Frailty and antineutrophil cytoplasmic antibody‐associated vasculitis: What do we know?

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is an autoimmune condition that mainly affects small vessels of the body. AAV is a condition that may have multisystem manifestations and has an increased prevalence among older individuals.1 AAV patients conventionally present with symptoms at 65 years of age or older. Previous studies have demonstrated worse clinical outcomes in the aging population. Many older patients live with various comorbidities in addition to potentially relapsing AAV. Dealing with the pathophysiological impact of AAV can be burdensome, as this multifaceted condition may lead to impairment of physical function and contribute to significant mental and emotional stress. The impact of aging on the pathophysiology of AAV is not fully known. Immune dysregulation induced by cell senescence is hypothesized to be a key factor, alongside a mixture of genetic and environmental factors.2 Frailty, an age-associated syndrome defined as a state of vulnerability to stressor events as the result of cumulative physiological decline, is associated with an increased risk of adverse outcomes—including falls, hospitalization, reduced quality of life (QoL), and earlier-than-expected death.3 Frailty status is independently linked with poor outcomes for a wide range of medical conditions. For aging patients with multimorbidities, the presence of frailty adds toward an already significant health burden. The combination of aging, frailty, and AAV increases the burden of chronic inflammation, with older individuals subject to malnutrition and sarcopenia, impaired mobility due to musculoskeletal and neurological pathology, decline in kidney function, cognitive deficits, and high levels of pain and fatigue affecting QoL (Figure 1). Evaluating the true extent of frailty and AAV disease severity with their variable phenotypical features is challenging for clinicians. It is difficult to identify at presentation what degree of illness is attributed to AAV disease activity or pre-existing frailty. There have been few studies that have investigated the relationship between frailty status and AAV outcomes. The emergence of original data on this topic recently suggests an increased interest and awareness of its clinical significance. We performed a scoping search in PubMed, Web of Science, EMBASE, Medline-ProQuest, and Google Scholar incorporating the keywords “frailty” and “vasculitis” to identify relevant indexed full articles and conference abstracts (Supporting Information: Table S1).4-9 Primarily, published studies aimed to determine the prevalence of frailty among older AAV patients, to address whether a more severe frailty status indicated worse AAV-associated outcomes including complication rates, and to determine if the perceived frailty status of older AAV patients improved with immunosuppressive treatment. These studies utilized various frailty assessment tools, allowing for comparisons to be made in relation to the application of frailty assessment tools within this context. From these early studies, we note the majority of included patients are classified in the robust, pre-frail, or mildly frail categories at the time point of baseline frailty status measurement, with relatively fewer individuals identified as being moderate or severely frail no matter which frailty assessment tool was used. Frailty assessment tools derived from the physical frailty (i.e., Clinical Frailty Scale [CFS] and FRAIL scale) and deficit accumulation models (i.e., Hospital Frailty Risk Score [HFRS] and Claims Frailty Index) are both used to measure baseline frailty status. When the CFS is used, there appears to be a significant association between frailty and mortality outcomes, with higher mortality rates being found in frailer AAV patients.4, 7 In reverse, the two studies that utilized the HFRS and Claims Frailty Index, respectively, did not conclude statistically significant associations between frailty status and mortality outcomes.6, 9 All of the studies illustrated no differences among AAV patients of varying frailty status in terms of progression toward kidney failure. Unsurprisingly, it was also concurred that frailty status is significantly associated with the occurrence of adverse events during follow-up, in particular infection-related complications. These findings provided preliminary conclusions relating to the utilization of frailty measurements when managing older AAV patients. It may help inform clinicians on the likelihood of adverse events (i.e., infective complications are most frequently immunosuppression related) according to the patient's degree of frailty, and in this respect, it provides guidance on whether treatment adjustments are needed. On the other hand, if used to decide whether early and aggressive intervention is beneficial, given many older patients are in the “robust” or “less frail” phase at baseline diagnosis, then-current results perhaps advise for a more cautious approach when using frailty measurements for this purpose. This is given a lack of clarity in the relationship between frailty status and AAV on a physiological level and also when we consider that links between frailty status and consequential outcome measures such as mortality and progression toward kidney failure remain unestablished within an AAV context. A similar issue applies when deciding how to treat and whether there is over- and undertreatment of older AAV patients based on frailty status alone. There are key limitations of these studies which should be recognized. First of all, most, if not all, of the frailty assessment tools included subjective components in the healthcare professional's assessment of frailty status. Though some extent of intra- and interobserver bias is likely inevitable, it may be helpful for future studies to use one of the frailty assessment tools as the reference standard to compare prognostic accuracies across numerous tools (e.g., for chronic kidney disease, the CFS demonstrated good diagnostic accuracy for frailty when using Frailty Phenotype as the reference standard).10 Furthermore, small sample sizes affected the study power and generalizability of results. Many of the studies were conducted retrospectively, and not all potential confounding factors (e.g., ethnicity) were statistically adjusted for. Prospective studies with larger data samples are required to form further conclusions. In summary, research on frailty and frailty assessment in AAV is of rising importance with the growth of an aging population worldwide. The intricate and multidimensional nature of the frailty syndrome and AAV suggest it is currently challenging to evaluate these elements independently to address their impact on the individual patient. Greater efforts in generating basic, translational, and clinical data on this topic are anticipated to hopefully provide better guidance toward a personalized frailty assessment and management approach for our older and potentially more vulnerable AAV patient population. Henry H. L. Wu: Conceptualization; investigation; writing—original draft; writing—review and editing. Nina Brown: Writing—review and editing. Rajkumar Chinnadurai: Writing—original draft; writing—review and editing; supervision. All the authors agree for the final version of the manuscript to be submitted for consideration of publication. The study is not funded by any organization. Nina Brown receives honorarium fees from CSL Vifor UK outside of this work. The remaining authors declare no conflict of interest. None declared. None declared. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.