Classification of antineutrophil cytoplasmic autoantibody vasculitides: The role of antineutrophil cytoplasmic autoantibody specificity for myeloperoxidase or proteinase 3 in disease recognition and prognosis

Objective

To compare the usefulness of 3 currently used classification systems in predicting the outcomes of treatment resistance, disease relapse, end‐stage renal disease (ESRD), and death in patients with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV).

Methods

Three classification systems were applied to 502 patients with biopsy‐proven AAV: 1) the Chapel Hill Consensus Conference (CHCC) definition with categories for granulomatosis with polyangiitis (GPA) (Wegener's), microscopic polyangiitis (MPA), and kidney‐limited disease; 2) the European Medicines Agency (EMA) system with categories for GPA and MPA; and 3) classification based on ANCA with specificity for myeloperoxidase (MPO ANCA) versus ANCA with specificity for proteinase 3 (PR3 ANCA). Outcomes included treatment resistance, relapse, ESRD, and death. Proportional hazards models were compared between systems using an information‐theoretic approach to rank models by predictive fit. Hazard ratios (HRs) with 95% confidence intervals (95% CIs) and P values are reported.

Results

ANCA specificity was predictive of relapse, with PR3 ANCA–positive patients almost twice as likely to relapse as those with MPO ANCA (HR 1.89 [95% CI 1.33–2.69], P = 0.0004), and ANCA specificity had the best predictive model fit (model rank 1) compared to the CHCC and EMA systems. The CHCC and EMA systems did not predict relapse. By ANCA specificity, categories of GPA, MPA, and kidney‐limited disease did not distinguish differences in probability of relapse‐free survival. None of the systems predicted treatment resistance, ESRD, or death.

Conclusion

ANCA specificity independently predicts relapse among patients with AAV with renal disease. Classification and diagnostic systems that incorporate ANCA specificity, such as PR3 ANCA–positive MPA and MPO ANCA–positive MPA, provide a more useful tool than the clinical pathologic category alone for predicting relapse.

     

Myeloperoxidase-ANCA-positive granulomatosis with polyangiitis is a distinct subset of ANCA-associated vasculitis: A retrospective analysis of 455 patients from a single center in China

Objective

Antineutrophil cytoplasmic antibody (ANCA) directed to proteinase 3 (PR3) used to be considered the serologic marker for granulomatosis with polyangiitis (GPA). However, patients with myeloperoxidase (MPO)-ANCA positive GPA have been increasingly reported. The aim of this study was to analyze the clinical and pathological characteristics and outcome of Chinese patients with MPO-ANCA positive GPA.

Current Concept and Epidemiology of Systemic Vasculitides

Although a new classification algorithm for systemic vasculitides was proposed by Watts et al. and the Chapel Hill Consensus Conference (CHCC) was updated in 2012, there are currently no validated diagnostic criteria for systemic vasculitides. The Diagnostic and Classification Criteria for Vasculitis study (DCVAS) is a global study to develop and improve the diagnostic criteria for systemic vasculitides. The epidemiology of systemic vasculitides differs widely among countries. For example, in the case of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, patients with microscopic polyangiitis (MPA) and with positivity for MPO-ANCA are predominant in Asian countries, whereas patients with granulomatosis with polyangiitis (GPA) and with positivity for PR3-ANCA are predominant in northern Europe and the United States. Interstitial lung disease (ILD) occurs more frequently in Asian patients compared with patients in Europe. The incidence and the prevalence of large-vessel vasculitis also differ significantly. Giant cell arteritis (GCA) occurs frequently in northern Europe, unlike Takayasu arteritis (TAK). The ethnic and regional differences in the incidence, prevalence and clinical characteristics of patients with vasculitis should be recognized when we diagnose and treat patients with vasculitis using criteria, and should also be considered when interpreting the results from clinical studies.     

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.     

