Chapters Transcript Video Sarcoidosis- A Contemporary Challenge in Clinical Practice incidentally it releases are quite awareness month. So this is a talk about sarcoidosis and what are the challenges the diagnosis and treatment? Uh, by the way, those who do not know me, my name is, they were brought to Bondo Prada. I'm a pulmonary critical care physician at USF and Tampa General Hospital. Well and I'm the director of interstitial lung disease. That's are quite program here. So a disclosure because it's a CMI event. I don't have any conflict of interest. Do say, wow. So since our card is a big chapter, what we decide to do, it will divide it into five segments. So we will discuss the each segments of it. And rather than taking all question at the end, I would encourage you to ask any question at the end of the each chapter so that it is fresh in their memory. So first is we talk about the etiology of sarcoidosis. What is sarcoidosis before that? It's a little bit of epidemiology. Whenever you open any sarcoidosis chapter and read it, you read the first life circle is a multi system granny liberties disorder of unknown origin And us prevalence of sarcoidosis is 149 or 1000 African American population and 49.8 per 1,100,000 Caucasian population. So it is a disease more prevalent in African American populations speak incidents for male is 30 between 30 and 50 years for the female, 50 to 60 years. Age adjusted annual mortality is 2.8 to 4.3 per million U. S. Population. That's all causes of mortality duties are in the stark white patients. Attributable mortality to the circuit is gradually increasing because as we make more diagnosis of sarcoidosis, the cause of death in USa most common cause of death and respiratory failure. But in the japan, the most common cause of death is cardiac sarcoidosis. That's why most of the study in cardiac sarcoidosis comes from japan. Incidentally, if you open the NIH site it will cease arc wide. Is among the rarest can't disease in the U. S. A. It is not that common sarcoidosis but still it is very important disease. We will know soon why And in in the C. D. C. Websites are quite is enlisted as an orphan disease. It looks like there's no one to care for sarkozy it and I think it partly reflects in our attitude to a stark white population as well. So what causes our car? This is the question I hear from anyone, any patient comes. Their invariable question is what causes the disease. So there are three factors and interaction of the three causes sarcoidosis. There is some external stimulus which may be a latent infection or some environmental factor which in some sensitive individual mounts a challenge immune challenge which leads to granuloma formation and that causes sarcoidosis. Actually, granuloma formation is not bad. This is a different mechanism to wall off. That knocks a stimulus spreading into the body. So don't scare the granuloma. Granuloma is a good thing. It is. If granuloma are multiple, they start causing organ damage. That is what we need to address. Not the granuloma. Remember that? Yeah, so further expanding this the last slide. So you can see there is interaction of four factors which led to sarcoidosis. One is occupation, certain occupations have higher sarcoidosis, firefighters, particularly physicians. We don't know why obstructive people have a hard incident of sarcoidosis. We don't know. Navy personals have sarcoidosis, certain occupations worst affected is form line. That's why it is essentially a rural disease. Somebody who's going to form always get sarcoidosis. Okay. And it is also seen in certain season the present more they got a cute X. Reservation of flare up of sarcoidosis, mold, mildew, insecticides, burning stoves or woods. All this contribute to sarcoidosis then infections. We'll talk in a detail in the next slide. The two specific infection is important. Micro bacteria and profiling bacterial acne and genetics females have had incidents sarcoidosis and particularly the most compelling evidence came from the twin study that was done in Norway. The conjoint this sorry the those twins twins have a 17% percent increase in sarcoidosis than non twin brothers. So that that was the first time there was some genetic component was established and subsequently we have come across more H. L. A. Class like H. L. A. D. R. Key one H L. A. P. To 1 15. All this can cost sarcoidosis. Okay so going through the slides quickly this is forget about the right thing. This is the slide. Uh This is actually from the chapter I wrote what the drug works with Dr Jackson. But if we what we describe so micro bacteria proteins or other infectious, organic and inorganic antigens. The they will go to the body inside the body. Antigen presenting cells present to macrophage. Macrophage activate the cells. So diesels this activation leads to lots of inflammatory intelligence and they are the one cause problem. This is not the problem Diesel. Then t cell activation leads to qualification of the diesels that is th oneself, this is The seminal offs are quite th one cells And eventually this th one cells leads to granuloma formation to wall off those knocks a stimulus. So problem is not this one initial problem is all these things are secreted on its path. So this is again important granuloma itself doesn't need treatment until unless all these things causes problems. So histological e non necrotizing granuloma can invade distort and cause organ dysfunction. Then we get worried. We treated not the presence of granuloma. Granuloma contains multi nuclear giant cells epistle or itself and lymphocytic infiltrates. In chronic cases they become harness and replaced by fibrous tissue and that fibrosis park Allex through surrounding area causing fibrosis of the organic. So it is not an inflammatory fibrosis we see in HP or hot tub like that or bad Ilias as HP or connective tissue disease. It is a granuloma and fibrosis spreads from granuloma. So there's a few common conditions where it there there there there are few common conditions like sarcoidosis. We come across hyper sensory pneumonitis. Some infection causes sarkar granuloma has some characteristics in most of those are quite not all. So it's a well circumscribed granuloma and non necrotizing granuloma, tight, compact granuloma. That's a classical description, compact, non necrotizing tight granulomas and they are along the lymph and genetic pathway. Unlike hypersensitivity pneumonitis, there are small, non necrotizing granuloma and there were airway centric and industry asian, so presence of granuloma where it is very important. And I think pathologist needs to specify that in the report, where are the location of granuloma which I often find missing and we have to go and review the slide. Same thing your brain. There's interstitial granuloma. They are non extraditing as well. So distribution and characteristics of granuloma defined sarcoidosis. Okay, so we talked about the potential ideology, so little bit going. Uh huh on those and elaborating micro bacteria so often granuloma is called is a cousin brother of tv. So there is a hypothesis and theory, the granuloma is a form of micro bacterial infection, tuberculosis where aberrant immunological chemical reaction leads to sarcoidosis proper. Usually immunological reaction leads to mycobacterium tuberculosis. Uh You probably heard there's a clear trial was done face to trial was conducted successfully faced. Re trial started funded by NIH multi center trial but still they are not able to recruit enough patients. That's why data is not published in which they look for cat G. Gene that present in the granuloma and 40% of the granuloma cod teaching