An interactive web application for exploring systemic lupus erythematosus blood transcriptomic diversity.

In the field of complex autoimmune diseases such as systemic lupus erythematosus (SLE), systems immunology approaches have proven invaluable in translational research settings. Large-scale datasets of transcriptome profiling have been collected and made available to the research community in public repositories, but remain poorly accessible and usable by mainstream researchers. Enabling tools and technologies facilitating investigators' interaction with large-scale datasets such as user-friendly web applications could promote data reuse and foster knowledge discovery. Microarray blood transcriptomic data from the LUPUCE cohort (publicly available on Gene Expression Omnibus, GSE49454), which comprised 157 samples from 62 adult SLE patients, were analyzed with the third-generation (BloodGen3) module repertoire framework, which comprises modules and module aggregates. These well-characterized samples corresponded to different levels of disease activity, different types of flares (including biopsy-proven lupus nephritis), different auto-antibody profiles and different levels of interferon signatures. A web application was deployed to present the aggregate-level, module-level and gene-level analysis results from LUPUCE dataset. Users can explore the similarities and heterogeneity of SLE samples, navigate through different levels of analysis, test hypotheses and generate custom fingerprint grids and heatmaps, which may be used in reports or manuscripts. This resource is available via this link: https://immunology-research.shinyapps.io/LUPUCE/. This web application can be employed as a stand-alone resource to explore changes in blood transcript profiles in SLE, and their relation to clinical and immunological parameters, to generate new research hypotheses.

Concordance and agreement between different activity scores in polymyalgia rheumatica.

OBJECTIVE: The C reactive protein polymyalgia rheumatica activity score (CRP-PMR-AS) is a composite index that includes CRP levels and was developed specifically for PMR. As treatments such as interleukin-6 antagonists can normalise CRP levels, the erythrocyte sedimentation rate (ESR) of PMR-AS, the clinical (clin)-PMR-AS and the imputed-CRP (imp-CRP)-PMR-AS have been developed to avoid such bias. Our primary objective was to measure the correlation of these activity scores. Our secondary objective was to evaluate the concordance between different cutoffs of the PMR-ASs. METHOD: Data from the Safety and Efficacy of tocilizumab versus Placebo in Polymyalgia rHeumatica With glucocORticoid dEpendence (SEMAPHORE) trial, a superiority randomised double-blind placebo-controlled trial, were subjected to post hoc analysis to compare the efficacy of tocilizumab versus placebo in patients with active PMR. The CRP-PMR-AS, ESR-PMR-AS, clin-PMR-AS and imp-CRP-PMR-AS were measured at every visit. The concordance and correlation between these scores were evaluated using kappa correlation coefficients, Bland-Altman correlations, intraclass correlation coefficients (ICCs) and scatter plots. RESULTS: A total of 101 patients were included in the SEMAPHORE trial, and 100 were analysed in this study. The correlation between the PMR-ASs was excellent, as the ICC and kappa were >0.85 from week 4 until week 24 (CRP-PMR-AS ≤10 or >10). Bland-Altman plots revealed that the differences between the CRP-PMR-AS and the other threescores were low. The cut-off values for the clin-PMR-AS were similar to those for the CRP-PMR-AS 86% of the time. CONCLUSION: The correlation between all the PMR-ASs was excellent, reflecting the low weight of CRP. In clinical trials using drugs that have an impact on CRP, the derived activity scores can be used. TRIAL REGISTRATION NUMBER: NTC02908217.

Estimated prevalence, incidence and healthcare costs of Sjögren's syndrome in France: a national claims-based study.

OBJECTIVES: To estimate prevalence, incidence and mortality rates, and annual healthcare costs of primary Sjögren's syndrome (pSS) and SS associated with other autoimmune disorders (SS+AID) in France. METHODS: French national healthcare claims-based study within the prospective Système National des Données de Santé database that includes the majority of the French population. An algorithm was developed to identify patients with SS and SS-related healthcare claims were analysed between 2011 and 2018. RESULTS: Overall, 23 848 patients with pSS and 14 809 with SS+AID were identified. From 2011 to 2018, the prevalence rate increased slightly for pSS (23-32 per 100000) and SS+AID (16-20 per 100 000), with females comprising 90%-91% and 92%-93% of cases, respectively. The incidence rate of SS per 100 000 persons decreased from 2012 (pSS: 4.3; SS+AID: 2.0) to 2017 (pSS: 0.7; SS+AID: 0.3). Mortality rates per 100 000 persons increased from 2012 to 2018 in patients with pSS (0.2-0.8) or SS+AID (0.1-0.5); mean age of death also increased. Artificial tears and hydroxychloroquine were the most common drug reimbursements. Less than half of patients received annual specialist care from a dentist or ophthalmologist. Healthcare costs associated with SS increased from 2011 to 2018 and exceeded the national estimate of expected costs for chronic diseases. CONCLUSION: In this large French population database study, the low prevalence of pSS confirms that it is an orphan disease. SS is clinically and economically burdensome; these findings may help clinicians better understand routine healthcare received by patients.

