Behçet’s disease is a refractory systemic inflammatory disease of unknown cause characterized by four major symptoms: oral aphthous ulcers, ocular lesions, genital ulcers, and skin lesions. Inflammation is acute and transient, but the disease is characterized by repeated relapses. It occurs in young to middle-aged adults (20s–50s) with a male-to-female ratio of approximately 1:1. Uveitis occurs in about 70% of male patients and 45% of female patients, with severe cases more common in young men.
It is frequently observed along the Silk Road from the Mediterranean to China and Japan. About 50% of patients are positive for HLA-B51 (15% in the general population)5), and HLA-A26 (A*2601) has also been reported as an independent risk allele. Immunogenetic predisposition and environmental factors are thought to be involved in the onset. This disease once had a high blindness rate, but advances in immunosuppressants and biologics have reduced the blindness rate.
Behçet’s disease is registered as a designated intractable disease (No. 56)8).
Disease characteristics
Age of onset: Young to middle-aged adults (20s–50s)
Sex difference: Male-to-female ratio approximately 1:1. Ocular lesions are often severe in young men.
Geographic distribution: High frequency along the Silk Road (Mediterranean to Middle East to East Asia).
Genetic background: HLA-B51 positive (about 50% of patients), HLA-A26 is also an independent risk factor 5).
4 Major Symptoms
Oral aphthous ulcers: Painful recurrent ulcers. Often the initial symptom.
Ocular symptoms: Acute iridocyclitis, retinal uveitis, retinal vasculitis.
Genital ulcers: Painful, well-defined aphthous ulcers.
Skin symptoms: Erythema nodosum, folliculitis-like rash, thrombophlebitis.
The proportion of Behçet’s disease among all uveitis cases has been decreasing over time. In the 2002 epidemiological survey, it was 6.2% (3rd most common), but in 2009 it decreased to 3.9% (6th most common) 5). In addition to a decrease in the number of patients, a milder disease course has also been reported 4).
Behçet’s disease is a systemic inflammatory disease that recurs repeatedly, characterized by four major symptoms: oral aphthous ulcers, ocular symptoms, genital ulcers, and skin symptoms. The cause is unknown, but an autoimmune mechanism is suspected. It is more common in regions along the Silk Road, and genetic background (HLA-B51) and environmental factors are thought to be involved. Ocular lesions are particularly important and can lead to blindness without appropriate treatment.
Ocular subjective symptoms include blurred vision, decreased visual acuity, and floaters during inflammatory attacks. Inflammation often recurs in one eye at different times, eventually becoming bilateral in about 90% of cases. In severe cases, attacks may occur several times a month, while in mild cases, attacks occur about once a year and continue for several years to over a decade. Retinitis localized to the macula may recur, causing irreversible vision loss.
Systemic symptoms mainly include oral aphthous ulcers (about 90%), skin lesions (about 75%), and genital ulcers (about 50%). Oral aphthous ulcers commonly occur on the tongue, buccal mucosa, lips, and gums, and are painful ulcers with surrounding redness. They are almost always present in this disease and are often the initial symptom. They heal without scarring within 10 days but recur repeatedly.
Secondary symptoms include arthritis without deformity or stiffness, epididymitis, gastrointestinal Behçet’s disease (ileocecal ulcers), vascular Behçet’s disease (vasculitis), and neuro-Behçet’s disease (meningoencephalitis). Since extraocular symptoms and ocular findings are not always linked, it is important to evaluate systemic status in addition to ophthalmologic observation3).
The following two ocular symptoms recur paroxysmally.
(1) Acute iridocyclitis, sometimes with hypopyon. (2) Diffuse vitreous opacities, retinochoroiditis, and retinal vasculitis.
Early and active phase findings of ocular attacks: Paroxysmal ocular inflammation. Fine keratic precipitates, anterior chamber inflammatory cells, and hypopyon. Fibrin exudation in the anterior chamber is usually absent. No iris or angle nodules (non-granulomatous). In the posterior segment, vitreous opacities, retinal exudates, and hemorrhages characteristically resolve relatively quickly (1–2 weeks)3).
Late findings3): Retinochoroidal atrophy, retinal vascular sheathing, optic disc pallor → leading to severe visual dysfunction.
Hypopyon in Behçet’s disease is fluid due to predominant neutrophil infiltration, forming a clean horizontal level. It characteristically shifts easily with changes in body position, differing from the viscous hypopyon of HLA-B27-associated uveitis3). Keratic precipitates are fine and dust-like, showing non-granulomatous findings.
During acute exacerbation of retinal uveitis, vitreous opacities, retinal vasculitis, white retinal exudates, and hemorrhages are observed. White exudates are due to leukocyte infiltration and ischemic swelling of nerve fibers, and characteristically resolve relatively quickly (within about a week). Occlusive vasculitis may cause hemorrhages resembling branch retinal vein occlusion.
Fluorescein angiography often reveals extensive, vigorous leakage from retinal capillaries (fern-like leakage) even when no ocular attack is present, which is considered characteristic of this disease.
