Developed. vascular immune deposits indicative of Henoch– There are numerous neutrophils in the alveolar septa and ex- Schönlein purpura, or IgM and IgG immune com- tensive hemorrhage into the alveolar spaces. (Hematoxylin and plexes that are consistent with cryoglobulinemic vas- cavitating radiographic densities. The acute inflam- Small-vessel vasculitis may be confined to the skin.
matory and necrotizing pulmonary lesions evolve The characteristic acute lesion is leukocytoclastic an- into chronic nonspecific sclerotic lesions, such as in- giitis involving dermal postcapillary venules (Fig. 4).
terstitial fibrosis, organized intraalveolar fibrosis, and This lesion is histologically identical to dermal le- bronchiolitis obliterans.70 sions occurring as a component of systemic small-vessel vasculitis.66 Therefore, the onus is on the phy- sician to rule out systemic disease.
There are no agreed-upon diagnostic criteria for Drug-induced vasculitis should be considered in the various categories of small-vessel vasculitis. In any patient with small-vessel vasculitis and will be 1990 the American College of Rheumatology pub- substantiated most often in patients with vasculitis lished an approach to classifying vasculitides for clin- confined to the skin. Drugs cause approximately 10 ical trials.71 These criteria were not designed for di- percent of vasculitic skin lesions.72,73 Drug-induced agnosis, although they are being widely used for this vasculitis usually develops within 7 to 21 days after purpose. They are not adequate for differentiating treatment begins.
among the various clinicopathological expressions of Drugs that have been implicated include penicil- small-vessel vasculitis. For example, a 20-year-old pa- lins, aminopenicillins, sulfonamides, allopurinol, thi- tient with small-vessel vasculitis who has purpura, leu- azides, pyrazolones, retinoids, quinolones, hydanto- kocytoclastic angiitis, myalgias, mononeuritis mul- ins, and propylthiouracil.74 Some drugs, such as tiplex, and nephritis would simultaneously fulfill the penicillins, cause vasculitis by conjugating to serum College's criteria for three different categories of vas- proteins and mediating immune-complex vasculitis culitis: hypersensitivity vasculitis, Henoch–Schönlein that is similar to serum-sickness vasculitis.75 Other purpura, and polyarteritis nodosa. The system does vasculitis-inducing drugs that cause immune-com- not have a category called "microscopic polyangii- plex formation are foreign proteins, such as streptoki- tis" or "microscopic polyarteritis"; thus, most cases nase, cytokines, and monoclonal antibodies.76 In ad- of ANCA-positive microscopic polyangiitis would be dition, such drugs as propylthiouracil and hydralazine called hypersensitivity angiitis, according to the Col- appear to cause vasculitis by inducing ANCA,77-80 al- lege's system.
though a cause-and-effect relation has not been In 1994 the Chapel Hill International Consensus Conference proposed names and definitions for se- Most patients with cutaneous leukocytoclastic an- lected categories of vasculitis1; however, no diagnos- giitis have a single episode that resolves spontaneous- tic criteria were suggested. ly within several weeks or a few months.81 Approx- The following discussion presents a number of ob- imately 10 percent will have recurrent disease at servations that can be made to help determine which intervals of months to years. In the absence of system- definition of vasculitis is met in a given patient, and ic disease, management is usually symptomatic. Drugs thus the diagnosis. This requires the knowledgeable that could cause the disease should be stopped. An- integration of clinical and laboratory data, both pos- tihistamines and nonsteroidal antiinflammatory drugs  November 20, 1997 Downloaded from www.nejm.org at HELLENIC SOCIETY OF ENDOCRINOL on December 23, 2004 . Copyright 1997 Massachusetts Medical Society. All rights reserved. help alleviate cutaneous discomfort and reduce asso- tivity are typically detectable in serum. Most patients ciated arthralgias and myalgias.81 Severe cutaneous have an associated infection with hepatitis C virus, disease may warrant oral corticosteroid therapy.81 If which is thought to be etiologic.53,86,87 A very dis- signs or symptoms of systemic vasculitis develop, tinctive and diagnostically useful complement ab- treatment should be based on the type of systemic normality is the presence of very low levels of early vasculitis the patient has.
