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Objective A decline in the frequency of AA amyloidosis secondary to RA and infectious diseases has been reported. We aimed to determine the change in the frequency of AA amyloidosis in our Behçet’s syndrome (BS) patients and to summarize the clinical characteristics of and outcomes for our patients, and also those identified by a systematic review. Methods We identified patients with amyloidosis in our BS cohort (as well as their clinical and laboratory features, treatment, and outcome) through a chart review. The primary end points were end-stage renal disease and death. The prevalence of AA amyloidosis was estimated separately for patients registered during 1976–2000 and those registered during 2001–2017, in order to determine whether there was any change in the frequency. We searched PubMed and EMBASE for reports on BS patients with AA amyloidosis. Risk of bias was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool. Results The prevalence of AA amyloidosis was 0.62% (24/3820) in the earlier cohort and declined to 0.054% (3/5590) in the recent cohort. The systematic review revealed 82 cases in 42 publications. The main features of patients were male predominance and a high frequency of vascular involvement. One-third of patients died within 6 months after diagnosis of amyloidosis. Conclusion The frequency of AA amyloidosis has decreased in patients with BS, which is similar to the decrease observed for AA amyloidosis due to other inflammatory and infectious causes. However, AA amyloidosis is a rare, but potentially fatal complication of BS.

Objective The performance of existing diagnostic criteria for Behçet’s disease (BD) is usually evaluated by comparison with expert opinions, which may be limited by misclassification and disagreement among experts. We aim to evaluate these criteria in the absence of a gold standard. Methods We obtained two datasets involving possible BD and other mimickers from a uveitis registry using case–cohort and nested case–control analyses, respectively. With a Bayesian inference approach, the sensitivity and specificity of International Study Group (ISG) and International Criteria for Behçet’s Disease (ICBD) criteria were simultaneously estimated when true BD state was unknown. Results A total of 2440 and 2224 participants were included in case–cohort and nested case–control analyses, respectively. In case–cohort analysis, with scores of ≥4 for BD diagnosis, ICBD criteria showed higher sensitivity (median 97.6%; 95% credible interval 96.9, 98.2) than ISG criteria (median 90.0%; 95% credible interval 88.8, 91.2) but had lower specificity (median 90.8%; 95% credible interval 89.4, 92.1) than ISG criteria (median 98.8%; 95% credible interval 98.3, 99.3). With scores of ≥5 for diagnosis, ICBD criteria demonstrated higher sensitivity (median 97.5%; 95% credible interval 96.8, 98.1) and specificity (median 99.6%; 95% credible interval 99.3, 99.8) than the sensitivity (median 92.3%; 95% credible interval 91.2, 93.3) and specificity (median 98.8%; 95% credible interval 98.2, 99.2) for ISG criteria. The highest diagnostic consistency was observed between ISG criteria and ICBD criteria with scores of ≥5 for diagnosis (Kappa = 0.999; P Conclusion ICBD criteria showed optimum discriminatory properties in sensitivity and specificity with scores of ≥5 for BD diagnosis in uveitis. The diagnostic threshold of ICBD criteria could be considered adjustable according to medical specialty, disease prevalence and local practice characteristics.

Objective Previous studies have indicated that Behçet’s disease (BD) has a genetic component, however population-level familial risk estimates are unavailable. We quantified the familial incidence and risk of BD in first-degree relatives (FDR) according to age, sex and type of family relationship. Methods Using the Korean National Health Insurance database, which has full population coverage and confirmed FDR information, we constructed a cohort of 21 940 795 individuals comprising 12 million families, which were followed for a familial occurrence of BD from 2002 to 2017. Age- and sex-adjusted incidence risk ratios for BD were calculated in individuals with affected FDR compared with those without affected FDR. Results Among the total study population, 53 687 individuals had affected FDR, of whom 284 familial cases developed BD with an incidence of 3.57/104 person-years. The familial risk (incidence) for BD was increased to 13.1-fold (2.71/104 person-years) in individuals with an affected father, 13.9-fold (3.11/104 person-years) with affected mother, 15.2-fold (4.9/104 person-years) with an affected sibling and the highest risk was 165-fold (46/104 person-years) with an affected twin. Familial risks showed age dependence, being higher in younger age groups. The sex-specific familial risk was similar in males and females. Conclusion This study provides quantified estimates of familial incidence and risk in FDR of BD patients in an entire population. Familial risks were higher within generation (sibling–sibling) vs between generations (parent–offspring). This implicates complex interactions between genetic factors and shared childhood environmental exposures in the pathogenesis of BD.