A scoring system that quantifies the degree of inflammation for each ocular attack. It consists of six items: anterior chamber inflammation (max 4 points), vitreous opacity (max 4 points), peripheral retinal lesions (max 8 points), posterior pole retinal lesions (max 4 points), foveal lesions (max 2 points), and optic nerve lesions (max 2 points), with a maximum total of 24 points. It is used for objective assessment of attack severity and evaluation of treatment efficacy6).
Additionally, intraocular inflammation may be accompanied by complicated cataract and secondary glaucoma, which can cause visual impairment.
Skin findings: Erythema nodosum commonly occurring on the lower legs, subcutaneous thrombophlebitis, and folliculitis-like or acneiform rashes on the face, neck, and back. Genital ulcers are painful, well-demarcated aphthous ulcers, commonly occurring on the scrotum and penis in men, and on the labia majora and minora in women.
In pediatric patients, severe ocular symptoms such as posterior uveitis, retinal vasculitis, and papillitis have been reported1), and diagnostic delay can average 11.3 ± 8.5 months1).
Hypopyon in Behçet’s disease is neutrophilic, thus “watery,” forming a clear horizontal level that shifts with changes in body position. In contrast, hypopyon in HLA-B27-associated uveitis is more viscous, does not form a level, and appears raised3). This difference in consistency can aid in diagnosis.
The cause of Behçet’s disease is unknown, but external factors such as involvement of pathogenic microorganisms like streptococci, and internal factors such as genetic background and immune abnormalities are suspected. Functional abnormalities of neutrophils and abnormalities of cytokines including TNF-α play a central role, leading to episodic and recurrent inflammatory reactions mainly in the oral mucosa, eyes, skin, and genitalia.
| Risk Factor | Details |
|---|---|
| HLA-B51 | Positive in approximately 50% of patients (15% in the general population). A major genetic marker5) |
| HLA-A26 | Reported as an independent risk allele2) |
| Region/Ethnicity | High frequency along the Silk Road (Mediterranean to Middle East to East Asia) |
| Sex and age | Onset between 20s and 50s. Severe ocular involvement is more common in young men. |
Pediatric cases account for approximately 1.6–7.7% of all Behçet’s disease cases 2), and severe ocular involvement has been reported in HLA-B51-positive cases 1).
:::tip Daily life precautions Colchicine must be taken long-term to prevent ocular attacks. Even if attacks seem to subside, do not stop medication on your own. Also, photocoagulation therapy is known to sometimes trigger severe attacks, so it is important to discuss thoroughly with your doctor. :::
The diagnosis of Behçet’s disease is based on the clinical guidelines of the Ministry of Health, Labour and Welfare’s Behçet’s Disease Research Committee (1987, minor revision 2016). For diagnosis based on ocular symptoms, refer to the Behçet’s Disease Ocular Lesion Clinical Guidelines (2012) 3).
Complete type is defined as the appearance of all four major symptoms during the course; incomplete type is defined as the appearance of three major symptoms, or two major symptoms plus two minor symptoms (or typical ocular symptoms plus one other major symptom and two minor symptoms).
Five minor symptoms (2016 minor revision) 8): (1) arthritis without deformity or stiffness, (2) epididymitis, (3) gastrointestinal lesions represented by ileocecal ulcers, (4) vascular lesions, (5) moderate to severe central nervous system lesions
| Type | Requirement |
|---|---|
| Complete type | All four major symptoms appear |
| Incomplete type | Three major symptoms, or two major symptoms + two minor symptoms |
| Special type | Intestinal type, vascular type, neurological type (when meeting criteria for complete or incomplete type and accompanied by special lesions) |
The International Diagnostic Criteria of the International Study Group for Behçet’s Disease (ISG criteria, 1990) 7) are also widely used internationally.
Ophthalmic examination:
Systemic examination:
In pediatric cases, diagnosis is often delayed; one report indicated an average of 11.3 ± 8.5 months from ocular symptom onset to diagnosis 1).
HLA-B27-associated uveitis: hypopyon is viscous and irregular with a slightly raised center. There is almost no posterior segment inflammation 3). Fungal endophthalmitis: forms hypopyon and vitreous opacities but is progressive. Diabetic iritis: rarely forms a hypopyon 3).
Oral colchicine (off-label use): 0.5–1.5 mg/day, usually 1 mg/day in two divided doses. Partial improvement is seen in about 60% of patients 3). Side effects: gastrointestinal symptoms such as diarrhea, teratogenicity. Long-term medication is required even after ocular attacks subside, and regular blood tests (monitoring for hepatorenal dysfunction, granulocytopenia, rhabdomyolysis) are necessary.
Cyclosporine (Neoral® 50 mg): Approximately 5 mg/kg/day in two divided doses. Monitor trough levels targeting 50–200 ng/mL.
:::caution Important side effects of cyclosporine Renal dysfunction occurs at a high rate. Furthermore, it is known that neuro-Behçet’s disease develops in about 20% of cases, so attention to neurological symptoms is necessary during long-term administration 3). Combination with colchicine carries a risk of myopathy. :::
In severe cases where visual function is difficult to maintain, early introduction without going through Step 3 should be considered 3).
