Association between the chemokine receptor 5 delta32 polymorphism and rheumatoid arthritis: a meta-analysis

Abstract

Objectives. In the study cohort enrolled in a prospective open-label, multicenter trial conducted by the Japanese Study Group for MPO-ANCA-associated vasculitis (JMAAV), we conducted this sub-analysis to establish the validity of the Birminghan vasculitis activity score (BVAS) for Japanese patients with MPO-ANCA-associated vasculitis.

Methods. We recorded the BVAS at the time of diagnosis, at 6 weeks after the diagnosis, and at 3, 6, 9, 12, 15 and 18 months after the diagnosis in this study.

Results. The most frequently involved organs in the patients were the lungs, kidneys and the nervous system. The kidney (BVAS; new/worse 69.2 %, persistent 40.4 %), general (BVAS; new/worse 67.3 %, persistent 53.8 %), chest (BVAS; new/worse 36.5 %, persistent 46.2 %) and nervous system (BVAS; new/worse 38.5 %, persistent 25.0 %) were the organ systems most frequently involved by the disease at the baseline. The BVAS for new/worse disease decreased immediately after induction therapy, while improvement of the BVAS for persistent disease after therapy differed among the organ systems.

Conclusions. BVAS was demonstrated to be a valuable guide for selection of the optimal treatment. Thus, BVAS was also found to be a useful tool in Japanese patients for the assessment of disease activity and degree of organ damage in patients with MPO-ANCA-associated vasculitis.     

抗中性粒细胞胞浆抗体阳性与阴性微型多血管炎的比较

目的比较抗中性粒细胞胞浆抗体(ANCA)阳性(ANCA+ve)与ANCA阴性(ANCA-ve)微型多血管炎(MPA)临床与病理的差异,探讨ANCA与MPA病情及预后的关系.方法31例微型多血管炎(MPA),其中男16例,女15例,同时采用标准间接免疫荧光(IF)和ELISA法检测血清ANCA,根据血清ANCA结果分为ANCA+ve组与ANCA-ve组,比较两组肾脏及肾外脏器损害、肾脏病理及预后.两组患者血管炎活动分数(BVAS1)无差异.结果①血清ANCA31例MPA中19例ANCA阳性(61.3%),其中IF-ANCA阳性者8例,ELISA法ANCA阳性者19例.血清抗-GBM抗体均阴性.②发病年龄及病程ANCA+ve组大于ANCA-ve组,分别为(56±11)岁vs(48.5±16.8)岁(P＜0.05)和(30.2±47.7)月vs(6.5±8.8)月(P＜0.01).ANCA+ve组女性多于男性(男/女8/11),而ANCA-ve组男性多见(男/女8/4).③ANCA+ve组需透析病例数及活检时SCr水平(588±334)μmol/L高于ANCA-ve(487±284)μmol/L(P＜0.05),贫血程度更为严重,Hb(78.9±16.2)g/Lvs(95.5±22.0)g/L(P＜0.01).肾活检显示ANCA+ve组新月体比例显著高于ANCA-ve组(61.7±33.2)%vs(33.4±32.8)%(P＜0.01),ANCA-ve组细胞性新月体所占比例高于ANCA+ve组.两组袢坏死、全球硬化、间质血管炎及酸性粒细胞浸润程度相似.④ANCA+ve组伴有2个以上肾外脏器受累比例高于ANCA-ve组(63.2%vs31.3%),肺损害较重,咯血(42.1%)及严重肺出血(15.8%)患者均见于ANCA+ve组.ANCA+ve组消化道出血及眼部受累多见,而皮肤损害ANCA-ve组发生率高于ANCA+ve组(41.7%vs15.8%).⑤ANCA-veMPA预后差.两组治疗方法相似,但治疗后ANCA+ve组仅1例肾功能恢复正常,绝大多数患者需维持透析或处于CRF,5例死亡,而ANCA-ve组3例需要维持性透析,4例肾功能恢复正常,无一例死亡,其余病例肾功能均显著改善.结论血清ANCA阳性与ANCA阴性MPA无论在临床表现、肾脏病理及预后方面均存在一定差异,临床应分别对待.造成这种差异的机制有待进一步研究.     