Objectives The epidemiology of Behçet’s disease (BD) has not been well characterized in the UK. Evidence on the risk of cardiovascular disease, thromboembolic disease and mortality in patients with BD compared with the general population is scarce. Methods We used a large UK primary care database to investigate the epidemiology of BD. A retrospective matched cohort study was used to assess the following outcomes: risk of cardiovascular, thromboembolic disease and mortality. Controls were selected at a 1:4 ratio (age and gender matched). Cox proportional hazard models were used to derive adjusted hazard ratios (aHR). Results The prevalence of BD was 14.61 (95% CI 13.35–15.88) per 100 000 population in 2017. A total of 1281 patients with BD were compared with 5124 age- and gender-matched controls. There was significantly increased risk of ischaemic heart disease [aHR 3.09 (1.28–7.44)], venous thrombosis [aHR 4.80 (2.42–9.54)] and mortality [aHR 1.40 (1.07–1.84)] in patients with BD compared with corresponding controls. Patients with BD were at higher risk of pulmonary embolism compared with corresponding controls at baseline [adjusted odds ratio 4.64 (2.66–8.09), P < 0.0001]. The majority of patients with pulmonary embolism and a diagnosis of BD had pulmonary embolism preceding the diagnosis of BD, not after (87.5%; n = 28/32). Conclusion BD has a higher prevalence than previously thought. Physicians should be aware of the increased risk of developing ischaemic heart disease, stroke/transient ischaemic attack and deep venous thrombosis in patients with BD at an earlier age compared with the general population. Risk of embolism in patients with BD might vary across the disease course.

Objectives CYC remains an important treatment option for Behçet’s syndrome (BS) patients with life-threatening manifestations. However, adverse events may occur with CYC and this has led to increased use of biologic agents in other vasculitides. We investigated short and long term adverse events associated with CYC use in BS patients. Methods We conducted a retrospective chart review of all BS patients treated with CYC between 1972 and 2006. Patients were called in and a standard form was used for collecting demographic characteristics, indication for CYC, its cumulative dose and short term adverse events, defined as those causing discontinuation of CYC, hospitalization and/or death, long term adverse events, including infertility and malignancy, and outcome. Results Of 5790 BS patients, 198 (3.4%) had used at least one dose of CYC. Main indications were vascular or neurological involvement. After a median follow-up of 17 years, 52 (26%) patients had died, 113 (57%) could be contacted, and 33 (17%) were lost to follow-up. Vascular involvement was the leading cause of death (n = 27). Seventeen (9%) patients experienced short term adverse events with haemorrhagic cystitis being the most common. After a median follow-up of 25 years (interquartile range: 15–26 years), 17 malignancies occurred in 15 (8%) patients. Infertility was experienced by 26 (30%) patients. Conclusion Long term adverse events such as malignancy and infertility were major problems in our BS patients treated with CYC. These results underline the need for safer treatment modalities that are at least as effective as CYC.

Objectives Lower extremity deep vein thrombosis (LEDVT) is a serious complication of Behçet’s syndrome. Management constitutes mainly of administration of immunosuppressives, but the predictors of relapse and the optimal choice of immunosuppressives remain unclear. In this prospective study, we aimed to detect the risk and predictors of relapse and treatment response to different modalities. Methods All Behçet’s syndrome patients who presented with a first episode of acute LEDVT between 2010 and 2014 were prospectively followed with a standard protocol. Acute LEDVT was confirmed by Doppler ultrasonography. Serial planned Doppler ultrasonography assessments were performed during follow-up and additionally repeated in case of clinical suspicion. Recanalization rate was assessed at each visit. Our first-line treatment strategy consisted of AZA and CSs. IFN-alpha was used in patients who were refractory to or could not tolerate AZA or had concomitant eye involvement requiring further treatment. Results Thirty-three patients with LEDVT (26 M/7 F) were prospectively followed for 40.7 ± 13.4 months. Among the 33 patients, 23 relapses were observed in 15 patients. Relapse rates were 29%, 37% and 45% at 6, 12 and 24 months, respectively. Among the possible predictors of relapse, poor recanalization was the only significant factor [hazard ratio 4.34 (95% CI 1.96, 10.0)]. Overall 29 patients were treated with AZA and 17 with IFN-alpha. The relapse rate was lower and recanalization rate was higher with IFN-alpha compared with AZA (12% vs 45% and 86% vs 45%). Conclusion The relapse rate for LEDVT in Behçet’s syndrome is high despite AZA treatment. IFN-alpha seems to be a promising agent for preventing LEDVT relapses and achieving good recanalization.

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.

