Ophthalmologic Manifestations of Behcet Disease

Behçet disease is a systemic disorder characterized by recurrent aphthous ulcers and intraocular inflammation. The clinical triad of uveitis with recurrent oral and genital ulcers bears the name of Hulusi Behçet, a Turkish dermatologist who described 3 patients who had this triad.

The Behçet's Disease Research Committee of the Ministry of Health and Welfare of Japan first proposed formal diagnostic criteria in 1972. This set of criteria, which has been used throughout the world, classifies disease findings into 4 major criteria and 5 minor criteria. When all 4 major criteria are met, the disease is said to be of the complete type, whereas the incomplete type consists of various combinations of major and minor criteria, with added weight given to ocular disease.

In 1990, The International Study Group (ISG) for Behçet's Disease proposed a separate set of diagnostic criteria for Behçet disease. Based on these criteria, a diagnosis of Behçet disease requires recurrent oral ulceration and at least 2 additional criteria, including recurrent genital ulcers, ocular lesions, skin lesions, and a positive pathergy test. The ISG criteria for Behçet disease have excellent specificity, but lack sensitivity. The International Criteria for Behçet’s Disease (ICBD) was created in 2006, as a replacement to the ISG criteria. For ICBD, vascular lesions were added, while oral aphthosis is no longer mandatory. Accruing 3 or more points is an indication of the diagnosis of Behçet disease (genital aphthosis, 2 points; eye lesions, 2 points; and the remaining each are 1 point).

A recent study compared the performance of the ISG and ICBD criteria. Their sensitivity, specificity, and accuracy (percent agreement), were tested in 3 independent cohorts of patients from the Far East (China), Middle East (Iran), and Europe (Germany). The sensitivity for ISG criteria was, respectively, 65.4%, 78.1%, and 83.7%, and, for ICBD, was 87%, 98.2%, and 96.5%. The specificity for ISG was, respectively, 99.2%, 98.8%, and 89.5%, and, for ICBD was 94.1%, 95.6%, and 73.7%. The accuracy for ISG was 74.2%, 85.5%, and 85.5%, and, for ICBD was 88.9%, 97.3%, and 89.5%. The conclusion is that ICBD has better sensitivity and accuracy than ISG.[1]

Other Medscape Reference articles on Behçet disease include Behcet disease (Dermatology) and Behcet disease (Rheumatology).

The cause and the pathogenesis of Behçet disease remain unknown. More than one mechanism seems to be operative in the pathogenesis of Behçet syndrome, including genetic and environmental factors, causing different manifestations of the syndrome. Several clues suggest the role of environmental factors and, especially, microorganisms, in the pathogenesis. These include clinical findings such as a decrease in the frequency of a positive pathergy reaction with surgical cleaning of the skin before the procedure, the acne-arthritis association carrying similar features to acne-associated reactive arthritis, a higher rate of tonsillectomy, cold sores, late birth order, higher number of siblings, history of travel to countries with a high incidence of Behçet syndrome, and earlier age at first sexual intercourse. Moreover, basic research on both viruses and bacteria suggests that microorganisms may be playing a role, possibly through heat-shock proteins and T-cell hypersensitivity.[2]

The tumor necrosis factor-alpha (TNF-alpha) pathway is likely involved in the pathophysiology of Behçet disease. The frequency of the R92Q TNFRSF1A mutation in patients with Behçet disease is significantly higher than that in control subjects (P = .006 by the Fisher exact test) and is associated with an increased risk of extracranial venous thrombosis.

Frequency

United States

The prevalence of Behçet disease is estimated to be only 1 case per 300,000 persons per year.

In a university hospital setting, Behçet disease was responsible for 12-20% of cases of uveitis in Japan, compared with only 0.2-0.4% in the United States.

International

Behçet disease occurs worldwide, with a predominance among Asians, North Africans, and Europeans who live between the latitudes of 30-45°N.

Behçet disease is one of the main causes of endogenous uveitis in Japan and Turkey, with prevalence rates of 1 case per 10,000 population and 8-30 cases per 10,000 population, respectively.

Race

The prevalence of Behçet disease exhibits a strong geographic variation and has a unique geographic distribution, being most prevalent along the ancient Silk Road linking Rome with China, which was used for centuries as a trade passage.[3]

The prevalence of Behçet disease is highest in Turkey, in the countries bordering the Mediterranean, in the Mideast, in the Far East, and in Japan, where it is 1 case per 1000 population.

