Hi Jessica, are you okay for me to start here? Yes, you can begin now, thank you. Okay, hi. Good afternoon or good evening everybody, depending on from where you're joining for the webinar. Thank you for being with us today. My name is Dr. Shaishav Dhage. I'm one of the endocrinology consultants at Christie Hospital in Manchester. Today's topic is immunotherapy induced endocrinopathies and I'm very thankful to Endocrine Society and the team for giving me this opportunity to be here with you today. So as far as this talk goes, I do not have any conflicts of interest to declare. What are our learning objectives today? So we will learn to identify and diagnose immune-related adverse events, endocrine events. We learn to interpret the diagnostic tests of these immune-related adverse events and we'll learn how to manage acute and long-term complications of these adverse endocrine events. So before going into the details of endocrinopathies, I think it is important to set the background with some information about immunotherapy and cancers and the other side effects and the principles of treatment. So as you all are aware, for any cancer there are five pillars of the treatment in the therapeutics. Obviously, surgery is the most important, followed by chemotherapy and radiation in most of the patients. However, as the cancers progress or any metastasis or any other complications develop, sometimes other therapies are indicated which include targeted therapies, specific molecular therapies, and immunotherapies which are relatively new in last few years. So what are the types of immunotherapies? There are various different types of immunotherapies being used and being developed like chimeric antigen receptor T-cell therapy or tumor infiltrating lymphocyte therapy. There are a few vaccines developed, dendritic cell vaccine, DNA, and peptide vaccines, and immune-activating cytokines. In this talk, we are going to concentrate on the immune checkpoint inhibitors. So before going into the details of this immune checkpoint inhibitors, it is important to know about the history. These are two most important scientists, Professor James Allison and Professor Tasuku Honjo from USA and Japan respectively, who have done separate work on the CTLA-4 and PD-1 receptors in 1990s. And based on this work, these new therapies have been developed. So they both were rightly awarded Nobel Prize in Physiology and Medicine in 2018. So we as mankind are really thankful to these two people who have really helped to develop these life-changing therapies and treatments for these patients. So as we know that there are two types of immune systems in our body, B-cell and T-cell. So T-cell immune system is specifically activated by binding of the antigen presenting cell. The antigen binds with the help of MHC to the TCR, the T-cell receptor, which activates the immune response. While to inhibit this immune response, there are three different ligands CTLA-4, PD-1 and PD-L1, which inhibit the activation of T-cell pathway, which is anti-cancer pathway as well. And the monoclonal antibodies have been developed against these immune checkpoints. They are called as immune checkpoints because they keep the immune system in check. So CTLA-4, PD-1 and PD-L1 are the monoclonal antibodies, are the receptors where the monoclonal antibodies have been developed against to prevent the deactivation of anti-cancer pathway. One of the newer molecule is LAG, that is the lymphocyte activation gene, which interacts with MHC. It up-regulates T-cell function and down-regulates TCR signal. So a drug has been developed against this one as well. So how does it normally work? Let's consider one of these cells. This is as antigen presenting cell and this is a cytotoxic T-cell. So with the help of MHC complex, the antigen is presented to the T-cell receptor and this begins the T-cell activation, the cytotoxic T-cell activation first signal. However, the second signal is also necessary for the T-cells to start doing their job. And that second signal comes from the binding of CD80 to 80 or 86 to CD28, which is a second signal which activates and helps them to proliferate and migrate to the site of action. At this point is the check where it inhibits the over activation of this T-cells normally. And this is the immune checkpoint, the first immune checkpoint, which is called a CTLA-4. The drug has been developed against this and it's called as ipilimumab and few other newer drugs are being developed. So now let's consider the cell on the other side is a cancer cell. So basically, as you use the anti-cancer agent, the CTLA-4, it basically attacks, helps the T-cells to be unleashed on the cancer cells and help them to destroy. There are a couple of other receptors. One is programmed death, which is self-destroying for the T-cells and the cancer cells usually use this mechanism for killing the T-cells easily or at least activating the killing of the T-cells. So PD-1 binds to PD-L1 ligand and that's how the T-cell deactivation happens. So antibodies have been developed against these two ligands as well. The one is PD-L1 ligand and the one is PD-1 ligand as we have seen and there are different antibodies or immune checkpoint inhibitors developed against them. So this diagram describes various different agents which are being used and there are a few more in development and a lot of trials are going on in different types of cancers. So today we are going to concentrate on these ones, the