Sunir J. Garg

BASICS

DESCRIPTION

• Systemic vasculitis characterized by triad of recurrent oral aphthous ulcers, genital ulcers, and uveitis. Skin lesions are common.

• Uveitis ranges from nongranulomatous anterior uveitis (classically with hypopyon) to chronic retinal vasculitis.

Pediatric Considerations

In Japan, 1.5% of cases of Behçet’s disease occur in children. Various forms, including a transient neonatal case, have been documented. In children, there is a greater frequency of uveitis and arthritis, but genital and oral ulcers are less common.

Pregnancy Considerations

Most studies show a good outcome in pregnancy, with the majority of patients showing no change during labor and after delivery, and no worsening of disease symptoms and no significant difference in frequency of congenital malformations, spontaneous abortions, and perinatal death.

EPIDEMIOLOGY

Incidence

• Greatest incidence is in Turkey and Japan, and along the ancient silk route connecting the two.

• More common in young patients (25–35 years), but occurs in all ages.

• Prior studies suggested a higher incidence in men; however, recent reports suggest a more even distribution between men and women.

Prevalence

• Prevalence in Japan is 8–10/100,000 and it comprises 20% of all uveitis cases in Japan. In Turkey, the incidence is 80–300/100,000.

• It is rare in the United States, with prevalence of 4/1,000,000 and comprises 0.2–0.4% of all uveitis cases.

RISK FACTORS

• Occurs most commonly in patients from Turkey, Japan, the Middle East, Pakistan, northern China, and Korea. Rare in North America.

• Poorly defined environmental and infections exposures due to streptococcus, HSV type 1, Hepatitis C Virus, and E. coli have been suggested.

Genetics

• HLA-B51 phenotype and its subtypes HLA-Bw51 and B^∗501 have been identified as risk factors.

• HLA-DR1 and HLA-DQw1 have been identified as significantly decreased in Behçet’s patients – possibly providing resistance to disease development.

PATHOPHYSIOLOGY

A nonspecific obliterative vasculitis of small blood vessels due to abnormal cellular immune responses including lymphocyte dysfunction

ETIOLOGY

• Unknown. It is postulated that a genetic predisposition combined with an environmental trigger produces the disease.

• Streptococcus and viruses (HSV-1, Hepatitis C) have been studied as possible triggers.

DIAGNOSIS

HISTORY

• Behçet’s disease is a clinical diagnosis.

• There is no specific laboratory test to confirm the diagnosis.

• There are various systems for diagnosis.

• The International Behçet Study Group criteria are:

– Recurrent oral aphthous ulcers occurring 3 times in 12 months.

– In addition to oral ulcers, 2 of the following must be present: Recurrent genital ulcers, uveitis, skin lesions, and/or positive pathergy test.

• The Behçet’s Disease Research Committee Criteria are:

– 1. Major criteria: Recurrent oral aphthous ulcers, recurrent genital ulcers, skin lesions, and uveitis

– 2. Minor criteria: Arthritis, intestinal ulcers, epididymitis, vascular disease, and neuropsychiatric symptoms

• Complete Behçet’s disease requires a history of all 4 major symptoms.

• Incomplete diagnosis requires 3 major symptoms or uveitis with 1 minor symptom.

• Suspect diagnosis requires 2 major symptoms, excluding uveitis.

• Possible diagnosis requires any major symptom.

• The most common symptom is oral aphthous ulcers which occur in 98% of patients. They are discrete white ulcerations with a red border that are 3–15 mm in size.

• Skin lesions are predominately erythema nodosum, superficial thrombophlebitis, and eruptions resembling acne vulgaris or folliculitis.

• Genital ulcers are recurrent and occur in the vagina or vulva in females, the penis or scrotum in males, and in the perianal area in both sexes. They can be painful or painless.

• Uveitis is present in ∼79% of patients and manifests as nongranulomatous inflammation with necrotizing obliterative vasculitis.

• Patients often complain of pain, redness, photophobia, and blurred vision.

• The anterior segment often has iridocyclitis without hypopyon. Hypopyon occurs in the “classical presentation”; however, it occurs in less than a third of ocular cases, likely due to more aggressive early treatment.

• Posterior segment involvement leads to greater morbidity. Retinal vasculitis affects both arteries and veins. Vitreitis can occur.

• CNS symptoms (due to vasculitis) may be motor, sensory, or psychiatric. Meningoencephalitis may be the most common manifestation (uncommon overall).

• Neuro-ophthalmic findings include 6th and 7th nerve palsies, central scotomas, and optic disc edema.

PHYSICAL EXAM

• Inspect for oral and genital ulceration, skin lesions, and other criteria listed above.

• Anterior uveitis and presence of a hypopyon. The hypopyon may change position with head movement.

• Posterior segment ocular involvement includes retinal vasculitis affecting both arteries and veins, profound nonperfusion, venous and capillary dilatation with engorgement, patchy perivascular sheathing with inflammatory exudates, yellow-white exudates deep in the retina, neovascularization, and vitreitis.

DIAGNOSTIC TESTS & INTERPRETATION

Lab

Initial lab tests

• None generally necessary.

• Pathergy skin reaction/Behcetine skin test (sterile pustules that develop at the site of spontaneous or induced trauma) is present in 40% of Behçet’s patients.

• HLA-B51 typing (present in >50% of Behçet’s patients of Mediterranean and Japanese origin) may be used to aid with diagnosis.

