Autoinflammation in Behçet’s Disease

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Behçet’s Disease

BD, also known as the Silk Road Disease, is a rare systemic vasculitis disorder of unknown etiology.2,17 While chronic inflammatory disorders are persistent in nature, BD is characterized by recurrent attacks of acute inflammation.2 Recurrent oral aphthous ulcers, genital ulcers, skin lesions, and ocular injuries are the most common manifestations that characterize BD, and are all self-limiting in time except for ocular lesions, which ordinarily lead to permanent impaired vision.2,17 Relapsing episodes of clinical manifestations represent a hallmark of BD; frequency and duration are unpredictable.2,17 Other less frequent, yet life-threatening, manifestations involve the central nervous system (CNS), the main large vessels and the gastrointestinal tract.2,17 BD is known to have a heterogeneous onset and is associated with significant morbidity and high mortality.
The first description of an illness that shared the clinical manifestations of BD was reported by Hippocrates in the 5th century BC, in the « Third Book of Endemic Diseases »; another early description of similar symptoms was reported by the Chinese physician Zhong-Jing Zhang in approximately 200 AD.1,19 However, until the 18th century, no further descriptions of patients with manifestations similar to those of BD were reported.1,19 In 1908, a triad of symptoms involving urogenital ulceration and iritis was reported by Bluthe et al.; subsequently, Planner and Remenovsky (1923) followed by Shigeta (1924) reported similar observations.19 However, these symptoms were thought to be caused by tuberculosis or syphilis, until they were proposed by Hulusi Behçet, a Turkish dermatologist, as a separate disease entity in 1937.
Born in Istanbul in 1889, Hulusi Behçet graduated from the Gulhane Military Medical School in 1910 and completed his specialization in dermatology and syphilology in 1914.19 In 1924, Behçet first documented the clinical examination of a patient with recurrent aphthous stomatitis, genital ulcers, erythema nodosa and visual disturbances.19 Behçet subsequently documented two other similar cases in 1930 and 1936, and proposed in 1937 that the three observed major signs (recurrent oral aphtae, genital ulcerations, and hypopyon uveitis) constituted an independent clinical syndrome.1,19 Behçet published his findings in both German and French journals in 1937 and 1938, respectively.1 Later in 1939-1940, he started using the term « triple-symptom complex » to refer to the triad of observed clinical signs.1 After Behçet’s descriptions, similar reports from different regions followed.2 The eponym « Behçet » was first used by Jansen, a Danish physician, in 1941 and subsequently become the norm.1 In 1947, the disease was recognized in the International Congress of Dermatology in Geneva, and was formally named as « Morbus Behçet » as proposed by Zurich Medical Faculty professor Mischner.1,19 Worth mentioning is that Benedictos Adamantiades reported a similar case in 1931, thus the disease is sometimes referred to as Adamantiades-BD.1,19 However, « Behçet’s Disease » remains the preferable name as recommended by the International Associations and Societies of Behçet.
BD is now recognized worldwide as a systemic vasculitis that, in addition to the triple-symptom complex, has neurological, gastrointestinal and cardiovascular involvements.1,19 Due to its high prevalence in countries that coincide with the Old Silk Route, an ancient trade route that extends between the Mediterranean, Middle East and Far East, the disease was designated by Ohno as the “Silk Road Disease” in 1982.1,19.
Reports reviewing the epidemiology of BD confirm that the disease mainly occurs along the Old Silk Route between latitudes 30° and 45° north in an area extending from the Mediterranean basin to eastern Asia and including Turkey, Iran, Iraq, Israel, India, Korea, China and Japan, with a prevalence ranging between 1 / 10,000 and 1 / 1,000.1,2,17 This peculiar geographical distribution of BD may be explained by the contribution of itinerant traders in spreading a genetic risk factor.19 Among the Old Silk Road countries, Turkey was reported to have the highest disease prevalence ranging from 80-420 cases per 100,000 depending on the geographical location.1,20 A cost-analysis study conducted in Turkey reported that BD imposes a significant economic burden both directly and indirectly.19,23 Following Turkey, Japan has the high reported prevalence of 7-8.5 / 10,000. Disease prevalence in Asian countries, including Japan, Korea, China, Iran and Saudi Arabia, was found to range from 13.5 to 20 cases per 100,000.1,20 Disease prevalence is lower in Western countries and ranges from 0.12 to 0.64 / 100,000, with 0.64 cases per 100,000 in the United Kingdom and 0.12-0.33 cases per 100,000 in the United States.184 In addition to a higher prevalence, BD was found to exhibit more severe manifestations, including ocular, vascular and neurological inflammation, in Old Silk Road countries versus Western countries. Interestingly, immigrants from countries with high prevalence tend to have a lower probability of developing the disease in relatively low prevalence regions; for instance, disease prevalence among Turkish individuals in Germany was found to be 21 / 100,000, which is lower than that of Turkey but higher than that of the German population (0.42-0.55 / 100,000) at large.
Whereas BD primarily affects males in the Middle East, it is more recurrent amongst females in Japan and Korea. However, the disease appears to be associated with worse clinical manifestations in males in all regions combined.19 Higher risk of ocular, neurological and cardiovascular involvement was noted amongst male individuals who generally exhibit an earlier disease onset and worse prognosis with regards to blindness and mortality.
BD rarely develops before puberty or after the age of 50. Typically, it occurs between the 3rd and the 4th decades of age. Onset age was correlated with disease severity. It was reported that earlier onset is associated with more severe clinical manifestations. However, studies from Korea and Turkey suggest the absence of a link between late disease onset (40 years of age or above) and mild clinical evolution.
Familial aggregation of BD was reported to occur in 1-18% of patients, most notably in Turkish, Israeli, and Korean patients.20 In addition, the incidence of familial aggregation was found to be higher in juvenile patients with BD. The frequency of the disease within families is 2-5%, except in the Middle East where it increases up to 10-15%. However, the frequency of concordance among twins remains unsettled. One study reported concordance for the disease among a pair of monozygotic twins, while a separate study reported discordance between two other pairs.20,22 Although no studies reported disease prevalence in a particular socio-economic group, a study was conducted in Turkey in order to assess the economic impact of BD patients. Compared to ankylosing spondylitis and inflammatory bowel disease patients, BD patients were observed to have lower monthly income, wealth score and education, and higher unemployment.
Collectively, the epidemiological data presented above suggest the involvement of both genetic and environmental factors in the development of BD.

