Good morning, everyone. Thanks for being here so early, and this session is about advanced sarcoidosis, so beyond steroids. So what do you do in patients who are end-stage sarcoid, who are advanced level? So we're going to get started. In the interest of time, since the previous session was running a little behind, I introduced Manny Ribeiro. He is director of the Sarcoid Center at Cleveland Clinic, and he will get us started on the advanced options and clinical trials and timing of the escalation. Thank you, Dr. Ali, for the invite. Good morning, everybody. Let's get started. And, yeah, Manny Ribeiro from Cleveland. I'm the disclosure, a local PI, and so buying two of the studies that I'll discuss today. And I guess this is an important slide, so use your QR code there and take a look at more details on the lecture. But those are the objectives. So we'll talk about fourth-line agents today, some of those fourth-line agents as I listed there, and then, of course, some current and future trials. And starting with a question, just to warm up, so take a look at your devices ready. Use the QR code there. So the 2021 ERS guidelines strongly recommend the following medication as a fourth-line agent in pulmonary sarcoidosis, tofacitinib, rituximab, RCI, or repository corticotropin injection, or none of the above. We have 12 votes so far. I'll give you a few seconds. I see maybe 85 people in the room. We'll see if we can get at least to 50, I guess. Okay. Almost there. There we go. Nice. 50 votes. 50 votes. So let's see. And, okay, so that was a tricky question because they actually list all of those medications as possibilities. They actually mentioned those are medications that the task force members use as a fourth-line, but they do not have enough data to make a recommendation or a strong or conditional recommendation. So sorry about this tricky question, but it was just to make this point that the data is not great. But we have to review the data anyways because we certainly have patients that need those fourth-line agents. So we'll take a look at those. And first one that I want to mention, tofacitinib, a JAK inhibitor. This is a landmark case report that was published a few years ago, as you know. And you can see in the pictures and in the green bar that the patient was on and off tofacitinib, and that was not, like, on purpose. The insurance was approving and denying the medication, approving and denying. So she was on and off, and they could see, based on the pictures and the score for the cutaneous sarcoidosis, that the response would fit with the timing of the medication. So this is, again, a landmark case report. But since then, we've had more case series and cohort studies showing the good use of tofacitinib as a fourth-line agent in other manifestations of sarcoid. So definitely a good recommendation, good indication, I think. Second one that I wanted to mention, rituximab. We have some case series in refractory pulmonary, cardiac, and ocular. I'll just show you two of those. So this is the case series on pulmonary sarcoid, including 10 patients. And you could see that, you know, three to five patients had some good response on FVC, six-minute walk distance to rituximab. So again, I think a viable option as a fourth line for pulmonary sarcoid. And this is for cardiac, a more recent series, showing that in six patients, the SUV max decreased with rituximab being used for cardiac sarcoidosis. Again, I think a fourth-line option would be reasonable here. Cyclophosphamide, I think, very important fourth line, especially for neurosarcoidosis. As you can see in this case series, 32 patients with neurosarcoidosis. Most of them were symptomatic at baseline. After six months of cyclophosphamide, 43% only were symptomatic. CSF cell count decreased. Most importantly, the imaging brain and spinal cord MRI improved in a good number of patients. Improvement in 11%, improvement in 30%, stability in 57. This is the one patient that I have on cyclophosphamide was refractory, including two TNF blockers, a really bad case of cervical spinal cord, neurosarcoid, extremely symptomatic. And we were able to improve his symptoms significantly, improve the MRI a little bit with the cyclophosphamide for six months, and then put him back at the limumab, and he's doing well now in this regimen. RCI, as we mentioned, some important case series as well. This one included patients with lung, CNS, eye, skin, liver, and calcium. And I think the importance of this figure is to show that out of those 42 patients, 47 patients maybe that they included, only 29 were able to use the RCI for a good amount of time, at least three months I see there, based on the side effects and costs and some other issues. But out of those patients, 11 improved, and more than 50% of those patients had a good steroid sparing effect. So that's a good point here to make about the RCI. This is a nice RCT. We rarely have RCTs in sarcoidosis, so any time that we do, I think it's nice to show. This is a small RCT, as usual in our field. But comparing the two doses of RCI, 40 versus 80 units subcu twice a week, and the message here is the patients using the lower dose, 40, did as good as patients using 80, so I think that's a good option with less side effects. IVIG, I wanted to show this, because I do think it's kind of like an advanced option, but just for small fiber neuropathy, we use that quite often in our center, mainly because my colleagues published this a few years ago, showing that 62 patients that were on IVIG for small fiber neuropathy, 76% of them improved on symptoms. Again, just a cohort study, retrospective, the outcome was very subjective, was improving based on the physician's assessment, so a lot of issues, but I think it's maybe the best available evidence that we have to guide us there, and we see patients getting better on IVIG. Moving on to trials, and this, I think it's the main one I wanted to show you. This is an active trial recruiting right now for patients with pulmonary sarcoidosis, and the reason I think it's the main one is it's testing this efsofetimod, which is a completely new pathway in sarcoidosis, looking at neuropilin-2 inhibitor, and again, I was learning as I was reading about this study a year ago before we joined, but this picture, I think you guys know well, this is just the formation of the granulomas and continuation of the granulomas in sarcoidosis patients, but the point is, if you look at all of those yellow receptors, you'll see that this neuropilin-2 receptor is in a lot of important cells, you know, microphages, monocytes, and the belief is that if you block the neuropilin-2 inhibitor, then you block the recruitment of macrophages, you know, granulomas into the lungs, so we are using this for pulmonary sarcoidosis. There is a phase 2 trial already published in