A 22-year-old male with no PMH or FH of autoimmune diseases and no substance use history presented with several days of worsening dyspnea, pleuritic chest pain, cough and hemoptysis. On evaluation, his vital signs were T 98.3oF, BP 103/64 mmHg, HR 86/min, RR 21/min, SpO2 93%. Physical exam was notable for auscultation of bilateral coarse lung sounds and dyspnea upon long sentences. CXR and CT chest revealed multiple bilateral patchy groundglass opacities and consolidations mainly in the middle to lower lobes consistent with organizing pneumonia or acute interstitial pneumonia. Laboratory studies revealed moderate leukocytosis with mild anemia, positive anti-PR3 antibody in high titer with negative other ANCAs, positive anti-GBM antibody in low titer, low C4 complement with normal C3, high total serum IgE, large microscopic hematuria, high random urine protein with normal urine and serum creatinine. Bronchoscopy, infectious diseases workup, and sonography of the abdomen and kidneys were all unrevealing. VATS lung wedge biopsy revealed giant cell granulomatous inflammation, focal acute angiitis, chronic organizing pneumonitis, microabscesses and hemorrhage all consistent with GPA. Kidney biopsy revealed focal necrotizing crescentic glomerulonephritis and acute interstitial inflammation all consistent with anti-GBM nephritis with moderate activity. Initial treatment included a short course of empiric antibiotics and prednisone tapered over several weeks. Induction therapy with cyclophosphamide was later started but clinical response was limited. Rituximab was then initiated as induction and maintenance therapy with significant clinical response. Over the next one to two years, serum creatinine increased slightly but remained stable at 1.4 mg/dL and proteinuria persisted with elevated urine protein-to-creatinine ratio. However, anti-PR3 and anti-GBM antibody titers remained low to almost undetectable with low ESR and CRP levels.
Discussion:
Anti-PR3 (cANCA) antibody is positive in approximately 90% of patients with active, generalized granulomatosis with polyangiitis (GPA, formerly Wegener granulomatosis), which typically affects the lungs and kidneys. Anti-GBM antibody is positive in Goodpasture syndrome (GPS), which causes rapidly progressive crescentic glomerulonephritis with or without pulmonary hemorrhage. About 10-40% of patients with anti-GBM disease are ANCA positive with anti-MPO (pANCA) predominance.
Conclusions:
This case illustrates the presence of anti-PR3 and anti-GBM antibodies in a patient with pulmonary and renal diseases consistent with both GPA and GPS. Here, the finding of anti-PR3 is a unique deviation from the most commonly found anti-MPO in double-positive patients. Some studies suggest the presence of both ANCA and anti-GBM is associated with a worse renal prognosis than is the presence of either antibody alone. Nevertheless, the true clinical significance of double-positive anti-PR3 and anti-GBM antibodies is unclear and warrants further investigation.