Toxicities from immunotherapy: From clinical trials to real-world clinical practice

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Overall, the majority of patients treated with CPI developed any irAEs, though the rate of grade 3 events is much lower (around 10%), rate higher with combinations.<a class="elsevierStyleCrossRef" href="#bib0325">5</a> They usually present within the first weeks of CPI, though they can occur anytime. For the effective management of irAEs, early diagnosis is critical.<a class="elsevierStyleCrossRefs" href="#bib0330">6–8</a> Herein we present a comprehensive review on management of main irAEs associated with immunotherapy, focusing not only on the current guidelines but real-world data.Gastrointestinal immune-related adverse eventsGastrointestinal symptoms are the most common adverse events reported by patients treated with CPI, especially within the six first months of treatment, with rates of 45% of diarrhoea and 19% increase of alanine aminotransferase (ALT) when nivolumab and ipilimumab are combined,<a class="elsevierStyleCrossRef" href="#bib0345">9</a> though a wide spectrum of sympthons has been described. Importance of gastrointestinal irAEs lies not in its overall prevalence, but in the considerable percentage of patients who present grade (G)3 or 4 adverse events, with colitis and hepatitis as the irAEs reported more frequently, with rates of 8% and 9% of patients treated with a combination of CPI.<a class="elsevierStyleCrossRefs" href="#bib0345">9,10</a>Immune-related hepatitisAsymptomatic increase of aspartate aminotransferase (AST) or ALT is a common analytical finding in patients undergoing therapy with CPI, especially in those treated with anti-CTLA-4 agents. In the CheckMate 238, the rate of patients who experienced any degree of increased ALT levels was 14.6% among those treated with ipilimumab, in contrast to 6.2% for those who received nivolumab.<a class="elsevierStyleCrossRef" href="#bib0355">11</a> This difference was also observed in case of severe ALT increase (5.7% vs 1.1%).<a class="elsevierStyleCrossRef" href="#bib0355">11</a> Incidence of acute liver failure has been reported to be as infrequent as 0.04%.<a class="elsevierStyleCrossRef" href="#bib0360">12</a>Immune-mediated hepatitis presentation ranges from asymptomatic increase ALT and AST levels to acute liver failure. As with the vast majority of irAEs, its diagnosis lies in the exclusion of other causes of acute hepatitis such as drugs or viral hepatitis,<a class="elsevierStyleCrossRef" href="#bib0330">6</a> especially Hepatitis B virus infection since cases of reactivation have been described.<a class="elsevierStyleCrossRef" href="#bib0365">13</a> Moreover, imaging is mandatory to rule out progression of the underlying malignancy.<a class="elsevierStyleCrossRef" href="#bib0330">6</a> To date, the role of liver biopsy is one of the hot topics concerning immune-mediated hepatitis. According to the ESMO guidelines, it may be useful in assisting in the differential diagnosis of severe hepatitis or refractory cases.<a class="elsevierStyleCrossRef" href="#bib0330">6</a> However real-world data has revealed the usefulness of liver biopsy showing specific findings according to the type of CPI (granulomatous hepatitis with endothelitis for anti-CTLA-4 agents and lobular hepatitis for anti-PD1/PD-L) and suggesting a relationship between the grade of lobular activity and the need of treatment with corticoids.<a class="elsevierStyleCrossRef" href="#bib0370">14</a>Management depends on its severity, ranging from neither specific therapy nor CPI discontinuation for G1 toxicity (AST±ALT>3x Upper limit of normality-ULN), withholding of immunotherapy with close analytical monitoring for G2 (AST±ALT 3–5xULN) to corticosteroids for G3 and 4 hepatitis at dose of 1–2mg/kg per day plus addition of mycophenolate mofetil (MMF) at 72h in absence of improvement.<a class="elsevierStyleCrossRef" href="#bib0330">6</a> Though corticosteroids have been the backbone for therapy of the most severe cases of immune-mediated hepatitis, a few real-world series have shown that interruption of immunotherapy without addition of immunosuppressant drugs can be a safe alternative in 38–50% of patients with G3 or 4 hepatitis.<a class="elsevierStyleCrossRef" href="#bib0370">14</a> However, avoidance of corticosteroids is not an option in those cases presenting with increased bilirubin levels or signs of liver failure such as INR>1.5. Moreover, acute liver failure may be treated aggressively so that liver transplantation is not a feasible choice. In this setting, plasma exchange or antithymocyte globulin therapy have been identified as useful options in addition to corticosteroids plus MMF.<a class="elsevierStyleCrossRef" href="#bib0375">15</a> As opposed to colitis, infliximab is not recommended, thought it has been recently reported as a safe option in isolated cases.<a class="elsevierStyleCrossRef" href="#bib0380">16</a> Differences between guidelines and proposed real-world management are summarized in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Another controversial issue is the re-introduction of immunotherapy after an episode of immune-mediated hepatitis. The FDA as well as the main Oncology societies recommends the permanent discontinuation of CPI in case of G3 or 4 immune-mediated hepatitis.<a class="elsevierStyleCrossRefs" href="#bib0330">6,8</a> Although it is well known that patients who have already developed an irAE are more prone to present another, there is growing real-world evidence supporting the re-introduction of immunotherapy, especially in those patients with no alternative options of treatment (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).<a class="elsevierStyleCrossRefs" href="#bib0385">17–19</a> To date there is no available data concerning the risk of flares in patients with underlying autoimmune hepatitis when they are exposed to CPI.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Immune-related colitisDiarrhoea is one of the most common irAEs reported in patients undergoing CPI, especially anti-CTLA-4.<a class="elsevierStyleCrossRefs" href="#bib0345">9,10</a> The use in solitary of ipilimumab has been associated with higher risk of both diarrhoea (27–54%) and colitis (8–22%) than anti-PD-1/PD-L1 in monotherapy.<a class="elsevierStyleCrossRef" href="#bib0355">11</a> Moreover, colitis is the leading cause for anti-CTLA-4 discontinuation, with an estimated mortality of 1%.Though its presentation is highly variable, the hallmark of immune-mediated colitis is diarrhoea, and in a lower rate abdominal pain, fever, and rectal blood loss.<a class="elsevierStyleCrossRef" href="#bib0400">20</a> In all patients undergoing CPI, especially anti-CTLA-4, stool culture and Clostridium difficile toxin testing should be performed in case of severe diarrhoea.<a class="elsevierStyleCrossRef" href="#bib0330">6</a> Endoscopy with biopsy is mandatory to confirm the diagnosis and rule out cytomegalovirus infection or presence of metastasis.<a class="elsevierStyleCrossRef" href="#bib0330">6</a> Though extensive colitis has been described in two thirds of patients, the sigmoid colon and rectum is present in up to 97% of patients so a flexible sigmoidoscopy is usually enough to confirm the diagnosis of immune-mediated colitis.<a class="elsevierStyleCrossRef" href="#bib0405">21</a> Real-world data from patients who developed diarrhoea on immunotherapy have suggested a poor correlation between the grade of diarrhoea and endoscopic or histological features for severity of colitis.<a class="elsevierStyleCrossRef" href="#bib0410">22</a> However, presence of ulcers or a pancolitis were associated with need for infliximab in 76–79% of cases, supporting the usefulness of early endoscopy for patients treated with CPI presenting with diarrhoea.<a class="elsevierStyleCrossRef" href="#bib0410">22</a>G1 colitis can usually be managed conservatively, with resolution of symptoms by treatment with loperamide or codeine without recourse to stopping CPI.<a class="elsevierStyleCrossRef" href="#bib0415">23</a> However, treatment of choice for G3 or more severe colitis or G2 with systemic symptoms is corticosteroids plus CPI withdrawal. In case of lack of improvement in 72h, infliximab at dose of 5mg/kg is recommended, with a single dose usually sufficient to control colitis.<a class="elsevierStyleCrossRefs" href="#bib0405">21,24</a> In case of non-response, endoscopic re-evaluation, including new biopsies for ruling out cytomegalovirus infection are highly recommended before repeating infliximab infusions.<a class="elsevierStyleCrossRef" href="#bib0415">23</a>Many patients, particularly with combination-induced colitis, tolerated anti-PD-1 rechallenge well, so this approach can be considered in selected patients (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). Recently, a large series including 167 patients with immune-mediated diarrhoea and colitis, 57 (34%) recurred, especially if retreatment with an anti-CTLA-4 agent.<a class="elsevierStyleCrossRef" href="#bib0425">25</a>Another important issue is treatment with CPI in patients with underlying inflammatory bowel disease (IBD). To date experience is scarce and provided by retrospective studies showing a rate of relapse ranging from 0 to 33%.<a class="elsevierStyleCrossRefs" href="#bib0430">26,27</a> Based on this data, pre-existing IBD cannot be considered a contraindication for immunotherapy, though previous endoscopic assessment and avoidance of concomitant non steroidal anti-inflammatory drugs would be highly recommended.<a class="elsevierStyleCrossRef" href="#bib0415">23</a>Endocrine system immune-related adverse eventsUp to 10% of patients treated with immunotherapy will present an irAE involving the endocrine glands, especially when CPIs are used in combination.<a class="elsevierStyleCrossRef" href="#bib0440">28</a> In case of monotherapy, anti-PD1/PD-L1 has been associated with higher risk of thyroid dysfunction whereas anti-CTLA-4 treatment was more commonly linked to hypophysitis.<a class="elsevierStyleCrossRef" href="#bib0445">29</a> The spectrum of endocrine disorders is wide (12 endocrinopathies affecting 5 different glands), with hypopituitarism, thyroid disorders and diabetes mellitus being the most frequent. Although in many cases presentation is asymptomatic, on the other hand, life-threatening cases have been reported, so monitoring of patients is recommended during treatment.<a class="elsevierStyleCrossRef" href="#bib0330">6</a>Immune-related hypophysitisHypophysitis has been reported basically in patients treated with an anti-CTLA-4, with an incidence ranging from 0.4 to 17%.<a class="elsevierStyleCrossRef" href="#bib0450">30</a> Onset of symptoms is usually 12 weeks after the beginning of CPI,<a class="elsevierStyleCrossRef" href="#bib0455">31</a> though cases within the first month of therapy have also been described.The symptoms are usually nonspecific and derived from the hormonal defect such as fatigue and/or muscle weakness, reported in up to 89% of subjects, or due to the compression caused by the growth of the pituitary, leading to headache and visual disturbance.<a class="elsevierStyleCrossRef" href="#bib0440">28</a>It is recommended to perform a baseline TSH determination and during follow-up in patients treated with CPI.<a class="elsevierStyleCrossRef" href="#bib0330">6</a> If symptoms of hypophysitis appear, the patient should be evaluated early through the determination of ACTH, cortisol, TSH and T4, and also gonadotropins and sex hormones, since reports of diabetes insipidus, hypogonadotropic hypogonadism, IGF1 deficiency and prolactin increase has been observed.<a class="elsevierStyleCrossRef" href="#bib0440">28</a>In case of hypophysitis G≥2, defined as moderate symptoms, CPI might be discontinued.<a class="elsevierStyleCrossRef" href="#bib0330">6</a> High dose corticosteroids treatment is indicated in patients with severe disease, but in most cases, the symptoms can be quickly resolved with low doses of corticosteroids.<a class="elsevierStyleCrossRef" href="#bib0460">32</a> In a study including 177 patients treated with immunotherapy, 11 (6%) cases of hypophysitis were observed. Five of them were asymptomatic, 5 developed symptoms and 1 debuted as an adrenal crisis. Interestingly, patients treated with combination CPI were more prone to symptomatic presentation in comparison with those treated with ipilimumab (83% vs 20%, p=0.036). All of them were treated with corticosteroids (5–7.5mg prednisone), and immunotherapy was not discontinued in any of the patients. No cases of secondary adrenal insufficiency or secondary hypothyroidism normalized, though secondary hypogonadism normalized without treatment in up to 27% of patients.