A role for IL-33-activated ILC2s in eosinophilic vasculitis

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare but serious disease with poorly understood mechanisms. Here, we report that patients with EGPA have elevated levels of TSLP, IL-25, and soluble ST2, which are well-characterized cytokine alarmins that activate or modulate type 2 innate lymphoid cells (ILC2s). Patients with active EGPA have a concurrent reduction in circulating ILC2s, suggesting a role for ILC2s in the pathogenesis of this disease. To explore the mechanism of these findings in patients, we established a model of EGPA in which active vasculitis and pulmonary hemorrhage were induced by IL-33 administration in predisposed, hypereosinophilic mice. In this model, induction of pulmonary hemorrhage and vasculitis was dependent on ILC2s and signaling through IL4Rα. In the absence of IL4Rα or STAT6, IL-33-treated mice had less vascular leak and pulmonary edema, less endothelial activation, and reduced eotaxin production, cumulatively leading to a reduction of pathologic eosinophil migration into the lung parenchyma. These results offer a mouse model for use in future mechanistic studies of EGPA, and they suggest that IL-33, ILC2s, and IL4Rα signaling may be potential targets for further study and therapeutic targeting in patients with EGPA

In vivo importance of homologous recombination DNA repair for mouse neural stem and progenitor cells

We characterized the in vivo importance of the homologous recombination factor RAD54 for the developing mouse brain cortex in normal conditions or after ionizing radiation exposure. Contrary to numerous homologous recombination genes, Rad54 disruption did not impact the cortical development without exogenous stress, but it dramatically

Primary vs. Secondary Antibody Deficiency: Clinical Features and Infection Outcomes of Immunoglobulin Replacement

<div><p>Secondary antibody deficiency can occur as a result of haematological malignancies or certain medications, but not much is known about the clinical and immunological features of this group of patients as a whole. Here we describe a cohort of 167 patients with primary or secondary antibody deficiencies on immunoglobulin (Ig)-replacement treatment. The demographics, causes of immunodeficiency, diagnostic delay, clinical and laboratory features, and infection frequency were analysed retrospectively. Chemotherapy for B cell lymphoma and the use of Rituximab, corticosteroids or immunosuppressive medications were the most common causes of secondary antibody deficiency in this cohort. There was no difference in diagnostic delay or bronchiectasis between primary and secondary antibody deficiency patients, and both groups experienced disorders associated with immune dysregulation. Secondary antibody deficiency patients had similar baseline levels of serum IgG, but higher IgM and IgA, and a higher frequency of switched memory B cells than primary antibody deficiency patients. Serious and non-serious infections before and after Ig-replacement were also compared in both groups. Although secondary antibody deficiency patients had more serious infections before initiation of Ig-replacement, treatment resulted in a significant reduction of serious and non-serious infections in both primary and secondary antibody deficiency patients. Patients with secondary antibody deficiency experience similar delays in diagnosis as primary antibody deficiency patients and can also benefit from immunoglobulin-replacement treatment.</p></div

Association of Gender with Clinical Expression, Quality of Life, Disability, and Depression and Anxiety in Patients with Systemic Sclerosis

