IBD Drive Time: Drs James Lewis and Laura Raffals on SPARC
Dr Raymond Cross hosts Drs James Lewis and Laura Raffals in a discussion of SPARC, a study of adults with inflammatory bowel disease in which patients are followed prospectively to collect data about to allow prediction of disease course and advance the field in IBD.
Raymond Cross, MD, is director of the IBD Center at Mercy Medical Center in Baltimore, Maryland, and professor of medicine at the University of Maryland. Laura James D. Lewis, MD MSCE, is professor of medicine and chief of gastroenterology at Penn Presbyterian Medical Center in Philadelphia, Pennsylvania. Laura E. Raffals, MD, is professor of medicine at the Mayo Clinic in Rochester, Minnesota.
TRANSCRIPT:
Dr Cross:
Welcome everyone to IBD Drive Time. I'm Raymond Cross from Mercy Medical Center in Baltimore and I'm delighted to have two return guests to IBD Drive Time. Jim Lewis from University of Pennsylvania and Laura Raffals from Mayo Clinic. And the topic today is going to be the SPARC IBD registry, Jim and Laura, welcome back to IBD Drive Time.
Dr Raffals:
Thank you for having us, Ray.
Dr Lewis:
Yes, thank you so much.
Dr Cross:
Laura, maybe I'll start with you. Many of the listeners may not have heard of SPARC IBD. So can you describe the registry and perhaps tell us how this fits into the overall IBD Plexus funded by the Crohn's and Colitis Foundation?
Dr Raffals:
Of course. So SPARC stands for a study of prospective adult research cohort with IBD. So really this is an incredible research project that Jim and colleagues thought of many years ago to really advance the field in allowing us to enroll patients and follow them prospectively over the course of time so that we can really study patients, a cohort of patients over time and see if we could collect bio samples and study their biomarkers and collect data about these patients so that we could start to predict disease course and do a better job managing our patients and advancing the science more quickly in order to really do a better job caring for our patients. And the idea was—and how it fits in with Plexus— is as we develop this cohort of patients and had better data about these patients, meaning we were collecting standardized data about the phenotype disease behavior of these patients and have the bio samples along with these patients that we could bring together investigators both from the academic realm as well as our partners and industry to really come together, work together to more quickly ignite the science, if you will, to understand how can we predict disease behavior, how can we identify targets in the underlying biology to manage our patients better and hopefully bring treatments to our patients, understand how those treatments will work.
And also there was this idea behind SPARC and Plexus as well as people utilize this resource. The idea is data that's generated from this resource would come back to the two plexus, if you will, and be available for others to use in the future so that people, it's a resource that continues to feed other investigators, other scientists to continue feeding the field and advancing the field for our patients. So really this sense that we're trying to build a resource that continues to grow, not build silos of research, but really building a community that as a whole will serve one common purpose, which is really benefiting our patients with that common goal in mind. So SPARC really is just a cohort of patients with IBD that fits under the umbrella of a very larger research program, which is Plexus, which has multiple cohorts, but SPARC is that adult cohort of IBD patients. Again, that is well characterized.
Dr Cross:
So I fortunately have been part of this from the beginning and when I'm talking to my patients about SPARC, I try to summarize it as this is a precision medicine initiative. We've been talking about that for maybe 15 years now and it seems like we're not much closer. So the goal here is to identify those predictors as you said, and I tell them that this is, I think broadly that this could be like the Framingham heart study in the Crohn's and colitis space and maybe overselling that a little bit, but I really think this is a super important initiative.
Jim, do you want to talk about the type, so Laura mentioned deeply phenotyping patients, the data is also linked to Epic so we can get information that's collected for routine clinical purposes from Epic, but what biospecimens are we collecting?
