Hello, I m Christopher Ritchlin, from the University of Rochester Medical Center, and I have the pleasure today of discussing with you abstracts

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1 Hello, I m Christopher Ritchlin, from the University of Rochester Medical Center, and I have the pleasure today of discussing with you abstracts presented at the 2012 American College of Rheumatology meeting in Washington DC that were centered on spondyl arthropathy. 1

2 And, the first slide really reviews the ASAS Classification Criteria for spondyloarthritis. And, these are new classification criteria that were meant to include a way of diagnosis of spondyl arthropathy that went beyond the New York Criteria, which was very much centered on X rays. And, the thinking behind this in part was that if we are able to identify patients with spondyloarthritis who have both x-ray changes and no x-ray changes. This will increase the number of patients we can diagnose and treat to hopefully prevent damage and improve quality of life and function. So, this slide is from the ASAS website, and is a review of the criteria for both axial spondyl arthropathy on the left and peripheral spondyl arthropathy on the right. So, I m just going to walk you through these because this slide will serve as a reference for the studies I m about to describe in the next couple of slides. So, in order to meet these criteria, you have to have three or more months of back pain, and age of onset of less than 45 years. So, this is the stem for axial spondyl arthropathy. And, one can arrive at that diagnosis and these new criteria by one of two means. One is to have sacryl ileitis on imaging, and this imaging can be plain x-ray or MRI plus one or more spondyl arthropathy features. And, those features are listed below and I m not going to read through them. You are familiar with them I m sure. Now, another way that you can reach the diagnosis of axial spondyl arthropathy is by having HLAB27 positivity plus two or more of these other spot features again listed below. And the sensitivity and specificity of these criteria are listed below on the left. Now, there are other patients, as you know, who have peripheral symptoms only, and they have been labeled peripheral spondyl arthropathy. So, the stem here is that patients have arthritis, or enthesitis, or dactylitis plus one or more of the spondyl arthropathy features listed below. And, again I m not going to read through these, or two or more of the other spondyl arthropathy features listed below that. Now, this can be very helpful in diagnosing peripheral spondyl arthropathy but I have to say a couple of things. One is that psoriatic arthritis tends to be somewhat different than your peripheral spondyl arthropathy in that these patients can be more rheumatoid like, meaning that they can have severe erosions and that they can have a very robust arthritis like mutilans, that s not type of joint problem you see in a patient with axial back pain and peripheral involvement which tends to be milder. So, there s a debate that s ongoing as to whether psoriatic arthritis should be included under this term peripheral spondyl arthropathy, but we ll leave more details on this for a later time. So, just please keep this in the back of your mind in terms of how we classify spondyl arthropathy in these new criteria, and now I m going to go directly to some clinical studies that were presented at the meeting

3 in Washington in November. 2

So, the first is the rapid axial SpA, this is Certolizumab and this AS and axial spondyl arthropathy, and this is the first randomized control trial of Certolizumab pegol in axial spondyl arthropathy

4 So, the first is the rapid axial SpA, this is Certolizumab and this AS and axial spondyl arthropathy, and this is the first randomized control trial of Certolizumab pegol in axial spondyl arthropathy using the criteria I just went over. It s placebo controlled to week 24, dose blinded to week 48 and then open label to week 158. And you can see it s randomized one to one, the placebo and the two doses Certolizumab given every two weeks in a 200 mg dose or four weeks in a 400mg dose after loading. And, you can see the clinical outcomes on the slides at week 12, which is the primary outcome measure in this time of the primary outcome measure in this study. So, on the left graph shows the ASAS 20 for the three groups of patients, the placebo in gray. And then, you can see the ASAS parts of remission please note the number of patients are listed below that. Now, if you divide those up as to whether they had ankylosing spondylitis, and as you recall ankylosing spondylitis is usually by the New York criteria so radiographic damage, you can see the response rates for both the ASAS 20 and ASAS partial remission, and then all the way to the right are the response in patients in the study who came out with radiographic axial spondyl arthropathy. And, what s really interesting here is the response and the non radiographic is superimposable on the patients that had met criteria for AS. Therefore, this study shows that in patients with ankylosing spondyl arthropathy whether they had ankylosing spondylitis according to the New York criteria, or non radiographical axial spondyl arthropathy according to the criteria I just presented; responses were pretty much identical. I think this underscores the idea that using radiographs as a solo way of diagnosing AS falls short and will not allow us to treat a number of patients who don t have radiographic disease that could benefit from therapy 3

5 The next study is the ABILITY II study was Adalimumab in patients with peripheral spondyloarthritis. So, again using the criteria I set out at the beginning of this presentation, peripheral SpA, 150 patients that met these criteria without significant back pain were randomized to Adalimumab 40 mg every other week, or placebo for 12 weeks. And, in this study they used a new outcome measure, which is the Peripheral SpA Response Criteria, or the PSPARC 40. Not yet validated, but certainly this is one of the first steps toward that validation procedure. So, here you see these patients meeting the peripheral spondyl arthropathy criteria, and they had either one or more SpA features, but they could not have psoriasis, so patients with psoriatic arthritis were not included in this study. And, you could see the other way they could reach the diagnosis by having two or more other SpA features. And, in this case, if you glance to the right it shows the primary endpoint at 12 weeks with a PSPARC 40. And, you can see here that there s a significant greater number of patients who achieved this end point at 12 weeks in the Adalimumab vs. placebo groups. So, this study confirms that Adalimumab is as effective in peripheral spondyl arthropathy patients who do not have accompanying psoriasis. And, we ll have to see how the PSPARC measure works out as an outcome instrument in trials moving forward, but this is very encouraging. 4

In the next slide, we re looking at the ABILITY II study that you just saw and trying to determine if patients that have oligoarticular disease or women have less severe disease in this group.

