Systematic literature review informing the EULAR recommendations for the non-pharmacological management of systemic lupus erythematosus and systemic sclerosis.

Through this systematic literature review, we assembled evidence to inform the EULAR recommendations for the non-pharmacological management of systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). We screened articles published between January 2000 and June 2021. Studies selected for data extraction (118 for SLE and 92 for SSc) were thematically categorised by the character of their intervention. Of 208 articles included, 51 were classified as robust in critical appraisal. Physical activity was the most studied management strategy and was found to be efficacious in both diseases. Patient education and self-management also constituted widely studied topics. Many studies on SLE found psychological interventions to improve quality of life. Studies on SSc found phototherapy and laser treatment to improve cutaneous disease manifestations. In summary, non-pharmacological management of SLE and SSc encompasses a wide range of interventions, which can be combined and provided either with or without adjunct pharmacological treatment but should not aim to substitute the latter when this is deemed required. While some management strategies i.e., physical exercise and patient education, are already established in current clinical practice in several centres, others e.g., phototherapy and laser treatment, show both feasibility and efficacy, yet require testing in more rigorous trials than those hitherto conducted.

Gastrointestinal involvement in adult IgA vasculitis (Henoch-Schönlein purpura): updated picture from a French multicentre and retrospective series of 260 cases.

OBJECTIVES: To describe the clinical presentation, treatments and prognosis of gastrointestinal (GI) involvement in adult IgA vasculitis (IgAV). METHODS: Data from 260 adults with IgAV included in a French multicentre retrospective survey were analysed. Presentation and outcomes of patients with (GI+) and without (GI-) GI involvement were compared. RESULTS: One hundred and thirty-seven (53%) patients had GI involvement. Initial manifestations were abdominal pain in 99%, intestinal bleeding in 31%, diarrhoea in 26% and acute surgical abdomen in only 4%. Abdominal imaging revealed thickening of intestinal wall in 61%, and endoscopies revealed abnormalities in 87%, mostly mucosal ulcerations. GI+ vs GI- patients were younger (46 ± 18 vs 54 ± 18 years; P = 0.0004), had more constitutional symptoms (43% vs 23%; P = 0.0005) and joint involvement (72 vs 50%; P = 0.0002), and higher CRP levels (3.7 vs 1.9 mg/dl; P = 0.001). Clinical response and relapse rates were comparable between groups, and all causes mortality (2 vs 4%) and IgAV-related mortality (1% vs 2%) as well. GI-related deaths were due to intestinal perforation and mesenteric ischaemia. CONCLUSION: GI involvement is frequent in adult IgAV. GI involvement is frequent in adult IgAV. Mortality is not uncommon but does not seem to be specifically related to GI. Immunosuppressants should not be preferred as first-line therapy for GI+ patients but may be required in case of acute surgical abdomen.

[Rheumatoid arthritis†: cardiovascular and pulmonary manifestations]. / Manifestations cardiovasculaires et pulmonaires de la polyarthrite rhumatoïde.

Rheumatoid arthritis (RA) often affects extra-articular structures. Treatments used for arthritis are often also effective on the extra-articular manifestations, but exceptions are numerous, particularly for cardiovascular and pulmonary problems. Cardiovascular disorders mainly include complications related to atherosclerosis : they are probably the main contributor to the increased mortality observed in RA, must be specifically taken into account and largely determine the choice of treatments used to treat RA. The most problematic pulmonary complications are the different types of interstitial lung disease ; they too must be specifically managed and condition the choice of treatments.

La polyarthrite rhumatoïde (PR) touche souvent des structures extra-articulaires. Les traitements efficaces sur l'arthrite le sont souvent aussi sur les manifestations extra-articulaires, mais les exceptions sont nombreuses notamment pour les problèmes ­cardiovasculaires et pulmonaires. Les atteintes cardiovasculaires comprennent surtout les complications liées à l'athérosclérose : elles représentent probablement le principal contributeur à l'augmentation de la mortalité observée dans la PR, doivent être prises en compte de manière spécifique et conditionnent largement le choix des traitements utilisés pour la PR. Les complications pulmonaires les plus redoutables sont les différents types de pneumopathies interstitielles diffuses (PID); elles aussi doivent être prises en charge spécifiquement et conditionnent le choix des traitements.

