Granulomatosis with Polyangiitis (Wegener's)

Granulomatosis with polyangiitis (GPA), formerly Wegener's granulomatosis, is an ANCA-associated vasculitis defined by necrotizing granulomatous inflammation of the upper and lower respiratory tract combined with pauci-immune crescentic glomerulonephritis; ANCA targeting proteinase 3 (PR3-ANCA, which gives the c-ANCA pattern) is found in most patients with active generalized disease, and without treatment the prognosis is poor (Kitching 2020).

Table of Contents

  1. Overview and Classification
  2. Pathophysiology
  3. ENT and Upper Airway Manifestations
  4. Pulmonary Manifestations
  5. Renal Manifestations
  6. Other Organ Involvement
  7. Diagnosis and ANCA Testing
  8. Induction Therapy
  9. Maintenance Therapy and Relapse
  10. Prognosis and Special Situations
  11. Key Research Papers
  12. Featured Videos

Overview and Classification

Granulomatosis with polyangiitis (GPA) was historically known as Wegener's granulomatosis, named after the German pathologist Friedrich Wegener (1907–1990), who first described the triad in the 1930s. In 2011 the American College of Rheumatology (ACR), the American Society of Nephrology and the European League Against Rheumatism (EULAR) jointly recommended the descriptive name “granulomatosis with polyangiitis (Wegener’s)” in place of the eponym (Falk 2011). The change followed a wider move away from eponyms and research that had documented Wegener’s Nazi Party membership and his wartime past (Woywodt and Matteson 2006). The name GPA is used in the 2012 Chapel Hill nomenclature and the 2022 classification criteria (Jennette 2013; Robson 2022).

GPA belongs to the family of ANCA-associated vasculitides (AAV), which also includes microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss syndrome). GPA is predominantly associated with c-ANCA targeting proteinase-3 (PR3-ANCA), whereas MPA more often carries p-ANCA targeting myeloperoxidase (MPO-ANCA), and EGPA may carry either. The distinction matters for relapse: in a 2021 meta-analysis, PR3-ANCA positivity at diagnosis was one of the risk factors for relapse (He 2021).

The classic GPA triad is: necrotizing granulomatous inflammation of the upper respiratory tract, necrotizing granulomatous inflammation of the lower respiratory tract, and necrotizing (pauci-immune) glomerulonephritis. Not all three must be present at diagnosis — limited GPA refers to disease confined to the upper or lower airways without renal involvement. A 2022 meta-analysis of 25 studies estimated a worldwide pooled GPA incidence of 9.0 per million person-years and a prevalence of 96.8 per million people, with ANCA-associated vasculitis more frequent in the northern hemisphere and rising over time (Redondo-Rodriguez 2022). GPA can occur at any age; in the US National Institutes of Health (NIH) series of 158 patients, men and women were equally represented, 97% were white and 85% were older than 19 (Hoffman 1992). Without therapy the prognosis is poor (Kitching 2020). With daily cyclophosphamide and prednisone, 79 of 85 NIH patients (93%) reached complete remission (Fauci 1983); in the larger NIH series of 158 patients, 91% improved markedly, 75% reached complete remission, and 50% of remissions were followed by one or more relapses (Hoffman 1992).

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Pathophysiology

The pathogenesis of GPA centers on anti-neutrophil cytoplasmic antibodies (ANCA). In GPA, ANCA directed against proteinase-3 (PR3), a serine protease stored in neutrophil azurophilic granules, is the dominant autoantibody and is found in most patients with active generalized disease; ANCA against myeloperoxidase (MPO) is found in a minority (Kitching 2020). ANCA levels track disease activity only loosely: in a prospective study of 156 patients with GPA, changes in PR3-ANCA levels explained less than 10% of the variation in disease activity, increases were not associated with relapse, and 40% (mature-PR3 assay) and 43% (pro-PR3 assay) of patients relapsed within a year of an increase; the authors concluded that ANCA levels cannot be used to guide immunosuppressive therapy (Finkielman 2007).

