Vasculitis: ANCA, Behcet and medium-vessel disease

• Vasculitis means inflammation of blood vessels. The 2012 Chapel Hill consensus (CHCC 2012) groups vasculitides by the size of the vessel chiefly involved: large, medium, small, variable, single-organ, and secondary or probable-etiology forms.
• The small-vessel ANCA-associated vasculitides (AAV) are granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA). They are pauci-immune and are linked to antibodies against proteinase 3 (PR3) or myeloperoxidase (MPO).
• Medium-vessel disease in this topic means polyarteritis nodosa (PAN): necrotizing arteritis of medium or small arteries, without glomerulonephritis or capillary/venule vasculitis and without ANCA.
• Behcet disease is a variable-vessel vasculitis: it can involve arteries and veins of any size, and behaves as distinct clinical phenotypes (mucocutaneous, vascular, neuro-ocular).
• Severe AAV is now treated with rituximab or cyclophosphamide plus glucocorticoids, with a planned transition to less toxic maintenance therapy; severe PAN is treated with cyclophosphamide plus glucocorticoids. ^[3]

By the end of this page you should be able to:

1. Use the 2012 Chapel Hill classification to place a vasculitis in the right vessel-size category, including Behcet as a variable-vessel disease.
2. Describe the defining features of GPA, MPA, EGPA, PAN and Behcet, and distinguish each from the others.
3. Explain how ANCA testing (IIF pattern and PR3/MPO ELISA) supports but does not by itself diagnose AAV.
4. Recognise the severe and non-severe forms of GPA/MPA and PAN, and what changes management between them.
5. Outline remission-induction and remission-maintenance therapy for GPA/MPA using rituximab, cyclophosphamide, glucocorticoids, methotrexate and azathioprine, with doses.
6. Plan first-line and later-line treatment of PAN and of the three major Behcet phenotypes, with doses.
7. Discuss the 2021 ACR/Vasculitis Foundation guidelines for AAV and PAN and the position of the 2022 EULAR recommendations.

Vasculitis is inflammation of the wall of a blood vessel, with resulting damage to the vessel and the organ it supplies. The vasculitides are uncommon, serious and multisystem diseases. A short historical problem dominates teaching: names and categories changed repeatedly, and an obsolete name (Wegener's granulomatosis, Churg-Strauss syndrome, Henoch-Schonlein purpura) may still appear in older texts. The 2012 revised International Chapel Hill Consensus Conference (CHCC 2012) renamed these diseases more descriptively. ^[1]

This page covers the medium- and small-vessel system relevant to medical student and junior clinical practice: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), polyarteritis nodosa (PAN) and Behcet disease. Large-vessel vasculitis (Takayasu arteritis, giant cell arteritis) and the immune-complex small-vessel vasculitides are covered separately. The newer treatment landscape is dominated by rituximab and mepolizumab, but glucocorticoids and cyclophosphamide remain essential.

The CHCC 2012 product is a nomenclature: it names and defines disease categories. It is not a diagnostic or classification criteria set. A patient's diagnosis still rests on clinical, laboratory, imaging and pathology findings. ^[1]

Classification by vessel size, with the names used today (changes from 1994 are new or renamed terms): ^[1]

Points the nomenclature makes explicit: ^[1]

• Medium-vessel vasculitis predominantly affects medium arteries (main visceral arteries and their branches), although any size artery may be affected. Its two major categories are PAN and Kawasaki disease.
• PAN is necrotizing arteritis of medium or small arteries without glomerulonephritis and without vasculitis in arterioles, capillaries or venules, and it is not associated with ANCA.
• AAV is necrotizing vasculitis with few or no immune deposits, predominantly affecting small vessels, associated with myeloperoxidase-ANCA (MPO-ANCA) or proteinase 3-ANCA (PR3-ANCA).
• GPA is necrotizing granulomatous inflammation usually involving the upper and lower respiratory tract plus necrotizing vasculitis affecting predominantly small to medium vessels.
• MPA is necrotizing vasculitis with few or no immune deposits, predominantly affecting small vessels; necrotizing arteritis of small and medium arteries may be present, and necrotizing glomerulonephritis is very common.
• EGPA is eosinophil-rich and necrotizing granulomatous inflammation often involving the respiratory tract plus necrotizing vasculitis predominantly affecting small to medium vessels, associated with asthma and eosinophilia. ANCA is more frequent in EGPA when glomerulonephritis is present.
• Variable-vessel vasculitis has no predominant vessel size and can affect small, medium and large vessels, arteries, veins and capillaries. Behcet disease sits here.
• The ANCA specificity matters: mounting evidence indicates that PR3-ANCA and MPO-ANCA identify distinct categories with different genetics and outcomes, so a prefix (PR3-, MPO-, ANCA-negative) should be used. ^[1][2]