Inflammasome Adaptor ASC Suppresses Apoptosis of Gastric Cancer Cells by an IL18-Mediated Inflammation-Independent Mechanism.

Inflammasomes are key regulators of innate immunity in chronic inflammatory disorders and autoimmune diseases, but their role in inflammation-associated tumorigenesis remains ill-defined. Here we reveal a protumorigenic role in gastric cancer for the key inflammasome adaptor apoptosis-related speck-like protein containing a CARD (ASC) and its effector cytokine IL18. Genetic ablation of ASC in the gp130F/F spontaneous mouse model of intestinal-type gastric cancer suppressed tumorigenesis by augmenting caspase-8-like apoptosis in the gastric epithelium, independently from effects on myeloid cells and mucosal inflammation. This phenotype was characterized by reduced activation of caspase-1 and NF-κB activation and reduced expression of mature IL18, but not IL1ß, in gastric tumors. Genetic ablation of IL18 in the same model also suppressed gastric tumorigenesis, whereas blockade of IL1ß and IL1α activity upon genetic ablation of the IL1 receptor had no effect. The specific protumorigenic role for IL18 was associated with high IL18 gene expression in the gastric tumor epithelium compared with IL1ß, which was preferentially expressed in immune cells. Supporting an epithelial-specific role for IL18, we found it to be highly secreted from human gastric cancer cell lines. Moreover, IL18 blockade either by a neutralizing anti-IL18 antibody or by CRISPR/Cas9-driven deletion of ASC augmented apoptosis in human gastric cancer cells. In clinical specimens of human gastric cancer tumors, we observed a significant positive correlation between elevated mature IL18 protein and ASC mRNA levels. Collectively, our findings reveal the ASC/IL18 signaling axis as a candidate therapeutic target in gastric cancer.Significance: Inflammasome activation that elevates IL18 helps drive gastric cancer by protecting cancer cells against apoptosis, with potential implications for new therapeutic strategies in this setting. Cancer Res; 78(5); 1293-307. ©2017 AACR.

Postmortem evaluation of cholesterol, triglyceride, and apolipoprotein levels.

Cholesterol and triglyceride levels have been analyzed in the forensic setting and their values correlated with atherosclerotic lesions found at autopsy and histology. Nevertheless, the results of these investigations have provided diverging information on postmortem molecule stability and postmortem measurement reliability. The aim of this study was to determine triglycerides, total cholesterol, low-density and high-density lipoprotein cholesterol, apolipoprotein B100, and apolipoprotein A-I in antemortem and postmortem serum samples in a series of cases (N = 10, including cardiac and noncardiac deaths) that underwent forensic investigations and had both samples available, measure the same molecules in postmortem serum from femoral blood and pericardial and pleural fluids (N = 39, including cardiac and noncardiac deaths), and evaluate whether different levels of these molecules could be observed in cases characterized by different degrees of coronary artery atherosclerosis (N = 39, including cardiac and noncardiac deaths). Preliminary results indicated that total cholesterol and low-density and high-density lipoprotein cholesterol levels in postmortem serum samples tended to be lower than those in antemortem specimens, whereas triglyceride levels in postmortem serum samples tended to be higher than those in antemortem samples. No relationship could be found between postmortem serum and pericardial fluid levels or between postmortem serum and pleural fluid levels of all tested biomarkers. Lastly, cases characterized by severe coronary artery atherosclerosis revealed higher postmortem serum levels of total cholesterol and apolipoprotein B. Globally considered, these data confirm that femoral blood postmortem serum levels of cholesterol and apolipoproteins may be considered suitable to estimate their antemortem values in forensic cases characterized by coronary artery atherosclerosis.

Characteristics and Management of IgA Vasculitis (Henoch-Schönlein) in Adults: Data From 260 Patients Included in a French Multicenter Retrospective Survey.

