Behçet's Syndrome

Meet the patient

A 28-year-old Turkish mechanic has suffered painful mouth ulcers since his mid-teens — six or seven bouts a year, each clearing in a fortnight without leaving a mark. This week he arrives with a deep scrotal ulcer that has already left a puckered scar, tender red nodules over his shins, and two days of blurred vision in the right eye.[2][5]

Three questions now decide his week, and they decide every Behçet stem: is this Behçet's? (oral aphthae plus two more — the ICBD score), which organ is threatened right now? (the eye, the pulmonary artery, the brain), and if there is a clot, is it inflammatory? Hold those three and the management writes itself.[1][6]

The only vasculitis on both sides of the tree

It is the only vasculitis that attacks arteries and veins, large and small, at once. Most vasculitides pick a calibre and a side; Behçet's does not, which is why one patient can carry a leg deep-vein thrombosis and a pulmonary artery aneurysm in the same week. That dual involvement is the single most exam-relevant fact on the page.[1][2]

The clinical skill is two-fold, and juniors miss the second half. First, recognise that recurrent mouth ulcers are not always benign — pair them with a genital ulcer, an inflamed eye, skin lesions or a vascular event and they become the gateway to a systemic vasculitis. Second, treat major-organ disease like the emergency it is: Behçet's is one of the few illnesses that can blind a young person, kill them with massive haemoptysis, or leave them with irreversible brainstem damage.[1]

The pivotal mechanism point that drives every management decision: thrombosis in Behçet's is inflammatory. The vessel wall is inflamed, the clotting cascade is normal, and the mainstay is immunosuppression — not anticoagulation. Reach for the heparin first and you have treated the clot but missed the disease.[1]

The classic trap: treating a Behçet thrombosis with anticoagulation alone. The clot is inflammatory, so immunosuppression is the mainstay — and an unseen coexisting aneurysm can bleed when you anticoagulate. Suppress the vessel wall first; anticoagulate only selectively, and only after you have imaged the arteries.[1]

Etymology for viva gold: Hulusi Behçet, the Turkish dermatologist, described the triad of oral aphthae, genital ulcers and uveitis in 1937 — but Benedictos Adamantiades, a Greek ophthalmologist, reported the same syndrome in 1930. Hence Adamantiades-Behçet disease, the name still used in parts of Europe.[2]

The mantra for the viva: oral ulcers are universal, genital ulcers scar, and thrombosis is inflammatory — immunosuppress, do not just anticoagulate.[1]

The ICBD 2014 score — clinical, no blood test

Diagnosis is entirely clinical — there is no confirmatory laboratory test. The International Criteria for Behçet's Disease (ICBD), revised in 2014 across 27 countries and over 900 patients, replaced the older 1990 ISG criteria by weighting eye and genital disease more heavily. A score of at least 4 makes the call, with better sensitivity than the ISG and preserved specificity.[4]

Geography, genes and the young man who does worst

Geography is the single highest-yield epidemiological fact. Behçet's is endemic along a band that traces the ancient Silk Road — the Mediterranean (Turkey, Greece, Italy), through the Middle East (Iran, Iraq, Saudi Arabia) to East Asia (Japan, China, Korea). Turkey has the highest prevalence in the world, up to 420 per 100,000 in some regions; Behçet's is rare in Northern Europeans and North Americans, at 1 to 8 per 100,000.[2][5]

That gradient tracks the HLA-B51 association, the strongest genetic link. HLA-B51 confers a relative risk of about 6 and is carried by over half of patients in endemic populations but is far less common in Europeans. The disease is more common in men in endemic regions, and men run the more severe course — particularly the vascular and ocular complications that drive mortality. Onset is typically in young adults, 20 to 40 years.[2]

Everyone forgets: HLA-B51 is supportive, not diagnostic. Roughly 10 to 20 per cent of true Behçet's patients are HLA-B51 negative, and most carriers never develop the disease. A positive test never makes the diagnosis; a negative test never excludes it.[2]

