Immune Checkpoint Inhibitor Adverse Events 2.0: 5 Pearls Segment

Core IM Podcast

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Time Stamps

• 02:01 Introduction
• 03:22 Pearl 1: Pneumonitis
• 13:39 Pearl 2: Colitis
• 24:35 Pearl 3: Skin IRAEs
• 30:28 Pearl 4: Endocrine IRAEs (Thyroid)
• 35:15 Pearl 5: Endocrine IRAEs (Pituitary)

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Show Notes

ICI: immune checkpoint inhibitor

IRAE: immune related adverse event

Pearl 1: Pneumonitis

• Time to onset:
  • 1.5 to 127 weeks; (median 34 weeks)
  • Clinical presentation: Ranges from asymptomatic to acute hypoxic respiratory failure.
  • Cough, dyspnea, chest pain, fever
• Differential:
  • Heart failure
  • COPD
  • Infection
  • Pulmonary embolism
  • Pneumonitis (radiotherapy, chemotherapy)
  • Malignancy
  • ILD flare
  • Neuromuscular disorder
  • Sarcoidosis.
• Work up:
  • Immunocompetent
    • CT Chest with contrast (CXR insufficient)
      • Often showed ground glass opacities in lower lobes
      • Five different types of imaging findings have been seen:
        • Chronic obstructive pneumonia–like
        • Ground-glass opacities
        • Hypersensitivity type
        • Interstitial type
        • Pneumonitis not otherwise specified
    • Infectious workup
      • Sputum culture
      • Respiratory viral panel
      • COVID-19
      • Blood culture
      • Urine legionella
      • Strep pneumo antigen
    • +/- Bronchoscopy w/ BAL and biopsy
      • Use is debated
      • Can help to rule out infection or lymphangitic spread of tumor
  • Immunocompromised
    • Above work up +
      • Fungal markers (B-glucan, galactomannan)
      • Endemic fungal antigens
      • TB
      • PJP
• Treatment: Guidelines based on grade
  • Grade 1 (asymptomatic/affecting one lobe or <25% of lung):
    • Hold ICI and monitorRepeat imaging in 3-4 weeks
      • If improved, can re-trial ICI
      • If NOT improved, treat as grade 2
  • Grade 2 (symptomatic/involving more than one lobe of the lung or 25-50% of lung parenchyma):
    • Hold ICI
    • Give Prednisone 1-2mg/kg/day and taper over 4-6 weeks
      • If no improvement after 48-72 hours, treat as grade 3 and consider bronchoscopy with BAL +/- biopsy
  • Grade 3 (hospitalization for severe symptoms or oxygen requirement/all lung lobes involved or >50% of lung parenchyma) or Grade 4 (life-threatening respiratory compromise/intubation required):
    • Permanently discontinue ICI
    • Give Methylprednisolone IV 1-2mg/kg/day and taper over 4-6 weeks
      • If no improvement in 48 hours, add an additional agent such as infliximab, mycophenolate mofetil, IVIG or cyclophosphamide. Consider bronchoscopy with BAL +/- biopsy
• Decisions about empiric treatment with antibiotics and diuretics should be made on a case by case basis.

Pearl 2: Colitis

• Time to onset:
  • 1 to 107.5 weeks (median 8 weeks)
• Clinical presentation:
  • Abdominal pain, nausea, diarrhea, blood or mucus in the stool, fever
  • Upper GI toxicity
    • Presents with dysphagia, nausea, vomiting or epigastric pain
    • Less common than lower GI toxicity (most commonly affects descending colon)
  • Associated with NSAID and prolonged PPI use
• Differential:
  • Infectious colitis (bacterial, viral, parasitic)
  • Ischemic colitis
  • Inflammatory bowel disease
  • Radiation colitis
  • Diverticulitis
  • Drug-induced colitis (chemotherapy, tyrosine kinase inhibitors)
  • Graft vs host disease in transplant patients
• Work up:
  • Bloodwork with CBC, CMP, TSH
    • Stool studies Culture
    • C. diff,
    • Ova and parasites
  • CMV
  • Norovirus
  • Fecal inflammatory markers lactoferrin,calprotectin)
  • Review medication list (antibiotics, prolonged PPI use, NSAID).
  • CT scan for abscess
    • Findings often mimic inflammatory bowel disease
      • Mesenteric vessel engorgement
      • Bowel wall thickening
      • Fluid filled colon distension
    • +/- Endoscopy and colonoscopy with biopsy
      • Perform if Grade 2 or positive fecal inflammatory markers
  • Patients on biologics:
    • HIV
    • Hepatitis A
    • Hepatitis B
    • TB
• Treatment: Guidelines based on grade
  • Grade 1 (increase of <4 stools per day over baseline):
    • Can continue ICI or hold temporarily until resolution of symptoms.
    • Supportive care with hydration and medications such as loperamide if infection has been ruled out.
  • Grade 2 (increase of 4-6 stools per day over baseline):
    • Hold ICI until symptoms resolve to grade 1.
    • Give prednisone 1mg/kg/day until symptoms improve to grade 1, then taper over 4-6 weeks.
    • If no improvement in 72 hours or there are high risk endoscopic features, then add infliximab or vedolizumab.
  • Grade 3 (increase of > or =7 stools per day over baseline/hospitalization):
    • Grade 2 recommendations apply.
    • Can consider IV methylprednisolone especially if concurrent upper GI inflammation.
    • If no improvement in 48 hours, consider adding biologics like infliximab or vedolizumab.
    • Consider permanent discontinuation of CTLA-4 agents.
  • Grade 4 (life threatening symptoms/urgent intervention required):
    • Grade 2 and 3 recommendations apply.
    • Give IV methylprednisolone 1-2mg/kg/day until symptoms improve to grade 1, then taper over 4-6 weeks.
    • If no improvement in 48 hours, consider adding biologics like infliximab or vedolizumab.
    • Permanently discontinue ICI.
• Resume ICI if fecal calprotectin is less than 116 or if repeat endoscopy shows mucosal healing.

