Elsevier

Cytokine

Volume 119, July 2019, Pages 47-51
Cytokine

Granulocyte colony-stimulating factor-associated aortitis in the Japanese Adverse Drug Event Report database

https://doi.org/10.1016/j.cyto.2019.02.013Get rights and content

Highlights

  • Anecdotal case reports have suggested association between G-CSF and aortitis.

  • Relationship between G-CSF and aortitis had remained unclear.

  • Japanese pharmacovigilance database JADER harbors 102,014 subjects with malignancies.

  • The adjusted odds ratio for aortitis in the malignancy cases with G-CSF was 45.87 [19.16, 109.8].

  • The difference was statistically significant. This supports the link between G-CSF and aortitis.

Abstract

Background

Granulocyte colony-stimulating factor (G-CSF) is the standard-of-care therapy for chemotherapy-associated neutropenia in patients with malignancies. Recent case reports have implied that G-CSF treatment may be associated with the development of aortitis, but the precise nature of the relationship is unclear. We investigated the association between G-CSF and risk for aortitis in patients with various malignancies.

Methods

We performed an observational study of 102,014 subjects with malignant neoplasms documented in the Japanese Adverse Drug Event Report (JADER) database between April 2004 and February 2018. The adjusted odds ratio (OR) and 95% confidence interval (CI) for aortitis in patients treated and not treated with G-CSF were estimated using multivariate logistic regression with R software.

Results

Among the 102,014 subjects, 25 developed aortitis. Of the 3409 and 98,630 subjects treated and not treated with G-CSF, 16 (0.47% [95% CI; 0.27, 0.76]) and 9 (0.01% [0.00, 0.02]) developed aortitis, respectively. Multivariate logistic regression indicated an association between G-CSF and aortitis (adjusted OR 45.87 [19.16, 109.8], p < 0.001). The values for filgrastim, pegfilgrastim, and lenograstim were 0.25% (0.07, 0.63), 1.58% (0.79, 2.81), and 0.24% (0.05, 0.69), respectively.

Conclusion

G-CSF treatment was associated with a signal of increased risk for aortitis among patients with malignant neoplasms. Three different G-CSF agents were associated with such risk, implying that it is a class effect. However, we do not recommend changing G-CSF prescriptions, because our results may have been influenced by the limitations of the JADER database and because the benefit of G-CSF treatment outweighs the potential risk.

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)

There are more references available in the full text version of this article.

Cited by (39)

  • A man with fever and aortitis

    2022, European Journal of Internal Medicine
    Citation 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 Communications
    Citation 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 Journal
  • Aortitis in a patient on chemotherapy

    2022, CMAJ. Canadian Medical Association Journal
View all citing articles on Scopus
View full text