Behcet's disease in Iran: Analysis of 7641 cases.

Objective: To analyze Behcet's Disease (BD) in Iran, from 1975 to 2018, and compare to 35 large/small reports from other countries.Methods: Patients from all over Iran, when suspected, were sent to the BD Unit. The diagnosis was done by expert opinion. All data were recorded in the BD registry (updated in each follow-up). The data are given in percentage with 95% confidence Intervals.Results: The mean age at onset was 25.6 years. Standard deviation (SD) was 9.8. The mean disease duration was 11.7 years (SD: 8.9). Males were 55.8% (54.7-56.9), Females 44.2% (43.1-45.3), Oral Aphthosis (OA) 97.5% (97.1-97.9), genital aphthosis (GA) 64.4% (63.3-65.5), skin lesions 62.2% (61.1-63.3), ocular lesions 55.6% (54.5-56.7), Joint Manifestations 38.1% (37.0-39.2), Gastrointestinal 6.8% (6.2-7.4), Vascular 8.9% (8.3-9.5), neurological (central-peripheral) 3.9% (3.5-4.3), epididymitis 4.6% (4.1-5.1). Lab tests were positive pathergy test 50.4% (49.3-51.5), elevated ESR 51.1% (50.0-52.2), abnormal urinalysis 13.4% (12.6-14.2). The International Study Group (ISG, 1990) criteria and the International Criteria for Behcet's Disease (ICBD, 2014) had respectively a sensitivity of 76.2% (75.2-77.2) and 96.6% (96.2-97.0). The specificity was 99.3% (99.1-99.5) and 97.3% (96.9-97.7). The accuracy was 86.4% (85.8-87.0) and 96.9% (96.6-97.2).Conclusion: The most frequent manifestations were OA, GA, skin manifestations, and ocular manifestations.

Paediatric Behçet's disease in Iran: report of 204 cases.

OBJECTIVES: This study proposed to report the characteristics of paediatric Behçet's disease (PED-BD) in a cohort of patients from Iran's registry and compare them with different reports throughout the world. METHODS: From a cohort of 7504 Iranian patients with Behçet's disease those diagnosed before the age of 16 years were included in this study. Data were collected on a standard protocol comprising 105 items, including demographic features, type of presentation, and different clinical and laboratory findings. RESULTS: PED-BD was seen in 2.7% of patients. The male/female ratio was 1.02/1, and the mean age at onset was 10.5±3.4. Positive familial history was present in 9.9%. As a first manifestation, oral aphthosis was the most frequent (75%) followed by ocular lesions in 19.1%. The prevalence rates of various manifestations were as follows: oral aphthosis: 91.7%; genital ulcer: 42.2%; skin: 51.5% (pseudofolliculitis: 43.1%, erythema nodosum: 10.3%); ocular lesions: 66.2% (anterior uveitis 52%, posterior uveitis 58.3%, retinal vasculitis 39.7%); articular manifestations: 30.9%; neurological involvement: 4.9%; vascular involvement: 6.4% (venous 4.9%, arterial 2.5%); gastrointestinal manifestations: 5.9%; epididymo-orchitis: 8.7% (boys); high ESR (≥20): 50.8%; abnormal urine: 14.1%; positive pathergy test: 57%; HLA-B5/51: 48.7%. ICBD criteria have the highest sensitivity for the classification of PED-BD patients in Iran (91.7%). CONCLUSIONS: The clinical spectrum of PED-BD in Iran in this study was similar to that of other reports; however, genital ulcers, skin lesions (notably erythema nodosum), and gastrointestinal involvement were noticed to occur less frequently, while ocular lesions were more frequent and more severe compared to other reports.

The association of pathergy reaction and active clinical presentations of Behçet's disease.

