ZSFG 9/12 Morning Report Pearls: PD-1 inhibitors and autoimmune DM

Coming at you this morning is a steamy cup of morning report pearls from yesterday’s extravaganza with the ZSFG ICU team.

Thank you to Alan, Braden, Evan and Ty (our pulmonary/critical care consultant expert) for a riveting discussion of an older man who presented with altered mental status and was found to have DKA in setting of PD-1 inhibitor (Pembrolizumab) precipitated autoimmune diabetes. 

Tell me (just a little) more about Pembrolizumab and these checkpoint inhibitors you say?!

Pembrolizumab:

  • Monoclonal antibody which inhibits programmed cell death-1 (PD-1) activity by binding to the PD-1 receptor on T-cells to block programmed death ligand 1 (PD-L1) from binding (see image below)
    • PemBROlizumab has a BRO, Nivolumab which also targets PD-1 receptor, and both were approved in 2014 for advanced melanoma
  • Mechanism involves T cell activation which attacks the tumors, but the immune response is nonspecific
  • Lack of direct activity against malignant cells means that there is immune-related adverse events (irAE’s) which occur secondary to reduced tolerance to antigens previously recognized as self-antigens
    • Common irAE’s: dermatologic, GI (colitis), hepatic, endocrine (thyroiditis, hypophysitis, DM, AI), and neurologic

pd-inhibitor-image

In this particular case, the pt presented with DKA and significant hyperglycemia, not improving despite increasing doses of an insulin gtt (up to 800u/hr), making the team wonder if there was something else creating insulin resistance or binding/blocking the receptor. In this situation, the bro Pembrolizumab may be the clue…

Autoimmune Diabetes with PD-1 inhibitors

  • Pembrolizumab has been implicated in precipitating type B insulin resistance with the production of autoantibodies to the surface insulin receptor (see Diabetes Journal article below)
  • Type B insulin resistance is characterized diabetes refractory to massive doses of insulin (800u/hr for this patient), along with dramatic weight loss, hyperandrogenism, acanthosis nigricans
  • Treatment of the autoimmune diabetes includes immunosuppression with rituximab, cyclophosphamide, corticosteroids and potentially plasmapheresis all aimed at controlling pathogenic autoantibody production (see first reference article)
  • Recent literature (Cancer Immunology editorial below) describes the potential role for evaluation of HLA type that may predispose to developing autoimmune diabetes when initiating a patient on PD-1 inhibitors

References:

http://link.springer.com/article/10.1007%2Fs00262-016-1845-2

Evernote: https://www.evernote.com/shard/s354/sh/5f640ca6-67c2-4afc-a298-0fb041550832/0bcd387c3554bfeb318d83051cdcc7d5 

 

 

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