Good afternoon, everybody. Thank you for staying around for the last session of CHEST, several sessions happening at this time. I'm really pleased to have the chance to introduce the three speakers and me that are going to be speaking. As you know, if you deal with sarcoidosis, to really take care of the patients well, it's great to be familiar with extra-pulmonary disease. You truly have to be an internist. And so I'm very happy that we're going through these topics today. We'll have some questions after the talks and some questions at the end. So if we run out of time, please stick around and the speakers will stay around to answer questions. The first speaker from East Carolina University is Dr. Obi, who will be talking about cardiac sarcoidosis. Good afternoon, everybody, and thank you so much, Dan, for having me do this. You're all welcome to our session this afternoon. I'll be talking to us today about cardiac sarcoidosis, the beat not to be missed. I am Dr. Obi, pulmonologist by training and coming to you from East Carolina University in Greenville, North Carolina. I hope at the end of the talk today to have addressed the clinical presentation, diagnosis, and medical management of cardiac sarcoidosis and will give us a bird's eye view of what the pulmonologist's role should be in cardiac sarcoidosis. So the true incidence and prevalence of cardiac sarcoidosis is somewhat unknown, but it's been shown to vary by gender, geography, race, and ethnicity. Clinically manifest disease occurs in about 2% to 5% of sarcoidosis patients in the U.S., but maybe as high as 25% in Japan. Overall, autopsy studies suggest much higher prevalence rates, up to 25% in the U.S. and Europe, and up to 80% in Japan. Cardiac sarcoidosis occurs more commonly in males, more commonly in African-Americans, with the highest incidence worldwide in Japanese. And we care about cardiac sarcoidosis because it's one of the leading causes of death in patients with sarcoidosis, accounting for up to 27% of deaths in the U.S., and maybe as high as 80% in Japan. CS usually occurs as part of a multi-organ disease, but may, depending on the series you're looking at, occur in isolation in up to 50% of patients. It usually presents in one of three major ways, with conduction system abnormalities affecting both the atrioventricular and the hispokinesia system, the most common presentation being with advanced AV block. It may also present with arrhythmias, both ventricular and supraventricular arrhythmias, most commonly with ventricular tachycardia, and may present with heart failure. Cardiological effusion is extremely rare. Now sudden cardiac death is also a common presentation in patients with cardiac sarcoidosis, and may be the initial presentation in up to 10 to 20% of patients. The extent of left ventricular dysfunction is the most important prognostic indicator. As with all of sarcoidosis, cardiac sarcoidosis is characterized by the presence of non-caseating granulomas in cardiac tissue, and no part of the heart is immune from sarcoid granuloma infiltration, but most commonly involved is the myocardium. Granuloma infiltration in the myocardium is usually patchy, and affects mostly the sub-epicardial and the mid-wall regions of the myocardium. In terms of myocardial parts affected, the left ventricular free wall, including the papillary muscles, and the basal interventricular septum are most commonly involved. The right ventricle and the atria are less commonly involved. It's important to remember that morbidity and mortality in cardiac sarcoidosis remains high, even when granulomas have been replaced by scar tissue and fibrosis. Now the granuloma burden, the presence and the extent of scar, as well as the location of the granulomas on scar, have significant implications for both the clinical presentation, the radiographic appearance, as well as diagnosis. For instance, the patchy and sub-epicardial involvement account for the poor yield from endomyocardial biopsy. Predominant involvement of the basal septal interventricular septum accounts for higher presentation with AV blocks, and both the patchy nature of involvement, as well as the mid-myocardial involvement, account for the imaging features of disease. Now there are three major imaging modalities used to investigate patients who have cardiac sarcoidosis. Cardiac MRI has emerged as one of the most commonly used advanced imaging modality, and presence of patchy, multifocal, mid-myocardial hyper-enhancement, mostly in the basal interventricular septum and the left ventricular free wall on late gadolinium-enhanced cardiac MRI imaging is characteristic of cardiac sarcoidosis. Now it's important to understand that presence of late gadolinium enhancement is not able to differentiate between scar and active myocardial inflammation. The presence, as well as the extent, of late gadolinium enhancement has prognostic implications. Now a cardiac PET scan has also become increasingly used in the diagnosis of cardiac sarcoidosis, and the principle behind it is active FDG uptake by active inflammatory cells, and presence of focal or focal undiffused myocardial uptake on cardiac PET scan is consistent with active inflammation, especially if it's involving the basal interventricular septum and the left ventricular free wall. Combining FDG uptake with basal perfusion scan improves your sensitivity and specificity and can help differentiate between scar and active disease. Both the presence of FDG uptake, as well as perfusion defect, has been associated with increased risk of death and ventricular tachycardia. Now a detailed preparation, including a prolonged fast associated with a low-carb diet, is important to suppress physiologic glucose uptake and avoid having false positive scans. Echocardiography is the most commonly available imaging modality in patients who have cardiac sarcoidosis, and presence of multifocal areas of increased echogenicity or thinning in non-coronary distribution is characteristic of CS. Presence of basal interventricular septal thinning, about 10 millimeters below the aortic annulus, has been shown in some studies to be 100% specific for cardiac sarcoidosis. The diagnosis of cardiac sarcoidosis is both an art and a science, and there have been