is present. So once the gene is those genes are present, they're treating with anti mycobacterium four drug not with steroid, not an immune suppression and the face to trial the short recovery the lung and improvement in the lung function by FCC. But the important thing is that 40% has got 60% does not have. So this is not the exclusive cause pro bono bacterium acne. Very innocuous back to their causing acne. So there is a cell deficient variant which can invade the skin and this is there's a common association of this bacteria with granuloma formation in sarcoidosis. Noninfectious. We went through mold million pesticides, Firefighters, we knew that from Wall Trade Center. First responders, 40% of them has developed sarcoidosis huge 40%. That's how we learned that firefighters have a higher incidence of granuloma prolonged photocopier use. I will talk about it in the subsequent slides. Al ammonium dust mining asked them if you see a patient, if they have worked alimony a mining that can lead to granuloma formation and certified like reaction. So there's a dis regulated immune response to nanoparticles derived from common metals and minerals in the environment. I know it's a small town in in the remote Pennsylvania which has a population between three and 4000. And you'll be surprised there are 55-66 archive patient in that small town. So there's a huge number in a 4000 in the in the town of 4000. So there must be something in there. We think some mineral or particles, particles in the soil which they're inhaling, causing granuloma. So what is the verdict? What we talked about theology? So essentially ideology is precisely unknown. We don't know what causes sarcoidosis. Any questions so far by anyone. Nothing yet. Doctor. Okay. Then we moved to the second part of our discussion National History of sarcoidosis. So essentially we saw ideologies unknown, but that's only one part of the story. This slide summarizes the enter sarcoidosis. How does it evolve? So in some genetically susceptible individuals and some mp genetic changes like SNP, we will talk in a minute in some host factors, nonsmokers, obesity, african, american individuals. And in exposure, some modify like photo copier and some if in that substrate, if there's an ideological trigger that leads to sarcoidosis and just photocopier is the most intriguing part of sarkozy. Sarkozy research recently. It is seen that Photograph appeared particularly 3rd world country. Like here, we don't see that often in the third world countries. That is a profession, that's a business. A lot of people open photography shop and they do photographic missions. They do photography for the whole days, that's their business. And inhalation of that ink is linked to sarcoidosis. It depends on duration like Less than one year. It doesn't cost three year higher incidents seven years. Even higher incidents. And at least more than 60 photography. They do in a the so but itself does not cause granny uh, sarcoidosis. So if somebody gets some ideological trigger, like somebody inhale program, a bacterium, acne inhale aluminum, dust. And if at the same time there fotografia, they will definitely have sarcoidosis then who are not photocopier. So it mortify eyes. The theological trigger does not itself caused the disease is that's an interesting concept. And when the sarcophagus is developed, you also, have you ever thought why? Some people have got left note, some people doesn't need treatment. Some people need treatment. Some people is more aggressive treatment. So there are lots of clinical phenotype. Why? So it depends on many factors. One is genetic factors. Yeah, Like H. L.A.B. If you have that they have a much higher incidence of fibrosis age. If our confidence level up at the older age, that leads to five protect genotype, modify Elif smokers. That leads to fight Roddick for no type. So again, depending on the background substrate and the modifier, They can go in different clinical federal types like spontaneous resolution progression of disease treatment In spite of treatment going into five process. So characteristics of these cases are concentrated in space and time, spontaneous remissions are common. Uh there was a study done on this from the last are quite centers of the country. So there was a referral bias and even those referred to those centres, only 40% actually need a treatment. So in spite of any reference bias, it is important to remember that only a small percentage of stark white people in his treatment, most of them do not. The challenge is how to find out at the onset who will lead, who will not need persistent disease does not always progress. And there's a considerably no racial and ethnic heterogeneity. So this is an assessment by Alicia Darkie from University of Iowa who incidentally was trained in USF University of South Florida. So Sarka, she published this paper in 2017. There were two more papers came up that year about the sarcoidosis burden. Sarcoidosis is a unique disease because when we talk about disease, we assess their survival, mortality for sarcoidosis. Survival is not that issue. Most of the patient has a chronic protracted illness. So with somebody as sarcoidosis because they do not die, which is a good thing. But at the same time they are suffering from chronic disease that leads to a lot of burden like somatic burden where there's an ob due to organ damage. Para sarcoidosis syndrome, we'll talk in a minute and toxicity of the medication psychological burden, it least depression, anxiety, loss of function, loss of job work, lost financial problem and treatment of self. It's a there's economic pardon from again, workdays, loss, loss of employment, rec current hospital visit tests their copies everything. So This study, another study assets that sarcoidosis patients. On an average the commercial pair. This is the assessment from all private insurance, not Medicare Medicaid. So 19,714 per year. Now it doesn't look as Lot of some. But if you consider this every year because they survived 10, 15, 20 years, then it becomes a lot. And this is 36% more than the age, age, gender and age, gender. And uh I think socioeconomic status matched Nonstarter, quite chronic chronic disease patients and total spending of private commercial payers when 2017 were Around $8.7 billion. That is just for treatment hospital visit and walk their loss between .2 to 1.5 billion. And if you there was a survey done by another paper under a commercial pair sarcoidosis, always among the top one person they have to pay to the patients. That's because of the color. That's because of chronic hospital visit, hospitalization, copay and walk their loss and loss of employment. So treating sarkar does not only makes the patient better remember sarcoidosis because trains money and that leads to increased scope, increased scope and increase increases our premier. So we have an economic benefit in treating sarcoidosis appropriately. So outcomes again, this is another paper published around 2017. So these are the major outcomes important hospitalization, oxygen requirement, mobility, loss of job, affect finance, new comorbidities, but death is not a major outcome of sarcoidosis in that way. Sarcoidosis is unique. Question now comes not everyone developed the problem to find out Who will develop problem who is at risk. That's the biggest challenge of sarcoidosis. So in general past 30 to 50% develop persistent disease. And 50 to 60 we develop whether some disease, so not all persistent disease are bothersome, so eventually Progresses. This is progresses to fibrosis in 10-13% and significant problem in 5-10%. So beach clinical challenges find