Granulomatosis with polyangiitis

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

GPA is a necrotising granulomatous small-vessel vasculitis with a predilection for upper airways, lungs and kidneys. Disease may begin as persistent sinusitis, otitis, deafness, nasal crusting or an orbital process before renal or pulmonary involvement becomes apparent. Ask about red eyes, haemoptysis, dyspnoea, urine, oedema, rash, joint symptoms and focal nerve deficits and examine ENT structures, eyes, lungs, skin, pulses and neurological power.

ANCA supports but does not define diagnosis. PR3-ANCA is common and predicts relapse more than organ activity; MPO-ANCA or negative assays occur. Infection, inflammatory bowel disease, medicines and cocaine can yield ANCA. Tissue establishes mechanism and excludes infection or cancer. A kidney biopsy is often rapid and high yield in active urine; superficial nasal biopsy is less sensitive, and necrotic tissue should be sent for microbiology as well as histology.

Severity directs induction. Organ-threatening kidney, lung, eye, nerve, cardiac or gastrointestinal disease receives rituximab or cyclophosphamide plus glucocorticoid, using reduced exposure when possible. Avacopan is a complement-C5a-receptor antagonist commissioned for eligible severe active GPA or MPA with standard induction. Non-organ-threatening disease still needs specialist disease-modifying therapy; prolonged steroid monotherapy is unsafe and inadequate.

Response is assessed by organ trajectory, urine, eGFR, imaging, haemoglobin, vision and neurological function rather than serial ANCA alone. Maintenance prevents relapse after remission. Rituximab is strongly suited to relapsing PR3 disease; azathioprine is an alternative. Persistent sinus symptoms may reflect damage or infection, and haematuria may persist from CKD. Before escalating, distinguish activity, scar, infection, malignancy and medicine toxicity.

Key points

Think GPA when chronic destructive sinus or ear disease, epistaxis, nasal crust, hearing loss, pulmonary nodules or haemorrhage, glomerular urine, scleritis or mononeuritis occur together.
Obtain FBC, CRP or ESR, creatinine, electrolytes, urinalysis, microscopy and quantitative protein immediately; a small creatinine rise can represent substantial loss from a low baseline.
Request PR3-ANCA and MPO-ANCA by antigen-specific immunoassay, but do not diagnose from ANCA alone or exclude tissue-proven disease after a negative result.
CT sinuses and HRCT chest define destructive, nodular, cavitating and haemorrhagic disease and identify the safest biopsy site.
Biopsy the kidney, lung, skin, nasal or orbital tissue that gives the highest diagnostic yield at acceptable risk; renal biopsy rapidly confirms pauci-immune crescentic injury and chronicity.
For organ- or life-threatening disease use rituximab or cyclophosphamide plus a reduced-dose glucocorticoid regimen; begin urgent treatment when delay is dangerous while obtaining tissue and cultures.
Rituximab is preferred for relapsing PR3 disease and when fertility or cumulative cyclophosphamide toxicity matters; cyclophosphamide remains an effective alternative for severe new disease.
Avacopan 30 mg twice daily can replace much oral glucocorticoid in eligible severe active GPA or MPA under NICE criteria, but it does not replace rituximab or cyclophosphamide.
Plasma exchange is not routine for all severe AAV; consider it selectively for very severe renal failure or hypoxaemic alveolar haemorrhage after specialist benefit-risk assessment.
Maintenance usually uses rituximab or azathioprine for at least 24–48 months, longer in high-relapse PR3 disease, with vaccination, Pneumocystis prevention and infection monitoring.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Genetic immune susceptibility

HLA-DP and immune-regulatory variants interact with environmental exposures to permit loss of tolerance toward neutrophil proteinase-3 in many patients.

Airway and environmental triggers

Silica, smoking-related airway injury, microbial colonisation and other exposures may influence disease onset or relapse without acting as a single sufficient cause.

