Behçet disease

Behçet's disease is a primary vasculitis with a lymphocytic or neutrophilic predominance depending on the age of the lesions, affecting vessels of all sizes but with a preference for small vessels. 

It is a rare disease with a prevalence varying from 0.1 to 7.5 per 100,000 inhabitants in Europe to 80 to 370 per 100,000 in Turkey. It usually begins between the ages of 20 and 30. Mortality is very low (cardiac and vascular involvement, intestinal perforations), but the functional prognosis quickly deteriorates (++ cumulative sequelae of neurological and ophthalmological involvement).

The etiology is unknown, presumably multifactorial (genetic predisposition, viruses, toxins, hormones, etc.). Some consider it to be a seronegative spondyloarthropathy.

Clinical Features

The disease progresses with irregular flares, without correlation between the cutaneous-mucosal and visceral lesions. Clear inflammatory states / fever are rare. The prognosis is determined by ocular and neurological involvement.

Joint involvement (5-70%)

Often early (a few years before other manifestations), ++ arthralgia/ fixed oligoarthritis of large joints, rarely destructive, recurrent and asymmetrical. X-rays are (almost) normal, and puncture → viscous inflammatory fluid.

Possible popliteal cysts, whose rupture is hard to distinguish from DVT ! Cases of osteonecrosis have been described (secondary to corticosteroid therapy?). Low back pain with pseudopottic stiffness may be a sign of an aortic aneurysm or inferior vena cava thrombosis.

Association described with true ankylosing spondylitis.

Muscle involvement

+++ diffuse/ proximal myalgia. Cases of true myositis have been reported. Biopsy shows muscle fiber degeneration with infiltration by mono/polynuclear cells. CK levels are usually normal → if elevated, consider a myopathy versus an iatrogenic Rhabdomyolysis due to colchicine.

Cutaneous-mucosal involvement (almost 100%)

Should always be sought as they are essential for diagnosis. Sometimes late

• Oral aphthae (98%) : painful, isolated/ multiple ulcerations with sharp edges, covered by a "fresh butter" coating, with an inflammatory border
• Genital aphthae (60-65%). In men : scrotum > penis > urethra. In women : vulva, vagina. They leave depigmented scars.
• Aphthae in the esophagus, stomach, intestines, anal margin… rarely cause perforations.
• Various : erythema nodosum, papules, vesicles, pustules, purpura, pseudo-folliculitis, hyper-reactivity to epithelial injuries.

Ocular involvement

→ Recurrent flares of intraocular inflammation with progressive retinal destruction. Bilateral involvement is frequent, occurring on average within 2 years. Anterior uveitis with hypopyon, posterior uveitis (very frequent) with occlusive and necrotizing vasculitis, hemorrhages, retinal edema, pre-retinal neovascularization, conjunctival aphthae, episcleritis, keratitis.

Generally severe progression → cataract, ocular hypertension, blindness (50% of cases within 5 years) due to posterior segment involvement.

Neurological involvement (4-42% of cases, ++ around 40-50 years)

Highly variable. Can occur in the context of a florid disease, after inappropriate treatment withdrawal, or after several years of evolution of non-specific cutaneous-mucosal lesions… and rarely as the initial symptom (→ major diagnostic issue!). Slight male predominance.

Neurological signs can be preceded or accompanied by inconsistent headaches/ fever… and include :

• Headaches (83%)
• Cranial nerve involvement (33%) : Oculomotor, Trigeminal, Facial, Vestibulocochlear nerves
• Pyramidal syndrome (33%) with or without deficits (hemi/mono/paraplegia)
• Sensory disturbances (25%) subjective/ objective
• Bilateral papilledema (21%)
• Cerebellar syndrome (21%)
• Swallowing disorders (4%), incontinence (4%), dysarthria (4%), internuclear ophthalmoplegia (4%), retrobulbar optic neuritis (4%)
• Psychiatric disorders (13% ! Difficult differential diagnosis with side effects from corticosteroid therapy or reactive psychiatric disorders)

The main neurological manifestations are :

• Meningo-parenchymal involvement (60-80% of neuro manifestations)
  • Lesions : inflammatory with meningoencephalitis and perivascular infiltrations indicating vasculitis / necrotic foci around medium and small caliber vessels indicating vascular thrombosis / neuronal damage with mild demyelination and gliosis
  • MRI and lumbar puncture are of low specificity
• Cerebral venous thromboses rarer (up to 30% of neuro cases in some series), difficult to diagnose (frequent spontaneous resolving symptoms of increased intracranial pressure), should be systematically considered in cases of headaches/ fluctuating or poorly localized neurological deficits/ seizures/ visual disturbances with papilledema
• Angio-Behçet involving cervico-encephalic arteries very rare, involvement of small arteries is exceptional
• Peripheral nervous system and cranial nerve involvement: Facial and Vestibulocochlear nerves, peripheral neuropathy of the lower limbs.

