Behçet disease (BD) is a chronic, relapsing, multisystem inflammatory disorder of unknown etiology. It can affect both the anterior and the posterior segments of the eye, often simultaneously. The disease symptoms have been described for more than 2500 years. They were formally characterized in the early 20th century by Adamantiades and Behçet as a triad of aphthous ulceration, genital lesions, and recurrent uveitis. It is now known to affect almost any organ system and occurs in a variety of ethnic populations all over the world. It is most common in the Northern Hemisphere in the countries of the eastern Mediterranean and on the eastern rim of Asia, particularly along the ancient Silk Road. The prevalence of BD varies from as high as 20–421 cases per 100,000 inhabitants in Turkey to 8–13.5 per 100,000 in Japan and 5.2 per 100,000 in the United States. The age of onset is typically in the third and fourth decades but can also occur after age 50 or in childhood. Both genders are affected equally, but BD may have a more severe course in males. Although there have been some familial cases of BD, most are sporadic.
Table 9-3 Diagnostic System for Behçet Disease (Japan)
Table 9-4 Diagnostic System for Behçet Disease (International Study Group for Behçet’s Disease)
The diagnosis of BD is clinical and is based on the presence of multiple systemic findings. The diagnostic system for BD in Table 9-3 was suggested by researchers in Japan, and another diagnostic system was suggested by the International Study Group for Behçet’s Disease (Table 9-4). Although BD is a multisystem disease, it can have its predominant effect on a single system; thus, special clinical types of BD occur—namely, neuro-BD, ocular BD, intestinal BD, and vascular BD. However, importantly, being free from major organ involvement early in the disease does not protect against its development later on. Epidemiologic studies also report significant regional variability in organ-specific disease expression.
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Nonocular systemic manifestations
Recurrent, painful oral aphthae are the most frequent finding and often the presenting sign in BD (Fig 9-60). They can occur on the lips, gums, palate, tongue, uvula, and posterior pharynx. They are discrete, rounded, white ulcerations with red rims varying in size from 2 to 15 mm. They typically last 7–10 days and heal with little scarring unless large.
Genital ulcers appear grossly similar to oral aphthous ulcers, but tend to be deeper and larger and heal with more scarring. In male patients, they can occur on the scrotum or penis. In female patients, they can appear on the vulva and vaginal mucosa. Genital scarring may be apparent on examination even if patients have no acute symptoms.
Skin lesions can include painful or recurrent erythema nodosum, often over extensor surfaces such as the tibia, but also on the face, neck, and buttocks. Acne vulgaris or folliculitis-like skin lesions may frequently appear on the upper thorax and face. Skin lesions may disappear spontaneously with minimal or no scarring. Nearly 40% of patients with BD exhibit cutaneous pathergy, which is characterized by the development of a sterile pustule at the site of a venipuncture or an injection but is not pathognomonic of BD.
Systemic vasculitis affecting any size artery or vein in the body may occur in up to 25% of patients with BD. Common manifestations are arterial occlusions and aneurysms, and superficial or deep venous occlusions and varices. Cardiac involvement can include granulomatous endocarditis, myocarditis, endomyocardial fibrosis, coronary arteritis, and pericarditis. Gastrointestinal lesions, such as ulcers involving the esophagus, stomach, and intestines, may be seen in over 50% of BD patients in Japan, where it is a significant cause of morbidity. Pulmonary involvement is mainly pulmonary arteritis with aneurysmal dilatation of the pulmonary artery. Fifty percent of patients with BD develop arthritis, commonly of the knee, elbow, hand, or ankle.
Neurologic involvement is among the most serious of all manifestations of BD. Lesions of the white matter of the brain and brainstem may lead to motor dysfunction, stroke, and cognitive/behavioral changes. Headaches and aseptic meningitis have been associated with CNS vasculitis and meningeal involvement, respectively. Ten percent of patients with neuro-BD can have ocular disease, and 30% of patients with ocular BD may have neurologic involvement. Mortality has previously been reported to be as high as 10% in patients with neuro-BD, but it may be lower currently, especially with the use of IMT. Neuro-ophthalmic involvement can include cranial nerve palsies, papillitis, and papilledema resulting from thrombosis of the superior sagittal sinus or other venous sinuses.
Figure 9-60 Behçet disease. Mucous membrane ulcers (oral aphthae).
