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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Management of immune checkpoint inhibitor‐related adverse events: A review of case reports</title><author><name sortKey="Si, Xiaoyan" sort="Si, Xiaoyan" uniqKey="Si X" first="Xiaoyan" last="Si">Xiaoyan Si</name><affiliation><nlm:aff id="tca13315-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Song, Peng" sort="Song, Peng" uniqKey="Song P" first="Peng" last="Song">Peng Song</name><affiliation><nlm:aff id="tca13315-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Ni, Jun" sort="Ni, Jun" uniqKey="Ni J" first="Jun" last="Ni">Jun Ni</name><affiliation><nlm:aff id="tca13315-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Di, Mingyi" sort="Di, Mingyi" uniqKey="Di M" first="Mingyi" last="Di">Mingyi Di</name><affiliation><nlm:aff id="tca13315-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="He, Chunxia" sort="He, Chunxia" uniqKey="He C" first="Chunxia" last="He">Chunxia He</name><affiliation><nlm:aff id="tca13315-aff-0002"></nlm:aff></affiliation></author><author><name sortKey="Zhang, Li" sort="Zhang, Li" uniqKey="Zhang L" first="Li" last="Zhang">Li Zhang</name><affiliation><nlm:aff id="tca13315-aff-0003"></nlm:aff></affiliation></author><author><name sortKey="Liu, Xiaowei" sort="Liu, Xiaowei" uniqKey="Liu X" first="Xiaowei" last="Liu">Xiaowei Liu</name><affiliation><nlm:aff id="tca13315-aff-0004"></nlm:aff></affiliation></author><author><name sortKey="Li, Yue" sort="Li, Yue" uniqKey="Li Y" first="Yue" last="Li">Yue Li</name><affiliation><nlm:aff id="tca13315-aff-0005"></nlm:aff></affiliation></author><author><name sortKey="Wang, Hanping" sort="Wang, Hanping" uniqKey="Wang H" first="Hanping" last="Wang">Hanping Wang</name><affiliation><nlm:aff id="tca13315-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Guo, Xiaoxiao" sort="Guo, Xiaoxiao" uniqKey="Guo X" first="Xiaoxiao" last="Guo">Xiaoxiao Guo</name><affiliation><nlm:aff id="tca13315-aff-0006"></nlm:aff></affiliation></author><author><name sortKey="Zhou, Jiaxin" sort="Zhou, Jiaxin" uniqKey="Zhou J" first="Jiaxin" last="Zhou">Jiaxin Zhou</name><affiliation><nlm:aff id="tca13315-aff-0007"></nlm:aff></affiliation></author><author><name sortKey="Duan, Lian" sort="Duan, Lian" uniqKey="Duan L" first="Lian" last="Duan">Lian Duan</name><affiliation><nlm:aff id="tca13315-aff-0008"></nlm:aff></affiliation></author><author><name sortKey="Yang, Xu" sort="Yang, Xu" uniqKey="Yang X" first="Xu" last="Yang">Xu Yang</name><affiliation><nlm:aff id="tca13315-aff-0009"></nlm:aff></affiliation></author><author><name sortKey="Wang, Mengzhao" sort="Wang, Mengzhao" uniqKey="Wang M" first="Mengzhao" last="Wang">Mengzhao Wang</name><affiliation><nlm:aff id="tca13315-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Zhang, Li" sort="Zhang, Li" uniqKey="Zhang L" first="Li" last="Zhang">Li Zhang</name><affiliation><nlm:aff id="tca13315-aff-0001"></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31970923</idno><idno type="pmc">7049490</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049490</idno><idno type="RBID">PMC:7049490</idno><idno type="doi">10.1111/1759-7714.13315</idno><date when="2020">2020</date><idno type="wicri:Area/Pmc/Corpus">000B13</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000B13</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Management of immune checkpoint inhibitor‐related adverse events: A review of case reports</title><author><name sortKey="Si, Xiaoyan" sort="Si, Xiaoyan" uniqKey="Si X" first="Xiaoyan" last="Si">Xiaoyan Si</name><affiliation><nlm:aff id="tca13315-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Song, Peng" sort="Song, Peng" uniqKey="Song P" first="Peng" last="Song">Peng Song</name><affiliation><nlm:aff id="tca13315-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Ni, Jun" sort="Ni, Jun" uniqKey="Ni J" first="Jun" last="Ni">Jun Ni</name><affiliation><nlm:aff id="tca13315-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Di, Mingyi" sort="Di, Mingyi" uniqKey="Di M" first="Mingyi" last="Di">Mingyi Di</name><affiliation><nlm:aff id="tca13315-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="He, Chunxia" sort="He, Chunxia" uniqKey="He C" first="Chunxia" last="He">Chunxia He</name><affiliation><nlm:aff id="tca13315-aff-0002"></nlm:aff></affiliation></author><author><name sortKey="Zhang, Li" sort="Zhang, Li" uniqKey="Zhang L" first="Li" last="Zhang">Li Zhang</name><affiliation><nlm:aff id="tca13315-aff-0003"></nlm:aff></affiliation></author><author><name sortKey="Liu, Xiaowei" sort="Liu, Xiaowei" uniqKey="Liu X" first="Xiaowei" last="Liu">Xiaowei Liu</name><affiliation><nlm:aff id="tca13315-aff-0004"></nlm:aff></affiliation></author><author><name sortKey="Li, Yue" sort="Li, Yue" uniqKey="Li Y" first="Yue" last="Li">Yue Li</name><affiliation><nlm:aff id="tca13315-aff-0005"></nlm:aff></affiliation></author><author><name sortKey="Wang, Hanping" sort="Wang, Hanping" uniqKey="Wang H" first="Hanping" last="Wang">Hanping Wang</name><affiliation><nlm:aff id="tca13315-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Guo, Xiaoxiao" sort="Guo, Xiaoxiao" uniqKey="Guo X" first="Xiaoxiao" last="Guo">Xiaoxiao Guo</name><affiliation><nlm:aff id="tca13315-aff-0006"></nlm:aff></affiliation></author><author><name sortKey="Zhou, Jiaxin" sort="Zhou, Jiaxin" uniqKey="Zhou J" first="Jiaxin" last="Zhou">Jiaxin Zhou</name><affiliation><nlm:aff id="tca13315-aff-0007"></nlm:aff></affiliation></author><author><name sortKey="Duan, Lian" sort="Duan, Lian" uniqKey="Duan L" first="Lian" last="Duan">Lian Duan</name><affiliation><nlm:aff id="tca13315-aff-0008"></nlm:aff></affiliation></author><author><name sortKey="Yang, Xu" sort="Yang, Xu" uniqKey="Yang X" first="Xu" last="Yang">Xu Yang</name><affiliation><nlm:aff id="tca13315-aff-0009"></nlm:aff></affiliation></author><author><name sortKey="Wang, Mengzhao" sort="Wang, Mengzhao" uniqKey="Wang M" first="Mengzhao" last="Wang">Mengzhao Wang</name><affiliation><nlm:aff id="tca13315-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Zhang, Li" sort="Zhang, Li" uniqKey="Zhang L" first="Li" last="Zhang">Li Zhang</name><affiliation><nlm:aff id="tca13315-aff-0001"></nlm:aff></affiliation></author></analytic><series><title level="j">Thoracic Cancer</title><idno type="ISSN">1759-7706</idno><idno type="eISSN">1759-7714</idno><imprint><date