Outcome Predictors for Intestinal Beh?et's Disease

Behçet''s disease (BD) is a multisystem inflammatory disorder that presents as recurrent oral and genital ulcers in conjunction with other dermatological and ocular manifestations. The prevalence of BD is higher in Middle and East Asia than in Western countries. Intestinal BD is a specific subtype of BD, characterized by intestinal ulcers and associated gastrointestinal symptoms. Similar to inflammatory bowel disease, intestinal BD exhibits a fluctuating disease course with repeated episodes of relapse and remission that necessitate adequate maintenance therapy after achievement of clinical remission. Medical treatment of intestinal BD is largely empirical since well-controlled studies have been difficult to perform due to the heterogeneity and rarity of the disease. To date, 5-aminosalicylic acid, systemic corticosteroids, and immunosuppressants have been used anecdotally to treat intestinal BD. The clinical course of intestinal BD shows considerable variability, and the exact point at which more potent agents such as immunosuppressants should be used has not yet been elucidated. Given the difficulty in predicting which patients will experience complicated disease courses and the fact that these drugs are related with certain risk resulting from immunosuppression, proper identification of prognostic factors in intestinal BD may allow physicians to implement tailored medical therapy and individualized patient monitoring based on risk stratification. In this review, the impact of baseline characteristics on the long-term course of intestinal BD, prognostic factors during various medical therapies, and outcome predictors related to surgery will be discussed.     

Carpal Tunnel Syndrome in Beh?et's Disease

Purpose

Behçet''s disease (BD) is a chronic inflammatory disease characterized by orogenital ulcers, skin and ocular lesions, in addition to articular, vascular, and neurologic symptoms. Carpal tunnel syndrome (CTS), can also occur in BD patients secondary to inflammation in the connective tissues, vessels, and tendons, as well as nerve involvement in BD itself. However, reports of patients who have CTS in BD are rare. The aim of this study was to evaluate the clinical characteristics of CTS in BD patients.

Materials and Methods

Retrospective analysis of the medical records of 1750 BD patients, and 14 (0.8%) BD patients who were diagnosed with CTS was performed at the BD Specialty Clinic of Severance Hospital. Patient demographics, disease activity/severity for both diseases, and the clinical characteristics of CTS in BD were recorded and analyzed.

Results

All 14 BD patients with CTS were women. Twelve patients (85.7%) were diagnosed with active BD. The CTS was mild in 8 patients (57.2%), moderate in 3 patients (21.4%), and severe in 3 patients (21.4%). Ten patients (71.4%) had BD prior to the diagnosis of CTS, and these 10 patients all had active BD.

Conclusion

CTS can occur as a result of the inflammation associated with BD and can also be the presenting symptom of nerve involvement in BD. CTS can also develop as the initial symptom of BD. Therefore, a higher degree of suspicion should be maintained for CTS in patients with BD and vice versa; however, the exact relationship is uncertain.     

Intestinal Beh?et's Disease: A True Inflammatory Bowel Disease or Merely an Intestinal Complication of Systemic Vasculitis?

Behçet''s disease (BD) is a multi-systemic inflammatory disorder of an unknown etiology and shows a chronic recurrent clinical course. When the disease involves the alimentary tract, it is called intestinal BD because of its clinical importance. Intestinal BD is more frequently reported in East Asian countries than in Western or Middle Eastern countries. While any part of the gastrointestinal tract can be involved, the most common location of intestinal BD is the ileocecal area. A few, large, deep ulcerations with discrete border are characteristic endoscopic findings of intestinal BD. Currently, there is no single gold standard test or pathognomonic finding of intestinal BD. However, recently developed novel diagnostic criteria and a disease activity index have helped in assessing intestinal BD. As intestinal BD shares a lot of characteristics with inflammatory bowel disease, including genetic background, clinical manifestations, and therapeutic strategies, distinguishing between the two diseases in clinical practice is quite difficult. However, biologic agents such as anti-tumor necrosis factor α antibody shows a considerable efficacy similar to inflammatory bowel disease cases. It is important to distinguish and treat those two disease entities separately from the standpoint of precise medicine. Clinicians should require comprehensive knowledge regarding the similarities and differences between intestinal BD and inflammatory bowel disease for making an accurate clinical decision.     