Fungal versus non-fungal supra-inguinal prosthetic vascular graft infections: A cohort study.

OBJECTIVES: Fungal prosthetic vascular graft infections are rare and mainly supra-inguinal. Current guidelines are based on the few studies that have specifically investigated this population, with few risk factors described. The objective of this study is to compare fungal and non-fungal supra-inguinal prosthetic vascular graft infections (PVGI), describing their specificities, identifying risk factors, and evaluating outcomes. PATIENTS AND METHODS: This is a single-center retrospective cohort study carried out at the Pitié-Salpêtrière Hospital in Paris, including all patients who were treated for a supra-inguinal PVGI between January 1st, 2009 and February 28th, 2021. Preoperative, intraoperative and postoperative data were compared between fungal and non-fungal PVGI. RESULTS: Out of the 475 patients screened, 148 developed a supra-inguinal PVGI: 32 fungal and 116 non-fungal. Factors independently associated with fungal PVGI were presence of a prostheto-digestive fistula (OR 5.98; 95% CI 2.29-15.62) and preoperative antibiotic therapy of seven days or more (OR 2.87; 95% CI 1.12-7.38). Mortality rate at 180 days was significantly higher for fungal as compared to non-fungal PVGIs (38% vs. 16% p = 0.009) and for fungal PVGI with prostheto-digestive fistula. However, there was no statistically significant relation between mortality due to prostheto-digestive fistula in contrast with fungal PVGI alone (p = 0.21). CONCLUSION: Prostheto-digestive fistula was strongly associated with fungal PVGI, which leads us to suggest that in such cases, an anti-fungal agent should be prescribed.

Comparison of Immediate, Medium, and Long-Term Postoperative Results of Open Surgery and Fenestrated/Branched Stent Grafts for Extended Thoracoabdominal Aortic Aneurysms.

The optimal surgical treatment for extended thoracoabdominal aortic aneurysms (TAAAs) is still a matter of debate. The historical treatment is open repair (OR), but over the past fifteen years, endovascular strategies have gained widespread acceptance. Although several endovascular techniques have been described for the treatment of TAAAs, fenestrated and branched stent grafts (F/BEVARs) are the most frequently used and best documented. They have become the first-line treatment for both high- and moderate-risk surgical patients in most vascular centers. However, no randomized study comparing OR and F/BEVAR has been published, and decision-making is mainly based on the physician's preference and/or hospital expertise. The objective of this manuscript is to provide an overview of current comparative data for OR and F/BEVAR.

Harnessing large language models (LLMs) for candidate gene prioritization and selection.

BACKGROUND: Feature selection is a critical step for translating advances afforded by systems-scale molecular profiling into actionable clinical insights. While data-driven methods are commonly utilized for selecting candidate genes, knowledge-driven methods must contend with the challenge of efficiently sifting through extensive volumes of biomedical information. This work aimed to assess the utility of large language models (LLMs) for knowledge-driven gene prioritization and selection. METHODS: In this proof of concept, we focused on 11 blood transcriptional modules associated with an Erythroid cells signature. We evaluated four leading LLMs across multiple tasks. Next, we established a workflow leveraging LLMs. The steps consisted of: (1) Selecting one of the 11 modules; (2) Identifying functional convergences among constituent genes using the LLMs; (3) Scoring candidate genes across six criteria capturing the gene's biological and clinical relevance; (4) Prioritizing candidate genes and summarizing justifications; (5) Fact-checking justifications and identifying supporting references; (6) Selecting a top candidate gene based on validated scoring justifications; and (7) Factoring in transcriptome profiling data to finalize the selection of the top candidate gene. RESULTS: Of the four LLMs evaluated, OpenAI's GPT-4 and Anthropic's Claude demonstrated the best performance and were chosen for the implementation of the candidate gene prioritization and selection workflow. This workflow was run in parallel for each of the 11 erythroid cell modules by participants in a data mining workshop. Module M9.2 served as an illustrative use case. The 30 candidate genes forming this module were assessed, and the top five scoring genes were identified as BCL2L1, ALAS2, SLC4A1, CA1, and FECH. Researchers carefully fact-checked the summarized scoring justifications, after which the LLMs were prompted to select a top candidate based on this information. GPT-4 initially chose BCL2L1, while Claude selected ALAS2. When transcriptional profiling data from three reference datasets were provided for additional context, GPT-4 revised its initial choice to ALAS2, whereas Claude reaffirmed its original selection for this module. CONCLUSIONS: Taken together, our findings highlight the ability of LLMs to prioritize candidate genes with minimal human intervention. This suggests the potential of this technology to boost productivity, especially for tasks that require leveraging extensive biomedical knowledge.