when="2020">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Abstract</title><p>Immune checkpoint inhibitors represent a major breakthrough in cancer therapy. Immune‐related adverse events (irAEs) may occur during treatment due to their unique mechanism of action. Management of irAEs is based on clinical experience because it is not easy to conduct prospective trials to evaluate the best treatment strategy. Using a combination of search terms in the PubMed and Embase databases, we reviewed all cases in the English language citing toxicities associated with either pembrolizumab, nivolumab, ipilimumab, atezolizumab, tremelimumab, durvalumab, avelumab or any combination of these agents published before 20 May 2019. A total of 128 reports with 239 cases were included in the study. Here, we summarize the spectrum of toxicities, safety in special patients, rechallenging after irAEs and agents used for treatment of irAEs in those reports.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct></listBibl></div1></back></TEI><pmc article-type="review-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Thorac Cancer</journal-id><journal-id journal-id-type="iso-abbrev">Thorac Cancer</journal-id><journal-id journal-id-type="doi">10.1111/(ISSN)1759-7714</journal-id><journal-id journal-id-type="publisher-id">TCA</journal-id><journal-title-group><journal-title>Thoracic Cancer</journal-title></journal-title-group><issn pub-type="ppub">1759-7706</issn><issn pub-type="epub">1759-7714</issn><publisher><publisher-name>John Wiley & Sons Australia, Ltd</publisher-name><publisher-loc>Melbourne</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31970923</article-id><article-id pub-id-type="pmc">7049490</article-id><article-id pub-id-type="doi">10.1111/1759-7714.13315</article-id><article-id pub-id-type="publisher-id">TCA13315</article-id><article-categories><subj-group subj-group-type="overline"><subject>Invited Review</subject></subj-group><subj-group subj-group-type="heading"><subject>Invited Review</subject></subj-group></article-categories><title-group><article-title>Management of immune checkpoint inhibitor‐related adverse events: A review of case reports</article-title><alt-title alt-title-type="right-running-head">Immunotherapy‐related adverse events</alt-title><alt-title alt-title-type="left-running-head">X. Si <italic>et al</italic>.</alt-title></title-group><contrib-group><contrib id="tca13315-cr-0001" contrib-type="author"><name><surname>Si</surname><given-names>Xiaoyan</given-names></name><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0003-2913-3045</contrib-id><xref ref-type="aff" rid="tca13315-aff-0001"><sup>1</sup></xref></contrib><contrib id="tca13315-cr-0002" contrib-type="author"><name><surname>Song</surname><given-names>Peng</given-names></name><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0002-6316-5123</contrib-id><xref ref-type="aff" rid="tca13315-aff-0001"><sup>1</sup></xref></contrib><contrib id="tca13315-cr-0003" contrib-type="author"><name><surname>Ni</surname><given-names>Jun</given-names></name><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0002-5939-8856</contrib-id><xref ref-type="aff" rid="tca13315-aff-0001"><sup>1</sup></xref></contrib><contrib id="tca13315-cr-0004" contrib-type="author"><name><surname>Di</surname><given-names>Mingyi</given-names></name><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0001-7540-8383</contrib-id><xref ref-type="aff" rid="tca13315-aff-0001"><sup>1</sup></xref></contrib><contrib id="tca13315-cr-0005" contrib-type="author"><name><surname>He</surname><given-names>Chunxia</given-names></name><xref ref-type="aff" rid="tca13315-aff-0002"><sup>2</sup></xref></contrib><contrib id="tca13315-cr-0006" contrib-type="author"><name><surname>Zhang</surname><given-names>Li</given-names></name><xref ref-type="aff" rid="tca13315-aff-0003"><sup>3</sup></xref></contrib><contrib id="tca13315-cr-0007" contrib-type="author"><name><surname>Liu</surname><given-names>Xiaowei</given-names></name><xref ref-type="aff" rid="tca13315-aff-0004"><sup>4</sup></xref></contrib><contrib id="tca13315-cr-0008" contrib-type="author"><name><surname>Li</surname><given-names>Yue</given-names></name><xref ref-type="aff" rid="tca13315-aff-0005"><sup>5</sup></xref></contrib><contrib id="tca13315-cr-0009" contrib-type="author"><name><surname>Wang</surname><given-names>Hanping</given-names></name><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0003-3540-2280</contrib-id><xref ref-type="aff" rid="tca13315-aff-0001"><sup>1</sup></xref></contrib><contrib id="tca13315-cr-0010" contrib-type="author"><name><surname>Guo</surname><given-names>Xiaoxiao</given-names></name><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0002-8583-5992</contrib-id><xref ref-type="aff" rid="tca13315-aff-0006"><sup>6</sup></xref></contrib><contrib id="tca13315-cr-0011" contrib-type="author"><name><surname>Zhou</surname><given-names>Jiaxin</given-names></name><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0002-1664-3495</contrib-id><xref ref-type="aff" rid="tca13315-aff-0007"><sup>7</sup></xref></contrib><contrib id="tca13315-cr-0012" contrib-type="author"><name><surname>Duan</surname><given-names>Lian</given-names></name><xref ref-type="aff" rid="tca13315-aff-0008"><sup>8</sup></xref></contrib><contrib id="tca13315-cr-0013" contrib-type="author"><name><surname>Yang</surname><given-names>Xu</given-names></name><xref ref-type="aff" rid="tca13315-aff-0009"><sup>9</sup></xref></contrib><contrib id="tca13315-cr-0014" contrib-type="author"><name><surname>Wang</surname><given-names>Mengzhao</given-names></name><xref ref-type="aff" rid="tca13315-aff-0001"><sup>1</sup></xref></contrib><contrib id="tca13315-cr-0015" contrib-type="author" corresp="yes"><name><surname>Zhang</surname><given-names>Li</given-names></name><xref ref-type="aff" rid="tca13315-aff-0001"><sup>1</sup></xref><address><email>zhanglipumch1026@sina.com</email></address></contrib></contrib-group><aff id="tca13315-aff-0001"><label><sup>1</sup></label><named-content content-type="organisation-division">Department of Pulmonary and Critical Care Medicine</named-content><institution>Peking Union Medical College Hospital</institution><city>Beijing</city><country country="CN">China</country></aff><aff id="tca13315-aff-0002"><label><sup>2</sup></label><named-content