Medicine-induced mimics

Levamisole-adulterated cocaine, hydralazine, propylthiouracil and other medicines can generate ANCA vasculitis phenotypes and require an exact exposure history.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
ANCA neutrophil activation
PR3-ANCA binds primed neutrophils, promotes degranulation, NET formation and complement-alternative-pathway amplification, injuring small vessels with little immune deposit.
2
Necrotising granulomatous inflammation
Granulomatous inflammation affects upper and lower respiratory tissues, producing nodules, cavitation, destructive sinus disease, orbital masses and airway stenosis.
3
Pauci-immune glomerulonephritis
Necrotising capillary injury creates focal crescents and rapidly reduces filtration while immunofluorescence shows few immune deposits.
4
Damage and relapse
Recurrent inflammation causes saddle-nose deformity, deafness, CKD, neuropathy and airway scar; infection and treatment toxicity can mimic active relapse.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Destructive ENT disease

Persistent bloody crusting, ulcers, septal damage, otitis, hearing loss or subglottic symptoms exceeds ordinary recurrent sinus infection.

Pulmonary nodules and haemorrhageRed flag

Multiple nodules, cavities or diffuse opacities with falling haemoglobin and hypoxia suggest granulomatous lung disease or alveolar haemorrhage.

GlomerulonephritisRed flag

Dysmorphic haematuria, casts, proteinuria, pressure rise and creatinine progression indicates pauci-immune renal capillary injury.

Eye and orbital disease

Scleritis, episcleritis, proptosis, diplopia and orbital pain may threaten sight or compress structures and require urgent ophthalmic assessment.

Mononeuritis multiplex

Painful stepwise asymmetric sensory loss, foot or wrist drop indicates vasculitic nerve infarction and organ-threatening disease.

Red flags requiring action

Haemoptysis may be absent in diffuse alveolar haemorrhage; falling haemoglobin, hypoxia and diffuse opacities with active urine is an emergency.
Rising creatinine, oliguria, glomerular haematuria, casts, hyperkalaemia or pulmonary oedema requires urgent renal biopsy and kidney-support planning.
Painful red eye, reduced vision, proptosis, diplopia or severe orbital pain requires same-day ophthalmology and imaging.
Stridor, voice change or increasing work of breathing may indicate subglottic stenosis and requires early expert airway assessment.
Fever and opacity during immunosuppression may be infection rather than relapse; investigate both before reflex escalation.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Urinalysis, microscopy, ACR or PCR and serial creatinineFirst step
Why
Detect glomerulonephritis early and quantify renal trajectory and complications.
Interpretation and limitations
Red-cell casts and dysmorphic blood support glomerular injury; modest protein does not make rapidly progressive disease safe.
02
PR3-ANCA and MPO-ANCA immunoassays
Why
Support diagnosis and phenotype in a compatible multisystem vasculitis presentation.
Interpretation and limitations
PR3 supports GPA but false positives and seronegative disease occur; titres do not replace direct organ assessment for relapse.
03
HRCT chest and CT sinuses or orbit
Why
Map nodules, cavities, haemorrhage, airway and destructive tissue and guide sampling.
Interpretation and limitations
Cavities require bacterial, mycobacterial, fungal and malignant assessment; ground glass can be haemorrhage, infection or oedema.
04
Kidney or other tissue biopsy
Why
Confirm pauci-immune necrotising vasculitis, granulomatous inflammation and chronicity and exclude mimics.
Interpretation and limitations
Kidney is often the reference tissue in active urine; choose lung, skin, nerve or ENT tissue when safer or more informative.
05
Cultures and pre-immunosuppression infection screen
Why
Identify sepsis and establish hepatitis, TB, HIV, immunoglobulin and vaccination baseline.
Interpretation and limitations
Obtain cultures before antibiotics when safe, but do not delay resuscitation; immunosuppression can blunt fever and CRP.
06
Organ-specific functional testing
Why
Measure vision, audiology, airway, pulmonary gas exchange and nerve injury for treatment targets.
Interpretation and limitations
Formal ophthalmology, audiogram, flow-volume loops, bronchoscopy, EMG or nerve biopsy is selected by threatened tissue.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Infection

Endocarditis, tuberculosis, fungal disease, septic emboli and chronic bacterial sinus disease can cause cavitation, renal injury, inflammation and even positive ANCA.