three published diagnostic guidelines for CS. The Heart Rhythm Society guideline correlates with the WASO guidelines, and we'll be discussing that today. The Japanese Circulation Society guidelines is more recent and is unique, because you can make a diagnosis of CS without any pathologic diagnosis, and for the first time, it also identifies patients or provides criteria for making a diagnosis of isolated cardiac sarcoidosis. Based on the HRS expert consensus statement, there are two pathways for making a diagnosis of cardiac sarcoidosis. The first pathway involves presence of histologic diagnosis from endomyocardial biopsy, providing other causes of non-caseating granulomas have been excluded, and the second pathway is a clinical diagnosis based on presence of established non-caseating granulomas in non-cardiac tissue associated with presence of any one of the following, either steroid-responsive cardiomyopathy, unexplained EF less than 40% or sustained ventricular tachycardia, a second or third degree AV block or abnormal PET scan, cardiac MRI, or gallium scans, all in the absence of any other potential etiology. The JCS guidelines also has two pathways, but I like to think of it as three pathways. The first pathway we're all familiar with, presence of non-caseating granulomas in endomyocardial tissue. The second pathway involves non-caseating granulomas in non-cardiac tissue associated with at least two major or two minor criteria as listed. The third pathway involves clinical findings consistent with pulmonary or ocular sarcoidosis and at least two labs or two common features that are seen in sarcoidosis patients, including a chest X-ray with bilateral hyaline lymphadenopathy, high serum ACE or lysozyme levels, a positive gallium 67 or FDG PET scan or BAL lymphocytosis with a CD4, CD8 ratio greater than 3.5. And this should be in the clinical context of having cardiac sarcoidosis. It also establishes a pathway for making a diagnosis of isolated cardiac sarcoid in patients who have no clinical evidence of sarcoidosis in any non-cardiac organ, who have a negative chest CT scan, and who have no evidence of uptake in any extra cardiac tissues on a PET scan or on a gallium scan. It also follows two pathways, either presence of non-caseating granulomas in endomyocardial tissue or an abnormal PET scan associated with either a high-degree AV block, basal thinning of interventricular septum, depressed LVEF, or an abnormal cardiac MRI. Treatment of sarcoidosis involves two concurrent therapies, corticosteroids and immune-suppressive therapy addressing the active ongoing inflammation and management of direct consequences of disease, including the heart failure, arrhythmias, conduction abnormalities, and use of devices as indicated. We'll be talking about use of immune-suppressive therapy. According to the most recently published ERS clinical practice guidelines, the clear indication for treating patients who have cardiac sarcoidosis with steroids or immune-suppressive therapy is presence of functional cardiac abnormalities. That includes heart blocks, dysrhythmias, or cardiac myopathies. The guidelines don't address what should be done in patients who have clinically silent disease. However, several centers have individualized therapy based on abnormal findings either on cardiac MRI or cardiac PET scan. Nonetheless, a stepwise treatment approach has been proposed, beginning with steroids given with or without other immune-suppressive therapy, including methotrexate, azathioprine, leflunomidas, or mycophenolate. And for patients who are refractory to steroids alone, definitely adding the second line immune suppressive therapy, and for patients who are refractory to both steroids as well as the second line immune-suppressive therapy, use of anti-TNF agents, including infliximab and adalimumab, have been endorsed. Now a few caveats about treatment. In treating patients with CS, more is not always better for prednisone. There's really no specific guidance on initial doses of prednisone to use, but the study by Yazaki and his colleagues showed that there was really no difference in survival in patients who received an initial therapy with high-dose prednisone versus those who received low-dose prednisone. And so most centers actually endorse using lower doses of prednisone, maximum of 30 to 40 milligrams a day, with rapid taper to about 10 milligrams over the next one to three months. It's also important to start treatment early. Early initiation of therapy has been shown to preserve left ventricular ejection fraction, and you can see that for patients who therapy was started with preserved ejection fraction, the EF remained normal, whereas it never really normalized for patients who had low ejection fraction. It's also been associated with improved survival and higher resolution of high-grade AV block versus those who have complete heart block. In general, heart blocks respond best to immune-suppressive therapy, ventricular tachycardia not as responsive. There's been a few studies suggesting that there's a small risk of paradoxical worsening of ventricular arrhythmias after steroids, but in the one study, it was in patients who were not on antiarrhythmic therapy. For patients who need devices, start steroids as soon as device implantation has been completed. More studies suggest that patients with cardiac sarcoidosis require prolonged, almost indefinite therapy. This study by Nagai and his colleagues showed that patients who discontinued therapy had overall lower survival and more likelihood of disease recurrence, and for those who had an initial improvement in the ejection fraction, after they stopped therapy, EF decreased. So if treatment is stopped, it's important that patients be monitored closely. Now, early initiation of steroids is recommended, first because early initiation of immune-suppressive therapy is recommended, and that's because most patients with CS are going to need prolonged therapy. There's also data suggesting that concomitant initiation of steroids and other immune-suppressive therapy has been associated with lower rates of relapse and a higher likelihood of stable LVEF. There's an ongoing study evaluating this treatment approach. Now, a quick word on device