Clinical Features of Behçet’s Disease

A systemic disease, BD may affect almost all vascularized body systems and is characterized by episodes of relapses and remissions leading to sequelae.1,11,12,185 Although several clinical manifestations are associated with BD, the triple-system complex of oral and genital aphthae and uveitis first described by Behçet in 1937 generally illustrates disease pattern. Clinical manifestations in children (<16 years) resemble those of adults.20,21 Children exhibit more frequent perianal aphthosis and arthralgia, less frequent genital ulcers and vascular involvement, and a more severe course of uveitis.1,186 Over the past few years, modern treatment strategies, involving immunosuppressant therapy and the use of aggressive approaches have led to improvements in the prognosis of severe forms of BD.4,187 Prognosis for the disease is usually reserved, especially when ocular, cardiovascular, neurological, and / or gastrointestinal manifestations appear.5,185,188

Oral Ulcers

Recurrent oral ulcers represent the earliest disease manifestation in 47-86% of patients.188 It may take years for the other symptoms to appear afterwards, and oral ulcers are observed in all patients during their clinical course. Lesions resemble common oral aphthous ulcers, but are more painful and wider. They have disciform appearance with round and sharp erythematous border, covered with a grayish-white pseudomembrane or a central yellowish fibrinous base and grow rapidly from a flat ulcer to a deep sore.1 They may occur as single ulcers or in crops and heal with little scarring.1,2 Oral ulcers most commonly affect the gingival and buccal mucosa, tongue and lips, yet may also appear in the soft and hard palates, pharynx and tonsils.1 In certain cases, oral ulcers derive from buccal trauma. Minor ulcers (<1 cm in diameter) heal without scarring in 4-14 days whereas major ulcers (>1 cm in diameter) are more painful and heal with scarring in 2-6 weeks. Herpetiform ulcers occur in recurrent crops of small sores that are 0.2-0.3 cm in diameter, are painful and may coalesce. Treatment is usually symptomatic and prognosis of oral ulcerations is favorable.2,188