CHESS just this year. As you can see, it was a phase 2 only, but showed some improvement on FEC, so now we have this phase 3 going, and just some key inclusion criteria, pulmonary sarcoid for more than 6 months, they have to be symptomatic with MMRC of at least 1, and they have to be using prednisone for at least 3 months with this dose range that you see there. If you have those patients, there are a lot of centers in this trial, you can check in clinicaltrials.org and refer to one of those centers. Second trial that I want to show you, this is again actively recruiting, the Milumab, this is an anti-GMCSF antibody, and as you can see from this classic picture that I bet all of you saw that already, GMCSF seems to have a key role in deformation of granulomas, so we are trying to block that with this trial. Key inclusion criteria, uncontrolled pulmonary sarcoidosis for more than 6 months, this means patients that are still symptomatic or having side effects to, you know, methotrexate, leflunomide or something. So, uncontrolled pulmonary sarcoid, they have to be a little bit more symptomatic than the afsofetimod trial, so MMRC of at least 2, and they have to have received treatment within the past 2 years. They don't need to be on prednisone, they don't need to be on treatment at the moment, but within the past 2 years, you know, they have to have received something. Now some future trials, those are not open yet as far as I know, but this is the Xtimab antibody, this is a TNF blocker, right? Not exactly the same as infliximab, they argue that there are some important differences, but you know, regardless, I think for us, it's still important to do trials on TNF blockers because even though we use it quite often, it's not FDA approved. So I think if we get more trials coming out, positive results, hopefully the FDA will approve this and then it'll be much, much easier to get those medications approved for our patients. A future trial, this KITE study, targeting this kinetinase one, hopefully I'm pronouncing this right, but it seems to be an important enzyme present in activated macrophages. So this is not open yet, hopefully soon this will be open and many centers across the world will be recruiting for this trial, so just keep an eye for that. Last trial that I wanted to point out, I think this is really cool, this actually, it's a small pilot that was published already by the Cleveland Clinic and OSU group, and 50 patients randomized to nicotine patch versus placebo, and even though it was a small study, just looking for dose and safety, they showed that the difference in FEC was significantly different between the nicotine group and the placebo group, so hopefully pretty soon we'll have a bigger trial recruiting patients for this nicotine trial, again, the follow-up study is not open yet, but hopefully coming up soon. And that's pretty much it, so take-home points, despite the paucity of data, I think it's reasonable to try advanced options in patients with refractory sarcoidosis, we all have those patients, we all need those drugs sometimes, and it's important to offer patients, I think also, the option to enroll in clinical trials, because that's the only way that I think will discover new drugs, get the FDA to approve some of those medications, get those medications to be approved much easier by insurance, and then help our patients. With that, I'll finish, and happy to take maybe some questions at the end, or, yeah, perfect. Thank you. All right, thank you very much, Manny, and you get extra points for staying within your time limit. So next, we introduce Dr. Slobin, she is Director of Pulmonary Hypertension at Inova Fairfax, and also Director of Medical Education, and they manage sarcoid patients, it's a lung transplant center as well, so I'm going to load their presentation, Oksana, let's see how it works. There you go. Great. Good morning. Great to see so many people here on the last day of CHESS, kudos for being here and not being at the beach. All right, so the QR code, just for quick questions, we'll review the pathophysiology of sarcoid-associated pH, I'll talk a little bit about different phenotypes, and very generally discuss approach to treatment, at least a theoretical one. So the first question is, what is the most frequent etiology of sarcoidosis-associated pH? Cast your votes. You guys are going to make me late. Come on, let's go. Chop, chop, chop. There you go. We'll wait until maybe 50. Still coming in. There you go. Okay, okay, all right, all right. Okay, all right, let's see. I think I clicked the point, right? Yeah. Okay, I think maybe I don't need to give a talk, maybe I can just leave at this point. So yes, that is correct, parenchymal lung disease is most frequently associated, or pH is most frequently associated with parenchymal lung disease, and I'll show you that. So the most recent 222 European Society of Cardiology and Respirology guidelines define pulmonary hypertension according to specific site of hemodynamic criteria. With mean pulmonary pressure of 20 millimeters of mercury or more, with a wedge less than 15 for pre-capillary pH, and the PVR cutoff lower than it used to be before, two wood units instead of three wood units. The entity of combined pre- and post-capillary pH is something that was introduced by the last World Symposium on Pulmonary Hypertension, and it is upheld in these guidelines, albeit with a lower PVR threshold. If you can see at the different classes or groups of pulmonary hypertension, sarcoid falls into group 5, and group 5 disease hemodynamically can have pre-capillary, post-capillary, and combined disease, and I'll show you that as well for sarcoid specifically. This is one of the pictures that we published, I think, in some iteration in many articles, but the goal is to summarize really different pathways that can contribute to pathogenesis of sarcoid-associated pH, and you can see that there are, you know, that really is the reason why it still sits in group 5 classification. So vascular-centric, parenchymal, extra-pulmonary involvement and comorbidities of sarcoidosis rarely actually cause pulmonary hypertension, but can contribute or be sort of a contributing mechanism to development of the disease, and then the hylomedicinal is something that happens not very frequently, and I'll show you some examples of that. So if you think about vascular-centric involvement of pulmonary vasculature in sarcoidosis, there is sort of a sarcoid-specific and non-sarcoid-specific, more like a pH-like histopathology that has been described. So granulomatous involvement usually affects all of the vessels, so both are on arterial and venous side, and their granulomas have been described in all of the layers of the vascular wall. So you can have a physiology which is really arteriopathy. You can have not physiology, but