Objective. To determine the predictors of all-cause mortality and infection during inducing treatment in a population-based cohort of ANCA-associated vasculitis (AAV).

Methods. The study included 198 cases of AAV diagnosed in Renji Hospital from May 2011 through May 2020. Outcome data were collected during follow-up of AAV patients. Severe infection events (requiring hospitalization and treatment with intravenous antibiotics) during induction therapy were also identified. Demographic, clinical and laboratory results were tested as potential predictors in multivariable models.

Results. A total of 198 patients were followed from time of disease diagnosis to August 2020 or death. 168 patients are alive with a median follow up of 36 (20-60) months. Leading causes of death within 6 months were infection (42%), respiratory failure (25%) and renal failure (17%). After 6 months, the major causes of death were infection (39%), respiratory failure (22%), cancer (17%) and cardiovascular / cerebrovascular events (11%). Multivariable analysis showed that older age (>65 years), higher Birmingham Vasculitis Activity Score (BVAS, ≥15), infection at diagnosis or during induction therapy and disease relapse (≥2 times) were independent predictors of all-cause mortality. Besides, higher S-creatinine, BVAS ≥15, myeloperoxidase (MPO) positivity and lack of prophylaxis with sulfamethoxazole (SMZ) were predictors of severe infection events during induction therapy. 

Conclusion. Patients with older age and higher disease activity are at increased risk of death. The events of infection at diagnosis or during induction therapy and disease relapse also threaten patients’ lives. Besides, poorer renal function, high disease activity and MPO positivity are associated with severe infection. SMZ prophylaxis during induction therapy may be an effective measure to reduce the risk of infection.

ANCA-associated vasculitis (AAV) is a group of autoimmune-related inflammation of small blood vessels with characteristic antineutrophil cytoplasmic antibodies (ANCA)[1]. Three phenotypic variants of AAV are defined, based on clinicopathological features: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophil granulomatosiswith polyangiitis (EGPA)[2]. With the precision of experimental indicators, the number of patients diagnosed with AAV is increasing in recent years[3,4].

Multiple organs may be involved in AAV, such as the respiratory tract, eyes, lungs, kidneys, skin, and nervous system. Among which, the kidney and lung particularly threatening patients’ health and lives. Poor outcomes are attributed to inappropriate treatments that have insufficient effects and toxic effects[5]. The treatment strategy of AAV has optimized with two phases: first aimed at inducing remission and the latter to maintain remission and prevent relapse. The induction therapy is usually the first 6 months after diagnosis. Severe infection in the early stage of the disease, including infection at disease diagnosis and infection during induction therapy, is quite common in clinical practice[6,7]. Infection not only aggravates the injury of organs, but also makes it more difficult to apply effective treatment, resulting in the increases of disease activity. Actually, mortality is extremely high in the first year after disease onset due to active vasculitis and infections.In cohorts observed in Western countries, one year survival rate was around 82~95%while that in Japan was 79.1%[8,9].In an earlier study, Bourgarit et al. showed that active vasculitis was the leading cause of deaths in the first year and that treatment with corticosteroid alone was associated with early death[10]. The study from Massachusetts General Hospital found that the most prominent cause of death for patients was still infection compared with the general population. Nowadays, with the widespread use of immunosuppressants, most patients are treated by glucocorticoid combined with CTX or RTX. Despite their quick effectiveness, the two drugs have comparable adverse effects[11] of increasing the incidence of infection by causing hypogammaglobulinemia and leukopenia. Insufficient treatment leads to the relapse of disease while aggressive treatment put patients under over-immunosuppressants[12,13]. Therefore, it is of great significance to balance the potent treatment as well as the adverse events alongside by exploring the prognosis of AAV patients and risk factors for infection.

The aim of our study is to determine the predictors of all-cause mortality and infection during induction therapy in a population-based cohort of ANCA-associated vasculitis (AAV) patients from Renji Hospital.

Population

We identified an incident cohort of AAV patients diagnosed between May 2011 and May 2020 in Renji Hospital. All had a clinical diagnosis of small vessel vasculitis established by clinical manifestation, diagnostic histology, and positive ANCA. The patients were followed up until death or the end (November 2020) of the study. Patients with incomplete information or secondary vasculitis including allergic purpura, tumor, drug associated AAV and cryoglobulinemia were excluded. As well as those followed up less than 6 months. All patients met the 2012 Chapel Hill Consensus Conference definition. The study was approved by the Ethics Committee of Renji Hospital, and all patients gave written informed consent. The study was performed in accordance with the Declaration of Helsinki.

Definition

The activity of AAV was assessed by Birmingham Vasculitis Activity Score (BVAS). Relapse was defined as the new appearance or recurrence of one or more symptoms with a BVAS ratio ≥1 after remission and it was likely to be attributable to vasculitis disease activity and not to alternative pathology such as infection after appropriate investigation[14]. Infection in the early stage of the disease included infection at diagnosis without treatment and infection during induction therapy. Severe infection was defined as an infection that required hospitalization and intravenous antibiotics for at least 3 days. End stage renal disease (ESRD) was defined by demand of chronic dialysis and/or an eGFR < 15>

Data collection

The baseline characteristics of these patients was recorded at diagnosis. The following data were collected: age, gender, ANCA serology, hemoglobin, albumin, erythrocyte sedimentation rate(ESR), C-reactive protein(CRP), 24h urine protein and creatinine(Cr). Severe infection during induction therapy was recorded. The follow-up was conducted by outpatient service or telephone calls. During the follow-up, major events including relapse, severe infection, ESRD, and death were recorded. Same laboratory data were collected at each relapse event. BVAS was calculated at diagnosis and each hospitalization. Death were also recorded. Of patients that died outside of hospital the exact cause of death could not be identified and was therefore designated unknown in these cases. Data of type and site of infection, pathogen results, and prescription of antibiotics were recorded when available.

