Time Stamps

  • 01:56 Pearl 1: Mechanism of checkpoint inhibitors and their adverse events
  • 07:15 Pearl 2: Organ systems affected by IRAEs
  • 13:42 Pearl 3: Timeline of IRAEs
  • 22:20 Pearl 4: Factors which increase susceptibility
  • 26:38 Pearl 5: Complementary medicine

Show Notes

Pearl 1: What are the mechanisms and adverse events of checkpoint inhibitors? 

  • Major Categories of Checkpoint Inhibitors
    • CTLA-4 inhibitors: 
      • Ipilimumab 
      • Tremelimumab
    • PD-1 inhibitors: 
      • Nivolumab 
      • Pembrolizumab
      • Pidilizumab 
      • Cemiplimab
    • PD-L1 inhibitors: 
      • Atezolizumab
      • Durvalumab 
      • Avelumab
  • Checkpoint inhibitors are used in the treatment of many cancers including: melanoma, lung cancer, renal cell carcinoma, Hodgkin lymphoma, head and neck squamous cell carcinoma and colorectal cancer. 
  • Mechanism of Adverse Events:
    • Background: CTLA-4 and PD-1 normally serve as “brakes” on the immune system 
      • Cancer cells will take advantage of these checkpoints to put “brakes” on the immune system and avoid dying!
    • Mechanism of Checkpoint Inhibitors: Inhibit CTLA-4 and PD-1/PD-L1 → prevents “brakes” on the immune system → Increase immune system activation to fight against cancer!   
      • Other mechanisms include:
        • Increasing levels of preexisting autoantibodies 
        • Increasing inflammatory cytokines 
        • Enhancing complement mediated inflammation

    • Mechanism of Immune Related Adverse Events: The immune system is over-activated by the checkpoint inhibitor and attacks the body’s own cells.

Pearl 2: What organ systems are affected by immune-related adverse events (IRAE)?

  • Any organ can be affected by IRAE!
    • Affected organs  and presentation  (framework for remembering IRAEs starting with most common):
      • General/Systemic: 
        • Fatigue 
        • Rash (Dermatitis)
        • Nausea
      • Glands: 
        • Thyroid (Thyroiditis)
        • Adrenal glands (Adrenal insufficiency)
        • Pituitary (Hypophysitis)
        • Pancreas (Type 1 Diabetes Mellitus)
      • Solid organs: 
        • Lungs (Pneumonitis)
        • Colon (Colitis) 
        • Kidney (Nephritis) 
        • Heart (Myocarditis)
  • Certain IRAEs are more common than others!
    • MORE common:
      • Skin
      • Gut
      • Endocrine
      • Lung
      • Musculoskeletal
    • LESS common:
      • Cardiovascular
      • Hematologic
      • Renal
      • Neurologic
      • Ophthalmologic
    • Certain IRAEs are more common with a specific drug class!
      • CTLA-4 inhibitors: 
        • All grade colitis 
        • Hypophysitis
        • Rash
      • PD-1 inhibitors: 
        • Pneumonitis
        • Hypothyroidism
        • Arthralgias
        • Vitiligo
  • Life threatening IRAEs are:  
    • Severe colitis, pneumonitis 
    • Encephalitis 
    • Toxic epidermal necrolysis 
    • Myocarditis
    • Autoimmune type I diabetes mellitus (Presenting as diabetic ketoacidosis)

Pearl 3: What is the timeline of IRAEs?

  • Usually within 3 months but can occur anytime even after the checkpoint inhibitor treatment has ended! 
  • Timeline may vary based  on CTLA-4 vs. PD-1/PDL-1 inhibitors mechanism!
    • CTLA-4 
      • Attenuates T-cell activation at a proximal step in the immune response in the lymph nodes
        • Adverse events occur on the EARLIER side 
    • PD-1/PDL-1 
      • Inhibit T cells at later stages of the immune response in peripheral tissues
        • Adverse events are NOT AS EARLY CTLA-4 

A.CTLA-4 inhibitor; B: PD-1/PD-L1 inhibitor; C: CTLA-4 inhibitor+ PD-1/PD-L1 inhibitor

  • Delayed IRAE vs. Chronic IRAE
    • Delayed IRAE 
      • Occurs 1 year or later after treatment starts
      • Most common presentation(s) 
        • Colitis 
        • Rash 
        • Pneumonitis 
      • Note: Many of these patients have had an acute IRAE already!
    • Chronic IRAEs 
      • Symptoms persist for >12 weeks after discontinuing checkpoint inhibitors!