The ANCA disease mechanism proceeds through a sequence of events. Pro-inflammatory cytokines such as TNF-α, released during infections or other stimuli, prime circulating neutrophils, causing PR3 and MPO to translocate from intracellular granules to the neutrophil surface membrane. ANCA then binds these surface-expressed antigens, triggering full neutrophil activation. Activated neutrophils degranulate, releasing proteases and reactive oxygen species that cause direct endothelial injury, thrombosis, and inflammatory infiltration. Neutrophil extracellular traps (NETs) also contribute by presenting ANCA autoantigens in a highly immunogenic form.

Granuloma formation is the histological hallmark of GPA. CD4+ Th1 lymphocytes and macrophages accumulate around foci of necrotic tissue, forming multinucleated giant cell granulomas with characteristic "geographic necrosis" — irregular, map-like areas of tissue destruction surrounded by palisading histiocytes. These granulomas differ from the caseating granulomas of tuberculosis and the non-caseating granulomas of sarcoidosis, though all three can affect the lungs and may be confused radiographically.

Infection as a trigger is supported mainly by studies of relapse. Chronic nasal carriage of Staphylococcus aureus is linked to relapse: in a Dutch cohort of 57 patients, chronic carriers had a higher relapse risk (adjusted relative risk 7.16), and the authors suggested a role for S. aureus in the disease’s pathophysiology (Stegeman 1994). In a placebo-controlled trial in patients in remission, trimethoprim-sulfamethoxazole (TMP-SMX) reduced relapses (Stegeman 1996; see TMP-SMX below).

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ENT and Upper Airway Manifestations

The ear, nose and throat region is one of the most common sites of ANCA-associated vasculitis, and its involvement often precedes the diagnosis by many months (Pendolino 2020). These manifestations can precede systemic vasculitis by months to years in limited GPA.

Nasal and Sinus Disease

Nasal involvement presents as chronic, bloody nasal crusting, recurrent epistaxis, nasal obstruction, and mucosal ulceration. Sinusitis — most commonly maxillary — is refractory to repeated courses of antibiotics and does not respond to standard treatments, a clinical clue that prompts further workup. CT imaging of the sinuses in GPA shows mucosal thickening, destruction of the nasal septum, and erosion of sinus walls, distinguishing it from simple chronic sinusitis. Progressive cartilage and bone destruction leads to septal perforation and ultimately the classic saddle nose deformity — a depressed nasal bridge from collapse of the nasal cartilage framework. This deformity, while cosmetically distressing, develops over months to years and is not present at initial diagnosis. Surgical reconstruction (rhinoplasty with cartilage grafts) can restore form and function; a 2020 systematic review states that nasal reconstruction is performed only when the disease is in remission, to maximise success and minimise complications (Pendolino 2020).

Subglottic Stenosis

Subglottic stenosis (SGS) developed in 43 of 189 patients with GPA followed at the NIH (Langford 1996) and is one of the most dangerous upper airway manifestations. Circumferential granulomatous inflammation of the subglottis produces fibrous scarring that narrows the airway below the vocal cords. Symptoms include stridor, progressive dyspnea on exertion, exercise intolerance, and hoarseness. Subglottic stenosis can progress — and even cause life-threatening airway compromise — when systemic GPA is otherwise quiet: in the NIH series it was diagnosed in the absence of other features of active disease in 21 of the 43 patients, and in another 21 it began while the patient was already receiving systemic immunosuppressive therapy; the authors concluded that SGS often occurs independently of other features of active GPA and is frequently unresponsive to systemic immunosuppression (Langford 1996). The treatments reported are endoscopic. In the NIH series, none of 20 patients treated with intratracheal dilation and glucocorticoid injection required tracheostomy and 6 with earlier tracheostomies were decannulated, whereas 10 of 18 treated with systemic immunosuppressive therapy needed a tracheostomy (Langford 1996). In a series of 21 patients (64 procedures), intralesional injection of a long-acting corticosteroid (methylprednisolone acetate) followed by dilation kept the airway open and none of the 21 needed a new tracheostomy; the authors describe it as their preferred therapy (Hoffman 2003). Tracheostomy is used for critical airway narrowing.

Ear Involvement

Serous otitis media from Eustachian tube dysfunction is common, producing conductive hearing loss. Tympanic membrane perforation and mastoiditis occur in more severe cases. Sensorineural hearing loss from vasculitis of the internal auditory artery is a less common but recognized complication. Conductive or sensorineural hearing loss is one of the items scored in the 2022 ACR/EULAR classification criteria for GPA (Robson 2022).

