Introduction
Granulomatosis with polyangiitis (GPA) is a rare antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis characterized by necrotizing inflammation of small- and medium-sized blood vessels. Although the disease classically affects the upper and lower respiratory tracts and kidneys, localized and atypical presentations are increasingly recognized and often contribute to delayed diagnosis. The annual incidence of GPA is estimated at 10–20 cases per million population, with prevalence rates ranging from 120 to 140 cases per million in Europe and North America.
Pathogenesis and diagnostic challenges
The pathogenesis of GPA involves a complex interplay of genetic susceptibility, environmental triggers, and immune dysregulation. Proteinase-3 ANCA (PR3-ANCA) is strongly associated with the disease and contributes to neutrophil activation, endothelial injury, and vascular inflammation.
Clinical manifestations are highly variable. Constitutional symptoms such as fatigue, fever, weight loss, myalgia, and arthralgia are common and may precede organ-specific involvement. Upper respiratory tract manifestations, including chronic sinusitis, nasal congestion, epistaxis, otitis media, anosmia, and ocular inflammation, are among the most frequent presenting features.
Diagnosis of GPA remains challenging because early symptoms are often nonspecific and can mimic infections, malignancies, or other autoimmune disorders. Localized disease may occur without renal or pulmonary involvement, making recognition particularly difficult. Furthermore, ANCA testing may occasionally be negative in localized disease, imaging findings are often nonspecific, and tissue biopsies can be inconclusive because of patchy granulomatous lesions.
Insights from a recent case report
A recent case report described a 28-year-old woman who experienced nearly two years of severe fatigue, musculoskeletal pain, chronic sinusitis, anosmia, headaches, painful eye movements, facial swelling, skin lesions, and secondary amenorrhea. Despite extensive multidisciplinary evaluation, no definitive diagnosis was initially established.
Further investigations revealed persistently elevated inflammatory markers, strongly positive PR3-ANCA, and extensive sinonasal inflammation on computed tomography. In the absence of pulmonary or renal involvement, a diagnosis of limited GPA was ultimately made. The patient showed rapid and significant improvement following treatment with high-dose corticosteroids.
Clinical implications
Recent studies highlight the importance of considering ANCA-associated vasculitis in patients with persistent sinonasal symptoms, unexplained systemic inflammation, anosmia, ocular complaints, or constitutional symptoms that fail to respond to conventional therapy. Atypical manifestations, including endocrine abnormalities such as amenorrhea, may further obscure the diagnosis and contribute to delays in treatment.
Localized GPA remains an underrecognized form of ANCA-associated vasculitis. Early PR3-ANCA testing, multidisciplinary evaluation, and timely initiation of immunosuppressive therapy are essential to prevent disease progression and irreversible organ damage. Greater awareness of atypical presentations may facilitate earlier diagnosis and improve long-term outcomes.
References
- Elmobark M, Ali W. When Fatigue Was Vasculitis: A Case of Limited PR3 ANCA-Positive Granulomatosis With Polyangiitis. Cureus. Published May 31, 2026.
- De Parisot A, Puéchal X, Langrand C, Raverot G, Gil H, Perard L, Le Guenno G, Berthier S, Tschirret O, Eschard JP, Vinzio S, Guillevin L, Sève P; and the French Vasculitis Study Group. Pituitary involvement in granulomatosis with polyangiitis: report of 9 patients and review of the literature. Medicine (Baltimore). 2015 Apr;94(16):e748.
- Potentas-Policewicz M, Fijolek J. Granulomatosis with polyangiitis: clinical characteristics and updates in diagnosis. Front Med (Lausanne). 2024 Aug 27;11:1369233.
- Rout P, Garlapati P, Qurie A. Granulomatosis with polyangiitis. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 Jan–. [Updated 2024 Aug 31; cited 2026 Jun 3].