Pearl 3: Skin IRAE

• Time to onset:
  • 2 to 150 weeks (median 7 weeks)
• Clinical presentation:
  • • Maculopapular rash
    • Bullae
    • Vitiligo
    • Stevens Johnson Syndrome
    • Toxic Epidermal Necrolysis
    • DRESS
  • Symptoms: ranges from itch +/- rash to fever, skin sloughing, pustules, blisters or mucosal erosions
• Differential:
  • Allergic or irritant contact dermatitis
  • Atopic dermatitis
  • Psoriasis
  • Seborrheic
  • Dermatitis
  • Infectious dermatitis (fungal, bacterial, viral)
  • Unrelated drug rash with eosinophilia and systemic symptoms (DRESS)
• Work up:
  • History and physical exam is very important including
  • Examination of oral mucosa
  • assessment of blisters and body surface area affected
  • Medication list should be reviewed
  • CBC and CMP should be obtained
  • Dermatology may obtain skin biopsy for further evaluation
• Treatment: Guidelines based on grade
  • • NOTE: Vitiligo is associated with treatment response
  • Grade 1 (rash<10% body surface area):
    • Continue ICI and give topical emollients and/or mild-moderately potent topical steroids.
  • Grade 2 (rash covering 10-30% BSA with or without symptoms):
    • Consider holding ICI. Give topical emollients, oral anti-histamines and medium-highly potent topical steroids.
    • Consider prednisone 0.5-1mg/kg and taper over 4 weeks.
  • Grade 3 (rash >30% BSA with moderate or severe symptoms):
    • Hold ICI and discuss with dermatology about the timeline for restarting.
    • Give topical emollients, oral antihistamines and highly potent topical steroids.
    • Start oral prednisone 1mg/kg/day and taper over 4 weeks.
    • If pruritus is present without rash, you can try gabapentin or pregabalin.
  • Grade 4 (severe symptoms requiring hospitalization):
    • Hold ICI,
    • Hospitalize patients and give IV methylprednisolone 1-2mg/kg/day.
    • Discuss with dermatology/oncology about appropriateness of restarting ICI

Pearl 4: Endocrine IRAEs (thyroid)

• Time to onset:
  • 1.5-130 weeks (median 14.5 weeks)
• Clinical presentation:
  • Pituitary dysfunction,
  • Hypothyroidism,
  • Hyperthyroidism,
  • Adrenal insufficiency
    • Nausea, vomiting, abdominal pain, weight loss, lightheadedness or orthostasis or syncope, and profound fatigue
  • T1DM
    • Polyuria or polydipsia, nausea or vomiting, abdominal pain, and/or visual blurring
  • Primary hypothyroidism
  • Cold intolerance, dry skin, constipation, weight gain, and/or fatigue
• Differential:
  • Hashimoto’s thyroiditis
  • Central hypothyroidism
  • Post-viral subacute thyroiditis
  • Induced by other drugs (lithium, amiodarone, anti-epileptics)
  • Induced by head and neck radiation
• Work up:
  • TSH and free T4
    • Low TSH and low free T4= central hypothyroidism (see hypophysitis below)
    • High TSH and low free T4= primary hypothyroidism
  • T3
  • TSH receptor antibody testing if suspicion for Graves’ Disease (ophthalmopathy or thyroid bruit).
• Treatment: Guidelines based on grade:
  • Grade 1 (4.5
    • Continue ICI and monitor TSH every 4-6 weeks.
  • Grade 2 (TSH>10 and symptomatic):
    • Can continue or hold ICI
    • Start levothyroxine
    • Check TSH levels every 6-8 weeks until TSH is in reference range.
  • Grade 3-4 (severe symptoms):
    • Hold ICI until symptoms resolve.
    • Hospital admission if concern for developing myxedema (bradycardia, hypothermia, altered mental status).
    • Discuss with endocrinology about IV levothyroxine and steroids.
    • Thyroid supplementation per grade 2 recommendations.
  • Consider referring to endocrine at grade 2; should be referred at grade 3 or higher.
• For thyrotoxicosis:
  • Grade 1 (asymptomatic or mild symptoms): Continue ICI. Beta blocker for symptoms. Monitor thyroid function 2-3 weeks to detect subsequent hypothyroidism (commonly occurs in transient subacute thyroiditis) in which case the patient should be treated for primary hypothyroidism.
  • Grade 2 (moderate symptoms): Consider holding ICI, give beta blocker for symptoms. If persistent >6 weeks, will need thyroid suppression.
  • Grade 3-4 (severe symptoms, unable to perform ADLs): Hold ICI until symptoms resolve and give beta blockers for symptoms. Discuss with endocrine about medical therapies such as steroids, potassium iodide, methimazole, propylthiouracil or surgery.
  • Refer to endocrine if thyrotoxicosis persists for more than 6 weeks.

Pearl 5: Endocrine IRAEs (pituitary)

• Time to onset:
  • Variable
    • Hypophysitis is most commonly seen with ipilimumab.
• Clinical presentation:
  • Fatigue
  • Loss of libido
  • Mood changes
  • Oligomenorrhea due to hormone imbalances
  • Headaches
  • Visual changes
• Work up:
  • AM cortisol
  • AM ACTH
  • TSH and free T4
  • Electrolytes
  • Hormone levels: LH, FSH, estrogen and testosterone.
  • +/- AM ACTH stimulation testing
    • Complete IF AM cortisol results are indeterminate (between 3 and 15)
  • +/- MRI brain with and without contrast with sellar cuts
    • Complete if visual changes, headache or diabetes insipidus
• Treatment: Use Guidelines based on grade
  • • NOTE :Principles are somewhat different because hormone replacement is the mainstay of treatment instead of immunosuppression for endogenous hormone production recovery.
  • Grade 1 (asymptomatic/mild symptoms):
    • Consider holding ICI until the patient stabilizes on hormones.
    • Steroid replacement for adrenal insufficiency if needed.
    • Thyroid replacement if needed with free T4 goal in upper half of reference range.
    • Testosterone or estrogen therapy if needed and no contraindications.
  • Grade 2 (moderate symptoms):
    • Consider holding ICI
    • Hormone replacement as grade 1 recommendations
    • If MRI shows pituitary swelling or optic chiasm compression, treat with prednisone 1mg/kg/day and taper over 1-2 weeks to maintenance therapy dose.
  • Grade 3-4 (severe symptoms/unable to perform ADLs):
    • Hold ICI until stabilized on hormones.
    • IV hydrocortisone 50-100mg q6-8 hours tapered down over 5-7 days or prednisone 1-2mg/kg/day tapered over 1-2 weeks to maintenance dose.
    • Hormone replacement as grade 1 and 2.
      

