Abstract
Background and Objective
Immune checkpoint inhibitors (ICIs) such as programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitors have greatly improved cancer treatment. However, they are associated with immune-related adverse events, including autoimmune diseases (ADs) owing to their immune enhancement effect. As there are few comprehensive studies of ADs by ICIs, it is necessary to analyze the period information of drug-induced ADs. We also assumed that the temporal information may be useful to estimate the similarity of the pathogenic mechanism between spontaneous and ICI-induced ADs.
Methods
A period analysis including the Weibull analysis was performed on ICI-induced ADs using the Japanese Adverse Drug Event Report (JADER) database. For evaluating the similarity of spontaneous and ICI-induced ADs, a hierarchical cluster analysis was conducted to compare the different onset-time ranges.
Results
Type 1 diabetes mellitus, autoimmune colitis, and pemphigoid occurred earlier with CTLA-4 inhibitors (median: 46, 29.5 and 28 days, respectively) than with PD-1 inhibitors (> 130 days). Myasthenia gravis had a median time to onset of approximately 1 month, and the risk of onset would increase over time in ipilimumab combination therapy. This result reveals ADs that require attention. Using cluster analysis, we estimated six clusters with different patterns of onset times. Based on these results and a detailed previous research survey, the possible pathogenesis of drug-induced ADs was also discussed.
Conclusions
This paper describes risk profiles with temporal information of ICI-induced ADs and proposes certain indicators for deciphering the mechanism of AD onset.
Similar content being viewed by others
Change history
23 September 2021
A Correction to this paper has been published: https://doi.org/10.1007/s40261-021-01084-9
References
Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. 2018;359:1350–5.
Larkin J, Chiarion-Sileni V, Gonzalez R, Grob J-J, Rutkowski P, Lao CD, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019;381:1535–46. https://doi.org/10.1056/NEJMoa1910836.
Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378:1277–90. https://doi.org/10.1056/NEJMoa1712126.
Hellmann MD, Paz-Ares L, Bernabe Caro R, Zurawski B, Kim S-W, Carcereny Costa E, et al. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N Engl J Med. 2019;381:2020–31. https://doi.org/10.1056/NEJMoa1910231.
Puzanov I, Diab A, Abdallah K, Bingham CO, Brogdon C, Dadu R, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer. 2017;5:95. https://doi.org/10.1186/s40425-017-0300-z.
Grangeon M, Tomasini P, Chaleat S, Jeanson A, Souquet-Bressand M, Khobta N, et al. Association between immune-related adverse events and efficacy of immune checkpoint inhibitors in non-small-cell lung cancer. Clin Lung Cancer. 2019;20:201–7. https://doi.org/10.1016/j.cllc.2018.10.002.
Michot JM, Bigenwald C, Champiat S, Collins M, Carbonnel F, Postel-Vinay S, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer. 2016;54:139–48. https://doi.org/10.1016/j.ejca.2015.11.016.
Almutairi AR, McBride A, Slack M, Erstad BL, Abraham I. Potential immune-related adverse events associated with monotherapy and combination therapy of ipilimumab, nivolumab, and pembrolizumab for advanced melanoma: a systematic review and meta-analysis. Front Oncol. 2020;10:91. https://doi.org/10.3389/fonc.2020.00091.
Geisler AN, Phillips GS, Barrios DM, Wu J, Leung DYM, Moy AP, et al. Immune checkpoint inhibitor-related dermatologic adverse events. J Am Acad Dermatol. 2020;83:1255–68. https://doi.org/10.1016/j.jaad.2020.03.132.
Sznol M, Postow MA, Davies MJ, Pavlick AC, Plimack ER, Shaheen M, et al. Endocrine-related adverse events associated with immune checkpoint blockade and expert insights on their management. Cancer Treat Rev. 2017;58:70–6. https://doi.org/10.1016/j.ctrv.2017.06.002.
Angelopoulou F, Bogdanos D, Dimitroulas T, Sakkas L, Daoussis D. Immune checkpoint inhibitor-induced musculoskeletal manifestations. Rheumatol Int. 2021;41:33–42. https://doi.org/10.1007/s00296-020-04665-7.
