Type 1 diabetes (T1D) in sub-Saharan Africa exhibits heterogeneity, characterised by alternative phenotypes that retain C-peptide levels. The T-cell pathology linked to these atypical phenotypes remains largely unexplored. CD25, the interleukin-2 receptor alpha chain, and IL2RA genetic variants are key T-cell factors implicated in T1D immunopathology and may contribute to the heterogeneity of T1D in an African context.This study examined IL2RA genotypes and T-cell phenotypes, both ex vivo and following in vitro stimulation, in Ghanaian individuals diagnosed with T1D and classified into groups of low, mid and high C-peptide levels, alongside healthy controls.Immunophenotyping showed increased CD25 expression on CD4 and CD8 T-cells in the diabetes cohorts, correlating with age, C-peptide and HbA1c. IL2RA genotyping revealed limited variability and no link to CD25 expression. An expansion of CD25/CD127 double-positive conventional T-cells, mainly in naïve and central memory subsets, was observed in T1D with mid and high C-peptide. Following age-matching, the low C-peptide group also demonstrated an increase in CD25/CD127 double-positive T-cells, both ex vivo and after in vitro stimulation.The findings indicate a common pattern of immune dysregulation characterized by the expansion of activated conventional T-cells in T1D with varying C-peptide levels in Ghana.
Objectives Detection of myositis-specific and myositis associated autoantibodies (MSA/MAA) aids in classification, diagnosis, and risk stratification of idiopathic inflammatory myopathies (IIM). To identify opportunities for harmonization, we assessed laboratory and clinical variability in IIM serological testing. Methods The European Autoimmunity Standardisation Initiative (EASI) developed questionnaires targeting laboratory medicine specialists and clinicians addressing test initiation, testing methods and algorithms, reporting and interpretation. This was distributed through two external quality assessment (EQA) providers (UK NEQAS and IfQ Lübeck) to laboratory medicine specialists and subsequently to clinicians involved in IIM diagnostics. Results In total 100 laboratory medicine specialists and 56 clinicians responded. Clinicians prefer to restrict requests for MSA/MAA to clinicians specialized in IIM and 97% of them agree with the indications that ask for MSA/MAA analysis as proposed during the 256th European NeuroMuscular Center (ENMC) workshop. Analysis was almost exclusively performed by commercially available assays (99%). Most laboratories test the ENMC recommended specificities (≥95%), with exception of HMGCR (22%). Both ISO15189 accreditation coverage (39-68%) and antigen-specific verification rates (33-64%) were suboptimal. Implementation of IQC was poor. Primary screening for MSA/MAA using HEp-2 indirect immunofluorescence was considered inappropriate by the majority of laboratory medicine specialists (59%) and clinicians (69%). Result reporting is most often done (semi-)quantitatively (75%) as also preferred by clinicians (91%). Conclusions Considerable variability exists in MSA/MAA test initiation, testing methods and algorithms, reporting and interpretation. Introducing clinical- and laboratory-specific recommendations may contribute to harmonizing the interpretation of routine diagnostics for IIM.
Systemic lupus erythematosus (SLE) is a complex autoimmune disease in which current immunosuppressive and biologic therapies often fail to achieve durable remission in refractory patients. The emergence of chimeric antigen receptor T-cell (CAR-T) therapy has introduced a fundamentally new therapeutic concept, shifting therapeutic strategies from transient immune suppression toward the possibility of durable immune reprogramming. Recent studies suggest that the benefit of CAR-T therapy extends beyond depletion of autoreactive B cells. By depleting disease-associated immune cell populations and promoting immune reconstitution, CAR-T therapy may contribute to immune reprogramming, providing a potential biological basis for sustained treatment-free remission. In this review, we summarize the rapidly evolving landscape of CAR-based therapies for SLE, including conventional and next-generation strategies, and discuss their mechanisms, clinical efficacy, durability, and safety. We further highlight emerging approaches aimed at improving precision, accessibility, and long-term outcomes. Rather than serving solely as a B-cell-depleting therapy, CAR-T may represent a platform for immune reprogramming. Future advances in target selection, biomarker-guided patient stratification, and engineered cellular platforms may further improve the precision and durability of CAR-based therapies, with the long-term goal of achieving durable immune reprogramming and treatment-free remission.
