Dr. Oliver Fitzgerald highlights recent breakthroughs in psoriatic arthritis (PsA) and elaborates on the HIPPOCRATES study, a health initiative focused on psoriasis and PsA research.
thank you very much thank you Johan that’s a very nice introduction uh and I’m delighted to be here uh in this August grouping uh I think there’s probably a inverse relationship between how scared you are in front of an audience uh with the with the size of the audience so the smaller it gets it’s probably more scary probably more scary um and you’d be scared both because of the Excellence of the talks before you uh but also the size of the cohorts are so impressive the uh the granularity of the data all all the um data presented this morning U just makes me think that um the sertic arthritis world where I work is a good bit behind where you are um I think we have moved though um certainly 20 years ago we were uh still in nappies um we have moved I think to being Adolescence in comparison to psoriasis and I think you’ll find that in the next few years in particular with investment in uh Research into unmet needs in seratic arthritis uh which is occurring both in Europe and in the United States and I’ll come back to the European effort uh later on I think you’ll find that the next 5 to 10 years uh we we’ll catch up pretty fast so I’m looking forward to that one of the things we need to do obviously is to develop a diagnostic test for seratic arthritis because one of the things that I can’t help but think when I see reference to seratic arthritis and the cohorts that you have is that most of the time you’re referring to patients self-identifying as having sertic arthritis and I know from studies both in our own department and elsewhere that if you’re relying on self assessment of seratic arthritis diagnosis or self-reporting of the diagnosis that you’re missing about 30% of cases um so we certainly need to um certainly need to work on that and that’s something we’re doing um I’m going to move on with the talk because I could go on forever um so I I’m here to talk today about uh where seratic arthritis is heading and um these are my disclosures and there are two I would mention in particular uh one is that I’m co-president of the group of graa um you’re familiar with the name um and I’m co-president with April Armstrong and that’s uh sending I think U I hope it’s sending out an important message because this is the first time we’ve had a dermatologist and a rheumatologist as co-president of Grappa and it’s trying to send out the message that we’re trying to collaborate with each other and I I think that’s the way forward um that we need to collaborate with each other I’m delighted that there have been recent contact from the IPC to Grappa uh in relation to how can we build on a collaboration because I think that’s the only way we can move forward uh is with a strong collaboration the other thing uh just to mention in disclosures is that I am the one of the coordinating partner I’m part of UCD which is the coordinating partner for the Innovative medicines initiative Consortium hypocrates which is one of those big consortia that has recently been funded which is addressing unmet needs and seratic arthritis and I’ll talk about that later so um what I’m going to talk about today is a little bit about unmet needs uh I’m going to talk about two competing uh theories relating to uh sertic arthritis pathogenesis um be focusing on work that we’ve done on HLA uh Al and Hypes Rel implicated in susceptibility to sertic arthritis studies of CDA positive te- cells and then some new Concepts that are emerging um relating to uh pathogenesis of spond arthop opathy and I’m talking not just about seratic arthritis but the broader area of spond arthropathy before finally uh telling you about hypocrates so this is psoriatic disease um it’s a complex disease uh heterogeneous uh in all sorts of ways um and it includes uh obviously psoriasis and and and nail disease uh but also includes involvement of the the the joint or sinovitis uh enthesitis uh dactylitis uh spinal inflammation um you’ve got this uh tendency to both cause uh joint erosion and bony resorption on the one hand but also you’ve got new bone formation uh being a feature in many of our patients as well and then you’ve got the comorbidity so it’s quite a heterogeneous uh clinical disease there have been recent significant Advan some of them perhaps not so recent but uh important to mention nonetheless the Caspar classification criteria because this is at least allowed us to have some uniformity about the inclusion of patients in studies and clinical trials uh whereas we didn’t have that before so the cpar criteria have been particularly important we also have uh composite outcome measures both the uh MDA and the pasdas uh in particular are uh significant advances uh we have an improved understanding of the genetic basis of the disease and I’ll go into that in a bit more detail and significant advances in treatment particularly targeting cyto kindes and I think it’s those advances in treatment it came in a sense the wrong way around um but I think it’s the advances in treatment that have been teaching us more about the disease and more about the pathogenesis so it came uh perhaps in a reverse order