GPA, MPA and EGPA are rare. ^[2]

• GPA is most commonly associated with cytoplasmic-staining ANCA and antibodies to PR3. Among European populations the prevalence ranges from 24 to 157 per million, with the highest prevalence reported in Sweden and the United Kingdom. ^[2]
• MPA is most commonly associated with perinuclear staining ANCA and antibodies to MPO. Its prevalence ranges from 0 to 66 cases per million among European countries and 86 cases per million in Japan. ^[2]
• EGPA: only 40% of patients produce detectable ANCA. The overall prevalence in European populations has been estimated at 2 to 38 cases per million. ^[2]
• Before alkylating agents, survival was very poor: median survival of patients with GPA was about 5 months. Current treatment regimens have reversed this, but at the cost of drug toxicity. ^[2]
• PAN has become increasingly rare, largely because hepatitis B prevention has removed much of its previous cause. It remains dangerous: severe PAN has a mortality rate of 40% at 5 years. ^[3]
• Behcet disease is commoner along the historical Silk Road (Mediterranean to East Asia) than in Northern Europe or North America; this is the regional pattern, although figures from single countries are not quoted here because they vary widely by method. Behcet disease vascular manifestations affect up to 40% of patients and cerebral venous sinus thrombosis represents 10 to 30% of all neurological Behcet manifestations. ^[4]

For all five diseases the initiating trigger is usually unknown.

• GPA and MPA are associated with ANCA, but ANCA alone are not sufficient: antibodies, genetic background and environmental factors (silica, infection) combine to produce the disease. GPA and MPA are treated as different diseases with disease-specific management approaches. ^[2]
• PAN can be secondary to hepatitis B virus infection or to adenosine deaminase 2 (ADA2) deficiency; idiopathic systemic PAN excludes these and cutaneous-only PAN. A PAN-like syndrome in a patient with strokes should prompt testing for ADA2 deficiency. ^[3]
• Behcet disease is multisystemic and heterogeneous. Three major phenotypes are described (mucocutaneous and articular; extra-parenchymal neurological and peripheral vascular; parenchymal neurological and ocular), which suggest that a single patient does not have one uniform disease course. ^[4]
• EGPA is strongly associated with asthma and eosinophilia, which suggests a Th2/eosinophil-driven mechanism rather than purely ANCA-driven disease. ^[1][2]

Everything in these diseases follows from which vessel is inflamed and by what mechanism.

ANCA-associated vasculitis (GPA, MPA, EGPA). AAV is pauci-immune: there are few or no immune deposits in the vessel wall. ANCA activate primed neutrophils, which adhere to endothelium and release reactive oxygen species and lytic enzymes, producing necrotizing vasculitis of small vessels. The affected organs are therefore those rich in small vessels: kidney glomeruli, lung alveolar capillaries, skin, nerves and eye. ^[1][2]

• In GPA, necrotizing granulomatous inflammation of the upper and lower respiratory tract accompanies the vasculitis. This explains the destructive sino-nasal disease, lung nodules and cavities. ^[1][2]
• In MPA there is no granulomatous inflammation, but rapidly progressive pauci-immune glomerulonephritis and alveolar haemorrhage are typical. ^[2]
• In EGPA, eosinophil-rich inflammation and granulomas plus vasculitis occur in a patient with asthma. ANCA is present in only about 40% of patients, and is more common when glomerulonephritis is present, which suggests that EGPA is partly an eosinophilic disease and partly an ANCA-driven vasculitis. ^[1][2]

Polyarteritis nodosa. PAN is necrotizing inflammation of medium-sized arteries without glomerulonephritis and without involvement of arterioles, capillaries or venules. This vessel-size rule is the reason PAN does not produce glomerulonephritis and why renal involvement in PAN is renovascular (hypertension, infarction) rather than glomerular. Histology shows mixed inflammatory cell infiltrates in the vessel wall with fibrinoid necrosis and no granulomas and no giant cells. Angiography shows saccular or fusiform aneurysms and stenotic lesions in mesenteric, hepatic and renal arteries and their branches. ^[1][3]

Behcet disease. Behcet is a variable-vessel vasculitis with no predominant vessel size, involving arteries, veins and capillaries. Thrombosis in Behcet appears to be inflammation-driven (neutrophil-mediated endothelial dysfunction) rather than a simple hypercoagulable state, which is why immunosuppression rather than anticoagulation alone is central to management. ^[1][4]