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Pulmonary Manifestations

The lungs are commonly involved over the course of GPA, though many pulmonary lesions are initially asymptomatic and discovered only on imaging performed for other reasons. When symptomatic, pulmonary GPA presents with cough (dry or productive), hemoptysis, dyspnea, and occasionally pleuritis with pleural effusion.

Pulmonary Nodules and Cavitation

The most characteristic pulmonary finding in GPA is the presence of bilateral cavitating nodules. These appear on chest CT as multiple, variably-sized nodules distributed throughout both lungs, often in the lower lobes. As nodules enlarge, their centers undergo geographic necrosis and eventually cavitate. Cavitary lesions can be mistaken for fungal infection (aspergillosis, cryptococcosis), septic emboli, or malignancy. Tissue biopsy — often via bronchoscopy or CT-guided approach — is needed for definitive diagnosis when clinical context is insufficient.

Diffuse Alveolar Hemorrhage

Diffuse alveolar hemorrhage (DAH) is the most life-threatening pulmonary complication of GPA. It results from capillaritis — neutrophilic destruction of alveolar capillary walls — leading to flooding of alveolar spaces with red blood cells. The clinical triad is hemoptysis, progressive anemia, and bilateral infiltrates on chest imaging. However, hemoptysis is absent in up to one-third of patients with DAH, which is one reason the diagnosis often rests on bronchoalveolar lavage (Lara and Schwarz 2010). Bronchoalveolar lavage (BAL) confirms the diagnosis: serial lavage aliquots return progressively bloodier fluid rather than clearing. Pulmonary function testing in DAH reveals an elevated DLCO because free hemoglobin in the alveoli avidly binds carbon monoxide — the paradoxical finding of high DLCO amid respiratory failure is a diagnostic clue. DAH is treated as an emergency: for organ- or life-threatening disease the 2022 EULAR update recommends high-dose glucocorticoids with either rituximab or cyclophosphamide (Hellmich 2024). The PEXIVAS trial enrolled patients with diffuse pulmonary hemorrhage as well as those with low kidney function, and adding plasma exchange did not reduce death or end-stage kidney disease (Walsh 2020).

Pulmonary Function Testing

Spirometry in GPA varies with disease location. Subglottic stenosis produces a fixed upper-airway obstruction pattern on flow-volume loops, with flattening of the inspiratory and expiratory limbs. Parenchymal disease with alveolar involvement reduces DLCO. The two patterns can occur together in the same patient with GPA.

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Renal Manifestations

Renal involvement is the most serious organ manifestation of GPA and is the primary determinant of long-term prognosis. The pathological lesion is necrotizing crescentic glomerulonephritis, characterized by fibrinoid necrosis of glomerular capillary loops, cellular crescents (proliferating parietal epithelial cells filling Bowman's space), and glomerular collapse. On immunofluorescence, the pattern is pauci-immune — little to no immunoglobulin or complement deposition — a key histological distinction from Goodpasture syndrome (linear IgG along the glomerular basement membrane) and lupus nephritis or IgA nephropathy (granular immune complex deposition).

Renal GPA can progress rapidly. Creatinine may double within days to weeks without treatment, and patients can progress from normal renal function to dialysis dependence within weeks if therapy is not initiated. Conversely, patients whose kidneys are already severely scarred at diagnosis are less likely to recover renal function regardless of treatment.

Clinical Findings

The urinalysis is the critical bedside test for detecting renal involvement. An active urinary sediment — the presence of dysmorphic red blood cells and red cell casts on urine microscopy — is the hallmark of active glomerulonephritis in GPA, even when creatinine is still normal. Dipstick proteinuria and hematuria are usually followed by microscopic examination of fresh urine, and a rising serum creatinine is a common reason for kidney biopsy. Renal biopsy provides the definitive histological diagnosis, characterizes severity (percentage of crescents and sclerotic glomeruli), and informs prognosis: an international pathology classification sorts ANCA-associated glomerulonephritis into focal, crescentic, mixed and sclerotic classes, and in its validation study of 100 biopsies the classes were of prognostic value for 1- and 5-year renal outcomes (Berden 2010).

