Chapter 176 – Behçet’s Disease
ANNABELLE A. OKADA
NARSING A. RAO
• A multisystem vasculitis of unknown cause primarily involving the eyes, the mucosal surfaces, and the skin.
• Recurrent anterior and posterior uveitis.
• Recurrent oral ulcers (aphthae).
• Genital ulcers.
• Skin lesions such as erythema nodosum.
• Arthritis of large joints.
• Intestinal ulcers.
• Vascular lesions such as thrombophlebitis, arterial occlusions, and aneurysms.
• Central nervous system or cranial nerve involvement.
Behçet’s disease is named after Turkish dermatologist Hulusi Behçet, who in 1937 described recurrent oral ulcers, genital ulcers, and uveitis in three patients. Similar cases had been reported earlier by Shigeta in 1924, Adamantiadis in 1931, and Whitwell in 1934. Inflammatory manifestations may also occur in other organ systems including the skin, the joints, the gastrointestinal tract, and the central nervous system.
EPIDEMIOLOGY AND PATHOGENESIS
Although Behçet’s disease occurs worldwide, it is a particularly common cause of uveitis in countries that line the ancient Silk Road, including Italy, Turkey, Greece, Israel, Saudi Arabia, Iran, China, Korea, and Japan. Prevalence varies from a high of 80–370/100,000 in Turkey to lower rates of 2–30/100,000 in East Asia. For comparison, the prevalence of Behçet’s disease is estimated to be only 0.12–0.33/100,000 in the United States and 0.64/100,000 in the United Kingdom. Isolated pockets of higher prevalence in countries of otherwise low prevalence also exist. For example, while the prevalence among German natives is reported to be 0.42–0.55/100,000, the Turkish community in Berlin is estimated to have a prevalence of 21/100,000.  Behçet’s disease appears to be rare among Japanese immigrants in Hawaii and California. Furthermore, recent figures indicate that the incidence and severity of Behçet’s disease are decreasing in Japan.  Taken together, these observations suggest that both genetic and environmental factors play a role in the pathogenesis of Behçet’s disease. The age of onset of uveitis is usually in the third to fourth decades of life, with men being more commonly affected than women. The uveitis of Behçet’s disease is believed to be most severe in young men between 15 and 25 years of age.
The pathogenesis of Behçet’s disease remains obscure. The disease has long been associated with the HLA-B51 allele; in Japan, 55% of patients with Behçet’s disease are positive for HLA-B51, as opposed to 10–15% of the general population. However, this HLA association appears to be true only in countries of high prevalence. For example, the relative risk of disease among HLA-B51–positive individuals is 6.7 in Japan but only 1.3 in the United States. A recent study analyzing polymorphic microsatellite markers near the HLA-B gene in Japanese, Greek, and Italian patients with Behçet’s disease strongly suggests that it is the HLA-B51 gene itself that is related to disease pathogenesis and not other genes located in the vicinity of HLA-B. The manner in which HLA-B51 relates to disease susceptibility is unknown.
It has been suggested that microbial infections may serve as a trigger in the onset of Behçet’s disease. For example, a higher proportion of patients who have Behçet’s disease have herpes simplex virus DNA and serum antibodies against the virus when compared with controls. Streptococcus sanguis and antibodies against the bacteria are also found more commonly in Behçet’s patients. Observations such as these have led to the hypothesis that exposure to various microbial antigens may trigger cross-reactive autoimmune responses in genetically susceptible individuals and lead to the onset of Behçet’s disease.
Ocular involvement is seen in about 70% of patients who have Behçet’s disease. In most cases, the onset of uveitis follows the onset of recurrent oral ulcers by 3–4 years, although ocular disease is the initial manifestation in about 20% of cases. Initial ocular involvement may be unilateral but progresses to bilateral disease in at least two thirds of cases.
Patients with Behçet’s disease often present to the ophthalmologist with decreased vision due to anterior chamber inflammation with or without hypopyon ( Fig. 176-1 ). Pain, redness, and photophobia may be present. The hypopyon typically shifts with changes in head position. A very small hypopyon may be discovered only upon gonioscopic examination. Usually little iris synechia formation occurs initially, although this can subsequently develop after repeated bouts of anterior segment inflammation. The intraocular pressure is often normal or low. Mild vitreous cells or mild to moderate vitreous opacification occurs commonly. Fundus examination may reveal scattered yellow-white retinal exudates, retinal hemorrhages, vascular engorgement, or disc hyperemia. However, the fundus may also appear entirely normal during an episode of anterior segment inflammation. Bouts of posterior segment inflammation can also occur in the absence of any anterior chamber cells.