out this 5-10% from the all star quite patients and their this is an unmet need of sarcoidosis. We have some risk factors like persistent disease. Has seen more in black rests older age, female gender, multiple organ, ascending scatting stage of sarcoidosis. This architectural distortion and airway disease is spleen. Omega is an important problems dynamically. Mhm And clinically bothersome disease, particularly in african american need for treatment within the first six months multiple organ, low socioeconomic status, I think economical is always a problem in sarcoidosis and we then to ignore it. So number of besides economically, number of organ also impacts outcomes If they have four or more organs. No most of them are symptomatic. Have some issues the significant organ dysfunction and they're equal not of assistance. Financial psychological and medical assistance rather than if they have one organ or 2-3 organs. Remember this is our focus stage for sarcoidosis as a fiber cavities are but does not predict mortality. We've seen a subsequent slide. It causes a lot of morbidity ease but does not cause death directly. So this is a study done in England, the same person who developed composite physiological index in I. P. F. So subsequently tried to apply the same principle and I. I. P. A patient and was successful in ensuring that those who have a C. P. I. C. P. A. Is a composite physiological index. So he developed a formula taking into account every C. F. Everyone and deal ceo and A. And E. L. C. O. Taking into those accounts. Sorry I skipped the slides. Okay sorry. So uh taking those into account and if the composite scores more than 40 they have a poor prognosis high risk of pet. If the score is less than 40. But if the remain paul Marie artery is dilated more than a ascending out, that means it's essentially if somebody has features of pulmonary hypertension and all HR cities those fibers is more than 20%. They are at high risk of time. So this is a good initial stage. We can predictive, somebody is at high risk or low risk. This is from Cincinnati cohort of course. You know they are one of the largest stark white coat in the world. They're the biggest center by bob Altman in that code. They found out the independent predictors. Mortalities, age, advanced age that is detected of sarcoidosis and advantage More than 20% Fibrosis presence of pulmonary hypertension. That's the biggest predictor of mortality and cardiac sarcoidosis. So, natural history of the disease. What we found out clinical phenotype is variable, disease, disease progression is unpredictable. Any question in that natural history of sarcoidosis? Yes, we had one come through. Are there any standard protocols such as genetic studies or DNA markers or special stains that are now done on pathology specimens such as granulomas or lymph nodes or lung biopsy specimens to help identify an ideology wants non cast stating granuloma identified. Okay, well, that's an interesting question. Uh there are some genetic markers have been done genetic studies, which I'll talk in a minute which shows that those patients have a potential of developing fiber optic stage of the sarcoidosis. So if they develop robotics says there are there are a lot of comorbidities and there's increased risk of death. So there is no direct, but there are some indirect evidence of who are likely to develop fibrosis sarcoidosis. Anything else? Yes, I'm sorry. One more. What are the risk factors for fibrosis in sarcoidosis? Oh, that's good. Okay, that's a good. That's that's what five or six Arkady is a lot of issues. Can we take this question in systemic sarcoidosis? Just, we will talk about it in a minute. Okay, of course. Anything else? That's all for now. Okay, thank you. All right. So remember Star Card is a multi organ disease. So the problem of this archive, they're going to cardiologist, cardiology say heart is okay, you don't worry about it. Go to the pulmonary is hey, your language is a stable that we don't need to do anything. So they circle among the physicians and physicians. Everybody focuses on one part, but they are depressed, they are fatigue, they're losing their job. They do not have any psychosocial support. So make their life miserable. So they are very unhappy. Sarcoma patients are one of the patients most unhappy going to the physicians. So that was one of the reasons that when I started start courting. Not here in my previous job is just to concentrate on the global sarcoidosis picture, not to focus on any organ. That's why I started Stark White Clinic there and we started clinic here To give the support to these patients from all aspects of sarcoidosis. So why we see sarcoidosis, which is sarcoidosis because parliament because of this, 90% of them has some pulmonary system involvement. That's why by default we are the stark white specialist, but it affects other organs as well. Like J. G. Yeah, Central nervous system is seen in between five and 15% of the cases. I involved in anything between five and and 50 or 50%. Depending on on which trial. You look at cardiac involvement perhaps most likely around 25%. That's important because when we talk about cardiac sarcoidosis, Bone sarcoidosis between 15 and 25 Hypothesis fundamentally scene between 15 and 25% again. So you can see sparkle and affect any organ. We have seen very atypical sarcoidosis, we have seen gastric sarcoidosis, we have seen testicular sarcoidosis. We see prospects sarcoidosis. So sarkozy is a multi system reasons that's why rheumatologists are also involved in this are quite treatment. So remember constitutional symptoms are frequent and that adversely affect quality of life and that does not. Unfortunately, that does not get address until unless you vote with are quite specific center hypercholesterolemia 4 to 7% and that is due to excessive production of 1 25 die hydroxy vitamin D. Because harper granuloma produces an enzyme called 25 hydroxy esters Fatigue, major, major problem of sarcoidosis. Those who deal with sarcoidosis have come across this problem more than 50% patients developed significant fatigue. So and that can be assessed by a fast code, fatigue associated stark white. So in our clinic we have developed a protocol that's why like those who come we do the first court every visit we there was a step wise eyes Approach algorithm and how to approach that fatigue. Approximately 25% of developed outside quite as a developed chronic progressive disease. Which important there are two variants of Saada sarcoidosis, Love brain syndrome and even parodied fever. The love brain syndrome is a fever Linford. No party and patients develop anything will notice them and if you're paranoid for the same thing acutely patient, dollar fever, UV itis facial policy and parodied enlargement. Their progress is in general is very good. I'll take time take some time to talk about love train syndrome. So at the beginning I said granulomas are good. Granulomas are protective mechanism. They wall off the noxious stimulus from getting inside the body. When granuloma becomes innumerable, start destroying the organ, then it becomes a problem. So until that happens, granuloma do not treat the granuloma. Lofgren's syndrome. Classic example, there's a large study done in Sweden I think 10, 15 years ago, that gave a nice insight in the disease process. Surprisingly, those who had Lofgren's syndrome, what treated with steroid, we sometimes treat with simple as salicylic acid are other anti inflammatory. So those who were treated with steroid, those Lofgren's syndrome developed recurrence of sarcoidosis is at a letter park. Those who were treated with anti inflammatory