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SYSTEMIC VASCULITIS

Paul F. Dellaripa

The vasculitides are a group of disorders that are characterized by the presence of inflammation in vessel walls, which leads to vascular occlusion and tissue necrosis. Systemic vasculitic syndromes can present clinically in protean fashion and may be due to a variety of mechanisms involving immune dysregulation that leads to endovascular inflammation. However, these immune mechanisms are still not well understood; thus one must rely on clinical, descriptive parameters for classification and treatment. This chapter focuses on well-recognized patterns of presentation, treatment guidelines, and emerging insights on pathogenic mechanisms, a new nomenclature, and implications for future treatment options.

    Classification of systemic vasculitides (SV) has traditionally involved dividing them along the lines of vessel size—for example, giant-cell arteritis representing large-vessel disease and hypersensitivity vasculitis representing small-vessel disease—although in reality there is significant overlap in terms of size of vessels, and such a classification offers no information on pathogenesis or unique characteristics of different vasculitic syndromes. In this discussion we focus on disease patterns most often associated with antineutrophil cytoplasmic autoantibody (ANCA) including granulomatosis with polyangiitis (GPA; formerly Wegener granulomatosis), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis, (EGPA; formerly Churg Strauss syndrome), and other vasculitides including polyarteritis nodosa, drug-induced and cryoglobulinemic vasculitis, Takayasu arteritis, giant-cell arteritis, and Behçet disease.

CLINICAL PRESENTATION

SV should be suspected in patients who present with systemic clinical findings or symptoms for which there is no readily identifiable source of infection or malignancy. For example, unexplained persistent fever will typically be investigated for underlying infection or lymphoma but can be a prominent feature of patients with giant-cell arteritis. Other signs and symptoms, such as weight loss, night sweats, rash, mononeuritis, arthritis, and malaise without identifiable etiology, can represent clinical features of an underlying vasculitis. Sometimes these findings may be embedded within a pattern that fits into a well-described syndrome, but often they do not. Clinical syndromes that can mimic vasculitis include endocarditis, atrial myxoma, atheroembolism, and hypercoagulable states such as antiphospholipid syndrome.

ANTINEUTROPHIL CYTOPLASMIC AUTOANTIBODY VASCULITIS

GPA, EGPA, and MPA are often considered together as a group of similar diseases because they have shared clinical features and are associated with ANCA in most cases. All three can frequently present with a pauci-immune necrotizing glomerulonephritis (GN) and pulmonary involvement. ANCA is detected by indirect immunofluorescence on ethanol-fixed neutrophils and can exhibit a cytoplasmic pattern (cANCA) or a perinuclear pattern (pANCA). If the immunofluorescence test is positive, then an enzyme-linked immunosorbent assay (ELISA) specific for proteinase 3 (PR3) or myeloperoxidase (MPO) is performed. Most patients with GPA are PR3 positive (up to 80%) and rarely MPO positive, and in microscopic polyangiitis up to 79–80% of cases are MPO positive and rarely PR3 positive. In some cases, patients with GPA may be ANCA negative. Generally speaking, patients with PR3-positive ANCA-associated disease have a greater degree of multiorgan involvement, more frequent granulomatous disease, and a higher frequency of relapse. ANCA-MPO positivity may also be seen in systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), scleroderma, and inflammatory bowel disease, and in certain drug-induced vasculitic syndromes (such as with propylthiouracil and allopurinol).

    It is thought that the pathogenesis of ANCA-associated vasculitis involves cytokines and other factors that cause the expression of ANCA antigens onto cell surfaces of neutrophils, which can then bind to existing circulating ANCA. This results in activated neutrophils, which can interact with endothelial cells via adhesion molecules and release reactive oxygen species and toxic granular enzymes, which can result in tissue necrosis. Activated neutrophils may also activate complement such as C5a and C3a, which results in inflammation and disruption of endothelial surfaces of blood vessels. Recently direct in vivo evidence has linked myeloperoxidase to pathogenesis in a murine model that developed necrotizing and crescentic GN after injection of mouse anti-MPO IgG.

GRANULOMATOSIS WITH POLYANGIITIS (WEGENER)

Granulomatosis with polyangiitis (GPA) is a systemic vasculitis characterized by granulomatous vasculitis of the upper and lower respiratory tract and segmental necrotizing GN that involves small blood vessels. Some patients with GPA have what is termed “limited GPA,” which is confined to the upper respiratory tract.