histopathology consistent with arterial granulomatous involvement, venous granulomatous involvement, and there are also granulomas in lymphatic tissue. On another hand, lesions which are similar to group 1 pH have also been described in patients with sarcoidosis. When you think about parenchymal involvement in patients who have pulmonary hypertension, the data comes mostly from registries. There are two bigger registries that have been published in the international registry is RESEF and mostly American centers, but there were some Middle Eastern and some European centers. And in that registry of mostly prevalent patients, the forced vital capacity was 62% of predicted as a mean, and most patients had parenchymal disease. French registry, which was a little bit smaller but still relatively large as far as the sarcoid population goes, again, prevalent patients, 72% had stage 4 disease, and a quarter of patients had FVC less than 50%. I don't need to tell you about different scouting stages of sarcoidosis, but you can see that if you look at the parenchymal fibrosis, then the reason that I put the picture there is really to look at the airways. Even in patients who don't have significant, significant lymphadenopathy, the airways and sarcoidosis are affected. If you think about the vasculature that is riding along the airway tree, you can also think that the vasculature, because of all of the lymph nodes that I even mildly enlarged, is probably not completely normal. Now, if you think about the precapillary hemodynamic phenotype of pulmonary hypertension, so this is the resub data that took out all of the patients that had a postcapillary or combined pre- and postcapillary disease, so purely precapillary phenotype of pulmonary hypertension. Again, most patients severely reduced FVC, so in this cohort, it was FVC of 62% of predicted with no obstruction and severely reduced DLCO. If you look there on the right, 6-minute walk distance was very severely reduced, 302 meters, and again, most patients had parenchymal fibrosis. So this is some pictures courtesy of Bob Buffman, so he probably has described the largest number of patients, so he has the largest number of case years of patients who have sort of granulomatous, not granulomatous, but lymph node enlargement that significantly affects the vasculature, but this is one of his patients that nicely demonstrates calcific lymph nodes in the high-low region that really cuts off the right upper lobe bronchi right there. So this is from a recent article published in 2022 by a French group that nicely outlined sort of a workup map of how to try to phenotype these patients according to at least hemodynamic classification. So if you look at their precapillary pH, then CAT scans are very important. You look to see whether there is a concordant parenchymal disease, and if it's yes, most of the time, pH is going to be related to parenchymal lung disease, but you have to remember that, and this is what I try to illustrate, that even in those patients, there may be other reasons that may be contributing to development of pulmonary hypertension, so you have to think about the extrinsic compression of pulmonary vasculature by lymph nodes. You have to consider portal hypertension sometimes, although it has been very, very rarely described. For postcapillary pulmonary hypertension, left-side heart disease usually does not come from sarcoid involvement of the heart. It's very rare that we've seen cardiac sarcoidosis with pulmonary hypertension. Usually diastolic dysfunction comes from obesity, high BMI, obstructive sleep apnea, and so forth, so forth. But this, I think, is a nice map on how you think about phenotyping patients into different categories. Right, with that, the second poll question, what is the first step of the treatment algorithm in sarcoid pH? Treat lung disease, treat sarcoid vasculopathy, treat comorbidities, figure out what phenotype of sap your patient has. This is like a giveaway. Everyone should get that very quickly. Okay, figure out what phenotype of SEP your patient has, okay. All right, let's walk through it a little bit, at least, you know, what I try to do is take together WASOC guidelines, our experience, and some publications, and at least offer a roadmap on how you may consider approaching it. So, again, going back to the phenotypes or hemodynamic phenotypes, pre-capillary combined pH and post-capillary pH. So if you have post-capillary pulmonary hypertension, especially with the echo evidence of diastolic dysfunction, so enlarged left atrium, you know, grade II diastolic dysfunction, LVH, obesity, diabetes, hypertension, sort of your typical sarcoid patient, in a way, management of left-sided heart failure should be number one thing that you want to do. So, right, aldoctone, Jardian, sparsifia, weight loss, and so forth, so forth, evaluations of coronary artery disease. If you have a pre-capillary or combined pre-post-capillary pulmonary hypertension, again, really identifying the cause is the big thing you want to do. So this is where looking at the CAT scan, considering how much of the lymph node involvement the patient has, and again, if you identify the left-sided heart disease, you want to be managing that in the sort of parallel pathway. So if there is a very significant vasculopathy without parenchyma lung disease, I would suggest trying to treat the vasculopathy with sort of a short trial of therapy. If you really don't have parenchyma lung disease of any kind, and you have significant pulmonary hypertension, then a short trial of steroids results in an improvement of pulmonary pressures. That has been described. It's not very frequent, but it does happen. And if you go down that road, I would suggest doing a very short trial of that and reevaluating it in a short order. You do want to, in those situations, consider CTAF. Again, the chronic thrombi in sarcoid have been described, but it's, again, very infrequent. And sarcoid can be a great mimicker of CTAF. So this is where you really have to collaborate with a CTAF center and make sure that you know exactly what you have in front of you, whether it is sarcoid vasculopathy, whether it's a CTAF patient. This is where it can become very complicated, I think. Again, this is something that's seen, I think, very rarely. Now, with extrinsic pulmonary vascular compression, so this is where you really have very significant lymph nodes without a lot of the parenchymal involvement. Some people suggest that, and that's what Bob Buffman does, I think, with his population, is if you can get a pet paid for trying to really figure out how much of the active disease you have. And if you have a lot of active disease, their treatment of that active disease with the re-evaluation of pH is what sort of people sometimes do. And then if you have persistent