Update on vasculitis

Update on vasculitis Atul Khasnis, MD,a and Carol A. Langford, MD, MHSa,b

Cleveland, Ohio

The primary systemic vasculitides comprise a broad group of diseases identified by their clinical, histopathologic, and therapeutic characteristics. These unique entities have a broad spectrum of organ involvement and severity, which influences the approach to diagnosis and treatment. Immunosuppressive and cytotoxic agents are used to manage most vasculitic diseases. Long-term outcome is influenced by chronic sequelae from organ damage, disease relapses, and medication side effects. Further research is needed to understand these diseases and discover more efficacious yet less toxic therapeutic options. This review will focus on vasculitic syndromes more likely to be presented to an allergist/immunologist in an outpatient setting. (J Allergy Clin Immunol 2009;123:1226-36.) Key words: Vasculitis, antineutrophil cytoplasmic antibodies, diagnosis, treatment

Vasculitis is defined as inflammation of the blood vessels. It can occur as a result of a diverse range of triggers and disorders or as a primary disease of unknown cause. Clinical features (Table I), laboratory tests, radiographic abnormalities, and histologic findings all play an essential role in the diagnosis of vasculitis. Disease severity can range from mild to potentially life-threatening. Treatment for most of the vasculitides is potentially toxic, necessitating careful therapeutic decision making and driving the need for safer and more effective therapeutic options. By nature of their symptoms, patients with a vasculitic disease can present to the allergist/immunologist (Table II). A comprehensive review of all vasculitides is beyond the scope of this article, which will focus on those vasculitides that are most likely to be diagnosed by the practicing allergist/immunologist.

CLASSIFICATION Classification systems have been important in the study of vasculitic disease, although the ideal structure remains yet to be determined. In 1990, the American College of Rheumatology established classification criteria for 7 primary vasculitides.1 These criteria are useful for clinical research but should not be used for the diagnosis of an individual patient. According to the 1994 Chapel Hill Consensus Conference,2 these diseases were grouped based on vessel size (large, medium, and small), From athe Department of Rheumatic and Immunologic Diseases and bthe Center for Vasculitis Care and Research, Cleveland Clinic. Disclosure of potential conflict of interest: C. A. Langford receives research support from Genentech and Bristol-Myers Squibb and serves on the professional meetings subcommittee and the continuous professional development subcommittee for the American College of Rheumatology. A. Khasnis has declared that he has no conflict of interest. Received for publication October 14, 2008; revised April 13, 2009; accepted for publication April 20, 2009. Reprint requests: Carol A. Langford, MD, MHS, Cleveland Clinic, 9500 Euclid Ave, A50, Cleveland, OH 44195. E-mail: [email protected]. 0091-6749/$36.00 Ó 2009 American Academy of Allergy, Asthma & Immunology doi:10.1016/j.jaci.2009.04.024

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Abbreviations used ANCA: Antineutrophil cytoplasmic antibodies AZA: Azathioprine cANCA: Cytoplasmic antineutrophil cytoplasmic antibodies CSS: Churg-Strauss syndrome CV: Cryoglobulinemic vasculitis CYC: Cyclophosphamide EIA: Enzyme immunoassay GCA: Giant cell arteritis HSP: Henoch-Sch€onlein purpura HUVS: Hypocomplementemic urticarial vasculitis syndrome IIF: Indirect immunofluorescence IVIG: Intravenous immunoglobulin KD: Kawasaki disease LTA: Leukotriene antagonist MPA: Microscopic polyangiitis MPO: Myeloperoxidase MTX: Methotrexate PAN: Polyarteritis nodosa pANCA: Perinuclear antineutrophil cytoplasmic antibodies PR3: Proteinase 3 TAB: Temporal artery biopsy TAK: Takayasu arteritis TMP-SMZ: Trimethoprim-sulfamethoxazole UV: Urticarial vasculitis WG: Wegener granulomatosis

reflecting the predominantly involved vascular bed, but individual vasculitic diseases often disrespect these boundaries when affecting various organ systems.

PATHOGENESIS The pathogenesis of the vasculitides remains poorly understood. The role of the immune response in vascular injury varies in each disease. Three possible (but not exclusive) mechanisms of vascular damage (Table III) include immune complexes, antineutrophil cytoplasmic antibodies (ANCA) (humoral), and T-lymphocyte responses and granuloma formation (cell mediated).3 The resulting effects on the blood vessel are a combination of the immune attack and the response of the endothelium and vessel wall. For almost all forms of vasculitis, the triggering event (eg, antigen) initiating and driving this inflammatory response is unknown. Identification of the determinants of patterns of organ involvement is an area of great interest that is being actively studied.4 ANCA ANCA were first described by Davies et al5 in 1982. There are 2 types of ANCA based on indirect immunofluorescence (IIF) patterns: cytoplasmic (cANCA) and perinuclear (pANCA). The most common corresponding antigens identified by means of enzyme immunoassay (EIA) are proteinase 3 (PR3), a 29-kd serine protease, for cANCA and myeloperoxidase (MPO) for pANCA.6 All positive ANCA results based on IIF should be

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TABLE I. Clinical signs that should raise suspicion for a primary systemic vasculitis Fever of unknown origin Unexplained migratory polyarthritis Mononeuritis multiplex Rapidly progressive glomerulonephritis Palpable purpura Diffuse alveolar hemorrhage Unexplained infarction in multiple vascular territories Unexplained multisystem disease

TABLE II. Presentations of vasculitic syndromes to the allergist/ immunologist Vasculitic syndrome

‘‘Sinus’’ headache Headache Recurrent sinusitis, nosebleed and nasal crusting, otitis media, cough, hoarseness, nonresolving ‘‘pneumonia’’/ pulmonary infiltrates

MPA

cough 6 hemoptysis, nonresolving ‘‘pneumonia’’/ pulmonary infiltrates Allergic rhinitis, nasal polyposis, asthma, nonresolving ‘‘pneumonia’’/pulmonary infiltrates, eosinophilia

PAN KD Cutaneous vasculitis CV HSP UV

Antibody mediated CSS MPA WG Immune complex mediated CV Drug-induced vasculitis HSP Hepatitis B–associated PAN Pathogenic T-cell response mediated CSS GCA TAK WG

