Anti-asparaginyl-tRNA synthetase antibody-positive pneumonitis in a patient with immune checkpoint inhibitor treatment: A case report and literature review

ABSTRACT

Introduction

In recent years, the number of cancer patients eligible for immune checkpoint inhibitors (ICIs) has been increasing, and the clinical spectrum of immune-related adverse events (irAEs) has also been expanding [1]. Therefore, connective tissue disease-like symptoms induced by ICIs have become problematic [2]. Cases of systemic lupus erythematosus and antineutrophil cytoplasmic antibody-associated vasculitis induced by ICIs have been reported [3, 4]. In contrast, known autoantibodies such as rheumatoid factor and anti-citrullinated peptide antibodies are often negative for joint symptoms of irAE, suggesting that the autoantibodies themselves are not directly related to the pathogenesis of the disease [5]. There are few reports on the association between ICI-induced pneumonitis and autoantibodies [6].

In this study, we report the first case of anti-aminoacyl-tRNA synthetase (anti-ARS) antibody syndrome (ASS) with anti-asparaginyl-tRNA synthetase (anti-KS) antibody positivity during ICI treatment. Patients with ASS are rarely positive for anti-KS antibodies. Although these patients present localised pulmonary manifestations, their characteristics are not widely recognised [7, 8]. We report a case of KS antibody-positive ASS developed after ICI use, the characteristics of ASS associated with ICIs, and a literature review.

Case presentation

The patient was a 71-year-old Japanese woman diagnosed with endometrial cancer 6 years prior to admission when she underwent abdominal hysterectomy. She had no specific medical history other than endometrial cancer and no smoking history. Five years back, she experienced postoperative recurrence and underwent six courses of paclitaxel and carboplatin. One year back, after a second recurrence, she received five courses of weekly paclitaxel and carboplatin but was determined to have progressive disease. Subsequently, treatment with pembrolizumab and lenvatinib was initiated, and six courses of treatment were administered 5 months prior to admission. She developed a cough 2 months prior to admission. She occasionally experienced low-grade fever and exertional dyspnoea 1 month prior to admission. During efficacy assessment, chest computed tomography (CT) revealed infiltrative shadows, predominantly in both the lower lung fields, leading to hospitalisation. As a comorbidity, the patient developed hypothyroidism after ICI therapy.

At the time of admission, the patient was febrile, and the oxygen saturation was 92% on room air. Fine crackles were heard bilaterally during physical examination. Laboratory tests revealed a white blood cell count of 3600/mm³, C-reactive protein level of 2.25 mg/dl, lactate dehydrogenase level of 239 U/l, and creatine kinase level of 74 U/l (Table 1).

Chest CT showed consolidation around bronchovascular bundles and subpleural regions, predominantly in the lower lobes of both lungs, with dilated bronchial airway lucency. Additionally, small ground-glass opacities were observed in the upper lobes (Figure 1). No abnormal findings were observed on CT scans taken prior to ICI administration and 2 months before admission, making worsening of the underlying lung disease unlikely. Since her admission, she was treated with antibiotics, but there was little improvement in the imaging findings of pneumonia.

Figure 1.

Chest CT revealed infiltrative shadows predominantly in both lower lung fields.

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Bronchoscopy was performed on the day after admission. Bronchoalveolar lavage and lung biopsy were obtained from the left B8. Bronchoalveolar lavage fluid cells were predominantly macrophages (Table 1). Considering pembrolizumab-induced or rare but possible lenvatinib-induced, grade 2 drug-induced pneumonitis according to the Common Terminology Criteria for Adverse Events version 5.0, treatment with prednisolone 60 mg was initiated.

On the seventh day of hospitalisation, the patient tested positive for anti-ARS antibodies (Table 1). Pathological findings in the lung tissue showed lymphocyte and plasma cell infiltration into the bronchial mucosa and scattered Masson bodies, consistent with organising pneumonia (OP). Additionally, fibrin deposition was observed in the alveoli, which was partially consistent with the findings of acute fibrinous and organising pneumonia (AFOP) (Figure 2a). Therefore, the patient was diagnosed with ASS. Pneumonia shadows did not worsen on CT 1 week after starting steroids; however, the improvement in shadows was not satisfactory. Therefore, tacrolimus was started, and she was discharged to home care on the 14th day of hospitalisation. Further detailed investigation of anti-ARS antibodies using immunoprecipitation revealed positive results for anti-KS antibodies (index: 68.9).

Figure 2.

(a) Haematoxylin–eosin stain shows organisation within the alveolar space (arrowhead). (b) Elastic Masson staining showing fibrin deposition and thrombus formation in the alveolar space (arrowhead).

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The pneumonitis exhibited a positive response to treatment, as evidenced by an improvement in the chest X-ray image, leading to a gradual reduction of prednisolone. ICI was discontinued, and medroxyprogesterone was started following the diagnosis of ASS. Prednisolone dosage was gradually reduced to 10 mg, and after 3 months of treatment, a follow-up chest CT scan revealed a marked improvement in pneumonia. However, recurrent lesions showed a progressive increase in size, prompting consideration of alternative treatment options.

