Thread by @alexshoushtari

Hey #tipsfornewdocs #medtwitter folks! I wanted to review side effects of immune checkpoint inhibitors (ICIs) for a non-#oncology audience. Immune-related adverse events (irAEs) present across all medicine specialties so we are all in this together. 1/x

The most common ICIs are against PD-1 (e.g. nivolumab, pembrolizumab) and PD-L1 (e.g. atezolizumab, durvalumab). I use a blanket term “PD-1” throughout. Anti-CTLA-4 (ipilimumab) is a distant second; often in combo or directly after PD-1 in #melanoma #lung #kidney cancers. 2/x

They have led to pharma riches and Nobel Prizes and lots of TV commercials because they work really well for some patients. People with advanced #melanoma, #lcsm etc who used to live ~1 year now can hope to live for several years or more. 3/x

As these patients live longer after ICI administration, more complications will arise from a disinhibited immune system. It behooves you as a medical professional to become more aware of the dark side of these agents… 4/x

General timing of irAE onset is well described (rash > diarrhea/hepatitis > endocrine) but there is lots of variance across patients. Best data are in patients with NO pre-existing autoimmune conditions. Review med list and include irAEs in your DDx for any symptom. 5/x

PD-1 is dosed every 2-4 weeks due to plasma levels in blood, but it efficiently blocks receptors on immune cells for up to **3-6 months after the last dose**. Pharmacodynamics vs pharmacokinetics, y’all! Your pharmacology teacher is cackling maniacally right now. 6/x

Almost any organ can become inflamed, and tx lasts a long time...so focus on finding what can kill people: hepatitis, pneumonitis, myocarditis, colitis, endocrine, neuro-MSK. Best data on fatal irAEs so far come from Doug Johnson's group @VUMChealth jamanetwork.com/journals/jamao… 7/x

@VUMChealth In severe irAEs, often >1 organ system is inflamed. When you see a sick patient w/ PD1 exposure, take organ-by-organ approach in ruling in/out autoimmunity. For example, fatal myocarditis rarely arrives unaccompanied by myasthenia, hepatitis, etc. Catalog those -itises! 8/x

@VUMChealth irAEs can be subtle early on. When in doubt, DELAY THERAPY and consider steroids. Remember: these drugs last a long time. If your immune system is raging, additional doses are not required for clinical benefit. Check out good OS for #melanoma stopping early for tox! 9/x

@VUMChealth For severe irAEs, steroids like prednisone at 1mg/kg daily are often mainstay of therapy. Other pathways can be targeted if needed, e.g. for colitis. Active area of research:

TNF-a, e.g. infliximab jitc.biomedcentral.com/articles/10.11…
Integrin a4b7, vedolizumab jitc.biomedcentral.com/articles/10.11…

10/x

@VUMChealth Not all irAEs respond to steroids, and when they don't, the etiology and therapy will likely differ by organ. Lots left to learn.

- B-cell/antibody inhibition in thrombocytopenia: jitc.biomedcentral.com/articles/10.11…
- IL-4 receptor blockade in skin tox: ascopubs.org/doi/full/10.12…

11/x

@VUMChealth A big area of concern is how to protect these patients with newly disinhibited immune systems on chronic prednisone and/or secondary immune suppression from influenza, opportunistic fungi, etc. Often afebrile until it's too late. Keep your differential broad! 12/x

@VUMChealth Recent/concurrent PD-1 use with other therapies may make those other therapies less tolerable, e.g.
- BRAF-MEK inhibition onlinelibrary.wiley.com/doi/full/10.10…
- ALK inhibition sciencedirect.com/science/articl…

13/x

@VUMChealth People with #melanoma who stopped nivo+ipi for toxicity are often rechallenged with PD1 alone but may develop new issues. @DrBetofMDPhD et al saw 1 fatal case of Stevens-Johnson. academic.oup.com/annonc/article…

Take careful prior irAE history and have high index of suspicion.

14/x

@VUMChealth @DrBetofMDPhD What is the long-term effect of increasing immune surveillance and inflammation? We @sloan_kettering and many others working to track long-term outcomes. Would not be surprised by cardiac, neurocognitive, other issues in #survivorship. For many, this is still a lofty goal.

15/x

@VUMChealth @DrBetofMDPhD @sloan_kettering Thanks for reading! I hope I've convinced you that irAEs from checkpoint inhibitors are really important. And I've only scratched the surface...plenty more to come given CAR T and other immune manipulations increasing. Blessed to be working in dynamic field to help pts.

16/16

@VUMChealth @DrBetofMDPhD @sloan_kettering Bonus tweet for @OncoAlert: feel free to retweet the thread from the beginning! 17/16