บทถอดความฉบับเต็มของ Vasculitis in Practice: Diagnosis, Treatment and When to Refer

on the size of the blood vessel that's affected and which diseases we're talking about. But there's blood vessels everywhere in the body. So, you can have, you know, skin changes, different types of rashes, eye inflammation, bleeding in the lungs, blood and protein in the urine, I mean, nerve damage. The list is long and sounds very scary. But really, I would say some of the patients we get are newly diagnosed patients kind of coming in fresh with all of these symptoms, and a lot of times it's really just paying attention to the fact that there's more going on than something in just one organ. And so, just recognizing that if you keep treating something and it's not getting better, like a sinusitis and you keep giving antibiotics, it's not getting better, really to just kind of step back, think bigger, and see if there's something else going on somewhere else in the patient's body. I think that's probably one of the best things that any provider can do regardless of their specialty to try to recognize that there's a systemic inflammatory process that's very severe. Eric Ruderman, MD (Moderator): Dr. Jaros, I mean, let me follow up on that. I mean, we frequently see people who take a long time to be diagnosed. When you see these delays or this uncertainty, how do you approach this, and where do things fall through the cracks? Brian Jaros, MD: Yeah, it's a good question. I think anytime I see a new patient, whether they're kind of early in their journey or late from their journey, I think, I almost try to start from the beginning, right? And get the entire picture from A to Z, where they've gone, what they've had done, what's led, you know, to their typically like winding or circuitous course to finally, you know, get to me or get to, you know, a potential diagnosis. And like Anisha was saying, I think there's a lot of factors that lead to that. These are just really rare conditions. They're not top of mind, especially for people that aren't rheumatologists. And I would say a lot of the time folks start not with rheumatology, they start with the organ or symptom that's affected. So, starting with ENT, if it's sinusitis, or starting with pulm, you know, if it's a recurrent pneumonia. And to Anisha's point, it kind of takes someone who thinks, "Hey, this isn't responding the way a pneumonia should respond," to kind of, you know, think down the line and say, "What else could be going on here?" I think, ultimately, we want to catch these people as early as possible because the whole kind of goal in vasculitis is preventing damage. We can treat inflammation, we can reverse inflammation. But once damage starts to happen to the blood vessels or to the organ systems, that can become long-lasting. And so, I think, you know, the great thing and the purpose of our center as like a referral network is, you know, in people who have uncertainty trying to shed light, you know, at this kind of pivotal point in their course, like are they on the right track? Do

they have the right diagnosis? Is there anything else we can offer them as far as recommendations for getting an answer for diagnosis or for like next treatment steps? Eric Ruderman, MD (Moderator): Let me follow up on something you mentioned and throw it out to both of you. And you mentioned rheumatologists. And rheumatologists will often recognize that this is an we clearly cannot see every vasculitis patient in the country, let alone Illinois at our center. So for rheumatologists who don't see high volumes of vasculitis, what are thetriggers? What are the times when they should really consider referring those patients to a more specialized center? I'll start with you, Dr. Dua. Anisha Dua, MD, MPH: Yeah. Honestly, these are rare diseases, and it can be overwhelming. And with the advancements in the field, honestly, that have been happening very rapidly over the past five, 10 years, I think it's reasonable to seek that specialized care whenever you want to. If you feel like you're not necessarily even in over your head, you just want another set of eyes, it doesn't mean that the patient has to come and be seen forever for the rest of their time at a specialized center, but, you know, we do have some of those abilities to talk with radiologists to re-review the path to get to that diagnosis. So if there's uncertainty, and you just know something is going on, but you're not quite sure, that's one reason to have someone in a specialized center look at the patient and say, you know, really lean one way or the other. Or if the patient's just not doing well and you're unsure what to add on or what else to do, I think that those are all totally reasonable times to just send someone over to get another set of eyes on it from people who have seen it, who that's basically all they see. So, I think, you know, the volume really does make it so you feel very comfortable feeling out those nuances and making minor adjustments and treatment plans that can improve outcomes that are not necessarily in a guideline or in a textbook. Brian Jaros, MD: Yeah. I would just echo that the concept, like we don't end up, you know, following all of these people long term. I think