ANCA associated vasculitis

01Definition and overview

Vasculitis of small vessels (capillaries, venules, arterioles and small arteries) falls into two groups by what is seen in the vessel wall. Immune complex vasculitis, such as IgA vasculitis, has abundant immunoglobulin and complement there. ANCA-associated vasculitis (AAV) has few or none, so it is called pauci-immune, and most patients carry anti-neutrophil cytoplasmic antibodies against one of two enzymes of the neutrophil granules: proteinase 3 or myeloperoxidase.

The 2012 Chapel Hill nomenclature defines the diseases:

The eponyms were dropped to name the diseases by their features, and because Friedrich Wegener had been a member of the Nazi party. A minority with otherwise typical GPA or MPA are ANCA-negative. The antibody tells more than the clinical label: PR3-AAV and MPO-AAV differ in genes, organs, relapse rate and outlook, so the disease is often named by both, as in "PR3-ANCA positive GPA". The one thing to remember: AAV can destroy the kidneys or flood the lungs within days, and treatment that starts early saves both.

02Etiology and pathophysiology

Who gets it

• Genes: PR3-AAV is linked to HLA-DP, to variants of SERPINA1 (which encodes alpha-1 antitrypsin, the main inhibitor of PR3) and of PRTN3, the gene for PR3 itself; MPO-AAV is linked to HLA-DQ.
• Environment: silica dust and farming exposure; infections, and nasal carriage of Staphylococcus aureus raises the risk of relapse in GPA; latitude, with GPA commoner in northern Europe and MPA in southern Europe and East Asia.

How ANCA injure vessels

1. 1

   Loss of tolerance

   For reasons that are not fully known, B and T cells lose tolerance to PR3 or MPO, perhaps after an infection, and plasma cells make IgG ANCA against them.
2. 2

   Priming

   Cytokines such as TNF and IL-1, and the complement fragment C5a, prime circulating neutrophils: PR3 and MPO move from the granules to the cell surface.
3. 3

   Activation

   ANCA bind the surface PR3 or MPO with their Fab arms, while their Fc ends engage Fc gamma receptors. The neutrophil degranulates, makes reactive oxygen species and throws out neutrophil extracellular traps (NETs), webs of DNA studded with PR3 and MPO that keep feeding the autoimmune response.
4. 4

   Vessel injury

   Activated neutrophils stick to the endothelium of small vessels and destroy it, causing fibrinoid necrosis. The alternative complement pathway is activated, and C5a acting on its receptor primes more neutrophils, a loop that amplifies the injury.
5. 5

   Organ damage

   In the glomerulus the capillary wall ruptures, and fibrin, macrophages and proliferating epithelial cells fill Bowman's space as crescents. In the lung, capillaritis lets blood into the alveoli. In GPA and EGPA, T cells and macrophages also build necrotising granulomas.

Because little immunoglobulin or complement stays in the tissue, immunofluorescence of an affected glomerulus is nearly negative: pauci-immune necrotising crescentic glomerulonephritis. This contrasts with linear IgG along the basement membrane in anti-GBM disease and the granular deposits of lupus or post-infectious nephritis.

EGPA

EGPA starts as an allergic, type 2 disease: Th2 cells and IL-5 drive eosinophil production and survival, and eosinophils infiltrate the airways, lungs, heart and gut. Vasculitis is added later. ANCA-positive patients have more vasculitic features (glomerulonephritis, neuropathy, purpura), ANCA-negative patients more eosinophilic tissue disease, especially of the heart and lungs. This is why blocking IL-5 works in EGPA but has no place in GPA or MPA.

Drug-induced ANCA vasculitis

Hydralazine, propylthiouracil (less often carbimazole), minocycline and levamisole-adulterated cocaine can induce ANCA, typically MPO-ANCA at very high titre, sometimes with PR3-ANCA too; hydralazine often adds ANA and anti-histone antibodies. Levamisole-cocaine causes necrotic purpura of the ears and cheeks, and snorted cocaine can destroy the nasal septum, mimicking GPA. Disease ranges from rash and joint pain to glomerulonephritis and alveolar haemorrhage. The drug is stopped for good; skin and joint disease often settle without more, and organ-threatening disease is treated as primary AAV, usually without long maintenance.

03Clinical features

Most patients have weeks to months of a flu-like illness before the diagnosis: fever, night sweats, weight loss, fatigue, aching muscles and joints. Organ disease then emerges:

Patients with AAV also have a higher risk of venous thromboembolism while the disease is active.

Pulmonary-renal syndrome

Alveolar haemorrhage with glomerulonephritis is the most dangerous presentation. Haemoptysis may be slight or absent despite a large bleed; a falling haemoglobin, new breathlessness, ground-glass shadowing on CT and increasingly bloody bronchoalveolar lavage give it away. The differential diagnosis is anti-GBM disease (which can coexist with ANCA), lupus, and infection with heart or kidney failure.

