Immune checkpoints, highly expressed on activated T and B cells, are vital for immune regulation and balance. CTLA-4 and PD-1 are the most studied, playing key roles in negatively regulating T cell activation (10). CTLA-4 outcompetes CD28 by binding CD80/CD86 with higher affinity, blocking T cell activation. Tregs’ high CTLA-4 expression is crucial for tumor immune evasion (11). Conversely, the interaction between PD-1 and its ligands, PD-L1 and PD-L2, serves as a negative regulator of T cell function, maintaining a delicate balance between T cell activation, tolerance and immune-mediated tissue damage (12, 13). PD-1 is highly expressed on Tregs, promoting their proliferation via ligands and suppressing anti-tumor immunity due to tumor-infiltrating Tregs. Blocking PD-1 enhances anti-tumor immunity by reducing Treg inhibition (14). These immune checkpoints are essential for maintaining immune homeostasis and ensuring the tolerance of normal tissues, thereby protecting organs from unnecessary damage while allowing the immune system to effectively eliminate pathogens (15) (Figure 1A). Other immune checkpoints, such as T cell immunoglobulin-3 (TIM3) (16), lymphocyte activation gene 3 protein (LAG3) and T cell immunoreceptor with Ig and ITIM domains (TIGIT) also play important roles in immunity regulation (17). Since the FDA’s 2011 approval of ipilimumab (the first CTLA-4-targeting ICI), cancer therapy, particularly for advanced melanoma, has undergone a revolutionary shift (18–20). Subsequently, pembrolizumab and nivolumab, targeting PD-1, received FDA approval from 2014 to 2015, for the treatment of advanced melanoma, mismatch repair defects (dMMR) and microsatellite instability-high (MSI-H) cancers and non-small cell lung cancer (20, 21). The approval of ipilimumab and nivolumab combination immunotherapy for advanced melanoma marked a milestone, yielding significant therapeutic benefits (20). Since May 2016, the FDA has OK’d three PD-L1 drugs—atezolizumab, durvalumab, and avelumab—for treating non-small cell lung and urothelial cancers (22–24). Overall, ICIs have revolutionized the field of oncology, significantly enhancing the long-term survival rates for patients with various types of cancer.

ICIs have revolutionized patient care in oncology, leading to a distinctive spectrum of organ-specific inflammatory toxicities known as irAEs (4). These toxicities are notably common, with approximately 50% of patients treated with ICIs experiencing some form of irAEs (25). A systematic review of ICI-irAEs from randomized controlled trials (RCTs) reported that 14% of patients treated with PD-1/PD-L1 inhibitors, 34% of patients receiving CTLA-4 inhibitors, 55% of patients undergoing combination ICI therapy, and 46% of patients receiving immunotherapy combined with chemotherapy experienced grade ≥ 3 irAEs (26). Interestingly, the occurrence of irAEs is usually associated with a more favorable response to tumor treatment (27). Among these adverse events, rheumatologic immune-related adverse events (rheumatic irAEs) represent a specific category of side effects induced by immunotherapies, including ICI-related arthralgia and arthritis, with reported frequencies ranging from 1% to 43% (28), highlighting their prevalence among rheumatic irAEs.

IrAEs occur more frequently in patients receiving both anti-PD-1 and anti-CTLA-4 inhibitors compared to those undergoing monotherapy (29). Interestingly, irAE-arthritis, reported to affect approximately 1-7% of patients (Table 1), did not exhibit a female predominance in these studies (30, 31). These events may emerge at any point during therapy, with onset occurring from 2 weeks to over a year after the initiation of ICI therapy (8, 32, 33). Notably, anti-PD-1/L1 therapies have been associated with a higher incidence of rheumatic irAEs compared to anti-CTLA-4 monotherapy (13, 34, 35). IrAE-arthritis can arise from either CTLA-4 or PD-1 inhibitor monotherapy or from combination therapy involving both agents (33). The incidence rates of arthralgia vary among different treatments: 9% to 12% in patients receiving pembrolizumab, 6% to 8% in those treated with nivolumab, 5% for ipilimumab, and 11% for patients undergoing combination therapy with nivolumab and ipilimumab (36). Interestingly, irAE-arthritis is predominantly polyarticular, affecting approximately 65% of patients, while about 35% experience oligoarticular involvement (37) (Table 1). Additionally, the prevalence of irAE-arthritis does not appear to correlate significantly with age and gender (38).