Typically, the clinical course is one of chronic or recurrent inflammation. Long-term complications in the anterior segment include iris neovascularization, glaucoma, and cataract. In the posterior segment, retinal vascular sheathing or occlusion, retinal or disc neovascularization ( Fig. 176-2 ), vitreous hemorrhage or progressive vitreous opacification, optic atrophy ( Fig. 176-3 ), and phthisis bulbi may ensue.
Figure 176-1 Conjunctival injection, hypopyon, and posterior synechia. The patient, who has Behçet’s syndrome, is having an acute inflammatory attack.
Figure 176-2 Acute retinal vasculitis with retinal hemorrhages and cotton-wool spots. Neovascularization at the optic disc is also present.
The diagnosis of Behçet’s disease is based on the constellation of systemic and ocular clinical findings rather than on specific laboratory test results. However, some tests are useful adjuncts in the evaluation of patients. Fundus fluorescein angiography shows marked dilatation or occlusion of retinal vessels. Affected retinal and optic nerve vessels leak fluorescein profusely during early transit, and their walls stain in late transit. Fluorescein leakage from the retinal vasculature may also be seen before any ophthalmoscopic signs of vasculitis. Even during presumably quiescent periods, in the absence of obvious inflammation in the fundus, dilatation of retinal capillaries with dye leakage is commonly observed ( Fig. 176-4 ). Fluorescein angiography may confirm cystoid macular edema or macular ischemia.
During episodes of acute inflammation, patients may have a high erythrocyte sedimentation rate, elevated C-reactive protein, or increased peripheral leukocytes. HLA typing may be helpful, depending on the patient population. In Japan, where Behçet’s disease is prevalent, a positive HLA-B51 result supports the diagnosis. However, an association with HLA-B51 has not been shown for some countries of low prevalence, such as the United States.
Infrequently used today, the pathergy test (also referred to as the “skin prick” test or “Behçetine” test) looks for a nonspecific inflammatory reaction to a needle prick or an intradermal injection of saline. This test is positive in 23.8–78.9% of patients, depending on the country,  and is an indication of cutaneous hypersensitivity, which is characteristic of Behçet’s disease. However, a history of cutaneous hypersensitivity may be elicited by careful
Figure 176-3 The fundus of a patient who has end-stage ocular Behçet’s syndrome. Note the severe retinal atrophy, vascular attenuation with sheathing, and optic atrophy.
Figure 176-4 Fluorescein angiogram of a patient who has Behçet’s syndrome. Typical findings include widespread (“fern-like”) leakage from the capillary tree and secondary vessels.
questioning, since patients may recall pustular inflammation after accidental skin injury such as that incurred while shaving.
There are two widely used diagnostic criteria for Behçet’s disease. The first was initially proposed in 1972 by the Behçet’s Disease Research Committee of the Japanese Ministry of Health and Welfare and relies on four major and five minor findings (updated version shown in Box 176-1 ). Behçet’s disease of the “complete type” is diagnosed when all four major findings (with or without minor findings) occur during the course of the disease. Behçet’s disease of the “incomplete type” is diagnosed when only three major findings (with or without minor findings) occur, when two major and at least two minor findings occur, or when there is characteristic uveitis with either one other major finding or at least two minor findings. The second diagnostic criterion was proposed in 1990 by the International Study Group for Behçet’s Disease ( Table 176-1 ). Using this, the diagnosis of Behçet’s disease requires the presence of recurrent oral ulceration plus at least two other findings among recurrent genital ulceration, uveitis, skin lesions, and positive pathergy test result. The major difference between the two criteria is that the Behçet’s Disease Research Committee gives more significance to uveitis, while the International Study Group for Behçet’s Disease places greater weight on oral ulcers.
Because Behçet’s disease can present as anterior uveitis, posterior uveitis, or panuveitis, the differential diagnosis must include a variety of diseases. The most common diseases mistaken for Behçet’s
Behçet’s Disease Research Committee Diagnostic Criteria
Recurrent ulcers of the oral mucosa
Follicular rash, acneiform rash (cutaneous hypersensitivity)
Presence of posterior iris synechia, pigment clumps on the anterior surface of the lens, chorioretinal atrophy, optic atrophy, secondary cataract, secondary glaucoma, or phthisis bulbi
Arthritis not associated with deformation or rigidity
Intestinal lesions such as ileocecal ulcer
Central nervous system findings
Complete type: all 4 major findings occur
3 major findings, or 2 major and 2 minor findings
Characteristic ocular disease, plus 1 other major finding or 2 minor findings
Diagnosis suspected: some major findings occur, but the criteria for incomplete-type disease are not met, and characteristic minor findings recur or are progressive
Special disease types based on predominance of findings
Skin-prick test positive
Evidence of inflammatory reaction present: elevated erythrocyte sedimentation rate, elevated serum C-reactive protein, increased peripheral white blood cells
disease with hypopyon formation are HLA-B27–associated acute anterior uveitis and infectious endophthalmitis. Diseases often mistaken for Behçet’s disease with posterior segment inflammation include sarcoidosis, tuberculosis, and syphilis. Behçet’s disease with panuveitis may look like acute retinal necrosis in the early stages. Numerous other noninfectious and infectious disorders can mimic the ocular findings of Behçet’s disease. Therefore, careful questioning of the patient for systemic signs or symptoms is crucial to making a diagnosis.