components (especially C4) with normal or slightlylow C3 levels.53,87 As with Henoch–Schönlein pur- pura, the main cause of morbidity is progressive glo- Henoch–Schönlein purpura is the most common merulonephritis, which most often has a type I systemic vasculitis in children.82 It is characterized by vascular deposition of IgA-dominant immune com- Mild disease, such as slight purpura and arthral- plexes,1,33 and preferentially involves venules, capil- gias, usually is adequately treated with nonsteroidal laries, and arterioles (Fig. 1).
antiinflammatory drugs alone. Serious visceral in- Henoch–Schönlein purpura is most frequent in volvement, such as in glomerulonephritis, usually re- childhood, with a peak incidence at five years quires treatment with corticosteroids combined with old.49,50,82 The disease often begins after an upper a cytotoxic drug (e.g., cyclophosphamide), which respiratory tract infection. Purpura, arthralgias, and improves the outcome of glomerulonephritis and colicky abdominal pain are the most frequent mani- also ameliorates purpura, arthralgias, and other vas- festations (Table 4). Approximately half the patients culitic symptoms.53,87 Plasmapheresis has been used, have hematuria and proteinuria, but only 10 to 20 but its value is unproved. Recently, interferon alfa percent have renal insufficiency. Rapidly progressive has been touted as a beneficial adjuvant in patients renal failure is rare. Pulmonary disease and peripher- with cryoglobulinemic vasculitis associated with hep- al neuropathy are uncommon.83,84 atitis C virus infection,53,87 but larger controlled tri- The overall prognosis is excellent; thus, supportive als are required before the value of this approach can care suffices for most patients. The main long-term be conclusively determined.
morbidity is from progressive renal disease. End-stagerenal disease develops in approximately 5 percent of patients.51 Treatment for aggressive Henoch–Schön- ANCA-associated small-vessel vasculitis is the most lein purpura glomerulonephritis is controversial.
common primary systemic small-vessel vasculitis in Corticosteroids, immunosuppressive drugs, and an- adults and includes three major categories: Wege- ticoagulant therapy have been tried with contradic- ner's granulomatosis, microscopic polyangiitis, and tory results, but a recent study suggests that com- Churg–Strauss syndrome. These histologically iden- bined therapy with corticosteroids and azathioprine tical small-vessel vasculitides preferentially involve may be beneficial.85 venules, capillaries, and arterioles, and may also in- Although the term "Henoch–Schönlein purpura" volve arteries and veins (Fig. 1).88 Wegener's granu- was originally used to designate a syndrome that can lomatosis is differentiated from the other two by the be characterized by many different types of small- presence of necrotizing granulomatous inflamma- vessel vasculitis (i.e., combinations of purpura, ab- tion in the absence of asthma; Churg–Strauss syn- dominal pain, and nephritis), the use of the term drome is differentiated by the presence of asthma, should now be restricted to the specific clinicopath- eosinophilia, and necrotizing granulomatous inflam- ological entity caused by vascular IgA-dominant im- mation; and microscopic polyangiitis is differentiat- mune complexes.1 The misuse of this term for pa- ed by the absence of granulomatous inflammation tients with ANCA-associated small-vessel vasculitis and asthma1 (Tables 2 and 3). Rapid diagnosis of who present with purpura, abdominal pain, and ne- ANCA-associated small-vessel vasculitis is critically phritis is particularly problematic, because these pa- important, because life-threatening injury to organs tients do not have a good prognosis and should be often develops quickly and is mitigated dramatically treated quickly with immunosuppressive therapy, as by immunosuppressive treatment.
will be discussed later in this review.
ANCA-associated small-vessel vasculitis affects peo- ple of all ages but is most common in older adults in their 50s and 60s, and it affects men and women Cryoglobulinemic vasculitis is caused by the local- equally.54,89 In the United States the disease is more ization of mixed cryoglobulins in vessel walls, which frequent among whites than blacks.89 Its incidence is incites acute inflammation. Venules, capillaries, and approximately 2 in 100,000 people in the United arterioles are preferentially involved (Fig. 1).