therapy in patients with CS. Patients with conduction abnormality should be treated with permanent pacemaker placement according to the established guidelines. That's a class one indication. For patients who have transient improvement in their blocks, pacemaker implantation may be useful. ICD implantation is recommended in patients with cardiac sarcoidosis and spontaneous ventricular tachycardia, or VFIB, and those who have an ejection fraction less than 35%, and may be useful in those who already have a permanent placemaker, or for whom a permanent placemaker is indicated, or for those who have unexplained syncope or near syncope. The pulmonologist and cardiac sarcoidosis. Up to 50% of patients with pulmonary sarcoidosis will have cardiac involvement, and in about a quarter of those patients, they will have clinically silent disease. And so patients with cardiac sarcoidosis may actually be presenting more to the pulmonologist than other non-cardiac specialists. So the pulmonologist should be able to recognize cardiac sarcoidosis, initiate therapy to make a confident diagnosis, and be comfortable managing the steroids and immune suppressive therapy in patients with CS. According to the recently published guidelines surrounding the diagnosis and detection of sarcoidosis, asymptomatic patients should be screened with clinical signs and symptoms and a baseline EKG, and so you're asking your patients at baseline as well as follow-up about presence of palpitations, chest pain, syncope, near syncope, dyspnea out of proportion to lung disease, and you're looking at the baseline EKG, looking for any evidence of sustained or non-sustained ventricular tachycardia, second or third degree AV block, or any bundle branch block. Now routine screening with more advanced imaging is not recommended, however, patients who are symptomatic or who have abnormal baseline EKGs should proceed with more advanced screening. And so to conclude my part, cardiac sarcoidosis is associated with increased morbidity and mortality in patients with sarcoidosis. Diagnosis can be made histopathologically or clinically if patient is unable to get an endomyocardial biopsy or if the endomyocardial biopsy is negative. Steroids and immune suppressive therapy are beneficial in the management of cardiac sarcoidosis, and the pulmonologist needs to be able to recognize early signs and symptoms of cardiac sarcoidosis, make a diagnosis, and feel comfortable managing the therapy. Thank you. Thank you. We'll save questions for the end. Thank you for that excellent presentation. Next is Dr. Sullivan Jacob from Houston, from Baylor. He'll be talking about cutaneous sarcoidosis. Please, Dr. Jacob. Hello all, my name is Sulvin Jacob, I am one of the chief fellows at UT Houston. Today I will be going over cutaneous sarcoidosis, its detection and management. I'd like to thank Dr. Colvin and Dr. Mira Avanano for this opportunity. I have nothing to disclose. For my objectives for today, I would like to identify the different cutaneous manifestations of sarcoidosis, discuss differentials and diagnosis, and discuss existing and upcoming forms of treatment. Now with cutaneous sarcoidosis, after the lung, it's the second most affected organ. It's often initial presentation of systemic disease and women, especially African American women, have a higher rate of cutaneous sarcoidosis. The skin manifestations can be very broad. It's known as the great imitator because it can mimic so many other diseases. Certain morphologies, which I'm going to go through, are associated with the worst prognosis. And certain morphologies can actually be a clue to internal organ involvement as well. The pathophysiology of sarcoidosis is a talk in itself. The exact mechanism is unknown. It's a complex interplay of genetics, environment, infectious pathogens, and the immune system. What we do know is that it's a Th1 predominant response involving interferon gamma and tumor necrosis factor. Today I'd like to go over the common presentations of sarcoidosis. The uncommon, the rare, and the nonspecific lesions. Starting with macules and papules, a macule and papule is anything that's less than one centimeter. A papule is raised while a macule is flat. It can vary depending on color. It's usually on the face, the eyelids, and the nasolabial folds. Here as you can see in the screen right here, this is an example of a erythematous macule. On the right here, we have a concentrated set of papules on a patient's elbow. It can be disseminated or concentrated, as I had mentioned. Here we have a patient with maculopapular lesions all over the face and on the extremities as well. Macules and papules are often an indicator of an acute presentation of the disease, not a chronic one. And these lesions usually will resolve without scarring. A plaque is a palpable lesion that's greater than one centimeter in diameter. A plaque can be elevated or depressed. It can be flat-topped or rounded. It's less often associated with an acute presentation of the disease and rather a chronic course predictor. Here we have different examples of a plaque. Here we have an erythematous indurated plaque. An annular plaque is anything that has heaped up borders with central clearing. A psoriaform is a form of plaque as well. It looks just like a lesion in psoriasis, a plaque with a silvery scale. Here we have more examples of an annular indurated plaque. Plaques can present on the skin, I'm sorry, on the back as well as the face. Compared to macules and papules, plaques may leave dispigmentation and scarring. Lupus perneo was first described in 1891, perneo meaning wolf-like. It's described as a chronic, labretto-violacious indurated plaque. It can occur on the ears, the nose, and the face. It is predictive of sinus and oropharynx involvement. And lupus perneo is more so associated with pulmonary fibrosis as compared to bone cysts and uveitis. Lupus perneo also portends a prolonged, chronic, and treatment-resistant course. Here we have different examples of a plaque, of a lupus perneo on the face, on the nose, and as well as a pedunculated nodule protruding from the dorsum. And in this patient, there was severe nasal destruction. Subcutaneous nodules in sarcoidosis, also known as dearerusy