Thymus alterations and susceptibility to immune checkpoint inhibitor myocarditis

doi:10.1038/s41591-023-02591-2

Meta-Analysis

. 2023 Dec;29(12):3100-3110.

doi: 10.1038/s41591-023-02591-2. Epub 2023 Oct 26.

Thymus alterations and susceptibility to immune checkpoint inhibitor myocarditis

Charlotte Fenioux^{1

2}, Baptiste Abbar^#^{1

3}, Samia Boussouar^#⁴, Marie Bretagne¹, John R Power⁵, Javid J Moslehi⁶, Paul Gougis¹, Damien Amelin⁷, Agnès Dechartres⁸, Lorenz H Lehmann⁹, Pierre-Yves Courand¹⁰, Jennifer Cautela¹¹, Joachim Alexandre¹², Adrien Procureur¹, Antoine Rozes⁸, Sarah Leonard-Louis¹³, Juan Qin⁶; International ICI-Myocarditis Registry; Rémi Cheynier¹⁴, Benedicte Charmeteau-De Muylder¹⁴, Alban Redheuil⁴, Florence Tubach⁸, Jacques Cadranel¹⁵, Audrey Milon¹⁶, Stéphane Ederhy¹⁷, Thomas Similowski¹⁸, Douglas B Johnson¹⁹, Ian Pizzo²⁰, Toniemarie Catalan²⁰, Olivier Benveniste²¹, Salim S Hayek²⁰, Yves Allenbach²¹, Michelle Rosenzwajg²², Charles Dolladille¹, Joe-Elie Salem^{23

24}

Collaborators, Affiliations

Collaborators

International ICI-Myocarditis Registry:
Nausheen Akhter, Nazanin Aghel, Kingsley Amidi, Elizabeth Anderson, Dimitri Arangalage, Mandar Aras, Aarti Asnani, Lauren A Baldassarre, Rocio Barovila, Ana Sofia Barroso, Wendy Bottinor, Anissa Bouali, Eve Cariou, Wei-Ting Chang, Richard K Cheng, Shanthini M Crusz, Anita Deswal, Pierre-Yves Dietrich, Grace Dy, Clemence Docq, Steven Ewer, Suran Fernando, Danette L Flint, Roberta Florido, Satoshi Fukushima, Elena Galli, Elizabeth Gaughan, Manhal Habib, Andrew Haydon, Lucie Heinzerling, Osnat Itzhaki Ben Zadok, Nahema Issa, Anja Karlstaedt, Kazuo Kitagawa, Michael Layoun, Michal Laufer-Perl, Carrie Lenneman, Darryl Leong, Chloe Lesiuk, Joshua Levenson, Teresa López-Fernández, Yan Liu, Kristen Machado, Pedro Moliner, Ryota Morimoto, Michel Obeid, Anna Narezkina, Nicolas Palaskas, Giovanni Peretto, Nicolas Piriou, Juan Carlos Plana, Peter P Rainer, Maxime Robert-Halabi, Fanny Rocher, Eugenia Rota, Francois Roubille, Theresa Ruf, Shahneen Sandhu, Francis Sanjeev, Nobuhiko Seki, Kazuko Tajiri, Yuichi Tamura, Franck Thuny, Romain Tresorier, Isik Turker, Ellen Warner, Vlad Zaha, Han Zhu