Liver involvement in ANCA-associated vasculitis

The aim of the study was to investigate the incidence, the clinical course and outcome of liver involvement and autoimmune hepatic diseases in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Liver function tests (LFT) (i.e. aspartate and alanine aminotransferase [AST, ALT], gamma-glutamyl transpeptidase [gamma-GT], alkaline phosphatase [ALP] and total bilirubin) were analysed at disease onset in therapy-naïve patients and during remission in patients with granulomatosis with polyangiitis (GPA, n?=?67), microscopic polyangiitis (MPA, n?=?28) and eosinophilic granulomatosis with polyangiitis (EGPA, n?=?14). Results were correlated to the Birmingham Vasculitis Activity Score version 3 (BVAS v.3). Also, serologic tests for other autoimmune hepatic diseases were performed in these patients. During the active state, LFT abnormalities could be detected in 54 AAV patients (49.4 %). ALT, gamma-GT and ALP were significantly higher in GPA patients compared to MPA or EGPA patients at disease onset (p?<?0.05). Increased values for gamma-GT in GPA patients correlated with the BVAS (p?<?0.01) and were associated with pulmonary involvement, pulmonary-renal syndrome and a longer time to remission. Increased LFT in GPA patients decreased subsequently towards normal levels after initiation of therapy (p?<?0.01). No case of severe liver involvement or autoimmune hepatic liver diseases was found in AAV patients. Liver involvement was mainly restricted to GPA patients, is associated with the disease activity and indicates a poorer outcome in patients with GPA. Progressive liver involvement or autoimmune hepatic diseases were not observed.     

Anti-neutrophil cytoplasmic antibodies and their clinical significance

Anti-neutrophil cytoplasmic antibodies (ANCA) are a group of autoantibodies that cause systemic vascular inflammation by binding to target antigens of neutrophils. These autoantibodies can be found in serum from patients with systemic small-vessel vasculitis and they are considered as a biomarker for ANCA-associated vasculitis (AAV). A conventional screening test to detect ANCA in the serum is indirect immunofluorescence study, and subsequently confirmed by enzyme-linked immunosorbent assay. A positive staining of ANCA can be classified into three main categories based on the staining patterns: cytoplasmic, perinuclear, and atypical. Patients with granulomatosis with polyangiitis (GPA) mostly have a positive cytoplasmic staining pattern (c-ANCA) whilst a perinuclear pattern (p-ANCA) is more common in microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA) patients. Atypical pattern (a-ANCA) is rarely seen in patients with systemic small-vessel vasculitis but it can be found in other conditions. Here, techniques for ANCA detection, ANCA staining patterns and their clinical significances are reviewed.     

Empfehlungen zum Einsatz von Rituximab bei ANCA-assoziierten Vaskulitiden

Rituximab (Rtx) has been approved in Germany since April 2013 for treatment of granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). This therapy can be used in severe manifestations of these diseases and in relapses. It is administered as infusions of 375 mg rituximab per m² every 4 weeks after high dose intravenous prednisolone for 3 days and continued parallel to concomitant oral prednisolone therapy. Recommendations for the indications and use for antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) are described in addition to previous publications on recommendations for rheumatoid arthritis.     

Four cases of MPO-ANCA-positive vasculitis with otitis media, and review of the literature

Otitis media is one of the common organ injuries that appear during the course of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We experienced four patients with myeloperoxidase (MPO)-ANCA-positive AAV with otitis media. All were elderly Japanese women. MPO-ANCA in our patients was reminiscent of microscopic polyangiitis (MPA), although chest computed tomography (CT) scans revealed characteristics of both granulomatosis with polyangiitis (GPA), showing bronchial lesions and nodule formation, and MPA, showing interstitial changes. Whether our cases should be classified as GPA or MPA is a matter of discussion. We detail their profiles, and review previous literature on MPO-ANCA-positive AAV with otitis media.     

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.     

