Validation of the PEDiatric Behçet's Disease classification criteria: an evidence-based approach.

OBJECTIVES: to validate the PEDiatric Behçet's Disease classification criteria (PEDBD) with an evidence-based approach. METHODS: 210 pediatric patients (70 Behçet's disease (BD), 40 Periodic Fever, Aphthous stomatitis, Pharyngitis, Adenitis, 35 familial Mediterranean fever, 26 hyper-IgD syndrome, 22 TNF-Receptor associated Periodic fever Syndrome, 17 undefined recurrent fevers) were randomly selected from the Eurofever Registry. A set of 11 experienced clinicians/researchers blinded to the original diagnosis evaluated the patients. Using the table consensus as gold standard (agreement ≥ 80%), the PEDBD, ISG and ICBD criteria were applied to BD patients and to confounding diseases with other autoinflammatory conditions in order to define their sensitivity, specificity and accuracy. RESULTS: At the end of the third round, a consensus was reached in 139/210 patients (66.2%). The patients with a consensus ≥80% were classified as confirmed-BD (n = 24), and those with an agreement of 60-79% as probable-BD (n = 10). When comparing these patients with the confounding diseases group, an older age at disease onset, the presence of oral and genital ulcers, skin papulo-pustular lesions, a positive pathergy test and posterior uveitis were BD distinctive elements. The ISG, ICBD and PEDBD criteria were applied to confirmed-BD and to the confounding disease group, showing a sensitivity of 0.50, 0.79 and 0.58, a specificity of 1.00, 0.97, 0.99, and an accuracy of 0.91, 0.94 and 0.92, respectively. CONCLUSIONS: the PEDBD criteria were very specific, while the ICBD resulted to be more sensitive. The complexity of childhood BD suggests larger prospective international cohorts to further evaluate the performance of the criteria.

Association between dietary intake of some antioxidant micronutrients with some inflammatory and antioxidant markers in active Rheumatoid Arthritis patients.

Background: Rheumatoid Arthritis (RA) is an autoimmune disease. Antioxidants intake and body antioxidants status are important in patients with RA. The aim of this study was to investigate the association between dietary intake of some antioxidant micronutrients with some inflammatory and antioxidant markers in patients with active rheumatoid arthritis and comparison with Recommended Dietary Allowance (RDA). Materials and Methods: In this cross-sectional study, eighty-seven patients with active rheumatoid arthritis were included. Dietary antioxidants intake was measured using 24-hour recall questionnaire and food record (3 days). Blood levels of inflammatory and antioxidant markers were determined by laboratory tests. The association between intake of antioxidants with inflammatory and antioxidant markers, and also with RDA were determined using Paired-Samples t-test and Pearson correlation by SPSS software. Results: The findings showed that intakes of vitamin E, zinc, and magnesium in patients were significantly lower and intakes of copper and selenium were significantly higher than RDA (P < 0.05). Significant negative correlations were observed between vitamin A intake with PGE2 [R = -0.31], vitamin C intake with IL-1ß [R = -0.25], zinc intake with PGE2 [R = -0.30], IL-2 [R = -0.23], and the activity of glutathione reductase enzyme [R = -0.21], magnesium intake with PGE2 [R = -0.24], IL-1ß [R = -0.23] and IL-2 [R = -0.25], and selenium intake with PGE2 [R = -0.21] (P < 0.05). Also, significant positive correlations were observed between intakes of vitamin E and copper with catalase enzyme activity [R = 0.22 and R = 0.21 respectively] (P < 0.05). Conclusion: Some of the antioxidant micronutrients play important roles in the reduction of inflammatory conditions and improve the function of antioxidant enzymes in patients with rheumatoid arthritis.

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.

The effect of ginger supplementation on IL2, TNFα, and IL1ß cytokines gene expression levels in patients with active rheumatoid arthritis: A randomized controlled trial.

