78: GRANULOMATOSIS WITH POLYANGIITIS (WEGENER)

PATIENT STORY

A 32-year-old man presented with a 3-month history of fever, weight loss, sinusitis, arthralgias, and dyspnea. He had been treated with several courses of antibiotics for presumed sinusitis with no improvement. Computed tomography (CT) of the chest to evaluate his dyspnea showed multiple cavitary, pulmonary nodules (Figure 78-1). He was a lifetime nonsmoker and denied risk factors for tuberculosis. Bronchoalveolar lavage with bacterial, fungal, and mycobacterial stains and cultures were all negative. Transbronchial biopsy showed nonspecific inflammation and was negative for malignancy. Laboratory evaluation revealed anemia, elevated sedimentation rate, elevated C-reactive protein (CRP), and acute kidney injury (creatinine [1.9 mg/dL]). Urinalysis showed microscopic hematuria, red blood cell casts, and proteinuria. A renal biopsy was pursued and showed a pauci-immune, necrotizing glomerulonephritis (Figure 78-2). Antineutrophil cytoplasmic antibody (ANCA) testing was positive for a cytoplasmic staining pattern (c-ANCA) with specificity to proteinase-3 (PR3). A diagnosis of granulomatosis with polyangiitis (GPA, Wegener) was made. The patient was treated with high doses of glucocorticoids and oral cyclophosphamide with successful induction of remission. Six months later, he was transitioned to azathioprine.

EPIDEMIOLOGY

• GPA is a necrotizing, granulomatous, systemic vasculitis affecting the small- to medium-sized blood vessels.

• Overall, estimated incidence is 8 to 10 cases per million per year. Estimated prevalence in the United States is 26 cases per million.¹

• Males are affected slightly more frequently than females.

• Peak age at onset is between 64 and 75 years; it is uncommon in the pediatric population.¹

ETIOLOGY AND PATHOPHYSIOLOGY

• The causative agent in GPA is unknown.

• Human leukocyte antigen (HLA)-DPB1, HLA-DRB1, and polymorphisms in genes encoding key regulators of the immune response such as CTL4A and PTPN22 have been associated with increased risk of GPA.^1,2

• Alpha-1-antitrypsin deficiency has been associated with GPA.³

• Infection with Staphylococcus aureus and silica exposure have also been associated with GPA.¹

• GPA is characterized by the presence of ANCA antibodies in c-ANCA with specificity to PR3.

• In vitro studies suggest a pathogenic role for ANCA antibodies. In these studies ANCA can activate neutrophils to damage endothelial cells and induce a necrotizing vasculitis.⁴

• While the exact mechanism of vasculitis in GPA is unknown, it has been hypothesized that the ANCA antibodies interact with target antigens on primed neutrophils and monocytes, causing ...