Affiliations

¹ Sorbonne Université, INSERM, CIC-1901 Paris-Est, Assistance Publique - Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Department of Pharmacology, Paris, France.
² Hôpitaux de Paris, Henri Mondor Hospital, Department of Oncology, Créteil, France.
³ Hôpitaux de Paris, Pitié Salpêtrière Hospital, Department of Oncology, Paris, France.
⁴ Hôpitaux de Paris, Pitié Salpêtrière Hospital, Department of Radiology, Paris, France.
⁵ Department of Medecine, University of California, San Diego, San Diego, CA, USA.
⁶ Department of Medecine, University of California, San Francisco, San Francisco, CA, USA.
⁷ Sorbonne Université, INSERM, Association Institut de Myologie, Center of Research in Myology, UMRS 974, Paris, France.
⁸ Sorbonne Université, INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Département de Santé Publique, Centre de Pharmacoépidémiologie (Cephepi), Unité de Recherche Clinique PSL-CFX, CIC-1901, AP-HP, Hôpital Pitié Salpêtrière, Paris, France.
⁹ Department of Cardiology, University Hospital Heidelberg; German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁰ Fédération de Cardiologie, IMMUCARE, Hôpital de La Croix-Rousse Et Hôpital Lyon Sud, Hospices Civils de Lyon; Université de Lyon, CREATIS UMR INSERM U1044, INSA, Lyon, France.
¹¹ Aix-Marseille University, University Mediterranean Center of Cardio-Oncology, Unit of Heart Failure and Valvular Heart Diseases, Center for Cardiovascular and Nutrition Research, INSERM 1263, INRAE 1260, Nord Hospital, Assistance Publique-Hôpitaux de Marseille, Paris, France.
¹² CHU de Caen Normandie, Department of Pharmacology, Pharmacoepidemiology Unit; Normandie Université, UNICAEN, INSERM U1086 ANTICIPE Centre François Baclesse, Caen, France.
¹³ Hôpitaux de Paris, Pitié Salpêtrière Hospital, Laboratoire de Neuropathologie, Paris, France.
¹⁴ Université Paris Cité, CNRS, INSERM, Institut Cochin, Paris, France.
¹⁵ Hôpitaux de Paris, Tenon Hospital, Department of Pulmonology and Thoracic Oncology and GRC Theranoscan Sorbonne University, Paris, France.
¹⁶ Hôpitaux de Paris, Tenon Hospital, Department of Radiology, Paris, France.
¹⁷ Hôpitaux de Paris, Saint-Antoine Hospital, Department of Cardiology, Paris, France.
¹⁸ Sorbonne Université, INSERM, UMRS 1158 Neurophysiologie respiratoire expérimentale et clinique'; Assistance Publique -Hôpitaux de Paris, Pitié-Salpêtrière Hospital, 'Département R3S', Paris, France.
¹⁹ Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
²⁰ Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, USA.
²¹ Department of Internal Medicine, Sorbonne University, AP-HP, INSERM UMRS 974, Pitié-Salpêtrière Hospital, Paris, France.
²² Hôpitaux de Paris, Pitié Salpêtrière Hospital, Department of Immunology, Paris, France.
²³ Sorbonne Université, INSERM, CIC-1901 Paris-Est, Assistance Publique - Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Department of Pharmacology, Paris, France. joe-elie.salem@aphp.fr.
²⁴ Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. joe-elie.salem@aphp.fr.

^# Contributed equally.

PMID: 37884625
DOI: 10.1038/s41591-023-02591-2

Meta-Analysis

Thymus alterations and susceptibility to immune checkpoint inhibitor myocarditis

Charlotte Fenioux et al. Nat Med. 2023 Dec.

. 2023 Dec;29(12):3100-3110.

doi: 10.1038/s41591-023-02591-2. Epub 2023 Oct 26.

Authors

Collaborators

International ICI-Myocarditis Registry:
Nausheen Akhter, Nazanin Aghel, Kingsley Amidi, Elizabeth Anderson, Dimitri Arangalage, Mandar Aras, Aarti Asnani, Lauren A Baldassarre, Rocio Barovila, Ana Sofia Barroso, Wendy Bottinor, Anissa Bouali, Eve Cariou, Wei-Ting Chang, Richard K Cheng, Shanthini M Crusz, Anita Deswal, Pierre-Yves Dietrich, Grace Dy, Clemence Docq, Steven Ewer, Suran Fernando, Danette L Flint, Roberta Florido, Satoshi Fukushima, Elena Galli, Elizabeth Gaughan, Manhal Habib, Andrew Haydon, Lucie Heinzerling, Osnat Itzhaki Ben Zadok, Nahema Issa, Anja Karlstaedt, Kazuo Kitagawa, Michael Layoun, Michal Laufer-Perl, Carrie Lenneman, Darryl Leong, Chloe Lesiuk, Joshua Levenson, Teresa López-Fernández, Yan Liu, Kristen Machado, Pedro Moliner, Ryota Morimoto, Michel Obeid, Anna Narezkina, Nicolas Palaskas, Giovanni Peretto, Nicolas Piriou, Juan Carlos Plana, Peter P Rainer, Maxime Robert-Halabi, Fanny Rocher, Eugenia Rota, Francois Roubille, Theresa Ruf, Shahneen Sandhu, Francis Sanjeev, Nobuhiko Seki, Kazuko Tajiri, Yuichi Tamura, Franck Thuny, Romain Tresorier, Isik Turker, Ellen Warner, Vlad Zaha, Han Zhu