Sato K, Mano T, Iwata A, Toda T. Neurological and related adverse events in immune checkpoint inhibitors: a pharmacovigilance study from the Japanese Adverse Drug Event Report database. J Neurooncol. 2019;145:1–9. https://doi.org/10.1007/s11060-019-03273-1.
Chen C, Wu B, Zhang C, Xu T. Immune-related adverse events associated with immune checkpoint inhibitors: an updated comprehensive disproportionality analysis of the FDA adverse event reporting system. Int Immunopharmacol. 2021;95:107498. https://doi.org/10.1016/j.intimp.2021.107498.
Tocut M, Brenner R, Zandman-Goddard G. Autoimmune phenomena and disease in cancer patients treated with immune checkpoint inhibitors. Autoimmun Rev. 2018;17:610–6. https://doi.org/10.1016/j.autrev.2018.01.010.
Haugh AM, Probasco JC, Johnson DB. Neurologic complications of immune checkpoint inhibitors. Expert Opin Drug Saf. 2020;19:479–88. https://doi.org/10.1080/14740338.2020.1738382.
Clotman K, Janssens K, Specenier P, Weets I, Block D, Christophe EM. Programmed cell death-1 inhibitor-induced type 1 diabetes mellitus. J Clin Endocrinol Metab. 2018;103:3144–54. https://doi.org/10.1210/jc.2018-00728.
Ono Pharmaceutical Co., Ltd. Request for appropriate use of intravenous infusion of Opdivo®. 2017. https://www.pmda.go.jp/PmdaSearch/iyakuDetail/GeneralList/4291427. Accessed 1 Feb 2021.
Amador-Patarroyo MJ, Rodriguez-Rodriguez A, Montoya-Ortiz G. How does age at onset influence the outcome of autoimmune diseases? Autoimmune Dis. 2012;2012:251730. https://doi.org/10.1155/2012/251730.
Ngo ST, Steyn FJ, McCombe PA. Gender differences in autoimmune disease. Front Neuroendocrinol. 2014;35:347–69. https://doi.org/10.1016/j.yfrne.2014.04.004.
Wahren-Herlenius M, Dörner T. Immunopathogenic mechanisms of systemic autoimmune disease. Lancet. 2013;382:819–31. https://doi.org/10.1016/S0140-6736(13)60954-X.
Japan Intractable Disease Information Center. https://www.nanbyou.or.jp/. Accessed 15 Mar 2021.
Pan PC-W, Haggiagi A. Neurologic immune-related adverse events associated with immune checkpoint inhibition. Curr Oncol Rep. 2019;21:108. https://doi.org/10.1007/s11912-019-0859-2.
Baden MY, Imagawa A, Abiru N, Awata T, Ikegami H, Uchigata Y, et al. Characteristics and clinical course of type 1 diabetes mellitus related to anti-programmed cell death-1 therapy. Diabetol Int. 2019;10:58–66. https://doi.org/10.1007/s13340-018-0362-2.
Hasegawa S, Ikesue H, Nakao S, Shimada K, Mukai R, Tanaka M, et al. Analysis of immune-related adverse events caused by immune checkpoint inhibitors using the Japanese Adverse Drug Event Report database. Pharmacoepidemiol Drug Saf. 2020. https://doi.org/10.1002/pds.5108.
Raschi E, Gatti M, Gelsomino F, Ardizzoni A, Poluzzi E, de Ponti F. Lessons to be learnt from real-world studies on immune-related adverse events with checkpoint inhibitors: a clinical perspective from pharmacovigilance. Target Oncol. 2020;15:449–66. https://doi.org/10.1007/s11523-020-00738-6.
Hosohata K, Inada A, Oyama S, Niinomi I, Wakabayashi T, Iwanaga K. Adverse cutaneous drug reactions associated with old- and new-generation antiepileptic drugs using the Japanese Pharmacovigilance Database. Clin Drug Investig. 2019;39:363–8. https://doi.org/10.1007/s40261-019-00754-z.
Katsuhara Y, Ogawa T. Acute renal failure, ketoacidosis, and urogenital tract infections with SGLT2 inhibitors: signal detection using a Japanese spontaneous reporting database. Clin Drug Investig. 2020;40:645–52. https://doi.org/10.1007/s40261-020-00925-3.
