InternalMed_Harrison

InternalMed_Harrison. In juvenile-onset SpA, which begins between ages 7 and 16, most commonly in boys (60–80%), an asymmetric, predominantly lower-extremity oligoarthritis and enthesitis without extraarticular features is the typical mode of presentation. The prevalence of B27 in this condition, which has been termed the seronegative enthesopathy and arthropathy (SEA) syndrome, is approximately 80%. Many, but not all, of these patients go on to develop AS in late adolescence or adulthood. Management of undifferentiated SpA is similar to that of the other spondyloarthritides. Response to anti-TNF-α therapy has been documented, and this therapy is indicated in severe, persistent cases not responsive to other treatment. Current pediatric textbooks and journals should be consulted for information on management of juvenile-onset SpA. A relationship between arthritis and IBD was observed in the 1930s. The relationship was further defined by the epidemiologic studies


InternalMed_Harrison

InternalMed_Harrison. A relationship between arthritis and IBD was observed in the 1930s. The relationship was further defined by the epidemiologic studies One or more of the following: disease or ulcerative colitis OR two or more of the following: aSensitivity 79.5%, specificity 83.3% bPeripheral arthritis, usually predominantly lower limb and/or asymmetric. Source: M Rudawaleit et al: Ann Rheum Dis 70:25, 2011. in the 1950s and 1960s and included in the concept of the spondyloarthritides in the 1970s.


InternalMed_Harrison

InternalMed_Harrison. Source: M Rudawaleit et al: Ann Rheum Dis 70:25, 2011. in the 1950s and 1960s and included in the concept of the spondyloarthritides in the 1970s. Both of the common forms of IBD, ulcerative colitis (UC) and Crohn’s disease (CD) (Chap. 351), are associated with SpA. UC and CD both have an estimated prevalence of 0.05–0.1%, and the incidence of each is thought to have increased in recent decades. AS and peripheral arthritis are both associated with UC and CD. Wide variations have been reported in the estimated frequencies of these associations. In recent series, AS was diagnosed in 1–10%, and peripheral arthritis in 10–50% of patients with IBD. Inflammatory back pain and enthesopathy are common, and many patients have sacroiliitis on imaging studies.


InternalMed_Harrison

InternalMed_Harrison. The prevalence of UC or CD in patients with AS is thought to be 5–10%. However, investigation of unselected SpA patients by ileocolonoscopy has revealed that from one-third to two-thirds of patients with AS have subclinical intestinal inflammation that is evident either macroscopically or histologically. These lesions have also been found in patients with undifferentiated SpA or ReA (both enterically and urogenitally acquired).


InternalMed_Harrison

InternalMed_Harrison. Both UC and CD have a tendency to familial aggregation, more so for CD. HLA associations have been weak and inconsistent. HLA-B27 is found in up to 70% of patients with IBD and AS, but in ≤15% of patients with IBD and peripheral arthritis or IBD alone. Three alleles of the NOD2/CARD15 gene on chromosome 16 have been found in approximately one-half of patients with CD. These alleles are not associated with the spondyloarthritides per se. However, they are found significantly more often in (1) CD patients with sacroiliitis than in those without sacroiliitis, and (2) SpA patients with chronic inflammatory gut lesions than in those with normal gut histology. These associations are independent of HLA-B27. In addition to NOD2, over 100 other genes have been found to be associated with CD, UC, or both. Around 20 of these are also associated with AS.


InternalMed_Harrison

InternalMed_Harrison. Available data for IBD-associated peripheral arthritis suggest a synovial histology similar to other spondyloarthritides. Association with arthropathydoesnotaffecttheguthistologyofUCorCD(Chap. 351). The subclinical inflammatory lesions in the colon and distal ileum associated with SpA have been classified as either acute or chronic. The former resemble acute bacterial enteritis, with largely intact architecture and neutrophilic infiltration in the lamina propria. The latter resemble the lesionsof CD,withdistortionof villi andcrypts,aphthoid ulceration, and mononuclear cell infiltration in the lamina propria.


InternalMed_Harrison

InternalMed_Harrison. Both IBD and SpA are immune-mediated, but the specific pathogenic mechanisms are poorly understood, and the connection between the two is obscure. The shared genetics evidently reflects shared pathogenic mechanisms. A number of rodent models showing various immune perturbations manifest both IBD and arthritis. Several lines of evidence indicate trafficking of leukocytes between the gut and the joint. Mucosal leukocytes from IBD patients have been shown to bind avidly to synovial vasculature through several different adhesion molecules. Macrophages expressing CD163 are prominent in the inflammatory lesions of both gut and synovium in the spondyloarthritides.


InternalMed_Harrison

InternalMed_Harrison. AS associated with IBD is clinically indistinguishable from idiopathic AS. It runs a course independent of the bowel disease, and in some patients, it precedes the onset of IBD, sometimes by many years. Peripheral arthritis may also begin before onset of overt bowel disease. The spectrum of peripheral arthritis includes acute self-limited attacks of oligoarthritis that often coincide with relapses of IBD, and more chronic and symmetric polyarticular arthritis that runs a course independent of IBD activity. The patterns of joint involvement are similar in UC and CD. In general, erosions and deformities are infrequent in IBD-associated peripheral arthritis, and joint surgery is infrequently required.IsolateddestructivehiparthritisisararecomplicationofCD, apparently distinct from osteonecrosis and septic arthritis. Dactylitis and enthesopathy are occasionally found. In addition to the ∼20% of IBD patients with SpA, a comparable percentage have arthralgias or fibromyalgia symptoms.


InternalMed_Harrison

InternalMed_Harrison. Other extraintestinal manifestations of IBD are seen in addition to arthropathy, including uveitis, pyoderma gangrenosum, erythema nodosum, and finger clubbing, all somewhat more commonly in CD than UC. The uveitis shares the features described above for PsAassociated uveitis. Laboratory findings reflect the inflammatory and metabolic manifestations of IBD. Joint fluid is usually at least mildly inflammatory. Of patients with AS and IBD,30–70% carry theHLA-B27gene, compared with >85% of patients with AS alone and 50–70% of those with AS and psoriasis. Hence, definite or probable AS in a B27-negative individual in the absence of psoriasis should prompt a search for occult IBD. Radiographic changes in the axial skeleton are the same as in uncomplicated AS. Erosions are uncommon in peripheral arthritis but may occur, particularly in the metatarsophalangeal joints. Isolated destructive hip disease has been described.


InternalMed_Harrison

InternalMed_Harrison. Diarrhea and arthritis are both common conditions that can coexist for a variety of reasons. When etiopathogenically related, ReA and IBD-associated arthritis are the most common causes. Rare causes include celiac disease, blind loop syndromes, and Whipple’s disease. In most cases, diagnosis depends on investigation of the bowel disease.


InternalMed_Harrison

InternalMed_Harrison. Treatment of CD has been improved by therapy with anti-TNF agents. Infliximab, adalimumab, and certolizumab pegol are effective for induction and maintenance of clinical remission in CD, and infliximab has been shown to be effective in fistulizing CD. IBD-associated arthritis also responds to these agents. Other treatment for IBD, including sulfasalazine and related drugs, systemic glucocorticoids, and immunosuppressive drugs, is also usually of benefit for associated peripheral arthritis. NSAIDs are generally helpful and well tolerated, but they can precipitate flares of IBD. As noted above for psoriasis, rare cases of IBD, either CD or UC, have apparently been precipitated by anti-TNF therapy, usually etanercept, given for any of several rheumatic diseases.


InternalMed_Harrison

InternalMed_Harrison. The syndrome of synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) is characterized by a variety of skin and musculoskeletal manifestations. Dermatologic manifestations include palmoplantar pustulosis, acne conglobata, acne fulminans, and hidradenitis suppurativa. The main musculoskeletal findings are sternoclavicular and spinal hyperostosis, chronic recurrent foci of sterile osteomyelitis, and axial or peripheral arthritis. Cases with one or a few manifestations are probably the rule. The ESR is usually elevated, sometimes dramatically. In some cases, bacteria, most often Propionibacterium acnes, have been cultured from bone biopsy specimens and occasionally othersites. IBD was coexistentin 8%of patients in onelarge series. B27 is not associated. Either bone scan or computed tomography scan is helpful diagnostically. An MRI report described characteristic vertebral body corner cortical erosions in 12 of 12 patients. High-dose NSAIDsmay provide relieffrom bone pain. A


InternalMed_Harrison

InternalMed_Harrison. tomography scan is helpful diagnostically. An MRI report described characteristic vertebral body corner cortical erosions in 12 of 12 patients. High-dose NSAIDsmay provide relieffrom bone pain. A number of uncontrolled series and case reports describe successful therapy with pamidronate or other bisphosphonates. Response to anti-TNF-α therapy has also been observed, although in a few cases this has been associated with a flare of skin manifestations. Successful prolonged antibiotic therapy has also been reported. Recent reports suggest a possible autoinflammatory pathogenesis and successful treatment with the IL-1 receptor antagonist anakinra.


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InternalMed_Harrison. 385 2179 the Vasculitis Syndromes Carol A. Langford, Anthony S. Fauci Vasculitis is a clinicopathologic process characterizedby inflammation of and damage to blood vessels. The vessel lumen is usually compromised, and this is associated with ischemia of the tissues supplied by the involved vessel. A broad and heterogeneous group of syndromes may result from this process, since any type, size, and location of blood vessel may be involved. Vasculitis and its consequences may be the primary or sole manifestation of a disease; alternatively, vasculitis may be a secondary component of another disease. Vasculitis may be confined to a single organ, such as the skin, or it may simultaneously involve several organ systems.


InternalMed_Harrison

InternalMed_Harrison. A major feature of the vasculitic syndromes as a group is the fact that there is a great deal of heterogeneity at the same time as there is considerable overlap among them. This heterogeneity and overlap in addition to a lack of understanding of the pathogenesis of these syndromes have been major impediments to the development of a coherent classification system for these diseases. Table 385-1 lists the major vasculitis syndromes. The distinguishing and overlapping features of these syndromes are discussed below.


InternalMed_Harrison

InternalMed_Harrison. Generally, most of the vasculitic syndromes are assumed to be mediated at least in part by immunopathogenic mechanisms that occur in response to certain antigenic stimuli. However, evidence supporting this hypothesis is for the most part indirect and may reflect epiphenomena as opposed to true causality. Furthermore, it is unknown why some individuals might develop vasculitis in response to certain antigenic stimuli, whereas others do not. It is likely that a number of factors are involved in the ultimate expression of a vasculitic syndrome. These include the genetic predisposition, environmental exposures, and the regulatory mechanisms associated with immune response to certain antigens. Although immune complex formation, antineutrophil cytoplasmic antibodies (ANCA), and pathogenic T lymphocyte responses (Table 385-2) have been among the prominent hypothesized Granulomatosis with polyangiitis Vasculitis associated with probable (Wegener’s) etiology


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InternalMed_Harrison. Granulomatosis with polyangiitis Vasculitis associated with probable (Wegener’s) etiology Eosinophilic granulomatosis with Hepatitis C virus–associated polyangiitis (Churg-Strauss) cryoglobulinemic vasculitis Polyarteritis nodosa Vasculitis associated with systemic Isolated aortitis Source: Adapted from JC Jennette et al: Arthritis Rheum 65:1, 2013. The Vasculitis Syndromes Production of antineutrophilic cytoplasmic antibodies Granulomatosis with polyangiitis (Wegener’s) Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) Granulomatosis with polyangiitis (Wegener’s) Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) Source: Adapted from MC Sneller, AS Fauci: Med Clin North Am 81:221, 1997. mechanisms, it is likely that the pathogenesis of individual forms of vasculitis is complex and varied.


