A Case of PMR‐Like irAE Developing After Treatment With Ipilimumab and Nivolumab for Lung Cancer

ABSTRACT

Immune‐checkpoint inhibitors (ICIs) have become one of the main strategies for advanced cancers. ICIs are associated with many immune side effects, called immune‐related adverse events (irAEs). Since irAE has various variations, it is important to carefully examine each individual case that develops irAE. We experienced a case of polymyalgia rheumatica (PMR)‐like irAE after three courses of administration of Ipilimumab and Nivolumab for stage IV lung adenocarcinoma. We also confirmed that the activity of this irAE was detectable on the PET‐CT scan performed to assess lung cancer progression. Given the limited reports of PMR‐like irAE occurring after treatment with two immune checkpoint inhibitors, we present this case along with a review of the literature.

We present a case of polymyalgia rheumatica (PMR)‐like irAE after three courses of administration of Ipilimumab and Nivolumab for Stage IV lung adenocarcinoma. We also confirmed that the activity of this irAE was detectable on the PET‐CT scan performed to assess lung cancer progression.

1. Introduction

Immune‐checkpoint inhibitors (ICIs) have become one of the most common strategies for various cancers. The combination of nivolumab (NIVO) and ipilimumab has been shown to prolong the survival of patients with non‐small cell lung cancer (NSCLC) expressing PD‐L1 at levels of 1% or higher [1]. They are employed as one of the first‐line treatments for Stage IV NSCLC.

Although ICIs are effective against cancers, they may cause adverse effects called immune‐related adverse events (irAEs), whose occurrence and timing depend on the type and dose of ICIs, the cancer type, and patient‐related factors [2].

Polymyalgia rheumatica (PMR)‐like irAE is one such adverse event. PMR is considered an autoimmune disease, characterised by the acute onset of stiffness and pain in the shoulder and pelvic musculature, often accompanied by systemic symptoms and predominantly affects individuals over the age of 50. The primary treatment for PMR is corticosteroid therapy [3]. PMR itself is common, but PMR‐like irAE is uncommon [4]. Due to the complex pathophysiology of irAEs, even after a decade of ICIs in clinical use, reports of rare irAE cases continue to provide valuable clinical insights.

2. Case Report

A 70‐year‐old man with no significant medical history began experiencing knee pain in July 2022. In October 2022, a CT scan identified a destructive bone lesion in the shaft of his left femur. PET‐CT showed increased uptake in the left femoral lesion, a nodule in the right lower lobe of the lung, and hilar lymph nodes. A needle biopsy of the femoral lesion confirmed adenocarcinoma (AE1/AE3+, EMA+, TTF‐1−). He was diagnosed with Stage IVB lung adenocarcinoma (cT1bN1M1c) with metastases to the left femur and the twelfth thoracic vertebra (Th12). The patient subsequently underwent wide resection of the left femur with prosthetic joint replacement. Pathological examination confirmed bone metastasis secondary to lung cancer, consistent with Stage IVB lung adenocarcinoma.

Oncomine DxTT of a bone metastasis biopsy specimen analysis detected no driver mutations in the tumour cells, and PD‐L1 expression was 20%. The patient opted against cytotoxic chemotherapy, so dual ICI therapy with IPI and NIVO was initiated in January 2023. During the second cycle of IPI + NIVO in March, he developed isolated adrenocorticotropic hormone deficiency (IAD) as an irAE. Since then, IPI + NIVO therapy has continued with low‐dose hydrocortisone.

Four months after initiating IPI + NIVO therapy, the patient experienced bilateral thigh pain accompanied by an elevated CRP level of 9.29 mg/dL, resulting in a delay of his third dose of NIVO. Head MRI and chest CT revealed no new abnormalities, while PET‐CT showed increased bilateral shoulder uptake compared to the baseline scan from 7 months earlier (Figure 1A). A week later, his pain worsened, with mild tenderness from the neck to both shoulders and spontaneous pain radiating from the buttocks to thighs, accompanied by an increase in CRP to 25.18 mg/dL. The painful sites corresponded with the enhancements detected by the PET‐CT. He was admitted to the hospital and treated with intravenous ampicillin and sulbactam. However, after 3 days without improvement in symptoms or inflammation markers, the antibiotics were discontinued, and an immune‐related cause was considered. Joint ultrasound revealed bilateral tenosynovitis of the long head biceps tendons (Figure 1B). Transthoracic echocardiography and temporal artery ultrasound showed no significant abnormalities. The patient reported morning stiffness lasting more than 45 min (score: 2) and limited joint range of motion (score: 1), with negative results for rheumatoid factor and anti‐citrullinated protein antibodies (score: 2). These findings satisfied the EULAR/ACR classification criteria for polymyalgia rheumatica (PMR), with a total score of 8. After consultation with a rheumatologist, treatment with prednisolone at 20 mg/day was initiated on hospital Day 8. His CRP levels and symptoms gradually improved, and he was discharged on Day 12. The correlation between glucocorticoid treatment and CRP levels is shown in Figure 2. A PET‐CT scan performed on Day 73 showed reduced uptake around both shoulders, suggesting that steroid treatment contributed to the improvement. Maximum intensity projection (MIP) images of PET‐CT scans are shown in Figure 3.

