Toxicities associated with checkpoint inhibitors—an overview
Identifieur interne : 000805 ( Pmc/Corpus ); précédent : 000804; suivant : 000806Toxicities associated with checkpoint inhibitors—an overview
Auteurs : Laura Spiers ; Nicholas Coupe ; Miranda PayneSource :
- Rheumatology (Oxford, England) [ 1462-0324 ] ; 2019.
Abstract
Immunotherapy has an increasing role in the management of cancer, both in metastatic disease and as an adjuvant therapy. However, sensitization of the immune system with checkpoint inhibitors comes with a unique side effect profile. Full appreciation of this can take some time to emerge as some adverse events are rare, or can be subtle and potentially overlooked. Clinician awareness of these side effects can be particularly important in patients with pre-existing autoimmune conditions. Here we describe common symptoms and diagnostic strategies for organ-specific side effects of anti-CTLA-4 and anti-PD-1/PD-L1 immunotherapy agents.
Url:
DOI: 10.1093/rheumatology/kez418
PubMed: 31816085
PubMed Central: 6900917
Links to Exploration step
PMC:6900917Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Toxicities associated with checkpoint inhibitors—an overview</title><author><name sortKey="Spiers, Laura" sort="Spiers, Laura" uniqKey="Spiers L" first="Laura" last="Spiers">Laura Spiers</name><affiliation><nlm:aff id="kez418-aff1"></nlm:aff></affiliation></author><author><name sortKey="Coupe, Nicholas" sort="Coupe, Nicholas" uniqKey="Coupe N" first="Nicholas" last="Coupe">Nicholas Coupe</name><affiliation><nlm:aff id="kez418-aff1"></nlm:aff></affiliation></author><author><name sortKey="Payne, Miranda" sort="Payne, Miranda" uniqKey="Payne M" first="Miranda" last="Payne">Miranda Payne</name><affiliation><nlm:aff id="kez418-aff1"></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31816085</idno><idno type="pmc">6900917</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900917</idno><idno type="RBID">PMC:6900917</idno><idno type="doi">10.1093/rheumatology/kez418</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000805</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000805</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Toxicities associated with checkpoint inhibitors—an overview</title><author><name sortKey="Spiers, Laura" sort="Spiers, Laura" uniqKey="Spiers L" first="Laura" last="Spiers">Laura Spiers</name><affiliation><nlm:aff id="kez418-aff1"></nlm:aff></affiliation></author><author><name sortKey="Coupe, Nicholas" sort="Coupe, Nicholas" uniqKey="Coupe N" first="Nicholas" last="Coupe">Nicholas Coupe</name><affiliation><nlm:aff id="kez418-aff1"></nlm:aff></affiliation></author><author><name sortKey="Payne, Miranda" sort="Payne, Miranda" uniqKey="Payne M" first="Miranda" last="Payne">Miranda Payne</name><affiliation><nlm:aff id="kez418-aff1"></nlm:aff></affiliation></author></analytic><series><title level="j">Rheumatology (Oxford, England)</title><idno type="ISSN">1462-0324</idno><idno type="eISSN">1462-0332</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Abstract</title><p>Immunotherapy has an increasing role in the management of cancer, both in metastatic disease and as an adjuvant therapy. However, sensitization of the immune system with checkpoint inhibitors comes with a unique side effect profile. Full appreciation of this can take some time to emerge as some adverse events are rare, or can be subtle and potentially overlooked. Clinician awareness of these side effects can be particularly important in patients with pre-existing autoimmune conditions. Here we describe common symptoms and diagnostic strategies for organ-specific side effects of anti-CTLA-4 and anti-PD-1/PD-L1 immunotherapy agents.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Cousin, S" uniqKey="Cousin S">S Cousin</name></author><author><name sortKey="Seneschal, J" uniqKey="Seneschal J">J Seneschal</name></author><author><name sortKey="Italiano, A" uniqKey="Italiano A">A. Italiano</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Puzanov, I" uniqKey="Puzanov I">I Puzanov</name></author><author><name sortKey="Diab, A" uniqKey="Diab A">A Diab</name></author><author><name sortKey="Abdallah, K" uniqKey="Abdallah K">K Abdallah</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kartolo, A" uniqKey="Kartolo A">A Kartolo</name></author><author><name sortKey="Sattar, J" uniqKey="Sattar J">J Sattar</name></author><author><name sortKey="Sahai, V" uniqKey="Sahai V">V Sahai</name></author><author><name sortKey="Baetz, T" uniqKey="Baetz T">T Baetz</name></author><author><name sortKey="Lakoff, Jm" uniqKey="Lakoff J">JM. Lakoff</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Topalian, Sl" uniqKey="Topalian S">SL Topalian</name></author><author><name sortKey="Hodi, Fs" uniqKey="Hodi F">FS Hodi</name></author><author><name sortKey="Brahmer, Jr" uniqKey="Brahmer J">JR Brahmer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Maughan, Bl" uniqKey="Maughan B">BL Maughan</name></author><author><name sortKey="Bailey, E" uniqKey="Bailey E">E Bailey</name></author><author><name sortKey="Gill, Dm" uniqKey="Gill D">DM Gill</name></author><author><name sortKey="Agarwal, N" uniqKey="Agarwal N">N. Agarwal</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Haanen, J" uniqKey="Haanen J">J Haanen</name></author><author><name sortKey="Carbonnel, F" uniqKey="Carbonnel F">F Carbonnel</name></author><author><name sortKey="Robert, C" uniqKey="Robert C">C Robert</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bertrand, A" uniqKey="Bertrand A">A Bertrand</name></author><author><name sortKey="Kostine, M" uniqKey="Kostine M">M Kostine</name></author><author><name sortKey="Barnetche, T" uniqKey="Barnetche T">T Barnetche</name></author><author><name sortKey="Truchetet, Me" uniqKey="Truchetet M">ME Truchetet</name></author><author><name sortKey="Schaeverbeke, T" uniqKey="Schaeverbeke T">T. Schaeverbeke</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Villadolid, J" uniqKey="Villadolid J">J Villadolid</name></author><author><name sortKey="Amin, A" uniqKey="Amin A">A. Amin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lin, Z" uniqKey="Lin Z">Z Lin</name></author><author><name sortKey="Chen, X" uniqKey="Chen X">X Chen</name></author><author><name sortKey="Li, Z" uniqKey="Li Z">Z Li</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Johnson, Db" uniqKey="Johnson D">DB Johnson</name></author><author><name sortKey="Sullivan, Rj" uniqKey="Sullivan R">RJ Sullivan</name></author><author><name sortKey="Ott, Pa" uniqKey="Ott P">PA Ott</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Oble, Da" uniqKey="Oble D">DA Oble</name></author><author><name sortKey="Mino Kenudson, M" uniqKey="Mino Kenudson M">M Mino-Kenudson</name></author><author><name sortKey="Goldsmith, J" uniqKey="Goldsmith J">J Goldsmith</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gupta, A" uniqKey="Gupta A">A Gupta</name></author><author><name sortKey="De Felice, Km" uniqKey="De Felice K">KM De Felice</name></author><author><name sortKey="Loftus, Ev" uniqKey="Loftus E">EV Loftus</name></author><author><name sortKey="Khanna, S" uniqKey="Khanna S">S. Khanna</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gonzalez, Rs" uniqKey="Gonzalez R">RS Gonzalez</name></author><author><name sortKey="Salaria, Sn" uniqKey="Salaria S">SN Salaria</name></author><author><name sortKey="Bohannon, Cd" uniqKey="Bohannon C">CD Bohannon</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Karamchandani, Dm" uniqKey="Karamchandani D">DM Karamchandani</name></author><author><name sortKey="Chetty, R" uniqKey="Chetty R">R. Chetty</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jain, A" uniqKey="Jain A">A Jain</name></author><author><name sortKey="Lipson, Ej" uniqKey="Lipson E">EJ Lipson</name></author><author><name sortKey="Sharfman, Wh" uniqKey="Sharfman W">WH Sharfman</name></author><author><name sortKey="Brant, Sr" uniqKey="Brant S">SR Brant</name></author><author><name sortKey="Lazarev, Mg" uniqKey="Lazarev M">MG. Lazarev</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kim, Kw" uniqKey="Kim K">KW Kim</name></author><author><name sortKey="Ramaiya, Nh" uniqKey="Ramaiya N">NH Ramaiya</name></author><author><name sortKey="Krajewski, Km" uniqKey="Krajewski K">KM Krajewski</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Beck, Ke" uniqKey="Beck K">KE Beck</name></author><author><name sortKey="Blansfield, Ja" uniqKey="Blansfield J">JA Blansfield</name></author><author><name sortKey="Tran, Kq" uniqKey="Tran K">KQ Tran</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Berman, D" uniqKey="Berman D">D Berman</name></author><author><name sortKey="Parker, Sm" uniqKey="Parker S">SM Parker</name></author><author><name sortKey="Siegel, J" uniqKey="Siegel J">J Siegel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Spain, L" uniqKey="Spain L">L Spain</name></author><author><name sortKey="Diem, S" uniqKey="Diem S">S Diem</name></author><author><name sortKey="Larkin, J" uniqKey="Larkin J">J. Larkin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cramer, P" uniqKey="Cramer P">P Cramer</name></author><author><name sortKey="Bresalier, Rs" uniqKey="Bresalier R">RS. Bresalier</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mekki, A" uniqKey="Mekki A">A Mekki</name></author><author><name sortKey="Dercle, L" uniqKey="Dercle L">L Dercle</name></author><author><name sortKey="Lichtenstein, P" uniqKey="Lichtenstein P">P. Lichtenstein</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Baraibar, I" uniqKey="Baraibar I">I Baraibar</name></author><author><name sortKey="Melero, I" uniqKey="Melero I">I Melero</name></author><author><name sortKey="Sarvise, Mp" uniqKey="Sarvise M">MP Sarvise</name></author><author><name sortKey="Castanon, E" uniqKey="Castanon E">E. Castanon</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Byun, Dj" uniqKey="Byun D">DJ Byun</name></author><author><name sortKey="Wolchok, Jd" uniqKey="Wolchok J">JD Wolchok</name></author><author><name sortKey="Rosenberg, Lm" uniqKey="Rosenberg L">LM Rosenberg</name></author><author><name sortKey="Girotra, M" uniqKey="Girotra M">M. Girotra</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hughes, J" uniqKey="Hughes J">J Hughes</name></author><author><name sortKey="Vudattu, N" uniqKey="Vudattu N">N Vudattu</name></author><author><name sortKey="Sznol, M" uniqKey="Sznol M">M Sznol</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Antinori, A" uniqKey="Antinori A">A Antinori</name></author><author><name sortKey="Arendt, G" uniqKey="Arendt G">G Arendt</name></author><author><name sortKey="Becker, Jt" uniqKey="Becker J">JT Becker</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Naidoo, J" uniqKey="Naidoo J">J Naidoo</name></author><author><name sortKey="Page, Db" uniqKey="Page D">DB Page</name></author><author><name sortKey="Li, Bt" uniqKey="Li B">BT Li</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sibaud, V" uniqKey="Sibaud V">V. Sibaud</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hua, C" uniqKey="Hua C">C Hua</name></author><author><name sortKey="Boussemart, L" uniqKey="Boussemart L">L Boussemart</name></author><author><name sortKey="Mateus, C" uniqKey="Mateus C">C Mateus</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Orditura, M" uniqKey="Orditura M">M Orditura</name></author><author><name sortKey="De Vita, F" uniqKey="De Vita F">F De Vita</name></author><author><name sortKey="Galizia, G" uniqKey="Galizia G">G Galizia</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Larkin, J" uniqKey="Larkin J">J Larkin</name></author><author><name sortKey="Chiarion Sileni, V" uniqKey="Chiarion Sileni V">V Chiarion-Sileni</name></author><author><name sortKey="Gonzalez, R" uniqKey="Gonzalez R">R Gonzalez</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lidar, M" uniqKey="Lidar M">M Lidar</name></author><author><name sortKey="Giat, E" uniqKey="Giat E">E Giat</name></author><author><name sortKey="Garelick, D" uniqKey="Garelick D">D Garelick</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cappelli, Lc" uniqKey="Cappelli L">LC Cappelli</name></author><author><name sortKey="Gutierrez, Ak" uniqKey="Gutierrez A">AK Gutierrez</name></author><author><name sortKey="Baer, An" uniqKey="Baer A">AN Baer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Belkhir, R" uniqKey="Belkhir R">R Belkhir</name></author><author><name sortKey="Burel, Sl" uniqKey="Burel S">SL Burel</name></author><author><name sortKey="Dunogeant, L" uniqKey="Dunogeant L">L Dunogeant</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Naidoo, J" uniqKey="Naidoo J">J Naidoo</name></author><author><name sortKey="Cappelli, Lc" uniqKey="Cappelli L">LC Cappelli</name></author><author><name sortKey="Forde, Pm" uniqKey="Forde P">PM Forde</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Touat, M" uniqKey="Touat M">M Touat</name></author><author><name sortKey="Maisonobe, T" uniqKey="Maisonobe T">T Maisonobe</name></author><author><name sortKey="Knauss, S" uniqKey="Knauss S">S Knauss</name></author><author><name sortKey="Ben, O" uniqKey="Ben O">O Ben</name></author><author><name sortKey="Salem, H" uniqKey="Salem H">H. Salem</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Eggermont, Amm" uniqKey="Eggermont A">AMM Eggermont</name></author><author><name sortKey="Chiarion Sileni, V" uniqKey="Chiarion Sileni V">V Chiarion-sileni</name></author><author><name sortKey="Grob, J" uniqKey="Grob J">J Grob</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nukui, T" uniqKey="Nukui T">T Nukui</name></author><author><name sortKey="Nakayama, Y" uniqKey="Nakayama Y">Y Nakayama</name></author><author><name sortKey="Yamamoto, M" uniqKey="Yamamoto M">M Yamamoto</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tanaka, R" uniqKey="Tanaka R">R Tanaka</name></author><author><name sortKey="Maruyama, H" uniqKey="Maruyama H">H Maruyama</name></author><author><name sortKey="Tomidokoro, Y" uniqKey="Tomidokoro Y">Y Tomidokoro</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gonzalez, Nl" uniqKey="Gonzalez N">NL Gonzalez</name></author><author><name sortKey="Puwanant, A" uniqKey="Puwanant A">A Puwanant</name></author><author><name sortKey="Lu, A" uniqKey="Lu A">A Lu</name></author><author><name sortKey="Marks, Sm" uniqKey="Marks S">SM Marks</name></author><author><name sortKey="Zivkovic, Sa" uniqKey="Zivkovic S">SA. Živkovic</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Levine, Jj" uniqKey="Levine J">JJ Levine</name></author><author><name sortKey="Somer, Ra" uniqKey="Somer