InternalMed_Harrison

InternalMed_Harrison. Deposition of immune complexes was the first and most widely accepted pathogenic mechanismof vasculitis.However, the causal role of immune complexes has not been clearly established in most of the vasculitic syndromes. Circulating immune complexes need not result in deposition of the complexes in blood vessels with ensuing vasculitis, and many patients with active vasculitis do not have demonstrable circulating or deposited immune complexes. The actual antigen contained in the immunecomplexhas only rarely been identifiedin vasculitic syndromes. In this regard, hepatitis Bantigenhas been identified inboth the circulating and deposited immune complexes in a subset of patients who have features of a systemic vasculitis, most notably in polyarteritis nodosa (see “Polyarteritis Nodosa”). Cryoglobulinemic vasculitis is strongly associated with hepatitis C virus infection; hepatitis C virions and hepatitis C virus antigen-antibody complexes have been identified in the cryoprecipitates of


InternalMed_Harrison

InternalMed_Harrison. vasculitis is strongly associated with hepatitis C virus infection; hepatitis C virions and hepatitis C virus antigen-antibody complexes have been identified in the cryoprecipitates of these patients (see “Cryoglobulinemic Vasculitis”).


InternalMed_Harrison

InternalMed_Harrison. The mechanisms of tissue damage in immune complex–mediated vasculitis resemble those described for serum sickness. In this model, antigen-antibody complexes are formed in antigen excess and are deposited in vessel walls whose permeability has been increased by vasoactive amines such as histamine, bradykinin, and leukotrienes released from platelets or from mast cells as a result of IgE-triggered mechanisms. The deposition of complexes results in activation of complement components, particularly C5a, which is strongly chemotactic for neutrophils. These cells then infiltrate the vessel wall, phagocytose the immune complexes, and release their intracytoplasmic enzymes, which damage the vessel wall. As the process becomes subacute or chronic, mononuclear cells infiltrate the vessel wall. The common denominator of the resulting syndrome is compromise of the vessel lumen with ischemic changes in the tissues supplied by the involved vessel. Several variables may explain why only certain


InternalMed_Harrison

InternalMed_Harrison. The common denominator of the resulting syndrome is compromise of the vessel lumen with ischemic changes in the tissues supplied by the involved vessel. Several variables may explain why only certain types of immune complexes cause vasculitis and why only certain vessels are affected in individual patients. These include the ability of the reticuloendothelial system to clear circulating complexes from the blood, the size and physicochemical properties of immune complexes, the relative degree of turbulence of blood flow, the intravascular hydrostatic pressure in differentvessels,andthepreexistingintegrityofthevesselendothelium.


InternalMed_Harrison

InternalMed_Harrison. ANCA are antibodies directed against certain proteins in the cytoplasmic granules of neutrophils and monocytes. These autoantibodies are present in a high percentage of patients with active granulomatosis with polyangiitis (Wegener’s) and microscopic polyangiitis, and in a lower percentage of patients with eosinophilic granulomatosis with polyangiitis (Churg-Strauss). Because these diseases share the presence of ANCA and small-vessel vasculitis, some investigators have come to refer to them collectively as “ANCA-associated vasculitis.” However,asthesediseasespossessuniqueclinicalphenotypesinwhich ANCAmaybeabsent,itremainsouropinionthatgranulomatosiswith polyangiitis (Wegener’s), microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis (Churg-Strauss) should continue to be viewed as separate entities.


InternalMed_Harrison

InternalMed_Harrison. There are two major categories of ANCA based on different targets for the antibodies. The terminology of cytoplasmic ANCA (cANCA) refers to the diffuse, granular cytoplasmic staining pattern observed by immunofluorescence microscopy when serum antibodies bind to indicator neutrophils. Proteinase-3, a 29-kDa neutral serine proteinase present in neutrophil azurophilic granules, is the major cANCA antigen. More than 90% of patients with typical active granulomatosis with polyangiitis (Wegener’s) have detectable antibodies to proteinase-3 (see below). The terminology of perinuclear ANCA (pANCA) refers to the more localized perinuclear or nuclear staining pattern of the indicator neutrophils. The major target for pANCA is the enzyme myeloperoxidase; other targets that can produce a pANCA pattern of staining include elastase, cathepsin G, lactoferrin, lysozyme, and bactericidal/permeability-increasing protein. However, only antibodies to myeloperoxidase have been convincingly associated


InternalMed_Harrison

InternalMed_Harrison. of staining include elastase, cathepsin G, lactoferrin, lysozyme, and bactericidal/permeability-increasing protein. However, only antibodies to myeloperoxidase have been convincingly associated with vasculitis. Antimyeloperoxidase antibodies have been reported to occur in variable percentages of patients with microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis (Churg-Strauss), isolated necrotizing crescentic glomerulonephritis, and granulomatosis with polyangiitis (Wegener’s) (see below). A pANCA pattern of staining that is not due to antimyeloperoxidase antibodies has been associated with nonvasculitic entities such as rheumatic and nonrheumatic autoimmune diseases, inflammatory bowel disease, certain drugs, and infections such as endocarditis and bacterial airway infections in patients with cystic fibrosis.


InternalMed_Harrison

InternalMed_Harrison. It is unclear why patients with these vasculitis syndromes develop antibodies to myeloperoxidase or proteinase-3 or what role these antibodies play in disease pathogenesis. There are a number of in vitro observations that suggest possible mechanisms whereby these antibodies can contribute to the pathogenesis of the vasculitis syndromes. Proteinase-3 and myeloperoxidase reside in the azurophilic granules and lysosomes of resting neutrophils and monocytes, where they are apparently inaccessible to serum antibodies. However, when neutrophils or monocytes are primed by tumor necrosis factor α (TNF-α) or interleukin 1 (IL-1), proteinase-3 and myeloperoxidase translocate to the cell membrane, where they can interact with extracellular ANCA. The neutrophils then degranulate and produce reactive oxygen species that can cause tissue damage. Furthermore, ANCA-activated neutrophils can adhere to and kill endothelial cells in vitro. Activation of neutrophils and monocytes by ANCA also induces the


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InternalMed_Harrison. species that can cause tissue damage. Furthermore, ANCA-activated neutrophils can adhere to and kill endothelial cells in vitro. Activation of neutrophils and monocytes by ANCA also induces the release of proinflammatory cytokines such as IL-1 and IL-8. Adoptive transfer experiments in genetically engineered mice provide further evidence for a direct pathogenic role of ANCA in vivo. In contradiction, however, a number of clinical and laboratory observations argue against a primary pathogenic role for ANCA. Patients may have active granulomatosis with polyangiitis (Wegener’s) in the absence of ANCA; the absolute height of the antibody titers does not correlate well with disease activity; and patients with granulomatosis with polyangiitis (Wegener’s) in remission may continue to have high antiproteinase-3 (cANCA) titers for years (see below).


InternalMed_Harrison

InternalMed_Harrison. The histopathologic feature of granulomatous vasculitis has provided evidence to support a role of pathogenic T lymphocyte responses and cell-mediated immune injury. Vascular endothelial cells can express HLA class II molecules following activation by cytokines such as interferon (IFN) γ. This allows these cells to participate in immunologic reactions such as interaction with CD4+ T lymphocytes in a manner similar to antigen-presenting macrophages. Endothelial cells can secrete IL-1, which may activate T lymphocytes and initiate or propagate in situ immunologic processes within the blood vessel. In addition, IL-1 and TNF-α are potent inducers of endothelial-leukocyte adhesion molecule 1 (ELAM-1) and vascular cell adhesion molecule 1 (VCAM-1), which may enhance the adhesion of leukocytes to endothelial cells in the blood vessel wall. APPROACH TO THE PATIENT: general principles of Diagnosis


InternalMed_Harrison

InternalMed_Harrison. The diagnosis of vasculitis is often considered in any patient with an unexplained systemic illness. However, there are certain clinical abnormalities that when present alone or in combination should suggest a diagnosis of vasculitis. These include palpable purpura, pulmonary infiltrates and microscopic hematuria, chronic inflammatory sinusitis, mononeuritis multiplex, unexplained ischemic events,andglomerulonephritiswithevidenceofmultisystemdisease. A number of nonvasculitic diseases may also produce some or all of these abnormalities. Thus, the first step in the workup of a patient with suspected vasculitis is to exclude other diseases that produce clinical manifestations that can mimic vasculitis (Table 385-3). It is particularly important to exclude infectious diseases with features that overlap those of vasculitis, especially if the patient’s clinical condition is deteriorating rapidly and empirical immunosuppressive treatment is being contemplated.


InternalMed_Harrison

InternalMed_Harrison. Once diseases that mimic vasculitis have been excluded, the workup should follow a series of progressive steps that establish the diagnosis of vasculitis and determine, where possible, the category of the vasculitis syndrome (Fig. 385-1). This approach is of considerable importance since several of the vasculitis syndromes requireaggressivetherapywithglucocorticoidsandotherimmunosuppressive agents, whereas other syndromes usually resolve spontaneously and require symptomatic treatment only. The definitive


InternalMed_Harrison

InternalMed_Harrison. Properly categorize to a specific vasculitis syndrome Determine pattern and extent of disease Presentation of patient with suspected vasculitis Clinical findings Laboratory workup Establish diagnosis Biopsy Angiogram where appropriate Look for offending antigen Look for underlying disease Characteristic syndrome (i.e., granulomatosis with polyangiitis [Wegener’s] PAN, Takayasu arteritis) Treat vasculitis Remove antigen Syndrome resolves Treat underlying disease No further action Treat vasculitis Yes No Yes No Yes No FIGUrE 385-1 Algorithm for the approach to a patient with suspected diagnosis of vasculitis. PAN, polyarteritis nodosa.


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InternalMed_Harrison. FIGUrE 385-1 Algorithm for the approach to a patient with suspected diagnosis of vasculitis. PAN, polyarteritis nodosa. diagnosis of vasculitis is usually made based on biopsy of involved tissue. The yield of “blind” biopsies of organs with no subjective or objective evidence of involvement is very low and should be avoided. When syndromes such as polyarteritis nodosa, Takayasu arteritis, or primary central nervous system (CNS) vasculitis are suspected, arteriogram of organs with suspected involvement should be performed.