IrAE-arthritis is characterized by joint stiffness and swelling (39). Additionally, a variety of other rheumatic syndromes have been reported, including arthralgia; mono-arthritis, oligoarthritis or polyarthritis; reactive arthritis; psoriatic arthritis (PsA); remitting seronegative symmetrical synovitis with pitting oedema (RS3PE); tenosynovitis; enthesitis; non-inflammatory musculoskeletal conditions; and osteoarthritis (39, 40). One earlier study described 9 patients who developed inflammatory arthritis as a result of ICIs, with some of presenting additional symptoms such as urethritis and conjunctivitis, which are consistent with a diagnosis of reactive arthritis (41). Unusual manifestations reported in case studies include inflammatory tenosynovitis affecting the hands and/or shoulders, as well as enthesitis and swan-neck deformities indicative of Jaccoud’s arthropathy (42–44). Moreover, some patients with pre-existing osteoarthropathy experienced aggravation of joint inflammation, indicating that inflammatory responses can be triggered in individuals with degenerative joint diseases following ICI treatment (45).

In general, imaging modalities such as MRI and musculoskeletal ultrasonography play a crucial role in identifying erosive disease, tenosynovitis, doppler-positive synovitis, and joint effusions in patients with inflammatory arthritis (41, 46). Medical imaging, including PET-MRI, has been effective in diagnosing inflammatory arthritis, demonstrating fluorodeoxyglucose uptake in the synovial tissue of multiple peripheral bilateral joints, and these manifestations were observed between 2 to 26 months following ICI therapy (47). According to Radiographic grading system for arthritis (Table 2), point-of-care musculoskeletal ultrasound (MSKUS) is a valuable tool for evaluating potential irAE-arthritis (48). The most commonly identified MSKUS features include grade 2 or higher synovial thickening (80%), hyperemia measured by color power Doppler signal (70%), and tenosynovitis (60%) (49).

Inflammatory polyarthritis is a frequently reported manifestation in patients undergoing ICI therapy. Clinical investigations showed that the majority of irAE-arthritis patients have received anti-PD-1/PD-L1 agents. Among these patients, a study showed that symptoms of arthropathy typically present with a time to onset of about 2–24 months following the initiation of ICI treatment (31). Additionally, some patients developed RA after ICI treatment, with a time to onset ranging from 1days to 2 months (50–52). PsA has been documented in six patients who were undergoing Immune Checkpoint Inhibitor (ICI) therapy, with the condition manifesting approximately 0.5 to 5 months after treatment initiation (50, 53–57). RS3PE was observed in 11 patients, with a median time to onset of 26 weeks (range: 4–126 weeks) from the start of ICI therapy (58). Similarly, the onset of polyarthritis was reported with a median time of 8 days (range: 2–27 days) (50) (Table 1).

Combining anti-CTLA-4 and PD-1/PD-L1 therapies can worsen arthritis. Two prior studies linked CTLA-4 (ipilimumab) and PD-1 inhibitors (nivolumab, pembrolizumab) to exacerbated RA and psoriatic arthritis (59, 60). The observed clinical features primarily included exacerbations of pre-existing disease, with no new manifestations of autoimmune disease reported (61).

Overall, anti-PD1 is more likely to induce the irAE-arthritis, and combination therapy significantly increases both the incidence and severity of these adverse events. Although arthritis symptoms often arise within the first few months of initiating ICI therapy, there have been instances of delayed onset arthritis that can persist even after the discontinuation of ICI treatment. Moreover, among patients with irAE-arthritis, approximately half also experienced non-rheumatic immune-related adverse events (62).

Immune checkpoint molecules are predominantly expressed on the surface of T cells, where they play a critical role in dampening the ongoing T cell response (67). ICIs primarily target these T cells, counteracting the function of these molecules by disrupting their interactions with ligands. This interference impairs the effective modulation of immune cell activation and proliferation, thereby destabilizing the balance of the immune system and making it more susceptible to hyperactivation (68, 69). Observations indicate that patients who progress to irAEs following anti-CTLA-4 therapy exhibit a tendency for the expansion of autoreactive CD4⁺ T cells, along with the proliferation of specific T cell clonal subsets, suggesting that anti-CTLA-4 treatment can elicit the differentiation and diversification of the T cell repertoire (70). When ICIs are administered systemically, they can activate autoreactive T cell clones that target autoantigens (Figure 1B). The majority of these activated T cells lack specificity, which can lead to systemic multi-organ toxicity and potentially life-threatening conditions (71).