R">RA Somer</name></author><author><name sortKey="Hosoya, H" uniqKey="Hosoya H">H Hosoya</name></author><author><name sortKey="Squillante, C" uniqKey="Squillante C">C. Squillante</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Burke, M" uniqKey="Burke M">M Burke</name></author><author><name sortKey="Hardesty, M" uniqKey="Hardesty M">M Hardesty</name></author><author><name sortKey="Downs, W" uniqKey="Downs W">W. Downs</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Williams, Tj" uniqKey="Williams T">TJ Williams</name></author><author><name sortKey="Benavides, Dr" uniqKey="Benavides D">DR Benavides</name></author><author><name sortKey="Patrice, K" uniqKey="Patrice K">K Patrice</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Feng, S" uniqKey="Feng S">S Feng</name></author><author><name sortKey="Coward, J" uniqKey="Coward J">J Coward</name></author><author><name sortKey="Mccaffrey, E" uniqKey="Mccaffrey E">E Mccaffrey</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Smith, Jl" uniqKey="Smith J">JL Smith</name></author><author><name sortKey="Menzies, Am" uniqKey="Menzies A">AM Menzies</name></author><author><name sortKey="Cohen, Jv" uniqKey="Cohen J">JV Cohen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Izzedine, H" uniqKey="Izzedine H">H Izzedine</name></author><author><name sortKey="Gueutin, V" uniqKey="Gueutin V">V Gueutin</name></author><author><name sortKey="Gharbi, C" uniqKey="Gharbi C">C Gharbi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Belliere, J" uniqKey="Belliere J">J Belliere</name></author><author><name sortKey="Meyer, N" uniqKey="Meyer N">N Meyer</name></author><author><name sortKey="Mazieres, J" uniqKey="Mazieres J">J Mazieres</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wanchoo, R" uniqKey="Wanchoo R">R Wanchoo</name></author><author><name sortKey="Karam, S" uniqKey="Karam S">S Karam</name></author><author><name sortKey="Uppal, Nn" uniqKey="Uppal N">NN Uppal</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cortazar, Fb" uniqKey="Cortazar F">FB Cortazar</name></author><author><name sortKey="Marrone, Ka" uniqKey="Marrone K">KA Marrone</name></author><author><name sortKey="Troxell, Ml" uniqKey="Troxell M">ML Troxell</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Belliere, J" uniqKey="Belliere J">J Belliere</name></author><author><name sortKey="Meyer, N" uniqKey="Meyer N">N Meyer</name></author><author><name sortKey="Mazieres, J" uniqKey="Mazieres J">J Mazieres</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lefebvre, J" uniqKey="Lefebvre J">J Lefebvre</name></author><author><name sortKey="Glezerman, Ig" uniqKey="Glezerman I">IG. Glezerman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lipson, Ej" uniqKey="Lipson E">EJ Lipson</name></author><author><name sortKey="Bodell, Ma" uniqKey="Bodell M">MA Bodell</name></author><author><name sortKey="Kraus, Es" uniqKey="Kraus E">ES Kraus</name></author><author><name sortKey="Sharfman, Wh" uniqKey="Sharfman W">WH. Sharfman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Delaunay, M" uniqKey="Delaunay M">M Delaunay</name></author><author><name sortKey="Cadranel, J" uniqKey="Cadranel J">J Cadranel</name></author><author><name sortKey="Lusque, A" uniqKey="Lusque A">A Lusque</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Johnson, Db" uniqKey="Johnson D">DB Johnson</name></author><author><name sortKey="Balko, Jm" uniqKey="Balko J">JM Balko</name></author><author><name sortKey="Compton, Ml" uniqKey="Compton M">ML Compton</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nishimura, H" uniqKey="Nishimura H">H Nishimura</name></author><author><name sortKey="Okazaki, T" uniqKey="Okazaki T">T Okazaki</name></author><author><name sortKey="Tanaka, Y" uniqKey="Tanaka Y">Y. Tanaka</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lucas, Ja" uniqKey="Lucas J">JA Lucas</name></author><author><name sortKey="Menke, J" uniqKey="Menke J">J Menke</name></author><author><name sortKey="Rabacal, Wa" uniqKey="Rabacal W">WA Rabacal</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kumar, V" uniqKey="Kumar V">V Kumar</name></author><author><name sortKey="Chaudhary, N" uniqKey="Chaudhary N">N Chaudhary</name></author><author><name sortKey="Garg, M" uniqKey="Garg M">M Garg</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kanno, H" uniqKey="Kanno H">H Kanno</name></author><author><name sortKey="Ishida, K" uniqKey="Ishida K">K Ishida</name></author><author><name sortKey="Yamada, W" uniqKey="Yamada W">W Yamada</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Thomas, M" uniqKey="Thomas M">M Thomas</name></author><author><name sortKey="Armenti, St" uniqKey="Armenti S">ST Armenti</name></author><author><name sortKey="Ayres, B" uniqKey="Ayres B">B Ayres</name></author><author><name sortKey="Demirci, H" uniqKey="Demirci H">H. Demirci</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Arai, T" uniqKey="Arai T">T, Arai</name></author><author><name sortKey="Harada, K" uniqKey="Harada K">K, Harada</name></author><author><name sortKey="Usui, Y" uniqKey="Usui Y">Y, Usui</name></author><author><name sortKey="Irisawa, R" uniqKey="Irisawa R">R, Irisawa</name></author><author><name sortKey="Tsuboi, R" uniqKey="Tsuboi R">R. Tsuboi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Atwal, D" uniqKey="Atwal D">D Atwal</name></author><author><name sortKey="Joshi, Kp" uniqKey="Joshi K">KP Joshi</name></author><author><name sortKey="Ravilla, R" uniqKey="Ravilla R">R Ravilla</name></author><author><name sortKey="Mahmoud, F" uniqKey="Mahmoud F">F. Mahmoud</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Michot, J" uniqKey="Michot J">J Michot</name></author><author><name sortKey="Vargaftig, J" uniqKey="Vargaftig J">J Vargaftig</name></author><author><name sortKey="Leduc, C" uniqKey="Leduc C">C Leduc</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Comito, Rr" uniqKey="Comito R">RR Comito</name></author><author><name sortKey="Badu, La" uniqKey="Badu L">LA Badu</name></author><author><name sortKey="Forcello, N" uniqKey="Forcello N">N. Forcello</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pfohler, C" uniqKey="Pfohler C">C Pföhler</name></author><author><name sortKey="Burgard, B" uniqKey="Burgard B">B Burgard</name></author><author><name sortKey="Muller, Csl" uniqKey="Muller C">CSL. Müller</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Donia, M" uniqKey="Donia M">M Donia</name></author><author><name sortKey="Pedersen, M" uniqKey="Pedersen M">M Pedersen</name></author><author><name sortKey="Svane, Im" uniqKey="Svane I">IM. Svane</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gettings, Ej" uniqKey="Gettings E">EJ Gettings</name></author><author><name sortKey="Hackett, Ct" uniqKey="Hackett C">CT Hackett</name></author><author><name sortKey="Scott, Tf" uniqKey="Scott T">TF. Scott</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lee, B" uniqKey="Lee B">B Lee</name></author><author><name sortKey="Wong, A" uniqKey="Wong A">A Wong</name></author><author><name sortKey="Kee, D" uniqKey="Kee D">D Kee</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Johnson, Db" uniqKey="Johnson D">DB Johnson</name></author><author><name sortKey="Sullivan, Rj" uniqKey="Sullivan R">RJ Sullivan</name></author><author><name sortKey="Ott, Pa" uniqKey="Ott P">PA Ott</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gutzmer, R" uniqKey="Gutzmer R">R Gutzmer</name></author><author><name sortKey="Koop, A" uniqKey="Koop A">A Koop</name></author><author><name sortKey="Meier, F" uniqKey="Meier F">F Meier</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Menzies, Am" uniqKey="Menzies A">AM Menzies</name></author><author><name sortKey="Johnson, Db" uniqKey="Johnson D">DB Johnson</name></author><author><name sortKey="Ramanujam, S" uniqKey="Ramanujam S">S Ramanujam</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Rheumatology (Oxford)</journal-id><journal-id journal-id-type="iso-abbrev">Rheumatology (Oxford)</journal-id><journal-id journal-id-type="publisher-id">brheum</journal-id><journal-title-group><journal-title>Rheumatology (Oxford, England)</journal-title></journal-title-group><issn pub-type="ppub">1462-0324</issn><issn pub-type="epub">1462-0332</issn><publisher><publisher-name>Oxford University Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31816085</article-id><article-id pub-id-type="pmc">6900917</article-id><article-id pub-id-type="doi">10.1093/rheumatology/kez418</article-id><article-id pub-id-type="publisher-id">kez418</article-id><article-categories><subj-group subj-group-type="heading"><subject>Supplement Articles</subject></subj-group></article-categories><title-group><article-title>Toxicities associated with checkpoint inhibitors—an overview</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Spiers</surname><given-names>Laura</given-names></name><xref ref-type="aff" rid="kez418-aff1"></xref></contrib><contrib contrib-type="author"><name><surname>Coupe</surname><given-names>Nicholas</given-names></name><xref ref-type="aff" rid="kez418-aff1"></xref></contrib><contrib contrib-type="author"><name><surname>Payne</surname><given-names>Miranda</given-names></name><xref ref-type="aff" rid="kez418-aff1"></xref><xref ref-type="corresp" rid="kez418-cor1"></xref><pmc-comment>Miranda.Payne@ouh.nhs.uk </pmc-comment>
</contrib></contrib-group><aff id="kez418-aff1"><institution>Department of Oncology, Churchill Hospital, Oxford University Hospitals Foundation Trust</institution>, Oxford,<country country="GB">UK</country></aff><author-notes><corresp id="kez418-cor1">Correspondence to: Miranda J. Payne, Department of Oncology, Churchill Hospital, Oxford University Hospitals Foundation Trust, Oxford OX3 7LJ, UK. E-mail: <email>Miranda.Payne@ouh.nhs.uk</email></corresp></author-notes><pub-date pub-type="ppub"><month>12</month><year>2019</year></pub-date><pub-date pub-type="epub" iso-8601-date="2019-12-09"><day>09</day><month>12</month><year>2019</year></pub-date><pub-date pub-type="pmc-release"><day>09</day><month>12</month><year>2019</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on the
<volume>58</volume><issue>Suppl 7</issue><issue-title>The rheumatic side-effects of immuno-oncology treatment</issue-title><fpage>vii7</fpage><lpage>vii16</lpage><history><date date-type="received"><day>24</day><month>5</month><year>2019</year></date><date date-type="rev-recd"><day>30</day><month>7</month><year>2019</year></date></history><permissions><copyright-statement>© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology.</copyright-statement><copyright-year>2019</copyright-year><license license-type="cc-by-nc" xlink:href="http://creativecommons.org/licenses/by-nc/4.0/"><license-p>This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc/4.0/">http://creativecommons.org/licenses/by-nc/4.0/</ext-link>), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com</license-p></license></permissions><self-uri xlink:href="kez418.pdf"></self-uri><abstract><title>Abstract</title><p>Immunotherapy has an increasing role in the management of cancer, both in metastatic disease and as an adjuvant therapy. However, sensitization of the immune system with checkpoint inhibitors comes with a unique side effect profile. Full appreciation of this can take some time to emerge as some adverse events are rare, or can be subtle and potentially overlooked. Clinician awareness of these side effects can be particularly important in patients with pre-existing autoimmune conditions. Here we describe common symptoms and diagnostic strategies for organ-specific side effects of anti-CTLA-4 and anti-PD-1/PD-L1 immunotherapy agents.</p></abstract><kwd-group><kwd>checkpoint inhibitor</kwd><kwd>adverse event</kwd></kwd-group><funding-group><award-group award-type="grant"><funding-source><named-content content-type="funder-name">National Institute for Health Research</named-content><named-content content-type="funder-identifier">10.13039/501100000272</named-content></funding-source></award-group><award-group award-type="grant"><funding-source><named-content content-type="funder-name">NIHR</named-content><named-content content-type="funder-identifier">10.13039/100006662</named-content></funding-source></award-group><award-group award-type="grant"><funding-source><named-content content-type="funder-name">BMS</named-content><named-content content-type="funder-identifier">10.13039/100002491</named-content></funding-source></award-group></funding-group><counts><page-count count="10"></page-count></counts></article-meta></front><body><p><boxed-text id="kez418-BOX1" position="float" orientation="portrait"><sec><title>Rheumatology key messages</title><p><list list-type="bullet"><list-item><p>The onset of checkpoint inhibitor side effects may follow a predictable temporal pattern.</p></list-item><list-item><p>Checkpoint inhibitor side effects can be diverse and serious; a multi-disciplinary approach is advised.</p></list-item></list></p></sec></boxed-text></p><sec sec-type="intro"><title>Introduction</title><p>Checkpoint inhibitors (CPIs) have now become a mainstay of treatment for a range of cancers, including melanoma, bladder cancer, non-small cell lung cancer and Hodgkin’s lymphoma [<xref rid="kez418-B1" ref-type="bibr">1</xref>]. </p><p>Currently there are six approved therapies. Ipilimumab is a cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) fully human IgG1 antibody, licensed for use in advanced melanoma [<xref rid="kez418-B2" ref-type="bibr">2</xref>]. Pembrolizumab and nivolumab are both IgG4 monoclonal antibodies that block the programmed cell death (PD-1) protein on T cells. Both are licensed for use in melanoma, non-small cell lung cancer and mismatch repair deficient (dMMR) and microsatellite instability high colorectal cancers [<xref rid="kez418-B2" ref-type="bibr">2</xref>]. Three monoclonal antibodies targeting the protein programmed death-ligand 1 (PD-L1) have been approved. Atezolizumab and durvalumab are both licensed for use in non-small cell lung cancer and urothelial carcinoma. Avelumab is also used to treat urothelial carcinoma [<xref rid="kez418-B1" ref-type="bibr">1</xref>, <xref rid="kez418-B2" ref-type="bibr">2</xref>]. Durable disease responses can result from treatment with these drugs, but potentially come at a cost of wide-ranging side effects. Immune-related adverse events (irAEs) are caused by activation of the immune system with the development of auto-antibodies and can affect almost any organ system, as summarized in <xref ref-type="fig" rid="kez418-F1">Fig. 1</xref>.