Sauzet O, Carvajal A, Escudero A, Molokhia M, Cornelius VR. Illustration of the weibull shape parameter signal detection tool using electronic healthcare record data. Drug Saf. 2013;36:995–1006. https://doi.org/10.1007/s40264-013-0061-7.
Pharmaceuticals and Medical Devices Agency. The Japanese Adverse Drug Event Report database. https://www.pmda.go.jp/safety/info-services/drugs/adr-info/suspected-adr/0003.html. Accessed 31 Jan 2020.
Kose E, Uno K, Hayashi H. Evaluation of the expression profile of extrapyramidal symptoms due to antipsychotics by data mining of Japanese Adverse Drug Event Report (JADER) database. Yakugaku Zasshi. 2017;137:111–20. https://doi.org/10.1248/yakushi.16-00219.
Medical Dictionary for Regulatory Activities (MedDRA/J, Version 23.1). https://www.jmo.gr.jp/jmo/servlet/mdrLoginTop. Accessed 20 Sep 2020.
Rothman KJ, Lanes S, Sacks ST. The reporting odds ratio and its advantages over the proportional reporting ratio. Pharmacoepidemiol Drug Saf. 2004;13:519–23. https://doi.org/10.1002/pds.1001.
Sawada K, Hirooka T. 3. Evaluation of drug induced severe eruption cases in the Japanese Adverse Drug Event Report database and commonality of the reported drugs. Jpn J Pharmacoepidemiol. 2014;19:31–7. https://doi.org/10.3820/jjpe.19.31.
Nishimura M, Obayashi H, Maruya E, Ohta M, Tegoshi H, Fukui M, et al. Association between type 1 diabetes age-at-onset and intercellular adhesion molecule-1 (ICAM-1) gene polymorphism. Hum Immunol. 2000;61:507–10. https://doi.org/10.1016/s0198-8859(00)00101-4.
Yamada H, Uchigata Y, Kawasaki E, Matsuura N, Otani T, Sato A, et al. Onset age-dependent variations of three islet specific autoantibodies in Japanese IDDM patients. Diabetes Res Clin Pract. 1998;39:211–7. https://doi.org/10.1016/s0168-8227(98)00008-4.
Cornelius VR, Sauzet O, Evans SJW. A signal detection method to detect adverse drug reactions using a parametric time-to-event model in simulated cohort data. Drug Saf. 2012;35:599–610. https://doi.org/10.2165/11599740-000000000-00000.
Ono Pharmaceutical Co., Ltd. Appropriate use of Opdivo®. 2016. https://www.pmda.go.jp/PmdaSearch/iyakuDetail/GeneralList/4291427. Accessed 1 Feb 2021.
Ji H-H, Tang X-W, Dong Z, Song L, Jia Y-T. Adverse event profiles of anti-CTLA-4 and anti-PD-1 monoclonal antibodies alone or in combination: analysis of spontaneous reports submitted to FAERS. Clin Drug Investig. 2019;39:319–30. https://doi.org/10.1007/s40261-018-0735-0.
Zamami Y, Niimura T, Okada N, Koyama T, Fukushima K, Izawa-Ishizawa Y, Ishizawa K. Factors associated with immune checkpoint inhibitor-related myocarditis. JAMA Oncol. 2019;5:1635–7. https://doi.org/10.1001/jamaoncol.2019.3113.
Buchbinder EI, Desai A. CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol. 2016;39:98–106. https://doi.org/10.1097/COC.0000000000000239.
Fife BT, Bluestone JA. Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways. Immunol Rev. 2008;224:166–82. https://doi.org/10.1111/j.1600-065X.2008.00662.x.
Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677–704. https://doi.org/10.1146/annurev.immunol.26.021607.090331.
Shankar B, Zhang J, Naqash AR, Forde PM, Feliciano JL, Marrone KA, et al. Multisystem immune-related adverse events associated with immune checkpoint inhibitors for treatment of non-small cell lung cancer. JAMA Oncol. 2020;6:1952–6. https://doi.org/10.1001/jamaoncol.2020.5012.