<a class="elsevierStyleCrossRef" href="#bib0465">33</a>Immune-related thyroid involvementThyroid disorders occur more frequently after administration of anti-PD-1/PD-L1 alone (1–6%) or in combination with anti-CTLA-4 (9.9–22%).<a class="elsevierStyleCrossRefs" href="#bib0350">10,28</a> The spectrum of symptoms is highly variable, from asymptomatic to thyrotoxic crisis. The diagnosis is established by the presence of high levels of TSH with low or normal values of free T3 and free T4.<a class="elsevierStyleCrossRef" href="#bib0330">6</a> Presence of thyroid autoantibodies is relatively low.<a class="elsevierStyleCrossRef" href="#bib0470">34</a> Since thyroid disorders associated with immunotherapy are often an analytical finding in the context of nonspecific symptoms such as fatigue, thyroid function must be monitored before the start of immunotherapy.<a class="elsevierStyleCrossRef" href="#bib0330">6</a> In case of hypothyroidism hormone replacement is recommended, whereas hyperthyroidism usually resolves spontaneously, with the subsequent appearance of hypothyroidism. In severe cases, it is indicated to suspend CPI treatment until the resolution of symptoms with later re-introduction of CPI.<a class="elsevierStyleCrossRef" href="#bib0475">35</a>Immune-related diabetes mellitusThe incidence of diabetes mellitus (DM) after treatment with immunotherapy is low (<1%) and seems to be more frequent after administration of anti-PD-1/PD-L1 or its combination with ipilimumab. Two main mechanisms of development have been described: destruction of pancreatic B cells leading to type 1 DM, and induction of insulin resistance in case of type 2 DM.<a class="elsevierStyleCrossRef" href="#bib0480">36</a> The diagnosis of type 1 DM is based on clinical and analytical findings and through the determination of antibodies against glutamic acid decarboxylase and islet cells which are detected in more than 50% of patients.<a class="elsevierStyleCrossRef" href="#bib0485">37</a> Patients who developed DM presented with rapid-onset hyperglycemia within days to weeks after the first dose of nivolumab or pembrolizumab, which evolved to life-threatening complications like diabetic ketoacidosis.<a class="elsevierStyleCrossRef" href="#bib0485">37</a> Periodic glucose determination should be performed in patients treated with CPI. Insulin treatment is recommended in patients who develop type 1 DM.<a class="elsevierStyleCrossRef" href="#bib0475">35</a> Immunotherapy can be resumed once glycemic control is established, and in most cases long-term insulin maintenance is necessary.Rheumatic immune-related adverse eventsThere is great evidence to consider joint manifestations, including arthralgia and inflammatory arthritis (IA), as one of the most frequent rheumatic irAEs in patients on CPI. However, although a recent systematic review reported a frequency of IA between 1 and 7%,<a class="elsevierStyleCrossRef" href="#bib0490">38</a> real incidence remains unknown since classification of rheumatic irAEs has not been consistent in clinical trials.<a class="elsevierStyleCrossRef" href="#bib0490">38</a> Despite the fact IA is not a life-threatening side effect it can critically affect the patient's quality of life. Hence, strategies to guarantee an early identification and treatment of IA are needed.Although there is scant information about pathogenesis of CPI-induced IA, genetic background probably plays an important role at least in some cases. Cappelli et al. reported 20% of patients with CPI-induced IA had a first degree relative with autoimmune disease.<a class="elsevierStyleCrossRef" href="#bib0495">39</a> CPI can also act as a trigger of a pre-clinical inflammatory joint disease. Nevertheless, this is not a common clinical setting, as most patients with IA are seronegative for RF or ACPAs. Finally, patients with previously diagnosed inflammatory arthritis (i.e. RA, psoriatic arthritis) seem to have an increased risk of disease flare in the setting of CPI<a class="elsevierStyleCrossRef" href="#bib0430">26</a> (40–50%), especially when they are combined.Pattern of joint involvement is very heterogeneous, and it has been linked with the immunotherapy regimen: patients receiving monotherapy usually show small joint involvement at onset, whereas those on combined CPI are more likely to have knee involvement first with small joints preserved.<a class="elsevierStyleCrossRef" href="#bib0500">40</a> Mean time to onset of joint symptoms after initiation of immunotherapy is variable, within 12 and 26 weeks.<a class="elsevierStyleCrossRef" href="#bib0505">41</a> Nevertheless, arthritis onset can even occur several months after CPI discontinuation.<a class="elsevierStyleCrossRef" href="#bib0505">41</a> Coexistence of other irAEs is frequent and can occur in almost 70% of patients who develop IA.<a class="elsevierStyleCrossRef" href="#bib0495">39</a>Nowadays there is limited data to guide treatment decisions in CPI-induced IA. For G1 and 2 IA, NSAIDs and medium doses of corticosteroids (≤20mg/day), are usually recommended. Intra-articular steroids are useful in cases of mono-oligoarthritis. For refractory patients or G3 to 4 IA, guidelines recommend the use of high doses of prednisone (0.5–1mg/kg/day).<a class="elsevierStyleCrossRef" href="#bib0340">8</a> Contrary to these strategies, recent studies have reported complete responses in patients with polyarthritis using lower doses of corticosteroids.<a class="elsevierStyleCrossRef" href="#bib0505">41</a> Of note, contrary to other irAEs, CPI-induced IA can be more persistent even after CPI discontinuation.<a class="elsevierStyleCrossRef" href="#bib0510">42</a> These findings support the need for continued immunosuppression may be more relevant to IA than other irAEs, and therefore, the use of corticosteroid-sparing agents more necessary. Synthetic disease-modifying antirheumatic drugs (DMARDs) are the most commonly corticosteroid-sparing agents used in CPI-induced IA. Methothrexate has demonstrated to be effective in several cases of CPI-induced IA.<a class="elsevierStyleCrossRef" href="#bib0515">43</a> Although recommended in guidelines, experience with leflunomide has scarcely been reported. Hydroxycloroquine (HCQ) at a dose of 200–400mg/day (based on weight), could be an interesting alternative according to the results of a recent pilot study where seven out of ten patients achieved complete resolution of their joint swelling and pain within the first two months of treatment.<a class="elsevierStyleCrossRef" href="#bib0505">41</a>In patients with severe symptoms or with a poor response to synthetic DMARDs, biologic treatment is recommended. Anti-TNFα and tocilizumab are the biologics most commonly used.<a class="elsevierStyleCrossRef" href="#bib0520">44</a> In general, biologics can reach peak efficacy more quickly than DMARDs. However, preclinical data demonstrated that TNFα inhibition may dampen CPI therapy antitumour benefits. In favour of the use of tocilizumab, IL-6 signalling pathway has been shown to play a role in the tumorigenesis of multiple cancers, associated with worse prognosis, and resistance to chemotherapy/immunotherapy. Nowadays, efficacy of tocilizumab in CPI-related IA has been only reported in a small number of cases.<a class="elsevierStyleCrossRef" href="#bib0520">44</a> Of note, tocilizumab has been associated with bowel perforation in patients with diverticulitis, so may not be a good choice if prior CPI-related colitis.Immune-related muscular involvementMusculoskeletal phenotypes are also vaguely documented. In a recent review by Cappelli et al. myalgia was the second most reported musculoskeletal irAE, with an incidence ranging from 2 to 21%.<a class="elsevierStyleCrossRef" href="#bib0495">39</a> Myositis occured in 1% of patients treated with anti-PD-1/PD-L1 agents with one fatality in the adjuvant pembrolizumab trial and in <1% of ipilimumab treated patients.<a class="elsevierStyleCrossRef" href="#bib0525">45</a>Muscular side effects include musculoskeletal pain, inflammatory myositis, polymyalgia rheumatica (PMR) syndrome characterized by severe pain and stiffness affecting the shoulders and pelvic girdle bilaterally, ocular myositis and myasthenia-like syndrome. Also, autoimmune myocarditis is more common than previously thought, and it can manifest in different ways such as cardiovascular death, cardiogenic shock, cardiac arrest and complete heart block.<a class="elsevierStyleCrossRef" href="#bib0530">46</a>Inflammatory myositis is a heterogeneous group of chronic conditions characterized by muscle inflammation associated with motor weakness. CPI-associated myositis harbours distinct clinical features that differentiate it from idiopathic myositis, such as a more acute onset, the occurrence of ocular myasthenia-like symptoms (ptosis and oculomotor weakness with diplopia), a higher frequency of myocarditis and a poor prognosis with higher mortality rates.<a class="elsevierStyleCrossRef" href="#bib0535">47</a> While some patients are highly symptomatic with severe pain with no creatinkinase (CK) elevation, others are asymptomatic, with only CK elevation as a sign of muscular involvement.<a class="elsevierStyleCrossRef" href="#bib0540">48</a> Thirty-one to 65% of patients present with increased CK, however myositis-associated antibodies and myositis-specific antibodies are usually negative.<a class="elsevierStyleCrossRef" href="#bib0540">48</a>Muscle biopsy findings range from nonspecific myopathy to inflammatory myopathies resembling dermatomyositis and necrotizing autoimmune myopathy. Since up to 30% of patients with CPI-myositis present concomitant myocarditis, it is important to perform an echocardiography in order to rule out this complication.<a class="elsevierStyleCrossRef" href="#bib0545">49</a>Myositis is graded according to the current oncologic guidelines<a class="elsevierStyleCrossRef" href="#bib0340">8</a>: G1 refers to a mild weakness with or without pain, G2 is a moderate weakness with or without pain, limiting age appropriate activity, G3 and G4 weakness is severe, with or without pain, limiting daily activity. In G2, 3 and 4 CK usually is elevated. Maintain treatment with CPI can be considered in G1 or in G2 if the CK is normal. For mild or moderate myalgias, analgesia with paracetamol and/or NSAIDs is recommended.<a class="elsevierStyleCrossRef" href="#bib0330">6</a> Steroids at dose of 0.5mg/kg/d may be additionally considered for moderate symptoms, while high-dose steroids and/or other steroid-sparing drugs may be needed for severe symptoms (1–1.5mg/kg/day). Moreira et al. describe a better outcome in patients that received treatment with steroids.<a class="elsevierStyleCrossRef" href="#bib0540">48</a> Patients presenting with severe myositis (G3 or 4) can require treatment with intravenous immunoglobulin at the same doses as other types of inflammatory myopathies.<a class="elsevierStyleCrossRef" href="#bib0340">8</a> If symptoms and CK levels do not improve or worsen after 4–6 weeks, another immunosuppressant therapy, like azathioprine, methotrexate or MMF, should be considered.<a class="elsevierStyleCrossRef" href="#bib0340">8</a> For severe myocarditis Salem et al. have recently reported the efficacy of intravenous Abatacept (a CTLA-4 agonist).<a class="elsevierStyleCrossRef" href="#bib0550">50</a> Patients affected with PMR-like syndrome usually respond to low dose corticosteroids, however there are cases which required treatment with tocilizumab.<a class="elsevierStyleCrossRef" href="#bib0540">48</a>Globally, half of the cases resolve under treatment. Sequelae can exist in 16% of patients.<a class="elsevierStyleCrossRef" href="#bib0540">48</a> Patients with severe myositis cannot be retreated, however this could be an option with those with mild symptoms and normal CK values. However, it should be highlighted that the only case of ventricular arrhythmias reported in the cohort by Santini et al. relapsed after reintroduction of CPI.<a class="elsevierStyleCrossRef" href="#bib0555">51</a>Neurological immune-related adverse eventsNeurological irAEs are heterogeneous and include central and peripheral nervous system involvement. To date, Myasthenia gravis (MG), Guillain-Barré syndrome, meningo-radiculo-neuritis, demyelinating polyradiculoneuropathies, encephalitis, granulomatous central nervous system inflammation, vasculitis, aseptic meningitis and multiple sclerosis have been described, with MG as the most frequent.