but all are contributing uh to significant outcomes in patient outcomes so there are however ongoing unmet needs in seratic arthritis and some of them you will be very familiar with um and these include uh the fact that we don’t know how to identify psoriasis patients who are at risk for psoriatic arthritis and if we could do that uh you could potentially consider disease prevention studies and this came up a little bit earlier on today but um there is in fact a disease prevention study either starting or about to start in the United States I think using gazel camab in patients with psoriasis who appear to be at high risk but I’m not sure how exactly you determine that yet um but they are going to go ahead with that study to see whether they can reduce the the um uh incidence or the development of sertic arthritis um the second unmet need relates to diagnosis as mentioned we don’t have uh diagnostic criteria our laboratory tests to discriminate PSA from either rheumatoid arthritis or other forms of arthritis um we don’t know how to predict outcome in particular radiographic outcome and a proportion of our patients about 50% will experience radiographic damage and some of them will experience very severe radiographic damage so if you could predict that uh you could potentially prevent it and the last unmet need relates to treatment so lots of new treatments um but we no KN no way of knowing which patient will respond to which treatment and we spend a lot of time cycling from one therapy to the other in an effort to try to find something that works so all of this is reflecting the problem uh that we poorly understand uh seratic arthritis pathogenesis in particular the underlying explanation for disease heterogeneity so there are essentially two major hypothesis circulating relating to seratic arthritis pathogenesis they’re not mutually exclusive um but they do present very different ideas about the initiation or causation of sertic arthritis and the first you will have heard of um perhaps from people like Dennis McGonigle in the in the UK who has been talking about seratic arthritis as being an enthal based autoinflammatory disease and the second is that seratic arthritis is an immune-based uh disease driven by HLA class 1 antigens presenting as yet unidentified path peptides to CDA positive T cells so this is the paper published by Dennis mcanal in the Lancet back in 1998 it was a a paper where they hypothesized that the sinovitis of spond arthropathy uh was secondary to the liberation of pro-inflammatory mediators from the enthesis um whereas uh in rheumatoid arthritis the sinovitis in rheumatoid arthritis was a primary event so they suggested that the the whole explanation of the disease uh stemmed from inflammation at the n thesis and over the last 25 years since this paper has been published um Dennis has produced and others as well some very um compelling papers that support this uh particular hypothesis um I won’t go into it all but um the certainly have shown uh very nice anatomical studies um and uh Imaging studies that highlight the role of an the anthesis in patients with seratic arthritis however um it would appear that the enthesitis mechanism lightly applies to only a minority of psoriatic arthritis patients uh because it’s only in a minority uh who where you exper where the patient will experience and enthesitis occurring in somewhere between 30 and 40% of patients so um it certainly I think would be the view of many people that enthesitis while important in some patients does not it does not explain the um occurrence of seratic arthritis in the manor in the majority of cases that it occurs so the other um suggested U hypothesis is that it it’s a an immun mediat disease and when I started working at this um now many years ago it was known at the time that serotic arthritis was associated with MHC complex genes although it was unclear as to which uh genes were important it was also shown that in HIV disease that both psoriasis and psoriatic arthritis can occur more frequently and more severely suggesting that CDA positive T cells may be driving the disease and not CD4 positive t- cells as in rheumatoid arthritis and it was also observed that rheumatoid arthritis did not seem to occur in association uh with HIV disease um seratic arthritis develops after syic bone marrow transplantation and that was shown and there was also response to therapy directed at activated te- cells and this was these were the various features that suggested that it was immune mediated disease uh when I started working at it and we started looking at sovial fluid and uh peripheral blood uh from patients with seratic arthritis and what we showed was that um in psoriatic arthritis that cd8 T cells uh predominated in the serotic arthritis synovial fluid uh with a reversal of the CD4 cd8 racio that is found in rheumatoid arthritis uh we also showed that these cells the CDA positive T cells were both activated and mature expressing cd45 Oro and hlor so I was presenting this paper at um the uh a uh what was called at the time um I’ve forgotten what it was called at the time the the AC or um and uh chap comes up to the poster to discuss the poster with me and uh we agreed to uh meet for coffee afterwards uh to go into it in more detail