OBJECTIVES: The pathergy skin test is a hypersensitivity reaction to a prick skin trauma caused by a pin or a needle, which is considered as a specific presentation in Behçet's disease (BD) and the precise mechanism of this test is not well elucidated. This study was designed to evaluate the association of pathergy reaction (PR) with the active clinical manifestations of BD patients, to assess the clinical importance of PR. MATERIALS AND METHODS: This was a cohort study on 1675 BD patients who fulfilled the entry criteria based on the International Criteria for Behçet's Disease (ICBD) from 1975 to 2011. The patients were divided into two groups; the pathergy positive group included 841 patients (50.2%) and the pathergy negative group 834 patients (49.8%). The active mucocutaneous and systemic disease manifestations were analyzed according to the presence of the PR. The odds ratio and 95% confidence interval (95% CI) were calculated for each item. RESULTS: In this study, 841 patients (50.2%) had a positive pathergy test. Patient's mean age and mean disease duration were similar in the two groups (pathergy positive and pathergy negative patients). There was no association between positive pathergy test and age of patients, or disease duration. The PR was associated with male gender (p = 0.013), oral aphthosis (p < 0.001), pseudofolliculitis (p < 0.001), anterior uveitis (p = 0.001) and posterior uveitis (p = 0.028). CONCLUSIONS: The presence of PR was associated with male gender, as well as some of mucocutaneous manifestations and uveitis in adult patients. There was no association with retinitis and vascular involvements. PR isn't associated with the severity of the disease.

FUT2: filling the gap between genes and environment in Behçet's disease?

OBJECTIVES: To identify new susceptibility loci for Behçet's disease (BD), we performed a genome-wide association study (GWAS) using DNA pooling. METHODS: Two replicate pools of 292 Iranian BD cases and of 294 age- and sex-matched controls were allelotyped in quadruplicate on the Affymetrix Genome-Wide Human SNP Array 6.0. Of the 51 top markers, 47 were technically validated through individually genotyping. Replication of validated single nucleotide polymorphisms (SNPs) was performed in an independent Iranian dataset (684 cases and 532 controls). RESULTS: In addition to the well-established HLA-B locus, rs7528842 in a gene desert on chromosome 1p21.2, and rs632111 at the 3'UTR of FUT2 were associated in both the discovery and replication datasets (individually and in combination). However, only the FUT2 SNP was associated in a previous GWAS for BD in Turkish people. Fine-mapping of FUT2 in the full Iranian dataset showed additional associations in five coding SNPs (2.97E-06

Non-corticosteroid risk factors of symptomatic avascular necrosis of bone in systemic lupus erythematosus: A retrospective case-control study.

OBJECTIVE: Avascular necrosis of bone (AVN) is an important complication of systemic lupus erythematosus (SLE). Corticosteroid therapy has been underlined as a main risk factor for osteonecrosis. However, AVN development in patients who have never received corticosteroid and the absence of AVN in the majority of the patients, who received corticosteroid, propose a role for non-corticosteroid risk factors in AVN development. METHODS: This case-control study included two subsets: oral corticosteroid (66 AVN and 248 non-AVN patients) and pulse-therapy subset (39 AVN and 312 non-AVN patients) who have attended our Lupus clinic from 1979 to 2009. Patients received similar cumulative dose corticosteroid, equal maximum dose and 1-year maximum dose of corticosteroid. The demographic data (including sex, age of disease onset, age at the diagnosis of AVN), organs involvement, SLE Disease Activity Index (SLEDAI), Systemic Lupus International Collaborating Clinics/American College of Rheumatology-Damage index (SLICC/ACR-DI), number of disease flare ups were compared between two subsets. RESULTS: The mean age of SLE onset was younger (P value = 0.04) in the AVN patients. In oral corticosteroid subset, malar rash (P value < 0.001) and oral ulcer (P value = 0.003) were seen more frequently in non-AVN patients, whereas psychosis (P value = 0.03) was significantly more prevalent AVN subset in oral corticosteroid subset. In corticosteroid pulse subset, no significant difference in clinical features was noted. CONCLUSION: In oral corticosteroid subset, younger age of disease onset and psychosis were significantly associated with AVN, whereas malar rash and oral ulcer showed negative association AVN.

Genital aphthosis in Behçet's disease: is it associated with less eye involvement?