OBJECTIVE: Data on adult IgA vasculitis (Henoch-Schönlein) (IgAV) are scarce. This survey was designed to better define the clinical spectrum of IgAV and efficacy of treatments in a French patient population. METHODS: Data on clinical characteristics, histologic features, and treatment response from 260 patients with IgAV included in a French multicenter retrospective survey were analyzed. Efficacy data were compared using different statistical models. RESULTS: The mean ± SD age of the patients with IgAV at diagnosis was 50.1 ± 18 years, and 63% of patients were male. Baseline manifestations included purpura (100%), arthralgias/arthritis/myalgia (61%), glomerulonephritis (70%), and/or gastrointestinal involvement (53%). Thirty percent of patients showed renal failure at baseline. In univariate analysis, the response to therapy was 80% (64 of 80) in patients treated with corticosteroids (CS) alone, compared to 77% (23 of 30) in patients treated with CS plus cyclophosphamide (CYC) and 59% (10 of 17) in patients treated with colchicine (P = 0.17). Multivariable analysis showed that treatment with CS or CS plus CYC was more effective than colchicine in achieving a response. Efficacy differences were demonstrated using different statistical models: in the multivariable logistic regression model, odds ratio (OR) 3.68, 95% confidence interval (95% CI) 1.10-12.33 (P = 0.03); in the inverse probability weighting on propensity score model, OR 3.75, 95% CI 1.28-10.99 (P = 0.02). The efficacy of CS plus CYC as compared to CS alone was discordant according to the analytic method used. Analysis with the multivariable logistic regression model did not demonstrate a difference between CS plus CYC and CS alone (OR 0.88, 95% CI 0.29-2.67; P = 0.82). In contrast, inverse probability weighting on propensity score showed that CS plus CYC was more effective than CS alone (OR 1.79, 95% CI 1.00-3.20; P = 0.049). CONCLUSION: This series constitutes the largest series of adults with IgAV reported in the literature so far. It provides data on clinical and histologic presentation and therapeutic efficacy, suggesting that CS alone appears to be a reasonable first-line therapy in patients with IgAV, while the benefit of adding CYC to CS remains uncertain.

Elevated serum levels of free interleukin-18 in adult-onset Still's disease.

OBJECTIVE: IL-18 is a pro-inflammatory cytokine of the IL-1 family that is naturally inhibited by IL-18 binding protein (IL-18BP). High levels of IL-18 have been described in the serum of adult-onset Still's disease (AOSD) patients, but only total IL-18 levels (including inactive IL-18 bound to IL-18BP) have been measured. With a specific immunoassay, we aimed to measure free IL-18 serum levels in AOSD patients and other rheumatic diseases. METHODS: An ELISA was developed to measure free IL-18. Its sensitivity and specificity were tested by spiking recombinant IL-18 or IL-18BP in serum and PBS supplemented with 5% BSA. The binding affinity of IL-18 to IL-18BP was calculated by titration experiments using the ELISA and by Biacore analysis. Sera of 37 AOSD patients and 138 controls (40 healthy controls, 30 RA, 29 SLE, 21 AS and 18 PsA) were assayed for free IL-18, IL-18BP, total IL-18 and other cytokines. Correlations were performed between free IL-18 and markers of disease activity in AOSD patients. RESULTS: Free IL-18 serum levels were significantly higher in AOSD patients (median 8.89 pg/ml) than in healthy and disease controls (1.37 pg/ml; P < 0.01). Free IL-18 serum levels correlated with AOSD activity. The affinity of IL-18 to IL-18BP was found to be much higher than previously described, with a dissociation constant ranging from 30 to 50 pM. CONCLUSION: Free IL-18 levels are specifically elevated in AOSD compared with other inflammatory diseases, suggesting that IL-18 represents a potential target for the treatment of AOSD.

Tracheobronchial Stenoses in Granulomatosis With Polyangiitis (Wegener's): A Report on 26 Cases.

Tracheobronchial stenoses (TBSs) are potentially severe manifestations of granulomatosis with polyangiitis (Wegener's) (GPA) that usually respond poorly to corticosteroids and immunosuppressive agents. We describe 26 GPA patients with ≥1 tracheal (mainly subglottic, SGS) and/or bronchial stenosis(ses) (BS(s)).Sixteen patients had solitary SGS and 10 had ≥1 BS(s). The male/female sex ratio was 9:17, and the median age at GPA diagnosis was 32 years (3:13 and 28 years, respectively, for SGS patients). Antineutrophil cytoplasm antibodies were proteinase 3-positive in 65.5% of the patients (50% of those with SGS).Despite conventional GPA therapy, 62% patients experienced ≥1 stenosis relapse(s) (81% of SGS patients, for a total of 1-8 relapses per patient). None of the several systemic or endoscopic treatments prevented future relapses. Cyclophosphamide induction therapy was effective in 4/6 patients with BS(s) and in 1 patient with SGS among the 7 treated. After many relapses, rituximab achieved remission in 3/4 SGS patients. Endoscopic treatments (dilation, laser, corticosteroid injection, etc.) had only transient efficacy. Other GPA manifestations relapsed independently of TBSs. One SGS patient died of acute respiratory distress syndrome.Our findings confirmed that TBSs are severe GPA manifestations that evolve independently of other organ involvements and do not respond to conventional systemic regimens. As previously described, our population was younger and comprised more females than usual GPA patients, especially those with SGS.The small number of patients and the wide variety of local and systemic treatments prevent us from drawing definitive conclusions about the contribution of each procedure. However, cyclophosphamide seemed to effectively treat BSs, but not SGS, and rituximab may be of interest for SGS management.