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Other Organ Involvement

GPA is a systemic vasculitis capable of affecting virtually any organ. When these extrapulmonary, extrarenal manifestations are not recognized as GPA, they can be attributed to unrelated conditions and treatment can be delayed.

Ocular Involvement

Orbital pseudotumor (retro-orbital granulomatous inflammation) produces proptosis, diplopia, and periorbital pain from a retro-orbital inflammatory mass, and compression of the optic nerve can cause irreversible blindness. Orbital masses are rare but damaging: in a single-centre cohort of 1,142 patients with GPA, 58 developed orbital masses; of 40 with complete assessments, 41% were refractory to intensive immunosuppression, 72% developed visual impairment and 19% became blind (Holle 2013). Other ocular manifestations include scleritis (deep, painful inflammation of the scleral coat), episcleritis (milder superficial redness), uveitis, corneal ulceration, and dacryocystitis (lacrimal duct inflammation).

Cutaneous Involvement

Skin manifestations in GPA include palpable purpura of the lower extremities (leukocytoclastic vasculitis), subcutaneous nodules (extravascular granulomas histologically similar to rheumatoid nodules), and necrotic ulcers. Skin biopsy can provide diagnostic tissue in patients who present predominantly with cutaneous disease.

Neurological Involvement

Peripheral neuropathy — particularly mononeuritis multiplex, the simultaneous or sequential infarction of multiple individual peripheral nerves — produces painful, asymmetric sensory and motor deficits. Cranial nerve palsies can involve, among others, cranial nerves VI (abducens, causing lateral gaze palsy), VII (facial), and VIII (vestibulocochlear, causing hearing loss and vertigo). Pachymeningitis (granulomatous inflammation of the dura mater) is a rare but recognized cause of headache, cranial neuropathy, and cerebellar dysfunction in GPA.

Joint and Constitutional Features

Arthralgias or frank non-erosive arthritis are common in GPA, typically affecting large joints in a migratory pattern that parallels systemic disease activity. Constitutional features — fever, weight loss, and profound fatigue — are present in the majority of patients at diagnosis and often precede the recognition of organ-specific disease by weeks to months.

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Diagnosis and ANCA Testing

GPA diagnosis requires the integration of clinical features, serology, and histology. No single test is pathognomonic, and the 2022 revised ACR/EULAR classification criteria reflect this complexity. The 2022 EULAR update recommends biopsies and ANCA testing to assist in establishing the diagnosis (Hellmich 2024). In the 2022 ACR/EULAR classification criteria, c-ANCA or PR3-ANCA positivity carries the most weight (+5 points), and in validation the criteria had 93% sensitivity and 94% specificity; they are designed for research classification rather than for diagnosing individual patients (Robson 2022). In atypical presentations or ANCA-negative disease, biopsy carries more of the diagnostic weight.

ANCA Testing

Two complementary methods are used:

The revised 2017 international consensus states that high-quality PR3- and MPO-ANCA immunoassays can be used as the primary screening test for GPA and MPA, without the categorical need for IIF (Bossuyt 2017).

Biopsy

When tissue is needed, site selection follows a risk-benefit hierarchy. Nasal or sinus biopsy is the most accessible option but carries the lowest diagnostic yield — it often shows only nonspecific inflammation or ulceration without diagnostic granulomas; in 126 head and neck biopsies, vasculitis, necrosis and granulomatous inflammation were seen together in only 16% (Devaney 1990). Open lung biopsy provides the highest diagnostic yield and can demonstrate the full histological triad (necrotizing granulomas, vasculitis, and geographic necrosis) — in a review of 87 open lung biopsies, vascular changes were seen in 94% of specimens and parenchymal necrosis in 84% (Travis 1991) — but requires general anesthesia and thoracotomy or VATS. Renal biopsy confirms pauci-immune crescentic GN and establishes the extent of renal involvement, but it cannot show pulmonary granulomas. Bronchoscopic transbronchial biopsy is often attempted but has limited yield for GPA-specific findings.