Behçet's disease (BD) is a multisystem disease classified among the vasculitides with various clinical features. Genital aphthosis (GA) is one of the major manifestations of BD. The aim of this study was to evaluate the characteristics of BD patients with GA. A cross-sectional sample of BD patients registered in 37 years was selected. We determined clinical and laboratory features of BD patients with GA (GA cases) and compared them with the patients who never developed GA (non-GA cases). The comparisons were performed by the chi-square test and logistic regression analysis. Odds ratios (ORs) with 95 % confidence intervals were calculated to estimate the precision of ORs. Among 6,935 BD patients, 4,489 cases (64.7 %) were ascribed to GA cases. Male to female ratio (1.11:1.00 vs. 1.48:1.00 OR 0.753, P value <0.001) and mean age of disease onset (OR = 0.9, P value <0.001) were lower in GA subset. In GA cases, oral aphthosis (OA) was a more common onset manifestation (OR 2.250, P value <0.001), while uveitis (OR 0.140, P value <0.001) and retinal vasculitis (OR 0.077, P value <0.001) were less common at the disease onset. In the whole course of disease, eye involvement was less common in GA cases (OR 0.215, P value <0.001). On the contrary, OA (OR 19.698, P value <0.001), skin (OR 1.762, P value <0.001), joint (OR 1.257, P value = 0.001), gastrointestinal (OR 1.302, P value = 0.009), neurological (OR 1.624, P value <0.001) and vascular involvements (OR 1.362, P value <0.001), epididymitis (OR 1.596, P value <0.001), positive pathergy test (OR 1.209, P value <0.001) and positive familial history of OA (OR 1.325, P value <0.001) were more common in GA subset. This study showed that GA subset of BD is associated with less eye involvement but higher rates of other BD manifestations.

Clinical features of Behcet's disease in patients without oral aphthosis.

OBJECTIVES: In current study we evaluated clinical features of Behcet's Disease (BD) in patients without oral aphthosis (NOA cases). METHODS: In a cohort of BD, patients registered during a period of 36 years were collected. We determined clinical features of BD NOA cases and compared them with patients with oral aphthosis (OA cases). The comparison was performed by chi square and Fischer's exact test. RESULTS: Among 6,821 BD patients, 175 patients (2.56%) were NOA cases. Male/Female ratio was less in NOA cases (p-value: 0.078). Mean age of disease onset was significantly higher in NOA cases (p-value: 0.001). Among NOA cases, the first manifestations comprised uveitis (70.3%), joint involvement (8.0%), retinal vasculitis (6.9%), and genital aphthosis (4.0%). During the course of disease, the prevalence of ocular lesions and positive pathergy test were significantly higher in NOA cases. Conversely genital aphthosis (OR: 0.048), mucocutaneous (OR: 0.470), joint involvement (OR: 0.478), and positive family history for BD (OR:0.138) were significantly less frequent in NOA cases. NOA cases fulfilled different criteria including International Criteria for BD (ICBD), Japan Revised, Iran, Dilsen, and Classification Tree. CONCLUSIONS: These results addressed the distinct clinical features in NOA subset of BD Including more prevalent eye involvement and positive pathergy.

Association study of IL10 and IL23R-IL12RB2 in Iranian patients with Behçet's disease.

OBJECTIVE: Independent replication of the findings from genome-wide association studies (GWAS) remains the gold standard for results validation. Our aim was to test the association of Behçet's disease (BD) with the interleukin-10 gene (IL10) and the IL-23 receptor-IL-12 receptor ß2 (IL23R-IL12RB2) locus, each of which has been previously identified as a risk factor for BD in 2 different GWAS. METHODS: Six haplotype-tagging single-nucleotide polymorphisms (SNPs) in IL10 and 42 in IL23R-IL12RB2 were genotyped in 973 Iranian patients with BD and 637 non-BD controls. Population stratification was assessed using a panel of 86 ancestry-informative markers. RESULTS: Subtle evidence of population stratification was found in our data set. In IL10, rs1518111 was nominally associated with BD before and after adjustment for population stratification (odds ratio [OR] for T allele 1.20, 95% confidence interval [95% CI] 1.02-1.40, unadjusted P [P(unadj) ] = 2.53 × 10(-2) ; adjusted P [P(adj) ] = 1.43 × 10(-2) ), and rs1554286 demonstrated a trend toward association (P(unadj) = 6.14 × 10(-2) ; P(adj) = 3.21 × 10(-2) ). Six SNPs in IL23R-IL12RB2 were found to be associated with BD after Bonferroni correction for multiple testing, the most significant of which were rs17375018 (OR for G allele 1.51, 95% CI 1.27-1.78, P(unadj) = 1.93 × 10(-6) ), rs7517847 (OR for T allele 1.48, 95% CI 1.26-1.74, P(unadj) = 1.23 × 10(-6) ), and rs924080 (OR for T allele 1.29, 95% CI 1.20-1.39, P = 1.78 × 10(-5) ). SNPs rs10489629, rs1343151, and rs1495965 were also significantly associated with BD in all tests performed. Results of meta-analyses of our data combined with data from other populations further confirmed the role of rs1518111, rs17375018, rs7517847, and rs924080 in the risk of BD, but no epistatic interactions between IL10 and IL23R-IL12RB2 were detected. Results of imputation analysis highlighted the importance of IL23R regulatory regions in the susceptibility to BD. CONCLUSION: These findings independently confirm, extend, and refine the association of BD with IL10 and IL23R-IL12RB2. These associations warrant further validation and investigation in patients with BD, as they may have implications for the development of novel therapies (e.g., immunosuppressive therapy targeted at IL-23p19).

