Intestinal Behcet’s : A Rare Presentation of Behcet’s Disease

We herein present a case of 48 years old female patient presented with fever, bloody diarrhea followed by palpable purpuric rash over the body along with recurrent oral and genital ulceration. These were associated with history of symmetric polyarthralgia. On examination moderate anemia, signs of anterior uveitis were found. In blood parameters thrombocytopenia along with elevated Erythrocyte Sedimentation Rate, C-Reactive Protein were noted. On further investigations the serological tests were found to be negative for Dengue, Chikungunya, HIV, HBV, HCV. Complement C3 found to be low. Colonoscopic biopsy is diagnostic of Indeterminate Crohn’s Disease with IgA, G, M, C3, Fibrinogen immunostaining in skin biopsy. ANA, P-ANCA, C-ANCA were found to be nonreactive for the patient. All of the above mentioned points were pointing towards Behcet’s disease. For confirmation, Anti Saccharomyces Cerevisae Antibody was found to be positive . Skin pathergy test was positive. So, we diagnosed this case as behcet’s disease.

Acometimento vascular na doença de Behçet: o processo imunopatológico / Vascular involvement in Behçet's disease: the immunopathological process

Resumo A doença de Behçet constitui uma forma rara de vasculite sistêmica, que acomete de pequenos a grandes vasos. É caracterizada por manifestações mucocutâneas, pulmonares, cardiovasculares, gastrointestinais e neurológicas. Sua apresentação clínica é bastante ampla, variando de casos mais brandos a casos graves, com acometimento multissistêmico, caracteristicamente com exacerbações e remissões. Suas causas ainda são desconhecidas; entretanto, há evidências genéticas, ambientais e imunológicas, como a associação com o alelo HLA-B51. Todas essas, em conjunto, apontam para um processo imunopatológico anormal, com ativação de células da imunidade inata e adaptativa, como as células natural killer, neutrófilos e células T, que geram padrões de respostas e citocinas específicos capazes de gerar mediadores que podem lesionar e inflamar o sistema vascular, resultando em oclusões venosas, arteriais e/ou formação de aneurismas.

Abstract Behçet's disease is a rare form of systemic vasculitis that affects small to large vessels. It is characterized by mucocutaneous, pulmonary, cardiovascular, gastrointestinal, and neurological manifestations. Its clinical presentation is quite wide, ranging from milder cases to severe cases, with multisystemic involvement, characteristically with exacerbations and remissions. Its etiopathogenesis is still unclear, although there is evidence of genetic, environmental, and immunological factors, such as the association with the HLA-B51 allele. In conjunction, all of these point to an abnormal immunopathological process, with activation of cells of innate and adaptive immunity, such as NK cells, neutrophils, and T cells, which generate specific response patterns and cytokines capable of generating mediators that can damage and inflame blood vessels, resulting in venous and arterial occlusions and/or aneurysm formation.

Clinical phenotypes of Korean patients with Behcet disease according to gender, age at onset, and HLA-B51

BACKGROUND/AIMS: The clinical manifestations of Behcet disease (BD) have been reported to differ according to country, region, and race. Gender, onset age, and human leukocyte antigen (HLA)-B51 have also been known as the factors that influence the clinical features of BD. The aim of this study is to investigate the clinical phenotypes of Korean patients who visited the rheumatology clinic with BD with respect to gender, onset age, and HLA-B51. METHODS: Total 193 Korean patients (129 females and 64 males) fulfilling the international criteria for BD were retrospectively assessed. RESULTS: The mean age at disease onset and disease duration of the BD patients were 32.2 ± 11.1 and 14.2 ± 9.3 years, retrospectively. Females suffered more frequently from genital ulcers (90.7% vs. 75.0%, p 40 years) suffered from neurologic involvement (15.9% vs. 4.2%, p = 0.007) more frequently than those with early onset of BD. The patients with HLA-B51 showed earlier onset of disease than without HLA-B51 (28.3 ± 11.4 years vs. 33.8±11.6 years, p = 0.02) and the neurologic and gastrointestinal involvements were more frequent in the patients without HLA-B51 than with HLA-B51 (17.2% vs. 2.5%, p = 0.02 and 20.7% vs. 2.5%, p = 0.01, respectively). CONCLUSIONS: The clinical phenotypes in Korean patients with BD may be influenced by gender, onset age and HLA-B51.