Behçet disease occurs less frequently in northern Europe, the United States, and the United Kingdom.

The prevalence of Behçet disease in African Americans is 1 case per 100,000 population.

Sex

The male-to-female ratio varies with ethnic origin; androtropism is still observed in Arabian countries, with a ratio of 2.3:1, whereas female predominance is seen in some European countries and in the United States.[3]

Age

The mean age at onset is in the third decade of life. However, when Behçet disease occurs in males aged 15-25 years, it takes a more serious form.

Spontaneous remissions and relapses characterize the natural history of ocular Behçet disease.

Visual prognosis in countries (ie, Japan, Turkey) that have the highest prevalence of Behçet disease is poor.

In Japan and Turkey, more than 50% of cases result in legal blindness within 4 years of onset.

The prevalence of blindness in Behçet disease patients in North America is 25%.

Possible explanation for this discrepancy includes genetic heterogeneity, with the occurrence of more severe disease in the Mideast and the Far East.

Ocular involvement in Behçet disease

Ocular involvement is seen in about 70% of patients who have Behçet disease.

In most cases, the ocular symptoms follow the oral and genital ulcers by 3-4 years, although ocular disease is the initial manifestation in about 20% of cases.

Behçet disease is characterized by severe recurrent attacks of intraocular inflammation. In one series, anterior uveitis was present in 59% of cases; posterior uveitis was present in 76% of cases; and panuveitis was present in 88.1% of cases.[4]

Symptoms include periorbital pain, redness, photophobia, and blurred vision.

Oral aphthous ulcers in Behçet disease

Recurrent painful oral aphthous ulcers are the most common lesions associated with Behçet disease and occur in 99.3% of cases.[5]

Skin involvement in Behçet disease

Cutaneous hypersensitivity is relatively common, occurring in 81.8% of cases. Acnelike lesions or folliculitis occurs frequently. Migratory thrombophlebitis also can develop.

Genital ulcers in Behçet disease

Recurrent painful genital ulcers occur in 62.8% of cases.

Initial ocular involvement may be unilateral in Behçet disease, but it progresses to bilateral disease in at least two thirds of cases.

In a large retrospective study of Behçet disease, the mean age at onset of uveitis was 28.5 years in male patients and 30 years in female patients. Ocular involvement was bilateral in 78.1% of patients and unilateral in 21.9% of patients. Panuveitis was the most common form in both sexes. Fundus lesions and sight-threatening complications were more common in male patients than in female patients. At the beginning of follow-up, potential visual acuity was 0.1 or less in 30.9% of eyes in male patients and 24.2% of eyes in female patients. The Kaplan-Meier survival analysis estimated the risks of losing useful vision (P >.10) at 5 and 10 years in male patients and female patients, with results of 21% versus 10% and 30% versus 17%, respectively.[6]

Ocular involvement in Behçet disease

This is described in 75% of patients, either anterior segment iridocyclitis or posterior segment involvement. Panuveitis and posterior uveitis/retinitis occur more frequently in males than in females (28.9% vs 11.5% and 57.9% vs 36.1%, respectively; P< .05).

The classic finding of Behçet disease, iridocyclitis with hypopyon, is present in about one third of cases. Gonioscopy may reveal an occult hypopyon in many cases. One characteristic feature of the hypopyon in Behçet disease is that it may change position with head movement, and it may form and disappear rapidly without sequelae. Recurrent attacks may result in posterior synechiae, peripheral anterior synechiae, iris atrophy, and secondary glaucoma.

Retinal disease is the most serious complication of Behçet disease. The classic fundus finding is retinal vasculitis, which affects both arteries and veins in the posterior pole.

Ophthalmoscopy shows venous engorgement, retinal hemorrhages, yellow-white exudates deep in the retina, white focal retinal infiltrates, retinal edema, and optic disc edema with hyperemia.

Severe vasculitis may lead to thrombosis of vessels and secondary ischemic retinal changes. Optic disc edema may be secondary to inflammation and may be seen during the acute phase in at least one fourth of cases.

Vitreous cellular infiltration almost always is present during the acute phase.

Retinal neovascularization, secondary to either retinal vein occlusion or chronic inflammation, may result in retinal or vitreous hemorrhage.

