Composite of Relevant Endpoints for Sjogren's Syndrome (CRESS):development and validation of a novel outcome measure

Background Recent randomised controlled trials (RCTs) in primary Sjogren's syndrome used the European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) as their primary endpoint. Given the heterogeneous and complex nature of primary Sjogren's syndrome, it might be more appropriate to also assess other clinically relevant disease features. We aimed to develop a novel composite endpoint for assessing treatment efficacy in patients with primary Sjogren's syndrome: the Composite of Relevant Endpoints for Sjogren's Syndrome (CRESS). Methods A multidisciplinary expert team selected clinically relevant items and candidate measurements for inclusion in the composite score. For each measurement, cutoff points for response to treatment were chosen based on expert opinion, previously published data on minimal clinically important improvements, and trial data, primarily the week-24 data of the single-centre ASAP-III trial of abatacept versus placebo. CRESS was validated using data from three independent RCTs: one trial of rituximab (TRACTISS), one of abatacept (multinational trial), and one of tocilizumab (ETAP). We calculated the number and percentage of patients who were responders in the separate CRESS items, and the percentage of responders based on the total CRESS at the primary endpoint visits (week 48 for TRACTISS, week 24 for the other two trials). Patients with fewer than three items available for evaluating CRESS response were imputed as non-responders. Findings Based on expert opinion, five complementary items were selected to assess response: (1) systemic disease activity by Clinical ESSDAI (less than 5 points); (2) patient-reported symptoms by EULAR Sjogren's Syndrome Patient Reported Index, assessed by a decrease of at least 1 point or at least 15% from baseline; (3) tear gland item by Schirmer's test and ocular staining score, assessed by an increase of at least 5 mm or decrease of at least 2 points, respectively, in patients with abnormal Schirmer's test or ocular staining score findings at baseline, or, in patients with normal baseline values, assessed by no change to abnormal for both; (4) salivary gland item, assessed by unstimulated whole saliva secretion (increase of at least 25%) and salivary gland ultrasonography (decrease of at least 25%); and (5) serology, assessed by rheumatoid factor (decrease of at least 25%) and IgG (decrease of at least 10%). Total CRESS response is defined as response on at least three of five items. Post-hoc assessment of phase 3 trial data showed that CRESS response rates at the primary endpoint visits were 60% (24 of 40) for abatacept versus 18% (seven of 39) for placebo (p Interpretation The CRESS is a feasible, well-balanced, composite endpoint for use in trials of primary Sjogren's syndrome. As a next step, the CRESS will require validation in a prospective RCT. Copyright (C) 2021 Elsevier Ltd. All rights reserved

Simple Nudges for Better Password Creation

Recent security breaches have highlighted the consequences of reusing passwords across online accounts. Recent guidance on password policies by the UK government recommend an emphasis on password length over an extended character set for generating secure but memorable passwords without cognitive overload. This paper explores the role of three nudges in creating website-specific passwords: financial incentive (present vs absent), length instruction (long password vs no instruction) and stimulus (picture present vs not present). Mechanical Turk workers were asked to create a password in one of these conditions and the resulting passwords were evaluated based on character length, resistance to automated guessing attacks, and time taken to create the password. We found that users created longer passwords when asked to do so or when given a financial incentive and these longer passwords were harder to guess than passwords created with no instruction. Using a picture nudge to support password creation did not lead to passwords that were either longer or more resistant to attacks but did lead to account-specific passwords

Identification de nouvelles cibles thérapeutiques au cours du syndrome de Gougerot-Sjögren primitif (SJp)

