Behcet's Disease

From EyeWiki
Original article contributed by: Majid Moarefi, Musa Abdelaziz, Mahdi Rostamizadeh, Baseer Ahmad
All contributors: Majid Moarefi, MD
Assigned editor: Majid Moarefi
Review: Assigned status Up to Date by Majid Moarefi, MD on November 25, 2015.



Behcet's Disease
Classification and external resources
ICD-10 [1]35.2
OMIM 109650
DiseasesDB 1285


Behcet’s disease (BD) is a systemic vascular disease that can affects a variety of organ systems. It was first described by Hippocrates, in the 5th century BC, in his Epidemion (book 3, case 7). [1] The disease was formally described by a Turkish dermatologist, named Dr. Hulusi Behcet [2], in 1922.

BD is commonly known as a triad of oral aphthous ulcers, genital ulcers, and ocular disease. In ocular disease, uveitis with hypopyon is the most common ocular finding. BD is a multisystem vasculitis of unknown etiology. The disease can be found most commonly in the Middle East and Far East, particularly Japan.

History

Dr. Hulusi Behçet (1889-1948) was a famous Turkish dermatologist, born in Istanbul on February 20, 1889. Dr. Behçet attended Gülhane Military Medical Academy for his medical education and then further specialized in dermatology and venereal disease after achieving his MD. His specialization training was completed in 1914, and by 1924, he had begun to make clinical observation of a new disease later to be named after him. Starting in 1924, Dr. Behçet noted and followed the symptoms of three of his patients for many years, before concluding that they marked a constellation of findings of this new disease entity. In 1936, he published these first cases in the Archives of Dermatology and Venereal Disease. Unfortunately, Dr. Behcet died from a sudden heart attack on March 8, 1948. Today, this disease has come be known as Behçet's Disease in medical literature. [50]

Hippocrates described symptoms similar to this disease in the 5th century BC, in his Epidemion (book 3, case 7).

Disease Entity/Epidemiology

BD is famously known to be prevalent along the Silk Road, which extends from eastern Asia to the Mediterranean [3,4]. It is most commonly noted in Turkey, but has high prevalence also in Japan, Korea, China, Iran, Iraq, and Saudi Arabia. [3] In North America and Northern European countries, the prevalence is much lower. [5] Onset is typically in the second to fourth decades of life [6,7,8]. BD is most commonly sporadic. [16,17]

The most common clinical feature, affecting 98-99% of patients, are oral aphthous ulcers. The second most common finding is genital ulcer, which occur in 80-87% of patients. Skin disease is another common finding occurring in up to 69-90%. An asymmetric, non deforming, large-joint polyarthritis can be seen in 44-59% of patients.

Disease

Ocular Manifestations

Ocular manifestations carry the most serious implications, affecting roughly 70% of patients. The severity is due to the explosive and recurrent nature of the uveitis, which can lead to permanent, often irreversible, ocular tissue damage. Up to 25% of patients with BD suffer from severe vision loss. Men are affected by ocular disease more commonly and it is often more severe. The entire uveal tract is at risk of inflammation, characterized as a nongranulomatous necrotizing obliterative vasculitis. The most significant damage is due to retinal vasculitis, which can cause vascular occlusions. The retina and optic nerve are also often damaged during the span of the disease and this often leaves patients with significant visual disability. [20,21]

The clinical finding of nongranulomatous anterior uveitis in BD patients usually presents with a transient hypopyon in 25% of cases. Patients will have signs and symptoms of redness, tearing, pain, photophobia, and blurry vision. The hypopyon in BD has been noted to disperse if the patient shakes their head or move around in accordance with the patient’s head position. Common inflammatory complications such as posterior synechiae, iris bombe, and angle-closure glaucoma are associated with the relapsing and recurrent nature of the disease. Glaucoma is generally a late feature associated with the relapses. Cataracts, keratic precipitates, episcleritis, scleritis, conjunctival ulcers, and corneal immune ring opacities are part of the list of other less common anterior segment findings in ocular BD. [19]

