Understanding Fatigue in Sjogren's Syndrome: Outcome Measures, Biomarkers and Possible Interventions.
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ABSTRACT:
SUBMITTER: Mæland E
PROVIDER: S-EPMC8267792 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background: Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease, where patients often suffer from fatigue. Biological pathways underlying fatigue are unknown. In this study aptamer-based SOMAscan technology is used to identify potential biomarkers and treatment targets for fatigue in pSS. Methods: SOMAscan® Assay 1.3k was performed on serum samples of healthy controls (HCs) and pSS patients characterized for interferon upregulation and fatigue. Differentially expressed proteins (DEPs) between pSS patients and HC or fatigued and non-fatigued pSS patients were validated and discriminatory capacity of markers was tested using independent technology. Results: Serum concentrations of over 1,300 proteins were compared between 63 pSS patients and 20 HCs resulting in 58 upregulated and 46 downregulated proteins. Additionally, serum concentrations of 30 interferon positive (IFNpos) and 30 interferon negative (IFNneg) pSS patients were compared resulting in 25 upregulated and 13 downregulated proteins. ELISAs were performed for several DEPs between pSS patients and HCs or IFNpos and IFNneg all showing a good correlation between protein levels measured by ELISA and relative fluorescence units (RFU) measured by the SOMAscan. Comparing 22 fatigued and 23 non-fatigued pSS patients, 16 serum proteins were differentially expressed, of which 14 were upregulated and 2 were downregulated. Top upregulated DEPs included neuroactive synaptosomal-associated protein 25 (SNAP-25), alpha-enolase (ENO1) and ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1). Furthermore, the proinflammatory mediator IL36a and several complement factors were upregulated in fatigued compared to non-fatigued pSS patients. ROC analysis indicated that DEPs showed good capacity to discriminate fatigued and non-fatigued pSS patients. Conclusion: In this study we validated the use of aptamer-based proteomics and identified a novel set of proteins which were able to distinguish fatigued from non-fatigued pSS patients and identified a so-called "fatigue signature."
| S-EPMC6399420 | biostudies-literature
Project description:Sjogren's syndrome (SS) is an autoimmune disease, among the most common ones, that targets mainly the exocrine glands as well as extra-glandular epithelial tissues. Their lymphocytic infiltration leads to manifestations from other organs (e.g., kidneys, lungs, liver, or thyroid), apart from sicca symptoms (xerostomia and keratoconjunctivitis). SS is more prevalent in women than in men (9:1). Moreover, p.SS patients are in increased risk to develop lymphoma. Certain autoantibodies (e.g., antibodies against ribonucleoprotein autoantigens Ro-SSA and La-SSB) are ultimate hallmarks for the disease. It was not known until recently that culture-independent techniques like next-generation sequencing (NGS) facilitate the study of the microbe communities in humans and scientists achieved to define the outlines of the microbiome contribution in health and disease. Researchers have started to investigate the alterations in diversity of the oral, ocular, or intestinal microbiota in SS. Recent studies indicate that dysbiosis may play a significant role in SS pathogenesis. At the same time, the cause or effect is not clear yet because the dysfunction of salivary glands induces alterations in oral and intestinal microbiome which is linked to worsen of symptoms and disease severity. If the human microbiome proves to play a key role in pathogenesis and manifestation of SS, the next step could be new and promising therapeutic approaches such as probiotics or prebiotics. This mini review focuses on the alterations of microbiome of SS patients, their connection with immune tolerance and new therapeutic strategies involving diet manipulation toward future personalized medicine.