syndrome, affects the deep dermis and subcutaneous tissue. It looks just like a lipoma. It's non-tender, freely mobile. It's in more women than men, and it can affect the extremities. It can be found in early or late in the disease course and usually associated with non-severe forms of systemic disease. Scar or tattoo, this can actually be one of the more presenting systems of sarcoidosis. Sarcoidosis on the skin has a predilection for trauma. Trauma via tattoos, injections, cosmetic fillers. The presentation can be very broad. Here we have a plaque-like form, and here we have nodularity within the tattoo. And this is an infiltration of an old scar after the pigment had resolved. And here we have more nodularity that's presenting onto the lesion. Some uncommon forms of cutaneous sarcoidosis, one is ulcerative. This is more so found in darker-skinned individuals. You have atrophy around the lesion, and this has a predilection for sites of trauma. Ulcerative cutaneous manifestations of sarcoidosis are usually found in African-Americans and Japanese people. Ichthyos form is anything that's described as erythematous. Not necessarily a silvery scale, but more fish-like. But there's no plaque. This is more diffuse. Interleukoid lesions are nodules or plaques with telangiectasias within them. Hyperkeratotic lesions differ from the psorias form lesions in that it appears more wart-like than a plaque. And it has much more heaped-up borders as compared to the psorias form lesions. Some of the rare manifestations of cutaneous sarcoidosis are mucosal. Alopecia can actually occur as well, both scarring and non-scarring. The presentations in the nails can vary in many ways. Hypopigmentation can occur, and it's more apparent in darker-skinned individuals. Now the more nonspecific lesions, the very famous erythema nodosum, it's only associated with 10% to 22% of sarcoidosis. This is more an acute presentation of the disease. And when it's involved with polyarthrologists and high-level lymphadenopathy, it's a syndrome called Lofgren syndrome. Usually these patients have a better prognosis in that they have an acute form with prompt resolution. Calcinosis cutus is whenever you have calcification involving the soft tissues. And Sweet's syndrome consists of neutrophilic dermatosis and digital clubbing with a neutrophil infiltration of the dermis. Next I would like to go over the diagnosis and the differentials of cutaneous sarcoidosis. It's very important that we get a clinical, a detailed clinical history. We need to go over medications, exposures, family history. One of the clues that you can use in a physical examination is a diascopy in which you put a test, a microscopic slide on the lesion in question. If it's blanchable and it reveals an apple jelly or yellow-brown discoloration, it is suggestive of cutaneous sarcoidosis. It is neither specific nor sensitive. And on the gold standard, it's going to be a biopsy. The biopsy is going to show non-CACID in granulomas within the dermis. Usually the pathologist would use polarized light to reveal a foreign body, which forms a zonitis for the granulomas. The differential for cutaneous sarcoidosis is very broad, from bacterial, fungal, vasculitides, drug-induced. It can be sarcoid-like lesions due to other diseases, or it could be affected by medications the patients are taking. Lastly, I would like to discuss existing and upcoming forms of management. Now the treatment of cutaneous sarcoidosis, it's a decision you have to make with the patient. If the patient has minimal symptoms, good organ function, low risk of disease, inactive disease, or higher likelihood of remission, observation is favored for cutaneous sarcoidosis. But if it's extensive and has organ function impairment, then treatment is favored. The European Restorative Society did give us a stepwise approach for this treatment of skin sarcoidosis. As I mentioned, the first thing we have to do is assess the need for treatment. If there is a need for treatment, depending on the lesion, we start with topical glucocorticoids. Next we use steroids. Steroids have been used for cutaneous sarcoidosis since 1948, and it has been well studied. It's cheap and readily accessible, however, with a multitude of side effects. Hydroxychloroquine and chloroquine, which are anti-malarial medications, have been used for cutaneous sarcoidosis in some case series. Hydroxychloroquine is much more tolerated and less potent than chloroquine, with less side effects. Next we use our steroid-sparing cytotoxic agents, such as methotrexate, which has been well studied in placebo-controlled trials, for the cutaneous sarcoidosis. With continued disease or relapse, then we turn to our TNF-alpha tumor necrosis antagonists, infliximab and adalumumab. Infliximab has been very well studied for the use of sarcoidosis and cutaneous sarcoidosis to be more specific. Adalumumab is a human chimeric murine TNF antagonist, and adalumumab is a fully monoclonal humanized antibody. Adalumumab is newer onto the field. There was one study in which they used 16 patients, a randomized double-blind placebo-controlled trial, which showed that there was some improvement of the lesions within 12 weeks. Adalumumab agents such as apremilast and tofacitinib can be used, but the data is sparse. On a case-by-case basis, our dermatology colleagues have been using photodynamic therapy for the treatment of lupus perineum, and here is an example with good resolution. I also want to mention, going back, infliximab can be used as first-line therapy for lupus perineum, and that has been well studied as well. Monitoring treatment is done by using the Sarcoidosis Activity and Severity Index, prior photographs, the King's Sarcoidosis Questionnaire, and the Sarcoidosis Assessment Tool. The SASI, or the Sarcoidosis Activity and Severity Index, is beneficial in that you can actually use desquamation as an index, and prior photographs are always helpful. In conclusion, cutaneous sarcoidosis is a very difficult diagnosis. It's very important to identify the different cutaneous manifestations. For diagnosis, the gold standard is going to be histopathology, and treatment, we went over it. It's sparse, but it definitely needs a little bit more research. Thank