ANCA Vasculitis and Anti-GBM Disease — Advanced

After a positive IIF ANCA, antigen-specific immunoassays for PR3 and MPO are the appropriate next tests to define the target antigen and improve diagnostic specificity. Because haemoptysis creates a pulmonary–renal syndrome, anti-GBM antibodies should also be sent urgently in parallel; however, the question asks specifically which test determines ANCA antigen specificity. Repeating IIF does not identify the antigen, and complement or ANA testing is not the key next test for this purpose.

ANCA-associated renal vasculitis classically produces a necrotising, crescentic glomerulonephritis with a 'pauci-immune' immunofluorescence pattern (minimal or absent immunoglobulin and complement deposits). Granular immune complex deposition suggests immune-complex GN (e.g. lupus, infection-related GN). Linear IgG on IF is the hallmark of anti-GBM disease. Mesangial IgA-dominant deposits are typical of IgA nephropathy/HSP. Thrombotic microangiopathy has a different aetiology (eg TTP/HUS) and distinct histology.

The definitive immunopathological hallmark of anti-GBM disease is linear IgG staining along the glomerular basement membrane on immunofluorescence. Mesangial IgA indicates IgA nephropathy. Segmental sclerosis with paucity of immune deposits is typical of ANCA-associated pauci-immune GN. Granular subepithelial 'humps' are seen in post-infectious GN. Linear C1q without IgG is not the pattern seen in anti-GBM disease; anti-GBM characteristically shows strong linear IgG (often with linear light chains) across the GBM.

Double-positive patients (ANCA and anti-GBM) commonly present with severe renal injury and pulmonary haemorrhage and are managed initially like anti-GBM disease: urgent plasma exchange to remove circulating anti-GBM antibodies, together with high-dose glucocorticoids and cyclophosphamide to suppress antibody production and inflammation. Immediate high‑dose steroids without plasma exchange is inadequate for anti-GBM disease with pulmonary haemorrhage. Oral prednisolone and azathioprine alone are insufficient in life‑threatening pulmonary–renal syndrome. Rituximab is effective in AAV induction but as monotherapy without steroids or plasma exchange it is inappropriate in acute anti-GBM presentations. Conservative management delaying disease‑directed therapy risks irreversible renal injury and ongoing alveolar haemorrhage.

For PR3‑ANCA positive patients, scheduled rituximab maintenance has been shown to reduce relapse risk compared with azathioprine in several trials and is an accepted maintenance strategy, particularly for patients at high relapse risk. No maintenance carries an unacceptable relapse risk. Long‑term low‑dose glucocorticoid monotherapy is not recommended as sole maintenance. Methotrexate is used for maintenance in patients with non‑severe renal disease but is less preferred in those with prior severe disease or PR3 positivity and higher relapse risk. Long‑term cyclophosphamide is avoided due to cumulative toxicity; it is not used for maintenance.

The Berden classification divides ANCA GN into focal, crescentic, mixed and sclerotic classes. The focal class (predominantly normal glomeruli) has the best renal prognosis. Sclerotic class has the worst prognosis. Crescentic and mixed have intermediate outcomes. 'Membranous class' is not part of the Berden classification and would imply immune complex–mediated membranous nephropathy rather than pauci‑immune ANCA GN.

Hydralazine is a well‑recognised cause of drug‑induced ANCA vasculitis, often associated with anti‑MPO antibodies and can present with pulmonary–renal syndrome. Other drugs classically implicated include propylthiouracil and certain antithyroid and anti‑arrhythmic agents. Allopurinol, amoxicillin and amlodipine are not typical causes of ANCA‑associated vasculitis; methimazole is less commonly implicated than propylthiouracil but is not the classic offender.

Double‑positive patients often present with severe renal disease and pulmonary haemorrhage similar to anti‑GBM disease and therefore are typically treated with plasma exchange plus immunosuppression (steroids and cyclophosphamide). Unlike isolated anti‑GBM disease, double‑positive patients have a higher longer‑term relapse risk (more similar to ANCA vasculitis), so close follow‑up for relapse is required. They do not have lower relapse risk, and plasma exchange is generally indicated in the acute setting. Cyclophosphamide is commonly used and not contraindicated because both antibodies are present—indeed it is part of standard therapy in severe presentations.

Avacopan is an oral C5a receptor antagonist that interferes with C5a‑mediated neutrophil activation and has been studied as a steroid‑sparing agent in induction therapy for AAV. It is not an anti‑C5 monoclonal antibody (that would be eculizumab), nor a C3 inhibitor, nor a B‑cell depleting agent. It does not replace rituximab for B‑cell depletion and is not an anticoagulant. Trials have shown avacopan can reduce steroid exposure as part of induction regimens, but its incorporation into routine practice should follow guideline recommendations and individual patient considerations.

Rising PR3‑ANCA titres may precede clinical relapse more often than MPO‑ANCA, but increases in titre alone, in an asymptomatic patient, should not be the sole trigger for re‑induction of immunosuppression. The appropriate action is closer clinical monitoring, re‑examination for symptoms/signs of active disease and targeted investigations. Immediate re‑induction, steroid boluses or escalation to cyclophosphamide based on titres alone is not recommended due to toxicity risk and imperfect predictive value of titres. It is also incorrect to ignore ANCA changes completely; they provide useful adjunctive information when combined with clinical assessment.