Malignancy and inflammatory masses

Lymphoma, lung cancer, IgG4-related disease and sarcoidosis can produce nodules, orbital or ENT masses and constitutional symptoms.

Other pulmonary-renal vasculitis

Microscopic polyangiitis, anti-GBM disease, lupus and cryoglobulinaemia cause glomerulonephritis and haemorrhage but lack the same granulomatous ENT pattern.

Cocaine-associated destructive disease

Intranasal cocaine and levamisole can cause midline destruction, skin disease and multiple ANCA specificities; exposure disclosure and toxicology are important.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01First-line confirmationMap organs and obtain tissueFirst stepFirst lineENT, lung, kidney, eye or nerve findings form a credible GPA pattern.

1Assess physiology and threatened organs, obtain blood, urine, PR3 or MPO assays, cultures and CT chest or affected anatomy.
2Choose the highest-yield safe biopsy, commonly kidney with active sediment, and send necrotic respiratory tissue for microbiology.
3Begin emergency induction before final histology when pulmonary haemorrhage, rapidly progressive renal or sight-threatening disease makes delay unsafe.

02Organ-threatening inductionCombine remission therapy and steroid reductionKidney, lung, eye, nerve, cardiac, gastrointestinal or airway disease threatens function or life.

1Give intravenous methylprednisolone for the most severe presentations, then a reduced-dose oral taper or eligible avacopan strategy.
2Use rituximab or intravenous cyclophosphamide, selecting by relapse, PR3, fertility, previous exposure, infection and access.
3Provide Pneumocystis and gastric or bone prophylaxis when indicated and measure the threatened-organ response frequently.

03MaintenancePrevent relapse after remissionInduction controls active vasculitis and irreversible damage has been distinguished.

1Use fixed-interval rituximab or azathioprine according to relapse and safety phenotype for at least two years, often longer in PR3 disease.
2Taper glucocorticoid, monitor immunoglobulin, infection, blood counts, renal and liver safety and update non-live vaccination.
3Review ENT, lung, renal, eye, nerve and cardiovascular damage separately and provide rapid access for recurrent organ features.

04Suspected relapseSeparate activity from infection and damageSymptoms, haematuria, opacity or inflammatory markers recur during or after treatment.

1Reassess exact organ findings, urine microscopy and eGFR, cultures, imaging, medicine exposure and immunoglobulin rather than acting on ANCA titre.
2AlternativeBiopsy or sample when infection, malignancy, chronic scar or an alternative mechanism remains plausible.
3Reinduce confirmed organ-threatening relapse, commonly with rituximab in PR3 disease, and revise maintenance and prophylaxis.

Key medicines and prescribing safety4 treatments · regimens, roles and cautions

Remission induction for severe GPA and preferred therapy for many relapsing PR3 cases; BSR maintenance protocols may individualise 500–1,000 mg every four to six months.

Rituximab

Licensed adult induction uses 375 mg/m² intravenously once weekly for four doses; 1,000 mg on days 1 and 15 is a common off-label specialist alternative. Licensed maintenance begins with two 500 mg infusions two weeks apart, then 500 mg every six months for at least 24 months; after rituximab induction, wait at least 16 weeks from the final induction infusion.

Screen hepatitis B, TB and infection, measure immunoglobulins and vaccinate before treatment where time permits, premedicate for infusion reactions and monitor late neutropenia and hypogammaglobulinaemia. Coordinate pregnancy and assess infant B cells and live-vaccine timing after later gestational exposure.

Alternative potent induction for new severe organ-threatening GPA, particularly when rituximab is unsuitable.

Intravenous cyclophosphamide

A common pulse regimen is 15 mg/kg intravenously at weeks 0, 2 and 4 and then every three weeks for three to six further pulses, reduced for age, renal function and leukopenia.

