The frequency of ANCA-associated vasculitis in a national database of hospitalized patients in China.

BACKGROUND: Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is a group of life-threatening autoimmune diseases. The epidemiological data on AAV in China are limited. The aim of the present study is to investigate the frequency, geographical distribution, and ethnic distribution of AAV in hospitalized patients in China, and its association with environmental pollution. METHODS: We investigated the hospitalized patients in a national inpatient database covering 54.1% tertiary hospitals in China from 2010 to 2015. Diagnosis of AAV was extracted according to the definition of International Classification of Diseases (ICD)-10 codes and free text. Variables from the front page of inpatient records were collected and analyzed, including frequency, geographic distribution, demographic characteristics and seasonal variations of AAV. The association between various environmental pollutants and frequency of AAV was further analyzed. RESULTS: Among 43.7 million inpatients included in the study period, 0.25‰ (10,943) were diagnosed as having AAV. The frequency of AAV was relatively stable during the study period (from 0.34‰ in 2010 to 0.27‰ in 2015). The proportion of AAV increased with latitude (0.44‰ in Northern China and 0.27‰ in Southern China in 2015). Hospitalizations were mostly observed in winter (30.2%). The Dong population, an ethnic minority of the Chinese population, had the highest frequency of patients with AAV (0.67‰). We also found a positive association between the exposure to carbon monoxide and the frequency of AAV (R2 = 0.172, p = 0.025). In Yunnan province, the frequency of AAV increased 1.37-fold after the Zhaotong earthquake, which took place in 2014. CONCLUSIONS: Our present investigation of hospitalized patients provided epidemiological information on AAV in China for the first time. A spatial and ethnic clustering trend and an association between pollution and the frequency of AAV were observed.

Global ethnic and geographic differences in the clinical presentations of anti-neutrophil cytoplasm antibody-associated vasculitis.

Objectives: There are few data on clinical profiles of ANCA-associated vasculitis (AAV) in different ethnic populations. The aim of this study was to examine the differences in the ANCA type and clinical features of AAV between populations using the Diagnostic and Classification Criteria in Vasculitis Study (DCVAS) dataset. Methods: The DCVAS is an international, multicentre, observational study recruiting in 133 sites. Eight ethnic categories were analysed: Northern European, Caucasian American, Southern European, Middle Eastern/Turkish, Chinese, Japanese, Indian subcontinent and other. ANCA type was categorized as myeloperoxidase (MPO), PR3 and ANCA negative. Organ system involvement was recorded using a standard dataset. Differences were analysed by chi-squared tests using a Bonferroni correction and logistic regression (adjusting for age and sex). Northern European was the reference population. Results: Data from 1217 patients with AAV were available and the 967 (79.5%) patients recruited by rheumatology departments were analysed to reduce confounding by recruitment specialty. There were differences in ANCA type between ethnic categories (P < 0.001): MPO-ANCA was more common than PR3-ANCA in Japanese, Chinese and Southern Europeans; PR3-ANCA was more common in the other groups. Compared with Northern Europeans, Japanese had a nearly 60-fold increased chance of having MPO-ANCA (vs PR3-ANCA) [odds ratio (OR) 59.2 (95% CI 8.0, 440.7), P < 0.001] and Chinese had a nearly 7-times increased chance [OR 6.8 (95% CI 2.6, 17.8), P < 0.001]. Ophthalmologic and otorhinolaryngologic involvement were less common in Japanese and Chinese populations than Northern Europeans; otherwise, there were few differences in organ involvement between ethnic groups. Conclusion: This study confirms the previously observed differential occurrence of MPO-AAV and PR3-AAV between different ethnic groups.

Incidence of ANCA-associated vasculitis in a UK mixed ethnicity population.