Precipitants are incompletely defined. Environmental triggers invoked include oral infection with Streptococcus sanguinis (a commensal that may drive neutrophil activation), herpes simplex virus, and exposure to heavy metals and pesticides. A positive family history raises risk in endemic populations, consistent with polygenic inheritance centred on the HLA region but extending to non-HLA loci such as IL10, IL23R and CCR1.[2][5]

Why the vessel wall fails

The model is an aberrant inflammatory response to an environmental trigger in a genetically susceptible host (HLA-B51). The unifying lesion is vasculitis of every vessel size and both the venous and arterial systems, with a predominantly neutrophilic and lymphocytic infiltrate of vessel walls, endothelial dysfunction and immune complex deposition.[1][2]

Behçet's is sometimes called a neutrophilic vasculitis because neutrophils are constitutively hyperactive — exaggerated chemotaxis, superoxide production and phagocytosis, even when the disease looks quiet. Gamma-delta T cells are over-represented and produce interleukin-17, bridging the innate and adaptive arms. This innate priming is the mechanism behind pathergy — the pustule that blooms at a needle prick, the bedside signature of an exaggerated non-specific inflammatory response.[2]

The adaptive response is dominated by Th1 and Th17 cells, with elevated IL-17, IL-1, IL-6, IL-8, TNF-alpha and interferon-gamma driving the relapsing cycle. The dominance of the IL-17 and IL-23 axis is exactly why phosphodiesterase-4 inhibition (apremilast) and anti-TNF biologics work — and why colchicine, which cripples neutrophil chemotaxis and microtubule assembly, earns its place in mucocutaneous disease.[3]

In veins, immune complex deposition and neutrophilic infiltration produce thrombophlebitis and venous thrombosis — and the thrombus is inflammatory, the clotting cascade typically normal. In arteries, the same process weakens the wall and produces aneurysm, most dramatically the pulmonary artery aneurysm that causes fatal haemoptysis. This dual venous-arterial involvement is the pathophysiological signature that sets Behçet's apart from nearly every other vasculitis.[1]

Deep dive — the HLA-B51 effect and why ERAP1 matters

Genome-wide association studies consistently identify HLA-B star 51:01 as the strongest susceptibility locus, but its carriage is neither necessary nor sufficient. The mechanistic link is incompletely understood but is thought to involve aberrant peptide presentation that drives autoreactive T-cell activation, and impaired natural killer cell function via the killer immunoglobulin-like receptor axis. Non-HLA loci — IL10, IL23R, CCR1, STAT4 and ERAP1 — point to Th17 polarisation and antigen processing as central. ERAP1 in particular shapes the MHC-I peptide repertoire, which is why its effect is most visible in HLA-B51 carriers: a gene-environment interaction written into the immunology.[1][2]

The clinical round, organ by organ

Behçet's runs a relapsing-remitting course, flares separated by variable intervals. Mucocutaneous lesions are universal; eyes, vessels, joints, gut, skin and nervous system join in varying patterns — which is why an organ-by-organ sweep of the history and examination is non-negotiable.[1][2][5]

Oral aphthous ulcers — universal and mandatory. The gateway lesion, present in nearly every patient: painful, multiple and recurrent (at least three episodes per year), on the buccal mucosa, tongue, lips, gingiva and soft palate — but rarely the hard palate, a useful discriminator from herpetic lesions. Round or oval with a yellow-grey floor and erythematous halo, a few millimetres to over a centimetre, and they heal without scarring in 1 to 3 weeks. Often the first manifestation, sometimes by years.[1]

Genital ulcers — the one that scars. The second mucosal hallmark, on the scrotum in men and the labia in women: larger and deeper than oral aphthae, and — critically — healing with scarring. That puckered stellate scar is a permanent diagnostic clue that can out a quiescent disease years later. Less recurrent than oral ulcers, but more destructive.[1]