Long-Term Outcome and Prognosis of Noninfectious Thoracic Aortitis.

BACKGROUND: Aortitis is a group of disorders characterized by the inflammation of the aorta. The large-vessel vasculitides are the most common causes of aortitis. Aortitis long-term outcomes are not well known. OBJECTIVES: The purpose of this study was to assess the long-term outcome and prognosis of noninfectious surgical thoracic aortitis. METHODS: This was a retrospective multicenter study of 5,666 patients with thoracic aorta surgery including 217 (3.8%) with noninfectious thoracic aortitis (118 clinically isolated aortitis, 57 giant cells arteritis, 21 Takayasu arteritis, and 21 with various systemic autoimmune disorders). Factors associated with vascular complications and a second vascular procedure were assessed by multivariable analysis. RESULTS: Indications for aortic surgery were asymptomatic aneurysm with a critical size (n = 152 [70%]), aortic dissection (n = 28 [13%]), and symptomatic aortic aneurysm (n = 30 [14%]). The 10-year cumulative incidence of vascular complication and second vascular procedure was 82.1% (95% CI: 67.6%-90.6%), and 42.6% (95% CI: 28.4%-56.1%), respectively. Aortic arch aortitis (HR: 2.08; 95% CI: 1.26-3.44; P = 0.005) was independently associated with vascular complications. Descending thoracic aortitis (HR: 2.35; 95% CI: 1.11-4.96; P = 0.031) and aortic dissection (HR: 3.08; 95% CI: 1.61-5.90; P = 0.002) were independently associated with a second vascular procedure, while treatment with statins after aortitis diagnosis (HR: 0.47; 95% CI: 0.24-0.90; P = 0.028) decreased it. After a median follow-up of 3.9 years, 19 (16.1%) clinically isolated aortitis patients developed features of a systemic inflammatory disease and 35 (16%) patients had died. CONCLUSIONS: This multicenter study shows that 82% of noninfectious surgical thoracic aortitis patients will experience a vascular complication within 10 years. We pointed out specific characteristics that identified those at highest risk for subsequent vascular complications and second vascular procedures.

Weaning Maintenance Therapy in Lupus Nephritis: For Whom, When, and How?

Lupus nephritis (LN) is one of the main determinants of the severity of systemic lupus erythematosus (SLE). LN flares can lead to organ damage with chronic kidney disease (CKD) or even end-stage kidney disease (ESKD) and impair patients' survival. The "treat-to-target" strategy, which aims at obtaining and maintaining remission or low disease activity of SLE to alleviate symptoms and prevent organ damage, also refers to the control of residual activity in the kidney. But damage in SLE can also come from treatments, and toxicities related to long-term use of treatments should be prevented. This may contribute to the frequent nonadherence in patients with SLE. The de-escalation or even weaning of treatments whenever possible, or "think-to-untreat" (T2U) strategy, is to be considered in patients with LN. This possibility of treatment weaning in LN was explored in retrospective cohorts, on the basis of long-term clinical remission. It was also proposed prospectively with a kidney-biopsy-based approach, combining clinical and pathologic remission to secure treatment weaning. The WIN-Lupus trial was the first randomized controlled trial comparing the continuation to the discontinuation of maintenance immunosuppressive therapy (IST) after 2 to 3 years in patients with LN in remission. It showed a higher risk of severe SLE flares in patients who discontinued treatment, but also a possibility of weaning without flare in some patients, who need to be better identified. We propose here a narrative review of the available literature on the weaning of treatment in LN and discuss how to secure a T2U strategy.

Complex relationships between inflammatory manifestations/type 1 and type 2 symptoms in systemic lupus erythematosus: A narrative literature review.

