Use of mesna prophylaxis in patients with cyclophosphamide-treated ANCA-associated vasculitis: cross-sectional survey of practitioners.

BACKGROUND: There may be some diversity in the practice of co-prescribing 2-mercaptoethane sodium sulfonate (mesna) with cyclophosphamide (CYC) for ANCA-associated vasculitis (AAV). OBJECTIVES: To assess the practice of prescribing mesna prophylaxis for CYC-treated patients with AAV. METHODS: We invited authors of publications on AAV referenced in MEDLINE over the previous 10 years to participate in an anonymous online survey. Respondents were eligible if they were involved in CYC treatments for AAV. The survey asked about the characteristics of the respondents and their practice in using CYC and mesna to treat AAV and the underlying rationale. We compared 18 variables between mesna prescribers and their counterparts to identify factors associated with mesna use. RESULTS: In total, 139 eligible individuals completed the survey. The participants were from 34 countries and were essentially physicians (98%). Overall, 68%, 19% and 13% of respondents prescribed mesna systematically, never, or on a selective basis. As compared with never/selective-prescribers, systematic-prescribers were more often ≤ 39 years old (P = 0.008), more often used intermittent pulse therapy as the exclusive/predominant CYC administration scheme (P < 0.001), were more frequently based in France/Germany/Italy than in England/United States (P < 0.001), and more often indicated adherence to local standards (P = 0.003) or (inter)national guidelines for AAV (P < 0.001) as a rationale for their mesna practice. Never/selective-prescribers more commonly reported that their mesna prescription pattern had changed as compared with their former practice (P < 0.001). CONCLUSIONS: Systematic co-prescription of mesna is the prevailing practice for CYC treatments for AAV. The practice seems to involve practicability considerations and differs between generations.

Risk loci involved in giant cell arteritis susceptibility: a genome-wide association study.

BACKGROUND: Giant cell arteritis is an age-related vasculitis that mainly affects the aorta and its branches in individuals aged 50 years and older. Current options for diagnosis and treatment are scarce, highlighting the need to better understand its underlying pathogenesis. Genome-wide association studies (GWAS) have emerged as a powerful tool for unravelling the pathogenic mechanisms involved in complex diseases. We aimed to characterise the genetic basis of giant cell arteritis by performing the largest GWAS of this vasculitis to date and to assess the functional consequences and clinical implications of identified risk loci. METHODS: We collected and meta-analysed genomic data from patients with giant cell arteritis and healthy controls of European ancestry from ten cohorts across Europe and North America. Eligible patients required confirmation of giant cell arteritis diagnosis by positive temporal artery biopsy, positive temporal artery doppler ultrasonography, or imaging techniques confirming large-vessel vasculitis. We assessed the functional consequences of loci associated with giant cell arteritis using cell enrichment analysis, fine-mapping, and causal gene prioritisation. We also performed a drug repurposing analysis and developed a polygenic risk score to explore the clinical implications of our findings. FINDINGS: We included a total of 3498 patients with giant cell arteritis and 15 550 controls. We identified three novel loci associated with risk of giant cell arteritis. Two loci, MFGE8 (rs8029053; p=4·96 × 10-8; OR 1·19 [95% CI 1·12-1·26]) and VTN (rs704; p=2·75 × 10-9; OR 0·84 [0·79-0·89]), were related to angiogenesis pathways and the third locus, CCDC25 (rs11782624; p=1·28 × 10-8; OR 1·18 [1·12-1·25]), was related to neutrophil extracellular traps (NETs). We also found an association between this vasculitis and HLA region and PLG. Variants associated with giant cell arteritis seemed to fulfil a specific regulatory role in crucial immune cell types. Furthermore, we identified several drugs that could represent promising candidates for treatment of this disease. The polygenic risk score model was able to identify individuals at increased risk of developing giant cell arteritis (90th percentile OR 2·87 [95% CI 2·15-3·82]; p=1·73 × 10-13). INTERPRETATION: We have found several additional loci associated with giant cell arteritis, highlighting the crucial role of angiogenesis in disease susceptibility. Our study represents a step forward in the translation of genomic findings to clinical practice in giant cell arteritis, proposing new treatments and a method to measure genetic predisposition to this vasculitis. FUNDING: Institute of Health Carlos III, Spanish Ministry of Science and Innovation, UK Medical Research Council, and National Institute for Health and Care Research.