Pemphigus vulgaris (PV) is a severe autoimmune blistering disease characterized by pathogenic autoantibodies primarily targeting desmoglein-3. B-cell depletion by rituximab (anti-CD20) is an effective first-line treatment for PV; however, relapses are frequently observed. Evidence suggests that PV is associated with immune dysregulation beyond the B-cell compartment. So far, existing studies have largely focused on selected immune components or populations, or specific clinical states such as active disease, remission, or immediate post-rituximab, leaving it unclear how prior rituximab treatment shapes the overall circulating immune landscape during active PV, including relapse.In this study, we performed high-dimensional immune profiling to characterize circulating immune-cell composition and cytokine/chemokine signatures using a 40-colour spectral flow cytometry panel and a 46-plex Luminex assay, respectively. We compared active PV patients with healthy controls and performed a subgroup analysis of rituximab-naive versus rituximab-experienced relapsed PV patients.High-dimensional immune profiling showed that active PV is associated with a redistribution of circulating immune cells, with increased monocytes and decreased lymphocytes and plasmacytoid dendritic cells, together with reduced frequencies of double-negative (CD4−CD8−) T cells and T follicular helper cells compared with healthy controls. When comparing rituximab-naive with rituximab-experienced PV patients, in rituximab-experienced patients, the cellular composition changes were confined to the B-cell compartment, showing a shift toward a naive-dominant B-cell subset distribution. In parallel, PV was characterized by elevated serum concentrations of CD40L, CCL11/eotaxin, G-CSF, IL-1RA, IL-7, CCL20/MIP-3α, PD-L1/B7-H1/CD274, PDGF-AB/BB, and CCL5/RANTES, while no differences were identified between rituximab-naive patients and rituximab-experienced relapsed PV patients. Correlation analysis revealed that prednisone dosage may increase the frequency of mature B cells, and levels of CCL11/eotaxin, and IL-7, while decreasing the frequency of plasmacytoid dendritic cells and T follicular helper cells.Together, these findings reveal a systemic immune signature of active PV involving changes in circulating monocyte, T-cell, and soluble immune compartments, whereas prior rituximab exposure in relapsed patients is associated with sustained remodelling confined to B-cell subset composition, without long-term restructuring of non–B-cell immune lineages.
Autoimmune diseases often persist despite effective suppression of overt inflammation, and many patients experience relapse after treatment tapering or withdrawal. This clinical pattern raises the possibility that disease activity is influenced not only by ongoing immune stimulation, but also by relatively stable biological states that preserve inflammatory potential. In this Review, we propose immunometabolic set points as an integrative framework for examining how immune-cell metabolic programs, tissue metabolic niches, metabolite signaling, and immune or metabolic memory may interact in chronic autoimmune disease. Rather than representing a single pathway or biomarker, an immunometabolic set point is proposed to describe a potentially reversible multicompartment state shaped by immune and tissue interactions. Experimental studies support important roles for cellular metabolism, local nutrient and oxygen conditions, mitochondrial stress, stromal activation, and metabolites such as lactate, succinate, and itaconate in regulating immune function. However, their integration into a unified disease-maintaining state has not been directly established. We therefore distinguish evidence-supported mechanisms from broader conceptual inferences concerning relapse-prone remission and therapeutic reset. We further discuss how longitudinal single-cell profiling, spatial omics, metabolomics, and metabolic flux analysis may be used to test the framework and determine whether treatment produces transient inflammatory suppression or more durable biological reconfiguration.
SARS-CoV-2 infection can generate IgG repertoires with functions beyond viral neutralization. We purified IgG from non-exposed healthy controls, moderate and severe COVID-19 patients, and IVIg, and assessed their effects on healthy-donor PBMCs. COVID-19 IgG bound CD4+ and CD8+ T cells without inducing apoptosis. Severe-COVID IgG reduced Treg frequencies, enhanced IFN-γ production, and expanded autoreactivity toward proteins linked to proteostasis, whereas moderate-COVID IgG promoted CD8+ IL-22 and selective miRNA downregulation. These findings identify disease-severity-associated antibody-mediated immune modulation in vitro and motivate patient-resolved longitudinal validation.