Objective: To assess the efficacy of tocilizumab (TCZ) in refractory uveitis of Behcet's disease (BD). Methods: Multicentre study of patients with BD-associated uveitis. Patients were refractory to conventional and biologic immunosuppressive drugs. The main outcome measures were intraocular inflammation, macular thickness, visual acuity and corticosteroid-sparing effects. Results: We studied 11 patients (7 men) (20 affected eyes); median age 35 years. Uveitis was bilateral in nine patients. The patterns of ocular involvement were panuveitis (n = 8, with retinal vasculitis in 4), anterior uveitis (n = 2) and posterior uveitis (n = 1). Cystoid macular oedema was present in seven patients. The clinical course was recurrent (n = 7) or chronic (n = 4). Before TCZ, patients had received systemic corticosteroids, conventional immunosuppressants and the following biologic agents: adalimumab (n = 8), infliximab (n = 4), canakimumab (n = 1), golimumab (n = 3), etanercept (n = 1). TCZ was used as monotherapy or combined with conventional immunosuppressants at 8 mg/kg/i.v./4 weeks (n = 10) or 162mg/s.c./week (n = 1). At TCZ onset the following extraocular manifestations were present: oral and/or genital ulcers (n = 7), arthritis (n = 4), folliculitis/pseudofolliculitis (n = 4), erythema nodosum (n = 2), livedo reticularis (n = 1) and neurological involvement (n = 2). TCZ yielded rapid and maintained improvement in all ocular parameters of the patients, with complete remission in eight of them. However, this was not the case for the extraocular manifestations, since TCZ was only effective in three of them. After a mean (S.D.) follow-up of 9.5 (8.05) months, TCZ was withdrawn in two cases, due to a severe infusion reaction and arthritis impairment, respectively. Conclusion: TCZ could be a therapeutic option in patients with BD and refractory uveitis.

Objective This report aimed to scrutinize the prevalence of Behcet's disease (BD)-related clinical manifestations based on age- and sex-specific subgroups using a Japanese nationwide registration database. Methods The database of newly registered BD was obtained from the Japanese Ministry of Health, Labour and Welfare. Patients who met the International Criteria for Behcet's Disease were selected and analysed. Results Among 6627 International Criteria for Behcet's Disease cases, 2651 (40.0%) were men and 3976 (60.0%) were women with a median age of 39 years (interquartile range: 31-50 years). Ocular lesion was more common in male [odds ratio (male: female) 2.64 (95% CI: 2.35, 2.95, P < 0.001)] and genital ulceration was more common in female (odds ratio = 0.29, 95% CI: 0.25, 0.32, P < 0.001). Ocular lesion (P < 0.001), arthritis (P < 0.001) and vascular lesions (P < 0.001) were more frequently observed in elderly registered patients. Contrarily, genital ulceration (P < 0.001), epididymitis of males (P = 0.023) and oral ulceration (P = 0.003) were more common in younger patients. Simultaneous assessment of sex and age revealed that male predominance of ocular involvement was found in the young adult generation, but not in patients over 70 year of age. A female predominance of genital ulcer was prominently observed in patients 20-59 year of age; however, the sex difference was not found in patients over 60 years of age. Sensitivity analysis using International Study Group criteria replicated the results. Conclusion We showed that clinical phenotype in early phase of BD was different depending on onset age and sex.

OBJECTIVE: The aim of this study was to assess the efficacy of anti-TNF-α therapy in refractory uveitis due to Behcet's disease (BD). METHODS: We performed a multicentre study of 124 patients with BD uveitis refractory to conventional treatment including high-dose corticosteroids and at least one standard immunosuppressive agent. Patients were treated for at least 12 months with infliximab (IFX) (3-5 mg/kg at 0, 2 and 6 weeks and then every 4-8 weeks) or adalimumab (ADA) (usually 40 mg every 2 weeks). The main outcome measures were degree of anterior and posterior chamber inflammation, visual acuity, macular thickness and immunosuppression load. RESULTS: Sixty-eight men and 56 women (221 affected eyes) were studied. The mean age was 38.6 years (s.d. 10.4). HLA-B51 was positive in 66.1% of patients and uveitis was bilateral in 78.2%. IFX was the first biologic agent in 77 cases (62%) and ADA was first in 47 (38%). In most cases anti-TNF-α drugs were used in combination with conventional immunosuppressive drugs. At the onset of anti-TNF-α therapy, anterior chamber and vitreous inflammation was observed in 57% and 64.4% of patients, respectively. In both conditions the damage decreased significantly after 1 year. At baseline, 50 patients (80 eyes) had macular thickening [optical coherence tomography (OCT) >250 μm] and 35 (49 eyes) had cystoid macular oedema (OCT>300 μm) that improved from 420 μm (s.d. 119.5) at baseline to 271 μm (s.d. 45.6) at month 12 (P < 0.01). The best-corrected visual acuity and the suppression load also showed significant improvement. After 1 year of follow-up, 67.7% of patients were inactive. Biologic therapy was well tolerated in most cases. CONCLUSION: Anti-TNF-α therapy is effective and relatively safe in refractory BD uveitis.

Objective. Some features of Behcet's syndrome (BS) tend to go together. We aimed to explore the association and timing of various vascular events in both the venous and the arterial vascular tree. Methods. We conducted a chart survey on the type and time of vascular involvement of BS. The cross- relationships of involvement were assessed by phi correlation coefficients. Multiple correspondence ana- lysis was used to identify patterns of vascular involvement. The risk of vascular recurrence was also estimated. Results. We identified 882 patients with vascular involvement among 5970 BS patients (14.7%). Deep vein thrombosis (DVT), almost always in the legs, was the most frequent single vascular event (592/882; 67.1%). The cumulative risk of a recurrent vascular event was 38.4% at 5 years. Patients with extrapul- monary artery involvement (EPAI) were significantly older than those with venous and pulmonary artery involvement (PAI). There were significant correlations between dural sinus thrombosis (DST) and PAI, BuddChiari syndrome (BCS) and inferior vena cava syndrome (IVCS) and between IVCS and superior vena cava syndrome (SVCS). Multiple correspondence analysis further indicated clustering of PAI, DST, BCS, IVCS and SVCS. However, EPAI and DVT clustered separately from forms of vascular disease, the separate clustering of the DVT being attributed to its propensity to occur solo. Conclusion. The most common type of vascular involvement in BS is solo DVT, almost always occurring in the legs. Various forms of venous disease in BS segregate together and PAI is included in this group. EPAI segregates separately.

