Antinuclear antibodies are seen in 20 \200\22370% of cases of JDM/JPM. Myositis-associated antibodies seen in adult disease (Jo-1) are rarely seen in childhood di sease. The increased frequency of malignancy seen in adults with DM within two years of onset of d isease is not seen in childhood DM or PM. Several agents have been associated with the onset of juvenile DM, which may also explain some temporal, seasonal, and regional differences in disease ons et. The most prominent agents to date have been RNA picornaviruses, group A B -hemolytic st reptococci, and Toxoplasma gondii . The true pathogenesis of juvenile DM in relation to inf ectious agents remains unclear. HLA associations include B8 and DRB1. \200 TNF- A promoter polymorphisms have also been i mplicated in pathogenesis. In general the clinical features of juvenile DM/PM are similar to adult disease. Fever, abd ominal pain, dysphagia, dyspnea and peripheral arthritis are seen. Skin ulceration is seen in 20% of patients and can be severe and disabling. Lipodystrophy is a recognized skin \201 nding. Calcinosis is more common in childhood (10 \200\22330% of patients) and the out come of this ranges from spontaneous resolution to chronic deposition and \202 exion cont ractures. Calcinosis is dif \201 cult to treat and causes long-term morbidity. Rapid disease control is important to help prevent damage. IV or oral corticosteroids are \201 rst line, followed by MTX. JDM in particular bene \201 ts from early and aggressive therapy, which may prevent calcinosis and other complications: \200 Methylprednisolone 30 mg/kg/dose (up to a maximum of 2g) twice weekly for one month \200 Prednisone 2 mg/kg/day \200 Intravenous immunoglobulin 2g/kg administered in divided doses over 5 days PM AND DM IN CHILDREN 415 Table 14.8 Bohan and Peter \200\231s criteria for the diagnosis of juvenile DM/PM Feature DM PM Characteristic rash Yes No Symmetrical proximal muscle weakness in the absence of other rheumatic/endocrine disease Yes Yes Elevated muscle enzymes Yes Yes Muscle histopathology Yes Yes Electromyographic changes of in \202 ammation Yes Yes Other treatments that have been used include IV immunoglobulin and cyclosporine A. Cyclopho sphamide is used for severe multisystem disease. In \202 iximab and IV bisphosphonates have shown some effect on muscle disease and calcinosis. Rituximab and autologous stem cell transplantation have been used in a small number of cases. Early physiotherapy and muscle strengthening is vital, and evidence suggests that this does not affect the in \202 ammatory process. \200 Disease activity a nd damage measures are now being used and validated, as in adult disease. This page intentionally left blank 417 Chapter 15 Primary vasculitides Introduction 418 Large-vessel vasculitis 421 Takayasu \200\231s arteritis 422 Polymyalgia r heumatica and giant cell arteritis 424 Polyarteritis nodosa 429 Granulomatosis with polyang iitis (Wegener \200\231s) 430 Other forms of ANCA-associated vasculitis: microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis (Churg-Strauss) 434 Small-ve ssel vasculitis 438 Kawasaki Disease 442 CHAPTER 15 Primary vasculitides 418 Introduction \200 The vasculitides are a heterogeneous group of relatively uncommon diseases that can arise as primary conditions or secondary to an established disease such a s RA (see Chapter 5) or SLE (see Chapter 10). The vasculitides are linked by the presence of vascular in \202 ammation, which can lead to one of two common outcomes: \200 Vessel wall destruction , leading to a neurysm or rupture \200 Stenosis , leading to tissue ischemia and necrosis In 1990, the American College of Rheumatology developed a classi \201 cation system based on vessel size, with the inclusion of a division between p rimary and secondary vasculitis (see Table 15.1). \200 In 1994, the Chapel Hill Consensus Conference (CHCC) developed a standard nomenclature for the primary systemic vasculitides based on clinical and laboratory features, and categorized by vessel size: \200 Large ves sel: Aorta and its major branches ( \200\234great vessels \200\235) \200 Medium vessel: M ain visceral arteries (e.g., renal, mesenteric) \200 Small vessel: Capillaries, arteriole s, and venules In 2012, the second Chapel Hill Consensus Conference recognized two additional categories of vasculitis: \200 Variable vessel vasculitis: Vasculitides th at can affect any caliber blood vessel Single organ vasculitis: Vasculitides that are inherently restricted to a single organ (as opposed to a very limited presentation of a systemic vasculitis). The 2012 Chapel Hill Consensus Conference also adopted a new nomenclature that de-emphasizes the use of eponyms: \200 Granulomatosis with polyangiitis (GPA) for Wegener \200\231s granulomatosis (WG) Eosinophilic granulomatosis with polyangiitis (EGPA) for the Churg- Strauss Syndrome (CSS) ANCA (see below) is helpful to de \201 ne a subset of the small vessel vasculitides that h ave a predilection for the respiratory tract and kidneys. These \200\234ANCA-associated va sculitides \200\235 include granulomatosis with polyangiitis, microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis. This classi \201 cation system is not perfect: Patients with \200\234large vessel vasculitis \200\235 and \200\234small vessel vasculiti s \200\235 can have disease that affects some medium-sized vessels. Not all patients with \200\234ANCA-associated vasculitis \200\235 have detectable levels of ANCA. This is still a useful framework for the clinician, however, since categorizing the patient into one of these groups can narrow the differential diagnosis con siderably. INTRODUCTION 419 Antineutrophil cytoplasmic antibody (ANCA) \200 ANCA exist in 2 main forms: Cytoplasmic (C-ANCA): caused by antibodies against proteinase-3 (PR3-ANCA), and is generall y associated with granulomatosis with polyangiitis (Wegener \200\231s granulomatosis) Perinuclear (P-ANCA): caused by antibodies against myeloperoxidase (MPO-ANCA), and is generally associated with microscopic polyangiitis and e osinophilic granulomatosis with polyangiitis (the Churg-Strauss Syndrome) Other ANCA-staining patterns (i.e., noncytoplasmic, nonperinuclear) can occur; moreover, the P-ANCA pattern may be caused by antibodies against antigens other than myeloperoxidase. These are sometimes referred to as \200\234atypical ANCA, \200\235 a nd do not predict the presence of vasculitis, although they can be found in Crohn \200\231s disease, immune-mediated neutropenia, and other autoimmune diseases. \200 Counterintuiti vely, patients with \200\234ANCA-associated vasculitis \200\235 can be ANCA-negative in up to 50% of cases. Therefore, the absence of ANCA does not completely exclude the diagnosis of an ANCA- associated vasculitis. Patients with active, untreated disease, however, are more likely to be ANCA-positive. The exact role that ANCA may play in the pathogenesis of vasculitis is still incompletely undersotood. Disease and damage assessment \200 To be complete, any description of a chronic disease ( such as primary systemic vasculitis) must include both a description of disease activity an d a description of disease damage. The concept of damage denotes the aspects of disease that are unlikely to reverse with immu nosuppression (such as pulmonary \201 brosis or renal insuf \201 ciency). Clinical trials of vasculitis commonly use the Birmingham Vasculitis Activity Score (BVAS) and Vasculitis Damage Index (VDI) to assess activity and damage, respectively. These instruments are most helpful for the assessment of the small- and medium-vessel vasculitides. Other clinical indices exist. The French Vasculitis Study Group (FVSG) has developed a prognostic Five Factor Score (FFS), which was revised in 2008 to include th e following elements: \200 Age > 65, \200 Renal insuf \201 ciency (i.e., serum creatin ine (cid:2) 1.7 mg/dL), \200 Cardiac involvement, \200 Gastrointestinal manifestations \200 ENT manifestations (for patients with granulomatosis with polyangiitis (Wegener \200\231s granulomatosis) only). Each of the \201 rst 4 items is worth 1 point. ENT manifestations in patients with granul omatosis with polyangiitis (Wegener \200\231s granulomatosis) are associated with decreased mortality; therefore, if present, 1 point is subtracted from the total score (so the maxim um FFS for any given patient is 4, not 5). CHAPTER 15 Primary vasculitides 420 Table 15.1 A classi \201 cation of systemic vasculitis Dominant vessel Primary disorders Secondary disorders Large arteries Giant cell arteritis. Takayasu \200\231s Aortitis in ankylosing spondylitis. Syphilitic aortitis Medium arteries Classic polyarteritis nodosa. Kawasaki disease Infection, e.g., hepatitis B. Hairy cell leukemia ANCA-associated (small/medium vessels) Granulomatosis with polyangiitis (Wegener \200\231s granulomatosis). Eosinophilic granuloma tosis with polyangiitis (Churg \200\223 Strauss syndrome). Microscopic polyangiitis Vasculitis secondary to autoimmune disease. Malignancy. Drugs. Infection, e.g., HIV Small vessels (leukocytoclastic) Henoch \200\223Sch nlein purpura. Essential mixedcryoglobulinemia Drugs. Malignancy. Infection, e.g., hepatitis B/C Variable vessel Beh et \200\231s disease, Cogan syndrome Single organ Primary CNS vasculitis, cutaneous angiitis The FFS is associated with the 5-year mortality of patients with ANCA-associated vasculitis and polyarteritis nodosa: \200 FFS=0 is associated with a 5-ye ar mortality of 7.5%. \200 FFS=1 is associated with a 5-year mortality of 20% \200 FFS> 1 is associated with a 5-year mortality of 47% LARGE-VESSEL VASCULITIS 421 Large-vessel vasculitis \200 The \200\234large vessels \200\235 include the aorta and it s main branches (i.e., the subclavian, axillary, carotid, and brachocephalic arteries). Pri mary and secondary forms of large vessel vasculitis are shown in Table 15.2. \200 The cla ssic forms of primary large vessel vasculitis are Takayasu \200\231s arteritis and giant cell arteritis. Because of the overlap in symptoms, polymyalgia rheumatica is often discussed with the larg e vessel vasculitides, as if it were a forme fruste of giant cell arteritis. Recent studies demonstrate, however, that it is probably more appropriate to think of polymyalgia rheumat ica as a syndrome comprised of bursitis, tenosynovitis, and synovitis that is frequently as sociated with giant cell arteritis. The clinical manifestations of large-vessel vasculitis can be predicted by the pattern of vessel involvement. \200 Arch aortitis leads to aneurysmal dilatation and aortic regurgitation. \200 Subclavian involvement causes arm claudication and diminished upper extremity pulses on examination. Carotid involvement may lead to visual loss, jaw claudication, and stroke. Involvement of any major blood vessel may cause bruits of physical examination. Unfortunately, a large vessel vasculitis may not be suspected until one of the above events has occurred. Table 15.2 The causes of large-vessel vasculitis Primary Takayasu \200\231s arteritis Giant cell arteritis* Secondary \200 Infection: bacterial, fungal, mycobacterial, spirochetal Rheumatoid arthritis Seronegative spondyloarthropathy Systemic lupus erythematosus Sarcoidosis Relapsing polychondritis Juvenile chronic arthritis Giant cell arteritis is discussed in this chapter in the section on polymyalgia rheumatica. \200 The secondary forms of large-vessel vasculitis are considerably less common that th e primary forms; these are discussed in their respective sections. CHAPTER 15 Primary vasculitides 422 Takayasu \200\231s arteritis \200 Takayasu \200\231s arteritis (TA) is a chronic granulom atous arteritis that affects the aorta and the great vessels. The pulmonary arteries can also be involved, altho ugh this is relatively uncommon. It is most common in Japan, Southeast Asia, India, and Mexico. In the United States, its an nual incidence is estimated at 2.6 per million. \200 TA tends to affect women (90% of cas es), with adolescents and young adults between 20 \200\22340 years at greatest risk. Classi \201 cation criteria distinguish TA from giant cell arteritis (GCA) by age at onset (i.e. , TA <40 years, GCA >50 years). Importantly, TA is not limited to patients of Asian descent; the majority of patients in the United States are white. The hallmark of the disease is arteritic in \202 ammatory in \201 ltrates that cause lumi nal narrowing or occlusion; clinically, this presents with bruits, claudication, and dimini shed (or asymmetric) pulses. \200 Lightheadedness, visual disturbance, and strokes can oc cur. Subclavian steal (i.e., dizziness caused by retrograde vertebral artery \202 ow) can be a n important cause of neurologic symptoms. Hypertension may develop as a consequence of (ostial) renal artery stenosis. Musculoskeletal symptoms , including arthralgias and myalgias, are not uncommon. Cardiovascular complications are an important cause of morbidity, and include aortic insuf \201 ciency, congestive heart failure, systemic hypertension, and ostial involvement of th e coronary arteries. \200 Traditionally, the diagnosis of TA has depended on angiography to demonstrate the characteristic changes of arterial dilatation, thrombosis, and aneurysm formation. \200 Conventional angiography has the added bene \201 t of allowing a comparison between central and peripheral blood pressures; because subclavian stenosis is a common consequence of this disease, a standard brachial (arm cuff) blood pressure readin g may underestimate central hypertension. Magnetic resonance imaging/angiography (MRI/MRA) has excellent resolution at the level of the large vessels, and may be the technique of choice for some patients. MR can also demonstrate evidence of vessel wall in \202 ammation, which could support a diagnosis of TA. High-resolution ultrasonography is sensitive for detecting carotid lesions. Ultrasonography has also been used to identify the presence of temporal ar teritis among patients with giant cell arteritis (due to the \200\234hypoechoic halo \200 \235 that forms around the in \202 amed artery), although this is not routinely used in th e United States due to widespread lack of expertise. PET scanning is useful to diagnose the presence of a large vessel vasculitis when more conventional technologies fail to demonstrate luminal abnormalities. T hat said, it is not clear whether it can be used to monitor response to therapy. TAKAYASU \200\231S ARTERITIS 423 Treatment \200 