The present study included 126 adult patients who were diagnosed with AAV, including GPA, MPA, and EGPA, based on the classification of the AAV by the European Medicines Agency algorithm , at Nephrology and Rheumatology centers in the Aichi Medical University in Japan between 2004 and 2018. After excluding 28 patients (22.2%) who were non-elderly (aged < 65 years; n = 20), were not on immunosuppressive therapy (n = 2), and those with missing BMI data (n = 6), 98 patients (77.8%) who received immunosuppressive therapy were included in the present study (Fig. 1).
The study protocol was approved by the Ethics Committees of Aichi Medical University (approval number 2018-H350, date November 3, 2019). The need to obtain patients’ informed consent was waived due to the retrospective nature of the study.
Baseline characteristics, at the start of immunosuppressive therapy, were collected retrospectively from patients’ medical records and included the following: age; sex; BMI; body weight loss > 10% within 6 months before diagnosis; serum creatinine level; serum albumin level; C-reactive protein level; serum IgG level; presence of diabetes mellitus; Birmingham Vasculitis Activity Score (BVAS) 2003 ; organ involvement; anti-myeloperoxidase (MPO) and anti-proteinase 3 (PR3) ANCA levels; use of immunosuppressive treatment, such as induction immunosuppressive therapy; methylprednisolone pulse therapy (0.5 or 1.0 g/day for 3 consecutive days); intravenous cyclophosphamide (CYC) or rituximab (RTX) use, and maintenance therapy; oral CYC use, azathioprine (AZA) use, methotrexate use, and RTX use.
All serum samples were tested by direct antigen-specific enzyme-linked immunosorbent assays for MPO and PR3-ANCA, using serial serum dilutions, as previously described . The samples were diluted 1:500 (Nipro Medical Corporation, Osaka, Japan) or 1:101 (Medical and Biological Laboratories Co., Ltd., Nagoya, Japan).
The primary exposure of interest was the BMI at the diagnosis of AAV. BMI was defined according to the World Health Organization Asian Standard ; underweight was defined as BMI < 18.5 kg/m2, normal weight as BMI 18.5–22.9 kg/m2, overweight as BMI 23.0–24.9 kg/m2, obesity I (moderate obesity) as BMI 25.0–29.9 kg/m2, and obesity II (severe obesity) as BMI ≥ 30 kg/m2. Because of the small number of overweight, obesity I and II patients, we combined these three groups into a “high BMI” group. Accordingly, we stratified patients into three BMI categories: low BMI (BMI < 18.5 kg/m2), normal BMI (BMI 18.5‒23 kg/m2), and high BMI (BMI > 23 kg/m2).
The main outcome of interest was the development of severe infection, which was defined as infection requiring hospitalization for any causes. Remission was defined as the absence of clinical signs and symptoms of active vasculitis (BVAS = 0) for more than 2 months. Relapse was defined as clinical signs of vasculitic activity in any organ system, followed by an increase in corticosteroid dosing and/or add-on use of immunosuppressive agents after development of remission, as previously described . Other outcome data, including information about end-stage renal disease (ESRD) requiring dialysis, death, and hospitalization due to causes other than infection, was collected. Patients were followed up until December 2019 and data were censored at death or on the last day of attending examination in our hospital before December 2019.
Baseline patient characteristics were summarized according to the three BMI categories, and are presented as a percentage for categorical variables and as median (interquartile range) for continuous variables with both normal and skewed distributions.
The associations of BMI with outcomes were assessed using univariate and multivariate Cox proportional hazards (CPH) models. The multivariate models were adjusted for the following potential confounding factors; age, sex, lung involvement, diabetes mellitus, serum creatinine level, use of methylprednisolone therapy, and BMI (low, normal, and high BMI), based on the clinical experience and theoretical considerations.
Furthermore, we assessed the effect of changes in body weight loss (> 10%) within 6 months before diagnosis and low BMI for the primary outcome in a multivariate model, adjusted for age, sex, lung involvement, diabetes mellitus, serum creatinine level, and use of methylprednisolone therapy.
The proportional hazard assumption for covariates was tested using scaled Schoenfeld residuals. For continuous variables, the Wilcoxon rank-sum test was used to evaluate the significance of intergroup differences. Categorical variables are expressed as percentages and were compared using the Fisher’s exact test. The cumulative probability of the development of a first severe infection was calculated using the Kaplan‒Meier method and log-rank test.
The level of statistical significance was set at P < 0.05. All statistical analyses were performed using JMP, version 14.0.0 (SAS Institute, Cary, NC, USA) and STATA version 13.0 (StataCorp LP, College Station, TX, USA).