Introduction to, and classification of, the systemic vasculitides.

This overview serves as an introduction to the systemic vasculitides, which are a group of heterogeneous disorders sharing a common pathophysiological mechanism leading to blood vessel inflammation and tissue necrosis. Our lack of understanding of the aetiology for most forms of vasculitis has resulted in the development of a classification system, which is primarily based on vessel size. Such a system assists in the grouping together of similar conditions for the purposes of multi-centre studies. Difficulties arise in classification of the vasculitides due to considerable overlap of clinico-pathological features; for example, microscopic polyangiitis (MPA), Wegener's granulomatosis (WG) and Churg-Strauss syndrome (CSS) may all cause the identical renal lesion of necrotizing glomerulonephritis. The rationale for treatment often depends on the type of vasculitis and on the extent of organ involvement. Treatment may be similar for different types of disease. The lack of validated diagnostic criteria has, however, resulted in the application of classification criteria in their place, and has highlighted the limited usefulness of classification criteria in clinical practice. Classification systems should assist in the determination of therapy and prediction of outcomes, but have many limitations, which are discussed further in this review.     

Incidence and predictors of urotoxic adverse events in cyclophosphamide‐treated patients with systemic necrotizing vasculitides

Objective

To assess hemorrhagic cystitis and urinary tract cancer incidence and predictors in cyclophosphamide (CYC)–treated patients with systemic necrotizing vasculitis (SNV).

Methods

The French Vasculitis Study Group database, which contains longitudinal data on SNV patients, was searched for urinary tract cancer and/or hemorrhagic cystitis occurrences in patients diagnosed as having Wegener's granulomatosis (WG), microscopic polyangiitis, Churg‐Strauss syndrome, or polyarteritis nodosa. The observed incidence of urinary tract cancer was compared to the expected incidence in the general population by calculating standardized incidence ratios (SIRs). Relationships between urinary tract cancer and/or hemorrhagic cystitis and 10 variables, including CYC dosage and administration route, were investigated by survival analyses for a nested subgroup of patients for whom detailed information on CYC exposure was available.

Results

Among the 805 patients observed over 4,230 patient‐years (mean followup 5.3 years), 22 cases of hemorrhagic cystitis and 7 of urinary tract cancer were identified in 27 patients. The SIRs for urinary tract cancer were 5.00 for all patients with SNV (P = 0.001) and 5.96 for patients with WG (P = 0.03). Based on 467 patients with detailed CYC information, cumulative CYC dose (hazard ratio [HR] for 10‐gm increments 1.09; P = 0.03), ever‐oral CYC administration (HR 5.50; P = 0.001), and WG (HR 2.96; P = 0.01) independently predicted urinary tract cancer and/or hemorrhagic cystitis. According to univariate analyses, smoking (ever) (HR 8.20; P = 0.02) and a prior hemorrhagic cystitis episode (HR 5.20; P = 0.046) significantly predicted urinary tract cancer.

Conclusion

Our findings indicate that CYC treatment of SNV is associated with a 5‐fold higher risk of developing urinary tract cancer. Urotoxicity risk in SNV is associated with the cumulative CYC dose and its oral administration, and might be higher in WG.

     

Detection of coronary artery lesions and myocardial necrosis by magnetic resonance in systemic necrotizing vasculitides

Objective

Myocardium and coronary arteries can occasionally be affected in patients with systemic necrotizing vasculitides; however, such involvement has not been systematically assessed using cardiovascular magnetic resonance imaging (MRI).

Methods

Magnetic resonance angiography and contrast‐enhanced MRI were applied for the assessment of coronary arteries (the left anterior descending [LAD], left circumflex [LCx], and right coronary artery [RCA]) and myocardium, respectively, in 39 patients with vasculitis who were asymptomatic for cardiac disease (16 with microscopic polyangiitis [MPA], 11 with Wegener's granulomatosis [WG], 9 with Churg‐Strauss syndrome [CSS], and 3 with polyarteritis nodosa [PAN]). Data were compared with age‐matched disease‐control patients with rheumatoid arthritis (n = 20) or systemic lupus erythematosus (n = 13), and with healthy control individuals with normal coronaries (n = 40).