EULAR recommendations for the management of ANCA-associated vasculitis: 2022 update.

BACKGROUND: Since the publication of the EULAR recommendations for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in 2016, several randomised clinical trials have been published that have the potential to change clinical care and support the need for an update. METHODS: Using EULAR standardised operating procedures, the EULAR task force undertook a systematic literature review and sought opinion from 20 experts from 16 countries. We modified existing recommendations and created new recommendations. RESULTS: Four overarching principles and 17 recommendations were formulated. We recommend biopsies and ANCA testing to assist in establishing a diagnosis of AAV. For remission induction in life-threatening or organ-threatening AAV, we recommend a combination of high-dose glucocorticoids (GCs) in combination with either rituximab or cyclophosphamide. We recommend tapering of the GC dose to a target of 5 mg prednisolone equivalent/day within 4-5 months. Avacopan may be considered as part of a strategy to reduce exposure to GC in granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). Plasma exchange may be considered in patients with rapidly progressive glomerulonephritis. For remission maintenance of GPA/MPA, we recommend rituximab. In patients with relapsing or refractory eosinophilic GPA, we recommend the use of mepolizumab. Azathioprine and methotrexate are alternatives to biologics for remission maintenance in AAV. CONCLUSIONS: In the light of recent advancements, these recommendations provide updated guidance on AAV management. As substantial data gaps still exist, informed decision-making between physicians and patients remains of key relevance.

Prevalence of anti-neutrophil cytoplasmic antibody-associated vasculitis in the south of France, using the capture-recapture method.

OBJECTIVES: This study aimed to estimate the prevalence of ANCA-associated vasculitis (AAV), ie granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA), in Southern France in 2018, and evaluate differences among Europeans and non-Europeans. METHODS: This population-based, cross-sectional study used four sources (hospitals, community-based physicians, laboratories, National Health Insurance) to identify adults ≥ 15 years diagnosed with GPA, MPA or EGPA, living in Hérault and Gard in 2018. Cases were defined using the ACR/EULAR classification criteria, and if necessary, the European Medicines Agency algorithm. Prevalence estimates were standardised to the world population and capture-recapture analysis was used to assess the comprehensiveness of the estimation. The influence of geographical origin was evaluated. RESULTS: 202 patients were selected, with 86 cases of GPA (42.6%), 85 cases of MPA (42.1%), and 31 cases of EGPA (15.3%). The standardised prevalence estimates per million inhabitants for 2018 were: 103 (95%CI 84 - 125) for AAV, 48 (95%CI 35 - 64) for GPA, 39 (95%CI 28 - 53) for MPA and 16 (95%CI 9 - 26) for EGPA, 36 (95%CI 25 - 50) for anti-PR3 positive AAV, 46 (95%CI 34 - 61) for anti-MPO positive AAV, and 16 (95%CI 9 - 26) for ANCA-negative AAV. The global estimation of comprehensiveness by capture-recapture analysis was 80.5%. The number of AAV cases was higher for non-European residents (P=0.001), particularly for MPA (P<0.0001). CONCLUSION: We provide a new estimate of AAV prevalence in France and show a higher prevalence of MPA in non-European patients.

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.