pulmonary hypertension, stenting, or sometimes BPA has been described in case reports. All right, let's go to the parenchymal lung disease. Parenchymal lung disease with active inflammation, again, I think that conversation of what's active inflammation and sarcoid is a whole different topic. Again, Bob Buffman has described in some of the case series where patients look like they may be fibrotic, but then they have a positive uptake on PET scan and treating those patients with biologics and then actually having improvement in the fibrosis in those patients, which is sort of very differently, different approach than what we have in other fibrotic lung diseases. But a trial of immunosuppression and then re-evaluation. Parenchymal disease with possible inflammation, I think you can sort of manage the patients the same way, but make sure that you are not leaving them without re-evaluation, but let's say with an echo for six months. So again, it's a three-month trial of therapy. And the last population is really who we see most of the time. So that's the box on the left. So stable parenchymal lung disease without active inflammation or with persistent pH. So this is where you want to stratify pH severity. Mild to moderate disease, if there is a clinical trial, we strongly encourage patients to be enrolled in the clinical trials because otherwise we just don't have the data. If there is no clinical trial, this is when you consider pulmonary vasodilator therapy on an end-to-end basis after talking to a patient and really telling them that you have no idea whether you're going to help them or hurt them. With a severe disease, again, consideration of pulmonary vasodilator therapy and referral for lung transplant. Just for people who don't do lung transplant, I would implore you to please consider referral for lung transplantation early because these patients have a lot of comorbidities. The comorbidities take time to fix. Often when we see those patients after years of prednisone, their BMI is above the cutoff for referral or for transplantation. They have, you know, and you sometimes just don't have time to fix their comorbidities to make them a transplant candidate. So refer them early. Let us help them become transplant candidates in the future. So really quickly, for the last couple of minutes, so this is a summary of the trials that have been done with pulmonary vasodilator therapy. You can see that there are various drugs have been tried. Very, very, very small numbers. And most of them describe some kind of positive outcome. You have to remember, again, people usually report positive findings, not negative findings in the literature. So huge bias. Having said that, in our clinical experience, we have seen improvement with pulmonary vasodilator therapy in patients with parenchymal sarcoidosis-induced pulmonary hypertension. The only trial that has been published in the last couple of years is a tiny, tiny, tiny trial of less than 20 patients. I think there were like 18 patients. Yeah, I think 18 patients there that looked at the Rye-Ciguat and the time to clinical worsening compared to placebo and the time to clinical worsening described there on the slide for you. Without going into the table in a lot of details, the patients who were there really had parenchymal lung disease. The authors did not exclude other possibilities of the other phenotypes, but when you look at the characteristics of the cohort, they looked like they had parenchymal sarcoidosis-associated pulmonary hypertension. And these are the results. So over 50% of placebo group met predefined endpoint of clinical worsening, and none of the patients in the Rye-Ciguat group did. Six-minute walk test, an improvement of almost 40 meters in the Rio group. Placebo group, a decline of 55 meters. And lastly, there were no significant adverse effects in the Rio group. No effect on oxygenation, at-rest oxygenation, and there was no effect on FEC. So with that, phenotype the disease, and treatment has to be really individualized. Thank you, Oksana. That was great. And with that, we're going to switch gears a little bit and go to the quality of life, which is key for patient-centric care and a major issue in our sarcoid population. I introduced Dr. Oksana to you. She has worked very hard to set up the center there and the local registry and is very active in the field. So thank you. Hello, and good morning, everybody. It's so good to see so many people here. Thank you for waiting to be with us on the last day of the CHESS conference. I'll be talking to us today about quality of life, and I'll be talking to you about the importance of quality of life, and I'll be talking to you about the importance of quality of life, and I'll be talking to you about the importance of quality of life. Thank you for waiting to be with us on the last day of the CHESS conference. I'll be talking to us today about quality of life determinants in sarcoidosis, the seen and unseen management options. I'm Oji Obi. I'm an associate professor at East Carolina University. These are my disclosures, and none of those disclosures have any influence on the topic I'll be talking about today. At the end of the next 15 minutes, I'm hoping that we'll be able to define health-related quality of life, understand the importance of assessing quality of life in our patients, discuss some of the main determinants of reduced health quality of life in sarcoidosis, and very briefly discuss management of sarcoidosis-associated fatigue. I decided to skip a question and instead present a clinical scenario because quality of life is all about our patients. So this is Mrs. YP. She's a 54-year-old female who has pulmonary and cutaneous sarcoidosis. She's currently managed on 15 milligrams of prednisone every day, and she's been on that for the last four months. She comes to your office today. She complains of persistent cough and shortness of breath. Her skin rash has improved. You note that she has gained 15 pounds since you last saw her, and she admits that she's not able to fit in her clothes. She can't go on a family cruise because she's coughing so much, and she's not able to play with her grandkids because she feels very short of breath. You get a pulmonary function test. It's stable. You get a chest X-ray. It actually looks better. And so you reassure her that things are going well. You continue prednisone at 15 milligrams, and you add methotrexate because she's still symptomatic. You advise her to stop gaining weight, and you ask her to come back in three months, and you throw a little bit of cherry into there and tell her that you'll win her prednisone if she's feeling better in three months. You feel really good about yourself. But the patient feels horrible. She feels horrible because she hasn't told you or you haven't elicited from her the fact