you so much for your time. I think we have time for a couple questions, if anybody has a question about cutaneous disease. Otherwise, we'll have some questions at the end. Okay, we'll save them for the end. Thank you very much. Thank you so much. Next, we have Dr. Parjot Sen from University of Kentucky to talk about calcium metabolism, which is something that I wrestle with personally a lot, so I'm interested to hear this. No pressure, as they say. Hi, I'm PJ, coming from Lexington, representing University of Kentucky. For those who know me, they know that I love to talk about sarcoidosis, but it gets even more exciting when I'm at a place like CHEST, and as a part of such an amazing panel. These are some of the things that I hope to review in today's talk. But let's start off with a case. We had a 52-year-old female who was in stage renal disease already on hemodialysis, has a medical history of multiple kidney stones, who had a CAT scan for whatever reason, and it was found to be abnormal. There were a lot of small centrilobular nodules with peribronchovascular distribution. There was some hyalolymphadenopathy, some of them calcified, so ended up getting referred to the lung doctor's clinic. But prior to the visit to the lung doctor's clinic, the primary care physician found that she had mildly elevated calcium levels. So the primary care physician did a thorough workup and found that there was low parathyroid hormone levels, parathyroid hormone-related protein levels, and an elevated 125-hydroxyvitamin D level. When the patient came to our clinic, we did as much noninvasive workup as we could, including a quantifier on gold and a fungal serology, which were negative, and renal function for this patient was normal. So we're dealing with hypercalcemia associated with sarcoidosis. Hypercalcemia and sarcoidosis tends to happen due to high levels of 125-hydroxyvitamin D. And this is because monocytes and macrophages tend to produce the 1-alpha-hydroxylase enzyme, which converts the 25-hydroxy into 125. This happens under normal situations as well, but the levels are not super high because there's a feedback regulation. But in sarcoidosis and other granulomatous diseases, this feedback mechanism is lost as a result of which there are really high levels of activity of 1-alpha-hydroxylase enzyme, and hence active vitamin D, which leads to hypercalcemia. The challenge with hypercalcemia and sarcoidosis is that it could happen at any point of time in the disease. So the patient may present with pulmonary sarcoidosis or other organ involvement, and a year or two later, start showing signs of hypercalcemia. And if you're not keeping an eye out, you may not detect it unless they start manifesting symptoms or end up with end-organ renal failure. However, what's more important to keep in mind is that hypercalcemia may be variable in incidence, but hypercalceria ends up being almost three times more prevalent. And a lot of people who are seeing patients with hypercalcemia may be more familiar with hypercalcemia and be checking for that, but not necessarily checking urine calcium levels to look for hypercalceria. And the challenge with hypercalceria is that a lot of these patients could be asymptomatic. Some of them may have recurrent kidney stones, but for some of these patients, they may not have any symptoms, but have progressively worsening renal function and eventually develop nephrocalcinosis, leading to chronic kidney disease and end-stage renal disease. The management of hypercalcemia and hypercalceria, like several other forms of sarcoids, revolves around steroids. With starting steroids, the serum response is fairly quick. In almost three to five days, you may normalize serum calcium levels. Urine tends to take a little longer, between seven to ten days, but the advantage is that we could go for a fairly quick taper, and a lot of times they do not need prolonged treatment. However, with monitoring of calcium levels, if it turns out that we cannot taper the dose of steroid or they're being refractory, hydroxychloroquine is a fairly acceptable alternative. One thing I would love to stress on here is that a lot of times when these patients are found to have low levels of 25-hydroxyvitamin D, they get started on supplemental vitamin D. This should be avoided because it could worsen the hypercalcemia, and then if possible, if it is refractory hypercalcemia, maybe we should also focus on not having calcium-rich diets. But how do we diagnose hypercalcemia in a patient who is not symptomatic? In my practice, I tend to, in their first visit, whether there's a new diagnosis or not, tend to screen with a serum ionized calcium level, as well as a urine calcium level. It may be difficult to get urine calcium level at each visit, but at least I tend to monitor serum calcium level at frequent intervals. Moving on to our next case. So this was a 73-year-old female with no past medical history who'd hit her arm. She was having continued pain for two weeks, so the first test she got was an MRI of the arm. That ended up revealing lytic lesions of the humerus. 73-year-old female, lytic lesion in the bone. The obvious first thought was this is cancer. So the physician did a thorough workup, got a breast mammogram, got a colonoscopy, got a pap smear. Everything was negative. She also ended up getting a CT of her chest, which is shown here, which showed lymphadenopathy and sort of a nodular infiltrative disease. At this point of time, the patient was referred to the lung clinic, and she ended up getting an E-bus with TBNA and transbronchial biopsies, which both showed non-caseating granulomas. I see this patient, and I have a hard time convincing myself still that this is not cancer. So I go ahead and order a PET scan, and this is the PET scan. She had extensive hypermetabolic lesions in her skull and throughout her spine, as well as in her hip bones. Once again, if you show me this PET scan nine out of 10 times, I would be worried about metastatic cancer. So we went ahead and ordered a bone biopsy, which also ended up revealing non-caseating granulomas. Osseous sarcoid by itself is fairly rare and often an incidental discovery because most of the time, they could be asymptomatic. And a lot of