Evidence-Based Guideline for the diagnosis and management of eosinophilic granulomatosis with polyangiitis.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, characterized by asthma, eosinophilia and granulomatous or vasculitic involvement of several organs. The diagnosis and management of EGPA are often challenging and require an integrated, multidisciplinary approach. Current practice relies on recommendations and guidelines addressing the management of ANCA-associated vasculitis and not specifically developed for EGPA. Here, we present evidence-based, cross-discipline guidelines for the diagnosis and management of EGPA that reflect the substantial advances that have been made in the past few years in understanding the pathogenesis, clinical subphenotypes and differential diagnosis of the disease, as well as the availability of new treatment options. Developed by a panel of European experts on the basis of literature reviews and, where appropriate, expert opinion, the 16 statements and five overarching principles cover the diagnosis and staging, treatment, outcome and follow-up of EGPA. These recommendations are primarily intended to be used by healthcare professionals, pharmaceutical industries and drug regulatory authorities, to guide clinical practice and decision-making in EGPA. These guidelines are not intended to limit access to medications by healthcare agencies, nor to impose a fixed order on medication use.

Management of giant-cell arteritis in Switzerland: an online national survey.

AIMS OF THE STUDY: To assess current practices in diagnosing, treating, and following-up giant-cell arteritis by specialists in Switzerland and to identify the main barriers to using diagnostic tools. METHODS: We performed a national survey of specialists potentially caring for patients with giant-cell arteritis. The survey was sent by email to all members of the Swiss Societies of Rheumatology and for Allergy and Immunology. A reminder was sent to nonresponders after 4 and 12 weeks. Its questions covered the following dimensions: respondents' main characteristics, diagnosis, treatment, and imaging's role during follow-up. The main study results were summarized using descriptive statistics. RESULTS: Ninety-one specialists, primarily aged 46-65 years (n = 53/89; 59%), working in academic or nonacademic hospitals or private practice, and treating a median of 7.5 (interquartile range [IQR]: 3-12) patients with giant-cell arteritis per year participated in this survey. Ultrasound of temporal arteries/large vessels (n = 75/90; 83%) and positron-emission-tomography-computed tomography (n = 52/91; 57%) or magnetic resonance imaging (n = 46/90; 51%) of the aorta/extracranial arteries were the most common techniques used to diagnose giant-cell arteritis with cranial or large vessel involvement, respectively. Most participants reported a short time to obtain imaging tests or arterial biopsy. The glucocorticoid tapering scheme, glucocorticoid-sparing agent, and glucocorticoid-sparing treatment duration varied among the participants. Most physicians did not follow a predefined repeat imaging scheme for follow-up and mainly relied on structural changes (vascular thickening, stenosis, or dilatation) to drive treatment choice. CONCLUSIONS: This survey indicates that imaging and temporal biopsy are rapidly accessible for diagnosing giant-cell arteritis in Switzerland but highlights heterogeneous practice in many disease management areas.

Long-term outcomes and prognostic factors for survival of patients with ANCA-associated vasculitis.

BACKGROUND: Despite newer treatments with immunosuppressive agents, there still exists a considerable morbidity and mortality risk among patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Since 1994 the European Vasculitis Society (EUVAS) has aimed for an improved outcome for patients with AAV, conducting several prospective randomized controlled trials (RCTs). The aim for the present study was to further evaluate the long-term survival of patients with AAV included in seven RCTs conducted by the EUVAS as well as to identify potential prognostic factors. METHODS: Long-term follow-up data were collected from questionnaires sent to the principal investigators of the original RCTs (1995-2012): MEPEX, NORAM, CYCAZAREM, CYCLOPS, IMPROVE, RITUXVAS and MYCYC, comprising 848 patients, all newly diagnosed with AAV. Relative survival estimates are presented for the study cohorts. Demographic, clinical and laboratory characteristics at trial entry were studied as potential prognostic factors in multivariable models. RESULTS: A total of 478 (56%) patients had granulomatosis with polyangiitis (GPA) and 370 (44%) had microscopic polyangiitis (MPA) with a mean age at diagnosis of 58 ± 14 years. The median follow-up time was 8 years (interquartile range 2.9-13.6). During the observation period there were 305 deaths and the main causes were infections (26%), cardiovascular disease (14%) and malignancies (13%). When compared with a matched cohort (regarding country, age group and sex) from the background population there were 14.2% more deaths among our cohort of AAV patients at 5 years, 19.9% at 10 years, 28.8% at 15 years and 36.3% at 20 years. The excess mortality occurred in all age groups. The estimated median survival time (from diagnosis) was 17.8 years (95% confidence interval 15.7-20). Among variables measured at baseline, advanced age, male sex, low estimated glomerular filtration rate and low platelet count were identified as predictors of death in a multivariate Cox model. CONCLUSIONS: Patients with AAV still have an increased risk of mortality compared with the general population despite newer therapeutic regimens. Treatment complications and organ damage are the main causes of limited survival and infections remain the leading cause of mortality among patients with AAV.

