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Objectives: Systemic inflammatory autoimmune diseases (SIADs) such as systemic lupus erythematosus (SLE), primary Sjögren's syndrome (pSS) and idiopathic inflammatory myopathies (myositis) are complex conditions characterized by shared circulating autoantibodies and clinical manifestations, including skin rashes, among others. This study aimed at elucidating the genetics underlying these common features., Methods: We performed targeted DNA sequencing of coding and regulatory regions from ~1,900 immune-related genes in a large SIAD cohort of 2,292 well-characterized Scandinavian patients with SLE, pSS and myositis, as well as 1,252 controls. A gene-based functionally-weighted genetic score for aggregate testing of all genetic variants, including rare variants, was complemented by in-silico functional analyses and in-vitro reporter experiments., Results: Case-control association analysis detected known and potentially novel genetic loci in agreement with previous genetic and transcriptomics findings linked to the SIAD autoimmune background. Intriguingly, case-case comparisons between patient subgroups with and without specific autoantibodies revealed that the subgroups defined by ANA and anti-dsDNA antibodies have unique genetic profiles reflecting their heterogeneity. When focusing on clinical features, we overall showed that DUSP1 protective genetic variants lead to increased gene expression and potentially to anti-inflammatory effects on the SIAD-associated skin phenotype. This is consistent with recent genetic findings on eczema and with the previously reported downregulation of the MAPK signaling-related gene DUSP1 in other skin disorders., Conclusion: Together, this suggests common molecular mechanisms potentially underlying overlapping clinical manifestations shared among different disorders and informs clinical heterogeneity, which could be translated to improve disease diagnostic and treatment, also in more generalized disease frameworks., (This article is protected by copyright. All rights reserved.)

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., Competing Interests: Competing Interests C.J.L.* and A.D.F. have an active collaborative research agreement with Janssen. E.B. has an active research collaboration with Pfizer. T.M. is employed as medical solutions lead in rheumatology at UCB. R.H.S. is a consultant for Jansen Pharmaceuticals. S.J.B. provided consultancy services for Abbvie, BMS, Galapagos, Iqvia, J&J, Kiniksa, and Novartis in 2020–2021. L.R. provided consultancy services for AstraZeneca. B.M.W. has active collaborative research agreements with Astellas Bio and Pfizer, Inc. M.R. received grants from Amgen, AstraZeneca, Bristol Myers-Squibb, Novartis, and Servier for clinical trials in Sjögren’s Syndrome and SLE. All other authors have reported that they have no competing interests to report.