Pre-treatment screening (TNF inhibitor guidelines) 9):
Contraindications 9): Active infections including tuberculosis (atypical mycobacterial infection, hepatitis B virus infection), congestive heart failure (NYHA class III or higher), malignancy, demyelinating diseases (e.g., multiple sclerosis)
Side effect monitoring 9): Regular peripheral blood tests (white blood cells, lymphocytes) and biochemical tests (including CRP). Monitor for tuberculosis and Pneumocystis pneumonia (chest X-ray, CT, β-D-glucan). Monitor for reactivation of past hepatitis B virus infection (HBV-DNA). Monitor for infusion reactions (during infusion and for 2 hours after). Also monitor for delayed hypersensitivity (muscle pain, rash, fever, joint pain occurring 3 or more days after infusion).
Physician and facility requirements 9): Must be a board-certified ophthalmologist of the Japanese Ophthalmological Society and a member of the Japanese Society of Ocular Inflammation, and have completed the society’s e-learning. The initiating facility must be registered with the Japanese Society of Ocular Inflammation. Collaboration with internists experienced in managing severe side effects, respiratory/infectious diseases, and TNF inhibitors is required.
Representative case: 32-year-old male, HLA-B51-positive complete type. Uncontrollable with cyclosporine, prednisolone, and colchicine → infliximab introduced. In the year before initiation, 3 ocular attacks in both eyes combined → attacks disappeared in the year after initiation. Corrected visual acuity improved from right 1.2/left 0.7 to right 1.2/left 0.9. Good vision maintained even after 3 years and 6 months3).
In some cases, severe ocular inflammatory attacks are triggered during dose reduction or discontinuation, worsening visual prognosis. Generally, long-term oral steroids are not recommended, but they may be used for a very short period of about one week when exudative changes in the macula are prominent3).
For minimally invasive intraocular surgery, discontinuation of TNF inhibitors is not an absolute indication. For extraocular surgery or highly invasive surgery of other organs, consider discontinuation (infliximab half-life approximately 8-9.5 days, adalimumab approximately 14 days).
It is used in refractory and severe cases where ocular attacks cannot be controlled with colchicine or cyclosporine. Only ophthalmologists who are certified by the Japanese Ophthalmological Society and members of the Japanese Society for Ocular Inflammation, and who have completed e-learning, can prescribe it9). After initial doses at weeks 0, 2, and 6, maintenance doses are given every 8 weeks. Screening for tuberculosis and hepatitis B is mandatory before administration.
The pathogenesis of Behçet’s disease is thought to involve a combination of immunogenetic predisposition and environmental factors.
Genetic factors: HLA-B51 is the strongest genetic marker associated with Behçet’s disease, positive in about 50% of patients (vs. 15% in the general population)5). HLA-B15, B27, B40, B44, B52, B57, and A26 have also been identified as independent risk alleles2).
Inflammatory mechanism: Functional abnormalities of neutrophils play a central role, and overproduction of cytokines such as TNF-α triggers inflammatory responses. In the eye, occlusive vasculitis occurs, manifesting as increased permeability of retinal capillaries (fern-like fluorescence leakage on fluorescein angiography). During acute exacerbations, infiltration of leukocytes (neutrophils) and ischemia lead to the formation of white exudates.
Characteristics of non-granulomatous inflammation: Non-granulomatous iridocyclitis, where inflammatory cells do not form clumps → mutton-fat keratic precipitates. This is an important feature for differentiation from granulomatous uveitis such as sarcoidosis and Vogt-Koyanagi-Harada disease3).
Recurrent inflammatory attacks: Repeated ocular attacks lead to retinal atrophy and optic nerve atrophy, resulting in severe visual impairment. The fact that hypopyon is neutrophilic and has a thin, watery consistency also reflects the neutrophil-dominated inflammatory mechanism.
In representative cases from the guidelines, a favorable course over 3 years and 6 months has been reported 3). The introduction of infliximab significantly reduces the frequency of ocular attacks and maintains or improves visual acuity 10). A review of long-term infliximab administration for refractory Behçet’s disease in Japan also demonstrates high efficacy in suppressing attacks and maintaining vision 11).
Comparison of patients from the 1980s and 1990s (Yoshida 2004) confirms a trend toward milder disease 4). The prevalence decreased from 6.2% to 3.9% between 2002 and 2009 5). Along with the widespread use of biologics, the incidence of severe visual impairment has also declined.
TNF inhibitors (infliximab, adalimumab) have been reported effective in multiple diseases including non-infectious uveitis associated with Behçet’s disease 12). Even in pediatric cases, aggressive treatment including infliximab has been reported to maintain good visual acuity 1). Evidence for adalimumab in Behçet’s disease is accumulating, and future research results are anticipated 9).
:::danger Disclaimer This article is intended to provide medical information and does not indicate individual diagnosis or treatment. Decisions regarding treatment should always follow the instructions of a specialist. Dosage and administration of medications vary depending on individual conditions, so please consult your physician for actual prescriptions. :::