Recurrent ulcers of the oral mucosa are the most common finding and usually the initial symptom in Behçet’s disease, although one must be careful because they also occur commonly in the general population. A 1991 study of 3316 Japanese patients with Behçet’s disease found the frequency of recurrent oral ulcers to be 98%. These lesions may appear anywhere in the mouth, including the lips, buccal mucosa, gingiva, tongue, hard palate, uvula, and oral pharynx. They tend to be painful but heal within 10 days, usually without scarring unless the lesion is particularly large. A typical lesion is round, with surrounding erythema and a pseudomembranous covering.
Skin lesions are the second most common systemic manifestation of Behçet’s disease, occurring in 87% of patients in the
TABLE 176-1 — INTERNATIONAL STUDY GROUP CRITERIA FOR THE DIAGNOSIS OF BEHÇET’s DISEASE*
Recurrent oral ulceration
Minor aphthous, major aphthous, or herpetiform ulcers observed by physician or patient, which have recurred at least 3 times over a 12-mo period
Plus at least 2 of the following criteria:
Recurrent genital ulceration
Aphthous ulceration or scarring observed by physician or patient
Anterior uveitis, posterior uveitis, or cells in vitreous on slit-lamp examination; or retinal vasculitis detected by an ophthalmologist
Erythema nodosum observed by physician or patient, pseudofolliculitis, or papulopustular lesions; or acneiform nodules observed by physician in postadolescent patients not on corticosteroid treatment
Positive pathergy test
Interpreted by physician at 24–48?hr
* Findings applicable only in absence of other clinical explanations.
1991 Japanese study. Together with uveitis and genital ulcers, skin lesions tend to occur after the onset of recurrent oral ulcers during the middle course of the disease. Skin manifestations include erythema nodosum, subcutaneous throm-bophlebitis, acneiform lesions, and follicular rash. Of these, erythema nodosum appears to occur most frequently and is characterized by a slightly raised red nodule with subcutaneous induration and tenderness. These lesions are usually found on the anterior surfaces of the legs, but they may also occur on the face, arms, and buttocks. They tend to involute in 10–14 days without scarring, although some hyperpigmentation may remain. A history of pustular inflammation after accidental skin injury is usually included as skin involvement in Behçet’s disease.
The 1991 Japanese study found genital ulcers in 73% of Behçet’s patients, which is similar to the frequency of ocular involvement. As mentioned earlier, genital lesions tend to occur during the middle course of disease, at about the same time as the ocular and skin manifestations. The genital ulcers may have deeper tissue involvement in comparison to oral ulcers, are generally painful, and often leave scars after healing. The lesions usually occur on the scrotum or vulva but may also be found on the penis and the perianal and vaginal mucosa.
Other manifestations are myriad. The most common are arthritis, intestinal ulcers, central nervous system disease, and epididymitis, in descending order of frequency. Although rare, myocarditis, various cardiac vascular lesions, pulmonary hypertension, and renal involvement have also been reported in association with Behçet’s disease. In general, all these manifestations tend to occur late in the course of the disease. The most debilitating manifestation by far is central nervous system involvement, which can affect both motor and sensory systems and may occur in up to 10% of patients. Signs and symptoms include headache, meningismus, nystagmus, tremor, ataxia, speech disturbances, memory impairment, behavioral changes, and dementia.
Only a few eyes with Behçet’s disease have been examined histologically. A characteristic feature is a necrotizing, leukocytoclastic, obliterative vasculitis affecting arteries and veins of all sizes. The vasculitic changes seen in the eyes are similar to those observed in other organs.
During acute inflammation, the iris, ciliary body, and choroid show diffuse infiltration with neutrophils. In the retina, severe vasculitis occurs with marked infiltration of leukocytes in and around blood vessels ( Fig. 176-5 ). During the chronic phase, a lymphocytic and plasma cell infiltration occurs. Retinal vessels develop thickened basement membranes with swollen endothelial cells, which can lead to thrombus formation and vascular obliteration. In late stages, there is neovascularization of the iris and retina, formation of cyclitic membranes, and sometimes hypotony and phthisis bulbi. The phthisical globe may reveal a disrupted lens capsule with histological features of phacoanaphylaxis and intralenticular or vitreous hemorrhage.