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., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objective: Complete genetic deficiency of the complement component C2 is a strong risk factor for monogenic systemic lupus erythematosus (SLE), but whether heterozygous C2 deficiency adds to the risk of SLE or primary Sjögren's syndrome (SS) has not been studied systematically. This study was undertaken to investigate potential associations of heterozygous C2 deficiency and C4 copy number variation with clinical manifestations in patients with SLE and patients with primary SS., Methods: The presence of the common 28-bp C2 deletion rs9332736 and C4 copy number variation was examined in Scandinavian patients who had received a diagnosis of SLE (n = 958) or primary SS (n = 911) and in 2,262 healthy controls through the use of DNA sequencing. The concentration of complement proteins in plasma and classical complement function were analyzed in a subgroup of SLE patients., Results: Heterozygous C2 deficiency-when present in combination with a low C4A copy number-substantially increased the risk of SLE (odds ratio [OR] 10.2 [95% confidence interval (95% CI) 3.5-37.0]) and the risk of primary SS (OR 13.0 [95% CI 4.5-48.4]) when compared to individuals with 2 C4A copies and normal C2. For patients heterozygous for rs9332736 with 1 C4A copy, the median age at diagnosis was 7 years earlier in patients with SLE and 12 years earlier in patients with primary SS when compared to patients with normal C2. Reduced C2 levels in plasma (P = 2 × 10 -9 ) and impaired function of the classical complement pathway (P = 0.03) were detected in SLE patients with heterozygous C2 deficiency. Finally, in a primary SS patient homozygous for C2 deficiency, we observed low levels of anti-Scl-70, which suggests a risk of developing systemic sclerosis or potential overlap between primary SS and other systemic autoimmune diseases., Conclusion: We demonstrate that a genetic pattern involving partial deficiencies of C2 and C4A in the classical complement pathway is a strong risk factor for SLE and for primary SS. Our results emphasize the central role of the complement system in the pathogenesis of both SLE and primary SS., (© 2022 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objective: Copy number variation of the C4 complement components, C4A and C4B, has been associated with systemic inflammatory autoimmune diseases. This study was undertaken to investigate whether C4 copy number variation is connected to the autoimmune repertoire in systemic lupus erythematosus (SLE), primary Sjögren's syndrome (SS), or myositis., Methods: Using targeted DNA sequencing, we determined the copy number and genetic variants of C4 in 2,290 well-characterized Scandinavian patients with SLE, primary SS, or myositis and 1,251 healthy controls., Results: A prominent relationship was observed between C4A copy number and the presence of SSA/SSB autoantibodies, which was shared between the 3 diseases. The strongest association was detected in patients with autoantibodies against both SSA and SSB and 0 C4A copies when compared to healthy controls (odds ratio [OR] 18.0 [95% confidence interval (95% CI) 10.2-33.3]), whereas a weaker association was seen in patients without SSA/SSB autoantibodies (OR 3.1 [95% CI 1.7-5.5]). The copy number of C4 correlated positively with C4 plasma levels. Further, a common loss-of-function variant in C4A leading to reduced plasma C4 was more prevalent in SLE patients with a low copy number of C4A. Functionally, we showed that absence of C4A reduced the individuals' capacity to deposit C4b on immune complexes., Conclusion: We show that a low C4A copy number is more strongly associated with the autoantibody repertoire than with the clinically defined disease entities. These findings may have implications for understanding the etiopathogenetic mechanisms of systemic inflammatory autoimmune diseases and for patient stratification when taking the genetic profile into account., (© 2022 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

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., (© 2022. The Author(s).)

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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 > mean controls +2SD controls (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 (p discovery =1.9x10 -8 , p replication =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., Competing Interests: 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., (Copyright © 2021 Imgenberg-Kreuz, Sandling, Norheim, Johnsen, Omdal, Syvänen, Svenungsson, Rönnblom, Eloranta and Nordmark.)

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., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Clinical presentation of primary Sjögren's syndrome (pSS) varies considerably. A shortage of evidence-based objective markers hinders efficient drug development and most clinical trials have failed to reach primary endpoints., Methods: We performed a multicentre study to identify patient subgroups based on clinical, immunological and genetic features. Targeted DNA sequencing of 1853 autoimmune-related loci was performed. After quality control, 918 patients with pSS, 1264 controls and 107 045 single nucleotide variants remained for analysis. Replication was performed in 177 patients with pSS and 7672 controls., Results: We found strong signals of association with pSS in the HLA region. Principal component analysis of clinical data distinguished two patient subgroups defined by the presence of SSA/SSB antibodies. We observed an unprecedented high risk of pSS for an association in the HLA-DQA1 locus of odds ratio 6.10 (95% CI: 4.93, 7.54, P=2.2×10-62) in the SSA/SSB-positive subgroup, while absent in the antibody negative group. Three independent signals within the MHC were observed. The two most significant variants in MHC class I and II respectively, identified patients with a higher risk of hypergammaglobulinaemia, leukopenia, anaemia, purpura, major salivary gland swelling and lymphadenopathy. Replication confirmed the association with both MHC class I and II signals confined to SSA/SSB antibody positive pSS., Conclusion: Two subgroups of patients with pSS with distinct clinical manifestations can be defined by the presence or absence of SSA/SSB antibodies and genetic markers in the HLA locus. These subgroups should be considered in clinical follow-up, drug development and trial outcomes, for the benefit of both subgroups., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

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., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

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.

