RESUMEN
Chronic fatigue, pain and depression are common in patients with primary Sjögren's syndrome. These phenomena mutually affect each other and have a considerable impact on the patients' quality of life. While pain is usually regarded as a fairly somatic phenomenon, both fatigue and depression have traditionally been regarded as more-or-less of psychological origin. There is an increasing understanding that this picture is multifaceted; that there is a genetic foundation, and that biological mechanisms regulate the clinical expression through activation of evolutionary, deeply conserved neuronal pathways in the brain. This pattern is evident not only in primary Sjögren's syndrome, but also in other systemic inflammatory autoimmune diseases, in cancer and in neurodegenerative diseases like Parkinson's disease. This article will mainly focus on the biology of pain and fatigue. We describe how these factors influence each other, and act with the overarching purpose of defending the organism against harm and danger.
RESUMEN
Sarcoidosis is characterised by granulomatous inflammation in one or more organs, including the heart. Cardiac sarcoidosis generally has non-specific symptoms, and the disease is often diagnosed at a late stage. The condition is associated with cardiomyopathy and arrhythmia and may be fatal.
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Cardiomiopatías , Sarcoidosis , Cardiomiopatías/complicaciones , Cardiomiopatías/diagnóstico , Cardiomiopatías/etiología , Cardiomiopatías/terapia , Humanos , Imagen por Resonancia Magnética , Pronóstico , Sarcoidosis/complicaciones , Sarcoidosis/diagnóstico , Sarcoidosis/etiología , Sarcoidosis/terapiaRESUMEN
OBJECTIVES: Increasing evidence suggests an epigenetic contribution to the pathogenesis of autoimmune diseases, including primary Sjögren's Syndrome (pSS). The aim of this study was to investigate the role of DNA methylation in pSS by analysing multiple tissues from patients and controls. METHODS: Genome-wide DNA methylation profiles were generated using HumanMethylation450K BeadChips for whole blood, CD19+ B cells and minor salivary gland biopsies. Gene expression was analysed in CD19+ B cells by RNA-sequencing. Analysis of genetic regulatory effects on DNA methylation at known pSS risk loci was performed. RESULTS: We identified prominent hypomethylation of interferon (IFN)-regulated genes in whole blood and CD19+ B cells, including at the genes MX1, IFI44L and PARP9, replicating previous reports in pSS, as well as identifying a large number of novel associations. Enrichment for genomic overlap with histone marks for enhancer and promoter regions was observed. We showed for the first time that hypomethylation of IFN-regulated genes in pSS B cells was associated with their increased expression. In minor salivary gland biopsies we observed hypomethylation of the IFN-induced gene OAS2. Pathway and disease analysis resulted in enrichment of antigen presentation, IFN signalling and lymphoproliferative disorders. Evidence for genetic control of methylation levels at known pSS risk loci was observed. CONCLUSIONS: Our study highlights the role of epigenetic regulation of IFN-induced genes in pSS where replication is needed for novel findings. The association with altered gene expression suggests a functional mechanism for differentially methylated CpG sites in pSS aetiology.