InternalMed_Harrison

InternalMed_Harrison. GENEraL PrINCIPLES OF TrEaTMENT Once a diagnosis of vasculitis has been established, a decision regarding therapeutic strategy must be made (Fig. 385-1). If an offending antigen that precipitates the vasculitis is recognized, the antigen should be removed where possible. If the vasculitis is associated with an underlying disease such as an infection, neoplasm, or connective tissue disease, the underlying disease should be treated. If the syndrome represents a primary vasculitic disease, treatment should be initiated according to the category of the vasculitis syndrome. Specific therapeutic regimens are discussed below for the individual vasculitis syndromes; however, certain general principles regarding therapy should be considered. Decisions regarding treatment should be based on the use of regimens for which there has been published literature supporting efficacy for that particular vasculitic disease. Since the potential toxic side effects of certain therapeutic regimens may be


InternalMed_Harrison

InternalMed_Harrison. use of regimens for which there has been published literature supporting efficacy for that particular vasculitic disease. Since the potential toxic side effects of certain therapeutic regimens may be substantial, the risk-versus-benefit ratio of any therapeutic approach should be weighed carefully. On the one hand, glucocorticoids and/or other immunosuppressive agents should be instituted immediately in diseases where irreversible organ system dysfunction and high morbidity and mortality rates have been clearly established. Granulomatosis with polyangiitis (Wegener’s) is the prototype of a severe systemic vasculitis requiring such a therapeutic approach (see below). On the other hand, when feasible, aggressive therapy should be avoidedforvasculitic manifestations that rarely result in irreversible organ system dysfunction and that usually do not respond to such therapy. For example, isolated


InternalMed_Harrison

InternalMed_Harrison. The Vasculitis Syndromes idiopathic cutaneous vasculitis usually resolves with symptomatic treatment, and prolonged courses of glucocorticoids uncommonly result in clinical benefit. Cytotoxic agents have not proved to be beneficial in idiopathic cutaneous vasculitis, and their toxic side effects generally outweigh any potential beneficial effects. Glucocorticoids should be initiated in those systemic vasculitides that cannot be specifically categorized or for which there is no established standard therapy; or other immunosuppressive therapy should be added in these diseases only if an adequate response does not result or if remission can only be achieved and maintainedwith an unacceptably toxic regimen of glucocorticoids. When remission isachieved,oneshouldcontinuallyattempttotaperglucocorticoids and discontinue when possible. When using other immunosuppressive regimens, one should base the choice of agent upon the available therapeutic data supporting efficacy in that disease, the


InternalMed_Harrison

InternalMed_Harrison. and discontinue when possible. When using other immunosuppressive regimens, one should base the choice of agent upon the available therapeutic data supporting efficacy in that disease, the site and severity of organ involvement, and the toxicity profile of the drug.


InternalMed_Harrison

InternalMed_Harrison. Physicians should be thoroughly aware of the toxic side effects of therapeutic agents employed that can include both acute and long-term complications (Table 385-4). Morbidity and mortality can occur as a result of treatment, and strategies to monitor for and prevent toxicity represent an essential part of patient care. Glucocorticoids are an important part of treatment for most vasculitides but are associated with substantial toxicities. Monitoring and prevention of glucocorticoid-induced bone loss are important in all patients. With the use of daily cyclophosphamide, strategies are particularly important and are directed toward minimization of bladder toxicity and prevention of leukopenia. Instructing the patient to take cyclophosphamide all at once in the morning with a large amount of fluid throughout the day in order to maintain a dilute urine can reduce the risk of bladder injury. Bladder cancer can occur several years after discontinuation of cyclophosphamide therapy;


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InternalMed_Harrison. amount of fluid throughout the day in order to maintain a dilute urine can reduce the risk of bladder injury. Bladder cancer can occur several years after discontinuation of cyclophosphamide therapy; therefore, monitoring for bladder cancer should continue indefinitely in patients who have received cyclophosphamide. Bone marrow suppression is an important toxicity of cyclophosphamide and can be observed during glucocorticoid tapering or over time, even after periods of stable measurements. Monitoring of the complete bloodcountevery1–2weeks foraslong asthepatient receives cyclophosphamide can effectively prevent cytopenias. Maintaining the white blood cell (WBC) count at >3000/μL and the neutrophil count at >1500/μL is essential to reduce the risk of life-threatening infections.


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InternalMed_Harrison. Methotrexate and azathioprine are also associated with bone marrow suppression, and complete blood counts should be obtained every 1–2 weeks for the first 1–2 months after their initiation and once a month thereafter. To lessen toxicity, methotrexate is often given together with folic acid, 1 mg daily, or folinic acid, 5–10 mg once a week 24 h following methotrexate. Prior to initiation of azathioprine, thiopurine methyltransferase (TPMT), an enzyme involved in the metabolism of azathioprine, should be assayed because inadequate levels may result in severe cytopenia.


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InternalMed_Harrison. Infection represents a significant toxicity for all vasculitis patients treated with immunosuppressive therapy. Infections with Pneumocystis jiroveci and certain fungi can be seen even in the face of WBCs that are within normal limits, particularly in patients receiving glucocorticoids. All vasculitis patients who are receiving daily glucocorticoids in combination with another immunosuppressive agent should receive trimethoprim-sulfamethoxazole (TMP-SMX) or another prophylactic therapy to prevent P. jiroveci infection. Finally, it should be emphasized that each patient is unique and requires individual decision-making. The above outline should serve as a framework to guide therapeutic approaches; however, flexibility should be practiced in order to provide maximal therapeutic efficacy with minimal toxic side effects in each patient.


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InternalMed_Harrison. Granulomatosis with polyangiitis (Wegener’s) isadistinctclinicopathologicentity characterizedbygranulomatous vasculitisofthe upperand lower respiratory tracts together with glomerulonephritis. In addition, variable degrees of disseminated vasculitis involving both small arteries and veins may occur. Granulomatosis with polyangiitis (Wegener’s) is an uncommon disease with an estimated prevalence of 3 per 100,000. It is extremely rare in blacks compared with whites; the male-to-female ratio is 1:1. The disease can be seen at any age; ∼15% of patients are <19 years of age, butonlyrarelydoesthediseaseoccur beforeadolescence;themeanage of onset is ∼40 years.


InternalMed_Harrison

InternalMed_Harrison. The histopathologic hallmarks of granulomatosis with polyangiitis (Wegener’s) are necrotizing vasculitis of small arteries and veins together with granuloma formation, which may be either intravascular or extravascular (Fig. 385-2). Lung involvement typically appears as multiple, bilateral, nodular cavitary infiltrates (Fig. 385-3), which on biopsy almost invariably reveal the typical necrotizing granulomatous vasculitis. Upper airway lesions, particularly those in the sinuses and nasopharynx, typically reveal inflammation, necrosis, and granuloma formation, with or without vasculitis. In its earliest form, renal involvement is characterized by a focal and segmental glomerulitis that may evolve into a rapidly progressive Osteoporosis Cataracts Glaucoma Diabetes mellitus Electrolyte abnormalities Metabolic abnormalities Suppression of inflammatory and immune responses leading to opportunistic


InternalMed_Harrison

InternalMed_Harrison. Osteoporosis Cataracts Glaucoma Diabetes mellitus Electrolyte abnormalities Metabolic abnormalities Suppression of inflammatory and immune responses leading to opportunistic Growth suppression in children Hypertension Avascular necrosis of bone Myopathy Alterations in mood Psychosis Pseudotumor cerebri Peptic ulcer diathesis Pancreatitis Gastrointestinal intolerance Pneumonitis Stomatitis Teratogenicity Bone marrow suppression Opportunistic infections Hepatotoxicity (may lead to fibrosis or


InternalMed_Harrison

InternalMed_Harrison. Gastrointestinal intolerance Pneumonitis Stomatitis Teratogenicity Bone marrow suppression Opportunistic infections Hepatotoxicity (may lead to fibrosis or FIGUrE 385-2 Lung histology in granulomatosis with polyangiitis (Wegener’s). Thisareaofgeographicnecrosishasaserpiginousbor-derofhistiocytesandgiantcellssurroundingacentralnecroticzone.Vasculitisisalsopresentwithneutrophilsandlymphocytesinfiltratingthewallofasmallarteriole(upper right).(Courtesy of William D. Travis, MD; with permission.) crescentic glomerulonephritis. Granuloma formation is only rarely seen on renal biopsy. In contrast to other forms of glomerulonephritis, evidence of immune complex deposition is not found in the renal lesion of granulomatosis with polyangiitis (Wegener’s). In addition to theclassictriadofdiseaseofthe upperandlowerrespiratorytracts and kidney, virtually any organ can be involved with vasculitis, granuloma, or both.


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InternalMed_Harrison. The immunopathogenesis of this disease is unclear, although the involvement of upper airways and lungswith granulomatous vasculitis suggests an aberrant cell-mediated immune response to an exogenous orevenendogenousantigenthatentersthroughorresidesintheupper airway. Chronic nasal carriage of Staphylococcus aureus has been reported to be associated with a higher relapse rate of granulomatosis with polyangiitis (Wegener’s); however, there is no evidence for a role of this organism in the pathogenesis of the disease.


InternalMed_Harrison

InternalMed_Harrison. Peripheral blood mononuclear cells obtained from patients with granulomatosis with polyangiitis (Wegener’s) manifest increased secretion of IFN-γ but not of IL-4, IL-5, or IL-10 compared to normal controls. In addition, TNF-α production from peripheral blood mononuclear cells and CD4+ T cells is elevated. Furthermore, monocytes from patients with granulomatosis with polyangiitis (Wegener’s) produce increasedamounts ofIL-12.Thesefindingsindicate anunbal-2183 anced TH1-type T cell cytokine pattern in this disease that may have pathogenic and perhaps ultimately therapeutic implications. FIGUrE 385-3 Computed tomography scan of a patient with granulomatosis with polyangiitis (Wegener’s). Thepatientdevel-opedmultiple,bilateral,andcavitaryinfiltrates. A high percentage of patients with granulomatosis with polyangiitis (Wegener’s) develop ANCA, and these autoantibodies may play a role in the pathogenesis of this disease (see above).


InternalMed_Harrison

InternalMed_Harrison. A high percentage of patients with granulomatosis with polyangiitis (Wegener’s) develop ANCA, and these autoantibodies may play a role in the pathogenesis of this disease (see above). Involvement of the upper airways occurs in 95% of patients with granulomatosis with polyangiitis (Wegener’s). Patients often present with severe upper respiratory tract findings such as paranasal sinus pain and drainage and purulent or bloody nasal discharge, with or without nasal mucosal ulceration (Table 385-5). Nasal septal perforation may follow, leading to saddle nose deformity. Serous otitis media may occur as a result of eustachian tube blockage. Subglottic tracheal stenosis resulting from active disease or scarring occurs in ∼16% of patients and may result in severe airway obstruction. aFewer than 1% had parotid, pulmonary artery, breast, or lower genitourinary (urethra, cervix, vagina, testicular) involvement. Source: GS Hoffman et al: Ann Intern Med 116:488, 1992.