Ocular manifestations affect up to 70% of patients with BD. They carry serious implications because they are often recurrent and relapsing, resulting in permanent ocular damage. Severe vision loss can occur in up to 25% of patients with BD. Ocular disease most often presents as panuveitis that appears to be more severe and more common in men; over 80% of cases are bilateral. Ocular involvement as an initial presenting problem is relatively uncommon, and there may be a delay of years between presenting signs in other organs and the first occurrence of uveitis. The intraocular inflammation is characterized by a nongranulomatous, necrotizing, obliterative vasculitis that can affect any or all portions of the uveal tract.
In a minority of cases, anterior uveitis may be the only ocular manifestation of BD, classically described as the sudden onset of a hypopyon that disappears over weeks with or without treatment (Fig 9-61). The anterior uveitis may be accompanied by redness, pain, photophobia, and blurred vision, though occasionally there is a striking lack of inflammatory signs and symptoms, manifesting as a relatively quiet eye, despite the presence of hypopyon. On clinical examination, the hypopyon can shift with the patient’s head position or disperse with head shaking, and it may not be visible unless viewed by gonioscopy. With relapses, posterior synechiae, iris bombé, and angle-closure glaucoma may all develop. Other less-common anterior segment findings of BD include cataract, episcleritis, scleritis, conjunctival ulcers, and corneal immune ring opacities.
Posterior segment manifestations of ocular BD are often profoundly sight threatening. The essential finding is an occlusive retinal vasculitis affecting both arteries and veins, which may be associated with multifocal areas of chalky white retinitis (Fig 9-62). Posterior and panuveitis are the most common types of BD ocular inflammation, seen in 50%–80% of cases of BD patients with uveitis. Other posterior manifestations can include retinal artery and vein occlusions, vascular sheathing with variable amounts of vitritis, and associated uveitic macular edema. Retinal ischemia can lead to the development of retinal and iris neovascularization with neovascular glaucoma. After repeated episodes of retinal vasculitis and vascular occlusions, retinal vessels may become white and sclerotic. The ischemic nature of the vasculitis and accompanying retinitis may produce a funduscopic appearance that may be confused with acute retinal necrosis syndrome or other necrotizing herpetic entities (Fig 9-63 and Chapter 11). The optic nerve is affected in 25% of patients with BD. Optic papillitis can occur, but progressive optic atrophy may occur as a result of the vasculitis affecting the arterioles that supply blood to the optic nerve.
Figure 9-61 Behçet disease. Hypopyon.
(Courtesy of Debra Goldstein, MD.)
Many environmental factors have been suggested as potential causes of BD, but none has been proven. No infectious agent or microorganism has been reproducibly isolated from the lesions of patients with BD. The disorder is clinically and experimentally unlike other autoimmune diseases.
HLA associations have been found in 2 systemic forms of BD: HLA-B12 with mucocutaneous lesions and HLA-B51 with ocular lesions. These associations are not reproducible in all populations, and testing lacks the sensitivity and specificity to support its use for diagnosis. Histologically, BD lesions resemble those of delayed-type hypersensitivity reactions early on; late lesions resemble those of immune-complex–type reactions. Histopathology may show an inflammatory occlusive vasculitis (Fig 9-64).
Laboratory tests—for example, HLA typing, cutaneous pathergy testing, and blood tests for ESR and CRP—are of little value in confirming the diagnosis.
Figure 9-62 Behçet disease. Fundus photograph of retinitis and vasculitis.
(Courtesy of Didar Ucar, MD.)
Figure 9-63 Behçet disease. Fundus photograph of retinitis and vasculitis with retinal hemorrhage. The retinitis shown here appears similar to necrotizing herpetic retinitis with retinal whitening and occlusive retinal vasculitis.
(Courtesy of Ramana S. Moorthy, MD.)
Figure 9-64 Behçet disease. Histologic view of perivascular inflammation.
Fluorescein angiography demonstrates marked dilatation and occlusion of retinal capillaries with perivascular staining, evidence of retinal ischemia, leakage of fluorescein into the macula with the development of macular edema, and retinal neovascularization that may leak (Fig 9-65). Subtle vascular leakage may be present on FA even during periods of clinical quiescence. Adjusting therapy in response to this leakage may prevent the development of inflammatory damage.
Because of the transient nature of posterior segment inflammatory episodes in BD, serial color photography may be of benefit in diagnosis.
OCT imaging can show structural alterations caused by the vasculitis in the form of macular edema and disruption of the retinal architecture (see Fig 9-65). Systemic investigations may be helpful, as indicated by clinical presentation.
Kaçmaz RO, Kempen JH, Newcomb C, et al; Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study Group. Ocular inflammation in Behçet disease: incidence of ocular complications and of loss of visual acuity. Am J Ophthalmol. 2008;146(6):828–836.