| S-EPMC5976780 | biostudies-other
Project description:We aim to identify the common genes, biological pathways, and treatment targets for primary Sjögren's syndrome patients with varying degrees of fatigue features. We select datasets about transcriptomic analyses of primary Sjögren's syndrome (pSS) patients with different degrees of fatigue features and normal controls in peripheral blood. We identify common differentially expressed genes (DEGs) to find shared pathways and treatment targets for pSS patients with fatigue and design a protein-protein interaction (PPI) network by some practical bioinformatic tools. And hub genes are detected based on the PPI network. We perform biological pathway analysis of common genes by Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. Lastly, potential treatment targets for pSS patients with fatigue are found by the Enrichr platform. We discovered that 27 DEGs are identified in pSS patients with fatigue features and the severe fatigued pSS-specific gene is RTP4. DEGs are mainly localized in the mitochondria, endosomes, endoplasmic reticulum, and cytoplasm and are involved in the biological process by which interferon acts on cells and cells defend themselves against viruses. Molecular functions mainly involve the process of RNA synthesis. The DEGs of pSS are involved in the signaling pathways of viruses such as hepatitis C, influenza A, measles, and EBV. Acetohexamide PC3 UP, suloctidil HL60 UP, prenylamine HL60 UP, and chlorophyllin CTD 00000324 are the four most polygenic drug molecules. PSS patients with fatigue features have specific gene regulation, and chlorophyllin may alleviate fatigue symptoms in pSS patients.
| S-EPMC8783724 | biostudies-literature
Project description:BACKGROUND:To assess the presence of a seasonal effect on fatigue, pain and dryness in primary Sjögren's syndrome (pSS). METHODS:Data (date; visual analogue scales (VAS) for pain, fatigue and dryness) were extracted from three randomised placebo-controlled trials (RCTs) evaluating infliximab (TRIPSS; n?=?103 patients), hydroxychloroquine (JOQUER; n?=?120 patients) and rituximab (TEARS; n?=?120 patients) and from the 5-year follow-up of the ASSESS prospective cohort (n?=?395 patients). Data were analysed at each visit for each patient, according to the day, the month of the year and the season. Linear mixed models were used to take into account the repeated structure of the data and to analyse a potential cyclic effect. RESULTS:A total of 744, 584, 848 and 682 pain, fatigue and dryness VASs were collected on 632 subjects in spring, summer, fall and winter, respectively. No significant difference was observed in pain, fatigue and dryness, according to the month of the year or the season (all p values >?0.05). CONCLUSION:In pSS, seasonality does not affect patient-reported outcomes (PROs) on fatigue, pain and dryness.
| S-EPMC7041128 | biostudies-literature
Project description:ObjectivesFatigue is a frequent and often disabling phenomenon that occurs in patients with chronic inflammatory and immunological diseases, and the underlying biological mechanisms are largely unknown. Because fatigue is generated in the brain, we aimed to investigate cerebrospinal fluid and search for molecules that participate in the pathophysiology of fatigue processes.MethodsA label-free shotgun proteomics approach was applied to analyze the cerebrospinal fluid proteome of 20 patients with primary Sjögren's syndrome. Fatigue was measured with the fatigue visual analog scale.ResultsA total of 828 proteins were identified and the 15 top discriminatory proteins between patients with high and low fatigue were selected. Among these were apolipoprotein A4, hemopexin, pigment epithelium-derived factor, secretogranin-1, secretogranin-3, selenium-binding protein 1, and complement factor B.ConclusionMost of the discriminatory proteins have important roles in regulation of innate immunity, cellular stress defense, and/or functions in the central nervous system. These proteins and their interacting protein networks may therefore have central roles in the generation and regulation of fatigue, and the findings contribute with evidence to the concept of fatigue as a biological phenomenon signaled through specific molecular pathways.