The aim of this thesis was to identify new therapeutic targets in primary Sjögren's syndrome (pSS). Using our 3 varied but complementary approaches, we were able to confirm the value of targeting BAFF, a molecule that is crucial for the survival and activation of B cells, combined with B depletion. Our drug repurposing study, based on transcriptomic analysis, confirmed the value of targeting interferons in pSS. It also identified potential new therapeutic targets, HDACs and PI3Ks. Finally, our search for new actors potentially involved in the pathophysiology of pSS led us to innate lymphoid cells (ILCs). Like Tregs, this rare and long-ignored cell population could play an important pathogenic role. Our results suggest that ILC3 may be responsible for the development of lymphocytic infiltrates in the salivary glands. This work adds to our knowledge of the pathophysiology of pSS and opens up new therapeutic prospects.L’objectif de cette thèse était d’identifier de nouvelles cibles thérapeutiques dans le syndrome de Sjögren primitif (SJp). Par nos 3 approches variées mais complémentaires, nous avons été en mesure de confirmer l’intérêt de cibler BAFF, une molécule cruciale pour la survie et l’activation des LB, combiné à une déplétion B. Cette efficacité passe, au moins en partie, par l’accumulation de Trég. Notre étude de repositionnement thérapeutique, basée sur une analyse transcriptomique, a permis de confirmer l’intérêt de cibles les interférons dans le SJp. Elle a également identifié de potentielles nouvelles cibles thérapeutiques, les HDAC et les PI3K. Enfin, notre recherche de nouveaux acteurs potentiellement impliqués dans la physiopathologie du SJp nous a mené vers les innate lymphoid cells (ILC). A l’instar des Trég, cette population cellulaire rare et longtemps méconnue pourrait jouer un rôle pathogène important. Nos résultats suggèrent que les ILC3 pourraient être à l’origine de la mise en place des infiltrats lymphocytaires au sein des glandes salivaires. Ainsi, ce travail complète notre connaissance de la physiopathologie du SJp et ouvre de nouvelles perspectives thérapeutiques

The 2023 pipeline of disease-modifying antirheumatic drugs (DMARDs) in clinical development for spondyloarthritis (including psoriatic arthritis): a systematic review of trials

Objectives The objective of this systematic review was to provide an overview of current developments and potentially available therapeutic options for spondyloarthritis (SpA) in the coming years.Methods We conducted a systematic review of 17 national and international clinical trial databases for all disease-modifying antirheumatic drugs (DMARDs) for SpA that are already marketed, in clinical development or withdrawn. The search was performed on February 2023 with the keywords “spondyloarthritis”, “ankylosing spondylitis” and “psoriatic arthritis”. For each molecule, we only considered the study at the most advanced stage of clinical development.Results Concerning axial SpA (axSpA), a total of 44 DMARDs were identified: 6 conventional synthetic DMARDs (csDMARDs), 27 biological DMARDs (bDMARDs) and 11 targeted synthetic DMARDs (tsDMARDs). Among the 18 targeted treatments (b+tsDMARDs) in current development, corresponding trials reached phase I (n=1), II (n=10) and III (n=7). Ten molecules are IL-17 inhibitors, two Janus kinase (JAK) inhibitors and two granulocyte-macrophage colony-stimulating factor inhibitors; four have another mode of action. Concerning psoriatic arthritis (PsA), 44 DMARDs were identified: 5 csDMARDs, 27 bDMARDs and 12 tsDMARDs. Among the 15 molecules in current development, corresponding trials reached phase II (n=8) and III (n=7). Six molecules are JAK inhibitors, six IL-17 inhibitors and one an IL-23 inhibitor; two have another mode of action.Conclusion This systematic review identified 18 and 15 molecules in clinical development for axSpA and PsA, respectively, which suggests a strengthening of the therapeutic arsenal in the coming years. However, with so many DMARDs but low target diversity, we will need to develop strategies or biomarkers to help clinicians make informed treatment decisions

Les traitements du lupus systémique : retour vers le futur

International audienceD’importants progrès ont été réalisés dans le diagnostic et la prise en charge thérapeutique du lupus érythémateux systémique (LES) au cours de ces dernières décennies. Après plus de onze siècles d’incertitude thérapeutique, la découverte des vertus thérapeutiques des glucocorticoïdes reste sans aucun doute l’avancée la plus marquante dans le domaine des maladies auto-immunes. Les nombreuses avancées liées au développement rapide de l’industrie chimique au 19e siècle ont permis d’identifier des molécules thérapeutiques d’intérêt tels que les antipaludéens, le cyclophosphamide, l’azathioprine, la ciclosporine et plus tard le mycophénolate mofétil, qui ont profondément modifié notre vision de la maladie. La nette amélioration de son pronostic, avec des taux de survie à 10 ans de plus de 90 % observés dans les centres spécialisés, en est la conséquence la plus concrète. À la suite du développement des biothérapies dans la polyarthrite rhumatoïde, la fin du 20e siècle a progressivement ouvert une nouvelle ère pour le traitement du LES : celle des thérapies ciblées. Après l’autorisation du bélimumab en 2011 et 74 thérapies ciblées en développement clinique, d’importants changements sont attendus dans la prise en charge thérapeutique du LES. Ces molécules ciblent les cytokines ou chimiokines pro-inflammatoires et leurs récepteurs, les lymphocytes B ou plasmatocytes, les voies de signalisation intracellulaire, les molécules de co-stimulation des cellules B/T, les interférons, les cellules dentritiques plasmacytoïdes ainsi que de nombreuses autres cibles d’intérêt. Les défis évoluent progressivement, passant de la découverte de nouveaux médicaments au choix du traitement (ou association de traitements) le plus adapté à chaque patient