a good portion of people come for, you know, another opinion, another set of eyes, just to make sure they're on the right track. They maybe will check in with us, you know, again once in six months or something like that, but they'll continue to follow with the primary rheumatologists. And I think that model kind of helps offset the volume that you're talking about. You know, we don't always need to be the most frequent touch point for all of these people. We can offer kind of our opinions or, you know, expertise. And then, they can go back and follow up with whoever referred them in the first place. Eric Ruderman, MD (Moderator): I can imagine for patients, it's nice to have somebody close to home who can be a sort of a primary source for you, but then you can go, , you know, somewhere else to

get an opinion on issues or changing, you know, therapies or— Brian Jaros, MD: Yeah, which I think is a good point also, is that, you know, this is a rare disease. So in terms of vasculitis centers, it's not like there's a plethora of centers, you know, all over the Illinois or surrounding areas. So for a lot of these folks, it is driving hours, you know, to see the center, and it's not necessarily feasible or the right decision to say, "You should come, you know, see us constantly in downtown Chicago when you're in southern Illinois." But having that, exactly, set of eyes, and then being able to have their kind of like local quarterback, I think is a nice, like happy medium between those things. Anisha Dua, MD, MPH: Yeah, totally agree. Eric Ruderman, MD (Moderator): Perfect All right. So, I'm going to pivot away from our center for a second and go back to something you mentioned before, Dr. Dua. You talked about the advances in the last five or 10 years. Maybe you can tell us a little bit more about that. What do you think the most important developments have really been in vasculitis treatment? And I know there are so many. But, you know, just the highlights of really where we've come in the last five to 10 years. And I agree with you that the number of options and the choices are sometimes both helpful and overwhelming. And so, thoughts what has really made the most difference in your mind? Anisha Dua, MD, MPH: I think we have, like I mentioned, come such a long way. It's not even across all the diseases. But in terms of having FDA-approved medications that actually target the pathophysiology of these different diseases, it's happening, you know? And then, not only do we have one option, now we have more than one option for certain diseases, which is great. We're also even looking at, you know, steroid-sparing strategies in, like, across all the vasculitides, which was something that was kind of imaginable to look at before. So, I think some of the, the biggest things, I mean, now we have for giant cell arteritis, we have tocilizumab and upadacitinib. For EGPA, we have mepolizumab and benralizumab. EGPA used to never even have any, like, basically randomized control trials looking at that disease. And this has really been a result of international collaborative research. I mean, because these are rare diseases, we really work closely with colleagues across the nation and the world to try to gather the patients to figure out what to do in terms of management. So, therapies have come a long way. Also, imaging modalities have come a long way. We all know about sort of AI and all of the advancements in the tech world. And so, I think our understanding of how to interpret some of the imaging studies, and even newer ways of getting those studies done has really advanced in the past, yeah, five, 10 years. Eric Ruderman, MD (Moderator): Dr. Jaros, let me talk to you. As we've developed all these new treatments, we're hitting something I think we've

never actually thought about before in these diseases, and that's the idea of getting patients into remission and maybe being able to not continue therapy forever. As you think about your patients, how do you think about the duration of therapy and decisions about the steroid-sparing strategies you've used and when it's time to think about pulling back in a patient who's in remission? Brian Jaros, MD: Yeah. It's probably, yeah, one of the most frequent and complicated questions that we get, you know, upfront from people. Understandably, everyone wants to know, like, "I have my treatment plan. How long do I need to continue this?" I frame it in different phases. I think, you know, the first priority, because we still do have a reliance on glucocorticoids upfront, they are important. But especially as rheumatologists, we all know we love them, we hate them. It's, you know, the quintessential double-edged sword. So, the first kind of phase is knocking that inflammation out, but then getting people off steroids in the safest but fastest way possible. And again, to Anisha's point, that's really become possible with a lot of these steroid-sparing therapies that we now have. And so, I initially think about, okay, let's get you into remission. Let's get things quiet, and let's get the steroids off, so we can avoid all the toxicities. Then, the question becomes, now you're just on your steroid-sparing therapy, how long do you need to continue that? And