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Metilación de ADN , Epigénesis Genética , Interferones/genética , Síndrome de Sjögren/genética , 2',5'-Oligoadenilato Sintetasa/genética , Adulto , Anciano , Antígenos/genética , Antígenos CD19/genética , Estudios de Casos y Controles , Proteínas del Citoesqueleto/genética , Femenino , Expresión Génica , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Proteínas de Resistencia a Mixovirus/genética , Proteínas de Neoplasias/genética , Poli(ADP-Ribosa) Polimerasas/genética , Glándulas Salivales Menores/patología , Síndrome de Sjögren/sangre , Síndrome de Sjögren/patologíaRESUMEN
Fatigue occurs in all chronic inflammatory diseases, in cancer, and in some neurological conditions. Patients often regard fatigue as one of their most debilitating problems, but currently there is no established treatment and the mechanisms that lead to and regulate fatigue are incompletely understood. Our objective was to more completely understand the physiology of this phenomenon. Twenty-four patients with rheumatoid arthritis (RA) naïve to treatment with biological drugs were enrolled for the study. Fatigue was measured with a fatigue visual analogue scale (fVAS). Ethylenediaminetetraacetic acid (EDTA) plasma samples were subjected to gas chromatography-time-of-flight mass spectrometry (GC/MS-TOF)-based metabolite profiling. Obtained metabolite data were evaluated by multivariate data analysis with orthogonal projections to latent structures (OPLS) method to pinpoint metabolic changes related to fatigue severity. A significant multivariate OPLS model was obtained between the fVAS scores and the measured metabolic levels. Increasing fatigue scores were associated with a metabolic pattern characterized by down-regulation of metabolites from the urea cycle, fatty acids, tocopherols, aromatic amino acids, and hypoxanthine. Uric acid levels were increased. Apart from fatigue, we found no other disease-related variables that might be responsible for these changes. Our MS-based metabolomic approach demonstrated strong associations between fatigue and several biochemical patterns related to oxidative stress.
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Artritis Reumatoide/metabolismo , Fatiga/metabolismo , Adulto , Anciano , Artritis Reumatoide/complicaciones , Fatiga/complicaciones , Femenino , Cromatografía de Gases y Espectrometría de Masas , Humanos , Masculino , Metabolómica , Persona de Mediana EdadRESUMEN
BACKGROUND: Inflammatory bowel disease is comprised mainly of ulcerative colitis and Crohn's disease. The prevalence of fatigue and its associations with different cofactors vary between studies. The aim of this article is to describe the extent of fatigue in inflammatory bowel disease, the factors that are most commonly associated with fatigue, and its treatment. We will also discuss challenges for future research on fatigue in inflammatory bowel disease. METHOD: We conducted literature searches in the Ovid Medline and The Cochrane Library databases using combinations of the keywords «inflammatory bowel diseases¼, «inflammatory bowel disease*¼, «IBD¼, «crohn*¼, «colitis¼, «fatigue¼, «fatigue manage¼ and «fatigue treat¼. The search was limited to articles published in the period 2000 15. RESULTS: Of the 156 articles identified, 28 were included in the review. Collectively, the studies used 13 different instruments for measuring fatigue and 11 measures of disease activity. Fatigue occurs more frequently in those who suffer from inflammatory bowel disease (22 77 %) than in the general population (2 12 %). Active disease and depression are associated with higher levels of fatigue. INTERPRETATION: Fatigue is a significant problem in inflammatory bowel disease. The use of differing measures of fatigue and of disease activity in heterogeneous study populations has contributed to variability in data on prevalence and possible risk factors.
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Fatiga , Enfermedades Inflamatorias del Intestino/complicaciones , Depresión/etiología , Fatiga/diagnóstico , Fatiga/epidemiología , Fatiga/etiología , Fatiga/terapia , Humanos , Enfermedades Inflamatorias del Intestino/epidemiología , Enfermedades Inflamatorias del Intestino/psicologíaRESUMEN
Fatigue is prevalent and disabling in primary Sjögren's syndrome (pSS). Results from studies in chronic fatigue syndrome (CFS) indicate that genetic variation may influence fatigue. The aim of this study was to investigate single nucleotide polymorphism (SNP) variations in pSS patients with high and low fatigue. A panel of 85 SNPs in 12 genes was selected based on previous studies in CFS. A total of 207 pSS patients and 376 healthy controls were genotyped. One-hundred and ninety-three patients and 70 SNPs in 11 genes were available for analysis after quality control. Patients were dichotomized based on fatigue visual analogue scale (VAS) scores, with VAS <50 denominated "low fatigue" (n = 53) and VAS ≥50 denominated "high fatigue" (n = 140). We detected signals of association with pSS for one SNP in SLC25A40 (unadjusted p = 0.007) and two SNPs in PKN1 (both p = 0.03) in our pSS case versus control analysis. The association with SLC25A40 was stronger when only pSS high fatigue patients were analysed versus controls (p = 0.002). One SNP in PKN1 displayed an association in the case-only analysis of pSS high fatigue versus pSS low fatigue (p = 0.005). This candidate gene study in pSS did reveal a trend for associations between genetic variation in candidate genes and fatigue. The results will need to be replicated. More research on genetic associations with fatigue is warranted, and future trials should include larger cohorts and multicentre collaborations with sharing of genetic material to increase the statistical power.