Background Systemic lupus erythematosus (SLE) has a complex polygenic architecture, but translating genome-wide association signals into biologically interpretable candidates remains challenging. We applied an integrative post-GWAS framework to refine SLE-associated loci and prioritize candidate regulatory mechanisms. Methods European-ancestry SLE GWAS summary statistics from FinnGen and Bentham et al. were meta-analysed, comprising 8,417 cases and 354,277 controls. After quality filtering, 6,782,131 SNPs were retained. Downstream analyses included LAVA regional prioritization, Bayesian colocalization with GTEx v8 whole-blood and spleen eQTLs, independent replication in the Julià et al. Spanish cohort, pathway enrichment, bivariate LAVA cross-trait local genetic correlation, and therapeutic annotation. Results The discovery meta-analysis identified 46 genome-wide significant SLE-associated loci, including putative novel signals requiring database/literature qualification. LAVA identified 14 candidate index variants across 12 high-confidence regions, of which nine index variants were retained as the primary prioritized set based on LAVA support and/or convergent regulatory evidence. The strongest association mapped to the chr6p21.3/MHC region (rs389884), where four genes showed colocalization support, including CLIC1 in whole blood and C4A in spleen. Because the chr6p21.3/MHC rs389884 region lead variant was unavailable for replication and no suitable proxy was identified, this signal was interpreted as an emerging candidate for functional validation rather than a replicated causal signal. Seven available variants replicated with concordant effects. An exploratory Roadmap immune chromatin-state overlap analysis placed 15 of 45 non-MHC lead variants (33.3%) directly, and 34 of 45 (75.6%) within ±10 kb, in active immune enhancer/promoter states. Pathway analyses highlighted type I interferon, JAK–STAT signaling, cytokine regulation, and antigen presentation, while bivariate LAVA analyses supported shared local genetic architecture with rheumatoid arthritis, systemic sclerosis, and Sjögren syndrome. Conclusions This integrative post-GWAS analysis refines SLE association signals into biologically interpretable candidate regions and supports interferon and JAK–STAT signaling as central genetically supported pathways in SLE.
Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) caused by IgG3-dominant is rare and incompletely characterized. We retrospectively reported seven male patients (median age 63 years) with IgG3-dominant monoclonal immunoglobulin-associated glomerulonephritis. All patients presented with proteinuria (1.2-16.4 g/24 h), five with nephrotic-range proteinuria, and serum creatinine at diagnosis ranged from 88 to 294 μmol/L. Serum immunofixation electrophoresis was negative in all cases, while urinary free light chains were variably increased. Renal biopsy predominantly demonstrated a membranoproliferative glomerulonephritis pattern (6/7), frequently accompanied by crescents and variable degrees of chronic glomerulosclerosis. Immunofluorescence consistently showed dominant IgG3 deposition. Therapeutic approaches included supportive therapy, corticosteroids combined with cyclophosphamide, ripertamab-based regimens, and bortezomib. Renal outcomes were heterogeneous, ranging from sustained remission to progression to end-stage renal disease or death from severe infectious complications. Patients receiving bortezomib-based clone-directed therapy achieved the most reduction in proteinuria. These findings highlight the marked clinicopathological heterogeneity of IgG3-dominant PGNMID and underscore the importance of early recognition, assessment of chronic histologic injury, and individualized clone-directed treatment to improve renal outcomes.
