INTRODUCTION
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of systemic vasculitides involving small vessels. On the basis of the 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides (the 2012 definitions), AAV is defined as vasculitis predominantly affecting small vessels such as small intraparenchymal arteries, arterioles, capillaries, venules, and occasionally medium-sized arteries and veins [
1]. AAV can be further classified into three variants such as microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) and eosinophilic granulomatosis with polyangiitis (EGPA) based on clinical manifestations and histological features such as necrotizing vasculitis, granulomas and eosinophilic infiltration [
1,
2]. Compared to other vasculitis, particularly Takayasu arteritis or immunoglobulin A vasculitis (Henoch-Schonlein), AAV tends to occur in elderly people. Both MPA and GPA mainly occur in 60 to 70-year-old persons, whereas, EGPA often occurs in 40 to 60-year-old persons [
3].
To date, there have been several studies comparing the clinical features and outcomes of young and elderly AAV patients: Early classification before advanced chronic kidney disease (CKD) and the use of immunosuppressive drugs improved the prognosis of AAV [
4]; moreover, ESRD occurred more frequently in patients who were not treated with immunosuppressive drugs at 1 year after diagnosis. However, the rate of all-cause mortality was not different between the two groups [
5]; elderly AAV patients exhibited higher incidence of both all-cause mortality and ESRD occurrence as well as the highest mortality rate within the first 6 months [
6].
To the best of our knowledge, however, there is no report yet on the comparative analysis of the clinical and laboratory features and the incidence of all-cause mortality and ESRD occurrence in Korean elderly patients with AAV. Hence, in this study, we compared the clinical and laboratory features of elderly and non-elderly AAV patients at diagnosis and investigated the predictors at diagnosis for all-cause mortality and ESRD occurrence during follow-up in Korean elderly patients with AAV.
DISCUSSION
In this study, we compared clinical and laboratory data between elderly and non-elderly AAV patients. We first investigated the predictors at diagnosis for all-cause mortality and ESRD occurrence during follow-up in elderly AAV patients in a monocentric retrospective cohort in Korea and obtained several interesting findings. In the cross-sectional comparative analysis of variables at AAV diagnosis, elderly AAV patients exhibited higher median BVAS and higher frequencies of MPO-ANCA (or P-ANCA) positivity, ANCA positivity and pulmonary manifestations than non-elderly AAV patients. Furthermore, elderly AAV patients exhibited higher median white blood cell count, BUN, ALP, ESR, and CRP and lower median hemoglobin than non-elderly AAV patients. In the cross-sectional comparative analysis of variables during follow-up, elderly AAV patients exhibited higher frequencies of CKD and ILD than non-elderly AAV patients. However, there were no significant differences in all-cause mortality and ESRD occurrence between elderly and non-elderly AAV patients.
With these results, we could make two assumptions. The first assumption is that highly active and severe AAV might occur more often in elderly people than in younger ones. The high median BVAS and increased frequencies of MPO-ANCA (or P-ANCA) and ANCA positivity in elderly AAV patients might support this assumption. Alternatively, even AAV, whose activity and severity are similar to those in non-elderly patients, could exaggerate the frequencies of AAV-specific manifestations due to low daily functionality in elderly AAV patients, leading to an increase in BVAS. The second assumption is that ageing itself might provoke enhanced autoimmunity and prolong autoinflammation. The detection rate of MPO-ANCA (or P-ANCA) is increased and the serological markers of chronic inflammation become apparent with age [
5,
11-
14].
The Kaplan-Meier survival analysis revealed that elderly AAV patients exhibited lower cumulative patients’ and ESRD-free survival rates than non-elderly AAV patients, which were similar to the results of previous studies [
4-
6]. In addition, because the incidences of all-cause mortality and ESRD occurrence may gradually increase with age, if the age cut-off for elderly AAV patients is raised, would the difference be greater? The age cutoff for elderly AAV patients was set at 75 years and the cumulative patients’ and ESRD-free survival rates were compared between the two groups. Similarly, elderly AAV patients exhibited lower cumulative patients’ and ESRD-free survival rates than non-elderly AAV patients but the statistical power was much higher (
Supplementary Fig. 1). However, as mentioned in the Methods section, the small number of elderly AAV patient could not warrant the statistical reliability. Therefore, we adopted the results of the comparative analysis of the cumulative survival rates between patients aged 65 years and above and those aged 65 years and below.