</p><fig id="kez418-F1" orientation="portrait" position="float"><label><sc>Fig</sc>. 1</label><caption><p>Immune-related adverse events</p><p>DRESS: drug rash with eosinophilia and systemic symptoms; SJS: Stevens–Johnson syndrome; TEN: toxic epidermal necrolysis.</p></caption><graphic xlink:href="kez418f1"></graphic></fig><p>Immune-related adverse events may affect a single organ system, but some patients can develop multiple side effects, not necessarily simultaneously. In a small study of 78 patients receiving either anti-CTLA-4 therapy (32%) or anti-PD-1 therapy (68%), over half developed irAEs, with 12 patients (15%) developing more than one [<xref rid="kez418-B3" ref-type="bibr">3</xref>]. These are often mild, but a small number can be life-threatening; in a randomized, multicentre phase 3 trial (Checkmate 067) involving 296 patients receiving either combination ipilimumab/nivolumab or monotherapy with either agent, grade 3 or 4 drug-related adverse events occurred in 32 (11%) patients, with three (1%) treatment-related deaths [<xref rid="kez418-B4" ref-type="bibr">4</xref>]. Urgent management may therefore be required which is beyond the scope of this review but has been extensively reviewed elsewhere [<xref rid="kez418-B6" ref-type="bibr">6</xref>]. Meta-analysis of CPI-related side effects has shown that these profiles follow a specific temporal pattern (<xref ref-type="fig" rid="kez418-F2">Fig. 2</xref>), which is consistent across solid tumour types [<xref rid="kez418-B5" ref-type="bibr">5</xref>].
</p><fig id="kez418-F2" orientation="portrait" position="float"><label><sc>Fig</sc>. 2</label><caption><p>Time to onset of grade 3–4 immunotherapy-related adverse events (amended from [<xref rid="kez418-B6" ref-type="bibr">6</xref>])</p></caption><graphic xlink:href="kez418f2"></graphic></fig><p>Adverse effects have been reported more frequently with CTLA-4 inhibitors compared with PD-1/PD-L1 inhibitors; a meta-analysis suggested all-grade irAEs of 75% with ipilimumab (24–43% grade 3 or above) [<xref rid="kez418-B7" ref-type="bibr">7</xref>], compared with up to 37% of patients receiving anti-PD-1/PD-L1 agents experiencing irAEs of any grade (10–20% grade 3 or above) [<xref rid="kez418-B4" ref-type="bibr">4</xref>, <xref rid="kez418-B5" ref-type="bibr">5</xref>, <xref rid="kez418-B8" ref-type="bibr">8</xref>]. Patient and drug factors, including dose and treatment setting (adjuvant <italic>vs</italic> metastatic) potentially influence the incidence of irAEs to CPIs [<xref rid="kez418-B9" ref-type="bibr">9</xref>]. Accurately estimating the incidence of specific side effects can be difficult, as there may be significant under-reporting, particularly with the less specific effects such as fatigue. Distinguishing new irAEs from a flare of pre-existing co-morbidities may add to the diagnostic challenge, as patients with pre-existing auto-immune or inflammatory diseases have often been excluded from trials involving CPI therapy [<xref rid="kez418-B10" ref-type="bibr">10</xref>]. The side effects reported with checkpoint therapy are discussed below, in order of prevalence, including common symptoms and suggested diagnostic approaches.</p></sec><sec><title>Gastrointestinal</title><p>Gastrointestinal irAEs are a significant side effect of CPIs, and occur in 44% of patients receiving combination anti-CTLA-4/anti-PD-1, 23–33% of patients receiving anti-CTLA-4 therapy and <20% of patients receiving single-agent anti-PD-1 therapy [<xref rid="kez418-B1" ref-type="bibr">1</xref>]. Symptoms, including bloody diarrhoea, abdominal pain and sometimes pyrexia, occur on average after three infusions, although they can occur earlier in treatment or even months after stopping checkpoint therapy [<xref rid="kez418-B2" ref-type="bibr">2</xref>]. In a phase 3 melanoma trial of 511 patients receiving ipilimumab, five (1%) developed intestinal perforation and 26 (5%) were hospitalized for severe enterocolitis [<xref rid="kez418-B8" ref-type="bibr">8</xref>]. Although any part of the colon can be involved, the descending colon has been most commonly reported to be affected, possibly because the proximal colon is viewed less frequently by endoscopy [<xref rid="kez418-B11" ref-type="bibr">11</xref>, <xref rid="kez418-B12" ref-type="bibr">12</xref>]. Colonoscopy is useful to visualize the mucosa, which may show mild erythema or severe inflammation with friability and ulceration [<xref rid="kez418-B13" ref-type="bibr">13</xref>, <xref rid="kez418-B14" ref-type="bibr">14</xref>]. The presence of ulceration is associated with steroid-refractory disease so mucosal appearances can be helpful in guiding treatment [<xref rid="kez418-B15" ref-type="bibr">15</xref>].</p><p>Similar to the endoscopic appearance of colitis from inflammatory bowel disease, these appearances may be diffuse or occur segmentally [<xref rid="kez418-B16" ref-type="bibr">16</xref>]. Although a full mechanism has not yet been elucidated, at least two typical histological appearances have been reported: neutrophilic infiltration into micro-abscesses and epithelial cell atrophy causing crypt atrophy, or lymphocytic infiltration into the epithelium as a response to epithelial injury [<xref rid="kez418-B17" ref-type="bibr">17</xref>, <xref rid="kez418-B18" ref-type="bibr">18</xref>]. The small bowel can be affected rarely, and cases of enteritis have been confirmed with CT after combination therapy has been given. The upper GI tract can also be affected, although less commonly so. Most obvious in terms of appearance, mucositis can present with inflamed lips or mouth, which if severe, can affect oral intake and may necessitate nutritional supplementation. Cases of oesophagitis and gastritis can present non-specifically with nausea and anorexia, with confirmation by endoscopy [<xref rid="kez418-B6" ref-type="bibr">6</xref>].</p><p>General treatment strategies include treatment interruption, fluid replacement and usually glucocorticoids. In the phase 3 Checkmate 067 study, this was sufficient for resolution of three cases of grade 3–4 diarrhoea [<xref rid="kez418-B4" ref-type="bibr">4</xref>]. A confirmed diagnosis with a detailed history and endoscopic analysis is very important before commencing treatment, as the management of upper GI pathology such as gastritis from non-immunotherapy related causes would not normally include steroids. Rarely, escalation to other immunosuppressive agents or even surgical intervention is required.</p></sec><sec><title>Hepatic</title><p>Immune-related hepatitis is the most common hepatic adverse event, affecting ∼5% of patients receiving anti-PD-1 therapy, 5–15% patients receiving ipilimumab monotherapy (dose dependent) and a third of patients receiving combination therapy [<xref rid="kez418-B2" ref-type="bibr">2</xref>]. In most cases, asymptomatic elevation of liver enzymes is noted, which occurs with median onset 6–14 weeks after receiving therapy [<xref rid="kez418-B19" ref-type="bibr">19</xref>].</p><p>Occasionally patients may present with symptoms that can include fatigue, fever and jaundice and, in very rare cases, death may occur. The radiological appearance is similar between checkpoint agents, with ultrasound and CT findings such as hepatomegaly, oedema and lymphadenopathy [<xref rid="kez418-B20" ref-type="bibr">20</xref>, <xref rid="kez418-B21" ref-type="bibr">21</xref>].</p><p>Liver biopsy may not change patient management, unless alternative diagnoses are suspected such as drug- and infection-related liver injury. Both anti-CTLA-4 and anti-PD-1/PD-L1 agents can cause histopathological appearances in keeping with either hepatocyte injury with endothelial inflammation, central hepatic vein damage and discrete areas of necrosis, or bile duct injury with portal vein inflammation. Additionally, in cases caused by anti-CTLA-4 treatment, confluent necrosis and histiocytic aggregates has been reported [<xref rid="kez418-B16" ref-type="bibr">16</xref>].</p><p>General management strategies include withholding immunotherapy until improvement is seen in hepatic enzyme blood parameters, with steroid as necessary. Immunotherapy should usually be stopped permanently in cases of grade 3 hepatic toxicity (aspartate transaminase or alanine transaminase >5 times upper limit of normal or total bilirubin >3 times upper limit of normal). These patients will receive immunosuppressive therapies such as intravenous methylprednisolone or mycophenolate mofetil, in discussion with hepatology specialists.</p></sec><sec><title>Endocrine</title><p>Endocrine-related irAEs are more common with anti-CTLA-4 antibody treatment than anti-</p><p>PD-1/PD-L1 therapy. Side effects include hypophysitis (13% <italic>vs</italic> 1%) and hypo-/hyperthyroiditis (∼6% <italic>vs</italic> 4% for anti-CTLA-4 antibody treatment <italic>vs</italic> anti-PD-1/PD-L1 therapy, respectively).</p><p>Other endocrinopathies such as primary adrenal insufficiency, type 1 diabetes mellitus (T1DM), hypercalcaemia and hypoparathyroidism are rare but can present acutely. They typically occur after three cycles of combination treatment (<xref ref-type="fig" rid="kez418-F2">Fig. 2</xref>), are often a later side effect of CPI monotherapy and are usually irreversible, requiring life-long hormone replacement [<xref rid="kez418-B1" ref-type="bibr">1</xref>].</p><p>Pre-treatment blood tests measuring thyroid function by thyroid-stimulating hormone and free thyroxine (fT4), and early morning adrenal function by adrenocorticotropic hormone (ACTH) and cortisol can act as a baseline to help identify changes. Many centres choose to monitor these routinely ahead of treatment to detect early changes and reduce the risk of an acute presentation. Due to the delayed nature of onset, there is some evidence to recommend continued monitoring even after treatment completion [<xref rid="kez418-B2" ref-type="bibr">2</xref>].</p></sec><sec><title>Hypophysitis</title><p>Inflammation of the pituitary gland can cause hypopituitarism, leading to central hypothyroidism, central adrenal insufficiency and hypogonadotropic hypogonadism. These endocrine abnormalities can be difficult to detect, especially in early stages as patients can experience non-specific symptoms such as fatigue, nausea or loss of appetite. If patients have already been commenced on steroids for other irAEs, interpretation of blood results potentially becomes more complex.</p><p>Severe cases can cause headache or postural hypotension, although visual disturbances are rare. Blood tests may demonstrate hyponatraemia with low thyroid-stimulating hormone, fT4 and ACTH; usually luteinizing hormone, follicle-stimulating hormone and prolactin are unaffected [<xref rid="kez418-B22" ref-type="bibr">22</xref>]. By the time clinical and biochemical changes are noted, changes on MRI are usually seen, such as enlargement and heterogeneous enhancement of the pituitary gland. These appearances often resolve after treatment of hypophysitis [<xref rid="kez418-B23" ref-type="bibr">23</xref>].</p></sec><sec><title>Thyroid dysfunction</title><p>Like patients with pituitary dysfunction, patients with thyroid dysfunction are often asymptomatic and the diagnosis is usually only initially by biochemistry. The pathophysiology is reported to be dissimilar to autoimmune diseases of the thyroid, with CPI-induced cases appearing to be part of a spectrum induced by T cell cytotoxicity, starting with acute thyroiditis (with raised fT4 and low thyroid-stimulating hormone) typically after 1 month of therapy and progressing to hypothyroidism after a further month [<xref rid="kez418-B22" ref-type="bibr">22</xref>]. Thyrotoxicosis, secondary to thyroiditis or Grave’s disease, is a rare complication of CPI therapy. Testing for antibodies such as anti-thyroid peroxidase and thyroid-stimulating immunoglobulin can be useful. Rarely, patients may have symptoms of acute hyperthyroidism (tachycardia, palpitations, diarrhoea or tremor) or hypothyroidism (constipation, weight gain, lethargy) [<xref rid="kez418-B23" ref-type="bibr">23</xref>].</p></sec><sec><title>Adrenal</title><p>Primary adrenal insufficiency is a rare irAE. It can present with non-specific symptoms such as fatigue, nausea or weight loss, although occasionally skin hyperpigmentation from raised </p><p>ACTH is noted. Diagnosis is therefore generally made from biochemistry results, with low cortisol and normal or high levels of ACTH. Anti-21-hydroxylase and adrenal cortex antibody levels should be checked to detect auto-antibodies induced by CPI therapy [<xref rid="kez418-B23" ref-type="bibr">23</xref>].</p></sec><sec><title>Diabetes mellitus type 1</title><p>This is a rare but potentially life-threatening immunotherapy-induced endocrinopathy, such that data for its incidence are scarce. Patients typically present acutely with weight loss, nausea, fatigue, polyuria and polydipsia. In addition to new cases, CPIs can cause worsening of pre-existing T1DM. Where suspected, management is like that for non-irAE-induced T1DM, including the management of acute ketoacidotic crises. The pathophysiology has not yet been fully elucidated but there is likely involvement of CD8<sup>+</sup> T cell response to T1DM antigen and T1DM-specific autoantibodies (GAD65) [<xref rid="kez418-B24" ref-type="bibr">24</xref>].</p></sec><sec><title>Skin</title><p>Cutaneous irAEs are common with both anti-CTLA-4 (experienced by up to 50% of patients) and anti-PD-1/PD-L1 agents (affecting 30–40% of patients) [<xref rid="kez418-B8" ref-type="bibr">8</xref>]. Symptoms can occur early on in treatment, especially with anti-CTLA-4 therapy, and range from a mild rash and intermittent pruritus to life-threatening Stevens–Johnson syndrome. Rash is the most common irAE with both PD-1 and CTLA-4 inhibitors; a systematic review suggests up to 20% of patients taking anti-PD-1 treatments develop a rash. Most of these are pruritic erythematous macules or papules [<xref rid="kez418-B25" ref-type="bibr">25</xref>]. Histological analysis of skin biopsies demonstrates a T cell heavy infiltrate [<xref rid="kez418-B26" ref-type="bibr">26</xref>]. Treatment usually consists of topical emollient, topical steroid, oral anti-histamine creams and occasionally oral steroids.