Presentation to allergist/immunologist

GCA TAK WG

CSS

TABLE III. Possible mechanisms of vasculitis

Suspected immunologic disease, postprandial abdominal pain with suspected food allergy Skin rash, soft tissue edema Skin lesions in which an allergy or drug reaction might be suspected Skin lesions in which an allergy or drug reaction might be suspected Purpura, soft tissue edema, or both in which an allergy might be suspected; food enterocolitis Chronic or subacute urticaria, angioedema

confirmed by means of EIA. The role of ANCA in disease pathogenesis remains unclear. In one hypothesis ANCA stimulate neutrophil degranulation, neutrophil activation, and apoptosis, causing direct and indirect endothelial damage.7 The strongest association of ANCA with disease has been the presence of PR3-cANCA in patients with Wegener granulomatosis (WG).8 MPO-pANCA are seen more commonly in microscopic polyangiitis (MPA) and Churg-Strauss syndrome (CSS). However, pANCAs have been reported in other conditions, such as infections, inflammatory bowel disease, and drug-induced vasculitis, in which they typically correspond to non-MPO antigens. This underscores the need to perform EIA antigenic identification to fully interpret positive ANCA results found on IIF. In patients with WG, the sensitivity of cANCA varies from 28% to 92%, depending on disease expression, but the specificity has been consistently as high as 80% to 100%. In patients with a high pretest probability of WG (sinusitis, active urine sediment, and pulmonary nodules/infiltrates in which infection has been excluded), the predictive value of PR3-cANCA exceeds 90%. In these cases initiation of treatment for WG might be justified without a tissue diagnosis. However, in cases with a lower probability of WG, such as isolated pulmonary disease, tissue

diagnosis before starting immunosuppressive therapy is important.9 The utility of PR3-cANCA to assess disease activity has been disappointing. A relationship between antibody titers and disease activity has not been observed.10-13 In a study of 156 patients with WG, decreasing ANCA titers did not predict time to remission, and increasing ANCA titers did not predict relapse.10 Increasing PR3-ANCA levels were associated with relapse in only 40% of cases over the next year. The decision to modify treatment in patients with WG should be based on clinical judgment and not on ANCA titers.

PRIMARY SYSTEMIC VASCULITIDES Giant cell arteritis Giant cell arteritis (GCA; also known as temporal arteritis) is a granulomatous large-vessel vasculitis that typically affects persons older than 50 years.14 Headache is a common feature of GCA, and patients can present to the allergist/immunologist with the symptom of ‘‘sinus’’ headache. Other symptoms of GCA can include fever, jaw or tongue claudication, and scalp tenderness. Coexistent symptoms of polymyalgia rheumatica occur in 40% to 50% of patients. Blindness from optic nerve ischemia (15% to 20% of patients) is the most dreaded complication of GCA. Other ocular manifestations from ischemia to extraocular muscles include diplopia and ptosis. Large-vessel (aorta and major branch) involvement occurs in approximately 27% of patients with GCA15 and can result in life-threatening aortic rupture or dissection.16 Findings on examination in patients with GCA include nodularity, tenderness or absent pulsations of the temporal arteries and other involved vessels, bruits, and asymmetric extremity blood pressure measurements. The erythrocyte sedimentation rate is usually, but not always, increased in patients with GCA. Other laboratory abnormalities include normochromic normocytic anemia, thrombocytosis, and increased alkaline phosphatase levels. Temporal artery biopsy (TAB) usually shows granulomatous inflammation of the media and adventitia, with histiocytes and mononuclear cells, giant cells, irregular fragmentation of the internal elastic lamina, neointimal proliferation, and sometimes luminal thrombosis (25%). A 3- to 5-cm segment of artery should be obtained and sectioned at multiple levels. Results of TAB are positive in 60% to 80% of patients with GCA; the yield is often

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FIG 1. Magnetic resonance angiography in a patient with TAK showing multiple stenoses at the origin of both common carotid arteries and the left subclavian artery.

lower in patients with large-vessel presentations. If the first biopsy result is negative, a contralateral TAB might be necessary. TAB can still yield useful information when performed within 4 weeks of starting treatment for GCA.17 Magnetic resonance angiography, computed tomographic angiography, or catheter-directed dye arteriography are established modalities for assessment of large-vessel involvement in patients with GCA. Temporal artery ultrasonography is an operator- and technique-dependent modality, which often diminishes its utility in the clinical evaluation of patients with GCA.18,19 In a patient in whom the suspicion of GCA is high, prompt treatment with glucocorticoids should be initiated, typically with prednisone at 40 to 60 mg/d. Glucocorticoids are the cornerstone of therapy and yield immediate symptomatic benefit and reduction in the risk of blindness. In a 5-year study of visual prognosis in patients with GCA, only 1% experienced visual loss after glucocorticoid therapy.20 Intravenous methylprednisolone (1 g for 3 days) is often administered to patients presenting with acute vision loss, with the goal of protecting vision in the unaffected eye. Antiplatelet therapy is beneficial in preventing ischemic complications of GCA, and 81 mg/d aspirin should be given to all patients with GCA without contraindications.21,22 Relapse occurs in more than 75% of patients,23 and 40% to 50% of patients with GCA are unable to taper prednisone completely, even after 2 to 3 years, with 35% to 65% of patients with prolonged prednisone exposure experiencing glucocorticoid-related toxicities. Methotrexate (MTX)23,24 and infliximab25 have not shown evidence of benefit as glucocorticoid-sparing agents in prospective randomized controlled trials. Other agents

have only been used in case reports or case series but should not be routinely used in the management of GCA. Acute mortality is uncommon in patients with GCA, although late mortality can occur from rupture or dissection of aortic aneurysms.16

Takayasu arteritis Takayasu arteritis (TAK) is a granulomatous large-vessel vasculitis that affects the aorta, its main branches, and the pulmonary arteries and that predominantly occurs in young women (Figure 1).26 Patients with TAK can present to the allergist/immunologist with headaches and dizziness. The symptoms of TAK typically reflect vascular hypoperfusion and include limb claudication, double vision or a rapid decrease in visual acuity, chest pain, congestive heart failure, transient ischemic attack, or stroke. Physical examination in patients with TAK might reveal hypertension, bruits (often involving the carotid or subclavian arteries), diminished pulses, asymmetric extremity blood pressure, aortic valvular regurgitation, and arterial tenderness. Glucocorticoids form the foundation of treatment in TAK, and once-weekly MTX is often also used.27 Surgical revascularization might be necessary to improve perfusion and should be preferably undertaken while the disease is clinically inactive. WG WG is a granulomatous, necrotizing, small- and mediumvessel vasculitis that most commonly involves the upper airways, lower airways, and kidneys (Table IV). However, WG is a

