Manifestation
Incidence
Oral aphthous ulcerations
76.6–100%
Genital ulcerations
40–94%
Skin lesions
29–94%
Pathergy phenomenon
19–70%
Arthritis
8–69%
Gastrointestinal manifestations
3–26%
Neurological manifestations
2–44%
Vascular manifestations
6–37%
Cardiac manifestations
1–6%
Epididymitis
5–22%
Oral aphthous ulcer on tongue
Ocular Disease
Anterior Segment
The primary manifestation of ocular BD may start unilateral most often as an anterior uveitis, but later on, bilateral posterior uveitis occurs in 78% of the cases, and 60% of the patients develop panuveitis with a chronic relapsing course (Tugal-Tutkun et al. 2004). The disease is more severe in men than in women. Recurrences are common.
Hypopyon iridocyclitis
Angle hypopyon
The inflammatory response in the anterior chamber in BD is non-granulomatous in nature. Patients often complain of redness, periorbital pain, photophobia, and blurred vision.
Posterior Segment
Mild ocular inflammatory attack in posterior pole with soft exudates and mild vitreous opacity
Severe ocular attack in the posterior segment, leading to retinitis and retinal vasculitis with retinal and vitreous hemorrhages
Due to necrotizing obliterative vasculitis, which may be found either in the anterior or posterior segment, or more commonly in both, neovascularization at the optic disc or at the periphery, can lead to retinal detachment with or without vitreous hemorrhage and neovascular glaucoma. This complication used to lead to enucleation.
Ocular fundus at the end stage with diffuse chorioretinal and optic nerve atrophy after recurrent ocular inflammation attacks
Fluorescein Angiography
Fern-like diffuse capillary fluorescein leakage from retinal vessels
Management
There is no standard treatment regimen that is common in the world. Therefore, different protocols for the treatment are used in each region. In addition, the clinical effects of each treatment seem to differ from one patient to another. Broadly, the strategy of BD treatment is classified in two ways: (1) treatment of acute inflammatory attacks, and (2) suppression of future recurrent inflammatory attacks.
Treatment of Acute Ocular Inflammatory Attacks
Acute inflammatory attacks should be treated immediately to minimize the damage to ocular tissues especially at the posterior segment. For anterior uveitis, subconjunctival injection of soluble corticosteroids, e.g., 2 mg of dexamethasone, is effective in addition to frequent administration of betamethasone or prednisolone acetate eye drops (e.g., every hour) besides mydriatic agents.
Regarding the local therapy, for posterior segment inflammation, posterior sub-Tenon’s injection of soluble corticosteroids, e.g., 4 mg of dexamethasone, is effective. Repeated daily injection may be required for a week according to the severity of ocular attacks. Instead of posterior sub-Tenon’s injection, intravitreal injection of corticosteroids may also be effective. Regarding the systemic therapy, there is general agreement that posterior segment inflammation needs systemic corticosteroid treatment, or in severe cases, additional immunosuppressive treatment.
Suppression of Future Recurrent Inflammatory Attacks
Colchicine
Colchicine has the effect to inhibit the migration of granulocytes into the inflamed tissue. The effects of colchicine to suppress the frequency of acute inflammatory attacks were reported in BD (Matsumura and Mizushima 1975). The adequate dose is 0.5–1.0 mg per day. Kotter et al. from Germany reported that colchicine was partially effective in 66% of their BD patients (Kotter et al. 1996). However, in a double blind study, Aktulga et al. could not show significant efficacy of colchicine in BD (Aktulga et al. 1980).
Cytotoxic Agents
Cytotoxic agents such as cyclophosphamide and chlorambucil are cheap. Therefore, today chlorambucil may be the choice of drug for mild BD, or in case of severe diseases, it is mostly ordered in developing countries. Azathioprine has been shown to maintain visual acuity and prevent the development of eye disease (Hamuryudan et al. 1997; Yazici et al. 1990); however, these drugs are not effective enough to completely suppress the recurrent inflammation in severe cases. Azathioprine is, besides cyclosporine, the only drug which has shown effective on BD by a RCT.
Cyclosporine
According to the results of a double-masked trial of cyclosporine versus colchicine, it was revealed that cyclosporine was more effective in reducing the frequency of ocular attacks than colchicine (Masuda et al. 1989). The initial dose of cyclosporine is usually 5 mg/kg/day and the dosage is adjusted according to the trough level or the area under the blood-concentration-time curve during the first 4 h after cyclosporine administration (AUC0–4). Colchicine is usually stopped to avoid interacting side effects including myositis. However, in severe cases, both colchicine and cyclosporine may be administered together.
