The medical records of 255 patients with AAV who were enrolled in the Severance Hospital ANCA-associated VasculitidEs (SHAVE) cohort were reviewed. The SHAVE cohort is a prospective and observational cohort of patients with AAV and was established in November 2016. Preferentially, 38 AAV patients were chosen who met the following inclusion criteria: i) the classification of AAV should be based on two guidelines namely the classification algorithm for AAV and polyarteritis nodosa proposed by the European Medicine Agency in 2007 (the 2007 algorithm) and the revised nomenclature of vasculitides suggested by the Chapel Hill Conference Consensus in 2012 (the 2012 definitions) [1,2]; ii) the classification of AAV should be made at the Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine; iii) RTX had been administered to patients with AAV after enrollment; iv) the medical records included the necessary information required for the clinical record form regarding clinical, laboratory, and AAV-specific data, medications, all-cause mortality, and infections; and v) the follow-up duration was >3 months after AAV diagnosis; The exclusion criteria were as follows: i) concurrent malignancies, infectious diseases, and systemic autoimmune vasculitis other than AAV at the time of AAV diagnosis as well as at the first RTX infusion; ii) AAV patients who had ever received immunosuppressive drugs for the treatment of AAV prior to AAV diagnosis. Secondarily, since diffuse large B-cell lymphoma developed in two patients with AAV after AAV diagnosis, and RTX was provided for the treatment of lymphoma, they were excluded from this study. Finally, 36 patients with AAV were included in this study (Figure 1). The present study was approved by the Institutional Review Board (IRB) of Severance Hospital (Seoul, Korea, IRB No. 4-2020-1071). The patient’s written informed consent was waived by the approving IRB, as this was a retrospective study. Given the retrospective design of the study and the use of anonymized patient data, the requirement for written informed consent was waived.

Age, male sex, body mass index, and smoking history were obtained as demographical data. Variables at the first RTX infusion and those for the first 6 months of follow-up, in particular, AAV-specific indices including AAV subtype, ANCA positivity, Birmingham vasculitis activity score (BVAS) [11], and five-factor score (FFS) [12], were collected (Table 1). The total follow-up duration was defined as the period between AAV diagnosis and the last visit for surviving AAV patients, and it was defined as that between AAV diagnosis and death for deceased AAV patients. Meanwhile, the follow-up duration was defined as the period during the first 6 months of follow-up after the first RTX infusion for surviving AAV patients, whereas it was defined as the period from the first RTX infusion to death for deceased AAV patients. Medications administered from the AAV diagnosis to 6 months after the first RTX infusion were evaluated. In particular, the cumulative doses of induction therapeutic regimens, glucocorticoids, RTX, and cyclophosphamide were calculated.

A weekly dose of 375 mg/m² RTX was administered for 4 weeks to all patients with AAV in this study as an induction therapeutic regimen [5]. Serious infections were defined as those requiring hospitalization, and only serious infection that occurred during the first 6 months of follow-up were assessed in this study.

All statistical analyses were performed using IBM SPSS Statistics for Windows, version 25 (IBM Corp., Armonk, NY, USA). Continuous variables are expressed as medians with interquartile ranges, and categorical variables are expressed as numbers (percentages). Significant differences between two categorical variables were analyzed using the chi-squared and Fisher’s exact tests. The Mann-Whitney U test was used to compare significant differences between two continuous variables. Comparison of the cumulative survival rates between the two groups was performed using Kaplan-Meier survival analysis with the log-rank test. The multivariable Cox hazard model using variables with statistical significance in the univariable Cox hazard model was used to obtain hazard ratios (HRs) during follow-up. p-values less than 0.05 were considered statistically significant.

At the first RTX infusion, the median age was 60.5 years, and 16 patients were male (19 patients were classified as having MPA, 16 as having GPA, and 1 as having EGPA). The mean body mass index was 24.0 kg/m² and eight patients (22.2%) had smoking history. The median BVAS, FFS, erythrocyte sedimentation rate, and C-reactive protein levels were 12.0, 1.0, 15.0 mm/h, and 2.1 mg/L, respectively. During the first 6 months of follow-up, 7 of 36 patients (19.4%) died of any cause. The median cumulative dose of RTX was 2,050.0 mg (Table 1).

At the first RTX infusion, there were no significant differences in variables at diagnosis between AAV patients with and without serious infections. The median total follow-up duration was 718.0 months, and that in AAV patients with serious infection was significantly lower than that in AAV patients without serious infection (113.0 vs. 802.0 months, respectively; p=0.018). The follow-up duration after the first RTX infusion exhibited a similar pattern to the total follow-up duration between the two groups (3.8 vs. 5.6 months, respectively; p<0.001). Conversely, patient with AAV with serious infection had a higher mortality rate than those without serious infection (66.7% vs. 15.2%, respectively), but the difference was not statistically significant. There were no significant differences in the number of patients receiving immunosuppressive drugs or the cumulative dose of induction therapeutic regimens between the two groups. In particular, before the first cycle of rituximab, cyclophosphamide had been administered to 28 patients, of whom 2 had serious infections during the first 6 months of follow-up after the first cycle of rituximab, and there were no differences in the frequency and cumulative doses of cyclophosphamide between AAV patients with serious infections and those without (Table 1).

Three patients with AAV experienced five cases of serious infection during the first 6 months of follow-up. One 79-year-old female patient with MPA (patient #1) had myeloperoxidase (MPO)-ANCA and exhibited general, otolaryngological, pulmonary, and renal manifestations at the first RTX. The patient had both concurrent enterocolitis and invasive pulmonary aspergillosis for 4.4 months after the first RTX. Another 54-year-old male patient with MPA (patient #2) also had MPO-ANCA and exhibited only renal manifestations at the first RTX. The patient had presented with atypical pneumonia, in which the pathogen was not identified, for 3.8 months after the first RTX. A third 28-year-old male patient had proteinase 3 (PR3)-ANCA and exhibited general, mucous and ocular, otolaryngological, cardiovascular, renal, and nervous systemic manifestations. The patients had both cytomegalovirus pneumonia and cellulitis. Two patients with MPA died (Table 2) and they died of the infection mentioned above. In AAV without serious infection, 5 patients died. The causes of death were brain hemorrhage, pneumonia, idiopathic pulmonary fibrosis, candida sepsis, and sepsis related cholangitis.

In the comparative analysis between the two groups based on the presence of current serious infections, patient with AAV with serious infections during the first 6 months of follow-up exhibited a significantly lower cumulative survival rate than those without serious infections (p<0.001) (Figure 2).

However, in the univariate analysis, there were no significant variables to predict the occurrence of serious infections. Chronic obstructive pulmonary disease tended to predict serious infection (HR=7.977; 95% confidence interval [CI]: 0.725, 88.203); however, this was not statistically significant (Supplementary Table 1).