2018 update of the EULAR recommendations for the management of Behçet's syndrome.

Several new treatment modalities with different mechanisms of action have been studied in patients with Behçet's syndrome (BS). The aim of the current effort was to update the recommendations in the light of these new data under the auspices of the European League Against Rheumatism (EULAR) Standing Committee for Clinical Affairs. A task force was formed that included BS experts from different specialties including internal medicine, rheumatology, ophthalmology, dermatology, neurology, gastroenterology, oral health medicine and vascular surgery, along with a methodologist, a health professional, two patients and two fellows in charge of the systematic literature search. Research questions were determined using a Delphi approach. EULAR standardised operating procedures was used as the framework. Results of the systematic literature review were presented to the task force during a meeting. The former recommendations were modified or new recommendations were formed after thorough discussions followed by voting. The recommendations on the medical management of mucocutaneous, joint, eye, vascular, neurological and gastrointestinal involvement of BS were modified; five overarching principles and a new recommendation about the surgical management of vascular involvement were added. These updated, evidence-based recommendations are intended to help physicians caring for patients with BS. They also attempt to highlight the shortcomings of the available clinical research with the aim of proposing an agenda for further research priorities.

Management of major organ involvement of Behçet's syndrome: a systematic review for update of the EULAR recommendations.

Objective: To assess the efficacy and safety of treatment modalities for major organ involvement of Behçet's syndrome (BS), in order to inform the update of the EULAR recommendations for the management of BS. Methods: A systematic literature review of all randomized controlled trials, controlled clinical trials, or open label trials assessing eye, vascular, nervous system or gastrointestinal system involvement of BS was performed. If controlled trials were not available for answering a specific research question, uncontrolled studies or case series were also included. Results: We reviewed the titles and abstracts of 3927 references and 161 studies met our inclusion criteria. There were only nine randomized controlled trials. Observational studies with IFN-α and monoclonal anti-TNF antibodies showed beneficial results for refractory uveitis. Meta-analysis of case-control studies showed that immunosuppressives decreased the recurrence rate of deep vein thrombosis significantly whereas anticoagulants did not. CYC and high dose glucocorticoids decreased mortality in pulmonary arterial aneurysms and postoperative complications in peripheral artery aneurysms. Beneficial results for gastrointestinal involvement were obtained with 5-ASA derivatives and AZA as first line treatment and with thalidomide and/or monoclonal anti-TNF antibodies in refractory cases. Observational studies for nervous system involvement showed improved outcome with immunosuppressives and glucocorticoids. Meta-analysis of case-control studies showed an increased risk of developing nervous system involvement with ciclosporin-A. Conclusion: The majority of studies related to major organ involvement that informed the updated EULAR recommendations for the management of BS were observational studies.

Cilostazol inhibits the expression of hnRNP A2/B1 and cytokines in human dermal microvascular endothelial cells.

OBJECTIVES: hnRNP A2/B1 has been identified as a target antigen of anti-endothelial cell IgA antibody in patients with Behçet's disease (BD). In addition, increased expression of cellular hnRNP A2/B1 is stimulated by Streptococcus sanguinis or the sera from patients with BD. We aimed to investigate the effects of cilostazol on the expression of hnRNP A2/B1 and chemokines in human dermal microvascular endothelial cells (HDMECs). METHODS: Expression of hnRNP A2/B1, cytokines, and chemokines in HDMECs was induced by tumour necrosis factor (TNF)-α, interleukin (IL)-1ß, and lipopolysaccharide (LPS). HDMECs were treated with cilostazol (10 µM) and the inhibitory effects were evaluated with real-time polymerase chain reaction and immunocytochemistry. RESULTS: Expression of hnRNP A2/B1, CXCL1, CXCL2, CXCL8, and IL-1ß mRNA was significantly increased in HDMECs treated with all three stimulants. In addition, mRNA expression of hnRNP A2/B1 and inflammatory mediators was significantly inhibited in HDMECs treated with various stimulants with cilostazol pretreatment. Immunocytochemistry demonstrated that cilostazol pretreatment effectively inhibited the stimulant-induced increased expression of hnRNP A2/B1 in the nucleus and cytoplasm of HDMECs. CONCLUSIONS: Cilostazol pretreatment can reduce the excessive expression of inflammatory cytokines and chemokines and hnRNP A2/B1 by the BD-related stimulants, including TNF-α, IL-1ß, and LPS, in HDMECs. We suggest that cilostazol may have therapeutic efficacy in inhibiting the major inflammatory reaction in the pathogenesis of BD.

