A Short Overview of Behcet’s Disease

Abstract

Behçet’s disease is a chronic, relapsing-remitting, occlusive vasculitis affecting multiple organ system. Greek physician Adamantiades had reported the disease as a classic trisymptom complex of hypopyon, iritis, and orogenital aphthosis. Behçet’s disease has an undulating course of exacerbations and remissions, and appears to be more severe in young, male, and Middle Eastern or Far Eastern patients. This article describes in brief Behçet’s disease in a new perspective.

1. Introduction

Behçet’s disease is a multisystemic, chronic disorder, characterized by oral and genital aphthous ulcers, arthritis, and cutaneous lesions, ocular, gastrointestinal and neurological manifestations. It was discovered by Prof. Hulusi Behçet a Turkish dermatologist in 1937–41 [1].

It is a chronic inflammatory disease of unknown etiology that can affect all body organ systems because of inflammatory effects on arteries and veins of all sizes with worldwide occurrence. The aetiopathological mechanisms of disease development remain unclear. The evidence base for treatment is limited but new knowledge is emerging and current treatment options range from symptomatic treatment, through to non-biological and biological immunosuppressive drugs, to cover the spectrum of clinical manifestations [2, 3].

2. Epidemiology

Traditionally known as the ‘silk route’ disease, Behçet’s disease is seen mainly along the historical Silk Route, which joined the East to the West suggesting that an inherited tendency to develop Behçet’s disease was spread by merchants who traveled these trading routes. The highest prevalence was seen in Turkey with 20–420 in 100,000 inhabitants while the lowest was in UK with a prevalence of 0.64. However, due to migration of people from various counties and environmental factors the disease is now prevalent worldwide. Predominant age of occurrence is between 3rd and 4th decades. Disease is more predominant in males with more severe disease manifestations in some Mediterranean areas [4, 5, 6, 7, 8, 9].

3. Etiopathogenesis

The etiology of Behçet’s disease remains uncertain but various studies suggest an infectious trigger with inflammatory mediators and immune deregulation as the cause in a genetically susceptible host. Studies have shown an association between Behçet’s disease and the allele HLA-B*51 (chromosome 6p21), which is relatively common in many ethnic groups [1, 10, 11, 12].

HLA-B*52, which differs from HLA-B*51 by only two amino acids in peptide binding groove, is not associated with Behçet’s disease in any population, suggesting selective peptide binding. Geographical distribution of HLA-B*51 among healthy subjects roughly corresponds with global disease distribution. But 1/3 of patients, even in countries with a high disease prevalence, do not possess this gene [1, 10, 11, 12].

In Japanese series prevalence of HLA-B*51 is only 57%. There is some evidence that HLA B51, as well as B12, B15, B27, B57, DR2, and DR7 may bear a relationship disease. A possible explanation for these data is that HLA-B*51 molecule expresses Bw4 motif, which itself may be causally related to disease [1, 10, 11, 12].

MHC class I chain related [MIC] gene locus is situated adjacent to HLA-B domain. MICA is expressed at gastrointestinal epithelial surfaces in response to bacterial infection. γδ T cells and NK cells are upregulated, recognize and kill MICA transfected cells. MICA ligand for NKG2D, also expressed on γδ T cells and NK cells. Association b/w MICA6 and Behçet’s disease may be a secondary phenomenon related to HLA-B*51. MEFV gene mutations is seen in persons with Mediterranean fever and is associated with vascular system [13, 14, 15].

ERAP1 variant associated with Behçet’s disease processes microbial proteins in such a way that they can be loaded onto HLA-B*51 molecule to trigger an abnormal immune response. A significant association of Behçet’s disease with variants near CCR1, KLRC4, AND STAT4 gene also found. Single nucleotide polymorphism [SNP] Gene encoding protein tyrosine phosphatase type 22 [PTPN22 620 W] has an inverse relationship with Behçet’s disease [13, 14, 15].

Environmental factors such as organophosphates, heavy metal intoxication, organochlorides and allergens may trigger initiation or exacerbate Behçet’s disease [16, 17].

Streptococcus sanguis and Streptococcus oralis may be found in the oral microbiome of Behçet’s disease patients. Hepatitis virus, parvovirus B19, mycobacteria, Escherichia coli Borrelia burgdorferi, Saccharomyces cerevisiae fungus can be elevated in Behçet’s disease [16, 17].