Genital Ulcers

Genital ulcers develop in 57-93% of patients.5 They are painful and morphologically resemble oral ulcers, but are larger, deeper, have more irregular margins and heal with white or pigmented scars.188 Male genital lesions most commonly involve the scrotum and usually leave a scar that will help with the diagnosis retrospectively. They may also affect the epididymis; penile lesions are less frequent.1 In females, vulvar, vaginal and cervical lesions are especially common.2 Rarely, deep vaginal lesions may perforate the bladder resulting in fistulae.5,188 Both males and females may develop perineal, perianal and groin lesions.188 In cases of fistulae and internal lesions, prognosis is unfavorable when the infectious risk is inadequately evaluated.

Ocular Manifestations

Ocular disease, involving the retina and the uvea, occurs in 30-70% of BD patients and is associated with high morbidity.4 It is the primary cause of blindness in approximately 25% of patients despite aggressive corticosteroid treatment.4 Ocular symptoms occur more frequently in males and are associated with disease severity, even though prognosis is improving with the use of aggressive immunosuppressant therapy.1,2 They usually occur two-three years after the onset of oral or genital ulcerations but remain the first disease manifestation in 10-20% of patients.1 Typically, ocular disease is a chronic relapsing bilateral non-granulomatous uveitis that may involve the anterior segment, the posterior segment, or both (panuveitis).185,186 The latter is associated with a worse prognosis and is more common among males.1 Ocular disease is characterized by the formation of hypopyon: a visible layer of pus in the anterior chamber observed in approximately one-third of patients.2 Episodes of anterior uveitis subside spontaneously yet repeated attacks result in irreversible structural deformities.7,186 Ocular inflammation also includes iridocyclitis, keratitis, episcleritis, scleritis, vitritis, vitreous hemorrhage, retinal vasculitis, retinal vein occlusion, retinal neovascularization, and optic neuritis.
Symptoms include blurred vision, photophobia, lacrimation, floaters, hyperemia and periorbital or global pain.1,2 Recurrent inflammatory attacks are associated with secondary complications such as posterior and peripheral anterior synechia, iris atrophy, cataracts resulting from inflammation or treatment, secondary glaucoma (occasionally neovascular), atrophic retina, optic atrophy, macular edema, macular degeneration, retinal veins occlusion, sheathed vessels, chorioretinal scars and proliferative vitreoretinopathy and phthisis bulbi.1,4 Prognosis is correlated with frequency, severity of ocular inflammation, and extent of lesions, and remains in many cases unfavorable.

Cutaneous Manifestations

Skin involvement affects 38-99% of BD patients.1,11 Cutaneous manifestations commonly include papulopustular (28-96%) and acne-like lesions.5,20 Wounds exhibit a wide distribution affecting the face, limbs, trunk and buttocks.1 Skin lesions are characterized by thrombosis and vasculitis.11 Early lesions exhibit leukocytoclastic vasculitis or neutrophilic vascular reactions whereas mature lesions are characterized by lymphocytic vasculitis.
Erythema nodosum lesions occur in 15-78% of patients, mainly in females and in the lower limbs.1,2 These lesions are painful, may form ulceration and usually heal leaving residual pigmentation. Cutaneous ulcers are rare and only affect 3% of BD patients.1 They resemble aphthous ulcers, are recurrent, and typically heal with scarring. They appear in the neck, breast, axillae, inguinal region, legs and interdigital skin of the feet.188 Prognosis for most cutaneous lesions in BD is usually favorable.1

