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Glucocorticoid-Induced Adrenal Insufficiency
Glucocorticoid-Induced Adrenal Insufficiency
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Please welcome to the stage, Endocrine Society President, Stephen Hammes. Hey, everybody. Thank you so much for being here. So this is a very exciting event because we always have guidelines and then we come out with our guidelines and then European Society of Endocrinology comes out with their guidelines, which are like 98% the same, but they're not always the same and it never made sense to us. And so we really worked hard for this diagnosis and therapy of glucocorticoid-induced adrenal insufficiency to do a joint guideline. And we presented this first at the European meeting and now we're going to present it here. And what I'd like to do is bring out the president of the European Society for Endocrinology, Jérôme Bertara, and he is going to introduce our panelists and then we'll get going. So Jérôme. Thank you very much, Steve. It's really a great pleasure for me to be here as the president of the European Society of Endocrinology. This is a grand premier of a joint guideline between our two society. And I think the topic is of special importance and I think is really filling an empty space in the literature. So that's really a great joint collaboration between our two society. And as you know, this is jointly published in the GCNM and EG. I will now introduce the chair of the guideline, Felix Böchlein from Switzerland. And I think Felix, you're going to introduce the panelists that are going to present the main fact of this guideline. Absolutely. All right, ladies and gentlemen, let's do this. Perfect. Here's our conflict of interest slide. The more important and more pleasant part is here. These are the 12 experts from six countries, endocrinologists, nurse practitioners, methodologists, epidemiologists. And we all came together to bring this guideline into fruition. So what are you going to expect? We are having a very small piece of definitions. Then we're going to hear on a systemic review and clinical questions from Olaf Dekkers. And then we go through the different recommendations of the guidelines. And in the end, bear with us, we will have questions and answers. And about that, please, now you're supposed to take out your smartphone, scan in this QR code, which will enable you to answer questions, because there will be questions also for you as the audience. All right. I keep this for another three and a half seconds. OK. We have one important definition. And this is here given in blue. And this is the background for some ambuities and some ranges that we are going to discuss in a minute. Let me read this. Glucocorticoid exposure should be considered as a multidimensional risk factor, including dose, frequency, administration mode, duration of the therapy, the potency of the individual glucocorticoid, and very important, the individual's accessibility. And that is the basis and the reason that we're talking about ranges. So the first range, duration of glucocorticoid therapy to post-risk for adrenal insufficiency, three to four weeks or greater. The dose of glucocorticoid therapy to post the risk for glucocorticoid-induced adrenal insufficiency is any dose greater than a daily hydrocortisone equivalent of 15 to 25 milligram. And you can do the calculation. That equals to four to six milligram of prednisone or prednisolone, three to five milligram of methyl prednisone, and 0.25 to 0.5 milligram dexamethasone. This is the basis for the next part of the definition, which is very easy. So this is the definition of the physiological daily dose equivalent. Everything above that, we name during the further guidelines supraphysiological glucocorticoid therapy. Then about the duration, short-term is anything below three to four weeks. And above that is long-term glucocorticoid therapy above three to four weeks with glucocorticoid doses greater than the physiological daily dose. And the final part of the definition is the glucocorticoid taper, which is initial guided by the management of the underlying glucocorticoid-dependent disease. And that we phrase therapeutic taper. And later, by the management of the glucocorticoid withdrawal and or adrenal insufficiency. We phrase this the endocrine taper. With this in mind, I would like to introduce Olaf Decker from Leiden as the epidemiologist. And he is going to get us through the clinical questions and the background. Please. Thank you, Felix. I think it was really fun, actually, to have a joint guideline to work together with two societies. And if my vote would count, I would say, let's continue with this project. So I would like to present to you a little bit about the background, about the evidence that is there or that is probably not there. And when my children asked me, what are you going to do in Boston? I said, well, I have to present for seven minutes. And they said, well, you're going to Boston for seven minutes. I thought a little bit about that and said, well, there are some people in the Olympics who go to Paris for even less than seven minutes when you have to run the 100 meters. So I think I'm pretty fine with seven minutes. So this is what you all know. And probably you think this is a boring slide. But it's good to have it in the back of your mind. So what is the great approach that we use for guidelines? The great approach starts with defining a clinical question. And a clinical question is the question that you pose when you have a patient in front of you. And based on this clinical question, you do your systematic research. And you then give the evidence a score, a quality of evidence score. And you have four categories for that, which I will come back to that later. And then finally, you formulate everything that is in the guideline in terms of recommendations where we have two grades. One is a strong recommendation where we say we recommend. And we have a weaker one, or some people say conditional one, where we say we suggest. And I would like to give you a short definition or definition in use of those two meanings of the recommendation. A strong recommendation means that most reasonably informed persons, the clinicians, politicians, patients, would want management in accordance with the recommendation. The weaker one leaves a little bit more open and say, well, most people would like to act in accordance with the guideline. But some, or even a substantial number, would not. And this is a sort of magic. This is the way we do the guidelines. We sit together. We bring the evidence in slides, in tables, sometimes even in a meta-analysis. The evidence is the starting point of a discussion. The evidence is not dictating what should be the recommendation. So you bring the evidence, or we as methodologists bring it. And then a lot of other things come in like values, preferences, doctor's preferences, for example, clinical experience. I think sometimes we are too harsh in saying, oh, that's only clinical experience. I think clinical experience really is of value for guidelines. Costs, also important point in this guideline is the resources, given the high number of people around the world to take leukocorticoids. And then finally, we come up with recommendation. And I think the bottom line is we hope they're reasonable. You can argue sometimes about them. They're probably not set in stone for the next 100 years, but I think they're reasonable. So then another discussion point is, should we have guidelines or should we have consensus statements? What is in a name? And some people say, well, you can only have guidelines if they're based on solid evidence. And I say, OK, that's fine. And probably we only have guidelines on osteoporosis and some areas of diabetes. But even there, there are so many questions out there, even for osteoporosis, that are not answered by randomized data. So saying that a consensus statement is preferred in the absence of evidence, I tend not to agree for several reasons. So first of all, I said already, even if you have evidence, there's no sort of logic that transforms evidence into recommendations. Secondly, every recommendation, even if you have strong data, requires consensus, requires discussion. And I think it's always important to search for evidence, because even if you have whatever number of very well-known people in the field, it might be that you missed some papers. So here's a poll for you. And the question now is, how strong do you think is the evidence for the optimal test algorithm or the tapering scheme in patients that take glucocorticoids and might want to stop, or the doctor may want them to stop? Okay, I think it's reasonably settled. More than half of the people here think it's low. Then, I think, what will it be, 20, a little bit percent say it's moderate, and a little bit more say it's very low. So, here's the point. So the evidence in glucocorticoid-induced adrenal insufficiency. There