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Cited by 441Cancer Immunotherapy and BiomarkersAdrenal Hormones and DisordersPituitary Gland Disorders and Treatments

Endocrine toxicities of immune checkpoint inhibitors

Open access
Wright, Jordan J., Powers, Alvin C., Johnson, Douglas B.·2021·Nature Reviews Endocrinology
DOI 10.1038/s41574-021-00484-3PMC PMC8769055
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Abstract

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that target two key signalling pathways related to T cell activation and exhaustion, by binding to and inhibiting cytotoxic T lymphocyte antigen 4 (CTLA4) or PD1 and its ligand PDL1. ICIs, such as nivolumab, pembrolizumab and ipilimumab, are approved for the treatment of numerous and diverse cancer types, in various combination regimens, and are now an established cornerstone of cancer therapeutics. Toxicities induced by ICIs are autoimmune in nature and are referred to as immune-related adverse events (irAEs); these events can affect any organ system in an unpredictable fashion. Importantly, irAEs can manifest as endocrinopathies involving the thyroid (hypothyroidism or thyrotoxicosis), pituitary (hypophysitis), adrenal glands (adrenal insufficiency) and pancreas (diabetes mellitus). These events are a frequent source of acute and persistent morbidity in patients treated with ICIs and can even be fatal. Over the past few years, there has been a growing understanding of the underlying pathogenesis of irAEs that has led to the development of more effective management strategies. Herein, we review the current understanding of the pathobiology, clinical manifestations and treatment approaches to endocrine toxicities arising from ICIs. Immune checkpoint inhibitors (ICIs) are now an established cornerstone of cancer therapeutics; however, ICIs are associated with toxicities in various organs, termed immune-related adverse events. This Review highlights current understanding in ICI-induced endocrinopathies, including epidemiology, aetiology, clinical manifestations and approaches to treatment. Immune checkpoint inhibitors (ICIs) are now a cornerstone of cancer therapies and are associated with long-term treatment responses, but they can also cause inflammatory toxicities in endocrine and other organs. The most common ICI-induced endocrine toxicity is hypothyroidism, which occurs in 10–20% of treated patients, is often preceded by transient thyrotoxicosis, and usually persists after ICI therapy completion. Hypopituitarism, which might co-occur with hypophysitis, is a condition nearly unique to ICI therapy, and is a clinically relevant cause of morbidity and rarely mortality. ICI-associated diabetes mellitus (ICI-DM) occurs rarely (<1% of treated patients) but resembles type 1 diabetes mellitus, and patients can present with diabetic ketoacidosis. Treatment for ICI-induced endocrinopathies involves hormone replacement therapy; patients can continue or resume their ICI once clinically stable. Immune checkpoint inhibitors (ICIs) are now a cornerstone of cancer therapies and are associated with long-term treatment responses, but they can also cause inflammatory toxicities in endocrine and other organs. The most common ICI-induced endocrine toxicity is hypothyroidism, which occurs in 10–20% of treated patients, is often preceded by transient thyrotoxicosis, and usually persists after ICI therapy completion. Hypopituitarism, which might co-occur with hypophysitis, is a condition nearly unique to ICI therapy, and is a clinically relevant cause of morbidity and rarely mortality. ICI-associated diabetes mellitus (ICI-DM) occurs rarely (<1% of treated patients) but resembles type 1 diabetes mellitus, and patients can present with diabetic ketoacidosis. Treatment for ICI-induced endocrinopathies involves hormone replacement therapy; patients can continue or resume their ICI once clinically stable.

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes the pathobiology, clinical presentation, monitoring, and management of endocrine toxicities from immune checkpoint inhibitors, especially thyroid, pituitary, adrenal, and pancreatic beta-cell events. It emphasizes that these endocrinopathies are common, often permanent, and generally managed with hormone replacement rather than high-dose steroids or ICI discontinuation.