Objectives There is no consensus on whether restarting TNF inhibitors (TNFis) after treatment of an active tuberculosis (TB) infection caused by previous TNFi exposure is safe. In this study we sought to determine the safety of resuming TNFis in patients following TB treatment. Methods The medical records of all patients (n = 683) that received TNFi treatment at a single rheumatology clinic between June 2003 and December 2012 were retrospectively reviewed. Among them, data from patients who developed active TB infection were collected and patient outcomes were evaluated for those who resumed TNFis after TB treatment. Results Of 683 patients, 13 patients developed an active TB infection during TNFi treatment (4 on etanercept, 4 on adalimumab and 5 on infliximab). The median duration of TNFi treatment before TB infection was 20 months. TNFi treatment was reinitiated in six patients: four within 2 months after TB treatment and two after completion of TB treatment. Four patients reinitiated with the same TNFi, whereas two patients started with another TNFi. During a mean follow-up of 30.6 months, all six patients successfully completed TB treatment with no TB infection relapses. Conclusion Our results suggest that resuming TNFi therapy in patients following adequate TB treatment is safe, even before completion of TB treatment.

Objectives: Activated innate immunity is implicated in the pathogenesis of Behcet’s Disease (BD). To clarify the mechanisms of innate immune responses, we investigated inflammasome activation in dendritic cells (DC) and neutrophils, following stimulation with two different pattern recognition receptors (PRR) “RIG-1 like” (RLR) and “NOD-like” (NLR) in patients with BD. Methods: Sixteen active BD patients with mucocutaneous lesions and 17 healthy controls (HC) were included in this study. Dendritic cells were generated from monocytes. DCs and isolated neutrophils were activated by RLR and NLR ligands. Caspase-1 activation and expressions of p38 and RIP2 were determined by flow cytometry. Levels of IL-1ß, IL-6, TNF-?, IFN-? and IL-18 in culture supernatants were measured by ELISA. Results: Activation of caspase-1 following intracellular PRR stimulation was found to be in similar levels in DCs and neutrophils of BD patients compared to HC. However, activation of DCs from BD patients to NOD2 stimulus measured with the expressions of RIP2, p38 as well as IL-18 levels was found to be slightly defective (p

Objective. To describe the experience of two tertiary Spanish centres (Hospital Clinico San Cecilio, Granada and Hospital Clinic, Barcelona) with the use of adalimumab for the treatment of severe clinical manifestations in patients with Behcet's disease (BD) in whom immunosuppressive therapy had failed. Methods. Retrospective chart review from patients with BD treated with adalimumab in two specialized Spanish centres (Hospital Clinico San Cecilio, Granada and Hospital Clinic, Barcelona). Results. From November 2006 to February 2011, 19 patients with BD were treated with adalimumab. The reason to initiate adalimumab was refractory disease in 17 (89.5%) patients and adverse events to CSA and infliximab in two (10.5%) patients, respectively. The main clinical manifestations leading to adalimu- mab administration were panuveitis in eight patients, severe bipolar aphthosis in eight, retinal vasculitis in three and severe folliculitis in three. Overall, adalimumab achieved clinical improvement in 17 of the 19 patients. Of note, ocular manifestations (panuveitis and retinal vasculitis) responded rapidly in all cases. In addition to clinical improvement, treatment with adalimumab was associated with reduction in the number and dose of standard immunosuppressive agents. Of interest, seven patients had received TNF-a inhibi- tors before adalimumab, five infliximab and the remaining two etanercept. Adalimumab was withdrawn in only one patient due to severe infusional reaction in the form of urticaria and angioedema. Conclusion. Adalimumab is a valid option for patients with BD and recalcitrant non-controlling manifestations with good safety profile.