I think that's really individualized. I think even within the same type of vasculitis, that answer is very different from one patient to another, and depends on a lot of factors, like how severe their initial presentation was, using data, you know, from cohorts around the world to inform what are risk factors for relapse in that specific type of vasculitis, and does that patient exhibit protective risk factors or risk factors that, you know, make them more prone to relapse. I think how they tolerate treatment. We also see everyone, you know, tolerates these therapies very differently. Some people are on rituximab for years and barely get a cold or a flu, and other people get, you know, very serious recurrent infections. And so, that's going to kind of move the needle either way of how long you continue therapy. But I think another overarching principle that I try to discuss with people is, while our therapies can put vasculitis into remission, we're not yet at the point of curative therapies. And so even when we do decide to pull back on treatment altogether, there really still needs to be active surveillance, active monitoring for recurrence, especially when a flare or recurrence of vasculitis can mean, you know, pretty quick onset of organ-threatening inflammation. And I think that's tough, you know, to hear sometimes that, you know, even when I'm off treatment, I'm still going to have to, you know, go through the rigmarole of testing and monitoring. But I think there's a lot of things on the horizon also that are really exciting, like CAR T therapy, for example. Like, we're starting to think about the idea of how do we induce long-lasting remission that, you know, I think if we're sitting here in 10, 15 years, we might be having, like, a very different, you know, conversation about that. Eric Ruderman, MD (Moderator): Dr. Dua, let me ask you a variation on that question from the patient perspective, because my clinical focus is often on inflammatory arthritis, and patients ask me, you know, "How long do I have to stay on this medicine?" And I always tell them, you know, "Wait till you take it and then ask me that question again." Because frequently they're like, "Do I ever have to stop this?" How do patients respond? Are patients anxious to stop medicine after they're done well, especially after they've been hunting for an answer for so long? Or do you get patients who say, "Do I have to stop?" Anisha Dua, MD, MPH: Yeah, definitely get both sides of that coin. There are people who still really, really just want to be off of medications. Aand there are people who are like, "I would rather be on this forever because I actually feel good and I'm functioning, and the thought of potentially having any setback or having to be re-exposed to glucocorticoids is just not worth it to me." And all of that goes to that shared decision-making, right? That all goes into the decision tree of how long you're going to keep on treatment, what you want to minimize. But I definitely have seen patients on both sides of that coin. I do tell them upfront, like Brian said, you know, we aren't yet at cure. And so, these are chronic diseases. It's not a pneumonia where you take a course of antibiotics and it goes away. This is a chronic disease. And so, we can get it calmed down. But you're going to be seeing me forever, you know? So, I think it's just important to frame it appropriately. I liken it more to like diabetes or something like that, where, you know, you can get it under control, you can prevent damage from the disease, but it is something that is going to be monitored and evaluated with your doctor. Eric Ruderman, MD (Moderator): And let me follow up on that, and this is a question where I am truly asking the expert—guidelines. You've been involved, Dr. Dua, with many of the recent guidelines that have been put forth by the American College of Rheumatology to address the treatment of vasculitis. How have they changed your treatment and our treatment in general? I mean, what have they done in terms of how we're managing these diseases? Anisha Dua, MD, MPH: I think, you know, we updated the guidelines, they were published in 2021. And now, we are about to undergo another revision of that. It is a lot of work to try to gather all of these different pieces of evidence from across the world to try to inform our guidelines. And I will say that even since the publication in 2021, there are so many new things. So, I do think it is something that we need to be