Kingdom90 and approximately 1 in 100,000 in Swe- Patients with this disease have an average age of den.54 Although Wegener's granulomatosis, micro- approximately 50 years. The most frequent manifes- scopic polyangiitis, and Churg–Strauss syndrome are tations are purpura, arthralgias, and nephritis (Table categorized as ANCA-associated small-vessel vasculi- 4).52 Mixed cryoglobulins and rheumatoid-factor ac- tis, it is important to realize that a minority of pa- Downloaded from www.nejm.org at HELLENIC SOCIETY OF ENDOCRINOL on December 23, 2004 . Copyright 1997 Massachusetts Medical Society. All rights reserved. tients with typical clinical and pathological features may be adequate for ameliorating indolent limited of these diseases are ANCA-negative.
disease but are inadequate for patients with general- Over 90 percent of ized disease.57 In patients with Wegener's granuloma- patients with Wegener's granulomatosis have upper tosis or microscopic polyangiitis who have aggressive or lower respiratory tract disease or both.55-57 Mani- disease, such as acute nephritis or pulmonary hem- festations of upper respiratory tract disease include orrhage, we recommend induction with intravenous sinus pain, purulent sinus drainage, nasal mucosal methylprednisolone at a dose of 7 mg per kilogram ulceration with epistaxis, and otitis media. More se- of body weight per day for three days, followed by rious complications include necrosis of the nasal tapering doses of prednisone. This treatment is com- septum with perforation or saddle-nose deformation bined with oral cyclophosphamide at 2 mg per kilo- and injury to the facial nerve by otitis media result- gram per day, or intravenous cyclophosphamide at ing in facial paralysis. Tracheal inflammation and 0.5 g per square meter of body-surface area per sclerosis, often in the subglottic region, cause stridor month, adjusted upward to 1 g per square meter on and may lead to dangerous airway stenosis, which the basis of the patient's leukocyte count.58 Com- occurs in approximately 15 percent of adults and al- bined therapy with corticosteroids and cyclophos- most 50 percent of children with this disease.57 A phamide induces improvement in over 90 percent of minority of patients initially have indolent or aggres- patients with Wegener's granulomatosis and com- sive upper respiratory tract disease alone, but most plete remission in 75 percent.59 A common strategy also have pulmonary disease.
is to discontinue corticosteroids after remission is Necrotizing granulomatous pulmonary inflamma- achieved, usually within 3 to 5 months, and to con- tion produces nodular radiographic densities, where- tinue cyclophosphamide for 6 to 12 months. An al- as alveolar capillaritis causes pulmonary hemorrhage ternative strategy for maintaining remission is con- with less fixed and more irregular infiltrates. Massive version from cyclophosphamide to azathioprine once pulmonary hemorrhage caused by capillaritis is the remission is achieved.90 Approximately 50 percent of most life-threatening manifestation of ANCA-associ- patients with Wegener's granulomatosis have at least ated small-vessel vasculitis and warrants rapid insti- one relapse within five years.59 The best treatment tution of aggressive immunosuppressive therapy.
for reversing relapses is controversial but usually in- Approximately 80 percent of patients with Wege- volves reinstituting treatment similar to the induc- ner's granulomatosis will go on to have glomerulone- phritis, although less than 20 percent have nephritis Both corticosteroids and cyclophosphamide pre- at the time of presentation.57 The glomerulonephri- dispose patients to life-threatening infections, and tis is characterized by focal necrosis, crescent forma- cyclophosphamide causes hemorrhagic cystitis, ovar- tion, and the absence or paucity of immunoglobulin ian and testicular failure, and cancer. For example, deposits.35,88 An identical pauci-immune necrotizing Talar-Williams et al. have estimated the incidence of and crescentic glomerulonephritis occurs in patients bladder cancer after the first exposure to cyclophos- with microscopic polyangiitis and Churg–Strauss phamide to be 5 percent 10 years after treatment syndrome, and also occurs as a disease limited to the and 16 percent after 15 years.95 The risks and bene- kidneys. Other manifestations of the disease include fits of aggressive immunosuppression must be as- ocular inflammation, cutaneous purpura and nod- sessed in each patient, and the treatment tailored ac- ules, peripheral neuropathy, arthritis, and diverse ab- cordingly. There should be vigilance for and prompt dominal visceral involvement (Table 4).55-57 treatment of complications arising from treatment.