Objective. Behcet's disease (BD) is a multisystemic inflammatory disease, mainly characterized by recurrent oral and genital ulcers (GUs), skin lesions and uveitis. Several genetic factors such as the TNF-� gene have been evaluated as contributors to the pathogenesis of BD. We aimed to evaluate the association between six TNF-� SNPs and susceptibility to BD, or the major clinical manifestations, in Moroccan patients. The six SNPs studied were: c.1211C>T (rs1799964), c.1043C>A (rs1800630), c.1037C>T (rs1799724), c.556G>A (rs1800750), c.488G>A (rs1800629) and c.418G>A (rs361525), known as 1031T>C, 863C>A, 857C>T, 376G>A, 308G>A and 238G>A, respectively. Methods. SNPs were genotyped by direct sequencing in 120 unrelated Moroccan BD and 112 ethnically matched healthy controls. Allele and genotype distributions were compared between groups using chi-square or Fisher's exact tests. Results. The frequency of the 1211C allele was higher in (i) BD patients than in controls (P = 0.02, odds ratio (OR) = 1.68, 95% CI 1.10, 2.56) and in (ii) patients with GUs than in those without (P = 0.002, OR = 3.84, 95% CI 1.55, 9.49). The 418A frequency was lower in patients with uveitis (P = 0.0003, OR = 0.19, 95% CI 0.07, 0.5). Conclusion. We report the first association between BD and TNF-a SNPs in Moroccan patients. We mainly observed that 1211C constitutes a susceptibility allele for both BD and GU, as previously re- ported for other populations. The 418A allele could be considered as a good prognostic factor for anterior uveitis, in Moroccan BD patients.

We have previously reported distinct symptom clusters among our patients with Behçet's syndrome (BS). The presence of such clusters suggests that more than one pathogenetic mechanism might be operative in BS. Increases in the frequency of certain clusters in familial BS cases, if present, would further support this notion. To test this hypothesis, we compared the frequency of symptom clusters between familial (group F) and non-familial (group NF) cases of BS.We identified 380 BS patients who had reported a first-degree relative by reviewing 6031 patient charts. We were able to contact 186 (Group F). From the same initial pool, 500 patients were randomly selected. Of those, patients who did not report a family history of BS and who had attended our clinic during the previous 3 months made up group NF (n = 221). Both groups were questioned about their symptoms within the previous 3 months. Data were analysed using factor analysis, cluster analysis and χ2 tests.The make-up of the symptom clusters were very similar for the factor and the cluster analyses. The frequency of papulopustular lesions and joint involvement cluster was significantly higher in group F (39.2 vs. 21.5%, P0.001). Furthermore, the same cluster was shared in 5/17 related pairs from group F and in only 5/110 unrelated pairs from group NF [29 vs. 4.5%, P = 0.004; risk ratio (RR) = 6.47, 95% CI 2.15, 18.89].The papulopustular lesions and arthritis cluster in BS appears to cluster in familial BS as well. This further supports the notion that the pathogenesis of BS may entail several distinct mechanisms resulting in separate phenotype clusters.

Objective. To investigate comprehensively the relationships between Behcet's disease (BD) clinical features and HLA-B51 or HLA-B5 (HLA-B51/B5) status using meta-analyses. Methods. Relevant publications were identified by a systematic literature search. Eligible studies had to provide frequencies for one or more BD characteristics according to HLA-B51/B5 status. Pooled relative risks (RRs) were calculated by random-effects meta-analysis for those BD characteristics for which five or more relevant studies were identified. Between-study variability was assessed with I 2 and Q-statistics, and modelled using meta-regression. Results. Among the 859 publications evaluated, 72 (representing 74 study populations) met eligibility criteria. Pooled RRs (95% CIs) of the association of HLA-B51/B5 with the 14 analysed clinical character- istics were male sex 1.14 (1.05, 1.23); eye involvement 1.13 (1.06, 1.21); genital ulcers 1.07 (1.01, 1.14); skin involvement 1.10 (1.03, 1.16); erythema nodosum 1.11 (0.96, 1.29); pseudofolliculitis 1.07 (0.93, 1.23); positive pathergy test 1.05 (0.94, 1.17); joint involvement 0.94 (0.86, 1.04); neurological involvement 0.95 (0.71, 1.27); gastrointestinal involvement 0.70 (0.52, 0.94); thrombophlebitis 1.17 (0.77, 1.76); vascular involvement 1.00 (0.68, 1.47); chest involvement 1.55 (0.75, 3.20) and orchiepididymitis 1.13 (0.59, 2.15). For most of the analysed outcomes, between-study heterogeneity was low or absent and most of the meta-regression models were statistically non-significant. Conclusion. The results of these meta-analyses showed that, in BD, HLA-B51/B5 carriage predominates in males and is associated with moderately higher prevalences of genital ulcers, ocular and skin mani- festations, and a decreased prevalence of gastrointestinal involvement.

