Immune checkpoint inhibitors (ICIs) enhance antitumor immunity by targeting inhibitory pathways that normally restrain T-cell activation and maintain peripheral immune tolerance, such as the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) pathways. By boosting the ability of the immune system to recognize and eliminate cancer cells, ICIs effectively inhibit tumor progression and markedly improve survival outcomes in patients with cancer (1). This mechanism has demonstrated notable efficacy in various malignancies, including melanoma, non-small cell lung cancer and urothelial carcinoma (2). However, ICIs are also associated with a risk of immune-related adverse events (irAEs), primarily caused by excessive immune system activation leading to damage to normal tissues (3). The clinical manifestations of irAEs reflect abnormal activation of the immune system and can affect nearly all organ systems with variations in onset time, duration and severity. For example, dermatological toxicities such as rash and pruritus often present early and are usually mild, whereas endocrine irAEs such as thyroid dysfunction tend to present later and are often more persistent. Cardiac or neurological irAEs, although uncommon, can be severe and progress rapidly (4,5). These events can prolong hospitalization, increase healthcare costs and compromise the efficacy of cancer therapy, especially if treatment discontinuation is required. In severe cases, irAEs such as myocarditis, pneumonitis, encephalitis and myasthenia gravis-like syndromes can be life-threatening. According to published data from international studies, among patients receiving ICI therapy, the incidence of ICI-induced inflammatory arthritis (ICI-IA) has been reported to be 4-6%, and ~43% of patients experience an impaired quality of life due to arthralgia (6-8). However, systematic research specifically focusing on ICI-IA remains limited. In the present report, 3 cases of ICI-IA are presented and analyzed, discussing their clinical features, diagnosis and treatment strategies in the context of existing literature. The aim of the current report is to provide clinicians with actionable insights and practical guidance in the recognition and management of this specific irAE.

ICI-IA encompasses a range of clinical phenotypes, most commonly presenting as inflammatory polyarthritis (12), but it may also manifest as oligoarthritis or monoarthritis and, in some cases, resemble psoriatic, reactive, remitting seronegative symmetrical synovitis with pitting edema or axial spondyloarthritis-like disease (13). The wrists, hands, shoulders and knees are the most frequently affected joints (14). These symptoms are temporally associated with ICI therapy (6). Published international studies have reported that 4-6% of patients receiving ICI therapy develop IA (6-8). The median time to the onset of ICI-IA is ~124 days (interquartile range, 56-252 days) after the initiation of ICI therapy (6). Other studies suggest that 60% of ICI-IA cases occur within the first 2-3 months of treatment and often present as a delayed-onset condition that may persist even after discontinuation of ICI therapy (15-18). In the present case series, two clinically important patterns of ICI-IA were highlighted that warrant heightened clinical attention: i) IA presenting after discontinuation of ICI therapy; and ii) recurrent IA following ICI rechallenge. Although these patterns have been previously described, they remain under-recognized in current clinical practice and the existing literature, and may influence management decisions and patient counseling. Therefore, sustained long-term vigilance is required, even after immunotherapy has been discontinued.

Evidence indicates that the type of ICI therapy may influence both the clinical presentation and persistence of ICI-IA (19,20). Combined CTLA-4 and PD-1 inhibition is more commonly associated with chronic inflammation involving large joints, particularly the knees, whereas PD-1/PD-L1 inhibitor monotherapy tends to affect small joints such as the wrists, metacarpophalangeal joints and proximal interphalangeal joints (20). Importantly, ICI-IA may persist after ICI discontinuation. Longer ICI exposure, combined CTLA-4/PD-1 blockade therapy and multiple concomitant irAEs have all been associated with more persistent arthritis after ICI discontinuation (18). In addition, arthritis symptoms tend to be more persistent in patients achieving a complete response or PR compared with those with SD or progressive disease (18). Pre-existing osteoarthritis (OA) has been recognized as an independent risk factor for ICI-IA, alongside higher body mass index and smoking (21). In a cohort of ICI-treated patients, OA was markedly more prevalent in those who developed ICI-IA compared with patients experiencing non-arthritic irAEs or no irAEs, indicating that OA may serve as a clinically relevant predictor and support baseline risk stratification before ICI therapy. In addition, higher serum levels of vascular endothelial growth factor A (VEGF-A) and tumor necrosis factor α (TNF-α) have been reported in patients with ICI-IA compared with ICI-treated patients who did not develop IA (22). These elevations are associated with more severe arthritis, persistent disease activity and an increased need for systemic corticosteroids or disease-modifying antirheumatic drugs (DMARDs), independent of cancer type or ICI regimen. Consequently, VEGF-A and TNF-α show promise as prognostic biomarkers, and may help guide precision medicine-oriented targeted interventions, including anti-TNF or anti-VEGF therapies, in selected patients.