The classic triad of respiratory tract granuloma- Less-toxic therapy may be sufficient in patients tous inflammation, systemic small-vessel vasculitis, with localized or mild Wegener's granulomatosis. For and necrotizing glomerulonephritis7 readily suggests example, Sneller et al. achieved remission with low- the diagnosis, but atypical presentations, such as iso- dose methotrexate plus prednisone in 71 percent of lated subglottic stenosis or orbital pseudotumor, patients with Wegener's granulomatosis that was may not. In patients with the latter presentation, a "not immediately life-threatening."96 Methotrexate positive ANCA test is helpful for substantiating a di- also may be useful for maintenance of remission.97 agnosis of Wegener's granulomatosis.91,92 Treatment with methotrexate is limited in patients Treatment of aggressive Wegener's granulomatosis, with renal disease because of increased toxicity.
as well as of microscopic polyangiitis, has three phas- Because relapses are associated with respiratory es: induction of remission, maintenance of remission, tract infections and with chronic nasal carriage of and treatment of relapse.93 After the seminal obser- Staphylococcus aureus,98 the antimicrobial agent tri- vations of Novack and Pearson,94 Fauci and his asso- methoprim–sulfamethoxazole has been evaluated for ciates documented the value of cyclophosphamide in maintenance of remission, with mixed results. Stege- the treatment of Wegener's granulomatosis.55 Cur- man et al.99 concluded that it is useful for maintain- rent induction therapy often uses cyclophosphamide ing remission, but de Groot et al. did not agree.97 combined with corticosteroids. Corticosteroids alone Microscopic polyangiitis  November 20, 1997 Downloaded from www.nejm.org at HELLENIC SOCIETY OF ENDOCRINOL on December 23, 2004 . Copyright 1997 Massachusetts Medical Society. All rights reserved. is characterized by pauci-immune necrotizing small- oids and cyclophosphamide, which induces remis- vessel vasculitis without clinical or pathological evi- sion in approximately 80 percent of patients.58,61 The dence of necrotizing granulomatous inflammation greatest risk factor for a poor renal outcome is a de- (Tables 2 and 3).1 Over 80 percent of patients with lay in treatment until renal insufficiency has devel- microscopic polyangiitis have ANCA, most often oped.63 Relapse occurs in about a third of patients perinuclear ANCA (MPO-ANCA).40-42,54 This helps within two years.54,58,61 Approximately two thirds of distinguish microscopic polyangiitis from ANCA- patients who relapse respond to an immunosuppres- negative small-vessel vasculitis but does not distin- sive regimen similar to the induction therapy.
guish microscopic polyangiitis from other types of Because the treatment of microscopic polyangiitis disease associated with ANCA. Positive ANCA and and Wegener's granulomatosis is essentially the same negative serologic tests for hepatitis B help differen- when there is major organ injury, it is not necessary tiate microscopic polyangiitis from polyarteritis no- to distinguish conclusively between these closely re- lated variants of ANCA-associated small-vessel vas- Pathologically, microscopic polyangiitis may cause culitis before starting treatment. For example, an necrotizing arteritis that is histologically identical to ANCA-positive patient with pulmonary infiltrates, that caused by polyarteritis nodosa. By the approach hemoptysis, and pauci-immune crescentic glomeru- advocated by the Chapel Hill Consensus Confer- lonephritis on renal biopsy may have either micro- ence (Table 2),1 polyarteritis nodosa and microscop- scopic polyangiitis or Wegener's granulomatosis. Re- ic polyangiitis are distinguished pathologically by solving this differential diagnosis should not delay the absence of vasculitis in vessels other than arteries the start of induction therapy with combined corti- in polyarteritis nodosa and the presence of vasculitis costeroids and cyclophosphamide.