Spotlight on anifrolumab and its potential for the treatment of moderate-to-severe systemic lupus erythematosus: evidence to date

International audienceAbstract: Previous reports have described the appearance of systemic lupus erythematosus (SLE) cases following interferon-α (IFN-α) therapy, IFN-regulated gene expression is significantly increased in SLE, and an association between SLE and gene variants belonging to IFN downstream pathways has been shown. Based on this, targeting of IFN and of their signaling pathways has appeared to be interesting developments within the field of SLE therapy. Different specific type I IFN antagonists have been studied in clinical trials and some of those have already reached Phase III. A potential approach would be to target IFN receptors rather than IFN themselves. Anifrolumab (previously MEDI-546) is a fully human monoclonal antibody (Ab) that binds to subunit 1 of the type I IFN receptor (IFNAR1), blocking the action of different type I IFNs (IFN-α, IFN-β and IFN-ω). This drug has been assessed in 11 clinical studies: 9 in SLE, 1 in systemic sclerosis and 1 in rheumatoid arthritis. In SLE, clinical development reached Phase I for 1 study and Phases II and III for 5 and 3 trials, respectively. The Phase IIb, randomized control trial (RCT), double-blind, placebo-controlled study of adults with moderate-to-severe SLE (MUSE trial) showed positive results on the composite primary endpoint SRI-4. Greater efficacy was seen in patients with high baseline IFN gene signature compared with those with low baseline IFN gene signature. Anifrolumab also demonstrated promising results on cutaneous and arthritic manifestations, especially among patients with a high IFN gene signature. The pivotal Treatment of Uncontrolled Lupus via the Interferon IFN Pathway (TULIP 1 and 2 studies are now completed. In August 2018, the promoter announced that the TULIP 1 Phase III trial did not reach its primary endpoint. The release of the completed but not yet published Phase II studies and of the TULIP pivotal trials results will further inform us on the actual therapeutic potential of anifrolumab

Avascular osteonecrosis in kidney transplant recipients: Risk factors in a recent cohort study and evaluation of the role of secondary hyperparathyroidism.

Avascular osteonecrosis (AVN) is a bone complication that indicates poor functional prognosis. Modern immunosuppressive and steroid-sparing drugs have significantly lowered the occurrence of AVN after kidney transplantation (KT). However, recent data on its incidence rates and risk factors are lacking. Using a large, recent cohort, we sought to investigate AVN incidence and risk factors, with a special focus on mineral and bone disorders. We conducted a cohort study in 805 patients who underwent KT between 2004 and 2014. AVN was identified in 32 patients (4%): before KT in 15 (1.8%) and after KT in 18 (2.2%) cases, including one patient with both. In the group with post-KT AVN, the median time intervals from KT to 1) first symptoms and 2) AVN diagnosis were 12 months [1-99] and 20 months [4-100], respectively. Being overweight/obese, having pre-transplant diabetes or hyperparathyroidism at transplantation, developing acute rejection, and receiving higher cumulative corticosteroid doses were associated with AVN occurrence. Multivariate analysis revealed that BMI ≥ 26 kg/m2 and higher cumulative corticosteroid doses were predictive of AVN. In conclusion, overweight/obesity is a strong risk factor for AVN. Despite a low maintenance dose, the use of corticosteroids-mostly for treatment of acute rejection-remains an independent risk factor

Characterization of auto-immune hepatitis associated with the use of anti-TNFα agents: An analysis of 389 cases in VigiBase