content-type="organisation-division">Department of Dermatology</named-content><institution>Peking Union Medical College Hospital</institution><city>Beijing</city><country country="CN">China</country></aff><aff id="tca13315-aff-0003"><label><sup>3</sup></label><named-content content-type="organisation-division">Department of Clinical Laboratory</named-content><institution>Peking Union Medical College Hospital</institution><city>Beijing</city><country country="CN">China</country></aff><aff id="tca13315-aff-0004"><label><sup>4</sup></label><named-content content-type="organisation-division">Department of Ophthalmology</named-content><institution>Peking Union Medical College Hospital</institution><city>Beijing</city><country country="CN">China</country></aff><aff id="tca13315-aff-0005"><label><sup>5</sup></label><named-content content-type="organisation-division">Department of Gastroenterology</named-content><institution>Peking Union Medical College Hospital</institution><city>Beijing</city><country country="CN">China</country></aff><aff id="tca13315-aff-0006"><label><sup>6</sup></label><named-content content-type="organisation-division">Department of Cardiology</named-content><institution>Peking Union Medical College Hospital</institution><city>Beijing</city><country country="CN">China</country></aff><aff id="tca13315-aff-0007"><label><sup>7</sup></label><named-content content-type="organisation-division">Department of Rheumatology</named-content><institution>Peking Union Medical College Hospital</institution><city>Beijing</city><country country="CN">China</country></aff><aff id="tca13315-aff-0008"><label><sup>8</sup></label><named-content content-type="organisation-division">Department of Endocrinology</named-content><institution>Peking Union Medical College Hospital</institution><city>Beijing</city><country country="CN">China</country></aff><aff id="tca13315-aff-0009"><label><sup>9</sup></label><named-content content-type="organisation-division">Department of Liver Surgery</named-content><institution>Peking Union Medical College Hospital</institution><city>Beijing</city><country country="CN">China</country></aff><author-notes><corresp id="correspondenceTo"><label>*</label><bold>Correspondence</bold><break></break>Li Zhang, Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, No. 1 Shuaifuyuan Wangfujing, Dongcheng District, Beijing, 100730, China.<break></break>Tel: +86 10 6915 8760<break></break>Fax: +86 10 6915 5039<break></break>Email: <email>zhanglipumch1026@sina.com</email><break></break></corresp></author-notes><pub-date pub-type="epub"><day>22</day><month>1</month><year>2020</year></pub-date><pub-date pub-type="ppub"><month>3</month><year>2020</year></pub-date><volume>11</volume><issue>3</issue><issue-id pub-id-type="doi">10.1111/tca.v11.3</issue-id><fpage>498</fpage><lpage>504</lpage><history><date date-type="received"><day>24</day><month>11</month><year>2019</year></date><date date-type="rev-recd"><day>28</day><month>12</month><year>2019</year></date><date date-type="accepted"><day>29</day><month>12</month><year>2019</year></date></history><permissions><pmc-comment> © 2020 China Lung Oncology Group and Wiley Publishing Asia Pty Ltd </pmc-comment>
<copyright-statement content-type="article-copyright">© 2020 The Authors. <italic>Thoracic Cancer</italic> published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd</copyright-statement><license license-type="creativeCommonsBy"><license-p>This is an open access article under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link> License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.</license-p></license></permissions><self-uri content-type="pdf" xlink:href="file:TCA-11-498.pdf"></self-uri><abstract><title>Abstract</title><p>Immune checkpoint inhibitors represent a major breakthrough in cancer therapy. Immune‐related adverse events (irAEs) may occur during treatment due to their unique mechanism of action. Management of irAEs is based on clinical experience because it is not easy to conduct prospective trials to evaluate the best treatment strategy. Using a combination of search terms in the PubMed and Embase databases, we reviewed all cases in the English language citing toxicities associated with either pembrolizumab, nivolumab, ipilimumab, atezolizumab, tremelimumab, durvalumab, avelumab or any combination of these agents published before 20 May 2019. A total of 128 reports with 239 cases were included in the study. Here, we summarize the spectrum of toxicities, safety in special patients, rechallenging after irAEs and agents used for treatment of irAEs in those reports.</p></abstract><kwd-group kwd-group-type="author-generated"><kwd id="tca13315-kwd-0001">Adverse event</kwd><kwd id="tca13315-kwd-0002">immune checkpoint inhibitor</kwd><kwd id="tca13315-kwd-0003">immunotherapy</kwd><kwd id="tca13315-kwd-0004">toxicity</kwd></kwd-group><funding-group><award-group id="funding-0001"><funding-source>CAMS Innovation Fund for Medical Sciences</funding-source><award-id>2016‐I2M‐1‐002</award-id></award-group></funding-group><counts><fig-count count="0"></fig-count><table-count count="2"></table-count><page-count count="7"></page-count><word-count count="4886"></word-count></counts><custom-meta-group><custom-meta><meta-name>source-schema-version-number</meta-name><meta-value>2.0</meta-value></custom-meta><custom-meta><meta-name>cover-date</meta-name><meta-value>March 2020</meta-value></custom-meta><custom-meta><meta-name>details-of-publishers-convertor</meta-name><meta-value>Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.6.1 mode:remove_FC converted:01.03.2020</meta-value></custom-meta></custom-meta-group></article-meta></front><body id="tca13315-body-0001"><sec id="tca13304-sec-1005"><title>Key points</title><p>This work summarizes the spectrum of irAEs, safety in special patients, rechallenging after irAEs and agents used for treatment of irAEs in 128 case reports.</p></sec><sec id="tca13315-sec-0001"><title>Introduction</title><p>Immune checkpoint inhibitors (ICIs) represent a major breakthrough in cancer therapy. Immune‐related adverse events (irAEs) may occur during treatment due to their unique mechanism of action. IrAEs are generally manageable but can be fatal in some cases.