Behçet’s Disease: A Clinical Review

Introduction In 1937, Hulusi Behçet, a Turkish dermatologist, described a syndrome characterized by recurrent oral ulcers, genital ulcers, and hypopyon uveitis of unknown cause.1 Over time, Behçet’s disease has come to be recognized as a complex, multisystem, inflammatory disease characterized not only by the above symptoms but also by vascular, neurologic, articular, pulmonary, and gastrointestinal involvement. The diverse range of clinical findings seems to stem from an underlying vasculitis; however, the ultimate etiologic agent remains unknown. Epidemiology Although first reported in modern medical literature in 1937, Behçet’s syndrome has almost certainly been present for hundreds of years. In 1956, Feigenbaum asserted the original description of patients suffering from Behçet’s disease could actually be found in the Hippocratic third book of disease where it is written: “Many had their mouths affected with aphthous ulcerations. There were also many defluxions about the genital parts, and ulcerations, boils externally and internally, about the groins. Watery ophthalmies of a chronic character, with pains; fungous excretions of the eyelids, externally and internally, called fici, which destroyed the sight of many persons. There were also attacks of carbuncle through the summer and large ecthymata and herpetes (rash) in many instances.”2 Although the triple symptom complex of oral aphthous ulcers, uveitis, and urogenital ulcers would be described multiple times in the late 1800s and early 1900s, these symptoms were typically attributed to other disease processes, such as tuberculosis or syphilis.3 It was not until Hulusi Behçet published a series of three patients displaying a combination of recurrent urogenital ulcers, iritis, and skin lesions in 1936 that Behçet’s disease began to be recognized as a distinct entity by the modern medical literature.3 Concurrent with Behçet’s publications were similar cases presented by Adamantiades; however, it is Behçet’s name that is most frequently attached to the syndrome today.4 Occurring most frequently in the Middle East, Behçet’s is endemic among populations clustered along the historic silk road, which extended from eastern Asia to the Mediterranean basin.5 In the Middle East, Europe, and the United States, young men are most often affected; however, in Japan and Korea there appears to be a slight female preponderance.6,7 Current prevalence is estimated to range from a low of 0.3 per 100,000 in Northern Europe to a peak of 16 to 100 per 100,000 in Iran.8 Clinical Features The most common cutaneous finding in Behçet’s disease is oral ulceration. In order to make a diagnosis of Behçet’s, a patient must experience oral ulceration occurring at least three times in one year. Most patients develop minor aphthous ulcers that resolve in 10 to 14 days. These lesions tend to be painful, shallow to deep, and have erythematous borders with yellow, fibrinous bases. Ten percent of patients, however, develop major aphthous ulcerations, which are lesions that are larger, more persistent, and may heal with scarring.9 The most common sites of involvement are the buccal mucosa, gums, tongue, lips, and pharynx.10 Herpetiform lesions may also occur. Genital lesions are also quite common. In men, such lesions tend to occur on the scrotum and penis, are typically painful, and may heal with scarring.8,10 Women most frequently develop lesions on the vulva but may also have involvement of the vagina and/or cervix.9 In women, such lesions are often asymptomatic.11 In appearance, genital lesions typically resemble oral aphthae with irregular borders. Other cutaneous findings include papulopustular eruptions, pyoderma-gangrenosum-like lesions, erythema-nodosum-like lesions, vasculitis, and pathergy. Pathergy is one of the diagnostic criterions for Behçet’s and consists of development of a small pustule within 24 to 48 hours after the skin has been pricked by a sterile needle. Although helpful if positive, its sensitivity is debatable with some studies finding it as low as 10 percent.12 Papulopustular eruptions seem to be the most common skin finding; however, in young patients or in patients receiving corticosteroids it can be difficult to identify which eruptions are truly disease related.9 Pyoderma gangrenosum-like lesions were first described by Munro, et al., in 1988; this was followed in 1990 by a series of four patients presented by Rustin, et al. (Figure 1).13,14 Interestingly, the pyoderma gangrenosum-like lesions seen in Behçet’s seem to share many similarities with the pathergy response described above. Like pathergy, the initial finding in pyoderma gangrenosum-like lesions may be a pustule, and both lesions can