</p><p>Vitiligo affects up to 10% patients receiving PD-1/PD-L1 therapy for melanoma, although interestingly is not seen with the same incidence in patients receiving CPIs for small cell lung cancer. Like the immune-related rashes, vitiligo lesions are usually symmetrical [<xref rid="kez418-B27" ref-type="bibr">27</xref>, <xref rid="kez418-B28" ref-type="bibr">28</xref>].</p><p>Similar to the observation that cetuximab-related skin rash correlates with better outcomes in patients with colorectal cancer, the presence of vitiligo in patients with melanoma also seems to have a positive correlation [<xref rid="kez418-B28" ref-type="bibr">28</xref>, <xref rid="kez418-B29" ref-type="bibr">29</xref>]. Although most dermatological irAEs are not severe, they can have psychological impact on patients due to the effect on appearance. Life-threatening skin manifestations such as Stevens–Johnson syndrome/toxic epidermal necrolysis, and drug rash with eosinophilia and systemic symptoms are very rare even when combination therapy is used [<xref rid="kez418-B19" ref-type="bibr">19</xref>, <xref rid="kez418-B30" ref-type="bibr">30</xref>]. These high grade side effects require permanent cessation of immunotherapy and specialist dermatology input to help with diagnosis and management. In patients with pre-existing skin disorders such as psoriasis, specialist opinion should be sought prior to treatment.</p></sec><sec><title>Rheumatological</title><p>Approximately 15% of patients treated with anti-PD-1/PD-L1 agents suffer with mild arthralgia and myalgia. These symptoms often occur later than non-rheumatological irAEs, and do not usually require dose interruption [<xref rid="kez418-B31" ref-type="bibr">31</xref>].</p><p>Inflammatory signs such as joint swelling, stiffness, tenderness and erythema suggest arthritis. This occurs after a median of months of treatment and can persist beyond 2 years, even after immunotherapy is stopped [<xref rid="kez418-B19" ref-type="bibr">19</xref>]. It is an important adverse effect as it can lead to rapid joint damage. Inflammatory arthritis is more common in patients treated with anti-PD-1/PD-L1 agents and combination therapy (up to 10% of patients) compared with anti-CTLA-4 monotherapy (<1% of patients). It usually occurs in patients who have already experienced at least one other organ irAE [<xref rid="kez418-B31" ref-type="bibr">31–33</xref>]. Symptoms fall broadly into three classes and reflect the range of the rheumatological spectrum of disease. The ‘reactive’ group mirrors reactive arthritis, with large joints affected, often with associated eye inflammation (conjunctivitis and uveitis). A second class reflects RA, with small joint polyarthritis of the hands. Like true RA, this group can have erosive changes on radiographs and may have positive serology for RF and ACPA. A ‘seronegative’ group present with synovitis of medium and large joints. An algorithm to aid the diagnosis of inflammatory arthritis has been published, as per <xref rid="kez418-T1" ref-type="table">Table 1</xref> [<xref rid="kez418-B34" ref-type="bibr">34</xref>].
</p><table-wrap id="kez418-T1" orientation="portrait" position="float"><label><sc>Table</sc> 1</label><caption><p>An algorithm to aid the diagnosis of inflammatory arthritis</p></caption><table frame="hsides" rules="groups"><colgroup span="1"><col valign="top" align="left" span="1"></col><col valign="top" align="left" span="1"></col><col valign="top" align="center" span="1"></col><col valign="top" align="center" span="1"></col></colgroup><thead align="left"><tr><th rowspan="1" colspan="1">Grade</th><th rowspan="1" colspan="1">Clinical exam</th><th rowspan="1" colspan="1">Lab testing</th><th rowspan="1" colspan="1">Imaging</th></tr></thead><tbody align="left"><tr><td rowspan="1" colspan="1">1</td><td align="left" rowspan="1" colspan="1">Joint examination and functional assessment</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td></tr><tr><td rowspan="1" colspan="1">2/3</td><td align="left" rowspan="1" colspan="1">Joint examination and functional assessment</td><td align="left" rowspan="1" colspan="1">ANA, RF, anti-CCP ESR, CRP</td><td align="left" rowspan="1" colspan="1">Consider plain X-ray, MRI and/or ultrasound of affected joints</td></tr></tbody></table></table-wrap><p>Other rheumatological syndromes because of immunotherapy are less common (<1%). These include vasculitides such as giant cell arteritis and polymyalgia rheumatica, Sicca syndrome (presenting with eye and mouth dryness) and systemic lupus erythematosus [<xref rid="kez418-B2" ref-type="bibr">2</xref>]. Polymyositis is seen in <1% of patients treated with anti-PD-1/PD-L1 agents and can present as a spectrum, from mild myalgia and weakness (with minimal associated creatinine kinase rise) to life-threatening myasthenia, rhabdomyolysis and myocarditis. These patients clearly require specialist input to co-ordinate myositis antibody panel testing, muscle biopsy and EMG [<xref rid="kez418-B35" ref-type="bibr">35</xref>].</p></sec><sec><title>Neurological (central/peripheral)</title><p>Neurological irAEs are uncommon, but are more common in patients receiving anti-PD-1/PD-L1 therapy (6%) than with anti-CTLA-4 treatment (4% in EORTC 18071 trial) [<xref rid="kez418-B36" ref-type="bibr">36</xref>]. With combination treatment, the incidence of all-grade neurological adverse events is ∼12%), and most symptoms are mild and non-specific, such as headache and vertigo [<xref rid="kez418-B2" ref-type="bibr">2</xref>]. Events of grade 3 and above are very rare (<1%) [<xref rid="kez418-B2" ref-type="bibr">2</xref>]. It is therefore important to rule out other causes of symptoms, such as disease progression (brain or leptomeningeal metastasis), infection and metabolic disturbance. It is also vital to consider managing patients with severe neurological irAEs in an intensive care setting, as patients with Guillain–Barré syndrome, encephalitis or myasthenia gravis may require respiratory support.</p><p>Peripheral neuropathy is one of the more common irAEs described in the literature and should be considered if patients describe sensory changes or paraesthesia. When accompanied by features such as ascending weakness and eye involvement (diplopia, reduced acuity), demyelination such as Guillain–Barré syndrome and transverse myelitis should be considered. These have a median onset of 4 weeks from commencing therapy [<xref rid="kez418-B22" ref-type="bibr">22</xref>]. Diagnostic tests include MRI of the spine, which can show uptake of contrast by nerve fibres, and EMG, which typically demonstrate reduced conduction velocity [<xref rid="kez418-B37" ref-type="bibr">37</xref>]. Lumbar puncture should be performed to test for the presence of anti-ganglioside antibodies. Rarely, nerve biopsies may be required; in cases of transverse myelitis these have shown necrosis and lymphocyte infiltration [<xref rid="kez418-B38" ref-type="bibr">38</xref>].</p><p>Production of antibodies to the acetylcholine receptor, which are pathognomonic of myasthenia gravis, can be enhanced by administration of CPIs. Ipilimumab has shown worsening of pre-existing myasthenia gravis and <italic>de novo</italic> cases have been reported. Patients present with fatigable weakness, which can affect limbs, as well as recti muscles to affect vision, and intercostal muscles to affect respiration. Serum samples can demonstrate the presence of anti-acetylcholine receptor and anti-muscle-specific kinase antibodies, to help make the diagnosis [<xref rid="kez418-B39" ref-type="bibr">39</xref>].</p><p>Central nervous system effects of CPIs are also seen; encephalitis, meningitis and encephalopathy can present with confusion, fever, seizures, upper motor neurone signs such as spasticity and cerebellar signs such as nystagmus [<xref rid="kez418-B40" ref-type="bibr">40</xref>, <xref rid="kez418-B41" ref-type="bibr">41</xref>]. MRI of the brain shows diffuse dural enhancement with parenchymal sparing. Lumbar puncture is used to check for anti-NMDA receptor antibodies and for cerebrospinal fluid analysis, which would typically show increased protein and mononuclear white cell count, but normal glucose [<xref rid="kez418-B42" ref-type="bibr">42</xref>].</p><p>Paraneoplastic syndromes can present with a variety of central and peripheral neurological symptoms. They occur due to autoantibodies against tumour antigens, which are released in response to treatment. In patients with ipilimumab-treated small cell lung cancer, almost half developed antineuronal antibodies (e.g. anti-Hu and anti-Yo). The antibody-positive patients were more likely to develop paraneoplastic syndromes but interestingly also had significantly longer median progression-free survival [<xref rid="kez418-B31" ref-type="bibr">31</xref>, <xref rid="kez418-B43" ref-type="bibr">43</xref>]. Imaging of the central nervous system, lumbar puncture for cerebrospinal fluid analysis and EMG for nerve conduction study are helpful for diagnosis [<xref rid="kez418-B22" ref-type="bibr">22</xref>].</p><p>Associations between the development of neurological irAEs and favourable response rate has also been observed; a case series of 40 patients with neurological side effects from CPI therapy has found a 90% overall response rate [<xref rid="kez418-B44" ref-type="bibr">44</xref>]. In a phase III trial, overall response rate was up to 30% (and median OS 11.2 months), compared with overall response rate of 70% (and median OS 45.7 months) in patients with a neurological irAE [<xref rid="kez418-B44" ref-type="bibr">44</xref>].</p></sec><sec><title>Renal</title><p>irAEs affecting the kidney occur rarely with anti-PD-1/PD-L1 therapy, anti-CTLA-4 therapy (2%) and combination checkpoint therapy (5%) [<xref rid="kez418-B45" ref-type="bibr">45</xref>]. However, as lower grades of adverse event are often symptomless, and only detected on blood tests, the true incidence could be higher. Patients who present with symptoms may have oliguria, haematuria or peripheral oedema, and up to 10% patients with immunotherapy-induced nephritis develop rash and fever [<xref rid="kez418-B46" ref-type="bibr">46</xref>]. The time of onset appears to be class-dependent, with onset at around two months following anti-CTLA-4 treatment, and between three and ten months with combination CPI [<xref rid="kez418-B47" ref-type="bibr">47</xref>]. In a case series of 13 patients who developed renal irAEs from checkpoint therapy; six had already experienced effects on other organs, and 12 of the 13 had acute interstitial nephritis, as confirmed by renal biopsy, with inflammatory infiltrate in the renal cortex and interstitial oedema [<xref rid="kez418-B48" ref-type="bibr">48</xref>]. Blood tests in patients with acute interstitial nephritis usually demonstrate acutely raised creatinine, eosinophilia and hyponatraemia [<xref rid="kez418-B49" ref-type="bibr">49</xref>]. Non-tubular renal irAEs are seen less commonly but cases of nephrotic syndrome have been reported, with either focal segmental sclerosis, membranous nephropathy or minimal change seen on biopsies [<xref rid="kez418-B50" ref-type="bibr">50</xref>].</p><p>Given the effects of CPIs on the immune system, clinicians have been understandably reluctant to use these treatments for patients with renal transplants, and therefore there are few data in this setting. Case reports of six such patients have had significant tumour response to CPIs. Four of these patients received anti-PD-1 therapy and developed acute rejection of the transplanted kidney [<xref rid="kez418-B50" ref-type="bibr">50</xref>]. This was not observed in the two transplant patients who received ipilimumab [<xref rid="kez418-B51" ref-type="bibr">51</xref>].</p></sec><sec><title>Pulmonary</title><p>A meta-analysis found the overall incidence of pneumonitis in patients receiving anti-PD-1/PD-L1 therapy is <5% [<xref rid="kez418-B2" ref-type="bibr">2</xref>]. Similar incidence is seen with anti-CTLA-4 inhibitor therapy. Although pneumonitis cases of grade 3 and above are rare (1–2%), it is one of the most common causes of immunotherapy-related death [<xref rid="kez418-B2" ref-type="bibr">2</xref>].</p><p>Common symptoms include new or increasing breathlessness, dry cough, wheeze or chest pain. Patients may describe reduced exercise tolerance, or even require supplementary oxygen. The onset of these symptoms is dependent on tumour type; patients with lung cancer experience symptoms earlier [median 2.1 (range 0.2–27.4) months] than patients with melanoma [median 5.2 (0.2–18.1) months] [<xref rid="kez418-B52" ref-type="bibr">52</xref>]. Monitoring oxygen saturation at rest and on ambulation may help identify affected patients. CT imaging of pneumonitis can show cryptogenic organizing pneumonia, non-specific interstitial pneumonitis, hypersensitivity pneumonitis, or usual interstitial pneumonitis/pulmonary fibrosis [<xref rid="kez418-B2" ref-type="bibr">2</xref>].</p><p>There have been case reports of CPI therapy causing pulmonary sarcoidosis; this can be symptom-less or present with breathlessness and dry cough. CT imaging demonstrates intrathoracic lymphadenopathy and irregular densities in keeping with granulomatous reactions [<xref rid="kez418-B2" ref-type="bibr">2</xref>].</p></sec><sec><title>Cardiology</title><p>Less than 1% of CPI-related adverse events are cardiac in nature [<xref rid="kez418-B2" ref-type="bibr">2</xref>]. Patients can present with a range of symptoms, from non-specific fatigue or muscle pain to chest pain, shortness of breath, palpitations or oedema. Side effects usually occur early, in the first few weeks of treatment [<xref rid="kez418-B53" ref-type="bibr">53</xref>]. As cardiac complications of CPI therapy are rare, most data so far come from pre-clinical models. Dilated cardiomyopathy has been described in genetically engineered mice; knocking out PD-1 caused sudden congestive heart failure, and in mice lacking PD-L1, autoimmune myocarditis was observed [<xref rid="kez418-B54" ref-type="bibr">54</xref>, <xref rid="kez418-B55" ref-type="bibr">55</xref>].