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Behind The Scenes YouTube Interview

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Transcript

Dr. Benjamin Schlechter: You have to think a little bit like a bone marrow transplant doctor, they have learned an amazing instinct for how inflammation and irritation resulted in misbehavior of the transplanted immune system. So you have to have a little bit of paranoia and you have to look for subtle things when dealing with checkpoint inhibitors, when dealing with the immune system. Anytime there’s something on a scan that doesn’t make sense, you’d kind of need to explain it. And anytime someone doesn’t get better, you kind of need to explain it.

Dr. Shreya Trivedi: That’s Dr. Schlecter, a GI oncologist from the Dana Farber Cancer Institute.

Intro

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, an internal medicine resident at Beth Israel Deaconess Medical Center. Today we’re doing part 2 of our podcast on immune checkpoint inhibitors and immune-related adverse events (or IrAEs).

Dr. Shreya Trivedi: In the first part we set the foundation for understanding how checkpoint inhibitors work and a framework to think of the adverse events that can happen.

Dr. Anuranita Gupta: In this episode, we are zeroing in on illness scripts to differentiate IRAEs from other medical conditions and we’ll share some crucial management tips too!

Dr. Shreya Trivedi: It was a hard job to pick out discussants’ brains to do most common solid organ problems we encounter.

Dr. Anuranita Gupta: With each of the solid organs, we will touch on the symptoms, diagnosis and management. Let’s get started with the pearls 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: Pneumonitis or inflammation of lung parenchyma.

Dr. Shreya Trivedi: How do we diagnose checkpoint inhibitor related pneumonitis? Once identified how do we treat it?

Dr. Anuranita Gupta: Pearl 2: Colitis or inflammation of the colon.

Dr. Shreya Trivedi: How do we diagnose checkpoint inhibitor related colitis? Once identified how do we treat it?

Dr. Anuranita Gupta: Pearl 3: Skin IRAEs.

Dr. Shreya Trivedi: How do we recognize dermatologic adverse events caused by checkpoint inhibitors? How are these conditions treated?

Dr. Anuranita Gupta: Pearl 4: Endocrine IRAEs, with a focus on thyroid adverse events.

Dr. Shreya Trivedi: With checkpoint inhibitor toxicity to the thyroid, what are the different presentations and at what TSH level do you stop an ICI?

Dr. Anuranita Gupta: Pearl 5: Endocrine IRAEs continued, with a focus of hypophysitis or pituitary inflammation.

Dr. Shreya Trivedi: How does hypophysitis present? Do steroids help?

Pearl 1: Pneumonitis

Dr. Shreya Trivedi: So let’s start with a case we have seen not too infrequently!

Dr. Anuranita Gupta: Mr. Johnson is a 64 year old male with hx of HFpEF and stage III non small cell lung cancer diagnosed two years ago. He has been receiving atezolizumab (a PDL-1 inhibitor) as part of his treatment plan for the past 5 months. He presents to the clinic with dry cough and shortness of breath for the past 4 weeks. On exam, he is satting 93% on room air and crackles are heard in the lower lung fields.

Dr. Shreya Trivedi: There’s so much to dig into here – this could be heart failure, infection, pulmonary embolism, pneumonitis from radiotherapy or medication and lymphangitic spread of malignancy. So are there any specific characteristics of checkpoint inhibitor pneumonitis that can help us tease things out?

Dr. Anuranita Gupta: So Pneumonitis, like all of the IrAEs, can present at any time, but the general rule of thumb is that pneumonitis is about 8 months after starting a checkpoint inhibitor.

Dr. Shreya Trivedi: And then in terms of symptoms, I imagine there aren’t any specific symptoms to help us differentiate if it’s a pneumonitis IRAE or not .

Dr. Anuranita Gupta: You are right, so someone can come in with acute hypoxic respiratory failure OR just have cough, dyspnea, chest pain or what’s crazy is some patients with checkpoint inhibitor pneumonitis.

Dr. Shreya Trivedi: So we also sat down with Dr. Warner, a melanoma oncologist at the Stanford who had a pro-tip about checking an ambulatory O2 sat:

Dr. Allison Betof Warner: One thing that I have found to be exceptionally useful is an ambulatory sat. So sometimes patients are sat very well and appropriately on room air at rest, and just like the old days of PCP, their oxygenation will plummet with any exercise. So I’ve found that to be very helpful and obviously as a test you can easily do in your office and that can be useful.

Dr. Shreya Trivedi: Alright we will look out for ambulatory sat plummeting! What kind of diagnostic workup would you do for Mr. Johnson?

Dr. Anuranita Gupta: Okay. So the approach is to really rule out the common things that we do have tests for. So I would want an infectious workup for sure. A sputum culture, respiratory viral panel, COVID-19, blood cultures and consider urine legionella and strep pneumo antigen. I would also throw in a BNP given his history of heart failure. And then for imaging I would think about chest x-ray but then would probably delete that order and order a CT chest with contrast both to rule out pulmonary embolism and see what the lung parenchyma looks like.

Dr. Shreya Trivedi: Yep that’s exactly what Dr. Narjust Florez, a thoracic oncologist at Dana Farber, recommended when we sat down with her.

Dr. Narjust Florez: So no checks X-ray in this case. We skip that. We go straight to CT chest and how the inflammation pattern will help you understand if it’s a ground glass, a diffuse infiltrates in both loaves, that’s a drug-induced pneumonitis.

Dr. Anuranita Gupta: And from my reading, there are actually 5 different radiographic subtypes that we see with pneumonitis. Ground glass opacities in the lower lobes are the most common subtype of pneumonitis.

Dr. Benjamin Schlechter: Now in this day and age, you’re usually told inflammatory processes in the lungs, ground glass, opacities, septal thickening, pneumonitis versus drug toxicity cannot rule out covid 19. And that will be the scan result that you get a hundred percent of the time.

Dr. Shreya Trivedi: I just appreciate his realness that we probably can’t hang your hat on the CT scan giving the slam dunk answer.