Severe sight threatening manifestations are related to posterior segment involvement. The most common form of uveitis with BD is an obliterative, necrotizing retinal vasculitis that has the unique feature of affecting both the arteries and the veins in the fundus. The complications of posterior segment disease can include branch retinal vein occlusion, variable amounts of vitritis, and cystoid macular edema. The retinal ischemia in BD can cause development  of neovascularization of the retina as well as the iris, and these can lead to neovascular glaucoma. Exam findings reflecting the chronic, damaging nature of the disease include retinal vessels that have become sclerotic and white after multiple episodes of retinal vasculitis and vascular occlusions. These post-inflammatory vascular findings are described by some as threadlike arterioles and veins or as completely occluded vessels that appear as white lines within an atrophic retina. Pigment hypertrophy with RPE clumping in the macula may also be seen as a sequela of chronic and recurrent macular edema. Ophthalmologist should be aware that the ischemic vasculitis and retinitis can sometimes give a fundus appearance that may be similar to necrotizing herpes infections or an acute retinal necrosis syndrome picture. A quarter of BD patients will have an affected optic nerve. This can be seen either as an optic papillitis or a progressive optic atrophy secondary to the vasculitis affecting the arterioles supplying the optic nerve. Ocular inflammatory findings and sequelae are more common in males. [22]

Non-ocular systemic manifestations

Oral aphthae ulcers are recurrent mucosal ulcers producing significant discomfort and pain for the patient and also the most frequent finding in BD. They tend to reoccur frequently and as much as every 5-10 days or every month. These ulcers can last for 7-10 days and when they heal, it is usually without much scarring except for ulcers that are large.

Skin lesions in BD have many presentations. These include erythema nodosum, which are painful, purple-colored, nodules that present over the extensor surfaces of the lower extremities, especially the tibias, but can also occur on the face, neck, and buttocks. A cutaneous pathergy is seen in about 40% of patients with BD, which is the development of a sterile pustule at the site of a venipuncture/injection. Although somewhat unique, pathergy is not pathognomonic of BD.

Genital ulcers grossly resemble oral aphthous ulcers. They can occur on the scrotum or penis in males or on the vulva and the vaginal mucosa in females. They can also appear on the anus in both sexes. The genital ulcers in BD are associated with variable amounts of pain. Healing takes longer than oral ulcers, generally up to 3 weeks, and unlike the oral ulcers they often scar.

Systemic vasculitis can be a significant cause of morbidity and mortality in BD patients and is seen in about 25% of cases. As with the retina, systemically both arteries and veins of any size may be affected. Arterial occlusion, aneurysm, venous occlusion, and varices are four of the common complications of the systemic vasculitis in BD.

Neurologic involvement occurs in about 10% of BD cases and is known to be the most serious of all manifestations. Interestingly, 30% of patients with ocular BD will have neurologic involvement, but only 10% of patients with neuro-BD will have ocular disease. Areas of motor control are mainly affected with neurologic involvement. Ocular signs and symptoms of neuro-BD include cranial nerve palsies, papillitis causing central scotoma, visual field defects, and superior sagittal sinus (or other venous sinuses) thrombosis causing papilledema. Other complications, in up to 25% of cases, include headaches, strokes, nerve palsies, and a confusional state due to widespread CNS vasculitis.

Other organ systems can be involved in Behçet’s disease.

Although rare, renal involvement in BD is characterized as a nephrotic syndrome. Other manifestations of active BD that can also be present include amyloidosis, myositis, and epididymitis. [28]

Etiology

Behçet’s disease still remains a disease of unknown etiology.

Given that HLA-B51 (particularly HLA-B5101) has been associated with BD, it is proposed that a genetic predisposition exists, but the actual association has not been well defined. [31] There are reports of familial clustering, but it is actually rare to see other family members affected with BD, even when many family members have the HLA-B51 gene. This fact makes the presence of HLA-B51 alone a minor factor.

Risk Factors

Given that BD is of unknown etiology, the highest prevalence of the disease is found in the Middle East and Far East, particularly Japan. Since the same clinical manifestations are found across different ethnic groups, it is presumed that environmental factors likely also play a role along with genetic predisposition.

General Pathophysiology

There are many postulated genetic and environmental factors that are presumed to play a role. Abnormal immune activity may be generated by exposure to infectious (viral and bacterial) or non-infectious (environmental sources, such as heavy metals or chemicals) antigens in patients with a genetic predisposition.

Pathology and Histology

Ocular Behçet’s disease displays a nongranulomatous panuveitis. Lesions within the eye may show blood vessel infiltration by leukocytes, retinal vasculitis with occlusions, and thrombosis. The anterior chamber, as well as the corneal epithelium, iris, ciliary body, and choroids may show neutrophil infiltration during active disease [40].

Primary prevention

No studies have been effective at producing definitive information regarding the primary prevention, given the etiology of BD is unknown.