Results

Patients with MPA, WG, and PAN (but not with CSS) were found to display significantly increased maximal diameters of coronary arteries compared with healthy controls (for MPA and WG; P < 0.001 for LAD and RCA, and P < 0.01 for LCx) and with both disease‐control groups (for only MPA; P < 0.01 for LAD and RCA, and P < 0.05 for LCx). Fusiform coronary aneurysms were detected in patients with MPA (4/16) and PAN (2/3), whereas coronary ectasias were evident in patients with MPA (14/16) and WG (2/11). The presence of myocardial necrosis (by assessment of late gadolinium‐enhanced images) was identified only in patients with MPA (2/16) and CSS (3/8 studied).

Conclusion

Cardiovascular MRI assessment of patients with systemic vasculitis revealed coronary ectatic disease in the majority of patients with MPA and PAN, as well as in several patients with WG. Myocardial necrosis can be detected in MPA and CSS.     

Development and validation of a consensus methodology for the classification of the ANCA-associated vasculitides and polyarteritis nodosa for epidemiological studies

BACKGROUND: The classification of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and polyarteritis nodosa (PAN) for epidemiology studies is confusing. The existing schemes such as American College of Rheumatology (ACR) criteria, Chapel Hill Consensus Conference (CHCC) definitions and Lanham criteria produce overlapping and conflicting classifications, making it difficult to compare incidence figures. Aim: To develop a consensus method of using these criteria and definitions for epidemiological studies to permit comparison without confounding by classification. METHODS: A stepwise algorithm was developed by consensus between a group of doctors interested in the epidemiology of vasculitis. The aim was to categorise patients with Wegener's granulomatosis, microscopic polyangiitis (MPA), Churg-Strauss syndrome (CSS) and PAN into single clinically relevant categories. The ACR and Lanham criteria for CSS, and ACR criteria for Wegener's granulomatosis were applied first, as these were considered to be the most specific. Surrogate markers for Wegener's granulomatosis were included to distinguish Wegener's granulomatosis from MPA. MPA was classified using the CHCC definition and surrogate markers for renal vasculitis. Finally, PAN was classified using the CHCC definition. The algorithm was validated by application to 20 cases from each centre and 99 from a single centre, followed by a paper case exercise. RESULTS: A four-step algorithm was devised. It successfully categorises patients into a single classification. There was good correlation between observers in the paper case exercise (91.5%; unweighted kappa = 0.886). CONCLUSION: The algorithm achieves its aim of reliably classifying patients into a single category. The use of the algorithm in epidemiology studies should permit comparison between geographical areas.     

EULAR/PReS endorsed consensus criteria for the classification of childhood vasculitides

BACKGROUND: There has been a lack of appropriate classification criteria for vasculitis in children. OBJECTIVE: To develop a widely accepted general classification for the vasculitides observed in children and specific and realistic classification criteria for common childhood vasculitides (Henoch-Sch?nlein purpura (HSP), Kawasaki disease (KD), childhood polyarteritis nodosa (PAN), Wegener's granulomatosis (WG), and Takayasu arteritis (TA)). METHODS: The project was divided into two phases: (1) the Delphi technique was used to gather opinions from a wide spectrum of paediatric rheumatologists and nephrologists; (2) a consensus conference using nominal group technique was held. Ten international experts, all paediatricians, met for the consensus conference. Agreement of at least 80% of the participants was defined as consensus. RESULTS: Consensus was reached to base the general working classification for childhood vasculitides on vessel size. The small vessel disease was further subcategorised into "granulomatous" and "non-granulomatous." Final criteria were developed to classify a child as HSP, KD, childhood PAN, WG, or TA, with changes introduced based on paediatric experience. Mandatory criteria were suggested for all diseases except WG. CONCLUSIONS: It is hoped that the suggested criteria will be widely accepted around the world because of the reliable techniques used and the international and multispecialist composition of the expert group involved.     

Systemic necrotizing vasculitides in Turkey: a comparative analysis of 40 consecutive patients

