New body mass index for predicting prognosis in patients with antineutrophil cytoplasmic antibody‐associated vasculitis

Abstract Objectives Body mass index (BMI) is a known indicator of all‐cause mortality. However, conventional BMI does not reflect the three‐dimensional human body. To overcome this limitation, a new BMI has been proposed that provides a closer approximation of real human body shape. This study investigated the associations between the new BMI and poor outcomes in patients with antineutrophil cytoplasmic antibody‐associated vasculitis (AAV). Method We retrospectively reviewed the medical records of 242 patients with AAV in a single tertiary medical center. Based on the new BMI, the patients were categorized into four groups: underweight (<18.5 kg/m2.5), healthy weight (18.5 to <25.0 kg/m2.5), overweight (25.0 to <30.0 kg/m2.5), and obese (≥30.0 kg/m2.5). The association among the new BMI and death, relapse, end‐stage renal disease (ESRD) development, cerebrovascular accident, and cardiovascular disease was analyzed. Results The underweight group, according to the new BMI, had higher hazard ratios (HRs) for all‐cause mortality (HR: 3.180, 95% confidence interval [CI]: 1.134–8.922, p = 0.028), relapse (HR: 2.141, 95% CI: 1.019–4.368, p = 0.036), and ESRD development (HR: 2.729, 95% CI: 1.190–6.259, p = 0.018) than the healthy weight group. However, according to the conventional BMI, there were no differences in the risks for all poor outcomes between the underweight and healthy weight groups. Multivariate logistic regression analysis demonstrated that being underweight, according to the new BMI, was an independent risk factor for all‐cause mortality (HR: 5.285; 95% CI: 1.468–19.018; p = 0.011). Conclusion Being underweight, according to the new BMI, is associated with poor outcomes in patients with AAV.


| INTRODUC TI ON
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a fatal disease that includes microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis (EGPA). 1,2 The causes of death within the first year include both vasculitis and infection, whereas those after the first year include cardiovascular disease (CVD), malignancy, and infection. 3,4 Prognosis has dramatically improved since the introduction of corticosteroids and cyclophosphamide, with 1-year mortality rate of 80% in untreated patients to a 5-year survival rate of 75% in treated patients. 3,5 However, the mortality rate remains as high as 10%-15%, despite sufficient treatment with newly suggested therapeutic regimens, such as rituximab and mycophenolate mofetil. Therefore, along with developing a novel therapeutic regimen, there is a need to identify a clinically useful biomarker for predicting the risk of all-cause mortality in AAV patients during follow-ups.

Body mass index (BMI) is a representative indicator of nutritional
status and can be used to classify individuals into four categories: underweight, healthy weight, overweight, and obese. In the general population, overweight and obesity enhance the incidence rate of CVD as a component of metabolic syndrome and, therefore, are risk factors for all-cause mortality. [6][7][8][9] Meanwhile, in critically ill patients, underweight is known to be an important risk factor for all-cause mortality as malnutrition has negative effects on normal body functions, including vital organ fueling, tissue oxygenation, water/electrolyte balance, body temperature maintenance, and clearance of cellular debris. [10][11][12] The conventional BMI is a two-dimensional variable, which is higher than expected in taller individuals, and lower in those with shorter height. 13 Recently, a new BMI has been proposed to overcome this limitation. It is a three-dimensional variable and is calculated as follows: new BMI = 1.3 × weight (kg)/height (m) 2.5. 14 Thus, it could be theoretically assumed that the new BMI at diagnosis can predict poor outcomes in patients with AAV during follow-up. To the best of our knowledge, there are three studies that have applied the new BMI in clinical practice, with conflicting results. [15][16][17] However, all of the studies were studies that analyzed postoperative outcomes, and there were no studies on AAV.
Hence, this study aimed to investigate the associations between the new BMI at diagnosis and poor outcomes during follow-ups in patients with AAV. Additionally, this study compared the predictive power of conventional BMI for poor outcomes with that of the new BMI in patients with AAV.