Pearl 4: What factors increase susceptibility to developing IRAE? What is the impact of treating an IRAE on the cancer?

  • Pre-existing autoimmune disease 
  • Host microbiota (i.e., GI flora) and germline factors
    • There is ongoing research on the impact of germline genetic factors and composition of host microbiota (ie. GI flora) on IRAE susceptibility
  • Combination therapy  and CTLA-4 inhibitors 
    • Can cause more severe IRAE 
  • Checkpoint inhibitors have to be used with caution in prior organ transplant to prevent rejection
  • Note: Immunosuppression to treat IRAE does not seem to decrease the anti-tumor effect of the checkpoint inhibitor! 

Pearl 5: What about complementary medicine?

Transcript

Dr. Shreya Trivedi: Welcome to the Core IM 5 Pearls Podcast, bringing you high-yield evidence-based pearls. This is Dr. Shreya Trivedi. 

Dr. Anuranita Gupta: And this is Dr. Anuranita or Anu Gupta, a resident at Beth Israel Deaconess Medical Center. Today we’re talking all about immune checkpoint inhibitors and immune-related adverse events, which we will be calling IRAEs.

Dr. Shreya Trivedi: Nice! This is going to be a two-part episode with this one really setting the foundation on immune checkpoint inhibitors. And then the next episode is going try to elevate the conversation by creating illness scripts to differentiate IRAEs from other conditions. 

Dr. Anuranita Gupta: So let’s get started with the pearls that we’ll be covering. 

Dr. Shreya Trivedi: Test yourself by pausing after each of the 5 questions. Remember the more you test yourself, the deeper your learning gains. 

Dr. Anuranita Gupta: Pearl 1 – Mechanism of checkpoint inhibitors and their adverse events

Dr. Shreya Trivedi: How do immune checkpoint inhibitors work and what goes wrong mechanistically when there’s an adverse effect?

Dr. Anuranita Gupta: Pearl 2 – Organ systems affected by IRAEs

Dr. Shreya Trivedi: How do you organize the different organ systems that are affected by these immune checkpoint inhibitors?

Dr. Anuranita Gupta: Pearl 3: – Timeline of IRAEs

Dr. Shreya Trivedi: What are rules of thumb for when different adverse events can present? 

Dr. Anuranita Gupta: Pearl 4 – Factors which increase susceptibility

Dr. Shreya Trivedi: What makes someone more likely to develop an adverse effect? 

Dr. Anuranita Gupta: Pearl 5 – Complementary medicine

Dr. Shreya Trivedi: What role does complementary medicine play in this patient population?

Pearl 1: Mechanism of checkpoint inhibitors and their adverse events

Dr. Shreya Trivedi: Anu, I am so glad you wanted to do and episode immune checkpoint inhibitors and IRAEs as a topic because i learned so much making this episode. I think this whole episode was a huge knowledge gap and so I am so grateful. 

Dr. Anuranita Gupta: I know, I love this topic, Shreya. I learned so much too. So lets start from basics and we’ll build up from there. When it comes to immune checkpoint inhibitors, there are two main players: CTLA-4 inhibitors and PD-1 or PDL-1 inhibitors.

Dr. Shreya Trivedi: Okay, and to simplify which one is which because all of them end in –mab, the good thing is that for the CTLA4-Inhibitors, if you see ipilimumab and tremelimumab. Am I saying that right, Anu?

Dr. Anuranita Gupta: That’s absolutely right.

Dr. Shreya Trivedi: So if you see the ipilimumab and tremelimumab on the patient’s med list– those are CTLA4-Inhibitors. All the other ones are PD-1 or PDL1 inhibitor which we can lump together.

Dr. Anuranita Gupta: And then to understand how immune checkpoint inhibitors work, we first have to understand how our immune system is set up. 

Dr. Shreya Trivedi: And if any of the mechanism goes over your head, don’t worry we are gonna repeat ourselves a bunch so it really sticks.