Initial medical treatment is with corticosteroids (prednisone 1 mg/kg/ day). Most patients should also be treated with methotrexate 20 \200\22325 mg po/ SQ weekly Resistant or severe cases may be treated with a TNF- A inhibitor (e.g., in \202 iximab 5mg /kg IV q 4 weeks) or cyclophosphamide 2mg/kg/day po. \200 Hypertension can be dif \201 c ult to manage, and may require angioplasty or surgery to address renal artery stenosis. Surgical management ranges from angioplasty to bypass procedures. \200 These are best per formed during the inactive phase of disease. \200 Angioplasty is often a temporizing meas ure, and lesions tend to restenose over time When intervention is required, surgical bypass is the treatment of choice. Overall operative mortality is 4%, associated mostly with aneurysm rupture. The prognosis depends mainly on the presence of hypertension and aortic incompetence. The m ajority of patients (75%) will have some impairment of daily living, and 50% are permanentl y disabled. \200 Mortality is low, 5- and 10-year survival rates reported as 80% and 90%, respectively. TA is not a contraindication to pregnancy. Cytotoxic agents should be stopped and steroids kept to as low a dose as possible. Obstetric decisions can be made on their own merits and not because of coexistence of TA. The main complications are exacerbation of hypertension a nd congestive cardiac failure. The anesthesiologist should be made aware of the diagnosis, as the patient may require invasive blood pressure monitoring during delivery. CHAPTER 15 Primary vasculitides 424 Polymyalgia rheumatica and giant cell arteritis Polymyalgia rheumatica (PMR) \200 The dia gnosis of PMR is based essentially on clinical symptoms and signs. The criteria of Jones an d Hazleman (1981) are succinct and practical (see Table 15.3). In 2012, the American College of Rheumatology and the European League Against Rheumatism pr oposed new classi \201 cation criteria for PMR. Using the new criteria, a patient 50 years old (or older) with bilateral shoulder pain may be classi \201 ed as having PMR in the pr esence of morning stiffness, new hip symptoms, and elevated acute phase reactants (see Tabl e 15.4). There may be apparent muscle weakness on testing, which is due to pain rather than intrinsic muscle disease. PMR is rare in patients <50 years old; the mean age of onset is 70. Prevalence among patients older than 50 years is 1 in 133, and women are affected more than men (ratio 2:1). There is also a higher frequency of diagnosis in northern latitudes. Parain \202 uenza, parvovirus B19, Mycoplasma pneumoniae and Chlamydia pneumoniae infectio ns have been shown to have a temporal relation to incidence peaks of PMR, although other st udies have found no relationship. HLA DRB1*04 and DRB*01 are associated with disease susceptibility. \200 Symptoms may star t asymmetrically but soon become bilateral. \200 Systemic features of malaise, weight los s, low-grade fever, and depression are common. Arthralgias and synovitis may occur. Up to 5% of patients with RA (see Chapter 5) have an initial PMR-like presentation. Pathological features of PMR are minor and include synovitis with a CD4+ T-cell in \201 ltrate similar to that seen in giant cell arteritis (GCA) (see text be low). The lack of speci \201 c clinical features, a speci \201 c laboratory test, and the prese nce of several conditions that can present with PMR-like symptoms, makes this a diagnosis o f exclusion (see Table 15.5). \200 Failure to respond to standard doses of corticosteroid s after a few weeks should trigger an aggressive evaluation for occult malignancy. \200 P MR and GCA have a close clinical relationship, although the reason for this is not clear. O ne-half of patients with GCA have symptoms of PMR and up to 20% of patients with PMR have h istological or clinical evidence of GCA. The pathogenesis for both conditions is not known. Giant cell arteritis (GCA) (Table 15.6) \200 GCA is a granulomatous arteritis of the aort a and larger vessels, with a predilection for the extracranial branches of the carotid arte ry. It is the most common form of primary systemic vasculitis in the United States; the ann ual incidence is estimated at 18 per 100,000. Like PMR, the female to male ratio is 2:1 POLYMYALGIA RHEUMATICA AND GIANT CELL ARTERITIS 425 Table 15.3 Criteria for the diagnosis of PMR 1. Shoulder and pelvic girdle pain which is primarily muscular in the absence of true muscle w eakness 2. Morning stiffness 3. Duration of at least 2 months (unless treated) 4. ESR >30 mm/h or CRP >6 mg/ml 5. Absence of in \202 ammatory arthritis or malignancy 6. Absence of muscle disease 7. Prompt and dramatic response to corticosteroids Jones JG and Hazeleman BL. The prognosis and management of polymyalgia rheumatica. Annals o f Rheumatic Diseases, 1981; 40: 1 \200\2235. Reprinted with permission of BMJ Publishing Gr oup, Ltd. Table 15.4 2012 ACR/EULAR Criteria for the Classi \201 cation of PMR A score of 4 or more is required to classify a patient as having PMR if the following crite ria are met: (1) (cid:2) 50 years old; (2) bilateral shoulder aching; (3) elevated ESR/CRP 1. Morning stiffness duration >45 minutes 2 points 2. Hip pain or limited range of motion 1 point 3. Absence of RF or ACPA 2 points 4. Absence of other joint involvement 1 point Dasgupta B et al. 2012 provisional classi \201 cation criteria for polymyalgia rheumatica: a European League Against Rheumatism/American College of Rheumatology collaborative initia tive. Ann Rheum Dis 2012; 71: 484 \200\22392. Table 15.5 Conditions that can mimic polymyalgia rheumatica 1. Rheumatic disease in the elderly, including rheumatoid arthritis and systemic lupus erythem atosus 2. In \202 ammatory myopathy 3. Hypo/hyperthyroidism 4. Carcinoma, myeloma 5. Chronic sepsis 6. Bilateral shoulder capsulitis 7. Osteoarthritis 8. Depression 9. Parkinsonism CHAPTER 15 Primary vasculitides 426 Infectious and genetic associations are also similar to PMR with evidence of disease \200\234clustering. \200\235 GCA is rare among African Americans. \200 Severe headache and scalp tenderness localized to the occiput or temporal area are common initial symptoms, and are present in 70% of cases. The temporal ar tery can be swollen, tender, and pulseless. Scalp necrosis has also been reported. Large arteries are affected in 15% of cases, leading to claudication, bruits, absent neck a nd arm pulses, and thoracic aorta aneurysm and dissection. Asymptomatic large-vessel abnorm alities, present on imaging studies, are considerably more common. Visual disturbance is usually an early \201 nding. Patients may complain of amaurosis fug ax, but visual loss due to retinal ischemia may be irreversible within hours. Diplopia and ptosis may also be seen. \200 Fundoscopy may show optic disc pallor, hemorrhages, and exu dates. Optic atrophy is a late \201 nding. Arteritic anterior ischemic optic neuropathy is the most common ophthalmologic \201 nding, and must be differentiated from nonarteritic anterior ischemic optic neuropathy, an idiopathic cause of painless visual loss that does not respond to ste roids. Jaw, arm, and tongue claudication are other common sinister features. Table 15.6 Diagnostic criteria for GCA Diagnostic scheme Criteria Jones and Hazleman (1981) Positive temporal artery biopsy or cranial artery tenderness One or more of: visual disturbance, headache, jaw pain, cerebrovascular insuf \201 ciency ESR > 30 mm/h or CRP > 6 mg/ml Response to corticosteroids American College of Rheumatology Three or more of: Age at onset >50 years New headache Temporal artery tenderness or decreased pulsation ESR over 50 mm/h Abnormal artery biopsies showing necrotizing arteritis with mononuclear in \201 ltrate or granulomatous in \202 ammation usually with multinucleated giant cells Jones JG and Hazeleman BL. The prognosis and management of polymyalgia rheumatica. Annals o f Rheumatic Diseases, 1981; 40: 1 \200\2235. Reprinted with permission of BMJ Publishing Gr oup, Ltd. POLYMYALGIA RHEUMATICA AND GIANT CELL ARTERITIS 427 Malaise, fatigue, weight loss, fever, and anemia are common. \200 Tongue claudication and dry cough are less common manifestations. \200 The ESR and CRP are characteristically el evated, but can be normal in up to 5% cases. Patients suspected of having giant cell arteritis should be evaluated with bilateral temporal artery biopsies, taking segments of 1.5 cm each. Treatment should n ot be delayed; biopsies may be helpful to con \201 rm the diagnosis up to two weeks after treatment with steroids was initiated. Unlike most forms of vasculitis, GCA does not cause \201 brinoid necrosis; the presence o f \201 brinoid necrosis on a temporal artery biopsy should prompt a search for another fo rm of vasculitis, such as granulomatosis with polyangiitis (Wegener \200\231s granulomatosi s), microscopic polyangiitis, or cryoglobulinemic vasculitis. Even following this protocol, temporal artery biopsies may be negative in up to 12% of pati ents with GCA. A negative temporal artery biopsy does not exclude this diagnosis. Doppler ultrasound and (more recently) MR have both been studied as possible substitutes fo r temporal artery biopsy, although this is not common practice in the United States. Ultras ound in particular is operator-dependent, and it may be dif \201 cult to \201 nd someone with the appropriate expertise to evaluate a patient for GCA. Similarly, PET is useful in showing abnormal metabolic activity in the aorta of many patien ts with GCA, but this is most useful to establish the initial diagnosis. It has not been va lidated to follow response to therapy. Treatment of PMR and