Background:The presence or absence of autoantibodies distinguishes patients with rheumatoid arthritis (RA) as seropositive (SP) or seronegative (SN), with SP generally associated with poorer prognosis. Extracellular vesicles (EVs) are important mediators of intercellular communication and may contribute to RA pathogenesis by disseminating immunologically active molecules that promote systemic inflammation. However, the protein cargo of circulating EVs associated with RA seropositivity remains poorly characterized. Therefore, we aimed to identify EV-associated proteins linked to RA and seropositivity and evaluate their relationship with clinical features. Methods:Blood-derived EVs were isolated from patients with SP and SN disease and from healthy donors (HD) and were characterized according to international guidelines. EV protein cargo was analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Differentially enriched proteins were identified in patients, and their associations with serum autoantibody levels, circulating cytokines, and disease activity were assessed. Results:A total of 358 proteins were identified in EVs, most of which have been previously reported in these structures. Several complement proteins, collagens, and immunoglobulins were lower in patients with RA than in HD. Notably, aggrecan (ACAN) and the polymeric immunoglobulin receptor (PIGR), not previously described in RA-derived EVs, were specifically enriched in SP patients compared with both patients with SN RA and HD. Their enrichment was significantly associated with autoantibody levels and disease activity. Conclusion:Our findings identify ACAN and PIGR as novel EV-associated proteins linked to RA seropositivity. Their association with autoantibody levels and disease activity suggests that circulating EVs may reflect biological pathways connecting cartilage remodeling, mucosal immunity, and systemic autoimmunity, supporting their potential utility as biomarkers and contributors to disease pathogenesis.
We report a 30-year-old male with a novel WAS mutation (c.252C > A, p.F84L) who was misdiagnosed with immune thrombocytopenia (ITP) for years. Despite persistent thrombocytopenia, his mean platelet volume remained normal, an atypical feature of Wiskott-Aldrich syndrome (WAS). His course was complicated by stage-5 chronic kidney disease, renal anemia, IgA nephropathy, and recurrent infections. Laboratory tests consistently showed low lymphocyte counts and reduced WAS protein (WASp) levels. After confirming WAS, the original plan of kidney transplantation alone was changed to combined hematopoietic stem cell and kidney transplantation to restore immunity and reduce graft failure risk. This case highlights that WAS can present with normal platelet volume; thus, WAS should be considered in patients with unexplained chronic kidney disease, recurrent infections, and poor ITP therapy response, even without typical microthrombocytopenia.
Background:Microvascular alterations can be detected with nailfold videocapillaroscopy, useful for systemic sclerosis (SSc) diagnosis upon identification of the "scleroderma pattern" (NVC-SP). However, this pattern is missing in a subset of SSc patients. Methods:This retrospective analysis on the multicenter Italian SPRING cohort of SSc patients assessed the prevalence and characteristics of patients without NVC-SP. Associations with demographic and clinical features were evaluated using logistic regression (cross-sectional) and mixed-effects models (longitudinal). Results:Out of 1689 SSc patients with available NVC information, 90 (5.3%) did not have the NVC-SP. These patients were older at SSc onset (53 vs. 49 years) and more frequently sine scleroderma (31% vs 12%, p < 0.001). The overall burden of vascular complications was milder in this subset, with a lower prevalence of pitting scars (33% vs 48%), telangiectasias (52% vs 74%), and calcinosis (3.4% vs 12%). During the follow-up, mRSS remained lower (60-month mean 4 vs 7, p = 0.002), as well as the estimated probability of vascular complications. Moreover, despite comparable values at baseline, DLCO remained significantly higher in patients without NVC-SP at the following time points (12, 24, and 60 months, p < 0.05). The presence of "late" NVC-SP was independently associated with ILD (OR 1.83, 95% CI 1.05-3.18). Conclusions:The absence of NVC-SP in 5.3% of SPRING SSc patients may identify a subset characterized by milder disease, with a lower burden of vascular and organ complications. Conversely, lung involvement was more frequently observed in patients with more severe NVC microangiopathy.