The pathogenesis of ICI-IA involves immune system activation, the participation of specific immune cell subsets and the formation of an inflammatory micro-environment. It is generally accepted that ICIs relieve T-cell inhibition by blocking immune checkpoint pathways such as PD-1/PD-L1, thereby enhancing antitumor immune responses. However, this may also enable autoreactive T cells to attack joint tissues (23). A previous study has identified a cytotoxic CD38^high/CD127^-/CD8⁺ T-cell subset in the synovial fluid and peripheral blood of patients with ICI-IA, which expresses high levels of effector molecules, such as perforin and granzyme B, exhibits proliferative activity and can contribute directly to arthritic damage (24). Upon antigenic stimulation, exhausted CD8⁺ T cells in the synovial fluid lose their regulatory function, releasing pro-inflammatory cytokines, such as interferon-γ and TNF-α. These cytokines act synergistically with IL-1β^high macrophages to promote synovitis and cartilage destruction (24,25). Additionally, the expansion of CD21^low B cells, a subset associated with enhanced autoreactivity and antigen presentation, in the circulation has been linked to a higher risk of severe irAEs, particularly after combined CTLA-4 and PD-1 blockade, whereas such changes were not significant with anti-PD-1 monotherapy in the reported cohort (26,27). More specifically, elevated levels of transitional CD19⁺/CD10⁺/CD24^high/CD38^high B cells have been observed in patients who develop ICI-IA compared with ICI-treated patients who did not develop arthritis. Notably, this increase can precede clinical symptom onset, suggesting its potential as an early predictive biomarker for arthritis development (28). Together, these specific cytotoxic T-cell and atypical B-cell signatures delineate the immune-driven pathophysiology of ICI-IA, while also highlighting promising options for risk stratification and precise future interventions aimed at these aberrant pathways.

Currently, no unified diagnostic criteria for ICI-IA have been established. In clinical practice, diagnosis relies on a comprehensive assessment integrating symptom characteristics, treatment history, laboratory findings and imaging results, while excluding alternative causes such as pre-existing rheumatic diseases or bone metastases. Existing frameworks proposed by Naidoo et al (29) and Choi and Lee (30), along with grading systems from the CTCAE version 5.0(9) and international oncology guidelines [European Society for Medical Oncology (ESMO) and American Society of Clinical Oncology (ASCO)] (31,32), provide a practical reference for clinical evaluation and severity assessment. Furthermore, for high-risk patients (such as those with a history of autoimmune diseases), a comprehensive baseline joint function assessment should be conducted, and joint symptoms should be closely monitored throughout the treatment process to enable early detection and intervention (4). For patients suspected of having myositis, assessing muscle weakness or myocarditis symptoms is critical, as these conditions often co-occur with other irAEs (33,34).

In the present cases, the diagnosis was primarily based on the following features: i) A clear temporal association between ICI therapy and the onset of arthritic symptoms; ii) physical examination revealing a characteristic pattern of joint involvement without overlying skin erythema or ulceration; iii) laboratory tests ruling out rheumatic diseases; iv) imaging findings showing abnormal joint metabolic activity; and v) a favorable response to corticosteroid therapy. In case 2, the diagnosis of pre-existing RA could not be definitively verified. Although the patient reported a prior history of RA, detailed medical records were unavailable and they declined further rheumatologic evaluation, including MRI/ultrasound imaging and RA-related serological testing (RF and anti-CCP); therefore, diagnostic uncertainty regarding the presence of existing RA or an underlying autoimmune background must be acknowledged. Despite this limitation, several features favor ICI-IA over a flare-up of conventional RA: i) The patient had been asymptomatic and untreated for several years before ICI initiation, consistent with stable remission if RA had existed; ii) arthritis onset showed a clear temporal association with ICI exposure, whereas RA has no established causal relationship with immune checkpoint blockade; iii) the distribution of joint involvement, including the ankle, knee, lumbar spine and sacroiliac joints, does not conform to the typical pattern of RA, which predominantly affects symmetric small joints, but is more compatible with reported ICI-IA phenotypes (35); iv) arthritis showed a rapid and marked response to systemic corticosteroids, and the prolonged treatment course during the second episode was largely attributable to poor medication adherence rather than steroid refractoriness, whereas active RA typically requires sustained DMARD therapy for adequate disease control; v) objective serological evidence supporting RA, such as RF or anti-CCP positivity, was lacking; and vi) markedly elevated inflammatory cytokines, particularly IL-6 and IL-10, are consistent with previously described irAEs (36). Taken together, although underlying RA cannot be entirely excluded, the clinical course, joint distribution, temporal relationship to immunotherapy, treatment response and cytokine profile collectively support the diagnosis of ICI-IA in this case.