4. Clinical features

Signs and symptoms can be recurring and may precede the onset of mucosal membrane ulcerations by 6 months to 5 years. Prior to onset of disease, patients may exhibit a symptoms including malaise, anorexia, generalized weakness, cachexia, decreased or elevated temperature headache, perspiration, lymphadenopathy, substernal and temporal pain. A history of repeated tonsillitis, sore throats, tonsillitis, myalgias, and migratory erythralgias without overt arthritis is common [18, 19, 20, 21].

Diagnostic criteria from Behçet syndrome research committee of Japan [1987 revision].

1. Complete – Four major features.

2. Incomplete – 3 major features, 2 major and 2 minor features, Typical ocular symptoms and 1 major or 2 minor features.

3. Possible – 2 major features, 1 major and 2 minor features.

Major features

• Recurrent aphthous ulceration of oral mucous membrane,

• Skin lesions -Erythema nodosum—like lesions, subcutaneous thrombophlebitis, cutaneous hypersensitivity and folliculitis.

• Eye lesions—Iridocyclitis, retinouveitis, chorioretinitis definite history of chorioretinitis or retinouveitis.

Minor features

• Arthritis without deformity,

• Ankylosis,

• Gastrointestinal lesions characterized by ileocecal ulcers,

• Vascular lesions epididymitis, and

• Central nervous system symptoms.

Recurrent oral ulcers occur in >90% of cases. They recur at least 3 episodes in a year. Grossly & histologically similar to common oral ulcers, but are more extensive and multiple ulcers. Lesions are multiple, painful,1–3 cm in diameter & sharply margined with fibrin coated base and surrounding erythema. They heal without scarring in 4–30 days [18, 19, 20, 21].

Genital ulcers [90%, M > F] resemble their oral counterparts but cause greater scarring. In males ulcers usually occur on scrotum, penis, and groin. In females they occur on vulva, vagina, groin, and cervix. Ulcers may also be found in urethral orifice and perianal area. Sometimes epididymitis may arise [18, 19, 20, 21].

Ocular manifestaions include anterior uveitis and posterior uveitis. Retinal vasculitis can lead to blindness.

Secondary complications such as cataract, glaucoma, tractional retinal detachment, chronic cystoid macular edema, vision loss & neovascular lesions can also occur. Blindness occurs within 4–5 years from onset of ocular symptoms [18, 19, 20, 21].

Arthralgia, thrombophlebitis, and central nervous involvement, cardiac and pulmonary manifestations are occasional complications of the disease [18, 19, 20, 21].

5. Histopathological features

The intraoral ulcers are nonspecific, and are similar to recurrent aphthous ulcers according to Lehner. Endothelial proliferation has been observed in the lesions of Behçet’s disease but not in the recurrent aphthous ulcer [1, 22, 23].

Perivascular infiltrate of mononuclear cells; mast cell infiltrate and neutrophilic vasculitis may be found. Papulopustular lesions with spongiosis, basal keratinocyte vacuolization, intraepidermal pustules and suppurative folliculitis are seen [1, 22, 23].

Vasculitis also appears to be an essential lesion in Behçet’s disease, thrombi in vessel lumens, perivascular inflammatory infiltrate are also observed [1, 22, 23].

6. Management

Type of management depends on the organ affected and its severity. Therapeutic options according to the disease type, severity, age, and sex of each patient must be categorized. Investigations are mainly nonspecific indices of inflammation that include leukocytosis, elevated ESR and CRP [24, 25, 26].

The severity of the syndrome usually abates with time. Ocular, vascular, and neurologic disease, require more aggressive treatment. Corticosteroids, colchicine, azathioprine, cyclosporine, thalidomide, cyclophosphamide, Interferon-α and tumor necrosis factor-α inhibitors can be prescribed [24, 25, 26].

Apart from patients with central nervous system- Behçet’s disease and major vessel disease, the life expectancy is normal. The only other serious complication is blindness [24, 25, 26].

7. Conclusion

Although the exact cause of Behçet’s disease is unknown, genes, environmental triggers, and an abnormal immune response may be possible causes. In severe cases, there’s a risk of serious and potentially life-threatening manifestations, such as blindness and strokes.

Majority of the people exhibit episodes where their symptoms are severe (flare-ups or relapses), followed by periods where the symptoms disappear (remission). Therefore, the importance of close scrutiny for lesions in Behçet’s disease cannot be overstated.