is not much out there, and what is out there is based on rather small data. Most evidence is descriptive and does not directly inform on optimal treatment, and literature on testing does not relate biochemical results to clinical outcomes. So, we concluded that the evidence for all recommendations is either low or very low, and please don't blame the guidelines for that. And I think we as clinical scientists should blame ourselves because 1% of the population takes glucocorticoids. How can it be that the evidence is so terribly weak? So there's a lot of work to do, but given this, we have to do something because in the absence of strong evidence, we should say something. We cannot say we can't give you guidance because the evidence is not solid. By the way, this is a picture of one of the most exciting days in the life of my wife, and I like this quote. It's a quote from 10 years ago, but I think it still holds. It is certain that high-quality evidence will not be available in all clinical situations, and in situations where high-quality evidence is not available, expert opinion and careful synthesis of low-quality evidence will continue to appropriately guide clinical practice. So what were the clinical questions that we posed for the guideline? I will highlight three of them. So the first was about the incidence of recovery of the HPA axis in patients with glucocorticoid-induced adrenal insufficiency. Then we searched for evidence on the optimal tapering scheme, and we searched for evidence on the diagnostic accuracy of the different tests. And I think this is a very well-known, at least it's a very well-cited paper. And actually, I'm still uncertain. I'm one of the authors, so I may say so. Still uncertain whether this is true. I'm still surprised by the high number, but it shows that sometimes even up to 50% of people who are on glucocorticoids have biochemical adrenal insufficiency. If you retest them, and that was the question for the clinical guideline, you can see that there's a decrease in adrenal insufficiency from 39% to 15% after four weeks. And even after six months, you can still see some people who recover from the adrenal insufficiency, and we knew this. However, it's hard to draw firm conclusions for this. First of all, small number of patients, different populations, different tests and cutoffs used, and an unclear selection of patients. Most importantly, and I think this is also a drawback of the MATES analysis, the data are not related to clinically relevant outcome, being it either symptoms or adrenal crisis. Second question, what is the optimal tapering scheme? That's the question we as endocrinologists very often face when we're called by the rheumatologist or by another doctor. Well, we gather data from only five studies, in asthma, in multiple sclerosis, and in all these studies, adrenal insufficiency was not a primary endpoint, but we looked at the data for adrenal insufficiency as a sort of side effect. In all these studies, biochemical testing was not performed. There were three studies where they compared stopping versus placebo, one comparing tapering, where we only took the tapering patients, and one study compared different individualized tapering algorithm. This was the largest one. The bottom line here is that in all these, what is it? I think approximately 860 patients, something, the bottom line is there were no cases of severe AI reported. Again, given the high number of patients that use it, this number of patients studied is still low. No data, as I said, on biochemical testing, so we can't say anything about the optimal tapering scheme or even the optimal stopping scheme is in patients who are trying to get off their glucocorticoids. And finally, we searched for evidence on the diagnostic accuracy of a morning cortisol versus an ACTH test, because if you can provide guidance with only a morning cortisol, that would be a big plus in terms of costs and resources. And there were three studies studying and comparing these two tests. Well, actually, a morning cortisol is probably not a test, but if you use the morning cortisol, and here are the cutoffs, both in nanomole per liter and in a microgram per deciliter, below 100, it quite accurately predicts an ACTH test that also shows adrenal insufficiency, and approximately above 300, and we will discuss this boundary in much more detail than I will do now, then in most of those cases, probably in almost all, you can see that the ACTH test is what we call positive, meaning it shows that there is no adrenal insufficiency according to the ACTH test. So, however, relatively small number of patients, and again, and I think this is really a drawback, no data on relation with clinical symptoms or adrenal crisis. And having said that, I would like to hand over the floor to Tobias Els, who was the co-chair of this guideline. All right. Thank you, Olaf. So, first, I wanted to say, actually, if you have questions along the talks here, please put them in the chat. We see them here, and we'll answer them later. The second thing I wanted to say is actually that this is a very special moment for me, professionally and personally. I joined the Endocrine Society Guidelines Enterprise about 10 years ago, and I was always wondering why we can't do guidelines together. But obviously, as I learned along the way, there were a lot of roadblocks, and I wanted to thank the leadership of the Endocrine Society and the ESE that helped to remove those roadblocks so that we actually arrived at this point here. This is fantastic. Thank you. Okay, and I will actually start here with a quick question. And we can poll this as well. I think I, no, we can't, right? How do I go back? Oh, but we don't have the, okay, anyway. So your favorite dermatologist calls to get your opinion on which of the following patients to refer to endocrinology, and now this already disappeared, but there's a patient with a cutaneous lymphoma for three years, varying doses of prednisone therapy, average 20 milligram daily, tapered to bring prednisone, tapered to five milligram prednisone and now experience a tiredness and fatigue, and the other one is a patient with three week course of combined oral prednisone, 20 milligram per day, and topical tremcinolone and a serum 8AM cortisol measurement of 4.2, and I do not see the other ones anymore, but they will appear later again, so we can continue the discussion at that point. I'll give it another minute here, but it's pretty clear what all of you are deciding, the patient with lymphoma is clearly the one that is presenting the most concern for the audience here. All right, so let's start with our first recommendation, and this is really about defining the population and responsibilities. So we recommend that in general, patients on or tapering off glucocorticoids for non-endocrine conditions do not need to be evaluated by an endocrinology specialist. Okay, glucocorticoids are used really for a variety of non-endocrine diseases such as inflammatory diseases, autoimmune disorders, atopic, allergic conditions, as well as for the prevention of transplant rejections, and overall, about 1%, like Olaf already mentioned, of the population is on chronic steroid use at all times. Glucocorticoid therapy is really a general skill, and that's something we wanted to point out with this first recommendation, and an endocrine specialist is not necessary for the treatment for glucocorticoid, and even for the tapering for glucocorticoid therapy. We really need to partner with prescribers, but need to realize that the glucocorticoid therapy, as well as the taper, is truly owned by the physician who starts this treatment. Second recommendation, we recommend that clinicians who implement treatment with glucocorticoids educate patients about various endocrine aspects of glucocorticoid therapy. This is simply good clinical practice, and we found that it's important to educate for heterogenic Cushing syndrome, bone health, hyperglycemia, as well as adrenal insufficiency, what these guidelines are about, and this should ideally actually happen at two places, one with the initiation of glucocorticoid therapy, and then also when the dose of physiologic daily dose account is reached, and also education about glucocorticoid withdrawal syndrome, where we really hope that that gets a little bit more traction, because this is simply still unknown outside the endocrine world in a lot of cases. Recommendation 1.3, we recommend that patients on glucocorticoid therapy have access to current, up-to-date, and appropriate information about different endocrine aspects of glucocorticoid therapy. That is also good clinical practice, and there will be actually, or is already in some cases, patient education material available, and this focuses on the ESE page currently with questions like what are glucocorticoids, what is glucocorticoid-induced adrenal insufficiency, what happens with TAPO in stopping glucocorticoids, how to treat glucocorticoid adrenal