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.

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.

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.

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.

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.

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.

Centennial History of Yonsei University Dermatology in Korea: 1917 to 2017.

Yonsei Dermatology celebrated its centennial in 2017, marking 100 years since Kung Sun Oh established the first Department of Dermatology and Urology in Korea in 1917. Following the footsteps of Kung Sun Oh, a pioneer of Korean dermatology, its members united and worked to provide the best medical service and achieve academic milestones in dermatology. Over the past hundred years, Yonsei Dermatology has played a pivotal role in the advancement of medical science and academia in Korea. The main activities of the department include medical care, education, and dermatologic research. Its research activities have encompassed a wide spectrum of dermatologic manifestations from skin immunology and pathology to introduction of newly developed treatment technologies. As Kung Sun Oh was the first Korean professor of dermatology at Severance Medical School and a passionate educator, we continue to serve his will by nurturing medical students and dermatology specialists to serve as global medical leaders. The Kung Sun Oh Memorial Lecture, first hosted in 1977, was the beginning of mutual international academic exchange in the field of dermatology in Korea. The memorial lecture has played a major role in advancing the academic status of Korean dermatological science by inviting distinguished dermatologists from around the world as guest lecturers. Yonsei Dermatology has played a key role in the history of modern medicine and dermatology in Korea over the last 100 years and continues to make an impact.

Thiopurine S-Methyltransferase Polymorphisms in Korean Dermatologic Patients.

BACKGROUND: Thiopurine S-methyltransferase (TPMT) is an important enzyme in the metabolism of thiopurines including azathioprine (AZA), 6-mercaptopurine, and 6-thioguanine. TPMT genotyping is widely used for screening of AZA-related toxicity during routine clinical practice in Korea. However, the data of TPMT genotypes and its AZA-related toxicity have not been studied in the field of dermatology. OBJECTIVE: The aim of this study was to evaluate the genetic basis of TPMT polymorphism in Korean dermatologic patients and subsequently to investigate the relationship between mutant TPMT and adverse responses to AZA treatment. METHODS: This study was retrospective, single-center study. One hundred forty-nine Korean dermatologic patients who underwent TPMT screening test were included. Each patient's medical records, the result of TPMT screening test, dose and treatment period of AZA, and side effects, were reviewed. Laboratory tests were assessed at each visit in order to monitor adverse drug reactions. Leukopenia grading was used in accordance with the common terminology criteria for adverse events (CTCAE) ver. 4.03. RESULTS: Behçet's disease was the leading disorder among the patients. The frequency of TPMT mutation was 4.0% (6/149) among the participants in this study. Four of the six patients with genetic alterations were treated with a low-dose AZA regimen, but no AZA-related adverse events were observed. CONCLUSION: Our results suggest that 1) TPMT polymorphisms in Korean dermatologic patients are similar to those previously reported in Asian patients with the most common mutant allele being TPMT*3C and 2) AZA can be used in the patients with these polymorphisms under a careful dosing regimen.

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.

Enhancement of Th1/Th17 inflammation by TRIM21 in Behçet's disease.

The etiology of Behçet's disease (BD), a chronic, multisystemic autoinflammatory and autoimmune disease, remains unknown; however, researchers have postulated that infectious agents, such as herpes simplex virus, are significant triggering factors of BD. Tripartite motif-containing (TRIM) proteins exhibit antiviral properties, mediating antiviral defense mechanisms. The purpose of this study was to investigate TRIM21 protein expression in the monocytes of BD patients and to identify the role of TRIM21 in immune dysregulation in BD. In this study, the expression of TRIM21 and related molecules, including interferon regulatory factor 8 (IRF8), was analyzed in monocytes from BD patients. Functional analyses using small interfering RNA and co-culture with responder T cells were performed to examine the pathological role of TRIM21 in BD. Peripheral blood monocytes from BD patients showed increased TRIM21 expression and decreased IRF8 expression compared with that in monocytes from healthy controls. TRIM21 was found to decrease IRF8 expression. BD monocytes facilitated Th1 and Th17 differentiation of co-cultured T cells, and knock-down of TRIM21 expression by small interfering RNA inhibited this differentiation. In conclusion, TRIM21 played a pivotal role in regulating the secretion of proinflammatory cytokines in monocytes of BD patients.