Discussion

We experienced a patient who was diagnosed with anti-KS antibody-positive ASS while receiving ICIs. In this case, interstitial pneumonia due to irAEs was also considered because the CT image and pathology showed an OP pattern; however, the diagnosis of ASS was finally made because the anti-KS antibody test was positive.

According to a PubMed search, our case is the first case of anti-KS antibody-positive ASS developed during ICI treatment, while four cases of ASS with other antibodies after ICI administration have been reported (Table 2). Of these, two were positive for the anti-PL-7 antibody and one each for the anti-PL-12 and anti-EJ antibodies [9–12]. The anti-PL-7, anti-PL-12, and anti-EJ antibodies are associated with a high incidence of interstitial pneumonia in patients with ASS. With the anti-PL-12 antibody, there have been reported cases in which the disease presents solely with interstitial pneumonia, complicating the diagnosis [7, 13]. Furthermore, the anti-KS antibody is a relatively rare antibody within ASS [7], and its presentation in half of the cases solely with interstitial pneumonia is a somewhat different disease pattern from other ASSs, further complicating the diagnosis [8]. In cases where ASS was induced during ICI administration, it was observed that in four of five cases, there were no accompanying skin symptoms or myositis. This could be a characteristic of ASS occurring during ICI treatment.

When focusing on the imaging patterns of interstitial pneumonia, two cases showed fibrosis with multifocal ground-glass opacities and one case presented a mix of nonspecific interstitial pneumonia (NSIP)-like ground-glass opacity consolidation and usual interstitial pneumonia (UIP)-like subpleural and basal predominant reticular shadows, cystic structures, and peripheral traction bronchiectasis with volume loss [9–11]. Additionally, a consolidation-dominant OP pattern was observed in two cases, including our case [12]. One patient who was presented with an OP pattern showed a fibrosis-OP pattern characterised by volume reduction in the lower lobes of both lungs and peribronchial consolidation, similar to our case.

To date, there have been no reports on the pathological patterns, and our case is the first such report. Generally, ASS often presents with NSIP or UIP patterns, and patients positive for KS antibodies tend to show a similar trend, with the occurrence of an OP pattern, as in this case being rare [14]. In contrast, OP patterns are more commonly observed in irAEs, making them difficult to differentiate [15]. Additionally, although rare, lenvatinib causes interstitial pneumonia [16]. However, the pathological findings showed fibrin deposition within the alveoli, a pattern closer to AFOP, which is less commonly reported in irAE and is recognised as one of the pathological patterns of connective tissue diseases, including ASS [17, 18]. Based on these findings, diagnosis of ASS was made.

The distinction between irAEs and ASS influences the treatment strategy. In ASS, combination therapy with immunosuppressants results in a lower recurrence rate than prednisolone monotherapy [19]. In Japan, given such a background, it is recommended to initiate combination therapy with calcineurin inhibitors from the initial stages in patients with dermatomyositis who present active interstitial lung disease [20]. Conversely, for ICI-triggered pneumonia, the recommended course of action depends on the severity, with options including discontinuation of ICIs with observation or treatment solely with steroids [21]. Additionally, discontinuation of steroids is recommended within 4–6 weeks. However, this rapid tapering rate may pose challenges for patients with ASS as many are unable to discontinue steroids [22]. In cases of irAE, reinfusion after treatment may be considered depending on disease severity. Nonetheless, reinfusion is often challenging in autoimmune diseases, as approximately half the patients who receive ICIs experience a relapse [23]. Therefore, distinguishing between the two conditions is crucial. In this case, the diagnosis of ASS prompted the initiation of tacrolimus therapy alongside discontinuation of ICIs.

It remains unclear whether ICI administration induces ASS. However, in the two previous cases, anti-ARS antibodies were already present before ICI administration, and their levels increased after treatment, suggesting a mechanism by which ICI acts as a trigger [10, 12]. ICIs have primarily focused on their action on T-cell immune checkpoints, leading to antitumour effects mediated by cytotoxic T-cells. However, its effect on B cells has recently garnered attention [24]. In addition to an increase in cytokines, an early increase in circulating transitional B cells and autoantibodies against joint-related proteins has been observed in patients with irAE arthritis, indicating B cell activation [24, 25]. Although there are few reports on B cells in irAEs, B cell activation may be related to an increase in anti-ARS antibodies and onset of disease due to ICIs. When considering antinuclear antibodies (ANAs), in previously reported cases, most had low ANA levels at diagnosis, and there was no significant increase in titres; in fact, one case showed seroconversion to a negative result (Table 2). In clinical practice, the progression of ANA titres may not be useful in differentiating between ASS and irAEs. Therefore, in patients with interstitial pneumonia during ICI treatment, it is important to consider not only ANAs but also specific antibodies for a detailed diagnosis.

Conclusion

We report a case in which a patient initially thought to have interstitial pneumonia as an irAE was diagnosed with ASS after testing positive for anti-KS antibodies. It is important to test for anti-ARS antibodies in patients with interstitial pneumonia developing during ICI therapy.

Acknowledgements

None declared.

Conflict of interest

None declared.

Funding

None declared.

Patient consent

Signed informed consent was obtained from the patient regarding the use of patient information for the purposes of writing a case report publication.

Ethical approval

Ethical approval is not applicable.

References