• Nonspecific factors of immune system activation: Elevated levels of serum proteins, circulating immune complexes, acute phase reactants, and other complement reactive proteins may be present during the acute phase.

Follow-up & special considerations

Lumbar puncture (not routinely needed) shows pleocytosis of CSF. In addition, MRI and CT imaging may be used to identify possible CNS lesions.

Imaging

Fluorescein angiography (FA) is helpful to analyze the extent of retina vascular damage, to evaluate neovascularization, and to assess response to therapy.

DIFFERENTIAL DIAGNOSIS

• Viral retinitis

• HLA-B27 associated anterior uveitis (hypopyon), especially reactive arthritis

• Sarcoidosis

• Tuberculosis

• Systemic lupus erythematosus (SLE)

• Polyarteritis nodosa (PAN)

• Wegener’s granulomatosis (WG)

• Oral ulcers: Stevens–Johnson syndrome, Reiter’s syndrome, trauma

• Genital ulcers: Herpetic ulcers, reactive arthritis (Reiter’s syndrome)

TREATMENT

MEDICATION

First Line

• Medication is based on disease severity. If complete Behçet’s disease, severe ocular/retinal involvement, CNS involvement, or other significant vasculitis, aggressive treatment is required. (Men, and people of Turkish/Japanese descent also usually require more aggressive treatment.)

• Oral (1–2 mg/kg per day) or pulse dose corticosteroids have a rapid onset of action. However, Behçet’s patients in need of high dose steroids require steroid sparing agents as high dose steroids cannot be used for long periods of time without severe side effects.

• Biologics such as the TNF inhibitors infliximab (Remicade) and adalimumab (Humira) should be considered. Cytotoxic agents (chlorambucil, cyclophosphamide), the antimetabolites azathioprine and mycophenolate mofetil, and the calcineurin inhibitors cyclosporine-A and tacrolimus are used in combination with corticosteroids.

Second Line

• Cyclophosphamide and chlorambucil are useful, especially in cases of severe CNS and gastrointestinal involvement.

• Colchicine and thalidomide can be useful in systemic disease, but do not control uveitis well.

• Neutrophilic apheresis has been shown to be helpful in some patients.

ADDITIONAL TREATMENT

Issues for Referral

• Patients with ocular involvement require prompt referral to a uveitis/retinal specialist as there can be up to a 90% rate of blindness with delayed/inadequate treatment.

• A multidisciplinary team is required to manage the various systemic effects of the disease.

SURGERY/OTHER PROCEDURES

• Surgery for cataracts can occur when visual improvement can be expected and the eye has been inflammation free for 3 months.

• As surgical trauma may induce recurrence of the inflammation, consider prophylaxis with systemic and topical steroids 1 week preoperatively with continuation postoperatively with a slow taper over several weeks. Any systemic immunosuppressive drugs should be continued.

• Laser photocoagulation can be used for retinal neovascularization and does not produce postoperative inflammation.

IN-PATIENT CONSIDERATIONS

Initial Stabilization

High dose oral or pulse dose corticosteroids for rapid anti-inflammatory effect

Admission Criteria

Any severe vision or life-threatening manifestation of Behçet’s disease should prompt consideration of hospitalization.

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

Patients will need very close monitoring until the disease is brought under control. They will also need continuous follow-up with other specialists as needed.

PROGNOSIS

• Prognosis is improved with prompt aggressive treatment, but visual outcomes can be guarded. Even with therapy, legal blindness has been noted to occur in >50% of cases within 4 years (but this was with earlier immunosuppressive agents).

• Systemic prognosis is good in the absence of CNS involvement, vascular involvement, or GI perforation. Remissions increase in duration with time and disease stabilization occurs after ∼10 years.

• Prognosis is better in the USA than in Mediterranean or East Asia, possibly due to a less severe form of the disease or more effective treatment.

COMPLICATIONS

• Bilateral vision loss due to ocular inflammation.

• Anterior uveitis can cause cataract formation or glaucoma. Posterior segment inflammation can result in macular and peripheral retinal ischemia, and optic nerve damage.

• Retinal neovascularization, retinal detachment, vitreous hemorrhage, and vitreous traction can also occur.

ADDITIONAL READING

• Kaçmaz RO, Kempen JH, Newcomb C, et al. Ocular inflammation in Behçet disease: Incidence of ocular complications and of loss of visual acuity. Am J Ophthalmol 2008;146(6):828–836.

• Marsal S, Falgá C, Simeon CP, et al. Behçet’s disease and pregnancy relationship study. Br J Rheumatol 1997;36(2):234–238.

• Sakane T, Takeno M, Suzuki N, et al. Behçet’s disease. N Engl J Med 1999;341:1284–1291.

• Tabbara KF, Al-Hemidan AI. Infliximab effects compared to conventional therapy in the management of retinal vasculitis in Behçet disease. Am J Ophthalmol 2008;146(6):845–850.

CODES

ICD9

• 136.1 Behçet’s syndrome

• 360.12 Panuveitis

• 364.3 Unspecified iridocyclitis

CLINICAL PEARLS

• The characteristic findings are uveitis, oral aphthous ulcers, genital ulcers, and skin lesions.

• As this is a generalized vasculitis, patients have numerous organ and life-threatening complications as a result.

• Prompt and aggressive immunosuppressive control is critical.

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