GCA \200 Both conditions require corticosteroid treatment; however, the amount and duration of treatment required are quite different. PMR responds dramatically to low dose corticosteroids (e.g., prednisone 10 \200\22320 mg daily) within 24 hours; many patients will report substantial r elief within hours after their \201 rst dose. After treatment for 2 \200\2234 weeks, the prednisone dose may be decreased by 2.5 mg every 2 weeks until the patient reaches a mainte nance dose of 10 mg/day. Prednisone may subsequently be tapered in 1 mg increments. GCA requires treatment with high-dose steroids (e.g., prednisone 1 mg/kg/day, up to 80 mg d aily), and the patient may take a week or longer to experience substantial relief. After tr eatment for 1 month, prednisone may be gradually tapered over 12 months. Some studies have demonstrated the ef \201 cacy of MTX as a steroid- sparing agent for both GCA and PMR. A recent meta-analysis of trials in GCA indicates that the use of adjunctive MTX lowers the risk of relapse and cumulative corticosteroid dose, al though the bene \201 t is very modest. Although MTX for the treatment of GCA and PMR is no t standard, it is worth considering for some patients. CHAPTER 15 Primary vasculitides 428 The treatment of GCA requires a few additional considerations: \200 Patients with visual symptoms associated with GCA should be treated with intravenous pulse methylprednisolone therapy (1 g daily for 3 days) prior to i nitiating therapy with prednisone Daily low-dose (e.g., 81 mg) aspirin may prevent cranial ischemic events such as stroke and blindness, and should be considered if there is no contraindication. POLYARTERITIS NODOSA 429 Polyarteritis nodosa \200 Polyarteritis nodosa (PAN) is a necrotizing vasculitis of mediu m-sized arteries, leading to cutaneous ulcers, kidney infarction, mesenteric angina, and mo noneuritis multiplex. Mesenteric angina (i.e., abdominal pain 1 hour after eating) may be a late manifestation of splanchnic vasculitis, which may present as diarrhea due to hypoperfusion of the intestine s. Some cases of PAN have been linked to infection with hepatitis B. Patients with PAN should be screened for viral hepatitis, since these patients may require antiviral therapy in addi tion to immunosuppression. The Chapel Hill Consensus Conference created a distinction between \200\234classic \200\235 PAN (i.e., an ANCA-negative, medium-vessel vasculitis ass ociated with renal infarcts) and microscopic polyarteritis nodosa (i.e., an ANCA-positive, medium- and small-vessel vasculitis characterized by glomerulonephritis). This re-classi \201 cation (and the hepatitis B vaccine) have made PAN increasingly uncommon. \200 \200 \234Classic \200\235 PAN should further be distinguished from cutaneous polyarteritis nodosa, which presents with large, painful ulcerations of the lower extremiti es in the absence of internal organ involvement, and therefore is associated with a much lo wer mortality rate. The clinical features are shown in Table 14.8. Patients often present with nonspeci \201 c features of systemic disease including myalgias, arthralgias, weight loss, and fever. About 50% of cases develop a vasculitic rash, often with \200\234punched out \200\235 ulcers in the lower extremities. GI and renal involvement is common; 50% in both cases. Non- speci \201 c abdominal pain, gut/gallbladder infarction, and pancreatitis are all features . Renal disease usually appears in the form of renal infarct. Renal impairment is often mild and present in around 20% of cases. \200 Isolated organ involvement is rare, but disease affecting the skin, testes, epididymis, breasts, uterus, appendix, and gallbladder has been reported. Treatment and prognosis in all the small- and medium-vessel vasculitides is discussed at th e end of this section. CHAPTER 15 Primary vasculitides 430 Granulomatosis with polyangiitis (Wegener \200\231s granulomatosis) \200 Granulomatosis w ith polyangiitis (GPA)is the most prevalent of the so-called ANCA-associated vasculitides ( AAV), a group of diagnoses that includes microscopic polyangiitis and eosinophilic granulom atosis with polyangiitis (EGPA; the Churg-Strauss syndrome). Renal-limited vasculitis and drug-induced ANCA-associated vasculitis are less-common members of this group. GPA is a worldwide disease with a variable incidence of 4 \200\2239 per million. GPA is slightly more common in men than women, and most often appears in the fourt h and \201 fth decades (see Table 15.7). \200 Classically, GPA is described as a clinic al triad, with manifestations affecting the upper respiratory tract, lower respiratory trac t, and kidneys. However, patients may present with a wide range of clinical manifestations. \200 Some patients may have an indolent presentation characterized by respiratory tract involvement, such