drugs, they did not have any records. Security was that there was some noxious stimuli, environmental or infection. We went through those and granuloma is being formed to wall that off And by simple anti inflammatory. We address those interleukin side effects of those inter adverse events of those interleukin six. As a result, patient got better. But when we treated with steroid, this disrupted granuloma formation so that knocks a stimulus stayed in the body. The moment we took off steroid again, it flared up because stimulation was not isolated. This is a seminal paper that told us about the pathogenesis treatment approach. So granuloma is a good thing, not a bad thing, this is for hepatic and spreading sarcoidosis, spooning sarcoidosis has a very adverse outcome. Remember? And what is my practices Whenever there is? It's just most of the question comes with the chest city in the clinic. I usually go down scroll down to look at the spleen because if there is associated screenings are quite, their prognosis gets a lot of wars. So I urge start developing practice to look at the spleen. When we look, when we look at the lung, this is a lady gave me permission to show a picture. This is a classical lupus, pan Borneo. You can see how horrible they are quite can become. This is the skin sarcoidosis. First one is a rare macular sarcoidosis, very rare condition. Second one is a no deal of sarcoidosis. Remember? 3rd, 3rd most important thing patient coming to our clinic gets counseling not to do the tattoo, whichever Sarkar do you treat cardiac love, pulmonary hypnotics are quite anything council them not to have tattoo. We have more than one patient I've seen lots of patients tattoo grows over sarcoidosis. Sorry, sarcoidosis no deals grows over the tattoos because sarcoidosis is a propensity to grow any scar in the body. So when the tattoos there's a micro scar and so archive tend to grow with it. We have seen horrible sarcoidosis over the tattoo quite a few patients so always counsel them not to get tattoo. Bone sarcoidosis more common. It's osteoblasts ticklish in usually they are paid positive and associated with hyperglycemia. So most often clinical diagnosis is multiple myeloma or metastasis. Then the under global C. E. And they found find it out it is sarcoidosis. In fact, our large chunk of our patient comes from Moffitt Cancer center for this reason pulmonary sarcoidosis, I've left it to speak a little bit more details. So this is the old skating stage which has hardly changed, So state zero, you know, knows. Al Qaeda says stage one is around 50%. When you see only lymphatic neuropathy. Stage two, When you see lymphedema apathy plus that infiltrates. Stage three is is only in filters, there is no lymph osteopathy. We'll talk about state, fall in a minute. So stage one, spontaneous resolution is 50-90%. So often do not need treatment. Stage two, significant high percentage patients undergo spontaneous remissions, so may may not need treatment. Stage Almost all needs treatment. Stage three. Remember this number goes down if they have associated splenic sarcoidosis, so always look at the spleen. Next is fiber of fiber cavity. Sarcoidosis is a stage for sarcoidosis, it's called fiber cavity sarcoidosis. 20% of sarcoidosis progress to it. So this was somebody asked a question. So important thing is that progression of sarcophagus is not related to Arlene association of antipsychotic therapy. So if somebody is susceptible to develop fibre optic disease you can treat them. They will still develop fibrosis, you cannot stop them from progressing what you can do slow down the progression of disease and symptomatic relief. That's why you need to treat. So there are a few we exactly do not know yet. We're still looking into any biomarkers which can predict so specific. There are few genetics things we have found, particularly those who have H. L. D. R. B. To 1 15. They have funded if they developed sarcoidosis that invariably progress to fiber optics sarcoidosis, it's A. B. D. N. L. Two gene is not to jean is a family of, not to jean. Any mutation leads to five products are keratosis. There are we have identified three SNPs, One is john WON T. G F three B to another one. This are that there's another one we'll see in a slide subsequent slide. So if you have those, those are SNPs then you will develop progressive sarcoidosis to five broad exchange whatever you do. Usually they have a higher, I'll five, I'll seven went into the lava at the beginning but not very specific. Remember Sarko, primary cavity sarkozy's concept has changed. It is no more end stage sarcoidosis anymore because we know sarcoidosis and inflammation progresses concurrently. So previously our concept was 500 health criticism in end stage sarcoidosis don't treat with antipsychotic therapy. Now we know both happens together. So fibra cavity sarcoidosis is now divided into two types of sarcoidosis. One is real and stage where there is no inflammation where inflammation fibrosis goes concurrently and they need to be treated. The big challenge is how to know which one. So sarcoidosis leads to lots of comorbidities. Now. Question is why do we follow them obviously? Hey, if you have fiber cavity sarcoidosis go at home, we can't do much. No, we should follow that because the level of bronchial illnesses Aspell G. Loma very important develop Pulmonary hypertension as high as 20% of them developed pulmonary hypertension and that's a major risk factor for mortality to develop frequent acute observation. Sometimes they are treated maybe appropriately or inappropriately because chronic therapy to develop always say diabetes high potential. So this is an interesting study. I think that was done at national jewish but mobile homes have published this paper. So if you see fiber optic sarcoidosis, no core more ratings. They have a pretty good outcome survivors. So they have a pretty stable disease Slow progressing for 10, 15, 20 years. But as soon as the devil of comorbidities, their survival goes down and they start dying. So we follow them to assess if they're developing this. Co morbidity is not for fiber optic lung disease. Cardiac sarcoidosis quickly cardiac involvement clinically 5%. But now we know because of emerging 25 why we are fearful, sudden cardiac death and life threatening particular item and maybe the initial presentation so they can die. So, I solid cardiac sarcoidosis. Now it is reported because of the increase application of MRI. We did a study in, when I was in Cleveland clinic. We find that most of them eventually we want to develop other organ sarcoidosis. There was a median age gap between 3.8 years, so they will progress to other organs development in future. Four times likely to hospitalize. Heart block is the most common. Second most commonest VT VF. And cardiomyopathy. Very rare is atrial dysrhythmia. Very rare and sometimes can pity God, I just can't happen. Cardiac imaging. Cardiac MRI is the best diagnostic. There was some debate initially paid versus cardiac scan. We know cardiac scan. Sorry, MRI scan is the best delayed gadolinium enhancement. This is what you see. The gadolinium does not clear here than from the normal tissue. And classical it is in intra septal wall. Now we have developed key to weight imaging to assess inflammation, to differentiate of the active force electronics sarkozy. Because the detailed get delayed gadolinium enhancement, he will see in all sarcoidosis, beat and all sarcoidosis or active sarcoidosis. So that superimposed the two way imaging is important. There's a recent study publication In which they 50 patients that tailor their therapy based on the T. To wait imagine