บทถอดความฉบับเต็มของ Recognizing and Managing Multisystem Lupus: Clinical Insights Across Specialties

for psoriasis or seborrheic dermatitis or eczema. There are common mimickers that are more common that patients are potentially getting misdiagnosed with, and that's why that cutaneous lupus diagnosis is not getting diagnosed early on. And I think in addition to that, I think a lot of patients don't know just how common skin findings are in lupus. And so, they may not even be attributing that to their lupus. So, I think those are some of the main reasons why the diagnosis gets kind of pushed back for patients. Irene Blanco, MD (Moderator): And I think you highlight something really important. So, you know, you'll oftentimes think of the rheumatologist as a little bit of the captain of the team in terms of a lupus patient. But oftentimes we really need to bring our subspecialty and multi-specialty colleagues into the fold because, you know, sometimes—and we've definitely seen this—where we get a kidney biopsy and we think it's going to be lupus nephritis and it's actually a different diagnosis. It's FSGS or a thin basement membrane. I'm actually thinking of two specific patients. You know, many times I've messaged you where the common patients of, you know, this person has a brand-new rash, it doesn't look like anything typical for one of our conditions. What do you think this may be? And, you know, the rheumatologist will reach our limits, and because this can involve every organ system, having those specialists on board is critical. And, you know, we're sitting here with both of you and it's wonderful. But, you know, we all know that we also work with neurologists, definitely cardiologists to really bring in that comprehensive care. You know, Dr. Vakharia, in thinking about how we bring in our other disciplines into care, oftentimes actually there are patients with cutaneous lupus that don't have systemic manifestations or don't yet have systemic manifestations. Paras Vakharia, MD: Correct. Irene Blanco, MD (Moderator): So, what are the things that make you start to think that a patient may be having systemic manifestations and actually doing the opposite? You know, where it's not so much rheum sending to derm, but derm actually sending to rheumatology. Paras Vakharia, MD: Yeah, that's a great point. You highlight it very well. So, patients can have cutaneous lupus only. They can have systemic lupus and cutaneous lupus. They can have systemic lupus without cutaneous lupus. So in that situation where patients have cutaneous lupus, what we tell and what's recommended in dermatology is every year we do screening for patients, and that includes blood work. So, we're checking, ANA, we're checking double-stranded DNA, we're checking complements, urine. And these are things that we should be doing every year in addition to a good review of systems. And those, if any of those come back positive, if review of systems comes back that they're experiencing more joint pain, fatigue, photosensitivity, ulcers in the mouth, those are things that prompt us that we need to kind of start roping in our rheumatology colleagues possibly. But in addition to that specifically, there can be cutaneous signs that can indicate that a patient might be progressing or at very high risk of progressing to systemic lupus. So, patients who do have a very photosensitive rash, if they have more generalized skin disease, so if it's not just localized to the scalp or the ears, let's say, but if it's over a larger part of their body surface area, that's a sign. We also know that patients of who are skin of color are at higher risk of developing systemic lupus if they have cutaneous lupus only. Other specific features, so if patients are presenting with blisters, or if they're presenting specifically with what we classically call the butterfly rash or acute cutaneous lupus. Those are other cutaneous signs that those patients might be at really high risk of progressing to systemic lupus. Irene Blanco, MD (Moderator): Great. Yeah. Thank you so much. So, you know, to piggyback off of that, and I think we can talk about this, you think about potentially one—I don't know if you hear this. I know I hear this a lot from patients. It's like, "Well, what kind of lupus do I have?" I'm like, "You have a little bit of everything." Oftentimes, right, if the patients are seeing me, they have a little bit of everything," and I think it's how do you prioritize the disease manifestations in terms of treatment management. You know, we could want to prioritize skin. We could want to prioritize the kidneys. And obviously, both very critical end organs. But thinking about, you know, how do we work together. And I think, you know, Yoni, if you can tell us a little bit about the Lupus Nephritis Clinic that you run with Dr. Mary Mahieu, because I think that gives just such a critical example of how bringing us all together really leads to great outcomes. Yoni Peleg, MD: No, of course. So, every other week, I have a clinic with Dr. Mahieu in the rheumatology clinic where we'll see patients together with lupus and lupus nephritis. And I think patients very much enjoy that clinic because they're seeing both of their specialists at once, and we're actively talking about the plan to target their systemic lupus and their nephritis. And sometimes during a visit it may be their systemic lupus is more active, and I might take a backseat to Dr. Mahieu. And then, sometimes it might be that they're having more active nephritic or nephrotic activity, or perhaps they've had lupus for a while and they have accruing chronic kidney disease, and we spend a lot of time in the visit talking about the management of chronic kidney disease, talking about perhaps dialysis considerations and transplant considerations in the future. I think one of the great things about working at Northwestern is that we aren't siloed as subspecialists as maybe in some other areas, but it's really easy to hop on the phone, hop on Epic, send an email to our colleagues that we can really

