Incidence of and mortality from epidermal necrolysis (Stevens-Johnson syndrome/toxic epidermal necrolysis) in France during 2003-16: a four-source capture-recapture estimate.

BACKGROUND: Because of its rarity, the exact incidence of and mortality from epidermal necrolysis (Stevens-Johnson syndrome/toxic epidermal necrolysis) is difficult to establish and closely depends on the size and type of the data source. OBJECTIVES: To estimate the incidence of and mortality due to epidermal necrolysis in France over a 14-year period. METHODS: Data from four national databases were analysed. A capture-recapture analysis was performed. RESULTS: A total of 2635 incident cases of epidermal necrolysis were recorded in at least one of the four databases during the study period [males: 47·9%; median age: 52 (interquartile range 25-72) years]. On capture-recapture analysis, the estimated total number of cases was 5686, for an overall estimated annual incidence of 6·5 (95% confidence interval 4·1-8·9) cases per million inhabitants. The estimated annual incidence rates were 4·1 (0·3-7·9) cases per million inhabitants < 20 years of age, 3·9 (1·5-6·3) cases per million inhabitants aged 20-64 years and 13·7 (5·4-22·0) cases per million inhabitants ≥ 65 years of age. The estimated overall annual mortality rate from epidermal necrolysis was 0·9 (0·1-1·8) case per million inhabitants. It was 0·6 (0·1-1·5) case per million inhabitants aged 20-64 years and 2·8 (0·9-6·6) cases per million inhabitants ≥ 65 years of age (deaths in people < 20 years old were too rare to provide an accurate estimate). CONCLUSIONS: The annual incidence of epidermal necrolysis is higher than the one to five cases per million inhabitants usually reported. Such estimations could be helpful in establishing appropriate healthcare plans for people with epidermal necrolysis, in particular the need for specialized care units. What's already known about this topic? Few data are available regarding incidence of and mortality from epidermal necrolysis in the general population. Experts in epidermal necrolysis have recently proposed an annual incidence of one to five cases per million individuals. The overall mortality rate is usually reported to be between 10% and 20%. What does this study add? Using a four-source capture-recapture method and data from a 14-year period (2003-16), the annual incidence of and mortality from epidermal necrolysis were estimated to be 6·5 (95% confidence interval 4·1-8·9) and 0·9 (0·1-1·8) cases per million French inhabitants, respectively. Such estimations could be helpful in establishing appropriate healthcare plans, in particular the need for specialized care units.

EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis.

In this article, the 2009 European League Against Rheumatism (EULAR) recommendations for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) have been updated. The 2009 recommendations were on the management of primary small and medium vessel vasculitis. The 2015 update has been developed by an international task force representing EULAR, the European Renal Association and the European Vasculitis Society (EUVAS). The recommendations are based upon evidence from systematic literature reviews, as well as expert opinion where appropriate. The evidence presented was discussed and summarised by the experts in the course of a consensus-finding and voting process. Levels of evidence and grades of recommendations were derived and levels of agreement (strengths of recommendations) determined. In addition to the voting by the task force members, the relevance of the recommendations was assessed by an online voting survey among members of EUVAS. Fifteen recommendations were developed, covering general aspects, such as attaining remission and the need for shared decision making between clinicians and patients. More specific items relate to starting immunosuppressive therapy in combination with glucocorticoids to induce remission, followed by a period of remission maintenance; for remission induction in life-threatening or organ-threatening AAV, cyclophosphamide and rituximab are considered to have similar efficacy; plasma exchange which is recommended, where licensed, in the setting of rapidly progressive renal failure or severe diffuse pulmonary haemorrhage. These recommendations are intended for use by healthcare professionals, doctors in specialist training, medical students, pharmaceutical industries and drug regulatory organisations.

[Clinical aspects and treatment of recurrent aphthous ulcers]. / Klinik und Therapie chronisch rezidivierender Aphthen.