OBJECTIVE: Recent studies have highlighted that systemic lupus erythematosus (SLE) is characterized by different types of symptoms: type 1 symptoms related to inflammation and disease activity and type 2 symptoms such as fatigue, anxiety-depression, and pain. Our aim was to investigate the relation between type 1 and type 2 symptoms, and their impact on health-related quality of life (HRQoL) in SLE. METHODS: A literature review was conducted about disease activity/type1 and type 2 symptoms. Articles in English published after 2000 were located on Medline via Pubmed. The articles chosen evaluated at least one type 2 symptom or HRQoL using a validated scale in adult patients. RESULTS: Overall, 182 articles were analyzed and 115 were retained including 21 randomized, controlled trials and corresponding to 36 831 patients. We found that in SLE, inflammatory activity/type 1 symptoms were mostly uncorrelated with type 2 symptoms and/or HRQoL. Several studies even showing an inverse relationship. No or weak correlation was observed in 85, 3% (92, 6%), 76, 7% (74, 4%) and 37, 5% (73, 1%) of studies (patients) for fatigue, anxiety-depression, and pain, respectively. For HRQoL, no or weak correlation was observed in 77, 5% of studies (88% of patients). CONCLUSION: Type 2 symptoms are poorly correlated with inflammatory activity/type 1 symptoms in SLE. Possible explanations and implications for clinical care and therapeutic evaluation are discussed.

Anti-spike protein to determine SARS-CoV-2 antibody levels: Is there a specific threshold conferring protection in immunocompromised patients?

BACKGROUND: Identifying a specific threshold level of SARS-CoV-2 antibodies that confers protection in immunocompromised patients has been very challenging. The aim was to assess the threshold of 264 binding antibody units (BAU)/ml using four different SARS-CoV-2 antibody assays (Abbott, Beckman, Roche, and Siemens) and to establish a new optimal threshold of protection for each of the four antibody assays. METHODS: This study was performed on data retrieved from 69 individuals, who received at least one dose of the Pfizer/BioNTech BNT162b2 or Moderna COVID-19 vaccine (Spikevax) at the Alphabio Laboratory in Marseille, France (European Hospital, Alphabio-Biogroup). The results were compared to the percent inhibition calculated using a functional surrogate of a standardized virus neutralization test (Genscript). RESULTS: Samples from 69 patients were analyzed. For a reference cutoff of 264 BAU/ml, assays showed moderate to good overall concordance with Genscript: 87% concordance for Abbott, 78% for Beckman, 75% for Roche, and 88% for Siemens. Overall concordance increased consistently after applying new thresholds, i.e., 148 BAU/ml (Abbott), 48 (Beckman), 559 (Roche), and 270 (Siemens). CONCLUSION: We suggest specific adjusted thresholds (BAU/ml) for the four commercial antibody assays that are used to assess pre-exposure prophylaxis in immunocompromised patients.

Concerted and multidisciplinary management of COVID-19 drug therapies during the first two epidemic waves in a tertiary hospital in Marseille, France: Results of the PHARMA-COVID study.

OBJECTIVES: To evaluate the impact of local therapeutic recommendation updates made by the COVID multidisciplinary consultation meeting (RCP) at the Hôpital Européen Marseille (HEM) through the description of the drug prescriptions for COVID-19 during the first two waves of the epidemic. METHODS: This retrospective observational study analysed data from the hospital's pharmaceutical file. We included all patients hospitalized for COVID-19 between February 1, 2020 and January 21, 2021 and extracted specific anti-COVID-19 therapies (ST) from computerized patient record, as well as patients' demographic characteristics, comorbidities and outcome. The evolution of ST prescriptions during the study period was described and put into perspective with the updates of local recommendations made during the first (V1, from 2/24/2020 to 7/27/2020), and second (V2, from 7/28/2020 to 1/21/2021) epidemic waves. RESULTS: A total of 607 COVID-19 hospitalized patients, 197 during V1 and 410 during V2. Their mean age was 65 years-old, and they presented frequent comorbidities. In total, 93% of hospitalized patients received ST: anticoagulants (90%), glucocorticoids (39%) mainly during V2 (49% vs 17%, P<0.001), and azithromycin (30%) mainly during V1 (71% vs 10%, P<0.001). Lopinavir/ritonavir and hydroxychloroquine were prescribed to 17 and 7 inpatients, respectively, and only during V1. Remdesivir was never administered. A total of 22 inpatients were enrolled into clinical trials. CONCLUSIONS: The effective dissemination of evidence-based and concerted recommendations seems to have allowed an optimized management of COVID-19 drug therapies in the context of this emerging infection with rapidly evolving therapeutic questions.

Gut microbiota in SLE: from animal models to clinical evidence and pharmacological perspectives.

