Cluster Analysis to Explore Clinical Subphenotypes of Eosinophilic Granulomatosis With Polyangiitis.

OBJECTIVE: Previous studies suggested that distinct phenotypes of eosinophilic granulomatosis with polyangiitis (EGPA; formerly known as Churg-Strauss syndrome) could be determined by the presence or absence of antineutrophil cytoplasmic antibodies (ANCA), reflecting predominant vasculitic or eosinophilic processes, respectively. This study explored whether ANCA-based clusters or other clusters can be identified in EGPA. METHODS: This study used standardized data of 15 European centers for patients with EGPA fulfilling widely accepted classification criteria. We used multiple correspondence analysis, hierarchical cluster analysis, and a decision tree model. The main model included 10 clinical variables (musculoskeletal [MSK], mucocutaneous, ophthalmological, ENT, cardiovascular, pulmonary, gastrointestinal, renal, central, or peripheral neurological involvement); a second model also included ANCA results. RESULTS: The analyses included 489 patients diagnosed between 1984 and 2015. ANCA were detected in 37.2% of patients, mostly perinuclear ANCA (85.4%) and/or antimyeloperoxidase (87%). Compared with ANCA-negative patients, those with ANCA had more renal (P < 0.001) and peripheral neurological involvement (P = 0.04), fewer cardiovascular signs (P < 0.001), and fewer biopsies with eosinophilic tissue infiltrates (P = 0.001). The cluster analyses generated 4 (model without ANCA) and 5 clusters (model with ANCA). Both models identified 3 identical clusters of 34, 39, and 40 patients according to the presence or absence of ENT, central nervous system, and ophthalmological involvement. Peripheral neurological and cardiovascular involvement were not predictive characteristics. CONCLUSION: Although reinforcing the known association of ANCA status with clinical manifestations, cluster analysis does not support a complete separation of EGPA in ANCA-positive and -negative subsets. Collectively, these data indicate that EGPA should be regarded as a phenotypic spectrum rather than a dichotomous disease.

Incidence of giant cell arteritis in six districts of Paris, France (2015-2017).

This prospective population-based study estimated the incidence of giant cell arteritis (GCA) in northeastern Paris. GCA cases diagnosed between 2015 and 2017 were obtained from local hospital and community-based physicians and the national health insurance system database. Criteria for inclusion were living in the study area at that time and fulfilling the 1990 American College of Rheumatology classification criteria and/or its expanded version. Cranial and large-vessel GCA cases were defined by the presence or absence of cranial signs and/or symptoms, respectively. Annual incidence was calculated by dividing the number of incident cases by the size of the study population ≥ 50 years old. Completeness of case ascertainment was assessed by a three-source capture-recapture analysis. Among the 62 included cases, 42 (68%) were women, mean (± SD) age 77.3 ± 9.1 years. The annual incidence of GCA in northeastern Paris and completeness of case ascertainment were estimated at 7.6 (95% CI 5.9-9.8) per 100,000 inhabitants ≥ 50 years old and 66% (95% CI 52-92%), respectively. Incidence increased with age, peaked at age 80-89 years, and was almost twice as high in women versus men. Large-vessel GCA cases, mean (± SD) age 68.6 ± 11.5 years, accounted for 8% of all GCA cases. In this study, GCA epidemiology was mainly driven by cases with cranial GCA signs or symptoms and incidence results were consistent with recent European and past French studies.

Sensitivity of temporal artery biopsy in the diagnosis of giant cell arteritis: a systematic literature review and meta-analysis.