until their edema subsided. So that's interesting for future and delayed gadolinium announcement. This lesion school relate with the survival as well. This is the digital scan averages can unmatched defected characteristic of inflammation match defective character characteristic of scar tissue. So I get often call from uh insurance companies they said well every teacher you were doing that's fine classes the inflammatory, why do you need another scan And they refuse to approve that why patient needs a perfusion scan. So I have to explain them. Some of them get convinced some are not. But that is the explanation why we need both perfusion as well as a digital scale. Yeah at risk wire at risk cardio white male cns and opulence are sarkar doses. They are at risk. We are trying to develop the screen because we cannot send everyone for MRI or uh pet scan who are the patients do sink. It's again an imperfect science like everything in sarcoidosis. So we take in our clinic it is advisable that we take a history of just pain palpitation and precinct opal episode. We check annually kg and annual echocardiogram BKG for heart block. If three or more of this are present then there's a 70% likelihood they have got cardiac sarcoidosis. Then we should send them for MRI scan. This imperfect, this is this data came from japan which has the highest number of cardiac sarcoidosis. Somehow we don't have anything better than this. So we follow this. This gives us some idea. Now there's a study going on in USA so they are doing basically GLS LV GL is a global longitudinal shortening. That's the earliest market of diastolic dysfunction when Elvis normal looks normal. So they're looking if that can be used as a market. So system is sarcoidosis is a multi system in nature. Always remember if patient comes to you for cardio cardiac sarcoidosis. Hepatic sarcoidosis, palma sarcoidosis, don't ignore other organs. Don't ignore constitutional symptoms. If you cannot manage them, consider sending to us are quite clinic. We have a couple of questions. Is that okay? I think the first one is referring back to your previous chapter, but it is. Does the risk score predict response to therapy? The risk or I mean that is called if the initial risk or we said no it does not predict to therapy. No. Nothing. Credit to therapy. That's the limitation of therapy. We don't know. There's no way to assess the response to therapy and outcome of therapy. That's a big limitation of starting treatment. Okay, next question. Do you follow vitamin d levels like 25 hydroxy vitamin d levels in patients with Sardo uh sarcoidosis. So this is a couple part question. And yeah, go ahead. Yeah, we follow that for some other reason. Vitamin is that's a very good question. Vitamin D. Deficiency in Stark White people causes fatigue. So they should get the supplement question is giving them vitamin D. Level. Well it's tricky because vitamin d. can lead to supplement can lead to hyper calcium and sarcoidosis. So we check it particularly those who have fatigue and it is seen. The goal should be kept between 28 and 30. That's the goal we try to achieve by given vitamin D. So if they have vitamin D. Level less than that when we treat to achieve that goal if higher we don't treat them. But it is important if you prescribe somebody vitamin D. Every six months check calcium and vitamin D. Level to make sure you're not over treating. And do you recommend that The blood levels are sorry that blood vitamin d. levels be kept on the lower side such as under 30. To avoid the excess high risk of calcium in the blood. Yes agreed between 28 and 30 is the goal in the studies that a couple of studies done on it. And also do you recommend that sarcoidosis patients should limit vitamin D. Intake or sun exposure? Yeah. No problem with that. Typically it is said that another thing I would like to say. Typically when we supplement vitamin D. We start with 50,000. So it is recommended in sarkozy people not to do that. 50,000 initial supplementation. The between 800 to 1200 units of vitamin D every day is recommended. And do you try to balance the risks of osteoporosis versus hyperglycemia risk in an older patient with sarcoidosis given the vitamin D. Issue? Well sarcoidosis patients are the sizes of osteoporosis because of hypercholesterolemia and steroid therapy. So they need to be aggressively treated for osteoporosis? Remember some of the osteoporotic medication can lead to sarkozy like reaction but not vitamin D. But yes they should be investigated and aggressively treated for osteoporosis. And the last part of the question is does this become more complex than a patients or in patients who are also receiving Press Dawson um predniSONE? Yes. Yes pregnancy on is a treatment any hypercholesterolemia response very well to predniSONE. Typically we treat initially with predniSONE and then we see them need maintenance therapy, maintenance therapy. We try to do it with hydroxychloroquine if not possible than methotrexate but hydroxychloroquine and pregnant on. These are the two drugs we tried in in case of hypercholesterolemia. But then that leads to osteoporosis. And then patients should have a treatment for osteoporosis. Again we do not give uh predniSONE for a long duration, maybe three months, maximum six months. We win them completely within six months. Excellent, that's all the questions we have now. Thank you audience. We have a couple more chapters, so keep them coming. Okay, thank you. So let's next go to diagnosis. So diagnostic algo algorithm. If you suspect sarcoidosis, you do the biopsy negative. No diagnosis. If you find granuloma and then consider two things before making a diagnosis of sarcoidosis. I will a little bit of go fast here because the time concept, but ask me any questions. It could be. This are quite like reaction, not sarcoidosis and many other multi system disorder can cause can be caused by granuloma, like rheumatoid arthritis Ukraine syndrome. So once you have ruled out then there are diagnosis of sarcoidosis, it is a diagnosis of exclusion. Once you have diagnosed sarcoidosis as as the disease activity and severity of the disease. Uh this is santiago and this is the this part suspects are by syndrome diagnosis. So what is syndrome diagnosis? Uh so, um question is sometimes bikes is non diagnostic or biopsy cannot be done and biopsy is not clear curd then how to make a diagnosis of sarcoidosis. So that was a very burning topic. And Wasabi came up with the access instrumentation. uh they formed the committee in 2015 to come up with a plan how to make a diagnosis in absence of biopsy, extra pulmonary sarcoidosis. So, I've just given this too, I was fortunately, I was one of the committee member who came up with the definition. So we divided stark white into four categories, highly probable, atlas probable possible and no consensus. So highly probable we should treat a sarcoidosis, atlas probable. We should treat with sarcoidosis even possible. We can wait and watch and concerns. No consensus. So I did go through it. I don't want to go through it. So if you have any issues, I suggest go to that paper that a war socks sarcoidosis organ instrument that was published in chairs. That was published in sarcoidosis Sarcoidosis journals in 2015 or 2016. And you'll find every organs. So sometimes you do not know you don't have the biopsy results available or non diagnostic or it cannot do. So then follow this pattern. Whether there's how probability is highly probable or at least probable, then decide treatment on the basis of that you'll find for every organ long hard uh kidney, liver spleen bone in that paper. So let's move on initial