Immune-related adverse events after immune checkpoint inhibitor exposure in adult cancer patients with pre-existing autoimmune diseases

Immune checkpoint inhibitor (ICI) therapy can predispose patients to immune-related adverse events (irAEs) and autoimmune disease (AD) flare-ups, but the characteristics of irAEs among patients with pre-existing ADs are largely unknown. We conducted this study to determine the clinical courses, irAEs, AD flares, treatment, and outcomes of patients with AD on ICIs. This was a retrospective study of adult cancer patients at a large cancer center who were diagnosed with ADs before undergoing ICI therapy. Patients’ clinical courses, complications, treatments, and outcomes related to both ADs flares and irAEs were collected and analyzed. The study included 197 patients. Most (55.4%) were women. Melanoma comprised the highest proportion (28.4%) of malignancies, and most (83.8%) patients received PD-1/PD-L1 inhibitors. Fifty (25.3%) patients developed a new irAE after starting ICI therapy, while 29 (14.7%) patients had an AD flare-up. Patients with inflammatory bowel disease had the highest incidence of AD flare-ups (31.7%), while patients with Hashimoto hypothyroidism had the highest incidence of new irAEs (39.2%). Patients with inflammatory bowel disease had more severe adverse events. In our cohort, patients with a new diagnosis of irAE were treated with immunosuppressive therapy. AD flares were managed similarly. With regard to irAE manifestations, the most common presentations were colitis (24 [12.1%] patients), hepatic transaminase elevations (8 [4%] patients), and pneumonitis (7 [3.5%] patients). Our findings suggest that patients with gastrointestinal and rheumatologic ADs had a higher incidence of AD flare-ups, while patients with Hashimoto hypothyroidism and neurologic ADs had a higher incidence of new irAEs. Patients with prior ADs experiencing flare-ups or new irAEs after ICI therapy tend to require aggressive immunosuppressive treatment. Thorough evaluation of baseline disease status, appropriate medical management before ICI therapy, and early recognition of inflammatory exacerbation may help ensure long-term success in treating and improving outcomes in these patients.


Introduction
Immune checkpoint inhibitors (ICIs) are an essential component in the treatment of advanced solid tumors and improve patient survival. To date, multiple ICI therapies inhibiting the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathways have been approved. While their survival benefit is well recognized, these agents also produce unique adverse events (AEs), especially in those with pre-existing autoimmune diseases (ADs); therefore, the safety profile of these therapies in this patient population remains a concern and a major reason for ICI therapy to be contraindicated. However, evidence about the safety of ICI therapy among patients with pre-existing ADs remains scarce.
ADs include over 50 disorders that share a common pathophysiology: inappropriate activation of the immune system, which leads it to attack the body's own organs (Rose 2016). By stimulating the activity of the immune system, ICI therapy may lead to immune-related AEs (irAEs), which show many clinical manifestations and pathophysiologic features similar to those of ADs (Kennedy et al. 2019). Although the exact mechanism of these irAEs has yet to be elucidated, the role of PD-1 and CTLA-4 in autoantigen tolerance has been widely recognized (Wieder et al. 2018;Zamani et al. 2016;Zhang and Vignali 2016); therefore, ICIs could theoretically exacerbate pre-existing ADs while also triggering irAEs. One possible link between irAEs and ADs is their effect on autoantibody production. For example, some of the autoantibodies that are present in ADs such as thyroid and lupus disorders could be affected in patients who have undergone ICI therapy. When Moel et al. (2019) screened 133 samples from patients with advanced melanoma before and after treatment with ipilimumab, they found that around 19% of patients who tested negative for anti-thyroperoxidase and anti-thyroglobulin before treatment tested positive for these autoantibodies after treatment (Yeung et al. 2021).
In light of this information and given the increasing reliance on ICIs for the treatment of many different cancer types, it is especially important to understand the influence of previous ADs on ICI treatment outcomes. Previous research has shown that the efficacy of ICI therapy is equivalent in patients with and without pre-existing ADs (Tang et al. 2021;Yeung et al. 2021); however, patients with AD are often excluded from clinical trials and research out of concern for their higher risk of developing irAEs (Tang et al. 2021). One meta-analysis suggested that the incidence of irAEs could be higher in patients with previous ADs and that patients with pre-existing ADs had more hospitalizations and complications than patients with no ADs .
Given this knowledge gap, the objective of this study was to expand our understanding of AD-related outcomes following ICI exposure and explore the risk of new irAE development among this population.