| Patients
We retrospectively reviewed the medical records of 242 immu-   20 and ANCA results and ii) the follow-up duration of at least >3 months. The exclusion criteria were as follows: (i) serious medical conditions, such as malignancy, serious infection, and other systemic vasculitides, other than AAV and (ii) administration of immunosuppressive drugs for AAV treatment before diagnosis. This study was approved by the institutional review board of Severance Hospital (IRB protocol number 4-2020-1071). The need for written informed consent was waived owing to the retrospective nature of the study.

| Definition of the new BMI
The new BMI was calculated using the following equation: new BMI = 1.3 × weight (kg)/height (m) 2.5 . All patients had their height (cm) and weight (kg) measured at diagnosis. According to the World Health Organization guidelines, the new BMI was categorized into four weight groups: underweight (<18.5 kg/m 2.5 ), healthy weight

| Clinical and laboratory data at diagnosis
We obtained baseline clinical and laboratory data, including complete blood count and biochemical tests, such as serum albumin, proteinuria, hematuria, myeloperoxidase (MPO)-ANCA (or perinuclear [P]-ANCA), and proteinase 3 (PR3)-ANCA (or cytoplasmic [C]-ANCA). The baseline characteristics and data on organ involvement; BVAS; FFS; and comorbidities, such as diabetes mellitus, hypertension, chronic kidney disease, and hyperlipidemia, were also collected.

| Poor outcomes
We defined all-cause mortality, relapse, end-stage renal disease (ESRD) development, cerebrovascular accident (CVA), and CVD as poor outcomes of AAV. Relapse was defined as an active status of AAV after achieving remission. ESRD was defined as a medical condition requiring renal replacement therapy for >3 months. The follow-up duration based on each poor outcome was defined as a period from the diagnosis to the time of the occurrence of each poor outcome. The follow-up duration for patients without poor outcomes was defined as a period from diagnosis to the last follow-up. were performed to evaluate the differences between the groups.

| Statistical analyses
The Kaplan-Meier curves and log-rank test were used to investigate the association between the new BMI and outcomes. The correlation coefficient was obtained using Pearson correlation analysis. The Cox proportional hazards regression model was used to evaluate the hazard ratios (HRs) and 95% confidence intervals (CI) for poor outcomes in each weight group, with the healthy weight group as the reference. The multivariate Cox proportional hazards model analysis was performed using variables that were statistically significant in the univariate analysis. p Values of <0.05 were considered statistically significant.

| Characteristics of patients with AAV
The baseline characteristics of patients and poor outcomes during the follow-up are described in Table 1

| Comparison of clinical characteristics among weight groups categorized according to the new BMI
We compared variables described in Table 1  no differences in demographic and AAV-specific data at diagnosis between the groups, except that the pulmonary involvement was more frequent in the underweight group than in other groups (p = 0.049).
Diabetes and hyperlipidemia were more frequent in the obese group than in the other groups, as expected (p = 0.020 and 0.009, respectively). A higher proportion of patients in the underweight group developed ESRD (p = 0.004). No other significant differences were observed in the poor outcomes at follow-ups between the groups ( Table 2).

| Association between poor outcomes and weight groups categorized according to new and conventional BMI
The HRs for poor outcomes were calculated in the underweight, overweight, and obese groups, categorized according to the new and conventional BMIs (

| Incidence rates of poor outcomes
Since significant associations were found between the underweight group and poor outcomes, we divided the patients into the underweight and healthy weight groups according to the ranges of the new BMI. The underweight group exhibited higher incidence rates than the healthy weight group for both all-cause mortality (31.3% vs. 10.6%, p = 0.034) and ESRD occurrence (43.8% vs. 19.2%, p = 0.048).
However, the incidence rate for relapse did not differ between the two groups ( Figure 1). Additionally, there were no differences in the incidence rates of CVA and CVD between the two groups.