Regarding the predictors for ESRD occurrence during follow-up based on ESRD, BUN, creatinine and serum albumin at diagnosis were significant in the multivariable analysis. Because BUN and creatinine are variables directly associated with renal function, it could easily be accepted that the initial BUN and creatinine levels could predict the development of ESRD occurrence during AAV follow-up. Reduced serum albumin might be associated with persistent proteinuria, which can, in turn, accelerate renal function deterioration and finally provoke ESRD. Therefore, BUN, creatinine, and serum albumin at diagnosis could predict ESRD occurrence during follow-up based on ESRD regardless of the relationship between these variables and the concurrent activity of AAV [
15].
Additionally, we assessed predictors at diagnosis for all-cause mortality and ESRD in non-elderly AAV patients using the univariable and multivariable Cox hazards model analysis; then we compared the differences between independent predictors for all-cause mortality and ESRD between elderly AAV patients and non-elderly AAV patients. Both elderly and non-elderly AAV patients showed no independent predictor for all-cause mortality (
Supplementary Table 1). On the other hand, elderly AAV patients exhibited three independent predictors, such as BUN, creatinine, and serum albumin, whereas non-elderly AAV patients showed four independent predictors, FFS ≥ 2, nervous manifestation, fasting glucose, and creatinine (
Supplementary Table 2). Although it is difficult to determine the exact mechanism of the differences between the two groups, we hypothesize that the current activity of AAV at diagnosis may influence the progression to ESRD in non-elderly AAV patients, whereas advanced renal disease with low serum albumin at diagnosis may accelerate progression to ESRD in elderly AAV patients.
We believe that our study will contribute to understanding ethnic features in Korean elderly patients with AAV. We first demonstrated the cross-sectional differences in the clinical and laboratory features at diagnosis and prognosis as well as the comorbidities during follow-up between elderly and non-elderly AAV patients in Korea. Additionally, we provided information on the differences between the cumulative patients’ and ESRD-free survival rates based on the age cut-off of 65 years and the initial independent predictors for allcause mortality and ESRD occurrence during follow-up based on each outcome in Korean patients with AAV. However, our study also has several limitations. First, since we reviewed medical records of AAV patients retrospectively, we could not control the initial variables at AAV diagnosis and prevent missing data such as autoantibodies related to other autoimmune connective tissue diseases, despite searching the concurrent diseases of each patient by ICD-10. Additionally, we could not collate the conventional risk factors for all-cause mortality at the time of diagnosis, such as medical history and duration of diabetes mellitus, hypertension and dyslipidemia, smoking history, alcohol intake, and occupational factors. Concerning medications, the limitations of detailed content in the medical records discouraged the authors from calculating the cumulative dose of each medication administered owing to the retrospective study design and patients’ compliance and adherence to the oral immunosuppressive drugs. For this reason, we had to count the number of patients who received each drug. Second, the number of patients in this study was not large enough to provide more validated and stronger evidence on the features of Korean elderly patients with AAV. Third, the number of AAV patients aged 75 years and above was only 20; therefore, we could not clearly analyze the clinical and laboratory features at diagnosis and prognosis as well as the comorbidities during follow-up between patients aged 75 years and above and below. Given that previous studies conducted in Western countries selected the age for elderly AAV patients as 75 or 80 years, we could not compare the results of those previous studies with our results. Future multi-centric prospective studies with a large number of AAV patients, particularly more patients aged 75 years and above, will overcome these issues and provide more information on the features of Korean elderly patients with AAV.
In conclusion, elderly AAV patients exhibited substantially higher rates of all-cause mortality and ESRD occurrence during follow-up than non-elderly AAV patients. Furthermore, BUN, creatinine and serum albumin at diagnosis were independent predictors for ESRD during follow-up in Korean elderly patients with AAV.