OBJECTIVES: Temporal artery biopsy (TAB) is a reference test for the diagnosis of GCA but reveals inflammatory changes only in a subset of patients. The lack of knowledge of TAB sensitivity hampers comparisons with non-invasive techniques such as temporal artery ultrasonography. We performed a systematic literature review and meta-analysis to estimate the sensitivity of TAB in GCA and to identify factors that may influence the estimate. METHODS: A systematic literature review involved searching electronic databases and cross-references. Eligibility criteria included publications reporting at least 30 GCA cases fulfilling the original or modified 1990 ACR classification criteria. The pooled proportion of TAB-positive GCA cases was calculated by using aggregated-data meta-analysis with a random-effects model and assessment of heterogeneity with the I2 statistic. Subgroup analyses and meta-regression were used to examine the effect of patient and study characteristics on TAB positivity. RESULTS: Among 3820 publications screened, 32 studies (3092 patients) published during 1993-2017 were analysed. The pooled proportion of TAB-positive GCA cases was 77.3% (95% CI: 71.8, 81.9%), with high between-study heterogeneity (I2 = 90%). The proportion of TAB-positive cases was slightly higher in publications before than in 2012 and after (P = 0.001). CONCLUSION: The estimated sensitivity of 77% provides indirect evidence that TAB is not less sensitive than temporal artery imaging. The unexplained high between-study heterogeneity could result from differences in TAB sampling, processing or interpretation. The decrease in TAB-positive GCA cases over time could reflect an increasing propensity for clinicians to accept a GCA diagnosis without proof by TAB.

Exploring the variability in Behçet's disease prevalence: a meta-analytical approach.

Background: Surveys of Behçet's disease (BD) have shown substantial geographic variations in prevalence, but some of these differences may result from methodological inconsistencies. This meta-analysis explored the effect of geographic location and study methodology on the prevalence of BD. Methods: We systematically searched the literature in electronic databases and by handsearching to identify population-based prevalence surveys of BD. Studies were eligible if they provided an original population-based prevalence estimate for BD with the number of prevalent cases identified in the study area. Pooled prevalence proportions across all studies were computed by using random effects models based on a Poisson normal distribution. Pre-defined subgroup analyses and meta-regression were used to investigate the effect of covariates on the prevalence proportions. Results: We included 45 reports published from 1974 to 2015 and covering worldwide areas. The pooled estimates of prevalence proportions (expressed as cases/100 000 inhabitants) were 10.3 (95% CI 6.1, 17.7) for all studies and 119.8 (59.8, 239.9) for Turkey, 31.8 (12.9, 78.4) for the Middle East, 4.5 (2.2, 9.4) for Asia and 3.3 (2.1, 5.2) for Europe. Subgroup analyses showed a strikingly greater prevalence for studies with a sample survey design than a census design [82.5 (95% CI 47.3, 143.9) vs 3.6 (2.6, 5.1)]. Metaregression identified study design as an independent covariate significantly affecting BD prevalence proportions. Conclusions: Differences in BD prevalence proportions likely reflect a combination of true geographic variation and methodological artefacts. In particular, use of a sample or census study design may strongly affect the estimated prevalence.

Incidence of IgA vasculitis in children estimated by four-source capture-recapture analysis: a population-based study.

Objectives: The aim was to describe the epidemiological characteristics of childhood IgA vasculitis (IgAV) defined by the EULAR/PRINTO/Paediatric Rheumatology European Society criteria in a population-based sample from France and ascertain its incidence over 3 years by a four-source capture-recapture analysis. Methods: Cases were prospectively collected in Val de Marne county, a suburb of Paris, with 263 874 residents <15 years old. Children with incident IgAV living in this area from 2012 to 2014 were identified by four sources of case notification (emergency departments, paediatrics departments, private-practice paediatricians and general practitioners). Annual incidence was calculated, and a capture-recapture analysis was used with log-linear modelling to estimate case-finding completeness. Results: We identified 147 incident cases [78 boys; mean age 6.5 (s.d.:2.6) years]. The annual incidence (95% CI) was 18.6 (13.6, 24.5)/100 000 children. Although only 10% of children were exclusively identified by non-hospital sources, the completeness of case finding was 62%, with an undercount-corrected annual incidence (95% CI) of 29.9 (23.7, 37.3)/100 000 children. The annual distribution of diagnoses consistently showed a trough in summer months; 72% of children had infectious symptoms (mainly upper respiratory tract) a few days before IgAV onset; and 23% had a North African background. Conclusion: Our study supports secular and geospatial stability in childhood IgAV incidence and adds further indirect evidence for a possible role of a ubiquitous, non-emerging infectious trigger. Incidence studies from understudied areas are needed to disentangle the role of genetic factors better. Capture-recapture analysis suggests that a substantial portion of IgAV cases may remain unrecognized in epidemiological surveys.