Nishimori I, Tamakoshi A, Kawa S, Tanaka S, Takeuchi K, Kamisawa T, et al. Influence of steroid therapy on the course of diabetes mellitus in patients with autoimmune pancreatitis: findings from a nationwide survey in Japan. Pancreas. 2006;32:244–8. https://doi.org/10.1097/01.mpa.0000202950.02988.07.
Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity. 1995;3:541–7. https://doi.org/10.1016/1074-7613(95)90125-6.
Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity. 1999;11:141–51. https://doi.org/10.1016/s1074-7613(00)80089-8.
Hosokawa Y, Hanafusa T, Imagawa A. Pathogenesis of fulminant type 1 diabetes: genes, viruses and the immune mechanism, and usefulness of patient-derived induced pluripotent stem cells for future research. J Diabetes Investig. 2019. https://doi.org/10.1111/jdi.13091.
McKinney EF, Lee JC, Jayne DRW, Lyons PA, Smith KGC. T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection. Nature. 2015;523:612–6. https://doi.org/10.1038/nature14468.
Wiedeman AE, Muir VS, Rosasco MG, DeBerg HA, Presnell S, Haas B, et al. Autoreactive CD8+ T cell exhaustion distinguishes subjects with slow type 1 diabetes progression. J Clin Invest. 2020;130:480–90. https://doi.org/10.1172/JCI126595.
Ansari MJI, Salama AD, Chitnis T, Smith RN, Yagita H, Akiba H, et al. The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice. J Exp Med. 2003;198:63–9. https://doi.org/10.1084/jem.20022125.
Inoue Y, Watanabe M, Inoue N, Kagawa T, Shibutani S, Otsu H, et al. Associations of single nucleotide polymorphisms in precursor-microRNA (miR)-125a and the expression of mature miR-125a with the development and prognosis of autoimmune thyroid diseases. Clin Exp Immunol. 2014;178:229–35. https://doi.org/10.1111/cei.12410.
Isayama H, Tazuma S, Kokudo N, Tanaka A, Tsuyuguchi T, Nakazawa T, et al. Clinical guidelines for primary sclerosing cholangitis 2017. J Gastroenterol. 2018;53:1006–34. https://doi.org/10.1007/s00535-018-1484-9.
Uchino M, Ikeuchi H, Matsuoka H, Bando T, Takesue Y, Tomita N. Clinical features and management of pouchitis in Japanese ulcerative colitis patients. Surg Today. 2013;43:1049–57. https://doi.org/10.1007/s00595-012-0377-4.
Hu Y, Gong J, Zhang L, Li X, Li X, Zhao B, Hai X. Colitis following the use of immune checkpoint inhibitors: a real-world analysis of spontaneous reports submitted to the FDA adverse event reporting system. Int Immunopharmacol. 2020;84:106601. https://doi.org/10.1016/j.intimp.2020.106601.
Safa H, Johnson DH, van Trinh A, Rodgers TE, Lin H, Suarez-Almazor ME, et al. Immune checkpoint inhibitor related myasthenia gravis: single center experience and systematic review of the literature. J Immunother Cancer. 2019;7:319. https://doi.org/10.1186/s40425-019-0774-y.
Makarious D, Horwood K, Coward JIG. Myasthenia gravis: an emerging toxicity of immune checkpoint inhibitors. Eur J Cancer. 2017. https://doi.org/10.1016/j.ejca.2017.05.041.
Kato E, Sawada T, Tahara K, Hayashi H, Tago M, Mori H, et al. The age at onset of rheumatoid arthritis is increasing in Japan: a nationwide database study. Int J Rheum Dis. 2017;20:839–45. https://doi.org/10.1111/1756-185X.12998.
Guo Y, Walsh AM, Canavan M, Wechalekar MD, Cole S, Yin X, et al. Immune checkpoint inhibitor PD-1 pathway is down-regulated in synovium at various stages of rheumatoid arthritis disease progression. PLoS ONE. 2018;13:e0192704. https://doi.org/10.1371/journal.pone.0192704.
Ando G, Taguchi K, Enoki Y, Yokoyama Y, Kizu J, Matsumoto K. Evaluation of the expression time of ganciclovir-induced adverse events using JADER and FAERS. Biol Pharm Bull. 2019;42:1799–804. https://doi.org/10.1248/bpb.b19-00156.