Diagnosis

Diagnosis of BD is based on clinical findings and the diagnostic criteria listed below. Many different tests can help aid towards inclusion or exclusion of BD, including HLA Testing and cutaneous pathergy testing. The nonspecific serologic markers of inflammation (i.e. ESR and C-reactive protein) usually provide little value in confirming the diagnosis. Fluorescein angiography performed on ocular BD patients may demonstrate marked dilatation and occlusion of retinal capillaries with perivascular staining. On angiography, there can also be evidence of retinal non-perfusion (hypofluorescence) and neovascularization (areas of intense, early hyperfluorescence along vascular distributions). There may also be petalloid macular leakage of fluorescein if CME is present. Based on the clinical presentation of a BD patient, certain radiologic imaging tests including chest x-ray, chest CT, and brain MRI with contrast enhancement, can be helpful.

Diagnostic System for Behcet Disease (Japan)
Major Criteria:
  • Recurrent Oral aphthous ulcers
  • Skin lesions (erythema nodosum, acneiform pustules, folliculitis)
  • Recurrent genital ulcers
  • Ocular Inflammatory disease
Minor Criteria
  • GI ulceration
  • Arthritis
  • Epididymitis
  • Systemic vasculitis or associated complications
  • Neuropsychiatric symptoms
Types of Behcet Disease
  • Complete (4 major criteria)
  • Incomplete (3 major criteria or ocular involvement with 1 other major complication)
  • Suspect (2 major criteria with no ocular involvement)
  • Possible (1 major criterion)
Diagnostic System for Behcet Disease (International Study Group for Behcet Disease)
Recurrent oral aphthous ulcers (at least 3 or more times per year) plus 2 of the following criteria:
  1. Recurrent genital ulcers
  2. Ocular Inflammation
  3. Skin Lesions
  4. Positive Cutaneous pathergy test

Physical examination/Signs and Symptoms

Eye

Behcet’s may cause anterior uveitis, posterior uveitis (sometimes both may be affected at the same time), and/or retinal vasculitis. Inflammatory eye disease can develop early in the disease course and lead to severe vision loss in 20% of cases.

Anterior uveitis presents with painful eyes, conjunctival redness, hypopyon, photophobia, tearing, blurry vision, and decreased visual acuity.

Posterior uveitis may be more dangerous and vision–threatening because it often causes fewer symptoms while damaging the retina. Symptoms include painless decreased visual acuity and floaters.

Retinal vasculitis may present with a painless decrease of vision. Patients may note floaters or visual field defects. [51]

Optic nerve atrophy is the most common cause of visual impairment. There are both primary and secondary causes of optic nerve involvement. Secondary causes of optic nerve atrophy include papilledema from dural sinus thrombosis [52] and atrophy from retinal disease. [53,54]

Signs and symptoms of acute optic neuropathy include painless loss of vision which may affect either one or both eyes, reduced visual acuity, reduced color vision, relative APD, central scotoma, swollen optic disc, macular edema or retrobulbar pain. When these symptoms occur with concurrent mucocutaneous ulcerations, they raise suspicion of acute optic neuropathy in Behçet's Disease. Progressive optic atrophy may result in decreased visual acuity or color vision.

Mouth

Aphthous ulcers affect almost all patients with Behcet's disease. Individual sores or ulcers are usually identical to canker sores, which are common in many people. These sores are usually a result of minor trauma. They are often the first symptom that a person notices and may occur long before any other symptoms appear. However, the lesions are more numerous, more frequent, and often larger and more painful.

Skin

Skin problems are a common symptom of Behcet's disease. Skin sores often look red or resemble pus-filled bumps or a bruise. The sores are red and raised, and typically appear on the legs and on the upper torso.

Pustular skin lesions that resemble acne, but can occur nearly anywhere on the body. This rash is sometimes called “folliculitis”.

Erythema nodosum: red, tender nodules that usually occur on the legs and ankles but also appear sometimes on the face, neck, or arms. Unlike erythema nodosum associated with other diseases (which heal without scars), the lesions of BD frequently ulcerate.

Lungs

Aneurysms of arteries in the lungs, rupture of which may lead to massive lung hemorrhage.

Joints

Arthritis occurs in more than half of all patients with Behcet's Disease. Arthritis causes pain, swelling, and stiffness in the joints, especially in the knees, ankles, wrists, and elbows. Arthritis that results from Behcet's Disease usually lasts a few weeks and does not cause permanent damage to the joints.