International audienceAuto-immune diseases, including auto-immune hepatitis may be associated with the use of drugs, such as anti-TNF-α inhibitors. The aim of the study was to analyze the characteristics of anti-TNF-α inhibitor-associated auto-immune hepatitis (ATIAIH) in a large international pharmacovigilance database. We analyzed all ICSRs classified as "Autoimmune hepatitis" according to the Medical Dictionary for Drug Regulatory Activities term (preferred term level) in VigiBase, the World Health Organization global pharmacovigilance database of adverse drug reactions collected by national drug authorities in >130 countries (>90% of the world population). Bayesian disproportionality analysis was used to compute IC025, which is the lower end of the 95% credibility interval for the association between a suspected treatment and an adverse event. IC025 > 0 are considered statistically significant. A total of 389 ATIAIH ICSRs were identified. The median age at ATIAIH onset was 44 years and the female to male sex ratio was 3.72. Infliximab (IC025 = 2.98), adalimumab (IC025 = 0.32) and etanercept (IC025 = 0.19) yielded a statistically significant signal in disproportionality analysis. Infliximab was the most frequently involved drug (50.1%). The median treatment duration before ATIAH occurrence was 4.9 months. ATIAIH was reported as serious adverse event in 91%. Death (directly linked to AIH or not) occurred in 10 cases (2.9% of ICSRs). The most frequent reported indication for anti-TNF-α agent was rheumatoid arthritis (31.9%). This study enables the identification and a detailed study of 389 new cases of ATIAIH and confirms a significant association of ATIAIH with infliximab, adalimumab and etanercept

Effect of SARS-CoV-2 Vaccination on Symptoms from Post-Acute Sequelae of COVID-19: Results from the Nationwide VAXILONG Study

Introduction: Few data are available concerning the effect of SARS-CoV-2 vaccination on the persistent symptoms associated with COVID-19, also called long-COVID or post-acute sequelae of COVID-19 (PASC). Patients and methods: We conducted a nationwide online study among adult patients with PASC as defined by symptoms persisting over 4 weeks following a confirmed or probable COVID-19, without any identified alternative diagnosis. Information concerning PASC symptoms, vaccine type and scheme and its effect on PASC symptoms were studied. Results: 620 questionnaires were completed and 567 satisfied the inclusion criteria and were analyzed. The respondents’ median age was 44 (IQR 25–75: 37–50) and 83.4% were women. The initial infection was proven in 365 patients (64%) and 5.1% had been hospitalized to receive oxygen. A total of 396 patients had received at least one injection of SARS-CoV-2 vaccine at the time of the survey, after a median of 357 (198–431) days following the initially-reported SARS-CoV-2 infection. Among the 380 patients who reported persistent symptoms at the time of SARS-CoV-2 vaccination, 201 (52.8%) reported a global effect on symptoms following the injection, corresponding to an improvement in 21.8% and a worsening in 31%. There were no differences based on the type of vaccine used. After a complete vaccination scheme, 93.3% (28/30) of initially seronegative patients reported a positive anti-SARS-CoV-2 IgG. A total of 170 PASC patients had not been vaccinated. The most common reasons for postponing the SARS-CoV-2 vaccine were fear of worsening PASC symptoms (55.9%) and the belief that vaccination was contraindicated because of PASC (15.6%). Conclusion: Our study suggests that SARS-CoV-2 vaccination is well tolerated in the majority of PASC patients and has good immunogenicity. Disseminating these reassuring data might prove crucial to increasing vaccine coverage in patients with PASC

Defective BTLA functionality is rescued by restoring lipid metabolism in lupus CD4+ T cells

International audienceCoinhibitory receptors play an important role in the prevention of autoimmune diseases, such as systemic lupus erythematosus (SLE), by limiting T cell activation. B and T lymphocyte attenuator (BTLA) is an inhibitory receptor, similar to cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD1), that negatively regulates the immune response. The role of BTLA in the pathogenesis of autoimmune diseases in humans and, more specifically, in SLE is largely unknown. We investigated BTLA expression on various T cell subsets, and we did not observe significant variations of BTLA expression between lupus patients and healthy controls. However, the enhancement of BTLA expression after activation was significantly lower in SLE patients compared with that in healthy controls. Furthermore, we found an impaired capacity of BTLA to inhibit T cell activation in SLE due to a poor BTLA recruitment to the immunological synapse following T cell stimulation. Finally, we demonstrated that defective BTLA function can be corrected by restoring intracellular trafficking and by normalizing the lipid metabolism in lupus CD4+ T cells. Collectively, our results evidence that the BTLA signaling pathway is altered in SLE T cells and highlight the potential of targeting this pathway for the development of new therapeutic strategies in lupus