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Comorbidities and multimorbidity, often complicating the disease course of patients with chronic inflammatory rheumatic diseases, may be influenced by disease-intrinsic and extrinsic determinants including regional and social factors. We analyzed the frequency and co-segregation of self-reported comorbid diseases in a community-based Mediterranean registry of patients (n = 399) with systemic lupus erythematosus (SLE). Predictors for multimorbidity were identified by multivariable logistic regression, strongly-associated pairs of comorbidities by the Cramer’s V-statistic, and comorbidities clusters by hierarchical agglomerative clustering. Among the most prevalent comorbidities were thyroid (45.6%) and metabolic disorders (hypertension: 24.6%, dyslipidemia: 33.3%, obesity: 35.3%), followed by osteoporosis (22.3%), cardiovascular (20.8%), and allergic (20.6%) disorders. Mental comorbidities were also common, particularly depression (26.7%) and generalized anxiety disorder (10.7%). Notably, 51.0% of patients had ≥3 physical and 33.1% had ≥2 mental comorbidities, with a large fraction (n = 86) displaying multimorbidity from both domains. Sociodemographic (education level, marital status) and clinical (disease severity, neurological involvement) were independently associated with physical or mental comorbidity. Patients were grouped into five distinct clusters of variably prevalent comorbid diseases from different organs and domains, which correlated with SLE severity patterns. Conclusively, our results suggest a high multimorbidity burden in patients with SLE at the community, advocating for integrated care to optimize outcomes.

ObjectivesGiant cell arteritis (GCA) is the most common primary vasculitis, preferentially affecting the aorta and its large-calibre branches. An imbalance between proinflammatory CD4+ T helper cell subsets and regulatory T cells (Tregs) is thought to be involved in the pathogenesis of GCA and Treg dysfunction has been associated with active disease. Our work aims to explore the aetiology of Treg dysfunction and the way it is affected by remission-inducing immunomodulatory regimens.MethodsA total of 41 GCA patients were classified into active disease (n=14) and disease in remission (n=27). GCA patients’ and healthy blood donors’ (HD) Tregs were sorted and subjected to transcriptome and phenotypic analysis.ResultsTranscriptome analysis revealed 27 genes, which were differentially regulated between GCA-derived and HD-derived Tregs. Among those, we identified transcription factors, glycolytic enzymes and IL-2 signalling mediators. We confirmed the downregulation of forkhead box P3 (FOXP3) and interferon regulatory factor 4 (IRF4) at protein level and identified the ineffective induction of glycoprotein A repetitions predominant (GARP) and CD25 as well as the reduced T cell receptor (TCR)-induced calcium influx as correlates of Treg dysfunction in GCA. Inhibition of glycolysis in HD-derived Tregs recapitulated most identified dysfunctions of GCA Tregs, suggesting the central pathogenic role of the downregulation of the glycolytic enzymes. Separate analysis of the subgroup of tocilizumab-treated patients identified the recovery of the TCR-induced calcium influx and the Treg suppressive function to associate with disease remission.ConclusionsOur findings suggest that low glycolysis and calcium signalling account for Treg dysfunction and inflammation in GCA.