Dr. Allison Betof Warner: It can be harder on a CT as well for lung cancer patients because their baseline lung parenchyma isn’t often normal, whereas a melanoma patient often has normal baseline lung parenchyma. Additionally, then you added the complication of radiation and we occasionally radiate lung lesions in melanoma as well. And we are all sitting there pulling our hair out trying to figure out what is happening. I know that’s the thing.

Dr. Shreya Trivedi: So Anu it does feel validating knowing that an oncologist may be pulling their hair too- if we’re still not sure from all of this workup if Mr. Johnson’s symptoms are from infection, cancer or pneumonitis IRAE- can we do a bronchoscopy to get more answers?

Dr. Anuranita Gupta: You may have opened up a can of worms here. It turns out the role of bronchoscopy is debated in the field.

Dr. Allison Betof Warner: You do sputum samples, maybe even a B A L from a bronch, it comes back, but it can come back non-infectious frequently even with pneumonia because the sensitivity of that test isn’t great. Often they’ve already gotten antibiotics before you’ve gotten the BAL, and so it may be sterile, they’re still infection there that you are already treating.

Dr. Anuranita Gupta: So yeah the bronch might NOT give you a clear cut answer but of course if the BAL does pick up an infection that can be helpful or in case that a trans-bronchial biopsy does show lymphangitic spread of the cancer that can be helpful.

Dr. Shreya Trivedi: Oof let’s close up that can of worms then and go back to Mr. Johnson. Say oncology sees him, sees that none of the workup has come back positive for something else, thinks of the clinical picture more and does think pneumonitis IRAE is high on the differential. With oncology’s blessing, let’s treat him for it!

Dr. Anuranita Gupta: So big picture is that-treatment of IRAEs is generally guided by what grade aka what severity they are and there are usually 4 grades, with 4 being the worst

Dr. Shreya Trivedi: ASCO guidelines which lay everything out clearly and is a great reference for the management of these toxicities based on that grade.

Dr. Anuranita Gupta: The higher grades often reflect a higher severity of symptoms and a larger amount of lung parenchyma affected. The lack of response to treatment of a lower grade can also upgrade the toxicity to a higher grade.

Dr. Shreya Trivedi: And just to give a contextualize of the severity scale, grade 3 is when the patient requires hospitalization for severe symptoms/new oxygen requirement or all lung lobes or >50% of parenchyma is affected.

Dr. Anuranita Gupta:And what most internists are thinking about is do we hold the ICI temporarily or permanently?

Dr. Narjust Florez: This is why I think a very good takeoff message is if you identify these immune adverse events early, it allows for the patient to maybe rechallenge in the future. Because if you identify as a grade one or grade two, you can rechallenge. But if it’s a grade three or grade four, there’s a no-no.

Dr. Anuranita Gupta: And then of course, all of the management plans involve steroids in different types and doses and pneumonitis is no exception. For the highest grade, oncologists consider treating with immunomodulators like infliximab, mycophenolate, IVIG and cyclophosphamide as well.

Dr. Shreya Trivedi: One helpful thing is the trajectory of checkpoint inhibitor pneumonitis. With steroids, the patient should start to feel better very soon especially at the lower grades.

Dr. Narjust Florez: The difference between the COPD and pneumonitis is that they get a lazarus effect. You start the patient on prednisone and the next day you call them, they’re like, doctor, I’m doing great, doing great. So you don’t get that with COPD. It takes a little bit longer.

Dr. Shreya Trivedi: But what about humble diuretics and antibiotics early on in the admission? Is there a role for them in this management plan?

Dr. Anuranita Gupta: Truthfully, a lot of these cases are not clear-cut pneumonitis, and it’s not easy to rule out infection and volume overload and you end up doing a bunch of things together like steroids, antibiotics, and diuretics.

Dr. Allison Betof Warner: We had a patient I remember clearly was starting to escalate to even needing high flow and was not responding to antibiotics, did have a fever which was leading us more towards the infection pathway, but inflammation can also cause fevers. We had a multidisciplinary conference. If we are letting pneumonitis fester without steroids, we are very much potentially getting into a very dangerous territory where patients can need to be intubated. And so there was a lot of concern obviously about giving steroids and lowering responsiveness to infection if this did happen to be infectious. And our infectious disease colleagues were certainly concerned about that, as was I. But at the end of the day, we really felt strongly that there was a very good chance this was also pneumonitis that was going untreated and that the patient was deteriorating. And so we did, we put them on HCAP level antibiotics as well as full dose steroids and thankfully that patient, I don’t know which one they got better in response to. Maybe it was both, but that patient did thankfully turn around.

Dr. Shreya Trivedi: I appreciate ending this pearl on pneumonitis reflecting on the humbling nature of medicine, and you have to work with colleagues to figure out if you are doing too much or little. Let’s recap this pearl, Anu. What do you want people to take away?

Dr. Anuranita Gupta: What I want ppl to remember is that the presentation for pneumonitis is nonspecific. One clue can be its presentation around 8 months from starting the medication. Having a CT with ground glass in the lower lobes is typical for checkpoint inhibitor pneumonitis, though many things can look like this. Also, if it is IRAE pneumonitis, the treatment- steroids- will make the patient feel better quickly at the lower grades.

Pearl 2: Colitis

Dr. Shreya Trivedi: Ok now that we did pneumonitis, lets move a little lower in the body to colitis. This is another tricky one because the symptoms are nonspecific and can mimic other conditions. So Anu give us a case so we can pick our experts brains on what we can and can’t hang our hats on for the the diagnosis

Dr. Anuranita Gupta: Yeah let’s jump right in. Ms. Moon has a history of stage IV metastatic melanoma which was diagnosed a year ago and has been undergoing treatment for the past 2 months with Nivolumab+Ipilimumab (so that’s a combination PD-1 and CTLA-4 inhibitor). She presents to the hospital with acute abdominal pain, N/V, diarrhea with 8 stools per day and inability to tolerate oral intake.

Dr. Shreya Trivedi: What to do… what to do…. For some spaced repetition from the IRAE 101 episode, with colitis IRAEs, the median time to onset is 8 weeks which fits with our case of presenting about 2 months later

Dr. Anuranita Gupta: And like most IRAEs, it’s the combination checkpoint inhibitors that are the most likely to cause checkpoint inhibitor toxicity

Dr. Shreya Trivedi: So in terms of symptoms, colitis IRAE, you can expect to see anywhere from a few to many of these symptoms.