do multidisciplinary care in real time. And I think patients very much appreciate that. Irene Blanco, MD (Moderator): I think we've all been—like the three of us have definitely been on Epic threads, email threads saying— Yoni Peleg, MD: More than once, yeah. Irene Blanco, MD (Moderator): Yeah, exactly. Saying, you know, "This is what's going on with patient X. You know, I'd love to use this medicine for this, but I think it won't work because they also have this manifestation going on. What do you think? What do you think we should do? What should we add? What should we take away?" And I think that as we develop new treatments for lupus, because it's actually an incredibly exciting time. We went decades having really very few options for patients. And now, it seems like we're going to have— Yoni Peleg, MD: And those options were toxic, right? Irene Blanco, MD (Moderator): Exactly. Yoni Peleg, MD: We used a lot more steroids. We used cyclophosphamide. And, you know, from a kidney perspective, they weren't that great. And they were quite toxic. And I think it's a really exciting time for lupus, all the newer therapies and trials that you have going on here as well. Irene Blanco, MD (Moderator): Exactly. So, I think it's going to be incredibly interesting to see how we further sub-categorize our patients and really take a personalized approach to treatment, especially when if it's predominantly skin manifestations, predominantly renal, neuro, cardiac, ophtho, you name it, to really tailor treatments for our patients. So, that being said, you know, Dr. Vakharia, can you give us a case where potentially this multidisciplinary care has helped to either adjust or think about the treatment plan in a different way, like the outcome of that multi-specialty, you know, Epic thread? Paras Vakharia, MD: Absolutely. Absolutely. And like you said, I think it's important also for, you know, our patients and, you know, we talk to them, and I tell them, "Yeah, I'm going to chat with Dr. Blanco, and we'll come up with a plan." And, you know, for patients to know that we're communicating so often about them, that this is really—you know, it's a privilege for us as well to be able to work in an environment like this, like you mentioned. But you are correct. There are various situations where I've communicated with, you know, you guys and other providers, and we've kind of tweaked the plan. We've kind of prioritized what might be important. And so, you know, for example, there are patients who have different manifestations, skin, kidneys, internal as well, and joint pain as well, which I've learned is a very problematic issue for patients. And I've learned that some medications maybe work a little bit better for, you know, joint pain or skin and sometimes certain medications like mycophenolate might really be desired for the kidneys. And so, for example, when, you know, for the couple patients I'm thinking about specifically, we do try to prioritize, you know, what

is very important to the patient, you know, and kidney function as well. And so, sometimes, for example, with dermatology, we can be very aggressive then with topical treatment. And we have a lot of really good topicals that we use for cutaneous lupus, a lot that are coming out as well. That's some of the research that we've done as well. And so, in that way, we can sometimes change the approach we initially had. So instead of thinking, "Oh, you know, just for the skin, I might have wanted to start anifrolumab or Saphnelo." Instead, you know, we can kind of work with our colleagues and figure out a good plan to still treat the skin and work with everyone else. Irene Blanco, MD (Moderator): So, I love the fact that you're highlighting all the new things coming out. So, I'll start with you, Dr. Peleg. What are you excited about potentially the new developments in lupus and lupus nephritis? Like, what do you see coming down the pike that really excites you in the terms of treatment for these patients? Yoni Peleg, MD: Yeah. I mean, I'm not that old. But I remember in training, I mean, we learned about the ALMS trial, which my mentor was actually a big PI on. And that was sort of the trying moving away from cyclophosphamide, but it still was a lot of steroids, was the issue. And, you know, we're treating a young patient population where steroid adverse effects are very concerning, not only in terms of, you know, cardiac morbidity from it, diabetes morbidity from it, but also just, like, quality of life. People don't feel good on steroids, and it causes a lot of issues. So, the thing I think has been really exciting in the glomerular disease field, you know, over the last decade is finding these other therapies that are steroid-sparing. And over my pretty short career post-fellowship, there's already been three FDA-approved medications for lupus nephritis. There's been Benlysta, voclosporin, and obinutuzumab. And I think all these therapies are quite exciting for lupus nephritis because even though, you know, if you look at the ALMS trials and the cyclophosphamide trials early on, I mean, we're still talking about half of patients not having a remission. And remission was a pretty loose term back then, because remission was just proteinuria less than 1 or 1.5. I mean, now we're looking for deeper complete remissions. And with the obinutuzumab trial, for example, that complete remission somewhere in the 40% range, which is just phenomenal. And just as importantly, we're getting patients off of steroids. So, the fact that we have these therapies that are more targeted, and also able to get off of these less targeted, more toxic therapies, I think it's a really exciting time to treat lupus patients and really give them the best possible kidney outcome and best possible overall outcome. Irene Blanco, MD (Moderator): Great. Dr. Vakharia? Paras Vakharia, MD: Yeah, I agree completely. what I tell people is this is the golden era for dermatology and when it