<xref rid="tca13315-bib-0001" ref-type="ref">1</xref> Management of irAEs is based on clinical experience because it is not easy to conduct prospective trials, although professional groups have developed guidelines of management. Using a combination of research terms in the PubMed and Embase databases, we reviewed all cases in the English language citing toxicities associated with either pembrolizumab, nivolumab, ipilimumab, atezolizumab, tremelimumab, durvalumab, avelumab or any combination of these agents published before 20 May 2019. A total of 128 reports with 239 cases were included in the study. Here, we summarize the spectrum of toxicities, safety in special patients, rechallenging after irAEs and agents used for treatment of irAEs in those cases.</p></sec><sec id="tca13315-sec-0002"><title>Toxicity profile</title><p>IrAEs occur in up to 90% of patients treated with an anti‐CTLA‐4 antibody and 70% of patients treated with a PD‐1/PD‐L1 antibody.<xref rid="tca13315-bib-0002" ref-type="ref">2</xref> The profile of irAE was different for PD‐1/PD‐L1 inhibitors and CTLA‐4 inhibitors. Several organ specific AE rates varied among tumor sites. The most frequent AEs of any grade with PD‐1/PD‐L1 inhibitors and CTLA‐4 inhibitors alone were diarrhea (11% and 36%), fatigue (21% and 25%) pruritus (15% and 25%) and rash (10% and 23%).<xref rid="tca13315-bib-0003" ref-type="ref">3</xref> The frequency of colitis ranged from 8% to 22%. It was reported that hypophysitis can affect up to 10% of patients treated with anti‐CTLA‐4 inhibitors.<xref rid="tca13315-bib-0002" ref-type="ref">2</xref> Hepatitis occurred in 5% to 10% of patients during treatment with ipilimumab, nivolumab and pembrolizumab.<xref rid="tca13315-bib-0004" ref-type="ref">4</xref> Thyroid dysfunction occurred in 5% to 10% patients receiving PD‐1/PD‐L1 inhibitors. Pneumonitis occurred in around 1% of patients treated with PD‐1/PD‐L1 or CTLA‐4 inhibitors.<xref rid="tca13315-bib-0002" ref-type="ref">2</xref></p><p>IrAEs can mimic autoimmune diseases and affect any organ system. irAEs in the case reports included in the study are summarized in Table <xref rid="tca13315-tbl-0001" ref-type="table">1</xref>. Besides common toxicities in different systems, the case reports also describe rare toxicities.</p><table-wrap id="tca13315-tbl-0001" xml:lang="en" orientation="portrait" position="float"><label>Table 1</label><caption><p>Spectrum of immune‐related adverse events in case reports</p></caption><table frame="hsides" rules="groups"><col align="left" span="1"></col><col align="left" span="1"></col><thead valign="bottom"><tr style="border-bottom:solid 1px #000000"><th align="left" valign="bottom" rowspan="1" colspan="1">System</th><th align="left" valign="bottom" rowspan="1" colspan="1">Immune‐related adverse events (number of case reports)</th></tr></thead><tbody valign="top"><tr><td align="left" valign="top" rowspan="1" colspan="1">Dermatologic (32)</td><td align="left" valign="top" rowspan="1" colspan="1">Vitiligo (1), granuloma annulare (2), bullous pemphigoid (3), psoriasis (22), erythema multiforme (1), lichenoid reaction (2), Grover's disease (1)</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Endocrinologic (52)</td><td align="left" valign="top" rowspan="1" colspan="1">Type 1 diabetes mellitus (38), hypophysitis (9), isolated adrenal insufficiency (1), thyroid storm (2), hypothyroidism (2)</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Gastrointestinal (47)</td><td align="left" valign="top" rowspan="1" colspan="1">Acute liver failure (1), hepatitis (8), bile duct obstruction (1), cholangitis (1), pancreatitis (1), hemorrhagic gastritis (1), ileitis (1), colitis (32), intestinal obstruction (1)</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Pulmonary (11)</td><td align="left" valign="top" rowspan="1" colspan="1">Organizing pneumonia (5), sarcoidosis (2), pneumonitis (4)</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Neurologic (20)</td><td align="left" valign="top" rowspan="1" colspan="1">Myasthenia gravis (5), Guillain‐Barre syndrome (3), cerebral edema (1), necrotizing encephalopathy (1), encephalitis (2), mononeuropathy multiplex with rhabdomyolysis (1), necrotic myelopathy (1), Bell's palsy (1), inflammation enteric neuropathy (1), brachial plexus neuritis (2), peripheral neuropathy (2)</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Cardiac (7)</td><td align="left" valign="top" rowspan="1" colspan="1">Myocarditis (2), cardiomyopathy (1), coronary spasm (1), pericardial effusion (3)</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Rheumatologic (28)</td><td align="left" valign="top" rowspan="1" colspan="1">Remitting seronegative symmetrical synovitis with pitting edema (1), arthritis (12), dermatomyositis/myositis (4), Goodpasture's disease (1), scleroderma (2), polymyalgia rheumatic (3), sicca syndrome (5)</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Nephrotic (7)</td><td align="left" valign="top" rowspan="1" colspan="1">Cystitis (1), renal failure (1), nephrotic syndrome (4), acute glomerulonephritis (1)</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Hematologic (16)</td><td align="left" valign="top" rowspan="1" colspan="1">Pancytopenia (2), neutropenia (6), aplastic anemia (2), pure red cell aplasia (1), thrombocytopenia (3), acute thrombosis (1), hemophagocytic lymphohistiocytosis (1)</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Ophthalmologic (17)</td><td align="left" valign="top" rowspan="1" colspan="1">Uveitis (7), Vogt‐Koyanagi‐Harada disease‐like uveitis (2), orbital inflammation (3), dry eye (2), ulcerative keratitis (1), ocular myositis (2)</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Otorhinolaryngologic (2)</td><td align="left" valign="top" rowspan="1" colspan="1">Sinusitis (2)</td></tr></tbody></table></table-wrap><p>The most frequent skin irAEs reported were rash and pruritus. Vitiligo, depigmented macules resulting from the loss of melanocytes, occurred mostly in melanoma patients treated with ICIs, while it also occurred in lung cancer patients.<xref rid="tca13315-bib-0005" ref-type="ref">5</xref> The PD‐L1/PD‐1 pathway probably mediates peripheral tolerance of melanosomal proteins, and PD‐1 inhibitor may induce vitiligo.<xref rid="tca13315-bib-0006" ref-type="ref">6</xref> Grover's disease, which presents as an intensely pruritic, papulovesicular rash, is a rare dermatologic toxicity. It has occasionally been reported during treatment with ipilimumab.