Dr. Benjamin Schlechter: It’s usually a subacute onset over three or four days on these two or three days where they get watery stool, increased frequency, feel a little bit off.

Dr. Anuranita Gupta: When thinking about diarrhea- other than the usual culprits that you already think of, don’t forget radiation colitis, graft vs host disease which doesn’t apply to this patient but does apply to certain bone marrow transplant patients and other drug effects such as from chemotherapy or tyrosine kinase inhibitors in this patient population.

Dr. Shreya Trivedi: Remind me what are tyrosine kinase inhibitors?

Dr. Anuranita Gupta: If you’re looking at a list of cancer therapies and see –tinib at the end of the name, there’s a good chance it’s a tyrosine kinase inhibitor.

Dr. Shreya Trivedi: I like that the T from tyrosine kinase inhibitors and the T in tinib. Now back to the drawing board- we’re admitting Ms. Moon to the hospital. What kind of diagnostic workup will be most helpful?

Dr. Benjamin Schlechter: You should check for common things like c diff, norovirus.

Dr. Anuranita Gupta: Yep in addition to C.diff, norovirus I’d get TSH, stool cultures, ova and parasites. For particular immunocompromised patients, I would add on the good old CMV, cryptosporidium, microsporidium, cyclospora tests.

Dr. Shreya Trivedi: That sounds good in terms of infectious workup, but for those fecal inflammatory markers like fecal calprotectin and lactoferrin

Dr. Anuranita Gupta: Yeah these inflammatory markers can represent the amount of mucosal damage there has been

Dr. Shreya Trivedi: So if it shows the amount of mucosal damage it may be helpful to monitor how much mucosal damage there is over time?

Dr. Anuranita Gupta: Yep and fun fact if it is checkpoint inhibitor colitis, the oncologist will monitor the fecal calprotectin to see if they can restart the checkpoint inhibitor and if it’s below 116 it might be the green light they are looking for.

Dr. Shreya Trivedi: Ok cool so below a certain level it helps know the inflammation has cooled down and less mucosal damage

Dr. Anuranita Gupta: One thing to keep in mind is if your patient has a GI malignancies, lactoferrin and fecal calprotectin may be higher than normal anyway without colitis.

Dr. Shreya Trivedi: Yeah these inflammatory markers can be high in any type of colitis so it’s not something we can hang our hats on.

Dr. Benjamin Schlechter: A flex sig with tissue biopsy, we’ll be diagnostic, although that’s not a nice thing to do to someone who’s got an inflamed colon and diarrhea.

Dr. Shreya Trivedi: Yeah I hear if on EGD and/or colonoscopy we find features like ulceration, that may let us know early that a biologic agent will be needed but i never know if i should pull the trigger to consult or not

Dr. Anuranita Gupta: Don’t overthink it because the decision to scope is a complex and worth the multidisciplinary discussion. In general, if symptoms are mild it may be reasonable to wait for the inflammation to cool down before scoping. But if the inflammation is severe, it is recommended to scope early.

Dr. Shreya Trivedi: And then last and most importantly with our diagnostic hats on, let’s look at the med rec. What should we look out for in the med rec when it comes to a patient with diarrhea who is on a checkpoint inhibitor?

Dr. Anuranita Gupta: Well I would ask about antibiotics with c diff in mind and also would ask about NSAID use and prolonged PPI use since they have been linked to checkpoint inhibitor colitis.

Dr. Shreya Trivedi: And then in terms of imaging, CT abd and pelvis (with or without contrast) can help in terms of the extent of colitis and to rule out an abscess. And of course, patients are allowed to have two things going on, like recently I took care of a patient whose CT scan pointed to diverticulitis so only treated that first but actually had both diverticulitis and checkpoint inhibitor colitis.

Dr. Benjamin Schlechter: I think it’s very legitimate if a patient presents with diverticulitis on a checkpoint inhibitor to treat them for diverticulitis. You’re not risking anything by doing that, but be worried that either there’s something else going on or something else could go on and just think about it. You should hear that whisper in the back of your mind, what about the pembro?

Dr. Anuranita Gupta: We love a good auditory hallucination! And what a great opportunity to talk about CT findings in colitis IRAE. I can’t imagine a radiology read explicitly identifying checkpoint inhibitor colitis but some clues to look for are that it often affects the descending colon. Some other buzzwords are mesenteric vessel engorgement, bowel wall thickening, and fluid filled colon distension.

Dr. Narjust Florez: Let’s look at the wall of the colon. Something that’s very unique to colitis induced by immunotherapy is they have wall edema. And you can see that in diverticulitis. You see the pouches that are inflamed, but they’re individual. But here it’s a continuous wall edema and it’s a malabsorption diarrhea. That’s what it is. It’s like a crohn induced by drugs. So the malabsorption diarrhea and the patient, we told you very different than the diverticulitis diarrhea is, how did they say it in their own words? Everything just goes through me. That’s a very common phrase. Everything just goes through me because the wall has so much edema. That’s why the physiology of medicine is so beautiful. The wall has so much edema because there’s T-cell infiltration that produces this humongous amount of inflammation. So there is no way that there is any villi able to absorb anything.

Dr. Shreya Trivedi: that physiology is so beautiful and makes me now want to pay more attention to the history that someone is giving and really look at the CT scan for significant wall edema. Ok now let’s talk about treatment for colitis and im sure mgmt based on grades/severity.

Dr. Anuranita Gupta: For the grades, it’s all about the number of stools. Less than four stools a day, you do the typical supportive treatment for diarrhea with hydration, meds like loperamide once you’ve ruled out c.diff or dysentery and you can continue or temporarily hold the ICI until symptoms resolve.