Laboratory and Imaging

Supporting laboratory findings include elevated ESR and CRP, normocytic anemia of chronic disease, leukocytosis, thrombocytosis, and elevated creatinine. Urinalysis with microscopy for casts is a standard part of assessment at diagnosis and during follow-up. Chest CT shows nodules, cavities, consolidation, and ground-glass opacities with greater sensitivity than plain radiography. PET-CT can map disease extent and guide biopsy site selection in difficult cases.

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Induction Therapy

The goal of induction therapy is complete remission — elimination of all detectable disease activity, ideally with ANCA negativity. Treatment intensity is calibrated to disease severity. The doses below are those used in the trials named, not instructions; decisions about treatment belong with a clinician.

Rituximab Plus Glucocorticoids

The 2021 ACR/Vasculitis Foundation guideline recommends rituximab (RTX) for remission induction and maintenance in severe GPA and MPA (all its recommendations are conditional) (Chung 2021); the 2022 EULAR update recommends high-dose glucocorticoids with either rituximab or cyclophosphamide for organ- or life-threatening disease (Hellmich 2024). The RAVE trial (Stone et al., NEJM 2010, PubMed PMID: 20647199) randomized 197 ANCA-positive patients with GPA or MPA to rituximab (375 mg/m² weekly ×4) or daily oral cyclophosphamide (2 mg/kg/day): 64% versus 53% reached remission without prednisone at 6 months, meeting the non-inferiority criterion, and in relapsing disease rituximab did better (67% versus 42%). Cyclophosphamide’s toxicity to the ovaries and testes is one reason rituximab is often discussed for people who may want children.

Cyclophosphamide

Cyclophosphamide (CYC) remains an important option, particularly when rituximab is unavailable or contraindicated. It can be administered as intravenous pulse therapy or as daily oral dosing. The CYCLOPS trial (de Groot et al., Ann Intern Med 2009, PubMed PMID: 19451574) randomized 149 patients with generalized ANCA-associated vasculitis and kidney involvement: pulse cyclophosphamide (15 mg/kg every 2–3 weeks) and daily oral cyclophosphamide (2 mg/kg/day) produced similar remission rates at 9 months (88.1% versus 87.7%), with a lower cumulative dose and fewer cases of leukopenia in the pulse group. In long-term follow-up (median 4.3 years), relapse was more frequent after pulse treatment (39.5% versus 20.8% of patients had at least one relapse), with no difference in survival or kidney function (Harper 2012). Cyclophosphamide carries a risk of hemorrhagic cystitis and bladder cancer linked to its urotoxic metabolite acrolein: in 145 NIH patients treated with it, half developed non-glomerular hematuria and 5% developed bladder cancer (Talar-Williams 1996). Mesna (2-mercaptoethane sulfonate sodium) and hydration are used to reduce bladder toxicity.

Glucocorticoids

High-dose glucocorticoids are part of the induction regimens tested in these trials; the original NIH regimen combined cyclophosphamide 2 mg/kg/day with prednisone 1 mg/kg/day (Fauci 1983), and regimens for severe disease often begin with intravenous methylprednisolone pulses. The 2022 EULAR update recommends tapering to a target of 5 mg prednisolone equivalent per day within 4–5 months (Hellmich 2024). In the PEXIVAS trial (Walsh et al., NEJM 2020, PMID 32053298), a reduced-dose oral glucocorticoid regimen was non-inferior to a standard-dose regimen for death or end-stage kidney disease, with fewer serious infections at 1 year (incidence rate ratio 0.69).

Plasma Exchange

Plasma exchange (PLEX) removes circulating ANCA and inflammatory mediators from the blood and was previously used widely for severe ANCA vasculitis with advanced renal failure. PEXIVAS enrolled patients with an eGFR below 50 mL/min/1.73 m² or diffuse pulmonary hemorrhage: death or end-stage kidney disease occurred in 100 of 352 patients (28.4%) with plasma exchange and 109 of 352 (31.0%) without it (hazard ratio 0.86, not statistically significant), so adding PLEX did not reduce death or ESKD (Walsh 2020). The 2022 EULAR update states that plasma exchange may be considered in patients with rapidly progressive glomerulonephritis (Hellmich 2024). It is also used when anti-GBM antibodies are present alongside ANCA.

