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Holistic Approach to Immune Checkpoint Inhibitor-Related Adverse Events

Remo Poto, Teresa Troiani, Gjada Criscuolo and 4 more

Frontiers in Immunology · 2022 · Review · CC BY

doi:10.3389/fimmu.2022.804597

Abstract

Immune checkpoint inhibitors (ICIs) block inhibitory molecules, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), or its ligand, programmed cell death protein ligand 1 (PD-L1) and enhance antitumor T-cell activity. ICIs provide clinical benefits in a percentage of patients with advanced cancers, but they are usually associated with a remarkable spectrum of immune-related adverse events (irAEs) (e.g., rash, colitis, hepatitis, pneumonitis, endocrine, cardiac and musculoskeletal dysfunctions). Particularly patients on combination therapy (e.g., anti-CTLA-4 plus anti-PD-1/PD-L1) experience some form of irAEs. Different mechanisms have been postulated to explain these adverse events. Host factors such as genotype, gut microbiome and pre-existing autoimmune disorders may affect the risk of adverse events. Fatal ICI-related irAEs are due to myocarditis, colitis or pneumonitis. irAEs usually occur within the first months after ICI initiation but can develop as early as after the first dose to years after ICI initiation. Most irAEs resolve pharmacologically, but some appear to be persistent. Glucocorticoids represent the mainstay of management of irAEs, but other immunosuppressive drugs can be used to mitigate refractory irAEs. In the absence of specific trials, several guidelines, based on data from retrospective studies and expert consensus, have been published to guide the management of ICI-related irAEs.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 26, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

Immune checkpoint inhibitors (ICIs) have revolutionized the management of several advanced cancers and can result in durable responses in a percentage of patients. ICIs are monoclonal antibodies (mAbs) that block inhibitory molecules involved in regulation of immune system pathways, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) (e.g., ipilimumab), programmed cell death protein 1 (PD-1) (e.g., nivolumab, pembrolizumab, cemiplimab), or its ligand programmed cell death protein ligand 1 (PD-L1) (e.g., atezolizumab, avelumab, durvalumab) in the tumor microenvironment, which leads to systemic immune cell activation ( Figure 1 ). Immune checkpoints constitute mechanisms of central relevance in the regulation of immune response to avoid autoimmunity and limit tissue damage. Immune checkpoints can be exploited by cancer cells as mechanisms of immunoevasion and immunoresistance.

ICIs activate T cells and are often associated with a large spectrum of autoimmune responses, which are commonly referred to as “immune-related Adverse Events” (irAEs). The pleiotropic manifestations of irAEs can affect almost any organ (e.g., skin, colon, endocrine organs, joints, heart and lungs) and clinicians should be able to recognize and treat the heterogeneous manifestations of irAEs. Several comprehensive reviews have examined in detail the toxicity of ICIs affecting the skin, the gastrointestinal and cardiovascular systems, the lung, the endocrine organs, the joints, the nervous and the hematologic systems. In this review, we summarize the most recent observations and the complex pathophysiology and clinical characteristics of irAEs and their putative predictors and emerging therapies.

Incidence/Prevalence of IrAEs

Distinct immunological mechanisms underlie anti-CTLA-4 (ipilimumab) and anti-PD-1/PD-L1 checkpoint blockade. Therefore, it is not surprising that the incidence of any irAEs with these two groups of ICIs varies greatly. The pattern, incidence and severity of irAEs vary according to the type of ICI (anti-CTLA-4 or anti-PD-1/PD-L1) and the treatment schedule (monotherapy or combination therapy). It has been estimated that the incidence of irAEs in patients treated with anti-CTLA-4 mAb (ipilimumab) is higher than in those treated with anti-PD-1/PD-L1 mAbs. The highest incidence and the high-grade irAEs are usually associated with combination therapy of ipilimumab plus anti-PD-1/PD-L1. In a large meta-analysis examining 16,485 patients, colitis and hypophysitis were more frequent with ipilimumab, while diabetes and pneumonitis were more frequent with anti-PD-1/PD-L1. Colitis, hepatitis, pancreatitis, and ICI-associated diabetes are more likely to be high-grade.

Timing Of IrAEs

In melanoma patients treated with ipilimumab, the time of onset of skin-related irAEs is two to three weeks after ICI initiation, gastrointestinal and hepatic irAEs after six weeks, and endocrine irAEs after six to nine weeks. Most high-grade irAEs resolve in two to five weeks with immunosuppression but some, such as arthritis, tend to persist. Endocrine irAEs (e.g., diabetes, thyroid dysfunctions) are usually irreversible and require prolonged hormone replacement therapy.

Fatal ICI-related irAEs tend to occur in the early phases of therapy and the incidence varies with the type of treatment. Fatalities are more common with combination therapy than with anti-PD-1/PD-L1 or anti-CTLA-4. Fatality rates were approximately 39% for myocarditis and 5% for colitis.

There are some similarities between autoimmune manifestations of ICI-related irAEs and their spontaneous autoimmune counterparts but also several differences. For instance, ICI-induced diabetes can manifest with diabetic ketoacidosis, similar to T1D. The frequency of autoantibodies in ICI-induced diabetes is lower than in T1D. ICI-induced hyperthyroidism is typically found at presentation and usually progresses to hypothyroidism. ICI-induced colitis differs from inflammatory bowel disease (IBD) because is usually reversible.

Long-Term Adverse Effects of ICIs

ICIs have been successfully introduced in the treatment of various cancers only a few years ago. Therefore, there is limited experience on the long-term side effects of ICIs. Acute irAEs have thus far attracted major attention owing to their dramatic clinical presentation and need for urgent treatment. However, increasing evidences indicate that chronic irAEs are more prevalent than originally recognized. Endocrinopathies (such as ICI-induced hypothyroidism and diabetes) and rheumatological toxicities (such as arthritis) are the most common chronic irAEs. Endocrinopathies provide classical examples of irreversible damage of the relevant hormone-secreting cells. These syndromes are usually irreversible and require the use of lifelong exogenous hormone replacement therapy. On the other hand, ICI-induced arthritis provides a classical example of smouldering inflammation in which ICIs trigger persistent subacute or chronic arthritis, closely mimicking that of rheumatoid arthritis.

Several experimental studies have demonstrated that CTLA-4 and PD-1/PD-L1 axes are critical negative regulators of atherosclerosis. A recent retrospective study by Drobni et al. reported an association between ICIs with accelerated progression of atherosclerosis and cardiovascular events. They found increased atherosclerotic inflammatory activity 5 months after ICI therapy. Another retrospective study on 20 patients with melanoma found by positron emission tomography/computed tomography with 2-[18F] fluorodeoxyglucose (18F-FDG) that ICI therapy induced inflammatory activity in large arteries. The results of these two studies will certainly influence the approach to cardiovascular care for individuals receiving ICIs. Cardiac evaluation before initiation of ICI treatment should focus on long-term prevention rather than focusing only on early irAEs. Moreover, cancer trials should prospectively examine not only early but also late cardiovascular events.

Pathophysiology of IrAEs

Several immunopathogenic mechanisms (i.e., cellular autoimmunity, autoantibodies, complement activation, cytokines/chemokines release, genetics and alterations of the gut microbiome) have been suggested to be involved in the development of ICI-related irAEs ( Figure 2 ).

Cellular Autoimmunity

The importance of T cells in the mechanisms of ICI-associated irAEs is supported by genetic loss-of-function studies in mice. Autoreactive T cells can be activated by shared antigens between tumor and peripheral tissues. Shared T cell clones in the tumor, heart, and skeletal muscle were found in melanoma patients, who died from fatal myocarditis and myositis after treatment with anti-CTLA-4/PD-1 mAbs. The exact mechanism of cardiac toxicity remains unknown, but it has been suggested that shared antigens may drive both antitumor responses and organ-specific autoimmunity. Shared T cell antigens were found in the skin and tumor of lung cancer patients who developed skin toxicities. Similarly, vitiligo is common in melanoma patients treated with ICIs. Recently, Lozano and collaborators demonstrated that in melanoma patients treated with anti-PD-1 or anti-PD-1 and anti-CTLA-4 combination, two pretreatment factors in peripheral blood - activated CD4 memory T cell abundance and TCR diversity - were associated with severe irAEs development.

CTLA-4 is a modulator of Tregs and these cells act as gatekeepers for the prevention of autoimmunity. The role of Tregs in ICI-induced irAEs deserves additional studies. It has been suggested that tissue-resident memory T cells (Trm) in tumor microenvironment can play a role in irAEs. Single-cell analysis of ICI-associated colitis patient samples found expansion of CTLA-4+ Treg cells and differentiation of CD8 Trm cells to cytotoxic effector cells.

Humoral Immunity

Anti-thyroglobulin (TG) and/or anti-thyroid peroxidase (TPO) autoantibodies are found in 13–70% of patients who develop ICI-related thyroid dysfunction. Thyroid autoantibodies increase the risk of ICI-induced thyroid dysfunction and β-cell autoantibodies are found in approximately 50% of patients with ICI-induced diabetes. Autoantibodies anti-BP180 can be found in the majority of patients with anti-PD-L1-associated bullous pemphigoid.

Human pituitary cells express CTLA-4 at both mRNA and protein levels and in an animal model the injection of anti-CTLA-4 antibodies induced lymphocytic infiltration and complement activation of the pituitary gland. Anti-pituitary antibodies were detected only in patients with ipilimumab-associated hypophysitis but not in those without hypophysitis. Autoantibodies against guanine nucleotide-binding protein G subunit alpha (GNAL) and integral membrane protein 2B (ITM2B) have been found associated with ICI-induced hypophysitis. These findings implicate both autoantibodies and T cell-mediated processes in ICI-associated pituitary destruction. Overexpression of pituitary CTLA-4 was reported in a patient with severe ipilimumab-associated hypophysitis. It has been suggested that hypophysitis is caused by complement activation from endogenous autoantibodies and/or exogenous IgG1 anti-CTLA-4 (ipilimumab). IgG1, used in ipilimumab, activates the classic complement pathway explaining the elevated frequency of pituitary gland damage compared with its occurrence in patients treated with anti-PD-1/anti-PD-L-1 IgG4 antibodies.

Anti-acetylcholine receptor antibodies can be found in approximately 50% of patients with ICI-induced myasthenia gravis. Patients with ICI-induced arthritis are commonly rheumatoid factor (RF) and cyclic citrullinated peptide (CCP) negative. Unfortunately, in the majority of these studies the presence of autoantibodies prior to ICI initiation has not been evaluated.

Cytokines and Chemokines

Cytokine release syndrome (CRS) is a systemic inflammatory disorder characterized by a massive release of cytokines. It can present with a variety of symptoms ranging from mild (e.g., fever, fatigue, nausea, rash) to life threating, sometime fatal. A recent analysis of WHO global pharmacovigilance database, found that ICI-related CRS can occur in ICI-treated patients. On similar ground, cytokines and chemokines are involved in different irAEs. Increased baseline IL-17 concentrations were temporally associated with subsequent development of ICI-associated colitis. Increased IL-6 and IL-10 concentrations were found in patients with skin irAEs. Increased concentrations of IL-1β, IL-2, and GM-CSF at baseline have been associated with ICI-related thyroid dysfunction. High concentrations of T cell chemotactic chemokines (i.e., CXCL9 and CXCL10) are associated with irAEs. A recent study in patients with melanoma treated with combined immune checkpoint blockade (CICB) targeting CTLA-4 and PD-1 who developed ≥ grade 3 colitis demonstrates an intestinal overexpression of IL1β and TNF compared to normal tissue.

Genetic Factors

Genetic factors influence the development and progression of several autoimmune disorders. The importance of genetic factors in the development of ICI-associated irAEs was originally highlighted by genetic loss-of-function studies in mice. Thus, the possibility exists that genetic susceptibility may play a role in the pathogenesis of irAEs. Experimental studies have demonstrated that CTLA-4 and PD-1 deletion or inhibition can cause autoimmune myocarditis with lymphocytic infiltration of cytotoxic T-cells. The majority (≅ 52%) of patients with ICI-related arthritis possess the RA-associated HLA-DR susceptibility allele. The majority of patients with ICI-related diabetes had at least one HLA-DR risk allele. HLA-DR4 predominance has been reported in patients with ICI-induced diabetes. HLA-DRB1*04:05 has been associated with ICI-induced arthritis and HLA-DRB1*11:01 with pruritis. A multicenter study found that a polygenic risk score (PRS) for thyroid disorders is associated with developing thyroid irAEs in patients with non-small cell lung cancer (NSCLC) treated with anti-PD-1 or anti-PD-1 and anti-CTLA-4 combination. In this study, thyroid irAEs were associated with better response to ICIs. Moreover, in a phase 3 randomized controlled trial (RCT), it was found that PRS for dermatological autoimmune diseases were associated with increased risk for skin irAEs and longer overall survival in bladder cancer patients treated with atezolizumab.