Key findings

  • Endocrine events affect up to 40% of ICI-treated patients; the most commonly affected organs are thyroid, pituitary, adrenal, and pancreatic beta cells.
  • Thyroid dysfunction occurs in approximately 10% of anti-PD-1/PD-L1 monotherapy patients, up to 15–20% with combination PD-1/CTLA-4 blockade, and only 5% with ipilimumab monotherapy; hypothyroidism predominates, preceded by destructive thyroiditis in 30–40% of anti-PD-1/PD-L1 cases and up to two-thirds of combination cases.
  • Hypophysitis/hypopituitarism occurs in up to 10% of anti-CTLA-4-based therapy patients but only 0.5–1% of anti-PD-1/PD-L1 monotherapy patients; median onset is 9–12 weeks for ipilimumab-treated patients and 26 weeks for anti-PD-1/PD-L1.
  • ICI-associated diabetes mellitus occurs in slightly less than 1% of ICI-treated patients, with approximately 97% of reported cases on anti-PD-1/PD-L1 or combination therapy; 38–71% present in diabetic ketoacidosis, and median onset is 7–17 weeks with a range of 1–228 weeks.

Methods

  • Narrative review of the current understanding of pathobiology, clinical manifestations, and treatment approaches to endocrine toxicities from immune checkpoint inhibitors.
  • No primary data collection or systematic review methodology is described; the paper synthesizes published literature, guidelines, case reports, and meta-analyses.
  • Organ-specific sections cover thyroid, pituitary, primary adrenal insufficiency, diabetes mellitus, and rare endocrinopathies, with monitoring and treatment recommendations.

Limitations

  • The paper states that all treatment for immune-related adverse events is based on expert opinion and clinical judgment rather than large-scale clinical trials or high-level evidence.
  • The paper notes that histologic confirmation of the hypothesis that endocrine toxicity destroys hormone-producing cells is lacking, human mechanistic studies are limited, routine pituitary/adrenal monitoring is controversial, and rare endocrinopathies are described only in case reports.
  • Evident from the text: as a narrative review, it does not describe a systematic search strategy, inclusion criteria, or formal quality assessment of the cited evidence.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41574-021-00484-3

Cites

119 of 119 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 85 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    A review of reported cases found that a large subset of patients (38-71%) present in diabetic ketoacidosis with relatively mild hemoglobin A1C elevation.

    “A review of reported cases showed that a large subset of patients (38-71%) present in diabetic ketoacidosis (DKA) with relatively mild hemoglobin A1C (A1C) elevation”
    Quote in the paperNot a substantial claim
  • Premisenone given

    The vast majority of ICI-related thyrotoxicosis is caused by thyroiditis from destruction of thyroid follicular cells with spillage of preformed thyroid hormone.

    “The vast majority of ICI-related thyrotoxicosis is caused by thyroiditis, resulting from destruction of thyroid follicular cells with spillage of preformed thyroid hormone.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Patients with pre-existing anti-thyroid antibodies have a much higher risk of thyroid dysfunction; three studies reported 20-50% versus 1-2.5% in antibody-negative patients.

    “three studies showed that patients with antithyroglobulin or anti-thyroid peroxidase antibodies had a much higher risk of thyroid dysfunction compared with patients negative for these antibodies (20-50% vs. 1-2.5%).41–43”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [41] Naidoo, J. et al. Pneumonitis in patients treated with anti-programmed death-1/programmed death ligand 1 therapy. J. Clin. Oncol. 35, 709–717 (2017). source

      Not checked in the free run.

    • cites [42] Brahmer, J. R. et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline. J. Clin. Oncol. 36, 1714–1768 (2018). Clinically useful guidelines from the American Society of Clinical Oncology for managing irAEs, including endocrine irAEs. source

      Not checked in the free run.

    • cites [43] Puzanov, I. et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J. Immunother. Cancer 5, 95 (2017). Clinically useful guidelines from the Society for Immunotherapy of Cancer for managing irAEs, including endocrine irAEs. source

      Not checked in the free run.

  • Interpretationreasoning

    Smoldering anti-thyroid autoimmunity present before treatment is unmasked by an additional removal of self-tolerance.

