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ObjectiveOrgan damage is a key determinant of poor prognosis and increased mortality in systemic lupus erythematosus (SLE). However, no validated clinical tools for predicting damage accumulation currently exist. We sought to develop a machine learning-based model to predict early organ damage in patients with SLE.MethodsClassification criteria (American College of Rheumatology (ACR)-1997, Systemic Lupus International Collaborating Clinics (SLICC)-2012, European League Against Rheumatism (EULAR)/ACR-2019) and non-criteria features of a cohort of 914 patients with SLE were analysed to predict damage (defined as SLICC/ACR Damage Index (SDI)) within 5 years since diagnosis. Feature selection and model construction were performed using the least absolute shrinkage and selection operator-logistic regression (LASSO-LR). The best model in 10-fold cross-validation was tested in an external cohort (n=50).ResultsA LASSO-LR model incorporating 16 criteria and non-criteria features predicted early organ damage with area under the receiver operating characteristic curve (AUC) values of 0.80 (95% CI 0.74 to 0.87) and 0.86 (95% CI 0.76 to 0.97) in the derivation and external validation cohorts, respectively, outperforming the ACR-1997 (AUC 0.70; 95% CI 0.62 to 0.78), SLICC-2012 (AUC 0.74; 95% CI 0.66 to 0.81) and EULAR/ACR-2019 (AUC 0.70; 95% CI 0.63 to 0.78) classification systems. Features most strongly associated with damage included the SLICC-2012 neurological disorder, EULAR/ACR-2019 class III/IV lupus nephritis and among non-criteria manifestations, myocarditis and interstitial lung disease. Operating the model as a binary classifier (early damage versus no damage), it demonstrated high specificity (0.90, 95% CI 0.78 to 0.95). The model can be converted to a simplified scoring system, with a threshold of ≥3 achieving an AUC of 0.86 (95% CI 0.75 to 0.96).ConclusionWe developed and validated a clinician-friendly model for early organ damage prediction in SLE, facilitating risk stratification.

The resulting inflammation and cellular necrosis releases the cell contents sustaining the chronic inflammation.Lofaro et al.developed a systematic review that includes 1,003 papers confirming the ever-increasing scientific attention on this Research Topic supported by the constant increase in the number of publications. While effective, corticosteroids have significant side effects, especially with long-term use, such as weight gain, osteoporosis, diabetes, and an increased risk of infection. Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Infections and autoimmunity exhibit a two-way alternate interaction. This report aims to present the case of severe disseminated sepsis leading to the diagnosis of antineutrophil cytoplasmic antibody (ANCA)-positive granulomatosis with polyangiitis. A 49-year-old male presented with fever, anemia, septic polyarthritis, bilateral pulmonary infiltrates with associated acute respiratory distress syndrome, deep vein thrombosis, and acute renal failure. was isolated from blood cultures and joint aspirates. Despite the initiation of targeted treatment, improvement was marginal; respiratory tract involvement worsened, and a parapneumonic fluid collection developed. The patient was investigated for immune system dysregulation. Investigation for hematological abnormalities or neoplasia was negative. An autoimmune antibody profile revealed high positivity for proteinase 3 cytoplasmic-ANCAs. Corticosteroids and rituximab were administered with a good clinical response. Although, in this case, the triggering of autoimmunity through a longstanding infection cannot be ruled out, the persistence of symptomatology despite control of the infection indicates the presence of an underlying autoimmune disease. Patients with ANCA-associated vasculitis are often diagnosed in the context of an infection, which can be encountered especially in the initial period after diagnosis. Accurate differential diagnosis is important to ensure appropriate treatment.

