Transcriptomic signatures of classical monocytes reveal pro-inflammatory modules and heterogeneity in polyarticular juvenile idiopathic arthritis.

Introduction: Polyarticular juvenile idiopathic arthritis (pJIA) is a childhood-onset autoimmune disease. Immune cells contribute to persistent inflammation observed in pJIA. Despite the crucial role of monocytes in arthritis, the precise involvement of classical monocytes in the pathogenesis of pJIA remains uncertain. Here, we aimed to uncover the transcriptomic patterns of classical monocytes in pJIA, focusing on their involvement in disease mechanism and heterogeneity. Methods: A total of 17 healthy subjects and 18 premenopausal women with pJIA according to ILAR criteria were included. Classical monocytes were isolated, and RNA sequencing was performed. Differential expression analysis was used to compare pJIA patients and healthy control group. Differentially expressed genes (DEGs) were identified, and gene set enrichment analysis (GSEA) was performed. Using unsupervised learning approach, patients were clustered in two groups based on their similarities at transcriptomic level. Subsequently, these clusters underwent a comparative analysis to reveal differences at the transcriptomic level. Results: We identified 440 DEGs in pJIA patients of which 360 were upregulated and 80 downregulated. GSEA highlighted TNF-α and IFN-γ response. Importantly, this analysis not only detected genes targeted by pJIA therapy but also identified new modulators of immuno-inflammation. PLAUR, IL1B, IL6, CDKN1A, PIM1, and ICAM1 were pointed as drivers of chronic hyperinflammation. Unsupervised learning approach revealed two clusters within pJIA, each exhibiting varying inflammation levels. Conclusion: These findings indicate the pivotal role of immuno-inflammation driven by classical monocytes in pJIA and reveals the existence of two subclusters within pJIA, regardless the positivity of rheumatoid factor and anti-CCP, paving the way to precision medicine.

Neuromodulation with aerobic exercise reduces fatigue in systemic lupus erythematosus: a randomised, sham-controlled, double-blind study.

OBJECTIVES: Transcranial direct current stimulation (tDCS) combined with aerobic exercise (tDCS-AE) effectively reduces fatigue in patients with fibromyalgia. However, no study has assessed this method in systemic lupus erythematosus (SLE) patients with significant fatigue. Therefore, we evaluated the safety and efficacy of tDCS-AE for significant fatigue symptoms in adult female SLE patients. METHODS: This randomised, sham-controlled, double-blind study included 25 patients with SLE in remission or low disease activity (SLEDAI-2K £4) and with significant fatigue [≥36 points on the Fatigue Severity Scale (FSS) or ≥38 points on the Modified Fatigue Scale (MFIS)]. The patients received sham or tDCS for five consecutive days. The anode and cathode were positioned at M1 and Fp2, respectively (international 10-20 EEG system). tDCS was applied at an intensity of 2mA, and density of 0.057mA/cm2 in the tDCS-AE group. Both groups underwent combined low-intensity treadmill exercise. FSS, MFIS, pain visual analogue scale, physical activity, and sleep quality were evaluated at baseline and on days 7, 30, and 60. Adherence and safety were assessed using a standardised questionnaire. RESULTS: Improvement in fatigue levels was observed in both groups. However, a sustained reduction in fatigue levels on days 30 and 60 occurred only with tDCS-AEs (p<0.05). No significant differences were observed in pain level, sleep quality, or physical activity. No disease flares occurred and the adverse effects were mild and transient. Finally, the patient's adherence to the treatment was satisfactory. CONCLUSIONS: Despite isolated AEs, there was an improvement in fatigue, however, only tDCS-AE maintained significant and sustained improvement.

Time to diagnosis in systemic lupus erythematosus: Associated factors and its impact on damage accrual and mortality. Data from a multi-ethnic, multinational Latin American lupus cohort.

BACKGROUND: Systemic lupus erythematosus (SLE) often mimics symptoms of other diseases, and the interval between symptom onset and diagnosis may be long in some of these patients. Aims: To describe the characteristics associated with the time to SLE diagnosis and its impact on damage accrual and mortality in patients with SLE from a Latin American inception cohort. METHODS: Patients were from a multi-ethnic, multi-national Latin-American SLE inception cohort. All participating centers had specialized lupus clinics. Socio-demographic, clinical/laboratory, disease activity, damage, and mortality between those with a longer and a shorter time to diagnosis were compared using descriptive statistical tests. Multivariable Cox regression models with damage accrual and mortality as the end points were performed, adjusting for age at SLE diagnosis, gender, ethnicity, level of education, and highest dose of prednisone for damage accrual, plus highest dose of prednisone, baseline SLEDAI, and baseline SDI for mortality. RESULTS: Of the 1437 included in these analyses, the median time to diagnosis was 6.0 months (Q1-Q3 2.4-16.2); in 721 (50.2%) the time to diagnosis was longer than 6 months. Patients whose diagnosis took longer than 6 months were more frequently female, older at diagnosis, of Mestizo ethnicity, not having medical insurance, and having "non-classic" SLE symptoms. Longer time to diagnosis had no impact on either damage accrual (HR 1.09, 95% CI 0.93-1.28, p = 0.300) or mortality (HR 1.37, 95% CI 0.88-2.12, p = 0.200). CONCLUSIONS: In this inception cohort, a maximum time of 24 months with a median of 6 months to SLE diagnosis had no apparent negative impact on disease outcomes (damage accrual and mortality).