    “This suggests that smoldering anti-thyroid autoimmunity was present prior to treatment and was unmasked by an additional removal of self-tolerance.”
    Quote in the paperSubstantial claim
  • Premisecitation

    TTF-1 expression in the tumor did not correlate with development of thyroid dysfunction after anti-PD-1.

    “TTF-1 expression in the tumor did not correlate with the development of thyroid dysfunction following anti-PD-1.44”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] Martins, F. et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat. Rev. Clin. Oncol. 16, 563–580 (2019). source

      Not checked in the free run.

  • May combine two claims. 31
  • Classified as probably not a substantial claim. 11

  • May combine two claims.

    Premisenone given

    Hypothyroidism comprises the overwhelming majority of thyroid events and is preceded by destructive thyroiditis in 30-40% of anti-PD-1/PD-L1 induced cases and up to two-thirds of combination-induced cases.

    “Hypothyroidism comprises the overwhelming majority of cases, and is preceded by a destructive thyroiditis in 30-40% of anti-PD-1/PD-L1 induced cases, and up to two-thirds of combination-induced cases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    One meta-analysis reported that about 68% of patients with thyroiditis progressed to hypothyroidism, with a median of 6 weeks from thyroiditis diagnosis to hypothyroid diagnosis.

    “One meta-analysis reported that ~68% of patients with thyroiditis progressed to hypothyroidism, with a median of 6 weeks from thyroiditis diagnosis to hypothyroid diagnosis47”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Winther, K. H. et al. Disease-specific as well as generic quality of life is widely impacted in autoimmune hypothyroidism and improves during the first six months of levothyroxine therapy. PLoS ONE 11, e0156925 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Endocrine events typically do not require drug discontinuation or high-dose steroids because long-term hormone insufficiency usually occurs regardless of treatment.

    “endocrine events typically do not require the first two pillars of management (drug discontinuation or high-dose steroids) since the long-term hormone insufficiency usually occurs regardless of treatment.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: ICI-induced endocrine toxicities result in permanent, irreversible endocrine dysfunction.
    • Rests on an assumption: The inflammatory phase of endocrine toxicity is often asymptomatic, and symptoms arise only after most hormone-secreting cells have been destroyed.

  • May combine two claims.

    Premisenone given

    ICI toxicities are autoimmune and can affect any organ system unpredictably, commonly including endocrine organs such as thyroid, pituitary, adrenal, and pancreas.

    “Toxicities from ICI are autoimmune in nature and may affect any organ system in an unpredictable fashion, commonly including endocrine manifestations involving the thyroid, pituitary, adrenal, and pancreas.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Thyroid events occur in about 10% of patients on anti-PD-1/PD-L1 monotherapy, up to 15-20% on combination PD-1/CTLA-4 blockade, and only 5% on ipilimumab monotherapy.

    “Thyroid events occur in approximately 10% of patients treated with anti-PD-1/PD-L1 monotherapy, and up to 15-20% of those treated with combination PD-1/CTLA-4 blockade (as opposed to only 5% of those treated with ipilimumab monotherapy).9,38”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] Eggermont, A. M. M. et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N. Engl. J. Med. 378, 1789–1801 (2018). source

      Not checked in the free run.

    • cites [38] Johnson, D. B. et al. Ipilimumab therapy in patients with advanced melanoma and preexisting autoimmune disorders. JAMA Oncol. 2, 234–240 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Most other organ systems affected by ICI have transient inflammation that resolves with steroids and normal organ function, though up to half of rheumatologic events and rarely other toxicities become chronic.

    “Most other systems are affected by transient inflammation that resolves with steroid therapy and restoration of normal organ function (although up to half of rheumatologic events and rarely other toxicities also become chronic in nature).25,26”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [25] Iwama, S. et al. Pituitary expression of CTLA-4 mediates hypophysitis secondary to administration of CTLA-4 blocking antibody. Sci. Transl. Med. 6, 230ra45 (2014). This paper reports a preclinical model of hypophysitis with translational correlates. source

      Not checked in the free run.

