A 21-year-old man with a past medical history of recurrent epistaxis, recent weight loss, joint pain, and lower extremity paresthesia presented with diffuse alveolar hemorrhage and upper airway ulcerations. High-resolution chest CT revealed multiple non-cavitary lung nodules with ground glass opacities. CRP was elevated at 252 mg/L and antibody serology testing was positive for antineutrophil cytoplasmic antibodies with a granular cytoplasmic staining pattern (c-ANCA), as well as PR3 and GBM autoantibodies. Antinuclear antibody (ANA) testing by Hep-2 substrate was negative. Urinalysis revealed hematuria with RBCs >100.
The correct answer is ...
Granulomatosis with polyangiitis (GPA) with renal involvement.
Antineutrophil cytoplasmic antibody (ANCA) associated vasculitides (AAV) are a group of small vessel vasculitis disorders in which the development of autoantibodies to the neutrophil proteins myeloperoxidase (MPO) and proteinase 3 (PR3) play a central role in pathogenesis. AAV include three clinical diseases, namely granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic GPA (EGPA), which are characterized by neutrophil-driven blood vessel inflammation, endothelial injury and tissue damage.1
Autoantibodies against PR3 and MPO produce unique staining patterns when indirect immunofluorescence (IIF) is performed on ethanol-fixed neutrophils. Although this technique is still routinely available, recent guidelines recommend antigen-specific immunoassays as the preferred screening test for patients with suspected AAV.2
Autoantibodies to PR3 (PR3-ANCA) occur in 75%3 of patients with GPA and produce a characteristic pattern of granular cytoplasmic fluorescence on ethanol-fixed neutrophils called the cANCA pattern (Figure 1A). Clinically, GPA is most often associated with upper and lower respiratory tract involvement.
Antibodies to MPO (MPO-ANCA) occur in approximately 60% of patients with MPA and 80%3 of patients with renal limited vasculitis and produce a pattern of perinuclear cytoplasmic fluorescence on ethanol-fixed neutrophils called the pANCA pattern (Figure 1B). MPA commonly manifests with severe renal involvement; however, pulmonary symptoms overlapping with GPA have been described.
Certain cases GPA or MPA may be associated with pANCA or cANCA patterns, making the differential diagnosis difficult.4 Additionally, 5%-10% of patients may have GPA, MPA, or renal limited vasculitis in the absence of and ANCA. Interestingly, Recent genetic and clinical evidence has suggested that these clinical syndromes may be more appropriately classified as PR3-positive AAV or MPO-positive AAV.5,6
In this case, the patient presented with upper respiratory symptoms including recurrent epistaxis and diffuse alveolar hemorrhage which are generally consistent with GPA. Further supporting this diagnosis, serology testing revealed PR3-ANCA with a cANCA staining pattern. The patient’s urinalysis, however, showed hematuria and additional serology testing revealed the presence of anti-GBM antibodies, which could be consistent with anti-GBM disease. To differentiate between the two, biopsies of the sinus mucosa and kidney were performed. Sinus mucosa biopsy could not definitively identify vasculitis; however, the renal biopsy revealed necrotizing glomerulonephritis with focal cellular crescents. The patient’s clinical presentation, serology results, biopsies, and additional laboratory studies finalized the diagnosis of GPA with renal involvement.
Patrick Vanderboom, Ph.D., M.S.
Fellow, Clinical Chemistry
Melissa Snyder, Ph.D.
Consultant, Clinical Biochemistry
Associate Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science