Tugal-Tutkun I, Ozdal P, Oray M, Onal S. Review for diagnostics of the year: multimodal imaging in Behçet uveitis. Ocul Immunol Inflamm. 2017;25(1):7–19.
The differential diagnosis for BD includes HLA-B27–associated anterior uveitis, reactive arthritis syndrome, sarcoidosis, Susac syndrome, and systemic vasculitides including systemic lupus erythematosus, PAN, and GPA. Necrotizing herpetic retinitis can also mimic occlusive BD retinal vasculitis.
Treatment of ocular Behçet disease
The goal of treatment is not only to treat the explosive onset of acute disease with systemic corticosteroids but also to control chronic inflammation and prevent or decrease the number of relapses of ocular inflammation with IMT. Posterior segment ocular BD is an absolute indication for prompt initiation of IMT.
An American expert panel has recommended TNF inhibitor therapy with infliximab (good-quality evidence) or adalimumab (moderate-quality evidence) as first- or second-line corticosteroid-sparing therapy. A European League Against Rheumatism panel has recommended using azathioprine (with corticosteroids) as first-line IMT for ocular BD and cyclosporine or infliximab as second-line treatment. When other major organs are involved, close collaboration with specialists in other fields is necessary, as treatment modifications based on severity and type of BD may be required.
Figure 9-65 Behçet disease. A, Color fundus photograph indicating vasculitis and localized retinitis. B, Fluorescein angiogram showing disc staining and perivascular leakage. C, Optical coherence tomography scan revealing macular edema and inflammatory disruption of the retinal microarchitecture.
(Courtesy of David J. Browning, MD, PhD.)
Corticosteroids Systemic corticosteroids (eg, 1.0–1.5 mg/kg/day of prednisone with a gradual taper) are extremely useful in controlling acute inflammation. Periocular and intravitreal steroids may also be a useful adjunct in selected patients. Corticosteroid monotherapy should be avoided in sight-threatening BD uveitis, as severe rebound attacks may occur during tapering.
Nonbiologic IMT Only azathioprine and cyclosporine have undergone randomized clinical trials indicating effectiveness in reducing uveitis recurrence and preserving vision. Uncontrolled trials have shown benefit with mycophenolate mofetil and tacrolimus as steroid-sparing agents; alkylating agents, while effective, are used less frequently due to serious side effects. Chlorambucil administration can help achieve a durable remission in ocular BD. Cyclophosphamide is an alternative to chlorambucil and can be used orally or as pulsed intravenous therapy. Both of these alkylating agents have been shown to be more effective than cyclosporine in the management of posterior segment ocular BD but carry a greater risk of systemic complications and require complex hematologic monitoring. The availability of biologic drugs has led most experts to reserve the use of alkylating agents for patients with severe refractory disease.
Biologic agents The use of systemic TNF inhibitors has heralded a new era in the treatment of ocular BD. A substantial body of literature has emerged demonstrating the long-term efficacy and relative safety of systemic infliximab use in severe refractory ocular BD, often achieving rapid and complete control of disease, with reduction in retinal vascular leakage, as shown in FA; preservation of vision; and reduced recurrences. Additional data suggest greater benefit of infliximab therapy when initiated early on in the disease course. Adalimumab has been studied to a lesser extent, although preliminary data are promising, including a cohort studied prospectively as a part of the phase 3 clinical trials of adalimumab for noninfectious posterior uveitis. Interferon alfa is a naturally occurring cytokine involved in immune regulation, which, when administered in ocular BD as interferon alfa-2a, has been shown in a number of observational studies to be a safe and effective therapy. Combined with its lower cost and compatibility with concomitant latent tuberculosis infection, some experts prefer it as first-line therapy specific to ocular BD.
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The prognosis for vision is guarded in patients with BD. Nearly 25% of patients worldwide with chronic ocular BD have visual acuity less than 20/200, most commonly caused by macular edema, occlusive retinal vasculitis, optic atrophy, and glaucoma. Adult men tend to have poorer vision outcomes. Patients appear to have a better visual prognosis because of earlier and more aggressive use of IMT. The presence of posterior synechiae, persistent inflammation, elevated IOP, and hypotony are all statistically significant predictive factors for vision loss. The chronic relapsing nature of this disease, with frequent exacerbations after long periods of remission, makes it difficult to predict visual outcomes.
Excerpted from BCSC 2020-2021 series: Section 9 - Uveitis and Ocular Inflammation. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.