Background: Heterogeneity is a major obstacle to developing effective treatments for patients with primary Sjögren's syndrome. We aimed to develop a robust method for stratification, exploiting heterogeneity in patient-reported symptoms, and to relate these differences to pathobiology and therapeutic response., Methods: We did hierarchical cluster analysis using five common symptoms associated with primary Sjögren's syndrome (pain, fatigue, dryness, anxiety, and depression), followed by multinomial logistic regression to identify subgroups in the UK Primary Sjögren's Syndrome Registry (UKPSSR). We assessed clinical and biological differences between these subgroups, including transcriptional differences in peripheral blood. Patients from two independent validation cohorts in Norway and France were used to confirm patient stratification. Data from two phase 3 clinical trials were similarly stratified to assess the differences between subgroups in treatment response to hydroxychloroquine and rituximab., Findings: In the UKPSSR cohort (n=608), we identified four subgroups: Low symptom burden (LSB), high symptom burden (HSB), dryness dominant with fatigue (DDF), and pain dominant with fatigue (PDF). Significant differences in peripheral blood lymphocyte counts, anti-SSA and anti-SSB antibody positivity, as well as serum IgG, κ-free light chain, β2-microglobulin, and CXCL13 concentrations were observed between these subgroups, along with differentially expressed transcriptomic modules in peripheral blood. Similar findings were observed in the independent validation cohorts (n=396). Reanalysis of trial data stratifying patients into these subgroups suggested a treatment effect with hydroxychloroquine in the HSB subgroup and with rituximab in the DDF subgroup compared with placebo., Interpretation: Stratification on the basis of patient-reported symptoms of patients with primary Sjögren's syndrome revealed distinct pathobiological endotypes with distinct responses to immunomodulatory treatments. Our data have important implications for clinical management, trial design, and therapeutic development. Similar stratification approaches might be useful for patients with other chronic immune-mediated diseases., Funding: UK Medical Research Council, British Sjogren's Syndrome Association, French Ministry of Health, Arthritis Research UK, Foundation for Research in Rheumatology. VIDEO ABSTRACT., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

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., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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.

Objective: Whether or not chronic fatigue is reflected in structural changes in the brain is a matter of debate. Primary SS (pSS) is characterized by dryness of the mouth and eyes, migrating muscle and joint pain and prominent fatigue. We aimed to investigate whether the severity of fatigue in pSS was associated with cerebral MRI findings., Methods: Fatigue was measured with the fatigue visual analog scale in 65 patients with pSS. Global grey matter (GM) and white matter volumes were estimated from magnetic resonance T1 images, and associations between fatigue and brain volumes were assessed in regression models. Voxel-based morphometric analyses of GM were performed to investigate possible associations between fatigue and GM volume changes in particular brain regions., Results: The fatigue scores in the patient group were spread across a wide range. Global volume analyses showed no significant effect of GM volumes and white matter volumes on fatigue. Voxel-wise analyses of GM did not identify any particular brain region associated with fatigue., Conclusion: Fatigue is a dominant phenomenon in pSS patients but is not reflected in structural abnormalities in the brain as visualized by conventional MRI. Our findings support the hypothesis of fatigue as a physiological phenomenon that does not lead to vascular changes or neuronal or glial death or damage.

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.

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 diseases», «inflammatory bowel disease*», «IBD», «crohn*», «colitis», «fatigue», «fatigue manage» and «fatigue treat». 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.

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., Competing Interests: Conflicts of Interest: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Objective: The aim of the study was to investigate the course of fatigue in a conventional inflammatory bowel disease treatment setting., Materials and Methods: Eighty-two patients with newly diagnosed ulcerative colitis were included in an observational cohort study and received conventional non-biological drug treatment for 3 months. Colonoscopy was performed at diagnosis and after 3 months, disease activity was assessed by Mayo score and measurements of serum C-reactive protein (CRP) and fecal calprotectin levels. Fatigue was evaluated using the fatigue visual analog scale (fVAS). Mood was assessed with the hospital anxiety and depression scale (HADS). Associations between fVAS scores and time; age; CRP, fecal calprotectin, hemoglobin, and ferritin levels; and Mayo scores, Mayo endoscopic scores, and HADS depression subscale (HADS-D) scores were explored., Results: Median fVAS scores decreased, as did Mayo scores and CRP and fecal calprotectin concentrations. HADS-D scores remained unchanged, whereas hemoglobin levels increased after 3 months. Increased fVAS scores were associated with higher ferritin, Mayo and HADS-D scores. There were no associations between fVAS scores and CRP, fecal calprotectin, or Mayo endoscopic scores. Colonic disease distribution did not influence fatigue significantly., Conclusions: Disease activity and fatigue improved after 3 months of conventional ulcerative colitis treatment. Over time, more severe fatigue was associated with more ulcerative colitis symptoms, but not with objective disease activity markers or colonic disease distribution. A clinical setting of standard treatment regimens and medical attention may alleviate fatigue in IBD patients.