investigation. So that's important. So wherever this patient goes, cardiologist, hematologist, pulmonologist, we should we cannot ignore the multi system involvement. We should focus. So when they come to our clinic inspired the lung problem. We make sure we follow this most of the test. We make sure they have a renal function. We do ultrasound, make sure they do not have a stone. Their calcium level is okay. The urine calcium is not excessive. Of course. We do lung function tests. We check for any liver or kidney involvement by checking in the liver function tests and we do cardiac screening and E. K. G. That's routine That should be done. Any patient Even presents with one organ of sarcoidosis. So these are the city feature of sarcoidosis. That's highly suggest sarcoidosis. I will go through it. You all know it. There's a three feature is very characteristic. Perry lymphatic no deals. They had to be around the bronco vascular margin. Don't know deals are as our supply. So that is the lymphatic channel and all bilateral Hyler lymph retinopathy. But if you have those, these are the differential consideration of any other Grand kilometers disease. No deal is spread along the lymphatic channel. Could be limp pancreatic tumor or just lymph fluid enlargement of lymph. Former Two things here, small airway disease often use sarcoidosis. Sarcoidosis. Small airway disease is very, very rare. And second thing I see is ground glass opposite ease their diagnosed diagnosed sarcoidosis. Ground Glass was, it is practically does not happen in sarcoidosis except when it is associated with no dealer thickening and along the bronco vascular bundle and inter lobular sector. So if we have ground I suppose it is look for any in the next slide, I'll show you better lymphatic spread like this. So along those lines, if there is a no deal clarity. If that is associated with ground glass stopper cities, then that is sarcoidosis. Just diffuse ground glass Super cities are not never do to sarcoidosis. So there is a classical what is called starry sky appearance of sarcoidosis. For more testing. So what are the test we should do? So every annually we should do calcium. We should make sure the eye checkup gets one card. They have a cardiac screening, of course. PFT. So these are the things we should do at every clinic visit. So why we should do? And what is the value of those tests? Now this is a this is again from national Jewish novel novel Hamza's paper of this identify study here arranged asking 15 countries stops are quite specialist so how to investigate and their answer. They came up with the answer they matched with what is the evidence we have got in literature. And practically surprising if there is no evidence. So, question is lymph nodes sampling. Is there any evidence? No, There there's a very low quality evidence. Reynolds screening. We do it. Oculus Training. We do it because we say that we have seen sarcoidosis can cause sudden blindness. Questions. Do we need to do what is the evidence you see? Every evidence is a low quality evidence. So whatever we do, there is not much evidence in his favor. So as a circuit specialist that makes me feel better because nobody can question my judgement because all counter argument has low quality. So no one seems to know what is going on. So that that is good for the archive specialist. So non cryogenic granuloma sign acumen for sarcoidosis. You all know this is important in that context. This eight year statement that diagnosis established when clinical radiological findings was supported by histological evidence of non cryogenic granuloma, an epithelial cell granuloma granuloma of known causes and local Talcott reactions must be excluded. So these are the various causes of Grand Lord. This is a study of 500 pathology slides showed granuloma, non cosmetic granuloma and they're correlated with clinical clinical diagnosis and that is done In worldwide. 500 slides were reviewed and only 30% of them were actually sarcoidosis. So most of them did not have sarcoidosis is important. Micro bacteria. NTM fungus and others. This is dr Michael newspaper. Uh he's uh if you want to read about his a pathologist from uh he was a student of Eisenstein and he's from upstate son in New york. So if you want to read about non cryogenic granuloma, he has 34 excellent papers. Read them. I always keep them in my desk so I'm not going to the cause. So these are the cause of non cash shooting granulomas. So once you make a sarcoidosis, we rule out all those. We don't know most of them initially. But remember we sometimes miss out. So every visit you think you think something unnatural, something not out of box thing. Think whether diagnosis was correct. Go back to this this list and try to find out if diagnosis was correct or not. So these are the granulomas that favor sarcoidosis we talked about before. There's a compact Titley from granulomas, epistolary granulomas present the numerous present along the lymph and genetic and perry lymphatic pathway and there is no interstitial infiltrate. So this is important difference between HP. Because sometimes you see necrotizing granulomas sarcoidosis, there's a necrotizing, stark white granular mitosis and non necrotizing granuloma can be seen tight granuloma in atypical HP. One of the big differences interstitial inflammation which is never seen in sarcoidosis but big thing in HP. Okay, so this is don't believe the pathologist's report. Pathologist is non cause unique. Vanilla will never make a diagnosis of sarcoidosis. Please. You're the specialist. So these are the six slides all were diagnosed pathology reported non graduating granuloma. Uh Sorry, diagnosis favor sarcoidosis strip and see only one. The left bottom had actual sarcoidosis. None of them have sarcoidosis. So this is a study I did with colour doctor culver when I was in Cleveland. Look, we looked through how many patients were diagnosed with pathological non caucasian granuloma well presented to us and referred to us for sarcoidosis management. And we find out of 2 30 for patients who are the well defined classical granuloma of sarcoidosis. Uh President was 36 after 2 34,000,000,036. That is 17% actually sarcoidosis was not the diagnosis. We made the diagnosis of HP. Whereas the C. V. I. D. Endemic fungal infection reactive granulomas by mm. DD discussion. So it is very important that Kanye Loma is not synonymous with sarcoidosis. Sarcoidosis is a clinical diagnosis. In fact, just give you quickly an example in I think a mother to three months ago, one patient was referred to me as a sarcoidosis with a lung audience. Single lung, no deal 86 years old, no symptoms, caucasian smoked in the past female. Uh it doesn't fit the picture, so patient was referred to because of the long consolidation is symptomatic patient. It turned out that this lady had a plasma site tomorrow of the plasmas item of the right shoulder. And this is a sar quite like reaction like granny kilometers reaction is very common with plasma saitama. So tinkle over what of that list? Whether it fits the clinical pattern fits with sarcoidosis, then go back to the list granuloma biomarkers, potential biomarkers are S. S. S. S. I. L. Two. TNF alpha. Dead limitation of biomarkers have low sensitivity, lack specificity, limited diagnostic value. S. S. A. And S. I. L. two may have some ruling prognostication. They are just additive. When the biopsies inconclusive, they do not take them, take into account, make a diagnosis with other features, not in isolation. So these three SNPs, I was talking about Graham one card 15 and T. G. Arbiter three. If you have those that means. And if a pulmonary