Skin lesions — several patterns at once. Erythema nodosum (tender red subcutaneous nodules on the shins, commoner in women), papulopustular lesions and acneiform nodules on the trunk and face (commoner in men), and a positive pathergy test — a papule or pustule 24 to 48 hours after a sterile needle prick. Skin pathergy, like the genital ulcer scar, is the innate immune hyper-reactivity made visible.[1]

Ocular disease (50 to 70 per cent, sight-threatening) — the leading cause of disability. The spectrum runs from anterior uveitis with hypopyon (a layered pus level in the anterior chamber, classic but now less common) to panuveitis and, most dangerously, retinal vasculitis with occlusive arterial and venular disease, retinal infiltrates, macular oedema and ischaemia. Untreated, ocular Behçet's marches to irreversible blindness, often within five years. Any visual symptom in a Behçet's patient is an emergency — urgent slit-lamp, now.[6]

Vascular disease (about 25 per cent) — the principal driver of mortality. Behçet's uniquely throws both venous thrombosis and arterial aneurysm. Venous disease runs from superficial thrombophlebitis and leg deep vein thrombosis to thrombosis of the vena cava and Budd-Chiari (hepatic vein thrombosis). Arterial disease produces aneurysms of the pulmonary, aortic, femoral, carotid and cerebral arteries. The pulmonary artery aneurysm is the single most feared lesion — it presents with massive haemoptysis and is the classic cause of death. Because the thrombosis is vasculitic, the coagulation screen is normal.[1]

Articular (about 50 per cent). A non-erosive, non-deforming oligoarthritis or monoarthritis of knees, ankles and wrists, riding along with flares and self-limiting over weeks.[1]

Gastrointestinal. The hallmark is ileocaecal ulceration that mimics Crohn's — right lower quadrant pain, diarrhoea, sometimes bleeding or perforation. Distinction from inflammatory bowel disease rests on endoscopic pattern and histology (see the mimics below).[1]

Neuro-Behçet (5 to 10 per cent) — two patterns with opposite prognoses. Parenchymal disease hits the brainstem and diencephalon: headache, pyramidal weakness, ataxia, cranial nerve palsies, cognitive and behavioural change, bladder and bowel disturbance — poor prognosis, cumulative deficit. Non-parenchymal disease is dominated by cerebral venous sinus thrombosis: raised intracranial pressure, headache, papilloedema, sixth-nerve palsy — generally a better outlook. Ciclosporin is contraindicated in any neurological involvement because it is neurotoxic in this context.[1]

Atypical and single-organ presentations. Disease may declare itself through one organ — isolated retinal vasculitis, a solitary pulmonary artery aneurysm, a deep vein thrombosis — months or years before the mouth ulcers arrive. In endemic populations, keep a high index of suspicion for any young man with an unexplained vascular event.[1]

Consultant confession — the single DVT that is not what it looks like

In a young Silk Road man with one unexplained deep vein thrombosis and a normal thrombophilia screen, I check the mouth. If there is a scrotal scar, I image the pulmonary artery before I reach for the warfarin. The clot is inflammatory, the aneurysm you have not yet found can bleed, and the warfarin can turn a survivable disease into a fatal one. This is not in a guideline — it is the difference between a registrar and a consultant on a vasculitis ward.[1]

The mimics — and the one-line discriminators

The pivotal differentials are the other ulcer-plus-multisystem syndromes. Behçet's is distinguished by recurrent painful scarring genital ulcers, sight-threatening eye disease, pathergy, venous thrombosis with or without arterial aneurysm, the Silk Road and HLA-B51 background, and typically negative autoantibodies.[2][4]

A second layer distinguishes Behçet's from the vasculitides and the mimics of neuro-Behçet. IgA vasculitis and polyarteritis nodosa target different vessels and age groups and lack the mucocutaneous triad; ANCA-associated vasculitis produces destructive upper-airway disease, glomerulonephritis and pulmonary haemorrhage with positive ANCA — none of which feature in Behçet's. Multiple sclerosis is the chief mimic of parenchymal neuro-Behçet: both hit young adults with relapsing deficits, but MS shows periventricular, corpus callosal and juxtacortical plaques on MRI with oligoclonal bands in CSF, whereas neuro-Behçet lights up the brainstem, thalamus and basal ganglia.[1]