Presentation of psoriatic arthritis in the literature: a twenty-year bibliometric evaluation.

Psoriatic arthritis is an inflammatory arthritis disabling patients with psoriasis. Bibliometric studies are tools for evaluating scientific productions in different countries, universities as well as publications related to a special topic. We aimed to perform a scientometric study to evaluate articles published under "Psoriatic arthritis" topic and also attempted to compare publications of different authors, countries, universities, and journals related to this topic. Study was performed on all articles published between 1989 and 2009. The ISI web of science was our main source. Two key words, "Psoriatic arthritis" and "Psoriatic arthropathy," were used to conduct search. Original articles were subject of further evaluation. A whole number of 3,727 article was result of our search. From this number, 1,961 (52.6 %) were original articles. Whole original articles were cited 38,613 times with average citations per item of 19.69. Gladman DD was the most popular author in this field. Articles were mostly in English (91.3 %). USA was the leading country in producing article under this topic with 463 (23.6 %) publications. University of Toronto was the first rank institution while publishing 125 (6.4 %) articles. More than half of articles were published under "Rheumatology" subject. "Journal of Rheumatology," "Annals of the Rheumatic Diseases," and "Arthritis and Rheumatism" were three journals with highest number of articles on this topic. There has been growing interest in psoriatic arthritis subject during these two decades. Between countries, institutions and journals; USA, university of Toronto, "Journal of Rheumatology," "Annals of The Rheumatic Diseases," and "Arthritis and Rheumatism" have special contributions to body of literature published under this topic, respectively.

Impact of the positive pathergy test on the performance of classification/diagnosis criteria for Behcet's disease.

BACKGROUND: The only diagnostic test that currently exists for Behcet's disease (BD) is the pathergy test. A positive pathergy test (PPT) is an important component of many of the 16 sets of classification/diagnosis criteria used to diagnose BD. The aim of this study was to determine the importance of a PTT in the performance of the diagnosis/classification criteria for BD. PATIENTS AND METHODS: All patients listed in the BD registry of the Rheumatology Research Center, Tehran (6,727) and 4,648 BD controls were enrolled in the study. The diagnosis was clinical when no other diagnosis could explain the patient's manifestations. The criteria were tested with and without PPT results. Sensitivity, specificity, and accuracy were calculated. RESULTS: Without PPT, all sets of criteria lost sensitivity, gained specificity, and lost accuracy, with the exception of the Cheng-Zhang criteria. The largest loss in sensitivity was for the Hubault-Hamza (35 %) and Dilsen (17.3 %) criteria; the least was for the Curth (1.9 %) and ICBD (6.5 %) criteria. The largest gain on specificity was for the Dilsen (4.7 %) and Curth (3.1 %) criteria; the least was for the Japan (0.1 %) and Japan revised (0.1 %) criteria. The greatest loss in accuracy was for the Hubault-Hamza (20.4 %) and Dilsen revised (9.3 %) criteria; the least was for the ICBD (3.6 %), while Curth gained 0.3 %. CONCLUSION: Without PPT as a criterion for the diagnosis of BD, the sensitivity and accuracy of the sets of classification/diagnosis criteria decrease, while the specificity improves.