CTLA-1 inhibitors, PD-1 inhibitors and PD-L1 inhibitors. So more than 17 different types of cancers, these antibodies have been approved for the use for. Majority are melanoma because of the high T-cell burden. They act quite quickly on these cancers. Other cancers like non-small cell cancer where there is a higher number of mutations, these immune checkpoint inhibitors work very well. In terms of effectivity, melanoma and skin cancer, the response rate is 40 to 60 percent. In cases like classic Hodgkin's lymphoma, it is 80 to 90 percent and the rest of the head, neck and solid tumors, the response rate can vary between 15 and 20 percent. These immune checkpoints can cause toxicity in a lot of organs like say hepatitis, colitis, skin issues, nephritis and similarly they can cause endocrine toxicities as well. The mechanism is removal of cell tolerance and activation of T-cells which leads to auto inflammation. Few risk factors, if there is shared antigen between the tumor and the tissue affected, it can cause more damage. Few environmental factors like microbial flora. Sometimes the patients may have smoldering inflammation or organ dysfunction or auto immunity in their body which has been kept in check. But if the immune checkpoint inhibitors inhibit this response, then they might unleash the immunity and it can cause damage. Older age can be a risk factor for certain issues like arthritis, rheumatological toxicities and gender can be a risk factors for some type of toxicities like myocarditis. Studies have shown that CTLA-4 blockage is dose dependent and PD-L1 or PD-1 blockage is not dose dependent of the immune checkpoint inhibitor antibodies. Now what are the principles of treatments of these various toxicities? Holding or discontinuation of the treatment is the first. Steroids, high dose steroids for four to six weeks depending on the severity of the toxicity. There is not much evidence based behind this. They are mainly based on the expert opinions and clinical judgments. Occasionally steroids don't work or resistance develops. In that case, second line agents like infliximab, mycophenolate are also used. And majority of the patients will require supportive management like say IV fluids, correction of electrolytes, antidiarrheal agents and in endocrine toxicities, supportive hormone treatment, etc. Now the endocrine toxicities are treated differently than these principles. We will come back to that a little bit later. So what are the different types of endocrine toxicities? As this diagram shows various possibilities, the most common ones are thyroid and pituitary disorders. Isolated ACTH deficiency is a relatively new entity, but we are seeing lots of these patients who can be entirely asymptomatic. Other manifestations could be gonadal disorders, primary adenoid disorders, either worsening of type 2 diabetes or development of new type 1 diabetes and some rare disorders like hypoparathyroidism or AVB deficiency, which is also called as diabetes insipidus or ACTH-dependent Cushing's has been described a case or two, and sometimes it can be polyglandular involvement. So endocrine manifestations are the most common toxicities in up to 40% of the patients, thyroid being the highest one, followed by pituitary. The onset can be quite predictable, sorry, quite unpredictable at any time during the treatment. It can be from few weeks to few months. For example, thyrotoxicosis or type 1 diabetes can develop quite rapidly, while few other side effects can develop down the line a few months later. The symptom spectrum also varies a lot. The symptoms can be very mild from minimal symptoms or completely asymptomatic things like hypothyroidism to severe and fatal illness like diabetes, ketoacidosis or acute adrenal crisis. Another issue is the symptoms can be very nonspecific and overlapping because these patients are having chemotherapy, radiation, other treatment. Because of this treatment, they may have side effects like fatigue, tiredness, lack of libido, and this can overlap with endocrine manifestations. The number of cells of the endocrine organs is really small normally, so most likely the damage is going to be permanent and irreversible. Drug discontinuation and high-dose steroid treatment is usually not indicated for endocrine toxicities. Even if the patient develops endocrine toxicity, most of the times they can safely continue their immune checkpoint inhibitor therapy. And supportive management with hormone replacements is the key. So let's start with the pituitary issues, hypophysitis. So this is the first case. Now most of the cases are melanoma, but we see a lot of other patients as well. This just happened to be the melanoma cases I have selected for the presentation. So this is a 52 years old man who was diagnosed with cutaneous melanoma which was treated and he remained under plastic surgery followed after surgery. A year ago, he developed chest wall lesion and which was unfortunately confirmed to be a small volume liver and bone metastasis. So he started on ipilimumab and nivolumab combination every three weeks and prior to cycle four, he's seen in the clinic and he complained of fatigue. Now when the patients are on these treatments, usually in addition to their routine full blood count, eugenics, LFTs and other blood tests, the oncologists, they also request a random cortisol level as well. So this is the workup for this patient. The biochemistry shows as you can see clearly the cortisol levels