Cyclosporine has some important side effects. Due to its nephrotoxicity, some patients are required to reduce the dosage or stop the treatment. Central nerve system (CNS) symptoms are also considered as side effects of cyclosporine especially in BD patients. In Behçet patients on cyclosporine, 25.5% developed CNS symptoms, whereas only 6.6% of the patients did without cyclosporine in Japanese patients (Kotake et al. 1999).
Corticosteroids
Systemic corticosteroids are used in some regions. However, rapid tapering leads to severe recurrence of ocular attacks. In refractory cases, low-dose systemic corticosteroids may be given in addition to immunosuppressive drugs.
Systemic corticosteroids are used in acute attacks for the suppression of tissue damage, as well as in chronic cases with no or minimal recurrence under the therapy. However, in very acute cases, the use of any immunosuppressive agent would not lead to a fast control of the disease. If the attacks are very severe, high-dose oral corticosteroids are needed, but should not be given alone. In refractory cases, another agent or combination of corticosteroids and immunosuppressive agents, depending on the disease severity, should be started immediately. This will lead to faster control and reduce the risk of a flare-up during corticosteroid tapering.
TNF-α Blocking Agents
TNF-α is closely associated with the immunopathogenesis of BD. There are data available in ocular BD for the two agents, infliximab and adalimumab.
Infliximab
Infliximab is an anti-TNF-α chimeric monoclonal antibody composed of an antigen-binding variable region from mice with high affinity to human TNF-α and a constant region of human IgG1. Infliximab shows an excellent efficacy to suppress BD. In Japan, an open label trial was performed in Behçet patients who were refractory to cyclosporine therapy (Ohno et al. 2004). Administration of 5 mg/kg of infliximab was approved in Japan from January 2007 for BD complicated with refractory posterior uveitis, which does not respond to conventional therapy.
Some complications have been reported including infusion reaction and infections. Especially, screening tests for tuberculosis and hepatitis B virus have to be performed before starting infliximab. If there is some suspicion for inactive tuberculosis, the additional administration of anti-tubercular drugs is recommended to prevent reactivation of the disease.
Adalimumab
Adalimumab is also an anti-TNF-α antibody, but it is fully humanized, whereas Infliximab is human-murine chimeric. In the first report of three cases who switched from infliximab to adalimumab, (Mushtaq et al. 2007), all three patients had sight-threatening bilateral panuveitis with BD that was poorly responsive to conventional immunosuppression. The introduction of infliximab therapy stabilized their ocular disease. Due to the difficulty in attending the hospital or coping with the intravenous infusion, they switched to adalimumab that could be self-administered as 40 mg subcutaneously. Switching to adalimumab has maintained their disease in remission and prevented relapse.
Interferon Alpha-2a (IFNα-2a)
At the induction of recombinant human interferon alfa-2a (rhIFNα-2a) treatment, three to six million international units (IU) of rhIFNα-2a are injected subcutaneously daily, which will be reduced according to the clinical effect, typically in between 3 weeks to 3 million IU every second day, and continued to taper until 6–12 months. Immunosuppressive drugs should be stopped and corticosteroids should be reduced one day prior to the initiation of IFN. The recurrence rate and the 5-year visual acuity rate for ocular BD after treatment with rhIFNα-2a were reported (Deuter et al. 2008). During a mean follow-up of 85 months (60–132 months) after initiation of rhIFNα-2a, 90.2% of 41 eyes improved or remained stable. There was no loss of originally better visual acuity. No patient had developed a pale optic nerve. The relapse-free period in the same group was at least 2 years in 60.9%, and at least 6 years in 26.1%, which shows that rhIFNα-2a can be stopped without resulting in recurrences.
Intravitreal Injection of Triamcinolone Acetonide (IVTA)
Repeated IVTA in BD refractory to conventional therapy has been shown to prevent the recurrence of posterior uveitis (Ohguro et al. 2006). However, recurrences developed once the TA particle disappeared from the vitreous cavity. The IVTA may need to be performed repeatedly before TA particle disappears. Despite preventing systemic complications, the high incidence of complications after intravitreal injection (progression of cataract and increased intraocular pressure) reduces its value, and today, this regimen may be only a second line treatment in care of active BD, which is vision threatening.
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