BOTTOM LINE

Behcet’s disease (BD) is a variable vessel vasculitis (affecting small to large vessels of the venous and arterial system) most often affecting young adults and more frequently in ethnicities along the “Silk Road” (Mediterranean to east Asia). Cardinal features include recurrent painful oral/genital ulcers, uveitis, skin rash (including folliculitis, erythema nodosum), bowel inflammation, inflammatory arthritis, vascular lesions (including venous and arterial thrombosis), and pathergy. Recurrent oral aphthous ulcers are common in the general population, but BD is rare; the diagnosis of BD should be considered only when compatible systemic manifestations accompany recurrent oral ulcers. No pathognomonic laboratory test exists; the diagnosis is made clinically. Treatment is organ based. Colchicine and apremilast are helpful for prevention of mucosal ulcers; azathioprine is helpful for most organ manifestations. Venous thrombosis requires immunosuppression; anticoagulation may be added, though not always indicated and carries risk of bleeding if any arterial aneurysmal involvement exists.
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EPIDEMIOLOGY

— Population

• Prevalence:
  higher along “silk road” (i.e.: Mediterranean to Asia)
  • Turkey: 200-4200/1,000,000
  • Japan: 70-130/1,000,000
  • Egypt: 76/1,000,000
  • Europe: 3-75/1,000,000
  • United States: 3-52/1,000,000
• Annual incidence:
  not well known
  • Japan 7.5/1,000,000
  • Europe 2.4-10.0/1,000,000 (Spain, Italy, Germany)
  • United States: 3.8/1,000,000
• Influence of genetics and environment:
  • BD prevalence among Middle-Eastern immigrants to Germany and Netherlands is higher than native Germans and Dutch, but lower than in their countries of origin

—Age, Sex

• Age:
  • 30-40 years-old; onset after age 40 is rare
• Sex:
  • Equal M:F sex ratio
• Severity:
  • Young men (<30 years) more likely have severe BD with ocular, vascular, cardiac and CNS involvement

—Risk Factors

• Genetics
  • HLA-B*51: allele carried by 50% of BD patients
  • Overall heritability of BD ~16%
• Environment
  • · Gut microbiome dysbiosis may alter intestinal epithelial barrier and promote Th1, Th17, Treg cells contributing to BD pathogenesis.

CLINICAL MANIFESTATIONS

— Phenotypic clusters

• Clinical manifestations may present more frequently together in clinical clusters. Proposed clusters include:
  • Mucocutaneous
  • Arthritis
  • Gastrointestinal
  • Ocular
  • Neurological, cardiovascular