Vascular involvement

Highly varied (Differential diagnosis of a florid vascular presentation = antiphospholipid antibody syndrome → should be systematically ruled out by laboratory tests, including anticardiolipin, protein C resistance).

• Venous thromboses (30% of patients) : superficial thrombophlebitis (++ fleeting and migratory), deep vein thrombosis (! Frequently affecting large vessels : iliac-femoral, inferior/ superior vena cava ! Hepatic vein thrombosis = Budd-Chiari syndrome), cerebral venous thrombosis. Less emboligenic than idiopathic venous thromboses.
• Arterial involvement : thromboses, aneurysms at high risk of rupture.

Pulmonary involvement

++ parenchymal infiltrates +- hemoptysis +- pleurisy. Always exclude pulmonary embolism, pulmonary artery aneurysm, or infection favored by treatments.

Cardiac involvement

Rare. Myocarditis (! arrhythmias), endocarditis (! valve disease of the aorta/ mitral, intracavitary thrombi), pericarditis (often recurrent ! associations with coronary artery disease), coronary artery disease (aneurysms and thromboses → risk of myocardial infarction, hemopericardium, sudden death).

Gastrointestinal involvement

Clinically similar to ulcerative colitis or Crohn's disease.

Other involvements

• Renal : rare. Proliferative or amyloid glomerulopathies.
• Testicular, epididymal or urethral involvement.

Diagnosis and Additional Tests

Diagnosis is mainly clinical, with complementary tests being of low sensitivity and specificity:

• Laboratory tests: elevated neutrophil count during flares, fibrinolysis abnormalities, elevated factor VIII, circulating immune complexes, cryoglobulinemia
• Ophthalmologic examination (fundus + fluorescein angiography)
• Skin biopsy from an intradermal saline injection → vasculitis with complement deposits
• In case of neurological flares :
  • Lumbar puncture → typically lymphocytic meningitis + elevated cerebrospinal fluid proteins
  • Brain MRI → diffuse T2 hypersignals (hypo T1) (highly suggestive if confluent into large areas towards the brainstem/ diencephalon/ basal ganglia) persistent in the medium term but decreasing in intensity. Possible punctiform vasculitic lesions hyper on T2.
• Angiographic tests (CT, MRI or conventional) in case of vascular manifestations

Behçet's disease should be systematically considered in cases of venous thrombosis in a young person without identified risk factors.

1990 International Diagnostic Criteria (Sensitivity 91%, Specificity 96%) :

Recurrent oral ulcers, recurring > 3 times in 12 months + 2 criteria among :

• Recurrent genital ulcers
• Ocular lesions (uveitis/ vasculitis) confirmed by an ophthalmologist
• Skin lesions: erythema nodosum, pseudofolliculitis, papulopustular lesions, acneiform nodules (in post-adolescent patients)
• Positive pathergy test (hyper-reactivity to intradermal saline injections)

Therapeutic Management - Treatments

Colchicine (1 to 2mg/day) + antiplatelet therapy (Aspirin 160 mg/day): for minor forms (articular, cutaneous-mucosal)

Corticosteroid Therapy:

• Indications: ocular forms, neurological forms, other severe manifestations
• Local treatment possible for anterior uveitis
• Attack boluses (1g/day of solumedrol over 3 hours for 3-5 days) in severe/progressive forms
• Start at 1mg/kg/day for 6 weeks, then reduce by 10% per week
• ! High risk of relapse during withdrawal → maintain a maintenance dose (5-10 mg/day) and prevent complications of long-term corticosteroid therapy
• Anticoagulation if predominant vascular involvement (e.g., cerebral venous thrombosis)! Be cautious of corticosteroid-induced osteoporosis

Immunosuppressants:

• ! Oncogenic risk → for major/severe involvement
• Allow corticosteroid tapering but with delayed action (long latency!)
• Azathioprine 2.5mg/kg/day
• Cyclophosphamide 2mg/kg/day PO or 750-1000mg IV once a month
• Chlorambucil 0.1-0.2mg/kg/day
• Methotrexate 7.5mg in 3 doses PO once a week

Controversial/Undemonstrated Efficacy: dapsone, thalidomide, plasmapheresis, IV immunoglobulins, interferons, antibiotic therapies

Bibliography

EMC, traité de médecine AKOS, Elsevier, 2018

Jameson JL et al., Harrison's Principles of Internal Medicine, 20th edition, McGraw Hill Higher Education, 2018