Recurrent aphthous ulcers are the most common inflammatory lesions of the oral mucosa, occurring in up to 10% of the population and even more common in children. The history, morphological characteristics, predilection sides and typical stages of aphthae help to distinguish them from other diseases that may exhibit aphthous-like lesions. Underlying diseases should be excluded. The main goals of therapy are to minimize pain and functional disabilities as well as decrease frequency and severity of recurrences. Topical symptomatic relief is the standard of care for simple cases of recurrent aphthosis. In cases of major aphthosis or systemic involvement, topical therapies are still useful but should be combined with systemic therapy, such as colchicine, pentoxifylline or prednisolone. In case of Adamantiades-Behçet disease, systemic immunomodulatory drugs can inhibit the development of new lesions. This overview summarizes morphological and presentation forms of aphthae, differential diagnoses and evidence-based therapeutic possibilities.

Incidence of malignancy in patients treated for antineutrophil cytoplasm antibody-associated vasculitis: follow-up data from European Vasculitis Study Group clinical trials.

OBJECTIVES: Because standard immunosuppressive treatment for antineutrophil cytoplasm antibody-associated vasculitis (AAV) (granulomatosis with polyangiitis (Wegener's) (GPA) and microscopic polyangiitis (MPA)) has been associated with a significant risk of developing cancer, the cancer incidence of treated AAV patients was assessed. METHODS: This analysis concerned 535 patients with newly diagnosed AAV from 15 countries who had been enrolled between 1995 and 2002 in four European clinical trials. Over the period 2004-7, study participants' follow-up events were updated, including cancers diagnosed. Age, sex and area-standardised incidence ratios (SIR) and their 95% CI were calculated by linkage to five national cancer databases. RESULTS: During the 2650 person-years' observation period, 50 cancers were diagnosed in 46 patients. SIR (95% CI) were 1.58 (1.17 to 2.08) for cancers at all sites, 1.30 (0.90 to 1.80) for cancers at all sites excluding non-melanoma skin cancer (NMSC), 2.41 (0.66 to 6.17) for bladder cancer, 3.23 (0.39 to 11.65) for leukaemia, 1.11 (0.03 to 6.19) for lymphoma and 2.78 (1.56 to 4.59) for NMSC. Subgroup SIR for cancers at all sites were 1.92 (1.31 to 2.71) for GPA and 1.20 (0.71 to 1.89) for MPA. CONCLUSIONS: Cancer rates for AAV patients treated with conventional immunosuppressive therapy exceeded those expected for the general population. This cancer excess was largely driven by an increased incidence of NMSC. The smaller cancer risk magnitude in this cohort, compared with previous studies, might reflect less extensive use of cyclophosphamide in current treatment protocols. Longer follow-up data are warranted to appraise the risk of developing cancers later during the course of AAV.

Synthesis of bioactive quinazolin-4(3H)-one derivatives via microwave activation tailored by phase-transfer catalysis.

A series of nine new 2,3-disubstituted 4(3H)-quinazolin-4-one derivatives was furnished starting from the 2-propyl-4(3H)-quinazo-line-4-one (2). The reinvestigation of the key starting quinazolinone 2 was performed under microwave irradiation (MW) and solvent-free conditions. Combination of MW and phase-transfer catalysis using tetrabutylammonium benzoate (TBAB) as a novel neutral ionic catalyst was used for carrying out N-alkylation and condensation reactions of compound 2 as a simple, efficient and eco-friendly technique. The structure of the synthesized compounds was elucidated using different spectral and chemical analyses. In vitro antimicrobial activity of the compounds was investigated against four bacterial and two fungal strains; very modest activity was achieved. Some of the synthesized compounds were screened for their antitumor activity against different human tumor cell lines. The screened compounds exhibited a significant antitumor activity on some of the cancer cell lines, melanoma (SK-MEL-2), ovarian cancer (IGROV1), renal cancer (TK-10), prostate cancer (PC-3), breast cancer (MCF7) and colon cancer (HT29). The most active, even more active than the reference 5-fluorouracil, were found to be ethyl 4-[(4-oxo-2-propylquinazolin-3(4H)-yl)methyl]benzoate (3c), 3-{2-[6-(pyrrolidin-1-yl-sulfonyl)-1,2,3,4-tetrahydroquinoline]-2-oxoethyl}-2-propylquinazolin--4(3H)-one (3e), N'-[(E)-(2H-1,3-benzodioxo-5-yl)methylidene]-2-(4-oxo-2-propylquinazolin-3(4H)-yl)acetohydrazide (10a), N'-[(E)-(4-hydroxyphenyl)methylidene]-2-(4-oxo-2-propylquinazo-lin-3(4H) -yl)acetohydrazide (10b) and N'-[(E)-(4-nitrophenyl)methyl idene]-2-(4-oxo-2-propylquinazolin-3(4H)-yl)acetohydrazide (10c).

