14th International Conference on Behçet's Disease

ISBD 2010 report

The 14th International Conference on Behcet™s Disease was held at Queen Mary University of London on 8th-10th July in 2010. Nearly 300 registrants from around the globe met for two and a half days of presentations and discussion about the immunology, genetics and pathogenesis of this complex disease. QMUL in the east end of London made for an excellent venue, with lectures held in the Michael Mason Lecture Theatre, and lunch and the Opening Cocktail Reception in the historic Octagon Library. A concurrent Behçet’s Disease Patients Conference, organised by the Behçet’s Syndrome Society, was held with speakers from the main Conference also presenting to the patients group

Professor Adrian Hayday (UK) talked about stressed epithelial cell biology. The ability of these cells to express NKG2D ligands such as MICA, (Rae-1 in the mouse) results in the attraction of resident gd and Natural killer T cells into the skin. Over expression of Rae-1 led to changes in the tissue resident cell population followed by migration of lymphocytes from the blood. These results show that this system capable of generating an immune response and acting synergistically with TLR stimulation to signal the adaptive immune response. The relevance of these findings to skin and mucosal lesions in BD should be addressed. The next speaker Professor Bahram Bodaghi (France) addressed the other side of the immune response the potential to induce regulation. In initial studies in a mouse model of haemagglutinin (HA) transfected into cells via adenovirus showed that HA specific T regulatory cells, directly injected into the posterior chamber of the eye, can inhibit disease. For BD there is no known antigen, and results with polyclonal T regulatory cells required their in vitro stimulation to induce similar inflammation, suggesting that such a protocol could be used in humans. There was discussion regarding the possibility that polyclonal T regulatory may inhibit other responses ie against persistent viruses, however the plan to inject these cells into the eye and not systemically should greatly reduce this prospect. Transfer of T regulatory cells is being considered for many inflammatory conditions and these studies in ocular diseases will be followed with interest. These talks were followed by a series of presentations from selected abstracts. Dr. Ji Hyun Sim (Korea) showed that dendritic cells from patients with active BD have reduced levels of the immunomodulatory molecues CTLA-4, PD-L1 and CD86, while Dr. Eun Chun Han (Korea) demonstrated that serum levels of S100A12 were significantly increased in patients with active BD, and that this may be related to neutrophil hyperreactivity. Professor Haner Direskeneli (Turkey) described microarray analysis of CD14+ monocytes and CD4+ lymphocytes, which revealed 279 and 109 genes overexpressed by 2-fold respectively. Validation of the increased expression of JAK1, a molecule involved in signalling that leads to IL-2, IL-6, IL-15 and IFNg, was shown. Dr. Jeleni Kezic (USA) described a mouse model of arthritis induced by challenge with proteoglycan, which also induces mild eye disease. However, in IFNg deficient mice while arthritis improved, eye disease was more severe. Finally,  Ms Seema Shafi (UK) showed intriguing data that HLA-B*51 was significantly more protective, than HLA-B*52, of MICA transfected CHO cells with peripheral blood mononuclear cells from patients with BD, a result not seen in healthy controls.

Professor Justin Mason (UK) gave a comprehensive and expert presentation of the future of non-invasive imaging for vascular disease. 18F deoxyglucose, a glucose analogue with high uptake and slow release, permits the identification of areas of high metabolic activity. Professor Mason showed the use of FDG in Takayasu’s arteritis and other conditions. FDG can also be coregistered with CT scanning to give added information. These techniques have led to new findings, such as 25% of patients with giant cell arteritis show no obvious vasculitis. PDG can also be used in partner with PET scanning. Other new technologies include the use of magnetic resonance angiography, CT angiography and high resolution ultrasound all provided greater resolution of vascular disease, allowing novel features to be identified. The relevance of the potential of these new technologies to BD was discussed by Professor Hasan Yazici (Turkey). Current understaning of erythema nodosum lesions suggest that only 50% show obvious vasculitis, and that leucocytoclastic vasculitis is rare in genital lesions. Perivascular inflammation is rare, while most lesions show intense inflammation. Interestingly, 30% of all vascular events occur before the onset of disease, and 78% occur in the first 5 years. The majority of early venous disease is pulmonary, while arterial disease occurs much later. 25% of patients with one vascular event will get a second within five years, so recurrent vascular events are not very common and anti-TNF therapy is not a panacea. 90% of patients with vascular disease are male. This comprehensive overview demonstrates they complex nature of vascular events in BD and the potential to use new imaging techniques as described by Professor Mason presents an exciting prospect. In the selected abstract presentations Dr. Puja Mehta (UK) addressed the question of anticoagulation in BD. According to the EULAR guidelines on BD this is not recommended as it may lead to excessive bleeding. However Dr Mehta reported that 90% of patients had been treated for thrombosis prior to the diagnosis of BD, and in many cases was the reason for diagnosis. This would fit with Professor Yazici’s data on prediagnosis vascular events. The patients in the current study were mainly young males with venous disease and embolism was uncommon. Dr. Emire Seyahi (Turkey) discussed the frequency of pulmonary hypertension in patients with BD, which was increased in patients with pulmonary artery involvement. The data presented suggests that BD may affect small, as well as large, pulmonary vessels. Ko-ron Chen (Japan) analysed skin lesions to determine the presence of cutaneous vasculitis in lesions in patients with BD. Cutaneous involvement was found in all four cases investigated demonstrating that erythema nodosum lesions show vasculitis, including dermal venulitis and neutrophil panniculitis. Professor Ahmet Gul (Turkey) returned to pulmonary disease in a talk on perfusion scintillography of lung disease in patients with BD. Nearly 50% of patients had abnormal perfusion findings, although there was no link to pulmonary embolism. This study supports Dr Seyahi’s findings that small pulmonary vessels must be considered as well as large vessels. Finally, Dr. Ignazio Oliviera (Italy) discussed the treatment of patients with BD, who had failed immunosuppressive therapy, with adalimumab. Complete remission was seen in 75% of patients with uveitis, 1/1 patient with CNS involvement, and 4/9 patients with muocutaneous disease. All other patients had partial remission except one individual whose mucocutaneous disease got worse. The remissions have been maintained and immunosuppressive therapy tapered off. This data suggests that adalimumab is safe and targets all sites of inflammation seen in BD

