Objective
Systemic sclerosis (SSc) is a complex autoimmune disease with a strong genetic component. However, most of the genes associated with the disease are still unknown because associated ...variants affect mostly noncoding intergenic elements of the genome. We used functional genomics to translate the genetic findings into a better understanding of the disease.
Methods
Promoter capture Hi‐C and RNA‐sequencing experiments were performed in CD4+ T cells and CD14+ monocytes from 10 SSc patients and 5 healthy controls to link SSc‐associated variants with their target genes, followed by differential expression and differential interaction analyses between cell types.
Results
We linked SSc‐associated loci to 39 new potential target genes and confirmed 7 previously known SSc‐associated genes. We highlight novel causal genes, such as CXCR5, as the most probable candidate gene for the DDX6 locus. Some previously known SSc‐associated genes, such as IRF8, STAT4, and CD247, showed cell type–specific interactions. We also identified 15 potential drug targets already in use in other similar immune‐mediated diseases that could be repurposed for SSc treatment. Furthermore, we observed that interactions were directly correlated with the expression of important genes implicated in cell type–specific pathways and found evidence that chromatin conformation is associated with genotype.
Conclusion
Our study revealed potential causal genes for SSc‐associated loci, some of them acting in a cell type–specific manner, suggesting novel biologic mechanisms that might mediate SSc pathogenesis.
Lymphoid interstitial pneumonia (LIP) is a rare form of interstitial pulmonary disease, which has been described in association with a wide range of autoimmune disorders. Although the association of ...this entity with Sjogren’s syndrome is well known, only a few cases are reported in relation to systemic lupus erythematosus (SLE). The aim of this paper is to review the cases reported in literature to date, as well as to describe the characteristics of these patients including the new case presented herein. We will be focusing on the case of a 36-year-old female patient diagnosed with SLE on hydroxychloroquine treatment who develops pleuritic chest pain and progressive dyspnea after 3 years of follow-up. The chest CT scan showed pleural thickening and both multiple and bilateral micronodules. A lung biopsy was also performed, revealing an infiltration of lymphocytes, plasma cells, and histiocytes in the alveolar septa suggestive of LIP. After conducting a review of the literature, we identified seven other cases describing SLE in association with LIP. The majority of them were young women, and LIP tends to appear early in the course of the disease, even as a form of initial presentation in some cases. Symptoms included cough, dyspnea, and pleuritic pain, with the exception of one case which was asymptomatic. It is noteworthy that half of the patients were positive for anti-SSA/anti-SSB autoantibodies, and some of them also met criteria for Sjogren’s syndrome. Treatment with steroids and other immunosuppressive agents improved symptoms in all of them.
Cytokine storm syndrome (CSS) is a serious complication of COVID-19 patients. Treatment is tocilizumab. The use of glucocorticoids (GC) is controversial. In other very similar CSS, such as macrophage ...activation syndrome (MAS) and hemophagocytic syndrome (HFS), the main treatment are corticosteroids. Our objective is to evaluate the efficacy of GC in the CSS by COVID-19.
We included 92 patients with CSS associated to COVID-19 who received GC, GC, and tocilizumab and only tocilizumab. We determine CSS markers. We evaluated mortality, intubation, and a combined variable.
In all cases the percentages of events were lower in the group of patients with GC was administered. The hazard ratio of the final variables with GC versus the group in which only tocilizumab was administered was lower as CGs were considered, with statistical significance for survival.
The early use of GC pulses could control SLC, with a lower requirement to use tocilizumab and a decrease in events such as intubation and death.
To verify the psychological and quality of life benefits of vaccination against COVID-19 in patients with systemic autoimmune diseases. In this study, levels of psychological stress, ...psychopathological symptoms, quality of life, and satisfaction with life were compared in patients with systemic autoimmune diseases vaccinated against COVID-19 (n = 132) versus unvaccinated patients (n = 254). To this end, we used the Perceived Stress Scale (PSS), Symptom Checklist-90-Revised (SCL-90-R), EUROQoL-5Q health questionnaire, and Satisfaction with Life Scale (SWLS), respectively. Statistically significant differences were found with better scores in the vaccinated group in the following quality of life dimensions: mobility (p ≤ 0.010), domestic activities (p ≤ 0.004), pain/discomfort (p ≤ 0.001), and anxiety/depression (p≤ 0.005). The scores were also significantly higher in the vaccinated group for the total values of quality of life (p ≤ 0.001), health status self-assessment on the EUROQoL-5Q (p ≤ 0.043), and satisfaction with life (p ≤ 0.015). In addition, the unvaccinated group presented higher scores with clinically pathological levels in depression and psychoticism for somatizations (p ≤ 0.006), depression (p ≤ 0.015), anxiety (p ≤ 0.003), and phobic anxiety (p ≤ 0.001). Finally, participants vaccinated with the complete regimen showed better levels of psychological well-being than those who were not vaccinated or those that had not completed the vaccination regimen. Our results reflect and confirm the positive effects reported elsewhere of the COVID-19 vaccine in autoimmune patients with systemic diseases, both in terms of quality and satisfaction with life as well as psychopathological symptoms and perceived stress. These benefits increased as the patients completed their vaccination schedule.