</p><p>Two cases of myocarditis and myositis occurred in a clinical trial of patients with melanoma receiving ipilimumab with nivolumab [<xref rid="kez418-B53" ref-type="bibr">53</xref>]. Literature suggests myocarditis occurs in <1% of patients receiving combination therapy, and the first presentation is potentially with isolated rhythm disturbance. A baseline ECG may make identification of subsequent change more straightforward. Serum troponin and brain natriuretic peptide are usually elevated [<xref rid="kez418-B22" ref-type="bibr">22</xref>]. Serial ECGs and cardiac imaging with MRI can be useful in diagnosis and monitoring. Myocardial biopsy demonstrates T cell and macrophage infiltration of the myocardium, cardiac sinus and atrioventricular nodes [<xref rid="kez418-B53" ref-type="bibr">53</xref>].</p><p>Autoimmune pericarditis is an extremely rare complication of CPI therapy. It presents similarly to infective pericarditis, with fever and chest pain that improves on sitting forward. A pericardial friction rub may be heard on auscultation. Aspiration of pericardial fluid for analyses typically demonstrates lymphocyte infiltration, but with no evidence of malignant cells or infective organisms [<xref rid="kez418-B22" ref-type="bibr">22</xref>].</p></sec><sec><title>Ophthalmological adverse events</title><p>The eye is an immune-privileged site, and so immune-related events are rare (<1% of patients). The most common ophthalmic irAE is anterior uveitis, for which there are case reports in patients receiving anti-PD-1/PD-L1 treatment [<xref rid="kez418-B8" ref-type="bibr">8</xref>, <xref rid="kez418-B56" ref-type="bibr">56</xref>]. This can present with a painful red eye (conjunctival injection), blurred vision or photophobia, between 3 and 8 weeks after commencing CPI therapy. Ophthalmic assessment, including fundoscopy, is warranted and should include both eyes as presentation is often asymmetrical [<xref rid="kez418-B2" ref-type="bibr">2</xref>]. As ophthalmic irAEs are so uncommon, it is unlikely that a non-eye specialist will have seen many (if any) complications and be able to diagnose with certainty, so specialist referral is encouraged.</p><p>Retinopathy and uveal effusions have been reported with anti-PD-1/PD-L1 agents. Both of these present with blurred vision, and uveal effusions can additionally cause a painful red eye [<xref rid="kez418-B57" ref-type="bibr">57</xref>, <xref rid="kez418-B58" ref-type="bibr">58</xref>]. There have been case reports of patients who have received nivolumab developing Vogt–Koyanagi–Harada-like syndrome (uveomeningitis syndrome) [<xref rid="kez418-B59" ref-type="bibr">59</xref>]. This has ophthalmic symptoms of blurred vision and bilateral uveitis, and can cause localized retinal detachment in addition to extra-ophthalmic symptoms in the skin and brain.</p></sec><sec><title>Haematological</title><p>Unlike with chemotherapy treatment, CPI therapy is not commonly known to cause myelosuppression or cytopenia. There are case reports of aplastic anaemia (bone marrow) and autoimmune haemolytic anaemia (peripheral blood) and immune thrombocytopenic purpura with anti-PD-1 agents, which seem to occur within 12 weeks of starting therapy [<xref rid="kez418-B60" ref-type="bibr">60–62</xref>]. However, given the rarity of these cases, patients with cytopenia should be evaluated for common causes too, such as cancer progression, gastrointestinal bleeding and drugs.</p><p>In cases of nivolumab-induced aplastic anaemia, blood work should include a Coombs test, reticulocyte count and haemolysis assays (lactate dehydrogenase, bilirubin and haptoglobin). Blood smears demonstrate pancytopenia with scattered lymphocytes. Bone marrow has a paucity of haematopoietic elements, with CD8<sup>+</sup> T cells accounting for around 50% of the aspirate on flow cytometry [<xref rid="kez418-B62" ref-type="bibr">62</xref>].</p><p>Autoimmune haemolytic anaemia is investigated in a similar way, with results showing a positive direct Coombs test, raised reticulocyte count and haemolysis assay of raised lactate dehydrogenase and bilirubin, and reduced haptoglobin. Blood smears show spherocytosis [<xref rid="kez418-B61" ref-type="bibr">61</xref>]. The development of immune thrombocytopenic purpura is likely related to raised PD-1 expression on B cells. Blood results show decreased platelet count, with anti-platelet antibodies present. Bone marrow biopsy demonstrates an abundance of megakaryocytes with immature platelets [<xref rid="kez418-B63" ref-type="bibr">63</xref>].</p></sec><sec><title>Activation of pre-existing autoimmune diseases</title><p>Autoimmune diseases encompass a spectrum of over 80 separate disorders, and can be localized to a specific organ, or multi-systemic. The prevalence globally is thought to be between 3 and 8% [<xref rid="kez418-B64" ref-type="bibr">64</xref>]. However, despite being relatively common, most patients with autoimmune diseases were excluded from clinical trials involving CPIs. Initial evidence for CPI use in these patients is therefore from case studies.</p></sec><sec><title>Anti-CTLA-4 therapy (ipilimumab)</title><p>A 56-year-old gentleman with relapsing and remitting multiple sclerosis (MS) was diagnosed with metastatic melanoma 15 years after his MS diagnosis, at which point he had good control of the neurological disorder with methotrexate and glatiramer acetate. These drugs were stopped on commencement of ipilimumab, and the patient subsequently experienced severe clinical relapses of his MS. The patient, however, responded to ipilimumab and the authors concluded that ipilimumab can be used with caution in patients with MS; however, each individual case requires as assessment or risk <italic>vs</italic> benefit [<xref rid="kez418-B65" ref-type="bibr">65</xref>].</p><p>In a series of seven patients with RA who developed metastatic melanoma and were treated with ipilimumab, four had a partial response, with two of these undergoing surgical resection for complete response. Of note, three of these four responders were sero-positive. Four of the seven patients had a flare of RA; three patients had grade 1 flares, managed with non-steroidal anti-inflammatory agents) and two patients had grade 3 flares, requiring prednisolone. New irAEs were also seen in addition to flares of existing autoimmune disease; four patients had grade 3 colitis requiring hospitalization [<xref rid="kez418-B66" ref-type="bibr">66</xref>]. This high response rate, coupled with manageable exacerbations of autoimmune disease is promising for the use of ipilimumab in patients with pre-existing RA. This is supported by a retrospective review of 30 patients who received ipilimumab for metastatic melanoma who had pre-existing autoimmune disease, including RA, psoriasis, inflammatory bowel disease, systemic lupus erythematosus, MS and autoimmune thyroiditis. Thirteen patients (43%) were receiving immunosuppressive therapy (prednisolone or hydroxychloroquine) at the time of commencing ipilimumab. Eight patients (27%) had an exacerbation of their autoimmune disease, managed with corticosteroids. In addition, 10 patients (33%) had new irAEs of grade 3 or above [<xref rid="kez418-B67" ref-type="bibr">67</xref>]. Notably, 15 patients (50%) had neither a flare of existing autoimmune disease nor new irAEs, and six patients (20%) had an objective response [<xref rid="kez418-B64" ref-type="bibr">64</xref>].</p></sec><sec><title>Anti PD-1 therapy</title><p>A German study of patients with melanoma receiving anti-PD-1 therapy included 19 patients with pre-existing autoimmunity, including psoriasis, RA, vasculitis, polymyalgia rheumatica, sarcoidosis, inflammatory bowel disease, Guillain–Barré syndrome, MS and autoimmune thyroiditis. Before anti-PD-1 therapy commenced, all patients had well-controlled autoimmune disease; six patients (32%) were taking anti-inflammatory therapies, six patients (32%) were receiving hormone replacement for autoimmune disease and seven patients (37%) were not on treatment. However, within 20 weeks of treatment, eight patients (42%) had suffered a flare of their autoimmune disease, the majority being in those with pre-existing rheumatological disorders (five of nine patients, 55%). These flares did not correlate with response; eight patients (42%) had a response but only three of these had experienced a flare of pre-existing autoimmune disease [<xref rid="kez418-B68" ref-type="bibr">68</xref>].</p><p>Similar results were seen in a larger, multicentre trial involving 52 patients with autoimmune disease who received anti-PD-1 treatment for advanced melanoma. Twenty patients (38%) experienced a flare of autoimmune disease, particularly those with RA, polymyalgia rheumatica and Sjögren’s syndrome. Interestingly, in this study, no patients with gastrointestinal or neurological autoimmune disorders experienced a flare (<italic>n</italic> = 6 and 5, respectively). Fifteen patients (29%) experienced other irAEs unrelated to their autoimmune disease, for which four (8%) stopped treatment, compared with two patients (4%) who stopped due to flare of pre-existing autoimmune disease. The overall response rate was 33% and was similar in those that did and did not have a flare of autoimmune disease (7/20, 35% <italic>vs</italic> 10/32, 31%) [<xref rid="kez418-B69" ref-type="bibr">69</xref>].</p><p>It seems, therefore, that anti-PD-1 agents may cause particular flare of existing rheumatological autoimmune disease, but anti-melanoma activity is also evident. Such patients should not be denied such treatments, but require an individual assessment and discussion of risks <italic>vs</italic> benefits.</p></sec><sec sec-type="conclusions"><title>Conclusions</title><p>Immunotherapy has heralded a new frontier in the adjuvant and metastatic treatment of some cancers. Clinicians must be alert to the range of adverse effects that have been seen with these drugs and vigilant for novel side effects. Overlapping symptoms in multiple organs can add to the challenge, as can the flare of autoimmune disease that was well controlled prior to CPI therapy. The timing of onset may follow a predictable pattern and this can assist in diagnosis. As we gain more experience, longer-term data will emerge that may help predict at-risk patients. In the meantime, a collaborative approach between specialties is advised.</p></sec></body><back><ack id="ack1"><title>Acknowledgements</title><p>L.S. is supported by the National Institute for Health Research (NIHR).</p><p><italic>Funding</italic>: This paper was published as part of a supplement funded by an educational grant from BMS.</p><p><italic>Disclosure statement</italic>: M.P. has received speaker’s fees, honoraria and support with travel from BMS, MSD, Amgen and Novartis. N.C. has received speaker’s fees from BMS. The other author has declared no conflicts of interest.</p></ack><ref-list id="ref1"><title>References</title><ref id="kez418-B1"><label>1</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Cousin</surname><given-names>S</given-names></name>, <name name-style="western"><surname>Seneschal</surname><given-names>J</given-names></name>, <name name-style="western"><surname>Italiano</surname><given-names>A.</given-names></name></person-group><article-title>Toxicity profiles of immunotherapy</article-title>. <source>Pharmacol Ther</source><year>2018</year>;<volume>181</volume>:<fpage>91</fpage>–<lpage>100</lpage>.<pub-id pub-id-type="pmid">28716652</pub-id></mixed-citation></ref><ref id="kez418-B2"><label>2</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Puzanov</surname><given-names>I</given-names></name>, <name name-style="western"><surname>Diab</surname><given-names>A</given-names></name>, <name name-style="western"><surname>Abdallah</surname><given-names>K</given-names></name></person-group><etal>et al</etal><article-title>Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group</article-title>. <source>J Immunother Cancer</source><year>2017</year>;<volume>5</volume>:<fpage>95</fpage>.<pub-id pub-id-type="pmid">29162153</pub-id></mixed-citation></ref><ref id="kez418-B3"><label>3</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Kartolo</surname><given-names>A</given-names></name>, <name name-style="western"><surname>Sattar</surname><given-names>J</given-names></name>, <name name-style="western"><surname>Sahai</surname><given-names>V</given-names></name>, <name name-style="western"><surname>Baetz</surname><given-names>T</given-names></name>, <name name-style="western"><surname>Lakoff</surname><given-names>JM.</given-names></name></person-group><article-title>Predictors of immunotherapy-induced immune-related adverse events</article-title>. <source>Curr Oncol</source><year>2018</year>;<volume>25</volume>:<fpage>403</fpage>–<lpage>10</lpage>.<pub-id pub-id-type="pmid">30607115</pub-id></mixed-citation></ref><ref id="kez418-B4"><label>4</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Topalian</surname><given-names>SL</given-names></name>, <name name-style="western"><surname>Hodi</surname><given-names>FS</given-names></name>, <name name-style="western"><surname>Brahmer</surname><given-names>JR</given-names></name></person-group><etal>et al</etal><article-title>Safety, activity, and immune correlates of anti-PD-1 antibody in cancer NIH public access</article-title>. <source>N Engl J Med</source><year>2012</year>;<volume>366</volume>:<fpage>2443</fpage>–<lpage>54</lpage>.<pub-id pub-id-type="pmid">22658127</pub-id></mixed-citation></ref><ref id="kez418-B5"><label>5</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Maughan</surname><given-names>BL</given-names></name>, <name name-style="western"><surname>Bailey</surname><given-names>E</given-names></name>, <name name-style="western"><surname>Gill</surname><given-names>DM</given-names></name>, <name name-style="western"><surname>Agarwal</surname><given-names>N.