Clinical presentation and outcome prediction of clinical,serological, and histopathological classification schemes in ANCA-associated vasculitis with renal involvement

Several classification schemes have been developed for anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), with actual debate focusing on their clinical and prognostic performance. Sixty-two patients with renal biopsy-proven AAV from a single center in Mexico City diagnosed between 2004 and 2013 were analyzed and classified under clinical (granulomatosis with polyangiitis [GPA], microscopic polyangiitis [MPA], renal limited vasculitis [RLV]), serological (proteinase 3 anti-neutrophil cytoplasmic antibodies [PR3-ANCA], myeloperoxidase anti-neutrophil cytoplasmic antibodies [MPO-ANCA], ANCA negative), and histopathological (focal, crescenteric, mixed-type, sclerosing) categories. Clinical presentation parameters were compared at baseline between classification groups, and the predictive value of different classification categories for disease and renal remission, relapse, renal, and patient survival was analyzed. Serological classification predicted relapse rate (PR3-ANCA hazard ratio for relapse 2.93, 1.20–7.17, p?=?0.019). There were no differences in disease or renal remission, renal, or patient survival between clinical and serological categories. Histopathological classification predicted response to therapy, with a poorer renal remission rate for sclerosing group and those with less than 25 % normal glomeruli; in addition, it adequately delimited 24-month glomerular filtration rate (eGFR) evolution, but it did not predict renal nor patient survival. On multivariate models, renal replacement therapy (RRT) requirement (HR 8.07, CI 1.75–37.4, p?=?0.008) and proteinuria (HR 1.49, CI 1.03–2.14, p?=?0.034) at presentation predicted renal survival, while age (HR 1.10, CI 1.01–1.21, p?=?0.041) and infective events during the induction phase (HR 4.72, 1.01–22.1, p?=?0.049) negatively influenced patient survival. At present, ANCA-based serological classification may predict AAV relapses, but neither clinical nor serological categories predict renal or patient survival. Age, renal function and proteinuria at presentation, histopathology, and infectious complications constitute the main outcome predictors and should be considered for individualized management.     

A model to predict cardiovascular events in patients with newly diagnosed Wegener's granulomatosis and microscopic polyangiitis

Objective

To create a prognostic tool to quantify the 5‐year cardiovascular (CV) risk in patients with newly diagnosed Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA) without premorbid CV disease.

Methods

We reviewed CV outcomes during the long‐term followup of patients in the first 4 European Vasculitis Study Group (EUVAS) trials of WG and MPA. CV events were defined as CV death, stroke, myocardial infarction, coronary artery bypass graft, or percutaneous coronary intervention. Logistic regression was performed to create a model to predict the absolute risk of a CV event. The model was tested using the Wegener's Granulomatosis Etanercept Trial (WGET) cohort.

Results

Seventy‐four (13.8%) of 535 patients with 5 years of followup from the EUVAS trials had at least 1 CV event: 33 (11.7%) of 281 WG versus 41 (16.1%) of 254 MPA. The independent determinants of CV outcomes were older age (odds ratio [OR] 1.45, 95% confidence interval [95% CI] 1.11–1.90), diastolic hypertension (OR 1.97, 95% CI 0.98–3.95), and positive proteinase 3 (PR3) antineutrophil cytoplasmic antibody (ANCA) status (OR 0.39, 95% CI 0.20–0.74). The model was validated using the WGET cohort (area under the receiver operating characteristic curve of 0.80).

Conclusion

Within 5 years of diagnosis of WG or MPA, 14% of patients will have a CV event. We have constructed and validated a tool to quantify the risk of a CV event based on age, diastolic hypertension, and PR3 ANCA status in patients without prior CV disease. In patients with vasculitis, PR3 ANCA is associated with a reduced CV risk compared to myeloperoxidase ANCA or negative ANCA status.     

Mycophenolate mofetil for induction and maintenance of remission in naïve patients with granulomatosis with polyangiitis without renal involvement

Antineutrophil cytoplasmic antibodies (ANCA) associated vasculitides include granulomatosis with polyangiitis (GPA, previously called Wegener's), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA), previously called Churg-Strauss). In this report we used mycophenolate mofetil (MMF) and steroids to induce and maintain remission in two newly diagnosed cases with c-ANCA associated GPA. The two patients’ maintained remission with no disease relapses during one year follow-up.     