<a class="elsevierStyleCrossRef" href="#bib0560">52</a> MG can present de novo in most patients, however up to 27% of patients with myasthenia-like syndrome may be related to exacerbations of pre-existing or sub-clinical MG.<a class="elsevierStyleCrossRef" href="#bib0560">52</a>Incidence of immune-related neurological irAEs is lower than 1% in patients undergoing anti-PD-1/PD-L1,<a class="elsevierStyleCrossRef" href="#bib0565">53</a> and few cases are associated with ipilimumab. The importance of neurological irAEs lies in its severity, since these entities are usually life-threatening, with an estimated mortality of 30.4%,<a class="elsevierStyleCrossRef" href="#bib0560">52</a> emphasizing the need for early diagnosis and treatment.When a neurological irAE is suspected, magnetic resonance imaging is recommended. Lumbar puncture may also be helpful, especially to rule out other neurological complications such as infections. In the case of MG, the anti–acetylcholine receptor (AChR) antibodies are present in 59% of patients, and its presence has been identified with better prognosis.<a class="elsevierStyleCrossRef" href="#bib0560">52</a> Approximately 47% of patients with MG present elevated CK levels suggestive of muscle inflammation, thus muscular biopsy usually does not appear to be consistent with inflammatory myositis.<a class="elsevierStyleCrossRef" href="#bib0570">54</a> Combination of MG and myocarditis has also been described in patients treated with nivolumab.Treatment for G1-2 neurological irAEs consists in delaying immunotherapy, starting prednisone at 0.5–1mg/kg/day and tapering sequentially until resolution of symptoms, with later possibility of restart of CPI. In G≥3 toxicity, prednisone at 1–2mg/kg/day should be initiated in addition to permanent discontinuation of CPI.<a class="elsevierStyleCrossRef" href="#bib0330">6</a> In patients with MG or myositis/MG syndrome treatment with corticosteroid and the acetylcholinesterase inhibitor pyridostigmine are mandatory.<a class="elsevierStyleCrossRef" href="#bib0560">52</a> In case of severe symptoms intravenous immunoglobulins and plasmapheresis may improved prognosis.<a class="elsevierStyleCrossRef" href="#bib0330">6</a> The few reports of severe neurologic toxicity that were retreated with CPI did not experience recurrences.<a class="elsevierStyleCrossRef" href="#bib0555">51</a>Pulmonary immune-related adverse eventsPneumonitis is one of the most commonly reported pulmonary irAE with an incidence around 6% in patients receiving anti-PD-1/PD-L1 and 12% in combined CPI.<a class="elsevierStyleCrossRef" href="#bib0330">6</a> Acute interstitial pneumonitis and diffuse alveolar damage are the most frequent and life-threating events, but organizing inflammatory pneumonia as well as sarcoidosis-like lesions have also been described.<a class="elsevierStyleCrossRefs" href="#bib0330">6,55</a> Median time from beginning of CPI to pneumonitis is 3 months, though cases after the first dose have been reported.<a class="elsevierStyleCrossRef" href="#bib0575">55</a> Estimated mortality rate is 12%.It is necessary to make a systematic study in patients with respiratory symptoms like dyspnoea or dry cough. A high-resolution computed tomography scan findings are heterogeneous, including ground-glass opacities (37%), interstitial infiltrates (7%), cryptogenic organizing pneumonia-like patterns (19%) or hypersensibility (22%).<a class="elsevierStyleCrossRefs" href="#bib0330">6,55</a>The possibility of added complications should be considered, especially respiratory infections or progression of underlying oncological disease.<a class="elsevierStyleCrossRefs" href="#bib0445">29,55</a> Thus, in G≥3 pneumonitis, bronchoscopy and bronchoalveolar lavage are highly recommended. Lung biopsy is not required except if radiological or clinical concerns about the diagnosis. Histopathologic patterns include acute cellular interstitial pneumonitis, alveolar damage, and organizing pneumonia.<a class="elsevierStyleCrossRefs" href="#bib0575">55,56</a>Treatment is based on corticosteroids, initially at dose of 1mg/kg/day, with tapering over no less than 4 weeks when symptoms improve. Broad spectrum antibiotics are highly recommended unless concomitant infection has been reliably ruled out.<a class="elsevierStyleCrossRef" href="#bib0330">6</a> In G≥3 pneumonitis the patient must be hospitalised and treatment should consist of high dose corticosteroids (2–4mg/kg/day). If there is no improvement in 2 days, additional immunosuppression with infliximab (5mg/kg), MMF or cyclophosphamide is recommended.<a class="elsevierStyleCrossRef" href="#bib0330">6</a> However, real-world data has suggested the potential role of the addition of either anti-thymocyte globulin or intravenous immunoglobulin for severe refractory pneumonitis.<a class="elsevierStyleCrossRef" href="#bib0445">29</a> Some patients experience recurrent pneumonitis during corticoid therapy after initial clinical improvement.Reintroduction of CPI after a severe pneumonitis is controversial and real-world data in this regard scarce (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).Renal immune-related adverse eventsRenal dysfunction is rare when CPIs are used in monotherapy, though its prevalence increases to 4.9% when they are combined.<a class="elsevierStyleCrossRef" href="#bib0585">57</a>Renal toxicity is graded according to creatinine levels, with increase 1.5–2, 2–3 and 3-fold over baseline creatine levels stand for G1, 2 and 3, respectively. G4 toxicity can be life-threatening and usually requires dialysis. The timing of onset of acute kidney injury is highly variable, with a median time of 91 days.<a class="elsevierStyleCrossRef" href="#bib0590">58</a>The underlying mechanism of renal toxicity in the setting of CPI is diverse and therefore a renal biopsy can be considered to clarify the cause.<a class="elsevierStyleCrossRef" href="#bib0590">58</a> The most common finding is nephritis with lymphocytic infiltration, though other entities such as ANCA associated vasculitis, granulomatous nephritis, or thrombotic microangiopathy has been described.<a class="elsevierStyleCrossRef" href="#bib0590">58</a> Renal damage is usually asymptomatic, with the presence of oliguria, pyuria or hypertension infrequent.CPI should be withheld in the event of significant renal dysfunction (G≥2).<a class="elsevierStyleCrossRef" href="#bib0330">6</a> After ruling out other causes of renal injury, the use of systemic corticosteroid therapy should be considered (0.5–2 mgr/kg/d). In the series from Cortazar et al. most patients reached a partial or complete response with steroids,<a class="elsevierStyleCrossRef" href="#bib0590">58</a> but in some refractory cases, treatment with other immunosuppressant drugs like MMF can be warranted (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). Patients who present microangiopathy in the biopsy can have worse response to treatment, requiring immunosuppression.<a class="elsevierStyleCrossRef" href="#bib0595">59</a> Reinitiating CPI can be considered when the toxicity is less than G2 and if there has been a favourable response to corticosteroids. On the contrary, if severity is G3 or 4 it is important to consider carefully the risk/benefit.<a class="elsevierStyleCrossRef" href="#bib0595">59</a>Despite scarce data on patients with chronic kidney disease, therapy with CPI appears to be safe. Patients with renal transplantation are at high risk of rejecting the allograft and requiring dialysis. Some data has shown that anti-CTLA-4 agents are safer that anti-PD-1/PD-L1, for which a near universal rejection has been reported.<a class="elsevierStyleCrossRef" href="#bib0600">60</a>ConclusionIn parallel with their high efficacy rates, immune checkpoint inhibitors have been linked to a large number of immune-related adverse events, with a wide diversity of manifestations and severity. Rising data from real-world cohorts are shedding new light on diagnosis and treatment of these adverse events, emphasizing the need for multidisciplinary management and data on biomarkers for identification of patients at risk prior to the beginning of immunotherapy.Conflict of interestAuthors have no personal interests to declare" "textoCompletoSecciones" => array:1 [ "secciones" => array:16 [ 0 => array:3 [ "identificador" => "xres1433276" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1308284" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1433275" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1308283" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Gastrointestinal immune-related adverse events" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Immune-related hepatitis" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Immune-related colitis" ] ] ] 6 => array:3 [ "identificador" => "sec0025" "titulo" => "Endocrine system immune-related adverse events" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0030" "titulo" => "Immune-related hypophysitis" ] 1 => array:2 [ "identificador" => "sec0035" "titulo" => "Immune-related thyroid involvement" ] 2 => array:2 [ "identificador" => "sec0040" "titulo" => "Immune-related diabetes mellitus" ] ] ] 7 => array:2 [ "identificador" => "sec0045" "titulo" => "Rheumatic immune-related adverse events" ] 8 => array:2 [ "identificador" => "sec0050" "titulo" => "Immune-related muscular involvement" ] 9 => array:2 [ "identificador" => "sec0055" "titulo" => "Neurological immune-related adverse events" ] 10 => array:2 [ "identificador" => "sec0060" "titulo" => "Pulmonary immune-related adverse events" ] 11 => array:2 [ "identificador" => "sec0065" "titulo" => "Renal immune-related adverse events" ] 12 => array:2 [ "identificador" => "sec0070" "titulo" => "Conclusion" ] 13 => array:2 [ "identificador" => "sec0075" "titulo" => "Conflict of interest" ] 14 => array:2 [ "identificador" => "xack500248" "titulo" => "Acknowledgments" ] 15 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2020-03-11" "fechaAceptado" => "2020-06-02" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1308284" "palabras" => array:5 [ 0 => "Immunotherapy" 1 => "Adverse drugs reaction" 2 => "Hepatitis" 3 => "Myositis" 4 => "Cancer" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1308283" "palabras" => array:5 [ 0 => "Inmunoterapia" 1 => "Reacción adversa a los medicamentos" 2 => "Hepatitis" 3 => "Miositis" 4 => "Cáncer" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "In recent years, immunotherapy has become an important pillar of cancer treatment, with high response rates regardless of tumour histology or baseline mutations. However, immune activation associated with check-point inhibitors is not selective and a large variety of immune-related adverse events have been associated with anti-PD1, anti-PD-1/L-1 and anti-CTLA-4 agents. Though diagnosis and treatment of these toxicities have been established according to the recommendations from clinical trials and in line with the autoimmune disorders that they mimic, increasing real-world data is coming up showing that these adverse events may have differential characteristics and management, especially in terms of the use of corticoids, second-line treatments, salvage therapy for life-threatening cases and reintroduction of immunotherapy. Herein we present a comprehensive review of current recommendations and real-world data on the main immune-related adverse events of immunotherapy." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "En los últimos años la inmunoterapia se ha convertido en un pilar fundamental para el tratamiento del cáncer, con altas tasas de respuesta, independientemente de la histología tumoral o de las mutaciones basales. Sin embargo, la activación inmune asociada a los inhibidores de control no es selectiva, habiéndose asociado una gran variedad de efectos adversos relacionados con la inmunidad a los agentes anti-PD1, anti-PD-1/L-1 y anti-CTLA-4. Aunque se han establecido el diagnóstico y el tratamiento de estas toxicidades en virtud de las recomendaciones de los ensayos clínicos, en consonancia con los trastornos autoinmunes que imitan, el incremento de los datos del mundo real refleja que dichos efectos adversos pueden tener características y manejos diferenciales, especialmente en términos de uso de corticoides, tratamientos de segunda línea, terapia de rescate para casos potencialmente letales, y reintroducción de la inmunoterapia. Presentamos aquí una revisión amplia de las recomendaciones actuales y los datos del mundo real sobre los principales efectos adversos de la inmunoterapia." ] ] "NotaPie" => array:1 [ 0 => array:3 [ "etiqueta" => "◊" "nota" => "Please see a list of the members of the Vall d’Hebrón Committee in <a class="elsevierStyleCrossRef" href="#sec0080">Appendix A</a>." "identificador" => "fn0005" ] ] "apendice" => array:1 [ 0 => array:1 [ "seccion" => array:1 [ 0 => array:4 [ "apendice" => "María Roca-Herrera (Medical Oncology Department. Hospital Universitari Vall d’Hebron, Barcelona, Spain. Vall d’hebron Institute of Oncology [VHIO], Barcelona, Spain) Ester Zamora (Medical Oncology Department. Hospital Universitari Vall d’Hebron, Barcelona, Spain. Vall d’hebron Institute of Oncology [VHIO], Barcelona, Spain) Ana Barreira-Díaz (Liver Unit, Internal Medicine Department. Hospital Universitari Vall d’Hebron, Barcelona, Spain) Eva Muñoz-Couselo (Medical Oncology Department. Hospital Universitari Vall d’Hebron, Barcelona, Spain. Vall d’hebron Institute of Oncology [VHIO], Barcelona, Spain)" "etiqueta" => "Appendix A" "titulo" => "Vall d’Hebrón Group for the study of Immunotherapy immune-related adverse events" "identificador" => "sec0080" ] ] ] ] "multimedia" => array:2 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="3" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Guidelines recommendation</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="3" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Real-world suggested management</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CPI discontinuation \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Corticoids \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Others \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CPI discontinuation \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Corticoids \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Others \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hepatitis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">✓ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">✓ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MMF if refractory \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">✓ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MMF, tacrolimus if refractory \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Colitis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">✓ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">✓ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Infliximab if refractory \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">✓ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">✓ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Infliximab, vedolizumab if refractory \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hypophysitis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">✓ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">✓ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hormone replacement \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">± \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">✓ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hormone replacement \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hypothyroidism \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hormone replacement \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">X \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hormone replacement \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hyperthyroidism \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">± \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">± \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Beta-blockers± Carbimazole \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">± \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">± \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Beta-blockers±Carbimazole \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Arthritis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">± \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anti-TNFα agents \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">± \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">± \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Metothrexato, anti-TNFα, hydroxycloroquine, tocilizumab \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Myositis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">± \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">✓ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">azathioprine, methotrexate or MMF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">± \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">✓ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ig's, azathioprine, MMF methotrexate, tocilizumab \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pneumonitis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">✓ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">✓ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Infliximab, MMF or Cyclophosphamide if refractory \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">± \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">✓ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Infliximab, anti-thymocyte globulin or Ig's if refractory \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neurological \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">± \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">✓ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ig's and plasmapheresis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">± \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">✓ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pyridostigmine, Ig's and plasmapheresis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Renal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">✓ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">✓ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">✓ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">✓ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MMF if refractory \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2464341.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "If lobular activity is not severe and bilirubin and clotting are within normal values. Check-point inhibitors, CPI; Ig's, Immunoglobulins; MMF, mycophenolate mofetil; ESMO, European Society for Medical Oncology." ] ] ] "descripcion" => array:1 [ "en" => "Management of the main grade 3 and 4 immune-mediated adverse events according to the ESMO guidelines in comparison with the current real-world data." ] ] 1 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "Pollack et al.: Retreatment with an anti-PD-1 agent after an irAE (all grades) with combined anti-CTLA-4 plus anti-PD-1 therapy for metastatic melanoma; Santini et al.: Subjects with non-small cell lung cancer retreated with anti-PD-1/PD-L1 after an irAE that led to immunotherapy (anti-PD-1/PD-L1±anti-CTLA-4) discontinuation (all grades); Simonaggio et al.: Retreatment with anti-PD-1/PD-L1 after an initial grade 2 or higher irAE." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">irAE \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Pollack et al.<a class="elsevierStyleCrossRef" href="#bib0385">17</a></th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Santini et al.<a class="elsevierStyleCrossRef" href="#bib0555">51</a></th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Simonaggio et al.<a class="elsevierStyleCrossRef" href="#bib0395">19</a></th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Recurrence \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">De-novo<a class="elsevierStyleCrossRef" href="#tblfn0010">a</a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Recurrence \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">De-novo<a class="elsevierStyleCrossRef" href="#tblfn0010">a</a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Recurrence \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">De-novo<a class="elsevierStyleCrossRef" href="#tblfn0015">b</a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hepatitis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5/29 (17%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1/51 (2%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1/3 (33%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2/35 (6%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3/5 (60%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0/5 (0%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Colitis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2/33 (6%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6/47 (13%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2/7 (29%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3/31 (10%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3/5 (60%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0/5 (0%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pneumonitis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1/3 (33%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3/77 (4%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1/6 (15%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2/32 (6%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1/5 (20%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1/5 (20%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hypophysitis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1/8 (13%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1/72 (1%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">N/A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">N/A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">N/A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">N/A \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Skin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1/4 (25%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5/76 (7%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1/5 (20%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1/33 (3%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3/7 (43%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1/7 (14%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Arthralgia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">N/A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3/5 (60%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1/33 (3%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5/6 (83%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1/6 (15%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Nephritis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1/2 (50%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0/78 (0%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1/2 (50%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0/36 (0%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">N/A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">N/A \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2464340.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "a" "nota" => "Cases of the irAE in the cohort of retreated patients who had previously presented a different irAE." ] 1 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "b" "nota" => "Cases of a different irAE in the cohort of patient who had previously presented the cited irAE. irAE, immune-related adverse event; N/A, not available." ] ] ] "descripcion" => array:1 [ "en" => "Real-world rates of recurrence or de-novo immune-related adverse events (irAEs) in patients who re-challenge immunotherapy after a prior irAE." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:60 [ 0 => array:3 [ "identificador" => "bib0305" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Antagonists of PD-1 and PD-L1 in cancer treatment" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "E.J. 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Toxicities from immunotherapy: From clinical trials to real-world clinical practice

Toxicidades de la inmunoterapia: de los ensayos clínicos a la práctica clínica en el mundo real

Mar Riveiro-Barcielaa,b, Ernesto Trallero-Araguásc, Fernando Martínez-Valled,

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ferranmartinezvalle@gmail.com

Corresponding author.