InternalMed_Harrison

InternalMed_Harrison. The Vasculitis Syndromes 2184 Pulmonary involvement may be manifested as asymptomatic infiltrates or may be clinically expressed as cough, hemoptysis, dyspnea, and chest discomfort. It is present in 85–90% of patients. Endobronchial disease, either in its active form or as a result of fibrous scarring, may lead to obstruction with atelectasis. Eye involvement (52% of patients) may range from a mild conjunctivitis to dacryocystitis, episcleritis, scleritis, granulomatous sclerouveitis, ciliary vessel vasculitis, and retroorbital mass lesions leading to proptosis. Skin lesions (46% of patients) appear as papules, vesicles, palpable purpura, ulcers, or subcutaneous nodules; biopsy reveals vasculitis, granuloma, or both. Cardiac involvement (8% of patients) manifests as pericarditis, coronary vasculitis, or, rarely, cardiomyopathy. Nervous system manifestations (23% ofpatients) includecranial neuritis,mononeuritis multiplex, or, rarely, cerebral vasculitis and/or granuloma. Renal disease


InternalMed_Harrison

InternalMed_Harrison. vasculitis, or, rarely, cardiomyopathy. Nervous system manifestations (23% ofpatients) includecranial neuritis,mononeuritis multiplex, or, rarely, cerebral vasculitis and/or granuloma. Renal disease (77% of patients) generally dominates the clinical picture and, if left untreated, accounts directly or indirectly for most of the mortality rate in this disease. Although it may smolder in some cases as a mildglomerulitis withproteinuria, hematuria, andredblood cell casts, it is clear that once clinically detectable renal functional impairment occurs, rapidly progressive renal failure usually ensues unless appropriate treatment is instituted. While the disease is active, most patients have nonspecific symptoms and signs such as malaise, weakness, arthralgias, anorexia, and weight loss. Fever may indicate activity of the underlying disease but more often reflects secondary infection, usually of the upper airway. Characteristic laboratory findings include a markedly elevated erythrocyte


InternalMed_Harrison

InternalMed_Harrison. may indicate activity of the underlying disease but more often reflects secondary infection, usually of the upper airway. Characteristic laboratory findings include a markedly elevated erythrocyte sedimentation rate (ESR), mild anemia and leukocytosis, mild hypergammaglobulinemia (particularly of the IgA class), and mildly elevated rheumatoid factor. Thrombocytosis may be seen as an acute-phase reactant. Approximately 90% of patients with active granulomatosis with polyangiitis (Wegener’s) have a positive antiproteinase-3 ANCA. However, in the absence of active disease, the sensitivity drops to ∼60–70%. A small percentage of patients with granulomatosis with polyangiitis (Wegener’s) may have antimyeloperoxidase rather than antiproteinase-3 antibodies, and up to 20% may lack ANCA. Patients with granulomatosis with polyangiitis (Wegener’s) have been found to have an increased incidence of venous thrombotic events. Although routine anticoagulation for all patients is not recommended, a


InternalMed_Harrison

InternalMed_Harrison. with granulomatosis with polyangiitis (Wegener’s) have been found to have an increased incidence of venous thrombotic events. Although routine anticoagulation for all patients is not recommended, a heightened awareness for any clinical features suggestive of deep venous thrombosis or pulmonary emboli is warranted.


InternalMed_Harrison

InternalMed_Harrison. The diagnosis of granulomatosis with polyangiitis (Wegener’s) is made by the demonstration of necrotizing granulomatous vasculitis on tissue biopsy in a patient with compatible clinical features. Pulmonary tissue offers the highest diagnostic yield, almost invariably revealing granulomatous vasculitis. Biopsy of upper airway tissue usually reveals granulomatous inflammation with necrosis but may not show vasculitis. Renal biopsy can confirm the presence of pauci-immune glomerulonephritis. The specificity of a positive antiproteinase-3 ANCA for granulomatosis with polyangiitis (Wegener’s) is very high, especially if active glomerulonephritisispresent.However, the presenceof ANCAshould be adjunctive and, with rare exceptions, should not substitute for a tissue diagnosis. False-positive ANCA titers have been reported in certain infectious and neoplastic diseases.


InternalMed_Harrison

InternalMed_Harrison. In its typical presentation, the clinicopathologic complex of granulomatosis with polyangiitis (Wegener’s) usually provides ready differentiation from other disorders. However, if all the typical features are not present at once, it needs to be differentiated from the other vasculitides, antiglomerular basement membrane disease (Goodpasture’s syndrome) (Chap. 338), relapsing polychondritis (Chap. 389), tumors of the upper airway or lung, and infectious diseases such as histoplasmosis (Chap. 236), mucocutaneous leishmaniasis (Chap. 251), and rhinoscleroma (Chap. 44) as well as noninfectious granulomatous diseases.


InternalMed_Harrison

InternalMed_Harrison. Of particular note is the differentiation from other midline destructive diseases. These diseases lead to extreme tissue destruction and mutilation localized to the midline upper airway structures including the sinuses; erosion through the skin of the face commonly occurs, a feature that is extremely rare in granulomatosis with polyangiitis (Wegener’s). Although blood vessels may be involved in the intense inflammatory reaction and necrosis, primary vasculitis is not seen. Upper airway neoplasms and specifically extranodal natural killer (NK)/T cell lymphoma (nasal type) are important causes of midline destructive disease. These lesions are diagnosed based on histology, which reveals polymorphous atypical lymphoid cells with an NK cell immunophenotype, typically Epstein-Barr virus (Chap. 134). Such cases are treated based on their degree of dissemination, and localized lesions have responded to irradiation. Upper airway lesions should never be irradiated in granulomatosis with


InternalMed_Harrison

InternalMed_Harrison. (Chap. 134). Such cases are treated based on their degree of dissemination, and localized lesions have responded to irradiation. Upper airway lesions should never be irradiated in granulomatosis with polyangiitis (Wegener’s). Cocaine-induced tissue injury can be another important mimic of granulomatosis with polyangiitis (Wegener’s) in patients who present with isolated midline destructive disease. ANCA that target human neutrophil elastase can be found in patients with cocaine-induced midline destructive lesions and can complicate the differentiation from granulomatosis with polyangiitis (Wegener’s). This has been further confounded by the high frequency of levamisole adulteration of cocaine, which can result in cutaneous infarction and serologic changes that may mimic vasculitis. Granulocytopenia is a common finding in levamisole-induced disease that would not be associated with granulomatosis with polyangiitis (Wegener’s).


InternalMed_Harrison

InternalMed_Harrison. Granulomatosis with polyangiitis (Wegener’s) must also be differentiated from lymphomatoid granulomatosis, which is an Epstein-Barr virus–positive B cell proliferation that is associated with an exuberant T cell reaction. Lymphomatoid granulomatosis is characterized by lung,skin, CNS,andkidneyinvolvementinwhich atypicallymphocytoid and plasmacytoid cells infiltrate nonlymphoid tissue in an angioinvasive manner. In this regard, it clearly differs from granulomatosis with polyangiitis (Wegener’s) in that it is not an inflammatory vasculitis in the classic sense but an angiocentric perivascular infiltration of atypical mononuclear cells. Up to 50% of patients may develop a true malignant lymphoma.


InternalMed_Harrison

InternalMed_Harrison. Prior to the introduction of effective therapy, granulomatosis with polyangiitis (Wegener’s) was universally fatal within a few months of diagnosis. Glucocorticoids alone led to some symptomatic improvement, with little effect on the ultimate course of the disease. The development of treatment with cyclophosphamide dramatically changed patient outcome such that marked improvement was seen in >90% of patients, complete remission in 75% of patients, and 5-year patient survival was seen in over 80%.


InternalMed_Harrison

InternalMed_Harrison. Despite the ability to successfully induce remission, 50–70% of remissions are later associated with one or more relapses. The determination of relapse should be based on objective evidence of disease activity, taking care to rule out other features that may have a similar appearance such as infection, medication toxicity, or chronic disease sequelae. The ANCA titer can be misleading and should not be used to assess disease activity. Many patients who achieve remission continue to have elevated titers for years. Results from a large prospective study found that increases in ANCA were not associated with relapse and that only 43% relapsed within 1 year of an increase in ANCA levels. Thus, a rise in ANCA by itself is not a harbinger of immediate disease relapse and should not lead to reinstitution or increase in immunosuppressive therapy. Reinduction of remission after relapse is almost always achieved; however, a high percentage of patients ultimately have some degree of damage from


InternalMed_Harrison

InternalMed_Harrison. or increase in immunosuppressive therapy. Reinduction of remission after relapse is almost always achieved; however, a high percentage of patients ultimately have some degree of damage from irreversible features of their disease, such as varying degrees of renal insufficiency, hearing loss, tracheal stenosis, saddle nose deformity, and chronically impaired sinus function. Patients who developed irreversible renal failure but who achieved subsequent remission have undergone successful renal transplantation.


InternalMed_Harrison

InternalMed_Harrison. Because long-term cyclophosphamide is associated with substantial toxicity, approaches have been developed that seek to minimize the duration of exposure to cyclophosphamide while still taking advantage of its efficacy for severe disease. Treatment of granulomatosis with polyangiitis (Wegener’s) is currently viewed as having two phases: induction, where active disease is put into remission, followed by maintenance. The decision regarding which agents to use for induction and maintenance is based on disease severity together with individual patient factors that include contraindication, relapse history, and comorbidities.


InternalMed_Harrison

InternalMed_Harrison. For patients with severe disease, daily cyclophosphamide combined with glucocorticoids has been repeatedly proved to effectively induce remission and prolong survival. At the initiation of therapy, glucocorticoids are usually given as prednisone, 1 mg/kg per day for the first month, followed by gradual tapering on an alternate-day or daily schedule with discontinuation after ∼6–9 months.


InternalMed_Harrison

InternalMed_Harrison. Cyclophosphamide is given in doses of 2 mg/kg per day orally, but as it is renally eliminated, dosage reduction should be considered in patients with renal insufficiency. Some reports have indicated therapeutic success with less frequent and severe toxic side effects using IV cyclophosphamide. In a recent randomized trial, IV cyclophosphamide 15 mg/kg, three infusions given every 2 weeks, then every 3 weeks thereafter, was compared to cyclophosphamide 2 mg/kg daily given for 3 months followed by 1.5 mg/kg daily. Although IV cyclophosphamide was found to have a comparable rate of remission with a lower cumulative cyclophosphamide dose and occurrence of leukopenia, the use of a consolidation phase and an insufficient frequency of blood count monitoring may have negatively influenced the results in those who received daily cyclophosphamide. Of note in this study was that relapse occurred in 19% of those who received IV cyclophosphamide as compared to 9% who received daily oral


InternalMed_Harrison

InternalMed_Harrison. the results in those who received daily cyclophosphamide. Of note in this study was that relapse occurred in 19% of those who received IV cyclophosphamide as compared to 9% who received daily oral administration. We continue to strongly favor daily cyclophosphamide with utilization of blood count monitoring every 1–2 weeks (as discussed above) and limiting the duration of induction exposure to 3–6 months.