Neovascular glaucoma occurs in as many as 6% of patients and often results in phthisis bulbi.

Repeated episodes of posterior segment inflammation cause sheathing of retinal vessels, chorioretinal scars, and retinal and optic nerve atrophy.

Oral aphthous ulcers in Behçet disease

Recurrent aphthous ulceration of the oral mucosa is the most common nonocular manifestation of Behçet disease. They are the first symptoms in 50-70% of patients and develop in as many as 98% of patients. The lesions are located on the gingiva, lips, tongue, buccal mucosa, hard palate, uvula, and posterior pharynx.

A nationwide study in Japan revealed that 97.7% of patients who have Behçet disease have recurrent aphthous ulcers. Ulcers tend to develop in crops, which recur at various frequencies.

White or yellowish pseudomembrane usually covers the surface of the ulcer.

They usually heal within 7-10 days with no scarring.

However, fusion of several small ulcers may produce a large ulcer that leads to scar formation.

Skin involvement in Behçet disease

Skin involvement appears in 70% of patients. Behçet disease may produce a variety of skin lesions in affected individuals.

Erythema nodosum, acneiform lesions, thrombophlebitis, and cutaneous hypersensitivity are most common.

Erythema nodosum lesions, which occur in more than two thirds of patients with Behçet disease, usually are found on the anterior surface of the legs but also may be seen on the face, arms, and buttocks. These lesions appear as slightly raised, red nodules with subcutaneous induration and tenderness. They tend to involute in 10-14 days without ulceration.

Acneiform lesions occur in almost 60% of patients and may occur in patients who receive corticosteroid treatment; therefore, their presence is of questionable diagnostic usefulness.

A peculiar feature of Behçet disease is cutaneous hypersensitivity, which results in small pustules that form on skin after it has been scratched, shaved, or pricked with a needle.

Genital ulcers in Behçet disease

Genital ulcers occur in 80% of patients. They are painful punched-out lesions similar to those that occur in mouth and usually are located in the scrotum or vulva.

These genital ulcers may be deep and, in many cases, result in scarring. These scars are indicators of old disease and may help in diagnosis.

Musculoskeletal involvement in Behçet disease

Painful swelling with redness of joints occurs in as many as 50% of patients.

Transient, recurrent, nondestructive, and nonmigratory arthritis commonly affects large joints such as the knee, ankle, elbow, and wrist. The knee joint is most commonly affected.

Gastrointestinal involvement in Behçet disease

At least 50% of patients who have Behçet disease develop gastrointestinal symptoms.

Intestinal erosions and ulcers may cause abdominal pain, melena, and perforation.

This constellation of intestinal signs and symptoms may simulate Crohn disease and other inflammatory bowel disorders.

Vascular involvement in Behçet disease

Thrombophlebitis is found in 15% of these patients.

Obliterating thrombophlebitis, arterial occlusion, and aneurysm may occur in vessels of all sizes.

Neurologic involvement in Behçet disease

Multiple neurologic disorders that involve pyramidal and extrapyramidal tracts, the cerebellum, the cranial nerves, and, rarely, the peripheral nerves occur more commonly in male patients and in 5-30% of cases.

Both the central nervous system and the peripheral nervous system can be involved. Central nervous system manifestations can be divided into 2 main groups: (1) parenchymal involvement, which includes brainstem involvement, hemispheric manifestations, spinal cord lesions, and meningoencephalitic presentations; and (2) nonparenchymal involvement, including dural sinus thrombosis, arterial occlusion, and/or aneurysms. Peripheral neuropathy and myopathy are relatively rare.

The etiology and the pathogenesis of Behçet disease are not clear but are presumed to be multifactorial, involving genetic, infectious, and immunological factors. Increasing evidence suggests that antigens derived from infectious agents (eg, Streptococcus sanguis, herpes simplex virus, heat shock proteins) are implicated in the pathogenesis of the disease, and it has also become increasingly apparent that these events, once triggered, may be influenced by numerous interdependent and independent genetic regions.