Data are presented as median with interquartile range(IQR) when appropriate. Cox regression analysis was applied to investigate predictors of all-cause mortality. The following variables were selected: age at diagnosis, sex, organ involvement, BVAS, clinical diagnosis, ESR, CRP, 24h protein urine, albumin, S-creatinine, ANCA serology, relapse. Risk factors for all-cause mortality with a p-value < 0 href="https://www.cnblogs.com/sddai/p/6279572.html">fisher’s exat test—when Chi-square test was not appropriate. 

To study the predictors of severe infection during induction therapy, only patients who did not get infected at diagnosis were included. Univariate and multivariate logistic regression models were developed to determine predictors of severe infection during induction therapy. The following variables were selected for univariate analysis: age at diagnosis, sex, BVAS, Hemoglobin, 24h protein urine, albumin, S-creatinine, ANCA serology, induction therapy, prophylaxis with SMZ. Risk factors for severe infection with a p-value < 0>

Baseline characteristics and major events during follow up 

The characteristics of 198 included patients(52

This population-based study followed 198 AAV patients, analysing their courses of infection and death, and discovered that age (>65 years) and BVAS (≥15) were the common predictors to infection and death. Infection in the early stage and relapse(≥2times) independently contributed to mortality while high levels of S-creatinine, MPO-ANCA+ and lack of prevention with SMZ increased the incidence of severe infection. The findings is instrumental in making clinical treatment strategies on the purpose of reducing patients mortality and infection rates, ultimately serving better clinical remission of AAV patients.

In the previous prognostic analysis of AAV, few studies concerning on the survival and infection of the Oriental population. Firstly, higher BVAS score means severer condition of the AAV patients and some studies believed that it predicted the refractory and recurrence of MPA and GPA[16,17]. Which is confirmed in our study that patients with BVAS(≥15) were prone to infection and death. The refractory and recurrence of AAV result in mroe damage to organs and require a higher dose of immunosuppressants. However, BVAS score is not only designed for small-vessel vasculitis, but also includes other vasculitis such as Takayasu arteritis. Therefore, an improved grading system specifically designed for AAV based on BVAS may be more sensitive and accurate. Secondly, it was not surprising that increasing age was associated with growing probability of mortality. A South Korean cohort of the elderly prognosis study also defined age as a risk factor for prognosis[18]. The older is more likely to occur treatment complications and infection. Besides, Rennie L. Rhee’s study [19] finded that the baseline creatinine level was a basic predictor of ESRD or death in a cohort of 554 patients. Severe renal dysfunction was identified a predictor of mortality in patients with AAV in other similar studies as well[20]. Although in our study, creatinine was not an independent risk factor in the multivariate cox analysis of prognosis (p=0.054), it affected the survival in univariate analysis. To be notice, the level of creatinine at diagnose is part of the BVAS grading, which may explained why creatinine is not an independent predictor while BVAS is. 

Infection has always been a troublesome adverse events of AAV. The impact of infection on the outcome of other rheumatic disease and chronic kidney diseases has been identified in a number of studies. However, the researches paid attention to that of AAV are limited. Our study showed that infection in the early stage of AAV contributed to morality independently. Which may resulted from the increasing disease activity along with infection aggravates the injury of multiple organs. Meanwhile, the severe infection could get in the way of the promptly use of immunosuppressants. To further determine the susceptible population during induction therapy, werestricted analysis to thoseweren’t infected at diagnosis. Itshowed that patients with poor renal function and high disease activity wereat higher risk of infection during induction therapy, which was in accordance with the prognosis analysis. It is also worth noticing that MPO-ANCA+ patients were more susceptible toinfection than PR3-ANCA+ patients, which was in accordance of thefindings of the research of Jens Rathmann et al[21]. Moreover, use of SMZ was a protective factor against infection. Hence, SMZ should be taken into consideration for patients with high risk of infection during induction therapy .Previous studies have demonstrated that high cumulative doses of CTX increased the risk of infection[22]. Hower, in our study, we did not observe significant difference between CTX and RTX recipients.In our cohort, the one-year survival rate was 88%. In a study from Massachusetts General Hospital, the leading cause of death in AAV patients was cardiovascular disease and infection[23]. Other Western studies have reached similar conclusions[24-26]. Intersetingly, in our cohort, interestingly, cardiovascular disease was not so significant as it was in Western researches. There differences may owing to different races, which highlighted further researches on Asian populationsto explain this difference.

Our study also has some limitations. Firstly, it is a single center study which may not be representative of all AAV patients, external validation is needed to confirm our findings. Secondly, detailed records of the dose of corticosteroids are not complete. Thus, the effect of the conticosteroids on prognosis and infection could not be analyzed. The are also some strengths in the study. Firstly, this study fills the gap in the Asian region of AAV patients of this kind of observation study. Then, by dividing the timespan into six months and later, it informs clinicians about different treatment priorities during induction therapy or maintenance therapy. During induction therapy, it is of great necessity to control infection while exerting potent immunosuppressants on patients to quickly contain the advancing of disease.