be precipitated by trauma. On biopsy, most of these findings have in common a leukocytoclastic/lymphocytic vasculitis or a neutrophilic reaction pattern in the dermis and subcutaneous tissue with a perivascular dermal infiltrate.15 One of the most serious clinical aspects of Behçet’s is ocular disease. Patients may complain of blurred vision, eye pain, loss of vision, and/or floaters.9 Occurring in 70 to 85 percent of patients, pathology ranges from posterior uveitis, conjunctivitis, and corneal ulceration, to papilledema and arteritis.16 Of these, posterior uveitis, characterized by severe vasculitis, is the most common and can lead to blindness. Later complications include glaucoma, cataracts, and neovascularization of the iris and retina.17 Neurologic symptoms range from benign headaches to much more serious findings, such as increased intracranial pressure, meningitis/ meningoencephalitis, cranial nerve palsies, seizures, personality changes, and cerebral venous thrombosis, among others.18 Patients with increased intracranial pressure seem to do much better than those with parenchymal or meningeal involvement. Of the latter groups, those with brain stem disease seem to have a better prognosis than those with strokes, meningoencephalitis, or meningomyelitis.19 Some researchers believe that silent neurologic disease may occur in Behçet’s; for this reason, they recommend that all patients have periodic neurologic exams, especially if ocular abnormalities have been detected.20 Vascular abnormalities are common and involve blood vessels of all sizes in both the arterial and venous systems.21 Manifestations of Behçet’s vasculopathy include cutaneous vasculitis, superficial thrombophlebitis, intracardiac thrombus or vasculitis of the coronary arteries, aortic aneurysm, pulmonary artery thrombosis, glomerulonephritis, and portal hypertension, among others.21–23 Arthritis, most often a nonerosive mono- or oligoarthritis of the knees, ankles, wrists, and elbow is seen in approximately 50 percent of patients.24 Patients with sacroiliitis should be examined carefully, for they are often best classified as having Reiter’s disease. Gastrointestinal involvement can manifest as ulcerations occurring at any point along the gastrointestinal tract. The most common region of involvement is at the junction of the small and large bowel. Such ulcerations lead to abdominal pain, diarrhea, melena, and perforation. Differentiation from inflammatory bowel disease is often difficult.25 A 1999 review by Balabanova, et al., examined the frequency of cutaneous manifestations of Behçet’s in the United States. They found that 64 percent of such patients exhibited cutaneous findings excluding oral, genital, and perirectal lesions. The most common form of cutaneous lesion was papulopustular; this was followed (in order of decreasing frequency) by erythema nodosum, pseudofolliculitis, aciniform nodules, and pyoderma gangrenosum type/ulcerative lesions. Almost all of these patients also exhibited oral ulcers. Other clinical findings (again in order of decreasing frequency) included genital ulcers, uveitis, arthritis, vasculitis/retinal vasculitis, and meningoencephalitis. The pathergy test was positive in 33 percent.26 Diagnosis In 1990, due to the myriad of clinical presentations, as well as the lack of diagnostic pathology or laboratory findings, the International Study Group for Behçet’s Disease proposed a series of diagnostic criteria (Table 1).27 In order to make the diagnosis of Behçet’s disease, a patient must have recurrent oral ulcerations and at least two of the following: recurrent genital ulceration, eye lesions, skin lesions, and/or a positive pathergy test. The pathergy test is performed by pricking the skin with a sterile needle. A positive test is characterized by the formation of a pustule greater than 2mm at the site of injury within 24 hours.6 It should be recognized that a positive pathergy test is not specific for Behçet’s. Although the International Study Group criteria are now the most frequently used, numerous other diagnostic algorithms exist, including those of O’Duffy and Goldstein,28 the Behçet’s Disease Research Committee of Japan,29 and Mason and Barnes.30 The differential diagnosis for Behçet’s includes herpes simplex infection, chronic oral aphthous ulcers, systemic lupus erythematosus, inflammatory bowel disease, Reiter’s syndrome, Sweet’s syndrome, HIV, lichen planus, bullous pemphigoid, pemphigus vulgaris, and erythema multiforme. Ghate and Jorizzo propose that the initial workup for a patient presenting with complex aphthous stomatitis should include complete history and detailed review of systems looking for rheumatologic, neurologic, gastrointestinal, or ocular complaints; full