Objective:To evaluate the disease-modifying potential of SM03, a novel humanized anti-CD22 monoclonal antibody, for B cell-mediated autoimmune diseases by investigating its mechanism for suppressing B cell dysregulation in autoimmune milieu. Methods:SM03's mechanism was assessed in-vitro using functional assays on stimulated human PBMC from healthy donors and patients with Systemic Lupus Erythematosus (SLE)/Sjögren's Syndrome (SS). The efficacy of SM03 to attenuate autoimmunity was then evaluated in-vivo in a humanized pristane-induced SLE mouse model as well as a preventive collagen-induced Rheumatoid Arthritis (RA) model in cynomolgus monkeys. Disease-specific biomarkers, histopathology, and immune cell phenotypes were analyzed. Results:SM03 attenuated T cell-dependent B cell activation by reducing class-switched B cells, plasmablast differentiation, and pro-inflammatory cytokine production in B cell lines, healthy and disease PBMCs, without inducing B cell depletion. In the SLE model, SM03 suppressed key disease manifestations (splenomegaly, anti-dsDNA, proteinuria, glomerular deposits) and reduced activated T cells without broad B cell depletion. In the RA model, SM03 dose-dependently suppressed joint scores, cartilage damage, synovial hyperplasia, anti-collagen II antibodies, and IL-6. Conclusion:By enhancing CD22's inhibitory signalling to disrupt autoreactive B-T cell interactions, SM03 functions as a disease-modifying therapy that attenuates dysregulation of lymphocytes in autoimmunity. This non-depleting mechanism supports its translational potential for SLE and RA and implicates its broader utility for other B cell-driven autoimmune diseases.
Background The pathogenesis of cutaneous lupus erythematosus (CLE) is driven by the overactivation of the type I interferon (IFN-I) system. Although dysregulated glucose metabolism has been implicated in autoimmune inflammation, its role in CLE remains largely unexplored. This study aims to elucidate the role of glucose metabolism in CLE, specifically exploring its correlation with IFN-I activity and its contribution to disease severity. Methods Skin biopsies were obtained from 51 patients with active, untreated CLE — including two of its most prevalent subtypes: 26 with subacute cutaneous lupus erythematosus (SCLE) and 25 with discoid lupus erythematosus (DLE) — and 8 healthy controls. Glucose uptake and IFN-I system activation was evaluated via GLUT1 (SLC2A1) and MxA (MX1) immunohistochemistry, respectively. Disease activity was measured using the CLASI-A score. Publicly available transcriptomic datasets were analyzed using Spearman's rank correlation to evaluate the association between SLC2A1 and MX1 mRNA levels. Results GLUT1 expression was significantly increased in both CLE subtypes compared to healthy controls (SCLE: p = 0.0344, DLE: p = 0.0356). MxA expression in keratinocytes and lymphocytes was also markedly elevated in CLE samples (p = 0.0031, p = 0.0059). Keratinocyte GLUT1 expression positively correlated with keratinocyte and lymphocyte MxA expression (p = 0.003, r = 0.41; p < 0.001, r = 0.483) and with CLASI-A scores (p < 0.001, r = 0.47). Additionally, a significant positive correlation was observed between SLC2A1 and MX1 mRNA expression across multiple cell lines. Conclusion Our findings identify a link between elevated GLUT1 expression, IFN-I pathway activation, and CLE disease activity, suggesting that enhanced glucose metabolism may contribute to the immunopathogenesis and clinical severity of CLE.
The fourth LBMR-Tim (Toulouse Referral Medical Laboratory of Immunology) symposium was convened on December 15th, 2025, in Toulouse, France, to discuss recent advances in the understanding and management of systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). Pathophysiological mechanisms underlying SSc and SLE were discussed from a genetic perspective, with particular emphasis on the X-chromosomal TLR7/TLR8 locus and the interferon signaling pathway. Cellular aspects were explored, highlighting the critical roles of regulatory T cells (Tregs), exhausted T cells, macrophage polarization, and endothelial cells. At the translational research frontier, significant initiatives are underway within the framework of the European Autoimmunity Standardization Initiative (EASI) aimed at enhancing routine biomarker application for diagnosis, disease monitoring, and prognostic considerations. Emerging biomarker candidates promise potential for improving prognostic assessment and follow-up in lupus nephritis (e.g., urinary sCD163/creatinine ratio), cardiovascular complications and vasculopathy associated with SSc (e.g., dephosphorylated-uncarboxylated matrix Gla protein [dp-ucMGP] and endothelial progenitor cells), as well as therapeutic response evaluation (e.g., IGRA-PHA assays and proteomic methodologies). Therapeutically, a paradigm shift is underway with the development of efficacious mono- and multi-targeted antibody treatments alongside cellular therapies designed to eliminate B cells through chimeric antigen receptor (CAR) T cells or to re-establish immune regulation through Treg restoration. The integration of these therapeutic modalities necessitates further investigation to optimize individualized patient selection and management strategies. The multidisciplinary expert panel advocates for a comprehensive approach encompassing fundamental science, translational research, clinical expertise, and therapeutic innovation to advance in the management of these two complex syndromes.