Serum reactivity against herpes simplex virus type 1 UL48 protein in Behçet's disease patients and a Behçet's disease-like mouse model.

Herpes simplex virus (HSV) infection is a possible pathogenic factor in Behçet's disease (BD). Using proteomics analysis, this study detected a target HSV protein. Serum IgA and IgG reactivities against the identified protein were evaluated in patients with BD and in BD-like mice. A total of 4 protein bands generated by immunoprecipitation were analysed by proteomics, and HSV UL48 was commonly found in both IgA- and IgG-reactive protein bands. Compared with controls, patients with BD and BD-like mice exhibited higher titres of IgA reacting with recombinant HSV UL48 protein. Further proteomics analysis revealed that human heat shock cognate 71 kDa protein (Hsc71) is a cross-reacting target antigen against anti-HSV UL48 antibody. In addition, our data demonstrated a very strong association between serum IgG reactivity against recombinant human Hsc71 and recombinant HSV UL48 in patients with BD. We suggest that HSV infection and impaired human Hsc71 activity may be associated with the activation of autoreactive lymphocytes.

Development and validation of an electronic medical record-based disease activity index for Behçet's disease.

OBJECTIVES: The disease activity of Behçet's disease is inadequately defined, and there is no consensus on how it should be measured. The aim of this study was to verify the usefulness of a simplified electronic medical record (EMR)-based activity index (EMRAI) for Behçet's disease. METHODS: A total of 73 Korean patients with Behçet's disease participated in this study. Two dermatologists interviewed each participant independently using two activity scoring systems: the EMRAI and the Behçet's Disease Current Activity Form (BDCAF). Overall agreement between raters, correlation between activity scoring indices, and total interview run-time were evaluated. RESULTS: The EMRAI significantly correlated with the BDCAF (Spearman's correlation coefficient, r=0.835), physician-assessed overall activity score (r=0.782), erythrocyte sedimentation rate (r=0.520) and C-reactive protein level (r=0.422). The weighted kappa score for inter-rater agreement of EMRAI showed very good reliability compared with that of BDCAF (0.894 and 0.693, respectively). The mean total run-time for the EMRAI was shorter than that required to administer the BDCAF (95 s and 115 s, respectively). CONCLUSIONS: The EMRAI, an EMR-based simplified activity index of Behçet's disease, facilitates rapid and simple gathering of disease activity data and clinical information.

Detection of the inflammatory process in a Behçet's disease-like mouse model using 18F-fluorodeoxyglucose positron emission tomography.

OBJECTIVES: The major role of herpes simplex virus (HSV) type 1 infection in Behçet's disease (BD) immunopathogenesis has been demonstrated and inoculating the earlobes of ICR mice with HSV produced a BD-like mouse model. (18)Ffluorodeoxyglucose positron emission tomography (FDG PET) is widely used for diagnosing numerous human diseases other than malignancies. The aim of our study was to evaluate the inflammatory activities of BD-like symptoms in a HSV type 1-induced BD-like mouse model by small-animal FDG PET. METHODS: Five HSV-infected ICR mice with BD-like lesions, two asymptomatic HSV-infected mice, and two untreated mice were scanned with microPET, and autopsy specimens were histopathologically assessed to evaluate for infiltration by mixed inflammatory cells. RESULTS: The histopathological evaluation of the inflammatory process in knee and elbow joints significantly correlated with the quantitative assessment of FDG accumulation in the same joints in BD-like ICR mice, HSV-infected asymptomatic mice, and untreated control mice. Small-animal FDG PET clearly detected asymptomatic joint inflammatory processes in both BD-like mice and HSV-infected asymptomatic mice. In addition, genital ulcers and skin ulcers with associated perilesional lymphadenopathies in BD-like models were detected by microPET. However, biodistributed PET-positive images from the stasis of secreted FDG into the bowel lumen could not be distinguished from the inflammatory bowel lesions of BD when compared to FDG uptake in control mice. CONCLUSIONS: Our data indicate that FDG PET can non-invasively and quantitatively detect the inflammatory process in an HSV-induced BD-like mouse model.