OBJECTIVES: We aimed to estimate the incidence of ANCA-associated vasculitis in the UK and how this varied by ethnic group. METHODS: We identified incident cases of ANCA-associated vasculitis between March 2007 and June 2013 in the Nottingham-Derby urban area from medical records using multiple sources. We derived the denominator population from the 2011 census, and we calculated incidence rate ratios using Poisson regression. RESULTS: Overall, we identified 107 cases of ANCA-associated vasculitis, giving an incidence of 23.1 per million person-years (95% CI: 18.9, 27.9). The incidence among the white population was 25.8 per million person-years (95% CI: 21.0, 31.3) and among the black and minority ethnic (BME) population 8.4 per million person-years (95% CI: 3.1, 18.3). After adjustment for age and sex, the difference between ethnic groups was not statistically significant (incidence rate ratio 0.7, 95% CI: 0.3, 1.5, P = 0.3). CONCLUSION: Overall, the incidence of ANCA-associated vasculitis was similar to other epidemiological studies. Crude incidence rates were lower in the BME than in the white population, but this was partly explained by the older age profile among the white compared with BME population.

Recent pathogenetic advances in ANCA-associated vasculitis.

Since the discovery of anti-neutrophil cytoplasmic autoantibodies (ANCA), great strides have been made in elucidating the etiology and pathogenesis of disease. In this article, we review recent published key breakthroughs in understanding the pathogenesis of ANCA vasculitis, including some that may lead to novel therapeutics. These breakthroughs have occurred in multiple areas of investigation. A European genome-wide association study (GWAS) revealed the importance of the genetic contribution of proteinase 3 (PR3) and its endogenous inhibitor, alpha (1)-antitrypsin as well as HLA risk. Epigenetic modification of autoantigen genes appears to contribute to perpetuation of disease and possibly relapse risk. Autoantigen excision, a novel method to detect autoantibody epitopes using mass spectrometry, not only revealed pathogenic epitopes in myeloperoxidase (MPO)-ANCA vasculitis and identified unique MPO-ANCA responsible for the majority of ANCA-negative small vessel vasculitis, but has vast applicability to other autoantibody-mediated diseases. An explosion of biomarker studies has revealed circulating cytokines and alternative complement pathway products that may predict active disease. Interestingly, alternative complement pathway blockade in the murine model of disease is protective and a clinical trial in humans using an oral alternative complement pathway inhibitor is underway. Increasing clarity of the role of B and T cells in disease pathogenesis is ongoing. B cell depleting agents have shown great utility in remission induction and maintenance, and monitoring specific B cell subsets during the disease course may have predictive power for remission maintenance. Despite these substantial advances, more research is needed including, but not limited to, validation of existing discoveries. As additional novel discoveries emerge, so will novel therapies, and it is with great hope that these collective insights will ultimately lead to prevention and cure.

ANCA-associated vasculitis in Hispanic Americans: an unrecognized severity.

This study aims to compare the severity and outcomes of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) between Hispanics and Caucasians living in the same geographical area. All patients diagnosed with AAV at two academic institutions in Chicago from January 2006 to December 2012 were retrospectively and prospectively identified. Disease activity was measured with the Birmingham Vasculitis Activity Score (BVAS), and disease damage was measured with the Vasculitis Damage Index (VDI). Student's t test and chi-square tests were employed; p ≤ 0.05 was considered significant. Seventy patients with AAV were identified; 15 patients were excluded. Fifty-five patients were included in the study: 23 Hispanics and 32 Caucasians, 35 patients with granulomatosis with polyangiitis (Wegener's), 12 with microscopic polyangiitis, 7 with eosinophilic granulomatosis with polyangiitis, and 1 with renal-limited vasculitis. Compared to Caucasians, Hispanics had a higher BVAS at presentation (16.3 ± 7.6 versus 10.7 ± 7.5, p = 0.006), a higher VDI at presentation (2.90 ± 1.50 versus 2.06 ± 1.30, p = 0.030), and a cumulative VDI (3.90 ± 1.70 versus 2.50 ± 1.90, p = 0.010). Renal involvement was more common among Hispanics (85 % of Hispanics versus 48 % of Caucasians, p = 0.01). Seventy percent of Hispanics had acute renal failure (mean creatinine = 3.37 ± 4.4 mg/dl) of whom seven (50 %) required dialysis, versus 25 % of Caucasians (mean creatinine = 1.78 ± 1.57 mg/dl, p = 0.03) and only two requiring dialysis. Compared to Caucasians, Hispanics with AAV present with more severe disease and higher damage indices. Larger studies are required to confirm these findings and delineate the respective roles of environment and genetics in the pathogenesis of the disease.