Despite 20 years of intense efforts to identify other associated genetic regions in chromosome 6 and elsewhere, human leukocyte antigen B51 (HLA-B51) remains foremost among candidate risk factors for the disease. MICA alleles in the major histocompatibility complex (MHC) have also been implicated, but their close linkage with HLA-B51 has made their independent contribution to the disease less easy to define.[3] A recent review of related genetic studies is available.[7]

In 2009, a known association of ACE gene and eNOS gene polymorphisms with Behçet disease in a group of Turkish patients with or without ocular involvement was been investigated. ACE gene polymorphism was found to not play a role in the pathogenesis of Behçet disease. The findings related to the eNOS gene polymorphisms confirmed the significant association with Behçet disease and even more in patients with ocular involvement.[8]

Since Behçet disease is characterized by a vasculitis, the underlying mechanism is believed to be an autoimmune process.

Human leukocyte antigen B5

Although familial occurrences have been reported, no consistent inheritance pattern has been established; however, human leukocyte antigen B5 (HLA-B5) is associated with Behçet disease and poor visual prognosis.

Considerable evidence now points toward a more specific association with HLA-B51, a split antigen of HLA-B5.

The frequency of HLA-B51 is 57% in Japanese patients with Behçet disease, compared with only 14% in the control group, which equates to a relative risk of 7.9 for this marker.

Meta-analysis has shown that HLA-B51/B5 carriage predominates in males and is associated with moderately higher prevalences of genital ulcers, ocular and skin manifestations, and a decreased prevalence of gastrointestinal involvement.[9]

Restriction fragment link polymorphism studies show linkage disequilibrium between the HLA-B51 locus and the gene for tumor necrosis factor-beta (TNF-beta). This finding may imply that lower levels of TNF-beta may contribute to activation of the inflammatory cascade in persons with Behçet disease.

In Japan, an association has been found between human leukocyte antigen A26 (HLA-A26) and Behçet disease.

The disease occurs more frequently in temperate, northern parts of Japan than in subtropical, southern parts, a distribution that suggests environmental factors influence the prevalence of disease.

With regard to the immunology of Behçet disease, several data suggest a direct role of Th1 lymphocytes in the pathogenesis of the disease lesions. Th1 cytokines, including interleukin 2 (IL-2), TNF-alpha, interferon gamma (IFN-gamma), interleukin 12 (IL-12), and interleukin 18 (IL-18), are elevated and probably contribute to neutrophil and endothelial cell activation.[3]

Other diagnostic considerations in Behçet disease

It is important to consider other forms of uveitis in the differential diagnosis, especially in those patients who have a mild or atypical presentation of Behçet disease.

Human leukocyte antigen B27 (HLA-B27)-related anterior uveitis also may cause recurrent iridocyclitis with hypopyon, but it is typically unilateral.

Since Behçet disease is a bilateral panuveitis, other inflammatory processes that affect both eyes must be considered. Syphilis causes a retinitis with vitreitis rather than a strict vasculitis. The diagnosis for syphilis is confirmed by serology.

Sarcoidosis, another bilateral inflammatory process, may have posterior pole findings similar to those in Behçet disease but is generally more indolent, in contrast to the explosive recurrent attacks of Behçet disease. Furthermore, the vasculitis seen in sarcoidosis usually is not occlusive in nature and typically involves only veins, compared with the involvement of both arteries and veins in Behçet disease.

Other conditions that may mimic the ocular changes of Behçet disease include collagen vascular diseases and viral retinitis.

Since there is no pathognomonic clinical sign or laboratory test to distinguish Behçet disease from other uveitic entities, the diagnosis must be made based on characteristic ocular and systemic findings in the absence of evidence of other disease that can explain the findings. Ancillary tests, including ocular and brain imaging studies, are used to assess the severity of intraocular inflammation and systemic manifestations of Behçet disease, to identify latent infections and other medical conditions that might worsen with systemic treatment, and to monitor for adverse effects of drugs used. There are 2 diagnostic or classification criteria in general use by the uveitis community, one from Japan and one from an international group; both rely on a minimum number and/or combination of clinical findings to identify Behçet disease. Finally, several grading schemes have been proposed to assess severity of ocular disease and response to treatment.[10]

The diagnosis of Behçet disease is based on clinical findings rather than on specific laboratory test results. Some tests are useful adjuncts in the evaluation of patients who have Behçet disease.

The pathergy test (or Behçetine test) may be useful in patient evaluation; the test result is a nonspecific inflammatory reaction to a needle prick or an intradermal injection of saline. The reaction, which varies from an indurated erythema to pustule formation, occurs in 40-60% of patients who have Behçet disease.