Brain

Behcet's Disease affects the central nervous system in about 23% of all patients with the disease in the United States. Behcet's Disease can cause meningoencephalitis, which can present with fever, headache, stiff neck, and difficulty coordinating movement. If left untreated, a stroke can result.

Central nervous system involvement is one of the most dangerous manifestations of Behcet’s. The disease tends to involve the white matter of the brain and brainstem, and may lead to headaches, confusion, strokes, personality changes, and (rarely) dementia. Behcet’s may also involve the meninges, leading to aseptic meningitis.

Genitals

Genital sores affect more than half of all people with Behcet's Disease. The sores look similar to the mouth sores and may be painful. After several outbreaks, they may cause scarring.

Male — painful genital lesions that form on the scrotum, similar to oral lesions, but deeper.

Female — painful genital ulcers that develop on the vulva.

Gastrointestinal

Behcet's Disease causes inflammation and ulceration throughout the digestive tract that are identical to the aphthous lesions in the mouth and genital area.

Ulcerations may occur anywhere in the gastrointestinal tract from the mouth to the anus. This leads to abdominal pain, diarrhea, and/or bleeding. Because these symptoms are very similar to symptoms of other diseases of the digestive tract, such as ulcerative colitis and Crohn's Disease, careful evaluation is essential to rule out these other diseases. 

Clinical diagnosis/Diagnostic Procedures/Laboratory Tests

Behçet’s disease has no pathognomonic laboratory tests for its diagnosis; therefore, a diagnosis is made based on clinical findings. ESR, CRP, circulating serum immune complexes, and other markers of inflammation may be elevated during active disease. However, they are nonspecific findings and not diagnostic.

One helpful diagnostic aid is the pathergy test, which is specifically defined as a papule equal or greater than 2 mm in size that develops 24-48 hours after a needle insertion 5mm deep into the skin. This test is usually performed on the forearm

The International Study Group (ISG) published the preferred criteria for BD in 1990 [56], which today still are the most widely used and accepted criteria among experts in Behçet’s disease. The criteria specifies a requirement for the presence of recurrent oral aphthae (at least three times in one year) plus two of the following in the absence of other systemic diseases:

  • Recurrent genital ulcers
  • Ocular lesions, which include anterior or posterior uveitis, retinal vasculitis, or cells in vitreous
  • Cutaneous lesions, which include erythema nodosum, pseudo-vasculitis, papulopustular lesions, or acneiform lesions consistent with Behçet’s
  • Positive pathergy test


These criteria appear to be relatively sensitive and specific [59,60].

Differential diagnosis

The DDx for BD includes HLA-B27 associated anterior uveitis, ankylosing spondylitis, reactive arthritis syndrome, sarcoidosis, psoriatic arthritis, and systemic vasculitides including systemic lupus erythematosus, polyarteritis nodosa, and Wegners Granulomatosis. Necrotizing herpetic retinitis can also mimic occlusive BD retinal vasculitis.

Management

Management of BD has now heavily shifted toward corticosteroids for acute disease with a quick shift to use of immunosuppressive therapy for control of active disease and maintenance of remission.

General treatment

The goal of treatment is based on treating the acute disease along with controlling the chronic inflammation and preventing relapses. Onset of acute disease is usually explosive and treated initially with systemic corticosteroids. Chronic inflammation and relapses of ocular inflammation have a dual approach with systemic corticosteroids combined with immunomodulatory therapy (IMT), which is essential.

There are a variety of medications that are used with variable effectiveness in the treatment of Behçet’s disease. The organ system involved, the severity of the inflammation, and the chronicity of the inflammation are all taken into consideration when deploying a treatment. This is important to consider given some medications that are very effective in short-term doses to treat acute disease, can be ineffective in long-term disease control. Attention to certain IMTs have to be made because of the high risk of toxicity and low therapeutic index, which limit long-term use.

Medical therapy

Corticosteroids: Most useful agent that is used in the treatment of explosive inflammation of the anterior and posterior segments. Prednisone doses of 1.5mg/kg/day (with taper) are most beneficial for controlling acute inflammation. Resistance to systemic corticosteroids with long-term use, as well as side effects of high dose steroids limit their usefulness for extended periods. This does not undermine the utility of corticosteroids in providing a relatively quick immunosuppressive effect. Therefore, for acute explosive onset of BD uveitis, corticosteroids should be employed. [21] Corticosteroids also have utility in treating oral or genital ulcers when used topically. They have been shown to decrease the discomfort and expedite resolution of these ulcers.