Effect of early treatment in polymyositis and dermatomyositis.

BACKGROUND: Idiopathic inflammatory myopathies, dermatomyositis (DM) and polymyositis (PM) are rare but are potentially treatable. AIM: To compare the effect of early and late treatment in patients with PM and DM. MATERIALS AND METHODS: The study included all the adult patients with definite diagnosis of PM or DM treated for at least 12 months. The patients were divided into two groups: Early Group - treatment within three months and Late Group - treatment after three months. The number of patients with positive therapeutic response, remission in less than one year and the mean time elapsed for reaching the remission were assessed and compared between the two groups. Chi-square test, Fisher's exact test, t-test and Pearson correlation test were used for data analysis. RESULTS: The analysis included 65 patients, 42 with DM and 23 with PM. Late Group included 24 patients (seven PM and 17 DM), while Early Group included 41 patients (16 PM and 25 DM). Positive therapeutic response, remission rate within one year was higher in Early Group (80% vs. 46%, P: 0.004). The mean time needed to achieve remission was much less with early treatment (5.5 vs. 11.9 months, P: 0.003). The relapse rate was also lower in Early Group (5% vs. 25%, P < 0.02). The comparison of treatment outcomes showed the same results in both PM and DM, but it was statistically significant in patients with DM. CONCLUSIONS: Early treatment in patients with PM and DM is associated with higher remission rates, shorter treatment period and low complication rates.

Comparison of existing disease activity indices in the follow-up of patients with Behçet's disease.

The objective of this study was to determine the concordance between the Iranian Behçet's disease dynamic activity measure (IBDDAM) or the Behçet's disease current activity form (BDCAF) and expert physician global assessment (PGA) in the evaluation of disease activity changes in Behçet's disease (BD). In a prospective study, 117 consecutive patients with BD were evaluated in their two consecutive follow-up visits by IBDDAM and BDCAF. The change in disease activity was determined (increased, unchanged or decreased) according to the PGA. We used receiver operating characteristic (ROC) curve to determine an appropriate cutoff point for disease activity change. Comparison was made by Stata and kappa analysis. Comparing the area under the ROC curve showed a significant difference between IBDDAM and BDCAF (p < 0.03). The difference was more significant between nonocular IBDDAM and BDCAF (p < 0.002). Better concordance was also observed for IBDDAM (nonocular and total) with PGA than BDCAF. The difference was not significant for ocular IBDDAM. The best cutoff point for nonocular IBDDAM was 0.45, for ocular IBDDAM was 3.5, and for BDCAF was 1 point. IBDDAM was the preferred method for the evaluation of disease activity change in patients with BD (without ocular involvement) considering a change of at least 0.45.

Colchicine versus placebo in Behçet's disease: randomized, double-blind, controlled crossover trial.

The effect of colchicine was evaluated in a large cohort of Behçet's disease (BD) patients and compared to placebo. In a randomized, double-blind, controlled crossover trial, 169 patients without major organ involvement were selected consecutively. They fulfilled the International Criteria for Behçet's Disease. Patients were randomly assigned to colchicine or placebo. At 4 months, they were swapped over (colchicine to placebo, placebo to colchicine) for another 4 months. The primary outcome was the overall disease activity index, the IBDDAM. The secondary outcome was the responses of the individual symptoms. A Student's paired t test was used to evaluate results within each group, and an ANOVA to check for differences between colchicine and placebo. Analysis was performed using the "intention to treat" method. For placebo, IBDDAM worsened from 3.17 to 3.63 (t = 1.750, P = 0.08). For colchicine, IBDDAM improved from 3.35 to 2.75 (t = 4.143, P < 0.0001). Oral aphthosis, genital aphthosis, pseudofolliculitis, and erythema nodosum improved significantly with colchicine but not with placebo. According to the ANOVA, the difference in IBDDAM between colchicine and placebo was highly significant (F = 14.674, P = 0.00016). The difference between the results for males and females was not significant (F = 0.181, P = 0.67). In conclusion, colchicine, but not placebo, significantly improved the overall disease activity index. The difference between the results for colchicine and placebo was also statistically significant.