— Systemic Manifestations

• MUCOSAL
  • Oral Ulcers (97-100%)
    • Look like recurrent aphthous ulcers (“canker sores”, round/oval with clear boundary and yellowish-white necrotic base and surrounding erythema) but more numerous, recurrent, and painful.
    • Appear in groups, 3-10+. <1cm on lips, gingiva, cheeks, tongue; rare palate tonsils, and pharynx
    • Non-scarring; spontaneously resolve 1-3 weeks but can recur or be constant
  • Genital ulcers (63-77%)
    • Look like oral ulcers, painful, around scrotum in men and labia majora in women.
    • Also: Epididymitis, salpingitis, varicocele; urethritis unusual.
    • Less recurrent than oral ulcers. More specific for BD
• SKIN (55-89%)
  • Acneiform lesions, papulo-vesiculo-pustular eruptions, pseudofolliculitis, nodules, erythema nodosum, superficial thrombophlebitis, pyoderma gangrenosum, palpable purpura, dermatographism, pathergy
  • Pathergy
    • Pathergy: erythematous papule/pustule 48-hours after skin prick by 20G needle
    • Pathergy not present at all times during disease; does not reflect disease activity
    • Pathergy prevalence higher in Middle Eastern and Asian patients; lower in European and in female patients
• OCULAR (18-59%)
  • Uveitis:
    • non-granulomatous anterior (pain/redness, photophobia), posterior (floaters, blurring, visual loss), pan-uveitis.
    • Onsets first 2-3 years of disease, rare >5 years.
    • Bilateral uveitis in 90%.
  • Hypopyon: severe anterior uveitis with purulent anterior chamber (10-15%)
  • Other:
    • retinal vasculitis, secondary cataracts, glaucoma, macular edema, conjunctival ulcer
  • Blindness possible if untreated, more often with posterior uveitis, retinal vasculitis, optic neuritis, vascular occlusion
  • Male patients more likely to get ocular disease and have worse ocular outcomes
• CENTRAL NERVOUS SYSTEM (3-10%)
  • Male > female for neuro-BD
  • Onsets after 5-6 years of Behcets; less often, occurs concurrently or predates Behcets diagnosis
  • Peripheral neuropathy is not common in Behcets and may suggest alternate diagnosis
  • Parenchymal CNS manifestations
    • 75% of patients with CNS involvement have parenchymal lesions.
    • Can affect brain stem, spinal cord, cerebrum, diffusely (all of above), optic neuritis
    • Can present acutely or chronic/progressive
    • Cerebral manifestations include: encephalopathy, meningitis, hemiparesis, dysarthria, decreased hearing, seizures, headache, psychiatric disorders and dementia
    • Brainstem manifestations include: ophthalmoparesis, cranial neuropathy, and cerebellar dysfunction
  • Non-parenchymal CNS manifestations
    • 25% of patients with CNS involvement have vascular lesions
    • Cerebral venous thrombosis, pseudotumor cerebri, meningitis
    • Headache in BD: can indicate central venous thrombosis, pseudotumor cerebri
• VASCULAR (8.5-35%)
  • BD is a variable vessel vasculitis (affecting small/medium/large vessels) in venous and arterial system Vasculitis is the cause of many BD manifestations (involving eye, mesentery, brain parenchyma and skin)
  • “Vascular lesions” in BD generally refers to damage to the vessel wall.
  • Timing: DVT and dural sinus thrombosis occur early in disease course, pulmonary artery occurs later
  • Venous
    • Includes DVT, superficial thrombophlebitis, SVC/IVC, Budd-Chiari/hepatic vein thrombosis, portal vein thrombosis, dural sinus
    • DVT is thought to result from inflammation of the vessel wall rather than hypercoagulability; post-thrombotic syndrome is frequent
  • Arterial
    • Most common: carotid, pulmonary, aortic, iliac, femoral, and popliteal arteries
    • Rare: intracardiac and coronarya rtery thrombosis.
    • Pulmonary artery aneurysms
      • Specific for BD; may also manifest pulmonary artery thrombosis.
      • Presents as hemoptysis, cough/dyspnea, pleurisy, fever. Requires CT-angiogram. Ddx pulmonary artery aneurysms: Hughes-Stovin syndrome
• GASTRO-INTESTINAL (0-25%)
  • More common in Asian countries (5-25%) than Mediterranean or Western countries (0-3%)
  • Mimic Crohn’s: pain, diarrhea, weight loss, bleeding, ulcers in mouth, terminal ileum, cecum, and ascending colon. Ulcers may appear “volcano shaped”; pathology shows nonspecific inflammation
  • Most typically: ileocecal ulcers mimicking Crohn’s disease, rare esophagoduodenal and small-bowel involvement
• MUSCULOSKELETAL (12-52%)
  • Non-erosive, asymmetric, nondeforming mono/oligoarticular medium/large joint inflammatory arthritis
  • Polyarticular small joint involvement in ~5%
  • Usually intermittent and self-limited, lasting 2-3 weeks at a time
  • Possible association between arthritis and papulopustular lesions
• RENAL
  • Mild hematuria, proteinuria, renal dysfunction; significant renal dysfunction and GN rare

INVESTIGATIONS

No pathognomonic laboratory tests for BD

• CBC
  • May see anemia (bleeding, inflammation), neutrophilia or thrombophilia (inflammation)
• ALT, creatinine
  • Baseline; typically normal
• ESR, CRP
  • May be elevated
• Antibodies
  • No associations
• Imaging
  • If indicated based on symptoms (Ex: CT (pulmonary) angiogram  for pulmonary thrombosis/aneurysm, MR head and lumbar puncture for CNS involvement, Doppler ultrasound for DVT).
• Pathology
  • Mucocutaneous: biopsy may show neutrophil-predominant infiltration with leukocytoclastic vasculitis with fibrinoid necrosis in blood vessel walls. Lymphocytic vasculitis is also seen in chronic lesions.