The Clinical Feature of Beh?et's Disease in Northeastern China

Purpose

Behçet''s disease (BD) is a chronic, relapsing, multi-system vasculitis of unknown aetiology with complicated and diversified clinical features predominantly involving oral and genital ulcers, and ocular and cutaneous lesions. The clinical features of this disease have been described to be different according to geographical areas and gender. We investigated the specific clinical features of BD patients in Northeastern China.

Materials and Methods

116 patients involved in this study fulfilled the classification criteria of the International Study Group for BD. The clinical manifestations and results of laboratory tests of BD were recorded in each patient.

Results

The onset was typically between 20-39 years with a slight female predominance. Oral ulcers were the most common manifestation, followed by skin lesions, positive pathergy reaction/genital ulcers, and ocular lesions. Vascular lesion and epididymitis were rare in patients with BD. The frequency of erythema nodosum-like lesion and articular involvement were significantly higher in females, while gastrointestinal involvement was significantly higher in males. The results of laboratory tests showed that the human leukocyte antigen (HLA)-B*51 alleles were positive in 30.9% of patients and the immunological abnormities were present in some patients.

Conclusion

The clinical features of BD showed geographical and gender difference. Genetic and immune factors might participate in aetiopathogenesis of BD.     

Renal Manifestations in 2007 Korean Patients with Beh?et's Disease

Purpose

Behçet''s disease (BD) theoretically affects all sizes and types of blood vessels and results in multi-organ involvement. However, renal BD has not been fully characterized, though the kidneys are histologically rich in blood vessels.

Materials and Methods

A total of 2007 patients who fulfilled the diagnostic criteria for BD were enrolled in this study. We reviewed the medical records and test results of the BD patients and used univariate and multivariate logistic regression analyses to determine the clinical significance of renal involvement in BD.

Results

Among the 2007 BD patients, we noted hematuria in 412 (20.5%) and proteinuria in 29 (1.4%). Univariate analysis showed that the BD patients with hematuria were predominantly female and older, had higher erythrocyte sedimentation rates (ESRs), and more frequently presented with genital ulcerations. BD patients with proteinuria had higher ESR levels compared to BD patients without proteinuria. In the multivariate analysis, age, sex, and ESR were found to be significantly associated with hematuria in BD patients, whereas only ESR was associated with proteinuria in BD patients. We also found that IgA nephropathy was the most common pathologic diagnosis in 12 renal BD patients who underwent renal biopsies.

Conclusion

We suggest that routine urinalysis and serum renal function tests be performed for the early detection of renal BD, especially in older female BD patients with recurrent hematuria, high ESR levels, and frequent genital ulcers, as well as in BD patients with proteinuria and high ESR levels.     

The comparison between Beh?et's disease and spondyloarthritides: does Beh?et's disease belong to the spondyloarthropathy complex?

This study was to clarify whether Behcet's disease (BD) could be classified into the spondyloarthropathy (SpA) complex. It was undertaken on 58 patients with BD (BD group), 56 patients with SpA (SpA group), and 3 patients who concurrently satisfied the criteria for BD and SpA (BDSpA group). The clinical parameters and known susceptible HLA antigens were compared between BD group and SpA group. In addition, 3 patients in BDSpA group were reviewed. The prevalence of definitive sacroiliitis (SI) in BD group and SpA group was 46.4% and 5.2%, respectively. However, none had a definitive SI in healthy controls. Enthesitis was observed in 3.4% of BD group and in 50% of SpA group. The patterns of eye involvement were different between these two groups. HLA-B27 was negative in all 49 patients of BD group, whereas it was positive in 67.9% of SpA group. The prevalence of HLA-B51 was 51.7% in BD group, and that in SpA group was 21.4%. One patient in BDSpA group was considered to have concurrent BD and ankylosing spondylitis (AS). Another patient was closer to AS, and the third to BD. Conclusively, it seems that BD could not be classified into the SpA complex.     

Correlation between Fluorescein Angiographic Findings and Visual Acuity in Beh?et Retinal Vasculitis

Purpose

To identify significant fluorescein angiographic (FA) characteristics associated with visual acuity (VA) in Behçet retinal vasculitis.

Materials and Methods

Retrospective review of 86 eyes of 48 patients (age: 35.6±10.2 years) with Behçet retinal vasculitis were performed. VA and FA findings as well as correlation between them were assessed.