insufficiency, and what is glucocorticoid withdrawal, and this is simply thought to actually empower the patient and induce the right understanding about all of these issues that can occur with glucocorticoid therapy, and while the guidelines itself are more thought as a guidance for physicians, this is the patient guidance. All right, they can be found here under this QR code, and we also thank all the patient organizations that actually contributed to this patient leaflet. All right, so the next question is when to taper and when not to taper. We suggest not to taper glucocorticoids in patient on short-term glucocorticoid therapy of three, less than three to four weeks, irrespective of the dose. In these cases, glucocorticoids can be stopped without testing due to low concern for HPA axis suppression. There are times and dose thresholds that's very important for suppressing the HPA axis and to develop a risk for glucocorticoid-induced adrenal insufficiency, and for the treatment, we decided this greater than three to four weeks, and the dose greater than 15 to 25 milligrams of hydrocortisone or equivalents of other steroids. And below this threshold, really a taper is not necessary, and I think I would like to point out here one more important message of these guidelines. You see that we're actually providing a range here greater than three to four weeks, and while this mathematically does not make too much sense, we really wanted to highlight that there is truly very low evidence in providing any kind of cutoff. There's an individual provider preference, and this can certainly be individualized from patient to patient as well, and that's what we try to recognize with providing these ranges here. Next recommendation is glucocorticoid taper for patients on long-term glucocorticoid therapy should only be attempted if the underlying disease for which glucocorticoids were prescribed is controlled, and glucocorticoids are not any longer required. In these cases, glucocorticoids are tapered until approach during the physiological daily dose equivalent is achieved, so about four to six milligrams of prednisone. So the bottom line here is, and that makes total sense as well, only taper when disease is controlled or the glucocorticoids are not necessary anymore. So to get back to the audience question here, which one of those patients of your favorite dermatologist should actually be referred to endocrinology? I think you can make a point that none of them actually needs to be referred. In terms of the cutoffs and the symptoms, if the dermatologist truly feels uncomfortable with providing further treatment and tapering for this patient, then the patient B would probably be appropriate to be seen by an endocrinologist, but I think it's very important to point out that there is no magic procedure or no magic tapering scheme that endocrinologists would provide in terms of getting this patient off glucocorticoids, but it's valuable to be seen in case they need long-term steroids and that would certainly be an endocrine task to pursue. Thank you very much. And with this, I would like to actually introduce Irina Bankos from the Mayo Clinic in Rochester, who will talk further. Well, I'll start my presentation with two cases from my adrenal clinic. Patient number one, a 47-year-old woman with history of surgically treated meningioma. She was diagnosed with large meningioma eight months ago, had surgery three months ago, postoperatively initiated on dexamethasone, four milligrams twice a day, and by the time she got to my clinic, she was on dexamethasone one milligram twice a day. And she was referred to endocrinology because cortisol was measured by her neurologist and was undetectable. So patient number two is a 53-year-old woman with history of remote arthritis, and she provided history of intermediate prednisone use for around four years, and then continuous prednisone use for around 18 months, at least 10 milligrams prednisone a day for the last 18 months. Six months ago, she was initiated on non-steroid agent, and it seems to be doing well as far as remote arthritis. The reason she was referred, because despite the fact that her rheumatologist advised her to taper and stop prednisone multiple times for the last four months, she was unsuccessful because she would develop fatigue, nausea, myalgia, and astralgias, and would need to go back on prednisone to feel better. So I just want to point out that the first patient is on dexamethasone one milligram twice a day, and the second patient currently is on prednisone 10 milligrams each morning. So I hope the poll is going to wait. I'm going to ask you about patient number one. Okay, so I think you are seeing the answers. This patient has three months history of dexamethasone use. To summarize the situation, currently on one milligram twice a day, and neurology recommendation is to decrease to one milligram dexamethasone for one week, and then stop. What do you recommend? And I hope you're seeing the answers, because I no longer do. It's still moving a bit, so I'll give it another few seconds. Okay well we're clearly having a winner here. So the the most common answer that people chose is once dexamethasone therapy is completed initiate hydrocortisone therapy 15 milligrams on waking and 5 milligrams in early afternoon. And the second most common answer is continue dexamethasone taper to 0.5 milligrams and then measure morning cortisol. Other answers was we're not particularly popular. Okay well my answer was one of the unpopular ones but we'll get there. So first is testing for adrenaline insufficiency necessary? And I would like to use this cool graph that Alessandro Preti developed and I would like to explain the graph because I think it's important before we go further. So the graph has three panels. The one on the left illustrates the patient who still takes supraphysiological glucocorticoid therapy above 5 milligrams prednisone a day. And you see the shaded area in the middle which is reference range for either cortisol or ACTH. The panel in the middle is a patient who is on physiological dose of glucocorticoids let's say 5 milligrams each morning. And what happens with HPA axis during that time? So ACTH is the hormone that usually recovers first because pituitary needs to recover first. And then it would usually even go to above normal ranges and then that drives cortisol production from the adrenal cortex. And again the panel on the right illustrates that patient recovered from adrenaline insufficiency and prednisone can be stopped. So our patient when cortisol was tested for her on dexamethasone 1 milligram twice a day it was still quite supraphysiological. So our patient would be placed in that first panel where it would be completely expected to have both undetectable ACTH and undetectable cortisol. So that brings me to recommendation 2.4. We recommend against routine testing for adrenaline insufficiency in patients on supraphysiological doses of glucocorticoids or if they're still in need of glucocorticoid treatment for the underlying disease. And the good example here would be let's say a patient with polymyalgia rheumatica who would not plan to stop prednisone. Now the patient is on dexamethasone. Does glucocorticoid type used in a patient of glucocorticoids impact the likelihood of adrenal recovery? And we think it does. Here's a table with glucocorticoids and we all know that glucocorticoids have different glucocorticoid potency, different half-lives, plasma half-lives and biological half-lives. The shorter acting glucocorticoids on the top, the intermediate ones in the middle and the longer acting glucocorticoids are on the bottom of this table. Recommendation number 2.5 suggests that patients taking long-acting glucocorticoids such as dexamethasone, our patient number one, should be switched to short-acting glucocorticoids such as hydrocortisone or prednisone when long-acting glucocorticoids are no longer needed. So going back to our audience question that you all voted on, I would say that what I would choose would be to start prednisone therapy 10 milligrams each morning. And just because this answer was very unpopular, let me explain why. So first recommendation 2.5 does recommend to change dexamethasone to a shorter acting glucocorticoids. Prednisone is one of the choices. Hydrocortisone or prednisone would have been fine. The second thing is, you may recall, well actually it's here in the stem, this patient has been on glucocorticoids for quite some time and it was supraphysiological glucocorticoid use. So it's very likely that this patient would not do very well if you would switch this patient to hydrocortisone physiological dose right away. You can certainly try, but in my experience, these patients would develop pretty severe glucocorticoid withdrawal if you go from 2 milligrams dexamethasone right away to 20 milligrams hydrocortisone a day. I will illustrate this concept which brings me to glucocorticoid withdrawal with