ObjectiveThis study aims to clarify whether T-bet+ B cells, as well as the sub-populations of age-associated B cells/ABCs (CD19+CD21-CD11c+T-bet+) and double-negative B cells/DN (CD19+IgD-CD27-CXCR5-T-bet+), serve as prognostic and/or therapeutic tools for systemic lupus erythematosus (SLE) in humans.MethodsFlow cytometry was used to enumerate and immunophenotype T-bet+ B cells and ABCs/DN subsets, found in the peripheral blood of 10 healthy donors and 22 active SLE patients, in order to identify correlations between the cell populations and the clinical profiles of the subjects. Moreover, in order to evaluate the effects of traditional and modern pharmaceutical agents on T-bet+ B cells’ percentage, 24h-long primary cell cultures combined with in vitro pharmacological treatments (of 1h) were performed. Various concentrations of hydroxychloroquine, anifrolumab and fasudil (a ROCK kinase inhibitor) have been tested. Last, data derived from previous published single-cell RNA sequencing (scRNA-seq) studies, regarding 6 healthy donors and 11 active SLE patients, were used for a meta-analysis focusing on T-bet+ B cells, so as to allow characterization of the genes and pathways associated with the biology of this specific transcription factor.ResultsT-bet+ B cells, as well as ABCs and DN, displayed a statistical significant expansion in the patients, compared to the healthy donors. Interestingly, percentages of T-bet+ B cells and DN B cells positively correlated with the SLEDAI scores of the patients. Cell culture experiments conducted, revealed that all three drugs tested are capable of depleting T-bet+ B cells (while leaving unaffected the total numbers of lymphocytes, T cells and B cells, respectively). According to bioinformatics analyses, moreover, T-bet in B cells seems to affiliate with transcription factors that play a role in germinal centers’ development (such as BCL6 and IRF8) in lupus patients, while in healthy individuals it affiliates with JUN. Additionally, an analysis regarding intracellular communications amongst B cell populations revealed that the transcription factor of interest is closely associated with inflammatory secretome during lupus.ConclusionsT-bet+ B cells associate with SLEDAI, thus can serve as a prognostic biomarker of lupus severity. Furthermore, these cells promote disease pathogenesis and can be targeted for therapeutic interventions.AcknowledgementsThe research work is supported by the Hellenic Foundation for Research and Innovation (HFRI) under the 3rd Call for HFRI PhD Fellowships (Fellowship Number: 5148, Awarded to AS). Moreover, the study is funded (partially) by the Hellenic Society of Rheumatology & Professional Association of Rheumatologists (Protocol Number: 1064, Research Grant awarded to CA)

Despite advances in the treatment, patients with systemic lupus erythematosus (SLE) often experience disease exacerbations (flares) of varying severity. Their diagnosis is primarily made on clinical grounds after exclusion of other diseases or disturbances, primarily infections, and can be assisted by the use of validated clinical indices. Serological tests such as serum complement fractions and anti-dsDNA autoantibodies, are helpful in monitoring SLE activity, but they lack high diagnostic accuracy. Flares are more frequent in patients with persistent immunological and clinical activity, and have been described as significant risk factor for development of irreversible end-organ damage. Accordingly, prevention of flares has been recognized as a distinct therapeutic target in SLE and involves adequate control of disease activity, use of hydroxychloroquine, maintaining immunosuppressive or biologic therapy for several years, and avoiding non-compliance issues. The future holds promise for the discovery of biomarkers that will accurately predict or diagnose SLE flares, thus allowing for the implementation of patient-tailored preventive strategies.

ObjectivesDiagnostic reasoning in systemic lupus erythematosus (SLE) is a complex process reflecting the probability of disease at a given timepoint against competing diagnoses. We applied machine learning in well-characterised patient data sets to develop an algorithm that can aid SLE diagnosis.MethodsFrom a discovery cohort of randomly selected 802 adults with SLE or control rheumatologic diseases, clinically selected panels of deconvoluted classification criteria and non-criteria features were analysed. Feature selection and model construction were done with Random Forests and Least Absolute Shrinkage and Selection Operator-logistic regression (LASSO-LR). The best model in 10-fold cross-validation was tested in a validation cohort (512 SLE, 143 disease controls).ResultsA novel LASSO-LR model had the best performance and included 14 variably weighed features with thrombocytopenia/haemolytic anaemia, malar/maculopapular rash, proteinuria, low C3 and C4, antinuclear antibodies (ANA) and immunologic disorder being the strongest SLE predictors. Our model produced SLE risk probabilities (depending on the combination of features) correlating positively with disease severity and organ damage, and allowing the unbiased classification of a validation cohort into diagnostic certainty levels (unlikely, possible, likely, definitive SLE) based on the likelihood of SLE against other diagnoses. Operating the model as binary (lupus/not-lupus), we noted excellent accuracy (94.8%) for identifying SLE, and high sensitivity for early disease (93.8%), nephritis (97.9%), neuropsychiatric (91.8%) and severe lupus requiring immunosuppressives/biologics (96.4%). This was converted into a scoring system, whereby a score >7 has 94.2% accuracy.ConclusionsWe have developed and validated an accurate, clinician-friendly algorithm based on classical disease features for early SLE diagnosis and treatment to improve patient outcomes.

