Introduction
Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) comprises granulomatosis with polyangiitis (GPA, previously known as Wegener’s granulomatosis), microscopic polyangiitis (MPA), and eosinophilic GPA (EGPA, previously known as Churg-Strauss syndrome) [
1]. A reclassification of AAV into three categories, according to the presence of ANCA, was recently suggested as follows: myeloperoxidase (MPO)-ANCA, proteinase 3 (PR3)-ANCA, and ANCA-negative vasculitis [
2]. In patients with AAV, renal involvement can often present as rapidly progressive glomerulonephritis (GN), and the upper or lower respiratory tract and the peripheral nervous system may be involved as extrarenal manifestations. Although AAV also occurs in younger patients, it presents more commonly in elderly patients. The peak age of AAV incidence is between 65 and 74 years [
3–
6]. In a study of 430 Chinese patients aged ≥65 years who underwent renal biopsy, AAV (44%) was the leading cause of secondary GN [
7]. In a recent study in Korea, AAV was more prevalent in those aged ≥65 years compared to those aged <65 years (3.9% vs. 0.3%) [
8].
Substantial morbidity and mortality occur with AAV, especially in elderly patients. In addition, rapidly progressive GN requires prompt diagnosis and the early initiation of adequate treatment. Although AAV predominantly affects older patients, appropriate treatment strategies have not been established clearly, and it is unclear whether the benefits of immunosuppressants surpass the risks. The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend reducing the cyclophosphamide (CYC) dose in patients over 60 years old [
9]. Data on the clinical characteristics and outcomes of elderly patients with AAV are scarce, especially in Asia. Therefore, this study aimed to investigate the demographic factors, treatments, and clinical outcomes of patients with AAV in Korea and to compare the characteristics of AAV among elderly and young patients.
Discussion
In the present study, 36 elderly patients (51.4%) with ANCA-positive AAV were enrolled over 14 years. During the study period, more elderly patients were diagnosed with AAV between 2013 and 2019 than between 2006 and 2012. In the follow-up period, 13 patients died, and most of these patients (11, 84.6%) were in the elderly group. Older age, lower hemoglobin, and higher serum creatinine were significant risk factors for all-cause mortality in the elderly group. Similar to our study, previous studies have also demonstrated that advancing age and impaired renal function are significant risk factors for mortality [
14,
15]. Kidney outcomes were not significantly different between the younger and elderly groups in the present study.
In elderly patients, decreased immunity and the increased risk of infection are of great concern in immunosuppressant treatment. Elderly patients are particularly vulnerable to the adverse effects of disease and the immunosuppressants used for treatment. In the present study, there was decreased all-cause mortality in the oral CYC + steroids treatment group compared to the untreated group at all ages. This demonstrates the effect of immunosuppressants even in the elderly. In addition, the mortality rate may have been lower because the immunosuppressants were more likely to be used in stronger patients. Infection was the main cause of death, and six patients (54.5%) died of an infection in the elderly group, three of who were treated with immunosuppressants (1 patient each was treated with intravenous CYC + steroids, oral CYC + steroids, or steroids alone) and the other three underwent only supportive treatment. The three patients who received immunosuppressant treatment were relatively older compared to those who received supportive treatment (73, 83, and 83 years vs. 65, 73, and 73 years). In the present study, there was no significant difference in mortality by infection in the elderly group, regardless of treatment with immunosuppressants. However, the small number of patients precludes a definite conclusion regarding this finding. In a previous retrospective study, patients that were older and receiving immunosuppressants had an increased risk of infection, particularly in the presence of leukopenia [
3]. However, other studies have shown that elderly patients with AAV receiving immunosuppressants had a better prognosis (lower mortality and/or lower frequency of end-stage renal disease [ESRD]) than those untreated or not treated via the standard method [
16,
17]. Overall, immunosuppressants can be used with caution in elderly patients with AAV, with careful monitoring for adverse events.
In our study, there were not many patients who underwent rituximab induction treatment. In previous studies, rituximab was not inferior compared to CYC as an induction treatment [
18,
19], and rituximab was more efficacious than CYC in patients with relapsing disease [
18]. Adverse events were comparable between the two treatments and there was no trend toward reduced infection rates [
20]. However, rituximab induction may be preferred in frail older adults according to the expert recommendation in the draft of the 2020 KDIGO clinical guideline on glomerular disease. Therefore, appropriate immunosuppressants in elderly patients can improve the prognosis of the patient. Further study is needed on the outcome of elderly AAV patients using rituximab.