Microbiome

The multiple interactions among tumor microenvironment, microbiome, host factors, and response to ICI, and the development of ICI-associated irAEs are largely unknown. There is evidence that the gut microbiome might play a role in tumor response. For instance, gut microbiome modulates response to anti-PD-1 in melanoma patients and epithelial tumors. Mice repleted with B. fragilis less likely developed irAEs after exposure to anti-CTLA-4 inhibitors. Moreover, microbiota-derived peptides from Bacteroides induced autoimmune myocarditis.

Melanoma patients treated with ipilimumab and with baseline gut microbiome enriched for Faecalibacterium and other Firmicutes had longer progression-free survival and overall survival. In a prospective study of melanoma treated with ipilimumab, patients with abundant Bacteroidetes phylum less likely developed ICI-induced colitis. A recent study found that gut microbiota signatures are associated with irAEs to CICB targeting CTLA-4 and PD-1 in melanoma patients and in experimental models. In this study, the rate of any grade of irAEs was high (93.5%) and 49% of patients experienced severe (≥ grade 3) irAEs. The alpha diversity of the gut microbiome in patients who did or did not develop severe irAEs was similar. However, Bacteroides intestinalis (B. intestinalis) were more abundant in patients with ≥ grade 3 irAEs versus those who did not. In melanoma patients who developed colitis there was an overexpression of mucosal IL1β and IL-17, but not TNF. These fascinating results were corroborated by results in experimental models in which mice, gavaged with different strains of B. intestinalis following gut sterilization with antibiotics, showed overexpression of Il1b. Moreover, fecal microbiota transplant (FMT) in antibiotic-treated animals using fecal material from human donors harboring high endogenous levels of B. intestinalis induced ileal overexpression of Il1b after administration of CICB. Collectively, these human and experimental studies highlight a contribution of commensal microbiota to intestinal damage associated with CICB.

Putative Biomarkers of Immune-Related Adverse Events

Several studies have or are evaluating the possibility of identifying biomarkers of irAEs associated with different types of ICIs. Table 1 lists genetic, clinical, immune, microbial and tumor biomarkers that have been linked to irAEs. In particular, some studies have identified an association between HLA and irAEs. The association of baseline antibodies, baseline cytokine levels, and immune cell changes suggests that humoral and cellular immunity play a role in some specific irAEs. In particular, activated CD4 memory T cell abundance and TCR diversity in peripheral blood are associated with severe irAEs development in patients with melanoma. The emerging results from parallel human and experimental models highlight a contribution of specific gut microbiota to the development of intestinal irAEs. It should be emphasized that the small size of these studies requires validation in larger cohorts of patients with different types of cancer.

Clinical Manifestations of ICI Associated Autoimmunity

The results of a meta-analysis of 35 trials demonstrated the extreme heterogeneity of manifestations and severity of autoimmune complications of ICIs. Figure 3 illustrates that irAEs can affect nearly every organ in association with ICIs.

Skin Rash

Skin manifestations during ICI therapy show the highest incidence of irAEs and appear higher in patients with melanoma than in patients with other malignancies. ICI-related skin manifestations include maculopapular, eczematous, psoriasiform, lichenoid, and bullous eruptions, frequently associated with pruritus. Vitiligo associated with anti-PD-1 therapy differs from canonical vitiligo because of a patchy distribution, occurring in sun-exposed areas, and lacking the Köebner phenomenon. Bullous skin disease tends to occur in patients treated with anti-PD-1/PD-L1 rather than ipilimumab. Rare cases of severe Stevens-Johnson syndrome/toxic epidermal necrolysis have been reported.

Most patients have mild skin reactions, while severe (grade 3-4) toxicities are found in a low proportion of patients (5.8% for the ipilimumab + nivolumab combination, even lower values for anti-PD-1 monotherapy), significantly lower than the toxicities of other sites (such as hepatic or gastrointestinal). The management of skin toxicities needs specific treatment for the type and severity of the condition: topical glucocorticoids are effective in treating low-grade skin reactions, whereas high-grade events must be treated with systemic glucocorticoids.

Diarrhea and Colitis

Diarrhea is the most frequent manifestation of gastrointestinal toxicity from ICI and is one of the main causes of emergency department visits for patients treated with ICI. Colitis occurs more commonly with ipilimumab and with CICB than with anti-PD-1/PD-L1 mAbs alone. No differences have been described in the incidence of diarrhea/colitis in different types of malignancy. The presence of ulcerative lesions appears to be related to a greater probability of glucocorticoid resistance and greater severity of diarrhea. Lesions primarily affect the distal colon, but lesions can occur in more proximal tracts. Colitis-associated autoantibodies are seldom present. Prophylactic budesonide is not effective against ipilimumab-induced colitis. Infliximab induces a shorter time to symptom resolution than glucocorticoids. Vedolizumab (an antibody directed against α4-β7 integrin), has also been used as glucocorticoid sparing agent. There is some evidence that early treatment with either infliximab or vedolizumab reduces symptom duration and glucocorticoid administration. Several clinical trials are evaluating the safety and efficacy of infliximab (NCT05034536, NCT03293784, NCT04407247) or certolizumab (NCT03293784) in clinical response of ICI-induced colitis.

Recent clinical and experimental models indicate that higher abundance of B. intestinalis is associated with high grade-colitis in melanoma patients treated with CICB. The gut microbiome appears to mediate intestinal toxicity via IL-1β and treatment of mice with an anti-IL-1R antagonist (anakinra) reduced intestinal inflammation. A clinical trial is evaluating the safety and efficacy of anakinra on irAEs and cytokine profiles in patients with different cancers (NCT04576429).

Hepatitis and Pancreatitis

Immune-mediated liver injury caused by ICIs can present with fatigue, fever, nausea, and jaundice. The severity of hepatic toxicity can be classified in relation to the increase in liver enzymes (AST and ALT) and bilirubinemia. The incidence of irAEs varies between 3% to 9% for anti-CTLA-4, and 0.7% to 1.8% for anti-PD-1/PD-L1. CICB (ipilimumab + nivolumab) is associated with an incidence of any-grade hepatotoxicity of 29% and high-grade hepatotoxicity of 17%. Approximately 50% of the patients with ICI-associated liver injury have antinuclear antibodies and 19% have anti-smooth muscle antibodies. Pancreatitis can also occur in response to ICIs.

Thyroiditis

Thyroid dysfunction is the most common endocrinologic irAEs due to ICIs. The median time of onset is approximately 6 weeks after the start of immunotherapy. ICI-associated thyroid dysfunction is more common after anti-PD-1/PD-L1 antibodies or combination therapy than with ipilimumab alone. Patients receiving ICIs should undergo regular thyroid testing (i.e., TSH and T4). Patients usually experience a first transient phase of hyperthyroidism, followed by euthyroidism or hypothyroidism. The presence of thyroid autoantibodies (anti-TPO and anti-TG) before ICI treatment increases the risk of thyroid dysfunction in patients treated with nivolumab or pembrolizumab. The mechanism responsible for ICI-induced thyroid dysfunction is unclear. It has been hypothesized that polymorphic variants of the PDCD1 in some individuals might predispose them to an increased risk of thyroid dysfunction. It is also unknown whether thyroid autoantibodies are the cause of thyroid dysfunction or the result of an immunological response to thyroid antigens released during ICI-related thyroiditis. ICI therapy can be continued with close follow-up and monitoring of TSH and T4 in the context of thyroiditis. In the presence of more severe irAEs, ICI should be held until symptoms resolve. Glucocorticoids do not improve the clinical course of thyroid dysfunction.

Hypophysitis

Hypophysitis is a specific complication of ipilimumab treatment and rarely occurs in anti-PD-1/PD-L1-treated individuals. Most patients present with headache and/or fatigue. Magnetic resonance imaging (MRI) of the brain highlights an expansion of the pituitary gland and/or infundibulum. Enlargement on MRI precedes the clinical diagnosis of ipilimumab-related hypophysitis. The pituitary gland decreases in size over 4-12 weeks leading to atrophy. Importantly, a normal MRI does not completely rule out hypophysitis, and therapy should be based on clinical symptoms and pituitary hormone levels. Glucocorticoids do not improve the degree or duration of hypophysitis. Hormone deficiencies are managed with the corresponding hormone replacement.

Diabetes

Although not very common, PD-1 pathway blockade can cause autoimmune ICI-induced diabetes mellitus, which usually (≅ 70%) presents as diabetic ketoacidosis. ICI-associated diabetes rarely occurs in patients treated with ipilimumab. In these individuals, C-peptide levels are very low and approximately 50% of patients have T1D associated antibodies (anti-glutamic acid decarboxylase). Human leukocyte antigen risk alleles (HLA-DR4, -DQ8, -DR3, and DR2) can be associated with high frequency of spontaneous T1D. In ICI-induced diabetes, there is a predominance of HLA-DR4, which is present in approximately 70% of patients. Other HLA alleles associated with high risk of spontaneous T1D are not overrepresented in ICI-associated diabetes. ICI-induced diabetes tends to be permanent and attempts with glucocorticoids administration showed no recovery.

Pneumonitis

Early clinical trials and meta-analyses suggested an incidence of ICI-associated pneumonitis of 3-5%; recent studies examining real-world populations suggest this could be as high as 13-19%. While the incidence of all-grade pneumonitis appears to be higher in the real-world population as opposed to clinical trials, the percentage of ≥ grade 3 pneumonitis appears to be relatively consistent across both populations.

Immune-related pneumonia represents one of the main causes of death during treatment with anti-PD-1/PD-L1 alone and the fourth cause during combined treatment with ipilimumab plus anti-PD-1/PD-L1 (14% of total cases) after colitis, myocarditis and hepatitis. Anti-CTLA-4 treatment causes a lower incidence of immune-related pneumonia compared to treatment with anti-PD-1/PD-L1 alone. Immune-related pneumonia are usually associated with CICB. One-third of these patients are asymptomatic, whereas the others present with dyspnea and/or cough. Radiographic findings on chest computed tomography (CT) do not highlight specific characteristics. Previous thoracic radiotherapy and previous lung disorders are predictors of pneumonitis associated with anti-PD-1. The differential diagnosis of these patients should be made after ruling out other causes of similar lung involvement. This issue is particularly relevant during the current outbreak of COVID-19. Guidelines on the management of ICI-related pneumonitis have been published from ESMO and ASCO/NCCN. A clinical trial is evaluating the safety and efficacy of infliximab versus intravenous immunoglobulin therapy (IVIG) in treating glucocorticoid-refractory pneumonitis (NCT04438382).

Arthritis

Arthritis is not very common (≅ 4%) in patients with ICIs. A systematic review encompassing 372 patients found that the time of onset of arthritis ranged from 1 day to 53 months (median time: 4 months); 49% had polyarthritis, 17% oligoarthritis, 10% arthralgia, and 21% polymyalgia rheumatica. More than half of patients had a “rheumatoid arthritis-like” presentation. RF and anti-citrullinated peptide antibodies (ACPA) are present in ≅19% of patients. Treatment of irAEs should be guided by severity. Most patients can be managed with non-steroidal anti-inflammatory drugs or intra-articular glucocorticoid injections. More severe patients, especially those who received CICB, require systemic glucocorticoids. Arthritis often persists even after stopping ICIs and may require prolonged immunosuppression with biological disease-modifying anti-rheumatic drugs (DMARDs). Diagnostic and management algorithms for rheumatoid irAEs have been recently proposed.

Myositis

ICI-related myositis can manifest in the form of acute or subacute myalgia or muscle weakness. When concomitant myocarditis and myasthenia gravis-like symptoms (e.g., ptosis and oculomotor weakness) occur, fatality rates are relatively high. Muscle biopsy shows inflammation and myonecrosis. Myositis-associated antibodies (anti-TIF1-y, SRP, Ro52; PL-7, PL-12, or SRP) can be detected in ICI-associated myositis. Anti-striated muscle antibodies can be found even without clinical evidence of myasthenia gravis. Glucocorticoids are the first-line therapy for ICI-associated myositis. Initial dosing can range from 0.5 mg/Kg prednisone daily up to 2,000 mg IV methylprednisolone. IVIG and plasmapheresis have been used in refractory cases.