Dr Lewis:
Sure. We collect a whole host of different biospecimens things that obviously we're going to, we collect plasma from patients and it's unbelievable the amount of plasma that we have given out to researchers over the last five years or so. But we also are collecting stool samples. We're collecting DNA, we're collecting RNA for RNA-Seq and mucosal biopsies, which some of them go into formalin and can be used for histology or even things like spatial transcriptomics. We also have some mucosal biopsies that are flash frozen and some in preservatives for RNA-Seq. So there's really a wealth of biosamples that are available for investigators. Many of them have already been used to generate data. And this is, Laura mentioned, if you generate data from these biosamples, it all goes back into plexus so that other investigators can use them. So for about half the people have genomic data and that number will, that proportion will go up to about 80 to 90% by the end of this calendar year. Lots of patients have already had, for example, stool sequenced for microbiome. There's patients who have RNA-Seq data from mucosal biopsies, peripheral blood. There's some data that just got generated on epigenetics from peripheral blood mononuclear cells that are about to be deposited back in. So if you have a creative idea, there's often a biosample there awaiting you.
Dr Cross:
So I think unique thing here is you get all the strengths of claims data because you have linked to EPIC and IQVIA, but you have deeply phenotyped patients with biospecimens. So it's really a unique registry.
Dr Raffals:
I think it's really unique in that sense and I think that's what is really exciting. The different modes of data is if you think about it just as you highlighted there, Ray, is incredible because what we didn't really highlight yet, and you just alluded to this, is the EHR data is the other piece to this. So all of the patients that sit within SPARC are carefully. So we have the standardized data in the sense all these patients are carefully, so that's standardized. They all have patient-reported outcomes. So we get that data and we collect that longitudinally, so we have that longitudinal aspect. But then you have all this unstructured data from the EHR that's collected on these patients as well. And especially now if you think about the powerful tools we have at our fingertips and that are continuing to evolve of what we can do with unstructured data, all that exists within the EHR, the data that's there. There's incredible amount of data in the EHR, so that's all available too through SPARC as well.
And then you have all the omics data that is generated through SPARC that Jim described as well. It's really incredible. And the other thing that's really cool is there's a lot of lab data that's generated through Plexus as well, on every patient that's enrolled. So not just what's generated by investigators, that's put back into the pool if you will, but that's automatically generated as part of the initiative that's available on every single patient. So a lot of these samples are processed as part of the overall study itself available to investigators.
Dr Cross:
So I'll throw this next question at Jim, but if I remember right, Jim, we started meeting about this, the vanguard sites, in around 2016 or so. So Laura was mentioning how big the registry is. So what are we talking about here as far as patient numbers and sort of average length of time that we've been following subjects?
Dr Lewis:
We have a little over 5500 patients who've been enrolled. This is a mix of Crohn's disease and ulcerative colitis and they've been enrolled for various lengths of time. Obviously during the heart of the pandemic enrollment really slowed dramatically. And so there's almost like 2 eras of enrollment. There was the early vanguard enrollment and then the subsequent enrollment. So some people have only a couple years of prospective data and others have much longer period of prospective data. But to Laura's point, many of these people also have retrospective data from before when they enrolled that goes back for several years and for some of these patients decades or longer.
Dr Cross:
And I don't know, I think that you and Laura have had the same experience that I have, but I think what's really remarkable about our patients with IBD is they seem to be very much engaged in paying it forward and trying to make living with Crohn's and colitis easier for future generations. So getting patients to agree to be part of this and give a periodic blood, stool collection, some biopsies, it's been very easy to enroll. I don't know if that's been you and both your experiences as well.
Dr Lewis:
Yeah, I tell patients that if you've never participated in research before, this is a low bar entry into the research experience. A lot of it, particularly once they're enrolled, a lot of it happens when you're there for endoscopy, for example, getting your blood drawn, they're putting your IV in and they just take your blood off while you get your IV placed. And so it's a very nice way for people who've never participated in research before to get started.
