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Ultrasound-Guided Synovial Biopsies: Rheumatoid Arthritis Meets Precision Medicine

Melanie Cole, MS (Host):   Welcome. This is Better Edge, a Northwestern Medicine podcast for physicians. I'm Melanie Cole and today we’re discussing ultrasound guided synovial biopsy. Joining me is Dr. Arthur Mandelin. He’s an associate professor of medicine in the division of rheumatology at Northwestern Medicine. Dr. Mandelin, it’s a pleasure to have you with us today. What a fascinating topic that we’re covering. Tell us a little bit about the Rheumatoid Arthritis Synovial tissue Network REASON. Why it was formed? Tell other providers what the objective of it was.

Arthur Mandelin, MD/PhD, RMSK, RhMSUS (Guest):   The reason that we formed the Rheumatoid Arthritis Synovial tissue Network, or REASON, is that we have one major problem that we’re facing right now in the treatment of rheumatoid arthritis not just in this country but everywhere in the world. I think everyone is aware and even our patients from watching direct to consumer advertising on TV and the radio, we’re all aware there’s been an explosion of treatments for rheumatoid arthritis in recent months and years. This by in large is an excellent thing. It gives us a lot of different options for treating our patients who have rheumatoid arthritis. The problem is we don’t have a way to guide precision medicine to treat each patient with the drug that they're most likely to respond to. We’re basically choosing medications on a trial and error basis based, if anything, on the statistics. We think that this drug is the most likely to work but maybe not. We don’t really have a way to test a patient to know what particular mechanism is active in their disease which we could specifically target with some of these very, very narrowly targeted drugs.

So what we really need to do is to steal a page from oncology. We need to be able to go in and get a piece of the diseased tissue and analyze that tissue and based on that know which drug to choose. It’s been tried for decades not to look for such a biomarker in the blood and unfortunately it’s not been found. So the conclusion that we’ve come to is the reason this biomarker can't be found in the blood is it just isn’t there. We’re going to need to get the direct sample of the inflamed tissue itself through a biopsy procedure. So that’s why we formed the Rheumatoid Arthritis Synovial tissue Network. Because the way that this is going to have to happen once the actual samples are obtained and the biobank is developed is we’re going to need to use big data to analyze a large number of samples to look for patterns that will give us these clues and hopefully, eventually, get us this test that we all want to have. This biopsy directed therapy that we’d all like to have.

To get such a large number of samples from a large range of rheumatoid patients, we need more than once facility. So Northwestern is the lead of the Rheumatoid Arthritis Synovial tissue Network. The principle investigator is my division chief Dr. Harris Perlman. We have a network of a total of six institutions that are participating in the REASON network, and that’s why the network was formed. That’s what we’re hoping to do is to eventually bring this era of trial and error switching to an end by launching prevision medicine.

Host:   How far out is it do you feel?

Dr. Mandelin:   That we don’t really know about. You can never really determine when you're in the middle of the research when you're going to reach and end point. If I had to conservatively guess I would say that we’re at least five if not ten or more years from having a really workable commercially available test. At this point we’re just sort of trying to find the patterns in the tissue that might guide us in that direction.

Host:   So then how has Northwestern Medicine utilized the ultrasound guided synovial tissue biopsies for your research? What have you been doing?

Dr. Mandelin:   Currently what’s being done is that the tissue is being digested and sorted on a flow cytometer so that certain particular cell types from the synovium can be isolated and analyzed individually. Right now we’re focusing mostly on macrophages. The reason for that what research does exist out there does suggest that macrophage abundance in the synovium is the one thing that may be to this point useful as a biomarker to disease activity. We’re hoping that therefore by studying these particular cells we can learn something about them that will give them more than just disease activity but things like treatment response or mechanism of action that would be the most useful against rheumatoid arthritis.

After we sort these cells out, we then do RNA sequencing on them. We’re basically asking the computer then after we do all of this RNA sequencing to look at the genome of these cells in what’s referred to as an unsupervised manor. In other words, we’re not giving the computer any particular instructions. We’re just saying, “Dear computer, here’s a whole bunch of RA patients. Why don’t you go ahead and put them into groups however you feel that’s appropriate. Show me some patients that are similar to each other and dissimilar from others in this RA population I've just shown you. Go ahead and make me some groups.” When we do this, the computer makes about six groups. The reassuring thing there is that when we do this is an animal model, the computer makes six groups. So at least we’re getting some reproducibility. Of course the major question now is what do these six groups mean if anything? Do these six groups represent genotypes within what phenotypically appears to be a very unified disease state of rheumatoid arthritis? Do we, for example—the dream would be—do we have a methotrexate responder group? Do we have a methotrexate group but TNF inhibitor responder group? Do we have a methotrexate non-responder but jak inhibitor group? So forth and so forth. That part we haven’t gotten to yet, but so far we’ve gotten the machine to show us some phenotypic variation and perhaps some genotypic variation and genotypic subtypes within what phenotypically looks like a single disease.