Myocarditis

The true incidence of ICI-associated myocarditis remains uncertain. Early ICI-based cancer trials did not prospectively screen for myocarditis. Moreover, because the diagnosis of myocarditis can be difficult, cases could easily be missed. Recent reports suggest that the incidence of ICI-associated myocarditis is 0.27% to 1.14%. Myocarditis is an infrequent, but often lethal complication of ICI therapy. Elevated troponin level and abnormal electrocardiogram were found in the majority of these patients with ICI-associated myocarditis. Interestingly, half of these patients showed preserved ejection fraction. The clinical manifestation of ICI-associated myocarditis is variable. Fulminant cases characterized by early-onset have been described. In these cases, cardiac arrhythmias are common. The association of skeletal myositis and myasthenia gravis following ICI therapy should orientate for myocarditis. “Smouldering” cases of myocarditis have been also reported.

Diagnosis of ICI-associated myocarditis is challenging and includes a combination of biomarker tests (troponin), cardiac MRI, late gadolinium enhancement, and possibly biopsy (T cell infiltrate). Major adverse cardiac events (MACE) can occur also in patients with preserved ejection fraction. A troponin T level ≥ 1.5 ng/mL was associated with a marked increase in MACE during follow-up. The precise mechanisms by which ICIs cause cardiotoxicity remain undefined. Existing data support T cell-mediated immunity as a major component in pathogenesis, but many fundamental questions remain. Early and aggressive treatment with high doses of glucocorticoids is critical. Treatment of ICI-associated myocarditis includes ICI discontinuation, supportive management, and glucocorticoids. Prednisone (0.5 to 2.0 mg/kg), followed by 4–6 week taper upon symptoms improvement, is recommended. Despite this treatment, mortality remains substantial, and individual case reports demonstrate successful treatment with alemtuzumab (anti-CD52 mAb), or abatacept (a fusion protein composed of the extracellular domain of CTLA-4 and the Fc region of human IgG1). Prospective clinical trials are needed to compare the safety and efficacy of different immunosuppressive therapies in ICI-associated myocarditis. Recent experimental data point to the hypothesis that anti-PD-1 therapy induces a smouldering disruption of cardiac immunity towards an inflammatory phenotype, with manifest consequences on cardiac function in the presence of a second hit, in the form of systemic stress induced by presence of a tumor. This also indicates the possibility that the inflammatory phenotype raises the risk for the development of myocarditis upon exposure to additional, yet unknown risk factors. Furthermore, treatment with anti-PD-1 may first produce only a latent inflammatory involvement associated to dysregulated cardiac metabolism that may progress to overt myocarditis in a subset of patients.

Neurological

Neurological complications of ICIs (headache, myasthenia gravis, peripheral neuropathy, meningitis, and encephalitis) are uncommon (≅ 1%). Myasthenia gravis and encephalitis are more common with anti-PD-1 antibodies, whereas Guillain Barré and meningitis are more common with ipilimumab. MG associated with myositis and myocarditis has a poor prognosis. Approximately 50% of MG patients have anti-acetylcholine receptor antibodies. Glucocorticoids and, in some patients, IVIG, are the mainstay of therapy.

Hematologic

In contrast to other anticancer therapies, hematological irAEs in patients treated with ICIs are uncommon. Neutropenia, autoimmune hemolytic anemia, and immune thrombocytopenia can occur rarely (≅ 5%). A positive direct antiglobulin test is present in the majority (≅ 60%) of patients with ICI-related autoimmune hemolytic anemia. Glucocorticoids are the first line of therapy; IVIG or rituximab can be considered in difficult cases. Neutropenic patients can be treated with G-CSF.

Renal

Renal dysfunction is rare with ipilimumab and with anti-PD-1/PD-L1 therapies occurring in <1% of patients. The incidence is higher with combination of ipilimumab plus anti-PD-1/PD-L1 reaching approximately 4%. Renal dysfunction is usually due to acute interstitial nephritis or, more rarely, to glomerulonephritis.

Ocular

irAEs of the eye are rare and occur in <1% of patients treated with ICIs. Uveitis can be a complication of ICI treatment. Few cases of Vogt-Koyanagi-Harada disease have been described in melanoma patients, which hinted a possible cross-reactivity between T lymphocytes targeting melanoma cells and the melanocytes of the eye. In the cases of ICI-associated sicca syndrome, oral manifestations are more common than the ocular ones. Anti-Ro (SS-A) and anti-La (SS-B) are usually negative.

Pre-Existing Autoimmune Disease and ICIs

Cancer patients with underlying autoimmune disease were initially excluded from ICI RCT. Therefore, the prevalence and incidence of exacerbations of pre-existing autoimmune disorders was not immediately appreciated. Patients with autoimmune disease, however, represent 20 to 50 million people in the United States alone, and one study reported that approximately 13% of lung cancer patients had a concurrent diagnosis of autoimmune disease.

There is now evidence that irAEs are more frequent and occur faster in cancer patients with several autoimmune diseases (psoriasis, rheumatoid arthritis, IBD, systemic lupus erythematosus, vasculitis). These findings suggest that a close monitoring is mandatory during early phases of treatment. The majority of autoimmune flares and irAEs can be managed without ICI discontinuation, but fatalities can occur. Conflicting results have been reported in studies concerning the risk of autoimmune flares or irAEs in patients with active versus inactive autoimmune disease. Patients with underlying autoimmune disorders should be carefully managed by multidisciplinary teams.

IrAEs and Efficacy of ICIs

In one large, retrospective study of ipilimumab, the treatment outcomes were similar in patients with and without irAEs. Subsequent studies reported that melanoma patients who develop vitiligo or endocrine complications have better tumor response and improved survival. The results of randomized trials have shown that patients who discontinue ICIs due to toxicity respond better than patients without irAEs. Patients that developed thyroiditis after PD-1 or PD-L1 blockade had longer overall survival compared to the thyroid irAE negative group. Prospective studies are needed to verify whether different irAEs are associated with improved tumor response to ICIs.

Management of IrAEs

No trials are evaluating the efficacy of different irAEs treatments. Therefore, management of irAEs are based on retrospective studies and expert consensus. Low-grade irAEs usually do not need ICI discontinuation and immunosuppressive treatment. Higher grade irAEs may require both therapeutic strategies. Table 2 schematically summarizes the anti-inflammatory and immunosuppressive drugs routinely used to treat ICI-related irAEs.

Glucocorticoids are powerful anti-inflammatory and immunosuppressive drugs commonly employed as first-line treatment in patients with ICI-induced irAEs. The efficacy of glucocorticoids varies tremendously in the treatment of different types of irAEs. For instance, these compounds are effective in most cases but do not reverse hypophysitis, and high doses may worsen outcomes. By contrast, initial high-dose glucocorticoids were superior to intermediate and low-dose steroid in the treatment of ICI-associated myocarditis. Another important issue is the timing of initiation of glucocorticoid administration. In the above retrospective, observational study, early (≤ 24 hours) administration of glucocorticoids can also vary in different irAEs. For example, arthritis is also unique since inflammation often persists even after stopping ICIs and may require prolonged glucocorticoid treatment and/or biological DMARDs.

Glucocorticoids are associated with potential multiple side effects and impact on anti-tumor response. Low doses of glucocorticoids used to treat irAEs do not affect the response rates and/or the survival of ICI-treated patients. A meta-analysis found that glucocorticoids do not negatively affect survival. However, glucocorticoids before or early during ICI treatment may negatively affect outcomes. Baseline treatment of lung cancer patients with anti-PD-1 and high doses (> 10 mg/day) of prednisone negatively affects outcomes compared to those treated with low dose glucocorticoids. The side effects of glucocorticoids depend on the daily dose, the cumulative dose administered and possibly the type of underlying disease. Therefore, awareness of specific glucocorticoid-induced side effects is required.

irAEs refractory to glucocorticoids may require the administration of a mAb targeting TNF-α (i.e., infliximab) to treat certain irAEs such as colitis and pneumonitis. Preclinical studies suggest that prophylactic TNF-α inhibition eliminated ICI-induced colitis without affecting anti-tumor response. There is conflicting evidence on the effect of short-term TNF-α inhibition with infliximab to treat ICI-induced irAEs on overall survival in cancer patients. A comprehensive review has examined in detail the role of different cytokines in the pathophysiology of irAEs. In addition, the authors provided an in-depth analysis of strategies to uncouple the cytokine response that participates in ICI-associated irAEs.

Potential Therapies and Prevention of IrAEs

The increasing use of ICIs in a growing number of solid and hematologic cancers requires us to offer the best-targeted therapies of irAEs. Table 3 summarizes the potential therapies of irAEs.

Understanding the pathophysiology of ICI-associated myocarditis and developing effective treatments is of great importance. The quest for novel therapies for glucocorticoid-resistant ICI myocarditis is a clinical unmet need. If symptoms and laboratory findings in ICI myocarditis do not regress upon high-dose glucocorticoids, other immunosuppressant agents [e.g. mycophenolate mofetil, methotrexate, calcineurin inhibitors, intravenous immunoglobulin (IVIG), anti-thymocyte globulin, rituximab and infliximab] may be considered for treatment of ICIs cardiotoxicity, but data are still controversial.

Alemtuzumab (anti-CD52 mAb) and abatacept, a protein consisting of the human CTLA-4 extracellular domain fused to the Fc portion of IgG, acting as a CTLA-4 agonist, have been employed for the treatment of single cases of glucocorticoid-refractory myocarditis. Concerns with abatacept are possible infections and tumor progression. Abatacept has also been used to treat ICI-induced MG. Alemtuzumab causes T cell depletion and its impact on tumor growth remains unknown. Overall, the evidence available at present is insufficient to support any of the anecdotal, albeit reasonable, strategies outlined above and more evidence-based guidance in this critical care is urgently needed. While blocking TNF-α in heart failure (HF) has been proven contraindicated in symptomatic (NYHA III and IV) patients, anti-TNF-α may be a promising approach to prevent the early stages of cardiotoxicity from anti-PD-1 immunotherapy.

Vedolizumab is a specific anti-integrin α4β7 antibody, used for the treatment of IBD. Preclinical studies have reported that vedolizumab induces remission in ICI-induced glucocorticoid-refractory colitis with good safety profiles. Early treatment with vedolizumab is a potential treatment of ICI-associated colitis. Two clinical trials are evaluating the safety and efficacy of vedolizumab in the treatment of ICI-induced colitis (NCT04407247, NCT04797325).

Rituximab, a mAb targeting CD20, has been used in glucocorticoid-refractory encephalitis and myasthenia gravis, bullous pemphigoid-like skin disease, renal vasculitis, and hematological complications.

Tocilizumab, a mAb anti-IL-6 receptor, has been used to treat ICI-associated arthritis and glucocorticoid-refractory irAEs. The safety and efficacy of tocilizumab on ICI-associated irAEs are under evaluation in two clinical trials (NCT03999749, NCT04691817).

IL-17 blockade has been used in few patients with colon cancer and melanoma. A recent study found that there is an upregulation of intestinal IL-1β in melanoma patients treated with CICB who developed high-grade colitis. In two mouse models, CICB was associated with intestinal inflammation characterized by upregulation of Il1b, but not Tnfa or Il6. Interestingly, mice concurrently treated with CICB and anakinra (anti-IL-1R) showed less intestinal inflammation. These parallel studies in humans and mice suggest that severe intestinal inflammation associated with CICB could be prevented by an IL-1R antagonist. A clinical trial is evaluating the safety and efficacy of anakinra on ICI-induced irAEs (NCT04576429).

Gut microbiome can influence efficacy of PD-1-based immunotherapy. A clinical trial is prospectively analyzing the intestinal microbiome as predictor of ICI-associated irAEs (NCT04107311). Fecal microbiota transplant (FMT), which transfers an entire microbiome from a healthy donor to a recipient, is a therapeutic tool with several potential applications but numerous caveats. FMT may be a potential mechanism for treating ICI-induced colitis. FMT can be performed via an oral capsule containing fecal extracts, colonoscopy-guided transfer or enema. Microbiome composition varies widely among healthy donors and can affects success rates. FMT involves the risk for transmission of infectious agents via FMT. Regulatory authorities have released specific guidelines to offer FMT with safety at the time of COVID-19 pandemic. Two patients with refractory ICI-associated colitis were successfully treated with FMT. Clinical and experimental studies are needed to evaluate the efficacy of this approach as well as to provide further mechanistic insights. In summary, there is some evidence that microbiome manipulation could potentially impact cancer course and perhaps ICI-associated irAEs. Several clinical trials are evaluating the safety and efficacy of FMT on the prevention/treatment of intestinal irAEs (NCT04038619, NCT04163289, NCT03819296).