are very low, the ACTS levels are low as well as the TSH levels are low. Rest of the anti-pituitary hormones look in the normal range. He had the scan of his pituitary gland. You can see the enlarged and inflamed gland with a little bit of enlargement of the pituitary stock as well. In the inset, I have shown you the normal pituitary gland, how it looks so you can make out the difference. It is enlarged. So the MR is reported as diffuse enlargement with slight heterogeneous enhancement and infundibulum is also a little bit bigger. So what's the diagnosis here? Hypophysite is causing ACTH and TSH deficiency. Now some of you, you might say that this could be a little bit of acute thyroidal, non-thyroidal illness like response as well. But because I have got the further information of the patients, I can confirm that it was TSH deficiency later on even though the free T4 is normal at this stage. Now the second patient, 68 years old man, again cutaneous melanoma, was treated by surgical treatment. He was found to have lung nodules which are followed down the line, which was confirmed as metastasis later on. He was started again, ipilimumab plus nivolumab combination and pre-cycle 4. He complains of headache, which is bifrontal with fatigue, not improving with the treatment, no visual field effects. The random cortisol is significantly low. So the blood sample is taken for antibiotic hormone profile and other bloods and he's administered hydrocortisone. The other investigations were completed in the clinic. So as you can see, the gonadotropins are low. So is the testosterone. Cortisol levels are low. ACTH is in the normal range at the moment. Rest of the other hormones are prolactin less than 50. Free T4 is high here and TSH is again undetectable. The MR pituitary, I will show in the next slide, which shows acute enlargement of the pituitary with no chiasmal compression. This is keeping with hypophysitis. Short synapse test with 250 micrograms of cosyntropin shows flat response, as you can see. Not much improvement in the 30 minutes and 60 minutes readings. So the diagnosis here is hypophysitis with ACTH, TSH and gonadotropin deficiency. So again, some of you could argue that in the acute phase, the FSH, LH or testosterone levels may not be as reliable, but during further fall of the patient has persistent deficiency. That's why I'm able to confirm that is the diagnosis. So you can see the scan of his pituitary here. Now, why I'm showing this scan is important to see that you can see after down the line, after about a year, there is significant reduction in the size of the pituitary gland. So this was the acute enlargement, which has settled later on, which is in keeping with the hypophysitis. Now, hypophysitis, it is taking over as possibly the commonest cause of autoimmune hypophysitis, which is drug induced. There is male preponderance and it's commonly seen in the men above age of 60. Time of onset could be variable from 11 to 27 weeks depending on the therapy being administered. CTLA-4 inhibitors, it develops earlier and that's the commonest cause for hypophysitis followed by PD-1 and then combination therapy. The pathogenesis of hypophysitis various studies have postulated various hypothesis both type 2 and type 4 hypersensitivity with some humoral response as well because circulating anti-PGT-3 antibodies, GNAL and IMT-2b also have been found to be positive in some patients. As I mentioned previously, it is dose dependent in terms of CTLA blockade while PD-1 or PD-L1 do not follow dose dependent pattern. Severe hypercortisolemia is seen in many of the patients and is likely to be irreversible in majority of the patients. Imaging is usually negative. It is abnormal only in 18% of the patients. Now the clinical and diagnostic consideration, secondary adrenaline insufficiency presents with the symptoms like fatigue, nausea while if the patient is presenting in the acute phase of hypophysitis and inflammation, they may have intractable headaches, nausea, diplopia, visual field defects and vomiting. Rarely patient may present with adrenal crisis with concurrent illness like a lot of them. They may have acute infections, pneumonias, neutropenic sepsis and things like that which might precipitate the adrenal crisis. So in the investigations, you normally find low ACTH, low cortisol, low sodium, hyponatremia. They may have low TSH and low free T4 or low FSH and LH. Now isolated ACTH deficiency is a relatively newer entity. One of my colleague is publishing on it soon and here the important thing is patient is entirely asymptomatic. So as I mentioned for the screening oncology colleagues, do the cortisol levels regularly, patient has the treatment, they go home and sometimes you get a phone call that the patient's cortisol levels are undetectable. When we call the patient back, the patient is entirely asymptomatic. So this is another new entity and it will probably take over as possibly the the commonest cause of pituitary hormone deficiencies because of ICICI, ICAI. The important thing is the rest of the pituitary axis is intact, so this is not hypophysitis and aldosterone levels will also be normal. Cosyntropin is used only in doubtful cases and down the line usually after three months or so. Now whether should we do a MR scan in every patient? It really depends at what time of the presentation or what phase of presentation you're seeing the patient. If you're seeing the patient in acute phase, I will probably