In the Regional Inflammation session Professor Dennis McGonagle (UK) discussed several concepts relating to BD including why do diseases that seem to have common causes only affect certain sites in the body, and what the reason for this site specificity may be. Professor McGonagle showed evidence for enthesitis, mechanical stress on tissue as a potential cause. For example at sites where tendons join bone, in rheumatoid arthritis patients there are significant levels of erosion. Interestingly, normal individuals also have such erosions but to a lesser degree, therefore less tissue damage and less potential antigen release. Furthermore enthesitis caused by microdamage may lead to inflammation at other sites such as the synovium. This microdamage is associated with tissue repair in normal individuals but in genetically predisposed people an inflammatory response can ensue accompanied by neovascularisation and this inflammation can spread to other sites. This genetic predisposition would include HLA molecules such as HLA-B*27 which is associated with ankylosing spondylitis and HLA-Cw*026 which has been implicated in several diseases. This novel view of pathogenesis of disease has potential importance for Behcet’s Disease and it will be of interest to investigate such responses in mucosal surfaces for example. Professor Ahmet Gul (Turkey)followed by discussing inflammation in BD. Attacks are variably recurrent and in many cases self-limiting and do not lead to scarring. However these recurrent attacks are characterised by increased pro-inflammatory cytokine expression and superoxide activity. Both Th1 and Th17 responses have been reported and in most recurrences high levels of IL-1 are produced. Attacks may be triggered by systemic or focal infections, but also by physical trauma as in the pathergy test. There is also evidence that stressful life events can drive recurrences in BD patients, as in other inflammatory conditions. Professor Gul pointed out that in many conditions, even between attacks, there is an ongoing, asymptomatic, low-grade inflammatory response. Continuous activation in BD has not been reported and does not occur at the same site, however the possibility inflammation is constantly waxing and waning at different sites should be addressed. Imaging protocols described above may help in such investigations. In selected papers Dr. Ilknur Tugal-Tutkun (Turkey) outlined the ongoing SHIELD Study trial of AIN457, a humanised anti-IL-17A monoclonal antibody, for posterior segment disease in patients with BD. This is a phase III, multicenter, randomised, double-masked placebo-controlled trial for which recruitment is now complete. The results which should be available at the end of 2010 are awaited with great interest. Professor Fereydoun Davatchi (Iran) presented another spectrum of treatment with his experience in a longitudinal study of methotrexate for ocular disease in BD. The results showed that methotrexate was effective in treating ocular disease, a response that was maintained over time. Professor Shunsei Hirohata (Japan) discussed a multicenter retrospective study of neuro-BD in Japan. Seventy-six patients had acute NBD, 35 chronic progressive disease. CSF cell count was greater in acute NBD, while IL-6 levels were raised in both but only decreased in acute NBD after treatment. Smoking and HLA-B*51 were correlated with chronic progressive NBD. Dr Hirohata recommended cut-off levels of cell number and IL-6 in NBD, which provoked lively discussion.Dr Aykut Celik (Turkey) discussed endoscopic findings of gastrointestinal disease in patients with BD and patients with Crohn’s disease. GIBD patients were significantly younger and more likely to display gross rectal bleeding and perforation. By comparison, CD patients were more likely to have fistula and perianal fistula. The local of lesions were the same in both disease, but GIBD lesions were more focal and usually single.