| S-EPMC6537061 | biostudies-literature
Project description:BackgroundFatigue is a debilitating condition with a significant impact on patients' quality of life. Fatigue is frequently reported by patients suffering from primary Sjögren's Syndrome (pSS), a chronic autoimmune condition characterised by dryness of the eyes and the mouth. However, although fatigue is common in pSS, it does not manifest in all sufferers, providing an excellent model with which to explore the potential underpinning biological mechanisms.MethodsWhole blood samples from 133 fully-phenotyped pSS patients stratified for the presence of fatigue, collected by the UK primary Sjögren's Syndrome Registry, were used for whole genome microarray. The resulting data were analysed both on a gene by gene basis and using pre-defined groups of genes. Finally, gene set enrichment analysis (GSEA) was used as a feature selection technique for input into a support vector machine (SVM) classifier. Classification was assessed using area under curve (AUC) of receiver operator characteristic and standard error of Wilcoxon statistic, SE(W).ResultsAlthough no genes were individually found to be associated with fatigue, 19 metabolic pathways were enriched in the high fatigue patient group using GSEA. Analysis revealed that these enrichments arose from the presence of a subset of 55 genes. A radial kernel SVM classifier with this subset of genes as input displayed significantly improved performance over classifiers using all pathway genes as input. The classifiers had AUCs of 0.866 (SE(W) 0.002) and 0.525 (SE(W) 0.006), respectively.ConclusionsSystematic analysis of gene expression data from pSS patients discordant for fatigue identified 55 genes which are predictive of fatigue level using SVM classification. This list represents the first step in understanding the underlying pathophysiological mechanisms of fatigue in patients with pSS.
| S-EPMC4687914 | biostudies-literature
Project description:Sjögren’s syndrome (SS) is a systemic autoimmune disease with a variety of presenting symptoms that may delay its diagnosis. We previously discovered a number of candidate salivary biomarkers for primary SS using both mass spectrometry and expression microarray analysis. In the current study, we aimed to verify these candidate biomarkers in independent patient populations and to evaluate their predictive values for primary SS detection.In total, 34 patients with primary SS, 34 patients with systemic lupus erythematosus (SLE), and 34 healthy individuals were enrolled for the validation studies. Salivary protein biomarkers were measured using either Western blotting or enzyme-linked immunosorbent assay, and the messenger RNA (mRNA) biomarkers were measured using quantitative polymerase chain reaction. Statistical analysis was performed using R software, version 2.9.Three protein biomarkers (cathepsin D [CPD], ?-enolase, and ß?-microglobulin [ß?m]) and 3 mRNA biomarkers (myeloid cell nuclear differentiation antigen [MNDA], guanylate binding protein 2 [GBP-2], and low-affinity IIIb receptor for the Fc fragment of IgG) were significantly elevated in patients with primary SS compared with both SLE patients and healthy controls. The combination of 3 protein biomarkers, CPD, ?-enolase, and ß?m, yielded a receiver operating characteristic (ROC) value of 0.99 in distinguishing primary SS from healthy controls. The combination of protein biomarkers ß?m and 2 mRNA biomarkers, MNDA and GBP-2, reached an ROC of 0.95 in discriminating primary SS from SLE.We have successfully verified a panel of protein and mRNA biomarkers that can discriminate primary SS from both SLE and healthy controls. If further validated in patients with primary SS and those with sicca symptoms but no autoimmune disease, these biomarkers may lead to a simple yet highly discriminatory clinical tool for diagnosis of primary SS.
| S-EPMC2995446 | biostudies-literature
Project description:To identify a panel of protein and messenger RNA (mRNA) biomarkers in human whole saliva (WS) that may be used in the detection of primary Sjögren's syndrome (SS).Mass spectrometry and expression microarray profiling were used to identify candidate protein and mRNA biomarkers of primary SS in WS samples. Validation of the discovered mRNA and protein biomarkers was also demonstrated using real-time quantitative polymerase chain reaction and immunoblotting techniques.Sixteen WS proteins were found to be down-regulated and 25 WS proteins were found to be up-regulated in primary SS patients compared with matched healthy control subjects. These proteins reflected the damage of glandular cells and inflammation of the oral cavity system in patients with primary SS. In addition, 16 WS peptides (10 up-regulated and 6 down-regulated in primary SS) were found at significantly different levels (P < 0.05) in primary SS patients and controls. Using stringent criteria (3-fold change; P < 0.0005), 27 mRNA in saliva samples were found to be significantly up-regulated in the primary SS patients. Strikingly, 19 of 27 genes that were found to be overexpressed were interferon-inducible or were related to lymphocyte filtration and antigen presentation known to be involved in the pathogenesis of primary SS.Our preliminary study has indicated that WS from patients with primary SS contains molecular signatures that reflect damaged glandular cells and an activated immune response in this autoimmune disease. These candidate proteomic and genomic biomarkers may improve the clinical detection of primary SS once they have been further validated. We also found that WS contains more informative proteins, peptides, and mRNA, as compared with gland-specific saliva, that can be used in generating candidate biomarkers for the detection of primary SS.
