Geoffrey Urbanski

Objective: Sjögren's disease (SjD) is a heterogeneous autoimmune disorder characterized by substantial clinical and molecular diversity. This heterogeneity raises key questions regarding the existence of distinct pathogenic mechanisms underlying disease subtypes. The objective of this study was to comprehensively characterize peripheral immune cell states associated with SjD and to identify features that could enable better patient stratification for targeted treatments. Methods: We performed single‐cell RNA sequencing with surface protein profiling on 1.5 million peripheral blood mononuclear cells from 333 participants. Individuals were stratified by SjD diagnosis and anti‐SSA status to enable comparative analyses between disease subgroups and controls. Results: Our analysis identified two immunologic endotypes of SjD, with SSA‐positive participants exhibiting a dominant and persistent type I interferon signature that was also associated with altered immune cell composition. Transitional B cells were particularly affected, displaying altered developmental states, reduced BCR diversity, shorter CDR3 regions, and increased predicted interactions with activated immune cell populations, findings consistent with perturbations of early B cell selection processes. By contrast, SSA‐negative participants with SjD exhibited limited transcriptional differences compared with symptomatic non‐SjD controls, highlighting substantial biologic heterogeneity within SjD. Conclusion: These findings support a two‐disease model of SjD and highlight transitional B cells as both a key biomarker and a therapeutic target. image

Le syndrome de Sjögren primaire (pSS)est une maladie auto-immune systémique souffrant d’un important retard diagnostique. Permettre un diagnostic plus précoce est donc un enjeu scientifique et clinique majeur. Les objectifs de ce travail étaient d’une part d’évaluer les marqueurs diagnostiques existants, et d’autre part de rechercher de nouveaux biomarqueurs par une approche métabolomique. Dans une première partie,nous avons effectué un travail critique sur les critères de classification actuels du pSS, démontré les limites des techniques actuelles de détection des anticorps anti-SSA, et du débit salivaire non stimulé au seuil de 0,1 ml/minute. Nous avons ensuite réalisé une revue de la littérature sur les biomarqueurs candidats dans le pSS. Dans la seconde partie, nous avons mené une étude métabolomique ciblée par spectrométrie de masse sur les larmes, la salive et les glandes salivaire accessoires, comparant des patients avec un diagnostic récent de pSS à une population présentant un syndrome sec. Le dosage de 188métabolites et une approche de type machine learning a permis de mettre en évidence une signature dans chacun des 3 types d’échantillons,avec des performances diagnostiques supérieures aux critères de classification actuellement en vigueur : AUC de 0,83 pour les larmes avec 9métabolites discriminants ; AUC de 0,86 sur 6métabolites pour les glandes salivaires accessoires; et AUC de 0,803 avec 11 métabolites dans la salive. Au total, ce travail nous a permis de faire le point sur les marqueurs diagnostiques actuels du pSS et d’en identifier de nouveaux, tout en révélant de nouvelles voies métaboliques potentiellement impliquées dans la maladie.

Background/Objectives: Cardiac sarcoidosis (CS) is a granulomatous inflammatory cardiomyopathy with heterogeneous presentations, from palpitations to heart failure and sudden cardiac arrest. Despite advances in imaging and immunosuppressive (IS) therapy, relapse patterns and long-term outcomes remain poorly defined. This study aimed to characterize relapse and identify predictors of relapse and major adverse cardiac events (MACE) in a real-world CS cohort. Methods: This retrospective single-center study included 25 adults diagnosed with CS at Geneva University Hospitals between 2016 and 2024, classified per the 2024 American Heart Association diagnostic criteria. Relapse was defined as clinical, arrhythmic, or imaging deterioration requiring treatment escalation. MACE included cardiovascular hospitalization, device therapy, left ventricular assist device, heart transplant, or death. Statistical methods included Kaplan–Meier analysis with log-rank tests and multivariable Cox regression adjusted for age and sex. Results: Relapse occurred in 13 patients (56%), frequently subclinical (61.5%) and detected incidentally on routine PET-CT during IS tapering. In the multivariate model, predictors of relapse included right ventricular FDG uptake (aHR 13.1; 95% CI 1.3–133.7; p = 0.03) and second-line immunosuppression duration ≤24 months (aHR 20.1; 95% CI 1.1–363.8; p = 0.04). Relapse-free patients were more often maintained on dual or triple IS therapy (71.4% vs. 15.4%; p = 0.02) and low-dose prednisone (p = 0.03). Conclusions: Relapse is common in CS, often subclinical, and associated with PET-CT findings and premature IS tapering. Maintenance therapy may reduce risk. Multimodal imaging remains critical for disease monitoring, though tracers with higher specificity are needed. Further research should refine relapse definitions and support personalized treatment strategies.