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TABLE IV. Clinical features of the medium- and small-vessel vasculitides

Sinus disease Subglottic stenosis Asthma Pulmonary nodules Cavitary lung disease Alveolar hemorrhage Glomerulonephritis Renal artery involvement Neuropathy Cardiac involvement Granuloma formation Eosinophilia ANCA positivity Microaneurysm formation

WG

MPA

CSS

PAN

111 11 2 111 11 11 111 2 1 1 111 2 111 2

2 2 2 1 2 11 111 2 1 1 2 2 111 2

11 2 111 1 2 1 1 2 11 11 11 111 1 2

2 2 2 2 2 2 2 11 111 1 2 2 2 11

multisystem disease with varied manifestations based on the site of involvement. WG can occur at any age (average, 40-55 years) and affects men and women equally.28 WG occurs at an estimated frequency of 3 per 100,000 persons; an increased familial risk has not been found.29,30 Patients with WG might present to the allergist/immunologist particularly for upper airways symptoms that can include recurrent or nonresolving sinusitis, nosebleeds, and nasal crusting. More than 90% of patients first seek medical attention for symptoms related to the upper airways, lower airways, or both. Nasal and sinus mucosal inflammation can produce sinus pressure and pain, epistaxis, persistent otitis media with effusion or decreased hearing, and cartilage ischemia with nasal septal perforation, resulting in a saddle nose deformity. Tracheal involvement can result in subglottic stenosis. Pulmonary involvement can present as radiographic abnormalities, such as single or multiple cavitating/noncavitating nodules (Fig 2) or ground-glass infiltrates reflecting diffuse alveolar hemorrhage (Fig 3). Renal involvement occurs as microscopic hematuria, active urinary sediment with red blood cell casts, proteinuria, and rapidly progressive renal failure. Other signs and symptoms include skin rash, migratory arthritis, ocular involvement (scleritis, corneal ulceration, and orbital disease; Fig 4), and peripheral (mononeuritis multiplex) or central nervous system involvement with or without pachymeningitis. Patients with active WG have a greater risk of venous thrombosis31 and should be aggressively evaluated for deep venous thrombosis and pulmonary embolism if suspected clinically. The underlying mechanisms for the increased propensity to venous thrombosis are unclear, with no thrombophilic abnormalities discovered thus far.32 WG is diagnosed based on the presence of characteristic histologic features in a clinically compatible setting.28 ANCA positivity is useful in the diagnosis of patients with a high pretest probability of WG and might obviate the need for biopsy. In a study of 180 patients (71% with severe disease and 29% with limited disease) with active WG, 96% with severe disease and 83% with limited disease had positive ANCA results; 82% has positive PR3-ANCA results, as determined by means of EIA.33 Surgically obtained biopsy specimens from abnormal pulmonary parenchyma demonstrate diagnostic changes in 91% of cases; upper airways biopsy specimens yield diagnostic features in only 21% of cases. The characteristic renal histology is focal, segmental,

FIG 2. WG involving the lungs with pulmonary nodules.

necrotizing, crescentic glomerulonephritis with few to no immune complexes on immunofluorescence and electron microscopy. Before the development of treatment, the mean survival of patients with WG was 5 months, with mortality occurring from renal or pulmonary failure. The introduction of treatment with cyclophosphamide (CYC) and glucocorticoids by Fauci and Wolff34 dramatically changed the outcome for patients with WG. Although effective therapy has resulted in long-term survival, relapse occurs in at least 50% of patients.28 The use of strategies to minimize and prevent therapy-related complications play an important role in the management of WG (Table V). Patients with active severe organ- or life-threatening WG should be treated with 2 mg/kg/d CYC and 1 mg/kg/d prednisone.28,35 Daily CYC is almost always administered orally, although hospitalized patients who are unable to take oral medications can receive the same dose of daily CYC intravenously as they would normally receive by mouth. With this therapy, 91% of patients had marked improvement and 75% achieved complete remission, and in 80% survival was observed.28 Fulminant disease can be treated with 1 g/d intravenous methylprednisolone in divided doses for 3 days and 3 to 4 mg/kg/d intravenous or oral CYC for 3 days, after which time it is reduced to 2 mg/kg/d.35 After 4 weeks, if there is improvement, the prednisone is tapered to discontinuation by 6 to 9 months. CYC should be used only for the first 3 to 6 months to induce remission, after which time CYC should be stopped and switched to weekly MTX or daily azathioprine (AZA) for remission maintenance. In a study of 31 patients who were induced with oral CYC and prednisone followed by MTX maintenance, remission was induced in 100% at a median of 3 months, with the ability to discontinue prednisone by 8 months.36 The initial recommended dose of MTX is 15 mg/wk and increased to 20 to 25 mg/wk over 2 to 4 weeks in the absence of toxicity (Table V).36 In a trial of 155 patients performed by the European Vasculitis Study Group, patients were initially treated with daily oral CYC and prednisolone for 3 to 6 months and then randomized to either 2 mg/kg/d AZA or to continue oral CYC for a total of 1 year.37 At the primary end point (relapse by 18 months), the relapse rate was no different

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FIG 3. WG involving the lungs with diffuse alveolar hemorrhage and pulmonary nodules.

