The DOI matches its Crossref record; 119 of the 120 references it cites were found in a registry or an index; 3 of the 85 sources its claims cite were checked for support.
Endocrine toxicities of immune checkpoint inhibitors
Open accessAbstract
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.
Overview
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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.
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Claims the paper makes
63 Not checked yet · 19 No basis given · 10 Own interpretation · 1 Couldn’t confirm · 1 Own method · accuracy not yet measured
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > Diabetes Mellitus > Clinical Presentation and Diagnosis
plain- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The vast majority of ICI-related thyrotoxicosis is caused by thyroiditis, resulting from destruction of thyroid follicular cells with spillage of preformed thyroid hormone.”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > Thyroid toxicities > Clinical Presentation and Diagnosis
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > Thyroid toxicities > Epidemiology/pathophysiology
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This suggests that smoldering anti-thyroid autoimmunity was present prior to treatment and was unmasked by an additional removal of self-tolerance.”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > Thyroid toxicities > Epidemiology/pathophysiology
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“TTF-1 expression in the tumor did not correlate with the development of thyroid dysfunction following anti-PD-1.44”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > Thyroid toxicities > Epidemiology/pathophysiology
What the sources say
- Not checked yetcites [44] Martins, F. et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat. Rev. Clin. Oncol. 16, 563–580 (2019). source
plain- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“There is no evidence that patients with a history of autoimmune thyroid dysfunction experience more prominent toxicities when treated with ICI.”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > Thyroid toxicities > Epidemiology/pathophysiology
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“Incidence of endocrine events varies based on type of ICI used (see Figure 2).38”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > Endocrine manifestations of ICI therapy
What the sources say
- Not checked yetcites [38] Johnson, D. B. et al. Ipilimumab therapy in patients with advanced melanoma and preexisting autoimmune disorders. JAMA Oncol. 2, 234–240 (2016). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“One study of 151 patients with ICI-thyroid disorders, administration of high-dose glucocorticoids did not alter the time from thyrotoxicosis to hypothyroidism, or mean dose of levothyroxine needed.57”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > Thyroid toxicities > Monitoring and Treatment
What the sources say
- Not checked yetcites [57] Okada, N. et al. Anti-thyroid antibodies and thyroid echo pattern at baseline as risk factors for thyroid dysfunction induced by anti-programmed cell death-1 antibodies: a prospective study. Br. J. Cancer 122, 771–777 (2020). source
plainn = 151- Asserted: passes — The authors put it forward as true.
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In the paper
“one fine needle aspiration obtained during active ICI-induced thyroiditis showed a lymphocytic infiltrate along with CD163+ histiocytes.46”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > Thyroid toxicities > Epidemiology/pathophysiology
What the sources say
- Not checked yetcites [46] Liu, J. et al. Reporting of immune checkpoint inhibitor therapy-associated diabetes, 2015-2019. Diabetes Care 43, e79–e80 (2020). source
plainSingle case- Asserted: passes — The authors put it forward as true.
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In the paper
“hypophysitis or hypopituitarism occurs in up to 10% of patients who receive anti-CTLA-4 based therapy (either with ipilimumab monotherapy, and slightly more commonly with combination CTLA-4/PD-1 blockade).38”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > Pituitary toxicities > Epidemiology/Pathophysiology
What the sources say
- Not checked yetcites [38] Johnson, D. B. et al. Ipilimumab therapy in patients with advanced melanoma and preexisting autoimmune disorders. JAMA Oncol. 2, 234–240 (2016). source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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- It may state two separate claims as one. 31
- Probably not a substantial claim. 11
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“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”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > ICI toxicities: Clinical Presentation
What the sources say
- Could not verifycites [30] Braaten, T. J. et al. Immune checkpoint inhibitor-induced inflammatory arthritis persists after immunotherapy cessation. Ann. Rheum. Dis. 79, 332–338 (2020). sourceExperimental — accuracy not yet measured
The Results (Baseline patient characteristics; page unavailable) note that two of 60 patients had a personal history of autoimmune disease, but do not compare their irAE risk with that of other patients. The Introduction and Results passages do not say whether irAEs in patients with pre-existing autoimmune disease were usually low-grade flares rather than de novo events. Searches for pre-existing disease, flares, severity, and de novo events found no passage addressing that distinction. (LLM, conf=0.75)
- Could not verifycites [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). sourceExperimental — accuracy not yet measured
The Introduction describes immune-related toxicities after ipilimumab, and the Results section on acute and chronic immune-related toxicities reports events in long-term survivors (page numbers unavailable). Neither addresses whether patients with pre-existing autoimmune disease have a higher risk of irAEs or whether their events are usually low-grade flares rather than new events. Searches for pre-existing autoimmune disease and flares found no passage establishing that comparison. (LLM, conf=0.73)
- Could not verifycites [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). sourceExperimental — accuracy not yet measured
The Results section on acute immune-related toxicities reports their frequency and severity, but does not compare patients with and without pre-existing autoimmune disease. Searches for pre-existing autoimmune disease, flares, and de novo events found no passage addressing the claimed difference in risk or type of event. Page numbers were not available in our copy. (LLM, conf=0.72)
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Could not verify
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > Thyroid toxicities > Epidemiology/pathophysiology
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > Thyroid toxicities > Clinical Presentation and Diagnosis
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > Endocrine manifestations of ICI therapy
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
- 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.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > Abstract
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > Thyroid toxicities > Epidemiology/pathophysiology
What the sources say
- Not checked yetcites [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 yetcites [38] Johnson, D. B. et al. Ipilimumab therapy in patients with advanced melanoma and preexisting autoimmune disorders. JAMA Oncol. 2, 234–240 (2016). source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > Endocrine manifestations of ICI therapy
What the sources say
- Not checked yetcites [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 yetcites [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).