Results

The mean initial VA of eyes with posterior pole-involved vasculitis (63 eyes; 73.3%) was significantly worse than that of those with peripheral vasculitis (23 eye; 26.7%) (logarithm of the minimum angle of resolution VA: 0.554±0.572 vs. 0.078±0.148; p<0.0001). Subgroup analysis revealed a more severe and diffuse pattern of vascular leakage in posterior pole-involved vasculitis compared to peripheral vasculitis (p<0.0001). Retinal vascular leakage (β=0.345; p<0.0001), optic disc hyperfluorescence (β=0.147; p=0.032), and macular leakage (β=0.107; p=0.047) were significantly associated with worse initial VA. During the follow up (mean: 33.3±17.9 months), the change of leakage showed no significant correlation with change of VA in posterior pole-involved vasculitis (τ=0.199, p=0.092).

Conclusion

Posterior pole involvement, the degree of retinal vascular leakage, optic disc hyperfluorescence, and macular leakage are significantly associated with VA in Behçet retinal vasculitis.     

Direct Immunofluorescence in Beh?et's Disease: A Controlled Study with 108 Cases

Purpose

Behçet''s disease (BD) is a disease of unknown etiology, which has multisystemic involvement. This multisystemic involvement might be the clue for an autoimmune pathogenesis. In order to evaluate an autoimmune pathogenesis, we examined immunoreactans depositions in the skin of BD patients.

Materials and Methods

The skin samples of 108 BD patients (28 perilesional skin, 44 positive pathergy test site, 22 negative pathergy test site, 14 normal skin) were examined for the depositions of immunoglobulin (Ig)M, IgG, IgA, complement 3 (C₃), and fibrinogen (F) using direct immunofluorescence (DIF). The data were statistically compared to the DIF of 36 systemic lupus erythematosus (SLE) patients and 20 healthy controls using χ² Fisher exact test.

Results

Highly significant immunoreactans depositions were obtained in BD (deposition rates: IgM 70.3%, IgG 0%, IgA 20.3%, C₃ 62.9%, F 83.3%). The comparison with SLE revealed no differences in IgM, IgA, and C₃. However, IgG deposition was higher in SLE while F deposition was higher in BD. In both BD and SLE, the Ig depositions were highly significant when the data were compared with the healthy controls.

Conclusion

The significant deposition of immunoreactans in BD, especially in the negative pathergy and the normal skin sites, were observed. This study is the first controlled study revealing positive Ig depositions in BD, and it is expected to help us to reconsider the autoimmune pathogenesis in BD.     

Natural Killer Cell Subsets and Their Functional Activity in Behçet’s Disease

Background: Behçet’s disease (BD) is a rare, chronic autoinflammatory disorder of unknown origin. Natural killer (NK) cells are one of the major immunoregulatory cell groups of the innate immune system, but their role in BD pathogenesis is not well documented.

Objectives: We aimed to investigate the role of NK cell subsets and their cytokine secretion and cytotoxic activity in patients with BD.

Patients and methods: The study group consisted of BD patients who had only mucocutaneous involvement, and they were compared with healthy subjects. BD patients were divided into two groups according to their frequencies of oral ulcerations. NK cell cytotoxicity was determined using CD107a expression and a CFSE-based cytotoxicity test. Expression of NK cell receptors and surface markers and the intracellular IL-5, IL-10, IL-17, and IFN-γ levels in CD16⁺ NK cells were assessed by flow cytometry.

Results: Although the cytokine secretion pattern was different, no difference was obtained in cytotoxic activity, expression of activatory receptors, or degranulation of NK cells.

Conclusion: Increases in NK1/NK2 ratio and CD16⁺IFN-γ⁺ NK1 cells might support the idea of a biased IFN-γ dominant immune response in the mucocutaneous involvement of BD pathogenesis. Although the cytokine secretion pattern was different, no difference was obtained in cytotoxic activity, expression of activatory receptors, or degranulation of NK cells.     