Objectives IFN-α has been used to treat patients with Behcet's disease (BD). Recent studies have implicated the IL-23/Th-17 pathway in the pathogenesis of BD. In this study, we investigated whether IFN-α could affect this pathway. Methods Peripheral blood mononuclear cells (PBMCs) obtained from patients with active BD and controls were cultured alone or with IFN-α and the levels of IL-17 and IL-10 in the supernatants were measured by ELISA. Similar experiments were performed with isolated CD4(+) T cells from controls. The levels of phosphorylated STAT1 (p-STAT1), p-STAT2, p-STAT3 and p-STAT5 in CD4(+) T cells from controls cultured with or without IFN-α were also evaluated by ELISA. Furthermore, an experiment using anti-IL-10 was performed to examine underlying mechanisms of action of IFN-α. Results Significantly higher levels of IL-17 and IL-10 were observed in the supernatants of PBMCs from BD patients as compared with controls. IFN-α significantly decreased IL-17 production by PBMCs from both patients and controls. On the other hand, IFN-α increased IL-10 production by PBMCs from patients and controls. Similar findings were obtained when using CD4(+) T cells from controls, IFN-α significantly increased p-STAT2 expression in control CD4(+) T cells. Anti-IL-10 antibody was able to neutralize the inhibitory effect of IFN-α on IL-17 by 35% as compared with controls. Conclusions In vitro experiments showed that IFN-α could inhibit IL-17 expression and increased IL-10 production by PBMCs and CD4(+) T cells. The inhibitory role of IFN-α on IL-17 was partly mediated by IL-10. IFN-α activity was mediated via STAT2 phosphorylation.

To compare a single infusion of the anti-TNF antibody infliximab vs CSs for acute panuveitis attacks in Behçet's disease (BD).A prospective, observational study of patients with panuveitis, who received either an infliximab infusion (5 mg/kg, 19 eyes) or high-dose methylprednisolone intravenously (1 g/day for 3 days, 8 eyes), or intra-vitreal triamcinolone acetonide (4 mg, 8 eyes) at attack's onset. Baseline maintenance therapy remained unchanged during the following 30 days. Visual acuity, anterior chamber cells, vitreous cells and inflammation of the posterior eye segment were assessed at baseline and at Days 1, 7, 14 and 29 (±1) post-treatment.While no significant differences were noted between i.v. and intra-vitreal CSs, infliximab was faster than CSs in decreasing total ocular inflammation scores and fundus inflammation scores (P = 0.01 and P 0.0001 for treatment × time(2) interaction, respectively, using generalized estimating equation analysis). Independently of time, infliximab was superior to CSs in clearing retinal vasculitis (P 0.003), as well as in resolution of retinitis (P = 0.008) and cystoid macular oedema (P 0.007). Moreover, a faster regression of cystoid macular oedema was observed with infliximab compared with CSs (P 0.03). The beneficial effects of the three treatment modalities on visual acuity were comparable from baseline to the end of follow-up. No side effects were noted with infliximab or methylprednisolone, whereas intra-vitreal triamcinolone acetonide caused ocular hypertension in four of the eight eyes, requiring surgical intervention in two.A single infusion of infliximab should always be considered, even as an adjunct therapy, for the control of acute panuveitis attacks in BD.

Objective To review the progress in the field of MHC-related genetic susceptibility to Behcet's disease (BD). Method Systematic review of the English literature between 1 January 1980 and 31 January 2010 using Medline. Case-control, population-based, observational cohort studies investigating the association between BD and HLA-B*51 subtypes, classical and non-classical HLA alleles and other HLA-related genes were selected. The geographical distribution of BD and these susceptibility genes was also taken into consideration. Case and familial case reports were excluded except for case series with more than two patients. Results Ninety articles plus 17 obtained from other sources were included in the systematic review. We have found high evidence that a core component of genetic susceptibility to BD is within the MHC region being primarily related to an HLA-B*51 subtype: HLA-B*5101/B*510101. Moreover, HLA-A*26, HLA-B*15, HLA-B*5701 and TNF-α -1031C were independently associated with BD. Data suggest that other HLA (HLA-C, HLA-DR) and HLA-related [MHC Class I chain-related gene A (MIC-A), TNF-α] genes may play a role in BD co-susceptibility or pathogenesis. Finally, the distinctive geographical distribution of BD suggested an evolutionary selection of HLA-B*51 subtypes as the major susceptibility factors for BD. Conclusion Further studies must be addressed to clarify the functional relevance of the different genes found to be associated with disease susceptibility and the potential interactions between genes located within and outside the MHC region.

OBJECTIVE: To set-up an international cohort of patients suspected with Behçet's disease (BD). The cohort is aimed at defining an algorithm for definition of the disease in children. METHODS: International experts have defined the inclusion criteria as follows: recurrent oral aphthosis (ROA) plus one of following-genital ulceration, erythema nodosum, folliculitis, pustulous/acneiform lesions, positive pathergy test, uveitis, venous/arterial thrombosis and family history of BD. Onset of disease is