Objective: The aim of this study was to analyze and compare the demographic and clinical features and prognosis of patients with different systemic necrotizing vasculitides (SNV) in Turkey. Patients and methods: Twenty-three patients with Wegeners granulomatosis (WG), 15 with polyarteritis nodosa (PAN), and two with Churg-Strauss syndrome were included in the study. The clinical and laboratory features of patients with WG and PAN were compared, and survival analysis was performed for the WG patients. Results: Twenty-one patients with WG had systemic disease involving kidneys, and two had localized disease. Fifteen patients were placed in the PAN group, 12 of whom were classified as having classic PAN and three with microscopic polyangiitis. Median follow-up time was 37 months (range 1–81) for WG patients and 41 months (range 5–132) for the PAN group. Upper respiratory tract, pulmonary, and renal involvement were significantly more frequent in the WG group than in PAN. Peripheral nervous system involvement was more frequent in the PAN group. In WG, survival was calculated as 59% at 35 months. High initial vasculitis damage index scores were found to be predictive for mortality. Conclusion: This study revealed that the most frequent type of SNV was WG in a tertiary rheumatology setting in Turkey. There was initial organ damage in most of the patients, frequently caused by severe renal involvement. In contrast to other published series, overt cardiovascular and gastrointestinal involvement were not observed in our patients with SNV.     

Long-term follow-up of different refractory systemic vasculitides treated with rituximab

There is increasing interest in rituximab (RTX) as an alternative to cyclophosphamide (CYC) for remission induction in systemic vasculitis. Recent studies have reported high remission rates, but it is not clear how long the initial remission lasts [1, 2]. A retrospective study was undertaken of 15 cases of refractory systemic vasculitis (11 Wegener's granulomatosis, 1 Churg–Strauss syndrome, 1 cutaneous polyarteritis nodosa and 2 cryoglobulinaemic vasculitis) treated with RTX, with a mean follow-up of 34 months. All had previously received CYC, and 14, at least one other immunosuppressive drug. All had active disease when treated (median Birmingham Vasculitis Activity Score (BVAS) 2003, 13). All cases achieved remission (BVAS 2003, 0). Thirteen required re-treatment, nine due to relapse (mean, 9 months after initial treatment) and four because of repopulation or rising ANCA in the context of CYC intolerance or previous CYC refractory disease. Relapsing cases have been successfully re-treated up to five further cycles, either at B cell repopulation or at six monthly intervals. Infections were rare. Mean IgG levels fell significantly, and IgM levels became subnormal in six cases. There were three cases of neutropenia, one severe at 10 months post-treatment. These results provide further evidence that RTX is an effective induction agent in systemic vasculitis. The optimal and long-term outcome of re-treatment remains to be defined.     

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.     

Evaluation of efficacy of pancreatic juice cytology for risk classification according to international consensus guidelines in patients with intraductal papillary mucinous neoplasm; a retrospective study

Objectives

Pancreatic juice cytology (PJC) for intraductal papillary mucinous neoplasm (IPMN) is a possible tool to enhance preoperative diagnostic ability by improving risk classification for malignant IPMN, but its efficacy is controversial. This study evaluated the efficacy of PJC for risk classification according to international guidelines.

Prognosis and outcome of 26 patients with systemic necrotizing vasculitis admitted to the intensive care unit

OBJECTIVES: To investigate presenting features, prognostic factors and outcomes of patients with systemic necrotizing vasculitis (SNV) admitted to the intensive care unit (ICU). METHODS: We retrospectively reviewed the medical records of all 210 SNV patients followed in our university hospital and admitted to the ICU between 1982 and 2001, with respect to clinical features, ICU disease severity scores (APACHE II and SAPS II), the Birmingham vasculitis activity score (BVAS), the five-factors score (FFS) and outcomes. RESULTS: Twenty-six patients (16 men, 10 women) with a mean age of 46.3+/-16.5 yr were included. The reasons for ICU admission were: active SNV, 20 (77%); infection, 3 (12%); others, 3 (12%). SNV was diagnosed in 11 (42%) patients in the ICU. The mean APACHE II and SAPS II scores were significantly higher for patients who died in the ICU (P = 0.01 and P = 0.01 respectively). After a mean follow-up of 31.4+/-29.2 months, the overall mortality rate was 39% (10 patients). Among patients admitted to the ICU with active SNV, BVAS calculated at ICU admission was significantly higher for non-survivors at the end of follow-up (26.9+/-13.0 vs 14.7+/-4.6, P = 0.02). CONCLUSION: The main reason for admitting SNV patients to the ICU was active vasculitis, which was often the first manifestation of SNV and led to its diagnosis. ICU disease severity scores at admission were associated with mortality in the ICU but did not predict long-term outcome, unlike BVAS, which accurately predicted long-term outcome but not ICU prognosis for patients admitted to the ICU with active SNV.     