Gender-specific differences in Adamantiades-Behçet's disease manifestations: an analysis of the German registry and meta-analysis of data from the literature.

OBJECTIVE: We investigated the effect of gender on the clinical Adamantiades-Behçet's disease (ABD) phenotype with data from the German ABD registry and a meta-analysis from a systematic literature review. METHODS: Using the German ABD registry data, we compared 36 clinical variables by gender (with women as the reference category) and investigated potential effect modification by HLA-B5 or ethnic background. The registry data were combined with those from a literature search to calculate pooled relative risks (RRs) for variables with data from ≥10 relevant datasets. RESULTS: The German ABD registry provided information for 747 subjects (58.1% males) and the systematic literature review identified another 52 datasets informing on 16 variables. Both analyses consistently revealed the association of male gender with ocular involvement (RR 1.28 and 1.34 from the ABD registry and meta-analysis, respectively), folliculitis (RR 1.30 and 1.26), papulopustular lesions (RR 1.23 and 1.25), vascular involvement (RR 2.31 and 2.27), superficial (RR 2.96 and 1.63) and deep venous thromboses (RR 2.56 and 2.16) and female gender with genital ulcers (RR 0.78 and 0.92) and joint involvement (RR 0.79 and 0.89). The ABD registry data additionally showed male gender associated with heart involvement (RR 10.60), whereas the meta-analyses revealed male gender associated with the pathergy test (RR 1.14) and female gender associated with erythema nodosum (RR 0.86). HLA-B5 and Turkish or German origin did not affect the observed associations. CONCLUSION: These analyses support gender-associated clinical variations in ABD and in particular a clinically meaningful risk of cardiovascular involvement for men.

Effect of race/ethnicity on risk, presentation and course of connective tissue diseases and primary systemic vasculitides.

PURPOSE OF REVIEW: Understanding the effects of race/ethnicity on the risk and expression of systemic rheumatic diseases has potential clinical implications and provides insight into their etiopathogeneses. This review summarizes knowledge of the effects of race/ethnicity on the following nine conditions: antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV), Behçet's disease, dermatomyositis/polymyositis, Henoch-Schönlein purpura, Kawasaki disease, large-vessel vasculitis (LVV), primary Sjögren's syndrome (pSS), systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). RECENT FINDINGS: Distinct racial/ethnic patterns have emerged for most of the conditions considered here. Areas of progress include the finding that the two AAVs, granulomatosis with polyangiitis (Wegener's) (GPA) and microscopic polyangiitis, exhibit distinct racial/ethnic susceptibilities in disease risk. In addition, nonwhites, with known high risk of SLE and SSc, may also be at a high risk for pSS and have more severe disease. Evidence is accumulating that nonwhites are rarely affected by the LVV giant-cell arteritis. Race/ethnicity-specific genetic risk factors were recently detected for GPA. SUMMARY: Epidemiologic data have allowed discerning the racial/ethnic profiles for many of the considered systemic rheumatic conditions. Future challenges will be to unravel the genetic, environmental and/or socio-econonomic determinants of the observed racial/ethnic disparities. More research is needed to clarify the impact of race/ethnicity on the AAV Churg-Strauss syndrome, dermatomyositis/polymyositis and Takayasu arteritis.

Relationships of HLA-B51 or B5 genotype with Behcet's disease clinical characteristics: systematic review and meta-analyses of observational studies.