OBJECTIVES: To assess the association of gender with clinical expression, health-related quality of life (HRQoL), disability, and self-reported symptoms of depression and anxiety in patients with systemic sclerosis (SSc). METHODS: SSc patients fulfilling the American College of Rheumatology and/or the Leroy and Medsger criteria were assessed for clinical symptoms, disability, HRQoL, self-reported symptoms of depression and anxiety by specific measurement scales. RESULTS: Overall, 381 SSc patients (62 males) were included. Mean age and disease duration at the time of evaluation were 55.9 (13.3) and 9.5 (7.8) years, respectively. One-hundred-and-forty-nine (40.4%) patients had diffuse cutaneous SSc (dcSSc). On bivariate analysis, differences were observed between males and females for clinical symptoms and self-reported symptoms of depression and anxiety, however without reaching statistical significance. Indeed, a trend was found for higher body mass index (BMI) (25.0 [4.1] vs 23.0 [4.5], p = 0.013), more frequent dcSSc, echocardiography systolic pulmonary artery pressure >35 mmHg and interstitial lung disease in males than females (54.8% vs 37.2%, p = 0.010; 24.2% vs 10.5%, p = 0.003; and 54.8% vs 41.2%, p = 0.048, respectively), whereas calcinosis and self-reported anxiety symptoms tended to be more frequent in females than males (36.0% vs 21.4%, p = 0.036, and 62.3% vs 43.5%, p = 0.006, respectively). On multivariate analysis, BMI, echocardiography PAP>35 mmHg, and anxiety were the variables most closely associated with gender. CONCLUSIONS: In SSc patients, male gender tends to be associated with diffuse disease and female gender with calcinosis and self-reported symptoms of anxiety. Disease-associated disability and HRQoL were similar in both groups

Patterns of patient-reported symptoms and association with sociodemographic and systemic sclerosis disease characteristics: a scleroderma Patient-centered Intervention Network (SPIN) Cohort cross-sectional study

Background Systemic sclerosis is a heterogenous disease in which little is known about patterns of patient-reported symptom clusters. We aimed to identify classes of individuals with similar anxiety, depression, fatigue, sleep disturbance, and pain symptoms and to evaluate associated sociodemographic and disease-related characteristics. Methods This multi-centre cross-sectional study used baseline data from Scleroderma Patient-centered Intervention Network Cohort participants enrolled from 2014 to 2020. Eligible participants completed the PROMIS-29 v2.0 measure. Latent profile analysis was used to identify homogeneous classes of participants based on patterns of anxiety, depression, fatigue, sleep disturbance, and pain scores. Sociodemographic and disease-related characteristics were compared across classes. Findings Among 2212 participants, we identified five classes, including four classes with “Low” (565 participants, 26%), “Normal” (651 participants, 29%), “High” (569 participants, 26%), or “Very High” (193 participants, 9%) symptom levels across all symptoms. Participants in a fifth class, “High Fatigue/Sleep/Pain and Low Anxiety/Depression” (234 participants, 11%) had similar levels of fatigue, sleep disturbance, and pain as in the “High” class but low anxiety and depression symptoms. There were significant and substantive trends in sociodemographic characteristics (age, education, race or ethnicity, marital or partner status) and increasing disease severity (diffuse disease, tendon friction rubs, joint contractures, gastrointestinal symptoms) across severity-based classes. Disease severity and sociodemographic characteristics of “High Fatigue/Sleep/Pain and Low Anxiety/Depression” class participants were similar to the “High” severity class. Interpretation Most people with systemic sclerosis can be classified by levels of patient-reported symptoms, which are consistent across symptoms and highly associated with sociodemographic and disease-related variables, except for one group which reports low mental health symptoms despite high levels of other symptoms and substantial disease burden. Studies are needed to better understand resilience in systemic sclerosis and to identify and facilitate implementation of cognitive and behavioural strategies to improve coping and overall quality of life

Risk factors for death and the 3-year survival of patients with systemic sclerosis: the French ItinérAIR-Sclérodermie study

Objectives. This longitudinal study investigated survival, risk factors and causes of death in the multicentre ItinérAIR-Sclérodermie cohort of patients with SSc without severe pulmonary fibrosis or severe left heart disease at baseline

Comparative Analysis of the Frequency and Distribution of Stem and Progenitor Cells in the Adult Mouse Brain