Background: Alternative polyadenylation (APA) is a common post-transcriptional gene regulatory mechanism. Although dysregulated APA is associated with various human diseases, its role in Systemic Lupus Erythematosus (SLE) remains largely unexplored. We systematically characterized immune-related APA alterations in SLE and investigated their potential for clinically useful patient stratification. Methods: We integrated RNA-seq data from multiple SLE cohorts involving peripheral blood samples and quantified APA using the DaPars2. We developed a scoring framework to identify key immune-related APA events (ImmAPA) and their utility for grouping SLE patients. And we used the Connectivity Map to explore potential differences in drug response across ImmAPA groups and examined these associations in an independent SLE cohort treated with an immunosuppressive drug. Results: SLE patients exhibited a recurrent trend in lengthening of the 3 ' untranslated region (3 ' UTR) across cohorts. Twenty key APA regulators showed enhanced associations with these changes in SLE patients. The ImmAPA score can group patients into ImmAPA-high and ImmAPA-low subtypes, reflects activation states, and correlates with disease severity. The ImmAPA score captured complementary transcriptomic variation compared with interferon signature. CMap analysis predicted drugs that could reverse these APA changes, and was supported by follow-up analysis. Conclusions: Our study reveals a recurrent and widespread shift toward 3 ' UTR lengthening in SLE at peripheral blood transcriptome level. The ImmAPA framework provides a new perspective for SLE patient stratification and offers insights into precision therapeutic strategies in SLE.
Distinguishing superimposed infection from disease flare in systemic autoimmune and autoinflammatory diseases remains challenging, because neutrophil CD64 (nCD64) is sensitive for infection but may have reduced specificity in this setting. We evaluated the monocyte-to-neutrophil CD64 ratio (mCD64/nCD64 ratio) as an adjunctive biomarker in a single-center retrospective study of 408 patients with inflammatory conditions (infection, n = 242; non-infectious inflammation, n = 166). Diagnostic performance of nCD64 and the ratio was assessed by receiver operating characteristic analysis and net reclassification improvement (NRI), including a prespecified subgroup of 86 patients with systemic autoimmune and autoinflammatory diseases to distinguish flares (n = 60) from superimposed infections (n = 26). In the overall cohort, nCD64 showed high accuracy for infection (AUC 0.791), similar to the ratio (AUC 0.764). In the autoimmune/autoinflammatory subgroup, the ratio outperformed nCD64 (AUC 0.926 vs 0.870; p = 0.030) with high sensitivity (96.2%), and improved reclassification (total NRI 0.76; p < 0.001), driven mainly by correct identification of non-infected patients (NRI non-events 0.53). These findings suggest that the mCD64/nCD64 ratio may better distinguish flares from superimposed infections than nCD64 alone in autoimmune/autoinflammatory disease, supporting rule-out decisions when immunosuppressive therapy is being considered.
Autoimmune mechanisms are increasingly recognized as contributors to cardiovascular disease, extending beyond the traditional view of autoantibodies as passive markers of tissue injury. Among functional autoantibodies, those targeting the angiotensin II type 1 receptor (AT1R) and the endothelin-1 type A receptor (ETAR) represent a distinctive class capable of inducing sustained, ligand-independent activation of vasoactive G protein-coupled receptors. Emerging experimental and translational evidence suggests that these agonistic autoantibodies may contribute to endothelial dysfunction, microvascular injury, and adverse cardiac remodelling through persistent receptor stimulation and downstream pro-inflammatory and pro-fibrotic signalling. Clinical observations, particularly in reperfused ST-elevation myocardial infarction, support an association with impaired myocardial reperfusion and unfavourable outcomes, although causality remains unproven. In this perspective, we aim to delineate the mechanistic framework of AT1R-and ETAR-targeting agonistic autoantibodies, critically appraise the available clinical evidence, and outline key priorities for their translational validation in cardiovascular disease. Further investigation is required to determine their potential role in risk stratification and as therapeutic targets. Integrating immunological markers into cardiovascular research may provide new avenues for translational advancement, while necessitating rigorous validation in well-designed clinical studies.