Background: Rheumatoid arthritis (RA) is a chronic autoimmune and inflammatory disease that affects the joints and consequently leads to the destruction of cartilage and bone lesions. Traditionally, ginger has been consumed in treatment of osteoarthritis, joint and muscle pain, neurological diseases, and inflammation of gums, tooth pain, asthma, stroke, diabetes, and constipation. The aim of this study was to determine the effect of ginger on some immunological and inflammatory markers in patients with rheumatoid arthritis. Methods: In this study, which was performed during 2013-2016, 66 patients with active rheumatoid arthritis who referred to the rheumatology clinic at Shariati hospital were en-rolled. Patients were randomly divided into 2 groups: one group consumed 1.5 gr ginger per day, and the other group took roasted wheat flour (placebo), respectively. To determine the effect of confounding factors on the findings of the study, questionnaires for nutrient intake, physical activity, and medication were filled, and BMI was measured. For each participant, at the beginning and end of the study, Serum hs-CRP and mRNA levels of IL-1ß, IL-2 and TNF-α were determined by ELISA and Quantitative Real Time PCR, respectively. Statistical analysis was performed using SPSS software. Significance level was set at p<0.05. Results: Results of the study showed ginger powder supplementation caused a significant decline in CRP (p=0.050) and IL-1ß mRNA level (p=0.021). TNFα mRNA levels reduced in ginger group compared to placebo groupalthough the difference was not significant between the 2 groups (p=0.093). Ginger had no effects on IL2 gene expression. Conclusion: This study showed that ginger reduces inflammatory factors hs-CRP and IL-1ß gene expression in patients with active RA and it seems that ginger can improve the inflam-mation in the patients.

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.

Curcumin reduces the expression of interleukin 1ß and the production of interleukin 6 and tumor necrosis factor alpha by M1 macrophages from patients with Behcet's disease.

OBJECTIVE: Behcet's disease (BD) is an auto-inflammatory disorder. Curcumin as a bio-active agent has anti-inflammatory properties. Effects of curcumin on the pathogenesis of BD are still not clear. In this study, we investigated the effect of curcumin on the inflammatory cytokines expression and production in M1 macrophages from BD patients compared with healthy controls. METHODS: Monocytes were collected from 10 healthy controls and 20 active BD patients, differentiated to macrophages by macrophage-colony stimulating factor for 7 d. Macrophages were then treated with interferon gamma, lipopolysaccharide, and curcumin (10 or 30 µg/ml) for 24 h. Analysis of tumor necrosis factor-alpha (TNFα), interleukin 1ß (IL-1ß), and IL-6 mRNA expression and protein production was performed using SYBR Green qPCR and ELISA method. RESULTS: Treatment with 30 µg/ml curcumin significantly down-regulated mRNA expression of IL-1ß (p < .05) and protein production of IL-6 (p < .05) in M1 macrophages from BD patients but not in M1 macrophage from controls. Treatment with 30 µg/ml curcumin also significantly diminishes the protein production of TNFα in BD patients (p < .01) and healthy controls (p < .05) M1 macrophages. CONCLUSIONS: We demonstrated that curcumin can inhibit the expression and production of inflammatory cytokines in M1 macrophages from BD patients. Our results suggest that curcumin can modulate inflammatory signaling more specifically in macrophages from BD patients than healthy macrophages.

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.

On the genetics of the Silk Route: association analysis of HLA, IL10, and IL23R-IL12RB2 regions with Behçet's disease in an Iranian population.