In case 3, MRI revealed early inflammatory changes (tenosynovitis, bursitis and synovial enhancement) with superior soft tissue resolution, while PET/CT demonstrated systemic polyarticular involvement. The PET/CT pattern of large joint FDG uptake with periarticular inflammation and shoulder-hip girdle involvement resembled IA rather than the typical small joint pattern of RA, supporting ICI-IA diagnosis (37-41). This multimodal approach aligns with the literature, which shows that MRI detects early ICI-IA changes before radiographic abnormalities, thereby guiding therapeutic decisions (11). These cases emphasize the critical role of comprehensive evaluation, multimodal imaging and differential diagnosis in ICI-IA recognition. Notably, data on ultrasound or MRI examinations were lacking in cases 1 and 2. This was primarily due to patients prioritizing cancer management over joint symptoms, refusing to invest time and financial resources into further arthritis diagnostic evaluations. This also reflects a common reality among patients with advanced malignant tumors, who often focus on managing life-threatening diseases while underestimating the importance of immune-related musculoskeletal complications.

According to current international guidelines, including those from the National Comprehensive Cancer Network, ASCO, ESMO, Society for Immunotherapy of Cancer and European Alliance of Associations for Rheumatology, corticosteroids remain the first-line treatment for patients with grade ≥2 ICI-IA (31,32,42-44). Treatment intensity is guided by symptom severity, with escalation to conventional synthetic DMARDs or biologic agents reserved for patients with corticosteroid-refractory or recurrent disease. In the present case series, all patients achieved meaningful symptom control with systemic corticosteroid therapy, although treatment duration and tapering strategies varied. Notably, case 2 required prolonged corticosteroid exposure following arthritis recurrence after ICI rechallenge, highlighting the importance of individualized treatment planning and close follow-up rather than rigid adherence to standardized dosing algorithms.

For patients with severe symptoms (grade ≥3) who show no improvement after 2 weeks of corticosteroid therapy, early use of DMARDs or biologics should be considered. Given that traditional synthetic DMARDs (such as methotrexate) have been demonstrated to be effective and well-tolerated, they are often the first-line treatment. For example, studies have shown that methotrexate can effectively control ICI-IA with minimal impact on tumor control (45,46). When additional treatment is required, biologics should be considered. IL-6 receptor antagonists (such as tocilizumab and sarilumab) can rapidly alleviate IA (47,48). Not only does tocilizumab treat ICI-IA effectively, but it may also serve as a secondary prophylactic agent, notably reducing the risk of recurrence and prolonging the duration of ICI rechallenge (47). TNF-α inhibitors can also quickly improve arthritis symptoms, but it has been suggested that they may accelerate cancer progression (46); therefore, caution is advised when administering TNF-α inhibitors. Ma et al (49) reported that treatment with secukinumab, an anti-IL-17A inhibitor, effectively managed ICI-IA in two patients with melanoma without leading to tumor progression.

Emerging treatment strategies for ICI-IA include targeted small-molecule drugs and advanced delivery systems. Janus kinase inhibitors (such as tofacitinib) have demonstrated good efficacy in severe corticosteroid-resistant irAEs (50). In the largest multicenter observational study to date, clinical remission rates were 54.5% in life-threatening irAE cases, 96.7% in steroid-resistant cases and 100% in steroid-taper-failure cases, with a median overall survival of 16.1 months from ICI initiation, suggesting no obvious short-term compromise in antitumor outcomes (50). More specifically for articular disease, tofacitinib induced rapid and sustained remission in a reported case of ICI-IA (51). Nevertheless, as the multicenter data were dominated by myocarditis, myositis and hepatitis rather than arthritis, and the arthritis-specific evidence is currently limited to case reports, the role of JAK inhibitors in ICI-IA remains investigational and warrants further validation. Bruton's tyrosine kinase (BTK) inhibitors can regulate B-cell activation and reduce the secretion of cytokines such as IL-1β, IL-6 and IL-17. Through precise immune modulation, BTK inhibitors may exert both anti-inflammatory and antitumor effects, although their application in ICI-IA remains in the experimental stage (52). Additionally, engineered extracellular vesicles, particularly exosomes, are being studied as novel anti-inflammatory drug delivery systems, enabling targeted, efficient and low-immunogenicity interventions (53). Although these strategies hold promise, further clinical validation is required before they can be routinely incorporated into ICI-IA management.