Clinical Experience of Interferon Alfa-2a Treatment for Refractory Uveitis in Beh?et's Disease

Behçet''s disease (BD) involves multisystem vasculitis of unknown origin. Ocular manifestations of BD mostly include bilateral panuveitis and retinal vasculitis, which are very challenging to treat. Interferon alfa-2a (IFN) has been recently introduced for treating refractory Behçet uveitis, mainly in Germany and Turkey. Nonetheless, there is so far no consensus about the ideal treatment regimen of IFN for Behçet uveitis. We report our experience of IFN treatment in five Korean BD patients with refractory uveitis. All patients complained of oral ulcers; one patient had a positive pathergy test and 2 showed the presence of HLA-B51. Immunosuppressive agents used prior to IFN treatment included cyclosporine and methotrexate. The IFN treatment was commenced with a dose of 6-9 MIU/day for 7 days, adjusted according to individual ocular manifestations, tapered down to 3 MIU three times in a week, and then discontinued. All patients showed positive response to IFN treatment; 50% of them showed complete response without additional major ocular inflammation during the follow-up period. Other BD symptoms also improved after IFN treatment in most cases. After treatment, the relapse rate and the required dose of oral corticosteroid were decreased in most cases, showing a significant steroid-sparing effect. However, the visual acuity was not improved in most cases due to irreversible macular sequelae. Despite the small sample size of this study, we suggest that, in Korean patients, IFN is an effective treatment modality for BD uveitis as was observed in German and Turkish patients.     

Interleukin-1β, Interleukin-1 Receptor Antagonist, and Soluble Interleukin-1 Receptor Type II Secretion in Chronic Fatigue Syndrome

Chronic fatigue syndrome is a condition that affects women in disproportionate numbers, and that is often exacerbated in the premenstrual period and following physical exertion. The signs and symptoms, which include fatigue, myalgia, and low-grade fever, are similar to those experienced by patients infused with cytokines such as interleukin-1. The present study was carried out to test the hypotheses that (1) cellular secretion of interleukin-1 (IL-1), interleukin-1 receptor antagonist (IL-1Ra), and soluble interleukin-1 receptor type II (IL-1sRII) is abnormal in female CFS patients compared to age- and activity-matched controls; (2) that these abnormalities may be evident only at certain times in the menstrual cycle; and (3) that physical exertion (stepping up and down on a platform for 15 min) may accentuate differences between these groups. Isolated peripheral blood mononuclear cells from healthy women, but not CFS patients, exhibited significant menstrual cycle-related differences in IL-1 secretion that were related to estradiol and progesterone levels (R ² = 0.65, P < 0.01). IL-1Ra secretion for CFS patients was twofold higher than controls during the follicular phase (P = 0.023), but luteal-phase levels were similar between groups. In both phases of the menstrual cycle, IL-1sRII release was significantly higher for CFS patients compared to controls (P = 0.0002). The only changes that might be attributable to exertion occurred in the control subjects during the follicular phase, who exhibited an increase in IL-1 secretion 48 hr after the stress (P = 0.020). These results suggest that an abnormality exists in IL-1 secretion in CFS patients that may be related to altered sensitivity to estradiol and progesterone. Furthermore, the increased release of IL-1Ra and sIL-1RII by cells from CFS patients is consistent with the hypothesis that CFS is associated with chronic, low-level activation of the immune system.Deceased     

Morbidity of Solid Cancer in Beh?et's Disease: Analysis of 11 Cases in a Series of 506 Patients

Purpose

Behçet''s disease (BD) is rarely reported to be associated with malignancies in the literature. However, the frequency of cancer in BD patients remains unknown. This study evaluated cancer morbidity in BD patients compared with that in the general population of Korea.

Materials and Methods

A retrospective chart review was performed on 506 patients visiting our hospital from 1994 to 2011 for BD. We analyzed the standardized morbidity rate (SMR), which is the ratio of observed to expected malignancies. Furthermore, we reviewed cases of solid cancer in BD patients in the literature.

Results

Of the 506 patients with BD, 11 (2.17%) developed cancer. We found a variety of solid cancers without predominance and no hematologic malignancies. The total number of cancers observed was less than expected, which was determined from the statistical data of the National Cancer Information Center of Korea, with an SMR of 0.023 (95% confidence interval, 0.012-0.039).

Conclusion

BD may be associated with a lower cancer-related morbidity compared with the general population of Korea.     