times, they end up having concomitant lung disease as well. But when it does present, it could happen in the small bones of the hand or the long bones like humerus and femur, and they could be lytic in nature, thus rising a confusion about possibility of metastatic cancer. If it does present in the spine, it could sometimes be sclerotic. So if it's a male, you're probably then worried about prostate cancer also, metastasizing to the spine. So one has to be really wary before making a diagnosis of osseous sarcoid, and often, it's really hard to make a diagnosis without a biopsy in these situations. On the other hand, sarcoid arthropathy is much more common, and most of the time, it does present as acute arthritis. One's been already discussed here, which is Lofgren syndrome, where you have bilateral ankle involvement most of the time. And these could be the first manifestations of sarcoid in these patients. The good thing is that they are fairly self-remitting and often need symptomatic management. Chronic sarcoid, on the other hand, is much, much less common and often present with concomitant pulmonary or cutaneous disease. But last but not the least, you could also have involvement of tendons and ligaments leading to tenosynovitis, which is more common in Achilles tendons or small tendons of the hand. You could have swelling, which is not truly arthralgia or arthritis, but just tenosynovitis. But even in these situations, symptomatic management works. Arthropathy, if it's acute, if it's minimally symptomatic, topical treatment. If it is more symptomatic, maybe treatment with NSAIDs would be helpful. In those rare situations when there's no response to these symptomatic managements, one could consider treating with other medications like steroids or immunosuppressants. With Osseous sarcoid, as we discussed, they're fairly asymptomatic and self-limiting. And by itself, without other organ involvement, do not warrant treatment. What we do not know, though, like metastatic disease to the bone, what would be the fracture risks over long-term associated with pure Osseous sarcoid. But with that, one has to keep in mind that if the treatment does involve steroid, you could run into trouble with osteopenia and osteoporosis, which by itself, again, is gonna increase the risk of fracture. So summarizing, hypercalcemia and sarcoidosis could be asymptomatic most of the time and has to be screened for and with a high degree of suspicion. Hypercalceria is much more common than hypercalcemia and it's something to actively look out for as well. Skeletal sarcoid, though, is rarer. When it does present, is a big mimicker for metastatic cancer to the bone. And last but not the least, arthropathy is most often managed symptomatically and does not need systemic therapy. That brings me to the end of the presentation. Please rate our session. Thank you. Must be a huge file. There it is. OK, I'm going to wrap up by talking about neurologic and ophthalmologic sarcoidosis. Here are my disclosures. As you know, sarcoidosis is a systemic disease. Here's a series from the Medical University of South Carolina clinic, more than 1,500 patients looking at overt organ involvement back in the days before we scanned everybody with PET scan. And you can see that the ocular involvement is the third most common involved organ, and that neurologic is kind of in the middle. Probably 5% to 10% of people have neurologic involvement. So you will see these patients in your clinic. And one thing I want you to think about is, how will you recognize it? And as you see the patient serially, what's your strategy for screening? That's changed a little bit in the last year or two, and I want to talk about that today. These are important organs because they have prognostic implications. I put a table here that shows the number of organs involved and the long-term outcome in a series of Japanese patients. Most patients with ophthalmologic and neurologic sarcoidosis will have at least two, if not more, organs involved. So these are automatically patients that you should be worried about, patients who need closer follow-up, multidisciplinary care, and perhaps a little bit more aggressive approaches to medications. The other thing that's been shown in multiple series is that these like to be friends. Eyes and brain like to go together in sarcoidosis, and so does the heart. And there are several different series that have demonstrated those correlations. We don't understand why, but anytime I see somebody with one of those organs involved, I really push on the history for the other organs every time I see that patient. So starting with the neurologic manifestations of sarcoidosis, I really categorize those into two. One is granulomatous, and one is non-granulomatous. Non-granulomatous is actually more common, but I won't dwell on that today. That's small fiber neuropathy. That's what drives a lot of the symptoms that our patients have. I'll talk mostly about the granulomatous manifestations. Here are some prevalence data looking at the number of patients with neurologic involvement. You can see a big range here, and it really depends on how the patients were ascertained. If you're looking for clinically overt disease that you can get by symptoms and by examination, you're really in the range of five to 10% in most series. If you look at autopsy series, you're probably getting up to around a quarter. And of course, as I said, small fiber neuropathy is the most common single cause of this, and that's what you see in that backer series at the end. So really five to 10% of patients, with about half of them presenting initially with neurologic problems, and about half of them coming out of the woodwork later. Neurologic manifestations can look like almost anything, and part of your job is to decide when does this look like possible neurosarcoidosis, and when is this a migraine headache? Because if you send everybody with a headache to the neurologist, they're not gonna like you very much anymore, and you're gonna gum up the access for them. So you really have to think a little bit about the likelihood of the symptom being related to sarcoidosis. Cranial neuropathy is the most common in most series. Headache is very common, although