Conclusions and Perspectives

Emerging real-world data suggests the incidence of ICI-associated irAEs may be higher than previously found in clinical trials. This trend has the potential to increase further as the use of canonical ICIs (anti-CTLA-4 and anti-PD-1/PD-L1), alone or in combination, is increasing exponentially and nearly 50% of patients treated will experience some form of irAEs. Furthermore, the combination of first and/or second generation of ICIs (e.g., anti-TIGIT) or with anti-angiogenic agents could open a new scenario of irAEs associated with novel forms of cancer immunotherapy.

Great efforts have been devoted to the identification of genetic, humoral and cellular biomarkers predictive of irAEs associated with ICIs. Although these putative biomarkers have not been incorporated into clinical practice, they have highlighted some novel aspects of irAE pathogenesis. For instance, recent human and experimental studies have highlighted the contribution of specific gut microbiota to intestinal damage caused by CICB in melanoma patients. This study also suggests that specific peripheral blood signatures are associated with a risk of developing toxicity after CICB. Of course, additional studies of larger cohorts of ICI-treated patients with different cancers will be needed to validate these findings.

Management of irAEs is essentially based on retrospective studies and expert consensus. Glucocorticoids, commonly employed as first-line treatment of irAEs, do not affect certain toxicities, and high doses may negatively affect outcomes. Awareness of glucocorticoid-induced side effects is required. A wide spectrum of emerging therapeutic options, including mAbs (anti-TNF-α, anti-IL-6, anti-CD20, anti-IL-1R) and FMT are under clinical and experimental investigations. There is currently no clinical evidence that irAEs can be pharmacologically prevented. However, there is experimental evidence that prophylactic administration anti-TNF-α or anti-IL-1R is associated with less intestinal inflammation caused by CICB in different tumor models.

Table 4 presents some of the outstanding pathophysiological and therapeutic questions that should be addressed to better understand the complexity of different irAEs. Due to the clinical complexity surrounding autoimmune disease development and management, Clinical Immunologists should be involved in the care of cancer patients before, during, and after checkpoint blockade. Perhaps, multidisciplinary irAE management teams, facilitating prompt diagnosis and treatment should be enlisted. Further research is needed to improve early diagnosis, understand immunological and genetic mechanisms, and develop management algorithms for these disorders.

Author Contributions

RP, GC, FC, CT, and GV wrote and edited the manuscript. All authors contributed to the article and approved the submitted version.

Funding

This work was supported in part by grants from the CISI-Lab Project (University of Naples Federico II) and TIMING Project and Campania Bioscience (Regione Campania).

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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  82. 82.
    Targeting Resident Memory T Cells for Cancer Immunotherapy · 2018
    Not checked
  83. 83.

    Luoma AM Suo S Williams HL Sharova T Sullivan K Manos M. Molecular Pathways of Colon Inflammation Induced by Cancer Immunotherapy. Cell (2020 ) 182:655–71.e622

    Not in our library10.1016/j.cell.2020.06.001

  84. 84.

    Luo J Martucci VL Quandt Z Groha S Murray MH Lovly CM. Immunotherapy-Mediated Thyroid Dysfunction: Genetic Risk and Impact on Outcomes With PD-1 Blockade in Non-Small Cell Lung Cancer. Clin Cancer Res (2021 ) 27:5131–40

    Not in our library10.1158/1078-0432.ccr-21-0921

  85. 85.

    Maekura T Naito M Tahara M Ikegami N Kimura Y Sonobe S. Predictive Factors of Nivolumab-Induced Hypothyroidism in Patients With Non-Small Cell Lung Cancer. In Vivo (2017 ) 31:1035–9

    Not in our library10.21873/invivo.11166

  86. 86.

    Kimbara S Fujiwara Y Iwama S Ohashi K Kuchiba A Arima H. Association of Antithyroglobulin Antibodies With the Development of Thyroid Dysfunction Induced by Nivolumab. Cancer Sci (2018 ) 109:3583–90

    Not in our library10.1111/cas.13800

  87. 87.

    Toi Y Sugawara S Sugisaka J Ono H Kawashima Y Aiba T. Profiling Preexisting Antibodies in Patients Treated With Anti-PD-1 Therapy for Advanced Non-Small Cell Lung Cancer. JAMA Oncol (2019 ) 5:376–83

    Not in our library10.1001/jamaoncol.2018.5860

  88. 88.

    Bingley PJ. Clinical Applications of Diabetes Antibody Testing. J Clin Endocrinol Metab (2010 ) 95:25–33

    Not in our library10.1210/jc.2009-1365

  89. 89.

    Lin HH Gutenberg A Chen TY Tsai NM Lee CJ Cheng YC. In Situ Activation of Pituitary-Infiltrating T Lymphocytes in Autoimmune Hypophysitis. Sci Rep (2017 ) 7:43492

    Not in our library10.1038/srep43492

  90. 90.

    Caturegli P Di Dalmazi G Lombardi M Grosso F Larman HB Larman T. Hypophysitis Secondary to Cytotoxic T-Lymphocyte-Associated Protein 4 Blockade: Insights Into Pathogenesis From an Autopsy Series. Am J Pathol (2016 ) 186:3225–35

    Not in our library10.1016/j.ajpath.2016.08.020

  91. 91.

    Brahmer JR Tykodi SS Chow LQ Hwu WJ Topalian SL Hwu P. Safety and Activity of Anti-PD-L1 Antibody in Patients With Advanced Cancer. N Engl J Med (2012 ) 366:2455–65

    Not in our library10.1056/nejmoa1200694

  92. 92.

    Robert C Ribas A Wolchok JD Hodi FS Hamid O Kefford R. Anti-Programmed-Death-Receptor-1 Treatment With Pembrolizumab in Ipilimumab-Refractory Advanced Melanoma: A Randomised Dose-Comparison Cohort of a Phase 1 Trial. Lancet (2014 ) 384:1109–17

    Not in our library10.1016/s0140-6736(14)60958-2

  93. 93.

    Godel P Shimabukuro-Vornhagen A von Bergwelt-Baildon M. Understanding Cytokine Release Syndrome. Intensive Care Med (2018 ) 44:371–3

    Not in our library10.1007/s00134-017-4943-5

  94. 94.
    Immune Checkpoint Inhibitor-Related Cytokine Release Syndrome: Analysis of WHO Global Pharmacovigilance Database · 2020
    No notice
  95. 95.
    Immune dysregulation in cancer patients developing immune-related adverse events · 2018
    No notice
  96. 96.

    Andrews MC Duong CPM Gopalakrishnan V Iebba V Chen WS Derosa L. Gut Microbiota Signatures are Associated With Toxicity to Combined CTLA-4 and PD-1 Blockade. Nat Med (2021 ) 27:1432–41

    Not in our library10.1038/s41591-021-01406-6

  97. 97.

    Lucas JA Menke J Rabacal WA Schoen FJ Sharpe AH Kelley VR. Programmed Death Ligand 1 Regulates a Critical Checkpoint for Autoimmune Myocarditis and Pneumonitis in MRL Mice. J Immunol (2008 ) 181:2513–21

    Not in our library10.4049/jimmunol.181.4.2513

  98. 98.

    Okazaki T Tanaka Y Nishio R Mitsuiye T Mizoguchi A Wang J. Autoantibodies Against Cardiac Troponin I are Responsible for Dilated Cardiomyopathy in PD-1-Deficient Mice. Nat Med (2003 ) 9:1477–83

    Not in our library10.1038/nm955nm955

  99. 99.

    Tarrio ML Grabie N Bu DX Sharpe AH Lichtman AH. PD-1 Protects Against Inflammation and Myocyte Damage in T Cell-Mediated Myocarditis. J Immunol (2012 ) 188:4876–84

    Not in our library10.4049/jimmunol.1200389

  100. 100.

    Khan Z Di Nucci F Kwan A Hammer C Mariathasan S Rouilly V. Polygenic Risk for Skin Autoimmunity Impacts Immune Checkpoint Blockade in Bladder Cancer. Proc Natl Acad Sci USA (2020 ) 117:12288–94

    Not in our library10.1073/pnas.1922867117

  101. 101.

    Anderson R Theron AJ Rapoport BL. Immunopathogenesis of Immune Checkpoint Inhibitor-Related Adverse Events: Roles of the Intestinal Microbiome and Th17 Cells. Front Immunol (2019 ) 10:2254

    Not in our library10.3389/fimmu.2019.02254

  102. 102.

    Sivan A Corrales L Hubert N Williams JB Aquino-Michaels K Earley ZM. Commensal Bifidobacterium Promotes Antitumor Immunity and Facilitates Anti-PD-L1 Efficacy. Science (2015 ) 350:1084–9

    Not in our library10.1126/science.aac4255science.aac4255[pii

  103. 103.

    Routy B Le Chatelier E Derosa L Duong CPM Alou MT Daillere R. Gut Microbiome Influences Efficacy of PD-1-Based Immunotherapy Against Epithelial Tumors. Science (2018 ) 359:91–7

    Not in our library10.1126/science.aan3706

  104. 104.

    Matson V Fessler J Bao R Chongsuwat T Zha Y Alegre ML. The Commensal Microbiome is Associated With Anti-PD-1 Efficacy in Metastatic Melanoma Patients. Science (2018 ) 359:104–8

    Not in our library10.1126/science.aao3290

  105. 105.

    Gopalakrishnan V Spencer CN Nezi L Reuben A Andrews MC Karpinets TV. Gut Microbiome Modulates Response to Anti-PD-1 Immunotherapy in Melanoma Patients. Science (2018 ) 359:97–103

    Not in our library10.1126/science.aan4236

  106. 106.

    Haanen J Ernstoff MS Wang Y Menzies AM Puzanov I Grivas P. Autoimmune Diseases and Immune-Checkpoint Inhibitors for Cancer Therapy: Review of the Literature and Personalized Risk-Based Prevention Strategy. Ann Oncol (2020 ) 31:724–44

    Not in our library10.1016/j.annonc.2020.03.285

  107. 107.

    Danlos FX Voisin AL Dyevre V Michot JM Routier E Taillade L. Safety and Efficacy of Anti-Programmed Death 1 Antibodies in Patients With Cancer and Pre-Existing Autoimmune or Inflammatory Disease. Eur J Cancer (2018 ) 91:21–9

    Not in our library10.1016/j.ejca.2017.12.008

  108. 108.

    Kehl KL Yang S Awad MM Palmer N Kohane IS Schrag D. Pre-Existing Autoimmune Disease and the Risk of Immune-Related Adverse Events Among Patients Receiving Checkpoint Inhibitors for Cancer. Cancer Immunol Immunother (2019 ) 68:917–26

    Not in our library10.1007/s00262-019-02321-z

  109. 109.

    Kobayashi T Iwama S Yasuda Y Okada N Tsunekawa T Onoue T. Patients With Antithyroid Antibodies Are Prone To Develop Destructive Thyroiditis by Nivolumab: A Prospective Study. J Endocr Soc (2018 ) 2:241–51

    Not in our library10.1210/js.2017-00432

  110. 110.

    Gowen MF Giles KM Simpson D Tchack J Zhou H Moran U. Baseline Antibody Profiles Predict Toxicity in Melanoma Patients Treated With Immune Checkpoint Inhibitors. J Transl Med (2018 ) 16:82

    Not in our library10.1186/s12967-018-1452-4

  111. 111.
    Sex and interleukin-6 are prognostic factors for autoimmune toxicity following treatment with anti-CTLA4 blockade · 2018
    No notice
  112. 112.

    Lim SY Lee JH Gide TN Menzies AM Guminski A Carlino MS. Circulating Cytokines Predict Immune-Related Toxicity in Melanoma Patients Receiving Anti-PD-1-Based Immunotherapy. Clin Cancer Res (2019 ) 25:1557–63

    Not in our library10.1158/1078-0432.ccr-18-2795

  113. 113.

    Das R Bar N Ferreira M Newman AM Zhang L Bailur JK. Early B Cell Changes Predict Autoimmunity Following Combination Immune Checkpoint Blockade. J Clin Invest (2018 ) 128:715–20

    Not in our library10.1172/jci9679896798[pii

  114. 114.