</given-names></name></person-group><article-title>Incidence of immune-related adverse events with program death receptor-1- and program death receptor-1 ligand-directed therapies in genitourinary cancers</article-title>. <source>Front Oncol</source><year>2017</year>;<volume>7</volume>:<fpage>56</fpage>.<pub-id pub-id-type="pmid">28421161</pub-id></mixed-citation></ref><ref id="kez418-B6"><label>6</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Haanen</surname><given-names>J</given-names></name>, <name name-style="western"><surname>Carbonnel</surname><given-names>F</given-names></name>, <name name-style="western"><surname>Robert</surname><given-names>C</given-names></name></person-group><etal>et al</etal><article-title>Management of toxicities from immunotherapy: eSMO Clinical Practice Guidelines for diagnosis, treatment and follow-up</article-title>. <source>Ann Oncol</source><year>2017</year>;<volume>28</volume>:<fpage>iv119</fpage>–<lpage>42</lpage>.<pub-id pub-id-type="pmid">28881921</pub-id></mixed-citation></ref><ref id="kez418-B7"><label>7</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Bertrand</surname><given-names>A</given-names></name>, <name name-style="western"><surname>Kostine</surname><given-names>M</given-names></name>, <name name-style="western"><surname>Barnetche</surname><given-names>T</given-names></name>, <name name-style="western"><surname>Truchetet</surname><given-names>ME</given-names></name>, <name name-style="western"><surname>Schaeverbeke</surname><given-names>T.</given-names></name></person-group><article-title>Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis</article-title>. <source>BMC Med</source><year>2015</year>;<volume>13</volume>:<fpage>211</fpage>.<pub-id pub-id-type="pmid">26337719</pub-id></mixed-citation></ref><ref id="kez418-B8"><label>8</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Villadolid</surname><given-names>J</given-names></name>, <name name-style="western"><surname>Amin</surname><given-names>A.</given-names></name></person-group><article-title>Immune checkpoint inhibitors in clinical practice: update on management of immune-related toxicities</article-title>. <source>Transl Lung Cancer Res</source><year>2015</year>;<volume>4</volume>:<fpage>560</fpage>–<lpage>75</lpage>.<pub-id pub-id-type="pmid">26629425</pub-id></mixed-citation></ref><ref id="kez418-B9"><label>9</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Lin</surname><given-names>Z</given-names></name>, <name name-style="western"><surname>Chen</surname><given-names>X</given-names></name>, <name name-style="western"><surname>Li</surname><given-names>Z</given-names></name></person-group><etal>et al</etal><article-title>PD-1 antibody monotherapy for malignant melanoma: a systematic review and meta-analysis</article-title>. <source>PLoS One</source><year>2016</year>;<volume>11</volume>:<fpage>e0160485</fpage>.<pub-id pub-id-type="pmid">27483468</pub-id></mixed-citation></ref><ref id="kez418-B10"><label>10</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Johnson</surname><given-names>DB</given-names></name>, <name name-style="western"><surname>Sullivan</surname><given-names>RJ</given-names></name>, <name name-style="western"><surname>Ott</surname><given-names>PA</given-names></name></person-group><etal>et al</etal><article-title>Ipilimumab therapy in patients with advanced melanoma and preexisting autoimmune disorders</article-title>. <source>JAMA Oncol</source><year>2019</year>;<volume>2</volume>:<fpage>234</fpage>–<lpage>40</lpage>.</mixed-citation></ref><ref id="kez418-B11"><label>11</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Oble</surname><given-names>DA</given-names></name>, <name name-style="western"><surname>Mino-Kenudson</surname><given-names>M</given-names></name>, <name name-style="western"><surname>Goldsmith</surname><given-names>J</given-names></name></person-group><etal>et al</etal><article-title>α-CTLA-4 mAb-associated panenteritis: a histologic and immunohistochemical analysis</article-title>. <source>Am J Surg Pathol</source><year>2008</year>;<volume>32</volume>:<fpage>1130</fpage>–<lpage>7</lpage>.<pub-id pub-id-type="pmid">18545145</pub-id></mixed-citation></ref><ref id="kez418-B12"><label>12</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Gupta</surname><given-names>A</given-names></name>, <name name-style="western"><surname>De Felice</surname><given-names>KM</given-names></name>, <name name-style="western"><surname>Loftus</surname><given-names>EV</given-names></name>, <name name-style="western"><surname>Khanna</surname><given-names>S.</given-names></name></person-group><article-title>Systematic review: colitis associated with anti-CTLA-4 therapy</article-title>. <source>Aliment Pharmacol Ther</source><year>2015</year>;<volume>42</volume>:<fpage>406</fpage>–<lpage>17</lpage>.<pub-id pub-id-type="pmid">26079306</pub-id></mixed-citation></ref><ref id="kez418-B13"><label>13</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Gonzalez</surname><given-names>RS</given-names></name>, <name name-style="western"><surname>Salaria</surname><given-names>SN</given-names></name>, <name name-style="western"><surname>Bohannon</surname><given-names>CD</given-names></name></person-group><etal>et al</etal><article-title>PD-1 inhibitor gastroenterocolitis: case series and appraisal of ‘immunomodulatory gastroenterocolitis</article-title>’. <source>Histopathology</source><year>2017</year>;<volume>70</volume>:<fpage>558</fpage>–<lpage>67</lpage>.<pub-id pub-id-type="pmid">28000302</pub-id></mixed-citation></ref><ref id="kez418-B14"><label>14</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Karamchandani</surname><given-names>DM</given-names></name>, <name name-style="western"><surname>Chetty</surname><given-names>R.</given-names></name></person-group><article-title>Immune checkpoint inhibitor-induced gastrointestinal and hepatic injury: pathologists’ perspective</article-title>. <source>J Clin Pathol</source><year>2018</year>;<volume>71</volume>:<fpage>665</fpage>–<lpage>71</lpage>.<pub-id pub-id-type="pmid">29703758</pub-id></mixed-citation></ref><ref id="kez418-B15"><label>15</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Jain</surname><given-names>A</given-names></name>, <name name-style="western"><surname>Lipson</surname><given-names>EJ</given-names></name>, <name name-style="western"><surname>Sharfman</surname><given-names>WH</given-names></name>, <name name-style="western"><surname>Brant</surname><given-names>SR</given-names></name>, <name name-style="western"><surname>Lazarev</surname><given-names>MG.</given-names></name></person-group><article-title>Colonic ulcerations may predict steroid-refractory course in patients with ipilimumab-mediated enterocolitis</article-title>. <source>World J Gastroenterol</source><year>2017</year>;<volume>23</volume>:<fpage>2023</fpage>–<lpage>8</lpage>.<pub-id pub-id-type="pmid">28373768</pub-id></mixed-citation></ref><ref id="kez418-B16"><label>16</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Kim</surname><given-names>KW</given-names></name>, <name name-style="western"><surname>Ramaiya</surname><given-names>NH</given-names></name>, <name name-style="western"><surname>Krajewski</surname><given-names>KM</given-names></name></person-group><etal>et al</etal><article-title>Ipilimumab-associated colitis: cT findings</article-title>. <source>Am J Roentgenol</source><year>2013</year>;<volume>200</volume>:<fpage>468</fpage>–<lpage>74</lpage>.<pub-id pub-id-type="pmid">23460984</pub-id></mixed-citation></ref><ref id="kez418-B17"><label>17</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Beck</surname><given-names>KE</given-names></name>, <name name-style="western"><surname>Blansfield</surname><given-names>JA</given-names></name>, <name name-style="western"><surname>Tran</surname><given-names>KQ</given-names></name></person-group>, <etal>et al</etal><article-title>Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4</article-title>. <source>J Clin Oncol</source><year>2007</year>;<volume>24</volume>:<fpage>2283</fpage>–<lpage>9</lpage>.</mixed-citation></ref><ref id="kez418-B18"><label>18</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Berman</surname><given-names>D</given-names></name>, <name name-style="western"><surname>Parker</surname><given-names>SM</given-names></name>, <name name-style="western"><surname>Siegel</surname><given-names>J</given-names></name></person-group><etal>et al</etal><article-title>Blockade of cytotoxic T-lymphocyte antigen-4 by ipilimumab results in dysregulation of gastrointestinal immunity in patients with advanced melanoma</article-title>. <source>Cancer Immun</source><year>2010</year>;<volume>10</volume>:<fpage>11</fpage>.<pub-id pub-id-type="pmid">21090563</pub-id></mixed-citation></ref><ref id="kez418-B19"><label>19</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Spain</surname><given-names>L</given-names></name>, <name name-style="western"><surname>Diem</surname><given-names>S</given-names></name>, <name name-style="western"><surname>Larkin</surname><given-names>J.</given-names></name></person-group><article-title>Management of toxicities of immune checkpoint inhibitors</article-title>. <source>Cancer Treat Rev</source><year>2016</year>;<volume>44</volume>:<fpage>51</fpage>–<lpage>60</lpage>.<pub-id pub-id-type="pmid">26874776</pub-id></mixed-citation></ref><ref id="kez418-B20"><label>20</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Cramer</surname><given-names>P</given-names></name>, <name name-style="western"><surname>Bresalier</surname><given-names>RS.</given-names></name></person-group><article-title>Gastrointestinal and hepatic complications of immune checkpoint inhibitors</article-title>. <source>Curr Gastroenterol Rep</source><year>2017</year>;<volume>19</volume>:<fpage>3</fpage>.<pub-id pub-id-type="pmid">28124291</pub-id></mixed-citation></ref><ref id="kez418-B21"><label>21</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Mekki</surname><given-names>A</given-names></name>, <name name-style="western"><surname>Dercle</surname><given-names>L</given-names></name>, <name name-style="western"><surname>Lichtenstein</surname><given-names>P.</given-names></name></person-group><article-title>Detection of immune-related adverse events by medical imaging in patients treated with anti-programmed cell death 1</article-title>. <source>Eur J Cancer</source><year>2018</year>;<volume>96</volume>:<fpage>91</fpage>–;<lpage>104</lpage>.<pub-id pub-id-type="pmid">29698933</pub-id></mixed-citation></ref><ref id="kez418-B22"><label>22</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Baraibar</surname><given-names>I</given-names></name>, <name name-style="western"><surname>Melero</surname><given-names>I</given-names></name>, <name name-style="western"><surname>Sarvise</surname><given-names>MP</given-names></name>, <name name-style="western"><surname>Castanon</surname><given-names>E.</given-names></name></person-group><article-title>Safety and tolerability of immune checkpoint inhibitors (PD-1 and PD-L1) in cancer</article-title>. <source>Drug Saf</source><year>2019</year>;<volume>42</volume>:<fpage>281</fpage>.<pub-id pub-id-type="pmid">30649742</pub-id></mixed-citation></ref><ref id="kez418-B23"><label>23</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Byun</surname><given-names>DJ</given-names></name>, <name name-style="western"><surname>Wolchok</surname><given-names>JD</given-names></name>, <name name-style="western"><surname>Rosenberg</surname><given-names>LM</given-names></name>, <name name-style="western"><surname>Girotra</surname><given-names>M.</given-names></name></person-group><article-title>Cancer immunotherapy – immune checkpoint blockade and associated endocrinopathies</article-title>. <source>Nat Rev Endocrinol</source><year>2017</year>;<volume>13</volume>:<fpage>195</fpage>–<lpage>207</lpage>.<pub-id pub-id-type="pmid">28106152</pub-id></mixed-citation></ref><ref id="kez418-B24"><label>24</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Hughes</surname><given-names>J</given-names></name>, <name name-style="western"><surname>Vudattu</surname><given-names>N</given-names></name>, <name name-style="western"><surname>Sznol</surname><given-names>M</given-names></name></person-group><etal>et al</etal><article-title>Precipitation of autoimmune diabetes with anti-PD-1 immunotherapy</article-title>. <source>Diabetes Care</source><year>2015</year>;<volume>38</volume>:<fpage>e55</fpage>–<lpage>e57</lpage>.<pub-id pub-id-type="pmid">25805871</pub-id></mixed-citation></ref><ref id="kez418-B25"><label>25</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Antinori</surname><given-names>A</given-names></name>, <name name-style="western"><surname>Arendt</surname><given-names>G</given-names></name>, <name name-style="western"><surname>Becker</surname><given-names>JT</given-names></name></person-group><etal>et al</etal><article-title>Characterization and management of dermatologic adverse events to agents targeting the PD-1 receptor</article-title>. <source>Eur J Cancer</source><year>2015</year>;<volume>69</volume>:<fpage>1789</fpage>–<lpage>99</lpage>.</mixed-citation></ref><ref id="kez418-B26"><label>26</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Naidoo</surname><given-names>J</given-names></name>, <name name-style="western"><surname>Page</surname><given-names>DB</given-names></name>, <name name-style="western"><surname>Li</surname><given-names>BT</given-names></name></person-group><etal>et al</etal><article-title>Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies</article-title>. <source>Ann Oncol</source><year>2015</year>;<volume>26</volume>:<fpage>2375</fpage>–<lpage>91</lpage>.<pub-id pub-id-type="pmid">26371282</pub-id></mixed-citation></ref><ref id="kez418-B27"><label>27</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Sibaud</surname><given-names>V.