in the AZA and CYC groups. These data support the use of induction-maintenance regimens to successfully induce remission while lessening the duration of exposure and risk of toxicity from CYC. A smaller body of data has been published with mycophenolate mofetil38 and leflunomide39 for remission maintenance. A combination of weekly MTX and daily prednisone can be used to induce remission of nonsevere WG. The favorable open-label experience from the National Institutes of Health40 was supported by a randomized controlled trial conducted by the European Vasculitis Study Group.41 In this study of 100 patients with nonsevere disease randomized to receive either weekly MTX or daily oral CYC, MTX was not inferior to CYC for the induction of remission at 6 months. A higher rate of relapse observed in this trial likely reflected the discontinuation of treatment after 12 months. Although the optimal duration of maintenance therapy remains unclear, in the absence of toxicity, maintenance treatment should be continued for at least 2 years before discontinuation is considered.42 Trimethoprim-sulfamethoxazole (TMP-SMZ) has been used for WG confined to the upper airways but should not be given alone for the treatment of disease involving other organs. In a study of TMPSMZ to prevent relapses in patients with WG, TMP-SMZ was shown to reduce only those relapses involving the upper airways.43 However, it has an important role as prophylaxis for Pneumocystis jiroveci infection, which can occur in up to 10% of patients with WG receiving induction therapy. In patients with severe renal vasculitis (defined as a serum creatinine value >5.8 mg/dL), the use of plasma exchange in addition to oral CYC and prednisolone reduced the risk of progression to end-stage renal disease by 24% over 1 year.44 Subglottic stenosis can be treated with mechanical dilatation and local glucocorticoid injection.45 Biologic therapies have been increasingly explored in WG. The Wegener’s Granulomatosis Etanercept Trial examined the role of etanercept to sustain remission in 180 patients with WG.46 In this trial patients were randomized to receive 25 mg of subcutaneous etanercept twice weekly or placebo in combination with standard induction treatment that included CYC and glucocorticoids for

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FIG 4. WG involving the right orbit and paranasal sinuses, resulting in an orbital mass and enophthalmos.

severe disease or MTX and glucocorticoids for mild disease. No significant differences were found between etanercept and placebo in rates of sustained remissions, sustained periods of low levels of disease activity, time to sustained remission, or numbers of disease flares. Of note, an increased number of solid cancers was noted in patients receiving concurrent etanercept and CYC, raising caution against the combination of anti-TNF therapies and alkylating agents. Although an open-label study suggested more favorable results with infliximab,47 this agent cannot be recommended in the absence of a randomized trial. Based on promising preliminary studies,48,49 rituximab is being studied prospectively to better define its role and efficacy in the treatment of WG.

MPA MPA is a necrotizing small-vessel vasculitis characterized by few or no immune deposits. MPA has many similarities to WG, which has provided useful insights regarding diagnosis and management pending further studies. It is more common in male subjects, and the average age of onset is 50 years. Clinical features of MPA (Table IV) include disease involving the kidneys (79%), lungs (12% to 29%), joints (65% to 72%), skin (44% to 58%), gastrointestinal tract (32% to 58%), and peripheral nerves (14% to 36%).50 Patients can present to the allergist/ immunologist for persistent cough with or without hemoptysis. MPA is diagnosed based on the presence of compatible clinical features and histologic findings on tissue biopsy. In contrast to WG, MPA is considered to lack granulomatous inflammation. Pulmonary pathology shows capillaritis and absence of linear immunofluorescence, differentiating this entity from antiglomerular basement membrane antibody disease (Goodpasture syndrome). The renal histology is similar to that of WG in being a focal segmental necrotizing glomerulonephritis with few to no immune complexes. Patients with severe disease involving the lung, kidney, or nerve should be treated initially with 2 mg/kg/d oral CYC and 1 mg/kg/d prednisone, followed by substitution with a less toxic agent, such as weekly MTX or daily AZA, after the 3- to 6-month

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TABLE V. Drug toxicity and monitoring recommendations Medication

Glucocorticoids

CYC

MTX

AZA

Mycophenolate mofetil

Adverse effects

Monitoring recommendations

Increased risk of infection Hypertension Hyperglycemia Cataract Osteoporosis Avascular necrosis Weight gain Dyslipidemia Mood changes (including psychosis) Striae and acne Poor wound healing Growth retardation in children Increased risk of infection Bone marrow toxicity Hemorrhagic cystitis Bladder cancer Myelodysplasia Infertility Pulmonary fibrosis (rare) Teratogenicity Increased risk of infection Hepatotoxicity Acute pneumonitis Bone marrow toxicity Mucositis Teratogenicity Possible lymphoma Increased risk of infection Bone marrow toxicity Hepatotoxicity Possible leukemia/lymphoma Increased risk of infection Bone marrow toxicity Gastrointestinal disturbance Teratogenicity

Periodic comprehensive metabolic panel Annual DXA scanning Prophylaxis for Pneumocystis jiroveci when combined with another agent

CBC once a week Urinalysis every 1-4 wk Adjust dose to keep WBC count >3500/mm3 Advise patient to take in the morning Drink a large amount of fluid to maintain a dilute urine Urine cytology every 6-12 mo Cystoscopy for nonglomerular hematuria Effective contraception CBC, AST, ALT, serum creatinine every 1-2 wk for the first month then every 4 wk thereafter Abstain from alcohol Folic acid, 1 mg daily, or folinic acid, 5 mg once a week, 24 hours after MTX Effective contraception Check TPMT activity before starting therapy CBC, AST, ALT every week for the first month, every 2 wk for the second month, and every 4 wk thereafter Effective contraception CBC every week for the first month, every 2 wk for the second month, and every 4 wk thereafter Pregnancy testing in women of child-bearing potential before initiation Effective contraception

DXA, Dual energy X-ray absorptiometry; CBC, complete blood count; WBC, white blood cell count; AST, aspartate aminotransferase; ALT, alanine aminotransferase; TPMT, thiopurine methyltransferase.

induction period.37,51 In a study of 595 patients (153 with MPA), 13 (9%) deaths and 140 survivors were observed.52 In one series the estimated 5-year survival rate of patients with MPA was 74%.53 Relapses occur in at least 38% of patients.