    Pavan A Calvetti L Dal Maso A Attili I Del Bianco P Pasello G. Peripheral Blood Markers Identify Risk of Immune-Related Toxicity in Advanced Non-Small Cell Lung Cancer Treated With Immune-Checkpoint Inhibitors. Oncologist (2019 ) 24:1128–36

    Not in our library10.1634/theoncologist.2018-

  115. 115.

    Giommoni E Giorgione R Paderi A Pellegrini E Gambale E Marini A. Eosinophil Count as Predictive Biomarker of Immune-Related Adverse Events (irAEs) in Immune Checkpoint Inhibitors (ICIs) Therapies in Oncological Patients. Immuno (2021 ) 1:253

    Not in our library10.3390/immuno1030017

  116. 116.

    Schindler K Harmankaya K Kuk D Mangana J Michielin O HoellerReinhard Dummer C. Abstract: Correlation of Absolute and Relative Eosinophil Counts With Immune-Related Adverse Events in Melanoma Patients Treated With Ipilimumab. J Clin Oncol (2014 ) 32:9096

    Not in our library10.1200/jco.2014.32.15_suppl.9096

  117. 117.

    Sakata Y Kawamura K Ichikado K Shingu N Yasuda Y Eguchi Y. The Association Between Tumor Burden and Severe Immune-Related Adverse Events in non-Small Cell Lung Cancer Patients Responding to Immune-Checkpoint Inhibitor Treatment. Lung Cancer (2019 ) 130:159–61

    Not in our library10.1016/j.lungcan.2019.02.011

  118. 118.

    Wright JJ Salem JE Johnson DB Lebrun-Vignes B Stamatouli A Thomas JW. Increased Reporting of Immune Checkpoint Inhibitor-Associated Diabetes. Diabetes Care (2018 ) 41:e150–1

    Not in our library10.2337/dc18-1465dc18-1465

  119. 119.

    Faje A Reynolds K Zubiri L Lawrence D Cohen JV Sullivan RJ. Hypophysitis Secondary to Nivolumab and Pembrolizumab is a Clinical Entity Distinct From Ipilimumab-Associated Hypophysitis. Eur J Endocrinol (2019 ) 181:211–9

    Not in our library10.1530/eje-19-0238eje-19-0238

  120. 120.

    Dougan M Pietropaolo M. Time to Dissect the Autoimmune Etiology of Cancer Antibody Immunotherapy. J Clin Invest (2020 ) 130:51–61

    Not in our library10.1172/jci131194131194

  121. 121.

    Ma C Hodi FS Giobbie-Hurder A Wang X Zhou J Zhang A. The Impact of High-Dose Glucocorticoids on the Outcome of Immune-Checkpoint Inhibitor-Related Thyroid Disorders. Cancer Immunol Res (2019 ) 7:1214–20

    Not in our library10.1158/2326-6066.cir-18-0613

  122. 122.

    Faje AT Lawrence D Flaherty K Freedman C Fadden R Rubin K. High-Dose Glucocorticoids for the Treatment of Ipilimumab-Induced Hypophysitis is Associated With Reduced Survival in Patients With Melanoma. Cancer (2018 ) 124:3706–14

    Not in our library10.1002/cncr.31629

  123. 123.

    Moslehi JJ Salem JE Sosman JA Lebrun-Vignes B Johnson DB. Increased Reporting of Fatal Immune Checkpoint Inhibitor-Associated Myocarditis. Lancet (2018 ) 391:933

    Not in our library10.1016/s0140-6736(18)30533-6

  124. 124.

    Eigentler TK Hassel JC Berking C Aberle J Bachmann O Grunwald V. Diagnosis, Monitoring and Management of Immune-Related Adverse Drug Reactions of Anti-PD-1 Antibody Therapy. Cancer Treat Rev (2016 ) 45:7–18

    Not in our library10.1016/j.ctrv.2016.02.003

  125. 125.

    Coleman E Ko C Dai F Tomayko MM Kluger H Leventhal JS. Inflammatory Eruptions Associated With Immune Checkpoint Inhibitor Therapy: A Single-Institution Retrospective Analysis With Stratification of Reactions by Toxicity and Implications for Management. J Am Acad Dermatol (2019 ) 80:990–7

    Not in our library10.1016/j.jaad.2018.10.062

  126. 126.

    Larsabal M Marti A Jacquemin C Rambert J Thiolat D Dousset L. Vitiligo-Like Lesions Occurring in Patients Receiving Anti-Programmed Cell Death-1 Therapies are Clinically and Biologically Distinct From Vitiligo. J Am Acad Dermatol (2017 ) 76:863–70

    Not in our library10.1016/j.jaad.2016.10.044

  127. 127.

    Aggarwal P. Disproportionality Analysis of Bullous Pemphigoid Adverse Events With PD-1 Inhibitors in the FDA Adverse Event Reporting System. Expert Opin Drug Saf (2019 ) 18:623–33

    Not in our library10.1080/14740338.2019.1619693

  128. 128.

    Lacouture M Sibaud V. Toxic Side Effects of Targeted Therapies and Immunotherapies Affecting the Skin, Oral Mucosa, Hair, and Nails. Am J Clin Dermatol (2018 ) 19:31–9

    Not in our library10.1007/s40257-018-0384-3

  129. 129.

    Soldatos TG Dimitrakopoulou-Strauss A Larribere L Hassel JC Sachpekidis C. Retrospective Side Effect Profiling of the Metastatic Melanoma Combination Therapy Ipilimumab-Nivolumab Using Adverse Event Data. Diagnostics (Basel) (2018 ) 8:76

    Not in our library10.3390/diagnostics8040076

  130. 130.

    El Majzoub I Qdaisat A Thein KZ Win MA Han MM Jacobson K. Adverse Effects of Immune Checkpoint Therapy in Cancer Patients Visiting the Emergency Department of a Comprehensive Cancer Center. Ann Emerg Med (2019 ) 73:79–87

    Not in our library10.1016/j.annemergmed.2018.04.019

  131. 131.

    Beck KE Blansfield JA Tran KQ Feldman AL Hughes MS Royal RE. Enterocolitis in Patients With Cancer After Antibody Blockade of Cytotoxic T-Lymphocyte-Associated Antigen 4. J Clin Oncol (2006 ) 24:2283–9

    Not in our library10.1200/jco.2005.04.5716

  132. 132.

    Wang DY Ye F Zhao S Johnson DB. Incidence of Immune Checkpoint Inhibitor-Related Colitis in Solid Tumor Patients: A Systematic Review and Meta-Analysis. Oncoimmunology (2017 ) 6:e1344805

    Not in our library10.1080/2162402x.2017.1344805

  133. 133.

    Wang Y Abu-Sbeih H Mao E Ali N Qiao W Trinh VA. Endoscopic and Histologic Features of Immune Checkpoint Inhibitor-Related Colitis. Inflamm Bowel Dis (2018 ) 24:1695–705

    Not in our library10.1093/ibd/izy1044989161

  134. 134.

    Marthey L Mateus C Mussini C Nachury M Nancey S Grange F. Cancer Immunotherapy With Anti-CTLA-4 Monoclonal Antibodies Induces an Inflammatory Bowel Disease. J Crohns Colitis (2016 ) 10:395–401

    Not in our library10.1093/ecco-jcc/jjv227

  135. 135.

    Weber J Thompson JA Hamid O Minor D Amin A Ron I. A Randomized, Double-Blind, Placebo-Controlled, Phase II Study Comparing the Tolerability and Efficacy of Ipilimumab Administered With or Without Prophylactic Budesonide in Patients With Unresectable Stage III or IV Melanoma. Clin Cancer Res (2009 ) 15:5591–8

    Not in our library10.1158/1078-0432.ccr-09-1024

  136. 136.
    Infliximab associated with faster symptom resolution compared with corticosteroids alone for the management of immune-related enterocolitis · 2018
    Corrected
  137. 137.
    Vedolizumab treatment for immune checkpoint inhibitor-induced enterocolitis · 2017
    No notice
  138. 138.
    Early introduction of selective immunosuppressive therapy associated with favorable clinical outcomes in patients with immune checkpoint inhibitor–induced colitis · 2019
    No notice
  139. 139.

    Suzman DL Pelosof L Rosenberg A Avigan MI. Hepatotoxicity of Immune Checkpoint Inhibitors: An Evolving Picture of Risk Associated With a Vital Class of Immunotherapy Agents. Liver Int (2018 ) 38:976–87

    Not in our library10.1111/liv.13746

  140. 140.

    De Martin E Michot JM Papouin B Champiat S Mateus C Lambotte O. Characterization of Liver Injury Induced by Cancer Immunotherapy Using Immune Checkpoint Inhibitors. J Hepatol (2018 ) 68:1181–90

    Not in our library10.1016/j.jhep.2018.01.033

  141. 141.
    Clinical characteristics and outcomes of immune checkpoint inhibitor-induced pancreatic injury · 2019
    No notice
  142. 142.

    Boutros C Tarhini A Routier E Lambotte O Ladurie FL Carbonnel F. Safety Profiles of Anti-CTLA-4 and Anti-PD-1 Antibodies Alone and in Combination. Nat Rev Clin Oncol (2016 ) 13:473–86

    Not in our library10.1038/nrclinonc.2016.58

  143. 143.

    Varricchi G Loffredo S Marone G Modestino L Fallahi P Ferrari SM. The Immune Landscape of Thyroid Cancer in the Context of Immune Checkpoint Inhibition. Int J Mol Sci (2019 ) 20:3934

    Not in our library10.3390/ijms20163934ijms20163934

  144. 144.

    Iyer PC Cabanillas ME Waguespack SG Hu MI Thosani S Lavis VR. Immune-Related Thyroiditis With Immune Checkpoint Inhibitors. Thyroid (2018 ) 28:1243–51

    Not in our library10.1089/thy.2018.0116

  145. 145.

    Orlov S Salari F Kashat L Walfish PG. Induction of Painless Thyroiditis in Patients Receiving Programmed Death 1 Receptor Immunotherapy for Metastatic Malignancies. J Clin Endocrinol Metab (2015 ) 100:1738–41

    Not in our library10.1210/jc.2014-4560

  146. 146.

    Delivanis DA Gustafson MP Bornschlegl S Merten MM Kottschade L Withers S. Pembrolizumab-Induced Thyroiditis: Comprehensive Clinical Review and Insights Into Underlying Involved Mechanisms. J Clin Endocrinol Metab (2017 ) 102:2770–80

    Not in our library10.1210/jc.2017-004483805504

  147. 147.

    Faje AT Sullivan R Lawrence D Tritos NA Fadden R Klibanski A. Ipilimumab-Induced Hypophysitis: A Detailed Longitudinal Analysis in a Large Cohort of Patients With Metastatic Melanoma. J Clin Endocrinol Metab (2014 ) 99:4078–85

    Not in our library10.1210/jc.2014-2306

  148. 148.

    Albarel F Gaudy C Castinetti F Carre T Morange I Conte-Devolx B. Long-Term Follow-Up of Ipilimumab-Induced Hypophysitis, a Common Adverse Event of the Anti-CTLA-4 Antibody in Melanoma. Eur J Endocrinol (2015 ) 172:195–204

    Not in our library10.1530/eje-14-0845

  149. 149.

    Min L Hodi FS Giobbie-Hurder A Ott PA Luke JJ Donahue H. Systemic High-Dose Corticosteroid Treatment Does Not Improve the Outcome of Ipilimumab-Related Hypophysitis: A Retrospective Cohort Study. Clin Cancer Res (2015 ) 21:749–55

    Not in our library10.1158/1078-0432.ccr-14-2353

  150. 150.

    Carpenter KJ Murtagh RD Lilienfeld H Weber J Murtagh FR. Ipilimumab-Induced Hypophysitis: MR Imaging Findings. AJNR Am J Neuroradiol (2009 ) 30:1751–3

    Not in our library10.3174/ajnr.a1623

  151. 151.

    Juszczak A Gupta A Karavitaki N Middleton MR Grossman AB. Ipilimumab: A Novel Immunomodulating Therapy Causing Autoimmune Hypophysitis: A Case Report and Review. Eur J Endocrinol (2012 ) 167:1–5

    Not in our library10.1530/eje-12-0167

  152. 152.
    The Price of Tumor Control: An Analysis of Rare Side Effects of Anti-CTLA-4 Therapy in Metastatic Melanoma from the Ipilimumab Network · 2013
    No notice
  153. 153.