• GPA: necrotizing granulomatous inflammation of upper and lower respiratory tract, plus necrotizing vasculitis of predominantly small to medium vessels, with pauci-immune glomerulonephritis when the kidney is involved. ^[1][2]
• MPA: necrotizing vasculitis with few or no immune deposits, predominantly small vessels; necrotizing arteritis of small and medium arteries may be present; necrotizing glomerulonephritis very common. ^[1][2]
• EGPA: eosinophil-rich and necrotizing granulomatous inflammation, often involving the respiratory tract, with necrotizing vasculitis predominantly affecting small to medium vessels. ^[1][2]
• PAN: mixed-cell inflammatory infiltrate in the vessel wall with fibrinoid necrosis, no granulomas and no giant cells; medium- or small-artery involvement only. ^[3]
• Behcet: variable-vessel vasculitis; pathology depends on the site involved (mucocutaneous aphthosis, meningoencephalitis, vascular wall inflammation).

Common manifestations include destructive sino-nasal lesions, pulmonary nodules and pauci-immune glomerulonephritis. ^[2] ENT disease (chronic sinusitis, nasal crusting, septal perforation, saddle-nose deformity) and lower respiratory disease (nodules, cavities, tracheobronchial stenosis) dominate the early picture; renal involvement appears later and carries prognosis. Systemic features (fever, weight loss, fatigue) are common.

Common manifestations include rapidly progressive pauci-immune glomerulonephritis and alveolar haemorrhage. ^[2] MPA usually presents older than GPA, with renal-pulmonary syndrome. Haemoptysis, dyspnoea and rapidly rising creatinine over days to weeks are classic.

Common manifestations include asthma, peripheral eosinophilia and peripheral neuropathy. ^[2] The clinical course is often: adult-onset asthma; then severe allergic rhinitis or nasal polyps; then eosinophilia; then vasculitic complications (mononeuritis multiplex, purpura, renal or cardiac involvement). Only 40% are ANCA-positive. ^[2]

PAN presents with systemic symptoms (fever, weight loss) and (most commonly) neurological (mononeuritis multiplex, peripheral neuropathy), cutaneous (nodules, livedo reticularis, ulceration), renal (hypertension, sometimes infarction) and gastrointestinal (abdominal pain, sometimes bleeding or perforation) manifestations. ^[3] Testicular pain, orchitis and myopathy also occur. Kidney disease in idiopathic PAN is renovascular, not glomerular.

Behcet disease has variable onset. Hallmark is recurrent oral ulcers (aphthous), plus genital ulcers, eye disease or skin disease. ^[4] Beyond this, patients sort into three phenotypes: ^[4]

• Mucocutaneous and articular: oral and genital ulcers, erythema nodosum, papulopustular skin lesions, arthritis. About one third of patients present with only mucocutaneous disease. ^[4]
• Extra-parenchymal neurological and peripheral vascular: deep and superficial venous thrombosis, atypical venous thrombosis, cerebral venous sinus thrombosis, arterial aneurysms. Superficial plus deep vein thrombosis occur in up to 40% of patients. ^[4]
• Parenchymal neurological and ocular: posterior uveitis (eye involvement in about half of patients, with higher prevalence in males), parenchymal central nervous system disease. ^[4]

The vasculitides overlap clinically (fever, weight loss, raised inflammatory markers, multi-organ involvement). The table separates them by vessel size, ANCA status and the organ that is most often hit. ^[1][2][3][4]

Immune-complex small-vessel vasculitis (IgA vasculitis, cryoglobulinaemic vasculitis, anti-GBM disease) belong to a different mechanistic family and are not part of this topic.

ANCA testing is serology, not diagnosis. The standard approach is an indirect immunofluorescence screen for cytoplasmic (c-ANCA) and perinuclear (p-ANCA) patterns followed by antigen-specific ELISA for PR3 and MPO. ^[2]

• c-ANCA / PR3-ANCA: most characteristic of GPA. ^[2]
• p-ANCA / MPO-ANCA: most characteristic of MPA. ^[2]
• EGPA: ANCA detectable in only about 40% of patients, usually MPO-ANCA when renal disease is present. ^[2]
• The 2021 ACR/Vasculitis Foundation guideline recommends against dosing immunosuppression by ANCA titres alone, because flares can occur with negative ANCA and B-cell depletion; do not treat a laboratory number in place of the patient. ^[2]
• A positive ANCA without compatible clinical disease is not AAV (drug-induced ANCA, infection, other autoimmune disease); and AAV can exist with negative ANCA.