肺血管炎的临床与影像学特点解析

肺部血管炎包括原发性与继发性两大类.继发性血管炎包括感染性疾病、结缔组织病、恶性肿瘤和过敏性疾病所致肺血管炎.原发性血管炎的分类通常根据受累血管的大小分为大血管炎、中血管炎和小血管炎.肺部血管受累常见于原发性大血管炎[大动脉炎(Takayasu arteritis),巨细胞动脉炎(giant cell arteritis,GCA),白塞病(Behcetdisease)]和原发性抗中性粒细胞胞浆抗体(anti-neutrophil cytoplasmic antibody,ANCA)相关性小血管炎[肉芽肿性多血管炎(granulomatosis with polyangiitis,GPA),显微镜下多血管炎(microscopic polyangiitis),嗜酸性肉芽肿性多血管炎(eosinophilic granulomatosis with polyangiitis,EGPA)].原发性肺血管炎的影像学表现极具多样性,包括血管壁增厚、结节影、空洞、磨玻璃影和实变影等.原发性肺部小血管炎常导致弥漫性肺泡出血(diffuse alveolar hemorrhage,DAH).相比于胸片,胸部CT更能够显示肺血管炎的病变特征和侵及范围.肺部血管炎的诊断极具挑战性,需要通过患者的临床特征、影像学特点、实验室检查结果和组织病理学特征作出综合判断.     

Antineutrophil cytoplasmic antibodies reacting with the pro form of proteinase 3 and disease activity in patients with Wegener's granulomatosis and microscopic polyangiitis

OBJECTIVE: Antineutrophil cytoplasmic antibodies (ANCA) directed against proteinase 3 (PR3) are diagnostic markers for the small vessel vasculitides Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA). Correlation of disease activity with PR3 ANCA levels, as determined by standard methods, is not apparent in every patient. PR3 ANCA react with yet to be identified conformational epitopes. We have identified PR3 ANCA subsets that react differentially with mature recombinant PR3 (rPR3; lacking the N-terminal activation dipeptide) and the pro form of this enzyme (pro-rPR3). The present study was performed to determine the association of these PR3 ANCA subsets with disease activity. METHODS: Sera from 61 PR3 ANCA-positive patients with WG or MPA were assayed by capture enzyme-linked immunosorbent assay using pro-rPR3 and rPR3 as target antigens, and were correlated with disease activity as determined by the Birmingham Vasculitis Activity Score (BVAS). RESULTS: Median levels of PR3 ANCA reacting with pro-rPR3 were higher during active (n = 32) than during inactive (n = 29) disease (P = 0.016). Reactivity with mature rPR3 was not significantly different (P = 0.71). Serial followup in individual patients also indicated better correlation of PR3 ANCA reactivity with pro-rPR3 than with mature rPR3. CONCLUSION: PR3 ANCA subsets reactive with epitopes accessible on pro-PR3 correlate better with disease activity than do subsets reactive with epitopes accessible only on mature PR3. This observation may explain why ANCA levels determined with current standard methods are suboptimal for monitoring disease activity. It raises new questions about the primary target of the PR3 ANCA immune response in patients with small vessel vasculitis.     

The cancer risk according to three subtypes of ANCA-associated vasculitis: A propensity score-matched analysis of a nationwide study

ObjectiveIt remains unknown whether cancer risk differs among the three subtypes of anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) and what the cancer risk factors are. We conducted a nationwide study in Korea to evaluate the risk of cancer in patients with AAV and to identify the risk factors for cancer.MethodsWe analyzed the Health Insurance Review and Assessment database of Korea and identified 1982 patients diagnosed with AAV between January 1, 2007 and December 31, 2017. The patients and controls with no history of AAV or cancer were matched 1:4 by propensity scores. The study outcome measure was incidence of cancer during 11 years of follow-up.ResultsPatients with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA) numbered 684, 606, and 692, respectively. The overall incidence of cancer was higher among patients with AAV than in controls (HR 1.32, 95% CI 1.08–1.61). The risk of hematological malignancy, lung cancer, and bladder cancer in the GPA group, lung cancer in the MPA group, and hematological malignancy in the EGPA group were significantly higher than in controls (HR 7.39, 3.20, 4.20, 2.86, and 4.65, respectively). Age, male sex, GPA subtype, and cyclophosphamide use were significantly associated with cancer risk in patients with AAV.ConclusionOverall cancer incidence was increased in patients with AAV. Cancer risk was higher in patients with GPA than in those with MPA or EGPA. The use of cyclophosphamide was associated with an increased risk of cancer, while rituximab was not.     

