Abstract
Immune checkpoint inhibitors are molecules that increase the endogenous immune response against tumors. They have revolutionized the field of oncology. Since their initial approval for the treatment of advanced melanoma, their use has expanded to the treatment of several other advanced cancers. Unfortunately, immune checkpoint inhibitors have also been associated with the emergence of a new subset of autoimmune-like toxicities, known as immune-related adverse events. These toxicities differ depending on the agent, malignancy, and individual susceptibilities. Although the skin and colon are most commonly involved, any organ may be affected, including the liver, lungs, kidneys, and heart. Most of these toxicities are diagnosed by excluding other secondary infectious or inflammatory causes. Corticosteroids are commonly used for treatment of moderate and severe immune-related adverse events, although additional immunosuppressive therapy may occasionally be required. The occurrence of immune-related toxicities may require discontinuation of immunotherapy, depending on the specific toxicity and its severity. In this article, we provide a focused review to familiarize practicing clinicians with this important topic given that the use of immune checkpoint inhibitors continues to increase.
Abbreviations and Acronyms:
CTLA-4 (cytotoxic T lymphocyte–associated antigen 4), ICI (immune checkpoint inhibitor), irAE (immune-related adverse event), PD-1 (programmed cell death protein 1), PD-L1 (programmed cell death ligand 1)CME Activity
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Learning Objectives: On completion of this article, you should be able to (1) describe the mechanisms by which immune checkpoint inhibitors lead to immune-related toxicities, (2) recognize the presence of immune-related adverse events in different organs depending on timing and clinical scenario, and (3) define an appropriate strategy for diagnosis and management according to the type and severity of each toxicity.
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The authors report no competing interests.
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Immunologic responses are a result of a complex set of interactions between stimulatory and counterbalancing inhibitory signals. Immune checkpoints are molecules that modulate the immune system, assist with self-tolerance, and minimize collateral tissue damage when immune responses are activated.
1
Malignant cells avoid immune recognition and destruction by exploiting immune checkpoint receptors, such as the cytotoxic T lymphocyte–associated antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed cell death ligand 1 (PD-L1).1
Immune checkpoint inhibitors (ICIs) are agents that interfere with these interactions, reactivate the immune system, and generate potent and long-lasting antitumor responses.1
, 2
Ipilimumab, an anti–CTLA-4 antibody, was the first ICI to be approved by the US Food and Drug Administration after demonstrating overall survival benefit in patients with melanoma.3
Subsequently, anti–PD-1 (eg, nivolumab, pembrolizumab, and cemiplimab) and anti–PD-L1 agents (eg, atezolizumab, avelumab, and durvalumab) have also been approved for different indications. Table 1 summarizes the targets of action and main uses of these therapies.Table 1Summary of Immune Checkpoint Inhibitor Targets and Indications
a
cHL = classic Hodgkin lymphoma; CTLA-4 = cytotoxic T lymphocyte–associated antigen 4; CRC = colorectal cancer; DLBCL= diffuse large B-cell lymphoma; dMMR = deficient mismatch repair; FDA = US Food and Drug Administration; HCC = hepatocellular carcinoma; HNSCC = head and neck squamous cell carcinoma; MCC = Merkel cell carcinoma; MSI-H = microsatellite instability-high; NSCLC = non–small cell lung cancer; PD-1 = programmed cell death protein 1; PD-L1 = programmed cell death ligand 1; RCC = renal cell carcinoma; SCC = squamous cell carcinoma; SCLC = small cell lung cancer.
| Agent | Target receptor | FDA-approved indications |
|---|---|---|
| Ipilimumab | CTLA-4 | Melanoma, MSI-H/dMMR CRC, intermediate- or poor-risk RCC (in combination with nivolumab) |
| Tremelimumab | CTLA-4 | Not yet approved; under investigation |
| Nivolumab | PD-1 | MSI-H or dMMR CRC, HNSCC, HCC, melanoma, cHL, NSCLC, RCC, urothelial cancer, SCLC |
| Pembrolizumab | PD-1 | Cervical cancer, gastric cancer, HNSCC, HCC, cHL, melanoma, MCC, MSI-H/dMMR cancers, NSCLC, primary mediastinal DLBCL, urothelial cancer |
| Cemiplimab | PD-1 | Cutaneous SCC |
| Atezolizumab | PD-L1 | NSCLC, urothelial cancer |
| Avelumab | PD-L1 | MCC, urothelial cancer |
| Durvalumab | PD-L1 | NSCLC, urothelial carcinoma |
a cHL = classic Hodgkin lymphoma; CTLA-4 = cytotoxic T lymphocyte–associated antigen 4; CRC = colorectal cancer; DLBCL= diffuse large B-cell lymphoma; dMMR = deficient mismatch repair; FDA = US Food and Drug Administration; HCC = hepatocellular carcinoma; HNSCC = head and neck squamous cell carcinoma; MCC = Merkel cell carcinoma; MSI-H = microsatellite instability-high; NSCLC = non–small cell lung cancer; PD-1 = programmed cell death protein 1; PD-L1 = programmed cell death ligand 1; RCC = renal cell carcinoma; SCC = squamous cell carcinoma; SCLC = small cell lung cancer.
b All FDA-approved indications stated above are for metastatic malignancies.