The one-line discriminator rule that earns the mark: if the oral ulcers are painless, think SLE; if the genital ulcers do not scar, think reactive arthritis or HSV; if there is a pulmonary artery aneurysm, think Behçet's (or its arterial-only cousin, Hughes-Stovin). Simple recurrent aphthous stomatitis — ulcers alone, no systemic features — is far commoner than Behçet's and must not be over-investigated in the absence of other criteria.[1]

The bedside round — find the scar, prick the skin

History and examination are structured and systematic because the diagnosis is clinical and hinges on documenting multi-organ involvement. Oral ulcers are the gateway: ask explicitly about at least three episodes per year, then sweep every other system.[1][2]

History. Recurrent oral ulcers (frequency, size, healing, scarring), genital ulcers and any residual scarring, eye symptoms (pain, redness, photophobia, blurring, floaters — all red flags for retinal vasculitis), skin lesions (leg nodules, pimples, pathergy), vascular events (leg swelling or pain suggesting DVT, haemoptysis suggesting pulmonary artery aneurysm, abdominal swelling suggesting Budd-Chiari), neurological symptoms (headache, weakness, ataxia, behavioural change), gastrointestinal symptoms, and joint pain. Always record geographic and ethnic origin and family history — both raise pre-test probability in endemic populations.[1]

Examination. Inspect the oral mucosa (buccal, tongue, lip, soft palate — aphthae are round, painful, with an erythematous halo) and the genitalia (scrotal or vulval ulcers and, crucially, the scars of previous attacks). Examine the skin for erythema nodosum, papulopustules, acneiform nodules and any pathergy site. Perform a focused eye examination — visual acuity, slit-lamp (cells and flare, hypopyon) and fundoscopy (retinal vasculitis, infiltrates, venous occlusion). Every patient, even asymptomatic, gets a formal ophthalmology referral: subclinical retinal vasculitis is common and sight-threatening.[1]

Vascular and neurological examination. Palpate peripheral pulses and listen for bruits; examine for DVT (calf swelling, tenderness, superficial thrombophlebitis); assess for pulmonary hypertension and right-heart strain; examine the abdomen for hepatomegaly and ascites (Budd-Chiari); check blood pressure for renovascular disease. Cranial nerves, cerebellar signs, pyramidal patterns (hemiparesis, hyperreflexia, upgoing plantar) and mental state; fundoscopy for papilloedema (cerebral sinus thrombosis). Joints show a non-erosive oligoarthritis of knees, ankles and wrists.[1]

The pathergy test — the bedside signature. Insert a sterile 20-gauge needle obliquely into the forearm skin to a depth of 5 mm, with or without saline. Read at 24 to 48 hours: an erythematous papule or pustule of at least 2 mm at the prick site is positive. Pathergy is highly specific in Silk Road populations but less sensitive in Europeans, which is why ICBD lists it as optional.[4]

Investigations — support, exclude, stage

There is no specific diagnostic test — diagnosis is clinical, using the ICBD criteria. Investigations serve three roles: to support the diagnosis, to exclude mimics, and to stage organ involvement before treatment.[1][2]

Bloods. Full blood count, CRP and ESR (raised in active disease and a useful longitudinal marker), urea and electrolytes, liver function tests and glucose to baseline before immunosuppression. The coagulation screen (INR, APTT, fibrinogen) is typically normal even in the presence of venous thrombosis — a critical teaching point, because thrombosis here is vasculitic and inflammatory, not a primary clotting disorder. Routine thrombophilia screening has no role unless coexisting antiphospholipid syndrome is suspected.[1]

Autoantibodies. ANA, anti-dsDNA, ANCA, rheumatoid factor and complement are typically negative or normal in Behçet's. Their main value is to exclude SLE and ANCA-associated vasculitis. HLA-B51 typing is supportive but neither sensitive nor specific enough to confirm or exclude the diagnosis.[1]