Predictors of treatment resistance and relapse in Chinese patients with antineutrophil cytoplasmic antibody-associated disease.

OBJECTIVE: The prevalence and significance of treatment resistance and relapse in patients from China with antineutrophil cytoplasmic antibody-associated (ANCA) disease are poorly understood. METHODS: A total of 98 patients with ANCA vasculitis, diagnosed between January 2003 and December 2009 in the China-Japan Friendship Hospital, were enrolled in this retrospective study. RESULTS: Fifteen patients (15.3%) were categorized as having cytoplasmic and/or proteinase 3 (PR3) ANCA and 83 patients (84.7%) had perinuclear and/or myeloperoxidase (MPO) ANCA. After the induction phase treatment, the disease was resistant to therapy in 24 (25%) of the patients. A response to initial treatment occurred in 74 patients (75%). Of these 74 patients, remission was achieved and sustained with or without maintenance therapy in 41 patients (55%). Multivariable logistic regression models revealed that female sex was a statistically significant predictor of treatment resistance (OR 2.85; 95% CI: 1.06-2.86; p = 0.036). Additionally, elevated serum creatinine level, with each increment of 150 µmol/l, predicted resistance (p = 0.002). Among the 74 patients where remission was achieved, Cox proportional hazards models detected that those with PR3 ANCA were 1.31 times more likely to experience a relapse than were patients with MPO ANCA (95% CI: 1.01-5.35; p = 0.0001). Lung involvement was associated with an increased risk of relapse (HR 1.87; 95% CI: 1.12-4.35; p = 0.014). Although not significant, advanced age tended to be associated with relapse (p = 0.08). CONCLUSION: Our findings highlight the important effect of female sex and severity of renal disease at presentation as predictors of treatment resistance, and PR3 ANCA and lung involvement as predictors of relapse.

ANCA-associated vasculitis: report from Korea.

We investigated the clinical features of Korean patients with anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) by reviewing the literature. The characteristics of AAV in Korean patients were as follows: (1) granulomatous and limited disease is prevalent in granulomatosis with polyangiitis (Wegener's) (GPA), (2) ANCA positivity is lower in GPA (56.6-68.9%) and eosinophilic granulomatosis with polyangiitis (EGPA) (5.9-8.3%), whereas it is higher in microscopic polyangiitis (MPA) (69-94%), (3) C-ANCA/proteinase 3 (PR3)-ANCA positivity is 71.5-100% in GPA and P-ANCA/myeloperoxidase (MPO)-ANCA positivity reached 94-100% in patients with MPA, (4) renal involvement or progression to end-stage renal disease was lower in Korean patients with GPA and EGPA than in Caucasians with GPA and EGPA (according to data provided in reports). The data provided here may need to be confirmed in large-scale studies.

Clinical findings on ANCA-associated renal vasculitis from the Japan RPGN registry obtained via a questionnaire survey.