Comparison of disease activity measures for anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis.

AIM: Currently, several different instruments are used to measure disease activity and extent in clinical trials of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, leading to division among investigative groups and difficulty comparing study results. An exercise comparing six different vasculitis instruments was performed. METHODS: A total of 10 experienced vasculitis investigators from 5 countries scored 20 cases in the literature of Wegener granulomatosis or microscopic polyangiitis using 6 disease assessment tools: the Birmingham Vasculitis Activity Score (BVAS), The BVAS for Wegener granulomatosis (BVAS/WG), BVAS 2003, a Physician Global Assessment (PGA), the Disease Extent Index (DEI) and the Five Factor Score (FFS). Five cases were rescored by all raters. RESULTS: Reliability of the measures was extremely high (intraclass correlations for the six measures all = 0.98). Within each instrument, there were no significant differences or outliers among the scores from the 10 investigators. Test/retest reliability was high for each measure: range = 0.77 to 0.95. The scores of the five acute activity measures correlated extremely well with one another. CONCLUSIONS: Currently available tools for measuring disease extent and activity in ANCA-associated vasculitis are highly correlated and reliable. These results provide investigators with confidence to compare different clinical trial data and helps form common ground as international research groups develop new, improved and universally accepted vasculitis disease assessment instruments.

The leucotriene receptor antagonist montelukast and the risk of Churg-Strauss syndrome: a case-crossover study.

BACKGROUND: There has been some concern that leucotriene receptor antagonists might precipitate the onset of Churg-Strauss syndrome (CSS). A study was undertaken to investigate the relationship between the leucotriene receptor antagonist montelukast and the onset of CSS. METHODS: Medication histories of 78 patients with CSS from France and Germany were retraced by questioning the patients, treating physicians and dispensing pharmacists, and from medical records. Using a case-crossover research design, exposures to montelukast and other asthma medications during the 3-month "index" period immediately preceding the onset of CSS were compared with those of four previous 3-month "control" periods. Odds ratios (ORs) were computed by conditional logistic regression. RESULTS: The ORs for CSS onset were 4.5 (95% CI 1.5 to 13.9) for montelukast, 3.0 (95% CI 0.8 to 10.5) for inhaled long-acting beta(2) agonists, 1.7 (95% CI 0.5 to 5.4) for inhaled corticosteroids and 4.0 (95% CI 1.3 to 12.5) for oral corticosteroids. Montelukast exposure during control periods increased temporally over three consecutive calendar periods of CSS onset from 1999 to 2003 (p(trend) <0.0001). CONCLUSION: Montelukast use was associated with a 4.5-fold higher risk of CSS onset within 3 months. However, the positive estimates obtained for other long-term asthma control medications suggest that this link might be confounded by a general escalation of asthma therapy before CSS onset. The association between montelukast and CSS observed in this study is probably also explained by the increasing use of this medication over time.

Infliximab efficacy and safety against refractory systemic necrotising vasculitides: long-term follow-up of 15 patients.

BACKGROUND: Results of uncontrolled studies have suggested that infliximab is efficacious against systemic necrotising vasculitides (SNV) refractory to conventional treatment. However, its safety and ability to induce and maintain remission over the long term remain unknown. OBJECTIVES: To report the use of infliximab to treat refractory SNV, focusing on patients' longer-term outcomes. METHODS: The medical charts of patients given adjunctive infliximab for refractory SNV >/=2 years before this evaluation were reviewed retrospectively. RESULTS: The 15 patients (median age 46 (range 20-69) years, median follow-up 35 (24-41) months) included 10 with Wegener's granulomatosis, 1 microscopic polyangiitis, 3 rheumatoid arthritis-associated and 1 cryoglobulinaemia-related vasculitides. Infliximab was taken for a median time of 8 (2-31) months; 2 patients are still being treated. By day 45, 11 patients had entered remission (Birmingham Vasculitis Activity Score (BVAS) = 0) and 4 others had responded (BVAS decrease >/=50%). Five patients achieved sustained remissions (>/=6 months, corticosteroids

Mortality and risk factors of scleroderma renal crisis: a French retrospective study of 50 patients.

