Introduction
Immune checkpoint inhibitors (ICIs) have markedly improved clinical outcomes across a range of malignancies (1). By inhibiting signal transduction pathways like programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein (CTLA)-4, ICIs enhance the T-cell-mediated anti-tumor immune response, leading to durable remissions and survival advantages, particularly in cancers historically considered refractory, including metastatic melanoma and non-small cell lung cancer (1). Despite their efficacy, ICIs are associated with immune-related adverse events (irAEs), which may involve nearly any organ system.
IrAEs are common, occurring in ~90% of patients receiving anti-CTLA-4 therapy and 70% of those treated with anti-PD-1/PD-L1 agents (2). Although less frequent than dermatologic or gastrointestinal irAEs, neurological irAEs, affecting ~1-3% of patients, are particularly concerning due to their potential severity and risk of long-term disability (3). Among these, polyradiculoneuropathy (PRN) and myocarditis represent severe manifestations of neurological and cardiac irAEs, respectively. Although rare, these events can be life-threatening: Severe PRN has been associated with mortality rates of up to 60% (4,5), while ICI-related myocarditis has a fatality rate approaching 50% (6). The pathogenesis of irAE has been reported to involve complex immune dysregulation, including autoreactive T-cell activation and cellular/humoral immune-mediated tissue damage (3).
The management of severe or refractory irAEs remains a significant clinical challenge. First-line treatment typically consists of high-dose corticosteroids combined with supportive care (1). However, second-line therapies such as intravenous immunoglobulin (IVIG) or plasmapheresis demonstrate variable efficacy and substantial mortality (4,5). This highlights the urgent need for novel therapeutic strategies targeting specific immune pathways. Efgartigimod, a neonatal Fc receptor (FcRn) antagonist, enhances the degradation of pathogenic IgG autoantibodies. Its established efficacy and favorable safety profile in antibody-mediated disorders like generalized myasthenia gravis (7) suggest its potential utility in treating refractory, antibody-mediated irAEs (8).
The present case report describes marked neurological and cardiac improvement in a patient with metastatic pancreatic cancer who developed severe, refractory ICI-induced PRN and myocarditis following treatment with efgartigimod. The findings underscore FcRn blockade as a promising therapeutic approach for managing life-threatening, treatment-resistant irAEs.
Discussion
ICIs can cause severe, though rare, neuroimmune complications, such as myositis, myocarditis and PRN, typically emerging after one to two treatment cycles (3). The incidence of ICI-induced PRN is estimated to be between 0.1 and 0.3% (13), with clinical manifestations, including limb weakness and bulbar symptoms. Although corticosteroids and IVIG are considered first-line therapies, the associated mortality rate remains high, reaching up to 60% (4,5). In the present case, the patient exhibited a limited clinical response to corticosteroids and IVIG. However, substantial neurological and cardiac improvement was achieved following administration of efgartigimod, a novel immunosuppressive agent and first-in-class FcRn antagonist.
During the course of treatment, cytokine and immunoglobulin levels were monitored, noting initial elevations indicative of immune activation. Although cytokine levels decreased following conventional treatment, no corresponding clinical improvement was observed, suggesting that cytokine-driven pathways may not be dominant in the pathogenesis of irAEs in the patient.
Importantly, antibody-mediated immune processes have been increasingly implicated in the development of irAEs. Previous studies have reported that up to 40% of patients developed encephalitis, 34.4% had myasthenia gravis and 22% of patients experienced peripheral neuropathy and Guillain-Barré Syndrome and tested positive for autoantibodies (14,15). The most frequently detected neuro-antibodies include anti-acetylcholine receptor antibodies, anti-Ma family member 2 antibodies and anti-Hu antibodies (15). Additionally, a range of autoantibodies has been detected in ICI-induced myocarditis, including those targeting myosin heavy chain, cardiac troponin I and other cardiac antigens, such as β-1 adrenergic receptor, muscarinic M2 receptor and Na-K-ATPase (16). Nonetheless, a significant proportion of patients remain negative for these antibodies, suggesting the involvement of alternative pathogenic mechanisms or the presence of unidentified antibodies.
In the patient of the current study, the presence of positive serum anti-double-stranded DNA antibodies, along with significant clinical improvement and a sustained reduction in IgG levels following efgartigimod treatment, supports the hypothesis that antibody-mediated immune responses play a central role in the pathogenesis of ICI-induced paraneoplastic neurological syndrome. Efgartigimod, originally developed for the treatment of myasthenia gravis and other autoimmune disorders, functions by binding to FcRn, thereby preventing the recycling of IgG and promoting its degradation (7). This mechanism reduces circulating IgG levels without inhibiting IgG synthesis, offering a promising therapeutic option for patients who are unresponsive to conventional immunosuppressive therapies. Within the therapeutic context of irAEs, efgartigimod shows potential efficacy through the targeted clearance of pathogenic autoantibodies, which in turn attenuates downstream inflammatory cascades. Furthermore, a previously reported case demonstrated the significant efficacy of efgartigimod in treating ICI-induced myositis, myocarditis and myasthenia gravis (8), further emphasizing the therapeutic potential of FcRn antagonists in eliminating pathogenic autoantibodies and supporting FcRn blockade as a promising strategy for managing severe neurological and cardiac irAEs.
While the present case demonstrates promising results, the generalizability of these findings is inherently limited by the single-patient design. Multicenter collaborations and larger cohorts of patients with refractory irAE are needed to validate the efficacy of efgartigimod. Although the patient exhibited positive serum anti-double-stranded DNA antibodies, anti-nucleosome antibodies and initially elevated immunoglobulin levels, further investigation is necessary to elucidate the role of these antibodies in the onset and progression of ICI-induced PRN. Comprehensive serological profiling, including testing for anti-ganglioside, onconeural, myositis-specific and myasthenia gravis-associated antibodies, along with advanced molecular analyses, will be essential for uncovering the underlying mechanisms of irAE pathogenesis (3).
In light of the findings of this case study, several clinical applications for efgartigimod may also be proposed. This agent may offer a particular benefit to patients with ICI-induced neuroimmune complications who are unresponsive to conventional treatments such as corticosteroids and IVIG. Therapeutic monitoring should include regular assessments of serum IgG levels and other immune markers to enable individualized treatment adjustments. Future research should focus on refining patient selection criteria and establishing standardized protocols for the clinical use of FcRn antagonists in the management of ICI-induced irAEs.
While this case provides compelling evidence supporting the efficacy of efgartigimod in treating ICI-induced PRN and cardiomyopathy, further research is required to establish its role in broader clinical practice. The limitations of this report, including the single-patient design and the short duration of follow-up, should be acknowledged. Future studies should aim to address these gaps to inform evidence-based clinical decision-making.