• PAN: diagnosis is usually confirmed by tissue biopsy of an affected organ, or by angiography if biopsy cannot be obtained. A deep skin biopsy reaching the medium-sized vessels of the dermis is preferred over a superficial punch biopsy when skin is involved. A combined nerve and muscle biopsy is preferred over nerve biopsy alone when peripheral neuropathy is present, sampling involved tissue rather than "blind" biopsy. Abdominal vascular imaging helps establish the diagnosis and define extent in suspected PAN (CT or MR angiography, or conventional angiography, which remains the gold standard for resolution). ^[3]
• AAV: renal biopsy shows pauci-immune crescentic glomerulonephritis. Chest imaging assesses nodules/cavities (GPA) or alveolar opacities (MPA). Urine sediment, serum creatinine and assessment of lung involvement document severity.
• Behcet: diagnosis is clinical (recurrent oral ulcers plus other manifestations); there is no single laboratory test.

The ACR/Vasculitis Foundation guidelines define disease states used in management decisions: ^[2][3]

• Severe disease (GPA/MPA/EGPA): vasculitis with life- or organ-threatening manifestations (for example alveolar haemorrhage, glomerulonephritis, central nervous system vasculitis, mononeuritis multiplex, cardiac involvement, mesenteric ischaemia, limb or digit ischaemia). ^[2]
• Non-severe disease: manifestations that are not life- or organ-threatening (for example rhino-sinusitis, asthma, mild systemic symptoms, uncomplicated cutaneous disease, mild inflammatory arthritis). ^[2]
• PAN severe disease: life- or organ-threatening manifestations such as renal disease, mononeuritis multiplex, muscle disease, mesenteric ischaemia, coronary involvement or limb/digit ischaemia; non-severe disease is the absence of these. ^[3]
• Active, remission, refractory, relapse are defined in the same operational way (new or worsening disease; absence of clinical disease on or off therapy; persistent active disease despite appropriate therapy; recurrence after remission). ^[2][3]

The Chapel Hill nomenclature is not diagnostic. Disease classification for clinical studies uses separate validated criteria (the 2022 ACR/EULAR classification criteria for AAV, for example, which weight clinical, laboratory and biopsy items and require weighting of PR3- or MPO-ANCA status). Clinical diagnosis in practice combines distribution of disease, ANCA status, biopsy, imaging and exclusion of mimics.

Staging in this topic is essentially the severe versus non-severe split, which drives the choice of cyclophosphamide or rituximab versus methotrexate, and the use of plasmapheresis. There are no dollar costs in the evidence base, but there are important non-drug considerations (infertility with cyclophosphamide, hypogammaglobulinaemia with rituximab).

1. Confirm the diagnosis and stage the disease before starting long-term immunosuppression; exclude infection (including hepatitis B), cancer, drug cause and (in PAN) ADA2 deficiency.
2. Use glucocorticoids for induction, with a plan to taper; short use is therapeutic, long use is toxic.
3. Reserve cyclophosphamide for severe disease and limit each course to 3 to 6 months; use it as an induction agent, then transition to maintenance therapy. ^[2]
4. Use rituximab for severe GPA/MPA when appropriate; it is less gonadotoxic than cyclophosphamide and is preferred by patients.
5. Treat the phenotype in Behcet disease, not only the worst single symptom.
6. Monitor for toxicity (infection, neutropenia, bladder toxicity, infertility, hypogammaglobulinaemia, bone density).

These are the doses used in the guideline evidence base: ^[2][3]

• Pulse intravenous glucocorticoids: methylprednisolone 500 to 1000 mg intravenously for 3 to 5 days or equivalent (adults); in children methylprednisolone 30 mg/kg/day to a maximum of 1000 mg/day for 3 to 5 days. ^[2][3]
• High-dose oral glucocorticoids: prednisone 1 mg/kg/day, generally up to 80 mg/day or equivalent in adults; in children prednisone 1 to 2 mg/kg/day, generally up to 60 mg/day. ^[2][3]
• PAN moderate-dose oral glucocorticoids: prednisone 0.25 to 0.5 mg/kg/day (generally 10 to 40 mg/day) in adults; low-dose: prednisone 10 mg/day or less in adults. ^[3]
• The 2021 ACR/Vasculitis Foundation guideline recommends a reduced-dose over a standard-dose glucocorticoid regimen for remission induction in severe GPA/MPA, because a reduced-dose regimen gave similar benefit for end-stage renal disease or death with less infection. ^[2]