Dr. Shreya Trivedi: Speaking of which… to hold or not hold the ICI always stresses me out and some days I find myself scrambling to get a hold of the oncologist to see if it’s okay to miss a dose or not

Dr. Benjamin Schlechter: There is no such thing as urgent checkpoint inhibitors. Okay? These are drugs whose onsets are in weeks to months. If you give someone a highly active chemotherapy, you could see benefit on a chemosensitive cancer in days. If you give people a highly active checkpoint inhibitor on a highly immune responsive cancer, you don’t see anything for weeks. There is no situation in which giving a checkpoint inhibitor is an emergency, and that’s also an important utilization discussion. Okay, sometimes, should we give this person inpatient checkpoint inhibitors? No, we should not. These drugs have an incredibly long half-life, usually over 20 days. Missing a dose is fine, but it’s very hard to reassure patients about that. And even doctors, I’ll be honest, I always want to order it when they’re in the hospital. You got to step back and be logical and missing a dose is okay.

Dr. Shreya Trivedi: That’s helpful- now we can rest assured if a dose of this medication is missed as long. What if the patient has more than 4 stools/day above baseline and has a higher grade severity?

Dr. Anuranita Gupta: Yep, for the higher grades aka more than 4 stools above baseline, we are of course going to reach for steroids (prednisone vs methylpred) and tapering over 4-6 weeks once symptoms improve.

Dr. Shreya Trivedi: Wow, taper takes over a month after symptoms improve? Why so long?

Dr. Allison Betof Warner: There are some patients who can do with a quick taper, but many will have their colitis flare again if you taper too quickly. So this isn’t a set it and forget it type of taper because as soon as the colitis flares again or whatever IRAE you’re treating, you have to go back up. And so this is an individual patient approach.

Dr. Anuranita Gupta: I had a patient just like this and I remembered the CORE IM steroids episode and pulled up the graphic to remind myself about PJP prophylaxis, osteoporosis prophylaxis as well as GI prophylaxis with a PPI.

Dr. Shreya Trivedi: Oh good throwback and connection to remember the prophylaxis! Okay that’s steroids but then I’m wondering when is colitis bad enough to reach for biologics?

Dr. Anuranita Gupta: A good rule of thumb is that if symptoms don’t improve in 3 days of steroids, it’s time to pull out the big gun biologics. And for colitis are anti-TNF (infliximab) and anti-integrin (vedolizumab).

Dr. Shreya Trivedi: Good to know that it’s the 3 day mark when we should be looking for backup help. What a whirlwind! Let’s recap this pearl. Yep so what i learned about IRAE colitis typically presents within 2 months of starting a checkpoint inhibitor and consists of numerous episodes of voluminous diarrhea. When working it up, we want to rule out a host of infectious causes and imaging can be helpful if there’s significant wall edema. A good nugget on mgmt is that it’s okay to hold the ICI while you are trying to sort out if it is an IRAE colitis or not. But if it’s above 4 stools above baseline, we are going to reach for steroids.

Pearl 3: Skin IRAEs

Dr. Shreya Trivedi: Now onto the skin.

Dr. Anuranita Gupta: With my sunscreen in hand I’m ready to talk about our next case! This is Ms. Singh who has a history of stage III melanoma and was recently started on adjuvant nivolumab (PD-1 inhibitor) 3 weeks ago. She presents to the clinic with a rash that developed over the past week. Exam shows erythematous macules over the chest which are pruritic with no vesicles.

Dr. Narjust Florez: It’s red macular. I’m not going to try to describe that anymore because every time an internist describes a rash, a dermatologist tears a little bit of blood somewhere, so I’m just going to at every, macco, poplar rash, that’s poetic as much as you get from me.

Dr. Shreya Trivedi: Yep, appreciate the realness. As a throwback, checkpoint inhibitor toxicity to the skin can happen relatively soon. If you look at the literature, the median time to onset is around 7 weeks but our oncologists have told us they often see it pretty quickly after starting a checkpoint inhibitorlike 3 weeks for our patient

Dr. Anuranita Gupta:And then the symptoms here can vary a bunch. Some patients just have an itch +/- rash, while some can have scarier symptoms like fever, skin sloughing, pustules, blisters or mucosal erosions.

Dr. Benjamin Schlechter: So first of all, make sure it’s a rash and make sure it’s not itching that they scratched that it’s a rash. The next thing you want to do is look at how extensive it is. Look at the body. You really have to undress the patient and see how extensive it is and use your B S A calculations to figure out how much of the body is covered. And then critically, you must look in the mouth. If there is skin toxicity in the mouth, you need to call for help.

Dr. Shreya Trivedi: Totally! Yep for the scarier stuff like bullae and are concerned about bullous dermatosis, vitiligo, Stevens Johnson Syndrome or DRESS we will of course loop in our friendly local dermatologist. For the rest of this pearl lets talk about the more common skin toxicity which is inflammatory dermatitis

Dr. Allison Betof Warner: You want to ask all the typical dermatology questions, right, any new exposures, any new foods, did you change your detergent?

Dr. Shreya Trivedi: Yep all good derm questions and of course my favorite as an internist is thinking about any recent medications or over the counter med changes

Dr. Anuranita Gupta: Yep, all this good history can help us rule out allergic or irritant contact dermatitis, eczema, psoriasis.

Dr. Shreya Trivedi: And doing a good exam to rule out infectious dermatitis like fungi with tinea, bacteria that we see in impetigo or a virus like shingles. Lots of things on the ddx

Dr. Anuranita Gupta: Ok Shreya I have to share this one fact about vitiligo that I learned while researching this topic that was so interesting to me.

Dr. Shreya Trivedi: Oh yeah go for it!

Dr. Anuranita Gupta: So apparently, vitiligo, which as a quick reminder is the loss of skin color in patches, hints at a stronger immune response of the drug against melanoma. So basically if you see vitiligo as a toxicity, it means the checkpoint inhibitor is kicking the melanoma’s butt.

Dr. Shreya Trivedi: Amazing! Okay so it’s like sorry you have these skin color patches loss but yay we are getting rid of cancer cells. So I’m curious what specific grades and management tips are out there for the skin IRAEs? When I try to force myself to think about it all I can think about is call derm.

Dr. Allison Betof Warner: Your index of suspicion has to be that this is I C I dermatitis from I C I is exceptionally common and can happen quite early even after the first dose. So there is very little harm in giving topical steroids. If this is on a small enough area of the body that you can use topical steroids, I always prefer that to systemic steroids. And I don’t necessarily biopsy these patients and get dermatologic biopsies unless it appears very abnormal, it doesn’t respond to typical treatments, then I certainly pull in my dermatology colleagues.