Study design and population
This retrospective chart review was a descriptive, singlecenter study that included patients aged 18 years or older who had cancer and who received ICI therapy at The University of Texas MD Anderson Cancer Center from 10/01/2014 to 04/30/2021. All patients included in the study had a confirmed AD diagnosis before the start of ICI therapy (Fig. 1). We identified patients aged 18 years or older who (1) were treated with ICI for various types of cancer and (2) had a diagnosis of autoimmune disease prior to the cancer diagnosis based on the past medical history. Patients excluded (1) were patients aged less than 18 years old and (2) did not have a past medical history of AD (Fig. 1). This study was approved by the Institutional Review Board with a waiver of patients' informed consent.

Clinical data
From the patients' electronic medical records, we extracted demographic and cancer-related information, such as patient age, sex, primary cancer type, stage, cancer treatments and doses received, and Charlson Comorbidity Index scores; AD-related information, including the organ or organ systems affected, type of diagnosis, medical and surgical treatments received, AD status before ICI initiation (based on changes in symptoms and/or treatments), AD flare-up after ICI (such as worsened clinical symptoms to higher CTCAE grade, worsened laboratory abnormalities, need to increase the dose of his previous medication or switch to different regimen from the same organ of AD), and treatment; and irAE information after ICI therapy, dates of irAEs occurrence, need for hospitalization, irAE treatment complications, and outcomes. We label the new onset of inflammatory condition from the organ without pre-existing AD as irAEs. AD was defined according to the codes in the International Classification of Diseases, 9th and 10th editions. IrAE severity was defined according to the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 5.0.

Statistical analysis
The statistical analyses performed were descriptive in nature. The distributions of continuous variables were summarized using medians and interquartile ranges. The distributions of categorical variables were summarized using frequencies and percentages. Calculations were performed using SPSS software, version 26.

Patient population
From October 1, 2014, to April 30, 2021, 13,991 patients at MD Anderson Cancer Center received therapy with at least 1 of the following ICI agents: ipilimumab, nivolumab, cemiplimab, pembrolizumab, tremelimumab, atezolizumab, durvalumab, and avelumab. Of that total, we identified 197 eligible patients who had been diagnosed with AD before receiving their first ICI dose (Fig. 1).

AD disease course
Among all included patients, rheumatological pathologies (i.e., rheumatoid arthritis, which affected 58 [29.4%] patients) were the most prevalent ADs reported followed by endocrinological pathologies (i.e., Hashimoto hypothyroidism, which affected 51 [25.8%] patients) and gastrointestinal disorders, (i.e., microscopic colitis, inflammatory bowel disease, and celiac disease, which affected a total of 30 patients [15.2%]). Patients were reported with AD at a median of 13 months before cancer diagnosis ( Table 1). Most of the patients did not have AD symptoms at the time of ICI treatment initiation. Exceptions were all 27 patients in the neurological AD subgroup (3 of whom were receiving active treatment for their AD) and 1 patient in the gastrointestinal subgroup (Table 2). Nineteen (9.6%) patients were receiving systemic steroids (e.g. prednisone) with a dose of > 10 mg per day at the time of ICI initiation.
After ICI therapy, 29 patients had an AD flare-up. These flare-ups were most common among patients with gastrointestinal AD, 14 (46.6%) of whom had a flare-up. Among the patients with gastrointestinal AD, flare-ups were more common in patients with previous microscopic colitis (8 of 10 patients with flare-ups). Of the 58 patients with rheumatoid arthritis, 15 (25.8%) patients had a flare-up. Only 2 (3.9%) of the 51 patients in the endocrinological AD group had an AD flare-up (Table 2).