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > Thyroid toxicities > Epidemiology/pathophysiology
What the sources say
- Not checked yetcites [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 yetcites [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
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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.”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > Thyroid toxicities > Clinical Presentation and Diagnosis
What the sources say
- Not checked yetcites [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
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“ICI-related thyrotoxicosis is characterized by an elevated FT4 or total T3 and a low or suppressed TSH.”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > Thyroid toxicities > Clinical Presentation and Diagnosis
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“These are distinct events from those caused by traditional cytotoxic chemotherapy or even newer molecular targeted therapies, which rarely cause endocrine dysfunction.”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > Endocrine manifestations of ICI therapy
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > Thyroid toxicities > Clinical Presentation and Diagnosis
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > Endocrine manifestations of ICI therapy
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- The authors state this as an assumption: ICI-induced endocrine toxicities result in permanent, irreversible endocrine dysfunction.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > Endocrine manifestations of ICI therapy
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > Endocrine manifestations of ICI therapy
hedged- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“whereas hypothyroidism is usually accompanied by mild symptoms, cases of diabetes mellitus have proven fatal when presenting in diabetic ketoacidosis (DKA).”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > Endocrine manifestations of ICI therapy
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“has been increasing in recognition and diagnosis.66”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > Diabetes Mellitus > Epidemiology/Pathophysiology
What the sources say
- Not checked yetcites [66] Min, L., Vaidya, A. & Becker, C. Thyroid autoimmunity and ophthalmopathy related to melanoma biological therapy. Eur. J. Endocrinol. 164, 303–307 (2011). source
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > ICI toxicities: Clinical Presentation
What the sources say
- Not checked yetcites [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
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > ICI Clinical Activity
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“other suggested a potentially causative role of Epstein-Barr Virus infection or reactivation in a case of ICI-encephalitis.20”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > ICI toxicities: Pathobiology
What the sources say
- Not checked yetcites [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
hedgedconditionalSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > ICI toxicities: Clinical Presentation
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > Pituitary toxicities > Clinical Presentation and Diagnosis
What the sources say
- Not checked yetcites [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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The targets of ICI (CTLA-4, PD-1, and PD-L1) are key regulators of immune tolerance, and prevent autoimmunity in the physiologic state.”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > ICI toxicities: Pathobiology
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > Pituitary toxicities > Clinical Presentation and Diagnosis
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Normal brain imaging does not rule out hypopituitarism/hypophysitis, however.”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > Pituitary toxicities > Clinical Presentation and Diagnosis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > Pituitary toxicities > Epidemiology/Pathophysiology
What the sources say
- Not checked yetcites [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
plaincorrelationalSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“pituitary glands expressed CTLA-4 in a subset of these cells, which were targets for CTLA-4 antibody binding, and resulted in complement deposition.”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > Pituitary toxicities > Epidemiology/Pathophysiology
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > ICI Clinical Activity
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > ICI toxicities: Pathobiology
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“One study suggested that ICI-colitis correlated with particular strains of microbial flora colonization,19”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > ICI toxicities: Pathobiology
What the sources say
- Not checked yetcites [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
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > Pituitary toxicities > Clinical Presentation and Diagnosis
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Male gender and older age may be risk factors although this has only been observed in one small series.58”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > Pituitary toxicities > Epidemiology/Pathophysiology
What the sources say
- Not checked yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > ICI Clinical Activity
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Secondary hypothyroidism and secondary hypogonadism are also quite common (see Figure 4).”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > Pituitary toxicities > Clinical Presentation and Diagnosis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > ICI toxicities: Clinical Presentation
What the sources say
- Not checked yetcites [24] Das, R. et al. Early B cell changes predict autoimmunity following combination immune checkpoint blockade. J. Clin. Invest. 128, 715–720 (2018). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“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”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > ICI toxicities: Pathobiology
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“though glucose management may be more challenging in ICI-DM”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > Diabetes Mellitus > Monitoring and Treatment
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“PD-L1 expression is increased in pancreatic beta cells of older mice and in mice with immune infiltration of their islets69,70”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > Diabetes Mellitus > Epidemiology/Pathophysiology
What the sources say
- Not checked yetcites [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 yetcites [70] Iadarola, C. et al. Nivolumab induced thyroid dysfunction: unusual clinical presentation and challenging diagnosis. Front. Endocrinol. 9, 813 (2018). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Approximately 40-50% of individuals with ICI-DM have detectable islet auto-antibodies at diagnosis, compared to >90% in T1D 64,65”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > Diabetes Mellitus > Epidemiology/Pathophysiology
What the sources say
- Not checked yetcites [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 yetcites [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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The somewhat predictable onset (at least in a defined proportion of patients) of ICI related endocrine toxicities”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > Conclusions
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
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”
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.