Decreased high-density lipoprotein cholesterol levels in polyarticular juvenile idiopathic arthritis

OBJECTIVES: To investigate the prevalence of dyslipoproteinemia in a homogeneous cohort of polyarticular juvenile idiopathic arthritis patients. METHODS: Based on the National Cholesterol Education Program, fasting lipoprotein levels and risk levels for coronary artery disease were determined in 28 patients with polyarticular juvenile idiopathic arthritis. The exclusion criteria included diabetes, thyroid dysfunction, smoking, proteinuria, lipid-lowering drugs, and hormone/diuretic therapy. Disease activity, disease duration, and therapy with corticosteroids and/or chloroquine were defined at the time of lipid measurements. RESULTS: Dyslipoproteinemia was identified in 20 of the 28 (71 percent) patients with polyarticular juvenile idiopathic arthritis. The primary lipoprotein risk factor was decreased high-density lipoprotein cholesterol (57 percent), followed by elevated levels of low-density lipoprotein cholesterol (18 percent), triglycerides (14 percent), and total cholesterol (7 percent). The male patients had decreased high-density lipoprotein cholesterol levels than the female patients (p<0.05). The incidence of decreased high-density lipoprotein cholesterol levels did not seem to be affected by disease activity or therapy because the incidence was similar in patients with active or inactive disease, with or without corticosteroid use and with or without chloroquine use. In addition, the frequency of decreased high-density lipoprotein cholesterol levels was similar in patients with short (≤5 years) vs. long (>5 years) disease duration. CONCLUSIONS: Dyslipoproteinemia is highly prevalent in patients with polyarticular juvenile idiopathic arthritis and is primarily related to decreased high-density lipoprotein cholesterol levels; therefore, early intervention is essential.

Desvendando a síndrome antifosfolípide catastrófica (síndrome de Asherson) / Catastrophic antiphospholipid syndrome (Asherson’s syndrome) revealed

O quadro clínico de trombose generalizada de múltiplos órgãos acompanhada de insuficiência ou falência dos mesmos, em associação com anticorpos antifosfolípides, é chamado de síndrome antifosfolípide catastrófica (síndrome de Asherson). Esta é uma variante da síndrome antifosfolípide, que pode ocorrer em pacientes sem este diagnóstico ou mesmo durante o curso da síndrome primária e/ou secundária, mesmo com terapêutica anticoagulante. Os pacientes apresentam, principalmente, oclusões de pequenos vasos e as manifestações clínicas dependem dos órgãos acometidos. Fatores desencadeantes podem ser observados em metade dos casos e, apesar dos tratamentos, a sua mortalidade ainda é alta. Esta revisão apresentará a evolução de nossos conhecimentos sobre esta condição e como nós a compreendamos na atualidade.

Myositis in mixed connective tissue disease: a unique syndrome characterized by immunohistopathologic elements of both polymyositis and dermatomyositis

OBJETIVO: Caracterizar as células do infiltrado inflamatório, o padrão de expressão das moléculas de adesão (ICAM-1 e VCAM-1), complexo de ataque à membrana (C5b-9) e antígenos de histocompatibilidade maior (MHC) em biópsias musculares de patientes com doença mista do tecido conectivo (DMTC). MÉTODO: Foram estudados14 pacientes com DMTC e comparadas com 8 pacientes com polimiosite (PM), 5 com dermatomiosite (DM) e 4 com distrofias. As células inflamatórias foram caracterizadas como CD4+, CD8+, células T de memória (CD45RO+) e virgens, células "natural killer" e macrófagos. As expressões de MHC-I e ûII, ICAM-1, VCAM-1 e C5b-9 foram caracterizadas em fibras musculares e vasos. RESULTADOS:A análise morfológica demonstrou um padrão tipo PM. O estudo imuno-histoquímico revelou diminuição do número de capilares, predomínio de células CD4+ e B nas regiões perivasculares e predomínio de CD8+ e CD45RO+ nas regiões endomisiais. A expressão de MHC-I nos vasos e nas fibras degeneradas, MHC-II nos vasos e fibras perifasciculares e expressão de ICAM-1 / VCAM-1 no endotélio indicaram uma associação de processos vascular e imune-celular mediando a lesão muscular. CONCLUSAO: Os achados revelaram duplo mecanismo na DMTC, imune-celular como na PM e vascular como na DM.