Despite that the association of Behçet's disease (BD) with the HLA-B5 was first established in the 1970s, a number of recent genome-wide association studies have both confirmed and furthered this association--in various populations--to individual SNPs both inside and outside the HLA. The former include HLA-B, MICA, and HLA-A, while the latter encompass IL10 and IL23R-IL12RB2 regions. The present study examined whether some of these SNPs could be replicated in an Iranian population, where the prevalence of disease is amply documented. Eight SNPs were selected and tested in 552 patients and 417 controls. These were rs7539328, rs12119179, rs1495965, rs1518111, and rs1800871 in IL10 and IL23R-IL12RB2 regions and rs114854070, rs12525170, and rs76546355 (formerly rs116799036) in the HLA locus. The well-known BD-associated genes HLA-B and MICA were independently genotyped. Although we were not able to formally replicate the association with IL10 and IL23R-IL12RB2, we do report that BD in Iran is strongly associated with HLA-B*51, MICA-A6, and the three HLA-linked SNPs (odds ratio (OR) = 3.38, P = 6.21 × 10(-14); OR = 2.08, P = 1.58 × 10(-13); and OR = 1.67-4.05, P = 1.45 × 10(-04) to 4.79 × 10(-34), respectively). Our data further indicate that the robust HLA-B/MICA association may be explained by a single variant (rs76546355) between the two genes. Overall, these data contribute to a better appraisal of the intriguing linkage between BD and the ancient Silk Route, spanning from the Mediterranean shores to Japan.

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).

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.

Osteonecrosis as a rare musculoskeletal complication in Behcet's disease- the largest case series with literature review.

BACKGROUND: Behcet disease (BD) as a variable vessel vasculitis is mainly characterized by ocular involvement, genital and oral aphthosis, and erythema nodosum. However, major organ involvements including gastrointestinal involvement, nervous system, and vascular involvement are among the severe complications. Osteonecrosis is a rare complication of patients with BD. We aim to report the largest series of BD patients suffering from osteonecrosis. METHODS: We have retrospectively reviewed all patients in Iran Behcet's Disease Registry and reported those with osteonecrosis. Patients' medication and clinical features, symptoms, and details of osteonecrosis will also be presented. Furthermore, previously reported cases will also be reviewed. RESULTS: Seven thousand eight hundred thirty-one patients were diagnosed with BD and registered. 18 patients developed ON with an incidence of 0.22%. The most common involvement during the disease progression was oral aphthosis which appeared in 100% of patients followed by ocular involvement in 85.7% and skin involvement in 71.4%. Vascular, ocular, and nervous system involvements are significantly higher in BD patients with osteonecrosis than the other BD patients. For the management of acute episode of uveitis, deep vein thrombosis, severe gastrointestinal involvement, arterial involvement, nervous system Involvement, and joint involvement high dose of glucocorticoids is indicated. CONCLUSIONS: ON tends to appear as a multifocal involvement in BD patients, hence, after diagnosis of ON in one joint other possible sites of ON should be investigated.

Clinical Manifestations of Behçet's Disease: A Retrospective Cross-Sectional Study.

Introduction: Behçet's Disease (BD) is a systemic vasculitis, highly prevalent in Eastern Asia to Mediterranean countries. Iran is among the countries with the highest prevalence of BD, and previous studies in different countries have shown a broad range of clinical manifestations of the disease. The present study is conducted to evaluate the prevalence of the clinical manifestations of BD in patients referring to rheumatology clinics of two distinct referral hospitals in Tehran and Zanjan, Iran. Methods: In this retrospective, cross-sectional study, the medical records of patients with BD were reviewed, and age at onset, sex, the delay between the onset of symptoms and diagnosis, clinical manifestations, HLA B27, HLA B51, HLA B5, haematuria, proteinuria, leukocyturia, Erythrocyte Sedimentation Rate (ESR), and pathergy phenomenon were included in the study. The collected data were analysed by χ2 test using SPSS 23. Results: A total of 188 patients (Male/female ratio = 1.47) were included in the study with mean ± SD age at onset of 27.98 ± 10.47 years and a mean ± SD of delay between the onset of symptom and diagnosis of 5.70 ± 7.16 years. The most common clinical manifestation was mucosal involvement (85.1%), followed by the ocular lesion (55.3%) and skin manifestations (44.7%). The Pathergy phenomenon was observed in 98 patients (52.1%). Moreover, 45.2% had positive HLA B5, followed by HLA B51 (35.1%) and HLA B27 (12.2%). Conclusion: This study demonstrated that male/female ratio and mean age at onset were comparable to the results of previous studies in Iran. Significant associations between HLAB5 and clinical manifestations underline the pivotal role of genetic factors in BD.

