Granulomatosis with polyangiitis (GPA) is one of the ANCA-associated vasculitides. It is characterized by the triad of necrotizing granulomas of the respiratory tract, necrotizing vasculitis of small blood vessels throughout the body, and focal necrotizing glomerulonephritis. The former name was Wegener granulomatosis. It was first reported by Klinger in 1931 and formally described by Wegener in 1936.
ANCA-associated vasculitis includes three diseases: granulomatosis with polyangiitis, microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA), with granulomatosis with polyangiitis being the most common. Granulomatosis with polyangiitis is further classified into limited type without renal involvement and systemic type with renal involvement. Women are more likely to develop the limited type.
Epidemiologically, the annual incidence is about 8 to 10 per million population, and the prevalence is about 3 per 100,000. The peak age of onset is 30 to 50 years, with no gender difference, and it tends to be more common in Caucasians. Ocular involvement occurs in more than 50% of patients, and in 15% ocular symptoms are the initial manifestation.
PR3-ANCA (c-ANCA) correlates with disease activity and is positive in over 80% of patients. In the uveitis clinical practice guidelines, GPA is classified as uveitis associated with collagen disease/vasculitis, and the importance of ophthalmologic screening is emphasized 3).
Before the introduction of immunosuppressive therapy, the median survival was 5 months and the 1-year mortality rate was over 80%. After the introduction of current standard treatment, the 5-year survival rate has improved to 95% and the 10-year survival rate to 80% 1). The main causes of death are respiratory infections and sepsis.
QHow common is granulomatosis with polyangiitis?
A
The prevalence of granulomatosis with polyangiitis is approximately 3 per 100,000 people, and the annual incidence is about 8 to 10 per 1,000,000 people, making it a rare disease. It commonly occurs in people aged 30 to 50 years and is more frequent in Caucasians.
Common initial systemic symptoms include fever, malaise, weight loss, and myalgia. Ocular symptoms include eye pain, diplopia, vision loss, visual field defects, and redness. It is often accompanied by systemic symptoms such as rhinitis, epistaxis, saddle nose deformity, hearing loss, hemoptysis, dyspnea, arthralgia, and neuropathy.
Scleritis: One of the most common ocular symptoms, occurring in about 50% of patients. It presents with deep severe pain, redness, and tenderness. Necrotizing scleritis can lead to severe visual impairment.
Episcleritis: Relatively common, but the course is mild and self-limiting.
Peripheral Ulcerative Keratitis (PUK): Accompanied by corneal stromal infiltration and vascular invasion from the limbus. Marginal corneal ulcers can cause severe visual impairment.
Orbital lesions: Proptosis is the most common symptom. It is accompanied by diplopia, swelling, and epiphora. Severe vision loss occurs in 20-50% of proptosis cases. Involvement of the optic nerve can lead to arteritic ischemic optic neuropathy (AION).
Optic neuropathy: Presents as compressive optic neuropathy (due to orbital granuloma) or ischemic optic neuropathy.
Retinal and choroidal lesions: Occur in 5–12% of cases. Cotton-wool spots, intraretinal hemorrhages, retinal vascular occlusion, vitreous hemorrhage, and neovascular glaucoma may occur.
Uveitis: Rare (approximately 3%). Primarily anterior uveitis. Often appears secondary to necrotizing scleritis.
Eyelid lesions: The “yellow lid sign” (xanthelasma-like discoloration) is a characteristic finding of granulomatosis with polyangiitis.
Upper respiratory tract: Present in up to 85% of patients, and in 81% the initial manifestation is otorhinolaryngological. Treatment-resistant chronic sinusitis and saddle nose deformity (nasal septum/cartilage destruction) are characteristic.
Lungs: Most patients eventually develop pulmonary involvement. Presents with nodules, cavities, and infiltrates.
Kidneys: Glomerulonephritis occurs in 75% of patients. 77% develop glomerular disease within 2 years.
Musculoskeletal system: Approximately 60% experience arthralgia and fatigue.
Central nervous system: Neurological symptoms appear in 20–50% of patients, and direct CNS involvement is seen in about 10% 2).
QWhat is the most common ocular manifestation of granulomatosis with polyangiitis?