DIAGNOSIS

Suspect BD in a younger patients (20-40 years, particularly if ethnically from the “Silk Road”) with recurrent/numerous/painful oral ulcers with systemic manifestations including genital ulcers, skin rash, pathergy, uveitis (especially panuveitis, hypopyon, or retinal vasculitis), CNS parenchymal disease, and thrombosis (particularly Budd-Chiari/hepatic vein thrombosis and cerebral venous thrombosis) and other vascular disease (especially if pulmonary artery aneurysm). Recurrent oral aphthous ulcers are common in the general population; BD should be considered only when compatible systemic manifestations accompany recurrent oral ulcers.

DIFFERENTIAL DIAGNOSIS

More unique to BD	Uncommon or not seen in BD
· Pathergy · Genital ulcers (scrotal) · Pulmonary artery aneurysms	· Overlap  systemic rheumatic disease features (ex: sicca, serositis, photosensitivity, Raynaud’s, auto-antibodies) · Hemolytic anemia · Sacroiliitis, Psoriasis · Urethral discharge

— Differential diagnosis of Oral Ulcers

• Idiopathic
  • Recurrent Apthous Stomatitis: prevalence is up to 10% of general population
• Infectious
  • Herpes simplex, HIV
• Gastrointestinal
  • Inflamatory bowel disease, celiac disease
• Nutritional
  • Vitamin B12, Iron, folate deficiency
• Dermatologic
  • Lichen planus, Pemphigoid, Pemphigus, Stevens-Johnson syndrome, Sweet syndrome, Erythema multiforme
• Hematologic
  • Cyclic neutropenia
• Rheumatologic
  • RA, SLE, spondyloarthritis
• Autoinflammatory
  • PFAPA (periodic fever, apthous stomatitis, pharyngitis cervical adenitis syndrome),
  • HIDS (Hyper-IgD syndrome)
  • MAGIC syndrome (overlap relapsing polychondritis and Behcet’s)
  • Haploinsufficiency of A20 (HA20)
• Drugs
  • Methotrexate, other chemotherapeutics

— Differential diagnosis of other BD manifestations

• Opthalmic BD
  • Sarcoidosis, central retinitis, spondyloarthropathy, toxoplasmosis
• Cutaneous BD
  • Erythema nodosum, drug eruption, reactive arthritis, purulent folliculitis, acne vulgaris, thrombophlebitis
• Inflammatory arthritis in BD
  • Rheumatoid arthritis, peripheral spondyloarthropathy, gout
• Neurologic BD
  • Multiple sclerosis, meningitis, brain tumors, sarcoidosis
• Gastrointestinal BD
  • Ulcerative colitis, Crohn’s disease, acute and chronic enteritis
• Vasculitis in BD
  • Takayasu arteritis, Budd–Chiari syndrome, aneurysm, deep vein thrombosis

CLASSIFICATION CRITERIA

BD is a clinical diagnosis. Classification criteria are not meant as diagnostic criteria to diagnose disease in a single specific patient. Classification criteria are a standardized way of recruiting a well-defined homogenous population of patients in research studies in order to ensure comparability across studies of a heterogenous disease. Numerous criteria exist; 3 presented below.

— INTERNATIONAL STUDY GROUP (ISG) CRITERIA (1990)

Mandatory	Recurrent oral ulcer1
Plus 2 of	Genital ulcer
	Skin lesion2
	Ocular lesion 3
	Pathergy test positive

1. Minor aphthous, major aphthous, or herpetiform ulceration ≥3 times in one 12-month period
2. Erythema nodosum, pseudofolliculitis, or papulopustular lesions; or Acneiform nodules in patients not on corticosteroid treatment
3. Anterior uveitis, posterior uveitis, Retinal vasculitis

— INTERNATIONAL CRITERIA BEHCETS (ICBD, 2013)

Ocular lesion1	2
Genital apthosis	2
Oral apthosis	2
Skin lesions2	1
Neurologic3	1
Vascular4	1
Pathergy test positive	1

1. Anterior uveitis, posterior uveitis, Retinal vasculitis
2. Pseudofolliculitis, Erythema nodosum, Skin aphthosis
3. Characteristic peripheral or central nervous system manifestations
4. Arterial thrombosis, large vein thrombosis, phlebitis, superficial phlebitis