    Kotwal A Haddox C Block M Kudva YC. Immune Checkpoint Inhibitors: An Emerging Cause of Insulin-Dependent Diabetes. BMJ Open Diabetes Res Care (2019 ) 7:e000591

    Not in our library10.1136/bmjdrc-2018-000591

  154. 154.

    Gaudy C Clevy C Monestier S Dubois N Preau Y Mallet S. Anti-PD1 Pembrolizumab Can Induce Exceptional Fulminant Type 1 Diabetes. Diabetes Care (2015 ) 38:e182–183

    Not in our library10.2337/dc15-1331dc15-1331

  155. 155.

    Mellati M Eaton KD Brooks-Worrell BM Hagopian WA Martins R Palmer JP. Anti-PD-1 and Anti-PDL-1 Monoclonal Antibodies Causing Type 1 Diabetes. Diabetes Care (2015 ) 38:e137–138

    Not in our library10.2337/dc15-0889dc15-0889

  156. 156.

    Hughes J Vudattu N Sznol M Gettinger S Kluger H Lupsa B. Precipitation of Autoimmune Diabetes With Anti-PD-1 Immunotherapy. Diabetes Care (2015 ) 38:e55–57

    Not in our library10.2337/dc14-234938/4/e55

  157. 157.

    James EA Mallone R Kent SC DiLorenzo TP. T-Cell Epitopes and Neo-Epitopes in Type 1 Diabetes: A Comprehensive Update and Reappraisal. Diabetes (2020 ) 69:1311–35

    Not in our library10.2337/dbi19-002269/7/1311

  158. 158.

    Gauci ML Laly P Vidal-Trecan T Baroudjian B Gottlieb J Madjlessi-Ezra N. Autoimmune Diabetes Induced by PD-1 Inhibitor-Retrospective Analysis and Pathogenesis: A Case Report and Literature Review. Cancer Immunol Immunother (2017 ) 66:1399–410

    Not in our library10.1007/s00262-017-2033-8

  159. 159.

    Naidoo J Wang X Woo KM Iyriboz T Halpenny D Cunningham J. Pneumonitis in Patients Treated With Anti-Programmed Death-1/Programmed Death Ligand 1 Therapy. J Clin Oncol (2017 ) 35:709–17

    Not in our library10.1200/jco.2016.68.2005

  160. 160.

    Topalian SL Hodi FS Brahmer JR Gettinger SN Smith DC McDermott DF. Safety, Activity, and Immune Correlates of Anti-PD-1 Antibody in Cancer. N Engl J Med (2012 ) 366:2443–54

    Not in our library10.1056/nejmoa1200690

  161. 161.

    Borghaei H Paz-Ares L Horn L Spigel DR Steins M Ready NE. Nivolumab Versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med (2015 ) 373:1627–39

    Not in our library10.1056/nejmoa1507643

  162. 162.

    Brahmer J Reckamp KL Baas P Crino L Eberhardt WE Poddubskaya E. Nivolumab Versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med (2015 ) 373:123–35

    Not in our library10.1056/nejmoa1504627

  163. 163.

    Nishino M Giobbie-Hurder A Hatabu H Ramaiya NH Hodi FS. Incidence of Programmed Cell Death 1 Inhibitor-Related Pneumonitis in Patients With Advanced Cancer: A Systematic Review and Meta-Analysis. JAMA Oncol (2016 ) 2:1607–16

    Not in our library10.1001/jamaoncol.2016.24532544610

  164. 164.

    Fukihara J Sakamoto K Koyama J Ito T Iwano S Morise M. Prognostic Impact and Risk Factors of Immune-Related Pneumonitis in Patients With Non-Small-Cell Lung Cancer Who Received Programmed Death 1 Inhibitors. Clin Lung Cancer (2019 ) 20:442–450 e444

    Not in our library10.1016/j.cllc.2019.07.006

  165. 165.

    Suresh K Voong KR Shankar B Forde PM Ettinger DS Marrone KA. Pneumonitis in Non-Small Cell Lung Cancer Patients Receiving Immune Checkpoint Immunotherapy: Incidence and Risk Factors. J Thorac Oncol (2018 ) 13:1930–9

    Not in our library10.1016/j.jtho.2018.08.2035

  166. 166.

    Cho JY Kim J Lee JS Kim YJ Kim SH Lee YJ. Characteristics, Incidence, and Risk Factors of Immune Checkpoint Inhibitor-Related Pneumonitis in Patients With non-Small Cell Lung Cancer. Lung Cancer (2018 ) 125:150–6

    Not in our library10.1016/j.lungcan.2018.09.015

  167. 167.

    Khunger M Jain P Rakshit S Pasupuleti V Hernandez AV Stevenson J. Safety and Efficacy of PD-1/PD-L1 Inhibitors in Treatment-Naive and Chemotherapy-Refractory Patients With Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis. Clin Lung Cancer (2018 ) 19:e335–48

    Not in our library10.1016/j.cllc.2018.01.002

  168. 168.

    Khoja L Day D Wei-Wu Chen T Siu LL Hansen AR. Tumour- and Class-Specific Patterns of Immune-Related Adverse Events of Immune Checkpoint Inhibitors: A Systematic Review. Ann Oncol (2017 ) 28:2377–85

    Not in our library10.1093/annonc/mdx286

  169. 169.

    Wu J Hong D Zhang X Lu X Miao J. PD-1 Inhibitors Increase the Incidence and Risk of Pneumonitis in Cancer Patients in a Dose-Independent Manner: A Meta-Analysis. Sci Rep (2017 ) 7:44173

    Not in our library10.1038/srep44173

  170. 170.

    Larsen BT Chae JM Dixit AS Hartman TE Peikert T Roden AC. Clinical and Histopathologic Features of Immune Checkpoint Inhibitor-Related Pneumonitis. Am J Surg Pathol (2019 ) 43:1331–40

    Not in our library10.1097/pas.0000000000001298

  171. 171.

    Cui P Liu Z Wang G Ma J Qian Y Zhang F. Risk Factors for Pneumonitis in Patients Treated With Anti-Programmed Death-1 Therapy: A Case-Control Study. Cancer Med (2018 ) 7:4115–20

    Not in our library10.1002/cam4.1579

  172. 172.

    Yamaguchi T Shimizu J Hasegawa T Horio Y Inaba Y Yatabe Y. Pre-Existing Pulmonary Fibrosis is a Risk Factor for Anti-PD-1-Related Pneumonitis in Patients With non-Small Cell Lung Cancer: A Retrospective Analysis. Lung Cancer (2018 ) 125:212–7

    Not in our library10.1016/j.lungcan.2018.10.001

  173. 173.

    Rossi E Schinzari G Tortora G. Pneumonitis From Immune Checkpoint Inhibitors and COVID-19: Current Concern in Cancer Treatment. J Immunother Cancer (2020 ) 8:e000952

    Not in our library10.1136/jitc-2020-000952

  174. 174.

    Haanen J Carbonnel F Robert C Kerr KM Peters S Larkin J. Management of Toxicities From Immunotherapy: ESMO Clinical Practice Guidelines for Diagnosis, Treatment and Follow-Up. Ann Oncol (2017 ) 28:iv119–42

    Not in our library10.1093/annonc/mdx2253958159

  175. 175.

    Brahmer JR Lacchetti C Schneider BJ Atkins MB Brassil KJ Caterino JM. 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 (2018 ) 36:1714–68

    Not in our library10.1200/jco.2017.77.6385

  176. 176.

    Gomatou G Tzilas V Kotteas E Syrigos K Bouros D. Immune Checkpoint Inhibitor-Related Pneumonitis. Respiration (2020 ) 99:932–42

    Not in our library10.1159/000509941

  177. 177.

    Thompson JA Schneider BJ Brahmer J Andrews S Armand P Bhatia S. Management of Immunotherapy-Related Toxicities, Version 1.2019. J Natl Compr Canc Netw (2019 ) 17:255–89

    Not in our library10.6004/jnccn.2019.0013

  178. 178.

    Kostine M Rouxel L Barnetche T Veillon R Martin F Dutriaux C. Rheumatic Disorders Associated With Immune Checkpoint Inhibitors in Patients With Cancer-Clinical Aspects and Relationship With Tumour Response: A Single-Centre Prospective Cohort Study. Ann Rheum Dis (2018 ) 77:393–8

    Not in our library10.1136/annrheumdis-2017-212257

  179. 179.

    Cappelli LC Gutierrez AK Bingham CO 3rd Shah AA. Rheumatic and Musculoskeletal Immune-Related Adverse Events Due to Immune Checkpoint Inhibitors: A Systematic Review of the Literature. Arthritis Care Res (Hoboken) (2017 ) 69:1751–63

    Not in our library10.1002/acr.23177

  180. 180.

    Smith MH Bass AR. Arthritis After Cancer Immunotherapy: Symptom Duration and Treatment Response. Arthritis Care Res (Hoboken) (2019 ) 71:362–6

    Not in our library10.1002/acr.23467

  181. 181.

    Calabrese C Cappelli LC Kostine M Kirchner E Braaten T Calabrese L. Polymyalgia Rheumatica-Like Syndrome From Checkpoint Inhibitor Therapy: Case Series and Systematic Review of the Literature. RMD Open (2019 ) 5:e000906

    Not in our library10.1136/rmdopen-2019-000906

  182. 182.

    Cappelli LC Brahmer JR Forde PM Le DT Lipson EJ Naidoo J. Clinical Presentation of Immune Checkpoint Inhibitor-Induced Inflammatory Arthritis Differs by Immunotherapy Regimen. Semin Arthritis Rheum (2018 ) 48:553–7

    Not in our library10.1016/j.semarthrit.2018.02.011

  183. 183.

    Cappelli LC Bingham CO 3rd. Expert Perspective: Immune Checkpoint Inhibitors and Rheumatologic Complications. Arthritis Rheumatol (2021 ) 73:553–65

    Not in our library10.1002/art.41587

  184. 184.

    Touat M Maisonobe T Knauss S Ben Hadj Salem O Hervier B Aure K. Immune Checkpoint Inhibitor-Related Myositis and Myocarditis in Patients With Cancer. Neurology (2018 ) 91:e985–94

    Not in our library10.1212/wnl.0000000000006124

  185. 185.

    Anquetil C Salem JE Lebrun-Vignes B Johnson DB Mammen AL Stenzel W. Immune Checkpoint Inhibitor-Associated Myositis: Expanding the Spectrum of Cardiac Complications of the Immunotherapy Revolution. Circulation (2018 ) 138:743–5

    Not in our library10.1161/circulationaha.118.035898

  186. 186.

    Moreira A Loquai C Pfohler C Kahler KC Knauss S Heppt MV. Myositis and Neuromuscular Side-Effects Induced by Immune Checkpoint Inhibitors. Eur J Cancer (2019 ) 106:12–23

    Not in our library10.1016/j.ejca.2018.09.033

  187. 187.

    Liewluck T Kao JC Mauermann ML. PD-1 Inhibitor-Associated Myopathies: Emerging Immune-Mediated Myopathies. J Immunother (2018 ) 41:208–11

    Not in our library10.1097/cji.0000000000000196

  188. 188.

    Shah M Tayar JH Abdel-Wahab N Suarez-Almazor ME. Myositis as an Adverse Event of Immune Checkpoint Blockade for Cancer Therapy. Semin Arthritis Rheum (2019 ) 48:736–40

    Not in our library10.1016/j.semarthrit.2018.05.006

  189. 189.

    Groarke JD Cheng S Moslehi J. Cancer-Drug Discovery and Cardiovascular Surveillance. N Engl J Med (2013 ) 369:1779–81

    Not in our library10.1056/nejmp1313140

  190. 190.

    Mahmood SS Fradley MG Cohen JV Nohria A Reynolds KL Heinzerling LM. Myocarditis in Patients Treated With Immune Checkpoint Inhibitors. J Am Coll Cardiol (2018 ) 71:1755–64

    Not in our library10.1016/j.jacc.2018.02.037

  191. 191.

    Hu JR Florido R Lipson EJ Naidoo J Ardehali R Tocchetti CG. Cardiovascular Toxicities Associated With Immune Checkpoint Inhibitors. Cardiovasc Res (2019 ) 115:854–68

    Not in our library10.1093/cvr/cvz0265304411[pii

  192. 192.

    Salem JE Manouchehri A Moey M Lebrun-Vignes B Bastarache L Pariente A. Cardiovascular Toxicities Associated With Immune Checkpoint Inhibitors: An Observational, Retrospective, Pharmacovigilance Study. Lancet Oncol (2018 ) 19:1579–89

    Not in our library10.1016/s1470-2045(18)30608-9

  193. 193.