Dermatoscopic and Mucoscopic Features of Lesions in Patients with Behcet's Disease.

OBJECTIVE: Behcet's disease (BD), as a vasculitis, can affect small and large vessels. As dermatoscopy has been shown to improve the accuracy in diagnosis of various skin lesions especially vascular patterns, we set this study to find if there is any characteristic pattern in the dermatoscopy of Behcet's mucocutaneous lesions. METHODS: This prospective cross-sectional observational study designed to evaluate dermatoscopic features of Behcet's mucocutaneous lesions. Fifty six consecutive patients presenting at the outpatient clinic of the BD Research Unit were included. If present, for each patient one oral, one skin and one genital lesion were evaluated by dermatoscopy. When indicated, pathergy test was performed according to a standard protocol and the results were evaluated by dermatoscopy. RESULTS: A total of 40 oral, 8 genital, 14 skin lesions and 14 pathergy tests were evaluated by dermatoscopy. While vascular component was the most prominent feature in oral aphthae, this component was less prominent in genital lesions. Dot vessels were the most common form of vessels in both oral and skin lesions. All the oral lesions were characterized by a central white structureless area. Skin lesions were characterized by a red structureless background. In pathergy tests, negative pricks showed absence of specific features while positive pricks were characterized by a structureless background in pink, purple or red. No obvious vascular component was detected in any of the pricks. CONCLUSION: It seems that these findings have no specific clues for the diagnosis of BD, but our study is the first study in this field and the findings may give way to further investigations.

The prevalence of oral aphthosis in a normal population in Iran: a WHO-ILAR COPCORD study.

This study was conducted to determine the prevalence of oral aphthosis in a normal population in Iran, using the data of the WHO-ILAR COPCORD study in Iran. We conducted this study in Tehran, the capital of Iran which was selected as the COPCORD study field. In 22 districts of Tehran, 50 clusters were randomly selected. Of the selected houses, 4,096 households were visited and 10,291 persons were interviewed (response rate of 75%). Out of the 10291 subjects interviewed, 2592 had aphthous ulcers which translated to a prevalence of 25.2% (95% confidence interval: 24.4% to 26.0%). The prevalence of oral aphthosis was rather high in this normal population.

Prospective study of articular manifestations in Behçet's disease: five-year report.

AIM: To evaluate different aspects of articular involvements (prevalence, types, relation to extra-articular manifestations, etc.) in Iranian patients with Behcet's disease (BD). METHODS: In a prospective study, all patients with BD attending an outpatient BD clinic were enrolled. The type of articular involvements (peripheral or axial), involved joints, duration of attacks and their relation to extra-articular manifestations, human leukocyte antigen (HLA)-B5 and HLA-B27 were evaluated. Data analysis was done by using descriptive statistical indices such as mean and confidence interval. The comparisons were done by chi-square test. RESULTS: In a 5-year period, 2312 patients were recruited. Musculoskeletal manifestations were recorded in 430 patients (190 without previous history of these involvements). The remaining 1882 patients showed no musculoskeletal involvements, of which 753 had past histories of musculoskeletal manifestations. The 5-year incidence rate was 18.6%, and the prevalence rate was 51.2%. History of previous musculoskeletal involvements has no effect in its new development (P = 0.2). Arthritis was the most common type of involvement (289/430, 67%). The most frequent pattern was monoarthritis (191/289, 66%), and the most frequent involved joints were knees (147/289, 50.9%). The arthritic attacks were unilateral in 82.4% of cases. Ankylosing spondylitis was seen in 44/430 (10.2%). There was no association between HLA-B5 or HLA-B27 and any type of musculoskeletal involvements (P > 0.5). Pseudofolliculitis was the only extra-articular manifestation related to arthritic attacks (P = 0.046). CONCLUSION: Musculoskeletal involvement is a common manifestation of BD seen in more than half of patients. Acute knee monoarthritis was the most common pattern of articular involvement in BD.

Behcet's disease: epidemiology, clinical manifestations, and diagnosis.