InternalMed_Harrison

InternalMed_Harrison. In patients with imminently life-threatening disease, such as rapidly progressive glomerulonephritis with a creatinine greater than 4.0 mg/dL or pulmonary hemorrhage requiring mechanical ventilation, a regimen of daily cyclophosphamide and glucocorticoids is the treatment of choice to induce remission. Adjunctive plasmapheresis was found to further improve renal recovery in a study of patients with rapidly progressive glomerulonephritis who had a creatinine of greater than 5.8 mg/dL.


InternalMed_Harrison

InternalMed_Harrison. After 3–6 months of induction treatment, cyclophosphamide should be stopped and switched to another agent for remission maintenance. The agents with which there has been the greatest published experience are methotrexate and azathioprine. Methotrexate is administered orally or subcutaneously starting at a dosage of 0.3 mg/kg as a single weekly dose, not to exceed 15 mg/week. If the treatment is well tolerated after 1–2 weeks, the dosage should be increased by 2.5 mg weekly up to a dosage of 20–25 mg/week and maintained at that level. Azathioprine, 2 mg/kg per day, has also proved effective in maintaining remission following induction with daily cyclophosphamide. In a randomized trial comparing methotrexate to azathioprine for remission maintenance, comparable rates of toxicity and relapse were seen. Therefore, the choice of agent is often based on toxicity profile, because methotrexate cannot be given to patients with renal insufficiency or chronic liver disease, as well as on other


InternalMed_Harrison

InternalMed_Harrison. were seen. Therefore, the choice of agent is often based on toxicity profile, because methotrexate cannot be given to patients with renal insufficiency or chronic liver disease, as well as on other individual patient factors. In patients who are unable to receive methotrexate or azathioprine or who have relapsed through such treatment, mycophenolate mofetil, 1000 mg twice a day, may also sustain remission following cyclophosphamide induction.


InternalMed_Harrison

InternalMed_Harrison. The optimal duration of maintenance therapy is uncertain. In the absence of toxicity, maintenance therapy is usually given for a minimum of 2 years past remission, after which time consideration can be given for tapering over a 6–12 month period until discontinuation. Patients with significant organ damage or a history of relapse may benefit from longer-term continuation of a maintenance agent.


InternalMed_Harrison

InternalMed_Harrison. Rituximab is a chimeric monoclonal antibody directed against CD20 present on normal and malignant B lymphocytes that is U.S. Food and Drug Administration (FDA) approved for the treatment of granulomatosis with polyangiitis (Wegener’s) and microscopic polyangiitis. In two randomized trials that enrolled ANCA-positive patients with severe active granulomatosis with polyangiitis (Wegener’s) or microscopic polyangiitis, rituximab 375 mg/m2 once a week for 4 weeks in combination with glucocorticoids was found to be as effective as cyclophosphamide with glucocorticoids for inducing disease remission. In the trial, which also enrolled patients with relapsing disease, rituximab was found to be statistically superior to cyclophosphamide.


InternalMed_Harrison

InternalMed_Harrison. Although the data support that rituximab is effective for remission induction of severe active granulomatosis with polyangiitis (Wegener’s) or microscopic polyangiitis, there remain a number of ongoing questions regarding rituximab that must be considered in weighing its use in the individual patient. The optimal approach to remission maintenance after treatment with rituximab remains unclear, as does whether this should include conventional maintenance agents such as methotrexate or azathioprine versus scheduled retreatment with rituximab. In addition, there are no long-term safety data with rituximab in granulomatosis with polyangiitis (Wegener’s) or microscopic polyangiitis.


InternalMed_Harrison

InternalMed_Harrison. Although rituximab does not have the bladder toxicity or infertility concerns, as can occur with cyclophosphamide, in both of the randomized trials, the rate of adverse events was similar in the rituximab and cyclophosphamide arms. Serious side effects of rituximab include infusion reactions, severe mucocutaneous reactions, and rare reports of progressive multifocal leukoencephalopathy. Because rituximab can bring about reactivation of hepatitis B, all patients should undergo hepatitis screening prior to treatment with rituximab. Etanercept, a dimeric fusion protein containing the 75-kDa TNF receptor bound to human IgG1, was not found to sustain remission when used adjunctively to standard therapy and should not be used in the treatment of granulomatosis with polyangiitis (Wegener’s).


InternalMed_Harrison

InternalMed_Harrison. For selected patients whose disease is not immediately life threatening, methotrexate together with glucocorticoids given at the dosages described above may be considered as an alternative for induction therapy, which is then continued for maintenance. Although certain reports have indicated that TMP-SMX may be of benefit in the treatment of granulomatosis with polyangiitis (Wegener’s) isolated to the sinonasal tissues, it should never be used alone to treat active granulomatosis with polyangiitis (Wegener’s) outside of the upper airway such as in patients with renal or pulmonary disease. In a study examining the effect of TMP-SMX on relapse, decreased relapses were shown only with regard to upper airway disease, and no differences in major organ relapses were observed.


InternalMed_Harrison

InternalMed_Harrison. Not all manifestations of granulomatosis with polyangiitis (Wegener’s) require or respond to immunosuppressive therapy. In managing non–major organ disease, such as that isolated to the sinus, joints, or skin, the risks of treatment should be carefully weighed against the benefits. Treatment with cyclophosphamide is rarely if ever justified for the treatment of isolated sinus disease in granulomatosis with polyangiitis (Wegener’s). Although patients with non–major organ disease may be effectively treated without immunosuppressive therapy, these individuals must be monitored closely for the development of disease activity affecting the lungs, The Vasculitis Syndromes 2186 kidneys, or other major organs. Subglottic stenosis and endobronchial stenosis are examples of disease manifestations that do not typically respond to systemic immunosuppressive treatment.


InternalMed_Harrison

InternalMed_Harrison. The term microscopic polyarteritis was introduced into the literature by Davson in 1948 in recognition of the presence of glomerulonephritis in patients with polyarteritis nodosa. In 1992, the Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitis adopted the term microscopic polyangiitis to connote a necrotizing vasculitis with few or no immune complexes affecting small vessels (capillaries, venules, or arterioles). Glomerulonephritis is very common in microscopic polyangiitis, and pulmonary capillaritis often occurs. The absence of granulomatous inflammation in microscopic polyangiitis is said to differentiate it from granulomatosis with polyangiitis (Wegener’s). The incidence of microscopic polyangiitis has not yet been reliably established due to its previous inclusion aspart of polyarteritis nodosa. The mean age of onset is ∼57 years of age, and males are slightly more frequently affected than females.


InternalMed_Harrison

InternalMed_Harrison. The vasculitis seen in microscopic polyangiitis has a predilection to involve capillaries and venules in addition to small and medium-sized arteries. Immunohistochemical staining reveals a paucity of immunoglobulin deposition in the vascular lesion of microscopic polyangiitis, suggesting that immune-complex formation does not play a role in the pathogenesis of this syndrome. The renal lesion seen in microscopic polyangiitis is identical to that of granulomatosis with polyangiitis (Wegener’s). Like granulomatosis with polyangiitis (Wegener’s), microscopic polyangiitis is highly associated with the presence of ANCA, which may play a role in pathogenesis of this syndrome (see above).


InternalMed_Harrison

InternalMed_Harrison. Because of its predilection to involve the small vessels, microscopic polyangiitis and granulomatosis with polyangiitis (Wegener’s) share similar clinical features. Disease onset may be gradual, with initial symptoms of fever, weight loss, and musculoskeletal pain; however, it is often acute. Glomerulonephritis occurs in at least 79% of patients and can be rapidly progressive, leading to renal failure. Hemoptysis may be the first symptom of alveolar hemorrhage, which occurs in 12% of patients. Other manifestations include mononeuritis multiplex and gastrointestinal tract and cutaneous vasculitis. Upper airway disease and pulmonary nodules are not typically found in microscopic polyangiitis and, if present, suggest granulomatosis with polyangiitis (Wegener’s).


InternalMed_Harrison

InternalMed_Harrison. Features of inflammation may be seen, including an elevated ESR, anemia, leukocytosis, and thrombocytosis. ANCA are present in 75% of patients with microscopic polyangiitis, with antimyeloperoxidase antibodies being the predominant ANCA associated with this disease. The diagnosis is based on histologic evidence of vasculitis or pauciimmune glomerulonephritis in a patient with compatible clinical features of multisystem disease. Although microscopic polyangiitis is strongly ANCA-associated, no studies have as yet established the sensitivity and specificity of ANCA in this disease.


InternalMed_Harrison

InternalMed_Harrison. The 5-year survival rate for patients with treated microscopic polyangiitis is 74%, with disease-related mortality occurring from alveolar hemorrhage or gastrointestinal, cardiac, or renal disease. Studies on treatment have come from trials that have included patients with granulomatosis with polyangiitis (Wegener’s) or microscopic polyangiitis. Currently, the treatment approach for microscopic polyangiitis is the same as is used for granulomatosis with polyangiitis (Wegener’s) (see “Granulomatosis with Polyangiitis [Wegener’s]” for a detailed description of this therapeutic regimen), and patients with immediately life-threatening disease should be treated with the combination of prednisone and daily cyclophosphamide or rituximab. Disease relapse has been observed in at least 34% of patients. Treatment for such relapses would be similar to that used at the time of initial presentation and based on site and severity of disease.


InternalMed_Harrison

InternalMed_Harrison. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) was described in 1951 by Churg and Strauss and is characterized by asthma, peripheral and tissue eosinophilia, extravascular granuloma formation, and vasculitis of multiple organ systems. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) is an uncommon disease with an estimated annual incidence of 1–3 per million. The disease can occur at any age with the possible exception of infants. The mean age of onset is 48 years, with a female-to-male ratio of 1.2:1.


InternalMed_Harrison

InternalMed_Harrison. The necrotizing vasculitis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss) involves small and medium-sized muscular arteries,capillaries,veins,andvenules.Acharacteristichistopathologic feature of eosinophilic granulomatosis with polyangiitis (Churg-Strauss) is granulomatous reactions that may be present in the tissues or even within the walls of the vessels themselves. These are usually associated with infiltration of the tissues with eosinophils.This process can occur in any organ in the body; lung involvement is predominant, with skin, cardiovascular system, kidney, peripheral nervous system, and gastrointestinal tract also commonly involved. Although the precise pathogenesis of this disease is uncertain, its strong association with asthma and its clinicopathologic manifestations, including eosinophilia, granuloma, and vasculitis, point to aberrant immunologic phenomena.