<xref rid="tca13315-bib-0007" ref-type="ref">7</xref> It has been suggested that Th2 cells may play a possible role in its pathogenesis, and systemic corticosteroids may improve pruritus.</p><p>It was reported that hypophysitis occurred mostly in patients treated with anticytotoxic T lymphocyte associated antigen‐4 (CTLA4) inhibitors due to CTLA‐4 expressed on pituitary cells.<xref rid="tca13315-bib-0008" ref-type="ref">8</xref> However, hypophysitis has also been reported in patients treated with atezolizumab or nivolumab.<xref rid="tca13315-bib-0009" ref-type="ref">9</xref> Hypophysitis induced by PD‐1/PD‐L1 inhibitor usually presents as isolated ACTH deficiency. The pituitary gland can be divided into two different parts: the anterior and posterior lobes. The anterior lobe of the pituitary gland is made up of several different types of cells that produce and release different types of hormones, including growth hormone, thyroid‐stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), follicle‐stimulating hormone, luteinizing hormone and prolactin. The order of hormone deficiency specific to hypophysitis is as follows: ACTH > TSH > luteinizing hormone/follicle‐stimulating hormone > prolactin > growth hormone.<xref rid="tca13315-bib-0010" ref-type="ref">10</xref> Immune‐related hypophysitis may not affect all pituitary cell lines, and isolated ACTH deficiency has been reported.<xref rid="tca13315-bib-0009" ref-type="ref">9</xref>, <xref rid="tca13315-bib-0011" ref-type="ref">11</xref></p><p>ICI‐induced bile duct obstruction and cholangitis have been reported, and they should be considered as causes of cholangitis.<xref rid="tca13315-bib-0012" ref-type="ref">12</xref> Patients presented with fever, abdominal discomfort, fatigue, predominant elevation of alkaline phosphatase (ALP) and gamma‐glutamyl‐transpeptidase (GGT), and moderate elevation of transaminases (ALT/AST) and total bilirubin. Liver biopsy showed a predominant CD8‐positive T cell infiltrate. The response to corticosteroids was disappointing.<xref rid="tca13315-bib-0013" ref-type="ref">13</xref></p><p>Sarcoidosis presenting with hilar and mediastinal lymphadenopathy was reported in a lung cancer patient who received carboplatin/pemetrexed and pembrolizumab.<xref rid="tca13315-bib-0014" ref-type="ref">14</xref> T helper‐1 and T helper‐17 cells may play a role in the development of sarcoidosis.<xref rid="tca13315-bib-0015" ref-type="ref">15</xref> It is important to take a biopsy to differentiate sarcoidosis and disease progression. Most patients required discontinuation of therapy completely for a short period of time as well as immunosuppressant treatment.</p><p>While cardiac irAEs are rare, ICI‐induced myocarditis has a high fatality rate.<xref rid="tca13315-bib-0001" ref-type="ref">1</xref> Coronary spasm was reported in a patient treated with nivolumab.<xref rid="tca13315-bib-0016" ref-type="ref">16</xref> It was found that exhausted T cells expressing programmed cell death protein 1 (PD‐1) existed in atherosclerotic plaques. Therefore, treatment with PD‐1 inhibitors may have unanticipated consequences in cancer patients with underlying cardiovascular disease.<xref rid="tca13315-bib-0017" ref-type="ref">17</xref></p><p>Most patients with inflammatory arthritis from ICIs were negative for rheumatoid factor and anticyclic citrullinated peptide antibodies traditionally associated with rheumatoid arthritis.<xref rid="tca13315-bib-0018" ref-type="ref">18</xref> Treatment of inflammatory arthritis included nonsteroidal anti‐inflammatory drugs (NSAIDs), prednisone, and both nonbiologic and biologic disease‐modifying antirheumatic drugs (DMARDs).<xref rid="tca13315-bib-0019" ref-type="ref">19</xref></p><p>Hematological irAEs, including autoimmune hemolytic anemia, immune thrombocytopenia, neutropenia and aplastic anemia, are rarely reported. Surveillance of the complete blood count is essential. Oncologists should keep ICIs in mind as a possible cause of monolineage cytopenia or pancytopenia. Acute thrombosis was reported in a lung cancer patient treated with pembrolizumab.<xref rid="tca13315-bib-0020" ref-type="ref">20</xref> As coagulation disorders are common in cancer patients, it was not certain that the thrombosis could be attributed to pembrolizumab.</p><p>Patients presenting with photosensitivity, blurred vision, lacrimation, and diplopia, need an ophthalmology referral, although ophthalmic irAEs, such as uveitis, orbital inflammatory, and ulcerative keratitis, are rare.<xref rid="tca13315-bib-0021" ref-type="ref">21</xref>, <xref rid="tca13315-bib-0022" ref-type="ref">22</xref> Most patients were treated with topical or systemic corticosteroids.</p><p>Two cases of sinusitis, presenting as sinus pressure and nasal congestion after treatment of nivolumab, were reported to have responded to anti‐TNF therapy.<xref rid="tca13315-bib-0023" ref-type="ref">23</xref></p></sec><sec id="tca13315-sec-0003"><title>Safety of ICIs in patients with immune system impairment</title><p>Patients with pre‐existing diseases, such as autoimmune diseases and human immunodeficiency virus (HIV) infection were excluded from most clinical trials of ICIs. Safety of ICIs in this population is unclear.</p><p>It was suggested that patients with autoimmune disease could benefit from immunotherapy and experience tolerable toxicities that are manageable with immunosuppressive regimens. But close clinical monitoring is essential.<xref rid="tca13315-bib-0024" ref-type="ref">24</xref> Calabrese <italic>et al</italic>. reported a patient with psoriatic arthritis who experienced a psoriasis flare 2.8 weeks after starting nivolumab, while the patient with rheumatoid arthritis remained without disease activity on hydroxychloroquine throughout his course of immunotherapy.<xref rid="tca13315-bib-0025" ref-type="ref">25</xref> Uemura <italic>et al</italic>. reported a patient with advanced melanoma and refractory Crohn's disease who was treated concurrently with pembrolizumab and tocilizumab, which did not result in Crohn's disease exacerbation. It suggests that targeted immunosuppression combined with checkpoint inhibitors may be a treatment strategy for patients with autoimmune diseases.