Objective. To assess the overall impact of Behcet's syndrome (BS) on quality of life and the specific impact of the type and number of symptoms on the quality of life of adults with BS. Methods. A questionnaire was mailed to the 641 adult members of the Behcet's Syndrome Society in the UK. Participants provided information on socio-demographic characteristics, disease duration, current symptoms (mouth ulcers, genital ulcers, skin lesions, fatigue, joint problems, stomach/bowel problems, eye problems, pathergy reaction, headaches and other neurological problems), symptom control and quality of life (the EQ-5D index). Linear regression was used to test the associations of the type and number of symptoms with the EQ-5D index. Results. Of the 447 members, 400 who returned the questionnaires had a confirmed diagnosis of BS. Of them, 362 had information on the variables selected for this analysis (76% females and 94% white British). The mean EQ-5D index was 0.47 (S.D. 0.38). Of the 10 symptoms assessed, joint problems had the strongest impact on quality of life, followed by neurological problems, pathergy reaction and stomach/ bowel problems (adjusted coefficients of 0.15, 0.13, 0.11 and 0.18, respectively). Furthermore, the number of symptoms was significantly related to the EQ-5D index after adjustment for socio-demographic characteristics, disease duration and symptom control. The EQ-5D index decreased by 0.05 U for every additional symptom reported. Conclusions. BS has a considerable impact on quality of life. Both the type and number of symptoms affect the quality of life of adults with BS.

Objective. We report the use of nicotine-patch therapy on active mucocutaneous lesions of Behcet's disease (BD). Methods. Five BD ex-smoker patients with refractory active mucocutaneous manifestations were treated with nicotine patches for 6 months. Results. Four out of five patients quickly responded to nicotine-patch therapy and experienced a complete regression of mucocutaneous lesions. Other manifestations of BD did not respond and new manifestations appeared during this treatment. One patient had no benefit from therapy but on restarting smoking it was promptly effective. Conclusions. Mucocutaneous lesions associated with BD may be modulated by smoking. Both smoking and nicotine-replacement therapy may be efficacious not only on oral aphthae, but also on other mucocutaneous manifestations, whereas the efficacy in the treatment and prevention of other systemic manifestations of BD is not proven. At least in ex-smokers, nicotine in its pure form is well tolerated and its use could be justified in selected cases of BD with predominant and recurrent refractory mucocutaneous manifestations.

Objectives. HLA-B51 is strongly associated with Behcet's disease (BD) in any ethnic background. We recently reported that another gene, Toll-like receptor-4 (TLR4) is also implicated in BD in a Japanese population. To confirm these results, we investigated polymorphisms in the TLR4 gene in Korean patients with BD. Methods. In this study, 119 patients with BD and 141 healthy controls were enrolled; every participant was a Korean. Nine single nucleotide polymorphisms previously detected in TLR4 by direct sequencing were analysed for an association with BD. Results. The most frequent haplotype, TAGCGGTAA, was significantly increased in HLA-B*51-positive BD patients (49.5%), compared with healthy control participants (32.3%; P ¼ 0.029; odds ratio (OR) ¼ 2.01; 95% CI 1.25-3.23). This haplotype was also significantly increased in BD patients with arthritis (48.2%; P ¼ 0.003; OR ¼ 1.96; 95% CI 1.26-3.26). There were no significant differences in the allele and genotype frequencies of patients and controls for each single nucleotide polymorphism. Conclusions. The haplotype of TLR4 may increase the risk for developing BD and the complication of arthritis in the Korean population.

Objective Intestinal Behcet's Syndrome (BS) is a difficult diagnosis to establish. We describe the use of wireless capsule endoscopy (WCE) in the investigation of 11 patients with suspected intestinal BS. Methods Out of 11 patients, 10 with suspected intestinal BS were found to have small intestinal ulcers on capsule endoscopy. Each case was retrospectively assessed for symptoms, signs, anaemia, other investigations, treatment and complications. Results All 11 patients had established diagnoses of BS as defined by the International Study Group criteria. Central abdominal pain and change in bowel habit were the predominant symptoms, both occurring in seven patients. Upper gastrointestinal (GI) endoscopy and colonoscopy identified duodenitis, ileitis and colitis in three patients. Barium studies and CT were normal in all cases. WCE revealed small intestinal ulcers throughout the ileum in five patients and ulcers located either in the proximal and/or distal ileum in five other patients. One patient had significant symptoms, signs and ulcers leading to a change in treatment to infliximab, and this resulted in resolution of symptoms and ulcers. Ten age- and sex-matched controls investigated for unexplained GI symptoms had no intestinal lesions on capsule endoscopy. Conclusion WCE is useful in the investigation of GI symptoms in BS. It is particularly helpful in those patients in whom conventional investigations have been normal or fail to account for symptoms and signs. This technique may guide treatment and provide a better understanding of intestinal pathology in BS.