InternalMed_Harrison

InternalMed_Harrison. Patients with eosinophilic granulomatosis with polyangiitis (Churg-Strauss) often exhibit nonspecific manifestations such as fever, malaise, anorexia, and weight loss, which are characteristic of a multisystem disease. The pulmonary findings in eosinophilic granulomatosis with polyangiitis (Churg-Strauss) clearly dominate the clinical picture with severe asthmatic attacks and the presence of pulmonary infiltrates. Mononeuritis multiplex is the second most common manifestation and occurs in up to 72% of patients. Allergic rhinitis and sinusitis develop in up to 61% of patients and are often observed early in the course of disease. Clinically recognizable heart disease occurs in ∼14% of patients and is an important cause of mortality. Skin lesions occur in ∼51% of patients and include purpura in addition to cutaneous and subcutaneous nodules. The renal disease in eosinophilic granulomatosis with polyangiitis (Churg-Strauss) is less common and generally less severe than that of


InternalMed_Harrison

InternalMed_Harrison. purpura in addition to cutaneous and subcutaneous nodules. The renal disease in eosinophilic granulomatosis with polyangiitis (Churg-Strauss) is less common and generally less severe than that of granulomatosis with polyangiitis and microscopic polyangiitis.


InternalMed_Harrison

InternalMed_Harrison. The characteristic laboratory finding in virtually all patients with eosinophilic granulomatosis with polyangiitis (Churg-Strauss) is a striking eosinophilia, which reaches levels >1000 cells/μL in >80% of patients. Evidence of inflammation as evidenced by elevated ESR, fibrinogen, or α2-globulins can be found in 81% of patients. The other laboratory findings reflect the organ systems involved. Approximately 48% of patients with eosinophilic granulomatosis with polyangiitis (Churg-Strauss) have circulating ANCA that is usually antimyeloperoxidase.


InternalMed_Harrison

InternalMed_Harrison. Although the diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss) is optimally made by biopsy in a patient with the characteristic clinical manifestations (see above), histologic confirmation can be challenging because the pathognomonic features often do not occur simultaneously. In order to be diagnosed with eosinophilic granulomatosis with polyangiitis (Churg-Strauss), a patient should have evidence of asthma, peripheral blood eosinophilia, and clinical features consistent with vasculitis. The prognosis of untreated eosinophilic granulomatosis with polyangiitis (Churg-Strauss) is poor, with a reported 5-year survival of 25%. With treatment, prognosis is favorable, with one study finding a 78-month actuarial survival rate of 72%. Myocardial involvement is the most frequent cause of death and is responsible for 39% of patient mortality. Echocardiography should be performed in all newly diagnosed patients because this may influence therapeutic decisions.


InternalMed_Harrison

InternalMed_Harrison. Glucocorticoids alone appear to be effective in many patients. Dosage tapering is often limited by asthma, and many patients require low-dose prednisone for persistent asthma many years after clinical recovery from vasculitis. In glucocorticoid failure or in patients who present with fulminant multisystem disease, particularly cardiac involvement, the treatment of choice is a combined regimen of daily cyclophosphamide and prednisone (see “Granulomatosis with Polyangiitis [Wegener’s]” for a detailed description of this therapeutic regimen). Recent studies of mepolizumab (anti-IL-5 antibody) in eosinophilic granulomatosis with polyangiitis (Churg-Strauss) have been encouraging, but this treatment requires further investigation.


InternalMed_Harrison

InternalMed_Harrison. Polyarteritis nodosa was described in 1866 by Kussmaul and Maier. It is a multisystem, necrotizing vasculitis of small and medium-sized muscular arteries in which involvement of the renal and visceral arteries is characteristic. Polyarteritis nodosa does not involve pulmonary arteries, although bronchial vessels may be involved; granulomas, significant eosinophilia, and an allergic diathesis are not observed. It is difficult to establish an accurate incidence of polyarteritis nodosa becausepreviousreportshave included polyarteritisnodosa andmicroscopic polyangiitis as well as other related vasculitides. Polyarteritis nodosa, as currently defined, is felt to be a very uncommon disease.


InternalMed_Harrison

InternalMed_Harrison. Thevascularlesion in polyarteritisnodosa isa necrotizinginflammation of small and medium-sized muscular arteries. The lesions are segmental and tend to involve bifurcations and branchings of arteries. They may spread circumferentially to involve adjacent veins. However, involvement of venules is not seen in polyarteritis nodosa and, if present, suggests microscopic polyangiitis (see below). In the acute stages of disease, polymorphonuclear neutrophils infiltrate all layers of the vessel wall and perivascular areas, which results in intimal proliferation and degeneration of the vessel wall. Mononuclear cells infiltrate the area as the lesions progress to the subacute and chronic stages. Fibrinoid necrosis of the vessels ensues with compromise of the lumen, thrombosis, infarction of the tissues supplied by the involved vessel, and, in some cases, hemorrhage. Asthelesionsheal,thereis collagendeposition,whichmay leadtofurtherocclusion ofthevessel lumen.Aneurysmaldilations upto 1 cm in


InternalMed_Harrison

InternalMed_Harrison. tissues supplied by the involved vessel, and, in some cases, hemorrhage. Asthelesionsheal,thereis collagendeposition,whichmay leadtofurtherocclusion ofthevessel lumen.Aneurysmaldilations upto 1 cm in size along the involved arteries are characteristic of polyarteritis nodosa. Granulomas and substantial eosinophilia with eosinophilic tissue infiltrationsarenotcharacteristically foundand suggesteosinophilic granulomatosis with polyangiitis (Churg-Strauss) (see above).


InternalMed_Harrison

InternalMed_Harrison. Multiple organ systems are involved, and the clinicopathologic 2187 findings reflect the degree and location of vessel involvement and the resulting ischemic changes. As mentioned above, pulmonary arteries are not involved in polyarteritis nodosa, and bronchial artery involvement is uncommon. The pathology in the kidney in classic polyarteritis nodosa is that of arteritis without glomerulonephritis. In patients with significant hypertension, typical pathologic features of glomerulosclerosis may be seen. In addition, pathologic sequelae of hypertension may be found elsewhere in the body.


InternalMed_Harrison

InternalMed_Harrison. The presence of a polyarteritis nodosa–like vasculitis in patients with hepatitis B together with the isolation of circulating immune complexes composed of hepatitis B antigen and immunoglobulin, and the demonstration by immunofluorescence of hepatitis B antigen, IgM, and complement in the blood vessel walls, strongly suggest the role of immunologic phenomena in the pathogenesis of this disease. A polyarteritis nodosa–like vasculitis has also been reported in patients with hepatitis C. Hairy cell leukemia can be associated with polyarteritis nodosa; the pathogenic mechanisms of this association are unclear.


InternalMed_Harrison

InternalMed_Harrison. Nonspecific signs and symptoms are the hallmarks of polyarteritis nodosa. Fever, weight loss, and malaise are present in over one-half of cases. Patients usually present with vague symptoms such as weakness, malaise, headache,abdominalpain,and myalgias that can rapidly progress to a fulminant illness. Specific complaints related to the vascular involvement within a particular organ system may also dominate the presenting clinical picture as well as the entire course of the illness (Table 385-6). In polyarteritis nodosa, renal involvement most commonly manifests as hypertension, renal insufficiency, or hemorrhage due to microaneurysms.


InternalMed_Harrison

InternalMed_Harrison. There are no diagnostic serologic tests for polyarteritis nodosa. In >75% of patients, the leukocyte count is elevated with a predominance of neutrophils. Eosinophilia is seen only rarely and, when present at high levels, suggests the diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss). The anemia of chronic disease may be seen, and an elevated ESR is almost always present. Other common laboratory findings reflect the particular organ involved. Hypergammaglobulinemia may be present, and all patients should be screened for hepatitis B and C. Antibodies against myeloperoxidase or proteinase-3 (ANCA) are rarely found in patients with polyarteritis nodosa. The diagnosis of polyarteritis nodosa is based on the demonstration of characteristic findings of vasculitis on biopsy material of involved Source: From TR Cupps, AS Fauci: The Vasculitides. Philadelphia, Saunders, 1981.


InternalMed_Harrison

InternalMed_Harrison. Source: From TR Cupps, AS Fauci: The Vasculitides. Philadelphia, Saunders, 1981. The Vasculitis Syndromes 2188 organs. In the absence of easily accessible tissue for biopsy, the arteriographic demonstration of involved vessels, particularly in the form of aneurysms of small and medium-sized arteries in the renal, hepatic, and visceral vasculature, is sufficient to make the diagnosis. This should consist of a catheter-directed dye arteriogram because magnetic resonance and computed tomography arteriograms do not have sufficient resolution at the current time to visualize the vessels affected in polyarteritis nodosa. Aneurysms of vessels are not pathognomonic of polyarteritis nodosa; furthermore, aneurysms need not always be present, and arteriographic findings may be limited to stenotic segments and obliteration of vessels. Biopsy of symptomatic organs such as nodular skin lesions, painful testes, and nerve/muscle provides the highest diagnostic yields.


InternalMed_Harrison

InternalMed_Harrison. The prognosis of untreated polyarteritis nodosa is extremely poor, with a reported 5-year survival rate between 10 and 20%. Death usually results from gastrointestinal complications, particularly bowel infarcts and perforation, and cardiovascular causes. Intractable hypertension often compounds dysfunction in other organ systems, such as the kidneys, heart, and CNS, leading to additional late morbidity and mortality in polyarteritis nodosa. With the introduction of treatment, survival rate has increased substantially. Favorable therapeutic results have been reported in polyarteritis nodosa with the combination of prednisone and cyclophosphamide (see “Granulomatosis with Polyangiitis [Wegener’s]” for a detailed description of this therapeutic regimen). In less severe cases of polyarteritis nodosa, glucocorticoids alone have resulted in disease remission. In patients with hepatitis B who have a polyarteritis nodosa–like vasculitis, antiviral therapy represents an important part of


InternalMed_Harrison

InternalMed_Harrison. nodosa, glucocorticoids alone have resulted in disease remission. In patients with hepatitis B who have a polyarteritis nodosa–like vasculitis, antiviral therapy represents an important part of therapy and has been used in combination with glucocorticoids and plasma exchange. Careful attention to the treatment of hypertension can lessen the acute and late morbidity and mortality rates associated with renal, cardiac, and CNS complications of polyarteritis nodosa. Following successful treatment, relapse of polyarteritis nodosa has been estimated to occur in 10–20% of patients.


InternalMed_Harrison

InternalMed_Harrison. Giant cell arteritis, historically referred to as temporal arteritis, is an inflammation of medium-and large-sized arteries. It characteristically involves one or more branches of the carotid artery, particularly the temporal artery. However, itis a systemic diseasethat caninvolve arteries in multiple locations, particularly the aorta and its main branches.