quite nonspecific. And you can see a range of other sorts of things that could be the manifestations that the patient will describe to you. Some of the less specific ones are listed on the bottom of this, but of course, these are some of the most bothersome to the patient, and just endorsing that this might be related to their sarcoidosis sometimes is very reassuring to them. How do we make the diagnosis? I really think it's LP and MRI for central nervous system sarcoidosis predominantly. There is no test that's 100% sensitive for CNS sarcoidosis, but I think MRI is the single best test, and it comes up above 90%. And I'll show you some MRI features in a minute. There's no LP test that's specific for sarcoidosis either, or none that's sensitive enough. There are several tests that are useful in other diseases like MS, or like infections, or like malignancy. And there are some patterns between these that could allow you to be more suspicious of neurosarcoidosis, or more suspicious of MS, or more suspicious of neuromyelitis optica. But really, you want a neurologist to help you interpret that pattern, unless you have a patient that already has clear-cut sarcoidosis elsewhere, and you're really comfortable that this is likely to be neurosarcoidosis. These are the things we routinely send, except for one. CSF ACE, not very useful. I wouldn't recommend sending it. Some people are sending CSF interleukin-2 receptor level. I'm not sold on that yet either. Save your money, don't send those tests. Here are the patterns I talked about a little bit. If you like to look at this reference, that would be easier than trying to remember all of these. None of these are 100% sensitive, or specific, or validated, but what this will do is this will help you lean one direction or another, as you see these different patterns of abnormalities in the CSF. How do you as lung doctors come into thinking about this? Where you'll often come in is a patient who either has established sarcoidosis, and develops a neurologic problem, and you've gotta help people think through that process as part of the team. Also, when a neurologist comes to you and says, oh my, there's a patient who might have spinal cord sarcoidosis, or CNS sarcoidosis, can you help me out? And I think one of the take home messages that I'd like you to get is that, yes, you can help them out. Even with really minimal findings on chest imaging, a bronchoscopy, just with a BAL, has a decent diagnostic yield, and I'd encourage you all to consider to do that. What about imaging? Like I said, MRI is, I think, the best single test that we have. Many of the imaging patterns are enhancing. That usually portends treatment responsiveness. The most common single MRI pattern is the periventricular white matter lesions that you see in diabetics and hypertensives. Rare case reports have shown those to be granulomatous, but I would say those are as rare as hand's teeth. In general, this just means microvascular disease that's unrelated to sarcoidosis, and I would not feel compelled to punish that with steroids or any other immunosuppressives, unless your neurologist tells you that this is way out of proportion to the patient's age and their other medical comorbidities. Here's leptomeningeal sarcoidosis. This is probably the most common single imaging feature. You can see on the areas there the post-contrast enhancement. As I mentioned, this usually signifies more responsiveness to therapy. Another form you should know about is dural disease. This is a little bit more chronic. This is a little bit more refractory to therapy. It's got a different differential diagnosis, and those patients quite often will pick off some of the cranial nerves. They'll often present with headaches. So dural involvement to me, I usually have a different conversation with the patient than I do with a patient presenting with a meningitis type of picture. And cranial nerve involvement, of course. MRI is pretty good for the lower cranial nerves, numbers two through about number six or seven. After you get to eight and higher, I don't find MRI is very sensitive. That's quite often a clinical diagnosis, and it's excluding alternative causes. And of course, there's a differential for all of these cranial neuropathies as well. Bell's palsy is one of the most common presentations, of course. Some series show that more common than optic neuritis. Other series have optic neuritis as the more common presentation. In my experience, I'd say it's Bell's palsy. And there will be a quiz on this table at the end, so please memorize this. Really, this is helpful to think about which structure is involved, and then to think about how the differential diagnosis should be constructed. There are several different criteria sets for defining neurologic involvement. All of them require a diagnosis of sarcoidosis outside of the nervous system to be comfortable about it. And importantly, and what none of these diagnostic criteria talk about is, you have to exclude other causes of the abnormal imaging findings. So the Wasak consensus to get highly probable, you either need an abnormal MRI, or you need CSF fluid in conjunction with an extra neurologic diagnosis. And you can see the other various categories there. And in fact, that's not something that you're going to memorize, but it just points out again that MRI and LP are the two things on which we really base most of our diagnostic certainty. Outcomes for neurologic sarcoidosis are a little bit challenging. This is a tough one to treat. The response rate is okay, but look at the top best response. It's just improvement. So most patients will not have resolution of their disease. Most of them will have some residual neurologic deficit. And so you can see in terms of the outcome here that many people will have less than ideal situations. This is one of the reasons why I think neurologic disease needs to be treated very aggressively. And out of all the organs in sarcoidosis, this is one of the ones where I'm most likely to come in with multidrug therapy very early on in the course. The longer you don't treat it adequately, the worse the outcome. Here's the ERS treatment guidelines on neurologic disease. And I actually disagree with these completely. These