Toxicity Profile
The CTLA-4, PD-1, and PD-L1 pathways mediate immune responses at different levels. CTLA-4 controls the amplitude of immunologic response at early stages of T-cell activation, whereas PD-1 and PD-L1 pathways act at later stages, limiting T-cell activity in the peripheral tissues.
1
, 4
These differences partly explain variations in toxicity profiles between anti–CTLA-4, anti–PD-1, and anti–PD-L1 agents and the higher frequency and severity seen with anti–CTLA-4 agents.4
, 5
In fact, the incidence of serious (severe) immune-related adverse events (irAEs) has been reported to be as high as 27% with the use of anti–CTLA-4 compared with 16% with anti–PD-1 agents and may increase to 55% when both therapies are used simultaneously.6
The occurrence of certain toxicities varies depending on the type of malignancy and/or pathway blocked. For instance, patients with melanoma appear to experience more rash and colitis and less pneumonitis compared with other malignancies such as renal cell carcinoma or non–small cell lung cancer.7
Also, the use of anti–CTLA-4 therapy has been associated more commonly with colitis, hypophysitis, and rash, whereas pneumonitis, thyroiditis/hypothyroidism, arthralgias, and vitiligo occur more often with anti–PD-1 agents.4
, 7
, 8
Importantly, toxicities are dose related with CTLA-4–blocking agents but not with anti–PD-1 therapy.9
Table 2 summarizes the most common irAEs.Table 2Summary of Common Immune Checkpoint Inhibitor–Related Adverse Events
| System | Type of irAE | Incidence | Weeks to occurrence | Comments |
|---|---|---|---|---|
| Dermatological | Skin rash/pruritus | 40%-60% | 2-3 | More commonly seen with anti–CTLA-4 therapy |
| Gastrointestinal | Diarrhea/colitis | 2%-7% (severe colitis) | 6-7 | More commonly seen with anti–CTLA-4 therapy |
| Hepatitis | 5%-10% | 8-12 | More commonly seen with anti–CTLA-4 therapy | |
| Endocrine | Hypothyroidism | 6% | 4-6 | More commonly seen with anti–PD-1 therapy |
| Hypophysitis | 0.1%-6% | 8-9 | More commonly seen with anti–CTLA-4 therapy | |
| Pulmonary | Pneumonitis | 5% | 12 | More commonly seen with anti–PD-1 therapy |
CTLA-4 = cytotoxic T lymphocyte–associated antigen 4; irAE = immune-related adverse event; PD-1 = programmed cell death protein 1.
Systemic Toxicities
Fatigue is one of the most common irAEs associated with the use of ICIs. Incidence rates range from 16% to 24% with the use of anti–PD-1 and anti–PD-L1 agents to 40% with anti–CTLA-4 therapy and up to 71% when ICIs are combined with one another or with other forms of anticancer therapy (eg, chemotherapy).
3
, 5
Fatigue is usually mild and does not interfere with daily activities. Although no specific treatment is needed, it is important to exclude more serious causes of fatigue, including cancer progression or coexistent endocrine irAEs such as hypothyroidism, hypophysitis, or adrenal insufficiency.2
Fever, chills, and infusion reactions can be a consequence of nonspecific cytokine release.
5
, 10
Fevers and chills are usually mild and managed with acetaminophen or nonsteroidal anti-inflammatory agents.- Puzanov I.
- Diab A.
- Abdallah K.
- et al.
Society for Immunotherapy of Cancer Toxicity Management Working Group
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
J Immunother Cancer. 2017; 5: 95
5
Infusion reactions occur in fewer than 10% of cases and are usually mild. Management requires the use of antihistamines and/or corticosteroids, often coupled with a dose reduction or discontinuation of the infusion.5
, 10
- Puzanov I.
- Diab A.
- Abdallah K.
- et al.
Society for Immunotherapy of Cancer Toxicity Management Working Group
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
J Immunother Cancer. 2017; 5: 95
Dermatological Toxicities
Dermatological toxicities are the most common reactions seen with ICIs and usually occur within the first 2 to 3 weeks after initiation of therapy.