Mucocutaneous manifestations of Behçet's disease: Pathogenesis and management from perspectives of vasculitis.

Behçet's disease (BD) is a systemic inflammatory disorder characterized by vasculitis affecting blood vessels of any caliber or type. It can present with a wide spectrum of vasculitic lesions, including erythema nodosum-like lesions and retinal vasculitis, and may also lead to larger vessel diseases, such as aortic aneurysm and deep vein thrombosis. The full etiology of BD remains unclear, but it is considered a polygenetic disease with multiple genetic risk factors that promote immune dysregulation and thrombophilia. Inflammation can be triggered by environmental factors, such as bacteria or viruses, and the dysregulation of innate and adaptive immune cell subsets. Neutrophils and lymphocytes are the primary players involved in BD pathogenesis, with specific innate (i.e., neutrophil-derived reactive oxygen species and neutrophil extracellular traps) and adaptive (i.e., anti-endothelial cell antibodies) processes inducing endothelial cell activation and chemotaxis of inflammatory cells, leading to coagulation and vasculitis. These inflammation-induced vasculitic or vasculopathic features are observed in most mucocutaneous BD lesions, although vasculitis per se is often pathologically evident only during a brief period of the disease process. Due to the multifactorial nature of BD-associated inflammation, broad-spectrum anti-inflammatory medications, including glucocorticoids and immunosuppressive drugs, have been the mainstay for managing BD. In addition, inhibitors of interleukin (IL)-1, tumor necrosis factor (TNF)-α, and IL-17, which target innate and adaptive immune functions dysregulated in BD, have emerged as promising new therapeutics. In this review, we discuss the muco-cutaneous manifestations of BD by focusing on the underlying vasculitic components in their pathologies, as well as the current array of treatment options.

Skin manifestation as an explaining factor of heterogeneity in Behçet's disease: A focused analysis in full-blown conditions.

Behçet's disease (BD), a chronic multi-systemic disorder, presents diverse clinical manifestations depending on patient ethnicity and geographic region. Use of varying diagnostic criteria augments clinical heterogeneity. We aimed to characterize heterogenous manifestations in patients with full-blown BD fulfilling the major diagnostic criteria in use. We retrospectively analyzed 338 patients diagnosed with complete BD based on Japanese diagnostic criteria, which fulfill both International Study Group (ISG) criteria and the International Criteria for BD (ICBD). Unbiased clustering analysis was performed to elucidate the heterogeneous spectrum, followed by subgroup analysis of identified clusters. Results of unbiased clustering analysis identify dominant skin lesion type as an important factor that determines clustering among the heterogenous BD patients. Regression analysis reveals that presence of predominantly papulopustular lesions has protective effect for vascular involvement compared to other skin phenotypes. In conclusion, unbiased clustering analysis highlights that dermatologic manifestation can be a factor to understand the heterogeneity of BD and determining the dominant type of skin lesions may help clinicians predict major vascular involvement.

Safety, Efficacy, and Drug Survival of Colchicine in Recurrent Aphthous Stomatitis in a Real-World Setting.

