ANCA-associated Vasculitis

Contents

Preface xiii

Barri J. Fessler and S. Louis Bridges Jr

The History of ANCA-associated Vasculitis 439

Gene V. Ball

An essential early step toward understanding vasculitis was recognition in1948 of the differences between the small artery disease of polyarteritis,essentially sparing the glomerulus and lungs, and disease of glomerularvessels and small veins, often involving the lungs. By 1951, Churg andStrauss drew on their knowledge of vasculitis literature and renal pathologyto provide an authoritative description of the syndrome bearing their names.One year later a paper from Australia described a syndrome of febrile sys-temic illness withmyalgias, arthralgias, microscopichematuria, and aserumantibody reacting with neutrophil cytoplasm antigens. Within 30 years,nephrologists and immunologists in northern Europe linked antineutrophilcytoplasm antibodies to a specific vasculitis, Wegener’s granulomatosis.Falk and Jennette later determined that pANCA reacted with cytoplasmicmyeloperoxidase, and that cANCA did not; the antigen with which cANCAreacted was soon identified as a novel serine proteinase. New and bettertreatments of AAV will follow progress in understanding their pathogenesis.

Epidemiology of ANCA-associated Vasculitis 447

Eleana Ntatsaki, Richard A. Watts, and David G.I. Scott

The epidemiology of the antineutrophil cytoplasm antibody (ANCA)-associ-ated vasculitides (AAV), comprising Wegener’s granulomatosis, microscopicpolyangiitis, and Churg-Strauss syndrome, poses considerable challengesto epidemiologists. These challenges include the difficulty of defininga case with a lack of clear distinction between the different disorders, casecapture, and case ascertainment. The AAV are rare and therefore a largepopulation is required to determine the incidence and prevalence, and thisposes questions of feasibility. Despite these difficulties a considerablebody of data on the epidemiology of the AAV has been built in the past 20years with an interesting age, geographic, and ethnic tropism gradually beingrevealed. Most of the data come from White populations of Europeandescent, and the overall annual incidence is estimated at approximately10–20/million with a peak age of onset in those aged 65 to 74 years.

Pathogenesis of ANCA-associated Vasculitis 463

Julia Flint, Matthew D. Morgan, and Caroline O.S. Savage

Antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV)comprises a group of systemic inflammatory vasculitides associated

Contentsviii

with circulating autoantibodies directed against the neutrophil granulecomponents proteinase 3 and myeloperoxidase. ANCA interact with theirtarget antigens on cytokine primed neutrophils, causing neutrophil activa-tion via several signaling pathways that culminates in endothelial interac-tion, degranulation, cytokine production, and endothelial and tissuedamage. The presence of autoantibodies implies the assistance of autor-eactive T-helper cells and B cells, and a failure of regulatory mechanisms.This article reviews the current evidence for the pathogenic mechanismsculminating in autoantibody production, the effects of ANCA-neutrophiland neutrophil-endothelial interactions, and the mechanisms of tissuedamage.

Autoantibodies in ANCA-associated Vasculitis 479

Allan S. Wiik

Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitidesare systemic or more limited conditions characterized by necrotizing de-struction of small and medium-sized vessels (eg, capillaries, venules,and arterioles). ANCAs are the most predominant autoantibodies inpatients affected by vasculitis, but other autoantibodies may also occur,probably reflecting pathogenetic events in affected tissue. These auto-antibodies are assumed to play a role in the intiation and propagation ofchronic inflammation. ANCAs are valuable for clinical diagnosis, follow-up, and guidance in therapy.

Diagnostic Approach toANCA-associated Vasculitides 491

Angelo L. Gaffo

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV)include Wegener’s granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome. Given their rarity, protean clinical manifestations,imperfect diagnostic tests, and wide differential diagnosis, they posea diagnostic challenge even to experienced clinicians. This articledescribes diagnostic approaches for patients suspected of having oneof the ANCA-associated vasculitides. The clinical findings at presentation,the role of laboratory and imaging tests, and the importance of tissuediagnosis are presented. In each section, issues relevant to the differentialdiagnosis of AAV are discussed.

Clinical Manifestations and Treatment of Wegener’s Granulomatosis 507

Julia U. Holle, Martin Laudien, and Wolfgang L. Gross

Wegener’s granulomatosis (WG) is characterized by granulomatouslesions and vasculitic disease manifestations. Granulomatous lesions arefound in the upper and lower respiratory tract (eg, granulomatous sinusitis,orbital masses, and pulmonary granuloma), whereas vasculitic manifesta-tions occur frequently in lung (alveolar hemorrhage) and kidney (glomeru-lonephritis). Vasculitis is typically associated with antineutrophilcytoplasmic antibodies (ANCA) directed against proteinase 3. WG has

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been traditionally associated with a poor outcome and increased mortalityas documented by numerous studies; however, recent cohort studies re-port an improved outcome, probably a consequence of increased aware-ness leading to an earlier diagnosis, and to improved treatment strategiesderived from evidence from controlled trials. Treatment regimens for WG,adapted to disease stage and activity, are reviewed and discussed in thisarticle.