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Fatiga/genética , Polimorfismo de Nucleótido Simple , Síndrome de Sjögren/genética , Adulto , Anciano , Estudios de Casos y Controles , Enfermedad Crónica , Fatiga/diagnóstico , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Proteínas de Transporte de Membrana Mitocondrial/genética , Noruega , Fenotipo , Proteína Quinasa C/genética , Factores de Riesgo , Índice de Severidad de la Enfermedad , Síndrome de Sjögren/complicaciones , Síndrome de Sjögren/diagnósticoRESUMEN
BACKGROUND: We investigated sensitivity of the 2020 Revised Comprehensive Diagnostic Criteria (RCD) and the 2019 ACR/EULAR classification criteria across the four identified IgG4-related disease (IgG4-RD) phenotypes: "Pancreato-Hepato-Biliary", "Retroperitoneum and Aorta", "Head and Neck-limited" and "Mikulicz' and Systemic" in a well-characterized patient cohort. METHODS: We included adult patients diagnosed with IgG4-RD after comprehensive clinical assessment at Oslo University Hospital in Norway. We assigned patients to IgG4-RD phenotypes based on pattern of organ involvement and assessed fulfillment of RCD and 2019 ACR/EULAR classification criteria. Differences between phenotype groups were analyzed using one-way ANOVA for continuous variables, and contingency tables for categorical variables. RESULTS: The study cohort included 79 IgG4-RD patients assigned to the "Pancreato-Hepato-Biliary" (22.8%), Retroperitoneum and Aorta" (22.8%) "Head and Neck-limited" (29.1%), and "Mikulicz' and Systemic" (25.3%) phenotype groups, respectively. While 72/79 (91.1%) patients in total fulfilled the RCD, proportion differed across phenotype groups and was lowest in the "Retroperitoneum and Aorta" group (66.7%, p < 0.001). Among the 57 (72.2%) patients meeting the 2019 ACR/EULAR classification criteria, proportion was again lowest in the "Retroperitoneum and Aorta" group (27.8%, p < 0.001). CONCLUSION: The results from this study indicate that IgG4-RD patients having the "Retroperitoneum and Aorta" phenotype less often fulfill diagnostic criteria and classification criteria than patients with other IgG4-RD phenotypes. Accordingly, this phenotype is at risk of being systematically selected against in observational studies and randomized clinical trials, with potential implications for patients, caregivers and future definitions of IgG4-RD.
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Enfermedad Relacionada con Inmunoglobulina G4 , Humanos , Noruega , FenotipoRESUMEN
Fine mapping and bioinformatic analysis of the DDX6-CXCR5 genetic risk association in Sjögren's Disease (SjD) and Systemic Lupus Erythematosus (SLE) identified five common SNPs with functional evidence in immune cell types: rs4938573, rs57494551, rs4938572, rs4936443, rs7117261. Functional interrogation of nuclear protein binding affinity, enhancer/promoter regulatory activity, and chromatin-chromatin interactions in immune, salivary gland epithelial, and kidney epithelial cells revealed cell type-specific allelic effects for all five SNPs that expanded regulation beyond effects on DDX6 and CXCR5 expression. Mapping the local chromatin regulatory network revealed several additional genes of interest, including lnc-PHLDB1-1. Collectively, functional characterization implicated the risk alleles of these SNPs as modulators of promoter and/or enhancer activities that regulate cell type-specific expression of DDX6, CXCR5, and lnc-PHLDB1-1, among others. Further, these findings emphasize the importance of exploring the functional significance of SNPs in the context of complex chromatin architecture in disease-relevant cell types and tissues.