Granulomatosis with polyangiitis: endoscopic management of tracheobronchial stenosis: results from a multicentre experience.

OBJECTIVES: Tracheobronchial stenosis (TBS) is noted in 12-23% of patients with granulomatosis with polyangiitis (GPA), and includes subglottic stenosis and bronchial stenosis. We aimed to analyse the endoscopic management of TBS in GPA and to identify factors associated with the efficacy of endoscopic interventions. METHODS: We conducted a French nationwide retrospective study that included 47 patients with GPA-related TBS. RESULTS: Compared with patients without TBS, those with TBS were younger, more frequently female and had less frequent kidney, ocular and gastrointestinal involvement and mononeuritis multiplex. Endoscopic procedures included 137 tracheal and 50 bronchial interventions, mainly endoscopic dilatation, local steroid injection and conservative laser surgery, and less frequently stenting. After the first endoscopic procedure, the cumulative incidence of endoscopic treatment failure was 49% at 1 year, 70% at 2 years and 80% at 5 years. Factors significantly associated with a higher cumulative incidence of treatment failure were a shorter time from GPA diagnosis to endoscopic procedure [hazard ratio (HR) 1.08 (95% CI 1.01, 1.14); P = 0.01] and a bronchial stenosis [HR 1.96 (95% CI 1.28, 3.00); P = 0.002]. A prednisone dose ≥30 mg/day at the time of the procedure was associated with a lower cumulative incidence of treatment failure [HR 0.53 (95% CI 0.31, 0.89); P = 0.02]. CONCLUSION: TBS represents severe and refractory manifestations with a high rate of restenosis. High-dose systemic CSs at the time of the procedure and increased time from GPA diagnosis to bronchoscopic intervention are associated with a better event-free survival. In contrast, bronchial stenoses are associated with a higher rate of restenosis than subglottic stenosis.

Bilateral angle-closure glaucoma and multifocal choroiditis as a first presentation in hodgkin lymphoma.

PURPOSE: To report atypical ocular manifestations in two patients with undiagnosed Hodgkin lymphoma. METHODS: Observational case report. RESULTS: The first patient, a 27-year-old man, presented with bilateral acute angle-closure glaucoma secondary to uveal effusion. Histopathology of chest lymph nodes obtained by mediastinoscopy revealed nodular sclerosing Hodgkin lymphoma. Ocular signs resolved after systemic chemotherapy. The second patient, a 56-year-old man, presented with bilateral multifocal choroiditis. Extensive biologic and microbiologic examinations were negative. Pathologic lymph nodes were detected in the anterior mediastinum. The histopathologic examination of the nodes after mediastinoscopy revealed nodular sclerosing Hodgkin lymphoma. Systemic chemotherapy was instituted. The patient encountered a major increase in the multifocal choroiditis within 3 days after the second chemotherapy injection. High-dose intravenous corticosteroid therapy was initiated. No recurrence of choroidal lesions was observed after the treatment completion. CONCLUSION: These two patients presented with bilateral paraneoplastic uveal tract involvement as initial presentation of Hodgkin lymphoma. Systemic corticosteroid therapy may be associated with systemic chemotherapy to obtain complete remission of the ocular inflammatory activity.

Atlantic leatherback migratory paths and temporary residence areas.