Dr. Anuranita Gupta: Yeah repetition is key here. So the immune system has careful checks and balances. CTLA-4 and PD-1 are basically checkpoints OR brakes and I want you to remember that– these checkpoints are like breaks for the immune system. 

Dr. Shreya Trivedi: So cancer being awful as it is of course goes after CTLA-4 and PD1 and really makes sure there is a  stop on the immune system so that the cancer can keep growing.

Dr. Anuranita Gupta: And then what do these drugs do?

Dr. Shreya Trivedi: Yep so oncologist give patients these immune checkpoint inhibitors to free the immune system and that unhinged immune system to kill cancer cells. We sat down with Dr. Benjamin Schlechter, an oncologist at Dana Farber Cancer Institute who thinks about this all the time and explain it so concisely from start to finish:

Dr. Benjamin Schlechter: So the second you activate a T-cell when it takes off into its inflammatory response, it immediately expresses receptors, proteins that put on the brakes. And CTLA-4 is that brake. So the T-cell, when it’s on it, it activates the off switch so that it doesn’t get out of hand. And what we’re drugging with a CTLA-4 inhibitor is the ability of the cancer to push back against amplification of the immune response. And so when you block engagement of CTLA-4, you allow the immune response to amplify early on and an unfettered way so that it takes off and can attack the cancer.

Dr. Shreya Trivedi: Okay, I’ve heard “turning off the off switch” quite a bunch of times, but it doesn’t really stick for me because its a double negative. So, Anu let’s look into that car brake analogy a bit more.

Dr. Anuranita Gupta: Okay, let’s do it! Imagine there is a car, which is essentially a patient’s immune system. It has off-switches or breaks like CTL-4 and PD-1 to keep things in balance. But then a stranger’s foot comes along aka the cancer and really slams on those breaks or the off-switch so as a result the cancer grows and grows. 

Dr. Shreya Trivedi: Okay so with immune checkpoint inhibitors, we are taking that cancer’s smelly foot off the brakes (hence turning off the off switch) and we are freeing the immune system to attack the cancer. 

Dr. Anuranita Gupta:Yes, I’m sure it’s smelly, I agree, Shreya. And let’s hear from Dr. Allison Warner, she’s an oncologist at Stanford Cancer Institute, and she has thoughts about what happens when the brakes are off and the immune system may have too much liberty to press on the accelerator pedal of the immune system.

Dr. Allison Betof Warner: So immune related adverse events are difficult because they are doing exactly what you’re hoping the drug is going to do, which is activate the immune response. The challenge is that your immune cells are looking for self versus non-self and we are trying to shift that balance so that immune cells recognize cancer as non-self, but when we over activate them so much, they start recognizing self and that can look like essentially inflammation anywhere in the body.  

Dr. Benjamin Schlechter: Your heart and your lungs and your thyroid and your gonads and everything in your body protects itself from T-cells by expressing the ligands of these receptors. So you need PD one so you don’t develop autoimmune responses against your endothelium, your myocardium, your brain, and whatever it is. And so that’s where we get into trouble with these drugs is that we use those pathways physiologically to protect us from our T cells.”

Dr. Anuranita Gupta: Ah so the very quality that helps the medication fight cancer can wreak havoc on the body by attacking the patient’s own cells. 

Dr. Shreya Trivedi: Alright, so let’s summarize the ground we’ve covered. Normally we have this checks and balance system where we express CTLA-4 and PD-1 to put the brakes on the immune system. Cancer really makes sure that off switch, CTLA4/PD1 is activated so without the immune system in its way, the cancer can grow. Oncologists give patients these immune checkpoint inhibitors to turn off that off switch, allow the floodgates of the immune system to bet let loose to attack the cancer. 

Dr. Anuranita Gupta:What we’re going to focus on for the rest of the episode is how these ICIs can cause T cells to be SO activated that they start attacking the patient’s own cells and that’s how we get our IRAEs.

Pearl 2: Organ systems affected by IRAEs

Dr. Shreya Trivedi: Alright, so now that we know how these drugs work, let’s talk about when these adverse events, or the IRAEs, immune-related adverse events, that you heme/onc people call it!