patient number 2. To remind you, this is a patient who has remitted arthritis for four months of prednisone therapy, but for 18 months it's continuous supraphysiological use of at least 10 milligrams prednisone a day, does not need it for remitted arthritis and keeps trying to discontinue it without a lot of success. So that's actually quite common in my clinic. I'm not sure if the same in yours. And that brings me to talk about glucocorticoid withdrawal, because as this patient was going down from 10 milligrams to 5 milligrams and then maybe to 2.5, she probably, at least at the initial stages of the state, but would experience glucocorticoid withdrawal. Maybe at a later stage is also unreplaced adrenal insufficiency. So let's look at difference between the symptoms, signs, timing of symptoms, the risk of adrenal insufficiency and glucocorticoid withdrawal versus adrenal insufficiency, and also comparing to underlying condition for which glucocorticoids were actually initially prescribed. For example, in my patient, the arthrologist and myologist she experienced, she was convinced it was a flare of remitted arthritis, despite the fact that her rheumatologist said, look, you don't have any indices of active disease. So glucocorticoid withdrawal is a clinical diagnosis. We expect patients to have a general feeling of unwell, fatigue, nausea, muscle and joint pain, sleep disturbances, and mood changes. That's what's important to know, that these symptoms usually happen when patient is still on supraphysiological glucocorticoid dose. Well, at least I should say not on under-physiological dose. So it would be 5 mg Sprednisone 7.5-10 in this case. So it is happening because of relative decline in glucocorticoid dose, not because of glucocorticoid insufficient or suboptimal replacement of adrenal insufficiency. Let's see what we want to do with this patient. So patient has an 18-month history of supraphysiological prednisone use, symptoms of fatigue, nausea, arthrologist, myologist, and every time she decreases prednisone to under 10 milligrams, she feels unwell. In addition to counseling about glucocorticoid withdrawal syndrome and what are the expected symptoms, what else would you recommend? So I see one of the option is to tape it on prednisone the second so that's currently most popular The second option would be to switch to hydrocortisone at a higher dose 20 milligrams twice a day Or that just not trust rheumatology It's like no, it's rheumatoid arthritis And I think that's all I see for now so Okay We'll talk about the answers in a bit First I would like to tell you what happened to this patient so This is a recommendation We recommend consideration of glucocorticoid withdrawal syndrome that may occur during glucocorticoid taper and when it is severe Glucocorticoid dose can be temporarily increased to the most recent one that was tolerated and duration of glucocorticoid taper could be increased So What we decided to do We decided to To taper down prednisone slowly from 10 to 5 milligrams by 1 milligram down each week And this is what most of you chose But I do want to point out that it would not have been inaccurate to actually try hydrocortisone 20 milligrams twice a day I feel like it's more work for patient, but it's certainly possible to give slightly Supraphysiological dose of hydrocortisone and taper that eventually to 20 milligrams a day So what happened to patient we did not test patient for adrenaline insufficiency while on 10 milligrams prednisone a day we thought that our pre-test probability of adrenaline insufficiency was 100% and Then we advised slow taper and it did take her quite a few time as you see by two months She was on eight milligrams of prednisone each morning by four months on six milligrams by six months after this taper She was on five milligrams of prednisone each morning and after a few weeks of that This is the first time we did test her cortisol in the morning She did not take prednisone in the morning until after the blood test cortisol was low We continued we actually went up one milligram of prednisone because she thought she was not doing well on five She did much better on six milligrams and then successfully was going was able to go down to five milligrams each morning And at that point by 11 months her cortisol was 5.7 microns per deciliter by 12 months It was 8.2 microns per deciliter. She no longer had glucocorticoid withdrawal symptoms And I guess we already talked about that I did advise her to slow taper prednisone one milligram decrease every one to two weeks But again option C would have been okay as well So, let's talk about Cortisol measurements first recommendation 2.6 We suggest that patients on physiologic daily dose equivalent of glucocorticoid aiming to discontinue glucocorticoids either one continue to gradually taper glucocorticoid dose while being monitored clinically for signs and symptoms of adrenaline insufficiency or to be tested with a morning serum cortisol and If confirmation of recovery of the HP axis is desired We recommend morning serum cortisol as the first test The value of morning serum cortisol should be considered as a continuum With higher values more indicative of HP axis recovery So let's look at this Cortisol gradient so it goes from zero to whatever it is, let's say it's 25 and Here with 10 microns per deciliter cut off and above We would recommend stopping glucocorticoids and to conclude that HPA recovery happened Here if cortisol is under 5 microns per deciliter We would can recommend continuing glucocorticoids for another couple of months three months for example And then again retest and here in between 5 and 10 micrograms per deciliter We recommend continuing glucocorticoids, but considering retesting first morning cortisol earlier than couple of months maybe in a few weeks now for People in the room who use different type of units like nanomoles per liter You may notice that the 300 nanomoles per liter does not equal 10 microns per deciliter it would actually would have been 270 if I remember correctly to equal 10 and Why is that why this cut-offs are not equivalent It's mainly to make it more memorable and to also highlight the fact that There is nothing magic about a specific cut-off here You have to use your pretest probability and clinical judgment to decide whether at 9.9 microns per deciliter You think that the patient still needs adrenaline sufficiency versus maybe concluding the patient has still adrenaline sufficiency at 10.1 microns per deciliter and With that I would like to introduce dr. Nan for idea All right, hello everybody welcome to Boston Okay, great, so we'll pick up where Irina left off with dynamic testing in patients who are tapering or stopping glucocorticoid therapy Recommendation 2.8 we suggest against routinely performing a dynamic test for diagnosing adrenal insufficiency in patients tapering or stopping glucocorticoid therapy So this is a suggest and so another way to word This is if you want to do dynamic testing or cosentropic stimulation testing you absolutely can but it is not necessary And I think most of you are clinical endocrinologist. So you have the experience and the nuances to know what that means So this is really for your non endocrinologist colleagues the ones who are prescribing the glucocorticoids Inducing glucocorticoid induced insufficiency and then referring them to to say help me Please do a cosentropic stimulation challenge while the patient is waiting weeks or months for that and a test that requires resources a room a nurse to blood draws sampling medication administration etc a a Morning cortisol measurement as Irina just mentioned can serve as a simple approach to assess the entire hypothalamic pituitary adrenal axis If the cortisol is normal It tells you that the entire HPA is functioning if the cortisol falls in that gray area that Irina just showed you on that spectrum it's your decision on whether to repeat on another occasion or whether a dynamic test might help you adjudicate whether the HPA axis is Restored or still needs more time to recover and We put this statement the decision to carry out dynamic testing should consider the tests availability Feasibility costs and regional accessibility, and I think even at major medical centers. We all struggle with the same issue So let's look at a case on how this plays out. This is a 53 year old patient I saw who was treated with long courses of high dose prednisone 60 milligrams in long stretches on and off for the course of one year for the treatment of idiopathic thrombocytopenic purpura ITP and She was referred to endocrinology because our ITP had resolved She no longer needed the prednisone and the hematologist said please help me remove this So actually as Toby mentioned earlier the responsibility to do. This is actually the hematologist I'm telling you the real true story at the time. I was Younger nicer, I'm a nice endocrinologist, and I had problems saying no I always said yes, but after this