<xref rid="tca13315-bib-0026" ref-type="ref">26</xref></p><p>It was reported that highly active antiretroviral therapy improved the survival of patients with HIV, which increased the incidence of malignancies.<xref rid="tca13315-bib-0027" ref-type="ref">27</xref> Li <italic>et al</italic>. reported that a patient with HIV infection and non‐small cell lung cancer was treated with pembrolizumab and SBRT, and then experienced massive pericardial effusion and interstitial pneumonia.<xref rid="tca13315-bib-0028" ref-type="ref">28</xref> However, this case failed to explain the relationship between HIV infection and AEs. ICIs for the treatment of advanced‐stage cancer in patients with HIV infection might be associated with no new safety signals.<xref rid="tca13315-bib-0029" ref-type="ref">29</xref></p></sec><sec id="tca13315-sec-0004"><title>Rechallenging with ICIs after irAEs</title><p>Whether patients who experienced irAEs should be rechallenged with immunotherapy is a question for clinicians. When a good response (complete or partial) is observed prior to the onset of irAEs that require a treatment delay, it may be better to suspend retreatment with ICIs. A total of 15 patients were rechallenged with ICIs after experiencing irAEs details of which are provided in Table <xref rid="tca13315-tbl-0002" ref-type="table">2</xref>. Recurrence of irAEs is possible during rechallenging. Guidelines recommend permanent discontinuation of ICIs following a CTCAE grade 4 toxicity except endocrine toxicities which can be treated with hormone replacement.</p><table-wrap id="tca13315-tbl-0002" xml:lang="en" orientation="portrait" position="float"><label>Table 2</label><caption><p>Rechallenging after immune‐related adverse events (irAEs) in case reports</p></caption><table frame="hsides" rules="groups"><col align="left" span="1"></col><col align="left" span="1"></col><col align="left" span="1"></col><col align="left" span="1"></col><col align="left" span="1"></col><col align="left" span="1"></col><col align="left" span="1"></col><col align="left" span="1"></col><thead valign="bottom"><tr style="border-bottom:solid 1px #000000"><th align="left" valign="bottom" rowspan="1" colspan="1">Reports</th><th align="left" valign="bottom" rowspan="1" colspan="1">Sex/age</th><th align="left" valign="bottom" rowspan="1" colspan="1">Malignancy</th><th align="left" valign="bottom" rowspan="1" colspan="1">Immunotherapy</th><th align="left" valign="bottom" rowspan="1" colspan="1">irAEs</th><th align="left" valign="bottom" rowspan="1" colspan="1">Management of irAEs</th><th align="left" valign="bottom" rowspan="1" colspan="1">Retreatment</th><th align="left" valign="bottom" rowspan="1" colspan="1">Outcomes</th></tr></thead><tbody valign="top"><tr><td align="left" valign="top" rowspan="1" colspan="1">Utsunomiya <italic>et al</italic>.<xref rid="tca13315-bib-0030" ref-type="ref">30</xref></td><td align="left" valign="top" rowspan="1" colspan="1">F/37</td><td align="left" valign="top" rowspan="1" colspan="1">Melanoma</td><td align="left" valign="top" rowspan="1" colspan="1">Nivolumab, ipilimumab</td><td align="left" valign="top" rowspan="1" colspan="1">Erythema multiforme major</td><td align="left" valign="top" rowspan="1" colspan="1">Systemic corticosteroid, IVIG<xref ref-type="fn" rid="tca13315-note-0002">‡</xref></td><td align="left" valign="top" rowspan="1" colspan="1">Nivolumab</td><td align="left" valign="top" rowspan="1" colspan="1">Not described</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Anastasopoulou <italic>et al</italic>.<xref rid="tca13315-bib-0032" ref-type="ref">32</xref></td><td align="left" valign="top" rowspan="1" colspan="1">M/48</td><td align="left" valign="top" rowspan="1" colspan="1">Melanoma</td><td align="left" valign="top" rowspan="1" colspan="1">Nivolumab</td><td align="left" valign="top" rowspan="1" colspan="1">Bullous pemphigoid</td><td align="left" valign="top" rowspan="1" colspan="1">Systemic corticosteroids</td><td align="left" valign="top" rowspan="1" colspan="1">Pembrolizumab, ipilimumab</td><td align="left" valign="top" rowspan="1" colspan="1">No recurrence</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Uemura <italic>et al</italic>.<xref rid="tca13315-bib-0007" ref-type="ref">7</xref></td><td align="left" valign="top" rowspan="1" colspan="1">M/73</td><td align="left" valign="top" rowspan="1" colspan="1">Melanoma</td><td align="left" valign="top" rowspan="1" colspan="1">Ipilimumab</td><td align="left" valign="top" rowspan="1" colspan="1">Grover's disease</td><td align="left" valign="top" rowspan="1" colspan="1">Systemic corticosteroids</td><td align="left" valign="top" rowspan="1" colspan="1">Ipilimumab</td><td align="left" valign="top" rowspan="1" colspan="1">Recurrence</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Kanie <italic>et al</italic>.<xref rid="tca13315-bib-0009" ref-type="ref">9</xref></td><td align="left" valign="top" rowspan="1" colspan="1">M/65</td><td align="left" valign="top" rowspan="1" colspan="1">NSCLC<xref ref-type="fn" rid="tca13315-note-0001">†</xref></td><td align="left" valign="top" rowspan="1" colspan="1">Atezolizumab</td><td align="left" valign="top" rowspan="1" colspan="1">Hypophysitis</td><td align="left" valign="top" rowspan="1" colspan="1">Hydrocortisone replacement</td><td align="left" valign="top" rowspan="1" colspan="1">Atezolizumab</td><td align="left" valign="top" rowspan="1" colspan="1">No recurrence</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Chae <italic>et al</italic>.<xref rid="tca13315-bib-0033" ref-type="ref">33</xref></td><td align="left" valign="top" rowspan="1" colspan="1">M/76</td><td align="left" valign="top" rowspan="1" colspan="1">NSCLC<xref ref-type="fn" rid="tca13315-note-0001">†</xref></td><td align="left" valign="top" rowspan="1" colspan="1">Pembrolizumab</td><td align="left" valign="top" rowspan="1" colspan="1">Diabetes mellitus</td><td align="left" valign="top" rowspan="1" colspan="1">Insulin</td><td align="left" valign="top" rowspan="1" colspan="1">Pembrolizumab</td><td align="left" valign="top" rowspan="1" colspan="1">No recurrence</td></tr><tr><td rowspan="2" align="left" valign="top" colspan="1">Imafuku <italic>et al</italic>.