The short-term goal of therapy for ocular involvement in Behçet’s disease is to suppress active inflammation. The long-term goals are to reduce the frequency and severity of recurrences, minimize involvement of the retina and the optic nerve, and avoid complications such as cataract, synechia formation, and glaucoma. Treatment must be started early to be effective. Drug selection should be determined based on the clinical history, location of intraocular inflammation, and severity of inflammation. As this disease often involves other organ systems, multidisciplinary approach is necessary. The drug armamentarium for ocular disease includes colchicine, corticosteroids, immunophylin ligands, and cytotoxic agents.
Colchicine is a plant alkaloid that acts by binding tubulin and inhibiting cell division. It is widely used in Japan as the systemic drug of first choice, based on the results of a retrospective study showing that patients treated with colchicine fared better than historical controls. However, the drug is viewed by many outside Japan as being ineffective, and a double-blind study from Turkey showed no benefit. Commonly used doses range between 0.5 and 1.5?mg/day orally. The major side effects are decreased fertility and azoospermia.
Figure 176-5 Behçet’s syndrome. Heavy inflammatory cell infiltration around a retinal vessel. (Hematoxylin and eosin.)
Corticosteroids are effective in the treatment of acute inflammation in Behçet’s disease by means of their potent suppressive effects on the immune system, including neutrophil and macrophage migration and lymphocyte activity. However, they may have limited efficacy in decreasing the frequency of recurrences and preserving visual function. Topical corticosteroids are used for anterior segment inflammation, while periocular injections (e.g., 20–40?mg triamcinolone) or systemic corticosteroids (e.g., starting dose of 30–80?mg/day prednisolone) are used for posterior segment inflammation. With systemic administration, the corticosteroid dose needs to be tapered slowly, often over years and in combination with a second “steroid-sparing” agent such as cyclosporine, to avoid a rebound effect. The major side effects of local corticosteroid therapy include elevated intraocular pressure, cataract progression, infection, and globe perforation in the case of injections. The major side effects of systemic corticosteroid administration are hypertension, diabetes mellitus, gastrointestinal ulceration, electrolyte abnormalities, osteoporosis, and reduced resistance to infections. Due to the frequency and severity of side effects of systemic corticosteroid treatment, it is unlikely that patients can remain on this therapy for prolonged periods. Other immunosuppressive agents, whether or not given in combination with low-dose corticoste-roids, should be considered for long-term treatment in severe cases of uveitis.
Cyclosporine and tacrolimus (FK506) are immunophilin ligands that bind to cytoplasmic receptors termed immunophilins in T cells, thereby selectively inhibiting T-cell activity. A Japanese study showed that cyclosporine at a dose of 5?mg/kg/day was effective in decreasing the frequency of ocular inflammatory attacks in 70% of Behçet’s patients who had previously refractory disease. Starting doses of 3–5?mg/kg/day for cyclosporine and 0.05–0.2?mg/kg/day for tacrolimus are commonly used, depending on the severity of disease and whether other agents are being used in combination. Major side effects of the immunophilin ligands are renal dysfunction, neurological abnormalities, and gastrointestinal upset, and hirsutism for cyclosporine. Because of variable absorption from the gut, periodic measurement of serum drug trough levels should be performed to determine the appropriate dose and help avoid side effects.
Both antimetabolites (e.g., azathioprine, methotrexate) and alkylating agents (e.g., cyclophosphamide, chlorambucil) have been used in refractory cases of ocular Behçet’s disease, particularly before the widespread use of cyclosporine. One masked trial showed that azathioprine, with or without concomitant corticosteroids, was better than placebo in controlling disease. Triple-drug therapy using corticosteroids, cyclosporine, and aza-thioprine has also been reported to successfully induce remission in some patients. The side effects of cytotoxic drugs may be serious and include bone marrow suppression, hepatotoxicity, secondary malignancies, and decreased fertility.
Laser and Surgical Treatment
Historically, laser surgery for an eye with Behçet’s disease was considered extremely risky, due to the recurrence of uncontrollable inflammation postoperatively. However, with advances in both medical therapies and surgical techniques, recent reports appear to be encouraging. Scatter laser photocoagulation has been used successfully to treat areas of retinal nonperfusion after the development of retinal or optic nerve neovascularization. Furthermore, cataract and even vitreous surgery has been performed
safely in selected patients with good control of inflammation, although postoperative inflammatory attacks need to be aggressively treated.
COURSE AND OUTCOME
The natural history of uveitis in Behçet’s disease is one of attacks and remissions. A poor visual outcome can be avoided if the frequency of attacks is limited and irreversible complications are prevented. Decades ago, the visual outcome of Behçet’s disease was uniformly dismal, with more than half of patients having visual acuity deterioration to worse than 20/200 in 5 years. However, advances in therapeutics since then have improved the prospects for maintaining useful vision.
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