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Enfermedades del Sistema Inmune , Inmunoglobulina G , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Diagnóstico Diferencial , Glucocorticoides/uso terapéutico , Humanos , Enfermedades del Sistema Inmune/diagnóstico , Enfermedades del Sistema Inmune/tratamiento farmacológico , Enfermedades del Sistema Inmune/patología , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Pancreatitis/inmunología , Pancreatitis/patología , Sialadenitis/inmunologíaAsunto(s)
Enfermedad de Whipple/diagnóstico , Anciano , Artralgia/microbiología , Artritis Reumatoide/diagnóstico , Diagnóstico Diferencial , Diarrea/microbiología , Femenino , Humanos , Persona de Mediana Edad , Tropheryma/aislamiento & purificación , Enfermedad de Whipple/complicaciones , Enfermedad de Whipple/tratamiento farmacológico , Enfermedad de Whipple/patologíaRESUMEN
Sjögren's disease is a complex autoimmune disease with twelve established susceptibility loci. This genome-wide association study (GWAS) identifies ten novel genome-wide significant (GWS) regions in Sjögren's cases of European ancestry: CD247, NAB1, PTTG1-MIR146A, PRDM1-ATG5, TNFAIP3, XKR6, MAPT-CRHR1, RPTOR-CHMP6-BAIAP6, TYK2, SYNGR1. Polygenic risk scores yield predictability (AUROC = 0.71) and relative risk of 12.08. Interrogation of bioinformatics databases refine the associations, define local regulatory networks of GWS SNPs from the 95% credible set, and expand the implicated gene list to >40. Many GWS SNPs are eQTLs for genes within topologically associated domains in immune cells and/or eQTLs in the main target tissue, salivary glands.
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Estudio de Asociación del Genoma Completo , Síndrome de Sjögren , Predisposición Genética a la Enfermedad , Humanos , Polimorfismo de Nucleótido Simple , Síndrome de Sjögren/genéticaRESUMEN
Primary Sjögren's syndrome (pSS) is an autoimmune inflammatory disease with profound clinical heterogeneity, where excessive activation of the type I interferon (IFN) system is considered one of the key mechanisms in disease pathogenesis. Here we present a DNA methylation-based IFN system activation score (DNAm IFN score) and investigate its potential associations with sub-phenotypes of pSS. The study comprised 100 Swedish patients with pSS and 587 Swedish controls. For replication, 48 patients with pSS from Stavanger, Norway, were included. IFN scores were calculated from DNA methylation levels at the IFN-induced genes RSAD2, IFIT1 and IFI44L. A high DNAm IFN score, defined as > meancontrols +2SDcontrols (IFN score >4.4), was observed in 59% of pSS patients and in 4% of controls (p=1.3x10-35). Patients with a high DNAm IFN score were on average seven years younger at symptom onset (p=0.017) and at diagnosis (p=3x10-3). The DNAm IFN score levels were significantly higher in pSS positive for both SSA and SSB antibodies compared to SSA/SSB negative patients (pdiscovery=1.9x10-8, preplication=7.8x10-4). In patients positive for both SSA subtypes Ro52 and Ro60, an increased score was identified compared to single positive patients (p=0.022). Analyzing the discovery and replication cohorts together, elevated DNAm IFN scores were observed in pSS with hypergammaglobulinemia (p=2x10-8) and low C4 (p=1.5x10-3) compared to patients without these manifestations. Patients < 70 years with ongoing lymphoma at DNA sampling or lymphoma at follow-up (n=7), presented an increased DNAm IFN score compared to pSS without lymphoma (p=0.025). In conclusion, the DNAm-based IFN score is a promising alternative to mRNA-based scores for identification of patients with activation of the IFN system and may be applied for patient stratification guiding treatment decisions, monitoring and inclusion in clinical trials.