that she feels tired all the time. She sleeps very poorly. She's not coping at work. She's run out of sick days. She feels depressed, and she's overwhelmed by her disease. She really doesn't care about her PFT or her chest X-ray. As far as she's concerned, it's all well and good for those tests. It has absolutely nothing to do with the way she feels. You've advised her to stop gaining weight. Well, even she herself has advised herself to stop gaining weight. Her entire family has advised her to stop gaining weight. But you really haven't offered any practical solutions. And as to the prednisone, she hates it. It makes her feel bloated. She's hungry all the time. She's eating nonstop. She's gaining so much weight. She feels and is starting in her own mind to look like a horse. And so even though you have had an excellent clinical visit, as far as this patient is concerned, you haven't in any way, shape, or form addressed anything that is of importance to her. And so that brings us to the topic of health-related quality of life in sarcoidosis. It describes an individual's perception of the impact of their disease, their current health status, and their treatment on the overall quality of life. It's a multidimensional construct that captures the composite impact of symptom burden, disease severity, treatment side effects, and healthcare interactions on a patient's physical, psychological, and social well-being. It can be positively and negatively influenced by many factors, including personal factors, environmental and social factors, and symptom burden. And so a patient's intrinsic, or more importantly, their learned ability to deal with or to cope with their disease will potentially positively impact their quality of life. A patient who has poor social or financial support or who has excessive medication side effects is likely to experience these as negative impacts on their quality of life. I like this diagram very much. It just shows the multidimensionality of quality of life on all aspects of a patient's life. Their family life, their work life, their participation in hobbies and sports, their emotional and psychological well-being, and their ability to care for themselves is all impacted by their disease and their perceived health-related quality of life. And on the flanks there, you actually see some really basic interventions that we as physicians can make to improve or to negatively impact a patient's quality of life. And so why do we care about quality of life in our patients? We care because it is the single outcome that is most highly reflective of our patient's treatment priorities. We also care because the most recently published treatment guidelines have emphasized the two key indications for treating patients with sarcoidosis. One being to improve health-related quality of life and the second being to avoid danger of disease progression or organ failure. By far, most of our patients choose improving health-related quality of life as the reason for treatment. And on the left-hand side is actually a study that was published. It's been a little bit of time now. But it's a survey of about 1,800 patients in Europe, and they were asked to rank about seven different aspects of their care as to what was of highest priority for them. And as you can see, patients ranked quality of life and functionality as most important, topmost priorities for their care. And in their words, it's really not that this test or scans don't mean anything. Of course, scans, tests, and examinations are critical in treatment, but well-being and quality of life determine how much I suffer from my sarcoidosis, and that is the most important thing. So some key facts. Our sarcoidosis patients consistently report a reduced health-related quality of life, and that's patients who have active disease compared to healthy controls. But even asymptomatic patients also report reduced quality of life, and there's actually a study that showed that patients, partners, and families also have reduced quality of life compared to healthy controls. I do want to emphasize that PFTs and chest X-rays do not correlate with health-related quality of life. It's completely independent of race and geoethnicity, so it really doesn't matter where you're practicing or who you're seeing. Sarcoidosis impacts health-related quality of life. It tends to be worse in females compared to males. The major determinants of health-related quality of life, fatigue is number one. It's one of the most common symptoms present in over 90% of our patients. It can persist well after resolution of active disease, and it's present even in the absence of organ manifestations of disease. It's also strongly correlated with some of the other drivers of decreased quality of life in our patients. Some disease-specific determinants, patients who have chronic disease, the longer the duration of disease, patients who have more symptom burden, presence of multi-organ disease, so pulmonary and extra-pulmonary versus pulmonary alone, and presence of chronic cough. So this study looked at patients who have chronic cough in sarcoidosis, and as you can see, the higher the burden of cough, the lower the quality of life. Let's talk a little bit about prednisone, because that's what we feed our patients. Sarcoidosis has a love-hate relationship with prednisone. It is the first-line treatment in our patients who have sarcoidosis, but study after study has shown that treatment with corticosteroids is associated with reduced quality of life, and the higher the prednisone dose, the worse the quality of life. And so at the bottom is a study by Mark Judson. It's a landmark study, remains very relevant, that looked at patients who received a cumulative dose of 500 mg of prednisone in a year. Think about that. The bottle on the left right there is 5 mg, 100 tablets, 0 refills. I can't tell you how many of my patients are running through each of those bottles in 2 to 3 months, but patients who received a cumulative dose of 500 mg of prednisone in the whole year, patients who received higher than that reported reduced quality of life, and patients who received less than that had reported a better quality of life. So prednisone, we should think about our patients being on long-term high-dose prednisone. Other determinants of decreased quality of life include depression, stress, anxiety, and cognitive dysfunction, chronic pain, and small fiber neuropathy. Now, how do we measure quality of life in sarcoidosis? It can be challenging, but it's not impossible. Typically, we use patient-reported outcome measures. These are validated questionnaires that directly report how a patient feels unfiltered. Most are time-consuming and are geared towards research. There are actually several groups. They are generic PROMs, which means they are used in sarcoidosis and other