    • cites [26] US Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE). Version 5.0 https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_5x7.pdf (2017).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Several studies suggest thyroid dysfunction is associated with improved overall cancer survival, though the mechanism is not well understood.

    “Several studies have suggested that thyroid dysfunction is associated with improved overall survival from a cancer standpoint, although the mechanism for this type of association is not well understood.39,40”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [39] Leonardi, G. C. et al. Safety of programmed death-1 pathway inhibitors among patients with non-small-cell lung cancer and preexisting autoimmune disorders. J. Clin. Oncol. 36, 1905–1912 (2018). source

      Not checked in the free run.

    • cites [40] Kanz, B. A. et al. Safety and efficacy of anti-PD-1 in patients with baseline cardiac, renal, or hepatic dysfunction. J. Immunother. Cancer 4, 60 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The median time to onset of thyroid dysfunction, most of which is hypothyroidism, is 6 weeks after ICI initiation, though it may occur at any time.

    “The median time to onset of thyroid dysfunction, most of which is hypothyroidism, is 6 weeks after ICI initiation47, although this may occur essentially any time on therapy.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Winther, K. H. et al. Disease-specific as well as generic quality of life is widely impacted in autoimmune hypothyroidism and improves during the first six months of levothyroxine therapy. PLoS ONE 11, e0156925 (2016). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    ICI-related thyrotoxicosis is characterized by elevated FT4 or total T3 and a low or suppressed TSH.

    “ICI-related thyrotoxicosis is characterized by an elevated FT4 or total T3 and a low or suppressed TSH.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    ICI-induced endocrine toxicities are distinct from those caused by traditional cytotoxic chemotherapy or targeted therapies, which rarely cause endocrine dysfunction.

    “These are distinct events from those caused by traditional cytotoxic chemotherapy or even newer molecular targeted therapies, which rarely cause endocrine dysfunction.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    ICI-related hypothyroidism may present with fatigue, depressed mood, mild weight gain, constipation, and altered cognition when severe, but many patients are asymptomatic.

    “ICI-related hypothyroidism, which is related to thyroiditis, may present with fatigue, depressed mood, mild weight gain, constipation, and altered cognition when severe, though many patients are completely or relatively asymptomatic.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Supportive management with hormone replacement is the foundation of treatment for endocrine irAEs, and lifelong supplementation of the deficient gland is generally required.

    “supportive management (in the form of hormone replacement) is the foundation of treatment and is particularly critical to achieving optimal patient outcomes. Lifelong hormone supplementation of the deficient gland is generally required.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: ICI-induced endocrine toxicities result in permanent, irreversible endocrine dysfunction.

  • May combine two claims.

    Premisenone given

    ICI-induced endocrinopathies are rarely fatal but can markedly affect quality of life, and hormone therapy often improves well-being.

    “While ICI-induced endocrinopathies are rarely fatal, these conditions can have dramatic effects on patients’ quality of life, and initiation of hormone therapy often markedly improves their sense of well-being.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Endocrine symptoms usually appear by six months after starting ICI, but onset is unpredictable and can happen at any time or months after stopping.

    “Symptoms typically present within 6 months of ICI initiation, but the timing of onset is quite unpredictable, and may arise any time on therapy or even several months after therapy discontinuation”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    The severity of endocrine events varies; hypothyroidism is usually mild, while diabetes can be fatal when presenting in diabetic ketoacidosis.

    “whereas hypothyroidism is usually accompanied by mild symptoms, cases of diabetes mellitus have proven fatal when presenting in diabetic ketoacidosis (DKA).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Recognition and diagnosis of immune checkpoint inhibitor-associated diabetes mellitus have been increasing.

    “has been increasing in recognition and diagnosis.66”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [66] Min, L., Vaidya, A. & Becker, C. Thyroid autoimmunity and ophthalmopathy related to melanoma biological therapy. Eur. J. Endocrinol. 164, 303–307 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Any type of irAE occurs in 80-90% of patients, with higher grade events in 15-20% of those on anti-PD-1/PD-L1 monotherapy and up to 60% of those on combination ipilimumab and nivolumab.