Protective effect of early immunomodulatory treatment on ocular involvement in Behcet's disease: Historical cohort of 1166 patients.

Objectives: Eye involvement is a main presentation of Behcet's disease. This study was performed to evaluate possible determinants affecting the occurrence of eye involvement, especially the role of early systemic treatment with immunomodulatory drugs on the incidence of ocular involvement. Methods: This is a retrospective cohort study performed on 1166 Behcet's patients in the Behcet's Clinic of Rheumatology Research Center. All patients were followed up for at least 10 years and a maximum of 15 years. Data analysis was performed using survival analysis models including Kaplan-Meier Survival analysis, Logrank test, and Cox's proportional hazards regression. Results: 1166 Behcet's patients were evaluated. 80 patients who had eye involvement as the first manifestation of the disease were excluded and 1086 participants entered the analysis. Among them, 647 patients (59.6%) developed ocular involvement 7.8 ± 6.7 years after the first symptom. Immunomodulatory treatment before ocular involvement reduced the risk by 3 times (P-value <0.001). Conclusion: This study demonstrated that the initiation of immunomodulatory treatment prior to eye involvement can reduce the risk of eye involvement in Behcet's patients. Therefore, reducing the onset time of disease symptoms and providing appropriate treatment can reduce Behcet's disease ocular complications.

Preliminary data revealing efficacy of Streptococcus salivarius K12 (SSK12) in Periodic Fever, Aphthous stomatitis, Pharyngitis, and cervical Adenitis (PFAPA) syndrome: A multicenter study from the AIDA Network PFAPA syndrome registry.

Objective: To evaluate the potential role of Streptococcus salivarius K12 (SSK12) in controlling febrile flares in patients with Periodic Fever, Aphthous stomatitis, Pharyngitis, and cervical Adenitis (PFAPA) syndrome. Further aims were to assess the impact of SSK12 on (i) flare duration, (ii) variation in the degree of the highest body temperature during flares, (iii) steroid-sparing effect, and (iv) change of PFAPA accompanying symptoms before and after SSK12 introduction. Patients and methods: The medical charts from 85 pediatric patients with PFAPA syndrome (49 males and 36 females) enrolled in the AIDA registry and treated with SSK12 for a median period of 6.00 ± 7.00 months in the period between September 2017 and May 2022 were examined. Children recruited had a median time of disease duration of 19.00 ± 28.00 months. Results: The number of febrile flares significantly decreased comparing the 12 months before [median (IQR), 13.00 (6.00)] and after SSK12 initiation [median (IQR), 5.50 (8.00), p < 0.001]. The duration of fever was significantly reduced from 4.00 (2.00) days to 2.00 (2.00) days [p < 0.001]. Similarly, the highest temperature in°C was found significantly lower in the last follow-up assessment [median (IQR), 39.00 (1.00)] compared to the period prior to SSK12 start [median (IQR), 40.00 (1.00), p < 0.001]. Steroid load (mg/year) of betamethasone (or any equivalent steroid) significantly decreased between 12 months before treatment with SSK12 [median (IQR), 5.00 (8.00) mg/year] and the last follow-up visit [median (IQR), 2.00 (4.00) mg/year, p < 0.001]. The number of patients experiencing symptoms including pharyngitis/tonsillitis (p < 0.001), oral aphthae (p < 0.001) and cervical lymphadenopathy (p < 0.001) significantly decreased following SSK12. Conclusion: SSK12 prophylaxis given for at least 6.00 months was found to reduce febrile flares of PFAPA syndrome: in particular, it halved the total number per year of fever flares, shortened the duration of the single febrile episode, lowered body temperature by 1°C in the febrile flare, provided a steroid-sparing effect, and significantly reduced the accompanying symptoms related to the syndrome.