Komada F, Nakayama Y, Takara K. Analysis of time-to-onset and onset-pattern of interstitial lung disease after the administration of monoclonal antibody agents. Yakugaku Zasshi. 2018;138:1587–94. https://doi.org/10.1248/yakushi.18-00094.
Wu J. Power and sample size for randomized phase III survival trials under the Weibull model. J Biopharm Stat. 2015;25:16–28. https://doi.org/10.1080/10543406.2014.919940.
Sasaoka S, Matsui T, Hane Y, Abe J, Ueda N, Motooka Y, et al. Time-to-onset analysis of drug-induced long QT syndrome based on a spontaneous reporting system for adverse drug events. PLoS ONE. 2016;11:e0164309. https://doi.org/10.1371/journal.pone.0164309.
Nakao S, Hatahira H, Sasaoka S, Hasegawa S, Motooka Y, Ueda N, et al. Evaluation of drug-induced photosensitivity using the Japanese Adverse Drug Event Report (JADER) database. Biol Pharm Bull. 2017;40:2158–65. https://doi.org/10.1248/bpb.b17-00561.
Miyake Y, Iwasaki Y, Kobashi H, Yasunaka T, Ikeda F, Takaki A, Yamamoto K. Autoimmune hepatitis with acute presentation in Japan. Dig Liver Dis. 2010;42:51–4. https://doi.org/10.1016/j.dld.2009.04.009.
Nobunaga M, Yoshioka K, Yasuda M, Shingu M. Clinical studies of polymyalgia rheumatica: a proposal of diagnostic criteria. Jpn J Med. 1989;28:452–6. https://doi.org/10.2169/internalmedicine1962.28.452.
Japan Intractable Diseases Information Center. “Pemphigoid”. https://www.nanbyou.or.jp/entry/4525. Accessed 1 Feb 2021.
Kurata Y, Fujimura K, Kuwana M, Tomiyama Y, Murata M. Epidemiology of primary immune thrombocytopenia in children and adults in Japan: a population-based study and literature review. Int J Hematol. 2011;93:329–35. https://doi.org/10.1007/s12185-011-0791-1.
Suzuki S, Utsugisawa K, Nagane Y, Satoh T, Kuwana M, Suzuki N. Clinical and immunological differences between early and late-onset myasthenia gravis in Japan. J Neuroimmunol. 2011;230:148–52. https://doi.org/10.1016/j.jneuroim.2010.10.023.
Masamune A, Kikuta K, Hamada S, Tsuji I, Takeyama Y, Shimosegawa T, Okazaki K. Nationwide epidemiological survey of autoimmune pancreatitis in Japan in 2016. J Gastroenterol. 2020;55:462–70. https://doi.org/10.1007/s00535-019-01658-7.
Acknowledgements
We are grateful to Dr. Yoshinobu Hirayama for providing a helpful discussion.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Funding
No funding was received for the conduct of this study or the preparation of this article.
Conflict of interest
Keiko Ogawa, Yoshihiro Kozuka, Hitomi Uno, Kosuke Utsumi, Osamu Noyori, and Rumiko Hosoki have no conflicts of interest that are directly relevant to the content of this article.
Ethics approval
Not applicable.
Consent to participate
Not applicable.
Consent for publication
Not applicable.
Availability of data and material
The data that support the findings of this study are available from the corresponding author, Hosoki Rumiko, upon reasonable request.
Code Availability
Not applicable.
Author contributions
Study design: Hosoki R., Ogawa K. Data processing and analysis: Ogawa K., Kozuka Y., Uno H., Utsumi K., Interpretation of the results: all authors. especially Ogawa K., Noyori O., Kozuka Y., Hosoki R. Writing manuscript: Ogawa K. Manuscript review and revisions: All authors. Final approval of manuscript: All authors.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Ogawa, K., Kozuka, Y., Uno, H. et al. Spontaneous and Immune Checkpoint Inhibitor-Induced Autoimmune Diseases: Analysis of Temporal Information by Using the Japanese Adverse Drug Event Report Database. Clin Drug Investig 41, 615–627 (2021). https://doi.org/10.1007/s40261-021-01042-5
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40261-021-01042-5