as sinusitis and pulmonary nodules. Others may have a more fulminant presentation, including rapidly progressive glomerulonephritis and pulmonary hemorrhage. \200 Different treatment strateg ies for these manifestations are discussed below. The clinical features of GPA Ear, nose, and throat \200 Up to 90% of patients have ear, n ose, and throat involvement. \200 Chronic sinusitis is a common initial presentation for GPA, and many patients will have been treated with several courses of antibiotics before th e correct diagnosis is reached. Other manifestations include nasal septal perforation, bloody nasal discharge ( \200\234cru sts \200\235), and nasal bridge collapse due to erosion of underlying cartilage ( \200\234s addle nose \200\235). Patients may also complain of diminished hearing, either due to sensorineural hearing loss or Eustachian tube dysfunction. Subglottic stenosis is a classic feature of GPA, and may present with hoarseness and strido r. Subglottic stenosis may worsen even when a patient is otherwise in remission, and respon ds better to localized therapy (i.e., direct steroid injections) than systemic therapy. In the oral cavity and oropharynx in \202 ammation can lead to mucosal ulcers or gingivitis ( \200\234strawberry gums \200\235) It is thought that Staphylococcus aureus has a role in disease pathogenesis. Nasal carriage in GPA patients is 3 times that of healthy populations. The ex act mechanisms leading to disease are unclear, but trimethoprim/sulfamethoxazole may bene \201 t patients with WG by eliminating S. aureus colonization. GRANULOMATOSIS WITH POLYANGIITIS 431 Table 15.7 Modi \201 ed American College of Rheumatology 1990 classi \201 cation criteria of granulomatosis with polyangiitis (Wegener \200\231s) \200\224 diagnosis requires 2 or m ore of the following: 1. Nasal or oral in \202 ammation: Development of painful or painless oral ulcers or purulent or bloody nasal discharge 2. Abnormal chest radiograph: The chest radiograph may show nodules, cavities, or in \201 ltr ate 3. Urinary sediment: Microscopic hematuria or red cell casts 4. Histological changes of granulomatous in \202 ammation on biopsy 5. PR3-ANCA (C-ANCA) positivity Pulmonary disease \200 80% of cases have pulmonary disease. \200 The classic pulmonary manifestation is cavitary parenchymal lesions, mimicking infection or malignancy. The tracheobronchial tree may be locally involved before any signs of generalized disease. Subglottic pseudotumors and/or stenosis cause stridor or dyspnea. Lower bronchial stenosis may cause atelectasis and obstructive pneumonia. Multiple nodules with or without cavitatio n may be found in the lungs of asymptomatic patients. Severe pulmonary disease is associated with alveolar capillaritis, hemorrhage, and hemoptys is, with ground glass in \201 ltrates on computed tomography (CT). The radiograph typicall y shows an alveolar or mixed alveolar \200\223interstitial pattern; the appearance may mimi c pulmonary edema and focal infection. Renal disease \200 Up to 90% of patients with generalized ( \200\234severe \200\235) GPA have renal involvement. Renal involvement can range from milder focal and segmental glomerulonephritis (GN) to fulminant diffuse necrotizing (rapidly progressive) and crescent ic GN, which may rapidly lead to end stage renal disease. The milder form of the condition is not common, manifesting in the asymptomatic patient as a nephritic picture of microscopic hematuria, active sediment, and mild renal impairment. Skin disease \200 40% of cases have skin disease. \200 Features include palpable purpur a due to a leukocytoclastic vasculitis, necrotic papules ( \200\234Churg-Strauss nodules \200\235), livedo reticularis, and pyoderma gangrenosum. CHAPTER 15 Primary vasculitides 432 Musculoskeletal symptoms \200 Musculoskeletal symptoms are observed in 60% of cases. \200 Symptoms can range from mild myalgias (in 50% of the cases) and arthralgias to overt arthritis. 20 \200\22330% of rheumatic symptoms may be related to a no nerosive and nondeforming polyarthropathy. Migratory arthralgias are a classic presentation for WG. Nervous system \200 About one-th ird of patients with GPA have involvement of the nervous system. Mononeuritis multiplex and distal sensorimotor polyneuropathy are the main lesions. Seizures and cerebritis are much less frequent events. Disseminated granulomatous lesions ( \200\234pachymeningitis \200\235) can spread to the retropharyngeal area and skull base with involvement of cranial nerves I, II, III, V I, VII, and VIII; pachymeningitis can also be associated with diabetes insipidus and mening itis. Eye disease \200 Granulomatous lesions may obstruct the nasolacrimal duct and cause orbit al pseudotumor, with optic nerve compression from masses developing in the retrobulbar spac e. Rarely a purulent