Identification of genetic susceptibility loci for intestinal Behçet's disease.

Several recent genome-wide association studies (GWAS) identified susceptibility loci/genes for Behçet's disease (BD). However, no study has specifically investigated the genetic susceptibility loci associated with intestinal involvement in BD. We aimed to identify distinctive genetic susceptibility loci/genes associated with intestinal involvement in BD and determine their roles in intestinal inflammation as well as their interactions with genes involved in inflammatory bowel disease (IBD). GWAS and validation studies showed intestinal BD-specific associations with an NAALADL2 gene locus (rs3914501, P = 3.8 × 10-4) and a YIPF7 gene locus (rs6838327, P = 3.5 × 10-4). Validation, haplotype, and pathway analyses showed distinct genetic architectures between intestinal BD and BD without intestinal involvement. Furthermore, network analysis revealed shared pathogenic pathways between intestinal BD and IBD. Gene functional analyses indicated that down-regulation of NAALADL2 and YIPF7 expression was associated with exacerbating intestinal inflammatory responses both in vitro and in vivo. Our results provide new insights into intestinal BD-specific genetic variations, which represents a distinct pathway from BD without intestinal involvement. Functional consequences of the intestinal BD-specific NAALADL2 and YIPF7 expression patterns proved a suggestive association with intestinal inflammation risk, which warrants further validation.

Predictive value of bone scintigraphy for the detection of joint involvement in Behçet's disease: Dermatologists' perspectives.

BACKGROUND: Behçet's disease (BD) is a multisystemic inflammatory disease with articular involvement. Non-specific arthralgia without objective signs of arthritis, such as swelling or effusion, is common in such patients. Thus, an accurate diagnosis of joint involvement may be challenging for dermatologists. OBJECTIVES: To evaluate the validity of (99m)Tc-methylene diphosphonate (Tc-99m-MDP) bone scintigraphy for joint involvement assessment in patients with BD. MATERIALS AND METHODS: In 211 patients with BD who had scintigraphic evaluations due to joint symptoms, agreement between bone scintigraphy findings and clinically evaluated joint complaints was retrospectively assessed using Cohen's kappa (κ) statistic. A patient subset (n = 104) showing agreement between joint complaints and scintigraphy results was re-evaluated by a rheumatologist to determine the level of diagnostic specificity attained by combining bone scintigraphy with clinical examinations of dermatologists. RESULTS: The total kappa value (211 patients) was 0.604, indicating fair agreement between joint complaints and scintigraphy results. Individual analysis of eleven joint categories revealed statistically significant correlations for wrist (κ = 0.677), shoulder (κ = 0.661), and foot joints (κ = 0.618). Of the 104 referrals to a rheumatologist, 95 (91.34%) were confirmed as having BD-associated articular involvement. Joint acral areas (e.g., foot, hand, wrist and shoulder) that had the highest kappa value correlations also ranked highest in diagnostic specificity. CONCLUSION: Bone scintigraphy presents a simple and useful option for dermatologists to assess joint involvement in BD patients, especially for specific anatomic sites.

IL-2/IL-2 antibody immune complex regulates HSV-induced inflammation through induction of IL-2 receptor alpha, beta, and gamma in a mouse model.

The differences of serum IL-2 levels were not consistent between Behçet's Disease (BD) patients and healthy controls, however, the correlation of interleukin-2 receptor (IL-2R) and BD has not been investigated. IL-2R is composed of three subunits; alpha, beta, and gamma. The expression frequencies of IL-2R subunits were analyzed in the peripheral blood mononuclear cells, spleens, and lymph node (LN) cells. The expression of IL-2R subunits was different between BD mice and controls. IL-2R beta expressing cell frequencies were also different between BD patients and healthy controls. The IL-2/anti-mIL-2 antibody complex administration regulated the IL-2R subunits in mice. The change of expression in IL-2R was accompanied by the increase of CD8+CD44+ memory T cells, CD3-NK1.1+CD11b+CD27+ natural killer cells, and improvement of symptoms. In this study, we elucidated the role of IL-2R subunits on BD, a finding that can be connected to therapeutic strategy for patients based on the results from the treatment of BD mice.

Carpal Tunnel Syndrome in Behçet'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.

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.