IrAEs
New irAEs, all of which occurred within 3 months of the last ICI dose, are summarized by organ system in Table 3 and Fig. 2A. Colitis was the most common new irAE and occurred in 24 (12.1%) patients. This was followed by hepatobiliary irAEs (elevated transaminases) in 8 (4%) patients and pneumonitis in 7 (3.5%) patients. A small number of patients developed irAEs from other organ systems such as the kidneys (nephritis), muscles (myositis), joints (arthritis), and the nervous system (hypophysitis) ( Table 4).

Treatments and outcomes
Almost all patients who developed a new irAE received immunosuppressive treatment, the only exception being patients with rheumatoid arthritis, of whom 75% received immunosuppression. Among the patients who received immunosuppression, steroids were used in 38 patients (97.4%), and biologics such as infliximab and vedolizumab were used in 19 (487%) patients. Of the patients with irAEs, 23 patients with colitis received steroids, 14 of whom were also treated with biologics; 7 patients with the hepatobiliary disease received both steroids and biologics; 7 patients with pneumonitis were treated with steroids only; and 2 patients with neurological irAEs received steroids only. Of the patients with AD flare-ups, 11 patients received steroids and 15 patients received biologics. Interestingly, only the patients with Hashimoto hypothyroidism flareups (2 patients) did not require immunosuppression; they only needed adjustment of their baseline dose of levothyroxine. Of the patients with a rheumatoid arthritis flare, 15 patients received steroids and 6 of them also received biologics. Of the patients with a colitis flare-up, 6 patients received steroids and 8 patients were treated with steroids and biologics.