5
, 11
Rash or pruritus has been reported in 50% of patients treated with anti–CTLA-4 antibodies, 40% of patients treated with anti–PD-1 or anti–PD-L1 therapy, and 60% of patients receiving combination therapy.8
The most common form of rash is a spongiotic dermatitis-like eczema described as maculopapular, faintly erythematous, and pruritic.8
Vitiligo has also been reported, particularly among patients with melanoma treated with ICIs.10
Other less common toxicities include lichenoid, eczematous, follicular, or psoriasiform dermatitides and bullous pemphigoid.- Puzanov I.
- Diab A.
- Abdallah K.
- et al.
Society for Immunotherapy of Cancer Toxicity Management Working Group
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
J Immunother Cancer. 2017; 5: 95
5
, 10
, - Puzanov I.
- Diab A.
- Abdallah K.
- et al.
Society for Immunotherapy of Cancer Toxicity Management Working Group
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
J Immunother Cancer. 2017; 5: 95
12
Mucosal involvement in the form of sicca syndrome can also occur, predominantly with anti–PD-1 agents.8
Some patients, particularly when using combination ICI therapy, may have development of severe blistering dermatoses such as bullous dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis.10
- Puzanov I.
- Diab A.
- Abdallah K.
- et al.
Society for Immunotherapy of Cancer Toxicity Management Working Group
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
J Immunother Cancer. 2017; 5: 95
When a rash is present, it is important to rule out infectious etiologies, medication-induced dermatitis, or other systemic illnesses, including autoimmune conditions.
12
Skin biopsy can be considered for more severe rashes or when diagnosis is unclear.2
, 10
- Puzanov I.
- Diab A.
- Abdallah K.
- et al.
Society for Immunotherapy of Cancer Toxicity Management Working Group
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
J Immunother Cancer. 2017; 5: 95
Management of mild to moderate rashes involves topical medium- to high-potency corticosteroids in conjunction with symptomatic control of pruritus with cold compresses, antihistamines, or γ-aminobutyric acid agonists.
5
, 8
Immunotherapy can usually be continued cautiously in patients with mild to moderate rashes and vitiligo. Interestingly, vitiligo has been correlated with improved response to therapy.8
, 12
Moderate to severe rashes usually require systemic therapy with prednisone, starting at a dose of 0.5 to 1 mg/kg daily, followed by a slow taper over at least 4 weeks.8
In addition, immunotherapy is withheld or permanently discontinued based on severity, percentage of body surface area involved, and response to corticosteroid therapy. Patients who experience severe blistering disorders require urgent dermatological consultation for possible hospitalization, intravenous immunosuppression, multidisciplinary consultation with disease-specific subspecialties, and permanent discontinuation of ICI therapy according to the latest National Comprehensive Cancer Network guidelines.12
, 13
Referral to a dermatologist should be considered for atypical presentations, mild rash that is not improving despite therapy, moderate to severe dermatological toxicities, or any rash with mucosal involvement.
10
- Puzanov I.
- Diab A.
- Abdallah K.
- et al.
Society for Immunotherapy of Cancer Toxicity Management Working Group
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
J Immunother Cancer. 2017; 5: 95
Gastrointestinal Toxicities
Diarrhea and Colitis
Diarrhea is defined as increased stool frequency and colitis as the presence of symptoms (eg, abdominal pain, nausea, vomiting, fever, bloody stools) or radiographic findings suggestive of inflammation.
14
, 15
These toxicities usually occur 6 to 7 weeks after therapy initiation and are more common with anti–CTLA-4 antibodies.10
, - Puzanov I.
- Diab A.
- Abdallah K.
- et al.
Society for Immunotherapy of Cancer Toxicity Management Working Group
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
J Immunother Cancer. 2017; 5: 95
11
Severe diarrhea is more common than colitis, particularly among patients receiving combination therapy or an anti–CTLA-4 agent alone.8
Severe colitis occurs more often with anti–CTLA-4 therapy, affecting up to 7% of patients compared with 1.8% receiving anti–PD-1 therapy.8
Initial work-up for patients with diarrhea includes the exclusion of infectious etiologies, such as Clostridium difficile, Salmonella, and other bacterial, parasitic, or viral causes, including cytomegalovirus.
2
, 8
, 14
, 16
Computed tomography should be considered for patients with severe, persistent, or progressive symptoms despite therapy.15
Colonoscopy is usually reserved for situations in which the diagnosis remains uncertain.14
Patients with mild diarrhea of less than 1-week duration can be managed symptomatically with bowel rest, adequate fluid and electrolyte replacement, and temporary delay in ICI therapy.