    “Any type of irAE occurs in 80-90% of patients, with higher grade events (as categorized by the Common Terminology Criteria for Adverse Events) occurring in 15-20% of patients treated with anti-PD-1/PD-L1 monotherapy, and up to 60% of patients treated with combination of ipilimumab and nivolumab.9”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Eggermont, A. M. M. et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N. Engl. J. Med. 378, 1789–1801 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The combination of ipilimumab and nivolumab has enhanced response rates in melanoma, lung cancer, renal cell carcinoma, and mismatch repair deficient colon cancer compared with single agent therapy, at the cost of increased toxicities.

    “The combination of ipilimumab and nivolumab has demonstrated enhanced response rates in melanoma, lung cancer, renal cell carcinoma, and mismatch repair deficient colon cancer compared with single agent therapy, although at a cost of increased toxicities (see next section).9–11”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [9] Eggermont, A. M. M. et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N. Engl. J. Med. 378, 1789–1801 (2018). source

      Not checked in the free run.

    • cites [10] Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010). source

      Not checked in the free run.

    • cites [11] Schadendorf, D. et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J. Clin. Oncol. 33, 1889–1894 (2015). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Another study suggested a potentially causative role of Epstein-Barr virus infection or reactivation in a case of ICI-encephalitis.

    “other suggested a potentially causative role of Epstein-Barr Virus infection or reactivation in a case of ICI-encephalitis.20”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Berner, F. et al. Association of checkpoint inhibitor-induced toxic effects with shared cancer and tissue antigens in non-small cell lung cancer. JAMA Oncol. 5, 1043–1047 (2019). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All treatment for irAEs is based on expert opinion and clinical judgment rather than large-scale clinical trials or high-level evidence.

    “It should be noted, however, that all treatment for irAEs are based on expert-opinion and clinical-judgment rather than large-scale clinical trials or high level evidence.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Median time to presentation is 9-12 weeks for ipilimumab-treated patients and 26 weeks for anti-PD-1/PD-L1-treated patients.

    “Median time to presentation is 9-12 weeks into treatment for ipilimumab-treated patients (monotherapy or combination) and 26 weeks into treatment for anti-PD-1/PD-L1.61”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] Kurimoto, C. et al. Predictive and sensitive biomarkers for thyroid dysfunctions during treatment with immune-checkpoint inhibitors. Cancer Sci. 111, 1468–1477 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    The targets of ICI, CTLA-4, PD-1, and PD-L1, are key regulators of immune tolerance and prevent autoimmunity in the physiologic state.

    “The targets of ICI (CTLA-4, PD-1, and PD-L1) are key regulators of immune tolerance, and prevent autoimmunity in the physiologic state.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisenone given

    Low morning cortisol (<5 mcg/dL) and low ACTH indicate secondary adrenal insufficiency; low TSH and low free T4 indicate secondary hypothyroidism; low sex hormones, FSH, and LH indicate secondary hypogonadism.

    “A low morning cortisol (< 5 mcg/dL) and low ACTH are indicative of secondary adrenal insufficiency, with low TSH and low free T4 indicative of secondary hypothyroidism, and low sex hormones, FSH, and LH indicative of secondary hypogonadism.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Normal brain imaging does not rule out hypopituitarism or hypophysitis.

    “Normal brain imaging does not rule out hypopituitarism/hypophysitis, however.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Autoantibodies targeting GNAL and ITM2B were identified in the serum of a patient who developed hypophysitis, and these proteins were expressed in the pituitary gland.

    “Another study using large scale autoantibody screening identified autoantibodies targeting guanine nucleotide-binding protien G(olf) subunit alpha (GNAL) and integral membrane protein 2B (ITM2B) in the serum of a patient who developed hypophysitis; further study revealed that these proteins were expressed in the pituitary gland.60”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Koyama, J. et al. Correlation between thyroid transcription factor-1 expression, immune-related thyroid dysfunction, and efficacy of anti-programmed cell death protein-1 treatment in non-small cell lung cancer. J. Thorac. Dis. 11, 1919–1928 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pituitary glands expressed CTLA-4 in a subset of cells, which were targets for CTLA-4 antibody binding and resulted in complement deposition.