Recent study showed that IL-7 is implicated in multiple stages of B cell progenitor development, including commitment, survival, differentiation, and proliferation (76). Furthermore, the interaction between PD-1 and PD-L1 can induce apoptosis in B cells (77). A particular genetic variant, rs16906115, has been shown to elevate IL-7 expression in the B cells of patients with irAEs who carry the risk allele. This increased IL-7 expression is independently associated with a higher likelihood of experiencing irAEs, alterations in antibody production, and a greater frequency of mutations in B cell receptors (78). Consequently, PD-1/L1 inhibitors can increase the IL-7 secretion to promote B cell proliferation and differentiation (77, 79) (Figure 1C). Recent research also indicates that patients with irAE-arthritis have higher proportions of CD19⁺ B cells compared to those without irAEs (80). Furthermore, individuals with irAE-arthritis exhibit an increase in both the proportion and absolute numbers of transitional CD19⁺CD10⁺CD24^hiCD38^hi B cells compared to non-irAE patients. Specifically, these transitional B cells increase prior to the onset of overt irAE-arthritis symptoms and decrease during the transition between the active and quiescent disease stages. Additionally, autoantibodies targeting type II collagen epitopes have been identified in up to 43% of irAE-arthritis patients, whereas no such autoantibodies were observed in non-irAE patients (80). Therefore, the increased proportion of B cells results in the secretion of autoantibodies, ultimately leading to the development of irAE-arthritis (Figure 1D).

It is widely recognized that CD4⁺CD25⁺Foxp3⁺ Tregs play a crucial role in maintaining immune homeostasis, and their interaction with co-suppressor molecules is critical for attenuating the activation of CD4⁺ and CD8⁺ T cell responses (96). Recent research has illuminated that ICIs lead to a reducing frequency of CD4⁺CD25⁺Foxp3⁺ Tregs (75). This reduction is partly attributed to the constitutive expression of CTLA-4, rendering antigen-specific Tregs susceptible to macrophage-mediated antibody-dependent cell-mediated cytotoxicity (ADCC), ultimately resulting in Treg depletion (75, 97), which may induce arthritis (Figure 1C). Intriguingly, transcriptomic analyses of Tregs suggested that these cells are markedly enriched in synovial fluid of patients with irAE-arthritis and exhibit effective Treg (eTreg) phenotypes characterized by enhanced suppressive functions compared to those their counterparts in the peripheral blood (63).

Moreover, PD-1 is mainly expressed in specific Treg subsets. The PD-1/PD-L1 pathway potentiates anti-tumor immunity by inhibiting iTregs production and Foxp3 expression, compromising Treg function and potentially breaking self-tolerance (96, 98). Additionally, a recent study highlighted significant inflammatory transcriptional reprogramming of Tregs in the periphery of cancer patients who developed irAEs following anti-PD-1 immunotherapy. Notably, transcripts such as IFNG, STAT1, RORC and STAT3 were found to be highly enriched in these Tregs (99). This finding underscores the reprogramming of peripheral Tregs toward an inflammatory signature upon ICI immunotherapy in individuals with irAEs. Further, Tregs from patients with irAEs demonstrated metabolic reprogramming (99), which aligns with the dysfunction of Tregs observed in various autoimmune diseases (100).

In summary, ICI therapy may enhance the secretion of inflammatory cytokines, thereby promoting the occurrence and development of irAE-arthritis.

For patients with milder forms of arthritis, nonsteroidal anti-inflammatory drugs (NSAIDs) are typically recommended as the first-line treatment. In cases of monoarthritis or oligoarthritis, intra-articular corticosteroids (CSs) can provide more targeted management (41).

Many patients may require systemic CSs, typically initiated at moderate doses of 10–20 mg of prednisone. Some patients may necessitate long-term, low- to moderate-dose CSs to facilitate continued treatment with ICIs in oncology (39).Certain rheumatic irAEs may require higher doses of CSs, and case series have shown that arthritis, which typically responds to low–medium doses, might require higher doses when treating irAEs (41). Additionally, exogenous CSs at clinically relevant concentrations exert immunosuppressive effects by impairing the ability of dendritic cells to present tumor antigens, as well as inhibiting T cell activation and anti-tumor activity (102). However, a systematic literature review indicated that the concomitant administration of CSs and ICIs may not necessarily lead to poorer clinical outcomes (103).