InternalMed_Harrison

InternalMed_Harrison. Giant cell arteritis is closely associated with polymyalgia rheumatica, which is characterized by stiffness, aching, and pain in the muscles of the neck, shoulders, lower back, hips, and thighs. Most commonly, polymyalgia rheumatica occurs in isolation, but it may be seen in 40–50% of patients with giant cell arteritis. In addition, ∼10–20% of patients who initially present with features of isolated polymyalgia rheumatica later go on to develop giant cell arteritis. This strong clinical association together with data from pathophysiologic studies has increasingly supported that giant cell arteritis and polymyalgia rheumatica represent differing clinical spectrums of a single disease process.


InternalMed_Harrison

InternalMed_Harrison. Giant cell arteritis occurs almost exclusively in individuals >50 years. It is more common in women than in men and is rare in blacks. The incidence of giant cell arteritis varies widely in different studies and in different geographic regions. A high incidence has been found in Scandinavia and in regions of the United States with large Scandinavian populations, compared to a lower incidence in southern Europe. The annual incidence rates in individuals ≥50 years range from 6.9 to 32.8 per 100,000 population. Familial aggregation has been reported, as has an association with HLA-DR4. In addition, genetic linkage studies have demonstrated an association of giant cell arteritis with alleles at the HLA-DRB1 locus, particularly HLA-DRB1*04 variants. In Olmsted County, Minnesota, the annual incidence of polymyalgia rheumatica in individuals ≥50 years is 58.7 per 100,000 population.


InternalMed_Harrison

InternalMed_Harrison. Although the temporal artery is most frequently involved in giant cell arteritis, patients often have a systemic vasculitis of multiple mediumandlarge-sizedarteries,whichmaygoundetected.Histopathologically, the disease is a panarteritis with inflammatory mononuclear cell infiltrates within the vessel wall with frequent giant cell formation. There is proliferation of the intima and fragmentation of the internal elastic lamina. Pathophysiologic findings in organs result from the ischemia related to the involved vessels.


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InternalMed_Harrison. Experimental data support that giant cell arteritis is an antigen-driven disease in which activated T lymphocytes, macrophages, and dendritic cells play a critical role in the disease pathogenesis. Sequence analysis of the T cell receptor of tissue-infiltrating T cells in lesions of giant cell arteritis indicates restricted clonal expansion, suggesting the presence of an antigen residing in the arterial wall. Giant cell arteritis is believed to be initiated in the adventitia where CD4+ T cells enter through the vasa vasorum, become activated, and orchestrate macrophage differentiation. T cells recruited to vasculitic lesions in patients with giant cell arteritis produce predominantly IL-2 and IFN-γ, and the latter has been suggested to be involved in the progression to overt arteritis. Recent data demonstrate that at least two separate lineages of CD4 T cells–-IFN-γ-producing TH1 cells and IL-17-producing TH17 cells—participate in vascular inflammation and may have differing levels of


InternalMed_Harrison

InternalMed_Harrison. data demonstrate that at least two separate lineages of CD4 T cells–-IFN-γ-producing TH1 cells and IL-17-producing TH17 cells—participate in vascular inflammation and may have differing levels of responsiveness to glucocorticoids.


InternalMed_Harrison

InternalMed_Harrison. Giant cell arteritis is most commonly characterized clinically by the complex of fever, anemia, high ESR, and headaches in a patient over the age of 50 years. Other phenotypic manifestations include features of systemic inflammation including malaise, fatigue, anorexia, weight loss, sweats, arthralgias, polymyalgia rheumatica, or large-vessel disease.


InternalMed_Harrison

InternalMed_Harrison. In patients with involvement of the cranial arteries, headache is the predominant symptom and may be associated with a tender, thickened, or nodular artery, which may pulsate early in the disease but may become occluded later. Scalp pain and claudication of the jaw and tongue may occur. A well-recognized and dreaded complication of giant cell arteritis, particularly in untreated patients, is ischemic optic neuropathy, which may lead to serious visual symptoms, even sudden blindness in some patients. However, most patients have complaints relating to the head or eyes before visual loss. Attention to such symptoms with institution of appropriate therapy (see below) will usually avoid this complication. Other cranial ischemic complications include strokes and scalp or tongue infarction.


InternalMed_Harrison

InternalMed_Harrison. Up to one-third of patients can have large-vessel disease that can be the primary presentation of giant cell arteritis or can emerge at a later point in patients who have had previous cranial arteritis features or polymyalgia rheumatica. Manifestations of large-vessel disease can include subclavian artery stenosis that can present as arm claudication or aortic aneurysms involving the thoracic and to a lesser degree the abdominal aorta, which carry risks of rupture or dissection. Characteristic laboratory findings in addition to the elevated ESR include a normochromic or slightly hypochromic anemia. Liver function abnormalities are common, particularly increased alkaline phosphatase levels. Increased levels of IgG and complement have been reported. Levels of enzymes indicative of muscle damage such as serum creatine kinase are not elevated.


InternalMed_Harrison

InternalMed_Harrison. The diagnosis of giant cell arteritis and its associated clinicopathologic syndromecanoftenbesuggestedclinicallybythedemonstrationofthecomplex of fever, anemia, and high ESR with or without symptoms of polymyalgia rheumatica in a patient >50 years. The diagnosis is confirmed by biopsy of the temporal artery. Since involvement of the vessel may be segmental, positive yield is increased by obtaining a biopsy segment of 3–5 cm together with serial sectioning of biopsy specimens. Ultrasonography of the temporal artery has been reported to be helpful in diagnosis. A temporal artery biopsy should be obtained as quickly as possible in the setting of ocular signs and symptoms, and under these circumstances, therapyshouldnotbedelayedpendingabiopsy.Inthisregard,ithasbeen reported that temporal artery biopsies may show vasculitis even after ∼14 days of glucocorticoid therapy. A dramatic clinical response to a trial of glucocorticoid therapy can further support the diagnosis.


InternalMed_Harrison

InternalMed_Harrison. Large-vessel disease may be suggested by symptoms and findings on physical examination such as diminished pulses or bruits. It is confirmed by vascular imaging, most commonly through magnetic resonance or computed tomography. Isolated polymyalgia rheumatica is a clinical diagnosis made by the presence of typical symptoms of stiffness, aching, and pain in the muscles of the hip and shoulder girdle, an increased ESR, the absence of clinical featuressuggestiveofgiantcellarteritis, and aprompt therapeutic response to low-dose prednisone. Acute disease-related mortality directly from giant cell arteritis is very uncommon, with fatalities occurring from cerebrovascular events or myocardial infarction. However, patients are at risk of late mortality from aortic aneurysm rupture or dissection as patients with giant cell arteritis are 18 times more likely to develop thoracic aortic aneurysms than the general population.


InternalMed_Harrison

InternalMed_Harrison. The goals of treatment in giant cell arteritis are to reduce symptoms and, most importantly, to prevent visual loss. The treatment approach for cranial and large-vessel disease in giant cell arteritis is currently the same. Giant cell arteritis and its associated symptoms are exquisitely sensitive to glucocorticoid therapy. Treatment should begin with prednisone, 40–60 mg/d for ∼1 month, followed by a gradual tapering. When ocular signs and symptoms occur, consideration should be given for the use of methylprednisolone 1000 mg daily for 3 days to protect remaining vision. Although the optimal duration of glucocorticoid therapy has not been established, most series have found that patients require treatment for ≥2 years. Symptom recurrence during prednisone tapering develops in 60–85% of patients with giant cell arteritis, requiring a dosage increase. The ESR can serve as a useful indicator of inflammatory disease activity in monitoring and tapering therapy and can be used to judge the


InternalMed_Harrison

InternalMed_Harrison. with giant cell arteritis, requiring a dosage increase. The ESR can serve as a useful indicator of inflammatory disease activity in monitoring and tapering therapy and can be used to judge the pace of the tapering schedule. However, minor increases in the ESR can occur as glucocorticoids are being tapered and do not necessarily reflect an exacerbation of arteritis, particularly if the patient remains symptom-free. Under these circumstances, the tapering should continue with caution. Glucocorticoid toxicity occurs in 35–65% of patients and represents an important cause of patient morbidity. Aspirin 81 mg daily has been found to reduce the occurrence of cranial ischemic complications in giant cell arteritis and should be given in addition to glucocorticoids in patients who do not have contraindications. The use of weekly methotrexate as a glucocorticoid-sparing agent has been examined in two randomized placebo-controlled trials that reached conflicting conclusions. Infliximab, a


InternalMed_Harrison

InternalMed_Harrison. contraindications. The use of weekly methotrexate as a glucocorticoid-sparing agent has been examined in two randomized placebo-controlled trials that reached conflicting conclusions. Infliximab, a monoclonal antibody to TNF, was studied in a randomized trial and was not found to provide benefit. Recent reports have shown favorable response of giant cell arteritis to tocilizumab (antiIL-6 receptor), but this treatment requires further study before use in clinical practice.


InternalMed_Harrison

InternalMed_Harrison. Patients with isolated polymyalgia rheumatica respond promptly to prednisone, which can be started at a lower dose of 10–20 mg/d. Similar to giant cell arteritis, the ESR can serve as a useful indicator in monitoring and prednisone reduction. Recurrent polymyalgia symptoms develop in the majority of patients during prednisone tapering. One study of weekly methotrexate found that the use of this drug reduced the prednisone dose on average by only 1 mg and did not decrease prednisone-related side effects. A randomized trial in polymyalgia rheumatica did not find infliximab to lessen relapse or glucocorticoid requirements. Takayasu arteritis is an inflammatory and stenotic disease of medium-and large-sized arteries characterized by a strong predilection for the aortic arch and its branches.


InternalMed_Harrison

InternalMed_Harrison. Takayasu arteritis is an inflammatory and stenotic disease of medium-and large-sized arteries characterized by a strong predilection for the aortic arch and its branches. Takayasu arteritis is an uncommon disease with an estimated annual incidence rate of 1.2–2.6 cases per million. It is most prevalent in adolescent girls and young women. Although it is more common in Asia, it is neither racially nor geographically restricted.


InternalMed_Harrison

InternalMed_Harrison. The disease involves medium-and large-sized arteries, with a strong predilection for the aortic arch and its branches; the pulmonary artery may also be involved. The most commonly affected arteries seen by arteriography are listed in Table 385-7. The involvement of the major branches of the aorta is much more marked at their origin than distally. The disease is a panarteritis with inflammatory mononuclear cell infiltrates and occasionally giant cells. There are marked intimal proliferation and fibrosis, scarring and vascularization of the media, and disruption and degeneration of the elastic lamina. Narrowing of the lumen occurs with or without thrombosis. The vasa vasorum are frequently involved. Pathologic changes in various organs reflect the compromise of blood flow through the involved vessels.