5
, 12
, 14
, 15
When symptoms last more than 7 days or are of moderate intensity (ie, >7 stools per day and abdominal pain), prednisone at a dose of 1 to 2 mg/kg daily is warranted.15
Severe symptoms may require hospitalization for intravenous administration of corticosteroids.5
, 15
Corticosteroids should be tapered over a period of 4 to 6 weeks or longer in order to prevent early relapses.15
Infliximab (tumor necrosis factor α inhibitor) can be used in patients with severe immune-related toxicities whose corticosteroid treatment cannot be tapered off or in those whose symtoms do not respond to intravenous corticosteroids within 48 to 72 hours.5
, 15
Patients with moderate to severe colitis should have their ICI therapy permanently discontinued.12
Hepatitis
Hepatitis of all grades occurs more often with anti–CLTA-4 than with anti–PD-1 or anti–PD-L1 therapy, with a reported incidence of 10% and 5%, respectively.
5
When these agents are used together, incidence increases to 30%.10
Hepatitis tends to occur within 8 to 12 weeks after initiation of therapy and usually consists of asymptomatic elevation of aspartate aminotransferase, alanine aminotransferase, and bilirubin (less common) levels and fever (rarely).- Puzanov I.
- Diab A.
- Abdallah K.
- et al.
Society for Immunotherapy of Cancer Toxicity Management Working Group
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
J Immunother Cancer. 2017; 5: 95
10
, - Puzanov I.
- Diab A.
- Abdallah K.
- et al.
Society for Immunotherapy of Cancer Toxicity Management Working Group
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
J Immunother Cancer. 2017; 5: 95
14
Patients taking ICIs should be monitored for abnormal findings on liver function tests before initiation of therapy and before each infusion.
10
, - Puzanov I.
- Diab A.
- Abdallah K.
- et al.
Society for Immunotherapy of Cancer Toxicity Management Working Group
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
J Immunother Cancer. 2017; 5: 95
12
If abnormal liver function test results are detected, secondary causes of liver damage should be ruled out, including viral hepatitis, alcohol use, medication toxicities, outflow tract thromboembolic events, and metastatic liver disease.2
, 10
, - Puzanov I.
- Diab A.
- Abdallah K.
- et al.
Society for Immunotherapy of Cancer Toxicity Management Working Group
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
J Immunother Cancer. 2017; 5: 95
12
Computed tomography of the abdomen may reveal hepatomegaly, periportal edema with associated lymphadenopathy, and attenuated liver parenchyma.17
Initiation of prednisone at a dose of 1 mg/kg daily with tapering over at least 3 weeks is indicated after secondary causes have been ruled out.5
, 11
Mycophenolate mofetil or tacrolimus can be considered in patients with elevations above 8 times the normal liver function test values.8
Infliximab should be avoided given the risk for idiosyncratic liver toxicity.12
Liver function tests should be obtained every 48 hours until improvement is noted, then weekly until results normalize. This may take up to 8 weeks.8
, 11
Although mild to moderate hepatitis may require temporary deferral of ICI administration, severe hepatitis requires permanent discontinuation of therapy.
12
Pancreatic Abnormalities
Asymptomatic elevation of pancreatic enzymes has been reported more often than clinical pancreatitis with anti–CTLA-4, anti–PD-1, and anti–PD-L1 therapy.
5
, 10
, - Puzanov I.
- Diab A.
- Abdallah K.
- et al.
Society for Immunotherapy of Cancer Toxicity Management Working Group
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
J Immunother Cancer. 2017; 5: 95
18
Given the rarity of clinical pancreatitis (less than 1.5% with anti–CTLA-4 therapy) and the high rate of asymptomatic elevation of pancreatic enzymes, routine follow-up monitoring of amylase and lipase levels is not indicated.11
, 14
If clinical pancreatitis is suspected, secondary etiologies, such as gallstones, alcohol, and malignancy, should be excluded.2
, 8
If these causes are ruled out, the patient should receive 1 mg/kg of prednisone daily, tapered over several weeks.8
Endocrine Toxicities
Endocrine irAEs often include thyroid dysfunction, hypophysitis, and, less often, primary adrenal insufficiency and type 1 diabetes mellitus.
10
As opposed to other irAEs, endocrine toxicities tend to be permanent and frequently require lifelong hormone replacement.- Puzanov I.
- Diab A.
- Abdallah K.
- et al.
Society for Immunotherapy of Cancer Toxicity Management Working Group
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
J Immunother Cancer. 2017; 5: 95
8
An endocrinology consultation should be offered in all cases of endocrine irAEs.10
, - Puzanov I.
- Diab A.
- Abdallah K.
- et al.
Society for Immunotherapy of Cancer Toxicity Management Working Group
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
J Immunother Cancer. 2017; 5: 95
12
Hypothyroidism is more common than hyperthyroidism, with an overall incidence of 6.6%.