guideline you can tell you're referring hematologist actually read this guideline. This is your responsibility So I'll tell you what I did Here in blue on the left axis is her cortisol value the right secondary axis in orange is her ACTH values So I tapered her from 60 milligrams of prednisone to 10 the hematologist should have done this and then I switched her to hydrocortisone 15 and 5 I arena would have kept going with prednisone. You can see stylistically I preferred hydrocortisone. I believe she said either option is right. So but Irina is usually right so you can see at the beginning cortisol and ACTH are both suppressed and Then shortly after getting the patient down to a sub physio physiologic or sub physiologic dose ACTH rises It actually goes above the reference range, which is this dotted line into a super physiologic range You can see it dragging the cortisol up into the normal territory and then ACTH starts coming down I start tapering the hydrocortisone and then stop it and at the end when the hydrocortisone is stopped The cortisol has plateaued in the normal range and ACTH has come down and I'm showing this to you How do you feel like how do I go back? Oh, here we go The right one, okay I'm showing this cartoon to you because this is real data Sorry And it looks a lot like this cartoon Irina showed you Okay, I mean obviously her cartoon is very beautiful and professional and mine is really wonky because I made it in Microsoft Excel But this is real data. You could see ACTH rose to an above super physiologic range until the cortisol normalized and then the entire HP axis normalized and that's depicted here in this more beautiful cartoon and So the patient has a morning cortisol without any dynamic testing In fact, this is the dynamic testing an endogenous ACTH stimulation no need for an exogenous stim when the patient demonstrates endogenous stimulation and the cortisol is now in this green range where the Probability that the HPA axis isn't restored and normal is very high The likelihood of adrenal insufficiency is very low and we can feel happy that the patient is off glucocorticoids What about other clinical scenarios that require awareness of possible glucocorticoid induced adrenal insufficiency? Recommendation 2.9. This is a big one We suggest awareness of possible glucocorticoid induced adrenal insufficiency in patients number one with current or recent use of non oral glucocorticoid formulations presenting with signs and symptoms indicative of adrenal insufficiency or number two using multiple glucocorticoid formulations simultaneously or number three using high dose inhaled or topical glucocorticoids or number four Using inhaled or topical glucocorticoids for more than one year or number five who received intra articular glucocorticoid injections in the previous two months or number six receiving concomitant treatment with cytochrome p450 3a inhibitors So here's a case that demonstrates that was a long recommendation one of those scenarios 40 year old woman was referred to me because her cortisol was low when she said she was tired Somebody checked the cortisol and it was low. She was asked. Do you take any steroids? And she said no She doesn't have any physical stigmata of Cushing syndrome. She actually had a pituitary MRI that shows no masses or lesions So when I asked her when I saw her I asked her in a more specific way. Have you taken any glucocorticoids? Steroid creams steroid inhalers, etc I reviewed her medication list and actually she was taking inhaled Glucocorticoids that she said were for a diagnosis of childhood asthma She was on and off and now she's been taking it for 15 20 years Her most recent dose was fluticasone. And when you review it with her, she's actually taking 220 micrograms two puffs twice daily So that's at least 880 micrograms So this is how you write a question can inhale glucocorticoids for asthma induce adrenal insufficiency Okay, so I was hoping it would be a perfect donut, but no. So even this, of course they can. There's always some systemic absorption, but it's the fact that all of you know this, and the fact that inhaled and other non-oral glucocorticoids are extremely commonly used and ubiquitous is alarming if you're aware of this. So here's some data. Compared to placebo, the use of the budesonide and fluticasone inhalers do lower cortisol, but it's a dose-dependent effect, probably dose-dependent duration and several other factors that are not measured in this study. You can see the higher the dose of inhaled fluticasone, the lower the cortisol. This is, I think, a nice but also alarming study in asthma cohorts. These are patients with asthma using inhaled glucocorticoids compared to other patients with asthma who are not using inhaled glucocorticoids. And what these investigators found was that cortisol was lower in the group taking inhaled glucocorticoids. Actually, all adrenocortical steroids were lower, so suggesting of a systemic effect suppressing ACTH, and this was replicated in multiple asthma cohorts. So kind of terrifying that there is enough systemic absorption that we can measure off a cortisol biomarker that there is ACTH suppression. So here's her cortisol and ACTH. When I first saw her, very low. My first question was, why are you on so much fluticasone? I asked her pulmonologist, and he said, I have no idea. I inherited her 10 years ago, and she was on that dose when I met her, so she's just been continuing it. And I said, I'm not a pulmonologist, so do you think you can help lower the dose? And so he worked with her over several months to lower the dose, and in fact, she was able to come off inhaled glucocorticoids without any flare-up of her asthma. So when that happens, I just wasn't sure. Does she need a safety net of glucocorticoid or not? So I made this slightly wimpy decision of giving her a tiny dose of hydrocortisone just in case, and you can see in the subsequent months, her cortisol and ACTH both rise. The ACTH actually went into the supraphysiologic territory before declining. I stopped the hydrocortisone, and now she has a normal cortisol and reference-ranged ACTH. Again, this is not the prettiest picture, but it does look kind of like this more professional picture. So other clinical scenarios. The general point here is that glucocorticoids are given ubiquitously by every specialty in medicine. Topically, as you've heard about inhaled, intranasal, intraarticular, the evidence and data to comment on the potency, the incidence of adrenal insufficiency is pretty weak. You just have to know that it's possible. And understanding when the doses were given, the potency of the dose, and many other systemic factors, including concomitant use of more than one of these glucocorticoid supplements can help you predict the likelihood that a patient has developed glucocorticoid-induced adrenal insufficiency. And then we have a comment specifically about metabolism by CYP3A4. Glucocorticoids are metabolized by CYP3A4, as are many other medications. Among CYP3A4 inhibitors, grapefruit juice, some antibiotics, antifungals, but importantly, ritonavir, one protease inhibitor that's given in many HIV medications, can potentiate the metabolism of glucocorticoids and induce both Cushing syndrome and glucocorticoid-induced adrenal insufficiency. For people who, at least definitely in the United States, and I think it's variable in other parts of the world, who just survived through this COVID pandemic where Paxlovid was given quite frequently, you probably know this, but ritonavir is part of COVID-19. So the last four years, we received tons of calls about this. Every time somebody was prescribed Paxlovid, we got calls, your patient is on hydrocortisone or prednisone, is it okay to give Paxlovid? Even eplerenone, I see a lot of patients with primary aldosteronism, is metabolized through this pathway. So the phone calls have subsided, so I think COVID has kind of gone away and Paxlovid use has declined. But it's important to know that CYP3A4 inhibition can potentiate glucocorticoids-induced Cushing's and cause adrenal insufficiency. Recommendation 2.10, we suggest that patients with current or previous glucocorticoid treatment who present with signs and symptoms of exogenous Cushing syndrome are assumed to have glucocorticoid-induced adrenal insufficiency. Good clinical practice. I think as clinical endocrinologist, this makes sense. If the patient has physical stigmata of Cushing syndrome while taking glucocorticoids, they almost certainly have a suppression of the HP axis. Your non-endocrine colleagues may not be aware of this, so now you can show them this document. And then finally, last two recommendations, 2.11, we suggest that patients aiming to discontinue glucocorticoids but without recovery of the HP axis in one year while on physiologic daily dose equivalent should be evaluated by an endocrinology specialist. We suggest that patients on glucocorticoids and a history of adrenal crisis should also be evaluated