CSS CSS is a rare disease characterized by asthma, fever, hypereosinophilia, and systemic vasculitis. It has a prevalence of 3 per million and has been observed in adults of all ages but is rare in children and adolescents and occurs equally between the sexes.54 In a study of the general population of a French suburb, the estimated prevalence was 10.7 per million.55 Allergists/immunologists might evaluate patients with CSS for recurrent allergic rhinitis, difficult-to-treat asthma, nonresolving ‘‘pneumonia’’/ pulmonary infiltrates, or persistent eosinophilia. CSS has been described as having 3 phases: a prodromal phase (allergic rhinitis and asthma), a phase characterized by peripheral eosinophilia and eosinophilic tissue infiltrates, and a vasculitic phase with visceral involvement (Table IV). This division is arbitrary because these phases might not be distinct, might not all occur, or might not occur in the above sequence. In a 32-year study

of 96 patients with CSS, asthma was the most common presentation, and mononeuritis was the second.56 Pulmonary imaging findings include subpleural ground-glass opacities, lobular consolidation, centrilobular nodules, bronchial wall thickening, interlobular septal thickening, hyperinflation, mediastinal or hilar lymphadenopathy, and pleural or pericardial effusion.57 Peripheral eosinophilia (absolute eosinophil count usually >1500) is typically present before glucocorticoid therapy. Other laboratory findings often include an increased erythrocyte sedimentation rate, C-reactive protein level, and IgE level. ANCA results are positive in approximately 50% of cases (predominantly MPO-pANCA).56 The histologic features of CSS include eosinophilic tissue infiltrates, extravascular ‘‘allergic’’ granulomas, and small-vessel necrotizing vasculitis.58 Vasculitis can be difficult to definitively establish, making clinical manifestations particularly important in the diagnosis. Whether there is an association between leukotriene antagonists (LTAs) and CSS remains unclear. In a retrospective analysis of 62 patients who had CSS while taking LTAs, 57 had CSS within the first year of starting LTAs, and 48 had CSS within 6 months.59 In 2 cases re-exposure to LTAs was associated with recurrence of CSS within 2 weeks, despite a steady dose of glucocorticoids. A possible

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relationship between exposure to different LTAs and specific organ system involvement in patients with CSS was also observed. Prednisone (1 mg/kg/d) alone is effective for many manifestations of CSS.60 Asthma is often the major component that flares during prednisone taper, even after the vasculitis is in remission. Combination therapy with glucocorticoids and oral CYC (2 mg/ kg/d) is reserved for life-threatening disease. Other agents with reported treatment success in uncontrolled studies include intravenous immunoglobulin (IVIG), MTX, and IFN-a. The prognosis in CSS is determined based on the severity. Cardiac involvement is the main cause of death and is a poor prognostic sign.

Polyarteritis nodosa Following its distinction from MPA in the Chapel Hill Consensus Conference, polyarteritis nodosa (PAN) became defined as a medium-vessel disease. The reported annual incidence rates of PAN have ranged from 2 to 9 per million annually. PAN appears to affect men and women, with approximately equal frequencies in all ethnic groups.61 The most common clinical manifestations of PAN include constitutional symptoms (fever, weight loss, malaise, and night sweats), hypertension, musculoskeletal symptoms, and symptoms from vasculitic involvement of nerves, gastrointestinal tract, skin, heart, and nonglomerular renal vessels (Table IV). Patients with PAN might be referred to an allergist/immunologist by colleagues for a suspected immunologic disease. PAN is diagnosed by means of biopsy or arteriography based on the organ system involved. Biopsy specimens reveal necrotizing inflammation involving the medium-sized or small arteries, with abundant neutrophils, fibrinoid changes, and disruption of the internal elastic lamina. Arteriography is often performed to assess the visceral and renal circulation, in patients with symptoms such as mesenteric ischemia and severe hypertension. Angiographic changes suggesting PAN include microaneurysms, stenoses, occlusion, or a beaded pattern (alternate narrowing and dilation). In an angiographic study of 56 patients with PAN, 98% showed occlusive changes, 48% showed aneurysmal changes, and 12% showed ectasia.62 Patients with severe life-threatening disease affecting the gastrointestinal tract, heart, or central nervous system should be treated with 2 mg/kg/d oral CYC and glucocorticoids.63 In patients with non–life-threatening or non–organ-threatening disease, glucocorticoids alone might be justified as initial therapy, with CYC added for worsening disease or in patients unable to taper prednisone. Plasma exchange might be necessary in severe cases.64 In a study of 595 patients (200 with PAN), 18 (9%) died in the first year, and 182 survived.52 The estimated 5-year survival rate with treatment was 80%, with death being influenced by disease severity and treatment. Relapses are infrequent (8% to 19% of patients) and most commonly occur off of therapy. A PAN-like vasculitis is also seen with viral infections, including hepatitis B and C and HIV. In a study of 115 patients with hepatitis B–associated PAN, treatment with glucocorticoids, antiviral treatment, and plasma exchange induced remission in 81% patients, with a 10% relapse rate.65 Seroconversion was associated with complete remission, underlining the importance of the viral infection driving the immune complex–mediated vasculitis. Plasma exchange might aid faster clearance of the immune complexes. Patients usually require glucocorticoids, alone or with CYC, depending on the disease severity to initially gain control of the

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active vasculitis. Once clinical improvement is observed, immunosuppression should be withdrawn while continuing antiviral treatment.

Cutaneous vasculitis Cutaneous vasculitis is the most commonly encountered vasculitic manifestation in clinical practice. Patients with cutaneous vasculitis might present to the allergist/immunologist because of a presumed drug allergy or chronic urticaria. Skin lesions appear as palpable purpura, necrotic papules, cutaneous infarcts, urticaria, hemorrhagic vesicles, indurated erythema, or ulcerative lesions. Histologically, dermal small-vessel inflammation is seen, often with leukocytoclasis. Deeper biopsy specimens, extending to the subcutaneous tissue and taken from the most tender, reddish, or purpuric skin lesions can show coexistence of pandermal, small-vessel vasculitis and subcutaneous mediumvessel vasculitis. Cutaneous vasculitis might be idiopathic or more commonly occur because of medications, infections, allergies, malignancies, connective tissue diseases, or a primary systemic vasculitis.66 Idiopathic cutaneous vasculitis is a diagnosis of exclusion but once diagnosed might not require specific treatment other than observation and measures such as leg elevation. Glucocorticoids are often used, but there is no optimal regimen for treatment. Other medications that have been used include nonsteroidal anti-inflammatory drugs, dapsone, colchicine, antihistamines, and pentoxifylline. MTX or AZA have been used for more severe idiopathic cutaneous vasculitis. Cryoglobulinemic vasculitis Cryoglobulins are monoclonal or polyclonal immunoglobulins that precipitate at temperatures of less than 378C and redissolve on warming. They occur in a variety of diseases, including lymphoid neoplasms, chronic infections, and inflammatory and autoimmune diseases. Hepatitis C infection is the leading cause of cryoglobulinemia. Cryoglobulinemic vasculitis (CV) is a smallvessel vasculitis caused by deposition of circulating immune complexes (cryoglobulins and complement) in concert with hemodynamic and local factors. C1q and its receptor binding in the cryoprecipitate have been shown to facilitate binding of the immune complex to endothelial cells. Similar to cutaneous vasculitis, patients with CV might initially be referred to the allergist/immunologist with concerns of a drug-induced or other allergy-related skin rash. In a series of 40 patients with mixed cryoglobulinemia and CV, a clinical triad consisting of recurrent palpable purpura (100%), polyarthralgias (73%), and renal disease (55%) was observed.67 Twenty-two patients had clinical renal disease manifesting as significant proteinuria, diastolic hypertension (64%), edema (77%), renal failure (46%), and nephritic syndrome (22%). Pathology of glomerular disease showed deposition of IgG, IgM, and complement, with coexistent renal arteritis in 15 cases. Follow-up over 21 years from the onset of symptoms revealed that renal involvement predicts poor prognosis. The treatment of CV can be approached based on the different pathophysiologic mechanisms at work and the cause. For patients with hepatitis C–associated CV, antiviral therapy should be firstline treatment. For severe manifestations, such as vasculitis, immunosuppression with glucocorticoids, CYC, or AZA can be administered. Plasma exchange serves to remove immune

