From our findings, the incidence of irAEs was higher in the AID group than in the non-AID group treated with ICIs. Specifically, AID-homogeneous irAEs are more likely to occur in the AID group than in the non-AID group, whereas no significant difference was detected for AID-heterogeneous irAEs. Survival outcomes in the AID group were almost unaffected compared to those in the non-AID group. To the best of our knowledge, we are the first to study types of irAEs that AID patients are prone to, and compare PFS and OS in cancer patients with and without AID on ICI therapy, thus filling a gap in previous studies of this kind.
As mentioned above, close relationship exists between cancer, autoimmune diseases, and immune-related adverse events. Immune checkpoints are a class of immunosuppressive molecules expressed on immune cells to regulate the degree of immune activation. Normally, the effector function of CD4+ T cells remains stable owing to the presence of immune checkpoints. Once the negative signal regulating T-cell activation is suppressed, T cells killing function is strengthen. Simultaneously, this may also enhance the immune response in normal body tissues. This process resembles that of AIDs recognized by existing theories, although the pathogenesis of AIDs is not fully understood. Hence, the fear of exacerbating AIDs during ICI administration is valid. Owing to abnormalities in the immune system of patients with AID, T cell activation levels are higher than those in normal individuals. ICIs further promote T cell function such that the balance of immune system is disrupted, which can easily cause irAEs to occur. This may partly explain the high incidence of irAEs in patients with AIDs.
The major pathological and clinical manifestations of AIDs mainly manifest in the system, indicating that the immune cells of this system are in an abnormal activation state. The immune cells of other systems are generally in a normal state; hence, the frequency of irAEs is similar to that in normal people. Clinicians should pay more attention to irAEs of the same system as pre-existing AID.
Although patients with AID are at a higher risk of developing irAEs, no statistically significant reduction in PFS and OS were observed in AID group compared to the non-AID group. Meanwhile, the curative effect of ICIs in patients with AID is worthy of affirmation. This may suggest that the abnormal immune system in AID does not affect the killing function of tumor cells by T lymphocytes, or aggravation of irAEs does not shorten survival of AID patients. Considering the fatality of some irAEs, means of controlling the occurrence of irAEs during treatment is yet to be determined. Clinically, immunosuppressants such as steroids are commonly used to control irAEs. Since only two studies have discussed the use of immunosuppressants to control irAEs, we cannot rely on the limited data to accurately analyze results[15, 19]. Zhang et al. found that the OS and PFS were significantly shortened in the administration of corticosteroids . However, Fausto et al. indicated that the use of steroids in cancer patients to control irAEs did not shorten OS[33, 34]. There are no definitive answers on whether, when and how steroids should be used in treatment with ICIs. Therefore, it is necessary to perform patient stratification strategies based on the severity of irAEs to determine subsequent treatment.
Previous studies reported that irAEs significantly correlated with better curative effect in cancer patients[36–40]. Therefore, some clinicians doubt that patients with AID may benefit more from ICIs because of their immune-activated tendency. Although our findings showed that patients with AID were at higher risk of developing irAEs, we did not conclude that the survival would be prolonged in the AID group. All the above studies were conducted in non-AID cancer patients, unlike the population we studied. Moreover, several factors can affect final PFS and OS. First, regarding the ECOG status of cancer patients, it is necessary to evaluate the survival time separately, according to the performance of ECOG status. Second, various AIDs may have mild or severe effects on the body. For instance, systemic lupus erythematosus (SLE) can affect nearly all organs and produces multiple autoantibodies, whereas psoriasis causes relatively minor impairments in other systems.
This study has some limitations. First, because most studies did not use ICIs in patients with AID, the number of included studies was insufficient. Second, most data collected were from retrospective studies rather than prospective clinical trials; therefore, the veracity of the information may not be sufficiently objective. Third, the included studies were mainly conducted in Asia and Europe; therefore, geographical and ethnic differences could not be excluded. Fourth, most of the malignancies included in the study were NSCLC and melanoma, with only few other cancers involved. Furthermore, six studies only reported survival curves; hence, HR was estimated from the survival curve using specialized tools. Thus, there may be a certain degree of deviation from the actual situation.