Immunomodulatory medications: When a patient presents with posterior segment inflammation that is sight-threatening, immediate implementation of systemic corticosteroids should be initiated. Along with steroids, the addition of IMT is prudent. The IMT most commonly used in treating ocular BD include Azathioprine, Infliximab, Cyclosporine, Tacrolimus, Mycophenolate Mofetil, Chlorambucil, or Cyclophosphamide. Azathioprine is a preferred first-line IMT based on preserving visual acuity.

Medical follow up

There will be a need for regular exams and testing to check for sequelae of Behçet’s disease. A multi-specialty approach is needed including coordination between an ophthalmology, rheumatology, dermatology, and primary care. The treatments are aimed at controlling symptoms, limiting recurrences and relapses, and maintaining health prior to irreversible damage from the disease. Patients should be made aware of the signs and symptoms ocular BD can present with, and educated to promptly be seen by a healthcare provider, as the acute and explosive nature of the disease makes the early initiation of treatment imperative for better long term outcomes.

Surgery

In general, when performing any intraocular surgery, careful pre-operative evaluation is necessary for all patients with chronic inflammation. Mild cataracts and or other mild visual opacities generally should be observed, as there are significant risks of severe postoperative inflammation with subsequent visual loss from inflammatory sequelae. In cases of significant cataract, surgery may be considered after a period of at least 3 months without intraocular inflammation. To avoid and prevent the risk of an acute explosive relapse in the immediate post-op period, an increased topical steroids regimen or oral steroid supplementation should be considered. Of note, satisfactory results have been seen in BD patients who undergo cataract extractions via phacoemulsification or Extracapsular cataract extractions. [86,87] Patients must understand that although studies have shown safety with intraocular lens implantations, vision may still be very limited if the patient has suffered from retinal vascular occlusions and chronic macular edema, which are commonly seen with posterior segment involvement. [88] Vitreoretinal surgery has been performed without an increase in the frequency or severity of inflammation, and patients should know that an increase in visual function could be provided and done so safely. [89]

Surgical follow up

Depending on the type of surgery elected, there will be a follow up based on the outcomes and complications that would be expected with the procedure. Post-operative inflammation should be treated aggressively as there can be a component of ocular BD manifestations which can be confused for the expected inflammation seen after common procedures. Strict medication adherence and follow ups should be described to the patients.

Prognosis

Behçet’s disease is characterized by its waxing and waning course. These typically seen exacerbations and remissions appear more severe when the patients are young, male, and of Middle Eastern or Far Eastern descent. [14,15]

Vision loss is the greatest cause of morbidity in BD patients and the prognosis for vision is guarded. The most common causes for significant visual disability worldwide are due to macular edema, occlusive retinal vasculitis, optic atrophy, and glaucoma that develop as manifestations of ocular BD. This leaves about 25% of BD patients with severe vision loss (a visual acuity less than 20/200). The severity of poorer visual outcomes is typically seen in adult men. Visual prognosis has been improving as of late due to the earlier and more aggressive use of IMT. Visual prognosis is sometimes hard to gauge for a patient because of the relapsing nature of BD. Patients will likely require complex medical and/or surgical interventions for the complications of ocular BD, such as macular edema, visually significant cataracts, glaucoma (late complication), neovascularization of the retina, optic disc and iris (which can lead to neovascular glaucoma), retinal detachments, and vitreous hemorrhages.

Given the heterogeneous collection of BD-associated eye complications and the unpredictable relapses and exacerbations, a concrete prognosis of visual outcomes is difficult. Ocular and neurologic lesions will generally continue to progress without aggressive therapy. In some cases, they may improve with IMT but often are not fully reversible. Regional variations, especially BD patients found in Turkey and Japan, are most likely to suffer progressive vision loss. Early initiation of IMT and suppression of recurrences is believed to be the best strategy for maintaining useable vision, avoiding severe vision loss, and limiting the complications of systemic disease.

Additional Resources

  • Patient information can also be obtained from:
    • The American Behçet’s Disease Association:
    • Telephone: 1-800-7BEHCET
    • www.behcets.com
  • American Academy of Ophthalmology. Retina/Vitreous: Behçet disease Practicing Ophthalmologists Learning System, 2017 - 2019 San Francisco: American Academy of Ophthalmology, 2017.

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