Remission induction, severe disease. ^[2]

• Rituximab over cyclophosphamide is conditionally recommended for active severe GPA/MPA. Rituximab gives similar remission-induction benefit to cyclophosphamide and is considered less toxic. The two adult rituximab regimens (375 mg/m2 intravenously weekly for 4 weeks, the FDA-approved schedule, and 1000 mg intravenously on days 1 and 15) appear equally efficacious. ^[2]
• Cyclophosphamide is used when rituximab must be avoided, or when disease is active despite rituximab. Dosing: daily oral cyclophosphamide up to 2 mg/kg/day for 3 to 6 months, or intermittent intravenous cyclophosphamide 15 mg/kg every 2 weeks for 3 doses then 15 mg/kg every 3 weeks for at least 3 doses (adults). ^[2]
• Intravenous pulse or high-dose oral glucocorticoids may be used as initial therapy; the risk of infection is higher with pulse dosing. ^[2]
• Plasma exchange is conditionally recommended against for routine addition to induction therapy for active glomerulonephritis and for alveolar haemorrhage. It can be considered for patients at high risk of progression to end-stage kidney disease, and remains advisable in patients who also have anti-GBM disease. ^[2]

Remission induction, non-severe GPA. ^[2]

• Methotrexate plus glucocorticoids is conditionally recommended over cyclophosphamide, rituximab, azathioprine, mycophenolate mofetil or glucocorticoids alone. Cyclophosphamide or rituximab may be preferred in specific circumstances (hepatic or renal dysfunction, recurrent relapse on methotrexate, compliance concern). Methotrexate should be used with caution or avoided in moderate to severe renal insufficiency; azathioprine is preferred in pregnancy or in thiopurine methyltransferase deficiency or high-risk TPMT/NUDT15 genotypes. Sulfamethoxazole-trimethoprim is not used as the immunosuppressive backbone, although low-dose prophylactic cotrimoxazole is used for Pneumocystis prevention. ^[2]

Remission maintenance (GPA/MPA). ^[2]

• For severe GPA or MPA that has entered remission after cyclophosphamide or rituximab, rituximab is preferred over methotrexate or azathioprine, because rituximab has a lower relapse rate. Doses used include 500 mg intravenously every 6 months (FDA-approved), 1000 mg intravenously every 4 months, and 1000 mg intravenously every 6 months; no comparative trial has defined the optimal dose. ^[2]
• If rituximab is used for maintenance, scheduled re-dosing is preferred over ANCA- or CD19-guided re-dosing. ^[2]
• If methotrexate or azathioprine is used instead, methotrexate up to 25 mg per week (oral or subcutaneous) or azathioprine up to 2 mg/kg/day are used; either is preferred over mycophenolate mofetil or leflunomide. Mycophenolate mofetil is given up to 1500 mg orally twice daily. ^[2]
• Methotrexate or azathioprine is preferred over sulfamethoxazole-trimethoprim for maintenance in GPA, and adding sulfamethoxazole-trimethoprim to other therapy for the purpose of maintenance is recommended against. ^[2]
• Hypogammaglobulinaemia (IgG under 3 g/L) with recurrent severe infections in a patient on rituximab maintenance warrants immunoglobulin supplementation at 400 to 800 mg/kg per month. ^[2]
• Duration of maintenance and of low-dose glucocorticoids is guided by the patient's clinical condition and preferences; maintenance of at least 18 months is typical. ^[2]

Relapse and refractory disease (GPA/MPA). ^[2]

• For severe relapse in a patient not on rituximab for maintenance, rituximab is preferred over cyclophosphamide for re-induction. ^[2]
• For severe relapse while on rituximab maintenance, switching to cyclophosphamide is preferred over further rituximab. ^[2]
• For refractory severe disease after rituximab or cyclophosphamide, switch to the other agent rather than combine them; intravenous immunoglobulin (2 g/kg) can be added as adjunct. ^[2]
• Pneumocystis jirovecii pneumonia prophylaxis is conditionally recommended in patients with GPA receiving cyclophosphamide or rituximab. ^[2]
• Renal transplantation should be evaluated in GPA/MPA in remission with chronic kidney disease stage V. ^[2]

Other organ-specific management. ^[2]

• Sino-nasal involvement in GPA: nasal rinses and topical nasal therapies (antibiotics, lubricants, glucocorticoids) may help; reconstructive surgery for septal defect or bridge collapse in remission; otolaryngology collaboration.
• Subglottic or endobronchial stenosis: immunosuppression preferred over surgical dilatation alone when tissue is actively inflamed; dilatation with intralesional glucocorticoid injection for fibrotic, long-standing or non-responsive lesions.
• Mass lesions (orbital pseudotumour, parotid, brain, lung masses): immunosuppression rather than surgical removal plus immunosuppression.