INTRODUCTION: Behcet's Disease (BD) is classified among vasculitides. The aim of this review was to put together different known reports in order to help the reader to better understand the disease, to avoid the frequent misdiagnosis, and to decide the best treatment. Areas covered: a) Epidemiology: BD is rare, and is seen along the Silk Road, from 20 to 420/100,000 in Turkey and 80/100,000 in Iran, to 0.64/100,000 in the UK. b) Clinical manifestations: oral aphthosis is seen in more than 95% of patients, genital aphthosis (60-90%), skin (pseudofolliculitis/erythema nodosum, 40-90%), eyes (uveitis/retinal vasculitis, 45-90%), gastrointestinal (diarrhea/hemorrhage/perforation/pain, 4-38%), vascular (venous/arterial thrombosis, aneurysm, 2.2-50%), neurological (all kinds, especially meningo-encephalitis, 2.3-38.5%), and articular (arthralgia/arthritis/ankylosing spondylitis, 11.6-93%). c) Pathergy test is positive in some patients: 8.6% (in India) to 70.7% (in China). This data was extracted from the five nationwide surveys and the largest case series from BD conference reports and a Pubmed search. Expert commentary: Diagnosis is clinical but classification/diagnosis criteria may help. The best criteria for BD is the International Criteria for Behcet's Disease (ICBD). BD is a multisystem disease progressing by attacks and remissions. Each attack may resemble the preceding or it may be different in duration, severity, and the systems involved.

IL10 low-frequency variants in Behçet's disease patients.

AIM: To explain the missing heritability after the genome-wide association studies era, sequencing studies allow the identification of low-frequency variants with a stronger effect on disease risk. Common variants in the interleukin 10 gene (IL10) have been consistently associated with Behçet's disease (BD) and the goal of this study is to investigate the role of low-frequency IL10 variants in BD susceptibility. METHODS: To identify IL10 low-frequency variants, a discovery group of 50 Portuguese BD patients were Sanger-sequenced in a 7.7 kb genomic region encompassing the complete IL10 gene, 0.9 kb upstream and 2 kb downstream, and two conserved regions in the putative promoter. To assess if the novel variants are BD- and/or Portuguese-specific, they were assayed in an additional group of BD patients (26 Portuguese and 964 Iranian) and controls (104 Portuguese and 823 Iranian). RESULTS: Rare IL10 coding variants were not detected in BD patients, but we identified 28 known single nucleotide polymorphisms with minor allele frequencies ranging from 0.010 to 0.390, and five novel non-coding variants in five heterozygous cases. ss836185595, located in the IL10 3' untranslated region, was also detected in one Iranian control individual and therefore is not specific to BD. The remaining novel IL10 variants (ss836185596 and ss836185602 in intron 3, ss836185598 and ss836185604 in the putative promoter region) were not found in the replication dataset. CONCLUSION: This study highlights the importance of screening the whole gene and regulatory regions when searching for novel variants associated with complex diseases, and the need to develop bioinformatics tools to predict the functional impact of non-coding variants and statistical tests which incorporate these predictions.

Dense genotyping of immune-related loci implicates host responses to microbial exposure in Behçet's disease susceptibility.

We analyzed 1,900 Turkish Behçet's disease cases and 1,779 controls genotyped with the Immunochip. The most significantly associated SNP was rs1050502, a tag SNP for HLA-B*51. In the Turkish discovery set, we identified three new risk loci, IL1A-IL1B, IRF8, and CEBPB-PTPN1, with genome-wide significance (P < 5 × 10-8) by direct genotyping and ADO-EGR2 by imputation. We replicated the ADO-EGR2, IRF8, and CEBPB-PTPN1 loci by genotyping 969 Iranian cases and 826 controls. Imputed data in 608 Japanese cases and 737 controls further replicated ADO-EGR2 and IRF8, and meta-analysis additionally identified RIPK2 and LACC1. The disease-associated allele of rs4402765, the lead marker at IL1A-IL1B, was associated with both decreased IL-1α and increased IL-1ß production. ABO non-secretor genotypes for two ancestry-specific FUT2 SNPs showed strong disease association (P = 5.89 × 10-15). Our findings extend the list of susceptibility genes shared with Crohn's disease and leprosy and implicate mucosal factors and the innate immune response to microbial exposure in Behçet's disease susceptibility.