Several other laboratory tests may help in the evaluation of a patient who has Behçet disease. During episodes of acute inflammation, patients may have high erythrocyte sedimentation rates, high C-reactive protein levels, or an increased number of peripheral leukocytes.

In neuro-Behçet disease, an analysis of cerebrospinal fluid reveals pleocytosis and elevated protein levels.[11]

Fundus fluorescein angiography

Fundus fluorescein angiography shows diffuse retinal vascular leakage and occlusion of retinal vessels.

Fluorescein leakage from retinal vessels may be seen before any clinical signs of vasculitis.

During acute inflammation, retinal vascular leakage is prominent, especially in the radial peripapillary area.

Affected retinal and optic nerve vessels leak fluorescein profusely during early transit and their walls stain in late transit.

Fluorescein angiography also may reveal macular ischemia and cystoid macular edema.

MRI

In neuro-Behçet disease, magnetic resonance imaging (MRI) is the imaging study of choice and often reveals iso-hypointense lesions in T1-weighted images and hyperintense lesions in T2-weighted images, mostly in the mesodiencephalic junction, cerebellar peduncles, and other parts of the brainstem.[11]

Histopathologic changes include necrotizing, leukocytoclastic, and obliterative vasculitis, which affect arteries and veins of all sizes and are probably immune-complex mediated. Only a few eyes that have had active disease have been examined histologically. Vasculitis is the key feature of Behçet disease. Underlying changes seen in the eye are similar to those that occur in other organs of the body.

During acute inflammation, the iris, the ciliary body, and the choroid show diffuse infiltration with neutrophils. In late stages, a proliferation of collagen fibers, thickening of the choroid, formation of cyclitic membrane, and sometimes hypotonia and phthisis bulbi are noted. Lymphocytic and plasma cell infiltration occurs during remission. Of all ocular tissues, the retina suffers the most damage. In the phase of acute inflammation, severe vasculitis with marked infiltration of leukocytes in and around blood vessels is seen. Recent and old hemorrhages are present. Retinal vessels have thickened basement membranes with swollen endothelial cells, which can lead to thrombus formation and vascular obliteration.

Treatment of the various manifestations of Behçet disease remains controversial because of the paucity of randomized, controlled trials and the absence of standardized outcome measures for this disease. For example, colchicine, which has historically been the drug of choice for the treatment of the various manifestations of Behçet disease, has been evaluated for its efficacy and safety in only one randomized, controlled trial. In this 2-year trial, colchicine was found to only decrease arthritis in male and female patients and to decrease genital ulcers and erythema nodosum in female patients.[12] A recent (2011) review of current ocular therapeutic approaches is available.[13]

The goals of therapy in Behçet disease are to suppress inflammation, to reduce the frequency and severity of recurrences, and to minimize involvement of the retina. To be effective, treatment must be started early. The extent of involvement and the severity of disease determine the choice of medication. Treatment options include corticosteroids, cytotoxic agents, cyclosporine, and colchicine. (See the image below.)

Corticosteroid therapy

Systemic corticosteroids effectively suppress all phases of ocular involvement in Behçet disease.

Although these drugs do not prevent visual deterioration, systemic corticosteroid therapy may still be helpful, especially when used in concurrence with other immunosuppressive agents.

Prednisone may be used in a pulse mode to treat Behçet disease, with a 1-g bolus given intravenously over 1 hour and repeated once a day for 3 days. The pulse treatment is repeated as needed.

In Japan, systemic corticosteroids are not used for ocular disease. This decision is based upon the findings of several retrospective studies that show long-term visual outcomes to be worse in patients who received systemic corticosteroids compared with those who did not.

Cytotoxic agents

Chlorambucil, cyclophosphamide, and azathioprine are the cytotoxic agents used most commonly for the treatment of Behçet disease.

Chlorambucil was the first cytotoxic drug to be used in the treatment of ocular Behçet disease. This slow-acting alkylating agent may be administered in an outpatient setting.

Cyclophosphamide is an alkylating agent that is superior to corticosteroids in the control of inflammation in Behçet disease, but profound bone marrow toxicity limits its use. Since cyclophosphamide acts faster and is more toxic than chlorambucil, its use is reserved for very refractory cases.