comes to rheumatic disease and specifically cutaneous lupus. You know, we talked about anaphrolumab. And anaphrolumab has been, you know, wonder drug when it comes to the skin and cutaneous lupus. It's currently finishing up its phase III trials. There are other medications that are currently in phase III and ongoing trials, some of which we're doing including litifilimab, daxdilimab, enpatoran, some of which are injectable, some of which are pill medications as well. And. You know, historically, like you mentioned, a lot of our medications were these same medications that we're talking about that we were using for the skin. And you know, prior to medical school, my background, I was a pharmacist before. And so, one of the big things that I really wanted to focus on was working on developing new treatments and, you know, being a clinical trialist to find some of those steroid-sparing medications. The benchmark for what we consider improvements in cutaneous lupus in clinical trials has now increased in terms of what we consider a positive response. So, we're seeing improvements in these trials that we haven't really seen before. And so, it's a very exciting time, not just with systemics, but topicals as well. So, like I said, this is a very exciting future for dermatology and cutaneous lupus and lupus overall. Irene Blanco, MD (Moderator): Yeah. We're incredibly privileged to be able to be a part of so many clinical trials here to really give our patients access to cutting-edge research and namely, you know, for our very severe patients, in addition to all of the monoclonal antibodies, as well as the new small molecules in pill form that are becoming available. But also we are a center for major CAR T cell therapy for lupus that so far has shown to be incredibly promising for those patients that have had very, very severe manifestations. The patients that we've enrolled here at Northwestern have just been incredibly sick from their lupus, have really been refractory to all treatments, and so far have been doing very, very well and very comparable to the national and international data that we see for the hopeful, you know, approval for CAR T in lupus, and to really think about how we might be able to give that to our patients because, you know, unfortunately we do have patients that fail the mycophenolate plus benlysta plus obinutuzumab, that fail the mycophenolate plus, you know, Saphnelo plus everything else that we throw on top of their treatment regimen. So to really think about how we use these cell-based therapies, you know. And I wonder as we move forward in terms of technology, et cetera, like, what the algorithms I think are going to be, you know? When do we start what, right? Like, I think for a very long time, to your point, we had very few meds and they were incredibly toxic. And so, we were always on the seesaw of toxicity and efficacy. And so, we would wait and we'd delay, and we'd depend too much on steroids. And so, you know, do we move to an era that we're—and hopefully we are—that we're very aggressive in the beginning, right? Really providing a very strong lupus regimen from the get-go as opposed to just waiting for the next manifestation, because we could always pull back, right? If we're chasing the inflammation, like I like to say, like not only has the horse left the barn, the barn and the farm are on fire, right? So if we're chasing that inflammation, we ultimately risk damage, right? Yoni Peleg, MD: Yeah. Yeah. I mean, that's a great point. I mean, to talk about that from the kidney side of things, I think we actually are transitioning to being more aggressive earlier on. I think the ACR guidelines and EULAR guidelines, KDIGO is a little bit more equivocal, but talk about doing triple therapy upfront. And by that, we mean typically a mycophenolate steroid plus something else, whether that be the novel CNI voclosporin, whether that be the anti-BAF Benlysta or belimumab, or that be—I think it's actually after the guidelines, but the anti-CD20, the new anti-CD20 obinutuzumab. And I think actually that makes a lot of sense because, you know, the ideal is to treat the inflammation before it leads to scarring. Because once a kidney's already scarred down, we have therapies that sort of slow the rate of scarring, but we don't have therapies that necessarily reverse the scarring. So, you know, if you imagine you're on a train and the train's taking you to advanced kidney disease, you want to halt the train or slow down the train earlier on as opposed to later on. So by offering these therapies that are less toxic early on, we're able to do that. Paras Vakharia, MD: Yeah. And you bring up a great point. You know, more aggressive doesn't necessarily mean—you know, not to look in that as a negative light, these newer treatments are very safe as well. Yoni Peleg, MD: Exactly. Exactly. Paras Vakharia, MD: So, they're more effective and safe. And so, we use the word aggressive, but it's all still very, you know, safe, and we're thinking about that for the patients. I think that's a great point. Irene Blanco, MD (Moderator): And I think, you know, especially in kind of bringing it all back to our patients, right, you know, the cutaneous manifestations of lupus can be really so severe and so scarring. And unfortunately, I think that—and I will say rheumatology may have been a bit complicit in this—we're dismissed, right? It's cosmetic. Paras Vakharia, MD: Sure. Yeah. Irene Blanco, MD (Moderator): You know, why does it bother you? Like, you can always wear makeup. But we live in a society globally that, you know, perceives people in certain ways, and people want to look and feel good. There's a multi-billion dollar, you know, industry in maintaining your hair, right? So when you're having severe alopecia from your lupus, when you're having scarring across, you know, the face, the chest, the back, the arms, right? How you're perceived when you then walk into a room, you

