Elsevier

Survey of Ophthalmology

Volume 50, Issue 4, July–August 2005, Pages 297-350
Survey of Ophthalmology

Major Review
Current Concepts in the Etiology and Treatment of Behçet Disease

https://doi.org/10.1016/j.survophthal.2005.04.009Get rights and content

Abstract

Behçet disease is an idiopathic, multisystem, chronic, and recurrent disease characterized by exacerbations alternating with phases of quiescence, episodic panuveitis, and aggressive non-granulomatous occlusive vasculitis of the arteries and veins of any size with explosive ocular inflammatory attacks that primarily affect the retinal and anterior segment vasculature of the eye. The disease is characterized by endothelial dysfunction and may produce a wide variety of symptoms. In mild cases, orogenital ulcers and skin lesions are the only findings during the entire clinical course, whereas ocular lesions that occur in more than half of the cases, frequently bilateral, can eventually lead to blindness. Pulmonary, gastrointestinal, and central nervous system involvements may sometimes be life-threatening. This review examines the epidemiology, frequency, immunology, and immunohistopathology of Behçet disease with recent theories of several agents, including phosphoantigens, superantigens, heat-shock proteins, and adenosine deaminase. Perspectives on the possible roles of new etiopathological molecules, such as nitric oxide, endothelin, and homocysteine, are presented. Ocular and systemic clinical features, diagnostic criteria, classifications, laboratory, fundus fluorescein angiography, and radiologic imaging are discussed. Differential diagnosis, disease in pregnancy and childhood, and prognosis with regard to Behçet-induced systemic and ocular complications are also evaluated. Traditional and current treatments with topical, paraocular and systemic corticosteroids, colchicine, dapsone, cyclosporine, azathioprine, methotrexate, cyclophosphamide and chlorambucil are summarized and recent insights into the pharmacology and effects of thalidomide, tacrolimus (FK-506), interferon-α, anti-TNF-α blocking monoclonal autoantibody (infliximab) and soluble TNF receptor (etanercept) are reviewed. Key clinical investigations with the status of ongoing clinical trials aimed at addressing the drug's efficacy, surgical care, and studies that have raised the possibility of new therapeutic uses are also presented. The challenges posed by the drug's teratogenicity and adverse effects are also considered, if present.

Section snippets

Definitions

Behçet disease (BD) was first described in 1937 by a Turkish dermatologist Dr. Hulusi Behçet from Istanbul as a triad of symptoms consisting of oral aphthae, genital ulcers, and hypopyon uveitis.50, 467 The disease is defined as a chronic, relapsing, multisystemic idiopathic inflammatory problem characterized by an episodic occlusive retinal vasculitis with no specific treatment,153 although there are some recent improvements regarding the management, especially of ocular BD, by new biological

Epidemiology

This ubiquitous disorder exhibits a distinct geographic variation and is endemically higher particularly in Turkey, Iraq, Iran, Korea and Japan, the population derived historically from the ancient Silk Road that was used for centuries as a trade-making passage from the East to the West.352 Behçet disease accounts for up to 20% of cases of endogenous uveitis in some of these countries, particularly in Japan and Turkey (when compared with only 0.2% in the USA), and the highest prevalence is

Frequency and Prevalence

The estimated prevalence of BD is between 1/10,000 and 1/1,000 in the Mediterranean countries, the Middle East, and the Far East. In Japan, the prevalence rate is about 1/10,000 and the disease occurs more frequently in the temperate northern than in subtropical southern parts of Japan, again suggesting environmental factors influencing the prevalence of the disease. In Turkey, the prevalence is 2–42 cases per 10,000, depending on the geographical differences.40, 71, 211 In Asia, it is

Age, Sex, and Severity

Although BD affects primarily young adults more frequently between the second and fourth decade of life and is rarely seen in children, the onset can occur at any age from infants to the elderly.58, 155, 254, 352, 458, 465 In general, the mean age of onset is the third decade of life.

Behçet disease is more common in men than in women with a 2–10:1 male:female ratio in the ancient Silk Road countries, whereas the trend is reversed in Western Europe and the USA.155, 352, 458 Indeed, male

Morbidity and Mortality

In general, the “disease burden” of BD is usually confined to the early years of its course that “burns out” during the following years. Although severe orogenital ulcerations can be debilitating for BD patients with a lower oral intake, the effects of the disease may be cumulative for CNS and vascular diseases, and the leading cause of chronic morbidity is high especially with ophthalmic inflammation. Indeed, overall survival analysis suggests that the risk of visual loss increases

Etiopathogenesis and Effector Mechanisms

The intermittent nature of the disease and the lack of consistent response to therapy make the underlying etiology difficult to define. However, it is probably mediated by a combination of genetics,116, 384 infectious agents,98, 352 immune dysregulation and inflammatory mediators,155, 200, 360 heat shock proteins (HSPs),439 oxidative stress,83, 463 lipid peroxidation (LPO),477 and environmental factors. Raised levels of circulating immune complexes, complements and acute phase proteins,

Immunohistopathology

Immunohistopathologic studies of specimens taken from active inflammatory sites of BD patients support the findings of those found in the peripheral blood and indicate immune-complex mediated disease. Necrotizing, neutrophilic (leukocytoclastic) obliterative perivasculitis (phlebitis) and venous thrombosis with lymphocytic and monocytic cellular infiltration of the veins, capillaries and the arteries of all sizes, with or without fibrin deposition in the vessel wall, is the hallmark of BD.153

Clinical Features

Ophthalmologists are concerned with the ocular inflammation and, in particular, retinal vasculitis during the course of BD. However, BD may produce distressing symptoms with the combinations of variable systemic involvements. It presents by exacerbations and remissions with varying healing time among patients. Although the severity of disease generally diminishes with time and stabilizes at any moment, it may become chronic in a given organ system.98, 155, 197, 364 Therefore, ophthalmologists

Treatment

Treatment of BD is symptomatic and empirical. The main objectives of a physician are the following: 1) to control and treat symptoms associated with mucocutaneous lesions; 2) to relieve the pain, discomfort, and functional disability; 3) to suppress and control active inflammation; 4) to reduce the frequency and severity of recurrences; and 5) to prevent end-organ damage.157

On the other hand, the ultimate goals of the ophthalmologist in treating this potentially blinding ocular disease for

Conclusion and Future Directions

We currently know considerably much more about BD as compared with two to three decades ago, and we can do more regarding the early diagnosis, follow-up, and treatment of the disease. Although a number of novel treatment opportunities have recently been introduced, no safe and conclusive treatment exists yet. Therefore, the outcome is still not satisfactory and clinical dilemmas continue to challenge, especially in sight-threatening panuveitis that is refractory to traditional therapy. Indeed,

Method of Literature Search

This article was prepared by using the database of National Library of Medicine by using the search words Behçet's disease or Behçet's syndrome from 1994 up to February 2005, our own published papers, and manual searches based upon articles cited in the texts of other articles. Many of the relevant full articles were obtained by personal communication with relevant authors, or downloaded, where available. Articles were included if they emanated from peer-reviewed journals. Clinical studies were

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