Azathioprine is a mercaptopurine derivative that is effective in the treatment of Behçet disease.

All of these cytotoxic agents may produce variable degrees of bone marrow suppression and may affect reproductive organs, resulting in azoospermia and amenorrhea.

Cyclosporine

Cyclosporine inhibits T-lymphocyte activation and consequently is safer than cytotoxic agents; however, renal complications may occur.

Usual starting dose is 5 mg/kg/d. Cyclosporine does not appear to induce permanent immunosuppression; therefore, patients need continuous treatment for many years.

A rebound phenomenon has been noted after withdrawal of cyclosporine therapy.

These factors have limited the use of cyclosporine for the treatment of Behçet disease, but a study conducted in Japan found that a starting dose of 5 mg/kg/d effectively limited the frequency of ocular inflammatory attacks in 70% of patients with Behçet disease who previously had refractory disease.

Colchicine

Colchicine is a plant alkaloid that interferes with microtubule function, which results in dysfunction of neutrophils.

Colchicine may be used with other drugs and may enable Behçet disease to be controlled using lower doses of immunosuppressants. The optimum dosage of colchicine is 0.5-1 mg/d.

In Japan, colchicine is considered the drug of choice because of its few adverse effects and because of the presumed poor long-term prognosis associated with systemic corticosteroid therapy.

When colchicine fails to limit recurrences, treatment is switched to or combined with cyclosporine.

Combination therapy

It appears that the best results may be obtained using a combination of drugs, such as corticosteroids with either cytotoxic agents or cyclosporine. Overall, no safe and conclusive treatment exists for patients with Behçet disease. The treatment regimen needs to be tailored to the severity and extent of disease in each individual patient.

Newer therapies

The goal of therapy is to suppress inflammation, to prevent sequelae, and to minimize the systemic adverse effects of treatment. Newer therapies have been advocated; see the Multimedia section for a complete review.[3]

Biological therapies

Interferons

Interferons (INFs) are a large family of glycoproteins that possess antiviral, antitumor, and immunomodulatory properties. The rationale for their use in Behçet disease is founded, firstly, on the putative association between the disease and viral infections and, secondly, on their biologic effects, including the ability to improve the activity of natural killer cells and to inhibit gamma delta T cells.[3]

The most impressive results have been achieved for severe and/or refractory ocular manifestations. Patients with mucocutaneous and articular manifestations also benefit from interferon alpha (IFN-alpha), but fewer complete remissions are achieved, and relapses often occur after discontinuation. Intermediate-to-high IFN-alpha doses are more effective than low-dose regimens, and long-term remissions are associated with higher IFN-alpha doses but not with longer treatment duration. Adverse effects are frequent but dose dependent and not severe. They are the same as those reported for IFN-alpha in the treatment of other disorders, such as chronic hepatitis B or C, or hematological diseases, such as chronic myelogenous leukemia or non-Hodgkin lymphoma.[3]

Tumor necrosis factor (TNF)–alpha inhibitors

The rationale for anti-TNF use in Behçet disease is founded on the strong implication of TNF-alpha in the pathogenesis of this disease. It is well known that Behçet disease is mediated by a variety of cytokines, including TNF-alpha released from Th1 lymphocytes. Patients with active disease demonstrate increased numbers of monocytes and T lymphocytes expressing gamma/delta receptors that overproduce TNF-alpha. Patients also show increased levels of circulating TNF-alpha and soluble receptors, and high TNF-alpha levels are observed in the aqueous humor from patients with uveitis associated with Behçet disease.[3]

Both infliximab (a chimeric monoclonal antibody to TNF-alpha) and etanercept (a dimeric, soluble p75 TNF receptor) have been shown to be effective in the treatment of various inflammatory disorders. Infliximab has been found to be effective when the disease has been refractory to most other regimens.[14]

Results of therapeutic studies suggest that this drug is highly effective in inducing short-term remission of virtually all manifestations of the disease, including sight-threatening panuveitis. In cases of ocular inflammation, remission was observed in some patients within 24 hours, and marked improvement of visual acuity was observed in other patients by 7 days. Infliximab was usually administered in doses of 3-5 mg/kg, with continuous treatment every 2 months for as long as 2 years in some patients. Complete remission has been maintained, with a reduction in concomitant immunosuppressive therapy. Continuous therapy has been reported in most studies, but a few patients have remained in remission for up to 12 months after treatment.