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Metilación de ADN/inmunología , Interferón Tipo I/inmunología , Síndrome de Sjögren/inmunología , Femenino , Humanos , Linfoma/inmunología , Masculino , Persona de Mediana Edad , Fenotipo , ARN Mensajero/inmunologíaRESUMEN
OBJECTIVES: Fatigue is common and severe in primary Sjögren's syndrome (pSS). The aim of this study was to identify genetic determinants of fatigue in pSS through a genome-wide association study. METHODS: Patients with pSS from Norway, Sweden, UK and USA with fatigue and genotype data available were included. After genotype imputation and quality control, 682 patients and 4 966 157 genetic markers were available. Association analysis in each cohort using linear regression with fatigue as a continuous variable and meta-analyses between the cohorts were performed. RESULTS: Meta-analysis of the Norwegian and Swedish cohorts identified five polymorphisms within the same linkage disequilibrium block at the receptor transporter protein 4 (RTP4)/MASP1 locus associated with fatigue with genome-wide significance (GWS) (p<5×10-8). Patients homozygous for the major allele scored 25 mm higher on the fatigue Visual Analogue Scale than patients homozygous for the minor allele. There were no variants associated with fatigue with GWS in meta-analyses of the US/UK cohorts, or all four cohorts. RTP4 expression in pSS B cells was upregulated and positively correlated with the type I interferon score. Expression quantitative trait loci effects in whole blood for fatigue-associated variants at RTP4/MASP1 and levels of RTP4 and MASP1 expression were identified. CONCLUSION: Genetic variations at RTP4/MASP1 are associated with fatigue in Scandinavian pSS patients. RTP4 encodes a Golgi chaperone that influences opioid pain receptor function and MASP1 is involved in complement activation. These results add evidence for genetic influence over fatigue in pSS.
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Síndrome de Sjögren , Alelos , Estudios de Cohortes , Fatiga/epidemiología , Fatiga/genética , Estudio de Asociación del Genoma Completo , Humanos , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa , Síndrome de Sjögren/complicaciones , Síndrome de Sjögren/genéticaRESUMEN
Primary Sjögren syndrome is an autoimmune disease that mainly affects exocrine glands such as the salivary and lacrimal glands. In addition, systemic involvement is common. Primary Sjögren syndrome is of particular interest to ophthalmologists as it constitutes an important differential diagnosis in conditions with dry eye disease. In addition, ocular tests for more precisely diagnosing and monitoring primary Sjögren syndrome have become increasingly important, and new therapeutics for local and systemic treatment evolve as a result of increased understanding of immunological mechanisms and molecular pathways in the pathogenesis of primary Sjögren syndrome. We provide an update of interest to ophthalmologists regarding pathogenesis, diagnosis, investigative procedures, and treatment options.
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Enfermedades Autoinmunes/diagnóstico , Autoinmunidad , Síndromes de Ojo Seco/diagnóstico , Aparato Lagrimal/patología , Síndrome de Sjögren/diagnóstico , Animales , Enfermedades Autoinmunes/inmunología , Biopsia , Síndromes de Ojo Seco/etiología , Síndromes de Ojo Seco/inmunología , Humanos , Síndrome de Sjögren/complicaciones , Síndrome de Sjögren/inmunologíaRESUMEN
Ménétriere´s disease is a rare disorder of the body and fundus of the stomach, characterized by a massive proliferation of the foveolar cells and subsequent excess mucous secretion. This results in hypoproteinemia due to loss of serum proteins across the gastric mucosa. The cause of Ménétriere´s disease is unknown, and due to the irreversible and premalignant character of the disorder, the patients affected have been subdued to gastrectomy as the only curable treatment. Epidermial growth factor (EGF) has been implicated in the pathogenesis, a finding that makes the disorder receptive to monoclonal antibody treatment against the EGF receptor. In this case report, we present a 41-year-old woman referred to our emergency department due to dizziness, nausea, and vomiting. A thorough medical investigation, combining clinical history, laboratory investigations, an upper endoscopy with full-thickness snare biopsies, and a CT scan confirmed Ménétriere´s disease, and she was successfully treated with the monoclonal antibody cetuximab.