do the MR pituitary. But it is important to keep in mind that you need to rule out the other alternative diagnosis or metastasis or sometimes incidental findings like adenomas. Another important consideration you have to give is a lot of these patients will be on high-dose steroids, really high dose of dexamethasone as part of their other treatment regimes. They might be on a lot of opioids like for the pain as pain medications or for other purposes. So these things are very important when you are interpreting the cortisol or other pituitary hormone levels because they are going to affect the cortisol and ACTH responses. Now coming to the acute management of these patients Here is a 76 years old man with known metastatic melanoma on pembrolizumab monotherapy since last five months. He presents to acute oncology unit with complaints of fatigue, confusion and falls. His evaluation shows important findings of serum sodium of 125 and blood pressure of 90 bar 40. What is the next step in his immediate management? Urgent MR brain with contrast. Blue light him to the nearest neurosurgical center or measure his cortisol, ACTH, urine sodium, urine and serum osmolar teeth, thyroid function tests because you want to work for the hyponatremia or send a sample for measuring cortisol and other blood tests and administered 100 milligrams intravenous hydrocortisone followed by continuous infusion. So the answer here is D. Sorry, I'm not able to make the presentation much interactive because of some technical issues. So this is basically acute problem where you cannot really wait for the diagnosis to be confirmed. So you need to take the blood sample and start the patient on treatment. So this is what the SFE guidelines for acute management says. When the patient presents with these symptoms, hypotension or shock-like symptoms, collapse, tachycardia, confusion, ideally you need to act quite quickly. So you take the blood sample, send it to the lab and while waiting for the results, administer the patient intravenous steroids. It's bolus dose followed by continuous infusion and also give rapid fluids to correct the cardiogenic shock while waiting for the results. So intravenous steroids are indicated in acute or crisis situation. High dose steroids only if there are neurological manifestations because of enlarged pituitary. Otherwise, there is no place for very high dose steroids to treat hypophysitis. Usual replacement is hydrocortisone 15 to 25 milligrams of total daily dose or equivalent agents. It is very important to educate the patients with the sick day rules, provide them steroid bracelet or cards, emergency pack and educate them about the steroid and increasing the doses when they need. Levothyroxine only if low free T4 and increase it slowly. You may not need to start levothyroxine in the acute phase. Especially if you have not confirmed cortisol levels properly, do not start on levothyroxine because it might precipitate the acute crisis. Testosterone and estrogen replacement is corrected only if it is persistent and in confirmed cases it doesn't have any role in acute phase. Also, there is no role of growth hormone treatment in active malignancy and testosterone is used only in confirmed AVP deficiency. Important to keep in mind that rule out other possibilities like post-reputatory metastasis, persistent hypokalemia or any other reasons which might be causing poliuria if your patient has. Now coming to the next complication, which is the primary adrenalitis because of the ICIs. The first case, 43 years old man presents with nuanced bleeding of long-standing pigmented lesion on his shin. Again, confirmed malignant melanoma, no evidence of metastasis, remains on follow-up. Next scan shows retroperitoneal nodal metastasis and he started on Neolumab every two weeks. Initial treatment well tolerated, follow-up scan show good response. And now what happens? Four cycles into the treatment, his sodium starts falling and it is dropped to 127 in the fifth cycle. He complains of fatigue, anorexia, weight loss and postural symptoms. Blood pressure is okay. No postural drop. Urine sodium is high. Serum osmolality is normal. Urine osmolality is on higher side with random cortisol of 192 which is 6.95 micrograms. The other entropy hormones are normal and testosterone is low. Co-syndrome stimulation test is performed and it again shows flat response, not much increase. The ACTH levels, however, at the zero minute of short-synaptic test was very high, 200 with high plasma renin activity and almost undetectable aldosterone. This is the PET scan. The MRPG treatment is unremarkable and the PET scan shows bilaterally increased adrenal activity. So just to show the normal imaging as you can see on the right side it is a v-shaped gland on the left side. It's called as inverted Eiffel Tower. So we can see that in the background there is increased uptake in the liver as well as on in both the adrenal glands there is increased activity. So based on this history what is the cause of hyponatremia in this gentleman? SIDH immune checkpoint inhibitor induced hypophysitis, steroid induced adrenal insufficiency, nevolumab induced adrenalitis or metastatic deposits in the adrenal glands. So the answer is nevolumab induced adrenalitis. So how do we differentiate between the hyponatremia of pituitary failure and hyponatremia of adrenal failure? So in hypophysitis there is acute drop in the ACTH levels which causes increased levels of CRH which