know, the fact that now we can have medicines like Saphnelo that's already approved, but the ones that are coming down the line that have really, in phase II and early phase III data, look so incredibly promising. Like, I'm so excited for the TL7, TL8. Paras Vakharia, MD: Yeah, absolutely. Yeah. Irene Blanco, MD (Moderator): Enpatoran. Paras Vakharia, MD: Enpatoran. We're doing that clinical trial here. Yeah. Irene Blanco, MD (Moderator): I'm so excited for that medication, because I think it's really been a switch for some patients. Paras Vakharia, MD: Yeah. Irene Blanco, MD (Moderator): So the fact that, you know, we could potentially clear up their skin, regrow hair, give them their sense of self-esteem back is incredibly important. Paras Vakharia, MD: Yeah. Yeah. You're absolutely correct. lupus and a lot of skin conditions are very, you know, visual. The skin is what we see, as you mentioned. And I don't think a lot of times, you know, just your average person realizes the quality of life impairments and how that really can affect a patient who has lupus. You know, I tell some patients that having lupus is like a full-time job, whether it's, you know, the fatigue, all the work you have to do to go to your appointments, your infusions, let alone to think about the mental health aspect of having lupus as a burden to patients. There's a lot that goes into it. You're correct. So being able to provide patients that, hey, you know, visually and for the skin, for these issues, which can be scarring and permanently scarring and permanent hair loss, that, you know, we can really treat that more aggressively, but safely as well. Irene Blanco, MD (Moderator): Great. Paras Vakharia, MD: Yeah. Irene Blanco, MD (Moderator): So, what's one thing you wish every doctor taking care of patients with lupus understood maybe a little bit better as we wrap up our discussion today? Yoni Peleg, MD: I guess firstly check the urine. Irene Blanco, MD (Moderator): Number one, number two, number three. Yoni Peleg, MD: Number one, number two, number three, check the urine. Don't be fooled by a normal creatinine. Now, remember, a creatinine of 1 for an otherwise young healthy woman may not be normal. So, really have a low threshold to refer early on so that we can start treatment if indicated sooner on to really preserve kidney function so the kidneys live as long. As I always like to tell my patients, like my goal is for my kidneys to outlive you. So, like, give us the best chance to do thatv by referring patients early. I think that's a big thing I'd like to encourage primary providers to do, is to check the urine and refer early. Irene Blanco, MD (Moderator): Great. Thank you. Paras Vakharia, MD: Yeah, I agree. I think, you know, the things we've talked about, but I think as mentioned, we're in this era of having better treatments now for lupus and cutaneous lupus as well. So, you know, for the average physician who's seeing a patient with lupus and they're seeing skin manifestations, you know, number one, you know, it could be lupus. It you know, could be another condition, but don't rule out that it's not part of their lupus. But two, also have in mind that, "Hey, we have these newer treatments now. Let me reach out to my dermatology friend. Let me text them. Let me shoot them an email. Reach out to one of us. You know, we're always happy to see patients. And, you know, we have ongoing trials as well." But, you know, reach out to your colleague about, "Hey, what might be the best option? What might be the best route to go for this patient?" Irene Blanco, MD (Moderator): Yeah. And I think the same, you know, when particularly lupus disproportionately affects women, right? So, that baseline, there's just, in general, a lot of issues that young women have faced in terms of getting care because a lot of things get blamed on fibromyalgia or blamed on chronic pain, depression, anxiety. And when you feel horrible, when, you know, you're getting a horrible rash in the sun, when you really feel unwell because your kidneys are starting to not work, you know, yeah, you're going to be depressed, you're going to be tired, you're going to be fatigued. And I think it's the really listening to patients, referring early, reaching out to us, because potentially we can get them a sooner appointment, we can get them seen, and we can work with our colleagues, both in the community and here broadly across, you know, our NM community to really take care of these patients. Because again, it's only the three of us in this room right now, but we are a large collective of really excellent physicians and caregivers that can really provide tremendous care for our lupus patients in the greater Chicagoland area. Paras Vakharia, MD: Couldn't agree more. Yoni Peleg, MD: Yeah. Yeah. Absolutely. Irene Blanco, MD (Moderator): So wonderful. Thank you so much for joining me today. Paras Vakharia, MD: Thanks again for having us. Thanks, everyone, for tuning in. Irene Blanco, MD (Moderator): Thanks for being here. Yoni Peleg, MD: Yeah. Melanie Cole, MS (Host): Thank you all so much for such an enlightening discussion. Thank you again for joining us. 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.