sinusitis may spread and cause secondary bacterial orbital infection. Manifestations in the generalized stage of GPA include scleritis, episcleritis (red eye), vasculitis of the optic nerve, and occlusion of retinal arteries, i n addition to the granulomatous lesions described above. Investigation of GPA \200 Laboratory investigation should include ANCA, CBC with differen tial, routine chemistries, ESR, CRP, and urinalysis to look for an active sediment. Not all patients with GPA will be ANCA-positive; a negative ANCA test does not necessarily exclude this diagnosis. When suspicion of kidney disease exists, renal biopsy may be useful to con \201 rm a diagn osis of GPA, and may provide prognostic information as well. Sinus biopsies con \201 rm a diagnosis of GPA in only 33% of cases; biopsy often shows non speci \201 c evidence of in \202 ammation, and is most useful to exclude concomitant infe ction or malignancy. Pulmonary nodules are often asymptomatic; a patient diagnosed with GPA should undergo some form of chest imaging, regardless of symptoms. Treatment and prognosis of GPA is discussed with the other AAV, below. This page intentionally left blank CHAPTER 15 Primary vasculitides 434 Other forms of AAV: microscopic polyangiitis (MPA) and eosinophilic granulomatosis with pol yangiitis (EGPA) Microscopic polyangiitis (MPA) \200 MPA is classi \201 ed as a pulmonar y-renal (hemorrhage) syndrome, a group that also includes Goodpasture \200\231s disease and systemic lupus erythematosus. GPA and cryoglobulinemic vasculitis may also present as a pu lmonary-renal syndrome. MPA lacks the granulomatous manifestations characteristic of WG, such as sinus disease, sub glottic stenosis, and pulmonary nodules. \200 Unlike GPA, MPA is characterized by MPO-ANC A antibodies, which are associated with a P-ANCA staining pattern. Up to 80% of patients wi th MPA will be ANCA-positive. Like PAN, the male:female ratio is 2:1, with the majority of patients being Caucasian. The mean age of presentation is 50 years. Most patients with MPA will present with renal involvement in the form of a necrotizing glomerulonephritis, similar to what can be seen with GPA. Unlike most forms of vasculitis, glomerulonephritis from AAV is \200\234pauci-immune \200\235 (i.e., there is only minimal immunoglobulin deposition on immuno \202 uorescence stains). Pulmonary hemorrhage presents as hemoptysis, and can be surprisingly subtle in some patients. Although classically described as a life-threatening manifestation, younger patients may be minimally symptomatic. Bronchoscopy with bronchoalve olar lavage will demonstrate hemosiderin-laden macrophages. Chronic pulmonary capillaritis may eventually lead to pulmonary \201 brosis. Other clinical features of the disease are shown in Table 15.8. Eosinophilic granulomatosis with polyangiitis (EGPA; Churg \200\223Strauss syndrome) \200 This condition is often described as a clinical triad of adult-onset asthma, eosinophilia, and vasculitis. Typically, the asthma gradually worsens in intensity until the patient requires daily oral steroids for symptom control. Many of these patients will have been treated with a leukotri ene inhibitor (although leukotriene inhibitors do not cause the disease). Peripheral blood hypereosinophilia is typically mild, and resolves quickly upon treatment with oral corticosteroids. Other manifestations of hypereosinophilia include \200\234 \202 eeting \200\235 pulmonary in \201 ltrates, myocarditis, and interstitial nephritis; frank glomerulonephrit is is much less common in this diagnosis. Nerve involvement is a common manifestation of vasculitis among patients with the CSS, and patients should be examined for evidence of a sensory neuropathy or mononeuritis multiplex. OTHER FORMS OF AAV 435 Table 15.8 Clinical features at presentation (as % of cases) in classic polyarteritis nodos a, microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis (Churg \200 \223Strauss syndrome) Clinical feature Polyarteritis nodosa Microscopic polyangiitis EGPA Renal impairment 25% 90% 50% Pulmonary disease 40% 50% General 50%, asthma 100% Fever 60% 40% Skin vasculitis 40% 50% 50% Gastrointestinal disease 45% 20% 60% Cardiovascular disease 15% 20% 45% Peripheral neuropathy 10% 10% 60% Ear, nose, and throat 10% 20% Ocular disease 10% 20% Classically, it is said that the asthmatic component improves dramatically after the onset of the vasculitis, although this is often not the case. Cutaneous granulomas that form along the elbows and \201 ngers are called \200\234Churg-Strauss nodules \200\235; ironically, they appear more commonly i n association with GPA. ANCA-associated vasculitis: treatment and prognosis The AAV are approached using the same t reatment strategy, which con- sists of a remission induction phase and a remission maintena nce phase.