Dr. Anuranita Gupta: So for low grades in skin toxicity (that is <10% of BSA and no systemic symptoms), treatment usually involves emollients aka moisturizing treatment in addition to topical steroids. And here we can continue the checkpoint inhibitor.

Dr. Shreya Trivedi: Just like lung and GI tract, with higher grades we’re treating with steroids and holding the checkpoint inhibitor. Ok so Ms. Singh probably with her grade 1 maculopapular eruption treated with topical steroids so maybe we avoided dermatology but just to say it outloud when do we think about referring to dermatology?

Dr. Anuranita Gupta: Generally, refer to dermatology at grade 3 or higher, which usually >30% body surface area, but if there is any concern at all for Stevens Johnson Syndrome (SJS), DRESS or mucus membrane involvement, please refer to dermatology at ANY grade.

Dr. Shreya Trivedi: Let me recap. In terms of ICI toxicity, taking a good history about exposure, meds, and ruling out infection can be helpful. Within that, look at blisters, body surface area affected, mucus membrane. If <10%, we’re doing topical steroids. So let’s recap, the history and physical exam to differentiate if its skin IRAEs or something else. In particular we should look at if there’s mucus membrane involvement, blisters and how much of the body is affected. Topical vs oral vs IV steroids may be needed to treat the IRAE among other medications.

Pearl 4: Endocrine IRAEs (Thyroid)

Dr. Shreya Trivedi: For pearl 4, we’re diving into the glands or the endocrine checkpoint inhibitor toxicities. We’ll be focusing this pearl on thyroid IRAEs and pearl 5 on pituitary IRAE.

Dr. Anuranita Gupta: Ok let’s jump right into our case then! Picture Mr. Williams who is a 58 year old man with stage IV non-small cell lung cancer who has been receiving treatment with pembrolizumab starting 5 months ago. Just a few weeks prior he felt very hot most of the time and was having frequent bowel movements. But now, he reports he’s had recent weight gain, goes a few days between his bowel movements and feels cold despite the weather being warm.

Dr. Shreya Trivedi: Wow, that sounds uncomfortable. His case fits with what we talked about in the last episode with thyroid issues often presenting with a hyperthyroid state at first, and then a hypothyroid one.

Dr. Anuranita Gupta: Yep so first there’s transient subacute thyroiditis which increases the release of thyroid hormone which is why he had heat intolerance and diarrhea and later as the gland burns out, he became hypothyroid with cold intolerance, constipation and weight gain.

Dr. Shreya Trivedi: Dr. Florez laid out how closely she follows a patient watching out for that transition point between that hyperthyroid to hypothyroid state

Dr. Narjust Florez: First dose of pembro, nothing happens. Second dose of pembro, TSH comes to 0.01 and then you’re like, hmm, let me get the T four. So the T four is elevated. And you’re like, well, you’re in thyroiditis now you have to let you cool down, but you don’t treat it at least the patient is symptomatic. If the patient is symptomatic in the thyroiditis phase, you do have to do propranolol, you do have to do the inhibition. But then we have very close follow-up at that point. I do call my endocrinologist because there’s a very fine line when the patient is hyperthyroid and then becomes hypothyroid.

Dr. Shreya Trivedi: It’s like balancing a seesaw- we have drugs at our disposal to treat symptomatic hyperthyroidism with propranolol but we need to monitor closely through the progression of the thyroid gland getting burnt out

Dr. Anuranita Gupta: Totally! Going back to our case with Mr. Williams, if I had to create a differential diagnosis from his current symptoms which are in line with a primary hypothyroidism, I would include Hashimoto’s thyroiditis, post-viral subacute thyroiditis and would think about other drugs like lithium, amiodarone and antiepileptics that could be contributing.

Dr. Shreya Trivedi: And for our cancer population- head and neck radiation as well as a central hypothyroidism from pituitary IRAE are on the ddx.

Dr. Anuranita Gupta: And then what’s really interesting about the endocrine glands is that giving steroids like we do for the solid organ and skin IRAEs doesn’t really resolve the toxicity.

Dr. Allison Betof Warner: The thing that’s different about endocrinopathies is that they tend to be permanent. That once whatever gland is affected is affected, it tends to stop making their hormone even if you aggressively treat the inflammation.

Dr. Shreya Trivedi: Well that’s really unfortunate. Glands can’t bounce back the way solid organs do but sounds like these patients do just fine with being on hormone replacement.

Dr. Anuranita Gupta: But the exception to being on hormone replacement is if its grade 1 thyroid toxicity. And grade 1 means asymptomatic with minimal TSH elevation. Here you would just continue the ICI and monitor the TSH

Dr. Shreya Trivedi: Okay then with grade 2 or higher that is which is going to be a TSH >10 milli international units/L and symptomatic – we hold the checkpoint inhibitor for grade 2 or higher and start levothyroxine at that point too.

Dr. Anuranita Gupta: Part of monitoring here is checking both TSH and T4 levels. The free T4 usually normalizes sooner than the TSH so it’s better to check both at once.

Dr. Shreya Trivedi: Once the TSH and T4 levels are back to normal ranges, the levothyroxine should be continued since the gland doesn’t bounce back and the thyroid function tests can be checked every 6 months or a year.

Dr. Anuranita Gupta: And that’s a wrap on thyroid IRAEs. Let’s recap this pearl. Thyroid IRAE usually presents with as a transient hyperthyroid state followed by a hypothyroid one.

Dr. Shreya Trivedi: And then for management, yes there is the ASCO guidelines for graded management that we will link in the show notes but big takeaway for the thyroid gland being affected is permanent and just giving steroids will not resolve it so ultimately these patients need levothyroxine.

Pearl 5: Endocrine IRAEs (pituitary)

Dr. Anuranita Gupta: Now onto the pituitary gland and its IRAE which is called hypophysitis.

Dr. Shreya Trivedi: Why do they call it hypophysitis? Why can’t they just call it pituitary-itis?

Dr. Anuranita Gupta: That would be too easy, Shreya.

Dr. Shreya Trivedi: Hypophysitis ! Let’s solidify it with a case!

Dr. Anuranita Gupta: This one is about Ms. Thompson, a 59F with stage IV renal cell carcinoma, who was treated with ipilimumab and nivolumab (CTLA-4 and PD-1 inhibitors) 1.5 years ago. She now presents to the hospital with fatigue, headache, N/V. Over the last week, she experienced episodes of dizziness.

