Clinical characteristics of and risk factors for serious infection in Japanese patients within six months of remission induction therapy for antineutrophil cytoplasmic antibody-associated vasculitis registered in a nationwide,prospective, inception cohort study

Objectives: The purpose of this study was to identify the clinical characteristics and predictors of serious infections (SIs) in the RemIT-JAV, a nationwide, prospective, inception cohort study for Japanese patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV).

Methods: We analyzed SIs within six months of remission induction therapy in 156 AAV patients. Hazard ratios with 95% confidence intervals (CIs) for SIs were calculated using the COX proportional hazard model.

Results: Sixty-three SIs in 42 patients were identified. The incidence rate (IR) of SIs was 87.59/100 patient-years. The median length of time to the onset of first SIs was 54 days. Hazard ratios (95%CI) for SIs were 1.97 (0.99–3.95) for age >65 years, 0.47 (0.25–0.89) for female sex, 2.11 (1.05–4.27) for the severe form of AAV, and 2.88 (1.49–5.88) for initial PSL >0.8?mg/kg/day in the first model, and 2.64 (1.39–5.01) for smoking and 3.27 (1.66–6.45) for initial PSL >0.8?mg/kg/day in the second model.

Conclusions: Lowering the IR of SIs in Japanese AAV patients is mandatory to improve the vital prognosis of these patients. For remission induction therapy of AAV patients with these risk factors, risk management of immunosuppressive treatment should be carefully considered.     

Clinical features and treatment outcomes of otitis media with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (OMAAV): A retrospective analysis of 235 patients from a nationwide survey in Japan

Objective: We aimed to analyze clinical features and treatment outcomes of otitis media caused by antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), i.e. otitis media with AAV (OMAAV).

Methods: This survey was performed between December 2013 and February 2014. The study began with a preliminary survey to 123 otolaryngology institutions in Japan to inquire about their experiences with OMAAV patients during the past 10 years, and was followed by a questionnaire survey to investigate clinical and laboratory findings. OMAAV was defined using the criteria described in the text.

Results: Two hundred and thirty-five patients classified as OMAAV were enrolled in this study. They were characterized as follows: (1) disease onset with initial signs/symptoms due to intractable otitis media with effusion or granulation, which did not respond to ordinary treatments such as antibiotics and insertion of tympanic ventilation tubes, followed by progressive hearing loss; (2) predominantly female (73%) and older (median age: 68 years); (3) predominantly myeloperoxidase (MPO)-ANCA-positive (60%), followed by proteinase 3 (PR3)-ANCA-positive (19%) and both ANCAs-negative (16%); (4) frequently observed accompanying facial palsy (36%) and hypertrophic pachymeningitis (28%); and (5) disease often involving lung (35%) and kidney (26%) lesions. Four factors associated with OMAAV were found to be related to an unfavorable clinical course threatening the patient's hearing and/or lives, namely facial palsy, hypertrophic pachymeningitis, both ANCAs-negative phenotype, and disease relapse. The occurrence of hypertrophic pachymeningitis was associated with facial palsy (p?p?p?p?=?0.03) and an improvement in hearing loss (OR =2.58, p?=?0.0002).

Conclusion: Since OMAAV has novel clinical features, the disease may be categorized as a subentity for the classification of AAV.     

抗中性粒细胞胞浆抗体相关血管炎的治疗

抗中性粒细胞胞浆抗体（ANCA）相关血管炎是成人最常见的原发性系统性小血管炎,多器官系统受累,临床表 现高度异质性,未早期有效治疗患者近期死亡率高。近年来随着对其发病机制的深入了解,可选择治疗药物和治疗 策略也在不断发展。需要根据患者临床-病理分型、受累器官、疾病活动性和严重性评价、ANCA血清型进行多维度 评价,并依据现有的循证医学证据,个体化地选择治疗方案。     