2
, 19
Hypothyroidism occurs more frequently with anti–PD-1 and combination therapy than with anti–CTLA-4 agents and has been highly linked to the presence of antithyroid antibodies.19
, 20
Thyroid dysfunction usually occurs a few weeks after initiation of therapy, with a median of 42 days.20
Most patients are asymptomatic or mildly symptomatic and many present with an initial transient and asymptomatic period of hyperthyroidism, consistent with thyroiditis.20
Thyrotropin levels should be screened before and periodically throughout ICI therapy.8
In the presence of abnormal thyrotropin levels, free triiodothyronine and thyroxine levels should be measured because patients can have primary or secondary hypothyroidism.14
Treatment with levothyroxine is indicated for patients with thyrotropin levels greater than 10 mIU/L and for those who are symptomatic.2
In the presence of thyroiditis with hyperthyroid features, patients benefit from nonselective β-blockers.2
, 5
, 8
Immune checkpoint inhibitor therapy should be continued in asymptomatic and mildly symptomatic cases but should be withheld until symptomatic improvement occurs in moderate or severe cases.12
Studies suggest that some thyroid function may be restored over time.9
Hypophysitis occurs more with anti–CTLA-4 therapy than with anti–PD-1 or anti–PD-L1, with an incidence of 6.4% for combination therapy, 3.2% for anti–CTLA-4, and less than 0.1% to 0.4% for anti–PD-1 and anti–PD-L1 agents.
19
Although the pathophysiology remains unclear, the presence of CTLA-4 molecules expressed by normal pituitary cells could play a role.19
, 21
Hypophysitis tends to present 8 to 9 weeks after initial dosing with decreased levels of prolactin, corticotropin, thyrotropin, or follicle-stimulating, luteinizing, or growth hormones.10
, - Puzanov I.
- Diab A.
- Abdallah K.
- et al.
Society for Immunotherapy of Cancer Toxicity Management Working Group
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
J Immunother Cancer. 2017; 5: 95
11
Symptoms are usually nonspecific and may include headache, fatigue, weakness, amenorrhea, impotence, hypotension, hypoglycemia, or gastrointestinal complaints.2
, 8
, 10
Central hypothyroidism is the most frequent deficiency, but diabetes insipidus or visual defects can also occur.- Puzanov I.
- Diab A.
- Abdallah K.
- et al.
Society for Immunotherapy of Cancer Toxicity Management Working Group
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
J Immunother Cancer. 2017; 5: 95
22
Diagnosis is based on clinical presentation, biochemical evidence of pituitary dysfunction, and radiographic evidence of pituitary enlargement and enhancement after ICI administration.14
, 22
When suspected, some clinicians advocate the use of high-dose corticosteroids (eg, prednisone, 1 mg/kg daily) to reduce the chances of irreversible damage.14
Nevertheless, most patients require long-term supplementation with corticosteroids and levothyroxine.10
, - Puzanov I.
- Diab A.
- Abdallah K.
- et al.
Society for Immunotherapy of Cancer Toxicity Management Working Group
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
J Immunother Cancer. 2017; 5: 95
12
Corticosteroids should be initiated several days before thyroid replacement therapy to avoid precipitating an adrenal crisis.10
, - Puzanov I.
- Diab A.
- Abdallah K.
- et al.
Society for Immunotherapy of Cancer Toxicity Management Working Group
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
J Immunother Cancer. 2017; 5: 95
12
Immunotherapy is usually deferred in all cases until the patient's condition has been stabilized with replacement hormones.12
The most serious endocrine irAE is primary adrenal insufficiency, which may occur in 0.7% of patients and present as an adrenal crisis.
8
, 19
A basic diagnostic examination should include morning corticotropin and cortisol measurements, electrolyte panel, and sepsis rule-out.12
Management mandates hospitalization, aggressive hydration, intravenous stress-dose corticosteroids, and withholding immunotherapy until the patient's condition is stable with hormone replacement therapy.12
, 14
Type 1 diabetes mellitus has been reported in 0.2% of patients receiving ICI therapy, particularly anti–PD-1 agents.
19
Patients may have asymptomatic hyperglycemia or present with overt symptomatic hyperglycemia or diabetic ketoacidosis.23
Therefore, monitoring for hyperglycemia or any suggestive symptom of diabetes mellitus during each treatment cycle is important.12
Management often requires lifelong insulin therapy and temporarily withholding ICI therapy until adequate glucose control is achieved.12
, 23
Pulmonary Toxicities
Pneumonitis is a potentially fatal irAE with an incidence of 5% in patients receiving ICIs, particularly with combination therapy and in patients with lung cancer.
5
, 24
It occurs more often with anti–PD-1 than anti–CTLA-4 therapy, with a median time to presentation of almost 3 months.8
, 24
Clinically, patients may be asymptomatic or present with progressive dyspnea, cough, wheezing, reduced exercise tolerance, or increased supplemental oxygen requirement.10
More than half of patients have additional irAEs, such as dermatitis, colitis, or thyroiditis.- Puzanov I.
- Diab A.
- Abdallah K.
- et al.