, on behalf of the Vall d’Hebrón Group for the study of Immunotherapy immune-related adverse events ◊

a Liver Unit, Internal Medicine Department, Hospital Universitari Vall d’Hebron, Universitat Autonoma de Barcelona, Barcelona, Spain

b Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain

c Rheumatology Unit, Hospital Universitari Vall d’Hebron, Barcelona, Spain

d Systemic Autoimmune Diseases Unit, Internal Medicine Department, Hospital Universitari Vall d’Hebron, Barcelona, Spain

Vall d’Hebrón Committee for management of Immunotherapy immune-related adverse events

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Immunotherapy has become an important pillar of cancer care&#44; complementing surgery&#44; cytotoxic therapy and radiotherapy in most tumour types&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">1</span></a> Description of the immune-editing by Schreiber as a process that enables escape from immune surveillance to establish overt malignancy<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">2</span></a> and description of cancer-immunity cycle by Chen and Mellman impacted on the development of multiple opportunities for therapeutic intervention that enhance tumour immunity&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">3</span></a> Immune check-point inhibitors &#40;CPI&#41; that target the programmed death protein 1 pathway &#40;anti-PD-1&#58; nivolumab and pembrolizumab&#41; and its ligand &#40;anti-PD-L1&#58; atezolizumab&#44; avelumab and durvalumab&#41; have generated the most interesting strategy with response rates across tumour types that average 20&#8211;30&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">1</span></a> The other group of CPI are the anti cytotoxic T-lymphocyte-associated antigen &#40;anti-CTLA-4&#58; ipilimumab and tremelimumab&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">4</span></a> These drugs engage T cells with inherent capacity for adaptability and memory that lead to durable responses and long-term survival is observed&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Safety profile of CPI differs from chemotherapy and immune-related adverse events &#40;irAEs&#41; result from immune activation driving autoimmune manifestations&#46; Overall&#44; the majority of patients treated with CPI developed any irAEs&#44; though the rate of grade 3 events is much lower &#40;around 10&#37;&#41;&#44; rate higher with combinations&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">5</span></a> They usually present within the first weeks of CPI&#44; though they can occur anytime&#46; For the effective management of irAEs&#44; early diagnosis is critical&#46;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">6&#8211;8</span></a> Herein we present a comprehensive review on management of main irAEs associated with immunotherapy&#44; focusing not only on the current guidelines but real-world data&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Gastrointestinal immune-related adverse events</span><p id="par0015" class="elsevierStylePara elsevierViewall">Gastrointestinal symptoms are the most common adverse events reported by patients treated with CPI&#44; especially within the six first months of treatment&#44; with rates of 45&#37; of diarrhoea and 19&#37; increase of alanine aminotransferase &#40;ALT&#41; when nivolumab and ipilimumab are combined&#44;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">9</span></a> though a wide spectrum of sympthons has been described&#46; Importance of gastrointestinal irAEs lies not in its overall prevalence&#44; but in the considerable percentage of patients who present grade &#40;G&#41;3 or 4 adverse events&#44; with colitis and hepatitis as the irAEs reported more frequently&#44; with rates of 8&#37; and 9&#37; of patients treated with a combination of CPI&#46;<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">9&#44;10</span></a></p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Immune-related hepatitis</span><p id="par0020" class="elsevierStylePara elsevierViewall">Asymptomatic increase of aspartate aminotransferase &#40;AST&#41; or ALT is a common analytical finding in patients undergoing therapy with CPI&#44; especially in those treated with anti-CTLA-4 agents&#46; In the <span class="elsevierStyleItalic">CheckMate 238</span>&#44; the rate of patients who experienced any degree of increased ALT levels was 14&#46;6&#37; among those treated with ipilimumab&#44; in contrast to 6&#46;2&#37; for those who received nivolumab&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">11</span></a> This difference was also observed in case of severe ALT increase &#40;5&#46;7&#37; vs 1&#46;1&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">11</span></a> Incidence of acute liver failure has been reported to be as infrequent as 0&#46;04&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">12</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Immune-mediated hepatitis presentation ranges from asymptomatic increase ALT and AST levels to acute liver failure&#46; As with the vast majority of irAEs&#44; its diagnosis lies in the exclusion of other causes of acute hepatitis such as drugs or viral hepatitis&#44;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">6</span></a> especially Hepatitis B virus infection since cases of reactivation have been described&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">13</span></a> Moreover&#44; imaging is mandatory to rule out progression of the underlying malignancy&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">6</span></a> To date&#44; the role of liver biopsy is one of the hot topics concerning immune-mediated hepatitis&#46; According to the ESMO guidelines&#44; it may be useful in assisting in the differential diagnosis of severe hepatitis or refractory cases&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">6</span></a> However real-world data has revealed the usefulness of liver biopsy showing specific findings according to the type of CPI &#40;granulomatous hepatitis with endothelitis for anti-CTLA-4 agents and lobular hepatitis for anti-PD1&#47;PD-L&#41; and suggesting a relationship between the grade of lobular activity and the need of treatment with corticoids&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">14</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Management depends on its severity&#44; ranging from neither specific therapy nor CPI discontinuation for G1 toxicity &#40;AST<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>ALT<span class="elsevierStyleHsp" style=""></span>&#62;3x Upper limit of normality-ULN&#41;&#44; withholding of immunotherapy with close analytical monitoring for G2 &#40;AST<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>ALT 3&#8211;5xULN&#41; to corticosteroids for G3 and 4 hepatitis at dose of 1&#8211;2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg per day plus addition of mycophenolate mofetil &#40;MMF&#41; at 72<span class="elsevierStyleHsp" style=""></span>h in absence of improvement&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">6</span></a> Though corticosteroids have been the backbone for therapy of the most severe cases of immune-mediated hepatitis&#44; a few real-world series have shown that interruption of immunotherapy without addition of immunosuppressant drugs can be a safe alternative in 38&#8211;50&#37; of patients with G3 or 4 hepatitis&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">14</span></a> However&#44; avoidance of corticosteroids is not an option in those cases presenting with increased bilirubin levels or signs of liver failure such as INR<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>1&#46;5&#46; Moreover&#44; acute liver failure may be treated aggressively so that liver transplantation is not a feasible choice&#46; In this setting&#44; plasma exchange or antithymocyte globulin therapy have been identified as useful options in addition to corticosteroids plus MMF&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">15</span></a> As opposed to colitis&#44; infliximab is not recommended&#44; thought it has been recently reported as a safe option in isolated cases&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">16</span></a> Differences between guidelines and proposed real-world management are summarized in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">Another controversial issue is the re-introduction of immunotherapy after an episode of immune-mediated hepatitis&#46; The FDA as well as the main Oncology societies recommends the permanent discontinuation of CPI in case of G3 or 4 immune-mediated hepatitis&#46;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">6&#44;8</span></a> Although it is well known that patients who have already developed an irAE are more prone to present another&#44; there is growing real-world evidence supporting the re-introduction of immunotherapy&#44; especially in those patients with no alternative options of treatment &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">17&#8211;19</span></a> To date there is no available data concerning the risk of flares in patients with underlying autoimmune hepatitis when they are exposed to CPI&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Immune-related colitis</span><p id="par0040" class="elsevierStylePara elsevierViewall">Diarrhoea is one of the most common irAEs reported in patients undergoing CPI&#44; especially anti-CTLA-4&#46;<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">9&#44;10</span></a> The use in solitary of ipilimumab has been associated with higher risk of both diarrhoea &#40;27&#8211;54&#37;&#41; and colitis &#40;8&#8211;22&#37;&#41; than anti-PD-1&#47;PD-L1 in monotherapy&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">11</span></a> Moreover&#44; colitis is the leading cause for anti-CTLA-4 discontinuation&#44; with an estimated mortality of 1&#37;&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Though its presentation is highly variable&#44; the hallmark of immune-mediated colitis is diarrhoea&#44; and in a lower rate abdominal pain&#44; fever&#44; and rectal blood loss&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">20</span></a> In all patients undergoing CPI&#44; especially anti-CTLA-4&#44; stool culture and <span class="elsevierStyleItalic">Clostridium difficile</span> toxin testing should be performed in case of severe diarrhoea&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">6</span></a> Endoscopy with biopsy is mandatory to confirm the diagnosis and rule out cytomegalovirus infection or presence of metastasis&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">6</span></a> Though extensive colitis has been described in two thirds of patients&#44; the sigmoid colon and rectum is present in up to 97&#37; of patients so a flexible sigmoidoscopy is usually enough to confirm the diagnosis of immune-mediated colitis&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">21</span></a> Real-world data from patients who developed diarrhoea on immunotherapy have suggested a poor correlation between the grade of diarrhoea and endoscopic or histological features for severity of colitis&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">22</span></a> However&#44; presence of ulcers or a pancolitis were associated with need for infliximab in 76&#8211;79&#37; of cases&#44; supporting the usefulness of early endoscopy for patients treated with CPI presenting with diarrhoea&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">22</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">G1 colitis can usually be managed conservatively&#44; with resolution of symptoms by treatment with loperamide or codeine without recourse to stopping CPI&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">23</span></a> However&#44; treatment of choice for G3 or more severe colitis or G2 with systemic symptoms is corticosteroids plus CPI withdrawal&#46; In case of lack of improvement in 72<span class="elsevierStyleHsp" style=""></span>h&#44; infliximab at dose of 5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg is recommended&#44; with a single dose usually sufficient to control colitis&#46;<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">21&#44;24</span></a> In case of non-response&#44; endoscopic re-evaluation&#44; including new biopsies for ruling out cytomegalovirus infection are highly recommended before repeating infliximab infusions&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">23</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Many patients&#44; particularly with combination-induced colitis&#44; tolerated anti-PD-1 rechallenge well&#44; so this approach can be considered in selected patients &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; Recently&#44; a large series including 167 patients with immune-mediated diarrhoea and colitis&#44; 57 &#40;34&#37;&#41; recurred&#44; especially if retreatment with an anti-CTLA-4 agent&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">25</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Another important issue is treatment with CPI in patients with underlying inflammatory bowel disease &#40;IBD&#41;&#46; To date experience is scarce and provided by retrospective studies showing a rate of relapse ranging from 0 to 33&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0430"><span class="elsevierStyleSup">26&#44;27</span></a> Based on this data&#44; pre-existing IBD cannot be considered a contraindication for immunotherapy&#44; though previous endoscopic assessment and avoidance of concomitant non steroidal anti-inflammatory drugs would be highly recommended&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">23</span></a></p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Endocrine system immune-related adverse events</span><p id="par0065" class="elsevierStylePara elsevierViewall">Up to 10&#37; of patients treated with immunotherapy will present an irAE involving the endocrine glands&#44; especially when CPIs are used in combination&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">28</span></a> In case of monotherapy&#44; anti-PD1&#47;PD-L1 has been associated with higher risk of thyroid dysfunction whereas anti-CTLA-4 treatment was more commonly linked to hypophysitis&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">29</span></a> The spectrum of endocrine disorders is wide &#40;12 endocrinopathies affecting 5 different glands&#41;&#44; with hypopituitarism&#44; thyroid disorders and diabetes mellitus being the most frequent&#46; Although in many cases presentation is asymptomatic&#44; on the other hand&#44; life-threatening cases have been reported&#44; so monitoring of patients is recommended during treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">6</span></a></p><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Immune-related hypophysitis</span><p id="par0070" class="elsevierStylePara elsevierViewall">Hypophysitis has been reported basically in patients treated with an anti-CTLA-4&#44; with an incidence ranging from 0&#46;4 to 17&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">30</span></a> Onset of symptoms is usually 12 weeks after the beginning of CPI&#44;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">31</span></a> though cases within the first month of therapy have also been described&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">The symptoms are usually nonspecific and derived from the hormonal defect such as fatigue and&#47;or muscle weakness&#44; reported in up to 89&#37; of subjects&#44; or due to the compression caused by the growth of the pituitary&#44; leading to headache and visual disturbance&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">28</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">It is recommended to perform a baseline TSH determination and during follow-up in patients treated with CPI&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">6</span></a> If symptoms of