In a 41-year-old man with a two‑month history of sinus pain and congestion with epistaxis, a productive cough of brown sputum, a purpuric rash on the lower legs, 20‑lb weight loss, myalgias, arthralgias, intermittent fever up to 102°F, an erythrocyte sedimentation rate of 60 mm/hr, positive cytoplasmic antineutrophil cytoplasmic antibody (c‑ANCA), positive rheumatoid factor, negative antinuclear antibody (ANA), and renal involvement evidenced by proteinuria, hematuria and red‑cell casts, what is the most likely diagnosis?

Granulomatosis with Polyangiitis (GPA)

The most likely diagnosis is granulomatosis with polyangiitis (GPA, formerly Wegener's granulomatosis). This patient presents with the classic triad of upper respiratory tract disease (persistent sinusitis with epistaxis), lower respiratory tract involvement (productive cough with brown sputum suggesting pulmonary hemorrhage), and renal disease (proteinuria, hematuria, and RBC casts indicating glomerulonephritis), combined with positive c-ANCA serology—a constellation that is pathognomonic for GPA 1, 2, 3.

Diagnostic Criteria Met

The diagnosis of GPA is established by combining clinical features with laboratory and serologic findings 1, 3:

• Upper respiratory tract involvement: Two months of persistent sinus pain, pressure, congestion, and epistaxis are hallmark presenting symptoms of GPA, occurring in >90% of patients 4, 2, 5

• Lower respiratory tract disease: Productive cough with brown sputum strongly suggests pulmonary involvement with possible alveolar hemorrhage, present in >95% of patients with lower respiratory tract GPA 2, 5

• Renal involvement: The urinalysis showing 2+ protein, RBCs, and RBC casts indicates pauci-immune necrotizing crescentic glomerulonephritis—a hallmark manifestation of GPA 4, 1, 6

• Systemic manifestations: The 20-pound weight loss, myalgias, arthralgias, and intermittent fever up to 102°F represent the constitutional symptoms seen in systemic vasculitis 2, 5

• Cutaneous findings: The dark purplish rash on lower legs represents palpable purpura from small vessel vasculitis 2, 7

Serologic Confirmation

PR3-ANCA (c-ANCA) positivity is present in 80-90% of GPA cases and is highly specific for this diagnosis 4, 1, 8. The positive c-ANCA in this patient with multisystem involvement strongly supports GPA over other vasculitides 8, 3.

The elevated ESR of 60 mm/hr reflects active systemic inflammation typical of vasculitis 4, 2.

Key Differentiating Features

Why Not EGPA (Eosinophilic Granulomatosis with Polyangiitis)?

EGPA is excluded because 4:

• EGPA requires blood eosinophilia >10% and elevated IgE, which are not mentioned in this case
• EGPA patients typically have adult-onset asthma as a prodromic feature
• Only 35-40% of EGPA patients are ANCA-positive, and when positive, it's usually p-ANCA/MPO rather than c-ANCA 4
• Cardiac involvement and gastroenteritis are more common in EGPA than the upper respiratory/renal pattern seen here 4

Why Not Polyarteritis Nodosa?

Polyarteritis nodosa affects medium-sized vessels and is ANCA-negative, making it incompatible with this presentation 4.

Why Not Rheumatoid Arthritis?

While rheumatoid factor is positive in this patient, RA does not cause:

• Necrotizing glomerulonephritis with RBC casts
• Severe sinusitis with epistaxis
• Pulmonary hemorrhage
• The positive RF is a non-specific finding that can occur in 5% of GPA patients with atypical c-ANCA 4

Why Not Systemic Lupus Erythematosus?

The negative ANA effectively excludes SLE 1, 2. Additionally, SLE does not typically present with destructive upper respiratory tract disease or c-ANCA positivity 1.

Renal Prognosis and Urgency

The renal involvement with RBC casts and proteinuria indicates "generalized" or "severe" GPA with high risk of progressive renal dysfunction and end-stage kidney disease 1. Without treatment, GPA has a mean survival of only 5 months, but with modern immunosuppressive therapy, 10-year survival improves to approximately 40% when kidneys are involved 1, 8.

Critical Next Steps

Immediate biopsy of affected organs (kidney or lung) is recommended to confirm necrotizing vasculitis and granulomatous inflammation 2, 3. Kidney biopsy typically shows crescentic necrotizing glomerulonephritis 2, 6.

Urgent initiation of immunosuppressive therapy is mandated, as detection of PR3-ANCA in the appropriate clinical context with multiorgan involvement requires immediate treatment 8. Initial therapy includes glucocorticoids combined with either rituximab or cyclophosphamide 2, 8.

Common Pitfall

A critical pitfall is misdiagnosing GPA as a more benign condition like chronic rhinosinusitis or upper respiratory infection, leading to delayed treatment and irreversible organ damage 2, 7. The combination of chronic rhinosinusitis with epistaxis, systemic symptoms, and renal abnormalities should always prompt ANCA testing 4, 2.