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Maintenance Therapy and Relapse

Achieving remission is only the first challenge; maintaining it over the long term without intolerable toxicity is equally demanding. Relapse is common: a 2021 meta-analysis of ANCA-associated vasculitis after cyclophosphamide induction estimated cumulative relapse at about 12% at 1 year, 33% at 3 years and 47% at 5 years, higher where more patients had GPA (He 2021), and in the CYCAZAREM trial relapse was less frequent in MPA than in GPA (Jayne 2003). Relapses can cause permanent organ damage.

Rituximab Maintenance

The MAINRITSAN trial (Guillevin et al., NEJM 2014, PubMed PMID: 25372085) randomized 115 patients in complete remission after cyclophosphamide (87 with GPA) to rituximab 500 mg on days 0 and 14 and at months 6, 12 and 18, or daily azathioprine until month 22; major relapse by month 28 occurred in 5% on rituximab versus 29% on azathioprine, with similar rates of severe adverse events. The 2021 ACR guideline and the 2022 EULAR update both recommend rituximab for maintenance of remission (Chung 2021; Hellmich 2024).

Azathioprine

The 2022 EULAR update lists azathioprine (AZA) and methotrexate as alternatives to biologics for remission maintenance (Hellmich 2024). In the CYCAZAREM trial, switching to azathioprine (2 mg/kg/day) after remission did not increase relapse compared with continued cyclophosphamide (15.5% versus 13.7% over 18 months) (Jayne 2003). Thiopurine methyltransferase (TPMT) genotyping or enzyme activity testing is commonly done before azathioprine is started, because people with absent TPMT activity are at risk of life-threatening myelosuppression at standard doses. In the WEGENT trial (Pagnoux et al., NEJM 2008, PubMed PMID: 19109574), 126 patients in remission after intravenous cyclophosphamide were randomized to azathioprine (2.0 mg/kg/day) or methotrexate (increased to 25 mg/week) for 12 months; adverse events and relapses (23 versus 21 patients) were similar, and the authors describe the two drugs as similar alternatives.

Methotrexate

Methotrexate (MTX; up to 25 mg/week in WEGENT) is used for maintenance and, in non-severe disease without significant kidney involvement, for induction. Methotrexate is cleared by the kidneys, so impaired kidney function raises the risk of accumulation and toxicity, which limits its use in people with renal impairment.

Avacopan

Avacopan, an oral complement 5a receptor (C5aR) antagonist, was approved by the US FDA in October 2021 as an adjunctive treatment for adults with severe active ANCA-associated vasculitis (GPA and MPA), in combination with standard therapy including glucocorticoids; the US label states that it does not eliminate glucocorticoid use. The approval rested mainly on the ADVOCATE trial (Jayne et al., NEJM 2021, PubMed PMID: 33596356), whose published report was retracted by the journal on 29 June 2026 (retraction notice PMID 42377355). The European Medicines Agency opened a review in January 2026 over the integrity of the ADVOCATE data and concluded in June 2026 that the trial was conducted in breach of good clinical practice and that the study data provided at the time of assessment were “incorrect and misleading” and could no longer be relied upon to show the medicine’s effectiveness; the EU marketing authorisation was revoked by European Commission decision on 4 August 2026 (EMA announcement, 26 June 2026). In the United States, the FDA’s Drugs@FDA record still listed the 2021 approval with prescription marketing status as of October 2026; whether the FDA has taken any action since the retraction could not be confirmed.

TMP-SMX for Relapse Prevention and PCP Prophylaxis

Trimethoprim-sulfamethoxazole (TMP-SMX) has two roles in GPA. First, relapse prevention: in a placebo-controlled trial of patients with GPA in remission (41 on TMP-SMX 800/160 mg twice daily for 24 months, 40 on placebo), 82% stayed in remission at 24 months versus 60% on placebo (relative risk of relapse 0.40), with fewer respiratory tract infections; 20% stopped the drug because of side effects (Stegeman et al., NEJM 1996, PMID 8637536). Second, TMP-SMX is used as prophylaxis against Pneumocystis jirovecii pneumonia (PCP), a potentially fatal opportunistic infection, during cyclophosphamide- or rituximab-based induction with glucocorticoids.