OBJECTIVE: To investigate comprehensively the relationships between Behçet's disease (BD) clinical features and HLA-B51 or HLA-B5 (HLA-B51/B5) status using meta-analyses. METHODS: Relevant publications were identified by a systematic literature search. Eligible studies had to provide frequencies for one or more BD characteristics according to HLA-B51/B5 status. Pooled relative risks (RRs) were calculated by random-effects meta-analysis for those BD characteristics for which five or more relevant studies were identified. Between-study variability was assessed with I(2) and Q-statistics, and modelled using meta-regression. RESULTS: Among the 859 publications evaluated, 72 (representing 74 study populations) met eligibility criteria. Pooled RRs (95% CIs) of the association of HLA-B51/B5 with the 14 analysed clinical characteristics were male sex 1.14 (1.05, 1.23); eye involvement 1.13 (1.06, 1.21); genital ulcers 1.07 (1.01, 1.14); skin involvement 1.10 (1.03, 1.16); erythema nodosum 1.11 (0.96, 1.29); pseudofolliculitis 1.07 (0.93, 1.23); positive pathergy test 1.05 (0.94, 1.17); joint involvement 0.94 (0.86, 1.04); neurological involvement 0.95 (0.71, 1.27); gastrointestinal involvement 0.70 (0.52, 0.94); thrombophlebitis 1.17 (0.77, 1.76); vascular involvement 1.00 (0.68, 1.47); chest involvement 1.55 (0.75, 3.20) and orchiepididymitis 1.13 (0.59, 2.15). For most of the analysed outcomes, between-study heterogeneity was low or absent and most of the meta-regression models were statistically non-significant. CONCLUSION: The results of these meta-analyses showed that, in BD, HLA-B51/B5 carriage predominates in males and is associated with moderately higher prevalences of genital ulcers, ocular and skin manifestations, and a decreased prevalence of gastrointestinal involvement.

Epidemiology and etiology of wegener granulomatosis, microscopic polyangiitis, churg-strauss syndrome and goodpasture syndrome: vasculitides with frequent lung involvement.

This review focuses on the epidemiological characteristics and etiologies of four primary systemic vasculitides with frequent lung involvement, namely Wegener granulomatosis (WG), microscopic polyangiitis (MPA), Churg-Strauss syndrome (CSS), and Goodpasture syndrome (GPS). Elucidation of the mechanisms underlying these vasculitides with frequent lung involvement is complicated by their rarity, which hampers the undertaking of large-scale studies; difficulties in classification; and their multifaceted clinical presentations, which infer the existence of several etiologic pathways. Notwithstanding, epidemiological research showed some evidence for international, interethnic, and temporal variations of the frequencies of these four vasculitides; led to the identification of several genetic and environmental risk factors; and provided insight on the extent to which genes and environment might contribute to their development. Available data support the concept that WG, MPA, CSS, and GPS have unique and shared risk determinants. Although the precise causes of these vasculitides are not yet fully understood and the development of prevention strategies is out of our reach at present, current knowledge enables the formulation of etiologic hypotheses to provide caregivers and their patients with valuable information on the nature of these rare entities.

[Risk of Burnout syndrome in medical professionals in Córdoba City, Argentina] / Riesgo de Síndrome de Burnout en profesionales médicos de la ciudad de Córdoba, Argentina.