A
Scleritis is the most common ocular manifestation, occurring in approximately 50% of patients. Among orbital lesions, proptosis is the most frequent finding. Severe vision loss can occur in 20–50% of cases with proptosis.
QHow often does uveitis occur in GPA?
A
Uveitis is rare among GPA ocular manifestations, occurring in about 3% of patients. It most often presents as anterior uveitis secondary to necrotizing scleritis or orbital inflammation. In the uveitis clinical guidelines, GPA is classified as uveitis associated with collagen disease/vasculitis 3).
The cause of granulomatosis with polyangiitis is unknown and is considered an autoimmune disease. The production of autoantibodies against PR3-ANCA (c-ANCA) and MPO-ANCA (p-ANCA) plays a central role in its onset.
Molecular mimicry by Staphylococcus aureus is thought to lead to the development of PR3-ANCA, and nasal carriage of staphylococci increases the risk of relapse. Environmental factors such as dust, silica exposure, smoking, and chemical exposure are associated, and it is more common in cold climates. Associations with drugs (e.g., hydralazine, propylthiouracil, levamisole, phenytoin, sulfasalazine, antithyroid drugs, allopurinol) have also been reported.
ANCA testing plays a central role in the diagnosis of granulomatosis with polyangiitis. The ANCA-associated vasculitis clinical practice guidelines (2017) recommend quantitative PR3-ANCA measurement for assessing disease activity and predicting relapse5).
Test
Characteristics
c-ANCA (PR3-ANCA)
Positive in 90% of patients with active granulomatosis with polyangiitis. May be negative in 40% of localized cases.
Quantitative PR3-ANCA
Correlates with disease activity. Positive in 80%. Useful for predicting relapse5).
ACR 1990 classification criteria: At least 2 of 4 criteria (nasal/oral inflammation, abnormal chest X-ray, abnormal urinary sediment, granulomatous inflammation on biopsy) yield sensitivity 88% and specificity 92%.
ACR/EULAR 2022 classification criteria: A 9-item scale is used; a score of 5 or more classifies as granulomatosis with polyangiitis 8).
Japanese diagnostic criteria (MHLW Research Group 2017): Diagnosis is made by combining major symptoms (upper respiratory tract, lung, kidney, vasculitis symptoms), major histological findings, and major laboratory findings (PR3-ANCA positivity) 5).
Lung biopsy: Characteristic findings include parenchymal necrosis (neutrophilic microabscesses) and granulomatous inflammation.
Kidney biopsy: Focal segmental necrotizing glomerulonephritis with crescent formation, without immune complex deposition (pauci-immune).
Orbital biopsy: Fat necrosis, lipid-laden macrophages, and giant cells may be present, but diagnosis can be difficult because overt necrotizing vasculitis may be absent.
PET/CT: Useful for detecting active lesions and differentiating from malignancy or infection. Sensitivity 90%, specificity 81%.
Orbital MRI: T2 hypointensity (characteristic of fibrotic granuloma), contrast enhancement. Ophthalmologic evaluation is also recommended for uveitis screening 3).
Differentiation from sarcoidosis, other vasculitis syndromes, IgG4-related disease, malignant lymphoma, and infectious diseases is important.
QIs it possible to have granulomatosis with polyangiitis even if ANCA is negative?
A
Even if negative, granulomatosis with polyangiitis cannot be excluded. In localized granulomatosis with polyangiitis, the rate of c-ANCA negativity reaches about 40%. Even when ANCA is negative, diagnosis must be made by integrating clinical symptoms, imaging findings, and biopsy findings.
The anti-CD20 monoclonal antibody rituximab shows equivalent therapeutic efficacy to CYC. In the RAVE trial (Stone 2010), 375 mg/m² weekly × 4 doses showed equivalent remission induction effect to CYC 4). In Japan, it is covered by insurance for initial cases, patients with high disease activity, and cases refractory to existing treatment 5).
Orbital decompression is considered for orbital lesions with severe pain or proptosis.
QIs there a possibility of relapse after remission with treatment for granulomatosis with polyangiitis?