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease driven by complex interactions between genetics and environmental factors. SLE is characterised by breaking self-immune tolerance and autoantibody production that triggers inflammation and damage of multiple organs. Given the highly heterogeneous nature of SLE, the treatments currently used are still not satisfactory with considerable side effects, and the development of new therapies is a major health issue for better patient management. In this context, mouse models significantly contribute to our knowledge of the pathogenesis of SLE and are an invaluable tool for testing novel therapeutic targets. Here, we discuss the role of the most used SLE mouse models and their contribution to therapeutic improvement. Considering the complexity of developing targeted therapies for SLE, adjuvant therapies are also increasingly proposed. Indeed, murine and human studies have recently revealed that gut microbiota is a potential target and holds great promises for successful new SLE therapies. However, the mechanisms of gut microbiota dysbiosis in SLE remain unclear to date. In this review, we propose an inventory of existing studies investigating the relationship between gut microbiota dysbiosis and SLE to establish microbiome signature that may serve as a potential biomarker of the disease and its severity as well as a new potential therapy target. This approach may open new possibilities for early diagnosis, prevention and therapeutic perspectives of SLE based on gut microbiome.

Categorization of patients with systemic lupus erythematosus using disease activity, patient-reported outcomes, and transcriptomic signatures.

OBJECTIVE: Patients with systemic lupus erythematosus (SLE) display symptoms that are not always related to disease activity and may distort clinical trial results. Recently, a clinical categorization based on the presence of type 1 (inflammatory manifestations) and/or type 2 (widespread pain, fatigue, depression) symptoms has been proposed in SLE. Our aim was to develop a type 2 score derived from the Short-Form health survey (SF-36) to categorize SLE patients and to compare immunological and transcriptomic profiles between groups. METHOD: Seventeen items from the SF-36 were selected to build a type 2 score for 50 SLE patients (100 visits; LUPUCE cohort), and the SLEDAI was used to define type 1 symptoms. Patients were categorized into four groups: minimal (no symptoms), type 1, type 2, and mixed (both type 1 and type 2 symptoms). Clinical, immunological, and transcriptomic profiles were compared between the groups. RESULTS: Type 2 scores ranged from 0 to 31, with a cutoff value of 14 (75th percentile). The sample categorization was minimal in 39%, type 1 in 37%, and type 2 in 9%, and mixed in 15%. Type 2 patients were older than minimal patients and had a longer disease duration than type 1 and mixed patients. Immunological data and modular interferon signatures did not differ between the groups. CONCLUSION: Patients with SLE can be categorized into four clinical groups using the SLEDAI score and our SF-36-derived type 2 score. This categorization is non-redundant with immunological or transcriptomic profiles and could prove useful to stratify patients in clinical trials. Key Points • A score derived from selected items of the SF-36 can be used to identify SLE patients with type 2 symptoms according to the Duke University categorization. • Using the SLEDAI and this type 2 score, SLE patients can be categorized into four clinical groups. • This categorization is not related to immunological activity or blood transcriptome profiles (and not to the interferon signature in particular). • This categorization could be useful in the daily care of patients as well as in clinical trials, for upstream patient stratification or for the interpretation of results.

Immune-checkpoint inhibitor use in patients with cancer and pre-existing autoimmune diseases.

Immune-checkpoint inhibitors (ICIs) have dramatically changed the management of advanced cancers. Designed to enhance the antitumour immune response, they can also cause off-target immune-related adverse events (irAEs), which are sometimes severe. Although the efficacy of ICIs suggests that they could have wide-ranging benefits, clinical trials of the drugs have so far excluded patients with pre-existing autoimmune disease. However, evidence is accumulating with regard to the use of ICIs in this 'at-risk' population, with retrospective data suggesting that they have an acceptable safety profile, but that there is a risk of disease flare or other irAE occurrence. The management of immunosuppressive drugs at ICI initiation in patients with autoimmune disease (or later in instances of disease flare or irAE) remains a question of particular interest in clinical practice, in which there is always a search for the balance between protecting against autoimmunity and ensuring a good tumour response. Although temporary use of immunosuppressants seems safe, prolonged use or use at ICI initiation might hamper the antitumour immune response, prompting clinicians to use the minimal efficient immunosuppressive regimen. However, a new paradigm is emerging, in which inhibitors of TNF or IL-6 could have synergistic effects with ICIs on tumour response, while also preventing severe irAEs. If confirmed, this 'decoupling' effect on toxicity and efficacy could change therapeutic practice in this field. Knowledge of the current use of ICIs in patients with pre-existing autoimmune disease, particularly with regard to the use of immunosuppressive drugs and/or biologic DMARDs, can help to guide clinical practice.