Renal involvement with significant organ damage is common in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). As a result, it is independently referred to ANCA-associated renal vasculitis. Clinically, ANCA-associated renal vasculitis is characterized by rapidly progressive glomerulonephritis. Pathologically, it is defined by pauci-immune type necrotizing and crescentic glomerulonephritis. According to previous reports from all over the world, the etiology, prevalence, and prognosis of RPGN including ANCA-associated renal vasculitis varies among races and periods. To elucidate the clinical characteristics of Japanese RPGN patients, a registry derived from a questionnaire survey was established in 1999 and maintained until 2006. As a result, 1,772 cases were collected, analyzed, and reported previously. In this mini-review, we outline the characteristic clinical findings of Japanese patients (Asian) with ANCA-associated renal vasculitis, based on the registry data.

Genetics of ANCA-associated vasculitis in Japan: a role for HLA-DRB1*09:01 haplotype.

The epidemiology of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is considerably different between European and Asian populations. Whereas granulomatosis with polyangiitis is the most common form of AAV in northern European populations, microscopic polyangiitis (MPA) accounts for the majority of AAV in Japan. This difference may at least in part derive from the difference in genetic background. In this review, I focus on our observation on HLA, an obvious candidate gene for immune disorders, and discuss its potential implication. In Japanese AAV, significant association was detected with HLA-DRB1*09:01, the carrier frequency of which was increased in MPA [P=0.0087, odds ratio (OR) 1.90, 95% confidence interval (CI) 1.17-3.08] and in myeloperoxidase (MPO)-ANCA-positive AAV (P=0.0016, OR 2.05, 95% CI 1.31-3.23) when compared with healthy Japanese controls. HLA-DRB1*09:01 is one of the most common HLA-DRB1 alleles in Asians but is rare in Caucasian populations. Interestingly, HLA-DRB1*09:01 has been shown to be associated with multiple autoimmune diseases, including type 1 diabetes, rheumatoid arthritis, and systemic lupus erythematosus, suggesting that either HLA-DRB1*09:01 itself or other genes in tight linkage disequilibrium may play a role in a molecular pathway shared by various autoimmune diseases in Japanese and possibly in other Asian populations.

Antineutrophil cytoplasmic autoantibody-associated vasculitis in Chinese patients.

Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is a common autoimmune disease in China. AAVs in the majority of Chinese patients are microscopic polyangiitis with antigenicity to myeloperoxidase. Propylthiouracil is the leading cause of drug-induced AAV. The genetic background and immunological characteristics of ANCA, such as the epitope, IgG subclass and avidity, might contribute to various clinical phenotypes of AAV.

Evaluation of weekly-reduction regimen of glucocorticoids in combination with cyclophosphamide for anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis in Japanese patients.

The current therapeutic regimen recommended by the European League against Rheumatism (EULAR) for anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) is continuation of initially administered doses of glucocorticoids (GCs) in combination with cyclophosphamide (CYC) for 1 month followed by gradual tapering. Considering the adverse effects of GCs, another tapering regimen of GCs with CYC, which was characterized by tapering GCs weekly, was reported by the British Society of Rheumatology (weekly-reduction regimen). The aim of the present study is to evaluate the safety and efficacy of this weekly-reduction regimen for Japanese AAV patients in comparison with the monthly-reduction regimen recommended by the EULAR. We retrospectively reviewed medical records of adult patients newly diagnosed with AAV during the period from April 2000 to December 2010. The outcome measures were rates of remission, relapse, infection, and GC-induced diabetes mellitus during the first 12 months. Clinical data in the two groups and categorial variables with a possible relation to the outcomes were compared by using the t test and chi-square test, respectively. Twenty-four patients were enrolled in our study. All of the patients achieved remission, and the rates of relapse during the first 12 months were not statistically different between the two groups (P = 0.16). Patients treated with the weekly-reduction regimen were less liable to have infection (P = 0.03) and impaired glucose tolerance (P = 0.017), compared with those treated with the monthly-reduction regimen. A therapeutic strategy using the weekly-reduction regimen of GCs would be effective and would have fewer side effects than the monthly-reduction regimen.

Clinical features and outcome of microscopic polyangiitis under a new consensus algorithm of ANCA-associated vasculitides in Korea.