    “pituitary glands expressed CTLA-4 in a subset of these cells, which were targets for CTLA-4 antibody binding, and resulted in complement deposition.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [59] Toi, Y. et al. Profiling preexisting antibodies in patients treated with anti-PD-1 therapy for advanced non-small cell lung cancer. JAMA Oncol. 5, 376–383 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ipilimumab was the first approved ICI in 2011 and produced approximately 15-20% response rates in melanoma, with 20% long-term survival persisting even 10 years beyond treatment.

    “Ipilimumab (anti-CTLA-4) was the first approved ICI, receiving approval in 2011. Substantial clinical activity was observed primarily in melanoma, producing approximately 15-20% response rates, with 20% long-term survival, persisting even 10 years beyond treatment.7”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Antonia, S. J. et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N. Engl. J. Med. 379, 2342–2350 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    General mechanisms of ICI toxicity are understood, namely removal of self-tolerance and T cell activation, but specific mechanisms of individual toxicities in particular patients are only beginning to be unraveled.

    “Although the general mechanisms of toxicity are understood (removal of self-tolerance and activation of T cells), the specific mechanisms of individual toxicities in particular patients are only beginning to be unraveled.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    One study suggested that ICI-colitis correlated with particular strains of microbial flora colonization.

    “One study suggested that ICI-colitis correlated with particular strains of microbial flora colonization,19”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Rini, B. I. et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N. Engl. J. Med. 380, 1116–1127 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Symptoms of hypophysitis commonly relate to neuro-compression, including headache, nausea, emesis, diplopia, and visual field defects, or to secondary adrenal insufficiency including fatigue and nausea.

    “These symptoms are commonly related to neuro-compression, including headache, nausea, emesis, diplopia, and visual field defects, or more often, to secondary adrenal insufficiency including fatigue and nausea.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Male gender and older age may be risk factors for hypophysitis, though this has only been observed in one small series.

    “Male gender and older age may be risk factors although this has only been observed in one small series.58”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58] Kobayashi, T. et al. Patients with antithyroid antibodies are prone to develop destructive thyroiditis by nivolumab: a prospective study. J. Endocr. Soc. 2, 241–251 (2018). This paper provides clinical characterization of thyroiditis associated with ICIs, and demonstrates that high-dose steroids do not affect clinical outcomes. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Anti-PD-1/PD-L1 agents paired with chemotherapy have improved response rates and survival in many diseases including lung cancer, triple negative breast cancer, and head and neck squamous cell carcinoma.

    “Anti-PD-1/PD-L1 agents pared with chemotherapy have also improved response rates and survival in many diseases including lung cancer, triple negative breast cancer, head and neck squamous cell carcinoma, and others.12–14”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [12] Yarchoan, M., Hopkins, A. & Jaffee, E. M. Tumor mutational burden and response rate to PD-1 inhibition. N. Engl. J. Med. 377, 2500–2501 (2017). source

      Not checked in the free run.

    • cites [13] Larkin, J. et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med. 381, 1535–1546 (2019). source

      Not checked in the free run.

    • cites [14] Motzer, R. J. et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N. Engl. J. Med. 378, 1277–1290 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Secondary hypothyroidism and secondary hypogonadism are also quite common in hypophysitis.

    “Secondary hypothyroidism and secondary hypogonadism are also quite common (see Figure 4).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Rarely, irAEs may be fatal, including about 0.35% of those treated with anti-PD-1/PD-L1 and 1.2% treated with combination therapy.

    “Rarely, some events may be fatal, including ~0.35% of those treated with anti-PD-1/PD-L1, and 1.2% treated with combination therapy.24”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Das, R. et al. Early B cell changes predict autoimmunity following combination immune checkpoint blockade. J. Clin. Invest. 128, 715–720 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pharmacologic blockade of immune checkpoints can result in anti-tumor immunity and autoinflammation at other sites, which clinically manifests as immune-related adverse events.