hypophysitis appear&#44; the patient should be evaluated early through the determination of ACTH&#44; cortisol&#44; TSH and T4&#44; and also gonadotropins and sex hormones&#44; since reports of diabetes insipidus&#44; hypogonadotropic hypogonadism&#44; IGF1 deficiency and prolactin increase has been observed&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">28</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">In case of hypophysitis G<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>2&#44; defined as moderate symptoms&#44; CPI might be discontinued&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">6</span></a> High dose corticosteroids treatment is indicated in patients with severe disease&#44; but in most cases&#44; the symptoms can be quickly resolved with low doses of corticosteroids&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">32</span></a> In a study including 177 patients treated with immunotherapy&#44; 11 &#40;6&#37;&#41; cases of hypophysitis were observed&#46; Five of them were asymptomatic&#44; 5 developed symptoms and 1 debuted as an adrenal crisis&#46; Interestingly&#44; patients treated with combination CPI were more prone to symptomatic presentation in comparison with those treated with ipilimumab &#40;83&#37; vs 20&#37;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;036&#41;&#46; All of them were treated with corticosteroids &#40;5&#8211;7&#46;5<span class="elsevierStyleHsp" style=""></span>mg prednisone&#41;&#44; and immunotherapy was not discontinued in any of the patients&#46; No cases of secondary adrenal insufficiency or secondary hypothyroidism normalized&#44; though secondary hypogonadism normalized without treatment in up to 27&#37; of patients&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">33</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Immune-related thyroid involvement</span><p id="par0090" class="elsevierStylePara elsevierViewall">Thyroid disorders occur more frequently after administration of anti-PD-1&#47;PD-L1 alone &#40;1&#8211;6&#37;&#41; or in combination with anti-CTLA-4 &#40;9&#46;9&#8211;22&#37;&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0350"><span class="elsevierStyleSup">10&#44;28</span></a> The spectrum of symptoms is highly variable&#44; from asymptomatic to thyrotoxic crisis&#46; The diagnosis is established by the presence of high levels of TSH with low or normal values of free T3 and free T4&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">6</span></a> Presence of thyroid autoantibodies is relatively low&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">34</span></a> Since thyroid disorders associated with immunotherapy are often an analytical finding in the context of nonspecific symptoms such as fatigue&#44; thyroid function must be monitored before the start of immunotherapy&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">6</span></a> In case of hypothyroidism hormone replacement is recommended&#44; whereas hyperthyroidism usually resolves spontaneously&#44; with the subsequent appearance of hypothyroidism&#46; In severe cases&#44; it is indicated to suspend CPI treatment until the resolution of symptoms with later re-introduction of CPI&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">35</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Immune-related diabetes mellitus</span><p id="par0095" class="elsevierStylePara elsevierViewall">The incidence of diabetes mellitus &#40;DM&#41; after treatment with immunotherapy is low &#40;&#60;1&#37;&#41; and seems to be more frequent after administration of anti-PD-1&#47;PD-L1 or its combination with ipilimumab&#46; Two main mechanisms of development have been described&#58; destruction of pancreatic B cells leading to type 1 DM&#44; and induction of insulin resistance in case of type 2 DM&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">36</span></a> The diagnosis of type 1 DM is based on clinical and analytical findings and through the determination of antibodies against glutamic acid decarboxylase and islet cells which are detected in more than 50&#37; of patients&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">37</span></a> Patients who developed DM presented with rapid-onset hyperglycemia within days to weeks after the first dose of nivolumab or pembrolizumab&#44; which evolved to life-threatening complications like diabetic ketoacidosis&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">37</span></a> Periodic glucose determination should be performed in patients treated with CPI&#46; Insulin treatment is recommended in patients who develop type 1 DM&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">35</span></a> Immunotherapy can be resumed once glycemic control is established&#44; and in most cases long-term insulin maintenance is necessary&#46;</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Rheumatic immune-related adverse events</span><p id="par0100" class="elsevierStylePara elsevierViewall">There is great evidence to consider joint manifestations&#44; including arthralgia and inflammatory arthritis &#40;IA&#41;&#44; as one of the most frequent rheumatic irAEs in patients on CPI&#46; However&#44; although a recent systematic review reported a frequency of IA between 1 and 7&#37;&#44;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">38</span></a> real incidence remains unknown since classification of rheumatic irAEs has not been consistent in clinical trials&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">38</span></a> Despite the fact IA is not a life-threatening side effect it can critically affect the patient&#39;s quality of life&#46; Hence&#44; strategies to guarantee an early identification and treatment of IA are needed&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Although there is scant information about pathogenesis of CPI-induced IA&#44; genetic background probably plays an important role at least in some cases&#46; Cappelli et al&#46; reported 20&#37; of patients with CPI-induced IA had a first degree relative with autoimmune disease&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">39</span></a> CPI can also act as a trigger of a pre-clinical inflammatory joint disease&#46; Nevertheless&#44; this is not a common clinical setting&#44; as most patients with IA are seronegative for RF or ACPAs&#46; Finally&#44; patients with previously diagnosed inflammatory arthritis &#40;i&#46;e&#46; RA&#44; psoriatic arthritis&#41; seem to have an increased risk of disease flare in the setting of CPI<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">26</span></a> &#40;40&#8211;50&#37;&#41;&#44; especially when they are combined&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Pattern of joint involvement is very heterogeneous&#44; and it has been linked with the immunotherapy regimen&#58; patients receiving monotherapy usually show small joint involvement at onset&#44; whereas those on combined CPI are more likely to have knee involvement first with small joints preserved&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">40</span></a> Mean time to onset of joint symptoms after initiation of immunotherapy is variable&#44; within 12 and 26 weeks&#46;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">41</span></a> Nevertheless&#44; arthritis onset can even occur several months after CPI discontinuation&#46;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">41</span></a> Coexistence of other irAEs is frequent and can occur in almost 70&#37; of patients who develop IA&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">39</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Nowadays there is limited data to guide treatment decisions in CPI-induced IA&#46; For G1 and 2 IA&#44; NSAIDs and medium doses of corticosteroids &#40;&#8804;20<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41;&#44; are usually recommended&#46; Intra-articular steroids are useful in cases of mono-oligoarthritis&#46; For refractory patients or G3 to 4 IA&#44; guidelines recommend the use of high doses of prednisone &#40;0&#46;5&#8211;1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">8</span></a> Contrary to these strategies&#44; recent studies have reported complete responses in patients with polyarthritis using lower doses of corticosteroids&#46;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">41</span></a> Of note&#44; contrary to other irAEs&#44; CPI-induced IA can be more persistent even after CPI discontinuation&#46;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">42</span></a> These findings support the need for continued immunosuppression may be more relevant to IA than other irAEs&#44; and therefore&#44; the use of corticosteroid-sparing agents more necessary&#46; Synthetic disease-modifying antirheumatic drugs &#40;DMARDs&#41; are the most commonly corticosteroid-sparing agents used in CPI-induced IA&#46; Methothrexate has demonstrated to be effective in several cases of CPI-induced IA&#46;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">43</span></a> Although recommended in guidelines&#44; experience with leflunomide has scarcely been reported&#46; Hydroxycloroquine &#40;HCQ&#41; at a dose of 200&#8211;400<span class="elsevierStyleHsp" style=""></span>mg&#47;day &#40;based on weight&#41;&#44; could be an interesting alternative according to the results of a recent pilot study where seven out of ten patients achieved complete resolution of their joint swelling and pain within the first two months of treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">41</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">In patients with severe symptoms or with a poor response to synthetic DMARDs&#44; biologic treatment is recommended&#46; Anti-TNF&#945; and tocilizumab are the biologics most commonly used&#46;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">44</span></a> In general&#44; biologics can reach peak efficacy more quickly than DMARDs&#46; However&#44; preclinical data demonstrated that TNF&#945; inhibition may dampen CPI therapy antitumour benefits&#46; In favour of the use of tocilizumab&#44; IL-6 signalling pathway has been shown to play a role in the tumorigenesis of multiple cancers&#44; associated with worse prognosis&#44; and resistance to chemotherapy&#47;immunotherapy&#46; Nowadays&#44; efficacy of tocilizumab in CPI-related IA has been only reported in a small number of cases&#46;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">44</span></a> Of note&#44; tocilizumab has been associated with bowel perforation in patients with diverticulitis&#44; so may not be a good choice if prior CPI-related colitis&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Immune-related muscular involvement</span><p id="par0125" class="elsevierStylePara elsevierViewall">Musculoskeletal phenotypes are also vaguely documented&#46; In a recent review by Cappelli et al&#46; myalgia was the second most reported musculoskeletal irAE&#44; with an incidence ranging from 2 to 21&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">39</span></a> Myositis occured in 1&#37; of patients treated with anti-PD-1&#47;PD-L1 agents with one fatality in the adjuvant pembrolizumab trial and in &#60;1&#37; of ipilimumab treated patients&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">45</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">Muscular side effects include musculoskeletal pain&#44; inflammatory myositis&#44; polymyalgia rheumatica &#40;PMR&#41; syndrome characterized by severe pain and stiffness affecting the shoulders and pelvic girdle bilaterally&#44; ocular myositis and myasthenia-like syndrome&#46; Also&#44; autoimmune myocarditis is more common than previously thought&#44; and it can manifest in different ways such as cardiovascular death&#44; cardiogenic shock&#44; cardiac arrest and complete heart block&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">46</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">Inflammatory myositis is a heterogeneous group of chronic conditions characterized by muscle inflammation associated with motor weakness&#46; CPI-associated myositis harbours distinct clinical features that differentiate it from idiopathic myositis&#44; such as a more acute onset&#44; the occurrence of ocular myasthenia-like symptoms &#40;ptosis and oculomotor weakness with diplopia&#41;&#44; a higher frequency of myocarditis and a poor prognosis with higher mortality rates&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">47</span></a> While some patients are highly symptomatic with severe pain with no creatinkinase &#40;CK&#41; elevation&#44; others are asymptomatic&#44; with only CK elevation as a sign of muscular involvement&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">48</span></a> Thirty-one to 65&#37; of patients present with increased CK&#44; however myositis-associated antibodies and myositis-specific antibodies are usually negative&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">48</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">Muscle biopsy findings range from nonspecific myopathy to inflammatory myopathies resembling dermatomyositis and necrotizing autoimmune myopathy&#46; Since up to 30&#37; of patients with CPI-myositis present concomitant myocarditis&#44; it is important to perform an echocardiography in order to rule out this complication&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">49</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">Myositis is graded according to the current oncologic guidelines<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">8</span></a>&#58; G1 refers to a mild weakness with or without pain&#44; G2 is a moderate weakness with or without pain&#44; limiting age appropriate activity&#44; G3 and G4 weakness is severe&#44; with or without pain&#44; limiting daily activity&#46; In G2&#44; 3 and 4 CK usually is elevated&#46; Maintain treatment with CPI can be considered in G1 or in G2 if the CK is normal&#46; For mild or moderate myalgias&#44; analgesia with paracetamol and&#47;or NSAIDs is recommended&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">6</span></a> Steroids at dose of 0&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;d may be additionally considered for moderate symptoms&#44; while high-dose steroids and&#47;or other steroid-sparing drugs may be needed for severe symptoms &#40;1&#8211;1&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day&#41;&#46; Moreira et al&#46; describe a better outcome in patients that received treatment with steroids&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">48</span></a> Patients presenting with severe myositis &#40;G3 or 4&#41; can require treatment with intravenous immunoglobulin at the same doses as other types of inflammatory myopathies&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">8</span></a> If symptoms and CK levels do not improve or worsen after 4&#8211;6 weeks&#44; another immunosuppressant therapy&#44; like azathioprine&#44; methotrexate or MMF&#44; should be considered&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">8</span></a> For severe myocarditis Salem et al&#46; have recently reported the efficacy of intravenous Abatacept &#40;a CTLA-4 agonist&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">50</span></a> Patients affected with PMR-like syndrome usually respond to low dose corticosteroids&#44; however there are cases which required treatment with tocilizumab&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">48</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">Globally&#44; half of the cases resolve under treatment&#46; Sequelae can exist in 16&#37; of patients&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">48</span></a> Patients with severe myositis cannot be retreated&#44; however this could be an option with those with mild symptoms and normal CK values&#46; However&#44; it should be highlighted that the only case of ventricular arrhythmias reported in the cohort by Santini et al&#46; relapsed after