Ophthalmology, imaging and endoscopy. Slit-lamp examination and fundus fluorescein angiography are mandatory even in asymptomatic patients, because subclinical retinal vasculitis and macular oedema are common, treatable and blinding. CT pulmonary angiography is the test of choice for a suspected pulmonary artery aneurysm — any haemoptysis in a Behçet's patient is a pulmonary artery aneurysm until proven otherwise. Doppler ultrasound and D-dimer assess DVT; CT or MR angiography defines peripheral aneurysms for embolisation; CT or MR venography documents vena cava or hepatic vein thrombosis. MRI brain shows the characteristic T2 and FLAIR hyperintensities of parenchymal neuro-Behçet in brainstem, thalamus and basal ganglia; MR venography detects sinus thrombosis. Ileocolonoscopy with biopsy distinguishes Behçet's ulcers (round, deep, discrete, no transmural inflammation, no granulomas) from Crohn's.[1]

Worked stem — oral and genital ulcers, normal coagulation

A 26-year-old Turkish man has recurrent painful oral aphthae (six episodes per year), scrotal ulcers that heal with scarring, and erythema nodosum on his shins. CRP is 58 mg/L, ANA and ANCA are negative, and the coagulation screen is normal. What is the diagnosis, the score, and the immediate next step?[1]

Diagnosis: Behçet's syndrome — oral aphthosis (2) plus genital aphthosis that scars (2) plus skin lesions (1) gives an ICBD score of 5 (above the threshold of at least 4), with negative autoantibodies and Silk Road origin supporting the clinical call.[1]

Immediate next steps: urgent ophthalmology referral with slit-lamp and fluorescein angiography to find subclinical retinal vasculitis; vascular screening with CT pulmonary angiography if any haemoptysis and Doppler ultrasound for DVT; baseline bloods and HLA-B51 typing (supportive); start colchicine 1 to 1.5 mg daily for the mucocutaneous and skin disease and arrange azathioprine if any ocular involvement is found; counsel on red flags — visual change, haemoptysis, headache, leg swelling.[1]

When Behçet's is an emergency

Behçet's is rarely an acute resuscitation emergency, but four scenarios are time-critical and demand immediate, coordinated action.[1]

Massive haemoptysis from a pulmonary artery aneurysm. Protect the airway (bleeding side down, consider a double-lumen tube), establish large-bore IV access, cross-match and correct coagulopathy. Obtain urgent CT pulmonary angiography. Start high-dose IV corticosteroids (methylprednisolone 500 mg to 1 g daily for 3 days, then oral prednisolone 1 mg/kg/day) plus IV cyclophosphamide (pulse therapy, 15 mg/kg every 2 to 4 weeks with mesna and hydration). Involve interventional radiology for embolisation and surgery for resection if embolisation fails. Anticoagulation is avoided because the aneurysm will bleed.[1]

Acute visual loss from retinal vasculitis or panuveitis. Urgent ophthalmology assessment and high-dose corticosteroids (IV methylprednisolone pulses, then oral prednisolone 1 mg/kg/day) with rapid institution of a steroid-sparing agent — azathioprine, or anti-TNF for severe disease. Sight is at risk within hours to days.[6]

Cerebral venous sinus thrombosis. Manage raised intracranial pressure (head elevation, acetazolamide, mannitol if severe). Anticoagulation is generally given for sinus thrombosis because the mechanism differs from peripheral Behçet thrombosis, but only after excluding a coexisting arterial aneurysm on CT or MR angiography. Add corticosteroids for the underlying vasculitis.[1]

Gastrointestinal perforation from an ileocaecal ulcer is a surgical emergency: resuscitate, broad-spectrum antibiotics, and laparoscopic or open resection.[1]