    “Pharmacologic blockade, therefore, can result in not only anti-tumor immunity, but autoinflammation at other sites, which clinically manifest as immune related adverse events.16”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] Horn, L. et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N. Engl. J. Med. 379, 2220–2229 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Patients with pre-existing autoimmune disease may have somewhat higher risk of irAEs, usually low-grade flares of their pre-existing disease rather than de novo events.

    “Patients with pre-existing autoimmune disease may have somewhat higher risk of irAEs, although these usually relate to increased risks of low-grade flares of their pre-existing disease rather than de novo events.30–32”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [30] Braaten, T. J. et al. Immune checkpoint inhibitor-induced inflammatory arthritis persists after immunotherapy cessation. Ann. Rheum. Dis. 79, 332–338 (2020). source

      Not checked in the free run.

    • cites [31] Johnson, D. B. et al. Survivorship in immune therapy: assessing chronic immune toxicities, health outcomes, and functional status among long-term ipilimumab survivors at a single referral center. Cancer Immunol. Res. 3, 464–469 (2015). source

      Not checked in the free run.

    • cites [32] Patrinely, J. R. Jr. et al. Survivorship in immune therapy: assessing toxicities, body composition and health-related quality of life among long-term survivors treated with antibodies to programmed death-1 receptor and its ligand. Eur. J. Cancer 135, 211–220 (2020). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Glucose management may be more challenging in immune checkpoint inhibitor-associated diabetes mellitus than in classic type 1 diabetes.

    “though glucose management may be more challenging in ICI-DM”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    PD-L1 expression is elevated in pancreatic beta cells of older mice and in mice whose islets have immune infiltration.

    “PD-L1 expression is increased in pancreatic beta cells of older mice and in mice with immune infiltration of their islets69,70”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [69] Azmat, U., Liebner, D., Joehlin-Price, A., Agrawal, A. & Nabhan, F. Treatment of ipilimumab induced Graves’ disease in a patient with metastatic melanoma. Case Rep. Endocrinol. 2016, 2087525 (2016).

      Not checked in the free run.

    • cites [70] Iadarola, C. et al. Nivolumab induced thyroid dysfunction: unusual clinical presentation and challenging diagnosis. Front. Endocrinol. 9, 813 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    About 40-50% of patients with immune checkpoint inhibitor-associated diabetes mellitus have detectable islet autoantibodies at diagnosis, compared with more than 90% in type 1 diabetes.

    “Approximately 40-50% of individuals with ICI-DM have detectable islet auto-antibodies at diagnosis, compared to >90% in T1D 64,65”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [64] Yu, C., Chopra, I. J. & Ha, E. A novel melanoma therapy stirs up a storm: ipilimumab-induced thyrotoxicosis. Endocrinol. Diabetes Metab. Case Rep. 2015, 140092 (2015).

      Not checked in the free run.

    • cites [65] Yonezaki, K. et al. Combination therapy of ipilimumab and nivolumab induced thyroid storm in a patient with Hashimoto’s disease and diabetes mellitus: a case report. J. Med. Case Rep. 12, 171 (2018). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    The onset of immune checkpoint inhibitor-related endocrine toxicities is somewhat predictable in at least a defined proportion of patients.

    “The somewhat predictable onset (at least in a defined proportion of patients) of ICI related endocrine toxicities”
    Quote in the paperNot a substantial claim
40 of 40

  • The authors state this as an assumption.

    ICI-induced endocrine toxicities result in permanent, irreversible endocrine dysfunction.

    “they are presumed to result in permanent, irreversible endocrine dysfunction.”

  • The paper relies on this without support.

    The inflammatory phase of endocrine toxicity is often asymptomatic, and symptoms arise only after most hormone-secreting cells have been destroyed.