OBJECTIVES: To describe presentation and outcome of patients with scleroderma renal crisis (SRC). METHODS: SRC was defined as rapidly progressive oliguric renal insufficiency and/or rapidly progressive arterial hypertension occurring during the course of systemic sclerosis (SSc). Chronic dialysis-free survival was analysed using multivariate Cox proportional hazards regression models. The risk for developing SRC associated with corticosteroid (CS) exposure during the preceding 1- or 3-month periods was analysed according to a case-crossover design. RESULTS: A total of 50 SSc patients aged 53.3 (14.5) (mean (SD)) years were included in the study. SRC occurred between 1979 and 2003, after a mean (SD) disease duration of 27.7 (49.1) months. A total of 43 (86%) patients had diffuse SSc, 5 (10%) had limited cutaneous SSc and 2 (4%) had SSc sine scleroderma. At the time of SRC, 10 (20%) patients were taking angiotensin converting enzyme inhibitors, and mean creatininaemia was 468 (293) micromol/l. A total of 28 (56%) patients required haemodialysis. In all, 11 patients underwent a renal biopsy, all of them had specific vascular lesions of SRC. Multivariate analyses retained age >53 years and normal blood pressure as independent predictors of decreased dialysis-free survival. Exposure to CS prior to SRC was identified in 30 (60%) patients. The odds ratios for developing SRC associated with CS exposure during the preceding 1- or 3-month periods were 24.1 (95% CI 3.0-193.8) and 17.4 (95% CI 2.1-144.0), respectively. CONCLUSION: SRC remains associated with severe morbidity and mortality. CS might increase the risk of developing SRC. Further studies are needed to confirm these results.

Outcomes from studies of antineutrophil cytoplasm antibody associated vasculitis: a systematic review by the European League Against Rheumatism systemic vasculitis task force.

OBJECTIVES: We undertook a systematic literature review as a background to the European League Against Rheumatism (EULAR) recommendations for conducting clinical trials in anti-neutrophil cytoplasm antibody associated vasculitis (AAV), and to assess the quality of evidence for outcome measures in AAV. METHODS: Using a systematic Medline search, we categorised the identified studies according to diagnoses. Factors affecting remission, relapse, renal function and overall survival were identified. RESULTS: A total of 44 papers were reviewed from 502 identified by our search criteria. There was considerable inconsistency in definitions of end points. Remission rates varied from 30% to 93% in Wegener granulomatosis (WG), 75% to 89% in microscopic polyangiitis (MPA) and 81% to 91% in Churg-Strauss syndrome (CSS). The 5-year survival for WG, MPA and CSS was 74-91%, 45-76% and 60-97%. Relapse (variably defined) was common in the first 2 years but the frequency varied: 18% to 60% in WG, 8% in MPA, and 35% in CSS. The rate of renal survival in WG varied from 23% at 15 months to 23% at 120 months. METHOD: used to assess morbidity varied between studies. Ignoring the variations in definitions of the stage of disease, factors influencing remission, relapse, renal and overall survival included immunosuppressive therapy used, type of organ involvement, presence of ANCA, older age and male gender. CONCLUSIONS: Factors influencing remission, relapse, renal and overall survival include the type of immunosuppressive therapy used, pattern of organ involvement, presence of ANCA, older age and male gender. Methodological variations between studies highlight the need for a consensus on terminology and definitions for future conduct of clinical studies in AAV.

[Epidemiology and natural history of giant cell arteritis]. / Épidémiologie et histoire naturelle de l'artérite à cellules géantes (Horton).