Prevalence of psoriatic arthritis in psoriasis patients according to newer classification criteria

The aim of this study is to determine the prevalence of psoriatic arthritis (PsA) according to CASPAR criteria, ASAS peripheral and axial SpA criteria, and New York criteria for AS. The first 100 patients consecutively attending a psoriasis dermatology clinic were assessed. Demographic and clinical data were collected; all patients were questioned and examined for joint manifestations. Rheumatoid factor and radiographies of hands, feet, cervical spine, and pelvis for sacroiliac joints were obtained. X-rays were read independently by two experienced observers in blind fashion. Patients with objective joint manifestations, both axial and peripheral, were evaluated for fulfillment of CASPAR, ASAS peripheral and axial, and New York criteria. Median age 48 years; 93 % of patients had psoriasis vulgaris and 56 % nail involvement. Seventeen patients had peripheral arthritis as follows: nine mono/oligoarticular and eight polyarthritis. Median arthritis duration was 8 years. Seventeen percent of patients fulfilled CASPAR and ASAS peripheral criteria, 6 % New York, and 5 % ASAS axial criteria. Patients who met CASPAR criteria showed a significantly higher psoriasis duration compared to those without arthritis (M 16 vs. 10 years, p?=?0.02), and a higher frequency of nail involvement (88.2 vs. 49.4 %, p?=?0.003). Five patients (29.4 %) fulfilled ASAS axial criteria; all of them had peripheral involvement as follows: mono/oligoarticular in three patients and polyarticular in two. Patients with peripheral and axial involvement presented a significantly higher frequency of erythrodermic psoriasis compared to the other patients (35.3 vs. 1.2 %, p?=?0.0006 and 80 vs. 16.7 %, p?=?0.02). Prevalence of PsA, for CASPAR and ASAS peripheral criteria, was of 17 %. Five percent of patients met ASAS axial criteria, while 6 % met New York criteria. Worth noting, few patients without signs or symptoms of arthritis had radiological changes, both axial and peripheral, precluding a proper classification.     

Prevalence of psoriatic arthritis in psoriasis patients according to newer classification criteria

The aim of this study is to determine the prevalence of psoriatic arthritis (PsA) according to Classification of Psoriatic Arthritis (CASPAR) criteria, Assessment of Spondyloarthritis International Society (ASAS) peripheral and axial SpA criteria, and New York criteria for AS. The first 100 patients consecutively attending a psoriasis dermatology clinic were assessed. Demographic and clinical data were collected; all patients were questioned and examined for joint manifestations. Rheumatoid factor and radiographies of hands, feet, cervical spine, and pelvis for sacroiliac joints were obtained. X-rays were read independently by two experienced observers in blind fashion. Patients with objective joint manifestations, both axial and peripheral, were evaluated for fulfillment of CASPAR, ASAS peripheral and axial, and New York criteria. Median age 48 years; 93 % of patients had psoriasis vulgaris and 56 % had nail involvement. Seventeen patients had peripheral arthritis as follows: nine mono/oligoarticular and eight polyarthritis. Median arthritis duration was of 8 years. Seventeen percent of patients fulfilled CASPAR and ASAS peripheral criteria, 6 % New York, and 5 % ASAS axial criteria. Patients who met CASPAR criteria showed a significantly higher psoriasis duration compared to those without arthritis (M 16 vs 10 years, p?=?0.02), and a higher frequency of nail involvement (88.2 vs 49.4 %, p?=?0.003). Five patients (29.4 %) fulfilled ASAS axial criteria; all of them had peripheral involvement as follows: mono/oligoarticular in three patients and polyarticular in two. Patients with peripheral and axial involvement presented a significantly higher frequency of erythrodermic psoriasis compared to the other patients (35.3 vs 1.2 %, p?=?0.0006 and 80 vs 16.7 %, p?=?0.02). Prevalence of PsA, for CASPAR and ASAS peripheral criteria, was of 17 %. Five percent of patients met ASAS axial criteria, while 6 % met New York criteria. Worth noting, few patients without signs or symptoms of arthritis had radiological changes, both axial and peripheral, precluding a proper classification.     