Monitoring for Relapse

Serial PR3-ANCA levels, urinalysis, serum creatinine, and chest imaging as clinically indicated are commonly used to watch for relapse. A rise in ANCA was one of the risk factors for relapse in a 2021 meta-analysis (He 2021), and in a Dutch cohort 22 of 33 patients who were persistently or intermittently ANCA-positive relapsed, against 1 of 21 who stayed negative (Stegeman 1994); in the prospective study of 156 patients, however, increases in PR3-ANCA were not associated with relapse (Finkielman 2007). New urinary sediment abnormalities or worsening pulmonary symptoms in a previously quiescent patient are common reasons for re-evaluation, sometimes including repeat biopsy.

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Prognosis and Special Situations

The prognosis of GPA has been transformed by cyclophosphamide-based treatment, first reported from the NIH (Fauci 1983), and later by rituximab (Stone 2010). Complete remission rates of 75% (Hoffman 1992) and 93% (Fauci 1983) were reported in the NIH series. In a European cohort of 535 patients with ANCA-associated vasculitis recruited to trials between 1995 and 2002, 25% had died over a median follow-up of 5.2 years, and mortality was 2.6 times that of an age- and sex-matched general population (Flossmann 2011). Nevertheless, the disease remains lifelong and carries significant burdens of relapse, infection, treatment toxicity, and permanent organ damage.

Causes of Death

Infection is the leading cause of early death: in the European cohort, infection caused 48% of deaths in the first year and active vasculitis 19%; after the first year the main causes were cardiovascular disease (26%), cancer (22%) and infection (20%) (Flossmann 2011). Early infections follow from intensive immunosuppression with cyclophosphamide or rituximab and high-dose glucocorticoids. Opportunistic infections including PCP, invasive aspergillosis, and disseminated herpes zoster account for a substantial proportion of early deaths. Antimicrobial prophylaxis and vaccination (pneumococcal, influenza, herpes zoster) are part of standard care during immunosuppression. Renal failure requiring long-term dialysis develops in some patients despite treatment, and an eGFR below 15 mL/min at presentation was associated with worse survival in the European cohort (Flossmann 2011). Malignancy, including bladder cancer and lymphoma, is a late concern after substantial cumulative cyclophosphamide exposure: in the NIH patients treated with cyclophosphamide, the estimated bladder-cancer incidence was 5% at 10 years and 16% at 15 years after first exposure (Talar-Williams 1996).

Permanent Organ Damage

Even in patients who achieve and sustain remission, permanent organ damage accumulates: in the NIH series, almost all patients had serious morbidity from irreversible features of the disease (86%) or side effects of treatment (42%) (Hoffman 1992). Subglottic stenosis may require repeated endoscopic procedures or permanent tracheostomy. Saddle nose deformity is permanent absent surgical correction. Sensorineural hearing loss, visual impairment from orbital or ocular disease, and peripheral neuropathy may persist despite remission. The Vasculitis Damage Index (VDI) quantifies this cumulative burden and is used in clinical research and practice.

Pregnancy in GPA

Pregnancy in GPA carries higher risk. A 2023 meta-analysis of six studies (92 pregnancies in women with ANCA-associated vasculitis) estimated disease flare in 28% of pregnancies, pre-term delivery in 18% and growth-restricted newborns in 20% (Partalidou 2023). Rituximab use in the third trimester is generally avoided because of neonatal B-cell depletion, though it has been used earlier in pregnancy when the benefit was judged to outweigh the risk. Azathioprine is among the immunosuppressants regarded as compatible with pregnancy. Cyclophosphamide is teratogenic and contraindicated in pregnancy. Methotrexate is teratogenic and is stopped before conception.

Subglottic Stenosis as an Independent Entity

Subglottic stenosis deserves special emphasis because it behaves differently from other GPA manifestations. The fibrous scar tissue that narrows the subglottis is not driven by ongoing vasculitis; instead, it is a mechanical consequence of prior inflammation that contracts and progresses even when systemic GPA is fully quiescent. Systemic immunosuppression does not reliably prevent progression. Endoscopic dilation, with or without intralesional injection of a long-acting corticosteroid, is the main treatment reported, and patients often need repeated procedures: in one series, patients without scarring from earlier procedures needed a mean of 2.4 procedures and those with established scarring a mean of 4.1 (Hoffman 2003). Tracheostomy provides definitive airway protection when dilation fails or when the stenosis is too severe for endoscopic management.