Dr Michael Beresford (UK) gave an excellent overview of the problems of dealing with paediatric cases of inflammatory disease. In complex disease like juvenile arthritis there is a lack of biomarkers to guide the physician. Drug therapy that may be appropriate for adults has to be re-evaluated on safety and efficacy grounds in young individuals. For example, the first trial of anti-TNF therapy (etanercept) did not have any effect in juvenile cases, while abatacept did work in some cases. In juvenile lupus there is more kidney disease and probably more neurological problems. It is also more severe based on the SLEDAI scoring system. Dr Beresford stressed the need for collaborative projects for juvenile disease to establish greater numbers for study and to combine experience and expertise. Such projects allow multicentre drug trials to be undertaken and more complete databases established for understanding disease in young people. With regards to BD Dr Isabelle Kone-Paut (France)discussed paediatric BD. Diagnosis is as difficult in children as it is in adult and a complete diagnosis before the age of 16 is rare, because onset is insidious. There are also many differential diagnoses to exclude. This causes many problems for the patient and their families who are often seen by several different specialists before a diagnosis can be made. In line with Dr Beresford, Dr Kone-Paut reported on the paediatric BD database (PED_BD) that she has established. Any clinician can add a patient to the database, selected on homogeneous criteria, not just the ISG criteria. The aims of the database are to identify patterns in disease manifestations that may define criteria for juveniles and information on treatment and outcome in young people. Dr Kone-Paut reported the current findings of the PED=BD register. Many of the patients are from Mediterranean countries and she asked the delegates for more samples if possible from the Far East to be included. Females had more genital ulceration while males had more ocular disease. With regards to diagnosis, genital ulceration and skin lesions were most prominent with the relevance of uveitis and neurological disease not yet clear. Treatment of juvenile patients should follow recommendations for adults, although steroids present a particular problem with the possibilities of osteoporosis, pubertal delay and growth impairment to be considered. Similarly, thrombosis presents a problem as anticoagulation is difficult and dangerous in children and there is no evidence of the utility of use. Dr. Nestor Papoutsis (Germany) discussed ethic and gender pattern of BD in Germany. Males and Turkish individuals were significantly younger on second manifestation and full diagnosis. The time from disease onset to diagnosis was also significantly less in these groups.Dr Omer Karadag (Turkey) analysed treatment in a relatively young population of patients with BD from all over Turkey. Colchicine, azathioprine and corticosteroids were the major drug used in this group, while infliximab use was very rare (0.4%). The data suggests that there may be differences in treatment regimes between these patients and large urban centres. Dr. Yusuf Yazici (USA)presented data from a cohort of patients with BD in the USA. Seventy-seven percent were female and the cohort was described as ethnic or non-ethnic based on background and generations in the country. The group showed a very high level of neuro-BD and psychiatric problems. Headache was reported in 87% half of which could be migraine-like. There was a problem with patients with neuro-BD being diagnosed as having meningitis or stroke, therefore better criteria should be addressed. Dr. Yilmaz Ozyagan (Turkey) described ocular disease in a cohort of 136 young patients (av 14.3 yrs) from Turkey. Ocular disease was present in about 50% at the intial visit and developed in another 6 during follow-up. Anterior uveitis was seen in 5% of eyes, posterior uveitis in 35% and panuveitis in 60%. Ocular disease was more common in boys than girls, however, it appears to have better outcome than in adults. Dr. Gulen Hatami (Turkey) addressed the problem of work disability in patients with BD. Out of 111 patients eligible for work 23 were unemployed and this was a higher percentage than the national average. 78% of these individuals considered BD as the cause of their unemployment. All manisfestations of BD were responsible for some individuals being unemployed and not just a single cause, although it was associated with active disease.