Dr Raffals:
I think it's like you said, Ray, it's that sense of purpose, that giving back, it's something they can do to contribute for, there's such a sense of loss of control with this disease so many times that this is something they can do as you said, to pay it forward. And it gives also that sense of community. They're sort of part of that sort of community that's doing something about this disease. So I found it also very easy to recruit to this study. And I also find patients are really excited. We've started to hit this momentum. So there was a tipping point with SPARC where, as you start a cohort like this, you have to have a certain number of patients for it to be worth anyone's while to use the resource. And so we hit this tipping point a couple of years ago. I would say, Jim, I don't know if you feel like when this tipping point was in my mind, it was maybe 2 or 3 years ago where we serve when we got to about 3000 or so patients, all of a sudden people really were interested in utilizing the resource because there were enough patients in there that you could find enough patients of this type on these medications or with this phenotype to answer the question you wanted to answer.
And so I think patients get excited now when they hear about the studies that are happening with SPARC and that generates more enthusiasm to participate or excitement that they are a part of this.
Dr Cross:
So before I go on to ask a few more questions, I just want to remind our listeners that we are sponsored by the AIBD Network. We're also available on Apple Podcast and Spotify. So you can subscribe to IBD Drive Time. And of course, the national Advances in IBD meeting will be taking place December 9th through December 11th in Orlando. So we hope to see you there.
So Laura mentioned, Jim, that at the beginning we were worried about getting bigger and growing and getting good sample size and we finally got there. So can you highlight for the listeners a couple projects that were really relevant to the bedside? And I have one in mind that I could highlight also.
Dr Lewis:
One of the first ones that comes to mind when I think about this is some work that was led by Jeff Yang interestingly as part of his PhD dissertation. His fundamental question was how we preach treat to target, how much do we practice treat to target? And particularly how much do we practice going beyond measuring CRP, calprotectin, and really doing that follow-up colonoscopy to see whether people had endoscopic healing. So he looked at people in the cohort who were new starters of advanced therapies and then looked in this sort of window. I mean he varied the window, but sort of the core window was within a year. How likely were you to get that follow-up colonoscopy? And it was interesting because it was really in sort of like that 50 to 60% range. Now there's a whole host of reasons of why people don't get a follow-up colonoscopy. One might be that the provider didn't think it was necessary. One might be that the patient just didn't want to have one done. But it does sort of give you kind of a benchmark of how often we're achieving that construct of getting the work done. It's not really the outcome, but it's much more of a process measure that we're doing.
Dr Cross:
And if I remember right Jim, you guys did a couple sensitivity analyses. One is you substituted a calprotectin for a scope and it got about 10 to 15% better. And then you looked at pre-COVID versus post COVID. And if you looked at pre- COVID it was a little bit better, but it wasn't getting us to that 80% threshold for doing treat to target. Is that right?
Dr Lewis:
That's correct. And interestingly, obviously calprotectin really came into its own during the pandemic because people didn't have to come in for a colonoscopy. And then I think obviously we're probably moving back, we're finding a new level of equilibrium of how we're going to move forward.
Dr Cross:
And I'm sorry, Jim, what was the other project you were going to mention?
Dr Lewis:
Oh, I wanted to bring this one up because you had talked about that we've been searching for precision medicine for the last 15 years or so in the world of IBD. I think one of the really interesting studies that was done using in part SPARC data focused on why are some people nonresponders to mesalamine. So people with ulcerative colitis We know it's a wonderful first-line therapy, but why do some people not respond? It may turn out that this is a product of your microbiome. The way this works is that mesalamine is essentially acetylated to deactivate it. And just like we as humans have these acetylase enzymes, so do our bacteria. It's interesting—the people had looked at this at the host at the human acetylase enzymes before and not really been able to show much of an association, but that may be because this is a drug that's really minimally absorbed, right? So the real action is what's happening in the lumen and all these bacteria are there with these enzymes.