in vessels smaller than arteries (i.e., arterioles, venules, Churg–Strauss syn- and capillaries) in microscopic polyangiitis. Accord- drome has three phases: allergic rhinitis and asthma; ing to this definition, the presence of dermal leuko- eosinophilic infiltrative disease, such as eosinophilic cytoclastic venulitis, glomerulonephritis, pulmonary pneumonia or gastroenteritis; and systemic small-ves- alveolar capillaritis, or vasculitis in any vessel smaller sel vasculitis with granulomatous inflammation.62,64,65 than an artery would exclude a diagnosis of polyar- The vasculitic phase usually develops within three teritis nodosa and indicate some form of small-vessel years of the onset of asthma, although it may be de- vasculitis. On the other hand, identification of nec- layed for several decades. Approximately 70 percent rotizing arteritis in a skeletal-muscle biopsy or pe- of patients with this disease have ANCA, usually ripheral-nerve biopsy, for example, indicates some perinuclear ANCA (MPO-ANCA).62 Virtually all pa- form of necrotizing vasculitis but is not diagnostic tients have eosinophilia (more than 10 percent eo- of polyarteritis nodosa, because many other necro- sinophils in the blood).65 tizing vasculitides, such as microscopic polyangiitis, As compared with Wegener's granulomatosis and Wegener's granulomatosis, and Churg–Strauss syn- microscopic polyangiitis, Churg–Strauss syndrome drome, can also affect arteries (Fig. 1).
involves much less frequent and less severe renal dis- Microscopic polyangiitis has the same spectrum of ease, but more frequent neuropathy and cardiac dis- manifestations of small-vessel vasculitis as Wegener's ease.62,65 Coronary arteritis and myocarditis are the granulomatosis but does not include granulomatous principal causes of morbidity and mortality, account- inflammation.54,58,61,62 Approximately 90 percent of ing for approximately 50 percent of deaths, and can patients have glomerulonephritis, which is accompa- be reduced by early treatment.
nied by a variety of other organ involvements (Table High-dose corticosteroid treatment alone is often 4). Microscopic polyangiitis is the most common adequate, although refractory or relapsing disease cause of the pulmonary–renal syndrome.22 may require the addition of a cytotoxic drug — for Microscopic polyangiitis that is causing major or- example, in a regimen similar to that used for Wege- gan damage is treated with a combination of corti- ner's granulomatosis or microscopic polyangiitis.62,64 costeroids and cytotoxic agents. Our treatment ap-proach is the same as that for aggressive Wegener's granulomatosis, which was described earlier in this Treatment of a patient with small-vessel vasculitis review, and uses intravenous methylprednisolone should include these steps: recognition that small- followed by prednisone combined with intravenous vessel vasculitis is present, determination of as spe- or oral cyclophosphamide.58 Alveolar capillaritis (Fig.
cific a diagnosis as possible, determination of the 5) with pulmonary hemorrhage is the most life-threat- prognosis, and initiation of therapy or referral to an ening complication and should be treated promptly appropriate specialist. In many patients, small-vessel with combined therapy,58,61 and possibly with plas- vasculitis will have a relatively benign, self-limited mapheresis.61 The glomerulonephritis is usually rap- course, especially if disease is limited to the skin; idly progressive if not promptly and appropriately however, for the patients with aggressive disease, treated with a combination of high-dose corticoster- such as generalized ANCA-associated small-vessel Downloaded from www.nejm.org at HELLENIC SOCIETY OF ENDOCRINOL on December 23, 2004 . Copyright 1997 Massachusetts Medical Society. All rights reserved. vasculitis, it is imperative to begin appropriate treat- rotizing or "allergic" angiitis: a study of 38 cases. Medicine (Baltimore) ment quickly. The goal should be neither to over- 1964;43:59-89.
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