Macular hole in Behçet's disease.

Objective: To investigate the clinical features, prevalence, role of surgical intervention and the visual prognosis of macular holes (MH) in patients with Behcet's disease (BD). Materials and Methods: Retrospective study of patients with BD and MH from January 1998 to November 2008. Results: Out of 159 patients, 21 eyes of 17 patients were identified with MH. The mean age was 38.59 (range 23-61) years and the mean follow-up period was 5.1 years (range 13-164 months). The prevalence of MH was 7%. Visual acuity (VA) at the time of presentation ranged from 20/70 to hand-motion. Optical coherence tomography (OCT) findings revealed intraretinal cysts at the edge of the MH. The mean size of MH was 983.6 um; 52% had elevated edges, 43% had flat edges and only one eye (5%) was closed postoperatively. Fluorescein angiography (FA) was consistent with macular ischemia in 76% of the cases. Human leukocyte antigen (HLA) B51 association was found in 14 of the 15 patients investigated. Six patients (out of 17) underwent pars plana vitrectomy. The final VA on their last follow-up ranged from 20/70 to 2/200. Surgical intervention for MH did not result in any visual improvement as compared to non-operated eyes. One patient lost vision completely due to elevated intraocular pressure post vitrectomy and silicon oil tamponade. Conclusions: MH in patients with BD may lead to significant visual disability. Surgical intervention does not seem to have any potential beneficial effect on the VA, probably due to significant macular ischemia and sequelae from the ocular inflammation.

Association between HLA-B51 alleles and Behcet's disease in Chinese Han nationality / 中华皮肤科杂志

Objective To investigate the possible association between HLA-B51 alleles and Behcet's disease (BD). Methods Totally, 61 Chinese patients of Han nationality, who were diagnosed with BD according to the International Study Group (ISG) criteria, were recruited. The control cohort consisted of 100 healthy individuals. Blood samples were obtained from all the subjects. PCR-sequenee specific primers (SSPs) were used to for the genotyping of HLA-B51 alleles (HLA-B5101-HLA-B5109). Results Com- pared with the control group (11 positive, 11% ), the frequency of HLA-B51 (18 positive, 29.5% ) was sig- nificantly increased in BD patients (χ2=8.79, P<0.01, RR=3.39). The HLA-B51-positive patients and controls consistently carried HLA-B5101 allele with no other alleles observed. There were 15 males and 3 females in HLA-B51 positive patients, 22 males and 21 females in HLA-B51-negative patients, and signifi- cant differences in gender distribution was observed between HLA-B51-positive and negative patients (P<0.05 ). Moreover, the average age of onset in HLA-B51-positive patients significantly differed from that in HLA-B51-negative patients (28.4±10 years vs 37.3±12 years, P<0.05). However, no significant differ- ences were noticed in the clinical types, course, skin lesions, prevalence of genital ulcer, eye damage, joint involvement, or pathergy reaction between HLA-B51-positive and -negative patients (P0.05). Conclu- sions This study supports that HLA-B5101 allele is associated not only with the development of BD, but also with the gender and onset age of patients with BD of Chinese Han nationality.