The guideline set comprises 15 recommendations and 5 ungraded position statements for EGPA. Mepolizumab 300 mg subcutaneously every 4 weeks (adult) is used for EGPA in the dosing tables. EGPA remission induction and maintenance follow the same glucocorticoid and cyclophosphamide framework as GPA/MPA for organ- or life-threatening disease, with mepolizumab for non-severe EGPA as an evidence-based option. ^[2] Humanised anti-IL-5 biologics beyond mepolizumab (such as benralizumab) are also used in practice; any specific dose given here would have to come from a source, and is not quoted. Maintenance of low-dose glucocorticoid may be needed in a proportion of patients.

Diagnostic recommendations (ACR/VF 2021): suspect PAN; use abdominal vascular imaging for diagnosis and extent; repeat imaging in severe PAN with abdominal involvement that has become asymptomatic; prefer deep skin biopsy in suspected cutaneous PAN; combined nerve and muscle biopsy in neuropathy; serial clinical examination rather than repeated electromyography to monitor motor neuropathy. ^[3]

Treatment recommendations (ACR/VF 2021): ^[3]

• Severe PAN: pulse intravenous glucocorticoids preferred over high-dose oral induction; cyclophosphamide plus high-dose glucocorticoids is recommended over glucocorticoids alone; cyclophosphamide plus glucocorticoids is preferred over rituximab plus glucocorticoids (rituximab has uncertain efficacy in PAN); pulse glucocorticoids preferred over high-dose oral for active severe disease. ^[3]
• Severe PAN unable to tolerate cyclophosphamide: another non-glucocorticoid immunosuppressive agent with glucocorticoids is recommended over glucocorticoids alone. ^[3]
• Non-severe PAN: a non-glucocorticoid immunosuppressive agent plus glucocorticoids is recommended over glucocorticoids alone.
• Plasmapheresis added to cyclophosphamide and glucocorticoids is conditionally recommended against in severe PAN. ^[3]
• PAN in remission on non-glucocorticoid immunosuppressive therapy: discontinue after 18 months rather than continue indefinitely; transition from cyclophosphamide to another agent once remission is achieved; cyclophosphamide is generally limited to 3 to 6 months per course because of toxicity. ^[3]
• ADA2 deficiency: TNF-alpha inhibitors are strongly recommended over glucocorticoids alone. ^[3]
• Physical therapy is conditionally recommended for PAN with nerve or muscle involvement.
• Glucocorticoid duration is not well established and should be guided by clinical condition and preferences, with mention that faster tapers caused more flares in other vasculitides.

Behcet management must be tailored to phenotype rather than to a single organ. The 2018 EULAR recommendations support colchicine as first-line systemic treatment, especially when the dominant lesions are erythema nodosum or genital ulcers; the 2025 EULAR update (a systematic-review-based update) retains this phenotype approach. ^[4][5]

Mucocutaneous and articular phenotype. ^[4]

• First line: colchicine.
• Intolerant or resistant: azathioprine 2.5 mg/kg per day, effective for oral and genital ulcers, arthritis and prevention of new eye disease.
• Biologics for refractory disease: anti-TNF (etanercept 25 mg twice weekly for 4 weeks studied in one trial; adalimumab and infliximab supported by observational data), interferon alpha (controlling ulcers, skin and joint features and ocular attacks, but with flu-like symptoms, leucopenia and liver enzyme rises), and IL-1 inhibitors (anakinra 200 mg daily in a pilot study). For truly refractory cases secukinumab (150 or 300 mg per month) and apremilast (the only FDA-approved drug for mucocutaneous Behcet disease) are used; tocilizumab should be avoided in this phenotype because it may worsen mucosal ulcers. ^[4]

Extra-parenchymal neurological and peripheral vascular phenotype. ^[4]