ANCA相关性血管炎患者的远期疗效分析

目的 了解抗中性粒细胞胞浆抗体相关性血管炎(antineutrophil cytoplasmic antibody-associated vasculitis,ANCA)患者免疫抑制治疗的远期疗效.方法 回顾分析在我院随访5年以上的所有ANCA相关性血管炎(AAV)患者的随访资料,计算其确诊时及每次随访时的伯明翰血管炎活动评分(BVAS),并就疾病活动性与时间变化及免疫抑制治疗等因素进行相关性评估.结果 共9例患者,这些患者均接受了糖皮质激素和免疫抑制剂的联合治疗,初治时的激素剂量相当于泼尼松(73.9±37.6)mg/d.治疗的第一个半年内缓解率达100％,BVAS在治疗后4年内稳定地降低,但第5年起又开始上升,以后出现反复波动.仅1例长期维持缓解,其余均有复发,其中5例表现为反复发作.平均首次复发时间在治疗后(54.6±23.3)m.复发的危险因素依次为无免疫抑制治疗、生存时间超过5年以及糖皮质激素相当于泼尼松≤10 mg/d.药物副作用包括激素相关糖尿病、骨质疏松、严重感染等,主要发生在前14月内.结论 ANCA相关性血管炎复发率高,多数患者需激素和/或免疫抑制剂不间断的长期维持治疗.     

Classification,diagnosis and treatment of ANCA-associated vasculitis

Diagnosis of anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis is usually not difficult in patient with systemic disease, including lung and kidneys involvement, and laboratory signs of inflammation. The presence of ANCA and the results of histological investigation confirm diagnosis of ANCA-associated vasculitis. Cyclophosphamide/azathioprine in combination with high dose steroids are used to induce and maintain remission of systemic vasculitis. The clinical trials also showed efficacy of rituximab that induces depletion of B-cells. Our understanding and management of ANCA-associated vasculitis improved significantly over the last decades but there is still a lot of debate over its classification, diagnostic criteria, assessment of activity and optimum treatment.     

Severity-based treatment for Japanese patients with MPO-ANCA-associated vasculitis: the JMAAV study

Abstract

We (JMAAV [Japanese patients with MPO-ANCA-associated vasculitis] Study Group) performed a prospective, open-label, multi-center trial to evaluate the usefulness of severity-based treatment in Japanese patients with myeloperoxidase-anti-neutrophil cytoplasmic antibodies (MPO-ANCA)-associated vasculitis. Patients with MPO-ANCA-associated vasculitis received a severity-based regimen according to the appropriate protocol: low-dose corticosteroid and, if necessary, cyclophosphamide or azathioprine in patients with mild form; high-dose corticosteroid and cyclophosphamide in those with severe form; and the severe-form regimen plus plasmapheresis in those with the most severe form. We followed up the patients for 18 months. The primary end points were the induction of remission, death, and end-stage renal disease (ESRD). Fifty-two patients were registered, and 48 patients were enrolled in this study (mild form, n = 23; severe form, n = 23; most severe form, n = 2). Among the 47 patients who received the predefined therapies, 42 achieved remission within 6 months, 5 died, and 1 developed ESRD. Disease flared up in 8 of the 42 patients with remission during the 18-month follow-up period. The JMAAV trial is the first prospective trial for MPO-ANCA-associated vasculitis to be performed in Japan. The remission and death rates were comparable to those in several previous clinical trials performed in western counties. The regimen employed in this trial was tailor-made based on patients’ disease severity and disease type, and it seems that standardization can be consistent with treatment choices made according to severity.     

Plasma exchange treatment improves prognosis of antineutrophil cytoplasmic antibody-associated crescentic glomerulonephritis: a case-control study in 26 patients from a single center

Twenty-six patients with Antineutrophil cytoplasmic antibody (ANCA)-associated crescentic glomerulonephritis (GN) were divided into two groups according to the acute phase treatment: drug therapy consisting of steroids and oral cyclophosphamide plus a plasma exchange (PE) course (group A, 13 patients) or drug therapy alone (group B, 13 patients). Group A patients had a more severe clinical picture and higher serum creatinine than group B (12.7 +/- 6.9 vs. 8.5 +/- 5.3 mg%); nine patients from group A (69%) and five from group B (38%) required dialysis. At follow up (mean 35 months) all patients treated with PE were alive: four of them were in end-stage renal disease. Among group B patients, three (23%) died in the acute phase; 6 (46%) needed renal replacement therapy at follow up. Of the dialysis-dependent patients, five out of nine from group A were free of dialysis, while in group B two out of five patients had died, two had entered a regular dialysis treatment and one had received a cadaver graft. These data suggest that PE may significantly improve the prognosis of patients with ANCA-associated crescentic GN even if they are not dialysis-dependent at the time of diagnosis.     