cells (NSCs) and progenitor cells, but it cannot discriminate between these two populations. Given two assays have purported to overcome this shortfall, we performed a comparative analysis of the distribution and frequency of NSCs and progenitor cells detected in 400 m coronal segments along the ventricular neuraxis of the adult mouse brain using the neurosphere assay, the neural colony forming cell assay (N-CFCA), and label-retaining cell (LRC) approach. We observed a large variation in the number of progenitor/stem cells detected in serial sections along the neuraxis, with the number of neurosphereforming cells detected in individual 400 m sections varying from a minimum of eight to a maximum of 891 depending upon the rostral-caudal coordinate assayed. Moreover, the greatest variability occurred in the rostral portion of the lateral ventricles, thereby explaining the large variation in neurosphere frequency previously reported. Whereas the overall number of neurospheres (3730 276) or colonies (4275 124) we detected along the neuraxis did not differ significantly, LRC numbers were significantly reduced (1186 188, 7 month chase) in comparison to both total colonies and neurospheres. Moreover, approximately two orders of magnitude fewer NSC-derived colonies (50 10) were detected using the N-CFCA as compared to LRCs. Given only 5% of the LRCs are cycling (BrdU/Ki-67) or competent to divide (BrdU/Mcm-2), and proliferate upon transfer to culture, it is unclear whether this technique selectively detects endogenous NSCs. Overall, caution should be taken with the interpretation and employment of all these techniques

THU0275 SEVERE PREECLAMPSIA RELATED TO ANTIPHOSPHOLIPID SYNDROME: AN EUROPEAN STUDY OF 40 WOMEN

Background:One of the 3 features of obstetrical antiphospholipid syndrome (APS) is severe preeclampsia (PE). Its time of occurrence, the associated risk of thromboses and systemic lupus erythematosus (SLE) have not been reported yet.Objectives:We analyzed severe PE in a series of women with APS.Methods:We retrospectively collected data of female patients from 5 French internal medicine and 1 Italian rheumatology units. Inclusion criteria were: a severe PE/eclampsia(1), that occurred before 34 weeks of gestation (WG) in patients who met the APS classification criteria(2).Results:40 patients were enrolled (Table 1). Because of known APS/positive aPL/previous obstetrical complications, 23(57.5%) patients were treated during the index PE: 4 with low dose aspirin (LDA), 4 with low molecular weight heparin (LMWH), and 15 with a combination of both. 7 patients were also treated with hydroxychloroquine, 8 with corticosteroids and 3 with immunosuppressants. 17(42.5%) patients received no treatment. 24(60%) live births were observed. During a follow-up period of 3 years, 26(65%) patients had at least 1 new pregnancy, with a total of 38 pregnancies which resulted in 33(86.8%) live births. 57.5% pregnancies who resulted in live births occurred without any maternal or fetal complications. All 26 patients who had at least 1 pregnancy after index PE were treated with LDA; LMWH was given at prophylactic and therapeutic dosage in 13(50%) patients, respectively. No patient experienced 3 consecutive miscarriages.Table 1.40 APS patients with severe PEOverall features (n, %)Patients40 (100)Age at PE, (median, IQR)30.5 (27-33)PE term, WG (median, IQR)25.5 (23-29) Live births24 (60) Birth term, WG (median, IQR)25.5 (23.7-30.3) Associated SLE12 (30)Maternal complications (n, %)25 (62.5) HELLP18 (45) E6 (15) CAPS3 (7.5) Placental abruptions3 (7.5)Fetal complications (n, %)31 (77.5) IUGR18 (45) IUFD11 (2.5) Preterm delivery22 (55)Obstetrical history (n, %) Primiparous21 (52.5) Index PE before APS12 (30)Thrombosis (n, %) Thrombosis before PE index14 (35.0) Thrombosis after PE index2 (5.0)Abs at APS diagnosis (n, %) aPL triple positivity21 (52.5) IgG/IgM anti-cardiolipin34 (85.0) IgG/IgM anti-β2GPI25 (62.5) LAC33 (82.5)Legend to Table 1:PE: preeclampsia; APS: antiphospholipid syndrome; IQR: interquartile range; WG: weeks of gestation; SLE: systemic lupus erythematosus; HELLP: Hemolysis, elevated liver enzymes, low platelet; E: eclampsia; CAPS: catastrophic APS; IUGR: intrauterine growth restriction; IUFD: intrauterine fetal death; CHB: congenital atrioventricular block; aPL: antiphospholipid antibodies; LAC: lupus anticoagulant.Conclusion:Among the APS criteria, "3 consecutive miscarriages criterion" was not found. The majority of patients also experienced thrombosis and SLE before the index PE.References:[1]Diagnosis and Management of preeclampsia and eclampsia. International Journal of Gynecology &Obestetrics 2002;77:67-75.[2]Miyakis S, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4:295e 306.Disclosure of Interests:Maddalena Larosa: None declared, Nathalie Morel: None declared, Meriem BELHOCINE: None declared, Amelia Ruffatti: None declared, Nicolas Martin Silva: None declared, Romain Paul: None declared, Luc Mouthon: None declared, Michel DREYFUS: None declared, Jean-Charles PIETTE: None declared, Odile Souchaud-Debouverie: None declared, Catherine Deneux-Tharaux: None declared, Vassilis Tsatsaris: None declared, Emmanuelle Pannier: None declared, Gaêlle Guettrot Imbert: None declared, Véronique LE GUERN Grant/research support from: UCB for GR2 study (to our institution), Andrea Doria Consultant of: GSK, Pfizer, Abbvie, Novartis, Ely Lilly, Speakers bureau: UCB pharma, GSK, Pfizer, Janssen, Abbvie, Novartis, Ely Lilly, BMS, Nathalie Costedoat-Chalumeau Grant/research support from: UCB to my institutio