skin exam with biopsy of suspicious lesions; HSV culture or polymerase chain reaction (PCR); complete blood count and determination of serum B12, folate, and iron levels to rule out hematologic abnormalities/nutritional deficiencies; urine-analysis to check for renal dysfunction; determination of glucose-6-phosphate dehydrogenase level (for patients who may be placed on dapsone); evaluation of HLA-B27 status to help rule out Reiter’s; and subspecialty referral to rheumatology, neurology, gastroenterology, and ophthalmology when indicated.11 Etiology The ultimate cause of Behçet’s disease remains unknown. Current evidence suggests that interplay of genetic and environmental factors may be responsible. Although the exact genetics are yet to be elucidated, familial Behçet’s has been reported.31 This occurs most frequently in the Middle East where rates run as high as 10 to 15 percent. In the remainder of the world, familial Behçet’s is seen in two to five percent of cases.32 Many studies have demonstrated an association between HLA-B51 and Behçet’s disease with relative risk ranging from 1.38 to 20.70.33–38 Like familial Behçet’s, HLA-B51 positivity seems to be most prevalent in the Middle East and less significant among White patients living in the Western world.6 The majority of evidence seems to suggest that HLA-B51 positivity is also associated with a worse prognosis.36,37,39 However, this assertion is still under debate, as studies by Salvarani and Gul failed to link the presence of HLA-B51 to subgroups experiencing poorer outcomes.38,40 The complete role of HLA-B51 is not yet known; however, HLA-B51 does act to present endogenous antigens to CD8+ cytotoxic-suppressor T cells. HLA-B51+ transgenic mice seem to exhibit enhanced neutrophil activation and superoxide release.41 Abnormal neutrophil function also seems to play a role in the underlying defects of Behçet’s disease. Not only is there the possible link between HLA status and enhanced neutrophil function, but many of the characteristic cutaneous findings of Behçet’s, such as pathergy reactions, pustular folliculitis, and hypopyon, have substantial neutrophilic infiltrates. Unfortunately, much of the research into this aspect of Behçet’s is conflicting with studies reporting everything from increased, to normal, to decreased neutrophil superoxide production and migration.42–44 Alterations in lymphocytes also appear to be involved in Behçet’s disease. Levels of interleukin 12, which encourages Th1-type differentiation of naive T cells, are elevated in patients with Behçet’s.45 This leads to increased peripheral CD4+ and CD8+ T cells producing interleukin 2 and interferon-a.46 Levels of TNF-a, IL-a, and IL-8 have also been reported as elevated.6 One study, however, did identify increased levels of IL-4, IL-10, and IL-13 levels (Th2-type cytokines) in vitro.47 Other factors proposed to play a role in Behçet’s include infectious agents, such as herpes simplex virus type I, parvovirus B19, hepatitis C, and streptococcus species.8,48–51 The data, however, is far from conclusive, and the true importance, if any, of such infections remains to be seen. Lehner has proposed that perhaps portions of infectious antigens, such as heat shock proteins, may be fairly homologous to their human counterparts and subsequently induce autoimmune pathology.52 Multiple studies have illustrated the presence of lymphocytes targeting self peptides derived from heat shock protein 60. Human heat shock protein 60 is very similar to bacterial heat shock protein 65.53,54 Pathology The pathology of Behçet’s disease varies according to the type of lesion sampled. Aphthous ulcers are characterized by the presence of lymphocytes, macrophages, and neutrophils perivascularly and in the ulcer base. Plasma cells are rare in early lesions but frequently seen in later stages.55 Erythema nodosum-like lesions display a perivascular pattern of inflammation in the deep dermis and fat septae. Lymphocytic invasion of vessel walls may take place; however, fibrinoid necrosis is not seen. Lesions produced on pathergy display a dense perivascular neutrophilic infiltrate extending into vessel walls. Once again, fibrinoid change is absent. Treatment The treatment of Behçet’s disease must be tailored to each patient’s individual clinical presentation. The mainstays of treatment for the most common symptoms, which are aphthous ulcers and mucocutaneous disease, have traditionally consisted of high potency class I or II topical steroids (ointments or gels) applied 5 to 10 times per day or intralesional triamcinolone 5mg/mL.11 Adjuvant treatments include topical anesthetics, such a viscous lidocaine two to five percent, chlorhexidine oral rinses, tetracycline mouthwash (250mg tetracycline in 5mL glycerine), and topical sucralfate.16,56 Although colchicine has often been used in the past, a recent double-blind study suggests that it does not have a significant role in the prevention of oral lesions, although it may decrease the occurrence of genital lesions, arthritis, and erythema nodosum, especially in women.57–58 Dapsone in doses ranging from 50 to 100mg per day has been theorized to be beneficial in Behçet’s disease due to possible antineutrophilic effects. Firm clinical evidence, however, is lacking. While an open trial of seven male patients described improvement in mucocutaneous disease after a few weeks of dapsone 100mg per day, another report of 14 male and two female patients showed response in only three patients.60,61 Systemic steroids are often used for severe mucocutaneous disease; however, well-designed, controlled trials illustrating their effectiveness have yet to be performed. Used in combination with other immunosuppressant drugs, such as azathioprine or cyclophosphamide, systemic steroids have been reported to be effective, especially for ophthalmologic and neurologic expression of disease.62,63 Methotrexate 7.5 to 20mg per week has been found to be efficacious for the neuropsychiatric as well as mucocutaneous manifestations of Behçet’s; however, patients must be monitored for liver toxicity.64,65 Azathioprine has been evaluated primarily in terms of oculocutaneous disease. Not only has it been found to maintain visual acuity and prevent emergence of new eye disease in the short term at a dose of 2.5mg per day, these results seemed to persist over a period at least as long as eight years. Patients seem to benefit most when the medication is started early in the course of disease.66,67 Numerous studies indicate that cyclosporine may be an effective treatment for mucocutaneous, ocular, and arthritic symptoms of Behçet’s.68,69 A four-month long, controlled study of 96 patients comparing cyclosporine 10mg/kg/d with colchicine 1mg per day found significant improvement in ulcers and eye lesions in patients treated with cyclosporine.58 One study, however, suggests that cyclosporine may actually accelerate the development of central nervous system symptoms.70 This, combined with cyclosporine’s well-known potential for renal toxicity, necessitates caution in its use. Cyclophosphamide may be effective for ophthalmologic symptoms as well as vasculitis, especially when combined with systemic corticosteroids; however, good clinical trials are lacking.71,72 For refractory mucocutaneous disease, much success has been reported with thalidomide.73,74 Although associated with serious side effects, such as teratogenicity and neuropathy, thalidomide has been approved for the treatment of Behçet’s. One double-blind, placebo-controlled trial found that thalidomide 100mg per day was effective at suppressing oral ulcers, genital ulcers, and follicular lesions. Recurrence did take place, however, soon after the drug was discontinued.75 Due to the obvious severity of thalidomide’s side effects, all patients need to be closely monitored. The incidence of polyneuropathy seems to range from 6 to 50 percent and can be irreversible if not detected early.75 Consequently, all patients should undergo nerve conduction studies every six months. Due to thalidomide’s infamous association with birth defects, use in female patients should be limited to those who have undergone hysterectomy or tubal ligation.76 Another significant, but much less dangerous, side effect is severe sedation, which may be intolerable in some cases. In a randomized, placebo-controlled, double-blind study of 44 patients, interferon alfa-2a, 6 x 106 IU, given subcutaneously three times per week was also shown to be useful against the development of oral and genital ulcerations, as well as papulopustular lesions, erythema nodosum-like lesions, thrombophlebitis, articular symptoms, and ocular disease.77 Like thalidomide, symptoms seem to recur after discontinuing of the medication. Major side effects include flu-like symptoms, nausea, vomiting, anorexia, diarrhea, weight loss, hematologic changes, transient increase of hepatic transaminase levels and alopecia.78 Multiple, prior, uncontrolled studies had similar results.79–82 Topical interferon gel does not seem to be effective.83 The typical course of Behçet’s disease is one of periodic remissions and flares. Over time, the disease typically becomes less severe; however, for the unlucky few, serious consequences may develop. Current therapies are often somewhat effective, yet frequently complicated by undesirable side effects. Until a deeper understanding of the pathogenesis of Behçet’s is developed, a final cure will likely remain elusive.