leads to increased levels of ADH hormone causing water retention and SIDH. So this is treated with hydrocortisone replacement and the sodium levels improve. However, if it is because of adrenalitis there is loss of aldosterone, increased renin levels, low aldosterone which leads to low sodium levels and this requires mineralocorticoid replacement. So in our patient when he was acutely annual he was receiving a high dose of steroids intravenous glucocorticoids, which were probably giving him some mineralocorticoid to cope with and when those levels were dropped then he was presenting with hyponatremia again. So unless you replace mineralocorticoid hyponatremia may not be restored. So this slide is just to give you flavor of the chronic long-term management of this patient. So he has completed more than five years of follow-up now, well in himself, completed two years of ICI therapy, PET scan is not showing any active disease, his antibodies were positives. He remains on relatively higher dose of steroids. In addition to fructocortisone and having annual endocrine follow-up. Coming to the second case, 72 years old man with history of hypertension, type 2 diabetes and atrial fibrillation. Again, metastatic melanoma treated with combination therapy. In between he developed dermatitis, steroids were used, improved, steroids were stopped. Then he developed acute kidney injury, treated with oral glucocorticoids. Then they were stopped. However, he developed persistent hyperkalemia, which was not really keeping with the renal damage. However, the cortisol remains relatively normal at this stage. Due to ongoing hyperkalemia, he was however commenced on mycophenolate for the nephritis. So he was treated with sodium zirconium and sodium bicarbonate for ongoing hyperkalemia. Investigative screen for hyperkalemia showed high renin, low aldosterone, normal sodium and potassium still being high at 7.1. So we're dealing with hyperreninemic hypoaldosteronism. However, as I mentioned his urea and creatinine were disproportionately normal or disproportionate to the electrolyte imbalance and the random cortisol still remained satisfactory. However, some of you might argue that that is a little bit on lower side. So he was treated with flutocortisone, which resulted in normalization of the potassium. Now two months later, he had further screening bloods and his cortisol was entirely undetectable. Then he was referred to endocrinology and hydrocortisone was added to his therapy. His ACTH was markedly high at almost 1,000, which was keeping with ICA induced adrenalitis and adrenal antibodies were negative. So this case highlights that the patient has presented with hyperkalemia, hyporeninemic hypoaldosteronism before going on to develop the cortisol deficiency. So primary adrenalitis is very rare, only few cases have been reported. There might be underlying autoimmune association with PD-1 or PD-L1 inhibitors. In some patients, 21 hydroxylase autoantibodies have been found. Usually the cortisol is low with high ACTH, at least more than twice of the normal range, with low aldosterone and high potassium. Cosintromin stimulation may be required in equivocal cases. Again, adrenal imaging may or may not be necessary, but it will be useful to rule out any primary or secondary malignancy in these kind of situations. The treatment is with hydrocortisone, 15 to 25 milligrams per 24 hour are equivalent and flutocortisone. Again, important to educate the patient about sick day rules, steroids, and emergency cards. Now coming to thyroid disorders. So here is another case with melanoma who was treated with pembrolizumab. He was having regular monitoring with TFTs and cortisol, complained of grade 1 fatigue in the fifth cycle, but overall remained very active and normal. So this is the spectrum of the abnormal TFTs he developed. As you can see, pretreatment is what was normal. In the thyroiditis phase, the TSH dropped, free T4 was high. Then the TSH started rising and free T4 started dropping, developing hypothyroidism at this stage. Then he was started on levothyroxine replacement and improvement has happened and then now completely u-thyroid on adequate dose of levothyroxine. So this patient's pembrolizumab was stopped six months after the treatment because of some other systemic side effects, not because of the endocrinopathy. So this is your immune therapy induced thyroiditis leading to hypothyroidism and most of the times the patients follow this pattern. But as I mentioned, sometimes they might be entirely asymptomatic and they're found only on the on the routine screening. Now the second patient, relatively rare complication. At last, this is not a melanoma. So 63 years old lady with lung cancer, adenocarcinoma. Treated with surgery in the past and she participated in the pembrolizumab pulse trial, which was going on at that time. Meanwhile, she had developed immune-mediated hypothyroidism. She also had type 2 diabetes and hypertension. However, on one of the visits, oncology colleagues noted that the patient has proctosis and she has developed double vision. Hence, she was referred to us in the thyroid eye clinic. So on clinical examination, her clinical activity score is low, just probably one for the eyelid swelling. The rest of the findings are fine. She has subjective diplopia score of three. That means it's a persistent diplopia, both at primary and any secondary position of the gaze. Gaze. CT orbit was performed, which showed left