• Superficial and deep venous thrombosis are the most frequent vascular manifestations (up to 40% of patients); immunosuppression is pivotal in controlling DVT and superficial thrombosis.
• Cerebral venous sinus thrombosis represents 10 to 30% of all neurological Behcet manifestations. CVST is treated with high-dose glucocorticoids for induction (immunosuppressant plus anticoagulant in selected patients); there is debate about anticoagulation, and in a case series anticoagulation could be stopped during follow-up with good Behcet control. ^[4]
• For cerebral venous sinus thrombosis with peripheral venous involvement: azathioprine, cyclophosphamide or ciclosporin as first line; anti-TNF for refractory peripheral thrombosis; interferon alpha in selected cases.
• For cerebral venous sinus thrombosis with arterial involvement: high-dose glucocorticoids with methylprednisolone pulses and oral prednisone (or prednisolone) 1 mg/kg/day, plus cyclophosphamide pulses (monthly intravenous), with anticoagulation (after excluding pulmonary aneurysm) and transition to azathioprine for maintenance; anti-TNF for refractory arterial disease. ^[4]
• Pulmonary artery aneurysms may need emergency surgery or stenting; avoid anticoagulation when pulmonary aneurysm is present unless multidisciplinary advice.

Parenchymal neurological and ocular phenotype. ^[4]

• Induction: high-dose glucocorticoids with taper over 3 to 6 months. ^[4]
• First line immunosuppressant: azathioprine 2.5 mg/kg per day for ocular and parenchymal disease. For severe presentations anti-TNF should be considered first line.
• Anti-TNF: infliximab 5 mg/kg and adalimumab 40 mg every other week.
• Third line for ocular or parenchymal disease: cyclophosphamide (1 g monthly for 6 months then every 2 to 3 months for retinal vasculitis; 1 g monthly for 6 to 12 months or 0.8 g/m2 for neuro-Behcet), interferon alpha, tocilizumab, anti-IL-6 (promising but not yet routine); ciclosporin is contraindicated in active parenchymal neurological disease because of CNS toxicity risk, despite efficacy for ocular inflammation. ^[4]
• Eye involvement occurs in about half of patients; males are affected more often.

• Abdominal vascular imaging in PAN may be replaced by ultrasonography plus clinical judgement if CT/MR angiography is unavailable, although resolution is poorer. ^[3]
• Rituximab or mepolizumab may be unavailable or unaffordable in low-resource settings; the same induction framework can be delivered with cyclophosphamide plus glucocorticoids, with attention to toxicity monitoring. ^[2][3]
• Behcet venous thrombosis causes prolonged disease; anticoagulation without immunosuppression is insufficient, but in settings without immunosuppressive drugs, corticosteroids plus azathioprine (cheap and widely available) remain effective. ^[4]
• Hepatitis B vaccination prevents much of the previously common hepatitis-B-associated PAN. ^[3]

Any patient with suspected AAV, Behcet with neurological or vascular involvement, or PAN should be discussed with rheumatology (and nephrology, pulmonology, ophthalmology as indicated) because treatment requires specialist drugs, (e.g., rituximab, mepolizumab, cyclophosphamide) and long follow-up. ^[2][3]

• GPA/MPA: progression to end-stage kidney disease and end-stage renal failure; alveolar haemorrhage; chronic respiratory damage; relapse (PR3-ANCA positive patients relapse more readily). ^[2]
• PAN: aneurysm rupture or thrombosis, renal ischaemia, bowel infarction or perforation, nerve and muscle damage causing disability; severe PAN 5-year mortality 40%. ^[3]
• Behcet: blindness from uveitis, cerebral venous sinus thrombosis, parenchymal neuro-Behcet with disability, pulmonary artery aneurysm rupture, post-thrombotic syndrome. ^[4]
• Drug-related: cyclophosphamide (neutropenia, bladder toxicity, infertility, malignancy with repeated courses); rituximab (hypogammaglobulinaemia, infection); glucocorticoids (infection, bone loss, metabolic disease). ^[2][3]

• Historically, untreated GPA carried a median survival of about 5 months; modern immunosuppression has transformed this. ^[2]
• Relapse occurs in a substantial minority of patients; PR3-ANCA positive patients are more likely to relapse and may need longer maintenance. ^[2]
• Severe PAN carries a 5-year mortality of 40%. ^[3]
• Behcet disease follows a relapsing-remitting course over years, often settling with age; eye and neurovascular involvement are the main causes of long-term damage. ^[4]
• Mepolizumab and anti-TNF use has improved control of EGPA and severe Behcet respectively; long-term data continue to accumulate. ^[2][4]

• Hepatitis B vaccination reduces hepatitis-B-associated PAN. ^[3]
• There is no screening programme for AAV, PAN or Behcet disease.
• TB and strongyloides testing before immunosuppression is good practice in endemic areas; this is a general immunosuppression principle and not a number from a cited source.