Dr. Anuranita Gupta: Yeah! I’ve spent my fair share of time shadowing oncologists and I’ve really heard oncologists describing to their patients that IRAEs can present as an “-itis” or inflammation of any organ from skin to gut.

Dr. Shreya Trivedi: Yeah, which is a little intimidated that they can do so much. So I really appreciated when  we sat down with Dr. Narjust Florez, an oncologist at Dana Farber Cancer Institute. I just really appreciated she had a good, nifty way of organizing all these adverse effects. I thought that would be a that a good foundation before we dive deeper into some of these organs in episode 2. 

Dr. Anuranita Gupta:She had a three-tier approach, starting with the most common adverse effects:

Dr. Narjust Florez: Let’s talk about the general ones. Fatigue is the most common side effect with immune checkpoint inhibitors and we often forget because it can get to a Grade 3 in which the patient is just bedbound and it’s only the immunotherapy. So while these drugs are great, they can have these common side effects. So fatigue, nausea is very common. And a skin rash. Itchy skin rash, it’s like an eczema kind of skin rash. Those are the most common rash, fatigue, and nausea.

Dr. Shreya Trivedi: Then we get into the second tier in terms most common, the glands and there are four – the thyroid, adrenals, pituitary and then the pancreas.

Dr. Narjust Florez: Let’s go over the second tier of common. Glands. Glands are the second most common and that’s why we have to have baseline TSH because one out of eight women we have some degree of hypothyroidism. So women should have TSH before they start these drugs. So hypothyroidism, but something important with the thyroid is the thyroid gets T cells right? They get very angry, they go and migrate to the thyroid and produce thyroiditis. So initially with thyroiditis you will see a decrease in TSH and an increase in T4 and it’s a hyperthyroid picture. Over time that thyroid burns down and it becomes hyperthyroid. That’s what you have to follow patients and be very careful before you start the hormone because if you started too soon you’re going to get into a very hyperthyroid state. But if you wait too long, they become very hypothyroid.

Dr. Anuranita Gupta: So thankfully with thyroid its usually a relatively easy fix with levothyroxine but the timing is really tricky to get down because patients get hyperthyroid before becoming hypothyroid. 

Dr. Narjust Florez: Another gland that can be commonly affected that is often missed is the adrenal glands. We can see significant fatigue and something that I really notice in these patients, they all feel very dizzy when they stand. So when a patient tells me that I trust that drinks enough water, I feel dizzy when I stand, I’m like, okay, let’s figure out what it is. And the cortisol in these patients, because many of them get steroids as pre-medication for chemo, most of them need a stimulation test.

Dr. Anuranita Gupta: We talked about thyroid, the adrenals, and now on to the pituitary. So this is usually a central hypopituitarism, or hypophysitis, so some of the hormones or many of them may be affected.

Dr. Narjust Florez: These patients need a whole brain MRI because you can see in these patients sometimes inflammation of the pituitary gland and the MRI. And the fourth gland is the pancreas. So you can have pancreatitis and you can have diabetes type I. Those two are very rare, but they’re life threatening events. I have three young women develop DKA, and I was like, all right, here we go again. 

Dr. Shreya Trivedi: Oh yeah here we go again, look up that DKA management chart. Alright so that was the glands. Last but not least, of her three tier way of organizing adverse events is thinking about the solid organs.

Dr. Narjust Florez: So solid organs, the lungs: pneumonitis. And the thing about the pneumonitis is that it can come all the sudden you can be doing fine and then in two days the patient is like, I’m very short of breath. They can have wheezing. So patients can have low grade fevers. Again, it’s a T-cell mediated process.

Dr. Anuranita Gupta: Next up, lets think about how these T-cell on overdrive can affect the colon.

Dr. Narjust Florez: The colitis pattern tends to be nonstop diarrhea. So the patient wakes up in the middle of the night for bowel movements. It’s very something characteristic of this diarrhea. It’s eight to 12 bowel movements from two days ago when you have one bowel movement a day, eight to 12 bowel movements. And these patients can decompensate very quickly when it comes to colitis because it’s dehydration, poor intake, and nothing gets absorbed. There is of course nephritis, which is an inflammation of the kidneys, rare cerebritis. Everybody likes to talk about cerebritis, but I’ve seen one case younger woman and myocarditis, the situation with myocarditis is rare but tends to be fatal if it’s missed.