inferior and medial recti being enlarged with the sparing of tendons, which is the typical finding in thyroid eye disease. TSH-2 antibodies were positive and the TPO was negative. So in this case, you have to consider the differential diagnosis is thyroid eye disease versus serotumor or metastasis. Now, it is very important in again, in this kind of patients if you have low suspicion especially when the antibodies are negative ideally you should scan these patients because sometimes you might find metastasis in the eye muscles. In fact we did have one patient with breast cancer or something similar which was which metastasized to the eye muscles. So this particular patient was treated with IV methylprednisol on 500 milligrams weekly after initial test dose of 250 milligrams. Other medications were used as usual like selenium lubricant eye drops. Her diplopia luckily completely resolved with 1.75 grams of IV methylprednisol on treatment. So this is thyroid eye disease secondary to immune therapy. Now what is the pathophysiology? Again immune mediated acute inflammation followed by destruction of the thyroid gland. As I mentioned previously high expression of PD-L1 and PD-L2 on the thyrocytes could be one of the reasons. Some patients may have under like chronic autoimmune thyroiditis which might be exposed or activated by these treatments. Prior exposure to tyrosine kinase receptors has been identified as a risk factors and when you are in doubt hypovascularity on ultrasound, low uptake on radioactive iodine scan or absent TSH receptor antibodies are the other clues. So thyroid problem is the most common endocrinopathy. In most cases it is mild and asymptomatic. Combination therapy is the maximum risk in develops thyroid problem in about 10 to 16 percent of the patients. Primary hypothyroidism is more common than thyrotoxicosis is more common in females and median interval post ICI treatment is about 8 to 12 weeks. The risk factors for developing thyroid issues after ICI are the related to drugs, non-thyroidal illness, raised BMI, high baseline TSH or high FDG PET uptake. So what are the differences in the hypothyroidism and thyrotoxicosis which develop because of ICI? Hypothyroidism maximum incidence is because of combination therapy same is with the thyrotoxicosis. However the second most common is anti-PD-1 in hypothyroidism while thyrotoxicosis is the second most common reason is CTLA-4 blockade. Thyrotoxicosis presents relatively early in about 4 to 6 weeks time from the treatment while hypothyroidism in about 8 to 12 weeks. And it is important to remember if the patient is on combination therapies these complications will develop relatively earlier. Hypothyroidism is most likely to be persistent in chronic and long term management while thyrotoxicosis may resolve lasting about 6 weeks or so but a percentage of these patients again may become hypothyroid in long term. Primary hypothyroidism incidence is higher and thyroiditis is more common as a cause of thyrotoxicosis as compared to Graves disease. Now coming to diagnostic consideration baseline thyroid function tests before starting the treatment are important. TSH and free T4 prior to each treatment cycle for 6 months and then every 2 to 3 months for 6 months and every 6 months thereafter. Depending on the clinical presentation if there are any suspicions you should do the TSH receptor antibodies or TPU antibodies and as mentioned previously in unclear diagnosis you can do ultrasound free T3 levels or radioactive iodine scintigraphies. So how do we manage these patients? Again high dose steroids are usually not indicated unless like in thyroiditis which one of our patient had are severe thyrotoxicosis. Mild and symptomatic thyrotoxicosis usually the beta blockers are used if the TSH is less than 10 usually monitor the patient if it is or if it is mild my mild thyrotoxicosis just monitor the patient. If the TSH is more than 10 with low free T4 treat with levothyroxine and monitor regularly. If the patients have required only very low dose of levothyroxine it is appropriate to challenge the recovery from thyroid function after cessation of the ICI treatments because a percentage of patients may recover from hypothyroidism. Coming to the next complication which is quite interesting one which is ICI's induced diabetes mellitus. Either there can be worsening of pre-existing type 2 diabetes or development of new type 1 like diabetes which is severe and persistent insulin deficiency. So this particular gentleman 56 years old man with past history of sarcoidosis on long-term steroids for 11 years no dysglycemia despite being on long-term steroids was undergoing immunotherapy with ipilimumab and nevolumab with recent diagnosis of immune therapy related thyroiditis. He presents acutely unwell with abdominal pain vomiting lethargy poor appetite polyuria nocturia pale stools and 7 kg weight loss in just 10 days quite acute presentation. On examination he complains of abdominal pain shortness of breath arterial blood gas confirms severe acidosis with high blood sugars and significant ketoneuria and patient also has acute kidney injury with hyperkalemia. She was treated as diabetic ketoacidosis and the samples were sent for anti-gad antibodies and insulin and anti-islet cell antibodies with hemoglobin A1c. So the diagnosis of this patient is immune therapy induced type 1 diabetes mellitus. So this is a very interesting case and it is mellitus. So this is a rare