Monitor blood counts, urine, infection and cumulative dose and provide antiemesis and bladder protection. Discuss infertility preservation, teratogenicity, bladder cancer and later malignancy before treatment.

C5a-receptor blockade reduces the need for oral glucocorticoid exposure; it is not standalone remission induction.

Avacopan

Take 30 mg orally twice daily with food alongside rituximab or cyclophosphamide induction for eligible severe active GPA or MPA under NICE criteria; trial exposure and product evidence extend to 52 weeks.

Check liver tests, hepatitis B and infection, avoid strong CYP3A4 inducers and grapefruit and monitor inhibitors and angioedema. Stop for serious hepatic injury. It is not recommended in pregnancy or without contraception when pregnancy is possible; make an individual breast-feeding decision.

Prevents Pneumocystis during high-dose glucocorticoid, rituximab, cyclophosphamide or combination immunosuppression.

Co-trimoxazole prophylaxis

When Pneumocystis prophylaxis is indicated, choose either two 480-mg tablets by mouth on three days each week or one 480-mg tablet daily; adjust for renal function and the local protocol.

Monitor FBC, creatinine and potassium and review sulfonamide allergy, rash and interactions with methotrexate or warfarin; dose and duration follow total immune risk.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Kidney failure

Crescentic glomerulonephritis can progress rapidly to dialysis, chronic kidney disease and transplant despite treatment, especially after diagnostic delay.

Respiratory and airway damage

Alveolar haemorrhage, fibrotic lung damage, cavitating infection and subglottic stenosis cause hypoxia, obstruction and recurrent procedural needs.

Sensory and structural disability

Orbital disease, scleritis, hearing loss, saddle-nose deformity and mononeuritis multiplex can leave permanent visual, auditory and motor deficits.

Treatment-related harm

Serious infection, hypogammaglobulinaemia, infertility, bladder malignancy, cytopenia, diabetes and osteoporosis arise from immunosuppression and cumulative cyclophosphamide or steroid.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

During induction review at least every one to four weeks with symptoms, examination, FBC, creatinine, electrolytes, liver tests, CRP or ESR, urine and organ-specific measures.
Track haemoglobin, oxygen, imaging and pulmonary function after haemorrhage; urine, eGFR and protein after nephritis; and formal vision, hearing, airway or nerve function when affected.
Measure immunoglobulins before rituximab and during recurrent infection or maintenance and coordinate immunology when sustained low IgG is clinically important.
Do not adjust treatment solely from ANCA titre; investigate a new clinical organ signal even if titre is unchanged.
Record cyclophosphamide cumulative dose, fertility, haematuria and malignancy surveillance and minimise cumulative glucocorticoid.
Provide written infection, haemoptysis, urine, visual, stridor and neuropathy return advice and vaccination and pregnancy plans.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

ENT disease can precede kidneys

Months of refractory otitis, deafness or bloody crusting may be the diagnostic window before glomerulonephritis appears.

Haemorrhage can lack haemoptysis

Diffuse alveolar bleeding may present through anaemia and hypoxia because blood is not always coughed out.

ANCA predicts phenotype imperfectly

PR3 supports GPA and relapse risk but cannot distinguish an infected cavity or chronic haematuria from active vasculitis.

Airway scar is not always activity

Subglottic stenosis may require local dilation or surgery even when systemic inflammation is controlled.

Biopsy includes chronicity

Renal tissue shows how much injury may recover and prevents futile escalation when glomeruli are predominantly scarred.

11Common pitfallsFrequent interpretation and management errors.

01
Treating recurrent sinusitis indefinitely without checking urine, hearing, lungs, eyes and destructive anatomy.
02
Diagnosing GPA from PR3-ANCA alone in endocarditis or cocaine-related disease.
03
Escalating immunosuppression for a new cavity before bacterial, fungal and mycobacterial sampling.
04
Using serial ANCA titre as the sole relapse trigger.
05
Giving cyclophosphamide without fertility, bladder, cumulative-dose and infection safeguards.
06
Calling persistent subglottic obstruction active systemic disease without airway imaging and specialist assessment.