The association between smoking and clinical manifestations in patients with Behcet's disease / 대한내과학회지

BACKGROUND/AIMS: There is controversy related to the role of smoking in affecting the clinical features of patients with Behcet's disease (BD). The aim of this study was to investigate the effect of smoking on clinical manifestations in Korean BD patients. METHODS: We enrolled 131 patients with BD who fulfilled the International Study Group (ISG) criteria of 1990. The disease-related clinical features of BD-oral ulcers, genital ulcers, ocular lesions, arthritis, vascular lesions, gastrointestinal lesions-and central nerve lesions, smoking history, disease duration, and the presence of HLA-B51 were retrospectively assessed through medical record reviews and patient interviews. Statistical analysis was performed using Chi-square, Fisher's exact, or student t-test, if appropriate. RESULTS: The frequencies of vascular and gastrointestinal lesions in smokers were significantly increased compared to those in non-smokers (p=0.040, OR=3.341, 95% CI 1.083-10.305; p=0.012, OR=3.878, 95% CI 1.379-10.906, respectively). Male smokers developed vascular lesions more frequently compared to female smokers, male non-smokers, and female non-smokers (p=0.025, OR=3.896, 95% CI 1.245-12.196). Moreover, smoking, male sex, and positive HLA-B51 may be risk factors for the development of gastrointestinal lesions in BD. Venous lesions were more frequently found in male smokers compared with other patients (p=0.038). CONCLUSIONS: Smoking may be associated with the development of vascular and gastrointestinal lesions in Korean BD patients. A large population prospective assessment of the clinical effect of smoking on BD is needed.

Behcet's Disease Presenting with Clinical Manifestations of Moyamoya Disease / 대한류마티스학회지

Central nervous system involvement of Behcet's disease (BD) shows various neuropsychiatric manifestations. The differential diagnosis may include many other systemic or neurologic diseases. Moyamoya disease (MD) is a progressive cerebrovascular occlusive disease of unknown etiology with a high incidence in Korea and Japan. HLA-B51 is significantly associated with both MD and BD. We first report a case of BD associated with MD in a 32-year-old woman with transient ischemic attacks of left hemiparesis and episodic dizziness. She was diagnosed as having BD manifested with oral ulcer, genital ulcer, erythema nodosum and positivity of pathergy reaction and HLA-B51. There was no evidence of cerebral infarction or hemorrhage in brain MRI. MR angiogram and 4-vessel angiography showed occlusion of bilateral internal carotid arteries and the development of collateral circulation, suggestive of MD. Bypass surgery was successfully performed. When evaluating the manifestations of MD, a chronic inflammatory disease, such as BD, needs to be considered as the underlying disease, especially in prevalent area of both diseases.

New Insights on the Pathogenesis of Behcet's Disease / 대한류마티스학회지

Behcet's disease (BD) is a chronic inflammatory disorder of unknown cause, characterized by recurrent oral ulcerations, genital ulcerations, ocular and skin lesions. Although the exact pathogenesis for BD is not completely understood, it has been suggested that the disease is triggered in genetically susceptible individuals by environmental factors, such as microbial agents. It is noted that multiple genes, including MHC and non-MHC genes, are implicated in the pathogenesis of BD. Although the HLA-B51 is known to be the candidate gene showing the strongest association with BD, it is necessary to be determined whether this HLA molecule is directly involved in the pathogenesis of BD. Cross-reactivity between microbial 65-kD and human 60-kD heat shock proteins is demonstrated to cause an increased T cell (particularly gammadelta T cell) response. The resultant overexpression of pro-inflammatory cytokines (mainly Th-1 type) from several immune cells seems to be responsible for the enhanced inflammatory reaction, and this may be associated with the genetic factors.

Behcet's Disease: The First Mongolian Case in Literature Showing HLA B51, MICA Gene Type *5/*6

Behcet's disease is a chronic multi-systemic disease of unknown origin that includes mucocutaneous, ocular, cardiac, vascular, renal, gastrointestinal, neurologic and cutaneous involvement. The disease is spread throughout the world, but it is most prevalent in the eastern Mediterranean region-along the Silk Road-, and in Japan, China, and Korea. Recently, we treated a Mongolian patient who had complete-type Behcet's disease. As far as we know, this case is the first report of a Mongolian with Behcet's disease in the English literature. HLA typing in this patient revealed A2, A24; B51, B35; Cw4, Cw7; DR9, DR11. Study of the MICA genetype showed *5, *6 positive. Our data provided adequate evidence, from an epidemiological aspect, to support the belief that Behcet's disease is most prevalent along the old Silk Road.