diseases. You also have sarcoid-specific PROMs, like the King's sarcoidosis questionnaire, and you have some symptom-specific PROMs, like the fatigue assessment score that I'll talk about. But we're all very busy clinicians. Quality of life is important to all of our patients. So what are some of the practical ways of assessing quality of life in clinic? First thing is patient-centered communication. Acknowledge that sarcoidosis impacts their quality of life. Actively ask about fatigue, their family and social interactions, medication side effects, coping at work, symptom burden treatment goals. And a multinational task force actually recommends that we assess quality of life using the KXQ, the King's sarcoidosis questionnaire, at least once a year in our patients. It's available free online. It takes less than 10 minutes to complete. And also a fatigue assessment score. Doing that every visit, it takes less than two minutes to complete. And I included links on there that we can access those questionnaires on. Increasingly also, I'm finding that just using a generic visual analog scale in my patients has been very helpful. Just simply saying, how would you rate your quality of life on a scale of zero to ten? It opens up dialogue and helps the patient express themselves. And so let's change gears and talk about improving quality of life. This is an overview of interventions to improve quality of life The most important thing in our patients is to ensure that their disease is well controlled and adequately managed. A lot of our patients have symptoms, they are real and it's not in their heads. The second thing is to adopt non-disease modifying pharmacological treatment, as well as to also address other potential causes. So one of the things I always talk to my fellows and residents about is, not every complaint in a sarcoidosis patient is due to their sarcoidosis and should be treated with prednisone. Explore other potential causes and where a patient has been adequately treated, consider symptom palliation for things like depression, cough and address chronic pain. Disease education is key. Set goals, empower your patients to manage their disease, incorporate social support, patient assistance programs or peer support groups, multidisciplinary collaboration, and that's just not other physicians, incorporate physical therapy, occupational therapy, nutrition, direct your patient to the resources that will be useful to them, oxygen supplementations for patients who have fibrotic lung disease, and lastly physical and psychological interventions. And so increasingly we're starting to find that exercise and pulmonary rehab improves quality of life in our patients, and so these are two studies. One is a prospective multi-center study that included about 300 patients, and the second is a small but nonetheless randomized study that randomized patients with fatigue to exercise therapy or to usual care, and in both studies patients who received active treatment had improvement in their six-minute walk distance, their dyspnea scores, their fatigue, anxiety, and depression, their quality of life, and for the randomized trial functional capacity and muscle strength. We're also finding that mindfulness training is also helpful to improve quality of life in our patients. These are two studies. One is the first study by Dr. Sarkatoos, fairly small study, 26 participants, that looked like a single 45-minute workshop on mindfulness training followed by 15 minutes of focusing on just body sensation and breathing techniques, and at the end of the intervention the participants had all reported improved physical and psychological symptoms, well-being, and motivation. The second is actually a fairly what I would consider large randomized trial that was recently published this year in Lancet that looked at about a hundred sarcoid patients with fatigue, randomized to about 12 weeks of an online mindfulness based cognitive therapy for fatigue, and at the end of the 12 week the patients reported improved fatigue, anxiety, depression, mindfulness, and health status. I'm going to finish us out with managing sarcoidosis-associated fatigue, not to talk about the fact that fatigue is multidimensional or that it is a disability that it's not visible or that we assess it using the fatigue assessment score, but more really to focus on how we manage this patient because it really is one of the biggest drivers of decreased quality of life in our patients. So first is to actively assess fatigue, give them a fatigue assessment score every visit, and ask is your patient's sarcoidosis well controlled? If the answer is no, then you need to optimize their therapy. If the answer is yes, then look for other potential causes of fatigue, sleep disordered breathing, other co-existing diseases like diabetes, hypothyroidism, are they on too much prednisone? If you've addressed all of these and your patient is still feeling fatigued, the most recently published guidelines actually recommend that patients who have persistent troublesome fatigue be enrolled in pulmonary rehab or an exercise training for 6 to 12 weeks, and if they have persistent fatigue after that, to consider neurostimulants such as amodafinil or d-methylphenidate. And so I'll end here. Take-home message. Sarcoidosis negatively impacts quality of life in our patients. Improving quality of life is number one priority for our sarcoidosis patients. Fatigue and symptom burden, and I should also add medication side effects, are the major drivers for reduced quality of life in our patients. PFT and imaging, as much as we as physicians rely on those, do not correlate with health-related quality of life, and patient-centered communication, shared decision-making, and attention to both pharmacological and non-pharmacological interventions are crucial to improving quality of life in our patients. Thank you all so much. All right, thanks a lot, Ogi. I can't overemphasize the value of Ogi's recommendations, but once you are fed your patient's prednisone, there's really limited options of what you can do once you go through the trials and once you go through your methotrexate and the TNF inhibitors. So that's where you want to think about additional interventions, where the patient, looking at a long-term outcome, would think about transplant. So here is your usual QR code. These are the learning points, and we're going to talk about indications and timing of transplant, some special considerations and outcomes. No disclosures. So we've come a long way in sarcoidosis. Many of you recognize this. The first Hutchison's patient, Mrs. Mortimer, and then the second one is Amy Warren. She's one of the most famous sarcoid patients who was undiagnosed for about 40 years, in spite of having uveitis that actually made her blind. Sausage fingers, lupus perneo, and