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complexes that form an important mechanism of organ damage. Rituximab can be used for resistant CVor in the setting of certain B-cell lymphoproliferative disorders. Recently, rituximab, along with interferon and ribavirin, has been studied with favorable results in the management of hepatitis C–associated CV.68

Kawasaki disease Kawasaki disease (KD) is an acute vasculitis that affects children in all parts of the world and represents the primary cause of acquired heart disease in children from the United States and Japan.69 Eighty percent of cases of KD occur before the age of 5 years, and boys are affected 1.5 times more often than girls. The long-term mortality from cardiac sequelae is also greater in male subjects.70 The incidence of KD in Japan and in children of Japanese ancestry is as high as 112/100,000 among children less than 5 years old. In the United States the median age of affection is 2 years. KD is most common among Americans of Asian and Pacific Island descent (32.5/100,000 among children <5 years old) and lowest in white subjects (9.1/100,000 among children <5 years old).71 KD begins as an acute febrile illness that is followed within the first 1 to 3 days by rash, conjunctival injection, and oral mucosal changes. Extremity changes, including brawny induration, occur early, followed by desquamation; 50% to 75% have cervical adenopathy. Together with fever for at least 5 days, these features constitute the diagnostic criteria for KD.72 KD can be diagnosed in the absence of some of these criteria when coronary artery abnormalities are present. Cardiac involvement is responsible for most of the disease-related morbidity and mortality. Aneurysms appear 1 to 4 weeks after the onset of fever and develop in 15% to 25% of untreated children. IVIG (2 g/kg) as a single infusion has been shown to prevent coronary aneurysm formation, lessen fever, and reduce myocardial inflammation.73 Aspirin (80-100 mg/kg/d) is given concurrently with IVIG, but it does not affect coronary artery aneurysm formation.74 For KD refractory to IVIG, there has been anecdotal experience with glucocorticoids, pentoxifylline, plasma exchange, ulinastatin, abciximab (for large aneurysms), infliximab, and CYC, although larger trials are needed to clearly establish efficacy. An echocardiogram is recommended at baseline and at 2, 6, and 8 weeks after onset of the disease. Follow-up echocardiography performed 1 year after the onset of the illness is unlikely to reveal coronary artery enlargement in patients whose echocardiographic findings were normal at 4 to 8 weeks.75 However, repeat echocardiography beyond 8 weeks in patients with previously normal findings might be considered because other abnormalities in the coronary artery vasculature (aneurysms) and aortic root (dilatation with or without valvular regurgitation) can potentially develop, even among patients with normal baseline echocardiograms. Other means to assess the coronary circulation in patients with KD include magnetic resonance imaging/magnetic resonance angiography, ultrafast computed tomography, pharmacologic cardiac stress testing, magnetic resonance imaging stress testing, myocardial perfusion studies, and conventional angiography. Overall, 50% to 67% of aneurysms resolve within 1 to 2 years depending on size, age of onset of disease, shape of the aneurysm (fusiform more likely than saccular), and location (distal more likely than proximal coronary artery).73 Children with multiple aneurysms, giant aneurysms, or coronary artery obstruction require close follow-up and possible long-term anticoagulation.

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€ nlein purpura Henoch-Scho Henoch-Sch€ onlein purpura (HSP) is a small-vessel vasculitis that predominantly affects children.76 The allergist/immunologist might see these patients for a suspected drug allergy or immunologic condition. The main clinical features of HSP include purpura (100%), arthritis (82%), abdominal pain (63%), gastrointestinal bleeding (33%), and nephritis (40%). Uncommon manifestations of HSP include bullous skin lesions, testicular involvement, seizures, and intestinal obstruction.77 Gastrointestinal involvement can be complicated by intussusception. Renal involvement can progress to end-stage renal disease in 2% to 5% of cases. Recurrence occurs in up to 40%, mostly within the first 3 months, but can occur up to 18 months later. HSP can be diagnosed on clinical grounds combined with laboratory testing in typical cases. In atypical cases tissue biopsies might be undertaken and reveal leukocytoclastic vasculitis with IgA deposition in the blood vessel walls. HSP is typically self-limited, but glucocorticoids might lessen tissue edema, arthritis, and abdominal discomfort and decrease the risk of intussusception. However, glucocorticoid therapy does not prevent recurrence of abdominal symptoms, skin involvement, or renal disease and does not appear to shorten the duration or lessen the likelihood of relapse.76 Glucocorticoids combined with a cytotoxic agent might be beneficial in patients with active glomerulonephritis and progressive renal insufficiency. Outcome is usually excellent in children, but in adults glomerulonephritis can be more severe and can lead to renal insufficiency in up to 13% of cases.78 Predictors of nephropathy in adults include purpura above the waist, recent history of infection, pyrexia, and increased markers of inflammation.79 In a British study of adults with HSP, predictors of progression to end-stage renal disease included proteinuria (>1 g/d) during follow-up, hypertension at presentation and during follow-up, renal impairment at presentation, age less than 30 years, male sex, crescents affecting less than 50% of glomeruli, and interstitial fibrosis and tubular atrophy on renal biopsy.80 In a systematic review permanent renal damage was never observed after normal urinalysis compared with being seen in 1.6% of those with isolated urinary abnormalities and 19.5% of those with nephritic or nephrotic syndrome.81 It was recommended that even with a normal baseline urinalysis, testing should be continued for 6 months. If renal function stays normal, no further follow-up is required. Urticarial vasculitis Urticarial vasculitis (UV) is characterized by a cutaneous presentation resembling urticaria and inflammation of dermal capillaries and postcapillary venules on skin biopsy. Patients with UV commonly present to the allergist/immunologist for evaluation of chronic or subacute urticaria. The characteristics of urticaria that suggest UV are the duration of symptoms (usually >24 hours), a violaceous color to the lesions, association with burning pain that is more frequent than pruritus, and residual pigmentation after resolution of the lesions. UV can involve organ systems beyond the skin, including the gastrointestinal, musculoskeletal, renal, and pulmonary systems (particularly chronic obstructive pulmonary disease) and, less commonly, the ocular and central nervous systems. The diagnosis of UV is suggested by a typical clinical presentation and supporting laboratory tests but always confirmed by means of skin biopsy. Skin biopsy features