— JAPANESE CRITERIA (2003)

Major symptoms	Oral ulcer
	Genital ulcer
	Skin lesion1
	Ocular lesion2
Minor Symptoms	Arthritis
	Epididymitis
	GI lesion3
	Vascular lesion4
	CNS lesion5

• Complete Type BD: 4 major symptoms
• Incomplete Type BD
  • 3 major symptoms
  • 2 major + 2 minor
  • Ocular   + 1 major
  • Ocular   + 2 minor  

1. Erythema nodosum, thrombophlebitis., folliculitis, acneform papules, skin hypersensitivity
2. Iridocyclitis, posterior uveitis
3. Ileocecal ulceration
4. Cardiac/aortic disorders, obstruction of middle vessels, obstruction of small vessels, thrombophlebitis, and others
5. Headache, dizziness, paralysis, mental symptoms, and others

TREATMENT

— Mucocutaneous

• Topical or oral steroids for acute oral/genital ulcers and other skin rash
• First line for maintenance:
  • Colchicine 1.2-1.8mg/d
• Second line for maintenance:
  • Apremilast 30mg BID, Azathioprine 2mg/kg/d, TNFi (etanercept, certolizumab, golimumab); Ustekinumab, secukinumab, anakinra

— Musculoskeletal

• Acutely:
  • Colchicine, PO/IA steroids
• Chronic/recurrent:
  • Azathioprine, methotrexate, sulfasalazine, TNFi, IFNα; anakinra, secukinumab

— Uveitis

• Isolated anterior uveitis
  • Topical steroids
• Posterior uveitis
  • Azathioprine, cyclosporine-A, IFNα, TNFi, steroids
  • If acute sight-threatening uveitis: high dose steroids, TNFi, or IFNα; tocilizumab

— Venous disease

• Acute DVT
  • Steroids, azathioprine, cyclophosphamide, Cyclosporine
  • Can consider anticoagulation once acute inflammation is controlled, though at risk of bleeding if arterial/aneurysmal disease is present
• Refractory/recurrent venous thrombosis
  • TNFi; if refractory, consider: anakinra, tocilizumab.
  • Prophylactic anticoagulation controversial; not proven to prevent recurrent venous thrombosis, but may decrease risk of post-thrombotic syndrome. May consider anticoagulation only if bleeding risk low and ruled out arterial aneurysms

— Arterial disease

• Pulmonary artery aneurysm
  • High dose steroids and cyclophosphamide
  • TNFi, tocilizumab if refractory. If high risk bleed: embolization over open surgery
• Aortic/peripheral aneurysms
  • High dose steroids and cyclophosphamide to control inflammation
  • Surgery once inflammation controlled (no delay if symptomatic)

— Gastrointestinal

• Steroids, 5-ASA, azathioprine; severe/refractory use TNFi; anakinra, tocilizumab

— Nervous System

• Parenchymal
  • High dose steroids and Azathioprine. If severe/refractory: TNFi; MMF, IFNα, cyclophosphamide, tocilizumab
• Central Venous thrombosis
  • High dose steroids and short duration anticoagulation.
  • Search for extra-cranial DVT

Duration of therapy is unclear; if severe manifestations,  maintenance immunosuppressives for ~24 months

PROGNOSIS

• Poor prognostic factors
  • Young, male, Middle-Eastern, Far-Eastern, or African ethnicity
• Disease Course
  • Early disease: mucocutaneous, articular, and ocular disease is worse
  • Later disease (~5-6 years): CNS and large vessel disease.
  • Patients with predominantly mucocutaneous and articular manifestations may get resolution of symptoms
• Causes of Morbidity and Mortality
  • Due to neurologic, ocular, and large-vessel disease (with complications of pulmonary disease, GI bleed, bowel perforation, SVC/IVC syndrome, cerebrovascular disease)
• Ocular outcomes
  • Prevalence of ocular involvement 80% within 5 years
  • If ocular involvement, loss of useful vision 17% at 5 years, 25% at 10 years, and 29% at 20 years
• Mortality rate
  • 7.7-years: 5% mortality
  • 20-year: 10% mortality

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