I think it's also particularly interesting when we think about that we've known for decade or longer to 2 decades probably now, that oral plus rectally administered mesalamine is better than oral alone, even though we're giving pretty big dose. And I think that maybe this is because you've sort of bypassed the bacteria when you administer it rectally. And whether we would ever move to the future where we would try to manipulate somebody's bacteria to make them a mesalamine responder or pick who would be treated based on their microbiome, I don't know. But I think it would just super interesting
Dr Cross:
And I'll put a plug in for a project that I did with a phenomenal medical student, Maddie Alazada and GI fellow Osman Ali. We had a theory that patients with extraintestinal manifestations are a more difficult to treat subgroup, that that may be a predictor of severe disease. And indeed what we found is at least in terms of biologic cycling, the patients that have extraintestinal manifestations on average were exposed to one more advanced therapy than those that were not. So that's very important clinically. If you see a patient in front of you who's had some uveitis and some inflammatory arthritis that may be a more difficult to treat patient, maybe help focus you on your types of therapy, we couldn't quite answer what types of therapy were best, although we might imagine what those might be for EIMs.
So Laura, what are the next steps and how can a researcher get involved with SPARC?
Dr Raffals:
So what I think what's really critical, these are a couple examples of great projects that have spun out of SPARC. And if folks have questions they want to answer, but they're not able to answer the question at their own institution because let's just say they don't have the patient population at their own institution to answer a question with the size of their IBD population, they can go to the Crohn's Colitis Foundation website and just go to the IBD Plexus tab. And if you just scroll down that page, you can request a consultation and you can also see the tab to submit a proposal. And that will take you to the site where you can submit a proposal to access the SPARC resource or even just request a consultation to learn more about accessing the SPARC resource, or reach out to Jim or myself. We'd always be happy to talk to anybody about the SPARC resource.
We have 21 sites I think now. So we have multiple PIs. Again, all of the PIs are listed on the Crohn's Colitis Foundation website, but the reason we have this resource is because we want people to use it. So it's here to be used and we want to get folks involved. It's an incredible resource for folks. So Jim and I are here to work with people and we're excited about it. And the more folks engaged with SPARC the better. Jim, anything you want to add to that?
Dr Lewis:
The only thing would add is it could be that you have the resource at your home institution, but you also want to validate, can you see the same thing in a second population? And so here's your sort of ready-made second population, so you should keep that in mind as well. And
Dr Cross:
I was just going to say that I worked pretty hard with Karen Muñoz to develop a good data set that we could pull that was usable, and I'm happy to let people know what we have in a data set as well. So Jim and Laura, I'm going to briefly put you on the spot with the last 1 or 2 minutes. So both of you are return guests. So you already told us something fun about yourself, but maybe since the last podcast, tell the listeners something new about yourself that they may not know.
Dr Raffals:
Geez, Jim, you have to go first.
Dr Lewis:
All right. So my wife Nancy and I have been on a journey to hit all 50 of the United States and turns out we've both now done all 48 of the continental United States. And the kicker of this story is that we celebrated completing the continental United States with dinner with Laura.
Dr Raffals:
In Minnesota. Yes.
Dr Cross:
You just have Hawaii and Alaska left, Jim?
Dr Lewis:
That's correct. We're going to go to Hawaii, God willing. We're going to go to Hawaii in about six months. So that'll leave us just Alaska after that.
Speaker 1:
You got to talk to Jordan Axelrad. Apparently he's the points king. So that was his fun fact that he doesn't pay for travel, he accumulates points for all his flights. So you have to talk to Jordan about how to do that best.
Dr Cross:
Laura, what about you? You can't use that one.
Dr Raffals:
I almost fell down the side of a mountain once in a very foolish hiking trip where we should have had better equipment. But sort of scrambling down side of a mountain slipped and fell and stopped my fall by throwing my arm into a crevice and had to be. One of my stupid escapades back when I was young and adventurous.
Dr Cross:
Alright guys, this has been great. Thanks for doing this and I hope to have you guys back on IB Drive time soon.
Dr Raffals:
It's great to see you all.
Dr Lewis:
Yes, thanks for having us.