The Sound of Interconnectivity; The European Vasculitis Society 2022 Report.

The first European Vasculitis Society (EUVAS) meeting report was published in 2017. Herein, we report on developments in the past 5 years which were greatly influenced by the pandemic. The adaptability to engage virtually, at this critical time in society, embodies the importance of networks and underscores the role of global collaborations. We outline state-of-the-art webinar topics, updates on developments in the last 5 years, and proposals for agendas going forward. A host of newly reported clinical trials is shaping practice on steroid minimization, maintenance strategies, and the role of newer therapies. To guide longer-term strategies, a longitudinal 10-year study investigating relapse, comorbidity, malignancy, and survival rates is at an advanced stage. Disease assessment studies are refining classification criteria to differentiate forms of vasculitis more fully. A large international validation study on the histologic classification of anti-neutrophil cytoplasmic antibody (ANCA) glomerulonephritis, recruiting new multicenter sites and comparing results with the Kidney Risk Score, has been conducted. Eosinophilic granulomatosis with polyangiitis (EGPA) genomics offers potential pathogenic subset and therapeutic insights. Among biomarkers, ANCA testing is favoring immunoassay as the preferred method for diagnostic evaluation. Consolidated development of European registries is progressing with an integrated framework to analyze large clinical data sets on an unprecedented scale.

Presentation and Real-World Management of Giant Cell Arteritis (Artemis Study).

Background: Few studies of daily practice for patients with giant cell arteritis (GCA) are available. This French study aimed to describe the characteristics and management of GCA in a real-life setting. Methods: Cross-sectional, non-interventional, multicenter study of patients ≥50 years old who consulted hospital-based specialists for GCA and were under treatment. Patient characteristics and journey, diagnostic methods and treatments were collected. Descriptive analyses were performed. Results: In total, 306 patients (67% females, mean age 74 ± 8 years old) were recruited by 69 physicians (internists: 85%, rheumatologists: 15%); 13% of patients had newly diagnosed GCA (diagnosis-to-visit interval <6 weeks). Overall median disease duration was 13 months (interquartile range 5-26). Most patients were referred by general practitioners (56%), then ophthalmologists (10%) and neurologists (7%). Most common comorbidities were hypertension (46%), psychiatric disorders (10%), dyslipidemia (12%), diabetes (9%), and osteoporosis (6%). Initial GCA presentations included cranial symptoms (89%), constitutional symptoms (74%), polymyalgia rheumatica (48%), and/or other extra-cranial manifestations (35%). Overall, 85, 31, 26, and 30% of patients underwent temporal artery biopsy, high-resolution temporal artery Doppler ultrasonography, 18FDG-PET, and aortic angio-CT, respectively. All patients received glucocorticoids, which were ongoing for 89%; 29% also received adjunct medication(s) (methotrexate: 19%, tocilizumab: 15%). A total of 40% had relapse(s); the median time to the first relapse was 10 months. Also, 37% had comorbidity(ies) related to or aggravated by glucocorticoids therapy. Conclusion: This large observational study provides insight into current medical practices for GCA. More than one third of patients had comorbidities related to glucocorticoid therapy for a median disease duration of 13 months. Methotrexate and tocilizumab were the most common adjunct medications.