Knowledge of the natural history and epidemiology of giant cell arteritis (GCA) is growing. With the recent conceptual change, GCA is no longer considered a disease with mandatory cranial symptoms but, rather, a larger disease spectrum also including idiopathic aortitis in people older than 50 and polymyalgia rheumatica with large-vessel involvement. The incidence peak between age 70 and 80 years, greater frequency in females and greater occurrence in Nordic countries are well-established epidemiological characteristics. Conversely, the notion that the incidence of GCA is increasing is challenged by several recent population-based studies suggesting a trend reversal for about 15 to 20 years. The known link with the allele HLA-DRB1*04 was confirmed by a genome-wide association study that also found associations with two other genetic polymorphisms. Recent studies indicating a link with varicella zoster virus infection have invigorated the hypothesis of an infectious cause for GCA. Smoking is the most solidly recognized environmental risk factor, but other traditional cardiovascular risk factors do not seem to predispose to GCA. Evidence is mounting that overall mortality in GCA patients is at best slightly higher than expected in relation to general population mortality data, but GCA is associated with an increase in morbidity and mortality specifically related to aortic aneurysm or other cardiovascular causes. Further studies are needed to integrate the current knowledge into a single etiological model.

Epidemiology of Wegener's granulomatosis: Lessons from descriptive studies and analyses of genetic and environmental risk determinants.

During the past 15 years, the epidemiology of Wegener's granulomatosis (WG) has become better understood. Descriptive epidemiological studies carried out primarily in European countries estimate a prevalence of WG ranging from 24 to 157 per million and annual incidence rates from 3 to 14 per million. These studies suggest a North-South declining gradient in disease risk in the Northern Hemisphere and an increase in incidence over time, although the latter is likely largely due to improved diagnostic ascertainment. Data also indicate the presence of potential secular and seasonal variations in WG incidence and a decreasing disease risk among non-Caucasians. Furthermore, analytic epidemiological studies have pointed out putative genetic and non-genetic risk factors for WG. Genetic investigations have identified various candidate genes, with alpha1-antitrypsin deficiency being the most consistently reported genetic susceptibility factor to date. Even though much less research has been devoted to environmental risk factors, evidence has grown for a possible relationship between WG and occupational exposure to crystalline silica. Thus far, data support the concept of WG as a multifactorial disease in which genetic and environmental determinants are involved but a major gap in understanding persists regarding the extent to which both factors contribute to its development. This and many other questions remain to be answered by future structured epidemiological research. This review focuses on the current knowledge of descriptive epidemiology and genetic and environmental factors associated with WG.

Management of giant cell arteritis: Recommendations of the French Study Group for Large Vessel Vasculitis (GEFA).

PURPOSE: Management of giant cell arteritis (GCA, Horton's disease) involves many uncertainties. This work was undertaken to establish French recommendations for GCA management. METHODS: Recommendations were developed by a multidisciplinary panel of 33 physicians, members of the French Study Group for Large Vessel Vasculitis (Groupe d'étude français des artérites des gros vaisseaux [GEFA]). The topics to be addressed, selected from proposals by group members, were assigned to subgroups to summarize the available literature and draft recommendations. Following an iterative consensus-seeking process that yielded consensus recommendations, the degree of agreement among panel members was evaluated with a 5-point Likert scale. A recommendation was approved when ≥ 80% of the voters agreed or strongly agreed. RESULTS: The 15 retained topics resulted in 31 consensus recommendations focusing on GCA nomenclature and classification, the role of temporal artery biopsy and medical imaging in the diagnosis, indications and search modalities for involvement of the aorta and its branches, the glucocorticoid regimen to prescribe, treatment of complicated GCA, indications for use of immunosuppressants or targeted biologic therapies, adjunctive treatment measures, and management of relapse and recurrence. CONCLUSIONS: The recommendations, which will be updated regularly, are intended to guide and harmonize the standards of GCA management.

[Pathogenesis of primary systemic vasculitides (I): ANCA-positive vasculitides]. / Pathogénie des vascularites systémiques primitives (I): vascularites ANCA-positives.