Affiliations

¹ Sorbonne Université, INSERM, CIC-1901 Paris-Est, Assistance Publique - Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Department of Pharmacology, Paris, France.
² Hôpitaux de Paris, Henri Mondor Hospital, Department of Oncology, Créteil, France.
³ Hôpitaux de Paris, Pitié Salpêtrière Hospital, Department of Oncology, Paris, France.
⁴ Hôpitaux de Paris, Pitié Salpêtrière Hospital, Department of Radiology, Paris, France.
⁵ Department of Medecine, University of California, San Diego, San Diego, CA, USA.
⁶ Department of Medecine, University of California, San Francisco, San Francisco, CA, USA.
⁷ Sorbonne Université, INSERM, Association Institut de Myologie, Center of Research in Myology, UMRS 974, Paris, France.
⁸ Sorbonne Université, INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Département de Santé Publique, Centre de Pharmacoépidémiologie (Cephepi), Unité de Recherche Clinique PSL-CFX, CIC-1901, AP-HP, Hôpital Pitié Salpêtrière, Paris, France.
⁹ Department of Cardiology, University Hospital Heidelberg; German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁰ Fédération de Cardiologie, IMMUCARE, Hôpital de La Croix-Rousse Et Hôpital Lyon Sud, Hospices Civils de Lyon; Université de Lyon, CREATIS UMR INSERM U1044, INSA, Lyon, France.
¹¹ Aix-Marseille University, University Mediterranean Center of Cardio-Oncology, Unit of Heart Failure and Valvular Heart Diseases, Center for Cardiovascular and Nutrition Research, INSERM 1263, INRAE 1260, Nord Hospital, Assistance Publique-Hôpitaux de Marseille, Paris, France.
¹² CHU de Caen Normandie, Department of Pharmacology, Pharmacoepidemiology Unit; Normandie Université, UNICAEN, INSERM U1086 ANTICIPE Centre François Baclesse, Caen, France.
¹³ Hôpitaux de Paris, Pitié Salpêtrière Hospital, Laboratoire de Neuropathologie, Paris, France.
¹⁴ Université Paris Cité, CNRS, INSERM, Institut Cochin, Paris, France.
¹⁵ Hôpitaux de Paris, Tenon Hospital, Department of Pulmonology and Thoracic Oncology and GRC Theranoscan Sorbonne University, Paris, France.
¹⁶ Hôpitaux de Paris, Tenon Hospital, Department of Radiology, Paris, France.
¹⁷ Hôpitaux de Paris, Saint-Antoine Hospital, Department of Cardiology, Paris, France.
¹⁸ Sorbonne Université, INSERM, UMRS 1158 Neurophysiologie respiratoire expérimentale et clinique'; Assistance Publique -Hôpitaux de Paris, Pitié-Salpêtrière Hospital, 'Département R3S', Paris, France.
¹⁹ Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
²⁰ Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, USA.
²¹ Department of Internal Medicine, Sorbonne University, AP-HP, INSERM UMRS 974, Pitié-Salpêtrière Hospital, Paris, France.
²² Hôpitaux de Paris, Pitié Salpêtrière Hospital, Department of Immunology, Paris, France.
²³ Sorbonne Université, INSERM, CIC-1901 Paris-Est, Assistance Publique - Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Department of Pharmacology, Paris, France. joe-elie.salem@aphp.fr.
²⁴ Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. joe-elie.salem@aphp.fr.

^# Contributed equally.

PMID: 37884625
DOI: 10.1038/s41591-023-02591-2

Erratum in

Author Correction: Thymus alterations and susceptibility to immune checkpoint inhibitor myocarditis.
Fenioux C, Abbar B, Boussouar S, Bretagne M, Power JR, Moslehi JJ, Gougis P, Amelin D, Dechartres A, Lehmann LH, Courand PY, Cautela J, Alexandre J, Procureur A, Rozes A, Leonard-Louis S, Qin J; International ICI-Myocarditis Registry; Cheynier R, Charmeteau-De Muylder B, Redheuil A, Tubach F, Cadranel J, Milon A, Ederhy S, Similowski T, Johnson DB, Pizzo I, Catalan T, Benveniste O, Hayek SS, Allenbach Y, Rosenzwajg M, Dolladille C, Salem JE. Fenioux C, et al. Nat Med. 2023 Dec;29(12):3268. doi: 10.1038/s41591-023-02690-0. Nat Med. 2023. PMID: 38012317 No abstract available.
Publisher Correction: Thymus alterations and susceptibility to immune checkpoint inhibitor myocarditis.
Fenioux C, Abbar B, Boussouar S, Bretagne M, Power JR, Moslehi JJ, Gougis P, Amelin D, Dechartres A, Lehmann LH, Courand PY, Cautela J, Alexandre J, Procureur A, Rozes A, Leonard-Louis S, Qin J; International ICI-Myocarditis Registry; Cheynier R, Charmeteau-De Muylder B, Redheuil A, Tubach F, Cadranel J, Milon A, Ederhy S, Similowski T, Johnson DB, Pizzo I, Catalan T, Benveniste O, Hayek SS, Allenbach Y, Rosenzwajg M, Dolladille C, Salem JE. Fenioux C, et al. Nat Med. 2024 Mar;30(3):910. doi: 10.1038/s41591-023-02771-0. Nat Med. 2024. PMID: 38172633 No abstract available.