Use and reporting of outcome measures in randomized trials for anti-neutrophil cytoplasmic antibody-associated vasculitis: a systematic literature review.

BACKGROUND: A comprehensive review of outcome measures used in randomized controlled trials (RCTs) of ANCA-associated vasculitis (AAV) could advance trial conductance for this disease. METHODS: A systematic literature review of outcome measures (as specified in methods section as primary and/or secondary outcomes) in RCTs of AAV was conducted. Medline, Cochrane CENTRAL, and ClinicalTrials.gov were searched from inception until April 30, 2019 for RCTs enrolling patients with granulomatosis with polyangiitis and/or microscopic polyangiitis. Outcome measures were organized according to domains (e.g. disease activity) and instruments [e.g. Birmingham Vasculitis Activity Score (BVAS)]. RESULTS: Out of 1101 identified records, 68 RCTs were eligible. Disease activity was an outcome domain collected in 67 (98%) of the RCTs. The BVAS was the most widely used instrument for disease assessment but definitions for remissions and relapse varied for the purpose of primary endpoint definitions. Damage, most often assessed by the Vasculitis Damage Index, was an outcome in 30 (44%) of the RCTs. Mortality was specified as an outcome in 26 (38%) studies. The following outcome domains were assessed: patient-reported outcomes (PROs) in 28 (41%), drug exposure/safety in 58 (85%), and biomarkers [acute phase reactants, ANCA levels] in 24 (35%). Timing for outcome assessment differed substantially, with 3, 6, or 12 months being the most frequent time points. CONCLUSION: Outcome measures used in trials in AAV commonly included vasculitis-specific tools for disease assessment, but with heterogeneity in endpoint-definitions and timing of assessments. Other core outcomes in AAV, including PROs, and damage measures, are often omitted in AAV trials.

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.

Characteristics and management of giant cell arteritis in France: a study based on national health insurance claims data.

OBJECTIVE: Few data are available on the epidemiology and management of GCA in real life. We aimed to address this situation by using health insurance claims data for France. METHODS: This retrospective study used the Echantillon Généraliste de Bénéficiaires (EGB) database, a 1% representative sample of the French national health insurance system. The EGB contains anonymous data on long-term disease status, hospitalizations and reimbursement claims for 752 717 people. Data were collected between 2007 and 2015. The index date was defined as the date of the first occurrence of a GCA code. Demographics, comorbidities, diagnostic tests and therapies were analysed. Annual incidence rates were calculated, and incident and overall GCA cases were studied. RESULTS: We identified 241 patients with GCA. The annual incidence was 7-10/100 000 people ⩾50 years old. Among the 117 patients with incident GCA, 74.4% were females, with mean age 77.6 years and mean follow-up 2.2 years. After the index date, 51.3% underwent temporal artery biopsy and 29.1% high-resolution Doppler ultrasonography. Among the whole cohort, 84.3% used only glucocorticoids. The most-prescribed glucocorticoid-sparing agent was methotrexate (12.0%). CONCLUSION: The incidence of GCA in France is 7-10/100 000 people ⩾ 50 years old. Adjunct agents, mainly methotrexate, are given to only a few patients. The use of temporal artery biopsy in only half of the patients might reflect a shift toward the use of imaging techniques to diagnose GCA.

Optimal length and usefulness of temporal artery biopsies in the diagnosis of giant cell arteritis: a 10-year retrospective review of medical records.