Studies in mouse models have shown that both endogenous and exogenous glucocorticoids can inhibit anti-cancer immune responses (104). One particular study assessed the influence of clinically relevant doses of dexamethasone and an anti-TNF monoclonal antibody in vitro, revealing that even low doses of CSs markedly impaired the anti-tumor activity of tumor-infiltrating lymphocytes, although this activity was restored upon withdrawal of steroids (105). Additionally, recent studies have revealed that CSs significantly abrogate the anti-tumor efficacy of ICIs at doses of ≥10 mg of daily prednisone or its equivalent (106, 107). Consequently, the therapeutic use of glucocorticoids for managing irAE-arthritis requires careful consideration and caution.

Early referral to a rheumatologist is recommended for patients exhibiting grade ≥2 symptoms prior to initiating corticosteroid therapy, particularly if there is an insufficient response to acceptable doses of CSs, or if a corticosteroid-sparing regimen is necessary. For these patients, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) should be considered, including methotrexate, hydroxychloroquine, or sulfasalazine (39). It is important to note that many patients with irAE-arthritis experience a milder disease course with clinical manifestations that deviate from typical inflammatory chronic arthritis and systemic rheumatic diseases. Consequently, the need for CSs or DMARDs may be diminished (108).

Recent clinical reports indicate that patients with irAEs who gradually reduced their does of CSs can obtain long-term remission following methotrexate treatment, and follow-up studies found that methotrexate exhibits favorable efficacy and safety, especially in cases of multiple irAE-arthritis (109). Additionally, a case report described that hydroxychloroquine was used in patients with inflammatory arthritis who exhibited minimal improvement in arthralgias after treatment with high-dose steroids. Nevertheless, during this treatment period, imaging evaluations revealed significant progression of melanoma, characterized by new bilateral lung metastases and an enlarging left inguinal adenopathy (110). Furthermore, other agents such as sulfasalazine, leflunomide, azathioprine, and apremilast have also proven to be highly effective in the management of irAE-arthritis (111).

Mild irAE-arthritis is initially treated with NSAIDs. If irAE-arthritis progresses to moderate or severe stages, CSs are typically initiated and ICI(s) may need to be withheld. In cases where irAE-arthritis does not adequately respond to CSs or the steroids cannot be tapered off (termed steroid resistance), steroid-sparing DMARDs are administered (112).

For severe irAEs or cases exhibiting inadequate responses to csDMARDs, biologic DMARDs (bDMARDs) may be considered. Over the past two decades, the development of selective immune-targeted therapeutics based on pathogenesis-driven principles has significantly expanded the therapeutic options available for various rheumatic diseases. Numerous monoclonal antibodies targeting key pro-inflammatory cytokines and immune cells have been proven effective against chronic rheumatic conditions while maintaining an acceptable safety profile (113). Notably, for arthritis cases, TNF and IL-6 blockade have been successfully employed. These two target cytokines play central roles in the immunopathogenesis of irAE-arthritis.

In recent years, a new category of DMARDs has emerged, known as targeted synthetic DMARDs (tsDMARDs), primarily consisting of the Janus Kinase (JAK) inhibitors. Clinical studies have reported that JAK inhibitors can be effective in treating ICI-related axial or peripheral arthritis (111). The activation of JAKs leads to the downstream activation of signal transducer and activator of transcription (STAT) proteins, which subsequently translocate to the nucleus to activate target genes (139). IL-6 is one of the cytokines that exerts its effects through the JAK/STAT pathway. Additionally, type I interferons transmits signals through JAK1 and JAK3, while type II interferon (IFN-γ) transmits signals through JAK2 (140). Considering the intimate relationship between the JAK/STAT pathway and inflammatory cytokines such as IL-6 and IFN (86), it is reasonable to hypothesis that JAK inhibition may aid in managing ICI-related adverse events. Indeed, preclinical studies have demonstrated that combining JAK inhibition with ICIs may help overcome resistance to ICI therapy, possibly through mitigating inflammation within the tumor microenvironment (141).

While various treatment options are currently available for irAE-arthritis, these therapies still have limitations, and further large-scale controlled studies are necessary to confirm their efficacy and safety. Additionally, there is an urgent need for the development of new therapeutic targets based on the underlying mechanisms of the irAE-arthritis.