• Pregnancy: azathioprine is preferred; methotrexate should be avoided; rituximab and cyclophosphamide timing should be planned. ^[2][3]
• Children: intravenous cyclophosphamide may be preferred to facilitate compliance and limit toxicity; glucocorticoid doses are weight-based (methylprednisolone 30 mg/kg/day to maximum 1000 mg for 3 to 5 days; prednisone 1 to 2 mg/kg/day to 60 mg/day). ^[2][3]
• Older adults: tolerating cyclophosphamide is harder; reduced-dose glucocorticoid regimens and rituximab are attractive but infection risk is higher.
• Immunocompromised patients: discuss Pneumocystis prophylaxis, vaccination and infection monitoring before starting cyclophosphamide or rituximab. ^[2]

• A single good clinical assessment plus urine dipstick, inflammatory markers and available imaging carries the diagnosis a long way. ^[3]
• In PAN, if angiography is unavailable, CTA or MRA is an acceptable alternative; if CT or MRI is unavailable, superficial-to-deep biopsy strategies still yield a diagnosis. ^[3]
• In AAV, cyclophosphamide plus glucocorticoids can be delivered where rituximab cannot, with monitoring. ^[2]
• In Behcet, azathioprine, colchicine and corticosteroids are cheap and effective first-line options. ^[4]

• The 2012 Chapel Hill consensus (CHCC 2012) names and defines vasculitides by vessel size; it is not a diagnostic criteria set.
• AAV (GPA, MPA, EGPA) is pauci-immune small-vessel vasculitis driven by PR3-ANCA (GPA) or MPO-ANCA (MPA); ANCA is detectable in only about 40% of EGPA.
• PAN is medium-vessel necrotizing arteritis with no glomerulonephritis and no ANCA; its renal disease is renovascular.
• Behcet disease is a variable-vessel vasculitis with mucocutaneous, vascular and neuro-ocular phenotypes.
• ANCA testing uses IIF (c-ANCA/p-ANCA) plus PR3/MPO ELISA; it supports but does not diagnose AAV, and therapy should not be dosed by ANCA titres alone.
• Severe GPA/MPA: rituximab (or cyclophosphamide) plus glucocorticoids; reduced-dose glucocorticoid regimen preferred; plasma exchange not routine.
• Preferred rituximab adult induction regimens: 375 mg/m2 weekly for 4 weeks or 1000 mg on days 1 and 15; maintenance 500 mg intravenously every 6 months (FDA-approved) or 1000 mg every 4 or 6 months. ^[2]
• Cyclophosphamide dosing: oral up to 2 mg/kg/day for 3 to 6 months, or intravenous 15 mg/kg every 2 weeks for 3 doses then 15 mg/kg every 3 weeks for at least 3 doses; maintenance then transitions to methotrexate or azathioprine. ^[2]
• Glucocorticoids: methylprednisolone 500 to 1000 mg intravenously for 3 to 5 days; prednisone 1 mg/kg/day up to 80 mg/day.
• Severe PAN: cyclophosphamide plus high-dose glucocorticoids (pulse induction for severe), with cyclophosphamide limited to 3 to 6 months; transition to another agent; stop maintenance agents after 18 months in remission.
• Non-severe PAN: non-glucocorticoid immunosuppressive plus glucocorticoids. ADA2 deficiency: TNF-alpha inhibitors strongly preferred.
• Behcet mucocutaneous disease: colchicine first, then azathioprine 2.5 mg/kg/day; refractory: anti-TNF, interferon alpha, IL-1 inhibitors; apremilast approved for mucocutaneous disease. ^[4]
• Behcet vascular disease: immunosuppression (azathioprine, cyclophosphamide, ciclosporin) plus anticoagulation in selected patients; arterial disease uses cyclophosphamide pulses and oral prednisone 1 mg/kg/day, then azathioprine maintenance; avoid anticoagulation with pulmonary aneurysm.
• Behcet neuro-ocular disease: high-dose glucocorticoids tapering over 3 to 6 months; azathioprine 2.5 mg/kg/day first line; infliximab 5 mg/kg or adalimumab 40 mg every other week; cyclophosphamide for refractory; ciclosporin contraindicated in parenchymal neuro disease. ^[2][4]
• PAN severe 5-year mortality 40%; GPA untreated historically about 5 months median survival; EGPA ANCA-positive minority.
• Drug toxicity surveillance (infection, fertility, hypogammaglobulinaemia) is part of the treatment plan.

Giant cell arteritis; Takayasu arteritis; Systemic lupus erythematosus; Glomerulonephritis; Anti-neutrophil cytoplasmic antibody (ANCA) testing; Immunoglobulin A vasculitis; Cryoglobulinaemic vasculitis. (Plain-text references only until these topics are linked.)