Society for Immunotherapy of Cancer Toxicity Management Working Group
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
J Immunother Cancer. 2017; 5: 95
24
Because drug-induced pneumonitis is a diagnosis of exclusion, clinicians should first assess for infectious etiologies or malignant pulmonary infiltration. Chest radiography may be inadequate to detect abnormalities in up to one-quarter of patients; therefore, computed tomography is preferred.
24
Imaging findings may include bilateral ground-glass opacities with peripheral distribution, resembling cryptogenic organizing pneumonia, or ground-glass opacities with interlobar septal thickening, as in nonspecific interstitial pneumonia.8
Bronchoscopy can be considered in moderate to severe cases to rule out infection.8
, 12
Management of mild pneumonitis may only require pausing ICI therapy, with clinical and radiologic follow-up within 2 to 4 weeks.
23
Moderate cases require withholding ICI therapy until symptomatic resolution and treatment with 1 to 2 mg/kg of prednisone daily or 0.5 to 1 mg/kg of methylprednisolone daily tapered over a period of 4 to 6 weeks to prevent early relapses.8
, 12
Severe cases of pneumonitis require not only permanent discontinuation of ICI therapy but also hospitalization, high corticosteroid doses (eg, intravenous methylprednisolone, 1-2 mg/kg daily), and possible additional immunosuppression with infliximab, mycophenolate mofetil, intravenous immunoglobulin, or cyclophosphamide.12
Up to 12% of patients have progressive and lethal disease despite immunosupression.24
Pulmonary and extrapulmonary sarcoidosis-like syndrome has also been described as part of the pulmonary spectrum.
10
Patients may be asymptomatic or present with pulmonary symptoms; ocular, myocardial, or renal involvement; or even sarcoid-induced hypercalcemia.- Puzanov I.
- Diab A.
- Abdallah K.
- et al.
Society for Immunotherapy of Cancer Toxicity Management Working Group
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
J Immunother Cancer. 2017; 5: 95
10
Overall, approaches to diagnosis and treatment are similar to pneumonitis.- Puzanov I.
- Diab A.
- Abdallah K.
- et al.
Society for Immunotherapy of Cancer Toxicity Management Working Group
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
J Immunother Cancer. 2017; 5: 95
8
, 10
- Puzanov I.
- Diab A.
- Abdallah K.
- et al.
Society for Immunotherapy of Cancer Toxicity Management Working Group
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
J Immunother Cancer. 2017; 5: 95
Rheumatologic Toxicities
Arthralgias have been reported in 15% of patients taking ICIs. Inflammatory arthritis has been reported in 1% to 7%, occurring more often with combination therapy.
10
, - Puzanov I.
- Diab A.
- Abdallah K.
- et al.
Society for Immunotherapy of Cancer Toxicity Management Working Group
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
J Immunother Cancer. 2017; 5: 95
25
, 26
Arthritis usually develops with other irAEs, occurs after 5 months of therapy, and can affect large, medium, or small joints.10
It may be destructive and persist after discontinuation of immunotherapy. Other rheumatoid-like toxicities include inflammatory myositis, rhabdomyolysis, giant cell arteritis, and polymyalgia-like syndrome.- Puzanov I.
- Diab A.
- Abdallah K.
- et al.
Society for Immunotherapy of Cancer Toxicity Management Working Group
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
J Immunother Cancer. 2017; 5: 95
10
An autoimmune panel can assist in differentiating autoimmune conditions from irAEs, while imaging modalities can exclude metastatic disease and assess for joint damage. A rheumatology consultation should be considered, particularly for patients with moderate to severe forms.- Puzanov I.
- Diab A.
- Abdallah K.
- et al.
Society for Immunotherapy of Cancer Toxicity Management Working Group
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
J Immunother Cancer. 2017; 5: 95
10
, - Puzanov I.
- Diab A.
- Abdallah K.
- et al.
Society for Immunotherapy of Cancer Toxicity Management Working Group
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
J Immunother Cancer. 2017; 5: 95
12
Mild arthritis requires temporary ICI discontinuation and a 4- to 6-week course of low-dose prednisone (≤10 mg daily). Moderate or severe forms also require only temporary ICI discontinuation, but prednisone doses are higher (0.5 mg/kg daily) and occasionally disease-modifying antirheumatoid drugs are required.2
, 12
Neurologic Toxicities
Neurologic toxicities have been reported in fewer than 5% of patients taking ICIs.
8
The most commonly reported symptom is headache, but peripheral and central nervous systems may also be involved.27
Motor or sensory peripheral neuropathies occur in fewer than 1% of patients, and diabetic neuropathy, thyroid pathology, or vitamin B12 deficiency should be excluded.10
, - Puzanov I.
- Diab A.
- Abdallah K.
- et al.