BACKGROUND: Recurrent aphthous stomatitis (RAS) is a common disorder characterized by episodic ulcerations in the oral mucosa. Although colchicine has been a common systemic treatment for RAS, there is still considerable uncertainty regarding its efficacy and drug survival in this setting. OBJECTIVE: We aimed to study drug survival, efficacy, and safety of colchicine for the treatment of RAS, especially in the real clinical setting. METHODS: Between 2012 and 2016, 150 patients given colchicine for RAS were selected for a single-centre retrospective study of real-world efficacy and drug survival. RESULTS: Among the 114 patients who qualified, 81.6% showed moderate or substantial responses (>25% improvement). Gastrointestinal complications (16.7%), neutropenia (3.5%), and liver enzyme elevation (4.4%) were reported within 2 weeks after initiating treatment. Delayed adverse manifestations were rare. One year after onset, colchicine use was sustained in roughly one-half (49.5%) of patients, whereas many (30.3%) had discontinued the drug, primarily due to lack of efficacy or adverse events. In Cox proportional hazard analysis, minor ulcers were identified as potential determinants of longer drug survival owing to less probability of non-efficacy. However, major ulcers had emerged as predictors of early discontinuation due to lack of efficacy. CONCLUSION: In patients with RAS, colchicine may be an effective and safe treatment amenable to long-term maintenance. Monitoring of adverse events within 2 weeks after initiating treatment is advisable to ensure safe administration.

CD4(+) CD25(+) regulatory T cells ameliorate Behcet's disease-like symptoms in a mouse model.

BACKGROUND AIMS: Behcet's disease (BD) is a chronic, multisystemic inflammatory disorder with arthritic, gastrointestinal, mucocutaneous, ocular, vascular and central nervous system involvement. It is well known that CD4(+) CD25(+) T-regulatory (Treg) cells prevent harmful immune responses to self- and non-self-antigens. In the present study, the role of Treg cells in herpes simplex virus (HSV)-induced BD-like symptoms was investigated. METHODS: HSV type 1 (F strain) inoculation of the earlobe of ICR mice has been shown to induce the development of BD-like symptoms. To determine whether the effect of Treg was associated with change in BD-like symptoms, CD4(+) CD25(+) T cells from the splenocytes of normal mice were adoptively transferred intravenously. Treg cells of splenocytes were significantly elevated following the transfer of 3 × 10(5) CD4(+) CD25(+) T cells to BD-like mice compared with the control group. RESULTS: The transfer of CD4(+) CD25(+) T cells to BD mice improved the symptoms, and the serum protein levels of interleukin (IL)-10, IL-6 and IL-17 were significantly altered compared with the control groups. Intravenous injection of anti-CD25 antibody to BD mice reduced the frequency of CD4(+) CD25(+) T cells and increased the BD severity score. We confirmed the influence of CD4(+) CD25(+) T cells on BD-like mice. CONCLUSIONS: These results show that up-regulation of the CD4(+) CD25(+) T cells in BD-like mice improves the inflammatory symptoms, while down-regulation of CD25(+) T cells is associated with deteriorated symptoms. Furthermore, these findings are correlated with changes in pro-inflammatory and anti-inflammatory cytokine levels.

Identification of streptococcal proteins reacting with sera from Behçet's disease and rheumatic disorders.

OBJECTIVES: We evaluated the reactivity of sera from Behçet's disease (BD), systemic lupus erythematosus (SLE), dermatomyositis (DM), rheumatoid arthritis (RA), and Takayasu's arteritis (TA) patients against human α-enolase and streptococcal α-enolase, and identified additional streptococcal antigens. METHODS: Enzyme-linked immunosorbent assay (ELISA) and immunoblotting were performed using sera from patients with BD, SLE, DM, RA, and TA and healthy volunteers (control) against human α-enolase and streptococcal α-enolase. Immunoblot analysis and matrix-assisted laser desorption ionisation-time-of-flight mass spectrometry were used to identify and recombine other streptococcal antigens. RESULTS: Specific positive signals against recombinant human α-enolase were detected by IgM ELISA of serum samples from 50% of BD, 14.3% of SLE, 57.1% of DM, 42.9% of RA, and 57.1% of TA patients. Specific positive signals against streptococcal α-enolase were detected from 42.9% of BD, 14.3% of DM, and 14.3% of TA patients. No SLE and RA sera reacted against streptococcal α-enolase antigen. Streptococcal proteins reacting with sera were identified as hypothetical protein (HP) for SLE and DM patients, acid phosphatase (AP) for RA patients, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) for TA patients. CONCLUSIONS: We observed that RA patients did not present serum reactivity against either HP or GAPDH though BD, SLE, DM, and TA patients did. Also, AP reacted with sera from BD, SLE, DM, RA, and TA patients.