Background: Cutaneous lupus erythematosus (CLE) represents one of the most frequent clinical manifestations of systemic lupus erythematosus (SLE), yet its relationship with internal organ involvement remains incompletely defined. Increasing evidence suggests that cutaneous inflammation may reflect systemic immune activation through dysregulated interferon signaling, immune complex deposition, and complement consumption. This systematic review and meta-analysis aimed to determine the association between CLE and major organ involvement in patients with SLE. Methods: A comprehensive literature search was conducted in PubMed, Scopus, Web of Science, and Google Scholar for studies published between 2014 and 2024. Observational studies assessing organ involvement among SLE patients with and without cutaneous manifestations were included. Two reviewers independently performed study selection, data extraction, and quality appraisal using the Newcastle-Ottawa Scale. A random-effects meta-analysis was conducted to estimate pooled odds ratios (OR) with 95% confidence intervals (CI) for renal, neuropsychiatric, hematologic, and cardiopulmonary involvement. Heterogeneity was quantified using I2, and publication bias evaluated with funnel plot and Egger's test. Results: Twenty-three studies met inclusion criteria for qualitative synthesis, and sixteen were eligible for quantitative pooling, comprising 8412 patients. Meta-analysis demonstrated that CLE was significantly associated with increased risk of lupus nephritis (OR 2.14, 95% CI 1.62-2.85), neuropsychiatric lupus (OR 1.78, 95% CI 1.29-2.46), and hematologic abnormalities (OR 1.95, 95% CI 1.40-2.71). A modest but significant association with cardiopulmonary involvement was also observed (OR 1.52, 95% CI 1.11-2.09). Subgroup analyses revealed stronger associations in acute CLE phenotypes and in patients with high interferon signatures. Sensitivity analyses confirmed robustness of findings, with no evidence of major publication bias. Conclusion: CLE is associated with significantly greater renal, neuropsychiatric, hematologic and cardiopulmonary involvement in patients with SLE compared with those without skin disease. These findings suggest that CLE is associated with increased systemic disease activity and a higher burden of internal organ involvement in SLE. CLE should therefore be considered an important clinical indicator of increased systemic risk in SLE.
Objective Patients with Sjögren’s disease (SjD) have an increased risk of developing B cell lymphomas, which may express rheumatoid factors (RhF). However, it remains unclear whether RhF-secreting cells undergo malignant transformation. To address this question, we longitudinally tracked the evolution of a RhF clone in a rare SjD case before and after lymphoma diagnosis. Methods Peripheral blood B cells, serum and malignant lymph node biopsy were collected from a 68-year-old male with SjD who developed diffuse large B cell lymphoma (DLBCL). Clonal RhF sequences were identified in serum by mass spectrometry and in B cells by mRNA sequencing. Recombinant IgM were generated from clonal sequences and assessed for RhF activity and cryoaggregation. Results A monoclonal RhF was detected in serum and circulating B cells six months before DLBCL diagnosis. The same clone was expressed by the lymphoma. Clonal analysis demonstrated divergence into two branches: one with seven antibody mutations expressed by blood B cells, and a second with twelve antibody mutations in the serum RhF and lymphoma. Recombinant IgM representing the blood and serum RhF demonstrated RhF activity, whereas the lymphoma clone acquired three additional mutations that impaired RhF binding. Conclusions Our prospective and longitudinal analyses provide direct evidence for a RhF secreting clone evolving into a lymphoma in a SjD patient. This work expands on previous cross-sectional studies of RhF expressing lymphomas in SjD and provides a proof-of-concept case, which potentially supports early therapeutic targeting of expanded RhF clones.