Association of MICA Polymorphism with HLA-B51 and Disease Severity in Korean Patients with Behcet's Disease

The HLA-B51 allele is known to be associated with Behcet's disease (BD) in many ethnic group. However, it has not yet been clarified whether the HLA-B51 gene itself is the pathogenic gene related to BD or whether it is some other gene in linkage disequlibrium with HLA-B51. Recently, the Triplet repeat (GCT/AGC) polymorphism in transmembrane region of the MHC class I chain-related A (MICA) gene was identified. To investigate the association of MICA with BD, we studied the MICA polymorphism in 108 Korean BD patients and 204 healthy controls in relation to the presence of HLA-B51 and clinical manifestations. The triplet repeat polymorphism was determined by polymerase chain reaction (PCR)-denaturing polyacrylamide gel electrophoresis (PAGE). The phenotype frequency of the MICA*A6 allele (relative risk, RR=2.15, p=0.002) and HLA-B51(RR=1.87, p=0.022) were significantly increased in the Korean patients with BD. A strong linkage disequilibrium was observed between the MICA*A6 and HLA-B51 in both the patients with BD and control subjects. Stratification analysis showed that MICA*A6 homozygosity was strongly associated with BD in the HLA-B51-negative population, and HLA-B51 was also associated with MICA*A6-negative population. In conclusion, MICA*A6 rather than HLA-B51 was strongly associated with Korean patients with BD, and the MICA*A6 allele is a useful susceptibility marker of BD, especially in the HLA-B5-negative

Influences of two different HLA-B antigens on receptors expression of NK cells from peripheral blood lymphocytes / 中国免疫学杂志

Objective:To investigate influences of two different HLA-B antigens expressed on K562 cells on receptors expression of NK cells from peripheral blood lymphocytes.Methods:Studied the alteration of the percentage of CD16+CD56+ cells and the percentage of KIR3DL1+ cells before and after PBMC interaction with K562 cells for 24 hours,and also compared the percentage of CD16+CD56+ cells and the percentage of KIR3DL1+ cells after PBMC interaction with two different kind of K562 cells transfected with HLA-B39 and HLA-B51 respectively.Results:After PBMCs were incubated with K562 cells for 24 hours,the percentage of CD16+CD56+ cells and the percentage of KIR3DL1+ cells were both increased.However,after PBMCs were incubated with K562-HLA-B51 cells for 24 hours,the percentage of KIR3DL1+ cells and the percentage of CD16+CD56+ cells were both decreased in comparison with that interaction with K562-HLA-B39 cells.Conclusion:CD16 up-regulation was associated with an up-regulation of inhibitory receptors(KIR3DL1).The interaction between HLA-Bw4 and KIR3DL1 would down-regulate the expression of KIR3DL1.In addition,KIR3DL1 down-regulation was associated with down-regulation of activating receptors(CD16).

Association of human leukocyte angtigen-B51 and Behet′s disease with uveitis / 中华眼底病杂志

0.10). Conclusions HLA-B51 might be a susceptible gene for BD, and there was a weak association between HLA-B51(HLA-B*5101) and BD patients with uveitis.