Discussion
The development of irAEs is a common limiting factor in the effective usage of ICI therapy, yet the mechanisms for the pathogenesis of irAEs have not been clearly defined. This makes it especially important to understand the relationship between ADs, which involve an exaggerated immune response, and ICI treatment outcomes, including irAEs. CTLA-4 cytotoxic T lymphocyte-associated protein 4, IQR interquartile range, PD-1 programmed cell death protein 1, PD-L1 programmed cell death ligand 1 a The cohort included 9 African American, 4 Asian/Middle Eastern, 21 Hispanic, and 163 White patients b The cohort included 9 patients with oral cavity cancer, 5 patients with breast cancer, 4 patients with thyroid cancer, and 2 patients with prostate cancer Table 2 Summary of AD flare-up characteristics by AD-affected organ system (N = 197)  AD autoimmune disease, CTLA-4 cytotoxic T lymphocyte-associated protein 4, IBD inflammatory bowel disease, GBS Guillain-Barré syndrome, ICI immune checkpoint inhibitor, ITP immune thrombocytopenia purpura, MS multiple sclerosis, PD-1 programmed cell death protein 1, PD-L1 programmed cell death ligand 1, TM transverse myelitis *All patients had low AD activity at baseline, the time of ICI initiation. Flare-ups occurred when the symptoms progressed from baseline activity and/or changes in the treatment were made In this study of patients with pre-existing ADs, we found that 14.7% had an AD flare-up and 25.3% developed a new irAE after undergoing ICI therapy for cancer. Of note, it is known that patients with a previous diagnosis of ADs are at risk of developing cancer, yet in those who develop the disease, treatment with cytotoxic chemotherapy can further dampen the activity of the immune system. Therefore, the incidence of AD flare is lower in patients treated with cytotoxic chemotherapy than in those treated with ICI therapy (Kumar et al. 2022).
Given the limited literature available on the clinical courses, complications, treatments, and outcomes of adult cancer patients with pre-existing ADs following ICI treatment, the current practice is to be cautious with the use of ICIs in patients with pre-existing ADs for fear of triggering an AD flare-up. The reported incidence of AD flare-ups in this population ranges between 18 and 52% and depends on many factors, such as the type of ICI administered or the type of pre-existing AD present (Leonardi et al. 2018;Tison et al. 2019;Hoa et al. 2021;Srinivas and Bajpai 2021). The incidence of AD flare-ups is frequently higher in patients with more active AD at baseline (Leonardi et al. 2018), while in our cohort, the majority of the patients had quiescent AD status given that only 9.6% were receiving systemic steroids at ICI starting. In addition, flare-ups after ICI therapy were most frequent in patients with gastrointestinal ADs, especially those with previous microscopic colitis and inflammatory bowel disease; the flare-up incidences  . 2 A Relationship between pre-existing AD and new irAE locations based on the organ or organ system involvement of new irAEs. B Relationship between pre-existing AD and new irAE locations based on the organ system involvement of pre-existing ADs were 80% and 31.7%, respectively, in these patients. Studies of patients with previous ADs who underwent ICI therapy (Leonardi et al. 2018) have shown that flare-up treatment (e.g., topical steroids, systemic steroids) varies; however, offering patients no treatment or supportive treatment is the most common approach. In our study, 11 patients received steroids and 15 patients received biologics for AD flare-ups. The relationship between receiving treatment for an AD flare while on ICI therapy to provide adequate control of the disease and the occurrence of irAEs has not been studied. Acquiring more knowledge of this subject will allow for the risk stratification of patients prior to the initiation of ICI treatment to predict the likelihood of an AD flare-up. In the future, this strategy will be essential in effectively guiding ICI use in patients with pre-existing ADs.
One of the main concerns about using ICIs in patients with underlying ADs is uncertainty regarding the potential for irAEs. IrAEs are the most common reason for ICI discontinuation, so it is important to explore the relationship between ADs and irAE development. In our cohort, the incidence of new irAEs was 25.3%, which is considerably higher than that in the general population. There is some evidence to suggest that a history of AD may predispose patients to the development of irAEs (Michailidou et al. 2021;Plaçais et al. 2022). One study mentioned that rheumatologic irAEs may be more common in patients with cutaneous or gastrointestinal ADs (Hoa et al. 2021). Similarly, our study showed an idiosyncratic AD-irAE cluster. Patients with endocrinological ADs most frequently developed new irAEs and were the only group to develop neurologic irAEs. The underlying mechanism behind these associations remains understudied. One study suggests that genetic polymorphisms in the PD-1 and CTLA-4 genes are linked to the development of ADs and could potentially play a role in the onset of irAEs (Abdel-Wahab et al. 2018). Another study indicated that patients with previous endocrinological ADs who exhibited endocrine autoantibodies were far more likely to develop endocrine irAEs than were patients without those antibodies (Labadzhyan et al. 2022). As such, there may be a general predisposition to both AD and irAEs or pre-existing ADs could directly increase the risk of developing a new irAE.
