Our results indicate that prevalence of autoimmunity increases by age, consistent with prior work and hypotheses in gerontology.13,14 In two multiple regression analyses, age >75 years old and Medicare status were factors that were strongly associated with autoimmunity. Patients with a history of non-cutaneous cancers compared to those without a history of non-cutaneous cancers had significantly higher prevalence of autoimmunity. History of both melanoma and non-cutaneous cancer exhibited the highest association with autoimmunity out of all potential factors. The data suggest that advanced age and non-cutaneous cancer each have an association with autoimmunity.
Our findings may be linked to the biological underpinning of aging physiology. Increased tumor burden, either in metastatic disease or advanced age, are likely associated with pro-inflammatory cytokines that contribute to autoimmunity.15,16 Aging is shown to promote the ability of CD4+ T cells to generate an IL-17 response that promote autoimmunity in humans.17 Tumor neoantigens have been linked to immune responses that have capacity to cross react with host tissues. Scleroderma is a well-studied example wherein patients diagnosed with lung cancer can develop interstitial lung disease through unique antibodies to tumor epitopes.18 Similarly, there are associations between occult malignancy and dermatomyositis, polymyositis, rheumatoid arthritis, and systemic lupus erythematosus.19,20 In fact, it has been posited that autoimmunity, in the absence of a known trigger, such as infection, may be reactive to an occult malignancy.21 This theory would provide some rationalization as to why rates of autoimmunity were high in patients with both benign and malignant cancers. Additionally, autoimmune disorders can promote an inflammatory state that leads to cancer, particularly in lymphomas.
While the connection between aging, cancer, and autoimmunity is well-established, this is the first large-scale observational study to our knowledge that analyzed how these clinical factors are relatively associated with autoimmunity. Current NCCN Guidelines for irAEs offer some guidance regarding ICI use in specific patient populations.22 For example, patients with neurologic and life-threatening autoimmune disease are recommended against receiving therapy. Recommendations for senior patients, however, are not included. Our findings serve to provide high-power, real-world data that suggest senior patients may be at higher risk for irAEs.
The marked increase in autoimmunity odds observed at age 75 suggest that age may not impact autoimmunity linearly. Instead, a critical age may be reached where there is age-associated immune dysregulation characterized by immunosuppression and autoimmunity. This is older than the empiric age of 65 years often used to define older adults in clinical trials. Patients greater than 70-80 years of age were shown to have a higher incidence of severe irAEs and irAEs overall in multiple small case reports, but the differences found were insignificant, possibly due to low power.11,23-25 While we did not study irAEs and survival, the significantly increased prevalence of autoimmunity among patients aged 75 and older implies that this group might be at higher risk for irAEs, because pre-existing autoimmunity has previously shown to increase this risk.3,4 Thus, close monitoring of irAEs may be useful in senior patients, as they are increasingly becoming eligible for ICI therapy, and autoimmune manifestations of underlying disease may be atypical, undiagnosed, or occult in this population.13
There do not exist many epidemiologic studies on autoimmune prevalence, and ones on cancer patients are often limited to select autoimmune conditions. Our results are consistent with a 2012 meta-analysis by Hayter and Cook done on autoimmunity data over 20 years, which found that the most common autoimmune conditions, rheumatoid arthritis and type 1 diabetes, have a worldwide prevalence of about 1%.26 Our overall autoimmunity prevalence of 7.3% is within the range of the NIH’s 2005 estimate in the U.S. (5-8%), but higher than the worldwide estimate from Hayter’s meta-analysis (4.6%).26, 27 Our dataset notably looked at 99 conditions instead of a list of 81 conditions reported previously by Hayter. As with all EHR studies, there are potential diagnostic inaccuracies that may impact our results. For example, urticaria secondary to an allergen can be incorrectly coded as “idiopathic” (ICD-9: 708.1, ICD-10: L50.1) when the condition should have been coded as “allergic urticaria” (ICD-9: 708.0, ICD-10: L50.0).
Our data demonstrate that cancer patients have a higher prevalence of autoimmunity compared to the non-cancer patient population. Cancer patients have an increased risk of subsequent autoimmunity, such as in paraneoplastic syndromes, and patients with certain autoimmune conditions have an increased risk of cancer.28,29 As autoimmune diagnoses were largely coded in the database at the time of cancer diagnosis, it remains uncertain which diagnosis came first. Thus, our work cannot support either directional arrow. Interestingly, while the autoimmune disease prevalence among melanoma patients (9.3%) was significantly higher than that of the non-cancer population (6.2%), the prevalence was significantly lower than those with a history of non-cutaneous cancer, with or without melanoma. The data are roughly consistent with limited past epidemiological studies on cancer patients. In those with lung and renal cancer, the prevalence of autoimmunity, using a shortened list of about 40 autoimmune conditions, is estimated to be 25%.30,31 In one study that examined melanoma patients and included 147 different autoimmune diagnoses, the prevalence of autoimmunity was found to be 20.5%, which is close to our rate of melanoma patients with non-cutaneous cancer.32 However, the irAE rate for nivolumab is 48% in melanoma33,34 compared to 30-33% in non-small cell lung cancer.35,36 Possibly, autoimmunity risk solely based on cancer type does not correlate precisely with irAE risk.
Our study showed a significant effect of metastases in patients with both melanoma and non-cutaneous cancers. These patients had a 26% metastases-associated increase in autoimmune prevalence. Our results are similar to a study that that used a looser case definition for autoimmunity and found a 43% relative increase in autoimmune disease prevalence among melanoma patients with metastases compared to those without.32 The disparate findings suggest that the specificity of autoimmune case definition may impact results.
The results also point to an influence of sex and race on autoimmunity. We found an odds ratio for autoimmunity of 1.53 for female sex vs male sex, which is slightly less than the relative risk of 2.4 calculated by Hayter et al.26 Our data also show that non-Hispanic black and Native American race are associated with autoimmunity, which is consistent with a recent large national database study that found an association with these groups and multiracial individuals.37 We did not find a significant association between Asian-American or multiracial race and autoimmunity, but their results were limited somewhat by small sampling. While the influence of sex and race on autoimmunity is incompletely understood, it is thought to be a combination of genetic and environmental factors.27
This study is limited by incomplete available clinical information and inherent issues of a single-institutional report. For example, severity, control, and activity of autoimmune conditions are unknown. Prognostic factors such as frailty, Charlson Comorbidity Index, ECOG score, and specific cancer stage or grade are unknown. Usage of ICIs, steroids, and other immune-modulating therapy are also unknown. In our study, however, we found that melanoma patients treated in the immunotherapy era (2011-) had a lower prevalence of autoimmunity (8.7%) than patients treated prior (12.7%), which does not suggest that ICIs are confounding autoimmune prevalence in our sample. Additionally, the database does not specify which primary site is linked to ICD codes of metastases, so it is uncertain whether melanoma metastases impact autoimmunity in the combined melanoma and non-cutaneous group. Selection bias related to cancer-free controls is possible because healthy patients, specifically young patients, are less likely to seek routine medical attention and may receive fewer diagnoses of autoimmunity as a result. However, in our cohort, patients without cancer aged 18-34 years old represented a considerably higher proportion of patients in their study group (9.6%) compared to those in the cancer groups (3.3-6.0%).