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > Thyroid toxicities > Monitoring and Treatment
“If the TSH is markedly elevated (> 10 uIU/ml), then further testing is not needed and thyroid hormone replacement should be started.”
§ Endocrine Toxicities of Immune Checkpoint Inhibitors > Thyroid toxicities > Monitoring and Treatment
“Hypothyroidism (whether or not preceded by thyroiditis) should be treated with thyroid hormone replacement when the TSH is > 10uIU/ml (on two occasions).”
Citations
Cites
PD-1 and PD-L1 Immune Checkpoint Blockade to Treat Breast Cancer
Hartkopf, A. D., Taran, F., Wallwiener, M., Walter, C. B., Krämer, B., Grischke, E., & Brucker, S. Y. (2016) · Breast Care · doi:10.1159/000453569 · Cited by 30,989
Improved Survival with Ipilimumab in Patients with Metastatic Melanoma
Hodi, F. S., O'Day, S. J., McDermott, D. F., Weber, R. W., Sosman, J. A., Haanen, J. B., Gonzalez, R., Robert, C., Schadendorf, D., Hassel, J. C., et al. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa1003466 · Cited by 15,155
Safety, activity, and immune correlates of anti–PD-1 antibody in cancer
Topalian, S. L., Hodi, F. S., Brahmer, J. R., Gettinger, S. N., Smith, D. C., McDermott, D. F., Powderly, J. D., Carvajal, R. D., Sosman, J. A., Atkins, M. B., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1200690 · Cited by 12,628
Cancer immunotherapy using checkpoint blockade
Ribas, A., & Wolchok, J. D. (2018) · Science · doi:10.1126/science.aar4060 · Cited by 6,791 · cited 1×
“Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III).”
BackgroundOverall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma
Wolchok, J. D., Chiarion-Sileni, V., Gonzalez, R., Rutkowski, P., Grob, J.-J., Cowey, C. L., Lao, C. D., Wagstaff, J., Schadendorf, D., Ferrucci, P. F., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1709684 · Cited by 5,357
Immune-Related Adverse Events Associated with Immune Checkpoint Blockade
Postow, M. A., Sidlow, R., & Hellmann, M. D. (2018) · New England Journal of Medicine · doi:10.1056/nejmra1703481 · Cited by 4,849
Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma
Motzer, R. J., Tannir, N. M., McDermott, D. F., Arén Frontera, O., Melichar, B., Choueiri, T. K., Plimack, E. R., Barthélémy, P., Porta, C., George, S., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1712126 · Cited by 4,656
Hollowell, J. G., Staehling, N. W., Flanders, W. D., Hannon, W. H., Gunter, E. W., Spencer, C. A., & Braverman, L. E. (2002) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.87.2.489 · Cited by 4,279
Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma
Larkin, J., Chiarion-Sileni, V., Gonzalez, R., Grob, J.-J., Rutkowski, P., Lao, C. D., Cowey, C. L., Schadendorf, D., Wagstaff, J., Dummer, R., et al. (2019) · New England Journal of Medicine · doi:10.1056/nejmoa1910836 · Cited by 3,723
Brahmer, J. R., Lacchetti, C., Schneider, B. J., Atkins, M. B., Brassil, K. J., Caterino, J. M., Chau, I., Ernstoff, M. S., Gardner, J. M., Ginex, P., et al. (2018) · Journal of Clinical Oncology · doi:10.1200/jco.2017.77.6385 · Cited by 3,713
First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer
Horn, L., Mansfield, A. S., Szczęsna, A., Havel, L., Krzakowski, M., Hochmair, M. J., Huemer, F., Losonczy, G., Johnson, M. L., Nishio, M., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1809064 · Cited by 3,586
Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma
Rini, B. I., Plimack, E. R., Stus, V., Gafanov, R., Hawkins, R., Nosov, D., Pouliot, F., Alekseev, B., Soulières, D., Melichar, B., et al. (2019) · New England Journal of Medicine · doi:10.1056/nejmoa1816714 · Cited by 3,403
Burtness, B., Harrington, K. J., Greil, R., Soulières, D., Tahara, M., de Castro, G., Psyrri, A., Basté, N., Neupane, P., Bratland, Å., et al. (2019) · The Lancet · doi:10.1016/s0140-6736(19)32591-7 · Cited by 3,336