Dr. Anuranita Gupta: Speaking of myocarditis, there is an overlap syndrome that has been described with checkpoint inhibitors that causes myositis, myasthenia gravis, and myocarditis and has a very high mortality rate.

Dr. Allison Betof Warner: This overlap syndrome is something that our colleagues have defined and is critically important that everybody know about, including non-oncologists.

Dr. Shreya Trivedi: Ah, I’m glad we went over that. I did not know that the overlap syndrome but will definitely keep a high threshold for myositis, myasthenia gravis, and myocarditis. But this has just been a whirlwind through the body and we will get a lot more into this in episode 2, especially with the solid organs. But why don’t we summarize Dr. Florez’s framework for how she organizes different adverse events based on how common they are. The most common being general symptoms of rash, nausea and fatigue. The second most common are being glands, the thyroid (initially a hyperthyroid then a hypothyroid state), the adrenals which we often need a cortisol stimulation test to assess, central hypopituitarism where all their hormones are low, and then pancreas causing either DKA or pancreatitis.

Dr. Anuranita Gupta: And then with solid organs, you can get pneumonitis with cough and dyspnea, colitis with profuse diarrhea. And then there is that spooky life-threatening trio of myositis, myasthenia gravis, and myocarditis.

Pearl 3: Timeline of IRAEs

Dr. Shreya Trivedi: Now that we know how these drugs work and what happens when things go awry, let’s talk about when these adverse events actually come up. I know as internists, our patients have these complaints and I am always thinking about that med list. And okay, is this timeline of these symptoms matching up with the immune check point inhibitor and can I blame it on that?

Dr. Anuranita Gupta: I totally hear you! And to make our lives extra difficult, not only can these adverse effects occur anywhere in the body, but they can also occur any time after exposure to checkpoint inhibitor. 

Dr. Shreya Trivedi: Any time! Man, that’s tough, are there any general rules of thumb?

Dr. Anuranita Gupta: So there are a few rules of thumbs. The 1st being that adverse effects typically show up within 3 months of starting the checkpoint inhibitor.

Dr. Allison Betof Warner: So different immune-related adverse events tend to  occur at different times. The highest risk for any immune-related adverse event is always in the first three months. Once we get past the first three months. Certainly you can have new adverse events that is always true, but I sort of take one deep breath and say, okay, we’re through that highest risk period.

Dr. Anuranita Gupta: And the type of inhibitor can also help us. We tend to see CTLA4 adverse effects on the sooner side than the ones from PD inhinitors. 

Dr. Shreya Trivedi: Is that because these inhibitors work at different checkpoints in the immune response, so they show up at different times? 

Dr. Anuranita Gupta: Yeah so CTLA-4 attenuates T-cell activation in lymph nodes, while PD-1 inhibits T cells in peripheral tissues. 

Dr. Shreya Trivedi: Hmm that’s kind of convenient in remembering that – the P in PD-1 can help us with remember it is inhibiting the checkpoints in the peripheral tissues. Going all the way to periphery takes time compared to activation in the lymph nodes, so PD-1/PDL-1 adverse effects happen later. May be one way to think about it!

Dr. Benjamin Schlechter: They do have different presentations and different onset of symptoms because CTLA-4 inhibitors, they really have to do with this escalation phase of the immune response. They tend to cause things more acutely. Alternatively, PD-1 inhibitors have to do with exhaustion. And so they are very uncommonly, not impossible. It’s unlikely to see early immune related adverse events in an average individual in the first 6-12 weeks. It can happen, but it’s just not that common.

Dr. Anuranita Gupta: So not only do the timelines vary by type of immune checkpoint inhibitor, Dr. Warner also told us about how the timeline varies by the organ system.

Dr. Allison Betof Warner: Things like dermatitis tend to happen on the earlier side, particularly the very worrisome, so myocarditis, which many people know about now and is very, very dangerous and potentially fatal often happens after the first dose, sometimes the second, but typically within 48 hours, 72 hours of that dose. Colitis can happen at any point, tends to be sort of a two to three months in type of immune related adverse event. Interestingly, nephritis tends to be even later in that three plus month range. The endocrinopathies are interesting. They can sort of occur kind of anywhere in the spectrum. They tend to not be right after the first dose. Though as I said anything is possible.