Endocarditis associated with antineutrophil cytoplasmic antibodies: a case report and review of the literature

We report a case of subacute bacterial endocarditis associated with small vessel vasculitis and a strongly positive cytoplasmic antineutrophil cytoplasmic antibody (c-ANCA) test. It is important to recognize this cause of positive c-ANCA because infectious endocarditis may closely mimic the clinical manifestations of ANCA-associated vasculitides such as Wegener granulomatosis or microscopic polyangiitis. Furthermore, ANCA-associated vasculitis may result in noninfectious endocarditis, which may be confused with bacterial endocarditis. In this paper, we review reported cases of ANCA-positive bacterial endocarditis and compare them to the reported cases of ANCA-associated idiopathic vasculitis with endocardial compromise. Julio A. Chirinos and Vicente F. Corrales-Medina contributed equally in the preparation of this manuscrip     

嗜酸细胞肉芽肿性血管炎抗中性粒细胞胞浆抗体阳性与阴性患者临床特征

嗜酸细胞肉芽肿性血管炎(EGPA)是以外周血和受累脏器组织中嗜酸性粒细胞增高并伴有坏死性肉芽肿为特征的系统性血管炎,依据血清抗中性粒细胞胞浆抗体(ANCA)检测结果可分为ANCA阳性及ANCA阴性表型,ANCA阳性患者更易出现神经系统、肾脏、皮肤紫癜和肺泡出血;心脏和肺受累在ANCA阴性患者中更常见。本文就ANCA阳性与阴性患者的临床表现及受累脏器特征进行文献复习,并综述如下。     

Antineutrophil cytoplasmic antibody-associated vasculitis with alveolar hemorrhage and ruptured renal aneurysm: A case report and literature review

Rationale:Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is characterized by necrotizing damage to small-vessel vasculitis and mainly occurs in the kidney or lung. We report a rare case of AAV manifesting as alveolar hemorrhage and a renal aneurysm.Patient concerns:A 50-year-old Chinese man presented with repeated coughing, expectoration, fever, hypoxemia, and respiratory failure. The patient suffered from rupture of the renal aneurysm during immunosuppressive therapy.Diagnosis:Considering the clinical picture (fever, progressive hypoxemia, renal insufficiency, hemorrhagic bronchoalveolar lavage fluid, and left retroperitoneal hematoma) along with cANCA-PR3 positivity, and lung biopsy findings, the patient was finally diagnosed with granulomatosis with polyangiitis complicated by alveolar hemorrhage and renal aneurysm.Interventions:The patient was initially treated with immunosuppressive therapy combined with plasma exchange and subsequently with renal arterial embolization due to rupture of the renal aneurysm.Outcomes:The general condition and inflammatory reaction improved with immunosuppressive therapy combined with plasma exchange. Unfortunately, the patient did not respond to treatment and eventually died of respiratory failure and acute kidney injury after the rupture of the renal aneurysm.Lessons:We encountered unprecedented difficulties and challenges with renal aneurysm rupture. The possibility of aneurysmal rupture should be carefully considered and frequently checked for immunosuppressive therapy for AAV.     

Update on the epidemiology,risk factors,and outcomes of systemic vasculitides

Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) and giant cell arteritis (GCA) are the most common primary systemic vasculitides of the adult population, while polymyalgia rheumatica (PMR) is a clinical syndrome often associated with GCA.Incidence and prevalence rates of AAV have been increasing in the last decades, whereas those of GCA and PMR have remained stable. The mutual interplay between environmental and genetic risk factors leading to the development of these diseases has been further analyzed in the last years. The role of infectious agents has repeatedly been studied with regard to Staphylococcus aureus, associated with relapse in granulomatosis with polyangiitis, and Herpes zoster, potentially contributing to GCA development.Remission of disease and prevention of disease-related complications are the most important outcomes for all systemic vasculitides. Although these goals are achieved in the majority of patients receiving modern therapies, the prevention of treatment-related complications, especially glucocorticoid side effects, is still an unmet need that is common to AAV, GCA, and PMR.     