and this guy was a chap called Bob Winchester Bob some of you may know um based at Columbia University in New York he’s now in his 80s um at the time he was a very senior rheumatologist um and he had uh published the shared epitope hypothesis in rheumato arthritis so he was a very respected and knowledgeable um person to have coffee with so I was delighted to meet with him and this began a collaboration which uh went on for it’s still goes on but uh certainly was much more active over a 20-year period um so the kind of questions that we’ve been addressing um firstly we decided to look at uh the HLA um Al and haplotypes uh implicated in susceptibility to sertic arthritis and we asked the questions what was the genetic relationship between psoriasis and psoriatic arthritis whether seratic arthritis was genetically heterogeneous and whether uh seratic arthritis genotypes were associated with different clinical phenotypes so I’ll go through these are some uh studies that date back to 2012 and 2016 um but uh I go through them nonetheless uh reasonably quickly so the first part was to compare two sas’s cohort cohorts in a homogeneous Irish population so the way this worked was we we we we provided all the clinical material um and we had uh I had a number of um uh PhD students uh who would travel over to Bob’s lab and do the work over there they’d actually live in Bob’s apartment the 42nd Floor on Fifth Avenue not fifth um fourth I think um and he uh you know he looked after them amazingly and and this went on for uh quite a number of years so the psoriasis cohort uh were patients uh who had no features of seratic arthritis spondilitis or enthesitis and each of these people have been assessed by a rheumatologist and they were presenting to a Dermatology Clinic the seratic arthritis cohort was presenting to a Rheumatology clinic and a diagnosis of seratic arthritis was U obtained so the question was whether the genotype of psoriatic arthritis was identical to that of psoriasis and whether the psoriatic arthritis um whether the genotype of seratic arthritis was homogeneous so the um what was known of course at the time was that in most studies uh patients with psoriasis about 60% of them uh expressed uh h62 um so the question was does the distribution of c602 and also of HLA b57 um uh in PSA parallel that that found in psoriasis so these were the results and I don’t know that there’s a pointer here but um anyway the um you can see there on the uh the first uh panel on the left is the seratic arthritis patients uh then you’ve got psoriasis patients and then the controls and you can see that that in comparison between the psoriasis patients and the controls that 57.5 or roughly 60% of the patients were c602 positive um in the sertic arthritis cohort versus controls um the percentage who were c602 positive was significantly reduced uh to 28.7% increased still over the controls um but significantly reduced compared to sasis um and the same as was true of B-57 um so we concluded that the um we could we felt we could reject the hypothesis of genetic homogeneity of the psoriasis phenotype and we went on to look to see whether or not there are other HLA BLS that are significantly increased in the Irish seratic arthritis cohort um so we looked at um I’ll just show some of them here U B27 7 b39 B8 and B44 and you can see that the percentage of people who were B27 b39 or B8 uh positive in the seratic arthritis was significantly increased compared to controls and also increase compared to the psoriasis patients uh B44 in contrast appeared to be protective as it was significantly reduced compared to both controls and psorasis so we concluded that um HLA B27 and b39 were susceptibility alals for psoriatic arthritis but not high-risk alals for psoriasis in the absence of arthritis and that h801 was associated with PSA susceptibility um but I didn’t mention it but appears to be uh somewhat protective uh for psoriasis so in conclusion from this first study um we felt that the development of sertic arthritis predominantly occurred in individuals who inherited any of the following alals or haplotypes uh is much less likely to develop in those who were HLA B44 positive and we came up with a new hypothesis that psoriasis was genetically heterogeneous with the muscular sceletal cutaneous phenotype of seratic arthritis defined by several unrelated HLA alals and Hypes lacking a relationship to H c602 so these results were validated uh shortly after we published in um 2012 by the group in Toronto uh so they produce very similar results uh to what we published uh which was great um so the second part then was uh so different genetic susceptibility genes imply different disease mechanisms and possibly different clinical course and therapeutic responses so the question was is there a phenotypic difference and the first thing we looked at was the time duration or time lag between the onset of psoriasis and the onset of psoriatic arthritis so on the left hand side there you see the years between psoriasis and psoriatic arthritis in the psoriatic the uh h602 uh patients and on the right hand side it’s the time gap between sasis and seratic arthritis in those who are either B27 or b39 positive and essentially they’re quite different so there is a time