In the final session of the Conference the genetic basis of BD was addressed. Dr Oliver Brand (UK)opened the session and described his research into another complex disease, Graves disease. He discussed initial studies by a candidate gene approach which identified several single nucleotide polymorphisms (SNP) which associated genes with the disease. However, such studies are based on assumed prior knowledge of the possibility that the gene product will be involved in the disease and therefore will miss the vast majority. Further studies using genome-wide analysis (GWAS) has allowed for the screening of hundred of thousands of SNP at the same time and therefore presents a much more comprehensive picture. However in Graves as in other conditions it was gratifying that GWAS selected many genes that have been analysed by the candidate gene approach. The next step was to probe deeper into those regions of the genome where associated SNP were found. Using this approach confirmed a link with the thyroid stimulating receptor and Graves. The final step is to show a functional relevance for the polymorphism with regards to protein function. Compared to Graves research genetic analysis of BD has some way to go, but subsequent talks demonstrated that we are not too far behind.Professor Eun-Bong Lee (Korea) gave a comprehensive overview of the candidate gene analysis performed so far in BD. He showed that HLA-B*51 was associated with disease in all populations tested, similarly SNP although not always the same one, in the TNF gene have been implicated in most studies. Professor Lee clearly pointed out the difficulty of the candidate gene approach in a disease like BD as other SNP were positive in one ethnic group, but not associated in another. Moreover, the risk incurred by each SNP is low, which suggests that many genes will be involved in BD. To emphasise the problem with the candidate gene approach Dr. Farhad Sharman (Iran) presented a study that showed no association between SNP in the gene encoding methyltetrahydrofolate reductase, an enzyme involved in thrombosis in several other diseases. Dr. Emire Seyahi (Turkey) in a retrospective study identified 6 pairs of twins with BD. Two sets were discordant and the others concordant. Based on analysis Dr Seyahi proposed a monozygotic concordance rate of 33%, which suggests significant genetic influence but also a role for environmental factors. The central role for HLA-B*51 and phenotype was assessed in a meta-analysis presented by Dr. Alfred Mahr (France). He showed a link between HLA-B*51 and male gender, genital, eye and skin involvement, but not CNS or articular disease, erythema nodosum, or thrombophlebitis. For GI manifestations HLA-B*51 may be protective. Finally, HLA-B*51 was not prognostic for mortality. In discussion, it was mentioned that those sites associated with HLA-B*51 form the core of the ISG criteria which supports the analysis. The session and the Conference finished on high note with Professor Shigeaki Ohno (Japan) and Dr. Elaine Remmers (USA) describing GWAS studies performed on BD patients. Professor Ohno used Japanese patients and controls, while Dr Remmers used Turkish patients and controls supplied by Professor Gul. In discussions between the two groups selected SNP were analysed in both initial cohorts and in validation cohorts supplied by many researchers covering several ethnic groups. The results show SNP in the HLA-A, IL-10 and IL-23R/IL-12R2 genes being associated with BD. These are exciting results as IL-10 is an anti-inflammatory cytokine and the reduced production induced by the SNP could explain a failure of resolution in response to infectious or mechanical stress. IL-23 and Il-12 by comparison are pro-inflammatory cytokines and SNP in their receptors provide many avenues for future studies.
The first two days provided interesting, and vibrant poster sessions with over 200 excellent presentations from across the world. Personal highlights for me, included the first description of a new drug targeting interleukin-1 that had promising results in a phase 1 study, also the use of alemtuzumab as a treatment for BD patients who had failed other drug therapies. Data on patients with BD from the United States was also of interest as there may be differences in disease type that could inform us. As I say personal highlights amongst a high quality field and the organisers are very grateful to the effort people put into their posters explaining their work
An innovation at the 14th Conference was the holding of debates on subjects of current interest in the field of BD. The first debate was between Professor Haner Direskeneli (Turkey) and Dr Graham Wallace (UK) who took the question “Autoinflammation of Autoimmunity?” as their theme. The second debate between Professor Shigeaki Ohno (Japan) and Professor Miles Stanford (UK)discussed “Geographical differences in BD”. Each participant was given 10 minutes to present heir argument then each had two minutes of rebuttal, before the debate was opened to questions from the audience. In both debates the presentations were thought-provoking and the discussion lively. The debates proved to be a popular and entertaining end to each day.
Finally, a special lecture given by Mr Chris Chapman (UK) and Dr Tom Greeves (UK) provided the end of the first day. They presented a photographic trail of the “Three Hares” motif from Devonshire churches to Xian at the end of the Silk Route and all points in between. The motif of three hares running after each other in a circle, has decorated Buddhist, Mongol, Islamic, Jewish, Catholic and Protestant icons and churches although its meaning is still unknown. Mr Chapman and Dr Greeves are experts on the motif and their enthusiasm and knowledge made for a hugely entertaining and appreciated presentation
In conclusion, the 14th International Conference provided many new insights to the nature of onset, the geographical spread, and the pathogenesis of Behçet’s Disease. On behalf of the Organising Committee I would like to thank so many colleagues for joining us in London particularly given the current economic climate, and the effect on science funding and sponsorship in most countries. I believe it demonstrates the strength of the desire of researchers and clinicians involved with BD to investigate and understand this complex disease, and to meet with friends and colleagues to discuss their findings. We will have the opportunity to do it all over again at the 15th Conference in Yokohama, Japan in 2012.

Dr Graham Wallace
University of Birmingham, UK