</given-names></name></person-group><article-title>Dermatologic reactions to immune checkpoint inhibitors</article-title>. <source>Am J Clin Dermatol</source><year>2018</year>;<volume>19</volume>:<fpage>345</fpage>–<lpage>61</lpage>.<pub-id pub-id-type="pmid">29256113</pub-id></mixed-citation></ref><ref id="kez418-B28"><label>28</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Hua</surname><given-names>C</given-names></name>, <name name-style="western"><surname>Boussemart</surname><given-names>L</given-names></name>, <name name-style="western"><surname>Mateus</surname><given-names>C</given-names></name></person-group><etal>et al</etal><article-title>Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumab</article-title>. <source>JAMA Dermatol</source><year>2016</year>;<volume>152</volume>:<fpage>45</fpage>–<lpage>51</lpage>.<pub-id pub-id-type="pmid">26501224</pub-id></mixed-citation></ref><ref id="kez418-B29"><label>29</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Orditura</surname><given-names>M</given-names></name>, <name name-style="western"><surname>De Vita</surname><given-names>F</given-names></name>, <name name-style="western"><surname>Galizia</surname><given-names>G</given-names></name></person-group><etal>et al</etal><article-title>Correlation between efficacy and skin rash occurrence following treatment with the epidermal growth factor receptor inhibitor cetuximab: A single institution retrospective analysis</article-title>. <source>Oncol Rep</source><year>2009</year>;<volume>21</volume>:<fpage>1023</fpage>–<lpage>8</lpage>.<pub-id pub-id-type="pmid">19288004</pub-id></mixed-citation></ref><ref id="kez418-B30"><label>30</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Larkin</surname><given-names>J</given-names></name>, <name name-style="western"><surname>Chiarion-Sileni</surname><given-names>V</given-names></name>, <name name-style="western"><surname>Gonzalez</surname><given-names>R</given-names></name></person-group><etal>et al</etal><article-title>Combined nivolumab and ipilimumab or monotherapy in untreated melanoma</article-title>. <source>N Engl J Med</source><year>2015</year>;<volume>373</volume>:<fpage>23</fpage>–<lpage>34</lpage>.<pub-id pub-id-type="pmid">26027431</pub-id></mixed-citation></ref><ref id="kez418-B31"><label>31</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Lidar</surname><given-names>M</given-names></name>, <name name-style="western"><surname>Giat</surname><given-names>E</given-names></name>, <name name-style="western"><surname>Garelick</surname><given-names>D</given-names></name></person-group><etal>et al</etal><article-title>Rheumatic manifestations among cancer patients treated with immune checkpoint inhibitors</article-title>. <source>Autoimmun Rev</source><year>2018</year>;<volume>17</volume>:<fpage>284</fpage>–<lpage>9</lpage>.<pub-id pub-id-type="pmid">29341936</pub-id></mixed-citation></ref><ref id="kez418-B32"><label>32</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Cappelli</surname><given-names>LC</given-names></name>, <name name-style="western"><surname>Gutierrez</surname><given-names>AK</given-names></name>, <name name-style="western"><surname>Baer</surname><given-names>AN</given-names></name></person-group><etal>et al</etal><article-title>Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab</article-title>. <source>Ann Rheum Dis</source><year>2017</year>;<volume>76</volume>:<fpage>43</fpage>–<lpage>50</lpage>.<pub-id pub-id-type="pmid">27307501</pub-id></mixed-citation></ref><ref id="kez418-B33"><label>33</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Belkhir</surname><given-names>R</given-names></name>, <name name-style="western"><surname>Burel</surname><given-names>SL</given-names></name>, <name name-style="western"><surname>Dunogeant</surname><given-names>L</given-names></name></person-group><etal>et al</etal><article-title>Rheumatoid arthritis and polymyalgia rheumatica occurring after immune checkpoint inhibitor treatment</article-title>. <source>Ann Rheum Dis</source><year>2017</year>;<volume>76</volume>:<fpage>1747</fpage>–<lpage>50</lpage>.<pub-id pub-id-type="pmid">28600350</pub-id></mixed-citation></ref><ref id="kez418-B34"><label>34</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Naidoo</surname><given-names>J</given-names></name>, <name name-style="western"><surname>Cappelli</surname><given-names>LC</given-names></name>, <name name-style="western"><surname>Forde</surname><given-names>PM</given-names></name></person-group><etal>et al</etal><article-title>Inflammatory arthritis: a newly recognized adverse event of immune checkpoint blockade</article-title>. <source>Oncologist</source><year>2017</year>;<volume>22</volume>:<fpage>627</fpage>–<lpage>30</lpage>.<pub-id pub-id-type="pmid">28576858</pub-id></mixed-citation></ref><ref id="kez418-B35"><label>35</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Touat</surname><given-names>M</given-names></name>, <name name-style="western"><surname>Maisonobe</surname><given-names>T</given-names></name>, <name name-style="western"><surname>Knauss</surname><given-names>S</given-names></name>, <name name-style="western"><surname>Ben</surname><given-names>O</given-names></name>, <name name-style="western"><surname>Salem</surname><given-names>H.</given-names></name></person-group><article-title>Immune checkpoint inhibitor-related myositis and myocarditis in patients with cancer</article-title>. <source>Neurology</source><year>2018</year>;<volume>91</volume>:<fpage>e985</fpage>–<lpage>94</lpage>.<pub-id pub-id-type="pmid">30089619</pub-id></mixed-citation></ref><ref id="kez418-B36"><label>36</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Eggermont</surname><given-names>AMM</given-names></name>, <name name-style="western"><surname>Chiarion-sileni</surname><given-names>V</given-names></name>, <name name-style="western"><surname>Grob</surname><given-names>J</given-names></name></person-group><etal>et al</etal><article-title>Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial</article-title>. <source>Lancet Oncol</source><year>2015</year>;<volume>16</volume>:<fpage>522</fpage>–<lpage>30</lpage>.<pub-id pub-id-type="pmid">25840693</pub-id></mixed-citation></ref><ref id="kez418-B37"><label>37</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Nukui</surname><given-names>T</given-names></name>, <name name-style="western"><surname>Nakayama</surname><given-names>Y</given-names></name>, <name name-style="western"><surname>Yamamoto</surname><given-names>M</given-names></name></person-group><etal>et al</etal><article-title>Nivolumab-induced acute demyelinating polyradiculoneuropathy mimicking Guillain-Barré syndrome</article-title>. <source>J Neurol Sci</source><year>2018</year>;<volume>390</volume>:<fpage>115</fpage>–<lpage>6</lpage>.<pub-id pub-id-type="pmid">29801870</pub-id></mixed-citation></ref><ref id="kez418-B38"><label>38</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Tanaka</surname><given-names>R</given-names></name>, <name name-style="western"><surname>Maruyama</surname><given-names>H</given-names></name>, <name name-style="western"><surname>Tomidokoro</surname><given-names>Y</given-names></name></person-group><etal>et al</etal><article-title> Nivolumab-induced chronic inflammatory demyelinating polyradiculoneuropathy mimicking rapid-onset Guillain-Barré syndrome: a case report</article-title>. <source>Jpn J Clin Oncol</source><year>2016</year>;<volume>46</volume>:<fpage>875</fpage>–<lpage>8</lpage>.<pub-id pub-id-type="pmid">27380808</pub-id></mixed-citation></ref><ref id="kez418-B39"><label>39</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Gonzalez</surname><given-names>NL</given-names></name>, <name name-style="western"><surname>Puwanant</surname><given-names>A</given-names></name>, <name name-style="western"><surname>Lu</surname><given-names>A</given-names></name>, <name name-style="western"><surname>Marks</surname><given-names>SM</given-names></name>, <name name-style="western"><surname>Živkovic</surname><given-names>SA.</given-names></name></person-group><article-title>Myasthenia triggered by immune checkpoint inhibitors: new case and literature review</article-title>. <source>Neuromuscul Disord</source><year>2017</year>;<volume>27</volume>:<fpage>266</fpage>–<lpage>8</lpage>.<pub-id pub-id-type="pmid">28109638</pub-id></mixed-citation></ref><ref id="kez418-B40"><label>40</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Levine</surname><given-names>JJ</given-names></name>, <name name-style="western"><surname>Somer</surname><given-names>RA</given-names></name>, <name name-style="western"><surname>Hosoya</surname><given-names>H</given-names></name>, <name name-style="western"><surname>Squillante</surname><given-names>C.</given-names></name></person-group><article-title>Atezolizumab-induced encephalitis in metastatic bladder cancer: a case report and review of the literature</article-title>. <source>Cli Genitourin Cancer</source><year>2017</year>;<volume>15</volume>:<fpage>e847</fpage>–<lpage>9</lpage>.</mixed-citation></ref><ref id="kez418-B41"><label>41</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Burke</surname><given-names>M</given-names></name>, <name name-style="western"><surname>Hardesty</surname><given-names>M</given-names></name>, <name name-style="western"><surname>Downs</surname><given-names>W.</given-names></name></person-group><article-title>A case of severe encephalitis while on PD-1 immunotherapy for recurrent clear cell ovarian cancer</article-title>. <source>Gynecol Oncol Reports</source><year>2018</year>;<volume>24</volume>:<fpage>51</fpage>–<lpage>3</lpage>.</mixed-citation></ref><ref id="kez418-B42"><label>42</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Williams</surname><given-names>TJ</given-names></name>, <name name-style="western"><surname>Benavides</surname><given-names>DR</given-names></name>, <name name-style="western"><surname>Patrice</surname><given-names>K</given-names></name></person-group><etal>et al</etal><article-title>Association of autoimmune encephalitis with combined immune checkpoint inhibitor treatment for metastatic cancer</article-title>. <source>JAMA Neurol</source><year>2016</year>;<volume>73</volume>:<fpage>928</fpage>–<lpage>33</lpage>.<pub-id pub-id-type="pmid">27271951</pub-id></mixed-citation></ref><ref id="kez418-B43"><label>43</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Feng</surname><given-names>S</given-names></name>, <name name-style="western"><surname>Coward</surname><given-names>J</given-names></name>, <name name-style="western"><surname>Mccaffrey</surname><given-names>E</given-names></name></person-group><etal>et al</etal><article-title>Pembrolizumab-induced encephalopathy: a review of neurological toxicities with immune checkpoint inhibitors</article-title>. <source>J Thorac Oncol</source><year>2017</year>;<volume>12</volume>:<fpage>1626</fpage>–<lpage>35</lpage>.<pub-id pub-id-type="pmid">28843363</pub-id></mixed-citation></ref><ref id="kez418-B44"><label>44</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Smith</surname><given-names>JL</given-names></name>, <name name-style="western"><surname>Menzies</surname><given-names>AM</given-names></name>, <name name-style="western"><surname>Cohen</surname><given-names>JV</given-names></name></person-group><etal>et al</etal><article-title>Neurotoxicity associated with anti-PD1 therapy: a multi-center case series</article-title>. <source>J Clin Oncol</source><year>2017</year>;<volume>35</volume>:<fpage>e21641</fpage>.</mixed-citation></ref><ref id="kez418-B45"><label>45</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Izzedine</surname><given-names>H</given-names></name>, <name name-style="western"><surname>Gueutin</surname><given-names>V</given-names></name>, <name name-style="western"><surname>Gharbi</surname><given-names>C</given-names></name></person-group><etal>et al</etal><article-title>Kidney injuries related to ipilimumab</article-title>. <source>Invest New Drugs</source><year>2014</year>;<volume>32</volume>:<fpage>769</fpage>–<lpage>73</lpage>.<pub-id pub-id-type="pmid">24687600</pub-id></mixed-citation></ref><ref id="kez418-B46"><label>46</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Belliere</surname><given-names>J</given-names></name>, <name name-style="western"><surname>Meyer</surname><given-names>N</given-names></name>, <name name-style="western"><surname>Mazieres</surname><given-names>J</given-names></name></person-group><etal>et al</etal><article-title>Acute interstitial nephritis related to immune checkpoint inhibitors</article-title>. <source>Br J Cancer</source><year>2016</year>;<volume>115</volume>:<fpage>1457</fpage>–<lpage>61</lpage>.<pub-id pub-id-type="pmid">27832664</pub-id></mixed-citation></ref><ref id="kez418-B47"><label>47</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Wanchoo</surname><given-names>R</given-names></name>, <name name-style="western"><surname>Karam</surname><given-names>S</given-names></name>, <name name-style="western"><surname>Uppal</surname><given-names>NN</given-names></name></person-group><etal>et al</etal><article-title>Adverse renal effects of immune checkpoint inhibitors: a narrative review</article-title>. <source>Am J Nephrol</source><year>2017</year>;<volume>45</volume>:<fpage>160</fpage>–<lpage>9</lpage>.<pub-id pub-id-type="pmid">28076863</pub-id></mixed-citation></ref><ref id="kez418-B48"><label>48</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Cortazar</surname><given-names>FB</given-names></name>, <name name-style="western"><surname>Marrone</surname><given-names>KA</given-names></name>, <name name-style="western"><surname>Troxell</surname><given-names>ML</given-names></name></person-group><etal>et al</etal><article-title>Clinicopathological features of acute kidney injury associated with immune checkpoint inhibitors</article-title>. <source>Kidney Int</source><year>2016</year>;<volume>90</volume>:<fpage>638</fpage>–<lpage>47</lpage>.