Dr. Shreya Trivedi: Yep anything is possible! But as a quick summary, the typical presentation by organ system is going to be skin, rash, itching, pruritus, myocarditis are going to present on the earlier side followed by colitis at the 4-week post exposure to immune checkpoint inhibitor mark. Endocrinopathies present later around the 6-week mark. And don’t worry, you don’t have to memorize any of this, we will link to great graphic in the show notes the shows the variabilities of these timeline.

Dr. Anuranita Gupta: And then another pro tip is that we often don’t see pneumonitis and nephritis with CTLA-4 inhibitors alone and we need PD-1/PDL-1 inhibitors or a combination of those CLTA-4 inhibitor with a PD inhibitor to cause pneumonitis and nephritis in the subacute period of around 3 months or so.

Dr. Shreya Trivedi: Ah, okay so we either need the big bad PD-1 inhibitors or both immune checkpoint inhibitors on board to go against the lungs and kidneys. 

Dr. Anuranita Gupta: Exactly! And then on top of that there is something called Delayed IRAEs! 

Dr. Shreya Trivedi: Oof, what?! I do not like the sound of that, Anu.

Dr. Anuranita Gupta:Yeah! It’s not good. Delayed IRAEs are adverse effects that actually occur 1 year after therapy starts. This could be while they are still getting the immune checkpoint inhibitor since treatment courses are long or after the last dose has been given.

Dr. Shreya Trivedi: Man thats such a good pearl because when we’re looking at these one liners and that huge onc history that is written, I guess it’s good to see when the ICI was started. When that last dose was. I mean are there things that make people more prone to delayed IRAEs 1 year after immune checkpoint inhibitor initiation? 

Dr. Anuranita Gupta: Generally, delayed IRAE usually is going to be people who unfortunately had an acute IRAE prior. Most frequently, these are colitis, rash, and pneumonitis. 

Dr. Shreya Trivedi: Okay! Have you seen delayed IRAEs come up?

Dr. Anuranita Gupta: Yeah Shreya, so I actually saw this recently when I was in ICU and we thought one of our patients had adrenal insufficiency but we weren’t sure because they had finished getting their immune checkpoint inhibitor a few months prior when treatment had event. And so we wondered if the timeline could fit. And now we know delayed IRAEs are a real thing. 

Dr. Shreya Trivedi: Yeah these timelines are so wild and I think just reinforces that things can happen truly whenever (even though you guys did give us rule of thumbs) and can also happen in delayed fashion.

Dr. Anuranita Gupta: Yeah, totally! And bear with me, Shreya, there’s one more distinction that we have to make. The third rule of thumb is that we can have something called chronic IRAEs and this is when the adverse effect persists for >12 weeks after the checkpoint inhibitor is stopped. 

Dr. Narjust Florez: We have data that this immunotherapy can stay in target for up to nine months from the last dose and patients can have immune-related adverse event. This is a very good point. Even after they stop getting the drug right after, because that monoclonal antibody is still there, your T-cells are still active.

Dr. Shreya Trivedi: So if the immunotherapy can stay in our system for 9 months after stopping it, it makes sense why we may see IRAE side effects say for 4 months out, which oof I just feel so bad for the patients who get that.

Dr. Anuranita Gupta: I know! It’s not ideal to say the least. So now that we’ve covered all this ground, why don’t we summarize this pearl!

Dr. Shreya Trivedi: Yeah, so things I’m taking away – yes, it is true that IRAEs can occur anytime, but some things to hang our hat on is thinking that acute IRAEs are most likely going to happen within 3 months of starting a checkpoint inhibitor. Within that- CTLA-4 inhibitors act on the T cells in on our lymph nodes and tend to cause adverse events on the earlier side, really within the first 3 months. PD-1 inhibitors, which act on T cells in the periphery, tend not to present as quickly. 

Dr. Anuranita Gupta: And then in terms of the organs, the skin and the heart may be affected the earliest. Colitis after a month or so and the nephritis after the first 3 months or so. But these are all general rules of thumb.