delay of up to a mean of 11 years between the onset of psoriasis and seratic arthritis and those were are HLA c602 positive and that’s reduced considerably uh to uh 3.84 on average um in those were B27 or b39 positive so it appeared that the time interval between psoriasis and psoriatic arthritis was a genetically determined quantitative trait and then we looked at other features and I’m not going to show them all um but one of the features we looked at was this um uh symmetricality uh or asymmetrical that occurs at the Saia joints in patients who have spinal involvement uh so what’s been observed over the years is that patients with seratic arthritis frequently have asymmetrical involvement they may either have no involvement on one side and a lot on the other or there may be quite a difference in the degree of envolvement between the two sides uh and what we showed and not surprisingly uh was that symmetrical citis uh which is what you find in ankal loing spondilitis was indeed associated with B 27 and the associated uh haplotypes uh whereas asymmetrical saitis um was not associated with B27 but was associated with b801 so we came up with the idea that um and this tree in the middle here is uh a reminder that the this this hypothesis emerged in a discussion we had um while walking through this Forest it’s the uh tropical uh red Forest um along the north uh East uh northwest coast of the United States and this is a tree which is a very strange phenotype associated with it um some growth on the side of it um but we came up with the idea that the there were essentially three types of um uh disease expression in serotic arthritis that was determined by genotype uh so you you have those who are HLA b57 or c602 positive which appears to be associated with early onset severe psoriasis but late onset low penetrance milder muscular sceletal disease in contrast those who were B27 positive this was associated with early onset muscular sceletal disease more synchronous with the onset of skin disease with symmetrical spinal involvement AB also associated with enthesitis dactylitis and with arthritis mutilans in particular when the patient was also expressing h62 HLA bo8 appears to be Associated more with sovial based disease uh with joint Fusion joint deformity with asymmetrical spinal involvement and also with dtis so um we then asked the question if if psoriatic arthritis is strongly associated with HLA class one uh genotypes um it made sense to further explore antigen presentation by CDA positive T cells and I’m going to very briefly just uh present uh some studies we did of the cd8 alpha beta t- cell receptor repertoire in seratic arthitis and just remember that these were studies conducted uh 10 or more years ago um so this was the first of the two studies um this was uh published in Journal of Immunology um the first author Patrick Costello spent probably the bones of two years living with Bob um he uh did some fantastic work focusing in particular on peripheral blood and covia fluid specimens which we had from uh patients with psoriatic arthritis and we shipped over to New York uh so we’re looking at the cd8 alpha beta TC receptor in the sovia fluid uh and what we showed that there was an average of 32 major oligoclonal expansions um there was a small number of expansions that were shared with peripheral blood U but most of the expansions were not seen in the peripheral blood emphasizing the specificity of the events uh clonal events within the inflamed joint there were some uh otonal expansions in uh the CD4 t- cell repertoire but they were fewer and smaller and also largely restricted to the joints in other words not shared with peripheral blood um there we did sequence a single cd8 otonal expansion and reveal that to be composed of a of a few structurally related clones um with beta chains that encoded identical or highly amous uh CD or3 uh motifs but these motifs were not shared among patients and we were unable to find evidence of antigen Drive uh occurring in these specific clones however we we concluded that um the data supported a model of sertic arthritis inflammation involving extensive and selective antigen and lightly autoantigen uh driven in Artic cd8 in particular but some CD4 t- cell clonal expansions um the second paper uh where Shane Curran was the main author uh Shane also spent time with Bob and uh we were focusing in this particular paper uh not on sovial fluid but on sovial tissue and what we did was we collected peripheral Blood and sovial Tissue um from patients uh before and after they commence treatment with methat tration and what you can see here on the left hand panel is that uh during active arthritis uh the uh t- cell receptors were largely uh polyclonal um but that during metat treatment uh the uh uh te- cell receptors became much more oligoclonal and I guess that what that suggested to me is that these uh otonal te- cells were remaining within the joints of patients with uh treated disease who’ responded well to treatment and then if you were to stop the methotraxate the disease would just come back up again uh so we weren’t getting rid of perhaps the disease pathogenic clones and it suggested that U during active disease U that we were getting a lot of non-specific te- cell infiltration