sarcoidosis is highly likely patient will go to fiber optics. Al Qaeda's stage and every geeks can is very important to dissociate between inflammation and actual fibrosis. So we started doing pretty much allow everyone, we're trying to do have to dip it uh with pulmonary fibrosis, it is not easy to get approval from insurance, but we try to do to differentiate between inflammation and fiber optic disease. So that may be useful in future. So, this is a patient with FDD scan. This patient presented with uh the syria had a prostate, irregular biopsy was done because of threatened prostate cancer. Found out to be granuloma, occurs inflammation of sarcoidosis. Then you can see patient had a pet scan and you can see lighter pets can hear here in the lung, in the bones, everything in the kidneys and patient that stark white all over this is actually a sarcoidosis. So, investigation, what did we learn in the divergent lacks specificity and you have to be a clinician? Can I quickly Christian? Can I quickly finish the 4th pot and then I can take questions both of them together? Yes, absolutely. Go ahead. Yeah, biggest time. So this is the I think the most important slide for you two years this was published by a paper of doctor Medusa and dr culver. Right in 2012. The road this paper and I or whenever I talk about sarcoidosis, I show them this one from the chapter book chapter. So patient patient preference. When do you favorite treatment? Not everyone needs to be treated. Sarkozy by itself doesn't need treatment. So minimal symptoms could organ function, low risk, highlight your remission observation is favored if the symptomatic organ function, impaired progressive disease, clear card activity, low like remission then treatment is favorite. There is no role of granuloma here. No question of granuloma. So that's what they said they assess is as as a relationship of granuloma occurs inflammation Like this lady I talked about considered diagnostic and therapeutic treatment trial and evaluate and manage coexisting illness which will see in a minute for comorbidities. And then if you decide that patient has a symptom burden, hi symptom burden and high organ dysfunction then treat. But before treatment defined goals and expectations, initial steroid sparing therapy oddly if symptom burden is low and and no organ dysfunction, observe. So this is i this was others with surprising in paper from published from F. S. A registry foundation of sarcoidosis research. The most common cause over 60% of cardia treated was treated. Now it is I should say it is nearly 100% after the F. S. R. Is uh if sorry hrs uh the heart rhythm society guidelines came most of them get treated. This is surprising to me. The one is iron calcium because we if they have a I. Sarcoidosis and hyper calcium A. We tend to treat them always because ISIL did can ocular psychologists can lead to blindness. I don't know if they're sitting on the top of optic to that's the problem. I don't know they are included neuro or not plus hyper calcium and we tend to treat. So this is this is the data from foundation of sarcoidosis research treatment effect. Remember treatment doesn't alter the national courts of illness. Treatment does not influence rate of radiological resolution. Early immuno suppression does not prevent progression of fiber optic stage. This is a bit of old study but useful. So all these patients in these countries were treated with high dose predniSONE for a longer cause But you see none of them their disease. The imaging normalized. This was the best after five years. Still there were 20% abnormality. So it does not. This disease does not clear up with treatment. So that's why I said a statement. It is unclear what we're trying to achieve by treatment and what is the end point and how to assess that. That's a difficult. So I put the slides is very important. Most common cause Of treatment ISIS Dystonia patients. This nick the effort to get referred to me, they are on 50 mg pregnancy hobbies get worse. This next are quite patient. Remember it could be due to lung disease, but remember there could be a western Asus steroid, noise, T conditioning steroid makes it worse. Cardiac sarcoidosis you have to look for. It could be anemia obesity. Giving steroid you make it worse, myopathy, diaphragmatic disorder, parliamentary hypertension or para sarcoidosis. Remember before treating steroid, whether it is actual lung disease, are this causing the problem? This is another thing. Para sarcoidosis syndrome. We looked about the three things fatigue, pain and despair. So it could be due to many other factors not directly related to sarcoidosis or grand millimeters disease like depression, fatty can be. Sarkar has a sleep pattern disturbance. They have a higher incidence of us, a pulmonary hypertension, de conditioning small fiber neuropathy because a severe shortness of breath do, but it is not due to the lung problem. So consider that before putting the patient on steroids. So basically, if you see that when you start steroid treatment wise, good prognosis, responsive organ, respond no cold war, it is an acute onset, you continue steroid and if you see these are the factors present chronic disease, poor prognostic factor, then you think of steroid sparing agent from the beginning So that you can give less steroid. This is the disease first diagnosed by the way, 1859 1st, they thought this are quiet because they used to talk, thing is a *** in Sarcoma. They knew about Sarcoma. That's how the diagnosis was established in King's College. So this is with the timeline of medications. It's a little bit of wrong, but I haven't found a better slide. Golimumab has been studied and found to be not effective in first retrial. A lot of including myself, a lot of oh most of the parliamentary uh are quite specially sneer at mike. Finally being an antipsychotic agent. Except if you're from john Hopkins. So a group called the card, First line of therapy most commonly used risk of complications is very high. So this is a study in which they looked at the I think M. U. S. C. Uh from M. U. S. C. So I looked at the outcome was new adversity, Ocular complication, bone density, Western high potential lipid and diabetes sarcoidosis. You can see there's a significantly hard with psychiatrists, I'm sorry, with glucocorticoids treatment. So there's a high risk of complications. Remember that before treating glucose with glucocorticoids. This is the general indication for other immuno suppressions. Bottom line is that if you anticipate that sick more than six months of therapy is needed, then give them at the beginning, Don't deliver and wait for steroid to give six months and gradually taken so steroid rapidly within three months. But if you think the disease progression disease will not progress and you have a feeling that you can take the steroid down less than 10 per to less than 10 mg, then do not give him, you know, separate at the beginning. Wait for six months to assess. So methotrexate is the only agent studies randomized control trial metrics that exerted moderate steroid sparing effect over 12 months. That's the evidence we have. Adelphi study of narcotics to reach a consensus Metrix that should be second line of agent steroid sparing agent case City's electricity reviews short the efficacy of left you know, mind there is some placebo control but non randomized trial with entity and I followed particularly in euros, are quite cardiac side, quite an Oculus are quite so it is effective recently. The study has been done with cyril Emus and this is an interesting fact. It has seen those who have TNF 30 G. L. L. Present non mutation there in