    Findings often include the following:

•  Rhinitis, epistaxis, otitis media

•  Hearing loss, chondritis of the ears and nose

•  Cough, dyspnea, hemoptysis, subglottic stenosis

•  Hematuria related to GN, progressive renal insufficiency

•  Mononeuritis multiplex, central nervous system (CNS) vasculitis

•  Scleritis, conjunctivitis

•  Palpable purpura, granulomatous skin lesions

•  Arthritis, arthralgias

    One of the more common clinical patterns that can present in GPA is lower respiratory tract symptoms with active GN, referred to as the pulmonary renal syndrome. In patients who present with GN and active pulmonary symptoms, especially alveolar hemorrhage, the differential diagnosis includes GPA, microscopic polyangiitis, SLE, cryoglobulinemia, and Goodpasture disease.

    Pathologically, the vessels involved in GPA include small arteries and veins. The pathology of vasculitis includes fibrinoid necrosis with inflammatory mononuclear cell infiltrates of vessel walls, focal destruction of the elastic lamina, and narrowing or obliteration of the vessel lumen. Granulomatous vasculitis may involve the lung, skin, CNS, peripheral nerves, heart, kidney, and other organs.

    Most patients with GPA present with symptoms referable to the upper respiratory tract including sinusitis, nasal obstruction, rhinitis, otitis media, hearing loss, ear pain, gingival inflammation, oral and nasal ulcers, epistaxis, sore throat, laryngitis, and nasal septal deformity. Upper respiratory tract involvement may lead to damage to nasal cartilage, resulting in the “saddle-nose” deformity.

    Lower respiratory tract involvement occurs in most patients, although it is seen less frequently as a presenting symptom; it may include cough, sputum production, dyspnea, chest pain, hemoptysis, and life-threatening pulmonary hemorrhage. GPA may also be associated with inflammation and subsequent scarring/stenosis of the subglottic region.

    Radiographic findings include multiple nodular, often bilateral, cavitary infiltrates, but infiltrates with less well-defined margins occur as well. Other less common chest radiographic abnormalities include paratracheal masses, large cavitary lesions, and massive pleural effusion. Computed tomography of the chest may reveal pulmonary lesions that are not well demonstrated on plain radiographs.

    Urinalysis reveals renal involvement in approximately 80% of patients at presentation. The typical renal lesion is segmental necrotizing glomerulonephritis. Functional renal impairment may progress rapidly if appropriate therapy is not instituted promptly.

Diagnosis

Diagnosis can be based on the clinical findings of upper and lower respiratory tract noninfectious inflammation with glomerulonephritis and positive anti-PR3 ANCA without necessarily proceeding with a biopsy, although this is the subject of some debate. In cases with more limited involvement, or where ANCA titers are negative or show the less typical MPO specificity, tissue diagnosis may be necessary and can be sought at sites of active disease including nasal biopsy, lung biopsy, kidney biopsy, nerve, and even conjunctival biopsy.

Treatment

Therapy with significant disease is typically based on establishment of remission with a combination of corticosteroids and cyclophosphamide or rituximab and then once remission is achieved, usually within 6 months, step-down therapy utilizing agents such as azathioprine, methotrexate, or mycophenolate is instituted, or if Rituxan is used instead of cyclophosphamide, then repeated doses of Rituxan may be considered. Trimethoprim sulfamethoxazole may limit flares of upper respiratory symptoms and is also indicated as a prophylactic agent against Pneumocystis pneumonia (PCP). Initial treatment with corticosteroids is generally given as prednisone, 1 mg/kg/day orally. In a critically ill patient with severe systemic involvement, pulse corticosteroid with intravenous methylprednisolone 1 g/day for 3 days is advocated, transitioning to prednisone 1 mg/kg/day orally or its intravenous equivalent. Cyclophosphamide can be administered as monthly intravenous boluses, every 3 weeks intravenous bolus, or as a daily oral dose. The risks associated with cyclophosphamide include hemorrhagic cystitis, opportunistic infections such as PCP and fungal infections, and the long-term, lifelong risk of bladder cancer, lymphoma, and leukemia. Rituxan carries risk for a variety of infections including an increased risk for the development of progressive multifocal leukoencephalopathy due to infection by the JC virus.

MICROSCOPIC POLYANGIITIS

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