Treatment by organ — the EULAR ladder

Management is organ-based and severity-stratified, following the EULAR recommendations. The central principle is non-negotiable: mucocutaneous disease is managed conservatively, while major-organ involvement — eye, vascular, nervous system, GI — requires aggressive immunosuppression.[1][2][3]

Mucocutaneous disease. Topical corticosteroids (mouthwash or cream for oral and genital ulcers) and colchicine 1 to 1.5 mg daily, especially effective for erythema nodosum and arthritis by inhibiting neutrophil chemotaxis. Dapsone is an alternative. For refractory oral ulcers, apremilast 30 mg twice daily (a phosphodiesterase-4 inhibitor) is backed by phase 3 randomised data showing significant reduction in oral ulcer burden. Interferon-alpha or anti-TNF (infliximab, adalimumab) is reserved for resistant, disabling mucocutaneous disease.[3][7]

Arthritis. NSAIDs and colchicine first-line; intra-articular or short-course oral corticosteroids for flares; azathioprine or methotrexate for recurrent or refractory disease.[1]

Ocular disease (sight-threatening). Azathioprine is first-line steroid-sparing immunosuppression, supported by a landmark randomised trial showing that early azathioprine reduces eye disease recurrence and improves long-term visual prognosis while also controlling oral and genital ulcers and arthritis. Corticosteroids (oral prednisolone 1 mg/kg/day, or IV methylprednisolone pulses for severe flares) cover the acute phase. For severe, resistant or posterior-segment disease, anti-TNF — infliximab 5 mg/kg or adalimumab — or interferon-alpha is added or substituted. Ciclosporin works for anterior uveitis but is avoided whenever there is any neurological involvement, because it is neurotoxic.[6]

Major vascular disease (aneurysm and thrombosis). First-line is high-dose corticosteroids plus cyclophosphamide — pulse IV cyclophosphamide with mesna and hydration, oral prednisolone 1 mg/kg/day tapered over weeks. Anti-TNF (infliximab) is an alternative or adjunct for refractory aneurysms. Embolisation or surgical repair is required for bleeding, expanding or ruptured aneurysms. Anticoagulation is individualised and controversial: because thrombosis is inflammatory and coexisting aneurysms can bleed, EULAR practice favours immunosuppression with selective anticoagulation rather than routine anticoagulation. Azathioprine maintains remission.[1]

Neuro-Behçet. Acute parenchymal disease: high-dose corticosteroids plus cyclophosphamide; azathioprine, mycophenolate or anti-TNF for maintenance or refractory disease. Ciclosporin is avoided because it is neurotoxic. For cerebral venous sinus thrombosis, corticosteroids plus carefully considered anticoagulation (after excluding an aneurysm) are standard.[1]

Gastrointestinal disease. First-line is corticosteroids with 5-ASA compounds (sulfasalazine, mesalazine) and azathioprine for steroid-sparing maintenance. Thalidomide (strict contraception, monitor for neuropathy) or anti-TNF is used for refractory ileocaecal ulcers. Segmental resection is reserved for perforation, refractory bleeding or stricturing.[1]

Phenotypes, prognosis and the burn-out

The course is relapsing-remitting, and disease activity often declines with age — Behçet's tends to burn out over decades — but vascular and neurological damage is cumulative and irreversible. Mortality is driven mainly by pulmonary artery aneurysm (haemoptysis) and severe neuro-Behçet. Young men with vascular disease carry the worst prognosis; isolated mucocutaneous disease carries an excellent outlook.[1]

Ocular prognosis has been transformed by early azathioprine and anti-TNF: without treatment, blindness was common within five years in endemic populations, whereas with modern immunosuppression useful vision is usually preserved. Disposition follows the organ: active eye disease, a new aneurysm or acute neurological disease is admitted for urgent imaging and pulse immunosuppression; stable mucocutaneous or articular disease is managed as an outpatient with at least annual ophthalmology review. Every patient gets structured education on the red flags — new visual change, haemoptysis, severe headache, leg swelling — and an open route to urgent reassessment.[1][6]