by an endocrinology specialist, both good clinical practice. So we started off by saying that the responsibility of the glucocorticoid taper belongs to the prescriber who started it, which I think we cannot reinforce enough. But when should you step in and help out? I think one year of attempting at a fairly physiologic dose is a good point to lend your expertise and say, let me use my experience talking to patients and weaning with my special magic to help you out. If a patient is experiencing multiple adrenal crisis, of course, endocrinology should be involved to make sure that the patient is being guided appropriately. And then recommendation 2.12, we recommend against the use of flutricortisone in patients with glucocorticoid-induced adrenal insufficiency. So glucocorticoid-induced adrenal insufficiency is a syndrome of ACTH suppression. You need ACTH to produce cortisol, but aldosterone and mineralocorticoid action, even in the absence of ACTH, will continue with regulation of ANG2 and potassium. So these patients should not be started on flutricortisone. They do not need it. And with that, I will hand over the microphone to our fearless leader, Felix. Yeah, thank you very much. All right. The last bit, the last stretch, and we're coming to emergency. And I would like to start with this patient, this case vignette here. So it's a 60-year-old female patient who was found by her husband in a state of disorientation and somnolence. And he does, in fact, call the emergency. The patient had been diagnosed with pulmonary fibrosis three years ago. And among other treatments, she is under long-term off on steroid medication with pregnancy alone. According to the husband, the current dosage had been 10 milligram, but he's not sure about the timing of the latest tapering. The emergency team occurs and applies oxygen. They take the vital signs, and they show blood pressure of 90 to 60 millimeter mercury, a pulse of 98, oxygen saturation of 95%, a temperature of 38.5. And the patient reacts when spoken to. So what do you do? So no emergency glucocortisol replacement, as this would require more specific information. You bring the patients into the hospital to measure baseline cortisol. And the third one, you react as this would be an atrial crisis. All right. OK. All right. So baseline cortisol measures get a little bit further up. But I think we have the maturity here. And indeed, this is what the recommendation 3.2 is suggesting. We suggest that in patients with current or recent glucocorticoid use who did not undergo biochemical testing to rule out glucocorticoids-induced adrenal insufficiency and present with hemodynamic instability, vomiting, or diarrhea, the diagnosis of adrenal crisis should be considered irrespective of any glucocorticoid type, mode of administration, and dose. You just assume the worst and that the patient has adrenal crisis. Patients with suspected adrenal crisis should be treated with parental glucocorticoids and fluid resuscitation. And again, this is good clinical practice. And this is indeed what happened. Under the clinical suspicion, maybe infection-driven of an adrenal crisis, the team applies hydrocortisone in high doses and initiate fluid administration. And the patient is admitted to the hospital. OK. Now, there are cases like this where a suspected adrenal crisis needs, as an emergency, immediate treatment. And this is not much different from any other form of primary or secondary adrenal insufficiency. And also prolonged vomiting and diarrhea is another situation which requires treatment because the absorption of all glucocorticoids may be reduced. Again, not very much different from situations of, say, for example, primary adrenal insufficiency. Also very similar, we recommend that patients with current or recent glucocorticoid use who did not undergo biochemical testing again and you just do not have enough information to rule out glucocorticoid-induced adrenal insufficiency should receive stress dose coverage and they are exposed to stress. So again, good clinical practicing. And again, this is also shown in this figure here. It's very similar to the situation of primary or other courses of secondary adrenal insufficiency where moderate to major stress might require then parenteral glucocorticoids or minor stress where stress dosing can be done. There are a few nuances here and exceptions. For example, for patients on minor stress, if the patient is already taking hydrocortisone above 40 milligram or predisolone above 10 milligram daily or dexamethasone above one milligram daily, there is typically no need to increase the dose unless, again, there are signs of hemodynamic instability. This is for minor stress. And the same is for moderate or major stress. If the patient is, in fact, already because of the glucocorticoid-dependent disease on a very high doses, then again, an increase of further doses might not be necessary. But of course, if there is a suspected reduced absorption IV or AM, glucocorticoids are required. And this is the very final bit. We have realized, and this has been mentioned now over and over again, that the evidence for the majority of our recommendations regarding glucocorticoid-induced adrenal insufficiency is low or very low. So what should be done? In the future, there is a number of homeworks that we as a community are charged with. And here are some examples. And this, of course, could be prolonged even more. So for example, define the true risk of clinical adrenal crisis and adrenal insufficiency. In most of the cases, we're talking about a biochemical result of either baseline or stimulated testing. And this does not necessarily mean that all those patients would develop an adrenal crisis. The second one is definition of risk factors contributing to the development and susceptibility of adrenal insufficiency. Understanding glucocorticoid withdrawal, we have seen that this is, in the end, a clinical judgment. And it would be nice to have more maybe objective measures to convince yourself that this is glucocorticoid withdrawal and not adrenal insufficiency. Harmonization of cortisol assays and establishment of cut-off values using mass spectrometry would be another one. And of course, identifying glucocorticoids by retaining their immunosuppressive and anti-inflammatory property but have less effects on HPA axis suppression so that problem might go away at some point in the future. With that, I would like to highlight also that here, the group is represented here on the stage. But we were larger here, as you can see. I would also like to point out that the guidelines can be found both in EGE and JCM. And below, again, there is a QR code of patient information. So please spread the word and use these sources for yourself and also forward them to your non-endocrine specialist. With that, we come to the questions. Thank you already for putting those questions in. And please continue doing so. And we will read those and get into the discussion. Thank you very much. So with regards to the questions, there are several questions which are about kind of, I think, things that were also clarified later in the talk. But I think there are some points which are very good to simply underscore and to repeat. So maybe we start with the first question here because that was almost in here before the session started. Do you have a cutoff of a morning cortisol for which adrenal insufficiency is more or less ruled out and further testing with cosetropin is not necessary? And maybe we'll just ask Olaf about that. Yeah. I think we discussed it on several occasions. And I think it's important not only to have a single number that was discussed by Irene, but if you want to have a number above which you think there's really no chance of having adrenal insufficiency, then probably you're up to a number of 400, somewhere between 350 and 400. That gives you probably most certainty. But I think it's practical to go a little bit lower. And then you're, I think, safe with a probability of 98% or something. That's what the literature tells you. But please also take into account how the patient feels. Be in contact with the patient if the patient doesn't feel well. So it's not only a number, it's also a patient. All right. And another question here, and there were actually several questions, but I think this is a very important point, is does it matter what cortisol assays you use and how you measure cortisol? Does it actually affect the cutoffs? And Anant, can you say something about that? Yeah. Yes. Well, for those of you who know me, I'm the anti-cutoff guy. I think what Olaf said is very appropriate. There's no single cutoff that can tell you everything. You have to use good clinical judgment. The number you're looking for is helping you ballpark how likely the HP axis is recovered and how likely your patient is vulnerable to a crisis. And I'll just add one more thing before I talk about assays that you started talking about is a morning cortisol is a proxy