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.

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., (© The Author(s) 2016.)

Background and Aims: The present study investigated the prevalence and severity of fatigue in patients with newly diagnosed and untreated ulcerative colitis (UC) and Crohn's disease (CD) and examined relevant disease variables that may influence the severity of fatigue., Methods: Eighty-one patients with inflammatory bowel disease (IBD) (60 with UC and 21 with CD) were assessed for fatigue using two fatigue instruments: the Fatigue Severity Scale (FSS) and a fatigue visual analogue scale (fVAS). Cut-off for fatigue was defined as ≥4 for FSS and ≥50 for fVAS. Results were compared with fatigue scores from age-and gender-matched healthy individuals. Disease activity was assessed by symptom scores using the Mayo score in UC patients and the Harvey-Bradshaw index for CD patients, as well as C-reactive protein (CRP) and faecal calprotectin., Results: The prevalence of fatigue based on FSS and fVAS was 47 and 42%, respectively, in UC and 62 and 48% in CD. In multivariate regression models, disease activity markers were not associated with fatigue, while a significant relationship was found with age and depression for both fatigue measures., Conclusions: Close to 50% of patients with IBD reported fatigue at the time of diagnosis. In newly diagnosed patients with active disease, the severity of fatigue was not associated with measures of disease activity., (Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To examine how fatigue may differ from ordinary tiredness in patients with primary Sjögren's syndrome (SS)., Methods: A purposive, heterogeneous sample of individuals with primary SS who had participated in a study that examined the effects of medication on fatigue was asked to participate in individual interviews. Patients were asked about their fatigue before and after the onset of illness, changes due to medications, and how fatigue was experienced in daily life. An inductive thematic analysis founded on a social constructionist perspective was performed., Results: Five women and 4 men ages 27-76 years participated. Two themes were identified. "A heavy, resistant body and ever-present lack of vitality" represented a profound, ever-present lack of energy along with an unfamiliar bodily heaviness quite different from the experience after alleviation by the drug and being healthy. The patients had scaled down their everyday life in different ways to manage this lack of energy. "Unpredictable and uncontrollable fluctuations in fatigue" expressed how the level of fatigue fluctuated from day to day and even within a particular day. The informants tried to portion out their energy without knowing exactly how much energy they would have at any time. On bad days, patients felt that their "batteries were flat," and they had to put their life on hold., Conclusion: Fatigue in primary SS clearly differs from ordinary tiredness. Patients describe it as an ever-present, fluctuating, and nonrelievable lack of vitality being beyond one's own control., (Copyright © 2014 by the American College of Rheumatology.)

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.

