| アブストラクト | BACKGROUND: There have been multiple reports of the anti-IL-4Ralpha agent, dupilumab, being associated with the onset and/or progression of cutaneous T-cell lymphoma (CTCL). OBJECTIVE: We sought to evaluate safety signals associated with dupilumab, with a focus on CTCL, and to evaluate the possible underlying mechanism or mechanisms for the potential association. METHODS: First, we used the Food and Drug Administration's pharmacovigilance database, FAERS (FDA Adverse Event Reporting System), to evaluate whether dupilumab was associated with CTCL, including both positive outcome controls (conjunctivitis, eosinophilia, and arthralgia) and exposure controls (other medications with similar indications, including JAK inhibitors and the anti-IL-13 agent, tralokinumab) to evaluate confounding bias. Thereafter, we used publicly available bulk and single-cell RNA sequencing datasets to probe possible underlying mechanisms through which dupilumab might be associated with CTCL. RESULTS: Between January 2017 and the fourth quarter of 2023, there were 181,575 unique reports of dupilumab-related adverse events (AEs) in FAERS, with 606 of these being for a neoplasm. Dupilumab had 30.0 times the proportional reporting ratio (PRR) (95% confidence interval, 25.0-35.9) for CTCL compared to all other medications in FAERS. The risk was highest in men aged 45 to 65. The PRR for conjunctivitis, eosinophilia, and arthralgia, known adverse effects of dupilumab, were 35.6 (34.4-36.8), 2.15 (2.00-2.31), and 2.14 (2.07-2.18), respectively. Using the log-count normalized PRR (AE score) to account for PRR inflation when reports were small, the top safety signals included conjunctivitis (AE score 8.3) and CTCL (AE score 4.9). Bulk RNA sequencing data showed changes in IL-4RA and IL-13RA1 expression in CTCL and in epidermal layers of atopic dermatitis (AD) biopsy samples. Single-cell transcriptomic studies revealed that this change was similar in AD and CTCL, and that keratinocytes seemed to be the most divergent cell type with regards to IL-4R and IL-13RA1. An effect on keratinocyte-specific gene expression was also independently observed in available bulk RNA sequencing data. CONCLUSION: These data suggest that dupilumab might be causing an unmasking or progression of CTCL via the same mechanism through which it improves AD: IL-13 receptor blockade, which leads to increased IL-13 in the local milieu, driving CTCL stimulation and progression. However, these associations need further evaluation given the inherent limitations of the FAERS database and our nonexperimental approach. |
|---|
| ジャーナル名 | The Journal of allergy and clinical immunology |
|---|
| Pubmed追加日 | 2024/11/13 |
|---|
| 投稿者 | Cabrera-Perez, Javier S; Carey, Vincent J; Odejide, Oreofe O; Singh, Sonal; Kupper, Thomas S; Pillai, Shiv S; Weiss, Scott T; Akenroye, Ayobami |
|---|
| 組織名 | Division of Allergy and Clinical Immunology, Brigham & Women's Hospital and;Department of Medicine, Boston, Mass; Harvard Medical School, Boston, Mass.;Harvard Medical School, Boston, Mass; Channing Division of Network Medicine,;Brigham & Women's Hospital and Department of Medicine, Boston, Mass.;Division of Population Sciences, Dana-Farber Cancer Institute, Boston, Mass;;Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, Mass.;Department of Family Medicine and Community Health, Health Systems Science,;Department of Medicine, UMass Chan Medical School, Worcester, Mass.;Harvard Medical School, Boston, Mass; Department of Dermatology, Brigham &;Women's Hospital, Boston, Mass.;Harvard Medical School, Boston, Mass; Ragon Institute of Massachusetts General;Hospital, Massachusetts Institute of Technology, Cambridge, Mass; Department of;Medicine, Massachusetts General Hospital, Harvard, Cambridge, Mass.;Department of Medicine, Boston, Mass; Harvard Medical School, Boston, Mass;;Channing Division of Network Medicine, Brigham & Women's Hospital and Department;of Medicine, Boston, Mass. Electronic address: aakenroye@bwh.harvard.edu. |
|---|
| Pubmed リンク | https://www.ncbi.nlm.nih.gov/pubmed/39521279/ |
|---|