Objectives. Recent studies have shown the immunomodulatory effect of vitamin D3 through down-regulation of Toll-like receptor (TLR) expression in human monocytes. To understand the implication of innate immunity with the role of vitamin D affecting TLR expression in Behcet's disease (BD), we focused on the association between the TLR expression and the serum vitamin D concentration in BD. Methods. The expression of TLR2, TLR4 and CD16 on monocytes was detected by flow cytometric analysis and RT-PCR. Serum 25-hydroxyvitamin D (25(OH)D) levels were measured in the patients with BD, psoriasis and healthy controls, and then the expression of TLRs was correlated with the value of serum 25(OH)D levels. To assess the influence of vitamin D3 on expression and function of TLRs in vitro, human monocytes were treated with increasing concentrations of 1,25(OH)2D3. Results. We found that the monocytes of active BD patients showed higher expressions of TLR2 and TLR4 than those of controls, and serum 25(OH)D levels tended to be lower in active BD. Furthermore, 25(OH)D levels were inversely correlated with the expressions of TLR2, TLR4 and clinical indicators. In vitro analysis showed that vitamin D3 was found to dose-dependently suppress the protein and mRNA expressions of TLR2 and TLR4. TNF-� synthesis was also decreased upon TLR ligand stimulation in vitamin D3-treated monocytes. Conclusion. These results suggest that the inflammation triggered through TLR2 and TLR4 is important in the pathogenesis of BD. And it seems possible that vitamin D may be used as a therapeutic option by modulating TLR2 and TLR4 expression of monocytes in BD.

Objective To report both the efficacy and safety of interferon-alpha-2a (IFN-alpha) therapy in corticodependent uveitis of paediatric Behcet's disease (BD). Methods Data from seven children affected with corticodependent uveitis of BD and treated with IFN-alpha were reviewed retrospectively. IFN-alpha was injected sub-cutaneously thrice a week at dosages of 1.5-3 M(ons) IU according to the children's weight. Efficacy was judged on the ability of IFN-alpha to induce a corticosteroid (CS)-sparing effect while maintaining remission. All adverse events (AE) were recorded. Results The children included four boys and three girls. Mean age at onset of uveitis was 8.6 yrs and mean follow-up duration was 7.14 yrs. All children had a high level of corticodependence and five of them received additional DMARDs. A remarkable CS-sparing effect with remission maintenance was achieved in 5 out of 7 patients after a mean period of 14.6 months of IFN-alpha administration. The remission was sustained in four of the five patients (mean = 4.8 yrs), even after IFN-alpha was discontinued in three of them. The other patient relapsed 1.5 yrs after IFN-alpha discontinuation. The last two patients faced early severe adverse events attributed to IFN-alpha: retinal venous thrombosis and major depression. Conclusion IFN-alpha has a potent CS-sparing effect in paediatric BD patients suffering from severe uveitis. However, the possibility of major side-effects with this treatment calls for careful monitoring.

Summary and conclusions The published evidence on the use of anti-TNF agents in BDconsists mainly of reports of the open use of infliximab,principally evaluated as an add-on therapy. The majority ofpatients suffered from relapsing, posterior segment ocularinflammation, inadequately controlled with available immuno-suppressive therapy. With infliximab, a fast-onset therapeuticeffect was repeatedly observed in patients with sight-threateninginflammation, including patients with retinal vasculitis. Thepaucity of effective and fast-acting therapies particularly forpatients with eye disease underscores the importance of thesefindings. As suggested by three independent, open-label, prospec-tive, self-controlled studies, repetitive infliximab infusions werealso effective in preventing ocular relapses, maintaining visualacuity and tapering immunosuppressive therapy in the majority ofpatients who had an inadequate response or were intolerant toconventional therapy. Infliximab was effective for extra-ocularmanifestations in these patients, as well as in other patients withrecalcitrant orogenital ulcers, arthritis, intestinal or centralnervous system involvement and in a single patient withpulmonary artery aneurysm. With short-term use, there were noserious side effects reported. The only randomized controlled trialwas a 4-week study of etanercept in patients with mucocutaneousmanifestations. Etanercept was beneficial for most of thesemanifestations, but no data are at hand from this study on eyeinvolvement.Anti-TNF agents have a number of disadvantages, includinginduction of potentially serious adverse events and high cost.However, based on the available evidence, physicians may decideto provide anti-TNF therapy to patients with definite BD.However, until results from adequately powered, randomizedcontrolled clinical trials are available, TNF blocking agentsshould be used with caution only for selected patients withsevere disease. Patients with two or more relapses of posterioruveitis per year, low visual acuity due to chronic cystoid macularoedema, or active CNS disease and/or selected patients withintestinal inflammation, or arthritic and mucocutaneous manifes-tations that reduce significantly the quality of life, would fit thiscategory. According to the experience accumulated so far,infliximab seems to be more efficacious than etanercept in diseasemanifestations other than mucocutaneous or joint involvement,while data on adalimumab are very limited. Infliximab oretanercept is recommended as an add-on therapy for selectedpatients with BD, who are refractory or intolerant to traditionalimmunosuppressive regimens. Moreover, a single infusion ofinfliximab (5mg/kg), can be used as a first-line agent for sight-threatening, bilateral posterior eye segment inflammation, whenthe fast-onset of response is considered to be critical to preventfixed retinal lesions and thus permanent visual loss. In those caseswhose ocular relapses are not controlled by azathioprine and/orciclosporin, a maintenance therapy with infliximab at the dose of5mg/kg every 6–8 weeks could be used for up to 2 years, providedno relapses occur between intervals. These recommendations donot constitute treatment guidelines but are intended to improvepractice uniformity and to help physicians in the management ofBD patients, until higher grades of evidence are available.