BACKGROUND: In giant cell arteritis, temporal artery biopsies often show vasculitis with giant cell formation, but optimal biopsy length for diagnosis is debated. We reviewed temporal artery biopsies from a 10-year period in the province of Alberta, Canada, to identify an ideal biopsy length in the diagnostic process for giant cell arteritis. METHODS: We retrospectively reviewed electronic medical records of patients who had undergone a temporal artery biopsy procedure in Alberta between Jan 1, 2008, and Jan 1, 2018, as reported in the Data Integration and Management Repository of Alberta Health Services. We extracted data on baseline demographic characteristics (sex and age), inflammatory markers (erythrocyte sedimentation rate [ESR] and C-reactive protein [CRP]), temporal artery biopsy characteristics (side of biopsy and postfixation length), and final pathological diagnoses. All positive biopsies were reviewed by a single pathologist to ensure uniformity of pathological interpretation, with subsequent discordant results removed from analysis. Predictors of positive pathological diagnosis of giant cell arteritis were modeled by logistic regression, and the Akaike information criterion was used to compare logistic regression models with varying biopsy length cutoffs (0·5, 1·0, 1·5, 2·0, and 2·5 cm) to determine a change point for diagnostic sensitivity in postfixation length. FINDINGS: We extracted data on 1203 temporal artery biopsies; after removal of 13 discordant biopsies, 1190 biopsies from 1163 patients were reviewed. The mean age of patients was 72·0 years (SD 10·3) and 799 (68·7%) patients were women. 222 (18·7%) temporal artery biopsies were positive for giant cell arteritis. In univariable analysis, increases in age (71·3 years [SD 10·6] in negative biopsies vs 75·3 years [8·3] in positive biopsies; odds ratio [OR] 1·04 [95% CI 1·02-1·06]; p<0·0001)), ESR (36 mm/h [IQR 18-62] in negative biopsies vs 57 [31-79] in positive biopsies; 1·01 [1·01-1·02]; p<0·0001), CRP (12·1 mg/L [IQR 3·3-35·1] in negative biopsies vs 41·8 [14·6-82·4] in positive biopsies; 1·01 [1·01-1·01]; p<0·0001), and biopsy length (1·2 cm [IQR 0·9-1·7] in negative biopsies vs 1·6 [1·1-2·0] in positive biopsies; 1·28 [1·09-1·51]; p=0·0025) were associated with a positive pathological diagnosis. In multivariable analysis adjusted for age, ESR, and CRP, age (adjusted OR 1·04 [95% CI 1·02-1·05]; p=0·0001), CRP (1·01 [1·00-1·01]; p=0·0006), and biopsy length (1·22 [1·00-1·49]; p=0·047) remained statistically significant predictors. The Akaike information criterion determined a change point of 1·5 cm for diagnostic sensitivity. INTERPRETATION: Accounting for postfixation shrinkage, our findings suggest a 1·5-2·0 cm prefixation length as the optimal biopsy length to diagnose patients with giant cell arteritis, with greater lengths unlikely to provide significant additional diagnostic yield to justify risks associated with surgery. FUNDING: None.

Management of Takayasu arteritis: a systematic literature review informing the 2018 update of the EULAR recommendation for the management of large vessel vasculitis.

Objective: To collect available evidence on management of large vessel vasculitis to inform the 2018 update of the EULAR management recommendations. Methods: Two independent systematic literature reviews were performed, one on diagnosis and monitoring and the other on drugs and surgical treatments. Using a predefined PICO (population, intervention, comparator and outcome) strategy, Medline, Embase and Cochrane databases were accessed. Eligible papers were reviewed and results condensed into a summary of findings table. This paper reports the main results for Takayasu arteritis (TAK). Results: A total of 287 articles were selected. Relevant heterogeneity precluded meta-analysis. Males appear to have more complications than females. The presence of major complications, older age, a progressive disease course and a weaker inflammatory response are associated with a more unfavourable prognosis. Evidence for details on the best disease monitoring scheme was not found. High-quality evidence to guide the treatment of TAK was not found. Glucocorticoids are widely accepted as first-line treatment. Conventional immunosuppressive drugs and tumour necrosis factor inhibitors were beneficial in case series and uncontrolled studies. Tocilizumab failed the primary endpoint (time to relapse) in a randomised controlled clinical trial; however, results still favoured tocilizumab over placebo. Vascular procedures may be required, and outcome is better when performed during inactive disease. Conclusions: Evidence to guide monitoring and treatment of patients with TAK is predominantly derived from observational studies with low level of evidence. Therefore, higher-quality studies are needed in the future.