Cardiovascular Manifestations

Behçet’s disease may affect blood vessels of different sizes and types, including arteries and veins as well as the heart organ.189 Cardiovascular features were reported to affect 7-49% of patients, more frequently males.1,190 They occur approximately 3-16 years after the onset of BD. Vascular BD commonly affects veins causing recurrent superficial thrombophlebitis and deep venous thrombosis in 30-40% of patients.7,191,192 Thromboses of the superior and inferior vena cava (0.2-9% of patients), dural sinuses and supra-hepatic veins (2-3.2% of patients), and pulmonary arterial aneurysms (1% of patients) may also occur and are associated with poor prognoses.1,189,192 Occlusion and aneurysms of major arteries commonly lead to bleeding, infarction, organ failure and restricted movements of arms and legs.2 Rupture of aneurysms may be fatal. At the level of lungs, thrombosis, aneurysm, and arteriobronchial fistula cause recurrent episodes of dyspnea, cough, chest pain and hemoptysis.
Cardiac involvement includes pericarditis, myocarditis, endocarditis, mitral valve prolapse, valve lesions, intracardiac thrombosis, endomyocardial fibrosis, myocardiopathy, and coronary artery lesions, and is the result of systemic vascular involvement.29,190,193 The prognosis in these cases is unfavorable with frequent recurrences.1,193 The highest direct mortality rate in cardiovascular involvement was attributed to large vessel vasculitis as a result of sudden death by aneurysm rupture or thrombosis (9.8% of patients in one study in Turkey).

Neurological Manifestations

Neurological involvement in BD (neuro-BD) occurs in 5-10% of patients and is more frequent in males.7,8,37 It usually occurs around five years after the onset of the disease and is associated with long-term morbidity and mortality.1,195 Neurological disease affects the CNS more frequently than the peripheral nervous system.196,197 Headache syndromes represent the most common neurological symptom and occur in 70% of patients.
Neuro-BD may be parenchymal (80% of patients), non-parenchymal, or mixed brain disease.1,7 Parenchymal brain disease affects the brainstem and / or basal ganglia and is correlated with a particularly poor prognosis.7,199 Non-parenchymal brain disease is characterized by dural sinus thrombosis, arterial vasculitis, and aseptic meningitis, and comprises the most devastating symptom category of BD.
Most parenchymal neuro-BD cases present as meningoencephalitis (75%) that exhibit subacute onset and are associated with exacerbation of systemic manifestations.195,196 Flare-ups peak within a few days and may last for periods of weeks. Brainstem involvement, including ophtalmoparesis, cranial neuropathy, and cerebellar or pyramidal dysfunction, has additionally been reported.1,7,197,200 Cerebral or spinal cord involvement was observed in association with subcortical dementia, accompanied by ataxia.195,199 Cerebral hemispheric involvement, including encephalopathy, hemiparesis, hemisensory loss, seizures and dysphasia, and mental changes, including cognitive dysfunction and psychosis, were observed as well.7,8,201 Spinal cord involvement, manifested by pyramidal signs in the limbs, sensory level perturbance and sphincter dysfunction, has also been reported.7,201,198 Other less common clinical symptoms involving the CNS were reported as well such as: stroke, epilepsy, brain tumor-like neuro-BD, movement disorders, acute meningeal syndrome, optic neuropathy, spinal cord involvement and asymptomatic and subclinical neurological involvement.

Table of contents :

Table of Contents
Table of Illustrations
1.! Introduction
2.! NOD Model of Autoimmunity
3.! Autoinflammation in Behçet’s Disease
4.! Systemic Vasculitides
5.! Behçet’s Disease
6.! Clinical Features of Behçet’s Disease
6.1.! Oral Ulcers
6.2.! Genital Ulcers
6.3.! Ocular Manifestations
6.4.! Cutaneous Manifestations
6.5.! Cardiovascular Manifestations
6.6.! Neurological Manifestations
6.7.! Articular Manifestations
6.8.! Gastrointestinal Manifestations
7.! Diagnosis of Behçet’s Disease
8.! Treatment of Behçet’s Disease
8.1! EULAR Guidelines
8.2.! Therapies
9.! Prognosis of Behçet’s Disease
10.! Study Cohort
10.1.! Methodology
10.2.! Results
10.3.! Discussion
11.! Conclusion


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