consistently incorporating the new data to inform guidelines . I think they were pivotal though in terms of trying to translate a lot of this information into, you know, bullet points and just decision-making trees that people who don't see these patients often can follow. Again, they're guidelines. They're not 100%. There are times where you're not going to follow them, but I do think that they were a major advancement just in terms of putting a lot of these diseases into context. How often should I be checking this? Do I need biopsies? Do I need to check these labs? You know, what's your primary, secondary, tertiary preferred agent for this disease state? But of course, there's so much nuance in each patient that's going to make it so you're not always going to follow it, you know, like an algorithm. Eric Ruderman, MD (Moderator): Yeah. For those of us out in the trenches, I think that the work you folks do on the guidelines is hugely helpful because every new trial that comes out is the latest and greatest things. But you need to really sort through it and say, "Well, how does that fit into the full scope of what's out there?" Anisha Dua, MD, MPH: Yeah, I know. And, yeah, all these patients, you know, have different things that might make them not eligible for that trial in the first place. And so, how do you apply that information to the person sitting in front of you that may have comorbidities or have other features that, you know, that make it a little bit more nuanced or tricky? Eric Ruderman, MD (Moderator): Let me shift a little bit again back to you, Dr. Jaros. You mentioned CAR T, but let me ask you about are there other emerging therapies or other ongoing clinical trials that you really see as bringing us some of our next steps in vasculitis care? Brian Jaros, MD: Yeah, it's a very, very exciting time to be in rheumatology, but including in vasculitis. And I think as Anisha was mentioning, there's a huge consortium of people who are really passionate about this disease internationally, and that's led to a lot of ongoing trials. Some of those are, you know, novel mechanisms of immunosuppressant therapies. So, you know, we have rituximab for B-cell depletion, but can other monoclonal antibodies like obinutuzumab, for example, give us even deeper, more robust B-cell depletion in ANCA vasculitis, for example, and get better outcomes for those people who are non-responders? I think some of those novel mechanisms are very exciting, especially because they give us options and choices for people. So, when you fail this medication or when you don't tolerate this medication, we have, you know, an arsenal of plan B, C, D for folks. And then, I do think things like CAR T, thinking, you know, even beyond, you know, the monoclonal antibodies or small molecule inhibitors, like are there ways and are there things we can learn from other fields like oncology to induce long-lasting, you know, almost curative therapy for rheumatologic diseases like

vasculitis? I think that really is probably the next frontier of our field. we're a site for CAR T in ANCA vasculitis, and I think, you know, it's early days. But seeing results from like lupus, for example, and seeing if we can achieve the same kind of long-lasting remission for ANCA patients will be very exciting. I think another kind of aspect that you touched on or asked about is duration of treatment. And so, I think a lot of trials that are also quite interesting, one of which we're involved in for GCA, is understanding how long we need to treat, how we should be tapering off therapy, what's the safest way to withdraw therapy and whom should we withdraw therapy. So for example, we're part of a tocilizumab withdrawal study in giant cell arteritis to try to understand, again, do people do better with abrupt stopping? Should we be tapering their dose slowly over time? And again, these are things, you know, that we use real world data sets, use our anecdotal experience to kind of inform in our shared decision-making, like Anisha mentioned. But having really tangible, concrete, you know, high quality evidence that you can discuss with a patient is always going to be, you know, the most powerful, I think, for everybody. Anisha Dua, MD, MPH: Yeah. I think it's kind of exciting also even just thinking about borrowing from other fields. So oncology, we're also looking at, like, T-cell engagers, right? And then, we're looking at, you know, borrowing from our allergy and immunology colleagues. Like, there's so much cool stuff happening. For example, in EGPA, we borrowed all of our stuff from them. And it works, you know? And so, it's, like, really exciting. There's right now a study looking at tepamokimab in EGPA, two shots a year potentially to control EGPA. I mean, that's incredible. So, we're just in a space that I don't think at least in terms of vasculitis, that we've been in ever before. And so, it's very exciting. It takes a long time for trials to enroll, conclude, get through the FDA, come to market. You know, so it's not like anything happens immediately, but I think we are on a sort of precipice where a lot will be just continuing to come through, you know, for the next, hopefully, many years. Eric Ruderman, MD (Moderator): We've covered a lot of ground. I wanted to give you both a chance to sort of give us some final thoughts, and I'll start with you, Dr. Jaros. And I think you've talked a lot about it, but what makes you the most hopeful? And more importantly, for the rheumatologists who are looking at this, um, listening to this, what do you want them to take away about the future of vasculitis care? Brian Jaros, MD: Yeah, yeah. Good questions. Well, I think in terms of most hopeful, I mean, like, as I mentioned before, you know, we just got back from the vasculitis symposium international symposium they put on for vasculitis patients, really. And it really is inspiring to see, like, such a profound community of not just vasculitis, you know, healthcare