Is granulomatosis with polyangiitis in Asia different from the West?

The incidence and clinical features of antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) have been shown to vary according to geographical areas, with granulomatosis with polyangiitis (GPA) being more common in northern Europe and microscopic polyangiitis (MPA) being more common in Asian countries. The annual incidence of GPA among Asians varies between 0.37/million to 2.1/million population. The prevalence of GPA has been estimated to be 1.94/100 000 in a Chinese population. Polymorphisms in class II major histocompatibility genes and ETS1 proto‐oncogene has been shown in Asian patients with GPA. There is a difference in mean age at onset and proteinase 3 (PR3) or myeloperoxidase (MPO) positivity in GPA patients from different Asian countries. Those from India had mean age of 40 years and those from Japan had mean age of 65 years. Sixty percent of GPA patients from China and Japan were MPO ANCA positive while the majority of patients from India and Korea were PR3 positive. Geographical variation with lower frequency of renal involvement in Indian studies and higher frequency in Chinese patients has also been noted. Treatment outcomes have been similar to those reported from other parts of the world. Remission was achieved in about two‐thirds of patients while relapses were noted in one‐third to half of the patients. Apart from minor differences in the organ systems involved, MPO‐ANCA GPA and PR3‐ANCA GPA had similar rates of remission and relapses.     

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.     

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.     

The complications of vasculitis and its treatment

Survival following a diagnosis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) has improved since the introduction of cyclophosphamide-based immunosuppressive regimens and is now almost 80% at 5 years. However, mortality remains 2.6 times greater in the population with AAV than in an age- and sex-matched general population. The greatest risk of harm for patients with AAV is during the first year of diagnosis and from the adverse events associated with treatment rather than with active vasculitis. Infection, cardiovascular disease (CVD) and malignancy are the most common causes of death during follow-up. New regimens including rituximab, although with an efficacy similar to that of cyclophosphamide, have not yet shown a clear reduction in adverse events. Therapy for AAV must currently encompass a much greater focus on preventing harm from treatment through vaccination, Pneumocystis jirovecii pneumonia (PJP) prophylaxis, CVD risk assessment and bone protection measures.     

ANCA-associated vasculitis in idiopathic pulmonary fibrosis: A case report and brief review of the literature

Rationale:Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor prognosis. Patients with IPF represent a heterogeneous population with several described clinical phenotypes. More recently, the development of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis in IPF patients, with an incidence higher than that in the general population, has drawn attention.Patient concerns:A 64-year-old woman previously diagnosed with IPF presented to the emergency department with hemoptysis and hypoxemic respiratory failure.Diagnoses:High-resolution chest computed tomography revealed bilateral ground-glass opacities associated with areas of consolidation superimposed on the patient''s fibrotic background pattern. Diffuse alveolar hemorrhage was confirmed by the presence of hemorrhagic bronchoalveolar lavage fluid. Hematological and biochemical investigations revealed an inflammatory syndrome, moderate anemia, and rapidly progressive glomerulonephritis. Serological analysis revealed perinuclear antineutrophil cytoplasmic antibody positivity and high levels of antimyeloperoxidase antibodies antibodies. The patient underwent kidney biopsy, which revealed necrotizing glomerulonephritis. Clinical and laboratory findings were diagnostic of microscopic polyangiitis with lung and renal involvement.Interventions:Cyclophosphamide in combination with methylprednisolone was administered as remission induction therapy. The maintenance therapy consisted of mycophenolate mofetil and prednisone.Outcomes:The patient achieved clinical, radiological, and serological remission within six weeks of treatment.Lessons:The association between IPF and ANCA-associated vasculitis may represent a distinct clinical phenotype. Autoimmune testing for ANCAs should be considered part of the diagnostic work-up and follow-up of patients with IPF because of the clinical and therapeutic implications of developing vasculitis in an already vulnerable patient.     