<xref rid="tca13315-bib-0031" ref-type="ref">31</xref></td><td align="left" valign="top" rowspan="1" colspan="1">M/62</td><td align="left" valign="top" rowspan="1" colspan="1">Melanoma</td><td align="left" valign="top" rowspan="1" colspan="1">Nivolumab</td><td align="left" valign="top" rowspan="1" colspan="1">Pneumonitis</td><td align="left" valign="top" rowspan="1" colspan="1">Systemic corticosteroids</td><td align="left" valign="top" rowspan="1" colspan="1">Nivolumab</td><td align="left" valign="top" rowspan="1" colspan="1">No recurrence</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">M/75</td><td align="left" valign="top" rowspan="1" colspan="1">Melanoma</td><td align="left" valign="top" rowspan="1" colspan="1">Nivolumab</td><td align="left" valign="top" rowspan="1" colspan="1">Pneumonitis</td><td align="left" valign="top" rowspan="1" colspan="1">Systemic corticosteroids</td><td align="left" valign="top" rowspan="1" colspan="1">Nivolumab</td><td align="left" valign="top" rowspan="1" colspan="1">Recurrence</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Shaheen <italic>et al</italic>.<xref rid="tca13315-bib-0034" ref-type="ref">34</xref></td><td align="left" valign="top" rowspan="1" colspan="1">F/70</td><td align="left" valign="top" rowspan="1" colspan="1">NSCLC<xref ref-type="fn" rid="tca13315-note-0001">†</xref></td><td align="left" valign="top" rowspan="1" colspan="1">Nivolumab</td><td align="left" valign="top" rowspan="1" colspan="1">Pericardial effusion</td><td align="left" valign="top" rowspan="1" colspan="1">Systemic corticosteroids</td><td align="left" valign="top" rowspan="1" colspan="1">Nivolumab</td><td align="left" valign="top" rowspan="1" colspan="1">No recurrence</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Abu Samra <italic>et al</italic>.<xref rid="tca13315-bib-0035" ref-type="ref">35</xref></td><td align="left" valign="top" rowspan="1" colspan="1">M/82</td><td align="left" valign="top" rowspan="1" colspan="1">Melanoma</td><td align="left" valign="top" rowspan="1" colspan="1">Pembrolizumab</td><td align="left" valign="top" rowspan="1" colspan="1">Uveitis</td><td align="left" valign="top" rowspan="1" colspan="1">Steroid eye drops</td><td align="left" valign="top" rowspan="1" colspan="1">Pembrolizumab</td><td align="left" valign="top" rowspan="1" colspan="1">Recurrence</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Theillac <italic>et al</italic>.<xref rid="tca13315-bib-0022" ref-type="ref">22</xref></td><td align="left" valign="top" rowspan="1" colspan="1">M/55</td><td align="left" valign="top" rowspan="1" colspan="1">Melanoma</td><td align="left" valign="top" rowspan="1" colspan="1">Nivolumab</td><td align="left" valign="top" rowspan="1" colspan="1">Uveitis</td><td align="left" valign="top" rowspan="1" colspan="1">Systemic corticosteroids, steroid eye drops</td><td align="left" valign="top" rowspan="1" colspan="1">Nivolumab</td><td align="left" valign="top" rowspan="1" colspan="1">No recurrence</td></tr><tr><td rowspan="2" align="left" valign="top" colspan="1">Papavasileiou <italic>et al</italic>.<xref rid="tca13315-bib-0036" ref-type="ref">36</xref></td><td align="left" valign="top" rowspan="1" colspan="1">F/54</td><td align="left" valign="top" rowspan="1" colspan="1">Melanoma</td><td align="left" valign="top" rowspan="1" colspan="1">Ipilimumab</td><td align="left" valign="top" rowspan="1" colspan="1">Uveitis</td><td align="left" valign="top" rowspan="1" colspan="1">Topical steroid</td><td align="left" valign="top" rowspan="1" colspan="1">Ipilimumab</td><td align="left" valign="top" rowspan="1" colspan="1">Hypophysitis, colitis</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">F/47</td><td align="left" valign="top" rowspan="1" colspan="1">Melanoma</td><td align="left" valign="top" rowspan="1" colspan="1">Ipilimumab</td><td align="left" valign="top" rowspan="1" colspan="1">Orbital inflammation</td><td align="left" valign="top" rowspan="1" colspan="1">Systemic corticosteroids</td><td align="left" valign="top" rowspan="1" colspan="1">Ipilimumab</td><td align="left" valign="top" rowspan="1" colspan="1">Recurrence</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Nguyen <italic>et al</italic>.<xref rid="tca13315-bib-0037" ref-type="ref">37</xref></td><td align="left" valign="top" rowspan="1" colspan="1">M/55</td><td align="left" valign="top" rowspan="1" colspan="1">Melanoma</td><td align="left" valign="top" rowspan="1" colspan="1">Nivolumab</td><td align="left" valign="top" rowspan="1" colspan="1">Dry eye, corneal perforation</td><td align="left" valign="top" rowspan="1" colspan="1">Topical cyclosporine, topical loteprednol, autologous serum tears, doxycycline</td><td align="left" valign="top" rowspan="1" colspan="1">Nivolumab</td><td align="left" valign="top" rowspan="1" colspan="1">No recurrence</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">Ngo <italic>et al</italic>.<xref rid="tca13315-bib-0038" ref-type="ref">38</xref></td><td align="left" valign="top" rowspan="1" colspan="1">M/70</td><td align="left" valign="top" rowspan="1" colspan="1">Melanoma</td><td align="left" valign="top" rowspan="1" colspan="1">Nivolumab, ipilimumab</td><td align="left" valign="top" rowspan="1" colspan="1">Synovitis</td><td align="left" valign="top" rowspan="1" colspan="1">Systemic corticosteroids</td><td align="left" valign="top" rowspan="1" colspan="1">Nivolumab</td><td align="left" valign="top" rowspan="1" colspan="1">No recurrence</td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">du Rusquec <italic>et al</italic>.<xref rid="tca13315-bib-0039" ref-type="ref">39</xref></td><td align="left" valign="top" rowspan="1" colspan="1">F/77</td><td align="left" valign="top" rowspan="1" colspan="1">Melanoma</td><td align="left" valign="top" rowspan="1" colspan="1">Ipilimumab</td><td align="left" valign="top" rowspan="1" colspan="1">Pancytopenia</td><td align="left" valign="top" rowspan="1" colspan="1">Systemic corticosteroids, IVIG<xref ref-type="fn" rid="tca13315-note-0002">‡</xref>, erythropoietin, filgrastim</td><td align="left" valign="top" rowspan="1" colspan="1">Ipilimumab</td><td align="left" valign="top" rowspan="1" colspan="1">Recurrence</td></tr></tbody></table><table-wrap-foot id="tca13315-ntgp-0001"><fn id="tca13315-note-0001"><label>†</label><p>Non‐small cell lung cancer.</p></fn><fn id="tca13315-note-0002"><label>‡</label><p>Intravenous immunoglobulin.</p></fn></table-wrap-foot></table-wrap><p>Utsunomiya <italic>et al</italic>. reported a patient retreated with nivolumab after grade 4 erythema multiforme major.