According to our findings, the incidence of irAEs is higher in AID group than non-AID group under ICIs treatment. Specifically, AID-homogeneous irAEs are more likely to occur in AID group than non-AID group, whereas no significant difference was detected on AID-heterogeneous irAEs. The survival outcomes in AID group are almost unaffected compared to non-AID group. As far as we know, we are the first to study what kinds of irAEs AID patients are prone to and compare PFS and OS in cancer patients with and without autoimmune disease under ICIs therapy, filling a gap in previous studies of this kind.
As mentioned above, there is a close relationship among cancer, autoimmune diseases and immune-related adverse events. Immune checkpoint is a class of immunosuppressive molecules expressed on immune cells to regulate the degree of immune activation. Normally, effector function of CD4+ T cell remains stable due to the presence of immune checkpoints. Once the negative signal regulating T cell activation is suppressed, it would strengthen the T cells killing function. At the same time, it may also enhance the immune response to the body’s normal tissues. This process resembles to that of autoimmune diseases recognized by existing theories although the pathogenesis of autoimmune diseases is still incompletely understood. Hence, it is reasonable to worry about exacerbating autoimmune diseases in the administration of ICIs. Owing to the abnormalities of immune system in patients with autoimmune disease, T cell activation levels are higher than normal people. ICIs further promoted T cell function so that the balance of immune system was broken, which can easily lead to irAEs. It may partly explain the high incidence of irAEs in AID patients. The major pathological and clinical manifestations of autoimmune diseases are mainly manifested in which system, indicating that the immune cells of this system are in abnormal activation state. The immune cells of the other systems are generally in a normal state, so the frequency of irAEs is similar to that in normal people. Clinicians are suggested to pay more attention to irAEs of the same system as the pre-existing AID.
Although AID patients are at a higher risk to develop irAEs, no statistically significant reduction in PFS and OS were observed in AID group compared to non-AID group. In other words, the curative effect of ICIs in patients with AID is worthy of affirmation. This may suggest that the abnormal immune system of autoimmune disease does not affect the killing function of T lymphocyte on tumor cells, or the aggravation of irAEs does not shorten the survival of AID patients. Considering some of the irAEs could be fatal, one question is how to control the irAEs occurring during treatment. Clinically, immunosuppressants like steroids are commonly used to control irAEs. Since only 2 studies have talked about the use of immunosuppressants to control irAEs, we cannot rely on the limited data to analyze the accurate results[15,19]. Zhang et al. finding showed that the OS and PFS were significantly shortened in the administration of corticosteroids . However, Fausto et al. results indicated that using steroids in cancer patients to control irAEs did not shorten OS[33,34]. There are no definitive answers on whether, when and how to use steroids in the treatment of ICIs. Therefore, it is necessary to perform patient stratification strategies depending on irAEs severity to determine next treatment.
Previous studies reported that irAEs were significantly related to a better curative effect in cancer patients[36-40]. So some clinicians doubt that AID patients may benefit more under ICIs for there is an immune-activated tendency in these patients. Although our findings showed AID patients had a higher risk to develop irAEs, we did not draw a conclusion that the survival would be prolonged in AID group. All of the above studies were conducted in non-AID cancer patients, unlike the population we studied. Moreover, many factors can affect the final PFS and OS. First, ECOG status of cancer patients, it is necessary to evaluate the survival time separately according to the performance of ECOG status. Second, different autoimmune diseases could have mild or severe effects on one’s body. For instance, systemic lupus erythematosus (SLE) can affect nearly all kinds of organs and produces multiple autoantibodies, whereas psoriasis does relatively minor impairment for other systems.
The limitations are following. First, because most studies did not use ICIs in AID patients, the number of included studies was not sufficient. Second, most of the data collected were from retrospective studies rather than prospective clinical trials, so the veracity of the information may be not objective enough. Third, the included studies were mainly conducted in Asia and Europe, so geographical and ethnic differences could not be excluded. Fourth, most of the malignancies included in the study were NSCLC and melanoma, but few of the other cancers were involved. In addition, 6 of the studies only reported survival curves, so HR was estimated from the survival curve using specialized tools，so there may be a certain degree of deviation from the actual situation.