professionals, but also patients. I do really think we're in an era where we're gaining a lot of awareness for the disease state, and I think that's really important in terms of, again, delays in diagnosis, in terms of patients not feeling isolated and feeling like, you know, there's a community out there. There's other people who are dealing with this who they can talk to, learn from, you know, share their experience with. And I would say, you know, leaving that conference, that to me was, is kind of like embodies hope, right? These patients, these practitioners coming together and saying, like, "We're continuing to make these marked strides together in the treatment of this disease." And I think kind of touching on that for other rheumatology providers, as Anisha was kind of mentioning, the updates in rheumatology and vasculitis are rapid. And so, there is a lot happening. There's a lot to keep up with. And that's where I think, you know, like, the role of the vasculitis center really comes in is, you know, it's a lot for any one person to keep up with all of this data and all of rheumatology, let alone in one disease state. And so to know for patients, it's always an option to have them, you know, get an opinion, see us. You know, these are complicated, rare diseases. And so, I think, yeah, asking for that kind of, like, extra set of eyes is always, you know, a good option for these folks. Eric Ruderman, MD (Moderator): Dr. Dua is the director of the center. I'm going to give you the last word. And I would say, you know, you've been involved in this area since before all of these treatments existed really. And you're dating me. Well, no, I mean, but it's not that dated because it's so recent. And I guess, my question for you is, you know, what are your thoughts on what you've seen over the last 10 years, and where are we going next, and what should other rheumatologists think about that? Anisha Dua, MD, MPH: I mean, it's incredible. That's why I keep saying, you know, the advancements and the pace of change and not just the pace, I mean, the precision with which things have changed is really incredible, and we've learned so much. And what gives me the most hope is Brian, right? So like that's what makes me optimistic. There are young, bright, amazing minds getting into this area. And I think with these developments, we've been able to attract some of the most bright people to buy into really researching and caring about this disease and taking care of patients who are the best patients. No offense to any other patients. But you know, they have so much grit. They're such a great community. And honestly, the vasculitis community nationally, internationally is just so collaborative. And I think that is why we've made so much advancements to date. I think there's a bright future sitting across from me, honestly. I'm really excited to be in this space. And yeah, it has changed. It's crazy how many more options. It's amazing to be able to sit across from somebody, you know, who I maybe managed like 10 years ago. And I gave them their options and we, you know, went through their process, and now they come in and they're either doing well, or if they have a relapse, now I'm like, "Hey, actually, we can do so many more things." And they're like, "What?" So, it's incredible to sort of live that change, which I'm sure you've experienced with your patients, too. Eric Ruderman, MD (Moderator): Yeah, I've seen that. You know, and what's been always fascinating to me over the years that I've been doing this is that when you have a treatment, research explodes. You know, as soon as you have something that actually works, then you get more and more work trying to figure out how do you best use that, how do you find the next best thing. And all the sudden, and I think we've really sort of crossed that line in vasculitis in the last 10 years that we, in many ways, did in rheumatoid arthritis when the biologics first came out. And it's just so exciting to see, you know, where we've come from and where we're going to go. Anisha Dua, MD, MPH: I absolutely agree. My hope is just that we start looking at some of the other more understudy disease states. I think we have exploded in some areas or niches in vasculitis. And there are some that we're still sort of using the same stuff I used when I trained in fellowship. And so, I'm hoping we can get more information there. Eric Ruderman, MD (Moderator): Terrific. Well, I want to thank everybody for joining us. I want to thank both of you for joining me here today for this discussion, Dr. Jaros, Dr. Dua, who lead our Northwestern Vasculitis Center. Appreciate your time. And to all those who've listened, we've appreciated you joining us, and I look forward to working with you and your patients down the road. Brian Jaros, MD: Thanks for having us. Anisha Dua, MD, MPH: Thank you. Thanks for moderating. Melanie Cole, MS (Host): Thank you all so much for such a lively discussion. And to refer your patient, or for more information, please visit our website at breakthroughsforphysicians.nm.org/rheumatology to get connected with one of our providers. That concludes this episode of Better Edge, a Northwestern Medicine podcast for physicians. I'm Melanie Cole.