Host:   Wow. That is absolutely amazing. So do these biopsies always generate a sufficient sample for your RNA sequencing in both quantity and quality? What are you finding?

Dr. Mandelin:   Generally speaking the answer is yes. There are various different research projects that this tissue is feeding into. It’s not just a single biobank. We’re also contributing to an NIH funded project which is part of the accelerated medicines program or AMP. Different research projects require different thresholds of quality and have different criteria for what is and is not an acceptable biopsy. By in large the vast majority of these biopsies do generate good quantity and good quality of tissue. For the testing that we’re doing specifically here at Northwestern that is not part of the national network, we have always gotten some type of data out of all the biopsies that we have done. There have been instances in which we’ve gotten usable data out of less than 100 cells.

Host:   Wow, how many have you done? Up ‘til now, how many have you performed to date?

Dr. Mandelin:   We’re in the high 70s. I would anticipate that certainly in the next couple of months we’re going to do our 80^th biopsy hopefully before midyear we’ll be even into the 90s.

Host:   Dr. Mandelin, I think the million dollar question I would suppose is how do you envision this research translating to patient care? You’ve given us not really a timeline but what you might envision it would be useful in that amount of time. What do you see it actually doing once it is?

Dr. Mandelin:   I think if everything goes the way that we would wish it to go, the ultimate outcome would be that patients who get diagnosed with rheumatoid arthritis would be treated in very similar manner to those who are diagnosed with any type of a malignant tumor. That is to say that once they get their clinical diagnosis they would be subjected to a synovial biopsy to a joint that is active at the time—a so called hot joint—to get a tissue sample. Then using this technology we would determine which particular genotype of RA they belong to. That would predict treatment response so that we would know which drug to choose from the get-go without having to use this sort of trial and error method, which by the way takes about three months per failed drug. So then the patient’s not very controlled. We estimate it could be as much as $3 billion are waster per year on drugs that ultimately just don’t work because we’re trying them sort of blindly. Right now when we do these biopsies we’re taking about a dozen very tiny fragments. It adds up to maybe the size of a grain in total. But a dozen tiny fragments out of the synovium. Of course the eventual clinically applicable biopsy I would envision would require fewer pieces because we know better what we’re looking for, perhaps only one or two bites would be needed.

Host:   Dr. Mandelin as we wrap up and you're telling other providers how much closer you are to predicting therapeutic responsiveness, what other research or what else would you like them to take away from this research or future studies? Please wrap it up for us.

Dr. Mandelin:   I think the most exciting thing about the program right now is that we’ve had enough success at this point in rheumatoid arthritis even though we haven’t yet answered the question that we are now ready to move into other forms of inflammatory systemic arthritis. Specifically we’re planning next to go into psoriatic arthritis and use the same technique to begin to ask the same questions and hopefully get us the same type of an answer—a directed biopsy specified personalized medicine for psoriatic patients as well as for rheumatoid patients. We would then envision that we can eventually expand this program into whatever form of arthritis once we get some of the successes under our belt here.

I think it’s important for clinicians to know that this technology is coming. That rheumatology and specifically Northwestern Medicine are cognizant for the need of personalized medicine in rheumatoid arthritis so that we can stop wasting time, get the patient back to their lives faster, stop wasting healthcare dollars on treatments that don’t work, and move us forward in the field of rheumatology and the treatment of rheumatoid arthritis.

Host:   Absolutely great information. Dr. Mandelin, thank you so much. For other providers, your research is invaluable. Thank you for explaining it so very well to us. That concludes this episode of Better Edge, a Northwestern Medicine podcast for physicians. To refer you patient or for more information on REASON, please head over to our website at nm.org to get connected with one of our providers. Please remember to subscribe, rate, and review this podcast and all of the other Northwestern Medicine podcasts. I'm Melanie Cole.