Clinical Manifestations and Treatment of Churg-Strauss Syndrome 527

Chiara Baldini, Rosaria Talarico, Alessandra Della Rossa,and Stefano Bombardieri

Churg-Strauss syndrome (CSS) is a systemic necrotizing vasculitis affect-ing small to medium-sized vessels, and characterized by asthma, bloodhypereosinophilia, and eosinophil-rich granulomatous inflammation ofthe respiratory tract. In the past few years the pathogenesis of the diseaseand its clinical manifestations have been clarified, fostering importantadvances in the treatment of CSS. Systemic corticosteroids are still con-sidered the cornerstone of treatment. Many issues need to be addressed,such as how to maintain remission, prevent disease relapses, and treatrefractory disease. This review provides a clinical overview of CSS anda summary of the current treatments and novel therapies.

Microscopic Polyangiitis 545

Sharon A. Chung and Philip Seo

In 1923, Friedrich Wohlwill described two patients with a ‘‘microscopicform of periarteritis nodosa,’’ which was distinct from the classical form.This disease, now known as microscopic polyangiitis (MPA), is a primarysystemic vasculitis characterized by inflammation of the small-caliberblood vessels and the presence of circulating antineutrophil cytoplasmicantibodies. Typically, microscopic polyangiitis presents with glomerulone-phritis and pulmonary capillaritis, although involvement of the skin, nerves,and gastrointestinal tract is not uncommon. Treatment of MPA generallyrequires use of a cytotoxic agent (such as cyclophosphamide) in additionto high-dose glucocorticoids. Recent research has focused on identifyingalternate treatment strategies that minimize or eliminate exposure to cyto-toxic agents. This article reviews the history, pathogenesis, clinical mani-festations, and treatment of MPA.

Pauci-Immune Necrotizing Glomerulonephritis 559

Abraham Rutgers, Jan S.F. Sanders, Coen A. Stegeman,and Cees G.M. Kallenberg

Pauci-immune necrotizing glomerulonephritis is the most frequent causeof rapidly progressive glomerulonephritis and, in most cases, is associatedwith antineutrophil cytoplasmic antibodies (ANCA). It is either the renalmanifestation of Wegener’s granulomatosis, microscopic polyangiitis ofChurg-Strauss syndrome, or a renal-limited vasculitis. In this review, thehistopathologic changes seen in renal biopsies of patients with pauci-immune glomerulonephritis are described. The authors also describe

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why the disease is sometimes limited to the kidneys, the clinical course ofrenal disease, treatment issues, how to deal with disease relapses, andhow to prevent them from occurring. Furthermore, the necessity of renalbiopsy and rebiopsy, the usefulness of rapid ANCA detection at diagnosis,and serial measurement of ANCA during follow-up are discussed. The ef-fect of dialysis on the disease process and the possibility of renal trans-plantation after disease remission are also debated.

Ocular Manifestations of ANCA-associated Vasculitis 573

Anup A. Kubal and Victor L. Perez

The antineutrophil cytoplasmic antibody (ANCA)-associated vasculiti-des—Wegener’s granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome—can present with various ophthalmic manifestations.In a subset of patients, these findings may be the earliest indicators of sys-temic disease. Orbital and anterior segment findings are most common,whereas posterior segment complications such as retinal vasculitis andoptic neuropathy occur much less frequently. This article describes thedistinguishing features of associated ophthalmic disease, focusing onthe manifestations clinicians are most likely to encounter and those withthe most significant ocular morbidity. Although the ANCA-associatedvasculitides require systemic workup and treatment, this article discussesdiagnostic and therapeutic modalities often used concurrently for ophthal-mic disease.

OutcomeMeasures in ANCA-associated Vasculitis 587

Ravi Suppiah, Joanna Robson, and Raashid Luqmani

The outcome in patients with antineutrophil cytoplasm antibody (ANCA)-associated vasculitis has considerably improved with the use of potentimmunosuppression. In the most severe cases, mortality remains animportant risk despite aggressive intervention. However, for most patientswho survive, quality of survival is affected by morbidity due to low-gradedisease activity, episodes of relapse, damage from the effects of diseaseand its treatment, development of associated comorbidity, and the socialand psychological problems of chronic disease. A rational approach tomanagement of patients with ANCA-associated vasculitis requires carefulmeasurement of these different facets of disease, so that treatment isappropriate. This article reviews the development of assessment toolsused to quantify disease in vasculitis, which have been extensively usedin clinical trials and are also appropriate for use in individual patient care.

The Future of ANCA-associated Vasculitis 609

Julia U. Holle, Stefan Wieczorek, and Wolfgang L. Gross

The introduction of cyclophosphamide for treatment and the detection ofantineutrophil cytoplasmatic antibodies (ANCA) as a seromarker forANCA-associated vasculitis (AAV) have been the most importantmilestones in the history of AAV. Nevertheless, there are still many issues

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to resolve to fully understand the pathogenesis of AAV and to improvepatient outcomes. There is a need for diagnostic criteria; treatment strat-egies need further improvement to reduce the toxicity of conventional im-munosuppressants such as cyclophosphamide. The elucidation of thegenetic background in patients with AAV and the role of granulomatous le-sions found in Wegener’s granulomatosis are required to fully understandthe pathophysiology of AAV.

Index 623