ObjectivesClassification criteria are biased towards classifying long-standing disease. We compared the European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR)-2019, Systemic Lupus International Collaborating Clinics (SLICC)-2012 and ACR-1997 criteria in an early (median 48 months) systemic lupus erythematosus (SLE) cohort.MethodsPatients diagnosed with SLE (n=690) or control diseases (n=401). Sensitivity, specificity of the criteria and time-to-classification were calculated. Modified classification algorithms were derived from a random 80% and validated in the remaining 20% of the dataset running multiple iterations.ResultsAt last assessment, sensitivities of ACR-1997, SLICC-2012 and EULAR/ACR-2019 criteria were 85.7%, 91.3% and 88.6%, with specificities 93.0%, 93.8% and 97.3%, respectively. Both SLICC and EULAR/ACR enabled earlier classification. Only 76.7% of patients with SLE met all three criteria suggesting non-overlapping groups. Notably, unclassified patients had high prevalence of British Isles Lupus Assessment Group moderate/severe manifestations (43.3%–60%) and SLICC/ACR organ damage (30%–50%). At diagnosis, criteria missed 25.6%–30.5% of patients. Modification of EULAR/ACR and SLICC algorithms to include hypocomplementaemia and/or positive anti-phospholipid antibodies as alternative entry criterion, and/or allow classification with fewer clinical criteria from multiple organs, increased their sensitivity at diagnosis (median 82.0% and 86.2%) and overall (93.7% and 97.1%) with modest decreases in specificity. Importantly, patients who were still missed by the modified criteria had lower incidence of major organ involvement, use of immunosuppressive/biological therapies and organ damage.ConclusionsThe SLICC and EULAR/ACR are more sensitive than the ACR and the EULAR/ACR criteria have superior specificity in early SLE, although patients with significant disease can be missed. Combination and/or modification of the classification algorithms may enhance their sensitivity, allowing earlier classification and treatment of more patients with high disease burden.

Despite advances in the management of systemic lupus erythematosus (SLE), it remains a chronic disease with frequent flares, requiring constant medical care, laboratory exams, hospitalisations, and the use of immunosuppressive drugs and corticosteroids, increasing the morbidity and mortality of these patients. The past decade of research has brought to light multiple observations on the role of interferons (IFNs) in the pathogenesis of SLE, which paved the way for the development of potential novel therapies targeting the interferon pathway. Following two phase III trials, anifrolumab, a monoclonal antibody which binds to the type I IFN receptor, blocking the activity of type I IFNs, was approved for active SLE. This review summarises the latest research on the role and mechanisms of type I IFNs in SLE and the development and advances on new therapeutic drugs based on IFN inhibition for SLE.

ObjectivesSeveral population-based studies on systemic lupus erythematosus (SLE) have been reported, yet community-based, individual-case validated, comprehensive reports are missing. We studied the SLE epidemiology and burden on the island of Crete during 1999–2013.MethodsMultisource case-finding included patients ≥15 years old. Cases were ascertained by the ACR 1997, SLICC 2012 criteria and rheumatologist diagnosis, and validated through synthesis of medical charts, administrative and patient-generated data.ResultsOverall age-adjusted/sex-adjusted incidence was 7.4 (95% CI 6.8 to 7.9) per 100 000 persons/year, with stabilising trends in women but increasing in men, and average (±SD) age of diagnosis at 43 (±15) years. Adjusted and crude prevalence (December 2013) was 123.4 (113.9 to 132.9) and 143 (133 to 154)/105 (165/105 in urban vs 123/105 in rural regions, p<0.001), respectively. Age-adjusted/sex-adjusted nephritis incidence was 0.6 (0.4 to 0.8) with stable trends, whereas that of neuropsychiatric SLE was 0.5 (0.4 to 0.7) per 100 000 persons/year and increasing. Although half of prevalent cases had mild manifestations, 30.5% developed organ damage after 7.2 (±6.6) years of disease duration, with the neuropsychiatric domain most frequently afflicted, and 4.4% of patients with nephritis developed end-stage renal disease. The ACR 1997 and SLICC 2012 classification criteria showed high concordance (87%), yet physician-based diagnosis occurred earlier than criteria-based in about 20% of cases.ConclusionsBy the use of a comprehensive methodology, we describe the full spectrum of SLE from the community to tertiary care, with almost half of the cases having mild disease, yet with significant damage accrual. SLE is not rare, affects predominantly middle-aged women and is increasingly recognised in men. Neuropsychiatric disease is an emerging frontier in lupus prevention and care.