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.     

Laboratory Diagnosis of ANCA-Associated Vasculitis (AAV) Using a Combination of Immunofluorescence Test (IIFT) and Line Immunoassay (LIA): Single-Centre Report From India

IntroductionAnti-neutrophil cytoplasmic autoantibodies (ANCA) associated vasculitis (AAV) is a small vessel vasculitis with insufficient epidemiological estimates in India. We aimed to determine demographic, clinical features, and laboratory diagnosis of AAV patients presenting to a large tertiary care centre in India.Material and methods1289 patient samples were screened for ANCA by indirect immunofluorescence test (IIFT) and confirmation of ANCA target antigens was done by line immunoassay. Association between IIFT and LIA was determined in AAV.ResultsBy IIFT, ANCA was detected in 13.0% (168 out of 1289), of which 23.8% (40/168) were positive with P-ANCA pattern, 25.0% (42/168) were positive with C-ANCA and 47.6% (80/168) showed an atypical pattern. On evaluation with a line immunoassay, 6.7% (86/1289) were positive out of which 52.3% (45/86), 41.9% (36/86), 8.8% (6/86) were positive for anti-MPO, anti-PR3, and anti-GBM respectively. In eosinophilic granulomatosis with polyangiitis (EGPA) 87.5% (7/8), and microscopic polyangiitis (MPA/RLV) 91.3% (21/23), anti-MPO was the predominantly observed antibody. In granulomatosis with polyangiitis (GPA) anti-PR3 antibody was predominant in 87.5% (28/32) cases. Out of 168 IIF positive samples 8, 32, and 23 cases of EGPA, GPA, and MPA/RLV were observed respectively.ConclusionsThe primary aim of the study was to provide single-centre data to determine the laboratory diagnosis of AAV. A combination of IIFT and LIA was found to be an optimum testing strategy for the laboratory diagnosis of AAV.     

Development of anti-neutrophil cytoplasmic antibody-associated vasculitis in a patient with Graves’ disease independent of anti-thyroid drug therapy

Abstract

Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) in patients with Graves’ disease (GD) is linked with the use of anti-thyroid drugs (ATDs). We report the co-occurrence of AAV and GD in a patient that was independent of ATD therapy. A 38-year-old white male presented with systemic symptoms, palpitations, tremors, purpuric skin lesions, and digital pain. Physical examination and biological tests confirmed GD. He quickly developed multiple digital gangrenes and testicular pain/mass. Skin and testicular biopsies showed granulomatous vasculitis of the small- and medium-sized vessels, while his serum contained anti-proteinase-3 antibody.     

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.     

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.     

Cytomegalovirus infection in systemic necrotizing vasculitis: causative agent or opportunistic infection?

We report on a 69-year-old woman who presented with myalgia, hearing impairment, fever, night sweats, weight loss, muscular weakness, paresthesia, hypesthesia, and hypalgesia. Sural nerve biopsy showed demyelinative and axonal polyneuropathy due to necrotizing vasculitis with fibrinoid necrosis. A positive test for antineutrophil cytoplasmic antibodies (ANCA) with a perinuclear immunofluorescence pattern directed against myeloperoxidase was more suggestive of microscopic polyangiitis (MPA) than of polyarteritis nodosa (PAN), the possible differential diagnoses. In addition, positive tests for cytomegalovirus (CMV) antibodies (immunoglobulin (Ig)M and IgG) and the detection of CMV-DNA in sputum specimens by polymerase chain reaction (PCR) were indicative of active CMV infection. Treatment with ganciclovir and anti-CMV immunoglobulin in addition to prednisolone medication for 6 months resulted in rapid improvement of the clinical symptoms without relapse. CMV infection has been described to be related to ANCA-associated vasculitis in non-immunocompromized patients and may be either a causative agent or an opportunistic infection. Identification of a viral etiology in patients with atypical ANCA-associated vasculitides may lead to different, less aggressive treatment approaches, including antiviral therapy. Received: 5 April 2000 / Accepted: 16 June 2000