EGPA, phase by phase

1. Prodrome: adult-onset asthma, often hard to control, allergic rhinitis and nasal polyps, sometimes for years.
2. Eosinophilic phase: blood eosinophilia, typically above 1.5 × 10⁹/L, with eosinophilic pneumonia (fleeting infiltrates) or gastroenteritis.
3. Vasculitic phase: mononeuritis multiplex, purpura, glomerulonephritis, and the dangerous ones, eosinophilic myocarditis and coronary vasculitis.

The phases overlap and need not come in order.

How severity is judged

European guidance sorts disease into two classes, which decide the treatment:

Activity is scored with the Birmingham Vasculitis Activity Score (BVAS), and permanent damage with the Vasculitis Damage Index. The revised Five Factor Score predicts death: age over 65, heart failure, gut involvement, a creatinine of 150 µmol/L or more, and, in GPA and EGPA, the absence of ear, nose and throat disease.

04Diagnosis and management

Tests

• ANCA: PR3 and MPO antibodies by a high-quality antigen-specific immunoassay are the first test; indirect immunofluorescence (c-ANCA, mostly PR3; p-ANCA, mostly MPO) is no longer needed first. A negative result does not exclude GPA limited to the airways or EGPA. ANCA also appear in infective endocarditis (often PR3), tuberculosis, inflammatory bowel disease and autoimmune liver disease (atypical ANCA without PR3 or MPO), and with the drugs above, so a positive test is read with the clinical picture.
• Urine: dipstick, microscopy for dysmorphic red cells and red cell casts, and the protein-to-creatinine ratio; creatinine and electrolytes, repeated often.
• Blood count: normocytic anaemia, neutrophilia, high platelets; eosinophils of 1 × 10⁹/L or more (or above 10 per cent) in EGPA. ESR and CRP are high.
• Tests that change the diagnosis: anti-GBM antibodies (in every patient with renal or lung disease), ANA, anti-dsDNA and complement (low in lupus, cryoglobulinaemia and infection-related nephritis, normal in AAV), cryoglobulins, hepatitis B and C and HIV serology, blood cultures and echocardiography when endocarditis is possible.
• Imaging: CT of the chest, CT or MRI of the sinuses and orbits; nerve conduction studies for neuropathy.
• In EGPA: ECG, troponin, echocardiography and cardiac MRI in every patient, and a search for other causes of eosinophilia, including Strongyloides serology before high-dose steroids.

Biopsy

A biopsy proves the diagnosis, but organ- or life-threatening disease is treated without waiting for it. Kidney biopsy is the most useful: it shows pauci-immune necrotising crescentic glomerulonephritis and, by the share of normal, crescentic or sclerosed glomeruli (the Berden classes: focal, crescentic, mixed, sclerotic), how much can recover. Nasal biopsies are easy but often show only nonspecific inflammation; lung, skin, nerve and muscle biopsies are taken where the disease is. EGPA tissue is rich in eosinophils.

The 2022 ACR/EULAR classification criteria

These criteria are for research and are applied only after small- or medium-vessel vasculitis has been diagnosed and mimics excluded; they are not a diagnostic test. Each item scores points, some negative:

Induction of remission

1. 1

   Judge severity, start at once

   Admit organ- or life-threatening disease to a centre with vasculitis and renal expertise. Screen for hepatitis B and C, HIV and latent tuberculosis, and check immunoglobulins, but do not let the results delay treatment of a failing kidney or bleeding lung.
2. 2

   Glucocorticoids

   Intravenous methylprednisolone, 250 to 1000 mg a day for 1 to 3 days, is often given in severe disease. Oral prednisolone then starts at 50 to 75 mg a day by body weight (60 mg for 50 to 75 kg) and is tapered quickly, to about half within two weeks and 5 mg a day by 4 to 5 months. This reduced-dose schedule, tested in the PEXIVAS trial, was as effective as the old standard for death or kidney failure and caused fewer serious infections.
3. 3

   Rituximab or cyclophosphamide

   For organ- or life-threatening GPA or MPA, glucocorticoids are combined with rituximab (375 mg/m² weekly for four weeks, or 1 g twice two weeks apart) or cyclophosphamide (intravenous pulses of 15 mg/kg, reduced for age and kidney function, at weeks 0, 2 and 4 then every three weeks, for 3 to 6 months; or daily by mouth). Rituximab is as effective, is preferred in relapsing disease, and spares fertility and the bladder; some centres combine low-dose cyclophosphamide with rituximab in severe kidney disease.
4. 4