Dr. Shreya Trivedi: Yeah! And then Anu, before closing out this pearl, I just can’t help but wonder what happens when IRAEs are treated with steroids? But the whole point of these immune checkpoint inhibitors is to let the immune system run free, so I’m curious doesn’t dampening the immune response with steroids decrease the anti-tumor effect that we’re hoping to get all along with these immune checkpoint inhibitors ICIs?

Dr. Anuranita Gupta: That is such a good question, Shreya, and I totally get where it’s coming from. Mechanistically, it makes sense. But really, it doesn’t pan out clinically. Steroids don’t take away the immune checkpoint inhibitor’s ability to attack the cancer but as with most things, we do need more research in this area.

Dr. Shreya Trivedi: Okay! At least that’s helpful to hear and as our patients ask us ‘hey, is the steroids going to affect my ability to battle this cancer?’ I think it’s at least good to say. Hey this doesn’t pan out clinically. And you should feel comfortable treating the adverse effect with steroids. 

Pearl 4: Factors which increase susceptibility

Dr. Shreya Trivedi: Now, let’s turn the spotlight to another critical aspect which is who are the patients that get IRAEs more? Are there some people that are just more susceptible to it! 

Dr. Anuranita Gupta: That’s really the question at the heart of personalized medicine! This is a hot research topic, and hopefully in the future, we’ll be able to tailor our decision making to the patient in front of us.

Dr. Shreya Trivedi: Okay, so if I were to take a guess and I’m thinking about how immune checkpoint points inhibitors can make the immune system attack our own organs, I bet preexisting autoimmune disease, or a prior organ transplant can make the immune system more sensitive and reactive to these immune checkpoint inhibits.. 

Dr. Anuranita Gupta: Right, it’s like having a security system that’s on high alert. Introducing these immune checkpoint inhibitors could push it into overdrive. 

Dr. Allison Betof Warner: So immune related adverse events, if we had a biomarker that predicted who would get immune related adverse events, we would be much further along in our field. The things that we do know make that more likely is having baseline autoimmune disease. So patients who have underlying autoimmune disease seem to be at much higher risk of both flares of their particular autoimmune disease as well as other autoimmune effects. And we think that it’s essentially that their set point is a little bit higher, their baseline immune activation is a little bit higher.

Dr. Benjamin Schlechter: If a patient has a distant history of immune dysfunction, Crohn’s disease, ulcerative colitis, something like that, some squirrelly diagnosis of RA or rheumatoid factor that was positive, I’m comfortable using these but carefully and I counsel the patients around them because you may reactivate that process.

Dr. Shreya Trivedi: So immune checkpoint inhibitors are NOT off the table in patients with autoimmune conditons but does merit careful consideration before starting treatment. And all our oncologists did warn us that our patients with transplants need more hands-on deck to avoid rejection of the transplanted organ. 

Dr. Anuranita Gupta: Yeah, that is so important! The risk factor I’m fascinated by is our own microbiota and GI flora plays into all of this. 

Dr. Shreya Trivedi: Ah! It’s fascinating how the gut flora is connected to so much. I am surprised it’s playing a role here too.

Dr. Anuranita Gupta: Yeah, definitely! With the mind-gut connection and now it’s really interesting to think about how the gut microbiome may even play a role in immune therapy response.

Dr. Benjamin Schlechter: So patients who are not heavily pre-treated with antibiotics have a much more diverse population of microbes in their gut and those who’ve been exposed to antibiotics chronically or multiple times have reduced reduced variety in their microbiome and that may promote immune dysfunction. So patients who have been heavily pretreated with antibiotics who have a decreased variety of microbes for the pyrus patches and the innate tissue immunity of the colon to manage, they’re more likely to have immune related adverse events. And that’s sort of borne out in a number of retrospective analysis. What we don’t have is prospective analysis trying to say add a microbiome, a stool microbiome transplant for example, or give probiotics.

Dr. Shreya Trivedi: So interesting! Makes me wonder how much antibiotic exposure does it take, or if PPIs and probiotics affect the GI flora in these cases. I’m sure people are doing active studies on that in the moment. But it definitely motivates me to diversify my microbiome and not just reach for the same old salad. But really hard when I have a 3 year old who just wants pizza and mac and cheese every night.