Dr. Benjamin Schlechter: So when I see a patient in a clinic with kind of the dwindles, they’re just not right. Their electrodes are a little bit off. They’ve got the hyperkalemic metabolic acidosis kind of funny, something’s wrong. They often are hyponatremic, they’re not eating well, they’re kind of weak and dizzy. You worry about endocrinopathy.

Dr. Shreya Trivedi: There so many hormones that the pituitary makes, a patient can present with so many different symptoms and conditions and in this case i’m thinking about adrenal insufficiency– those vague symptoms fatigue, n/v, dizziness

Dr. Anuranita Gupta: So true. You know Shreya when I’m thinking about the hormone axes and specifically the pituitary gland- I always think back to learning the FLAT PiG mnemonic in med school to remember the anterior pituitary hormones of FSH, LH, ACTH, TSH, prolactin and growth hormone. The posterior pituitary too and that makes oxytocin and ADH.

Dr. Benjamin Schlechter: Hypophysitis is not the most common, definitely the most dramatic. They often have that tunnel vision thing you learn about in doctor school where they bounce off the doorframe, and when you ask them, they will say, oh yeah, it’s so weird. I keep hitting my shoulder on the door. I had a patient who worked at Home Depot and he’s like, I kept bumping into the racks.

Dr. Shreya Trivedi: Oh man, yes we definitely ask good Qs and listen really well to see if we pick on the visual changes – right because that means the optic nerve is being affected from physical compression.

Dr. Anuranita Gupta: Definitely. So what’s the diagnostic workup we’re getting for Ms. Thompson and these vague symptoms if we are concerned about hypophysitis?

Dr. Benjamin Schlechter: So you’re going to check your TSH and your free T four because you might have high in the axis thyroid dysfunction. You want to check your A C T H I check prolactin because sometimes prolactin is actually really high or really low. Maybe cortisol, random cortisol and am cortisol, and if you see evidence of this sort of hypo Pitt presentation, it’s probably a hypophysitis.

Dr. Shreya Trivedi: We CAN also think about getting LH, FSH, estrogen and testosterone but if there aren’t overt symptoms of hormone imbalance, we may not need these

Dr. Benjamin Schlechter: You can often prove it with an M R I with a pituitary protocol, but you can also prove it by labs. And that’s probably faster than getting an M R I in a lot of cases.

Dr. Anuranita Gupta: And that’s an MRI brain with and without contrast with sellar cuts and you are especially going to want to get that if there are red flags for visual changes

Dr. Allison Betof Warner: So early sitis, so brand new imaging, you can actually see on a dedicated brain M R I, you have to get thin cuts through the pituitary. If there is acute inflammation that you’ve caught early, there is a thought that pulse dose steroids might be able to rescue some of those patients to maintain some endocrine function.

Dr. Shreya Trivedi: Ok so not to bury the lead but her labs showed TSH and free T4 were normal but her AM cortisol of 1.2 ug/dl and low ACTH so both are low, which suggests a central process higher put in the pituitary rather than a primary adrenal insufficiency at the level of the adrenal gland (where ACTH would be high.)

Dr. Anuranita Gupta: And then unsurprisingly her MRI showed pituitary enlargement with inflammation.

Dr. Shreya Trivedi: Now that we know we’re dealing with hypophysitis let’s talk grades. The grading here is a bit subjective because it depends on the severity of symptoms and how a patient may describe it.

Dr. Anuranita Gupta: That’s true… and but the difference here is that treatment really depends on which hormone axes have been hit.

Dr. Shreya Trivedi: For example, we can talk about how we would give levothyroxine for thyroid replacement and testosterone and estrogen therapy if there are no contraindications like prostate or breast cancer respectively.

Dr. Anuranita Gupta: But in our patient, we know that the adrenal axis was hit so we could give hydrocortisone or prednisone for the secondary adrenal insufficiency (and again, its secondary because it’s affecting the pituitary gland, not the adrenal gland).

Dr. Shreya Trivedi: And if there are vision changes from the optic chiasm being compressed from pituitary swelling, we would certainly be reaching for higher dose steroids and taper over 1-2 weeks to a maintenance therapy dose.

Dr. Anuranita Gupta: Let’s recap this high yield pearl on Hypophysitis. It can present with a wide range of symptoms given all of the hormones affected by the pituitary gland. In addition to evaluating hormone levels, headache and visual changes are clues that should prompt MRI imaging of the pituitary gland.

Dr. Shreya Trivedi: Once hypophysitis is identified, hormone replacement is a major part of treatment; however, if there is pituitary swelling or the optic nerve is compressed, more potent steroids have to be given to preserve vision.

Ending

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 and colleagues and 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 as part of the Digital Education Track at BIDMC. Thank you to all the educators and mentors! Thank you to our peer reviewers Dr. Meng Wu and Dr. Sharon Elad.

Dr. Shreya Trivedi: Thank you to Jerome Reyes for the audio editing and Dr. Cathy Cichon for the accompanying graphics. As always, we love hearing feedback, email us at [e-mail]. Opinions expressed are our own and do not represent the opinions of any affiliated institutions.

References

• Qian Qin et al. Type, timing, and patient characteristics associated with immune-related adverse event development in patients with advanced solid tumors treated with immune checkpoint inhibitors. JCO 38, e15160-e15160(2020).
• Naidoo J, Wang X, Woo KM, et al. Pneumonitis in Patients Treated With Anti-Programmed Death-1/Programmed Death Ligand 1 Therapy [published correction appears in J Clin Oncol. 2017 Aug 1;35(22):2590.
• Bryan J Schneider et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update. JCO 39, 4073-4126(2021).
• Hua C, Boussemart L, Mateus C, et al. Association of Vitiligo With Tumor Response in Patients With Metastatic Melanoma Treated With Pembrolizumab. JAMA Dermatol. 2016;152(1):45-51.
• Ryder M, Callahan M, Postow MA, Wolchok J, Fagin JA. Endocrine-related adverse events following ipilimumab in patients with advanced melanoma: a comprehensive retrospective review from a single institution. Endocr Relat Cancer. 2014;21(2):371-381. Published 2014 Mar 7.

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