2025 年 11 巻 1 号 論文ID: cr.25-0177
INTRODUCTION: Although immune-related adverse events (irAEs) associated with immune checkpoint inhibitors (ICIs) are widely recognized, ICI-related aortitis is very rare and challenging to diagnose.
CASE PRESENTATION: A 70-year-old man with esophageal squamous carcinoma recurring after esophagectomy received paclitaxel therapy after nivolumab therapy. Nivolumab therapy was administered for 26 months; however, no adverse events occurred during treatment. One month after the initiation of paclitaxel therapy, the patient developed a fever lasting for 2 weeks. Thoracoabdominal contrast-enhanced computed tomography (CT) revealed aortic wall thickening and increased fat density in the descending thoracic aorta; however, no other cause of inflammation was detected. Further examination ruled out infectious or autoimmune disease, and the patient was eventually diagnosed with ICI-related aortitis. Methylprednisolone was administered intravenously at a dose of 80 mg, and the fever subsided on the second day after administration. As the inflammation improved, methylprednisolone was switched to oral prednisolone, and the dose was gradually tapered without symptom relapse. Two months after diagnosis, a follow-up CT scan confirmed the resolution of both aortic wall thickening and the increased fat density.
CONCLUSIONS: ICI-related aortitis should be considered as a differential diagnosis for unexplained fever after ICI administration.
American Society of Clinical Oncology
CIAclinically isolated aortitis
CRcomplete response
CTcomputed tomography
GCAgiant cell arteritis
irAEimmune-related adverse event
ICIimmune checkpoint inhibitors
NCCNNational Comprehensive Cancer Network
The development of immune checkpoint inhibitors (ICIs) targeting programmed cell death-1 and cytotoxic T-lymphocyte antigen 4 (CTLA4) has significantly improved the treatment of various cancers. Therefore, the diagnosis and management of immune-related adverse events (irAEs) have also advanced.1,2) The incidence of dermatological, gastroenterological, hormonal, and pulmonary irAEs is relatively common, and the treatment strategy is well established. However, the diagnosis and treatment strategies for rare irAEs, such as ICI-related aortitis remain underdeveloped.
Here, we report a case of ICI-related aortitis due to nivolumab treatment for esophageal squamous cell carcinoma, which was challenging to diagnose and treat.
The patient was a 70-year-old man diagnosed with stage III esophageal squamous cell carcinoma (UtCe cT3N2M0), according to the Japanese Esophageal Society classification.3) He underwent thoracoscopic esophagectomy with D3 lymph node dissection. The pathological diagnosis was UtCe, 30 × 30 mm, type2, SCC, pT3N3M0, pStage IV A; therefore, he received fluorouracil and cisplatin as adjuvant chemotherapy. Five months after completing adjuvant chemotherapy, computed tomography (CT) revealed recurrence in the mediastinal lymph node area (#104R, #106pre). The patient subsequently underwent radiotherapy at a total dose of 59.4 Gy and received two courses of fluorouracil and cisplatin chemotherapy, and achieved a complete response (CR). However, 6 months after chemoradiotherapy, CT showed regrowth of the mediastinal lymph nodes, leading to the initiation of biweekly intravenous nivolumab therapy at a dose of 240 mg per dose as second-line treatment. After 4 cycles of nivolumab therapy, definite tumor shrinkage was observed, and a total of 41 nivolumab cycles were administered. Owing to tumor regrowth, the treatment was switched to third-line intravenous paclitaxel therapy at a dose of 100 mg/m2 on days 1, 8, and 15 every 28 days.
One month after initiating paclitaxel therapy, the patient developed a persistent fever lasting 2 weeks and visited a local hospital. The patient had no chest or back pain and skin findings characteristic of vasculitis, such as purpura or erythema, were not observed. Although oral antibiotics were administered, the fever persisted, and the patient was referred to our hospital. As the fever did not subside despite continued antibiotic therapy, he was admitted to our hospital for further investigation and treatment. Thoracoabdominal contrast-enhanced CT revealed wall thickening limited to the descending thoracic aorta (Fig. 1) compared with that before nivolumab therapy (Fig. 2), and blood culture result was negative. Therefore, the patient was diagnosed with nivolumab-induced ICI-related aortitis.
As shown in Fig. 3, methylprednisolone (80 mg) was administered intravenously. Because the fever subsided on the second day, methylprednisolone was switched to oral prednislone, and the dose was gradually decreased to 30 mg. As his general condition and inflammatory response improved, he was discharged on day 15 of hospitalization. Two months after diagnosis, a follow-up enhanced CT showed resolution of aortic wall thickening, as shown in Fig. 4, and paclitaxel therapy was restarted while decreasing the prednisolone dose.