Tumor mutational burden and response rate to PD-1 inhibition
Yarchoan, M., Hopkins, A., & Jaffee, E. M. (2017) · New England Journal of Medicine · doi:10.1056/nejmc1713444 · Cited by 3,230
Ross, D. S., Burch, H. B., Cooper, D. S., Greenlee, M. C., Laurberg, P., Maia, A. L., Rivkees, S. A., Samuels, M., Sosa, J. A., Stan, M. N., et al. (2016) · Thyroid® · doi:10.1089/thy.2016.0229 · Cited by 2,938
Nivolumab plus ipilimumab in advanced non-small-cell lung cancer
Hellmann, M. D., Paz-Ares, L., Bernabe Caro, R., Zurawski, B., Kim, S.-W., Carcereny Costa, E., Park, K., Alexandru, A., Lupinacci, L., de la Mora Jimenez, E., et al. (2019) · New England Journal of Medicine · doi:10.1056/nejmoa1910231 · Cited by 2,823
Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC
Antonia, S. J., Villegas, A., Daniel, D., Vicente, D., Murakami, S., Hui, R., Kurata, T., Chiappori, A., Lee, K. H., de Wit, M., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1809697 · Cited by 2,798
Wang, D. Y., Salem, J.-E., Cohen, J. V., Chandra, S., Menzer, C., Ye, F., Zhao, S., Das, S., Beckermann, K. E., Ha, L., et al. (2018) · JAMA Oncology · doi:10.1001/jamaoncol.2018.3923 · Cited by 2,674
Self-citationAdverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance
Martins, F., Sofiya, L., Sykiotis, G. P., Lamine, F., Maillard, M., Fraga, M., Shabafrouz, K., Ribi, C., Cairoli, A., Guex-Crosier, Y., et al. (2019) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-019-0218-0 · Cited by 2,314
Fulminant Myocarditis with Combination Immune Checkpoint Blockade
Johnson, D. B., Balko, J. M., Compton, M. L., Chalkias, S., Gorham, J., Xu, Y., Hicks, M., Puzanov, I., Alexander, M. R., Bloomer, T. L., et al. (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1609214 · Cited by 2,308
Self-citationAdjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma
Weber, J., Mandala, M., Del Vecchio, M., Gogas, H. J., Arance, A. M., Cowey, C. L., Dalle, S., Schenker, M., Chiarion-Sileni, V., Marquez-Rodas, I., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1709030 · Cited by 2,246
Schadendorf, D., Hodi, F. S., Robert, C., Weber, J. S., Margolin, K., Hamid, O., Patt, D., Chen, T.-T., Berman, D. M., & Wolchok, J. D. (2015) · Journal of Clinical Oncology · doi:10.1200/jco.2014.56.2736 · Cited by 2,141
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“Another worrisome adverse event of IO is endocrine toxicities of ICIs involving the thyroid, pituitary, adrenal, and pancreas.(437) The potential mechanisms of ICIs-associated endocrine toxicities are similar to ICIs-associated pneumonitis.”
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Immune-related adverse events of immune checkpoint inhibitors: a review
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“Organs most commonly affected by ICI-related endocrine toxicity include the thyroid gland (which typically manifests as hypothyroidism, often secondary to thyroiditis; Graves’ disease-like hyperthyroidism is very rare), pituitary gland (hypophysitis or hypopituitarism), and islet beta cells (presentation similar to ty…”
Background
Metadata
- Authors
- Wright, J. J., Powers, A. C., & Johnson, D. B.
- Affiliations
- Vanderbilt-Ingram Cancer Center (US)
- Vanderbilt University (US)
- Corresponding author
- Johnson, Douglas B.
- Venue
- Nature Reviews Endocrinology
- Published
- 2021-04-19
- Volume
- 17
- Issue
- 7
- Pages
- 389-399
- ISSN
- 1759-5029 (ISSN-L)
- 1759-5037
- 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
- green
- www.ncbi.nlm.nih.gov
- 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.
A language model drew the claims from the paper on 2026-10-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-09 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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