Role of Macrophage Migration Inhibitory Factor in Granulomatosis With Polyangiitis.

OBJECTIVE: To examine the association between macrophage migration inhibitory factor (MIF) promoter polymorphisms and granulomatosis with polyangiitis (GPA) in human subjects, and to assess the role of MIF in a murine model of granulomatous vasculitis. METHODS: The human study involved 1,077 patients with GPA and healthy controls whose serum was genotyped by capillary electrophoresis for the MIF -794 CATT5-8 promoter microsatellite (rs5844572). MIF promoter, CATT-length-dependent gene expression in response to ß-glucan was assessed by gene reporter assays. In mouse studies, granulomatous disease was induced by injection of Candida albicans ß-glucan into wild-type (WT) or Mif-knockout (Mif-KO) C57BL/6 mice and C57BL/6 mice transgenically overexpressing Mif in lung epithelium (Mif lung-Tg2.1). Mice were treated with a neutralizing anti-MIF antibody and analyzed for the density of pulmonary granulomas, expression of inflammatory chemokines, and frequency of mortality. RESULTS: The percentage of human subjects carrying >5 CATT repeats in each MIF allele (high genotypic MIF expressers) was 60.2% among patients with GPA and 53.9% among healthy controls (adjusted P = 0.049). In response to granulomatous stimulation, human MIF gene expression increased proportionally with CATT length. Mif lung-Tg2.1 mice exhibited more pulmonary granulomas than WT mice, which in turn showed more granulomas than Mif-KO mice. A significantly higher percentage of Mif lung-Tg2.1 mice, compared to Mif-KO or WT mice, died when injected with Candida albicans ß-glucan, and treatment of these mice with an anti-MIF monoclonal antibody protected against a lethal outcome. Levels of MIF-dependent neutrophil/macrophage chemokines were elevated in the bronchoalveolar lavage fluid or plasma of Mif lung-Tg2.1 mice. CONCLUSION: Patients with GPA have an increased frequency of high MIF expression CATT alleles. Higher Mif expression increases the incidence of mortality and pulmonary granulomas in Mif lung-Tg2.1 mice, while anti-MIF treatment protects these mice against death. Blockade of MIF in high genotypic MIF expressers may therefore offer a selective pharmacologic therapy for GPA.

2018 update of the EULAR recommendations for the management of Behçet's syndrome.

Several new treatment modalities with different mechanisms of action have been studied in patients with Behçet's syndrome (BS). The aim of the current effort was to update the recommendations in the light of these new data under the auspices of the European League Against Rheumatism (EULAR) Standing Committee for Clinical Affairs. A task force was formed that included BS experts from different specialties including internal medicine, rheumatology, ophthalmology, dermatology, neurology, gastroenterology, oral health medicine and vascular surgery, along with a methodologist, a health professional, two patients and two fellows in charge of the systematic literature search. Research questions were determined using a Delphi approach. EULAR standardised operating procedures was used as the framework. Results of the systematic literature review were presented to the task force during a meeting. The former recommendations were modified or new recommendations were formed after thorough discussions followed by voting. The recommendations on the medical management of mucocutaneous, joint, eye, vascular, neurological and gastrointestinal involvement of BS were modified; five overarching principles and a new recommendation about the surgical management of vascular involvement were added. These updated, evidence-based recommendations are intended to help physicians caring for patients with BS. They also attempt to highlight the shortcomings of the available clinical research with the aim of proposing an agenda for further research priorities.