complication seen in less than 1% of the patients treated with ICI's. 97% of the times it is PD-1 or PD-L1 therapy blocker therapy or combination anti-CTLA therapy causing diabetes is rare. Anti-PD-1 is the commonest which is the 76% followed by PD-L1 and then CTLA-4. Again age more than 60 years male preponderance rapid onset diabetes with about 50 to 70% of the patients developing decay at the time of diagnosis. Onset can vary as I said can be quite stormy from 1 week to 12 months in or with after the treatment of ICI's. So what is the pathophysiology here autoimmune destruction of beta cells? Some studies have found PD-L1 expression on the beta cells which might be the reason why it is commonly seen in those patients. Increased peri-islet CD8 plus T lymphocytes in 40 to 50% of the patients they may have islet set or auto antibodies at the onset. GAD antibodies is most prevalent and there is also HLA-DR4 association. Exocrine pancreatic inflammation is not uncommon and asymptomatic raised amylase or lipase levels may be seen in about 30% of the patients. If you see carefully our patient did complain of some PAILs tools as well. So this is quite an interesting area and more studies are required for this. So usual presentation is polyuria, polydipsia and fatigue. Abdominal pain and nausea if the patient has decay. Random blood glucose, basal metabolic panel, blood pH and urine ketones are important for early diagnosis. Now hemoglobin avens is not really very useful in these patients as you saw the rapidity of the onset. However, it may help you to distinguish type 2 diabetes steroid or stress-related hyperglycemia in some patients. Amylase and lipase again they have supportive value, no diagnostic value though. Insulin and C-peptide will help to assess the endogenous insulin secretion. Wherever you can send antibodies, it's important to send antibodies for GAD, anti-islet cell, ZN8 or anti-insulin antibodies. Treatment, again intravenous insulin and fluid resuscitation for the diabetic ketoacidosis management. And once they settle long-acting insulin once or twice daily with short-acting insulin before meals. So basically treated as type 1 diabetes. There is no role of high-dose steroids in these patients and target hemoglobin avens are usually individualized depending on the patient's situation and diagnosis of the cancer and other comorbidities. In acute stage the routine screening for long-term complications isn't necessary at least in first few years and it also depends on the patient's prognosis and other comorbidities as mentioned. If the patient has type 2 diabetes then usually routine screening protocols should be followed. Coming to the rare form of endocrinopathies. As I mentioned, arginine vasopressin deficiency, diabetes insipidus or ACTH related Cushing syndrome or hypothyroidism or polyendocrinopathies. These are relatively rare complications. A few cases of hypothyroidism have been described. There are a few case reports. The patients usually present with symptomatic hypocalcemia and other usual biochemical findings, low calcium, low PTH, sometimes ECG changes and they should be treated same as any other patients with hypothyroidism. Polyendocrinopathies, the autoimmune polyendocrine syndrome type 2 has been reported in a few cases and almost always it is associated with PD-1 or PD-L1 inhibitors. Thyroid problems may be associated with pituitary issues or diabetes or adrenal. Now this is the most important thing in terms of acute as well as long-term management of the patients. So ideally all the patients who are going on immune checkpoint inhibitor therapy should be counseled about these possible complications and what could be the signs and symptoms. Because if the patients are able to note some signs or symptoms themselves, they can easily report them earlier and acute presentations or sometimes even life-threatening presentations can be avoided if the patients are aware and educated about adverse events. It also helps to prevent medical legal cases because I remember having a couple of very difficult conversations with the patients when the patients have developed life-changing diagnosis like type 1 diabetes because of the immunotherapy and they had not previously taken in probably the education and then it becomes difficult. So it is important to reinforce that possibility of the side effects being developing and the symptoms and that will help for the effective management of the hormone replacement. Because most of these hormone replacements are going to be lifelong say like hydrocortisone or type 1 diabetes you have to treat them rest of the life depending on their life expectancy. There is a lot of improvement in the life expectancy 5 year and 10 year survivals with these treatments. So it is very important that we help the patient to be educated for these and improve their quality of life. With the hydrocortisone and steroids it is important that the sick day rules are explained to them practically giving them as well as the relatives or the next of the skin the education about the sick day rules administration and preparation of the injection hydrocortisone injection pack. Because hydrocortisone powder and water comes separately in some of the preparations and they have to learn how to prepare the injection and how to administer. So it's very important that the patient and family are educated about this. They should also be educated about the medical devices so in case of emergency