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Cetuximab/administración & dosificación , Gastritis Hipertrófica/tratamiento farmacológico , Fármacos Gastrointestinales/administración & dosificación , Adulto , Esquema de Medicación , Femenino , Humanos , Infusiones Intravenosas , Uso Fuera de lo Indicado , Resultado del TratamientoRESUMEN
OBJECTIVES: Fatigue 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. METHODS: A 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. RESULTS: A 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. CONCLUSION: Most 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.
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BACKGROUND: Despite men being less prone to develop autoimmune diseases, male sex has been associated with a more severe disease course in several systemic autoimmune diseases. In the present study, we aimed to investigate differences in the clinical presentation of primary Sjögren's syndrome (pSS) between the sexes and establish whether male sex is associated with a more severe form of long-term pSS. METHODS: Our study population included 967 patients with pSS (899 females and 68 males) from Scandinavian clinical centers. The mean follow-up time (years) was 8.8 ± 7.6 for women and 8.5 ± 6.2 for men (ns). Clinical data including serological and hematological parameters and glandular and extraglandular manifestations were compared between men and women. RESULTS: Male patient serology was characterized by more frequent positivity for anti-Ro/SSA and anti-La/SSB (p = 0.02), and ANA (p = 0.02). Further, men with pSS were more frequently diagnosed with interstitial lung disease (p = 0.008), lymphadenopathy (p = 0.04) and lymphoma (p = 0.007). Conversely, concomitant hypothyroidism was more common among female patients (p = 0.009). CONCLUSIONS: We observe enhanced serological responses and higher frequencies of lymphoma-related extraglandular manifestations in men with pSS. Notably, lymphoma itself was also significantly more common in men. These observations may reflect an aggravated immune activation and a more severe pathophysiological state in male patients with pSS and indicate a personalized managing of the disease due to the influence of the sex of patients with pSS.
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Síndrome de Sjögren/fisiopatología , Autoanticuerpos/metabolismo , Biomarcadores/sangre , Comorbilidad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Síndrome de Sjögren/complicaciones , Síndrome de Sjögren/diagnósticoRESUMEN
Fatigue occurs frequently in patients with cancer, neurological diseases and chronic inflammatory diseases, but the biological mechanisms that lead to and regulate fatigue are largely unknown. When the innate immune system is activated, heat shock proteins (HSPs) are produced to protect cells. Some extracellular HSPs appear to recognize cellular targets in the brain, and we hypothesize that fatigue may be generated by specific HSPs signalling through neuronal or glial cells in the central nervous system. From a cohort of patients with primary Sjögren's syndrome, 20 patients with high and 20 patients with low fatigue were selected. Fatigue was evaluated with a fatigue visual analogue scale. Plasma concentrations of HSP32, HSP60, HSP72 and HSP90α were measured and analysed to determine if there were associations with the level of fatigue. Plasma concentrations of HSP90α were significantly higher in patients with high fatigue compared with those with low fatigue, and there was a tendency to higher concentrations of HSP72 in patients with high fatigue compared with patients with low fatigue. There were no differences in concentrations of HSP32 and HSP60 between the high- and low-fatigue groups. Thus, extracellular HSPs, particularly HSP90α, may signal fatigue in chronic inflammation. This supports the hypothesis that fatigue is generated by cellular defence mechanisms.