Comparison of severity classification in Japanese patients with antineutrophil cytoplasmic antibody-associated vasculitis in a nationwide,prospective, inception cohort study

Objective: To compare disease severity classification systems for six-month outcome prediction in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).

Methods: Patients with newly diagnosed AAV from 53 tertiary institutions were enrolled. Six-month remission, overall survival, and end-stage renal disease (ESRD)-free survival were evaluated.

Results: According to the European Vasculitis Study Group (EUVAS)-defined disease severity, the 321 enrolled patients were classified as follows: 14, localized; 71, early systemic; 170, generalized; and 66, severe disease. According to the rapidly progressive glomerulonephritis (RPGN) clinical grading system, the patients were divided as follows: 60, grade I; 178, grade II; 66, grade III; and 12, grade IV. According to the Five-Factor Score (FFS) 2009, 103, 109, and 109 patients had ≤1, 2, and ≥3 points, respectively. No significant difference in remission rates was found in any severity classification. The overall and ESRD-free survival rates significantly differed between grades I/II, III, and IV, regardless of renal involvement. Severe disease was a good predictor of six-month overall and ESRD-free survival. The FFS 2009 was useful to predict six-month ESRD-free survival but not overall survival.

Conclusions: The RPGN grading system was more useful to predict six-month overall and ESRD-free survival than the EUVAS-defined severity or FFS 2009.     

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.     

Classification of vasculitis: From historical controversies to present day pragmatic consensus

The classification of the systemic vasculitides has been controversial for several decades. However, over the past twenty years there have been several major developments, which means that there is pragmatic consensus regarding classification. These include the American College of Rheumatology criteria first published in 1990, and the Chapel Hill Consensus Conference definitions originally promulgated in 1994, but revised and extended in 2012. More recently the classical division of the ANCA vasculitides using clinical phenotype has come under scrutiny with evidence from epidemiological, genetic and outcome studies that perhaps these conditions should be classified on the basis of ANCA specificity into PR3-ANCA positive and MPO-ANCA positive groups. There remains, however, a major need for validated classification and diagnostic criteria, a need which hopefully the DCVAS project will address.     

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.     

2017 Clinical practice guidelines of the Japan Research Committee of the Ministry of Health,Labour, and Welfare for Intractable Vasculitis for the management of ANCA-associated vasculitis

Objective: The Japan Research Committee for Intractable Vasculitis has fully revised the clinical practice guidelines (CPG) for the management of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) to improve and standardize the medical treatment of the disease in Japan.

Methods: The previous CPG was published in a classical review style in Japanese in 2011 and 2014. We adopted the Grading of Recommendations Assessment, Development and Evaluation system for this revision, and various stakeholders, including patients, participated in it. The expected users of this CPG are AAV patients in Japan and their families and healthcare professionals, including both AAV specialists and non-specialists. We set clinical questions concerning the three important clinical topics of remission induction therapy, plasma exchange, remission maintenance therapy, and developed eight recommendation statements.

Results: For remission induction therapy for newly developed AAV, we weakly recommend glucocorticoid (GC) plus intravenous cyclophosphamide pulse (IVCY) or oral cyclophosphamide (POCY) rather than GC alone, and IVCY rather than POCY. We also weakly recommend CY rather than rituximab. In the case of AAV with severe renal impairment, we weakly recommend plasma exchange as a conjunction therapy. We weakly recommend azathioprine for remission maintenance therapy.

Conclusion: The revised CPG has demonstrated evidence-based treatment recommendations for AAV.     

第487例——双眼突出、头痛、视物模糊

患者男性,51岁。因双眼突出、头痛、视物模糊半年就诊。主要临床特征为球后炎性假瘤及腹膜后纤维化,初诊为肉芽肿性多血管炎(GPA),先后予地塞米松10 mg/d静脉输液5 d,口服泼尼松1 mg·kg^-1·d^-11个月后逐渐减量,同时联合口服环磷酰胺100 mg/d治疗后,病情曾一度维持稳定,但诊治过程中发现硬脑膜占位、骨质硬化等无法用GPA解释,经病理活检及基因检查诊断为脂质肉芽肿病(ECD),加用维罗替尼治疗(480 mg,2次/d),目前患者病情稳定,仍在随访中。临床医生应提高对ECD的认识与重视。     

Systematic review and meta-analysis for 2017 clinical practice guidelines of the Japan research committee of the ministry of health,labour, and welfare for intractable vasculitis for the management of ANCA-associated vasculitis

Objectives: To provide evidence for the revision of clinical practice guideline (CPG) for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) by the Japan Research Committee for Intractable Vasculitis.

Methods: PubMed, CENTRAL, and the Japan Medical Abstracts Society were searched for articles published between January 1994 and January 2015 to conduct systematic review (SR), and the quality of evidence was assessed with GRADE approach.

Results: Nine randomized controlled trials (RCTs) and two non-RCTs were adopted for remission induction therapy, three RCTs and two non-RCTs for plasma exchange, and five RCTs and one non-RCT for remission maintenance therapy. A significant difference was found in efficacy and safety for the following comparisons. In the non-RCT adopted for remission induction therapy, glucocorticoid (GC)?+?cyclophosphamide (CY) was significantly superior to GC monotherapy regarding remission. GC?+?intravenous CY for remission induction therapy was superior to GC?+?oral CY regarding death at one year, serious adverse events, and serious infection. Concomitant use of plasma exchange for remission induction therapy of AAV with severe renal dysfunction reduced risk of end-stage renal disease versus non-users at month 3.

Conclusion: This SR provided necessary evidence for developing CPG for the management of ANCA-associated vasculitis.     

Vasculitis research: Current trends and future perspectives

We discuss recent and prospective research in small and large vessel vasculitis. Large cohorts of Takayasu arteritis (TA) have been recently published from across the world, clarifying our understanding of this uncommon disease. Novel open‐ended approaches like large‐scale genotyping, proteomics and metabolomics have helped gain novel insights into TA, giant cell arteritis (GCA) and anti‐neutrophil cytoplasmic antibody‐associated vasculitis (AAV). Recent advances in the imaging of TA and GCA offer promise for earlier diagnosis and better monitoring of response to therapy. Although two randomized controlled trials of abatacept and tocilizumab failed to meet their primary end‐points, successful large‐scale studies of abatacept and tocilizumab in GCA hold promise for better disease control. While cyclophosphamide has revolutionized the management of AAV, increasing use of rituximab as an alternative induction regimen, as well as use of novel approaches involving reduced or no corticosteroid use for AAV and alternative agents such as avacopan (a complement 5a receptor antagonist) hold promise for lesser toxic induction regimens in the future. Increasingly, the risk of cardiovascular events and comorbidities such as osteoporosis are being recognized as factors affecting long‐term prospects of patients with vasculitis. There is a shift in emphasis to utilize patient‐reported outcomes to more accurately gauge the impact of vasculitides and their treatment.     

老年患者嗜酸细胞肉芽肿性血管炎的临床特征

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,以呼吸系统受累（如哮喘）最为常见。影像学表现为肺部非固定性斑片状浸润影、磨玻璃影、实变、结节、胸腔积液等,也可出现肺间充质改变。该病在成年人中常见,无明显性别差异;年龄是预后不良的影响因素之一。临床研究分析发现老年患者有更高的患病率和死亡率,本文就老年患者EGPA的临床特征进行文献复习,并综述如下。     

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.