situations either layman or passerby people or paramedics can help them earlier. Management of diabetes again type 1 diabetes lifestyle management can be quite intensive especially with regular blood glucose monitoring using the insulin injections regularly identification and management of hypoglycemia. So it can be quite a few things to take in and you need to revisit these things again and again and reinforce the importance of these medications on chronic and long term follow up. Diet and physical activity is also important in these patients and last but not the least the patient support groups patient can talk to different people who are in similar situation exchange a conversation about the life changing experiences and learn from each other. So it's very important to direct them to these patient support groups depending on availability locally. So that is the end of my presentation. Thank you for that. Jessica are there any questions? There are questions. Are you able to view the Q&A? Okay let me just go to the section. Yes yes now I can. Yeah great. Okay so should I should I start answering from the beginning? Yes please. Stephanie Lee. Yeah so the first question Stephanie the free T4 is high this is not consistent with TSH deficiency. Yeah in early stages that is that that could be right but but the patients do develop these deficiencies later on. So I have given you the readings in in the presentation at the time of presentation not not in the chronic long term follow-up. So the second question is could you please comment on why treatment with dual therapy less frequently causes hypophysitis compared to CTLA-4. Again not very not very clear but CTLA-4 probably have specific predisposition and I think more more studies are required. Would you send blood for ACTH as well with cortisol before treating the patient with acute adrenal insufficiency? If you can yes I would say yes if you can. What is the role of measuring urinary cortisol? No role for measuring urinary cortisol I'm afraid. Okay so it's moving I'm just seeing which so the next one is quite quite big question so maybe I will look into it and and answer it later on. Thyroid hormone potential then the next one by Timothy thyroid hormone potentiates insulin signaling and attenuates hyperglycemia and insulin resistance in mouse model type 2. Okay thank you thanks for that comment and the link. Okay I have seen flat shots and active response and low ACTH post-IPA and NIVO without any exposures to steroids other pituitary axis normal so it it really depends as I as I mentioned it really depends what time you are you're doing the the shots and actin tests so that the timing of shots and actin test is is important. The next one is in case of severe thyrotoxicosis what is the dose of steroids and how long they should be used? Okay so normally I wouldn't really advise using steroids in even in severe thyrotoxicosis if you have other options available and and there is no no right or wrong answers for what if you are using it what duration you you should use it I don't think there is any right or wrong answer. Okay is there any role is there any role for methimazole in ICR related thyroiditis? No mostly not unless the patient is really symptomatic is despite your replacement your propranolol or beta blocker treatment sometimes occasionally or if the patient has TRAB antibodies positives then sometimes you can you can use it so so beta blockers are useful you're right yeah. Okay can we use radioidine in ICR induced graves? No the answer is no there is no the so the the European guidelines they do not support the use of this thing. Okay, so somebody from Christie has, do you think primary care can stand to the challenges of this fairly new and complex issues? Yeah. You're, you're right. It is, it is quite difficult because some of these complications can develop quite acutely. The communication with the primary team is, the primary care team like GPs and, and nursing colleagues is, is important. So yes, centralized care will be, will be useful. You're right. So maybe we can discuss it later on when you're free. Would you ever get pituitary labs in asymptomatic patients or you do only screen for thyroid abnormalities in patients without symptoms? So that's a very good question. And yes, so we, we do not do the whole pituitary screening in all the patients. We do only thyroid and cortisol levels as, as a screening, depending on their, the agent being used. If there is preponderance for developing thyroid problems or pituitary problems or type of malignancy, but routine pituitary screening in all the asymptomatic patients, no, we don't do that. Are there any predictors of ICM-related endocrinopathies? Do you screen patients with any antibody testing? If yes, which antibodies? Okay. So as I mentioned in each section, there are a few different antibodies are found, but, but these antibodies, they do not have any screening values at this stage, Neha. So we do not screen the patients with the, with, for any antibodies before administrating the agents. Is that it? I think I have answered almost all the questions. Yes. Thank you, Dr. Dej. I really appreciate the talk today. Yeah. All right. Well, everyone have a wonderful day. Thank you. Bye.

immunotherapy induced endocrinopathies

immune checkpoint inhibitors

immune system response to cancer

endocrine toxicities

thyroid disorders

pituitary disorders

adrenalitis

type 1 diabetes mellitus

thyroid eye disease