into the joint uh these were U uh not driver clones these were uh associated with inflammation but not associated with driving disease um but the certainly seeing evidence of uh perhaps much more Al clonal expansion uh during uh treated um uh synovial tissue so we came up with this autoimmune hypothesis um and that was that HLA class one antigens recognized self peptides derived from proteins found in enthal sites perhaps or sovial sites um CD cell clones were specific for these self-peptide MHC complexes becoming activated with the activated state perpetuated by the continual supply of self peptides so this the classic explanation for autoimmune disease and there was some support for this uh with some studies coming from uh Kings college and Bruce kirkham’s team in London who showed uh clonally driven cd8 population containing an enriched population of is 17 expressing um producing CDA positive te cells in the seratic arthritis covia fluid which was not seen in rheumatoid arthritis so the nothing much happened in the area for then a number of years until this paper appeared um in I think 2020 and this was coming from Hussein Al maswabi U who was working in Oxford and he used a different approach which wasn’t available to us at the time but in the intervening years single cell sequencing became available and he showed dat that was very similar to the data that we had previously published revealing clonal expansions of pro-inflammatory sovial CDA positive T cells uh which you can see on the right in panel D um significantly elevated in the sertic arthritis patients and expressing uh tissue homing receptors so there was a three-fold expansion of these sovia fluid memory CDA positive t- cells uh pronounced CDA T cell clonal expansions um they show transcripton analysis uh show them to be uh expressed cycling uh activation tissue homing and tissue residency markers um TCR comparison between patients uh suggested some clonal convergence and they also showed that um the chemy receptor CXC or3 was upregulated while two uh CX or three lians were also elevated in seratic arthritis anovia fluid uh so it certainly appeared to uh Provide support for the suggestion that these cdat cells in in serotic arthritis may be of importance so these the implications of these observations was that they were um firstly consistent with Mullen right identifying skin predominant senovia predominant and axial predominant psoriatic arthritis each having different HLA associations um since different HLA molecules bind different peptides uh this suggested that distinct autoimmune responses Drive the different phenotypes um these autoimmune responses may result in one or another cyto dominating as in the skin uh meaning a differential treatment response may occur in different genetic subsets and how these genotypes might result in a particular clinical phenotype is unclear but work in cutaneous psoriasis from uh yorg Prince’s group confirms the proof of concept whereby CDA positive te cells have been shown to react against melanocytes and these melanocytes then secrete psoriasis promoting cyto specifically after the regulation of an autoantigenic melanite peptide processed by Ira 1 and presented uh by disease Associated MHC class uh h602 so meanwhile what’s been happening in axial spond arthritis and I’m going to go through this quite quickly uh just to highlight two reviews that have uh summarized the work that’s been going on in spond arthropathy in particular in anoing spondilitis in recent years um all suggesting that spondo arthritis is not simply an autoinflammatory disease but is also characterized by imul regulatory uh disbalance I would highlight just two particular papers uh one from uh Bob inman’s group in Toronto this was um small number of patients proteomic and transcriptomic Analysis uh helped to identify a mature CDA T Cell subpopulation enriched in gut Associated trafficking molecules uh which was elevated in anoing spondilitis sovial fluid and these cells were reminiscent of uh trm cells um this population possibly got derived appeared to have Jewel cytotoxic and Regulatory profile in the second paper um they looked at gut derived cd8 uh uh T trm cells which appear to be expanded in peripheral blood and synovium of spond arthropathy patients and it appeared that these uh trm cells um expressed the intestinal homing receptor alpha4 beta7 uh suggesting that they’re of gut origin so the data confirmed the expansion of trm cells in spond orthopathy joint joints providing evidence of expansion in peripheral blood and in gut with Alpha Beta Alpha 4 beta 7 expression by peripheral blood trms supporting the recirculation of these cells from the gut to the peripheral joint and the inflamed joints peripheral blood to the inflamed joints so that leads us to um a new development M within UL uh which is a group um which is called mhc1 opathy um which has recently uh been set up um and there was a recent publication describing the purpose of the group but it describes a family of inflammatory conditions with overlapping clinical manifestations and a strong genetic link to mhc1 antigen presentation pathway and these diseases include um both analing spondilitis and psoriatic arthritis vets disease psoriasis and birdshot uh uiis so all have