| S-EPMC2856841 | biostudies-literature
Project description:IntroductionSjögren's Syndrome Symptom Diary (SSSD) and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) are patient-reported outcome (PRO) instruments assessing Sjögren's symptoms. Original SSSD items have demonstrated content validity, however qualitative evidence supporting the updated 'tiredness' item and two new supplementary items is lacking. Although well established and validated in other rheumatic diseases, there is no qualitative evidence supporting content validity of FACIT-F in Sjögren's. This study addressed these evidence gaps to support use of SSSD and FACIT-F as clinical trial endpoints, in clinical practice and in other research settings.MethodsQualitative, semi-structured telephone interviews were conducted with patients with Sjögren's (n = 12) and expert Sjögren's physicians (n = 10). Patient interviews explored content validity (e.g., understanding and relevance) of the new and updated SSSD items, perceptions of item and total score meaningful change on SSSD, and understanding and relevance of FACIT-F items. Physician interviews explored opinions on various SSSD scoring approaches.ResultsThe new and updated SSSD items and FACIT-F demonstrated good content validity. Most patients considered a two-point improvement on most SSSD items meaningful, as well as a one- or two-point total score improvement. Most physicians reported tracking changes in patient responses to individual items as the most appropriate SSSD scoring approach.ConclusionsSSSD and FACIT-F are content valid in a Sjögren's population, meeting an important criterion to support their use as clinical trial endpoints, but also their use in clinical practice and other research settings. Qualitative data exploring meaningful change will be valuable in supporting psychometrically derived responder definitions.
| S-EPMC9561476 | biostudies-literature
Project description:Objectives The aim of this study was to investigate serum biomarkers linked to primary Sjögren's syndrome (pSS)-associated interstitial lung disease (ILD). Methods 69 pSS patients were consecutively enrolled and evaluated via quantitative ILD scoring based on high-resolution computed tomography (HRCT). Biomarkers of interest were assessed by multiplex enzyme-linked immunosorbent assays (ELISAs). Results Among consecutively enrolled patients with pSS, the presence of pSS–ILD was 50% based on the presence of radiographically defined interstitial lung abnormalities (ILA) meeting specified criteria for mild/moderate (ILA 2) or severe (ILA 3) disease. Age, immunoglobulin M (IgM), C-reactive protein (CRP), and serum levels of eotaxin/CCL11, Krebs von den Lungen-6 (KL-6), TNFα, and TGFα were significantly higher in the combined pSS–ILD group (ILA 2 + ILA 3) than in the pSS–no-ILD and pSS–indeterminate ILD groups (ILA 0 and ILA 1, respectively) in unadjusted analyses (p < 0.05 for all variables). A binary logistic regression model revealed that disease duration and KL-6 levels were associated with the presence of pSS–ILD (p < 0.05). Complementary least absolute shrinkage and selection operator (LASSO) modeling showed that age, KL-6, and TNF-α effectively differentiated pSS–ILD (ILA 2 + ILA3) from pSS without ILD (ILA 0 + ILA 1), with an area under the curve (AUC) of 0.883 (p value < 0.0001). Conclusions Patient age, disease duration, and serum levels of both KL-6 and TNFα were the most discriminating factors associated with the presence of ILD in our pSS patients. Higher levels of CRP, IgM, eotaxin, TGFα, and TNFα should also prompt the search for occult as well as clinically evident lung involvement based on statistically significant univariate associations with pSS–ILD. Clinical trial registration None. Supplementary Information The online version contains supplementary material available at 10.1186/s40001-022-00828-3.
| S-EPMC9549683 | biostudies-literature