Treatment with glucocorticoids is the standard means of managing moderate-to-severe, newly developed irAEs. It has been proposed that corticosteroids induce transient lymphocytopenia by altering lymphocyte recirculation, promoting lymphocyte death, and -most importantlyinhibiting cytokine and effector molecule production, limiting T-cell activation (Fauci 1983). Typically, patients with irAEs are treated with 1 to 2 mg/kg/day of prednisone or methylprednisolone (Brahmer et al. 2018) and nonsteroidal immunosuppressants or immunomodulators, such as biologic agents (e.g., infliximab), are added in select cases to achieve more potent immunosuppression (Luo et al. 2021).  Patients exposed to high-dose steroids, the use of which is especially common in patients with ADs or irAEs, are at risk for a variety of side effects. In Mouri et al.'s (2021) study of patients with irAEs who were treated with systemic steroids, interstitial lung disease, adrenal insufficiency, and diarrhea were among the most common side effects. The steroid-sparing effects of selective immunosuppressive therapies, such as biological therapies, make them an attractive alternative to steroids. Although their use may prevent the patient from suffering from the side effects associated with steroid use, they have their own disadvantages, and there is not enough evidence to recommend using them as first-line treatment for ADs and irAEs. As a result, the decision on the type of immunosuppression to initiate varies on a caseby-case basis, and more research is needed to establish the ideal treatment regimen.
The efficacy of ICI therapy is well established except in patients with a history of ADs, who have been excluded from most clinical studies. However, one systematic review of 17 articles found that cancer outcomes in ICI-treated patients with and without ADs were comparable (Tang et al. 2021) while another found that ICI therapy was even more effective in patients with ADs. On their own, irAEs have been shown to confer a survival benefit in the general population (Wang et al. 2018). Similarly, AD flare-ups following ICI therapy also improve patient survival (Kumar et al. 2022). This is likely because irAEs and AD flare-ups reflect a strong immune response to ICI treatment and, hence, a more potent effect. To the best of our knowledge, though, no studies have looked at the effect of both irAEs and AD flare-ups on survival; rather, the focus has been on their individual associations with survival. Therefore, in future studies, it would be interesting to investigate whether patients who develop both an irAE and an AD flare have better treatment outcomes than patients with only one of these developments.
A pre-existing AD is not necessarily an absolute contraindication to ICI therapy. We advocate not withholding ICI treatment from cancer patients with pre-existing ADs who would otherwise be candidates for the therapy, as ICI therapy may be beneficial to these individuals. In such cases, it would still be important to closely monitor for potential irAEs and AD flares, especially because patients with preexisting ADs represent a not-inconsequential proportion of cancer patients. A large registry-based analysis of surveillance, epidemiology, and end results data, which included 210,509 patients with lung cancer, identified 24.6% of these patients as having an AD of any type (Coureau et al. 2020). The most frequent ADs were rheumatoid arthritis (5.9%), psoriasis (2.8%), polymyalgia rheumatica (1.8%), Addison disease (1%), systemic lupus erythematosus (0.9%), ulcerative colitis (0.8%), giant cell arteritis (0.8%), sicca syndrome (0.6%), regional enteritis (0.5%), and Ménière disease (0.5%) (Khan et al. 2016). A study by Gulati et al. (2021) showed that female patients with melanoma and a pre-existing AD who received ICI therapy had improved overall survival. This evidence shows the importance of better understanding the use of ICI therapy in patients with pre-existing ADs.
This study is noteworthy for being the largest study to date of patients with cancer and pre-existing ADs who underwent ICI therapy. However, it has some limitations. First, it involved a single center and was retrospective in nature, and its results depended upon the availability of information in the patients' medical records. Second, its small sample size limited the power of the subgroup analysis. Third, the data were generated from a tertiary cancer center that sees more advanced cancer conditions and possesses better resources, expertise, treatment options, and support than many other treatment centers. As a result, our findings may not be generalizable to patient populations and medical practices outside our cancer center. Since our institution is dedicated to cancer care, the general management of patients offered at our institution may differ widely from the general management of patients offered at other centers.

Conclusions
ADs are fairly common in the general population and are even more common in patients with a previous diagnosis of cancer. We found that 14.7% of patients had a flare of their pre-existing AD after being treated with ICI therapy, and 21.3% of our cohort developed a new irAE. Our findings suggest that patients with gastroenterological and rheumatological ADs experience more frequent disease flare-ups, while patients with thyroid ADs more frequently develop new irAEs. Early recognition and prompt management are essential to mitigate the effects of these immune sequelae. Further prospective studies are warranted to clarify the triggering factors for both AD flares and irAEs as well as identify potential markers to predict irAE and flare onset.
Author contributions YW was the senior author of the study. She developed the concept, designed the study, interpreted the results, ensured the preservation of data accuracy and integrity at all stages, agreed to be accountable for all aspects of the study, oversaw the overall direction and planning of the study, and contributed to the writing of the manuscript with input from all authors. APM and MS collected the data and created tables/figures. The rest of the authors revised the manuscript. All authors had access to the study data and reviewed and approved the final manuscript.
Funding Supported by the NIH/NCI under award number P30CA016672.

Data availability
The data sets used and analyzed in this study are available from the corresponding author upon reasonable request.