6 In the next slide, we re looking at the ABILITY II study that you just saw and trying to determine if patients that have oligoarticular disease or women have less severe disease in this group. And, the way this was analyzed on the table on the left. You can see here the oligoarticular patients, 34 of them, vs. the polyarticular group, the oligoarticular had three tender and two swollen joints compared to the polyarticular which you see to the right. And what s really fascinating is these groups really were not different in terms of duration of disease, HLAB27 positivity, or their activity is determined by the BASDAI or the Patient Global Assessment. And, the table to the right breaks it down according to male and female, and once again the oligoarticular was not different than the polyarticular according to gender in terms of duration disease, HLAB27, the level of, number of patients who had high sensitivity CRP abnormalities or in the patient reported instruments. So, these data suggest that in non PSA periphal SpA patients, those who were in ABILITY II that disease activity was similar regardless of gender or whether the disease was oligoarticular or polyarticular. This is very important because there has been this sense that people with oligoarticular disease were less likely to have severe problems and less likely to need more aggressive treatment. And, at least in this particular subgroup that does not appear to be the case. 5

7 This is the SENTINEL study, the next slide, which is the prevalence of SpA in anterior uveitis patients. This is a prospective, multi center, non comparative cohort study in which patients had to have clinically significant anterior uveitis as defined by recurrent anterior uveitis two or more episodes separated by three months, or non recurrent HLAB27 associated uveitis. And, the ASAS criteria were used to diagnose spondyl arthropathy, and we ve gone through those. And they had 231 patients from 30 referral centers including those existing disease. And, what s really I think informative here is of those patients with anterior uveitis, 65% of those had an associated underlying spondyloarthritis. So, on the graph to the right one can see the bar graph, you can see that 36% did not have a spondyl arthropathy, about 50% had axial and 15% peripheral SpA. So, these data really tell us that ophthalmologists need to be aware that in their patients coming in with anterior uveitis, that more than half almost to the two thirds of those patients will likely have an accompanying axial or peripheral spondyl arthropathy, and they need to be thinking about some critical questions or referral to a rheumatologist to help make that diagnosis. 6

Now, one of the questions that s really been on the forefront of the biology of ankylosing spondylitis is whether or not this is a disease that is auto immune, or whether it s primarily of innate

8 Now, one of the questions that s really been on the forefront of the biology of ankylosing spondylitis is whether or not this is a disease that is auto immune, or whether it s primarily of innate immunity. And, one of the problems that we have in trying to think about being an auto immune disease is we ve not been able to identify an auto antigen, and secondly it s associated with HLAB27, which is a Class I MHC molecule, which is different than the types of auto immune diseases we see in practice, such as rheumatoid arthritis and lupus, which are classically Class II MHC molecules. Nonetheless, in this study the authors looked at the presence of antibodies to CLIP, which is Class II Associated Invariant Chain Peptide. And, the cartoon here explains this molecule in terms of its function. So, you see in the endoplasmic reticulum to the left there s a Class II MHC molecule, and I have to say that this looks like an antibody. I apologize for that; it should not. This is a Class II MHC which you know has that sort of hot dog bun appearance and crystallography, and associated with that Class II MHC molecule is the CLIP peptide, which you can see is bound to it with a little ball and then that long peptide chain representation. And so, this stays with the Class II MHC molecule in the endoplasmic reticulum, but then undergoes as you cast your eyes to the right, proteolytic degredation. And you can see that it s degraded and the CLIP is released from the MHC molecule, so that the peptide antigen shown in blue can be inserted into the arms of that MHC Class I molecule, which then of course then goes to the cell surface and presents the antigen to the awaiting T cell. So, these authors asked whether or not patients with ankylosing spondylitis have an increased frequency of antibodies to CLIP, and they developed an ELIZA and they showed that indeed 85% of 94 axial spondyl arthropathy patients had these auto antibodies, but only 8% of the 51 controls. Moreover, higher levels of anti CLIP antibodies were noted in the axial spondyloarthritis vs non spondyloarthritis with very significant difference in these levels as shown, 14.5 vs absorbency units. So, these are fascinating in the sense that we have not talked about or seen auto antibodies associating with ankylosing spondylitis. Obviously, confirmatory studies are needed but this is an area I think we should be watching closely, not only from a diagnostic point of view but also in helping us think about novel pathogenic pathways. 7

In the next slide, this was a biomarker that was examined in ankylosing spondylitis, and we have precious little in the way of biomarkers to help us with trying to determine which patients are more

9 In the next slide, this was a biomarker that was examined in ankylosing spondylitis, and we have precious little in the way of biomarkers to help us with trying to determine which patients are more likely to progress. The factors we tend to look at are baseline syndesmophytes and elevated C reactive protein as measures that may indicate patients were likely to develop bony syndesmophytes. But in this study they looked at VEG-F levels and they used again ELIZA looking at the serum levels, and they took two groups of patients. One group of AS patients that had no low presence of syndesmophytes at baseline and those that had syndesmophytes. And, they showed that the baseline VEG-F levels was significantly higher in the progressors vs. the non progresssors. And, that an elevated VEG-F at baseline had a positive predictive value of 56% and a negative predictive value of 92% for progression. So, from a clinical prospective, if your VEG-F level was not elevated at baseline, it was highly likely that you were not going to progress over two years. Now, you can see the ROC curve on the right and it shows a sensitivity and specificity of VEG-F and the cut off of 494. So, this again is very exciting as a predictive biomarker of progression, but we will need confirmatory studies to confirm whether or not this is a valid and reliable biomarker for this purpose. This concludes my presentation on abstracts presented at the 2012 ACR Meeting in Washington DC in the area of spondyloarthritis and I hope you found this session helpful. Have a good day. 8

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