A comprehensive overview on the genetics of Behçet's disease.

Behçet's disease (BD) is a systemic and inflammatory disease, characterized mainly by recurrent oral and genital ulcers, eye involvement, and skin lesions. Although the exact etiopathogenesis of BD remains unrevealed, a bulk of studies have implicated the genetic contributing factors as critical players in disease predisposition. In countries along the Silk Road, human leukocyte antigen (HLA)-B51 has been reported as the strongest genetically associated factor for BD. Genome-wide association studies, local genetic polymorphism studies, and meta-analysis of combined data from Turkish, Iranian, and Japanese populations have also identified new genetic associations with BD. Among these, other HLA alleles such as HLA-B*15, HLA-B*27, HLA-B*57, and HLA-A*26 have been found as independent risk factors for BD, whereas HLA-B*49 and HLA-A*03 are independent protective alleles for BD. Moreover, other genes have also reached the genome-wide significance level of association with BD susceptibility, including IL10, IL23R-IL12RB2, IL12A, CCR1-CCR3, STAT4, TNFAIP3, ERAP1, KLRC4, and FUT2. Also, several rare nonsynonymous variants in TLR4, IL23R, NOD2, and MEFV genes have been reported to be involved in BD pathogenesis. According to genetic determinants in the loci outside the MHC region that are contributed to the host defense, immunity, and inflammation pathways, it is suggested that immune responses to the pathogen as an important environmental factor and mucosal immunity contribute to BD susceptibility.

TNFAIP3 mutation causing haploinsufficiency of A20 with a hemophagocytic lymphohistiocytosis phenotype: a report of two cases.

BACKGROUND: A20 haploinsufficiency (HA20) is a newly introduced autosomal dominant autoinflammatory disorder, also known as Behcet's-like disease. Some of the most common symptoms of the disease are recurrent oral, genital, and/or gastrointestinal (GI) ulcers, episodic fever, musculoskeletal symptoms, cutaneous lesions, and recurrent infections. Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition of multi-organ failure due to excessive immune activation. HLH has been reported in a few HA20 patients. Herein, we report two children with the primary presentation of HLH, with a mutation in TNFAIP3, in favor of HA20. CASE PRESENTATIONS: Our first patient was a 4-month-old boy who presented with fever, irritability, pallor, and hepatosplenomegaly. Pancytopenia, elevated ferritin, and decreased fibrinogen levels were found in laboratory evaluation. He was diagnosed with HLH and was treated with methylprednisolone and cyclosporine. Two years later, whole exome sequencing (WES) indicated a mutation in TNFAIP3 at NM_001270507: exon3: c.C386T, p.T129M, consistent with A20 haploinsufficiency. Etanercept, a TNF inhibitor, was prescribed, but the parents were reluctant to initiate the therapy. The patient passed away with the clinical picture of cerebral hemorrhage. The second patient was a 3-month-old boy who presented with a fever and hepatosplenomegaly. Laboratory evaluation found pancytopenia, hyperferritinemia, hypoalbuminemia, hypertriglyceridemia, and hypofibrinogenemia. With the establishment of the HLH diagnosis, he was treated with etoposide, dexamethasone, and cyclosporine, and recovered. WES results revealed a heterozygous de novo variant of TNFAIP3 (c. T824C in exon 6, 6q23.3) that leads to a proline to leucine amino acid change (p. L275P). He was treated with etanercept and has been symptom-free afterward. CONCLUSIONS: This report is a hypothesis for developing of the HLH phenotype in the presence of TNFAIP3 mutation. Our results provide a new perspective on the role of TNFAIP3 mutation in HLH phenotypes, but more extensive studies are required to confirm these preliminary results.