| Kaplan-Meier analysis for poor outcomes in underweight patients with AAV according to the new BMI
Based on the new BMI, patients in the underweight group exhibited lower cumulative (p = 0.020), relapse-free (p = 0.032), and ESRDfree survival rates (p = 0.013) than those in the healthy weight group ( Figure 2).

| Cox proportional hazards model analyses
We performed the Cox proportional regression analysis to investigate whether the underweight category defined according to the new BMI could independently predict all-cause mortality. In the

| DISCUSS ION
Our study demonstrated that patients categorized in the underweight group based on the new BMI at the time of AAV diagnosis had significantly higher incidence of all-cause mortality, relapse, and ESRD development as compared to those in the healthy weight group.
Furthermore, our data demonstrated that underweight based on the new BMI may be a significant and independent predictor for allcause mortality in patients with AAV during follow-ups. To the best of our knowledge, ours is the first study to identify the association between the new BMI and poor outcomes in AAV.
Previous studies have demonstrated that in critical conditions, underweight patients were at a higher risk of mortality. [22][23][24][25] Since AAV is a fatal disease that may result in critical illness if not properly treated, we hypothesized that underweight is associated with poor outcomes in AAV. Some may argue with this hypothesis, asserting that underweight is not a prognostic factor, rather is an epiphenomenon of the disease. However, our results indicated no correlation between the new BMI at diagnosis and baseline BVAS, FFS, or CRP levels. Furthermore, adjusted HRs demonstrated that the new BMI was associated with mortality independently of age, baseline BVAS, FFS, and CRP levels. Therefore, it is reasonable to suggest that underweight, an indicator of nutritional status, is a poor prognostic factor in patients with AAV.
Malnutrition significantly increases mortality in critically ill patients 24 and in those with chronic diseases. 26,27 In critical illness, energy usage is prioritized for vital organs, such as the brain or heart, and nutrients stored in the muscle or adipose tissue are catabolized to produce energy substrates. 28 Furthermore, inflammatory cytokines, such as interleukin (IL)-1, IL-6, and tumor necrosis factorα, accelerate the catabolic process. 29 However, underweight patients

TA B L E 3 (Continued)
may not have enough nutrient reserves; therefore, they are susceptible to malnutrition. Based on these findings, it is reasonable to assume that underweight patients with AAV would have worse outcomes than healthy weight patients; however, there were no previous data regarding the association between underweight and AAV.
Assuming that the new BMI reflects the actual shape of the human body, our finding is significant in revealing the association between underweight and poor outcomes in patients with AAV.
Underweight patients, according to the new BMI at diagnosis, experienced more frequent relapse and ESRD development than healthy weight patients. The exact mechanism underlying these associations is unclear. Our team had previously evaluated prognostic nutritional index, an index that reflects nutritional status, in patients with AAV and revealed that it correlated with the BVAS and predicted relapse. 30 Similarly, we demonstrated that a poor nutritional status was associated with a higher BVAS, and that it was a risk factor for ESRD occurrence. 31 One explanation for these findings is that underweight patients are at an increased risk of low muscle mass, 32,33 and muscle mass is associated with chronic kidney disease. 34,35 The new BMI was proposed since the conventional BMI, which is defined as weight divided by height squared, has limitations in reflecting the three-dimensional human body.   may be used as an independent prognostic factor in patients with AAV.
In conclusion, our study demonstrated the association between underweight, according to the new BMI, and poor outcomes in patients with AAV. Based on our results, we suggest evaluating the nutritional status of patients with AAV during diagnosis using the new BMI as a prognostic factor. Further prospective studies are required to validate our findings and to establish the underlying mechanisms of our observed findings.

CO N FLI C T O F I NTE R E S T
The authors declare that they have no conflicts of interests.

DATA AVA I L A B I L I T Y S TAT E M E N T
The datasets of the current study are available from the corresponding author on reasonable request. Note: Values are expressed as mean ± standard deviation or number (percentage).
Bold indicates statistically significant.