Objective: Vacuoles E1 enzyme X‐linked autoinflammatory somatic syndrome (VEXAS) is a recently identified rare genetic disorder associated with somatic mutations in the UBA1 gene. VEXAS presents with a combination of inflammatory and hematologic manifestations, leading to increased morbidity and mortality. Methods: Given the variability in disease presentation and the limited number of studies to date, no clinical documents currently exist to provide guidance to health care providers about the management of VEXAS. To address this gap, we formed an international multidisciplinary panel of VEXAS experts. Results: Through formalized meetings and a voting process, the group developed consensus clinical guidance considerations for the management of VEXAS. These considerations offer practical advice on several key topics: (1) clinical features of VEXAS, (2) UBA1 screening methods, (3) the diagnosis of myelodysplastic syndromes (MDSs) in patients with VEXAS, and (4) prognosis and management. The aim is to provide expert guidance on which patients to test, how to test for VEXAS, how to approach MDS in the context of VEXAS, and considerations for management. Conclusion: This work marks the first formal international consensus guidance for VEXAS and is intended to be used as a resource for clinicians seeking to understand the disease and its management.

Objectives: Pernicious anemia (PA) is a common cause of vitamin B12 deficiency and requires a robust diagnosis to guide lifelong treatment. Anti-parietal cell antibodies (APCA) are frequently used as a diagnostic marker, but their poor specificity raises concerns about overdiagnosis, particularly in patients lacking the more specific but less sensitive anti-intrinsic factor antibodies (IFA). We compared the diagnostic performance of two APCA detection methods: indirect immunofluorescence (IIF) and immunodot assay. Methods: We prospectively enrolled patients with B12 deficiency and APCA positivity without IFA. PA diagnosis was adjudicated by blinded expert based on histology and response to oral B12. Patients were classified as true PA (APCA-PA), false positive (APCA-FP), or undetermined. Only APCA-PA and APCA-FP cases were analyzed. Results: Among 56 included patients, 19 were classified as APCA-PA and compared to 24 APCA-FP. APCA immunodot assay was positive in 19/19 APCA-PA vs. 23/24 APCA-FP (p>0.99), while APCA IIF was positive in 13/19 APCA-PA vs. 2/24 APCA-FP (p<0.001), with higher IIF titers among APCA-PA (p<0.001). Only IIF positivity was significantly associated with PA (68.4 % vs. 8.3 %, p<0.001), with 92 % specificity. This association was confirmed in multivariate analysis (OR 37.1 [95 % CI: 6.1–439.4]). APCA IIF titer was also associated with PA diagnosis (AUC 0.82 [95 % CI: 0.68–0.96]), and titer ≥1:80 further improved specificity to 96 %. Conclusions: IIF is more specific than immunodot for PA diagnosis, and its result should prevail over immunodot when deciding whether to perform EGD, when EGD is not feasible, and when establishing the diagnosis if biopsies are inconclusive.

Sjögren’s disease (SjD) is a heterogeneous autoimmune disorder with significant clinical and molecular diversity. While anti-SSA antibodies serve as a hallmark serological biomarker, nearly half of patients lack them, raising fundamental questions about distinct pathogenic mechanisms. To address this, we performed single-cell RNA sequencing with surface protein profiling on 1.5 million PBMCs from 333 participants in the Sjögren’s International Collaborative Clinical Alliance cohort, comparing those with and without SjD and stratifying them by anti-SSA status. Our analysis identified two immunologically distinct subtypes of SjD, with SSA-positive patients exhibiting a dominant and persistent IFN-I signature, profoundly impacting immune cell maturation. Notably, transitional B cells were disproportionately affected, displaying signs of premature maturation, reduced BCR diversity, and shorter CDR3 regions, reinforced interactions with proinflammatory cells, thereby fostering an environment conducive to autoreactivity. By contrast, SSA-negative SjD participants lacked an upregulated IFN-I signature, challenging prevailing pathogenic models and suggesting alternative immune dysregulation pathways. These findings support a two-disease model of SjD and highlight transitional B cells as both a key biomarker and a potential therapeutic target. Targeting IFN-I signaling and transitional B cell maturation may represent a novel therapeutic avenue to modulate immune dysregulation and prevent autoreactivity in SjD.