Role of plasmapheresis performed in hemodialysis units for the treatment of anti-neutrophilic cytoplasmic antibody-associated systemic vasculitides

Anti‐neutrophilic cytoplasmic antibody (ANCA) positivity is seen in some systemic necrotizing vasculitides. Wegener's granulomatosis and microscopic polyangiitis are among the ANCA‐associated systemic vasculitides (AASV) and mortality is very high when renal failure occurs together with alveolar hemorrhage. The role of plasmapheresis in the treatment of these diseases has been studied retrospectively. Twelve patients with AASV who had plasmapheresis together with immunosuppressive medications have been involved. Primary diseases, immunosuppressive protocols, the number of plasmapheresis sessions, the amount of plasma that has been exchanged, urea and creatinine levels before and after treatment, pulmonary findings, the need for hemodialysis, and the outcome of patients were recorded. The mean age of patients was 52.9 ± 18.2 years. Wegener's granulomatosis was diagnosed in seven (58.3%) and microscopic polyangiitis in five (41.7%) patients. All patients had pulse cyclophosphamide and methylprednisolone followed by maintenance doses and plasmapheresis. Seven patients had hemodialysis at the beginning, and hemodialysis needed to be continued in three patients. Partial and complete remission was seen in 6 (50%) and 3 (25%) patients, respectively, and pulmonary findings regressed in all patients. End‐stage renal disease develops generally in AASV due to rapidly progressive glomerulonephritis causing severe irreversible glomerular damage. The mortality rate rises to 50% in cases of renal failure with diffuse alveolar hemorrhage; therefore, pulse immunosuppressive treatment with plasmapheresis may be life‐saving, as shown in our study.     

A case of ANCA-associated vasculitis with glomerular eosinophilic infiltration: a possible pathogenic implication

We present a 58-year-old male patient with myeloperoxidase antineutrophil cytoplasmic antibody-associated vasculitis with rapidly progressive glomerulonephritis. He failed to fulfill the common American College of Rheumatology criteria for eosinophilic granulomatosis with polyangiitis and was tentatively diagnosed with microscopic polyangiitis. Kidney biopsy showed pauci-immune crescentic necrotizing glomerulonephritis with neutrophilic and eosinophilic infiltration. Previous reports implicate eosinophils in the pathogenesis of this disease. Therefore, this case suggests that infiltrated eosinophils as well as neutrophils might play roles in the development of tissue injury in systemic vasculitis.     

Autoreactive T-cell responses to myeloperoxidase in patients with antineutrophil cytoplasmic antibody-associated vasculitis and in healthy individuals

Abstract

The aim of this study was to evaluate the characteristics of autoreactive T cells to myeloperoxidase (MPO) in patients with MPO-antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Peripheral blood T cells from 15 patients with MPO-ANCA-associated vasculitis and 14 healthy individuals were cultured with three recombinant proteins that together comprised the entire MPO sequence (L, all 112 amino acids (AA) of the light chain; HI, AA 1-227 of the heavy chain; HII, AA 212-467 of the heavy chain), and the antigen-specific T-cell proliferative response was measured by ³H-thymidine incorporation. T-cell responses to MPO-L and HI were both detected in four patients and three healthy donors, and responses to MPO-HII were detected in four patients and seven healthy donors. These findings indicate that at least three independent T-cell epitopes exist on the MPO molecule. Interestingly, the patients whose T cells showed these MPO-induced responses were mainly in remission. Peripheral blood T cells reactive with MPO were primarily of the HLA-DR-restricted CD4⁺ phenotype. In summary, we successfully used recombinant MPO fragments to detect autoreactive CD4⁺ T cells to multiple MPO epitopes in blood samples from patients with MPO-ANCA-associated vasculitis and healthy individuals.