Recognisable phenotypes guide prognosis and therapy. Mucocutaneous Behçet (ulcers and skin only) is the commonest and most benign phenotype — colchicine, topical steroids and apremilast, excellent prognosis. Ocular Behçet is sight-threatening and the leading cause of disability — azathioprine first-line with corticosteroids and anti-TNF or interferon-alpha for severe disease. Vascular Behçet is the principal driver of mortality — corticosteroids plus cyclophosphamide, anticoagulation individualised. Neuro-Behçet splits parenchymal brainstem disease (poor prognosis, cumulative deficit) from non-parenchymal sinus thrombosis (better prognosis); ciclosporin is contraindicated. Gastrointestinal Behçet mimics Crohn's and is treated medically, with surgery reserved for complications. Articular Behçet is a non-erosive oligoarthritis of knees and ankles — NSAIDs and colchicine. Paediatric Behçet is rare, often family-history-positive and milder, with a longer interval between the first oral ulcer and full-blown disease.[1][2][5]

Hughes-Stovin syndrome is the arterial-pulmonary-aneurysm subset of the Behçet spectrum — pulmonary artery aneurysms with or without systemic arterial aneurysm and venous thrombosis, but without the full mucocutaneous criteria. Treat it identically to vascular Behçet.[1]

Special populations

Young men of Silk Road origin carry the most severe phenotype: maintain a high index of suspicion for vascular and ocular complications and start aggressive early immunosuppression. This is the group in which a single pulmonary artery aneurysm can be fatal.[1]

Pregnancy. Multidisciplinary management is essential. Continue pregnancy-compatible immunosuppression (azathioprine, corticosteroids, colchicine, calcineurin inhibitors). Avoid thalidomide, methotrexate, cyclophosphamide, mycophenolate and leflunomide (all teratogenic). Inflammatory thrombosis is treated with immunosuppression; anticoagulation is individualised, with low-molecular-weight heparin preferred over warfarin. Disease activity often improves in pregnancy but may flare postpartum.[1]

Paediatric Behçet. Rare; family history is frequently positive and the course generally milder, with a longer interval between the first oral ulcer and full clinical expression. Treatment follows adult principles, with weight-based dosing and careful attention to growth and steroid toxicity.[1]

Elderly. Late-onset Behçet is uncommon and tends to run a milder course, but comorbidity (diabetes, hypertension, osteoporosis) raises the risk of steroid and immunosuppressant toxicity — favour steroid-sparing strategies.[1]

Eye disease in any Behçet patient. Mandatory urgent ophthalmology referral is the rule, because subclinical sight-threatening retinal vasculitis is common and asymptomatic until vision is lost. Thrombosis in Behçet is inflammatory: the coagulation screen is normal, immunosuppression is the mainstay, and anticoagulation is selective rather than universal.[1]

Evidence, guidelines and regional differences

Landmark evidence. The Hamuryudan 1997 randomised trial established that azathioprine reduces ocular disease recurrence and improves long-term visual prognosis while also controlling oral and genital ulcers and arthritis — the foundation of azathioprine as first-line steroid-sparing therapy in ocular Behçet. The 2018 to 2022 phase 3 programme confirmed that apremilast significantly reduces the burden of oral ulcers, including in Japanese and other endemic subgroups.[6][7]

Regional delta — anticoagulation. The most contentious issue is anticoagulation for Behçet venous thrombosis. European (EULAR) practice favours immunosuppression with selective anticoagulation, on the grounds that thrombosis is inflammatory and coexisting aneurysms bleed. Some Asian centres use anticoagulation more liberally, particularly for deep vein thrombosis without aneurysm. There is no high-quality randomised evidence to settle this.[1][5]

Where the evidence is weak. Optimal duration of maintenance immunosuppression, the role of IL-6 (tocilizumab) and IL-17 (secukinumab) blockade, and the place of JAK inhibitors remain under investigation. Paediatric and pregnancy registries are limited.[1]