Lower-fluence, higher-density versus higher-fluence, lower-density treatment with a 10,600-nm carbon dioxide fractional laser system: a split-face, evaluator-blinded study.

BACKGROUND: Adequate laser settings in the treatment of scars using a carbon dioxide fractional laser system (CO(2) FS) have not been established. OBJECTIVE: To compare the efficacy and safety of low-fluence, high-density with high-fluence, low-density treatment with CO(2) FS on acne scars and enlarged pores. METHODS: Ten patients with mild to severe atrophic acne scars and enlarged pores were enrolled. Half of each subject's face was treated with a single session of CO(2) FS with a fluence of 70 mJ and a density of 150 spots/cm(2) ; the other half was treated with a fluence of 30 mJ and a density of 250 spots/cm(2) . RESULTS: Follow-up results 3 months after a single low-fluence, high-density treatment with CO(2) FS showed that four of 10 participants had clinical improvement of 51% to 75% from baseline. After the high-fluence, low-density CO(2) FS treatment, five of 10 patients demonstrated marked clinical improvements of more than 76%. CONCLUSION: Higher-energy, lower-density laser settings seem to be more effective than lower-energy, higher-density settings for acne scars and enlarged pores, although our results do not constitute a conclusive comparison of the two different modes of CO(2) FS.

Treatment of striae distensae using an ablative 10,600-nm carbon dioxide fractional laser: a retrospective review of 27 participants.

BACKGROUND: Late-stage striae distensae is a type of scar characterized by a loss of collagen and elastic fibers in the dermis. Ablative 10,600-nm carbon dioxide fractional laser systems (CO2 FS) have been used successfully for the treatment of various types of scars. OBJECTIVE: To investigate the therapeutic efficacy of using CO2 FS for the treatment of striae distensae. METHODS: Twenty-seven women with striae distensae were treated in a single session with a CO2 FS. Deep FX mode with a pulse energy of 10 mJ and a density of 2 (percent coverage of 10%) was used. Clinical improvement was assessed by comparing pre- and post-treatment clinical photographs and participant satisfaction rates. RESULTS: The evaluation of clinical results 3 months after treatment showed that two of the 27 participants (7.4%) had grade clinical 4 improvement, 14 (51.9%) had grade 3 improvement, nine (33.3%) had grade 2 improvement, and two (7.4%) had grade 1 improvement. None of the participants showed worsening of their striae distensae. Mean clinical improvement score was 2.6. Surveys evaluating overall participant satisfaction administered after the treatment was completed showed that six of the 27 participants (22.2%) were very satisfied, 14 (51.9%) were satisfied, five (18.1%) were slightly satisfied, and two (7.4%) were unsatisfied. CONCLUSION: Our observations demonstrated that the use of CO2 FS can have a positive therapeutic effect on late-stage striae distensae.

Use of 532-nm Q-switched Nd:YAG laser for smoker's gingival hyperpigmentation.

Laser treatments using 532-/1064-nm Q-switched neodymium-doped yttrium aluminum garnet (Nd:YAG) lasers are popular non-ablative and selective photothermolysis therapies for pigmentary disorders. We treated three male Korean patients (aged 23, 27 and 24 years) for smoker's gingival hyperpigmentation using a 532-nm Q-switched Nd:YAG laser. At each treatment session, the laser was delivered at 1.2 J/cm(2) with a 5-mm spot size and appropriate overlap. Clinical improvement as well as complete healing of the treated gingiva was noted within 2 weeks after each treatment. We also observed that the therapeutic effects lasted more than 6 months.

Clinical and Radiographic Characteristics of Neuro-Behçet's Disease in South Korea.