Abstract

Immune checkpoint inhibitors (ICI) have transformed the therapeutic landscape in oncology. However, ICI can induce uncommon life-threatening autoimmune T-cell-mediated myotoxicities, including myocarditis and myositis. The thymus plays a critical role in T cell maturation. Here we demonstrate that thymic alterations are associated with increased incidence and severity of ICI myotoxicities. First, using the international pharmacovigilance database VigiBase, the Assistance Publique Hôpitaux de Paris-Sorbonne University data warehouse (Paris, France) and a meta-analysis of clinical trials, we show that ICI treatment of thymic epithelial tumors (TET, and particularly thymoma) was more frequently associated with ICI myotoxicities than other ICI-treated cancers. Second, in an international ICI myocarditis registry, we established that myocarditis occurred earlier after ICI initiation in patients with TET (including active or prior history of TET) compared to other cancers and was more severe in terms of life-threatening arrythmias and concurrent myositis, leading to respiratory muscle failure and death. Lastly, we show that presence of anti-acetylcholine-receptor antibodies (a biological proxy of thymic-associated autoimmunity) was more prevalent in patients with ICI myocarditis than in ICI-treated control patients. Altogether, our results highlight that thymic alterations are associated with incidence and seriousness of ICI myotoxicities. Clinico-radio-biological workup evaluating the thymus may help in predicting ICI myotoxicities.

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References

1. Geraud, A. et al. Clinical pharmacology and interplay of immune checkpoint agents: a yin-yang balance. Annu. Rev. Pharmacol. Toxicol. 61, 85–112 (2021). - PubMed - DOI
1. Nguyen, L. S. et al. Systematic analysis of drug-associated myocarditis reported in the World Health Organization pharmacovigilance database. Nat. Commun. 13, 25 (2022). - PubMed - PMC - DOI
1. Salem, J. E. et al. Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study. Lancet Oncol. 19, 1579–1589 (2018). - PubMed - PMC - DOI
1. Wang, D. Y. et al. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol. 4, 1721–1728 (2018). - PubMed - PMC - DOI
1. Power, J. R. et al. Association of early electrical changes with cardiovascular outcomes in immune checkpoint inhibitor myocarditis. Arch. Cardiovasc. Dis. 115, 315–330 (2022). - PubMed - DOI

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[1] Geraud, A. et al. Clinical pharmacology and interplay of immune checkpoint agents: a yin-yang balance. Annu. Rev. Pharmacol. Toxicol. 61, 85–112 (2021). - PubMed - DOI

[2] Geraud, A. et al. Clinical pharmacology and interplay of immune checkpoint agents: a yin-yang balance. Annu. Rev. Pharmacol. Toxicol. 61, 85–112 (2021). - PubMed - DOI

[3] Nguyen, L. S. et al. Systematic analysis of drug-associated myocarditis reported in the World Health Organization pharmacovigilance database. Nat. Commun. 13, 25 (2022). - PubMed - PMC - DOI

[4] Nguyen, L. S. et al. Systematic analysis of drug-associated myocarditis reported in the World Health Organization pharmacovigilance database. Nat. Commun. 13, 25 (2022). - PubMed - PMC - DOI

[5] Salem, J. E. et al. Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study. Lancet Oncol. 19, 1579–1589 (2018). - PubMed - PMC - DOI

[6] Salem, J. E. et al. Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study. Lancet Oncol. 19, 1579–1589 (2018). - PubMed - PMC - DOI

[7] Wang, D. Y. et al. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol. 4, 1721–1728 (2018). - PubMed - PMC - DOI

[8] Wang, D. Y. et al. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol. 4, 1721–1728 (2018). - PubMed - PMC - DOI

[9] Power, J. R. et al. Association of early electrical changes with cardiovascular outcomes in immune checkpoint inhibitor myocarditis. Arch. Cardiovasc. Dis. 115, 315–330 (2022). - PubMed - DOI

[10] Power, J. R. et al. Association of early electrical changes with cardiovascular outcomes in immune checkpoint inhibitor myocarditis. Arch. Cardiovasc. Dis. 115, 315–330 (2022). - PubMed - DOI

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Thymus alterations and susceptibility to immune checkpoint inhibitor myocarditis

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Thymus alterations and susceptibility to immune checkpoint inhibitor myocarditis

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