    Allenbach Y Anquetil C Manouchehri A Benveniste O Lambotte O Lebrun-Vignes B. Immune Checkpoint Inhibitor-Induced Myositis, the Earliest and Most Lethal Complication Among Rheumatic and Musculoskeletal Toxicities. Autoimmun Rev (2020 ) 19:102586

    Not in our library10.1016/j.autrev.2020.102586

  194. 194.
    Smoldering myocarditis following immune checkpoint blockade · 2017
    No notice
  195. 195.

    Bonaca MP Olenchock BA Salem JE Wiviott SD Ederhy S Cohen A. Myocarditis in the Setting of Cancer Therapeutics: Proposed Case Definitions for Emerging Clinical Syndromes in Cardio-Oncology. Circulation (2019 ) 140:80–91

    Not in our library10.1161/circulationaha.118.034497

  196. 196.

    Mir H Alhussein M Alrashidi S Alzayer H Alshatti A Valettas N. Cardiac Complications Associated With Checkpoint Inhibition: A Systematic Review of the Literature in an Important Emerging Area. Can J Cardiol (2018 ) 34:1059–68

    Not in our library10.1016/j.cjca.2018.03.012

  197. 197.
    Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group · 2017
    No notice
  198. 198.

    Esfahani K Buhlaiga N Thebault P Lapointe R Johnson NA Miller WH Jr. Alemtuzumab for Immune-Related Myocarditis Due to PD-1 Therapy. N Engl J Med (2019 ) 380:2375–6

    Not in our library10.1056/nejmc1903064

  199. 199.

    Thackeray JT Pietzsch S Stapel B Ricke-Hoch M Lee CW Bankstahl JP. Insulin Supplementation Attenuates Cancer-Induced Cardiomyopathy and Slows Tumor Disease Progression. JCI Insight (2017 ) 2 e93098

    Not in our library10.1172/jci.insight.9309893098

  200. 200.

    Michel L Helfrich I Hendgen-Cotta UB Mincu RI Korste S Mrotzek SM. Targeting Early Stages of Cardiotoxicity From Anti-PD1 Immune Checkpoint Inhibitor Therapy. Eur Heart J (2022 ) 43:316–29

    Not in our library10.1093/eurheartj/ehab4306352226

  201. 201.

    Varricchi G Galdiero MR Tocchetti CG. Novel Actors on the Stage of Cardiac Dysfunction Induced by Anti-PD1 Oncological Treatments. Eur Heart J (2021 ) 43:330–2

    Not in our library10.1093/eurheartj/ehab5846359545[pii

  202. 202.

    Cuzzubbo S Javeri F Tissier M Roumi A Barlog C Doridam J. Neurological Adverse Events Associated With Immune Checkpoint Inhibitors: Review of the Literature. Eur J Cancer (2017 ) 73:1–8

    Not in our library10.1016/j.ejca.2016.12.001

  203. 203.
    Neurologic toxicity associated with immune checkpoint inhibitors: a pharmacovigilance study · 2019
    No notice
  204. 204.

    Delanoy N Michot JM Comont T Kramkimel N Lazarovici J Dupont R. Haematological Immune-Related Adverse Events Induced by Anti-PD-1 or Anti-PD-L1 Immunotherapy: A Descriptive Observational Study. Lancet Haematol (2019 ) 6:e48–57

    Not in our library10.1016/s2352-3026(18)30175-3

  205. 205.

    Kramer R Zaremba A Moreira A Ugurel S Johnson DB Hassel JC. Hematological Immune Related Adverse Events After Treatment With Immune Checkpoint Inhibitors. Eur J Cancer (2021 ) 147:170–81

    Not in our library10.1016/j.ejca.2021.01.013

  206. 206.

    Leaf RK Ferreri C Rangachari D Mier J Witteles W Ansstas G. Clinical and Laboratory Features of Autoimmune Hemolytic Anemia Associated With Immune Checkpoint Inhibitors. Am J Hematol (2019 ) 94:563–74

    Not in our library10.1002/ajh.25448

  207. 207.

    Hofmann L Forschner A Loquai C Goldinger SM Zimmer L Ugurel S. Cutaneous, Gastrointestinal, Hepatic, Endocrine, and Renal Side-Effects of Anti-PD-1 Therapy. Eur J Cancer (2016 ) 60:190–209

    Not in our library10.1016/j.ejca.2016.02.025

  208. 208.

    Murakami N Motwani S Riella LV. Renal Complications of Immune Checkpoint Blockade. Curr Probl Cancer (2017 ) 41:100–10

    Not in our library10.1016/j.currproblcancer.2016.12.004

  209. 209.

    Martins F Sofiya L Sykiotis GP Lamine F Maillard M Fraga M. Adverse Effects of Immune-Checkpoint Inhibitors: Epidemiology, Management and Surveillance. Nat Rev Clin Oncol (2019 ) 16:563–80

    Not in our library10.1038/s41571-019-0218-0

  210. 210.

    Cortazar FB Marrone KA Troxell ML Ralto KM Hoenig MP Brahmer JR. Clinicopathological Features of Acute Kidney Injury Associated With Immune Checkpoint Inhibitors. Kidney Int (2016 ) 90:638–47

    Not in our library10.1016/j.kint.2016.04.008

  211. 211.
    Nephrotoxicity of immune checkpoint inhibitors beyond tubulointerstitial nephritis: single-center experience · 2019
    No notice
  212. 212.

    Antoun J Titah C Cochereau I. Ocular and Orbital Side-Effects of Checkpoint Inhibitors: A Review Article. Curr Opin Oncol (2016 ) 28:288–94

    Not in our library10.1097/cco.0000000000000296

  213. 213.

    Zhou L Wei X. Ocular Immune-Related Adverse Events Associated With Immune Checkpoint Inhibitors in Lung Cancer. Front Immunol (2021 ) 12:701951

    Not in our library10.3389/fimmu.2021.701951

  214. 214.

    Bitton K Michot JM Barreau E Lambotte O Haigh O Marabelle A. Prevalence and Clinical Patterns of Ocular Complications Associated With Anti-PD-1/PD-L1 Anticancer Immunotherapy. Am J Ophthalmol (2019 ) 202:109–17

    Not in our library10.1016/j.ajo.2019.02.012

  215. 215.

    Noble CW Gangaputra SS Thompson IA Yuan A Apolo AB Lee JM. Ocular Adverse Events Following Use of Immune Checkpoint Inhibitors for Metastatic Malignancies. Ocul Immunol Inflamm (2020 ) 28:854–9

    Not in our library10.1080/09273948.2019.1583347

  216. 216.

    Warner BM Baer AN Lipson EJ Allen C Hinrichs C Rajan A. Sicca Syndrome Associated With Immune Checkpoint Inhibitor Therapy. Oncologist (2019 ) 24:1259–69

    Not in our library10.1634/theoncologist.2018-0823

  217. 217.

    Robert C Schachter J Long GV Arance A Grob JJ Mortier L. Pembrolizumab Versus Ipilimumab in Advanced Melanoma. N Engl J Med (2015 ) 372:2521–32

    Not in our library10.1056/nejmoa1503093

  218. 218.

    Ferris RL Blumenschein G Jr. Fayette J Guigay J Colevas AD Licitra L. Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med (2016 ) 375:1856–67

    Not in our library10.1056/nejmoa1602252

  219. 219.

    Postow MA Chesney J Pavlick AC Robert C Grossmann K McDermott D. Nivolumab and Ipilimumab Versus Ipilimumab in Untreated Melanoma. N Engl J Med (2015 ) 372:2006–17

    Not in our library10.1056/nejmoa1414428

  220. 220.

    Khan SA Pruitt SL Xuan L Gerber DE. Prevalence of Autoimmune Disease Among Patients With Lung Cancer: Implications for Immunotherapy Treatment Options. JAMA Oncol (2016 ) 2:1507–8

    Not in our library10.1001/jamaoncol.2016.2238

  221. 221.

    Abdel-Wahab N Shah M Lopez-Olivo MA Suarez-Almazor ME. Use of Immune Checkpoint Inhibitors in the Treatment of Patients With Cancer and Preexisting Autoimmune Disease: A Systematic Review. Ann Intern Med (2018 ) 168:121–30

    Not in our library10.7326/m17-20732667695

  222. 222.

    Tison A Quere G Misery L Funck-Brentano E Danlos FX Routier E. Safety and Efficacy of Immune Checkpoint Inhibitors in Patients With Cancer and Preexisting Autoimmune Disease: A Nationwide, Multicenter Cohort Study. Arthritis Rheumatol (2019 ) 71:2100–11

    Not in our library10.1002/art.41068

  223. 223.

    Horvat TZ Adel NG Dang TO Momtaz P Postow MA Callahan MK. Immune-Related Adverse Events, Need for Systemic Immunosuppression, and Effects on Survival and Time to Treatment Failure in Patients With Melanoma Treated With Ipilimumab at Memorial Sloan Kettering Cancer Center. J Clin Oncol (2015 ) 33:3193–8

    Not in our library10.1200/jco.2015.60.8448

  224. 224.

    Weber JS Hodi FS Wolchok JD Topalian SL Schadendorf D Larkin J. Safety Profile of Nivolumab Monotherapy: A Pooled Analysis of Patients With Advanced Melanoma. J Clin Oncol (2017 ) 35:785–92

    Not in our library10.1200/jco.2015.66.1389

  225. 225.

    Kotwal A Kottschade L Ryder M. PD-L1 Inhibitor-Induced Thyroiditis Is Associated With Better Overall Survival in Cancer Patients. Thyroid (2020 ) 30:177–84

    Not in our library10.1089/thy.2019.0250

  226. 226.

    Hua C Boussemart L Mateus C Routier E Boutros C Cazenave H. Association of Vitiligo With Tumor Response in Patients With Metastatic Melanoma Treated With Pembrolizumab. JAMA Dermatol (2016 ) 152:45–51

    Not in our library10.1001/jamadermatol.2015.2707

  227. 227.

    Larkin J Hodi FS Wolchok JD. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med (2015 ) 373:1270–1

    Not in our library10.1056/nejmc1509660

  228. 228.

    Kociol RD Cooper LT Fang JC Moslehi JJ Pang PS Sabe MA. Recognition and Initial Management of Fulminant Myocarditis: A Scientific Statement From the American Heart Association. Circulation (2020 ) 141:e69–92

    Not in our library10.1161/cir.0000000000000745

  229. 229.

    Ammirati E Frigerio M Adler ED Basso C Birnie DH Brambatti M. Management of Acute Myocarditis and Chronic Inflammatory Cardiomyopathy: An Expert Consensus Document. Circ Heart Fail (2020 ) 13:e007405

    Not in our library10.1161/circheartfailure.120.007405

  230. 230.
    Association of Steroids Use with Survival in Patients Treated with Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis · 2020
    No notice
  231. 231.

    Arbour KC Mezquita L Long N Rizvi H Auclin E Ni A. Impact of Baseline Steroids on Efficacy of Programmed Cell Death-1 and Programmed Death-Ligand 1 Blockade in Patients With Non-Small-Cell Lung Cancer. J Clin Oncol (2018 ) 36:2872–8

    Not in our library10.1200/jco.2018.79.0006

  232. 232.

    Scott SC Pennell NA. Early Use of Systemic Corticosteroids in Patients With Advanced NSCLC Treated With Nivolumab. J Thorac Oncol (2018 ) 13:1771–5

    Not in our library10.1016/j.jtho.2018.06.004

  233. 233.
    Modulation of peripheral blood immune cells by early use of steroids and its association with clinical outcomes in patients with metastatic non-small cell lung cancer treated with immune checkpoint inhibitors · 2019
    Not checked
  234. 234.

    Chasset F Pages C Biard L Roux J Sidina I Madelaine I. Single-Center Study Under a French Temporary Authorization for Use (TAU) Protocol for Ipilimumab in Metastatic Melanoma: Negative Impact of Baseline Corticosteroids. Eur J Dermatol (2015 ) 25:36–44

    Not in our library10.1684/ejd.2014.2471

  235. 235.

    Ricciuti B Dahlberg SE Adeni A Sholl LM Nishino M Awad MM. Immune Checkpoint Inhibitor Outcomes for Patients With Non-Small-Cell Lung Cancer Receiving Baseline Corticosteroids for Palliative Versus Nonpalliative Indications. J Clin Oncol (2019 ) 37:1927–34

    Not in our library10.1200/jco.19.00189

  236. 236.