BACKGROUND AND PURPOSE: Neurological involvement in Behçet's disease [neuro-Behçet's disease (NBD)] is uncommon, but it is worth investigating since it can cause substantial disability. However, difficulties exist in understanding the clinical features of NBD due to regional variations and the lack of studies utilizing well-established diagnostic criteria. We therefore analyzed the clinical features of patients with NBD based on the recent international consensus recommendation. METHODS: We retrospectively searched electronic databases for patients with Behçet's disease (BD) between 2000 and 2017, and reviewed their medical records. Based on the recent international consensus recommendation, patients with definite or probable NBD were included. RESULTS: Of 9,817 patients with the diagnosis code for BD, 1,682 (17.1%) visited the neurology clinic and 110 (1.1%) were classified as NBD. Ninety-eight patients exhibited parenchymal NBD and 12 exhibited nonparenchymal NBD. Their age at the onset of NBD was 37.6±10.6 years and the male-to-female ratio was 1.24:1. Brainstem syndrome (43.9%) was the most common condition in the 98 patients with parenchymal NBD, followed by multifocal (32.7%) and spinal cord (12.2%) syndromes. 72.4% exhibited acute NBD and 27.6% exhibited a progressive disease course. Frequent manifestations included pyramidal signs (52.0%), headache (45.9%), dysarthria (42.9%), and fever (31.6%). A frequent pattern in brain MRI was an upper brainstem lesion extending to the thalamus and basal ganglia. CONCLUSIONS: Approximately 1% of the patients with suspected BD exhibited NBD. Neurologists must understand the clinical characteristics of NBD in order to perform the differential diagnosis and management of these patients.

Management of skin, mucosa and joint involvement of Behçet's syndrome: A systematic review for update of the EULAR recommendations for the management of Behçet's syndrome.

OBJECTIVES: The aim of this systematic review was to inform the update of European League Against Rheumatism (EULAR) Recommendations for the management of Behçet's syndrome (BS), on the evidence for the treatment of skin, mucosa and joint involvement of BS. METHODS: A systematic literature search, data extraction, statistical analyses and assessment of the quality of evidence were performed according to a pre-specified protocol using the PRISMA guidelines. Studies that assessed the efficacy of an intervention in comparison to an active comparator or placebo for oral ulcers, genital ulcers, papulopustular lesions, nodular lesions or arthritis were included. Where possible, risk ratios were calculated for binary outcomes and mean difference for continuous outcomes. RESULTS: Among the 3927 references that were screened, 37 were included in the analyses. Twenty-seven of these assessed mucocutaneous and 17 assessed joint involvement. Twenty-one of these studies were randomised controlled trials (RCTs). RCTs with colchicine, azathioprine, interferon-alpha, thalidomide, etanercept and apremilast showed beneficial results with some differences according to lesion type and gender. These agents were generally well tolerated with few adverse events causing withdrawal from the study. CONCLUSIONS: RCTs comprised more than a half (21/37, 57%) of the sources included in the evidence synthesis related to skin, mucosa and joint involvement applicable for the EULAR Recommendations for the management of BS. Differences in the outcome measures that were used across the included studies often made it difficult to combine and compare the results.

Tumor necrosis factor alpha small interfering RNA decreases herpes simplex virus-induced inflammation in a mouse model.