The classification system for antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis and polyarteritis nodosa had its limitations due to numerous overlapping features of these disease entities. The aim of this study is to investigate the clinical features and outcome of patients diagnosed with microscopic polyangiitis (MPA) according to the newly proposed consensus algorithm of ANCA-associated vasculitides and polyarteritis nodosa. Fifty-five cases of MPA, comprised of 33 men and 22 women, diagnosed according to a new consensus algorithm at a single tertiary hospital were identified for analysis. The main clinical features were constitutional symptoms (78.2%), followed by renal involvement (74.5%), musculoskeletal symptoms (67.3%), skin manifestations (50.9%), neurologic involvement (43.6%), and lung involvement (41.8%). P-ANCA and/or anti-myeloperoxidase antibody were present in 69.1%. Five Factor Score and Birmingham Vasculitis Activity Score (BVAS) at diagnosis were 1.1 ± 0.9 and 10.9 ± 4.9, respectively. Forty-four patients were available for a long-term follow-up, and six patients (13.6%) resulted in death. Mortality was associated with BVAS > 9 at the time of diagnosis, age > 60 years, and presence of cardiomyopathy and interstitial lung disease. The survival rate at 1 and 3 years was 93.9 and 89.2%, respectively. Eight patients (14.5%) required dialysis at the time of diagnosis. This is the first study to demonstrate the clinical features in patients with MPA using a new consensus algorithm. Survival rate was higher than previously reported, and interstitial lung disease was a new risk factor for death in patients with MPA.

Epidemiology of ANCA-associated vasculitis.

The epidemiology of the antineutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV), comprising Wegener's granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome, poses considerable challenges to epidemiologists. These challenges include the difficulty of defining a case with a lack of clear distinction between the different disorders, case capture, and case ascertainment. The AAV are rare and therefore a large population is required to determine the incidence and prevalence, and this poses questions of feasibility. Despite these difficulties a considerable body of data on the epidemiology of the AAV has been built in the past 20 years with an interesting age, geographic, and ethnic tropism gradually being revealed. Most of the data come from White populations of European descent, and the overall annual incidence is estimated at approximately 10-20/million with a peak age of onset in those aged 65 to 74 years.

Off-label use of rituximab in 196 patients with severe, refractory systemic autoimmune diseases.

OBJECTIVES: To analyse the safety and efficacy of the off-label use of rituximab in patients with severe, refractory systemic autoimmune diseases. METHODS: In 2006, the Study Group on Autoimmune Diseases of the Spanish Society of Internal Medicine created the BIOGEAS project, a multicenter study devoted to collecting data on the use of biological agents in adult patients with systemic autoimmune diseases refractory to standard therapies (failure of at least two immunosuppressive agents). RESULTS: One hundred and ninety-six patients with systemic autoimmune diseases treated with rituximab have been included in the Registry (158 women and 38 men, mean age 43 years). Systemic autoimmune diseases included systemic lupus erythematosus (107 cases), inflammatory myopathies (20 cases), ANCA-related vasculitides (19 cases), Sjögren's syndrome (15 cases) and other diseases (35 cases). A therapeutic response was evaluable in 194 cases: 99 (51%) achieved a complete response, 51 (26%) a partial response and 44 (23%) were classified as non-responders. After a mean follow-up of 27.56+/-1.32 months, 44 (29%) out of the 150 responders patients relapsed. There were 40 adverse events reported in 33 (16%) of the 196 patients. The most frequent adverse events were infections, with 24 episodes being described in 19 patients. Thirteen (7%) patients died, mainly due to disease progression (7 cases) and infection (3 cases). CONCLUSIONS: Although not yet licensed for this use, rituximab is currently used to treat severe, refractory systemic autoimmune diseases, with the most favourable results being observed in Sjögren's syndrome, inflammatory myopathies, systemic lupus erythematosus and cryoglobulinemia.