reintroduction of CPI&#46;<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">51</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Neurological immune-related adverse events</span><p id="par0155" class="elsevierStylePara elsevierViewall">Neurological irAEs are heterogeneous and include central and peripheral nervous system involvement&#46; To date&#44; Myasthenia gravis &#40;MG&#41;&#44; Guillain-Barr&#233; syndrome&#44; meningo-radiculo-neuritis&#44; demyelinating polyradiculoneuropathies&#44; encephalitis&#44; granulomatous central nervous system inflammation&#44; vasculitis&#44; aseptic meningitis and multiple sclerosis have been described&#44; with MG as the most frequent&#46;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">52</span></a> MG can present de novo in most patients&#44; however up to 27&#37; of patients with myasthenia-like syndrome may be related to exacerbations of pre-existing or sub-clinical MG&#46;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">52</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">Incidence of immune-related neurological irAEs is lower than 1&#37; in patients undergoing anti-PD-1&#47;PD-L1&#44;<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">53</span></a> and few cases are associated with ipilimumab&#46; The importance of neurological irAEs lies in its severity&#44; since these entities are usually life-threatening&#44; with an estimated mortality of 30&#46;4&#37;&#44;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">52</span></a> emphasizing the need for early diagnosis and treatment&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">When a neurological irAE is suspected&#44; magnetic resonance imaging is recommended&#46; Lumbar puncture may also be helpful&#44; especially to rule out other neurological complications such as infections&#46; In the case of MG&#44; the anti&#8211;acetylcholine receptor &#40;AChR&#41; antibodies are present in 59&#37; of patients&#44; and its presence has been identified with better prognosis&#46;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">52</span></a> Approximately 47&#37; of patients with MG present elevated CK levels suggestive of muscle inflammation&#44; thus muscular biopsy usually does not appear to be consistent with inflammatory myositis&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">54</span></a> Combination of MG and myocarditis has also been described in patients treated with nivolumab&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Treatment for G1-2 neurological irAEs consists in delaying immunotherapy&#44; starting prednisone at 0&#46;5&#8211;1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day and tapering sequentially until resolution of symptoms&#44; with later possibility of restart of CPI&#46; In G<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>3 toxicity&#44; prednisone at 1&#8211;2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day should be initiated in addition to permanent discontinuation of CPI&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">6</span></a> In patients with MG or myositis&#47;MG syndrome treatment with corticosteroid and the acetylcholinesterase inhibitor pyridostigmine are mandatory&#46;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">52</span></a> In case of severe symptoms intravenous immunoglobulins and plasmapheresis may improved prognosis&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">6</span></a> The few reports of severe neurologic toxicity that were retreated with CPI did not experience recurrences&#46;<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">51</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Pulmonary immune-related adverse events</span><p id="par0175" class="elsevierStylePara elsevierViewall">Pneumonitis is one of the most commonly reported pulmonary irAE with an incidence around 6&#37; in patients receiving anti-PD-1&#47;PD-L1 and 12&#37; in combined CPI&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">6</span></a> Acute interstitial pneumonitis and diffuse alveolar damage are the most frequent and life-threating events&#44; but organizing inflammatory pneumonia as well as sarcoidosis-like lesions have also been described&#46;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">6&#44;55</span></a> Median time from beginning of CPI to pneumonitis is 3 months&#44; though cases after the first dose have been reported&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">55</span></a> Estimated mortality rate is 12&#37;&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">It is necessary to make a systematic study in patients with respiratory symptoms like dyspnoea or dry cough&#46; A high-resolution computed tomography scan findings are heterogeneous&#44; including ground-glass opacities &#40;37&#37;&#41;&#44; interstitial infiltrates &#40;7&#37;&#41;&#44; cryptogenic organizing pneumonia-like patterns &#40;19&#37;&#41; or hypersensibility &#40;22&#37;&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">6&#44;55</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">The possibility of added complications should be considered&#44; especially respiratory infections or progression of underlying oncological disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0445"><span class="elsevierStyleSup">29&#44;55</span></a> Thus&#44; in G<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>3 pneumonitis&#44; bronchoscopy and bronchoalveolar lavage are highly recommended&#46; Lung biopsy is not required except if radiological or clinical concerns about the diagnosis&#46; Histopathologic patterns include acute cellular interstitial pneumonitis&#44; alveolar damage&#44; and organizing pneumonia&#46;<a class="elsevierStyleCrossRefs" href="#bib0575"><span class="elsevierStyleSup">55&#44;56</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">Treatment is based on corticosteroids&#44; initially at dose of 1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day&#44; with tapering over no less than 4 weeks when symptoms improve&#46; Broad spectrum antibiotics are highly recommended unless concomitant infection has been reliably ruled out&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">6</span></a> In G<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>3 pneumonitis the patient must be hospitalised and treatment should consist of high dose corticosteroids &#40;2&#8211;4<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day&#41;&#46; If there is no improvement in 2 days&#44; additional immunosuppression with infliximab &#40;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#41;&#44; MMF or cyclophosphamide is recommended&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">6</span></a> However&#44; real-world data has suggested the potential role of the addition of either anti-thymocyte globulin or intravenous immunoglobulin for severe refractory pneumonitis&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">29</span></a> Some patients experience recurrent pneumonitis during corticoid therapy after initial clinical improvement&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">Reintroduction of CPI after a severe pneumonitis is controversial and real-world data in this regard scarce &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Renal immune-related adverse events</span><p id="par0200" class="elsevierStylePara elsevierViewall">Renal dysfunction is rare when CPIs are used in monotherapy&#44; though its prevalence increases to 4&#46;9&#37; when they are combined&#46;<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">57</span></a></p><p id="par0205" class="elsevierStylePara elsevierViewall">Renal toxicity is graded according to creatinine levels&#44; with increase 1&#46;5&#8211;2&#44; 2&#8211;3 and 3-fold over baseline creatine levels stand for G1&#44; 2 and 3&#44; respectively&#46; G4 toxicity can be life-threatening and usually requires dialysis&#46; The timing of onset of acute kidney injury is highly variable&#44; with a median time of 91 days&#46;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">58</span></a></p><p id="par0210" class="elsevierStylePara elsevierViewall">The underlying mechanism of renal toxicity in the setting of CPI is diverse and therefore a renal biopsy can be considered to clarify the cause&#46;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">58</span></a> The most common finding is nephritis with lymphocytic infiltration&#44; though other entities such as ANCA associated vasculitis&#44; granulomatous nephritis&#44; or thrombotic microangiopathy has been described&#46;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">58</span></a> Renal damage is usually asymptomatic&#44; with the presence of oliguria&#44; pyuria or hypertension infrequent&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">CPI should be withheld in the event of significant renal dysfunction &#40;G<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>2&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">6</span></a> After ruling out other causes of renal injury&#44; the use of systemic corticosteroid therapy should be considered &#40;0&#46;5&#8211;2 mgr&#47;kg&#47;d&#41;&#46; In the series from Cortazar et al&#46; most patients reached a partial or complete response with steroids&#44;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">58</span></a> but in some refractory cases&#44; treatment with other immunosuppressant drugs like MMF can be warranted &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Patients who present microangiopathy in the biopsy can have worse response to treatment&#44; requiring immunosuppression&#46;<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">59</span></a> Reinitiating CPI can be considered when the toxicity is less than G2 and if there has been a favourable response to corticosteroids&#46; On the contrary&#44; if severity is G3 or 4 it is important to consider carefully the risk&#47;benefit&#46;<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">59</span></a></p><p id="par0220" class="elsevierStylePara elsevierViewall">Despite scarce data on patients with chronic kidney disease&#44; therapy with CPI appears to be safe&#46; Patients with renal transplantation are at high risk of rejecting the allograft and requiring dialysis&#46; Some data has shown that anti-CTLA-4 agents are safer that anti-PD-1&#47;PD-L1&#44; for which a near universal rejection has been reported&#46;<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">60</span></a></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Conclusion</span><p id="par0225" class="elsevierStylePara elsevierViewall">In parallel with their high efficacy rates&#44; immune checkpoint inhibitors have been linked to a large number of immune-related adverse events&#44; with a wide diversity of manifestations and severity&#46; Rising data from real-world cohorts are shedding new light on diagnosis and treatment of these adverse events&#44; emphasizing the need for multidisciplinary management and data on biomarkers for identification of patients at risk prior to the beginning of immunotherapy&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Conflict of interest</span><p id="par0230" class="elsevierStylePara elsevierViewall">Authors have no personal interests to declare</p></span></span>"
    "textoCompletoSecciones" => array:1 [
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          "identificador" => "xres1433276"
          "titulo" => "Abstract"
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        1 => array:2 [
          "identificador" => "xpalclavsec1308284"
          "titulo" => "Keywords"
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        2 => array:3 [
          "identificador" => "xres1433275"
          "titulo" => "Resumen"
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            0 => array:1 [
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        3 => array:2 [
          "identificador" => "xpalclavsec1308283"
          "titulo" => "Palabras clave"
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        4 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
        ]
        5 => array:3 [
          "identificador" => "sec0010"
          "titulo" => "Gastrointestinal immune-related adverse events"
          "secciones" => array:2 [
            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Immune-related hepatitis"
            ]
            1 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Immune-related colitis"
            ]
          ]
        ]
        6 => array:3 [
          "identificador" => "sec0025"
          "titulo" => "Endocrine system immune-related adverse events"
          "secciones" => array:3 [
            0 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "Immune-related hypophysitis"
            ]
            1 => array:2 [
              "identificador" => "sec0035"
              "titulo" => "Immune-related thyroid involvement"
            ]
            2 => array:2 [
              "identificador" => "sec0040"
              "titulo" => "Immune-related diabetes mellitus"
            ]
          ]
        ]
        7 => array:2 [
          "identificador" => "sec0045"
          "titulo" => "Rheumatic immune-related adverse events"
        ]
        8 => array:2 [
          "identificador" => "sec0050"
          "titulo" => "Immune-related muscular involvement"
        ]
        9 => array:2 [
          "identificador" => "sec0055"
          "titulo" => "Neurological immune-related adverse events"
        ]
        10 => array:2 [
          "identificador" => "sec0060"
          "titulo" => "Pulmonary immune-related adverse events"
        ]
        11 => array:2 [
          "identificador" => "sec0065"
          "titulo" => "Renal immune-related adverse events"
        ]
        12 => array:2 [
          "identificador" => "sec0070"
          "titulo" => "Conclusion"
        ]
        13 => array:2 [
          "identificador" => "sec0075"
          "titulo" => "Conflict of interest"
        ]
        14 => array:2 [
          "identificador" => "xack500248"
          "titulo" => "Acknowledgments"
        ]
        15 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2020-03-11"
    "fechaAceptado" => "2020-06-02"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1308284"
          "palabras" => array:5 [
            0 => "Immunotherapy"
            1 => "Adverse drugs reaction"
            2 => "Hepatitis"
            3 => "Myositis"
            4 => "Cancer"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec1308283"
          "palabras" => array:5 [
            0 => "Inmunoterapia"
            1 => "Reacci&#243;n adversa a los medicamentos"
            2 => "Hepatitis"
            3 => "Miositis"
            4 => "C&#225;ncer"
          ]
        ]
      ]