for the peak of the diurnal rhythm cortisol. Now if your patient wakes up at 5 a.m. but arrives to the lab at 8 a.m., you have no idea if that cortisol is the peak, one hour post-peak, or one hour pre-peak, you're estimating. So the entire measurement is an estimate with a bell curve, probability that you've come within 5, 10, 15, 20% of the peak. So all of this is a game of probability. So to apply precision with a cutoff or with an assay is just a flawed scheme for clinical care. And at the end of the day, you're trying to help your patient safely come off of glucocorticoids. So with that, the older cutoffs in the United States were something like 18 micrograms per deciliter. I actually don't remember what the nanomole conversion of that is. And that was from older studies that tried to adjudicate what a normal HP axis was using older radioimmunoassays and immunoassays. On modern immunoassays like Roche ELIXIS-2 and mass spec assays, that calibrates lower. These immunoassays pick up fewer interfering or similar steroids. So that number comes down to 12, 13, 14 micrograms per deciliter. Again, I would not anchor or fixate on that. And it comes down to tapering your patient off glucocorticoids and using a ballpark morning number. We came up with 10 or 300 as a ballpark estimate that the HP axis is normal or near normal. And you can be reassured that their vulnerability to a crisis is low or very low. And if you don't feel comfortable, you can push it a little bit more. But repeating the morning cortisol doesn't guarantee a higher number at a later time because there's still the fluctuation of their diurnal rhythm and what time they arrive in the lab, et cetera. Yeah, thank you very much. So several of the other questions were about specific scenarios, specific glucocorticoids such as inhaled glucocorticoids or budesonide, where it's very often marketed as not having any systemic effect or less systemic effect, topical steroids and intra-articular steroids. So one common theme there is, can all of these actually suppress the adrenal axis? Yes, they can. All of them in the right dose and in the right frequency can do this. It's much harder to establish any kind of cut-offs there again, but I think it's fair to assume for clinical purposes that they all can. And there was also a specific question whether, for example, for intra-articular, whether there is the same three to four week threshold. Probably not, because they can linger around somewhat longer. And I think that also gets to another point, which is very important when you look at guidelines. I mean, guidelines are really for guidance. And I already saw with a lot of questions that they are actually getting into the endocrine field and the endocrine questions where we deal with different specific scenarios. Like, for example, how do you test somebody who has liver cirrhosis? Can you use the total cortisol? What about shift workers? So those are all those things which I think are true endocrine expertise, where guidelines will not comment on this, because they will give you the broader guidance, but not those specific scenarios. But those are exactly the questions where you would tell your favorite dermatologist, sure, I'll see the patient. All right, let's see. We have a couple of more questions here. One, a patient stopped chronic steroid use and has adrenal insufficiency symptoms. AM cortisol is in the gray area. Cosentropin test is done. During cosentropin simulation test, baseline is 2.5, and 30 minute value is 26. Should this patient be back on steroids? Irina? Well, thank you for this question. OK, well, I think it's important to understand the situation. The patient, you said, has symptoms of adrenal insufficiency and has high pre-test probability for glucocorticoid-induced adrenal insufficiency. And morning cortisol was borderline. So my question is, like, why cosentropin simulation test was done? That's what I would be asking. But let's interpret the test. So morning cortisol of 2.5, well, was it in the morning? Was it in the shift worker? Was it in the afternoon? Is there, like, opioid therapy on board that suppresses that cortisol? Is there fluticasone on board that suppresses cortisol? Can we trust that baseline cortisol? That would be my question. What are the scenarios where we have low baseline cortisol and normal peak cortisol? Well, these are all partial second adrenal insufficiency scenarios. Clearly, if cortisol goes to 23 or 28, don't recall exactly, it means that adrenal cortex can respond to ACTH. So it means it's not atrophied. So that's what this test tells us. But it does not exclude second adrenal insufficiency. Because physiologically, we have no idea whether ACTH production is sufficient, because baseline cortisol was very low. So going back to the patient, symptoms of adrenal insufficiency, low baseline cortisol, yeah, I would treat with glucocorticoids. All right, thank you very much. There is another question here, whether the guidelines actually recommend the provision of a home emergency kit for those who are at risk for adrenal insufficiency. Can I make a point on that? Yes, of course. Parental emergency kit are as important as in other forms of adrenal insufficiency, and specifically in patients vomiting, and we're not sure that the resorption of the oral glucocorticoid is maintained. There is, however, one particular difference between, say, a patient with an Addison's disease and the patients under glucocorticoid treatment. And the difference is that the patients under real primary adrenal insufficiency will likely never recover. And the likelihood over a lifetime that really emergency is a cure is overall higher. The situation with a patient where the tapering can be done, that the systemic glucocorticoid treatment is not required anymore, it's very likely that these patients will get off glucocorticoids altogether and will maybe never require an emergency kit. Having said that, we all know that these are often rheumatological diseases, are chronical ones, and although there are biologicals that do not require glucocorticoids as often as they used to be, patients are often on and off glucocorticoids over their lifetime. And again, we get into a more messy and a more chronic situation. But I would personally never give up on an HPA-access recovery on a patient who has solely been under glucocorticoid treatment. Thank you very much. One other question, maybe for Anand or Irina, because you both actually showed the timeline of ACTH surge following cessation of glucocorticoid treatment. Would measuring just an ACTH level be a good indicator of recovery of adrenal function and can discontinue the taper while just checking serial measurements over time confirm adrenal sufficiency? Yeah, I would not recommend that. I would use the cortisol as the main metric. I showed the ACTH just to show that the real life scenario is like the cartoon that Irina had showed and that wasn't just a fictional cartoon. ACTH is a small peptide. There are more errors in measurement and processing. Cortisol is a stable steroid. Your lab has much more experience in measuring that. If you want to get a cortisol with an ACTH, you can. But the bare bones is cortisol. I totally agree. But just to add a little bit, so I suppose it may be reassuring to measure ACTH in someone with borderline cortisol as finding it at higher. So going from suppressed to above normal ranges at least tells us that pituitary gland is recovering. And hopefully, we'll see some adrenal atrophy recovery as well. But I just want to point out that the guidelines are not what we want to do is for most of those patients to be managed by non-endocrinologists. And I would not add ACTH to the list of hormones they have to remember. Thank you. So we have another question here. And Olaf, maybe that is something you can answer. Do you recommend the low-dose cosyntrope and one-microgram test for dynamic testing? Well, from an epidemiological point of view, we actually do not know what is the best test. So we have few data on the 250. We have fewer data on the low dose. And still, you could argue this is still super physiological. But I would not go there. I think this number is already blurry enough. Adding another test is adding blurriness to a field where we need more evidence in large databases and large cohorts. And to reiterate, the guidelines said we do not recommend or we do not suggest dynamic testing at all. OK, thank you. And probably a little bit along the lines what Felix already commented on, patient with chronic prednisone, lower doses, 4 to 5 milligrams over 30 years. Do they actually need to have testing? And that actually goes along also with the question, is there any time frame when we should consider suppression will be permanent? Or do you recommend falling indefinitely? Maybe I take this up again. But I'm happy to hear also that from the others. So from my part of physiological understanding, I think you cannot permanently. It's not very