    “the inflammatory phase of the toxicity is often asymptomatic, and symptoms arise only in the terminal phase when most hormone-secreting cells have been destroyed and anti-inflammatory therapy is unlikely to be of benefit.”

  • The authors state this as an assumption.

    The immune activation damages or destroys all or nearly all hormone-producing cells, precluding resumption of hormone production.

    “A possible explanation for this difference is that the immune activation damages or destroys all (or nearly all) of the relatively small number of hormone producing cells, thus precluding the ability to resume hormone production, though histologic confirmation of this hypothesis is lacking.”

  • The paper relies on this without support.

    Severe adrenal insufficiency, whether primary or secondary, is life-threatening.

    “Given the life-threatening nature of severe adrenal insufficiency, whether primary or secondary”

  • The paper relies on this without support.

    Immune checkpoint inhibitor-associated diabetes mellitus is generally insulin-dependent diabetes.

    “Since ICI-DM is generally insulin-dependent diabetes”

  • The paper relies on this without support.

    Presenting symptoms of immune checkpoint inhibitor-associated diabetes mellitus include polyuria, polydipsia, fatigue, and, if presenting in diabetic ketoacidosis, abdominal pain and nausea.

    “Presenting symptoms of ICI-DM include polyuria, polydipsia, and fatigue, as well as abdominal pain and nausea if presenting in DKA.”

  • The paper relies on this without support.

    Primary adrenal insufficiency clinically resembles secondary hypocortisolism with malaise, fatigue, and nausea, but more often includes hypotension and/or adrenal crisis.

    “Clinical presentation is similar to secondary hypocortisolism, with malaise, fatigue, and nausea, but differs in that it is more frequently associated with hypotension and/or adrenal crisis”

  • The paper relies on this without support.

    Immune checkpoint inhibitor-associated diabetes mellitus frequently co-occurs with other immune-related adverse events, including pancreatitis, thyroiditis, hypophysitis, or colitis.

    “ICI-DM is frequently co-morbid with other irAEs, including pancreatitis, thyroidits, hypophysitis, or colitis”
8 of 8

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Conflicting requirements before starting thyroid hormone replacement

    Major

    One passage says a markedly elevated TSH requires no further testing before replacement is started. A later passage requires TSH to exceed the same threshold on two occasions before treatment.

1 of 1

Cites

Flagged first, then by citations

1 of the 120 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
Wright, J. J., Powers, A. C., & Johnson, D. B.
Affiliations
  • Vanderbilt-Ingram Cancer Center (US)
  • Vanderbilt University (US)
Corresponding author
Johnson, Douglas B.
ORCID
Venue
Nature Reviews Endocrinology
Publisher
Springer Science and Business Media LLC
Published
2021-04-19
Volume
17
Issue
7
Pages
389-399
ISSN
  • 1759-5029 (ISSN-L)
  • 1759-5037
DOI
10.1038/s41574-021-00484-3
PMC
PMC8769055
OpenAlex
W3153081776
Semantic Scholar
cf0e2a7189ebdf14ff89f7c9c25d50834d8c55e9
Cited by
441
References
120
Citations by year
2026: 93 · 2025: 101 · 2024: 93 · 2023: 85 · 2022: 56 · 2021: 13
FWCI
7.51
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Reviews Endocrinology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Heart, Lung, and Blood Institute (R01HL155990)
  • National Cancer Institute (K23CA204726, R01CA227481)
  • National Institute of Diabetes and Digestive and Kidney Diseases (P30DK020593, T32DK007061)
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
Keywords
immune checkpoint inhibitors, immune-related adverse events, endocrine toxicity, CTLA-4, PD-1/PD-L1, hypothyroidism, thyrotoxicosis, hypophysitis, adrenal insufficiency, autoimmune endocrine disease, nivolumab, pembrolizumab, ipilimumab, pathobiology, treatment options
MeSH terms
Antineoplastic Agents, Immunological, Immune Checkpoint Inhibitors, Endocrine System Diseases, Humans, Immune System, Immunotherapy, Neoplasms, Drug-Related Side Effects and Adverse Reactions

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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