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include leukocytoclastic vasculitis, and about 80% will have immunoglobulin, complement, or fibrin deposition at the dermalepidermal junction and around the blood vessels, as seen with immunofluorescence. UV can be classified as normocomplementemic UV or hypocomplementemic UV based on complement levels (C3, C4, CH50, and C1q). Complement values should be repeated on 2 or 3 occasions over several months of observation during both activity and quiescence to be conclusively stated as normal. Most cases of normocomplementemic UV are idiopathic, with the remainder being associated with a monoclonal gammopathy, neoplasia, ultraviolet light sensitivity, or repeated cold exposure. Hypocomplementemic UV can be due to systemic lupus erythematosus, Sj€ogren syndrome, serum sickness reaction, or neoplasia or might represent a hypocomplementemic urticarial vasculitis syndrome (HUVS). HUVS is a specific autoimmune disorder that involves more than 6 months of UV with hypocomplementenia in the presence of systemic findings. These include angioedema (occurs in 50% and can be the presenting feature), moderate-to-severe chronic obstructive pulmonary disease (occurs in 50%), ocular inflammation (uveitis occurs in 30%), and glomerulonephritis. In patients with HUVS, C3 and C4 levels can be undetectable to low normal, C1q levels are low in all patients when disease is active, and anti-C1q antibody levels (C1q precipitins) are detectable in all patients. Diagnostic criteria for HUVS have been proposed.82 The treatment of UV is determined based on the severity and the presence of an underlying disease. Idiopathic UV confined to the skin can be treated with antihistamines, a short course of glucocorticoids, or both. Other agents for cutaneous disease include colchicine, dapsone, hydroxychloroquine, pentoxifylline, and indomethacin. In a study of 47 patients with biopsy-proved UV, montelukast, cyclosporine A, and AZA were used in varying combinations as sequential treatment if patients had a suboptimal response to treatment with cinnarizine and glucocorticoids for 6 months.83 Patients with HUVS or systemic disease require initial glucocorticoid therapy with an aim to taper the medication as dictated by disease activity. In case reports of UV, AZA, anakinra, mycophenolate mofetil, CYC, cyclosporine A, IVIG, plasma exchange, and rituximab have all been used independently or in combination with glucocorticoids, depending on the severity of the disease and response to initial therapy.

SUMMARY The systemic vasculitides are rare disorders that can be presented to the allergist/immunologist as a range of different symptoms and signs. Recognizing the possibility of vasculitis is essential because many of these diseases can be potentially life- or organ-threatening. It is important to remember that the treatment of vasculitis is fraught with considerable toxicity, and the risk/ benefit ratio should always be factored into therapeutic decision making. In looking toward the future, studies of disease pathogenesis will increase our knowledge about the causes of vasculitis and generate hypotheses for the exploration of novel therapeutic approaches. REFERENCES 1. Hunder GG, Bloch DA, Michel BA, Stevens MB, Arend WP, Calabrese LH, et al. The American College of Rheumatology 1990 criteria for the classification of giant cell (temporal) arteritis. Arthritis Rheum 1990;33:1122-8.