A
Granulomatosis with polyangiitis typically follows a course of remission and relapse. Even if systemic symptoms remit, ocular sequelae (optic neuropathy, necrotizing scleritis, peripheral corneal ulcer) may persist. A re-elevation of PR3-ANCA is a sign predicting relapse, so regular testing is important.
6. Pathophysiology and Detailed Mechanism of Onset
The onset of granulomatosis with polyangiitis involves central roles of abnormal neutrophil activation and autoantibody production. Production of autoantibodies against PR3-ANCA and MPO-ANCA is key, and production of IL-17 and IL-23 by CD4+ T cells contributes to organ damage (especially in the kidneys). Molecular mimicry of Staphylococcus aureus is thought to promote PR3-ANCA production, along with superantigen stimulation of B and T cells.
Pathologically, the triad of vasculitis, granulomatous inflammation (with or without giant cells), and tissue necrosis is characteristic. Neutrophilic microabscesses form granulomas, which eventually progress to necrosis. Unlike tuberculosis and sarcoidosis, the granulomas have indistinct borders and contain giant cells surrounded by lymphocytes, plasma cells, and dendritic cells. Renal involvement presents as necrotizing crescentic glomerulonephritis without immunoglobulin deposition (pauci-immune type).
Histologically, necrotizing granulomatous lesions with neutrophil infiltration are observed, with a mixture of granulomatous, necrotic, and vasculitic lesions. Orbital biopsy reveals fat necrosis, lipid-laden macrophages, and giant cells, but it is often difficult to detect appropriate histopathological findings in ophthalmic tissue examinations.
The sclera and orbital tissues are rich in connective tissue, making them susceptible targets for granulomatous vasculitis. PR3-ANCA also directly damages vascular endothelial cells, leading to vascular necrosis of the sclera and corneal limbus.
7. Latest Research and Future Perspectives (Investigational Reports)
Avacopan (Tavneos®) was approved in Japan in 2022 as a steroid-sparing therapy for ANCA-associated vasculitis. In the ADVOCATE trial, the avacopan group showed non-inferior remission induction rates compared to the prednisolone group while reducing steroid-related side effects7). Specific data on its impact on ocular complications are a topic for future research.
Wei et al. (2021) reported a case of granulomatosis with polyangiitis of the eyelid refractory to steroid and cyclophosphamide therapy, which achieved complete response after radiation therapy with 9 MeV electron beam at 30 Gy in 15 fractions1). Radiation therapy is not standard treatment, but efficacy has been shown in a small number of cases.
Infliximab, a tumor necrosis factor alpha (TNF-α) inhibitor, has been reported to improve cases of granulomatosis with polyangiitis with necrotizing scleritis, but it is currently at the clinical research stage.
Multiple cases of new-onset granulomatosis with polyangiitis after COVID-19 infection have been reported, and a review of 13 cases has been published. SARS-CoV-2 infection has been reported to increase the ANCA positivity rate (significantly higher in COVID-19 patients compared to 0.9% in the general population). It has been suggested that elevated inflammatory mediators due to SARS-CoV-2 infection may promote neutrophil priming and ANCA-induced degranulation, but the mechanism is not fully understood.
Wei J, Zhao Q, Yao M, et al. Radiotherapy of granulomatosis with polyangiitis occurring in the eyelid: a case report and literature review. Medicine. 2021;100(3):e22794.
Li Z, Zhang Q, Wang X, Shi F. Granulomatosis with polyangiitis presenting headache: A case report and review of literature. Medicine. 2024;103(2):e36972.
日本眼炎症学会 ぶどう膜炎診療ガイドライン. 日眼会誌. 2019;123(6):635-696.
Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis (RAVE trial). N Engl J Med. 2010;363:221-232.
Guillevin L, Pagnoux C, Karras A, et al. Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis (MAINRITSAN). N Engl J Med. 2014;371:1771-1780.
Jayne DRW, Merkel PA, Schall TJ, et al. Avacopan for the treatment of ANCA-associated vasculitis (ADVOCATE). N Engl J Med. 2021;384:599-609.
Robson JC, Grayson PC, Ponte C, et al. 2022 ACR/EULAR classification criteria for granulomatosis with polyangiitis. Ann Rheum Dis. 2022;81:315-320.
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