now we're talking about lung transplants. So we've come a long way, but it took us time. So once we talk about the lung transplant, the question is what's the scope of the problem? How many patients develop respiratory failure and need transplant? So I've listed some studies here, and so about three to eight percent of pulmonary sarcoidosis patients end up with respiratory failure and needing lung transplant evaluation. I can't say transplant. So what are, can you identify these three to eight percent patients and kind of in and find out what are the highest features so we can think about these things early? So one of this Mayo Clinic cohort looked at chronic respiratory insufficiency defined as a DLCO of less than 40 percent, FECO of less than 50 percent, and they found that the predictor of CRI in this in this cohort was the stage of pulmonary sarcoidosis, as you can see with the high hazard ratios for the outcomes. And again, the 10-year event rate in this also was between that three to eight percent, which is about four percent in this one. Now that there have been multiple studies, including Bob Bauchman's study, Steve Nathan's study, that looked at other factors, and this has been reproduced multiple times that African-Americans have a high risk for death with sarcoid. Supplemental oxygen use, pulmonary hypertension, as well as more than 20 percent fibrosis on SCT is predictor of outcomes. As you can see those two curves on the side with pulmonary hypertension and pulmonary fibrosis more than 20 percent, the curves separate quite early. So looking at, unfortunately there are no recommendations, there are no guidelines or consensus statements for referral to lung transplant for sarcoidosis. We do have guidelines that, this is a 2021 consensus statement by ICHLT, that looked at ILD patients, obstructive lung disease, cystic fibrosis, and pulmonary hypertension. So some of it is extrapolation for ILD. So any patient with pulmonary fibrosis with FEC of less than 80 percent, or DLCO of less than 40 percent, or any progression over the last two years with a decline of more than 10 percent in your FPC and 15 percent in DLCO, any supplemental oxygen requirement, and any radiological progression over the last two years should be considered for referral to a transplant center. And like Oksana was talking about, this should be done early because of all the comorbidities that we have. And stemming from these indications, we have some listing indications too. I'm not going to go into detail, this is just a rapid progression. So instead of two years, you see progression within six months, and complications like hospitalization, pneumothorax, recurrent acute flare-ups, hemoptysis, all of those would be indications to refer them early to a transplant center. Extrapolating from the data, again, you will see that this is a recurrent theme in sarcoidosis. High pulmonary pressures, high oxygen use, race, as well as female sex, are predictors of poor waitlist outcomes in sarcoidosis. So this theme with pulmonary hypertension will come in again and again, both pre- and post-transplant. So you will see that some of my studies have dates at the top. The reason for that is in lung transplant world, we used to, we changed from a time-based allocation in 2005 to LAS, which was the equity-based and severity-based allocation. So prior to that, a lot of the diseases had poor outcomes, including sarcoidosis. After that, because of when we are considering severity, that those outcomes improved somewhat. But you can still see sarcoidosis really doesn't have a place in the grouping of LAS. So it's grouped in two places. It's grouped with COPD in a group A and ILD in group D, based on pulmonary pressures. If your pressures are low, you get lumped with COPD. If your pressures are high, you get lumped with IPF. So this study was interesting. It's looking at the OPTN database and you can see that it showed 94% higher chance of dying on the wait list when compared to COPD for those group A patients. So we have a long ways to go in the transplant world of where exactly sarcoidosis fits in that grouping, once we list them. Now once you send them to a transplant center, we do look at certain things that optimize the patient outcome. They have comorbidities. There could be renal involvement, there's cardiac sarcoidosis, neuroinvolvement, chronic infections in their cavities like mycobacteria. Then there are surgical considerations, including the mediastinal calcifications and fibrosis that you see, as well as bronchiectasis and the pleural adhesions. I'm going to talk a little bit about a couple of these in the interest of time because I want to keep a few minutes for questions. So pulmonary hypertension, again, as you look at these curves, it is an independent determinant of early complications. So if you see this graph, as you see the pulmonary pressure is going up, you will also see the adjusted probability of grade 3 PGD, which is the primary graft dysfunction, increase with time. And the same thing in the other graph. So pulmonary hypertension is a risk factor for early poorer outcomes for sarcoid. Going to myasotoma, all of you have seen this image in your patients. You can see myasotoma in that apex there. So during surgery, it makes explantation difficult. The dissection is difficult because of pleural adhesions. The pleura is adhering to the chest wall and there's a lot of bleeding. The other issue is that with this myasotoma, you can have pleural contamination, leading to pleural aspergillus or whatever, you know, the fungus is in there. And also hemothorax. So these patients have to go back to the OR after surgery many times for hemothorax because of these adhesions there. The prolonged dissection also increases the ischemic time because, you know, there's more time that the lung is out of the body. So that also increases the graft dysfunction. At Duke, we did a study way back that showed that the one-year survival was 55% for those with myasotoma compared to about 77%. Now for disclaimer, this is a pre-LAS study, again, and also the treatment of the myasotomas was different at that time. So we haven't reproduced the data post-LAS. Now there's a poll question for you. We're gonna rush through this. So which statement is true regarding outcomes of lung transplantation in sarcoidosis? Now that you've sent your patient to us, sarcoidosis has a significantly lower median five-year survival. They have similar long-term outcomes post-transplant, and early complications patients with TAH are similar to non-sarcoid and none of the above. I don't think we want to wait till 50, so make it fast. All right, well, it's evenly split, but we didn't give you guys enough time. So let me show you some data. So this is a pre-LAS data, and pre-LAS, like we said, they had a higher mortality on the wait