Short-term prediction of mortality in patients with systemic lupus erythematosus: classification of outcomes using random forests

OBJECTIVE: To identify demographic and clinical characteristics that classify patients with systemic lupus erythematosus (SLE) at risk for in-hospital mortality. METHODS: Patients hospitalized in California from 1996 to 2000 with a principal diagnosis of SLE (N = 3,839) were identified from a state hospitalization database. As candidate predictors of mortality, we used patient demographic characteristics; the presence or absence of 40 different clinical conditions listed among the discharge diagnoses; and 2 summary indexes derived from the discharge diagnoses, the Charlson Index and the SLE Comorbidity Index. Predictors of patients at increased risk of mortality were identified and validated using random forests, a statistical procedure that is a generalization of single classification trees. Random forests use bootstrapped samples of patients and randomly selected subsets of predictors to create individual classification trees, and this process is repeated to generate multiple trees (a forest). Classification is then done by majority vote across all trees. RESULTS: Of the 3,839 patients, 109 died during hospitalization. Selecting from all available predictors, the random forests had excellent predictive accuracy for classification of death. The mean classification error rate, averaged over 10 forests of 500 trees each, was 11.9%. The most important predictors were the Charlson Index, respiratory failure, SLE Comorbidity Index, age, sepsis, nephritis, and thrombocytopenia. CONCLUSION: Information on clinical diagnoses can be used to accurately predict mortality among hospitalized patients with SLE. Random forests represent a useful technique to identify the most important predictors from a larger (often much larger) number and to validate the classification.     

选择性血浆分离器行双重血浆置换对抗中性粒细胞胞质抗体清除的研究

目的：选择性血浆分离器行双重血浆置换(DFPP),观察其对髓过氧化物酶型抗中性粒细胞胞质抗体(MPO-ANCA)清除。方法：15例临床诊断血管炎且血清MPO-ANCA阳性患者共接受44例次DFPP治疗。DFPP分三种方式,即MPS07/EC50W组合(血浆分离器MPS07作一级滤器,血浆成分分离器EC50W作二级滤器);MPS07/EC20W组合(MPS07及EC20W分别作一、二级滤器);EC50W/EC20W组合(EC50W及EC20W分别作一、二级滤器)。治疗剂量为处理2倍血浆容量,每次治疗补充人体白蛋白30～40g。其中1例患者采用MPS07/EC50W组合治疗3次,9例患者采用MPS07/EC20W组合治疗27次,余5例患者采用EC50W/EC20W组合治疗14次。DFPP采用间断弃浆方式,在弃浆前再使用生理盐水800 ml使二级滤器中蛋白再滤过后再弃浆。测定三种滤器对血浆白蛋白、IgA、IgG及IgM的筛选系数(SC),及单次治疗前后血浆这些蛋白下降百分率,MPO-ANCA下降百分率,及清除指数。结果：MPS07血浆分离器能滤过血浆中多数蛋白,SC＞0.6;EC50W滤器能滤过血浆白蛋白及IgG,滤过IgA略差,IgM则不能滤过(SC 0.06),EC20W滤器只能部分滤过白蛋白及IgG,滤过IgA更少,IgM不能滤过(SC 0.03)。三种方式DFPP单次治疗对血浆白蛋白影响不明显,MPS07/EC50W组合对血浆IgM清除最明显,IgA其次,IgG相对较差;MPS07/EC20W组合对三种免疫球蛋白清除都较好,尤以IgM及IgA更好;EC50W/EC20W组合对IgA及IgG清除较好,而对IgM无影响。采用EC50W/EC20W组合治疗单次IgG下降率达(43.5±13.8)％,MPO-ANCA滴度下降率(34.6±14.3)％,IgG清除指数0.47±0.15,MPO-ANCA清除指数0.34±0.09,白蛋白清除指数0.29±0.08。弃浆前采用生理盐水冲滤器可使废液中IgG/白蛋白比例提高24.2％。结论：对于清除以IgG为主的治疗,应选择EC50W/EC20W滤器组合方式以提高IgG清除的选择性,避免其他大分子物质丢失,有效降低血清MPO-ANCA滴度。     

Prognostic significance of skin reactivity in patients with bronchogenic carcinoma grouped according to the TNM classification

Untreated patients with bronchogenic carcinoma of the epidermoid type showed a marked depression of cutaneous delayed hypersensitivity reactions to DNCB, PPD and Varidase. As compared to a control group of healthy individuals and to a control group of patients with non-malignant chest diseases, 46% of cases responded to the DNCB skin test, 56% to the PPD skin test and 39% to the Varidase skin test. The patients were subsequently divided according to the TNM classification in stage I, II and III groups. Correlation of the skin test positivity to the stage of the disease and to the survival of patients was followed.