InternalMed_Harrison

InternalMed_Harrison. Immunopathogenic mechanisms, the precise nature of which is uncertain,aresuspected inthisdisease.Aswith severalof thevasculitis syndromes, circulating immune complexes have been demonstrated, but their pathogenic significance is unclear. Takayasu arteritis is a systemic disease with generalized as well as vascular symptoms.Thegeneralizedsymptomsincludemalaise,fever,nightsweats, arthralgias,anorexia,andweightloss,whichmayoccurmonthsbeforevesselinvolvementisapparent.Thesesymptomsmaymergeintothoserelated to vascular compromise and organ ischemia. Pulses are commonly absent in the involved vessels, particularly the subclavian artery. The frequency of arteriographic abnormalities and the potentially associated clinical Percentage of The Vasculitis Syndromes Pulmonary 10–40 Coronary <10 Arm claudication, Raynaud’s phenomenon Visual changes, syncope, transient ischemic attacks, stroke Abdominal pain, nausea, vomiting


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InternalMed_Harrison. The Vasculitis Syndromes Pulmonary 10–40 Coronary <10 Arm claudication, Raynaud’s phenomenon Visual changes, syncope, transient ischemic attacks, stroke Abdominal pain, nausea, vomiting Hypertension, renal failure Aortic insufficiency, congestive heart failure Visual changes, dizziness Abdominal pain, nausea, vomiting Abdominal pain, nausea, vomit ing Leg claudication Atypical chest pain, dyspnea Chest pain, myocardial infarc aArteriographic lesions at these locations are usually asymptomatic but may potentially cause these symptoms. Source: G Kerr et al: Ann Intern Med 120:919, 1994. 2190 manifestationsarelistedinTable385-7.Hypertensionoccursin32–93%of patients and contributes to renal, cardiac, and cerebral injury. Characteristic laboratory findings include an elevated ESR, mild anemia, and elevated immunoglobulin levels.


InternalMed_Harrison

InternalMed_Harrison. The diagnosis of Takayasu arteritis should be suspected strongly in a young woman who develops a decrease or absence of peripheral pulses, discrepancies in blood pressure, and arterial bruits. The diagnosis is confirmed by the characteristic pattern on arteriography, which includes irregular vessel walls, stenosis, poststenotic dilation, aneurysm formation, occlusion, and evidence of increased collateral circulation. Complete aortic arteriography by catheter-directed dye arteriographyormagneticresonancearteriographyshouldbeobtained in order to fully delineate the distribution and degree of arterial disease. Histopathologic demonstration of vessel wall inflammation that is predominantly lymphocytic with granuloma formation and giant cells involving the media and adventitia adds confirmatory data; however,tissueisrarelyreadilyavailableforexamination.IgG4-relateddisease is a potential cause of aortitis and periaortitis that is histologically differentiated from Takayasu arteritis by a


InternalMed_Harrison

InternalMed_Harrison. data; however,tissueisrarelyreadilyavailableforexamination.IgG4-relateddisease is a potential cause of aortitis and periaortitis that is histologically differentiated from Takayasu arteritis by a dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, a storiform pattern of fibrosis, and obliterative phlebitis.


InternalMed_Harrison

InternalMed_Harrison. The long-term outcome of patients with Takayasu arteritis has varied widely between studies. Although two North American reports found overall survival to be ≥94%, the 5-year mortality rate from other studies has ranged from 0 to 35%. Disease-related mortality most often occurs from congestive heart failure, cerebrovascular events, myocardial infarction, aneurysm rupture, or renal failure. Even in the absence of life-threatening disease, Takayasu arteritis can be associated with significant morbidity. The course of the disease is variable, and although spontaneous remissions may occur, Takayasu arteritis is most often chronic and relapsing. Although glucocorticoid therapy in doses of 40–60 mg prednisone per day alleviates symptoms, there are no convincing studies that indicate that it increases survival. The combination of glucocorticoid therapy for acute signs and symptoms and an aggressive surgical and/or arterioplastic approach to stenosed vessels has markedly improved outcome and


InternalMed_Harrison

InternalMed_Harrison. survival. The combination of glucocorticoid therapy for acute signs and symptoms and an aggressive surgical and/or arterioplastic approach to stenosed vessels has markedly improved outcome and decreased morbidity by lessening the risk of stroke, correcting hypertension due to renal artery stenosis, and improving blood flow to ischemic viscera and limbs. Unless it is urgently required, surgical correction of stenosed arteries should be undertaken only when the vascular inflammatory process is well controlled with medical therapy. In individuals who are refractory to or unable to taper glucocorticoids, methotrexate in doses up to 25 mg per week has yielded encouraging results. Preliminary results with anti-TNF therapies have been encouraging, but will require further study through randomized trials to determine efficacy.


InternalMed_Harrison

InternalMed_Harrison. IgA vasculitis (Henoch-Schönlein) is a small-vessel vasculitis characterized by palpable purpura (most commonly distributed over the buttocks and lower extremities), arthralgias, gastrointestinal signs and symptoms, and glomerulonephritis. IgA vasculitis (Henoch-Schönlein) is usually seen in children; most patients range in age from 4 to 7 years; however, the disease may also be seen in infants and adults. It is not a rare disease; in one series it accounted for between 5 and 24 admissions per year at a pediatric hospital. The male-to-female ratio is 1.5:1. A seasonal variation with a peak incidence in spring has been noted.


InternalMed_Harrison

InternalMed_Harrison. The presumptive pathogenic mechanism for IgA (Henoch-Schönlein) vasculitis is immune-complex deposition. A number of inciting antigens have been suggested including upper respiratory tract infections, various drugs, foods, insect bites, and immunizations. IgA is the antibody class most often seen in the immune complexes and has been demonstrated in the renal biopsies of these patients.


InternalMed_Harrison

InternalMed_Harrison. In pediatric patients, palpable purpura is seen in virtually all patients; most patients develop polyarthralgias in the absence of frank arthritis. Gastrointestinal involvement, which is seen in almost 70% of pediatric patients, is characterized by colicky abdominal pain usually associated with nausea, vomiting, diarrhea, or constipation and is frequently accompanied by the passage of blood and mucus per rectum; bowel intussusception may occur. Renal involvement occurs in 10–50% of patients and is usually characterized by mild glomerulonephritis leadingtoproteinuriaandmicroscopic hematuria, with redblood cell casts in the majority of patients (Chap. 338); it usually resolves spontaneously without therapy. Rarely, a progressive glomerulonephritis will develop. In adults, presenting symptoms are most frequently related to the skin and joints, while initial complaints related to the gut are less common. Although certain studies have found that renal disease is more frequentandmore severe


InternalMed_Harrison

InternalMed_Harrison. are most frequently related to the skin and joints, while initial complaints related to the gut are less common. Although certain studies have found that renal disease is more frequentandmore severe inadults,thishasnot beenaconsistent finding. However, the course of renal disease in adults may be more insidious and thus requires close follow-up. Myocardial involvement can occur in adults but is rare in children.


InternalMed_Harrison

InternalMed_Harrison. Laboratory studies generally show amildleukocytosis, a normalplateletcount,andoccasionallyeosinophilia.Serumcomplementcomponents are normal, and IgA levels are elevated in about one-half of patients. ThediagnosisofIgAvasculitis(Henoch-Schönlein)isbasedonclinical signsandsymptoms.Skinbiopsyspecimencanbeusefulinconfirming leukocytoclastic vasculitis with IgA and C3 deposition by immunofluorescence. Renal biopsy is rarely needed for diagnosis but may provide prognostic information in some patients.


InternalMed_Harrison

InternalMed_Harrison. The prognosis of IgA vasculitis (Henoch-Schönlein) is excellent. Mortality is exceedingly rare, and 1–5% of children progress to end-stage renal disease. Most patients recover completely, and some do not require therapy. Treatment is similar for adults and children. When glucocorticoid therapy is required, prednisone, in doses of 1 mg/kg per day and tapered according to clinical response, has been shown to be useful in decreasing tissue edema, arthralgias, and abdominal discomfort; however, it has not proved beneficial in the treatment of skin or renal disease and does not appear to shorten the duration of active disease or lessen the chance of recurrence. Patients with rapidly progressive glomerulonephritis have been anecdotally reported to benefit from intensive plasma exchange combined with cytotoxic drugs. Disease recurrences have been reported in 10–40% of patients.


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InternalMed_Harrison. Cryoglobulins are cold-precipitable monoclonal or polyclonal immunoglobulins.Cryoglobulinemiamaybeassociatedwithasystemicvasculitis characterized by palpable purpura, arthralgias, weakness, neuropathy, and glomerulonephritis. Although this can be observed in association with a variety of underlying disorders including multiple myeloma, lymphoproliferative disorders, connective tissue diseases, infection, and liverdisease,inmanyinstancesitappearstobeidiopathic.Becauseofthe apparent absence of an underlying disease and the presence of cryoprecipitate containing oligoclonal/polyclonal immunoglobulins, this entity was referred to as essential mixed cryoglobulinemia. Since the discovery of hepatitis C, it has been established that the vast majority of patients who were considered to have essential mixed cryoglobulinemia have cryoglobulinemic vasculitis related to hepatitis C infection.


InternalMed_Harrison

InternalMed_Harrison. The incidence of cryoglobulinemic vasculitis has not been established. It has been estimated, however, that 5% of patients with chronic hepatitis C will develop cryoglobulinemic vasculitis. Skin biopsies in cryoglobulinemic vasculitis reveal an inflammatory infiltrate surrounding and involving blood vessel walls, with fibrinoid necrosis, endothelial cell hyperplasia, and hemorrhage. Deposition of immunoglobulin and complement is common. Abnormalities of uninvolved skin including basement membrane alterations and deposits in vessel walls may be found. Membranoproliferative glomerulonephritis is responsible for 80% of all renal lesions in cryoglobulinemicvasculitis.


InternalMed_Harrison

InternalMed_Harrison. TheassociationbetweenhepatitisCandcryoglobulinemicvasculitis has been supported by the high frequency of documented hepatitis C infection, the presence of hepatitis C RNA and anti–hepatitis C antibodies in serum cryoprecipitates, evidence of hepatitis C antigens in vasculitic skin lesions, and the effectiveness of antiviral therapy (see below). Current evidence suggests that in the majority of cases, cryoglobulinemic vasculitis occurs when an aberrant immune response to hepatitisC infectionleads totheformationofimmunecomplexesconsisting of hepatitis C antigens, polyclonal hepatitis C–specific IgG, and monoclonal IgM rheumatoid factor. The deposition of these immune complexes in blood vessel walls triggers an inflammatory cascade that results in cryoglobulinemic vasculitis.


InternalMed_Harrison

InternalMed_Harrison. The most common clinical manifestations of cryoglobulinemic vasculitis are cutaneous vasculitis, arthritis, peripheral neuropathy, and glomerulonephritis. Renal disease develops in 10–30% of patients. Life-threatening rapidly progressive glomerulonephritis or vasculitis of the CNS, gastrointestinal tract, or heart occurs infrequently. The presence of circulating cryoprecipitates is the fundamental finding in cryoglobulinemic vasculitis. Rheumatoid factor is almost always found and may be a useful clue to the disease when cryoglobulins are not detected. Hypocomplementemia occurs in 90% of patients. An elevated ESR and anemia occur frequently. Evidence for hepatitis C infection must be sought in all patients by testing for hepatitis C antibodies and hepatitis C RNA.