Behçet's disease (BD) is an immune-mediated systemic disorder with a well-established association with HLA class I and other genes. BD has clinical overlap with many autoinflammatory diseases (AIDs). ...The aim of this study was to investigate the role of rare variants in seven genes involved in AIDs: CECR1, MEFV, MVK, NLRP3, NOD2, PSTPIP1 and TNFRSF1A using a next generation sequencing (NGS) approach in 355 BD patients. To check global association of each gene, 4 tests: SKAT, CollapseBt, C(α) and weighted KBAC were used. Databases: 1000 Genomes Project Phase 3, Infevers, HGMD and ClinVar and algorithms: PolyPhen2 and SIFT were consulted to collect information of the 62 variants found. All the genes resulted associated using SKAT but only 3 (MVK, NOD2 and PSTPIP1) with C(α) and weighted KBAC. When all the genes are considered, 40 variants were associated to AIDs in clinical databases and 25 were predicted as pathogenic at least by one of the algorithms. Including only MVK, NOD2 and PSTPIP1, the associated to AIDs variants found in BD were 20 and the predicted as pathogenic, 12. The maxima contribution corresponds to NOD2. This study supports influence of rare variants in genes involved in AIDs in the pathogenesis of BD.
: Familial cold autoinflammatory syndrome, Muckle-Wells syndrome (MWS), and chronic, infantile, neurological, cutaneous and articular (CINCA) syndrome are dominantly inherited autoinflammatory ...diseases associated to gain-of-function NLRP3 mutations and included in the cryopyrin-associated periodic syndromes (CAPS). A variable degree of somatic NLRP3 mosaicism has been detected in ≈35% of patients with CINCA. However, no data are currently available regarding the relevance of this mechanism in other CAPS phenotypes.
To evaluate somatic NLRP3 mosaicism as the disease-causing mechanism in patients with clinical CAPS phenotypes other than CINCA and NLRP3 mutation-negative.
NLRP3 analyses were performed by Sanger sequencing and by massively parallel sequencing. Apoptosis-associated Speck-like protein containing a CARD (ASC)-dependent nuclear factor kappa-light chain-enhancer of activated B cells (NF-κB) activation and transfection-induced THP-1 cell death assays determined the functional consequences of the detected variants.
A variable degree (5.5-34.9%) of somatic NLRP3 mosaicism was detected in 12.5% of enrolled patients, all of them with a MWS phenotype. Six different missense variants, three novel (p.D303A, p.K355T and p.L411F), were identified. Bioinformatics and functional analyses confirmed that they were disease-causing, gain-of-function NLRP3 mutations. All patients treated with anti-interleukin1 drugs showed long-lasting positive responses.
We herein show somatic NLRP3 mosaicism underlying MWS, probably representing a shared genetic mechanism in CAPS not restricted to CINCA syndrome. The data here described allowed definitive diagnoses of these patients, which had serious implications for gaining access to anti-interleukin 1 treatments under legal indication and for genetic counselling. The detection of somatic mosaicism is difficult when using conventional methods. Potential candidates should benefit from the use of modern genetic tools.
Objectives
We aimed to investigate the rate of non-adherence to antimalarials and glucocorticoids (GCs) and to analyze their potential relationships with sociodemographic characteristics, disease ...activity and accumulate damage in a cohort of Systemic lupus erythematosus (SLE) patients.
Methods
A cross-sectional study was conducted among 670 patients. The Systemic Lupus Erythematosus Activity Questionnaire (SLAQ) and the Lupus Damage Index Questionnaire (LDIQ) were used to assess disease activity and accumulated damage.
Results
The prevalence of non-adherence to antimalarials and GCs were 10.67% and 39.61%. 86.9% of participants indicated that the reason for stopping therapy was the presence of side effects. SLE patients with non-adherence to antimalarials and GCs had significantly higher scores in disease severity (SLAQ) compared to adherence patients (5.03 (2.12) vs 4.39 (2.61); p = .004 and (4.75 (2.29) vs 4.05 (2.78); p ≤ .001).
Conclusion
Adherence to the treatment indicated in SLE differs from drug to drug. Findings highlight the importance of developing interventions to support adherence and improve outcomes among patients.
Two main different clinical phenotypes of giant cell arteritis (GCA) have been described, the classic cranial pattern and the extracranial large-vessel (LV) pattern. Since interferon gamma (IFNG) has ...shown to be a pivotal cytokine in the pathophysiology of GCA, our aim was to evaluate for the first time the influence of IFNG and IFNG receptor 1 (IFNGR1) polymorphisms in the different clinical phenotypes of GCA.
Two IFNG polymorphisms (rs2069718 G/A and rs1861493 A/G) and one polymorphism in IFNGR1 (rs1327474 G/A) were genotyped in 191 patients with biopsy-proven cranial GCA, 109 with extracranial LV-GCA and 490 healthy controls. A comparative study was conducted between patients with cranial and extracranial LV-GCA.
No significant differences in genotype, allele, and haplotype frequencies of IFNG polymorphisms were found between GCA patients with the classic cranial pattern and the extracranial LV-GCA pattern. Similar results were found for genotype and allele frequencies of IFNGR1 polymorphism. It was also the case when patients with extracranial LV-GCA were compared with healthy controls.
Our results show that IFNG and IFNGR1 polymorphisms do not influence the clinical phenotype of expression of GCA. Classic cranial GCA and extracranial LV-GCA seem to share a genetic pattern of IFNG pathway.
PDF