likely you can kill the HPA axis just by giving glucocorticoids. And be it high or long, at some point, I would expect that they recover. Having said that, of course, there are situations where it had been done several times and multiple times. And the patient refuses to do this any longer. And I would completely understand that. But I would be happy to hear what the other experts are saying. I agree. That's boring. OK. There's another one here for Irina. We talked about ACTH cortisol. What about DHEAS in this scenario? Yeah, so DHEA sulfate, adrenal androgens are produced by zona reticularis and actually quite sensitive to glucocorticoid suppression. I usually see recovery of cortisol way before recovery of adrenal androgens. And this is why I do not find it helpful. So a good analogy would be patients recovering from adrenal cushings who already present with low DHEA sulfate, and let's say remove their cortisol-producing tumor, the remaining atrophic adrenal gland maybe takes a year, two, or three to recover cortisol production. But their DHEA sulfate would remain pretty low for years afterwards, in my experience. I do think that measuring DHEA sulfate at baseline for diagnosis of adrenal insufficiency other than glucocorticoid-induced adrenal insufficiency is helpful, because it's basically a reflection of ACTH status. And obviously, in primary adrenal insufficiency, it would be low, but that's a minority of situations. Thank you. So there's one general question, and I think, Anant, you commented on this a little bit in the guidelines. Have you had any experience with adrenal insufficiency induced by supplements that have glucocorticoid activity, but are not clearly specified on the label as such? Maybe that's also for the whole panel, whether anybody has any experience with this at all. Yes, I'm sure we all have. It's just a matter of whether we know it. The supplement industry, it varies probably by different parts of the world. In the United States, it's completely unregulated. So you can make dubious claims, and you're not regulated by the FDA on those claims, and you're not inspected by the FDA. So what the supplement says is in the pills or tablets may not be in there, and things that are not listed on the ingredients may be in there. So many kind of energy vitality-like supplements have been found, and there's some nice JAMA papers that have examined supplements from a local pharmacy or a nutrition store, have things that are usually stimulants, caffeine, thyroid hormone, dexamethasone, joint pain supplements. I recently had a colleague show me what was in their patient's supplement, and it had dexamethasone. Their joint pain went away because it had dexamethasone in it. So definitely possible. Again, glucocorticoids are so ubiquitous that it's a little bit terrifying. Thank you very much. And probably for everyone, the question whether you actually adjust the doses in accordance with the patient's BMI, do you take this into consideration? I don't, because BMI is one of many factors of what is considered physiological. I'm sure some of it is definitely weight-based. I know my pediatric endocrinologists definitely use weight-based approach, but we cannot measure individual susceptibility. And unfortunately, we don't have a biomarker of glucocorticoid action as of now. So no, I don't consider BMI. Not BMI, but I do kind of clinically use body size. So when we say, what is a physiologic dose of glucocorticoids for a patient? If your patient is 6 foot 8, 200 pounds, or if your patient is 5 feet and 100 pounds, you might have a different sense of what a glucocorticoid dose that's physiologic is. So in that sense, I think body habitus or body size do influence all of our clinical judgments, but there's no precision to that. Yeah, so one other question is particularly about the non-oral steroids. So the glucocorticoids, like the topicals, the glucocorticoids, intra-articular, and inhaled. If the patient, or if you have a concern for adrenal insufficiency in these patients, do you actually switch them to oral preparations, and what do you use? Toby. Well, the first question, as with the oral ones, is whether the treatment with this is further necessary or not, right? Because anything that actually suppresses the adrenal gland, or the adrenal axis, should be probably also sufficient to replace this supplement, steroids for this. And if it's really not used or needed anymore, and there is a concern for adrenal insufficiency, then I think switching it to one of the short-acting steroids is the right consideration for those patients. Maybe just to make the point that has been done before, so we realized also by listening to each other on daily practice, of course there are differences, and among those, there seem to be centers and people who rather give hydrocortisone and others rather give prednisone or prednisolone. And it's not to say that any is better than the other. Again, the evidence is weak to non-existent, and this can be done. I think this is rather about the overall dosage and equivalent doses, but if you feel more comfortable because you always did it this way or that way, the guidelines are not saying that you should change your practice in that regard. All right. There are several other questions. Again, the BMI. And just to say, we have seven minutes and seven seconds left. We don't need to use this, but, you know. Okay, let me see. Well, there's actually several questions which are more geared towards the replacement following pituitary or adrenal surgery for endogenous Cushing syndrome, and I think that's actually something which we would like to point out specifically and not the topic of this guideline. This is about exogenous steroids, and it is an interesting point because obviously several of the cut-offs and also some of the evidence that we use to generate the recommendations are actually derived from those scenarios because endocrinologists do a much more excellent job in looking at the excess recurrence in those scenarios than with exogenous steroids. Yeah, so I think this covers really most of the questions. There are several other essay questions. Again, ideally with different essays, you would like to know what you use in your clinical setting and what cut-offs for those essays would be. I know that's not always achievable, but for that reason, we're also providing these ranges where, you know, concerns should be more or less. But I think the last thing, we talk a lot about measuring and cut-off values, and I think it's important to point out that in the usual scenario, you do not need to get any laboratory values when tapering patients off glucocorticoids. This is a medical scenario that can live entirely without any laboratory values, simply with clinical observation. Yeah, I think I would propose that these are the final words of wisdom, aren't they? There is one more here, actually. Oh, one more question. Okay. And that is actually, thank you for somebody putting this in, because I think this is really important about these guidelines. Guidelines always have an audience. You're our audience today. And I think for endocrinologists, the knowledge about this is much more detailed and present than with other subspecialties. So there was actually a recommendation to share this, particularly with family practitioners and ACP and primary care societies. And I think this is definitely something which we would like to do to distribute it with them, because really those guidelines have other subspecialties in primary care just as much as an audience, if not even more so than endocrinologists. Thank you.
Video Summary
In the video, experts present joint guidelines on diagnosing and managing glucocorticoid-induced adrenal insufficiency, emphasizing education for patients on glucocorticoid therapy, monitoring morning serum cortisol levels, and clinical judgment in assessing adrenal function. A case example illustrating tapering prednisone to hydrocortisone is discussed, with recommendations on monitoring cortisol and ACTH levels. The guidelines stress awareness of adrenal insufficiency in various clinical situations and considering factors beyond BMI for dosages. The significance of cortisol and ACTH levels, body size in dosing decisions, and sharing guidelines with non-specialists are highlighted. The need for further research on adrenal insufficiency from supplements and different adrenal surgeries is mentioned. The experts emphasize clinical observation in tapering patients, alongside laboratory assessments. Overall, the guidelines provide a practical framework for safe and effective management of patients on glucocorticoid therapy.
Keywords
glucocorticoid-induced adrenal insufficiency
diagnosis guidelines
management guidelines
patient education
morning serum cortisol levels
clinical judgment
tapering prednisone
hydrocortisone
monitoring cortisol levels
ACTH levels
dosage considerations
adrenal function assessment
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