Background: Burnout syndrome is a chronic, adaptive disorder, being considered the most important cause of work injury of psychosocial cause. The objective was to know the risk of burnout in Córdoba city's physician and its relationship with sociodemographic factors and clinical and surgical specialties. Methods: An observational cross-sectional study was performed in 10 care centers in Córdoba City. Physicians were interviewed, we ask about sociodemographic variables and the Maslach Burnout Inventory questionnaire was done to objectify the risk of Burnout. The age was stratified by decades from 20 to 60 years. p < a 0,05 was considered significant. Results: 483 physicians were interviewed, 62,1% were women, 70% were between 20 and 40 years of age; 54.2% single, 42.9% had a time of exercised in the profession below 5 years. 66 of the total (16,5%) had a high risk of burnout, it was associated with the fact to work in a public establishment (p < 0.00001), to be single (p < 0.009), to work more than 60 h (p<0.001), sleeping less than 42 h per week (p < 0.005), less than five years of profession (p < 0.0002); to be from 20 to 29 years old ( p <0.0005) , the protective factor was to have children (p <0.006).There were no differences between clinical and surgical specialties. Young professionals, with lower family restraint and greater labor demand, are those that present a greater risk of burnout. Institutions should identify their risk professionals and develop mechanisms for the protection and treatment of those affected.

Introducción: El Síndrome de Burnout es un trastorno adaptativo, crónico, asociado con inadecuado afrontamiento de las demandas psicológicas del trabajo, es el origen de daño laboral de causa psicosocial más importante. Objetivo: Conocer el riesgo de Burnout en médicos de la ciudad de Córdoba, su relación con factores sociodemográficos y con especialidades clínicas o quirúrgicas. Métodos: Se realizó un estudio observacional de corte transversal en 10 centros asistenciales públicos y privados de la Ciudad de Córdoba. Se entrevistaron 483 médicos, recogiendo variables sociodemográficas y cuestionario Maslach Burnout Inventory evaluando el riesgo de Burnout. La edad fue estratificada desde los 20 años, de 10 en 10 hasta 60. p < 0,05 fue significativa. Resultados: Se entrevistaron 483 médicos, 62,1% mujeres, el 70% entre los 20 y los 40 años; 54,2% solteros, 42.9% ejerció < de 5 años la profesión; el 66 del total (16,5%) tuvo alto riesgo de Burnout, las variables asociadas fueron: trabajar en un establecimiento público (p < 0,00001), ser soltero (p < 0,009), trabajar más de 60 hs (p < 0,001), dormir menos de 42 hs semanales (p< 0,005), tener entre 20 y 29 años (p <0.0005) y tener menos de cinco años de profesión p < 0,0002; se identificó como factor protector tener hijos (p < 0,006). No hubo diferencias entre especialidades clínicas y quirúrgicas. Conclusiones: Los profesionales jóvenes, con menor contención familiar y mayor demanda laboral son los que presentan mayor riesgo de Burnout. Se deberían identificar y desarrollar mecanismos para proteger y tratar los afectados.

Epidemiology of primary Sjögren's syndrome in a French multiracial/multiethnic area.

OBJECTIVE: To describe the epidemiology of primary Sjögren's syndrome (SS) in a multiracial/multiethnic population. METHODS: A cross-sectional study with 5 case-retrieval sources identified adults with primary SS living in the Greater Paris area (population 1,172,482 adults) in 2007. Diagnoses were verified by the American-European Consensus Group (AECG) criteria and study-specific enlarged criteria based on the presence of ≥3 of 4 AECG items among subjective oral or ocular dryness, anti-SSA/SSB positivity, and positive minor salivary gland biopsy results. Prevalence estimates were standardized to those for the world population and a 5-source capture-recapture analysis (CRA) was used. Racial/ethnic differences in primary SS features were evaluated. RESULTS: In all, 133 subjects met the AECG criteria and 203 met the enlarged criteria. The 2007 prevalence of primary SS was 1.02 cases per 10,000 adults (95% confidence interval [95% CI] 0.85-1.22) for the AECG criteria and 1.52 cases per 10,000 adults (95% CI 1.30-1.76) for the enlarged criteria. The CRA indicated completeness of case findings of ∼90%. Compared to subjects with European backgrounds, those with non-European backgrounds had 2.1-2.3 times higher primary SS prevalence and were younger (P < 0.0001) and were more likely to have polyclonal hypergammaglobulinemia (P < 0.0001) and anti-SSA/SSB antibodies (P = 0.0005 and P < 0.0001 for the AECG and enlarged criteria, respectively). CONCLUSION: The figure of 1.02­1.52 cases per 10,000 adults we found and estimates from the few other population-based census surveys support that the prevalence of diagnosed primary SS is between 1 and 9 cases per 10,000 (0.01-0.09%) [corrected] in the general population. Non-European race/ethnicity may be associated with increased primary SS risk and a distinct disease profile.

