What is the diagnosis for a patient with a 6-month history of cough, sinusitis, and fever, found to have nasopharyngeal ulceration, nodular and cavity lesions on chest x-ray, positive PR3-ANCA (antineutrophil cytoplasmic antibodies against a cytosolic component), negative ANA (antinuclear antibodies), impaired renal function (elevated serum creatinine), and vasculitis with granulomatous inflammation on lung biopsy?

Granulomatosis with Polyangiitis (GPA)

A. Diagnosis

This patient has Granulomatosis with Polyangiitis (GPA), formerly known as Wegener's granulomatosis. 1

The diagnosis is established by the combination of:

• Clinical features: 6-month history of upper respiratory tract involvement (sinusitis, nasopharyngeal ulceration), lower respiratory tract involvement (nodular and cavitary lung lesions), and renal involvement (elevated creatinine) 1

• Positive PR3-ANCA serology: PR3-directed c-ANCA is present in 80-90% of GPA cases and is highly specific for this diagnosis 1

• Histopathological confirmation: The lung biopsy demonstrates the three cardinal pathological features of GPA:

  • Necrotizing vasculitis of small arteries 1
  • Granulomatous inflammation with epithelioid cells and giant cells 1, 2
  • Geographic necrosis (implied by the vasculitis pattern) 3

• Negative ANA: This helps exclude other autoimmune conditions like systemic lupus erythematosus 1

This represents generalized GPA with multi-organ involvement (upper respiratory tract, lungs, and kidneys), which is the more severe form compared to localized disease limited to the respiratory tract. 1

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B. Explanation of Elevated Serum Creatinine

The elevated serum creatinine indicates renal involvement from pauci-immune necrotizing crescentic glomerulonephritis, a hallmark manifestation of GPA. 1

The mechanism involves:

• ANCA-mediated glomerulonephritis: PR3-ANCA antibodies bind to and activate neutrophils, causing release of oxygen radicals, lytic enzymes, and inflammatory cytokines that damage the glomerular capillaries 1

• Necrotizing vasculitis of renal vessels: Small vessel vasculitis affects the glomerular capillaries, leading to necrotizing glomerulonephritis 2

• Crescent formation: The necrotizing injury leads to pauci-immune crescentic glomerulonephritis (minimal immune complex deposition), which rapidly destroys nephrons 1

• Progressive renal dysfunction: Without treatment, this can progress to end-stage kidney disease 4, 5

The renal involvement is classified as "generalized" or "severe" GPA according to the European Vasculitis Study Group (EUVAS) criteria, as opposed to "localized" (respiratory tract only) or "early systemic" (without renal involvement). 1

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C. Course of Disease

Without treatment, GPA has a mean survival of only 5 months, but with modern immunosuppressive therapy, mean survival has improved to 21.7 years from diagnosis. 1

Natural History and Prognosis:

• Mortality risk: The 10-year survival rate is approximately 40% when kidneys are involved (as in this case) versus 60-70% without renal involvement 5

• Treatment response: Despite modern therapy, approximately 10% of patients never achieve remission, and relapses occur in up to 50% of individuals 1

• Mortality rates: Current mortality rates remain at 5% or higher even with treatment 1

Expected Treatment Course:

Remission Induction Phase (0-6 months):

• High-dose systemic corticosteroids plus either cyclophosphamide or rituximab 1, 6
• Rituximab 375 mg/m² once weekly for 4 weeks has been shown to be non-inferior (and possibly superior) to cyclophosphamide for achieving complete remission 6, 3
• Complete remission (defined as BVAS/GPA score of 0 and off glucocorticoids) is achieved in approximately 64% of patients by 6 months 6

Maintenance Phase (6-18+ months):

• If cyclophosphamide was used for induction, switch to azathioprine for maintenance 6, 5
• If rituximab was used, additional maintenance therapy may not be required, though this remains controversial 6, 3
• At 18 months, approximately 38% of rituximab-treated patients maintain complete remission 6

Long-term Complications:

• Relapse risk: Disease activity can recur even decades after initial presentation—relapses have been documented up to 38 years after initial diagnosis 4

• Permanent organ damage: Early aggressive treatment is imperative to prevent irreversible damage, particularly end-stage kidney disease 4, 5

• Staphylococcus aureus colonization: Found in 72% of GPA patients and strongly implicated in disease relapses; prophylactic trimethoprim/sulfamethoxazole reduces relapse rates 1

Critical Pitfall:

Treatment must continue until complete immunological recovery is achieved, not just clinical improvement. Premature discontinuation of immunosuppression significantly increases the risk of relapse and further loss of renal function, even after prolonged remission. 4