The study of HLA antigens in a familial Behcet? disease / 대한류마티스학회지

OBJECTIVE: Behcet? disease (BD) is a chronic inflammatory disorder affecting several organs. The etiology of BD remains unclear, although genetic factors, infectious agents, and immune mechanisms have been studied. The association of BD with certain genetic factors, especially HLA-B51 antigen, is well known in some geographical areas. Nevertheless, the familial occurrence of BD is rare. In this paper, HLA phenotype was evaluated in one family member showing the clustering of BD. METHODS: The serological tissue typing of HLA class I and class II antigens was performed by standard National Institutes of Health microlymphocytotoxicity method in seven family members in which four siblings were affected by BD. The diagnosis of BD was established by the criteria of the International Study Group of BD in these four siblings. RESULTS: In this family study, all members had HLA-A2 and DQ3 antigens. Although HLA-B51 antigen was positive in six out of seven family members, BD was developed in three of the six having HLA-B51 antigen. Three siblings had the exact same HLA phenotype. However, only one person had BD among three siblings with identical HLA phenotype. In addition, all siblings who developed erythema nodosum-like lesion had HLA-B51 antigen. CONCLUSION: This family suggests that the familial clustering of BD may not be explained solely by a susceptible HLA phenotype. The environmental factor or other genetic factors besides HLA-B51 might play a role in the development of BD. Furthermore, more studies and information will be needed to clarify the role of A2 and DQ3 antigens in BD.

Molecular genetics (HLA) of Behcet's disease

Behcet's disease (BD) has been known to be strongly associated with the human leukocyte antigen (HLA) B51. This B51 association has been confirmed in many different ethnic groups between the Middle East and Japan, and it has been proposed that BD is prevalent in those ethnic groups along the old Silk Route. The hypothesis could be made that B51 molecules are primarily involved in BD development through specific antigen presentation. However, polymorphic analyses of the TNFB gene and Tau-a microsatellite between the HLA-B and TNF genes indicate that the pathogenic gene of BD is not the HLA-B51 gene itself but another gene located around the HLA-B gene. HLA-C genotyping by the PCR-SSP method also suggests that the BD pathogenic gene is not the HLA-C gene itself but other gene located near the HLA-B gene. Recently we sequenced a single contig of 236,822 bp from the MICA gene (58.2 kb centromeric of HLA-B) to 90.8 kb telomeric of HLA-C and identified 8 novel genes designated NOB1-8 (NOB: new organization associated with HLA-B). During the course of the genomic sequence analysis we clarified the genetic structure of the MICA (MHC class I chain-related gene A) gene and found a triplet repeat microsatellite polymorphism of (GCT/AGC)n in the transmebrane (TM) region. Furthermore, the microsatellite allele consisting of 6 repetitions of GCT/AGC (MICA A6 allele) was present at a significantly higher frequency in the BD patient group than in the control group and a significant fraction of B51-negative patients were positive for this MICA A6 allele. These results suggest the possibility of a primary association of BD with MICA rather than HLA-B.

Etiopathology of Behcet's disease: immunological aspects

Behcet's disease is recognized as a systemic inflammatory disease of unknown etiology. The disease has a chronic course with periodic exacerbations and progressive deterioration. Previous reports have shown at least three major pathophysiologic changes in Behcet's disease; excessive functions of neutrophils, vasculitis with endothelial injuries, and autoimmune responses. Many reports suggested that immunological abnormalities and neutrophil hyperfunction may be involved in the etiology and the pathophysiology of this disease. HLA-B51 molecules by themselves may be responsible, in part, for neutrophil hyperfunction in Behcet's disease. T cells in this disease proliferated vigorously in response to a specific peptide of human heat shock protein (hsp) 60 in an antigen-specific fashion. T cells reactive with self-peptides produced Th1-like proinflammatory and/or inflammatory cytokines. This leads to tissue injury, possibly via delayed-type hypersensitivity reaction, macrophage activation, and activation and/or recruitment of neutrophils. These data shed new light on the autoimmune nature of Behcet's disease; molecular mimicry mechanisms may induce and/or exacerbate Behcet's disease by bacterial antigens that have activated T cells which are reactive with self-peptide(s) of hsp. This would lead to positive selection of autoreactive T cells in this disease.