Using Optimal Test Assembly Methods for Shortening Patientâ Reported Outcome Measures: Development and Validation of the Cochin Hand Function Scaleâ 6: A Scleroderma Patientâ Centered Intervention Network Cohort Study

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134498/1/acr22893_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134498/2/acr22893.pd

S.11.1 Influence of digital ulcer healing on disability and daily activity limitations in SSc

Objective. We previously showed that DU significantly increased global and hand disability with a significant impact on activities of daily living (ADLs) and work disability. This study aims to evaluate the impact of digital ulcer (DU) healing on disability and daily activity limitations in SSc. Methods. From January 2008 and June 2009, we prospectively evaluated 189 SSc patients for DU history, disability, employment and occupational status during meetings of the French SSc Patient Association (n = 86, 45.5%) or during hospitalization (n = 103, 54.5%)1. Among the 60 patients with at least one active DU at baseline (M0), 40 patients were followed longitudinally over 6 (3) months. These patients were evaluated for DU history, global and hand disability, health-related quality of life (HRQoL), daily activity limitation and employment status. Results. The median (IQR) age was 57.5 (43.5-68) years and the median (IQR) disease duration was 8.3 (3-16.5) years. Twenty-two (55%) patients had diffuse SSc and 34 (85%) were females. At baseline, a mean of 2.9 (2.8) DU per patient was reported. Thirty-three (82.5%) patients had ischaemic DU, 7 (17.5%) patients had >1 DU associated with calcinosis and 13 (32.5%) patients had mechanical DU. Thirteen (32.5%) patients had >4 DU at baseline. Among the 40 patients, 16 (40%) patients showed complete ulcer healing. In these patients with DU, the presence of calcinosis was associated with a lower probability of healing (P = 0.03). Comparison between healed and no-healed DU patients showed an improvement of hand disability provided by an improvement of the Cochin Hand Function score (P = 0.05)) and a trend towards HAQ domain dressing and grooming (P = 0.06) between M0 and M6 (3) visit in healed patients but not in no-healed patients. Concerning HRQoL, there were no difference for Mental and Physical component Scores of SF-36 but significant improvement of Bodily Pain score (P = 0.04) and Physical Role score (P = 0.05) between M0 and M6 (3) visit in patients with healed DU. The absence of healing was associated with significantly decreased work productivity (P = 0.05), whereas the performance in ADL was not significantly decreased (P = 0.15). Patients who were on sick-leave and who received some help for household tasks at the time of active DU were more likely to heal. Conclusion. For the first time, we provide prospective data with evidence that DU healing is associated with an improvement in hand function. Sick leave was associated with better healing of D