BACKGROUND: Sea turtles are long-distance migrants with considerable behavioural plasticity in terms of migratory patterns, habitat use and foraging sites within and among populations. However, for the most widely migrating turtle, the leatherback turtle Dermochelys coriacea, studies combining data from individuals of different populations are uncommon. Such studies are however critical to better understand intra- and inter-population variability and take it into account in the implementation of conservation strategies of this critically endangered species. Here, we investigated the movements and diving behaviour of 16 Atlantic leatherback turtles from three different nesting sites and one foraging site during their post-breeding migration to assess the potential determinants of intra- and inter-population variability in migratory patterns. METHODOLOGY/PRINCIPAL FINDINGS: Using satellite-derived behavioural and oceanographic data, we show that turtles used Temporary Residence Areas (TRAs) distributed all around the Atlantic Ocean: 9 in the neritic domain and 13 in the oceanic domain. These TRAs did not share a common oceanographic determinant but on the contrary were associated with mesoscale surface oceanographic features of different types (i.e., altimetric features and/or surface chlorophyll a concentration). Conversely, turtles exhibited relatively similar horizontal and vertical behaviours when in TRAs (i.e., slow swimming velocity/sinuous path/shallow dives) suggesting foraging activity in these productive regions. Migratory paths and TRAs distribution showed interesting similarities with the trajectories of passive satellite-tracked drifters, suggesting that the general dispersion pattern of adults from the nesting sites may reflect the extent of passive dispersion initially experienced by hatchlings. CONCLUSIONS/SIGNIFICANCE: Intra- and inter-population behavioural variability may therefore be linked with initial hatchling drift scenarios and be highly influenced by environmental conditions. This high degree of behavioural plasticity in Atlantic leatherback turtles makes species-targeted conservation strategies challenging and stresses the need for a larger dataset (>100 individuals) for providing general recommendations in terms of conservation.

Yield of bone marrow examination in diagnosing the source of fever of unknown origin.

BACKGROUND: Fever of unknown origin (FUO) still remains a diagnostic challenge, while diagnosis may remain obscure for several weeks or months. The role of tissue biopsy is crucial in the diagnostic approach. We report a series of 130 consecutive patients with FUO who had undergone a bone marrow biopsy (BMB). METHODS: Among 280 consecutive nonimmunocompromised patients hospitalized between 1995 and 2005 for a febrile illness of uncertain cause, lasting at least 3 weeks, with no diagnosis after an appropriate minimal diagnostic workup, 130 underwent BMB. RESULTS: Overall, a specific diagnosis was achieved by BMB and histological examination in 31 cases (diagnostic yield, 23.7%). Three types of diseases were found: hematological malignant diseases in 25 cases, including 19 patients with malignant lymphoma, 4 with acute leukemia, 1 with hairy cell leukemia, and 1 with multiple myeloma; infectious diseases in 3 cases; systemic mastocytosis in 2 cases; and disseminated granulomatosis in 1 case. Thrombocytopenia (odds ratio, 4.9; 95% confidence interval, 1.04-9.30) and anemia (odds ratio, 3.24; 95% CI, 1.13-9.34) were the most reliable predictive factors regarding the usefulness of BMB. Bone marrow cultures had very limited value in our cohort. Finally, corticosteroid use did not seem to affect the yield of BMB. CONCLUSIONS: Bone marrow biopsy is a useful technique for the diagnosis of prolonged fever in immunocompetent patients. Thrombocytopenia and anemia seem to be correlated with the value of this test.

Marine turtles use geomagnetic cues during open-sea homing.

Marine turtles are renowned long-distance navigators, able to reach remote targets in the oceanic environment; yet the sensory cues and navigational mechanisms they employ remain unclear [1, 3]. Recent arena experiments indicated an involvement of magnetic cues in juvenile turtles' homing ability after simulated displacements [4, 5], but the actual role of geomagnetic information in guiding turtles navigating in their natural environment has remained beyond the reach of experimental investigations. In the present experiment, twenty satellite-tracked green turtles (Chelonia mydas) were transported to four open-sea release sites 100-120 km from their nesting beach on Mayotte island in the Mozambique Channel; 13 of them had magnets attached to their head either during the outward journey or during the homing trip. All but one turtle safely returned to Mayotte to complete their egg-laying cycle, albeit with indirect routes, and showed a general inability to take into account the deflecting action of ocean currents as estimated through remote-sensing oceanographic measurements [7]. Magnetically treated turtles displayed a significant lengthening of their homing paths with respect to controls, either when treated during transportation or when treated during homing. These findings represent the first field evidence for the involvement of geomagnetic cues in sea-turtle navigation.