are really step-up therapy. And they say, oh, do steroids, wait and see. Do methotrexate, wait and see. Add infliximab. If you have serious, moderate, or severe neurologic sarcoidosis, I would suggest you start with two drugs right out of the gate and really have a low threshold for adding a TNF antagonist. Maybe that's overkill, but given the disability that a lot of these patients experience, I would rather have overkill than I would have permanent neurologic disability from early undertreatment. That's just the Dan Culver opinion on that. So turning our attention to the eye, ophthalmologists really classify eye involvement based on three anatomic locations. And as you go from the front to the back, it gets harder to treat, less likely to resolve, and more likely to result in permanent damage. So anterior uveitis, intermediate uveitis, and posterior uveitis. And there will be no quiz on anatomy of this. So starting from front to back, the conjunctiva. That's a place to look when you suspect sarcoidosis. You can see this lumpy, bumpy appearance. That's a good place to biopsy. There are actually series suggesting that if you send those patients to an ophthalmologist, you can get a diagnosis without even a bronchoscopy. So look at the conjunctiva, look at the lacrimal glands in patients with suspected sarcoidosis. Episcleritis is common. That tends to be recurrent. Sometimes it can be triggered or prompted by viral syndromes, usually treatable with topical therapy. We always like to have a slit lamp examination. That's really looking for these immune cells floating in the aqueous humor. This is a picture of so-called mutton fat carotid precipitates. This is a fairly specific finding for ocular involvement in sarcoidosis. And if you get chronic anterior uveitis, you end up with cataracts and you end up with this abnormally shaped iris because the back of the iris is sticking to the ciliary body called a synechiae. And this patient will be unable to accommodate well. When you see those funky shaped irises, think about chronic uveitis as something that might have caused that in your patient. This is a particularly bad example, of course. Moving back into the intermediate uveitis, vitreous snowballs, I think this might, this is a really dramatic example. You can see those snowballs there. But I think the way that we can recognize that is by patients complaining about a lot of floaters. And when you look in the back of the eye, which I know you all do on every single one of your exams, it's a little harder to see the vessels than normal. When you see that, think about vitreitis. Patients may get vascular leakage periflebitis or papillitis. And sometimes you'll get these so-called candle wax drippings, which are really a form of vasculitis in the retina. And this portends a little bit more difficult patient to treat, a little bit more aggressive therapy needed. And I think it's important for us to know in terms of treatment that as you get to the back of the eye, your topical therapies are not going to be so helpful. Sometimes steroid injections can control it. Sometimes steroid implants can control it. But really what you're mostly looking at is systemic, non-steroid-centered therapies because of the steroid toxicity risks with the eye that you want to avoid. Here's an optic nerve involvement with retinal vasculitis. I think almost any of us that looked in the eye would recognize that this optic disc doesn't look normal, and we would emergently send the patient over to our ophthalmologist. How do you diagnose this? Really two different kinds of strategies. One is patients with known sarcoidosis. I send all of them to the ophthalmologist once. The change in the ATS guideline in 2020 is that we do not need to do that on a repeated basis. That was pretty much a consensus with the ophthalmologists and with the pulmonologists on the panel, that it's very rare if you don't get ocular involvement in the first two years that repeated annual screening with ophthalmologic examinations is going to be useful. And so that's a symptom-driven thing. It's not something that we routinely do annually. So that's a change from a practice before. I mentioned already that if patients don't have a diagnosis of sarcoidosis, the benefits of getting a CT scan and considering a bronchoscopy, at least with a BAL, in patients who have any kind of abnormality on their CT scan at all, even if it's not entirely typical for sarcoidosis. Here's one diagnostic criteria for ocular sarcoidosis. This is the International Workshop on Ocular Sarcoidosis. And again, there won't be a quiz on this, but if you're interested in having the diagnostic criteria I would turn your attention to this particular reference, which shows you many of the lesions that the ophthalmologists are looking for. And there is a differential diagnosis to ocular sarcoidosis as well. Fortunately, the ophthalmologists have to work through this much more than I do. But if you can pronounce all the diseases on this list, then I think you get bonus points. How do we treat ocular sarcoidosis? It really depends on the structure involved and the chronicity. As I mentioned, topical therapy is usually enough initially for anterior uveitis. As you get into intermediate or posterior panuveitis, we think about cytotoxic medications like methotrexate and luflunomide. We think about TNF antagonists. And there are a number of studies across uveitis generically that have shown benefit to those therapies. So in conclusion, if you're going to take care of sarcoidosis, you want to think about all the systems. You want to approach the patient holistically. As you start to get some of these extra pulmonary involvements, be more nervous about that patient. Be a little more attentive, perhaps a little more aggressive with therapy. Gear your management for longer term approaches that many of these organs need. And please, somebody take the reins. Be the quarterback for the patient. Don't piecemeal them between all the specialists. Help the patient. So I'll close with that. Thank you very much. Thank you.

neurologic sarcoidosis

cranial neuropathy

diagnosis

MRI

treatment

multidrug approach

ophthalmologic involvement

slit lamp examination

systemic therapies