肺脏受累的原发性抗中性粒细胞胞浆抗体相关性小血管炎43例临床分析

目的 探讨肺脏受累的原发性抗中性粒细胞胞浆抗体（ANCA）相关性小血管炎患者的临床特征,为肺部受累的原发性ANCA相关性小血管炎的诊断提供帮助.方法 回顾性分析2009年3月至2013年9月在湘雅二医院住院的符合2012年美国Chapel Hill会议关于系统性小血管炎诊断标准,并血清ANCA阳性的43例肺脏受累的的原发性ANCA相关性小血管炎患者的临床资料.结果 43例患者中,肺部症状首发就诊者22例,常见肺部症状依次为咳嗽咯痰、活动后气促、咯血、哮喘等,肺外受累器官依次为肾脏、神经系统、眼、鼻;肺外症状首发就诊者21例,肾脏为最常见受累器官;显微镜下多血管炎（MPA） 34例,其中抗髓过氧化物酶（MPO）抗体（P-ANCA）阳性率97.1％（33/34）,抗蛋白酶3（PR3）抗体（C-ANCA）阳性率2.9％ （1/34）;肉芽肿性多血管炎（GPA）（韦格纳肉芽肿）8例,抗蛋白酶3（PR3）抗体（C-ANCA）阳性率62.5％（5/8）,抗髓过氧化物酶（MPO）抗体（P-ANCA）阳性率为37.5％（3/8）;嗜酸细胞性肉芽肿性多血管炎（EGPA）1例,为抗髓过氧化物酶（MPO）抗体阳性;胸部影像学表现多为双肺间质病变,如双肺网格样改变、磨玻璃影、蜂窝肺、多发条索状及结节性病变等,或为条索或斑片状病变、支气管扩张、胸腔积液及肿块病变等.经激素和免疫抑制剂治疗多数患者病情可缓解,19例患者（44.2％）于住院及随访期间因血管炎活动并肺部感染、大咯血及肾功能衰竭等原因死亡.结论 肺脏受累的原发性ANCA相关性小血管炎临床表现无特异性,多数患者合并有肾脏受累,影像学多为肺间质病变,具有提示诊断价值,血清ANCA检查有特殊诊断价值,此类患者死亡率高,多为疾病活动并感染致死,应积极控制感染并合理采用抑制免疫治疗.     

Clinicoepidemiological manifestations of RPGN and ANCA-associated vasculitides: an 11-year retrospective hospital-based study in Japan

Antineutrophil cytoplasmic antibody (ANCA)-associated small-vessel vasculitides are major causes of rapidly progressive glomerulonephritis (RPGN). Although recent papers suggest differences in clinicoepidemiological manifestations of ANCA-associated vasculitis between Japan [microscopic polyangiitis (MPA) ? Wegener’s granulomatosis (WG)] and Europe (WG ?MPA), little is known about the prevalence and serological pattern. We retrospectively analyzed 27 RPGN patients who were admitted in our hospital over the past 11 years and who could be basically followed for more than 1 year, concerning the incidence of ANCA-related vasculitis, the presence of (MPO)/proteinase 3 (PR3)-ANCA and their clinical outcomes. As there were no PR3-ANCA single positive and/or WG patients, all patients were serologically divided into four groups; Groups I: MPO-ANCA single-positive patients (N = 11), II: MPO-ANCA and PR3-ANCA double-positive patients (N = 3), III: antiglomerular basement membrane antibody (anti-GBM Ab)-positive patients (N = 6), and IV: all negative patients (N = 7). Patients in Groups II/III showed more severe manifestation at admission. However, in Group I, only 36.3% patients avoided death and/or dialysis-dependent end-stage renal disease. Most patients in Group IV were women (85.7%), and 50% of these patients was diagnosed as having rheumatic diseases. Every patient in Groups I?III was treated with oral corticosteroid and/or methylprednisolone pulse therapy. Most patients treated with immunosuppressants showed severe prognosis because of frequent recurrences of vasculitis and infectious episodes after repeated and prolonged treatments with immunosuppressants. Present analysis further confirms the epidemiological and serological differences in ANCA-related RPGN between Japan and Europe, and reinforced the fact that ANCA-associated vasculitis is the most serious causal disease for RPGN.     