them entity NFL for works much better three times better response. So you can personalize your therapy if you have to give anti TNF alpha find if they have got this L. A. Or not. These are the from the emerging potential years. I have put the slide. This is from a paper I wrote with Dr Jackson. So these are the small trials you basically use when it's a kitchen thing method, you're trying Kitchen thing method. Everything you tried failed including inflicts the map. I think only thing is after jail and cycle of of somebody is important. But after this the slowly mistrial came so with a good effect. So if I have to go to this stage where anti TNF alpha is not working, so either I'll try cycle for some might or now serially Majali's So suggested treatment algorithm, first line of a corticosteroid. You can wait for six months and try to bring it down 10 mg or if you think potentially they will need longer than six months of therapy. Start a second agent. Second agenda metrics said as a higher plane. If they fail, put on a third agenda you can try another second agent 30 in fixing a bad anymore, if they do not work, then put the patient on those medications I showed. But now it is answer just inflict uh, synonymous. So, caveats. No. All actives are quite modest treatment. Yes. R and C. Are we have no role entity. NFL for dozing. We don't know the ideal those we follow the diabetes treatment Sienna. This has no role in sarcoidosis. This is very important to remember and micro finality is of little benefit. The only place I would be microfinance has the beginning is Reynolds sarcoidosis. That is the word Microfinance has been found to be effective. I just saw a patient I think in the last few days, reverent U. V. A. It is treated with microphone knowledge. Did not respond. I will not try that. That's the only indication is one of the sarcoidosis. Spine on a tree is helpful. Not decisive because we utilize EVC pet scan has a potential role littering inflammation. So that is evolving. Maybe we'll be doing more pet scan to assess inflammation versus non inflammation future. Remember, we still used too much steroid, that's important. So Salgado's optimal treatment is unclear. No clear cut 10 points. So have a couple of slides were finishing so ideology of sarcoidosis. We do not know how sarcoidosis happens. We do not know how sarcoidosis evolves. We do not have the ideal investigation classes the disease activity and we do not know what the treatment does and now you know why have become a stark white export. It is easy, you don't need to know anything because there is everything is unknown in south Korea but that's the challenge as well. So Unmet needs better understanding of Ethiopia to genesis. Exane trial is going on that will give a good modeling biomarkers. Eight year study is completed. They will publish their data. They have assets biomarker in the study, a better prognostic stratification who will get at risk, we saw it to find it out. Grad studies working on that targeted management. So this is a study pan european study. They have divided quite in five clinical phenotype. They're trying different medicines and still we need to know inflammatory and stage for sarcoidosis, a precise role of antibiotic versus anti inflammatory therapy. So as we discussed this patient needs a lot of care tender loving care besides just treating with steroids. That was the whole idea with the established house are quite center and T. G. H. We have a dedicated SAR quite clinic now Parliamentary and extra pulmonary sarcoidosis. We have built a well established guidelines which we which we line with the Fs are guidelines and we treat all types of sarcoidosis, pulmonary ski in cardiac. Everything we have in the process of developing and what a multidisciplinary team who meet regularly and discuss about the cases. There's a pulmonologist, pathologist, cardiologist, neurologist, and most importantly, as a result of this effort, we are the sarkozy recognized market Center of Excellence in florida. Now, only one center has got it. So these are the team members of sarcoidosis. I think this is an opportunity to thank them for their contribution. They work hard, make the patients like better and they have done a great job so far in establishing and making this clinical success in summary. Sarcoidosis is a disease of large phanatic variability due to complex combination of genetic susceptibility, immune network and still unknown infectious environment still causing agents, diagnosis of star quad request clinical correlation plus presence of non caucasian granuloma. But remember not all non engagement in granulomas are due to sarcoidosis, mortality are not the key outcome. So do not go for survival in sarko and unlike other disease we have seen, it causes tremendous hermetic burden, psychological burden and economic burden in sarcoma to try to address this issue issue. Only 40 points are quite questions require therapy. I talked about the study from the last are quite centers. All aunties are quite medication are toxic. I did not get time to go through those and associated with significant side effects. More often, they are problematic in the disease itself. You have to consider that before treating and the critical decision is still who to treat, when to treat and how long to treat. And if you have any problem, that's why you need to send the patient to see archive specialist. Thank you. And I'll take any further question. Yeah, sure. We have um, one more question in the Q. And to the audience. If you have any other comments or questions, please use this time to chat or type them in the chat box. Um So doctor, are there any current biomarkers favored or are there still considered investigational or experimental or research tools only. They are all research tools only. We do not have any biomarkers biomarkers. So biomarkers depend on diagnosis and prognostic uh prognostication soluble until look into and uh solution to look into and S. S. S. A. S. Uh systemic uh false. Is a systemic amyloid proteins. S. A. So um allowed associated putting this to have been found to be good to prognosticate. But some studies showed some did not show. I think most important market will be emerging in future. If we can do pets. Candace is the disease activity Like MRI scan. We have a duty to wait imaging to assess oedema of sarcoidosis and tell us the treatment so that will be the future. And I think it is more of an imaging biomarker than chemical biomarkers. Sorry. One more question came through. How do we refer a patient? Sorry can you repeat the question once more questions of course. How do we refer a patient? Okay I cannot tell you this. This is cmi uh We have a clinic. Our clinic is in the under the disease of Center for Advanced lung Disease and lung transplantation where you refer for I. L. D. Parliamentary high potential lung transplant where we do this are quite clinic. So please refer in the same stark white clinic uh Same place it is uh under the lung lung transplant and center for Advanced lung disease in the Tampa General Hospital. Thank you. And if anyone does have a referral information I'm happy to send that out by direct request. You all should have my email. So I just want to end with a thank you to everyone for joining us and thank you for thank you to Dr Vandy for your time this evening and just a reminder to the audience, I'll email you all with directions on how to clean your CMI or CPU credits within the next couple of days. So thank you from everyone at T. J. H. And have a good rest of your night. Thank you very much. Thank you. Great question. Thanks. Thanks. Published June 14, 2021 Created by