Society for Immunotherapy of Cancer Toxicity Management Working Group
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
J Immunother Cancer. 2017; 5: 95
11
Other peripheral toxicities include a myasthenia gravis–like syndrome, which may cause diaphragmatic involvement, and a fatal Guillain-Barré-like syndrome toxicity.5
, 11
Central toxicities include aseptic meningitis, autoimmune encephalitis, posterior reversible encephalopathy syndrome, and transverse myelitis.2
, 8
, 10
, - Puzanov I.
- Diab A.
- Abdallah K.
- et al.
Society for Immunotherapy of Cancer Toxicity Management Working Group
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
J Immunother Cancer. 2017; 5: 95
27
Evaluation of neurologic irAEs should exclude infection, metastatic disease, or paraneoplastic syndromes with magnetic resonance imaging and lumbar puncture.10
, - Puzanov I.
- Diab A.
- Abdallah K.
- et al.
Society for Immunotherapy of Cancer Toxicity Management Working Group
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
J Immunother Cancer. 2017; 5: 95
27
A high lymphocyte count in the cerebrospinal fluid suggests, but does not confirm, an immune-mediated etiology.8
Corticosteroids (eg, prednisone, 1 mg/kg daily) can be used in addition to specific treatment strategies such as pyridostigmine for myasthenic syndromes and intravenous immunoglobulin or plasmapheresis for Guillain-Barré–like toxicities.8
, 12
Neurology consultation should be sought and immunotherapy permanently discontinued if severe adverse events develop.12
Ocular Toxicities
Ocular toxicities occur in fewer than 1% of patients and include conjunctivitis, episcleritis, keratitis, blepharitis, and uveitis.
10
They present at a median of 2 months after initiation of therapy and appear to be more common with anti–CTLA-4 therapy.- Puzanov I.
- Diab A.
- Abdallah K.
- et al.
Society for Immunotherapy of Cancer Toxicity Management Working Group
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
J Immunother Cancer. 2017; 5: 95
11
, 14
Uveitis may cause photophobia, blurry vision, pain, and eye dryness. Examination may reveal a diffusely erythematous sclera with prominent blushing.11
Patients should be referred for ophthalmologic evaluation and managed according to the degree of severity.10
Mild uveitis requires temporarily withholding ICI therapy and using topical corticosteroids. Moderate and severe cases require systemic corticosteroids and permanent discontinuation of immunotherapy.- Puzanov I.
- Diab A.
- Abdallah K.
- et al.
Society for Immunotherapy of Cancer Toxicity Management Working Group
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
J Immunother Cancer. 2017; 5: 95
12
, 14
Renal Toxicities
Renal toxicities occur in 2% of patients receiving anti–CTLA-4 or anti–PD-1 therapy and 5% receiving combination therapy.
10
No cases have been reported with anti–PD-L1 agents. Toxicities usually occur 3 to 10 months into therapy with anti–PD-1 and 2 to 3 months with anti–CTLA-4.- Puzanov I.
- Diab A.
- Abdallah K.
- et al.
Society for Immunotherapy of Cancer Toxicity Management Working Group
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
J Immunother Cancer. 2017; 5: 95
10
, - Puzanov I.
- Diab A.
- Abdallah K.
- et al.
Society for Immunotherapy of Cancer Toxicity Management Working Group
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
J Immunother Cancer. 2017; 5: 95
28
The most common forms of nephrotoxicity include acute interstitial nephritis, lupus-like nephritis, granulomatous nephritis, diffuse interstitial nephritis, or minimal change disease.5
, 28
Presentation varies from asymptomatic to oliguria, hematuria, and peripheral edema.10
After ruling out secondary causes (eg, contrast nephrotoxicity, volume depletion, or medications), patients can be managed with a prednisone taper for 4 to 6 weeks starting at 1 to 2 mg/kg daily.- Puzanov I.
- Diab A.
- Abdallah K.
- et al.
Society for Immunotherapy of Cancer Toxicity Management Working Group
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
J Immunother Cancer. 2017; 5: 95
12
For mild nephrotoxicities, ICI can be temporarily discontinued, but for moderate to severe toxicities, immunotherapy should be permanently stopped and nephrology consulted.12
Hematologic Toxicities
Anemia, reported in 5% of patients taking ipilimumab and fewer than 10% of patients receiving anti–PD-1 agents, can be hemolytic and autoimmune mediated.
8
Neutropenia, immune thrombocytopenic purpura, pure red cell aplasia, disseminated intravascular coagulopathy, and acquired hemophilia A have also been reported.2
, 8
, 10
, - Puzanov I.
- Diab A.
- Abdallah K.
- et al.
Society for Immunotherapy of Cancer Toxicity Management Working Group
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
J Immunother Cancer. 2017; 5: 95
14
Therefore, a complete blood cell count should be obtained before each administration of ICI therapy.8
In the presence of cytopenias, secondary causes, including gastrointestinal bleeding, bone marrow metastasis, medication-induced toxicities, or hemolysis, should be excluded.10
Bone marrow biopsy should be considered for unclear diagnoses.- Puzanov I.