<pub-id pub-id-type="pmid">27282937</pub-id></mixed-citation></ref><ref id="kez418-B49"><label>49</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Belliere</surname><given-names>J</given-names></name>, <name name-style="western"><surname>Meyer</surname><given-names>N</given-names></name>, <name name-style="western"><surname>Mazieres</surname><given-names>J</given-names></name></person-group><etal>et al</etal><article-title>Acute interstitial nephritis related to immune checkpoint inhibitors</article-title>. <source>Br J Cancer</source><year>2016</year>;<volume>115</volume>:<fpage>1457</fpage>–<lpage>61</lpage>.<pub-id pub-id-type="pmid">27832664</pub-id></mixed-citation></ref><ref id="kez418-B50"><label>50</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Lefebvre</surname><given-names>J</given-names></name>, <name name-style="western"><surname>Glezerman</surname><given-names>IG.</given-names></name></person-group><article-title>Kidney toxicities associated with novel cancer therapies</article-title>. <source>Adv Chronic Kidney Dis</source><year>2017</year>;<volume>24</volume>:<fpage>233</fpage>–<lpage>40</lpage>.<pub-id pub-id-type="pmid">28778363</pub-id></mixed-citation></ref><ref id="kez418-B51"><label>51</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Lipson</surname><given-names>EJ</given-names></name>, <name name-style="western"><surname>Bodell</surname><given-names>MA</given-names></name>, <name name-style="western"><surname>Kraus</surname><given-names>ES</given-names></name>, <name name-style="western"><surname>Sharfman</surname><given-names>WH.</given-names></name></person-group><article-title>Successful administration of ipilimumab to two kidney transplantation patients with metastatic melanoma</article-title>. <source>J Clin Oncol</source><year>2014</year>;<volume>32</volume>:<fpage>e69</fpage>–<lpage>71</lpage>.<pub-id pub-id-type="pmid">24493726</pub-id></mixed-citation></ref><ref id="kez418-B52"><label>52</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Delaunay</surname><given-names>M</given-names></name>, <name name-style="western"><surname>Cadranel</surname><given-names>J</given-names></name>, <name name-style="western"><surname>Lusque</surname><given-names>A</given-names></name></person-group><etal>et al</etal><article-title>Immune-checkpoint inhibitors associated with interstitial lung disease in cancer patients</article-title>. <source>Eur Respir J</source><year>2017</year>;<volume>50</volume>:<fpage>1700050</fpage>.<pub-id pub-id-type="pmid">28798088</pub-id></mixed-citation></ref><ref id="kez418-B53"><label>53</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Johnson</surname><given-names>DB</given-names></name>, <name name-style="western"><surname>Balko</surname><given-names>JM</given-names></name>, <name name-style="western"><surname>Compton</surname><given-names>ML</given-names></name></person-group><etal>et al</etal><article-title>Fulminant myocarditis with combination immune checkpoint blockade</article-title>. <source>N Engl J Med</source><year>2016</year>;<volume>375</volume>:<fpage>1749</fpage>–<lpage>55</lpage>.<pub-id pub-id-type="pmid">27806233</pub-id></mixed-citation></ref><ref id="kez418-B54"><label>54</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Nishimura</surname><given-names>H</given-names></name>, <name name-style="western"><surname>Okazaki</surname><given-names>T</given-names></name>, <name name-style="western"><surname>Tanaka</surname><given-names>Y.</given-names></name></person-group><article-title>Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice</article-title>. <source>Science</source><year>2001</year>;<volume>291</volume>:<fpage>319</fpage>–<lpage>23</lpage>.<pub-id pub-id-type="pmid">11209085</pub-id></mixed-citation></ref><ref id="kez418-B55"><label>55</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Lucas</surname><given-names>JA</given-names></name>, <name name-style="western"><surname>Menke</surname><given-names>J</given-names></name>, <name name-style="western"><surname>Rabacal</surname><given-names>WA</given-names></name></person-group><etal>et al</etal><article-title>Programmed death ligand 1 regulates a critical checkpoint for autoimmune myocarditis and pneumonitis in MRL mice</article-title>. <source>J Immunol</source><year>2008</year>;<volume>181</volume>:<fpage>2513</fpage>–<lpage>21</lpage>.<pub-id pub-id-type="pmid">18684942</pub-id></mixed-citation></ref><ref id="kez418-B56"><label>56</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Kumar</surname><given-names>V</given-names></name>, <name name-style="western"><surname>Chaudhary</surname><given-names>N</given-names></name>, <name name-style="western"><surname>Garg</surname><given-names>M</given-names></name></person-group><etal>et al</etal><article-title>Current diagnosis and management of immune related adverse events (irAEs) induced by immune checkpoint inhibitor therapy</article-title>. <source>Front Pharmacol</source><year>2017</year>;<volume>8</volume>:<fpage>49</fpage>.<pub-id pub-id-type="pmid">28228726</pub-id></mixed-citation></ref><ref id="kez418-B57"><label>57</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Kanno</surname><given-names>H</given-names></name>, <name name-style="western"><surname>Ishida</surname><given-names>K</given-names></name>, <name name-style="western"><surname>Yamada</surname><given-names>W</given-names></name></person-group><etal>et al</etal><article-title>Uveitis induced by programmed cell death protein 1 inhibitor therapy with nivolumab in metastatic melanoma patient</article-title>. <source>J Infect Chemother</source><year>2017</year>;<volume>23</volume>:<fpage>774</fpage>–<lpage>7</lpage>.<pub-id pub-id-type="pmid">28527652</pub-id></mixed-citation></ref><ref id="kez418-B58"><label>58</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Thomas</surname><given-names>M</given-names></name>, <name name-style="western"><surname>Armenti</surname><given-names>ST</given-names></name>, <name name-style="western"><surname>Ayres</surname><given-names>B</given-names></name>, <name name-style="western"><surname>Demirci</surname><given-names>H.</given-names></name></person-group><article-title>Uveal effusion after immune checkpoint inhibitor therapy</article-title>. <source>JAMA Ophthalmol</source><year>2018</year>;<volume>136</volume>:<fpage>553</fpage>–<lpage>6</lpage>.<pub-id pub-id-type="pmid">29677240</pub-id></mixed-citation></ref><ref id="kez418-B59"><label>59</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Arai</surname><given-names>T,</given-names></name>, <name name-style="western"><surname>Harada</surname><given-names>K,</given-names></name>, <name name-style="western"><surname>Usui</surname><given-names>Y,</given-names></name>, <name name-style="western"><surname>Irisawa</surname><given-names>R,</given-names></name>, <name name-style="western"><surname>Tsuboi</surname><given-names>R.</given-names></name></person-group><article-title>Case of acute anterior uveitis and Vogt–Koyanagi–Harada syndrome-like eruptions induced by nivolumab in a melanoma patient</article-title>. <source>J Dermatol</source><year>2017</year>;<volume>44</volume>:<fpage>975</fpage>–<lpage>6</lpage>.<pub-id pub-id-type="pmid">27649838</pub-id></mixed-citation></ref><ref id="kez418-B60"><label>60</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Atwal</surname><given-names>D</given-names></name>, <name name-style="western"><surname>Joshi</surname><given-names>KP</given-names></name>, <name name-style="western"><surname>Ravilla</surname><given-names>R</given-names></name>, <name name-style="western"><surname>Mahmoud</surname><given-names>F.</given-names></name></person-group><article-title>Pembrolizumab-induced pancytopenia: a case report</article-title>. <source>Perm J</source><year>2017</year>;<volume>21</volume>:<fpage>17-004</fpage>.</mixed-citation></ref><ref id="kez418-B61"><label>61</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Michot</surname><given-names>J</given-names></name>, <name name-style="western"><surname>Vargaftig</surname><given-names>J</given-names></name>, <name name-style="western"><surname>Leduc</surname><given-names>C</given-names></name></person-group><etal>et al</etal><article-title>Immune-related bone marrow failure following anti-PD1 therapy</article-title>. <source>Eur J Cancer</source><year>2017</year>;<volume>80</volume>:<fpage>1</fpage>–<lpage>4</lpage>.<pub-id pub-id-type="pmid">28527392</pub-id></mixed-citation></ref><ref id="kez418-B62"><label>62</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Comito</surname><given-names>RR</given-names></name>, <name name-style="western"><surname>Badu</surname><given-names>LA</given-names></name>, <name name-style="western"><surname>Forcello</surname><given-names>N.</given-names></name></person-group><article-title>Nivolumab-induced aplastic anemia: a case report and literature review</article-title>. <source>J Oncol Pharm Pract</source><year>2019</year>;<volume>25</volume>:<fpage>221</fpage>–<lpage>5</lpage>.<pub-id pub-id-type="pmid">28825374</pub-id></mixed-citation></ref><ref id="kez418-B63"><label>63</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Pföhler</surname><given-names>C</given-names></name>, <name name-style="western"><surname>Burgard</surname><given-names>B</given-names></name>, <name name-style="western"><surname>Müller</surname><given-names>CSL.</given-names></name></person-group><article-title>A case of immune thrombocytopenia as a rare side effect of an immunotherapy with PD1-blocking agents for metastatic melanoma</article-title>. <source>Transfus Med Hemother</source><year>2017</year>;<volume>44</volume>:<fpage>426</fpage>–<lpage>8</lpage>.<pub-id pub-id-type="pmid">29344020</pub-id></mixed-citation></ref><ref id="kez418-B64"><label>64</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Donia</surname><given-names>M</given-names></name>, <name name-style="western"><surname>Pedersen</surname><given-names>M</given-names></name>, <name name-style="western"><surname>Svane</surname><given-names>IM.</given-names></name></person-group><article-title>Cancer immunotherapy in patients with preexisting autoimmune disorders</article-title>. <source>Semin Immunopathol</source><year>2017</year>;<volume>39</volume>:<fpage>333</fpage>–<lpage>7</lpage>.<pub-id pub-id-type="pmid">27730287</pub-id></mixed-citation></ref><ref id="kez418-B65"><label>65</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Gettings</surname><given-names>EJ</given-names></name>, <name name-style="western"><surname>Hackett</surname><given-names>CT</given-names></name>, <name name-style="western"><surname>Scott</surname><given-names>TF.</given-names></name></person-group><article-title>Severe relapse in a multiple sclerosis patient associated with ipilimumab treatment of melanoma</article-title>. <source>Mult Scler</source><year>2015</year>;<volume>21</volume>:<fpage>670</fpage>.<pub-id pub-id-type="pmid">25257614</pub-id></mixed-citation></ref><ref id="kez418-B66"><label>66</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Lee</surname><given-names>B</given-names></name>, <name name-style="western"><surname>Wong</surname><given-names>A</given-names></name>, <name name-style="western"><surname>Kee</surname><given-names>D</given-names></name></person-group><etal>et al</etal><article-title>The use of ipilimumab in patients with rheumatoid arthritis and metastatic melanoma</article-title>. <source>Ann Oncol</source><year>2016</year>;<volume>27</volume>:<fpage>1174</fpage>–<lpage>7</lpage>.<pub-id pub-id-type="pmid">26861600</pub-id></mixed-citation></ref><ref id="kez418-B67"><label>67</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Johnson</surname><given-names>DB</given-names></name>, <name name-style="western"><surname>Sullivan</surname><given-names>RJ</given-names></name>, <name name-style="western"><surname>Ott</surname><given-names>PA</given-names></name></person-group><etal>et al</etal><article-title>Ipilimumab therapy in patients with advanced melanoma and preexisting autoimmune disorders</article-title>. <source>JAMA Oncol</source><year>2016</year>;<volume>2</volume>:<fpage>234</fpage>–<lpage>40</lpage>.<pub-id pub-id-type="pmid">26633184</pub-id></mixed-citation></ref><ref id="kez418-B68"><label>68</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Gutzmer</surname><given-names>R</given-names></name>, <name name-style="western"><surname>Koop</surname><given-names>A</given-names></name>, <name name-style="western"><surname>Meier</surname><given-names>F</given-names></name></person-group><etal>et al</etal><article-title>Programmed cell death protein-1 (PD-1) inhibitor therapy in patients with advanced melanoma and preexisting autoimmunity or ipilimumab-triggered autoimmunity</article-title>. <source>Eur J Cancer</source><year>2017</year>;<volume>75</volume>:<fpage>24</fpage>–<lpage>32</lpage>.<pub-id pub-id-type="pmid">28214654</pub-id></mixed-citation></ref><ref id="kez418-B69"><label>69</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Menzies</surname><given-names>AM</given-names></name>, <name name-style="western"><surname>Johnson</surname><given-names>DB</given-names></name>, <name name-style="western"><surname>Ramanujam</surname><given-names>S</given-names></name></person-group><etal>et al</etal><article-title>Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab</article-title>. <source>Ann Oncol</source><year>2017</year>;<volume>28</volume>:<fpage>368</fpage>–<lpage>76</lpage>.<pub-id pub-id-type="pmid">27687304</pub-id></mixed-citation></ref></ref-list></back></pmc></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Sante/explor/ChloroquineV1/Data/Pmc/Corpus
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000805 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd -nk 000805 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Sante
|area= ChloroquineV1
|flux= Pmc
|étape= Corpus
|type= RBID
|clé= PMC:6900917
|texte= Toxicities associated with checkpoint inhibitors—an overview
}}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/RBID.i -Sk "pubmed:31816085" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd \
| NlmPubMed2Wicri -a ChloroquineV1
| This area was generated with Dilib version V0.6.33. |  |