An Imperfect Correlation between DNA Replication Activity of Epstein–Barr Virus Nuclear Antigen 1 (EBNA1) and Binding to the Nuclear Import Receptor,Rch1/importin α

Epstein–Barr virus (EBV) replicates as a stable multicopy episome in latently infected mammalian cells. Latent cycle DNA replication requires only two viral elements, the cis-acting origin of plasmid replication (oriP) and the trans-acting origin binding protein (EBNA1). EBNA1 binds multiple recognition sites in oriP, but has no other enzymatic activities associated with replication functions. To identify human cellular proteins that mediate EBNA1 function, we designed a one-hybrid assay in yeast to select for proteins that bind to EBNA1 when bound to oriPin vivo.A human cDNA encoding the Rch1/hSRP1α/importinα protein was isolated and shown to bind to full-length EBNA1, but not to an amino terminal deletion mutant of EBNA1 when bound to oriP in yeast. The interaction of EBNA1 with Rch1 was confirmed biochemically by coimmunoprecipitation from nuclear extracts and by direct binding of recombinant proteinsin vitro.Internal deletion mutations in EBNA1 which compromised DNA replication activity were similarly reduced for binding to Rch1. Mutations with no effect on DNA replication activity were similarly unaffected for Rch1 binding. Rch1/importin α has been shown to bind to the nuclear localization sequence (NLS) of several proteins and stimulate nuclear import. A substitution mutation in the EBNA1 nuclear localization sequence reduced Rch1 binding, but had no effect on DNA replication function, indicating that Rch1 binding affinity does not correspond precisely with replication activity. Nevertheless, the identification of a stable interaction between Rch1 and EBNA1 at the origin of viral DNA replication raises the intriguing possibility that Rch1 contributes to the nuclear functions of EBNA1.     

Soluble TNF-�� Receptor I Encoded on Plasmid Vector and Its Application in Experimental Gene Therapy of Radiation-Induced Lung Fibrosis

Post-radiation inflammatory reaction leads to an irreversible pulmonary fibrosis which may cause lethal respiratory insufficiency. Pathological inflammatory and fibrotic changes might be attenuated by inhibiting tumour necrosis factor (TNF)-α activity using TNF-α soluble receptors. Thus, an experimental antifibrotic gene therapy with the plasmid vector encoding a mouse soluble receptor I for TNF-α (psTNFR-I) was assessed. Soluble TNFR-I encoding gene was cloned into pcDNA3.1 plasmid. The ability of psTNFR-I expressing vector to transfect cells, and its biological activity in vitro and in vivo were examined by PCR, RT-PCR, MTT assay and ELISA. The C57Bl/6J mice received single intramuscular injection of psTNFR-I, conjugated with polyetylenimine (PEI) 25 kDa, equally divided to both hind legs, 3 days before irradiation (20 Gy, Co60), and either a single injection or ten injections once a week after irradiation. The data proved the effectiveness of psTNFR-I product to neutralise TNF-α activity in vitro. The in vivo plasmid incorporation and maintenance was confirmed. Measurements of plasma soluble TNFR-I levels showed that the in vivo gene transfer was effective. PEI was found to enhance transfection efficiency in vivo. The psTNFR-I/PEI complexes caused no toxicity in the transfected mice. C57Bl/6J mice that received prolonged psTNFR-I/PEI injections developed lethal fibrotic syndrome and died 8 weeks later than the mice treated with a double plasmid injection and the control mice treated with a control plasmid. Sequential administration of soluble TNFR-I by a nonviral, intramuscular gene transduction in the early and late post-radiation inflammatory phase prolonged survival of irradiated mice and attenuated the symptoms of lung fibrosis. The psTNFR-I gene transduction may provide a safe and simple method to partially neutralise TNF-α activity and prevent radiation-induced lung injury.     

Gender-related Distribution of the Interleukin-1β and Interleukin-1 Receptor Antagonist Gene Polymorphisms in Patients with End-stage Liver Disease

Interleukin-1β (IL-1β) genetic polymorphisms and IL-1 receptor antagonist (IL1RN) variable number tandem repeat (VNTR) seem to be related with the occurrence of chronic diseases. This study aimed to verify whether IL-1β -511>C/T, -31>T/C, +3953>C/T and IL1RN VNTR were associated to the development of liver cirrhosis. Two hundred forty cirrhotic patients were involved in the study. A significant trend was detected, for increasing cirrhosis frequencies, grouping the patients as follows: females and males carrying neither the IL-1β (-511 -31) T-C/T-C or T-C/(T-T or C-C) diplotypes nor any IL1RN A2 allele (138/292), males carrying either the IL-1β T-C/T-C or T-C/(T-T or C-C) diplotypes or at least one IL1RN A2 allele (74/147) and males carrying either the IL-1β T-C/T-C or T-C/(T-T or C-C) diplotypes and at least one IL1RN A2 allele (28/37) (p?<?0.01). IL-1β polymorphisms are associated with the occurrence of end stage liver disease. IL-1β inflammatory activity appears more pronounced in males.