Although irAEs associated with ICIs are widely recognized and reported to occur in approximately 13%–14%,4,5) ICI-related aortitis is a rare irAE that remains challenging to diagnose. A single-center retrospective study of 1293 patients receiving ICIs reported only three cases (0.3%) of ICI-related vasculitis.6)
To the best of our knowledge, only 4 cases of aortitis associated with irAEs, including our case, have been reported.7–9)
Table 1 shows all 4 case reports of ICI-related aortitis, including cancer type, immunotherapy, treatment used for aortitis, and final clinical outcomes. The types of cancer included squamous cell carcinoma of the lung, melanoma, and esophageal squamous cell carcinoma. The ICIs administered were nivolumab, ipilimumab, and pembrolizumab. The time from immunotherapy initiation to the onset of aortitis ranged from 2 to 27 months.7,8) Every case was treated by discontinuing the ICI and administering either methylprednisolone or prednisolone. One patient was treated with tocilizumab. All cases showed improvement in aortitis. Among the 4 patients, our patient exhibited the latest onset of aortitis, with a 27-month period from nivolumab therapy initiation. While most irAEs occur within 3 months after the initiation of immunotherapy, onset may occur at any time during or after treatment.2) Based on our experience, follow-up for 2 or more years may be recommended.
| Type of cancer | Age | Male/Female | ICI | Immune checkpoint molecule | Time of onset after therapy | Treatment of immune related adverse events | Author | |
|---|---|---|---|---|---|---|---|---|
| 1 | Squamous cell carcinoma of the lung | 57 | M | Nivolumab | PD-1 | 9 months | Nivolumab discontinued. Methylprednisolone 60 mg IV once. Then the dose is reduced to oral over 4-week period | Roy et al.7) |
| 2 | Melanoma | 51 | F | Ipilimumab | CTLA-4 | 2 months | Prednisone 1 mg/kg/day for 3 weeks | Ban et al.8) |
| 3 | Melanoma | 67 | F | Pembrolizumab | PD-1 | 15 months | High-dose prednisone and tocilizumab | Bloomer et al.9) |
| 4 | Esophageal cancer | 70 | M | Nivolumab | PD-1 | 27 months | Methylprednisolone 80 mg IV, then tapered to oral over 2 weeks | Our case |
CTLA4, cytotoxic T-lymphocyte antigen 4
Aortitis is a group of disorders that cause inflammation of the aortic wall. Systemic diseases are associated with non-infectious aortitis that include giant cell arteritis (GCA), Takayasu arteritis, rheumatoid arthritis, systemic lupus erythematosus, Cogan’s syndrome, Behçet’s disease, ankylosing spondylitis, and IgG4-related disease. Infectious aortitis can be caused by bacterial or fungal infections. There are currently no established diagnostic criteria for aortitis as an irAE. In our case, all examinations, including complete blood count, erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor, antinuclear antibodies, antineutrophil cytoplasmic antibodies such as p-ANCA and c-ANCA, complement levels, and blood culture, were negative. One differential diagnosis in such cases is Takayasu arteritis, which can sometimes be detected incidentally in the early phase. However, Takayasu arteritis usually affects younger women and often shows characteristic imaging findings such as concentric wall thickening of multiple large vessels. Based on the clinical presentation and negative workup for other causes, the patient was diagnosed with nivolumab-induced ICI-related aortitis.
Although the treatment of vasculitis is not clearly discussed in the American Society of Clinical Oncology or National Comprehensive Cancer Network guidelines, steroids were administered and tapered according to treatment protocols for peripheral vasculitis caused by GCA or other irAEs.10) In prednisolone-resistant cases, the administration of immunosuppressants might be an alternative treatment.11–13)
Managing irAEs such as aortitis can be particularly challenging in patients undergoing cancer treatment. Although steroid therapy is commonly used for irAEs, there is limited clinical evidence about how well it works, especially for vascular inflammation.
It remains unclear how immunosuppressive agents like methotrexate or tocilizumab should be used in cases that are resistant to steroids or show recurrence, which is a clinical concern.
ICI-related aortitis should be considered a differential diagnosis for unexplained fever after ICI administration.
This research did not receive any specific grant funding.
Authors' contributionsNA, SS, KS, and TS wrote the first draft of this manuscript.
All authors provided feedback on previous versions of the manuscript and have read and approved the final manuscript.
Availability of data and materialsThe data and materials used in this case report are not publicly available due to patient privacy concerns.
Ethics approval and consent to participateThis work does not require ethical considerations or approval. Informed consent to participate in this study was obtained from the patient.
Consent for publicationVerbal consent was obtained from the patient for publication of the details of this case and any accompanying images.
Competing interestsThe authors declare that they have no competing interests.
The disclosed honoraria are not directly associated with the content or findings presented in this case report.