BACKGROUND: Anti-TNFalpha antibodies have been used for treating inflammation in patients. But, more effective and safer drugs need to be developed for improved future therapeutic use. OBJECTIVES: To inhibit the expression of TNFalpha, we used small interfering RNAs (siRNAs) to reduce over expression of TNFalpha in vitro in cell cultures and in an in vivo Behcet's disease-like (BD) mouse model for amelioration of chronic inflammation. METHODS: TNFalpha siRNA was injected intraperitoneally twice with a 1-week interval. To compare the efficacy of TNFalpha siRNA versus an anti-TNFalpha antibody, Infliximab and Etanercept were administered to symptomatic mice with inflamed tissue. RESULTS: Intraperitoneal delivery of TNFalpha siRNA effectively decreased BD symptoms in 18 of 32 cases (56.3%). Scrambled siRNA treatment decreased BD symptoms in 2 of 19 cases (10.5%). Infliximab was effective in 11 of 27 cases (40.7%) and Etanercept was also effective in 9 of 25 cases (36.0%) at the end of the second week after treatment. TNFalpha siRNA reduced serum levels of TNFalpha (1.57 +/- 0.43pg/ml), compared to levels in mice not injected (84.02 +/- 24.59pg/ml) (p<0.01) or scramble injected (118.89 +/- 20.08pg/ml) (p<0.01). After single injection of TNFalpha siRNA, improvement of BD symptoms showed at 9 +/- 7th day on an average, contrary, in Infliximab injected group, improvement was apparent at 15 +/- 4th day after injection (p<0.05). CONCLUSION: We show that siRNAs can be employed to inhibit cytokine gene expression in an in vivo disease mouse model. This inhibition may, therefore, be attributed to the improvement of inflammatory symptoms.

Rebamipide affects the efficiency of colchicine for the herpes simplex virus-induced inflammation in a Behcet's disease mouse model.

Rebamipide inhibits free radicals derived from activated neutrophils and decreases the inhibiting inflammatory cytokine. Behcet's disease (BD) is a chronic, multi-systemic inflammatory disorder with arthritic, gastrointestinal, mucocutaneous, ocular, vascular, and central nervous system involvement. This disease has a chronic course with periodic exacerbations and progressive deterioration. To study the effect of rebamipide treatment to BD-like mice, combination treatment with rebamipide and colchicine was compared to colchicine treatment. Colchicine is one of the most frequently prescribed medicine to the patients with BD. For each BD mouse, 200 microl gastric fluid or 2 microg colchicine or 150 microg rebamipide or 2 microg colchicine plus 150 microg rebamipide was treated orally once per day. Treatment was done for 5 consecutive days. Two hour or 20 days after last administration, spleens were isolated for RT-PCR and real time PCR, and serum was collected for ELISA. In the combination treated group, TNF alpha, MIP-1 alpha, p22 phox, p47 phox, and gp91 phox mRNA expressions were lower than rebamipide treated or colchicine treated groups by reverse transcriptase PCR. NADPH oxidase subunits mRNA were markedly downregulated compared to the colchicine treated group by real time PCR. At 20 days after administration, combination treatment decreased 23.5% of the severity score compared to before administration. In contrast, colchicine treatment decreased 14.3% of the severity score compared to before administration. Rebamipide helped the function of colchicine to improve the HSV induced BD-like symptoms by inhibiting the expression of NADPH oxidase in vivo mouse model.

Clinical manifestations associated with high titer of anti-streptolysin O in Behcet's disease.

To evaluate the association of chronic infection with clinical features of Behcet's disease (BD), we studied epidemiological and clinical features of 149 patients with only aphthous ulcer and 294 patients with BD. The incidence of chronic infection history was compared between both groups with age- and sex-matching and clinical manifestations of BD associated with high anti-streptolysin O (ASO) titer were investigated. BD patients had more common history of tonsillitis and dental caries than aphthous ulcer patients (P = 0.002 and P = 0.043, respectively). BD patients with persistently high anti-streptolysin O titers had more frequent history of tonsillitis (P = 0.001, odds ratio [OR] = 2.99, 95% confidence interval [CI] 1.53-5.82) and erythema nodosum (EN)-like lesions (P = 0.001, OR = 3.02, 95% CI 1.54-5.93) and fewer history of genital ulcer (P = 0.027, OR = 0.21, 95% CI 0.05-0.84) than BD patients with normal anti-streptolysin O titer. Our results suggest persistently high ASO titers in BD patients could indicate that streptococcal infections such as tonsillitis are related to BD symptoms such as EN-like lesions. In these patients, ASO titer can be used in the evaluation of BD disease activity and antibiotic treatments might be effective to control the symptoms of BD.