Data about hydroxychloroquine (HCQ) levels during pregnancy are sparse. We assessed HCQ whole blood levels at first trimester of pregnancy as a potential predictor of maternal and obstetric/fetal outcomes in patients with systemic lupus erythematosus (SLE). We included pregnant SLE patients enrolled in the prospective GR2 study receiving HCQ, with at least one available first-trimester whole-blood HCQ assay. We evaluated several cut-offs for HCQ whole blood levels, including ≤200 ng/ml for severe non-adherence. Primary outcomes were maternal flares during the second and third trimesters of pregnancy, and adverse pregnancy outcomes (APOs: fetal/neonatal death, placental insufficiency with preterm delivery, and small-for-gestational-age neonates). We included 174 patients (median age: 32.1 years, IQR 28.8–35.2). Thirty (17.2%) patients had flares, 4 (2.3%) being severe. APOs occurred in 28 patients (16.1%). There were no significant differences in APOs by HCQ level for either those with subtherapeutic HCQ levels (≤500 ng/ml vs >500 ng/ml: 23.5% vs 14.3%, p = 0.19) or those with non-adherent HCQ levels (≤200 ng/ml vs >200 ng/ml: 20.0% vs 15.7%, p = 0.71). Similarly, the overall rate of maternal flares did not differ significantly by HCQ level cut-off, but patients with subtherapeutic (HCQ ≤500 ng/ml: 8.8% vs 0.7%, p = 0.02) and non-adherent HCQ levels (≤200 ng/ml: 13.3% vs 1.3%, p = 0.04) had significantly more severe flares. In this large prospective study of pregnant SLE patients, first-trimester subtherapeutic (≤500 ng/ml) and severe non-adherent (≤200 ng/ml) HCQ levels were associated with severe maternal flares, but not with APOs. ClinicalTrials.gov, NCT02450396

Summary: Background: Diagnosing iron deficiency is challenging in the presence of systemic inflammation. Aim: To investigate the relationship between plasma C-reactive protein (CRP), serum ferritin (SF) and transferrin saturation (TS), with the objective of establishing a straightforward ratio applicable in the presence of inflammatory syndrome. Design: Test prospective cohort and validation retrospective cohort. Methods: A prospective cohort of inpatients (n = 140) assessed the correlation between CRP and SF/TS levels. The diagnostic performance of a determined ratio was evaluated for identifying iron deficiency (ID) using different definitions and in the presence of inflammation and/or chronic heart and/or kidney failure. A large validation cohort (n = 795) further assessed the predictive power of this ratio. Results: In a training cohort (median age 76 years [57–84]), a linear relation was observed between SF (µg/l) and CRP (mg/l), unlike with TS. The SF/CRP ratio accurately predicted ID, with receiver operating characteristic-area under the curve (ROC-AUC) values ranging from 0.85 to 0.92 for different ID definitions. A threshold of ≤6 demonstrated the highest Youden index (0.61). In the validation cohort (age 72 years [57–84]), the SF/CRP ratio exhibited an ROC-AUC of 0.88 [95% CI: 0.85–0.90], with an odds ratio of 37.9 [95% CI: 20.3–68.9] for the threshold of ≤6. Conclusion: In this study, we demonstrated that the SF/CRP ratio, with a threshold of ≤6, is a simple and effective biomarker for ID, even in the presence of systemic inflammation or comorbidities. This ratio could potentially replace the complex set of criteria currently recommended by learned societies.

Introduction: Assessing labial salivary gland exocrinopathy is a cornerstone in primary Sjögren’s syndrome. Currently this relies on the histopathologic diagnosis of focal lymphocytic sialadenitis and computing a focus score by counting lym=phocyte foci. However, those lesions represent advanced stages of primary Sjögren’s syndrome, although earlier recognition of primary Sjögren’s syndrome and its effective treatment could prevent irreversible damage to labial salivary gland. This study aimed at finding early biomarkers of primary Sjögren’s syndrome in labial salivary gland combining metabolomics and machine-learning approaches.Methods: We used a standardized targeted metabolomic approach involving high performance liquid chromatography coupled with mass spectrometry among newly diagnosed primary Sjögren’s syndrome (n=40) and non- primary Sjögren’s syndrome sicca (n=40) participants in a prospective cohort. A metabolic signature predictive of primary Sjögren’s syndrome status was explored using linear (logistic regression with elastic-net regularization) and non-linear (random forests) machine learning architectures, after splitting the data set into training, validation, and test sets.Results: Among 126 metabolites accurately measured, we identified a discriminant signature composed of six metabolites with robust performances (ROC-AUC = 0.86) for predicting primary Sjögren’s syndrome status. This signature included the well-known immune-metabolite kynurenine and five phospholipids (LysoPC C28:0; PCaa C26:0; PCaaC30:2; PCae C30:1, and PCaeC30:2). It was split into two main components: the first including the phospholipids was related to the intensity of lymphocytic infiltrates in salivary glands, while the second represented by kynurenine was independently associated with the presence of anti-SSA antibodies in participant serum.Conclusion: Our results reveal an immuno-lipidomic signature in labial salivary gland that accurately distinguishes early primary Sjögren’s syndrome from other causes of sicca symptoms.