Mortality causes and trends associated with giant cell arteritis: analysis of the French national death certificate database (1980-2011).

OBJECTIVES: Comprehensive analyses of cause-specific death patterns in GCA are sparse. We studied the patterns and time trends in GCA-related mortality using a large death certificate database. METHODS: We obtained multiple-cause-of-death data from the French national death certificate database for 1980-2011. GCA-associated deaths were defined as decedents ⩾55 years old with GCA listed as an underlying or non-underlying cause of death. Time trends of death rates were analysed and the mean age at death with GCA and in the general population ⩾55 years old were calculated. Standardized mortality odds ratios (SMORs) were calculated for 17 selected causes of death (based on 2000-11 data). RESULTS: The analyses pertained to approximately 15 000 death certificates listing GCA (including approximately 6300 for 2000-11). Annual standardized death rates for GCA increased to a peak in 1997 and then decreased (Spearman's correlation test, both P < 0.0001). Mean age at death was higher for GCA than for general population decedents (Student's t-test, P < 0.0001). GCA deaths were frequently or strongly associated with aortic aneurysm and dissection (1.85% of death certificates, SMOR: 3.09, 95% CI: 2.48, 3.82), hypertensive disease (20.78%, SMOR: 2.22, 95% CI: 1.97, 2.50), diabetes mellitus (11.27%, SMOR: 1.96, 95% CI: 1.72, 2.23), certain infectious and parasitic diseases (12.12%, SMOR: 1.76, 95% CI: 1.55, 2.00) and ischaemic heart disease (16.54%, SMOR: 1.45, 95% CI: 1.35, 1.64). CONCLUSION: GCA is associated with increased risk of dying from large-vessel disease, other cardiovascular diseases and potentially treatment-related co-morbidities. These findings help provide better insights into the outcomes of GCA.

Clinical and microbiological characteristics of the infections in patients treated with rituximab for autoimmune and/or malignant hematological disorders.

INTRODUCTION: Rituximab is commonly used for the treatment of hematological malignancies and autoimmune diseases. Despite a reputation for good tolerance, case-series and registries reported rituximab-related infections of variable severity including opportunistic infections. We aimed at describing the natural history of infectious events (IE) after treatment by rituximab providing clinical and microbiological features and outcome. PATIENTS AND METHODS: We retrospectively analyzed the medical records of patients treated with rituximab in an internal medicine department of a tertiary hospital between 2007 and 2015, and identified all IE after this therapy. Events' severity was assessed using the Common Terminological Criteria of Adverse Events (version 4.3) definitions. RESULTS: Among 101 patients treated with rituximab, we identified 228 IE in 74 (73.3%) of these patients (median follow-up 30.4months). Indication for rituximab was either autoimmune disease (AID) (52.5% of patients), or monoclonal hematological disease (MHD) (47.5%). Patients received an overall median number of 5 rituximab infusions [interquartile range: 4-8], representing a cumulative dose of 4340mg [2620-6160]. After last rituximab infusion, IE occurred after 3.1months [0.7-9.4]. Respectively, IE were severe in 28.1% of cases in patients treated for AID vs 58.0% in patients treated for MHD (p<0.001), due to opportunistic pathogens in 7.8% vs 11.0% (p=0.49) and fatal in 4.7% vs 13.0% (p=0.044). Factor associated with mortality were polymicrobial infection (p<0.001), monoclonal hematological disease (p=0.035), use of steroids over 10mg/d within the last two weeks (p=0.003), and rituximab cumulative dose (p<0.001). We identified a group of 10 patients (9.9%) showing life-threatening, polymicrobial, and opportunistic infections constituting a 'catastrophic infectious syndrome', which was lethal in 7 cases. CONCLUSION: IE after treatment by rituximab can be extremely severe, especially in patients immunocompromised by several other drugs. Further studies should focus on the group with life-threatening polymicrobial infections.