Exam pearls

Ward-round test

Stem 1 — the clot that is not what it looks like

A 30-year-old Iranian man presents with a swollen, tender left calf and a proximal leg deep vein thrombosis on Doppler. He mentions recurrent mouth ulcers and points to a puckered scar on his scrotum. INR, APTT and platelets are normal. What is the diagnosis, and what is the single most important management principle?[1]

Answer: Behçet's vascular disease — the DVT plus recurrent oral aphthae plus a scarring genital ulcer make the diagnosis, and the normal coagulation screen is not reassurance but the mechanism made plain: this is an inflammatory, vasculitic thrombosis. Immunosuppression (corticosteroids plus cyclophosphamide) is the mainstay, not anticoagulation. Anticoagulate only selectively, and only after CT or MR angiography has excluded a coexisting pulmonary or systemic arterial aneurysm that could bleed.[1]

Stem 2 — haemoptysis at 3am

A young Turkish man with known Behçet's coughs up a cup of bright red blood. What is the assumed diagnosis until proven otherwise, and what do you do in the first 15 minutes?[1]

Answer: A pulmonary artery aneurysm — the classic cause of death in Behçet's. Protect the airway (bleeding side down, consider a double-lumen tube), establish large-bore IV access and cross-match, and obtain urgent CT pulmonary angiography. Start high-dose IV methylprednisolone (500 mg to 1 g daily for 3 days) plus IV cyclophosphamide, and involve interventional radiology for embolisation. Do not anticoagulate — the aneurysm will bleed.[1]

Stem 3 — the drug that turns a brain worse

A patient with Behçet's and active brainstem neuro-Behçet is started on ciclosporin for a concurrent anterior uveitis flare. He deteriorates neurologically over 48 hours. What went wrong, and what is the correct ocular regimen?[1][6]

Answer: Ciclosporin is neurotoxic in Behçet's and is contraindicated in any neurological involvement — it can precipitate or worsen neurotoxicity. Stop it. The correct approach for the eye in a patient who also has neuro-Behçet is azathioprine (first-line steroid-sparing, supported by the Hamuryudan 1997 randomised trial) with corticosteroids, escalating to anti-TNF (infliximab or adalimumab) or interferon-alpha for severe posterior-segment disease. For the brain itself: high-dose corticosteroids plus cyclophosphamide for the acute phase, azathioprine or mycophenolate for maintenance.[1][6]

References

1. [1]Ozguler Y, Leccese P, Christensen R, et al. Management of major organ involvement of Behçet's syndrome: a systematic review for update of the EULAR recommendations Rheumatology (Oxford), 2018.PMID 30107448
2. [2]Hatemi G, Seyahi E, Fresko I, et al. One year in review 2018: Behçet's syndrome Clin Exp Rheumatol, 2018.PMID 30582516
3. [3]Leccese P, Ozguler Y, Christensen R, et al. Management of skin, mucosa and joint involvement of Behçet's syndrome: A systematic review for update of the EULAR recommendations for the management of Behçet's syndrome Semin Arthritis Rheum, 2019.PMID 29954598
4. [4]International Team for the Revision of the International Criteria for Behcet's Disease (ITR-ICBD). The International Criteria for Behçet's Disease (ICBD): a collaborative study of 27 countries on the sensitivity and specificity of the new criteria J Eur Acad Dermatol Venereol, 2014.PMID 23441863
5. [5]Davatchi F, Chams-Davatchi C, Shams H, et al. Adult Behcet's disease in Iran: analysis of 6075 patients Int J Rheum Dis, 2016.PMID 26258691
6. [6]Hamuryudan V, Ozyazgan Y, Hizli N, et al. Azathioprine in Behcet's syndrome: effects on long-term prognosis Arthritis Rheum, 1997.PMID 9125262
7. [7]Takeno M, Dobashi H, Tanaka Y, et al. Apremilast in a Japanese subgroup with Behçet's syndrome: Results from a Phase 3, randomised, double-blind, placebo-controlled study Mod Rheumatol, 2022.PMID 34894266