Granulocyte colony-stimulating factor-associated aortitis in the Japanese Adverse Drug Event Report database
Introduction
Granulocyte colony-stimulating factor (G-CSF) is the standard-of-care therapy for chemotherapy-associated neutropenia in patients with malignancies, including hematological malignancies and solid tumors. There are a few case reports of the development of aortitis after G-CSF treatment [1], [2], [3], [4]. However, no study has quantitatively evaluated the risk for G-CSF-associated aortitis. Thus, we analyzed the risk for aortitis associated with G-CSF treatment using the Japanese Adverse Drug Event Report (JADER) adverse drug reaction (ADR) database.
The JADER is maintained by the Japan Pharmaceuticals Medical Devices Agency (PMDA). The database collects ADRs from throughout Japan, and is available at the PMDA website (http://www.pmda.go.jp/). The most recent version of JADER (June 2018) contains 513,764 ADRs registered between April 2004 and February 2018. We hypothesized that if aortitis was incidental, the frequency of ADRs would be similar irrespective of G–CSF use.
Section snippets
Database and data handling
The JADER (513,764 ADRs) was obtained from the PMDA website (https://www.pmda.go.jp/). We extracted information on patients with various malignant solid tumors or hematological malignancies, including malignant lymphoma and leukemia. As of June 2018, three wild-type human recombinant G-CSF agents are approved for use in Japan: filgrastim, lenograstim, and pegfilgrastim. Aortitis events were identified based on the MedDRA PT code.
Software and data manipulation
We used multivariate logistic regression to compare the frequency
G-CSF and aortitis
Of the 102,014 patients with malignant neoplasms (8422 breast cancer, 6473 colon cancer, 5516 prostate cancer, and 5358 lung adenocarcinoma), 3409 were treated with G-CSF. The mean (standard deviation) ages of those treated and not treated with G-CSF were 53.98 (17.50) and 60.38 (14.36) years, respectively. The percentages of females treated and not treated with G-CSF were 46.7% and 40.9%, respectively (Table 1). The numbers of patients with aortitis among those treated and not treated with
G-CSF and aortitis
We investigated potential factors associated with aortitis in patients with malignant disease. We hypothesized that if aortitis was incidental, the frequency of ADRs would be similar irrespective of G–CSF use. The frequencies of aortitis in patients treated and not treated with G–CSF were 0.47 (95%CI 0.27, 0.76) and 0.01 (95% CI 0.00, 0.02), respectively (OR 49.50 [95% CI 21.86, 112.11]; p < 0.001) (Table 2). These data imply an association between G-CSF and aortitis.
We evaluated subjects with
Conclusions
G-CSF treatment is associated with a signal of an increased risk for aortitis, irrespective of the G-CSF agent used. Due to the limitations of the JADER database, we do not recommend that clinicians alter their prescribing of G-CSFs, although appropriate monitoring should be considered.
Limitations
There are limitations to using ADR databases; for example, they do not contain information on persons who did not develop an ADR or (in the version available to the public) their locations. The latter prevented analyses of the geographic distribution of aortitis. The data may also be subject to reporting bias and the lack of a research protocol means that ADR reports are not collected systematically. Finally, data on possible confounding factors (e.g., background information, underlying
Disclaimers
The findings and views expressed in the submitted article are his or her own and not an official position of the institution.
Declaration of interests
Dr. Oshima reports personal fees from Novartis Pharma K.K., personal fees from sanofi K.K., outside the submitted work; Dr. Tani reports grants from Neo Pharma Japan Co.,Ltd, grants from Shinnihonseiyaku Co., Ltd, outside the submitted work; Dr. Tojo reports grants from Bristol-Myers, grants from Pfizer, grants from Chugai Pharmaceutical, grants from Daiichi Sankyo, grants from Sumitomo Dainippon-pharma, personal fees from Taiho Pharmaceutical, personal fees from Rohto Pharmaceutical, personal
Acknowledgments
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Dr. Oshima had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
References (12)
- et al.
Aortitis after G-CSF injections
Rev. Med. Interne
(2004) - et al.
Non-aneurysmal infectious aortitis: a case report
J. Emerg. Med.
(2007) - et al.
Takayasu’s arteritis. Clinical study of 107 cases
Am. Heart J.
(1977) - et al.
Tomii K. Thoracic aortitis and aortic dissection following pegfilgrastim administration
Eur. J. Cardiothorac. Surg.
(2017) - et al.
Isolated abdominal aortitis following administration of granulocyte colony stimulating factor (G-CSF)
Clin. Rheumatol.
(2016) - et al.
Abdominal aortitis after use of granulocyte colony-stimulating factor
Clin. Drug Investig.
(2009)
Cited by (39)
Pegfilgrastim-related thoracic aortitis: A case report and literature review
2023, Current Problems in Cancer: Case ReportsA man with fever and aortitis
2022, European Journal of Internal MedicineCitation Excerpt :Furthermore, the patient was negative for IgG4, and based on the history, we diagnosed granulocyte colony-stimulating factor (G-CSF)-induced vasculitis. Among G-CSF preparations, pegfilgrastim is the most frequently reported cause of vasculitis [1]. Vasculitis has been reported to occur for an average of 5 days (range: 1–8 days) after the last dose of G-CSF [2].
Granulocyte-colony stimulating factor-associated aortitis in cancer: A systematic literature review
2021, Cancer Treatment and Research CommunicationsCitation Excerpt :Severe adverse events include acute lung injury, acute coronary syndrome, and acute aortitis [1]. Based on the Japanese Adverse Drug Event Report provided by the Pharmaceuticals and Medical Devices Agency and the Adverse Event Reporting System of the Food and Drug Administration, aortitis that occurs after G-CSF administration is considered an adverse effect of G-CSF [2, 3]. G-CSF-associated aortitis has been reported to be exceedingly rare, occurring in only 0.3–0.47% of patients treated with G-CSF; it presents as more systemic symptoms, including high fever and increased levels of c-reactive protein, than those of peripheral vasculitis [2, 4].
Aortitis in a patient receiving chemotherapy
2023, CMAJ. Canadian Medical Association JournalAortitis in a patient on chemotherapy
2022, CMAJ. Canadian Medical Association Journal