a strong sociation with MHC Al and Gene variants um of the antigen processing aminopeptidase erap 1 and erap 2 um the hope is to present new insights into the biology of these mhc1 oathes um and they feel that this will strongly advocate for disease overarching and integr ated molecular and clinical investigations um and it’s a collaboration between Rheumatology Dermatology of thology and also fundamental and translational researchers so I think it’s an exciting new uh development within the field so just in conclusion um several amut needs have been identified psoriasis is genetically heterogeneous um with the muscular sceletal cutaneous phenotype to defined by several unrelated HLA Al and haplotypes different Al and haplotypes um are associated with different phenotypes and covia fluid te cells are Clon clonally expanded expanded in particular the cd8 um uh population uh which uh is is particularly found in the uh patients who are on treatment with methat tration with similar findings now evolve emerging from spond arthropathy anoing spondilitis and other conditions there’s the emergence of the mhc1 opathy concept so last couple of minutes just to mention the ocres project um so this is as mentioned a large um a Consortium across Europe um which includes uh 26 Partners um the uh Consortium is being led uh from UCD by uh Steve Pennington my colleague there professor proteomic and myself um and it includes um five FP Partners it includes a strong patient um participation from both um graa uh from UL par and from urso um and it also includes uh a wider Network which is which I refer to there as the Grappa EU Network all of the these um centers uh would have uh a lot of experience with um patients with sasis and seratic arthritis and including them allows us to potentially access additional cohorts of patients uh with those conditions um the uh project started in July 2021 so it’s going just over two years um the budget is it’s it’s actually 27 Partners I see that’s because ABY have joined the Consortium the budget is 22.5 million with a duration of 5 years a similar Consortium has been set up in the United States it’s just been started uh under the amp aim program um so there um that’s uh just getting up and going with Chris Richland and Jose Sher uh uh involved in that one and we certainly plan uh to collaborate closely uh with that group so what are we doing uh we’re addressing the areas of unmet need including the development of a diagnostic test including the um ability to predict which patients with psoriasis who will develop psoriatic arthritis uh we want to predict damage progression and we also want to look at treatment response so the data um which will include clinical data Imaging data multiomic data uh signal find studies um will all be put together in work package 5 which is all about data integration and Analysis um so we’ve just signed off on a consortium-wide data sharing agreement which will allow all of these data to be uh shared on a single platform based at the sib in Switzerland um I’m going to just give a shout out to one study within the Consortium which is a relevance uh to you all here and that’s the hypocrates uh prospective observational study or the HPA study uh which is being led by Laura coats in Oxford um and which is addressing the whole area of can we identify uh those at risk of developing uh uh seratic arthritis in order that we potentially can prevent it so this a patient Le web-based longitudinal study of 25,000 people which surved across Europe um and I’ve listed some of the countries involved there are more um the patients will enroll themselves um consent will also be obtained remotely uh and we will collect bio samples initially we are funding to collect bio samples from 3,000 participants um but we are hoping to obtain additional funding uh to collect more samples and different types of samples uh from as many as the patients as possible possible so this study is based on the concept that roughly 2.7% perom will develop seratic arthritis so the patients at Baseline are not supposed to have a diagnosis of seratic arthritis they have psoriasis and we anticipate that 60 out of 25,6 75 um patients will develop seratic arthritis per year um so if we can identify risk factors either clinical molecular are Imaging risk factors which reliably detect which person will develop um seratic arthritis uh then we we can begin to design and conduct studies aimed at preventing psoriatic arthritis so we’re not going to do any studies on prevention but we’re going to certainly uh consider uh the design of such studies in the future so we’re collecting information from patients with skin or nail psoriasis who are over 18 years of age who do not have a diagnosis of seratic arthritis they may have some symptoms um they may on assessment have some disease but they don’t have a formal diagnosis of seratic arthritis at Baseline we intend to follow the people prospectively every 6 months for the development of seratic arthritis until 20126 and hopefully further and I’ve mentioned the blood sample these are the data we’ll be collecting so demographic lifestyle uh data about psoriasis including treatment self assessed pzy um questionnaires related to muscular sceletal involvement um the pest P said