In the present study, we conducted a meta-analysis of six reports to elucidate the influence of ICI therapy on irAEs in patients with PAD. We observed that PAD was significantly associated with a higher risk of irAE incidence (OR = 2.14). The incidence of irAEs in the PAD group was 62.1%, which was similar to a previous pooled analysis (60%) that included PAD single-arm observational studies . Therefore, we believe that the population of this study was relevant in evaluating the risk of irAEs. Furthermore, the results of our subgroup analysis were similar to those of the main analysis. The heterogeneity among studies was low, and the integrated effects were significant, suggesting that the results of our meta-analysis could be generalized. Our statistical test (Begg’s test and Egger’s test) revealed that publication bias was low. In the funnel plot, it was difficult to assess symmetry owing to a lack of data on the base side; therefore, additional studies are needed.
In a previous report, Bender et al. have researched hospitalization rates, which implied clinically severe cases, in patients with melanoma receiving PD-1 inhibitors and showed that PAD significantly increased the hospitalization rates when compared with non-PAD cases (24.1% vs. 5.8%, p < 0.0001) . In another study, PAD was reportedly associated with hospitalization following irAE diagnosis (HR 1.81, 95%CI [1.21–2.71], p < 0.05) . These reports support our results and suggest that irAE management in patients with PAD is more challenging than that in non-PAD patients, necessitating additional monitoring of symptoms and statements for appropriate ICI therapy. In the present study, the association between PAD and severe irAEs was not evaluated. Thus, further studies, such as a meta-analysis of hospitalization in patients with PAD during ICI treatment, are required.
In clinical settings, an autoimmune disease can develop owing to an increase in autoantibodies such as rheumatoid factor in rheumatoid arthritis, antithyroglobulin antibody, thyroid-stimulating hormone (TSH) receptor antibody in autoimmune thyroid disease, and antinuclear antibody (ANA) in connective tissue disease. Hence, it is considered that preexisting autoantibodies are also associated with irAE incidence and may be valuable clinical biomarkers. Indeed, a study was conducted to assess whether preexisting autoantibodies were associated with the safety and efficacy of ICI treatment in patients with non-small cell lung cancer and revealed that these preexisting antibodies were associated with irAE incidence, and ICI efficacy was higher in patients with any of the preexisting antibodies . The study also supports our results that PAD increases the risk of irAEs, although autoantibodies do not consistently result in an autoimmune disease. Conversely, ANA was not associated with any grade irAEs, although only a small number of patients were evaluated . The efficacy tended to be superior in patients without ANA, which was not statistically different . Further research is required to elucidate the association between PAD, preexisting autoantibodies, and irAE incidence.
In the present study, Cortellini et al. reported that the incidence rate of irAEs of any grade was significantly higher in patients with inactive and active PAD than in those without PAD (64.3%, 73.3%, and 39.9%, p = 0.0001 and p = 0.0402, respectively) . This rate was similar to that observed in the systematic review of patients with inactive and active PAD (67% and 75%, respectively) . Based on these findings, it can be suggested that the incidence of irAEs is related to PAD, regardless of the baseline autoimmune disease activity.
In general, autoimmune diseases are caused by environmental and genetic factors. The accumulation of these triggers induces the breakdown of immune tolerance and the production of autoreactive B cells, T cells, and autoantibodies, which lead to excessive activation of both innate and adaptive immune cells. Finally, the aberrant immune system induces chronic inflammation and organ-specific or systemic damage [20, 21]. Additionally, autoimmune diseases cause various systemic symptoms. For example, inflammatory bowel disease presents extraintestinal manifestations such as in the joints, skin, or eyes , and rheumatoid arthritis is a risk factor for interstitial lung disease , indicating that the immune reactions occur in various tissues in autoimmune diseases, like irAEs. Consequently, we propose a potential mechanism of irAE development in patients with PAD. First, patients with PAD present systemic immune state instability, although clinical symptoms may be absent. The administration of ICIs blocks the immune checkpoint pathways and enhances T-cell effector function. Finally, T-cell activation can easily disrupt the balance of the immune system owing to the fragility of the host immune state, inducing flares of autoimmune disease and systemic irAEs. However, the molecular mechanisms involved, such as regulatory T cells, interleukin (IL), and tumor necrosis factor-alpha (TNF-α), remain elusive. Further basic research is required to reveal detailed underlying mechanisms.
To avoid irAEs in patients with PAD, immunosuppressive therapy during the early stages may be effective. In the previously discussed systematic review, patients receiving immunosuppressive therapy at the initiation of ICI treatment demonstrated a marginally lower incidence rate of irAEs than those without treatment (67% vs. 74%) . In contrast, baseline corticosteroid use (≥ 10 mg) was associated with worse progression-free survival (hazard ratio, 1.31; 95% CI [1.03–1.67], p = 0.03) and overall survival (hazard ratio, 1.66, 95% CI [1.28–2.16], p < 0.01) . Therefore, it is necessary to consider corticosteroid administration in patients with PAD depending on symptom severity.
This study has some limitations. First, the number of included reports was small, and four out of six studies used secondary outcome data. Therefore, the quality of evidence was low, and the evaluation of the funnel plot symmetry might have been insufficient, indicating a potential publication bias. Second, the treatment type (ICI monotherapy or combination with cytotoxic chemotherapy or molecular targeted therapy) was not described in some studies. Third, patient characteristics (cancer type, treatment agent, and PAD type) were not unified, and baseline characteristics were not balanced in the meta-analysis. In general, autoimmune diseases are common in women, which may affect the incidence rate of irAEs, although baseline characteristics did not affect irAE incidence . Additionally, we were unable to determine the relationship between these factors and irAEs. Fourth, the severity of irAEs was not evaluated. Although the frequency of irAEs and hospitalization rates were increased in patients with PAD, further investigations on severe irAEs are required. Finally, the reported irAEs in patients with PAD might have included PAD flare and de novo irAEs, which were not described in detail in the included studies. It is difficult to assess whether the PAD flare could be attributed to ICI treatment. Thus, we might have overestimated irAEs in patients with PAD.
In conclusion, we performed a meta-analysis and identified that PAD is a risk factor for irAE incidence. We believe that this study suggests the importance of carefully monitoring patients with PAD receiving ICIs for early detection with appropriate countermeasures. Accordingly, the establishment of co-treatments and suitable strategies to promptly collect information regarding patient conditions are required.