The pathogenesis of different types of systemic vasculitis positive for antineutrophil cytoplasmic antibodies (ANCA) remains incompletely understood. ANCA constitute a heterogeneous group of antibodies that are associated with different types of small-vessel vasculitis, including Wegener's granulomatosis (WG), microscopic polyangiitis (MPA) and Churg-Strauss syndrome (CSS). Anti-proteinase 3 ANCA are present in more than 90% of patients with systemic WG, and anti-myeloperoxidase (MPO) ANCA in 50-75% of those with MPA and 40-60 % of those with CSS. The pathogenic role of ANCA has been well documented in vivo: passive transfer of anti-MPO ANCA in an MPO knockout mouse model immunized with MPO is sufficient to induce the disease. In vitro, mouse and human anti-proteinase 3 ANCA can activate neutrophils primed with TNF-a and contribute to vasculitic lesions. T-cells are also involved: type 1 helper cytokines have been detected in tissue lesions of limited forms of WG, while type 2 helper cytokines have been identified in its systemic forms. Eosinophils may play a key role in the development of vasculitic lesions in CSS, although this remains to be proved.

Usability of semiautomatic segmentation algorithms for tumor volume determination.

RATIONALE AND OBJECTIVES: Tumor volume is an important parameter for clinical decision making. At present, semiautomatic image segmentation is not a standard for tumor volumetry. The aim of this work was to investigate the usability of semiautomatic algorithms for tumor volume determination. METHODS: Semiautomatic region- and volume-growing, isocontour, snakes, hierarchical, and histogram-based segmentation algorithms were tested for accuracy, contour variability, and time performance. The test were performed on a newly developed organic phantom for the simulation of a human liver and liver metastases. The real tumor volumes were measured by water displacement. These measured volumes were used as the gold standard for determining the accuracy of the algorithms. RESULTS: Variability of the segmented volumes ranging from 3.9 +/- 3.2% (isocontour algorithm) to 11.5 +/- 13.9% (hierarchical segmentation) was observed. The segmentation time per slice varied between 32 (volume-growing) and 72 seconds (snakes) on an IBM/RS6000 workstation. CONCLUSIONS: Only the region-growing and isocontour algorithms have the potential to be used for tumor volumetry. However, further improvements of these algorithms are necessary before they can be placed into clinical use.

Determination of the identity and organization of messenger RNAs within DNA.

We outline methods for identifying DNAs containing sequences complementary to specific mRNAs, and provide a number of complementary approaches for mapping the arrangement of mRNAs along the DNA. These methods, together with S1 nuclease mapping and the direct visualization of R-loops with the electron microscope, provide a comprehensive approach to defining the architecture of mRNAs coding for specific polypeptides and the arrangement of RNA transcripts along the genome. This detailed cartographic information can then be used to study the steps in the processing of mature mRNAs and determine the modes by which the expression of specific genes is regulated.

[Central nervous system and systemic vasculitides]. / Système nerveux central et vascularites systémiques.

Central nervous system (CNS) involvement can occur in large, medium, or small-sized vessel vasculitides. It is present in less than 10p. cent of systemic vasculitides. Clinical symptoms are heterogeneous and reflect the various mechanisms involved: vasculitis, blood hypertension, thrombosis and embolism. The symptoms can be present initially, at the time of relapse or occur as a treatment side effect. A primary angiitis of the CNS can also be observed. This granulomatous vasculitis is rare and isolated. Its diagnosis is difficult. The prognosis has improved but the disease remains severe. Diagnosis can be made by histology but is suggested by the association of clinical symptoms and brain imaging. Cognitive modifications, sometimes severe can also be observed but can improve with treatment. Prognosis of CNS manifestations is severe. It counts for one point in the Five Factor Score (FFS) which has been validated in some systemic vasculitides. The death rate is 12p. cent when the score is 0 and 50 percent for 2 points. Patients should be treated with a combination of steroids and cyclophosphamide which improves CNS vasculitis outcome.

[Systemic necrotizing vasculitides: classifications and therapeutic strategies]. / Les vascularites nécrosantes systémiques: classification et stratégies actuelles de traitement.

OBJECTIVES: The knowledge of systemic necrotizing vasculitides improved since new classifications have been established along with a better understanding of pathogenesis of the diseases. The major vasculitides are described herein. CURRENT KNOWLEDGE AND KEY POINTS: Pathogenesis plays now a major role for classifying diseases and influences the diagnostic strategies. The prospective therapeutic trials established by French and European groups are largely based on our better knowledge of the diseases. FUTURE PROSPECTS AND PROJECTS: Despite the good results obtained with and demonstrated in prospective trials, the vasculitides remain severe and deserve new studies testing new drugs but also strategies based on prognostic factors and scores which should play a major role in treatments decision.