FIGURE 1.

(A) A PET‐CT scan taken 7 days before admission shows enhancements on both shoulders compared to the baseline. After glucocorticoid therapy, the enhancements improve to near baseline levels. (B) Ultrasound shows synovial fluid around bicep tendons.

FIGURE 2.

The clinical progress chart primarily shows trends in steroid usage and CRP levels. CRP levels gradually decrease as glucocorticoids therapy is initiated.

FIGURE 3.

MIP images showing abnormal FDG uptake in the left thigh, consistent with the site of the lesion.

3. Discussion

The reported incidence of PMR‐like irAE ranges from 0.2% to 2.1% across all cancer types [4], with onset times varying from less than 1–53 months [5]. At present, it remains unclear whether the mechanism of PMR‐like irAE is the same as that of conventional PMR. Although both conditions share overlapping clinical features, PMR‐like irAE often presents with atypical manifestations, tends to be more severe, and frequently requires more intensive treatment [6, 7]. In this case, low‐dose oral hydrocortisone did not prevent the onset of PMR‐like irAE. However, high‐dose glucocorticoid proved effective in controlling his symptoms and reducing inflammatory markers. Bicipital tendinitis, a common finding in PMR‐like irAE (seen in 6 out of 10 cases) was also observed by ultrasound [8]. Based on these ultrasound findings, the lack of response to antibiotics, and in consultation with a rheumatologist, we finally diagnosed the patient with PMR‐like irAE. Although there is a concern that immunosuppressive treatment may diminish the efficacy of immune checkpoint inhibitors (ICIs), in this case, high‐dose glucocorticoids were deemed necessary to manage the irAE. Recent studies [9] have reported that corticosteroid use for irAE management does not necessarily compromise the therapeutic efficacy of ICIs, suggesting that timely and appropriate treatment of irAEs should be prioritised.

Previous reports on PMR‐like irAE associated with lung cancer treatment are summarised in Table 1 [10, 11, 12, 13, 14, 15]. To our knowledge, this is the first reported case of a PMR‐like irAE occurring with the combination of anti‐PD‐1 and anti‐CTLA‐4 antibodies in lung cancer. Although a recent systematic review involving multiple cancer types [16] has described PMR‐like irAEs in the context of ICI combination therapy, no such cases have been reported specifically in lung cancer. This may be partly due to the more common use of PD‐1/PD‐L1 inhibitors alone in lung cancer and does not necessarily imply a limited role of CTLA‐4 inhibition in the development of PMR‐like irAEs.

TABLE 1.

Reported Cases of PMR‐like irAEs in thoracic malignancies treated with immune checkpoint inhibitors.

Age (years)	Sex	Drugs	Pathological diagnosis	Dosing period	PSL	References
65	F	Nivolumab	NSCLS	NR	15 mg	[7]
66	M	Pembrolizumab	Adenocarcinoma	NR	20 mg	[7]
63	M	Nivolumab	NSCLS	NR	None	[7]
69	M	Nivolumab	NSCLC	13 courses	60 mg	[10]
79	F	Nivolumab	Adenocarcinoma	5 courses	NR	[11]
50	F	Anti‐PD‐1 antibody	Adenocarcinoma	118 days	30 mg	[12]
73	M	Nivolumab	Squamous cell carcinoma	NR	5 mg	[13]
74	M	Pembrolizumab	Squamous cell carcinoma	NR	7.5 mg	[13]
63	F	Nivolumab	Squamous cell carcinoma	NR	7.5 mg	[13]
59	F	Pembrolizumab	Adenocarcinoma	NR	None	[13]
65	M	Nivolumab	NSCLC	NR	NR	[14]
76	F	Anti‐PD‐L1 antibody	Mesothelioma	9 m	20 mg	[15]
70	M	IPI + NIVO	Adenocarcinoma	4 m	20 mg	This case

We believe that reports detailing PET‐CT changes before the onset of PMR, as well as following steroid dose escalation, are highly valuable. PET‐CT is commonly used in lung cancer management for disease evaluation, and as demonstrated by this case, it may also be helpful in assessing irAEs like PMR. Given the crucial role of ICIs in advanced cancer treatment and their relatively recent introduction, studying each unique case is essential for improving our understanding and management.

Author Contributions

Ryuichi Utsumi: writing – original draft. Hideki Terai: writing – original draft. Tetsuya Arai: writing – review and editing. Yu Iwabuchi: writing – review and editing. Mitsuhiro Akiyama: writing – review and editing. Shigenari Nukaga: writing – review and editing. Keiko Ohgino: writing – review and editing. Hiroki Kabata: writing – review and editing. Shotaro Chubachi: writing – review and editing. Hiroyuki Yasuda: writing – review and editing. Koichi Fukunaga: writing – review and editing.

Consent

The authors declare that written informed consent was obtained for the publication of this manuscript and accompanying images using the consent form provided by the journal.

Conflicts of Interest

The authors declare no conflicts of interest.

Utsumi R., Terai H., Arai T., et al., “A Case of PMR‐Like irAE Developing After Treatment With Ipilimumab and Nivolumab for Lung Cancer,” Respirology Case Reports 13, no. 6 (2025): e70242, 10.1002/rcr2.70242.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.