Data that continue to accumulate strongly suggest that infliximab and etanercept are effective and safe in the treatment of Behçet disease. Whether infliximab is more effective than etanercept in the treatment of Behçet disease remains unclear.

IFN and TNF blockers

Both IFN and TNF blockers seem to be effective in the management of ocular and extraocular manifestations of Behçet disease. However, the data need to be further verified by randomized, controlled trials in larger numbers of patients with longer follow-up periods.[3]

Other alternative therapeutic strategies

Tolerizing agents

Tolerance induction has primarily been used for the treatment of autoimmune uveitis, because it is known to be caused by lymphocytes that recognize and attack self-protein antigens within the eye. S-antigen (S-Ag) and interphotoreceptor retinoid-binding protein (IRBP) are the best characterized self-antigens. Conventional therapeutic approaches suppress the activity of the leukocytes (anti-inflammatory) and lymphocytes (immunosuppressive) in an unspecific manner, leading to suppression of the entire immune system. New immunoregulatory approaches that suppress only the aberrant immune response to ocular antigens are under development. One of these approaches is mucosal tolerance, a mechanism of specific immune tolerance to soluble antigens applied via mucosal surfaces.[3]

To date, various oral antigens have been applied to patients with uveitis. They have included IRBP, retinal S-Ag, retinal extracts, and a peptide from the sequence of associated HLA-B-antigens mimicking retinal S-Ag peptide.[3]

Oral tolerance seems to be safe and effective in Behçet disease. Yet, clinical trials have been performed on a limited number of patients; therefore, these results have to be interpreted cautiously.[3]

Immunoablation

Several case series have demonstrated the efficacy of autologous hematopoietic stem cell transplantation (HSCT) in inducing remission in patients with Behçet disease.[3]

See the list below:

• Uveitis service if available

• Gastroenterologist

• Rheumatologist

• Neurologist: Neuro-Behçet disease must be considered in the differential diagnosis of stroke in young adults, multiple sclerosis, movement disorders, intracranial hypertension, intracranial sinovenous occlusive diseases, and other neurologic syndromes.

Patients with Behçet disease should receive follow-up care as needed.

Treatment is aimed toward individual symptoms as they occur. Medication is given to reduce the inflammatory response.

Class Summary

Systemically interfere with events leading to inflammation.

Colchicine

Decreases leukocyte motility and phagocytosis in inflammatory responses. Used to prevent recurrent attacks.

Class Summary

Systemic corticosteroids are not useful in the long-term management of Behçet disease. Some authors use corticosteroids as initial therapy, especially in mild cases. However, other authorities state that corticosteroids have no role in the treatment of Behçet disease. Systemic corticosteroids should be used only for short periods and probably in combination with immunosuppressive therapy. Topical or sub-Tenon corticosteroids have proven effective.

Prednisone (Deltasone, Orasone, Meticorten)

May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Use smallest dose for shortest duration to achieve therapeutic effect. Use in combination with immunosuppressive therapy. Also may use pulse IV therapy over a 3-d period.

Prednisolone acetate 1% (Pred Forte)

Treats acute inflammations following eye surgery or other types of insults to eye. Decreases inflammation and corneal neovascularization. Suppresses migration of polymorphonuclear leukocytes and reverses increased capillary permeability. In cases of bacterial infections, concomitant use of anti-infective agents is mandatory; if signs and symptoms do not improve after 2 days, reevaluate patient. Dosing may be reduced, but advise patients not to discontinue therapy prematurely.

Useful for acute iritis. Frequent dosing (q1-2h) useful initially, followed by gradual taper.

Class Summary

Used to treat acute attacks and reduce frequency of recurrences.

Cyclophosphamide (Cytoxan, Neosar)

Chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of cells. DOC for severe Behçet disease. Must be administered by an experienced clinician.

Chlorambucil (Leukeran)

Aromatic nitrogen mustard derivative that acts as a bifunctional alkylating agent. Alkylation takes place through the formation of a highly reactive ethylenimonium radical. Probable mode of action involves cross-linkage of the ethylenimonium derivative between 2 strands of helical DNA and subsequent interference with replication.

Cyclosporine (Sandimmune)

Potent immunosuppressive agent with narrow therapeutic range, shown to decrease number and severity of attacks of Behçet disease.