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2. Jennette JC, Falk RJ, Andrassy K, Bacon PA, Churg J, Gross WL, et al. Nomenclature of systemic vasculitides: proposal of an international consensus conference. Arthritis Rheum 1994;37:187-92. 3. Sneller MC, Fauci AS. Pathogenesis of vasculitis syndromes. Med Clin North Am 1997;81:221-42. 4. Cid MC, Vilardell C. Tissue targeting and disease patterns in systemic vasculitis. Best Pract Res Clin Rheumatol 2001;15:259-79. 5. Davies DJ, Moran JE, Niall JF, Ryan GB. Segmental necrotizing glomerulonephritis with antineutrophil antibody: possible arbovirus etiology? BMJ 1982; 285:606. 6. Falk RJ, Jennette JC. Anti-neutrophil cytoplasmic autoantibodies with specificity for myeloperoxidase in patients with systemic vasculitis and idiopathic necrotizing and crescentic glomerulonephritis. N Engl J Med 1988;318:1651-7. 7. Kallenberg CGM. Pathogenesis of PR3-ANCA associated vasculitis. J Autoimmun 2008;30:29-36. 8. van der Woude FJ, Rasmussen N, Lobatto S, Wiik A, Permin H, van Es LA, et al. Autoantibodies to neutrophils and monocytes: a new tool for diagnosis and a marker of disease activity in Wegener’s granulomatosis. Lancet 1985;2:425-9. 9. Langford CA. The diagnostic utility of c-ANCA in Wegener’s granulomatosis. Cleve Clin J Med 1998;65:135-40. 10. Finkielman JD, Merkel PA, Schroeder D, Hoffman GS, Spiera R, St Clair EW, et al. Antiproteinase 3 antineutrophil cytoplasmic antibodies and disease activity in Wegener granulomatosis. Ann Intern Med 2007;147:611-9. 11. Kerr GS, Fleisher TA, Hallahan CW, Leavitt RY, Fauci AS, Hoffman GS. Limited prognostic value of changes in antineutrophil cytoplasmic antibody titer in patients with Wegener’s granulomatosis. Arthritis Rheum 1993;36:365-71. 12. Girard T, Mahr A, No€el LH, Cordier JF, Lesavre P, Andre´ MH, et al. Are antineutrophil cytoplasmic antibodies a marker predictive of relapse in Wegener’s granulomatosis? A prospective study. Rheumatology (Oxford) 2001;40:147-51. 13. Boomsma MM, Stegeman CA, van der Leij MJ, Oost W, Hermans J, Kallenberg CG, et al. Prediction of relapses in Wegener’s granulomatosis by measurement of antineutrophil cytoplasmic antibody levels: a prospective study. Arthritis Rheum 2000;43:2025-33. 14. Lawrence RC, Felson DT, Helmick CG, Arnold LM, Choi H, Deyo RA, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum 2008;58:26-35. 15. Klein RG, Hunder GG, Stanson AW, Sheps SG. Large artery involvement in giant cell (temporal) arteritis. Ann Intern Med 1975;83:806-12. 16. Evans JM, Bowles CA, Bjornsson J, Mullany CJ, Hunder GG. Thoracic aortic aneurysm and rupture in giant cell arteritis. A descriptive study of 41 cases. Arthritis Rheum 1994;37:1539-47. 17. Achkar AA, Lie JT, Hunder GG, O’Fallon WM, Gabriel SE. How does previous corticosteroid treatment affect the biopsy findings in giant cell (temporal) arteritis? Ann Intern Med 1994;120:987-92. 18. Karassa FB, Matsagas MI, Schmidt WA, Ioannidis JP. Meta-analysis: test performance of ultrasonography for giant-cell arteritis. Ann Intern Med 2005;142:359-69. 19. Salvarani C, Silingardi M, Ghirarduzzi A, Lo Scocco G, Macchioni P, Bajocchi G, et al. Is duplex ultrasonography useful for the diagnosis of giant-cell arteritis? Ann Intern Med 2002;137:232-8. 20. Aiello PD, Trautmann JC, McPhee TJ, Kunselman AR, Hunder GG. Visual prognosis in giant cell arteritis. Ophthalmology 1993;100:550-5. 21. Nesher G, Berkun Y, Mates M, Baras M, Rubinow A, Sonnenblic M. Low-dose aspirin and prevention of cranial ischemic complications in giant cell arteritis. Arthritis Rheum 2004;50:1332-7. 22. Lee MS, Smith SD, Galor A, Hoffman GS. Antiplatelet and anticoagulant therapy in patients with giant cell arteritis. Arthritis Rheum 2006;54:3306-9. 23. Hoffman GS, Cid MC, Hellmann DB, Guillevin L, Stone JH, Schousboe J, et al. A multicenter, randomized, double-blind, placebo-controlled trial of adjuvant methotrexate treatment for giant cell arteritis. Arthritis Rheum 2002;46:1309-18. 24. Jover JA, Herna´ndez-Garcı´a C, Morado IC, Vargas E, Ban˜ares A, Ferna´ndezGutie´rrez B. Combined treatment of giant-cell arteritis with methotrexate and prednisone. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2001;134:106-14. 25. Hoffman GS, Cid MC, Rendt-Zagar KE, Merkel PA, Weyand CM, Stone JH, et al. Infliximab for maintenance of glucocorticosteroid-induced remission of giant cell arteritis: a randomized trial. Ann Intern Med 2007;146:621-30. 26. Kerr GS, Hallahan CW, Giordano J, Leavitt RY, Fauci AS, Rottem M, et al. Takayasu arteritis. Ann Intern Med 1994;120:919-29. 27. Hoffman GS, Leavitt RY, Kerr GS, Rottem M, Sneller MC, Fauci AS. Treatment of glucocorticoid-resistant or relapsing Takayasu arteritis with methotrexate. Arthritis Rheum 1994;37:578-82. 28. Hoffman GS, Kerr GS, Leavitt RY, Hallahan CW, Lebovics RS, Travis WD, et al. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med 1992;116: 488-98.

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Mycophenolate mofetil for remission maintenance in the treatment of Wegener’s granulomatosis. Arthritis Rheum 2004; 51:278-83. 39. Metzler C, Fink C, Lamprecht P, Gross WL, Reinhold-Keller E. Maintenance of remission with leflunomide in Wegener’s granulomatosis. Rheumatology (Oxford) 2004;43:315-20. 40. Sneller MC, Hoffman GS, Talar-Williams C, Kerr GS, Hallahan CW, Fauci AS. An analysis of forty-two Wegener’s granulomatosis patients treated with methotrexate and prednisone. Arthritis Rheum 1995;38:608-13. 41. De Groot K, Rasmussen N, Bacon PA, Tervaert JW, Feighery C, Gregorini G, et al. Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 2005;52:2461-9. 42. Molloy ES, Langford CA. Does the dose of methotrexate influence the rate of relapse in patients with Wegener’s granulomatosis? Nat Clin Pract Rheumatol 2008; 4:12-3. 43. 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Prospective study of TNFalpha blockade with infliximab in anti-neutrophil cytoplasmic antibody-associated systemic vasculitis. J Am Soc Nephrol 2004;15:717-21. 48. Keogh KA, Wylam ME, Stone JH, Specks U. Induction of remission by B lymphocyte depletion in eleven patients with refractory antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 2005;52:262-8. 49. Keogh KA, Ytterberg SR, Fervenza FC, Carlson KA, Schroeder DR, Specks U. Rituximab for refractory Wegener’s granulomatosis: report of a prospective, open-label pilot trial. Am J Respir Crit Care Med 2006;173:180-7. 50. Guillevin L, Durand-Gasselin B, Cevallos R, Gayraud M, Lhote F, Callard P, et al. Microscopic polyangiitis: clinical and laboratory findings in eighty-five patients. Arthritis Rheum 1999;42:421-30. 51. Agard C, Mouthon L, Mahr A, Guillevin L. Microscopic polyangiitis and polyarteritis nodosa: how and when do they start? Arthritis Rheum 2003;49:709-15. 52. 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