Background: Oxidative stress has been associated with many diseases and can among others be assessed as increased levels of advanced oxidation protein products (AOPP). Current AOPP methods suffer from poor reproducibility and accuracy due to precipitation of lipids in plasma samples. We therefore aimed to develop a robust method in which plasma lipids are solubilized., Methods: Plasma was diluted with citric acid, and AOPP measured as absorbance at 340 nm. The method was optimized and validated, and then used to analyze AOPP levels in plasma from healthy control subjects (HC), and in three patients groups; chronic kidney disease (CKD), primary Sjögren's Syndrome (pSS) and systemic lupus erythematosus (SLE)., Results: AOPP was detected with improved precision compared to established methods where lipids precipitate. Within- and between days variations were less than 1.4% and 2.2%, respectively. A control chart was established and the long-term reproducibility followed over six months., Conclusions: This improved method detects plasma AOPP with significantly better reproducibility and accuracy compared to previously reported methods. Solubilization of plasma lipids before spectrophotometric measure of AOPP levels is novel. It prevents both loss of lipoproteins due to precipitation and overestimation as a result of light scattering., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Objective: Oxidative stress is an imbalance between the production of reactive oxygen species (ROS) and physiological antioxidant defences. It occurs frequently in conditions characterized by immune activation and inflammation. Plasma levels of oxidized end products have never been evaluated in primary Sjøgren's syndrome (pSS). The aim of this study was to investigate the level of oxidative stress in primary Sjøgren's syndrome. As a secondary outcome, the association between oxidative stress and fatigue was explored., Methods: A cross-sectional study of 26 pSS patients was carried out. Oxidative stress was assessed using two markers of protein oxidation, protein carbonyl (PC) and advanced oxidation protein products (AOPP). Reference values for the oxidative stress markers were obtained from 15 healthy subjects., Results: AOPP and PC levels were increased in the pSS patients compared to the healthy subjects. This is a novel finding. There were no associations between oxidative stress measures and fatigue in the patients., Conclusions: Patients with pSS have increased levels of oxidative stress compared to healthy subjects.

Objectives: Fatigue is a major cause of disability in primary Sjögren's syndrome (pSS). Fatigue has similarities with sickness behaviour in animals; the latter mediated by pro-inflammatory cytokines, in particular interleukin (IL)-1, acting on neuronal brain cells. We hypothesised that IL-1 inhibition might improve fatigue in pSS patients; thus, we examined the effects and safety of an IL-1 receptor antagonist (anakinra) on fatigue., Methods: Twenty-six pSS patients participated in a double-blind, placebo-controlled parallel group study. Patients were randomised to receive either anakinra or a placebo for four weeks. Fatigue was evaluated by a fatigue visual analogue scale and the Fatigue Severity Scale. The primary outcome measure was a group-wise comparison of the fatigue scores at week 4, adjusted for baseline values. Secondary outcome measures included evaluation of laboratory results and safety. The proportion of patients in each group who experienced a 50% reduction in fatigue was regarded as a post-hoc outcome. All outcomes were measured at week 4., Results: There was no significant difference between the groups in fatigue scores at week 4 compared to baseline after treatment with anakinra. However, six out of 12 patients on anakinra versus one out of 13 patients on the placebo reported a 50% reduction in fatigue VAS (p = 0.03). There were two serious adverse events in each group., Conclusions: This randomised, double-blind, placebo-controlled trial of IL-1 blockade did not find a significant reduction in fatigue in pSS in its primary endpoint. A 50% reduction in fatigue was analysed post-hoc, and significantly more patients on the active drug than on placebo reached this endpoint. Although not supported by the primary endpoint, this may indicate that IL-1 inhibition influences fatigue in patients with pSS., Trial Registration: ClinicalTrials.gov NCT00683345.

This article reports a case of Goodpasture's syndrome and microangiopathic haemolytic anaemia developing in a patient with a 2-year history of systemic sclerosis. Goodpasture's syndrome usually presents with lung haemorrhage and acute renal failure, and kidney biopsy typically shows crescentic glomerulonephritis with linear immunoglobulin staining on the glomerular basement membrane. Treatment of choice for Goodpasture's syndrome is immunosuppressive therapy and plasma exchange, which has greatly improved morbidity and mortality. This unusual case highlights that seemingly unrelated autoimmune diseases may coexist in one patient, and thorough clinical examination combined with serology and histology may be necessary for correct diagnosis.

Chronic fatigue is a common, poorly understood and disabling phenomenon in many diseases. We aim to provide an overview of fatigue in chronic autoimmune and inflammatory disease. Fatigue measurement, prevalence and confounding factors such as depression, sleep disorders and pain are reviewed in the first half of the article. In the second half of the article, we describe explanatory models of fatigue and fatigue signalling, with an emphasis on cytokines and sickness behaviour, oxidative stress, mitochondrial dysfunction and the impact of certain genes on fatigue.