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    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">In recent years&#44; immunotherapy has become an important pillar of cancer treatment&#44; with high response rates regardless of tumour histology or baseline mutations&#46; However&#44; immune activation associated with check-point inhibitors is not selective and a large variety of immune-related adverse events have been associated with anti-PD1&#44; anti-PD-1&#47;L-1 and anti-CTLA-4 agents&#46; Though diagnosis and treatment of these toxicities have been established according to the recommendations from clinical trials and in line with the autoimmune disorders that they mimic&#44; increasing real-world data is coming up showing that these adverse events may have differential characteristics and management&#44; especially in terms of the use of corticoids&#44; second-line treatments&#44; salvage therapy for life-threatening cases and reintroduction of immunotherapy&#46; Herein we present a comprehensive review of current recommendations and real-world data on the main immune-related adverse events of immunotherapy&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">En los &#250;ltimos a&#241;os la inmunoterapia se ha convertido en un pilar fundamental para el tratamiento del c&#225;ncer&#44; con altas tasas de respuesta&#44; independientemente de la histolog&#237;a tumoral o de las mutaciones basales&#46; Sin embargo&#44; la activaci&#243;n inmune asociada a los inhibidores de control no es selectiva&#44; habi&#233;ndose asociado una gran variedad de efectos adversos relacionados con la inmunidad a los agentes anti-PD1&#44; anti-PD-1&#47;L-1 y anti-CTLA-4&#46; Aunque se han establecido el diagn&#243;stico y el tratamiento de estas toxicidades en virtud de las recomendaciones de los ensayos cl&#237;nicos&#44; en consonancia con los trastornos autoinmunes que imitan&#44; el incremento de los datos del mundo real refleja que dichos efectos adversos pueden tener caracter&#237;sticas y manejos diferenciales&#44; especialmente en t&#233;rminos de uso de corticoides&#44; tratamientos de segunda l&#237;nea&#44; terapia de rescate para casos potencialmente letales&#44; y reintroducci&#243;n de la inmunoterapia&#46; Presentamos aqu&#237; una revisi&#243;n amplia de las recomendaciones actuales y los datos del mundo real sobre los principales efectos adversos de la inmunoterapia&#46;</p></span>"
      ]
    ]
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0030">Please see a list of the members of the Vall d&#8217;Hebr&#243;n Committee in <a class="elsevierStyleCrossRef" href="#sec0080">Appendix A</a>&#46;</p>"
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          0 => array:4 [
            "apendice" => "<p id="par0240" class="elsevierStylePara elsevierViewall">Mar&#237;a Roca-Herrera &#40;Medical Oncology Department&#46; Hospital Universitari Vall d&#8217;Hebron&#44; Barcelona&#44; Spain&#46; Vall d&#8217;hebron Institute of Oncology &#91;VHIO&#93;&#44; Barcelona&#44; Spain&#41;</p> <p id="par0245" class="elsevierStylePara elsevierViewall">Ester Zamora &#40;Medical Oncology Department&#46; Hospital Universitari Vall d&#8217;Hebron&#44; Barcelona&#44; Spain&#46; Vall d&#8217;hebron Institute of Oncology &#91;VHIO&#93;&#44; Barcelona&#44; Spain&#41;</p> <p id="par0250" class="elsevierStylePara elsevierViewall">Ana Barreira-D&#237;az &#40;Liver Unit&#44; Internal Medicine Department&#46; Hospital Universitari Vall d&#8217;Hebron&#44; Barcelona&#44; Spain&#41;</p> <p id="par0255" class="elsevierStylePara elsevierViewall">Eva Mu&#241;oz-Couselo &#40;Medical Oncology Department&#46; Hospital Universitari Vall d&#8217;Hebron&#44; Barcelona&#44; Spain&#46; Vall d&#8217;hebron Institute of Oncology &#91;VHIO&#93;&#44; Barcelona&#44; Spain&#41;</p>"
            "etiqueta" => "Appendix A"
            "titulo" => "Vall d&#8217;Hebr&#243;n Group for the study of Immunotherapy immune-related adverse events"
            "identificador" => "sec0080"
          ]
        ]
      ]
    ]
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t" scope="col">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CPI discontinuation&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CPI discontinuation&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t">&#10003;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">&#10003;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">MMF if refractory&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#10003;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">X<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">MMF&#44; tacrolimus if refractory&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Colitis&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Infliximab&#44; vedolizumab if refractory&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Hypophysitis&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#10003;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#10003;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hormone replacement&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#177;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#10003;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hormone replacement&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hypothyroidism&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hormone replacement&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">X&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hormone replacement&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hyperthyroidism&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#177;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#177;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Beta-blockers&#177; Carbimazole&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#177;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#177;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Beta-blockers<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>Carbimazole&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Arthritis&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#177;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anti-TNF&#945; agents&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#177;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#177;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Metothrexato&#44; anti-TNF&#945;&#44; hydroxycloroquine&#44; tocilizumab&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Myositis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#177;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#10003;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">azathioprine&#44; methotrexate or MMF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#177;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#10003;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ig&#39;s&#44; azathioprine&#44; MMF methotrexate&#44; tocilizumab&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pneumonitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#10003;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#10003;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Infliximab&#44; MMF or Cyclophosphamide if refractory&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#177;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#10003;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Infliximab&#44; anti-thymocyte globulin or Ig&#39;s if refractory&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Neurological&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#177;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#10003;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ig&#39;s and plasmapheresis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#177;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#10003;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pyridostigmine&#44; Ig&#39;s and plasmapheresis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Renal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#10003;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#10003;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#10003;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#10003;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MMF if refractory&nbsp;\t\t\t\t\t\t\n
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          "leyenda" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Pollack et al&#46;&#58; Retreatment with an anti-PD-1 agent after an irAE &#40;all grades&#41; with combined anti-CTLA-4 plus anti-PD-1 therapy for metastatic melanoma&#59; Santini et al&#46;&#58; Subjects with non-small cell lung cancer retreated with anti-PD-1&#47;PD-L1 after an irAE that led to immunotherapy &#40;anti-PD-1&#47;PD-L1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>anti-CTLA-4&#41; discontinuation &#40;all grades&#41;&#59; Simonaggio et al&#46;&#58; Retreatment with anti-PD-1&#47;PD-L1 after an initial grade 2 or higher irAE&#46;</p>"
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                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">irAE&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " colspan="2" align="center" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Pollack et al&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">17</span></a></th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Santini et al&#46;<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">51</span></a></th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Simonaggio et al&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">19</span></a></th></tr><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Recurrence&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">De-novo<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Recurrence&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">De-novo<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Recurrence&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">De-novo<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hepatitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#47;29 &#40;17&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#47;51 &#40;2&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#47;3 &#40;33&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#47;35 &#40;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#47;5 &#40;60&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#47;5 &#40;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Colitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">2&#47;33 &#40;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">6&#47;47 &#40;13&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#47;7 &#40;29&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#47;31 &#40;10&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#47;5 &#40;60&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#47;5 &#40;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pneumonitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#47;3 &#40;33&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#47;77 &#40;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#47;6 &#40;15&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#47;32 &#40;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#47;5 &#40;20&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#47;5 &#40;20&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hypophysitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#47;8 &#40;13&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#47;72 &#40;1&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#47;A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#47;A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#47;A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#47;A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Skin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#47;4 &#40;25&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#47;76 &#40;7&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#47;5 &#40;20&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#47;33 &#40;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#47;7 &#40;43&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#47;7 &#40;14&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Arthralgia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#47;A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#47;5 &#40;60&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#47;33 &#40;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#47;6 &#40;83&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">1&#47;6 &#40;15&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Nephritis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#47;2 &#40;50&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#47;78 &#40;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#47;2 &#40;50&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#47;36 &#40;0&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#47;A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#47;A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Real-world rates of recurrence or de-novo immune-related adverse events &#40;irAEs&#41; in patients who re-challenge immunotherapy after a prior irAE&#46;</p>"
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                    0 => array:2 [
                      "titulo" => "Antagonists of PD-1 and PD-L1 in cancer treatment"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "E&#46;J&#46; Lipson"
                            1 => "P&#46;M&#46; Forde"
                            2 => "H&#46;J&#46; Hammers"
                            3 => "L&#46;A&#46; Emens"
                            4 => "J&#46;M&#46; Taube"
                            5 => "S&#46;L&#46; Topalian"
                          ]
                        ]
                      ]
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                    0 => array:2 [
                      "doi" => "10.1053/j.seminoncol.2015.05.013"
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                        "tituloSerie" => "Semin Oncol"
                        "fecha" => "2015"
                        "volumen" => "42"
                        "paginaInicial" => "587"
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26320063"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Cancer immunoediting&#58; from immunosurveillance to tumor escape"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "G&#46;P&#46; Dunn"
                            1 => "A&#46;T&#46; Bruce"
                            2 => "H&#46; Ikeda"
                            3 => "L&#46;J&#46; Old"
                            4 => "R&#46;D&#46; Schreiber"
                          ]
                        ]
                      ]
                    ]
                  ]
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                    0 => array:2 [
                      "doi" => "10.1038/ni1102-991"
                      "Revista" => array:6 [
                        "tituloSerie" => "Nat Immunol"
                        "fecha" => "2002"
                        "volumen" => "3"
                        "paginaInicial" => "991"
                        "paginaFinal" => "998"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12407406"
                            "web" => "Medline"
                          ]
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                    ]
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                ]
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Oncology meets immunology&#58; the cancer-immunity cycle"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "D&#46;S&#46; Chen"
                            1 => "I&#46; Mellman"
                          ]
                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.immuni.2013.07.012"
                      "Revista" => array:6 [
                        "tituloSerie" => "Immunity"
                        "fecha" => "2013"
                        "volumen" => "39"
                        "paginaInicial" => "1"
                        "paginaFinal" => "10"
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                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23890059"
                            "web" => "Medline"
                          ]
                        ]
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                    ]
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              ]
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              "etiqueta" => "4"
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                0 => array:2 [
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                      "titulo" => "CTLA-4 engagement inhibits IL-2 accumulation and cell cycle progression upon activation of resting T cells"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "M&#46;F&#46; Krummel"
                            1 => "J&#46;P&#46; Allison"
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