Synovial proinflammatory cytokines and their correlation with matrix metalloproteinase-3 expression in Behçet’s disease. Does interleukin-1β play a major role in Behçet’s synovitis?

The objective of this study has been the well established fact that proinflammatory cytokines and metalloproteinases play a crucial role in the pathogenesis of chronic arthritis as well as the development of pannus, with the eventual erosive changes. Among the proinflammatory cytokines, interleukin-18 (IL-18) has been shown to contribute to the pathogenesis of chronic synovitis by increasing the secretion of interleukin-1beta (IL-1β) and the tumor necrosis factor-alpha (TNF-α) and also stimulating angiogenesis. The aim of this study is to investigate the synovial IL-18, IL-1β, TNF-α and matrix metalloproteinase-3 (MMP-3) levels in patients with Behçet’s disease (BD), and compare them with the levels of patients with rheumatoid arthritis (RA) and osteoarthritis (OA). 30 patients with BD, 20 with RA, and 20 with OA were included in the study. The synovial levels of IL-18, IL-1β, TNF-α and MMP-3 were detected using the two-step sandwich ELISA method. The synovial IL-18, TNF-α and MMP-3 levels were significantly higher in RA patients than patients with BD (P=0.004, 0.019, 0.025, respectively) and with OA (P=0.004, 0.045, 0.032, respectively). There were no differences, with respect to the cytokine levels, when patients with BD were compared with those with OA. Patients with RA and BD had higher IL-1β levels than patients with OA (P=0.017, 0.013, respectively). However, no such difference was found for IL-1β between BD and RA patients. Among patients with RA, positive correlations were found between TNF-α and MMP-3 (r=0.683, P=0.001). Our results showed that MMP-3 and proinflammatory cytokines, except IL-1β, were expressed in relatively small quantities in Behçet’s synovitis. Detection of the lower levels of these cytokines and metalloproteinases might explain the non-erosive character of Behçet’s arthritis. We suggest that IL-1β may be involved in the pathogenesis of Behçet’s synovitis.     

Systemic, secondary and infectious causes for cerebral vasculitis: clinical experience with 16 new European cases

Cerebral vasculitis represents a rare form of vascular inflammatory involvement caused by heterogeneous conditions. In this study, the wide spectrum of cerebral vasculitis despite primary angiitis of the CNS is analyzed. Our cohort included 16 white patients with cerebral vasculitis treated in a single German institution between 2003 and 2008. Clinical and diagnostic features were obtained by retrospective chart review; follow-up information and outcome were obtained prospectively. The spectrum of conditions responsible for cerebral vasculitis included seven patients with Behçet syndrome and one case each of giant cell arteritis, Wegener’s granulomatosis and Churg–Strauss syndrome, respectively. Vasculitis secondary to systemic diseases included two patients with systemic lupus erythematodes, one with sarcoidosis and one with ANA-positive systemic vasculitis. Two patients suffered from infectious angiitis caused by borreliosis and syphilis. The mean age at onset of cerebral symptoms was 41.38 years. The most frequent clinical symptoms were headache, gait disturbances and unilateral numbness. None of the patients with Behçet syndrome experienced any ischemic event, which was a significant difference compared with the other patients (P = 0.011). Gadolinium-enhancing lesions were significantly more frequent in Behçet syndrome compared to the other types of vasculitis (P = 0.041). There was no significant difference between vasculitis patients with or without Behçet syndrome regarding outcome parameters. The differential diagnosis of conditions responsible for cerebral vasculitis includes a wide spectrum of diseases. Clinical features and the course of cerebral vasculitis are highly variable. The enigma of cerebral vasculitis will only be solved by implementing large, prospective, multicenter databases.     

Use of infliximab and other biologics in Behçet disease

Behçet disease is a multisystem vasculitis characterised by recurrent oral ulceration in conjunction with other manifestations. Neurological involvement or neuro‐Behçet disease is not common, but typically affects young men at its onset between the ages of 20 and 40 with significant long‐term morbidity and mortality. There is substantial case literature to support the use of tumour necrosis factor antagonists, notably infliximab, in the treatment of neuro‐Behçet disease.