Saddle Nose Reconstruction

Correction of saddle nose deformity restores the shape and function of the nose and does not change the course of the disease. A 2020 systematic review of sinonasal surgery in ANCA-associated vasculitis states that nasal reconstruction is performed only when the disease is in remission, to maximise success and minimise complications (Pendolino 2020). Reconstruction typically uses rib or ear (auricular) cartilage grafts.

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Key Research Papers

  1. Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis (RAVE trial). N Engl J Med. 2010;363(3):221-232. — PubMed PMID: 20647199
  2. Guillevin L, Pagnoux C, Karras A, et al. Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis (MAINRITSAN). N Engl J Med. 2014;371(19):1771-1780. — PubMed PMID: 25372085
  3. Walsh M, Merkel PA, Peh CA, et al. Plasma exchange and glucocorticoids in severe ANCA-associated vasculitis (PEXIVAS). N Engl J Med. 2020;382(7):622-631. — PubMed PMID: 32053298
  4. Jayne DRW, Merkel PA, Schall TJ, et al. Avacopan for the treatment of ANCA-associated vasculitis (ADVOCATE). N Engl J Med. 2021;384(7):599-609. — PubMed PMID: 33596356 — Retracted (retraction notice: PubMed PMID: 42377355)
  5. Fauci AS, Haynes BF, Katz P, Wolff SM. Wegener's granulomatosis: prospective clinical and therapeutic experience with 85 patients for 21 years. Ann Intern Med. 1983;98(1):76-85. — PubMed PMID: 6336643
  6. Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013;65(1):1-11. — PubMed PMID: 23045170
  7. Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med. 1992;116(6):488-498. — PubMed PMID: 1739240
  8. de Groot K, Harper L, Jayne DR, et al. Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis (CYCLOPS). Ann Intern Med. 2009;150(10):670-680. — PubMed PMID: 19451574
  9. Pagnoux C, Mahr A, Hamidou MA, et al. Azathioprine or methotrexate maintenance for ANCA-associated vasculitis (WEGENT). N Engl J Med. 2008;359(26):2790-2803. — PubMed PMID: 19109574
  10. Holle JU, Voigt C, Both M, et al. Orbital masses in granulomatosis with polyangiitis are associated with a refractory course and a high burden of local damage. Rheumatology (Oxford). 2013;52(5):875-882. — PubMed PMID: 23293138
  11. Stegeman CA, Tervaert JW, de Jong PE, Kallenberg CG. Trimethoprim-sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener's granulomatosis. N Engl J Med. 1996;335(1):16-20. — PubMed PMID: 8637536
  12. Ntatsaki E, Carruthers D, Chakravarty K, et al. BSR and BHPR guideline for the management of adults with ANCA-associated vasculitis. Rheumatology (Oxford). 2014;53(12):2306-2309. — PubMed PMID: 24729399
  13. Kitching AR, Anders HJ, Basu N, et al. ANCA-associated vasculitis. Nat Rev Dis Primers. 2020;6(1):71. — PubMed PMID: 32855422
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PubMed Topic Searches

The following PubMed topic searches retrieve current peer-reviewed literature on Granulomatosis with Polyangiitis. Each link opens a live PubMed query.

  1. PubMed: Granulomatosis with polyangiitis treatment rituximab
  2. PubMed: ANCA vasculitis cyclophosphamide induction
  3. PubMed: Wegener granulomatosis diagnosis c-ANCA PR3
  4. PubMed: GPA renal involvement glomerulonephritis
  5. PubMed: Avacopan ANCA vasculitis steroid sparing
  6. PubMed: Granulomatosis polyangiitis subglottic stenosis
  7. PubMed: ANCA vasculitis relapse rituximab maintenance
  8. PubMed: GPA saddle nose orbital pseudotumor
  9. PubMed: Granulomatosis polyangiitis pulmonary manifestations
  10. PubMed: PEXIVAS plasma exchange ANCA vasculitis

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