Clinical observations suggest a potential link between the development of rheumatic irAEs, including ICI-IA, and enhanced antitumor immune responses. In a prospective cohort, patients with rheumatic irAEs had a higher tumour response rate than patients without irAEs (85.7 vs. 35.3%) (54). Similarly, in another single-centre analysis, the tumour response rate was 94.4% in patients with rheumatic irAEs, compared with 43.5% in patients without rheumatic irAEs, and the median progression-free survival was 20 months in the rheumatic irAE cohort vs. 2 months in patients without irAEs (55). In a longitudinal ICI-IA cohort, 53.3% of patients continued to have active arthritis at the most recent follow-up, and persistent IA was associated with a trend toward better tumour response, while immunosuppressive treatment did not appear to adversely affect tumour outcomes (18,56). These findings are consistent with the treatment responses and survival outcomes observed in the present cases.

International guidelines recommend that most irAEs can be managed by temporarily discontinuing ICI therapy ± corticosteroid treatment, except for severe or life-threatening irAEs requiring permanent discontinuation (57). Clinical data indicate that ICI rechallenge following adjustments to the treatment regimen, such as changing from combination to monotherapy, generally has a favorable safety profile and remains effective (58). Among patients experiencing ICI-IA for the first time, spontaneous symptom resolution during continued ICI treatment is rare (~16%), and most patients require temporary discontinuation until symptoms resolve before rechallenging with ICI therapy (56). However, a study has shown that ~52% of patients experienced arthritis recurrence upon rechallenge, often with a severity similar to that of the initial episode, with the median time to recurrence being only 1 month (59). In the present case series, the patient in case 2 maintained PR after two ICI treatment interruptions, confirming that short-term discontinuation does not compromise long-term antitumor efficacy. However, close monitoring for joint symptom recurrence is essential.

In conclusion, through the analysis of 3 cases and a literature review, the present report highlighted key clinical patterns of ICI-IA, particularly delayed onset after therapy cessation and recurrence upon rechallenge, and discussed their diagnostic and therapeutic implications. The current study found that ICI-IA is characterized by typical symptoms, delayed onset and a prolonged disease course, while its clinical manifestations are influenced by treatment regimens and host-related factors. A comprehensive diagnosis approach is required, incorporating treatment history, exclusionary laboratory tests and multimodal imaging. The response to corticosteroids provides notable diagnostic value. Graded management strategies can effectively control ICI-IA symptoms; however, multidisciplinary team consultation and long-term follow-up are essential for patients with recurrent, persistent or complex symptoms. Moreover, the pathogenesis of ICI-IA may be linked to enhanced antitumor immunity, and appropriate ICI rechallenge is safe and feasible in most patients. Nevertheless, the limitations of the present study should be acknowledged. Firstly, the findings are based on a small number of cases from a single center. Secondly, imaging examinations, such as ultrasound or MRI, were not performed on all patients, which may limit the generalizability and comprehensiveness of the evaluation. Additionally, the retrospective nature of the study and the limited availability of certain laboratory and serological data, such as serial cytokine measurements, complete autoantibody testing including RF, anti-CCP and ANA, prevented a more in-depth exploration of the underlying immunological mechanisms. Further multicenter prospective studies involving larger cohorts are required to clarify the clinical spectrum, pathogenesis and optimal management strategies of ICI-IA more effectively.

Although ICI-IA is increasingly recognized in clinical practice, future efforts should focus on elucidating its immunological mechanisms and validating predictive biomarkers, such as specific immune-cell subsets, VEGF-A and TNF-α, to facilitate early identification of high-risk populations and guide preventive strategies. Simultaneously, the establishment of prospective multicenter clinical trials is essential to delineate the full disease spectrum and generate robust real-world evidence, which will underpin the development of standardized diagnostic and therapeutic guidelines. These advances are expected to optimize long-term management, refine ICI rechallenge protocols and strengthen multidisciplinary care. Collectively, such initiatives will enhance the understanding of ICI-IA and ultimately support the dual goals of maximizing antitumor efficacy while preserving patient quality of life.