- Diab A.
- Abdallah K.
- et al.
Society for Immunotherapy of Cancer Toxicity Management Working Group
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
J Immunother Cancer. 2017; 5: 95
12
, 14
Similar to other irAEs, the use of corticosteroids is indicated, and discontinuation of immunotherapy should be temporary or permanent depending on the degree of toxicity. Refractory cases may require use of additional immunosuppressive agents (eg, cyclosporine).8
Cardiac Toxicities
Cardiac toxicities from ICIs include myocarditis, pericarditis, arrhythmias and heart block, and new-onset heart failure. Incidence is less than 1% and appears to be more common among patients undergoing combination therapy.
10
Before initiation of ICIs, some experts suggest obtaining baseline troponin and brain natriuretic peptide measurements, a fasting lipid profile, and an electrocardiogram.- Puzanov I.
- Diab A.
- Abdallah K.
- et al.
Society for Immunotherapy of Cancer Toxicity Management Working Group
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
J Immunother Cancer. 2017; 5: 95
10
Myocarditis presents with nonspecific symptoms, extremely elevated troponin levels, and conduction abnormalities and can have a fulminant course.- Puzanov I.
- Diab A.
- Abdallah K.
- et al.
Society for Immunotherapy of Cancer Toxicity Management Working Group
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
J Immunother Cancer. 2017; 5: 95
29
When suspected, patients should be hospitalized immediately and evaluated for secondary causes, with emergent cardiology consultation.10
Because of its potentially fatal outcome, myocarditis requires high-dose corticosteroids (eg, prednisone, 1-2 mg/kg daily), additional immunosuppressive agents (eg, mycophenolate mofetil) when response to initial therapy is not adequate, and permanent ICI therapy discontinuation.- Puzanov I.
- Diab A.
- Abdallah K.
- et al.
Society for Immunotherapy of Cancer Toxicity Management Working Group
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.
J Immunother Cancer. 2017; 5: 95
12
Conclusion
Immune checkpoint inhibitors have revolutionized cancer management and improved prognosis and outcomes in many malignancies. Given their expanding use and the heterogeneity of immune-related toxicities, these patients are often seen by different specialists besides oncologists. Furthermore, because these irAEs can affect any organ, diagnosis can be challenging, and a high level of suspicion should be maintained. Exclusion of secondary causes, including cancer progression, is also important. Because toxicities can be fatal and have a fulminant progression, timely recognition and treatment are imperative. Management strategies, however, should be the result of a conjunctive effort between disease-specific subspecialists and the primary hematologist/oncologist. Referral to a tertiary center may be needed for patients with multisystem or severe immune-related toxicities. Immunosuppression with corticosteroids is considered the criterion standard for management, but occasionally additional immunosuppressive agents are required. An early consultation with subspecialties when pertinent, early initiation of immunosuppressive therapy, and good communication between clinical teams positively impact outcomes of affected individuals.
Supplemental Online Material
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Potential Competing Interests: The authors report no competing interests.
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- In Reply — Immune Checkpoint Inhibitor–Induced Type 1 Diabetes: An Underestimated RiskMayo Clinic ProceedingsVol. 95Issue 3
- PreviewWe thank Drs Akturk and Michels1 for their interest in our article and for further expanding on the importance of immune checkpoint inhibitor (ICI)–induced diabetes. The incidence of ICI-induced diabetes has increased from a few case reports in 2015 to a recently reported incidence of 1.8% based on our experience at Mayo Clinic.2,3 The increased incidence may be associated, at least in part, with the expanding use of these medications.4 In addition, according to this retrospective analysis from our institution, this adverse event appears to occur more often with the anti–programmed cell death 1 ligand agent pembrolizumab, followed by the anti–programmed cell death 1 agent nivolumab.
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- Immune Checkpoint Inhibitor–Induced Type 1 Diabetes: An Underestimated RiskMayo Clinic ProceedingsVol. 95Issue 3
- PreviewDrs Marin-Acevedo and colleagues nicely summarize the toxicities associated with immune checkpoint inhibitor therapy.1 We want to further emphasize immune checkpoint inhibitor–induced type 1 diabetes (ICI-T1D), as it frequently presents with life-threatening diabetic ketoacidosis. The authors report the frequency of ICI-T1D as 0.2% citing a meta-analysis that assessed premarketing registration trials. We believe this is an underestimate for several reasons. First, premarketing clinical trials excluded patients with a pre-existing autoimmune disorder, and in recent years immune checkpoint inhibitor use and indications have dramatically increased.
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- In the Limelight: September 2019Mayo Clinic ProceedingsVol. 94Issue 9
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