Dr. Anuranita Gupta: You know, thats very relatable, Shreya! But I agree – variety is the spice of life, they say. And then the last risk factor we can be on the lookout for is someone whose on a combination of both CTLA-4 and PD/PDL-1 inhibitors. 

Dr. Shreya Trivedi: Yeah and that makes sense, two immune checkpoint inhibitors, together, we’re just really firing up that immune system, dialing up intensity of an IRAEs to happen

Dr. Anuranita Gupta: So to recap – who is at higher risk of complications? It’s gonna be people with pre-existing autoimmune disease, solid organ transplants, and if they are on both types of immune checkpoint inhibitors. Lastly, we are still learning more about the impact of prior antibiotic exposure and the gut microbiome.

Pearl 5: Complementary medicine

Dr. Anuranita Gupta: Let’s talk about an overlooked topic by most of us and something that we really should get comfortable asking all our patients about.

Dr. Narjust Florez: One of the most common things in patients with cancers is complementary medicine. I believe in it, but I also believe in honesty and stigmatize it. So when I see a patient with liver dysfunction, my first question is, did somebody send you a message via Facebook that you should try a tea? And sometimes it’s yes. So I have seen a lot of patients that have been called hepatitis induced by immunotherapy, but it has to be sometimes it’s complementary medicine. So a very good med rec is very important. Patients with cancer, they want to do everything they can and that includes teas, alkaline water, coffee ground enemas, these pills here, this influencer there.

Dr. Shreya Trivedi: Oh, I am so glad she is bringing this up! I certainly need to do a better job asking specifically what else my patient may be taking, especially when hepatitis is on the table.

Dr. Narjust Florez: And then I say, if you have started something, go home, look at it. If you found something new, send a picture and send me to the patient portal. Boom. When they go home, they remember and they remember when they go home and it was a tea, it was a root based tea that somebody brought from Taiwan that has these mushrooms. Then what we did is we are like, no more complementary medicine, no more immunotherapy. Let’s see how your liver behaves in two weeks. And so that we saw the liver improving. So I didn’t start here on steroids. So hepatitis induced by immune checkpoint inhibitors doesn’t get better on their own because that monoclonal antibodies stays in target for a very, very long time. 

Dr. Shreya Trivedi: And that is how she typically discovers that liver dysfunction is related to things that are not showing up on someone’s typical med rec and saves them from steroids they did not need!

Dr. Anuranita Gupta: What a win! That being said, when we do see possible hepatitis, we must do our due diligence and workup other causes as well. 

Dr. Narjust Florez: And we have to rule out the common culprits. So hepatitis virus needs to be done and high alcohol consumption and also high acetaminophen intake. Because a lot of patients with cancer have metastasis to bone and they can take a lot of acetaminophen. So hepatitis is very common. You will see AST and ALT to be elevated at the same time as it rises, then the bilirubin follows and that’s when we get in trouble.

Dr. Shreya Trivedi: So to recap this quick but important pearl. Our patients may be using complementary medicine and it certainly does have its place! And so we should ask about teas, powders, and other supplements they may be taking. There is a link to specific website that we learned from a Core IM alternative Medicine At the Bedside Episode that make it easy to look up complimentary medicine and its side effects.

Dr. Anuranita Gupta: And If we are concerned about hepatitis, we should still do our general workup of assessing for hepatitis virus, DILI, alcohol use, etc. There are plenty of helpful schemas and algorithms that help us to do just this. 

Dr. Anuranita Gupta: That wraps up our clinical pearls on immune checkpoint inhibitor adverse events. 

Dr. Shreya Trivedi: If you found this episode helpful, please share with your team, colleagues, give it a rating on Apple podcasts or whatever podcast app you use! It really does help people find us! 

Dr. Anuranita Gupta: This episode was made in part of the Digital Education Track at BIDMC. Thank you to all the educators and mentors! Thank you to our peer reviewers Dr. Tian Zhang and Dr. Hollis Viray. 

Dr. Shreya Trivedi: Thank you to Daksh Bhatia for the audio editing and Dr. Cathy Cichon for the accompanying graphics. As always, we love hearing feedback, email us at hello@coreimpodcast.com. Opinions expressed are our own and do not represent the opinions of any affiliated institutions.

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