for an impact on uh for impact on life um and if P said negative patients will fill out a treatment satisfaction questionnaire uh we will also provide participants with feedback on the scores and interpretation and advice if necessary that they should seek a rheumatological opinion so this um platform has all been designed by a team at the University of Oxford uh and significant input um from patients uh into the design of this platform so I would like to acknowledge that um I won’t go through all of this but just to say that the um study has now launched in the UK launched at the end of June uh it’s launched just in the last couple of weeks in Ireland uh we’re going through the translations which are required to launch this in other countries R uh but the roll out is expected to occur in other you EU countries across um Europe uh before the end of the year that certainly would be our Target um and just to say that uh these patients are self-recruiting um uh the ad advertisement if you like will be online um but we’re also asking our Dermatological uh colleagues uh to provide uh psoriasis patients under their care with a flyer and encouragement to self uh consent and uh sign up to this study um because I think it will be an important study particularly when it comes to validation of uh any markers that we identify in smaller studies uh it’ll be very important to have this kind of size of study um uh available uh for us to study so with that I’d like to thank everybody um for listening to me um I just acknowledge some of my former mentors my colleague Bob Winchester the Epocrates Consortium and my colleague in Dublin on the bottom right Steve Pennington um who have uh who’s certainly a huge support in uh all of these uh studies and work so thank you very much everybody we have time for questions thank you for for a great talk but questions um I what I see commonly is morning stiffness without Frank arthritis or ositis um you you call you put that are you a lumper do you call that PC arthritis or do you um to me it’s part of the spectrum PC arthritis it responds to therapy as well um talk a little bit about your ideas about morning stiffness yeah well morning sence and joint pain are certainly some of the features that patients with uh evolving if like seratic arthritis may experience and they may experience for um years before they eventually develop anything that you can see um so those patients May well be on their way to seratic arthritis there are of course other muscular sceletal problems that can occur in the same population and you do have to be careful to differentiate it from commonly things like osteoarthritis rheumato arthritis and other forms of disease but yeah many of those people uh are evolving and certainly the work from Toronto would suggests that stiffness and arthralgia are the key symptoms to look out for in your patients who are likely to go that way screening for screening them how with yeah um yeah it it it may be helpful and um but the the ultrasound is certainly very much uh user dependent uh so it’ll depend on the skill and the expertise of the person that’s doing the ultrasound um there’re also are you know many many uh anal sites in the body so you have to decide which anal sites you’re going to choose yeah yeah yeah yeah I think it will pick up some people yes um I don’t know that it would I I don’t know that it’s the future to be honest I think it’s very labor dependent uh and I I’m very hopeful that we will find something that’s a little bit easier to apply to a lot more people than having to do an ultrasound of all their enal sites or even six sites would be difficult I got one one question for you um so one of the back as well I’ll let you take you go first or your three groups of have any studies about therapetic response for formal studies no um but there I suppose the the study mentioned earlier uh relating to uh H6 positivity and its response to is kinab would suggest that those patients may be responding uh differently um I think that study yet needs to be done I think it’s an important study I think the pharmaceutical companies will have a lot of those data they’ve done H typing on a lot of the patients and would be able to do more of that analysis but hasn’t been done yet well one quick quick question um maybe not an easy one but um so we clearly have two you know closely associated diseases orasis and sorc arthritis both genetically both inflammatory genetically determined clearly with a key role for cd8 positive t- cells and and and L 17 any insight into why there is this lack time between psoriasis and and typically the development of sertic arthritis is their onset completely unrelated or disconnected or is there a relationship between the two yeah I mean certainly there appears to be a a difference in lag time depending on what HLA type you have how that relates to CDA positive t- cell I’m not sure that I understand that mechanism or what the explanation for the L time it’s a good very good question I don’t know I know the answer to that have you a suggestion yourself I have no idea so often I find that if people laugh as difficult questions they know the answer yeah yeah no no we’re we’re on the same page so so thank you I think thank you very much great talk thank you