In the present study, oral CYC was prescribed more often than intravenous CYC in older patients. The CYCLOPS study showed that intravenous pulse and oral continuous CYC were equally efficacious and pulse intravenous therapy had lower side effects, including leukopenia [
21]. The long-term follow-up of the CYCLOPS study demonstrated that pulse CYC was not associated with increased mortality or long-term morbidity; however, it was associated with a higher risk of relapse than oral CYC [
22]. In the present study, the reasons for the greater use of oral CYC compared to intravenous CYC in the elderly could be the following. First, patients from before the CYCLOPS study era were also included in the study, and because of concerns about relapse, which would have required repeat high-dose immunosuppressants, oral CYC may have been prescribed more often than intravenous CYC. Furthermore, intravenous CYC may have been less prescribed in the elderly because the administration method is more cumbersome than oral therapy and occasionally needs short-term admission. In a previous study, oral CYC was prescribed more often than intravenous CYC in very elderly AAV patients (oral vs. intravenous: 58% vs. 24%) [
17]. In another observational study, patients receiving oral CYC were older than those receiving intravenous CYC (72 years [65–78 years] vs. 55 years [44–68 years], p < 0.001) [
23].
Lower hemoglobin was a significant risk factor for all-cause mortality in the entire study population, including the elderly group. Anemia-related markers, such as mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), ferritin, iron, total-iron binding capacity (TIBC), and transferrin saturation (TSAT) were evaluated. MCV was 88.6 ± 4.8 fL and MCHC was 33.4 ± 1.7 g/dL. Serum ferritin, iron, TIBC, and TSAT values were available only in 42 patients. Serum ferritin was 552.0 ng/mL (251.8–837.3 ng/mL) and serum iron was 29.0 μg/dL (22.0–51.5 μg/dL). Serum ferritin was significantly higher in the elderly group than in the younger group (younger vs. elderly: 308.2 ng/mL [168.6–646.9 ng/mL] vs. 571.1 ng/mL [375.6–1,092.5 ng/mL]; p = 0.04). Iron (p = 0.428) and TSAT (p = 0.35) were not significantly different between the younger and elderly groups. The presence of anemia is known to increase with age, and anemia is common in the elderly [
24]. In one study, anemia was prevalent in >10% of people aged ≥65 years and in >20% of those aged ≥85 years in the United States [
24]. In a recent study, 13.8% of people aged ≥65 years who participated in a Korean national survey had anemia [
25]. Aging is a proinflammatory condition that may cause altered iron handling or the suppression of erythroid progenitors [
26]. Anemia in the elderly is related to various adverse outcomes, including hospitalization, morbidity, and mortality [
27]. In our study, ferritin was higher in the elderly, which may reflect inflammatory conditions and lower hemoglobin associated with patient death.
The presence of kidney involvement or impaired renal function is a common negative prognostic factor for elderly patients [
14,
15]. In the present study, higher serum creatinine was a significant risk factor for all-cause mortality in the elderly group. AAV-associated kidney involvement often presents as rapidly progressive GN [
28] and can cause poor morbidities and mortality. Therefore, if elderly patients with AAV have kidney involvement or impaired renal function, meticulous care and close follow-up and monitoring are needed.
In the present study, ANCA-positive AAV was not classified as GPA, MPA, or EGPA. AAV classification according to clinical phenotype, especially GPA or MPA, has significant overlap in clinical features and often ambiguous distinctions, adding to the controversial issues in AAV classification [
29]. A classification system according to ANCA specificity (MPO-ANCA vs. PR3-ANCA disease) has been proposed. Relapse rates and clinical outcomes are better associated with ANCA specificity [
29]. Therefore, in the present study, ANCA-positive AAV was classified as MPO/P-ANCA, PR3/C-ANCA, or double-positive AAV. In a previous study, there were no differences in mortality or time to remission between MPO-positive and PR3-positive patients, but PR3-positive patients had a higher rate of relapse and relapsed earlier than MPO-positive patients [
30]. In the present study, there were no significant differences in mortality between MPO/P-ANCA and PR3/C-ANCA; however, further large-scale studies are needed to clarify our findings.
The strength of our study is that we investigated the outcomes of patients with AAV, especially elderly patients. In previous randomized controlled trials of induction immunosuppressant in AAV, the mean ages of patients were 57 years [
10], 53 years [
18], and 60 years [
31], and in another study, elderly patients aged above 75 years were excluded [
15]. In previous studies, similar responses to immunosuppressive treatment were found in elderly AAV patients compared to younger people [
3], and one study found that they did not respond well [
32]. Bomback et al. [
17] showed that immunosuppressants were associated with a lower risk of ESRD or combined ESRD or death risk at 1 year in very elderly patients over 80 years of age. In a recent study, older age and infection were major risk factors for 1-year mortality in AAV patients over 65 years but failed to show a statistical significance between therapeutic strategy and mortality [
33]. In our study, we investigated outcomes according to immunosuppressant use in elderly AAV patients and entire study patients, which is an advantage in our study. However, our study also has several limitations. First, we could not exclude the possibility of residual confounders because of the retrospective nature of the study. Moreover, we could not conduct a multivariable analysis for all-cause mortality in the younger group because mortality events (only two patients [2.9%]) were low during the follow-up period. In addition, this was a single-center study in Korea; thus, caution is required when generalizing our findings to other ethnicities.
In conclusion, patients aged 65 years or older had higher mortality rates than younger patients, which was associated with older age, lower hemoglobin, higher serum creatinine, and nontreatment compared to oral CYC + steroids.