Limited value of temporal artery ultrasonography examinations for diagnosis of giant cell arteritis: analysis of 77 subjects.

OBJECTIVE: Use of TA-US for diagnostic investigation of giant cell arteritis (GCA) has been proposed but remains a matter of debate because of the heterogeneous findings. We retrospectively evaluated operating characteristics of temporal artery ultrasonography (TA-US) in a single teaching hospital. METHODS: All subjects with suspected GCA had been seen between 2002 and 2008 and had undergone TA-US with continuous-wave Doppler (until 2004) or color duplex ultrasonography (after 2004), followed within 30 days by a temporal artery biopsy (TAB). TA-US findings were compared with TAB-proven GCA and clinically diagnosed GCA. Results are expressed as sensitivities, specificities, and positive (LR+) and negative likelihood ratios (LR-) of stenoses, occlusions, and the halo sign; for the latter, only color duplex TA-US was considered. RESULTS: Seventy-seven patients fulfilled the selection criteria; 13 had TAB-proven and 19 had clinically defined GCA. Stenoses/occlusions were seen on 45.5% of TA-US and the halo sign was seen only once (3.2%) in 31 duplex TA-US. Respective sensitivities, specificities, LR+, and LR- for GCA diagnosis (using TAB-proven/clinically defined GCA as reference standards) were 69%/53%, 59%/57%, 1.7/1.2, and 0.5/0.8 for stenoses and/or occlusions, and 17%/10%, 100%/100%, infinite/infinite, and 0.8/0.9 for the halo sign. CONCLUSION: The halo sign showed 100% specificity for GCA but only 10%-17% sensitivity. Stenoses/occlusions were of low diagnostic value. These observations suggest that TA-US is neither an effective substitute for TAB nor a reliable screening test to decide which patients can be safely spared TAB.

HLA-B51/B5 and the risk of Behçet's disease: a systematic review and meta-analysis of case-control genetic association studies.

OBJECTIVE: To quantify by meta-analysis the genetic effect of the HLA-B5 or HLA-B51 (HLA-B51/B5) allele on the risk of developing Behçet's disease (BD) and to look for potential effect modifiers. METHODS: Relevant studies were identified using the PubMed Medline database and manual searches of the literature. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by using the random-effects model. Subgroup meta-analyses and meta-regression analyses were undertaken to investigate the effects of selected study-level parameters on the pooled OR. Heterogeneity was assessed using the I2 statistic. Pooled results were used to calculate population-attributable risks (PAR) for BD in relationship to HLA-B51/B5. RESULTS: A total of 4,800 patients with BD and 16,289 controls from 78 independent studies (published 1975-2007) were selected. The pooled OR of HLA-B51/B5 allele carriers to develop BD compared with noncarriers was 5.78 (95% CI 5.00-6.67), with moderate between-study heterogeneity (I2 = 61%). The subgroup analyses stratifying studies by geographic locations (Eastern Asia, Middle East/North Africa, Southern Europe, Northern/Eastern Europe) yielded consistent OR ranges (5.31-7.20), with I2 ranges of 52-70%. Univariate random-effects meta-regression indicated the percentage of male BD cases (P = 0.008) as a source of heterogeneity. The PAR within the various geographic areas were estimated at 32-52%. CONCLUSION: The strength of the association between BD and HLA-B51/B5, and its consistency across populations of various ethnicities, lends further support to this allele being a primary and causal risk determinant for BD. Variations according to sex support an interaction of this allele with BD characteristics.