    Draghi A Borch TH Radic HD Chamberlain CA Gokuldass A Svane IM. Differential Effects of Corticosteroids and Anti-TNF on Tumor-Specific Immune Responses: Implications for the Management of irAEs. Int J Cancer (2019 ) 145:1408–13

    Not in our library10.1002/ijc.32080

  237. 237.

    Verheijden RJ May AM Blank CU Aarts MJB van den Berkmortel F van den Eertwegh AJM. Association of Anti-TNF With Decreased Survival in Steroid Refractory Ipilimumab and Anti-PD1-Treated Patients in the Dutch Melanoma Treatment Registry. Clin Cancer Res (2020 ) 26:2268–74

    Not in our library10.1158/1078-0432.ccr-19-3322

  238. 238.

    Lesage C Longvert C Prey S Maanaoui S Dreno B Machet L. Incidence and Clinical Impact of Anti-TNFalpha Treatment of Severe Immune Checkpoint Inhibitor-Induced Colitis in Advanced Melanoma: The Mecolit Survey. J Immunother (2019 ) 42:175–9

    Not in our library10.1097/cji.0000000000000268

  239. 239.

    Chen AY Wolchok JD Bass AR. TNF in the Era of Immune Checkpoint Inhibitors: Friend or Foe? Nat Rev Rheumatol (2021 ) 17:213–23

    Not in our library10.1038/s41584-021-00584-4

  240. 240.

    Suijkerbuijk KPM Verheijden RJ. TNF Inhibition for Immune Checkpoint Inhibitor-Induced irAEs: The Jury is Still Out. Nat Rev Rheumatol (2021 ) 17:505

    Not in our library10.1038/s41584-021-00640-z

  241. 241.

    Perez-Ruiz E Minute L Otano I Alvarez M Ochoa MC Belsue V. Prophylactic TNF Blockade Uncouples Efficacy and Toxicity in Dual CTLA-4 and PD-1 Immunotherapy. Nature (2019 ) 569:428–32

    Not in our library10.1038/s41586-019-1162-y

  242. 242.

    Zhang L Zlotoff DA Awadalla M Mahmood SS Nohria A Hassan MZO. Major Adverse Cardiovascular Events and the Timing and Dose of Corticosteroids in Immune Checkpoint Inhibitor-Associated Myocarditis. Circulation (2020 ) 141:2031–4

    Not in our library10.1161/circulationaha.119.044703

  243. 243.

    Galdiero MR Morelli E Triggianese P Carucci L Punziano A Pinto A. First Report of De Novo Nivolumab-Induced Oligoarthritis in a Young Man With Relapsing Classic Hodgkin Lymphoma. J Clin Rheumatol (2020 ) 27:S877–8

    Not in our library10.1097/rhu.0000000000001459

  244. 244.

    Shimba A Ikuta K. Control of Immunity by Glucocorticoids in Health and Disease. Semin Immunopathol (2020 ) 42:669–80

    Not in our library10.1007/s00281-020-00827-8

  245. 245.
    Concurrent therapy with immune checkpoint inhibitors and TNFα blockade in patients with gastrointestinal immune-related adverse events · 2019
    No notice
  246. 246.

    Kalisz KR Ramaiya NH Laukamp KR Gupta A. Immune Checkpoint Inhibitor Therapy-Related Pneumonitis: Patterns and Management. Radiographics (2019 ) 39:1923–37

    Not in our library10.1148/rg.2019190036

  247. 247.

    Kang JH Bluestone JA Young A. Predicting and Preventing Immune Checkpoint Inhibitor Toxicity: Targeting Cytokines. Trends Immunol (2021 ) 42:293–311

    Not in our library10.1016/j.it.2021.02.006

  248. 248.
    Outcomes of vedolizumab therapy in patients with immune checkpoint inhibitor–induced colitis: a multi-center study · 2018
    No notice
  249. 249.

    Frohne CC Llano EM Perkovic A Cohen RD Luke JJ. Complete Response of Metastatic Melanoma in a Patient With Crohn’s Disease Simultaneously Receiving Anti-Alpha4beta7 and Anti-PD1 Antibodies. J Immunother Cancer (2019 ) 7:1

    Not in our library10.1186/s40425-018-0484-x

  250. 250.

    Salem JE Allenbach Y Vozy A Brechot N Johnson DB Moslehi JJ. Abatacept for Severe Immune Checkpoint Inhibitor-Associated Myocarditis. N Engl J Med (2019 ) 380:2377–9

    Not in our library10.1056/nejmc1901677

  251. 251.

    Ito M Fujiwara S Fujimoto D Mori R Yoshimura H Hata A. Rituximab for Nivolumab Plus Ipilimumab-Induced Encephalitis in a Small-Cell Lung Cancer Patient. Ann Oncol (2017 ) 28:2318–9

    Not in our library10.1093/annonc/mdx252

  252. 252.

    Crusz SM Radunovic A Shepherd S Shah S Newey V Phillips M. Rituximab in the Treatment of Pembrolizumab-Induced Myasthenia Gravis. Eur J Cancer (2018 ) 102:49–51

    Not in our library10.1016/j.ejca.2018.07.125

  253. 253.

    Mamlouk O Lin JS Abdelrahim M Tchakarov AS Glass WF Selamet U. Checkpoint Inhibitor-Related Renal Vasculitis and Use of Rituximab. J Immunother Cancer (2020 ) 8:e000750

    Not in our library10.1136/jitc-2020-000750

  254. 254.

    Stroud CR Hegde A Cherry C Naqash AR Sharma N Addepalli S. Tocilizumab for the Management of Immune Mediated Adverse Events Secondary to PD-1 Blockade. J Oncol Pharm Pract (2019 ) 25:551–7

    Not in our library10.1177/1078155217745144

  255. 255.

    Kim ST Tayar J Trinh VA Suarez-Almazor M Garcia S Hwu P. Successful Treatment of Arthritis Induced by Checkpoint Inhibitors With Tocilizumab: A Case Series. Ann Rheum Dis (2017 ) 76:2061–4

    Not in our library10.1136/annrheumdis-2017-211560

  256. 256.

    Esfahani K Miller WH Jr. Reversal of Autoimmune Toxicity and Loss of Tumor Response by Interleukin-17 Blockade. N Engl J Med (2017 ) 376:1989–91

    Not in our library10.1056/nejmc1703047

  257. 257.

    Johnson D Patel AB Uemura MI Trinh VA Jackson N Zobniw CM. IL17A Blockade Successfully Treated Psoriasiform Dermatologic Toxicity From Immunotherapy. Cancer Immunol Res (2019 ) 7:860–5

    Not in our library10.1158/2326-6066.cir-18-0682

  258. 258.

    Wang Y Wiesnoski DH Helmink BA Gopalakrishnan V Choi K DuPont HL. Fecal Microbiota Transplantation for Refractory Immune Checkpoint Inhibitor-Associated Colitis. Nat Med (2018 ) 24:1804–8

    Not in our library10.1038/s41591-018-0238-9

  259. 259.

    Zhang RS Padegimas A Murphy KM Evans PT Peters CJ Domenico CM. Treatment of Corticosteroid Refractory Immune Checkpoint Inhibitor Myocarditis With Infliximab: A Case Series. Cardiooncology (2021 ) 7:13

    Not in our library10.1186/s40959-021-00095-x

  260. 260.

    Cautela J Zeriouh S Gaubert M Bonello L Laine M Peyrol M. Intensified Immunosuppressive Therapy in Patients With Immune Checkpoint Inhibitor-Induced Myocarditis. J Immunother Cancer (2020 ) 8:e001887

    Not in our library10.1136/jitc-2020-001887

  261. 261.

    Kumar B Ballas Z. Adverse Events Associated With Immune Checkpoint Blockade. N Engl J Med (2018 ) 378:1164

    Not in our library10.1056/nejmc1801663

  262. 262.

    Mann DL. Innate Immunity and the Failing Heart: The Cytokine Hypothesis Revisited. Circ Res (2015 ) 116:1254–68

    Not in our library10.1161/circresaha.116.302317

  263. 263.

    Frantz S Falcao-Pires I Balligand JL Bauersachs J Brutsaert D Ciccarelli M. The Innate Immune System in Chronic Cardiomyopathy: A European Society of Cardiology (ESC) Scientific Statement From the Working Group on Myocardial Function of the ESC. Eur J Heart Fail (2018 ) 20:445–59

    Not in our library10.1002/ejhf.1138

  264. 264.

    Feagan BG Rutgeerts P Sands BE Hanauer S Colombel JF Sandborn WJ. Vedolizumab as Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med (2013 ) 369:699–710

    Not in our library10.1056/nejmoa1215734

  265. 265.

    Sandborn WJ Feagan BG Rutgeerts P Hanauer S Colombel JF Sands BE. Vedolizumab as Induction and Maintenance Therapy for Crohn’s Disease. N Engl J Med (2013 ) 369:711–21

    Not in our library10.1056/nejmoa1215739

  266. 266.

    Sands BE Peyrin-Biroulet L Loftus EV Jr. Danese S Colombel JF Toruner M. Vedolizumab Versus Adalimumab for Moderate-To-Severe Ulcerative Colitis. N Engl J Med (2019 ) 381:1215–26

    Not in our library10.1056/nejmoa1905725

  267. 267.

    Varricchi G Poto R Ianiro G Punziano A Marone G Gasbarrini A. Gut Microbiome and Common Variable Immunodeficiency: Few Certainties and Many Outstanding Questions. Front Immunol (2021 ) 12:712915

    Not in our library10.3389/fimmu.2021.712915

  268. 268.
    Effectiveness of fecal-derived microbiota transfer using orally administered capsules for recurrent Clostridium difficile infection · 2015
    No notice
  269. 269.

    Kao D Roach B Silva M Beck P Rioux K Kaplan GG. Effect of Oral Capsule- vs Colonoscopy-Delivered Fecal Microbiota Transplantation on Recurrent Clostridium Difficile Infection: A Randomized Clinical Trial. JAMA (2017 ) 318:1985–93

    Not in our library10.1001/jama.2017.17077

  270. 270.

    Youngster I Russell GH Pindar C Ziv-Baran T Sauk J Hohmann EL. Oral, Capsulized, Frozen Fecal Microbiota Transplantation for Relapsing Clostridium Difficile Infection. JAMA (2014 ) 312:1772–8

    Not in our library10.1001/jama.2014.13875

  271. 271.

    Allegretti JR Korzenik JR Hamilton MJ. Fecal Microbiota Transplantation via Colonoscopy for Recurrent C. Difficile Infection. J Vis Exp (2014 ) 52154

    Not in our library10.3791/52154

  272. 272.

    Silverman MS Davis I Pillai DR. Success of Self-Administered Home Fecal Transplantation for Chronic Clostridium Difficile Infection. Clin Gastroenterol Hepatol (2010 ) 8:471–3

    Not in our library10.1016/j.cgh.2010.01.007

  273. 273.

    Tariq R Pardi DS Bartlett MG Khanna S. Low Cure Rates in Controlled Trials of Fecal Microbiota Transplantation for Recurrent Clostridium Difficile Infection: A Systematic Review and Meta-Analysis. Clin Infect Dis (2019 ) 68:1351–8

    Not in our library10.1093/cid/ciy7215078604

  274. 274.
    Donor metabolic characteristics drive effects of faecal microbiota transplantation on recipient insulin sensitivity, energy expenditure and intestinal transit time · 2019
    No notice
  275. 275.
    The Super-Donor Phenomenon in Fecal Microbiota Transplantation · 2019
    No notice
  276. 276.

    Marcella C Cui B Kelly CR Ianiro G Cammarota G Zhang F. Systematic Review: The Global Incidence of Faecal Microbiota Transplantation-Related Adverse Events From 2000 to 2020. Aliment Pharmacol Ther (2021 ) 53:33–42

    Not in our library10.1111/apt.16148

  277. 277.

    Ianiro G Mullish BH Kelly CR Kassam Z Kuijper EJ Ng SC. Reorganisation of Faecal Microbiota Transplant Services During the COVID-19 Pandemic. Gut (2020 ) 69:1555–63

    Not in our library10.1136/gutjnl-2020-321829

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    Esfahani K Elkrief A Calabrese C Lapointe R Hudson M Routy B. Moving Towards Personalized Treatments of Immune-Related Adverse Events. Nat Rev Clin Oncol (2020 ) 17:504–15

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