   Plasma exchange for some

   Plasma exchange removes ANCA but did not reduce death or kidney failure in the PEXIVAS trial; pooled trials suggest it may spare some kidneys at 12 months, at the cost of more serious infections. European recommendations consider it only for a creatinine above 300 µmol/L from active glomerulonephritis, and advise against its routine use for alveolar haemorrhage. Kidney guidance considers it more widely: also for patients needing dialysis or with a rapidly rising creatinine, and for alveolar haemorrhage with hypoxaemia. It is added to the first treatment when anti-GBM antibodies are present too.
5. 5

   Check the response

   Remission (no active disease, a BVAS of 0) is usually reached in 3 to 6 months. Disease that does not respond is reassessed: is it active vasculitis, infection, damage or another diagnosis? Then treatment is changed, usually by switching drug (rituximab for cyclophosphamide or the reverse), with intravenous immunoglobulin as a possible add-on, together with a vasculitis centre.

Disease that threatens neither life nor organ, in GPA or MPA, is treated with glucocorticoids and rituximab; methotrexate (with a normal kidney function) or mycophenolate mofetil are the alternatives.

Maintenance of remission

• Rituximab is the first choice after induction with either drug, for example 500 mg every six months, a regimen that prevented major relapse much better than azathioprine in a trial. Azathioprine (about 2 mg/kg a day, after checking TPMT activity) or methotrexate are the alternatives.
• It continues for 24 to 48 months after induction in new disease, longer after a relapse or with PR3-ANCA, balancing relapse risk against infection.
• Prednisolone is kept at 5 mg a day or less, or withdrawn.

EGPA

The asthma and nasal disease continue to need their own inhaled and nasal treatment, and they often outlast the vasculitis.

Protection from the treatment

• Co-trimoxazole, 480 mg daily or 960 mg three times a week, prevents Pneumocystis pneumonia and other infections in everyone on rituximab, cyclophosphamide or high-dose glucocorticoids.
• Serum immunoglobulins before each rituximab course: low IgG with recurrent infections may need immunoglobulin replacement.
• Vaccination against influenza, pneumococcus, COVID-19 and herpes zoster (recombinant vaccine), ideally before rituximab; no live vaccines while immunosuppressed.
• Bone protection, cardiovascular risk control, and with cyclophosphamide, fluids, mesna and a talk about fertility.
• Kidney care: an ACE inhibitor or ARB for proteinuria once stable, dialysis when needed, transplantation once in remission.

Follow-up and relapse

Each review checks symptoms, urine and creatinine and scores activity. A rising or returning ANCA raises the risk of relapse and prompts closer watching, but treatment is not changed on the ANCA alone. A major relapse is treated with induction again, usually rituximab; a minor one with a short rise in glucocorticoids and a review of maintenance. Persistent haematuria can be scarring rather than activity, and infection mimics relapse.

05Epidemiology

AAV affects about 13 to 20 people per million each year in Europe, with some recent counts higher, and roughly 200 to 400 per million live with it, a number that grows as survival improves. It is a disease of later life, with a peak between 65 and 74 years, and both sexes are affected about equally. GPA and PR3-ANCA predominate in northern Europe; MPA and MPO-ANCA in southern Europe, Japan and China, where most AAV is MPO-AAV. EGPA is the rarest, at about 1 to 2 per million a year, with onset usually between 40 and 60 in people with asthma. Children are rarely affected. Recognised cases have increased with better ANCA testing and older populations, and drug-induced cases follow prescribing and cocaine use.

06Prognosis

Untreated, generalised GPA killed most patients within a year. With modern treatment, 5-year survival is about 75 to 85 per cent, though mortality stays two to three times that of the general population. Deaths in the first year come from infection more often than from vasculitis, which is why glucocorticoid doses have fallen.

What shapes the outcome:

• Kidney function at presentation: about a fifth to a quarter of patients with glomerulonephritis reach kidney failure, more when the creatinine is high or most glomeruli are sclerosed at biopsy, but many recover enough to come off dialysis.
• Alveolar haemorrhage, older age, heart and gut disease (the Five Factor Score).
• Relapse: about 30 to 50 per cent within five years, more with PR3-ANCA, disease of the ear, nose, throat and lungs, nasal Staphylococcus aureus carriage and early withdrawal of maintenance. MPO-AAV relapses less but presents older, with more kidney damage and lung fibrosis.
• Long-term harms: cardiovascular disease, infections, low immunoglobulins after rituximab, bladder and skin cancer after cyclophosphamide, and glucocorticoid toxicity; damage accumulates on the Vasculitis Damage Index.

EGPA has a better outlook, with 5-year survival above 90 per cent; heart involvement is the main cause of death, and many patients stay dependent on low-dose glucocorticoids for their asthma. All patients with AAV are followed for life, with the urine tested at every visit.