list. But this patient, again, the demographics are interesting. It's always the same demographics, 70% African American, more females, and younger group of patients. So the outcomes, univariate analysis showed that they have a poor outcome early on at one year, but once you account for the confounders, there was no difference than non-sarcoid lung transplant patients. So basically the outcomes were the same. And this is a similar group with IPF, and you can see that their survival and chronic rejection, which is the broncholitis obliterans, is very similar. There are two recent studies. These are post-LAS study. This is a US data. It's an OPTN database, about 690 patients. And again, the incidence was 3% of patients were sarcoid. And these are only sarcoid patients. So median survival was similar to non-sarcoid patients, and it was not, and this is a long-term survival as well. And this is, and they divided this both between pre and post-LAS era. And you can see these closely hugging curves here. There's a European study that came out recently, and they looked at their patient population, and they saw that early survival was a little bit worse with the fibrotic phenotype, as well as age, that older patients and pulmonary hypertension again. But if you look at the median survival, it's very interesting. Their median survival in this group was 9.7 years, which is way higher than the US OPTN survival, which is closer to like six years. So interestingly, sarcoid patients in their population did better long-term, in spite of having an early harder time. So the complications, again, we've talked about primary gap dysfunction, hemothorax. We're not going to go details into this. And PGD risk, again, pulmonary hypertension is a higher risk, longer ischemic time. And one of the things, hemothorax, I wanted to kind of highlight this again. It's about a quarter of our patients with sarcoidosis that we transplant have to be kind of taken back because of bleeding, because of these adhesions. And that's one of the factors that accounts for that early, early poorer outcome. Now there are some diseases, unfortunately, that recur after transplant. And sarcoidosis, if you look, is at the top of them. And so there's your poll question number two. Oh, sorry. Okay, go ahead. Which statement is true for recurrence of granulomas in lung allograft after sarcoid? No recurrence, 10 to 50 percent, 5 percent or less after five years. And granuloma typically leads to progressive lung disease. All right, my cutoff is 35. All right, so 10% to 50% recurrence. That is actually correct. So recurrence of granulomas. It's been seen all the way from 10% to even 70%, so even up to two-thirds in certain series. So on an average, you can see that half of the patients, 25% to 50%, will develop granulomas. And if you look at the age range, typically it happens within two years. But interestingly, there have been granulomas that we see in biopsies as early as six weeks. I just had a patient last week that we biopsied six months after transplant, and they have granulomas. And these are patients on steroids and immune suppression. So that tells you something about the pathogenesis. So there are actually a couple of studies that looked at the recurrence of granulomas, and what is the correlation? So interestingly, the presence of granulomas on explanted lungs was the strongest predictor of happening again. So this may mean that there was active disease at the time of transplant, so that recurred earlier. But we don't know. I mean, this is just conjecture. But the good news is that these granulomas do not progress to lung disease for most of our cases. And we've followed these patients up to five, six years, and there is no fibrosis and no related sarcoid complications. We actually presented our data for explants on Monday, and 20% of our patients did not have granulomas on explants. And 17% actually had an alternate diagnosis. So that gives you that perspective of that granuloma and what we call granuloma being a diagnosis of exclusion. And all of what we see may not typically be sarcoid. So another issue is that, well, not an issue, but it has improved over time. So we've seen over the last decade less recurrence of granulomas, and that may be because immune suppression has changed somewhat. We're using tacrolimus more than cyclosporine. And in the kidney world, the mTOR inhibitors. So there's a recent paper as well, two series that I've shown here, that showed people on mTORs like sirolimus, they had smaller amount of recurrence of granulomas than even people on CNIs, cyclosporine or tacrolimus. So that brings up an interesting point, and I was talking to my dermatologist. They've been using mTORs more for skin sarcoid. Another question that comes up is bilateral versus single. So universally we usually do bilateral transplants for sarcoidosis because of these patients being younger, these patients having infection issues, and a lot of early complications, which they need more reserve. So 90% of the cohort will get bilateral lung transplants. Now the last slide is about multisystem transplants. As you know, sarcoid is a multisystem disease, and heart transplant, renal transplant, as well as liver transplants have had similar outcomes to non-sarcoid diseases. But in cases with the multisystem involvement, we do consider multi-organ transplants, but this population is super highly selective, and you have to be careful. These patients need to be really worked up in a multidisciplinary fashion, free from other comorbidities. BMI has to have a strict kind of strict limits. It's a multidisciplinary discussion, no other organ involvement. For example, if we do heart and lung, sarcoid is one of the causes of heart-lung transplants in the U.S., about 5% in the sarcoid population. So take-home points, 3% to 8% of your pulmonary sarcoid patients develop respiratory failure. Early referral for high-risk patients, and referral for any pulmonary hypertension, increasing oxygen needs, DLCO less than 40%, fibrotic phenotypes, rapid progression, any complications which would include more than three, that's what I use, but more than three flare-ups or prednisone bumps within a year, hemoptysis, myositomas, and multisystem sarcoids. Because these patients need a lot of time to optimize them. So the earlier they come to us, the better chance of them being a transplant candidate, which is key in the longer-term outcomes for your patients. And post-transplant survival for sarcoid patients is comparable to non-sarcoids, so we should not have any issues with that, and that's a common misconception. So I think that's it. ♪

advanced sarcoidosis

Tofacitinib

Rituximab

Cyclophosphamide

neurosarcoidosis

repository corticotropin injection

quality of life

fatigue assessment

lung transplantation

optimizing disease control