<xref rid="tca13315-bib-0030" ref-type="ref">30</xref> However, they did not recommend retreatment after grade 4 dermatologic toxicities according to NCCN and ESMO guidelines. For cases of interstitial pneumonitis consistent with a diffuse alveolar damage (DAD) pattern, it is suggested that the corticosteroid dose should be gradually reduced over time, and ICIs should be discontinued.<xref rid="tca13315-bib-0031" ref-type="ref">31</xref></p><p>A retrospective study showed the risk‐reward ratio for an anti‐PD‐1 or anti‐PD‐L1 rechallenge appeared to be acceptable, although these patients require close monitoring.<xref rid="tca13315-bib-0040" ref-type="ref">40</xref></p></sec><sec id="tca13315-sec-0005"><title>Agents used for treatment of irAEs</title><p>Most irAEs are steroid‐sensitive and resolve within six to 12 weeks. If irAEs show insufficient improvement despite the use of adequate corticosteroids, immunomodulatory agents should be considered after exclusion of other causes.</p><p>Intravenous immunoglobulin (IVIg) has been used with corticosteroid in patients with immunotherapy‐related erythema multiforme major,<xref rid="tca13315-bib-0030" ref-type="ref">30</xref> myasthenia gravis,<xref rid="tca13315-bib-0041" ref-type="ref">41</xref> Guillain‐Barré syndrome,<xref rid="tca13315-bib-0042" ref-type="ref">42</xref> encephalopathy,<xref rid="tca13315-bib-0043" ref-type="ref">43</xref> peripheral neuropathy,<xref rid="tca13315-bib-0044" ref-type="ref">44</xref> scleroderma,<xref rid="tca13315-bib-0045" ref-type="ref">45</xref> ocular myositis,<xref rid="tca13315-bib-0046" ref-type="ref">46</xref> pancytopenia,<xref rid="tca13315-bib-0039" ref-type="ref">39</xref>, <xref rid="tca13315-bib-0047" ref-type="ref">47</xref> and neutropenia.<xref rid="tca13315-bib-0048" ref-type="ref">48</xref> Most irAEs showed improvement, while myasthenia gravis, Guillain‐Barré syndrome, and necrotizing encephalopathy worsened in some patients.</p><p>Infliximab is a chimeric monoclonal antibody binding to tumor necrosis factor‐α. Infliximab was used in patients with immunotherapy‐related polymyalgia rheumatic,<xref rid="tca13315-bib-0025" ref-type="ref">25</xref> peripheral neuropathy,<xref rid="tca13315-bib-0044" ref-type="ref">44</xref> necrotic myelopathy,<xref rid="tca13315-bib-0043" ref-type="ref">43</xref> Guillain‐Barré syndrome,<xref rid="tca13315-bib-0049" ref-type="ref">49</xref> hemorrhagic gastritis,<xref rid="tca13315-bib-0050" ref-type="ref">50</xref> and organizing pneumonia.<xref rid="tca13315-bib-0051" ref-type="ref">51</xref> Infliximab is recommended to be used in patients with severe immunotherapy‐related toxicities whose symptoms cannot be controlled by corticosteroids within 48 to 72 hours according to the National Comprehensive Cancer Network (NCCN) guidelines.<xref rid="tca13315-bib-0052" ref-type="ref">52</xref> However, Abu‐Sbeih <italic>et al</italic>. reported that infliximab should be introduced early in the disease course of immunotherapy‐related colitis instead of waiting until failure of corticosteroid therapy or corticosteroid taper.<xref rid="tca13315-bib-0053" ref-type="ref">53</xref></p><p>Adalimumab is a recombinant human monoclonal antibody that binds specifically to tumor necrosis factor‐α, blocking interaction with its cell surface receptors and thereby reducing the impact of inflammation. Adalimumab was used in two cases of sinusitis induced by ICIs.<xref rid="tca13315-bib-0023" ref-type="ref">23</xref></p><p>Tocilizumab is a recombinant humanized anti‐human interleukin 6 (IL‐6) receptor monoclonal antibody. Tocilizumab was used in patients with immunotherapy‐related pneumonitis<xref rid="tca13315-bib-0054" ref-type="ref">54</xref> and arthritis.<xref rid="tca13315-bib-0055" ref-type="ref">55</xref></p><p>Rituximab is a chimeric monoclonal antibody binding to CD20 proteins. Rituximab was used in patients with autoimmune encephalitis associated with nivolumab and ipilimumab.<xref rid="tca13315-bib-0056" ref-type="ref">56</xref></p><p>Martins <italic>et al</italic>. proposed a so‐called shut‐off strategy aimed at inhibiting key inflammatory components involved in the pathophysiological processes of irAEs, and limited potential adverse effects of drug immunosuppression on tumor response.<xref rid="tca13315-bib-0057" ref-type="ref">57</xref> The biological immunosuppressive agents are important to manage refractory irAEs.</p></sec><sec id="tca13315-sec-0006"><title>Limitations of review</title><p>The limitations of this review are potential selection bias and publication bias based on case reports. Authors and editors usually choose rare and successfully managed cases to publish. Our study is limited by information available in the original reports. This review did not include cases of immunotherapies combined with chemotherapy, which may cause a higher incidence and severity of irAEs.</p><p>In conclusion, as immune‐related toxicity can affect any organ system, clinicians should keep this in mind as a possible cause of any symptom or abnormality during treatment of ICIs. Rechallenging with ICIs after irAEs requires close monitoring. The biological immunosuppressive agents will be important to manage refractory irAEs. Further research establishing optimal guidelines on how to manage irAEs is necessary.</p></sec><sec id="tca13315-sec-0008"><title>Disclosure</title><p>The authors have no potential conflicts of interest to disclose.</p></sec></body><back><ack id="tca13315-sec-0007"><title>Acknowledgments</title><p>This work was supported by a grant from CAMS Innovation Fund for Medical Sciences (CIFMS; No. 2016‐I2M‐1‐002).</p></ack><ref-list id="tca13315-bibl-0001" content-type="cited-references"><title>References</title><ref id="tca13315-bib-0001"><label>1</label><mixed-citation publication-type="journal" id="tca13315-cit-0001"><string-name><surname>Wang</surname><given-names>DY</given-names></string-name>, <string-name><surname>Salem</surname><given-names>JE</given-names></string-name>, <string-name><surname>Cohen</surname><given-names>JV</given-names></string-name><italic>et al</italic><article-title>Fatal toxic effects associated with immune checkpoint inhibitors: A systematic review and meta‐analysis</article-title>. <source xml:lang="en">JAMA Oncol</source><year>2018</year>; 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