Interleukin-1 Inhibition and Fatigue in Primary Sjögren's Syndrome – A Double Blind, Randomised Clinical Trial

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 i

Heat-shock protein 90α in plasma reflects severity of fatigue in patients with Crohn’s disease

Heat-shock proteins (HSPs) are evolutionarily conserved proteins with important cellular homeostasis functions during harmful conditions, including inflammation. Some HSPs are secreted extracellularly and act on distant cells by downregulating inflammation and increasing cellular stress defence mechanisms. HSP90a has been postulated to signal fatigue in chronic inflammation. We investigated whether HSP90a is associated with fatigue in patients with Crohn’s disease. Fifty-three patients with newly diagnosed Crohn’s disease were included in a cross-sectional study. Data on demographics and disease distribution were obtained. Fatigue was measured by the fatigue visual analogue scale (fVAS). Disease activity was assessed by the Simple Endoscopic Score for Crohn’s disease and Harvey Bradshaw Index. C-reactive protein, faecal calprotectin and HSP90a were also measured. The median fVAS score was 52 mm, indicating significant fatigue. HSP90a scores correlated significantly with fVAS (r¼0.31, P¼0.03). In a multivariate regression model, HSP90a was the only significant contributor to fVAS scores (b¼0.31, P¼0.03). When patients were dichotomised into groups with high and low HSP90a concentrations, significantly higher fVAS scores were demonstrated in the group with high HSP90a (M¼62.4, confidence interval 53.0–71.8 vs. 43.3, 31.6–55.0; P¼0.01). Thus, HSP90a may contribute to fatigue generation and/or modulation in patients with Crohn’s disease.publishedVersio

The Effect of Biological Treatment on Fatigue in Inflammatory Bowel Disease: A Systematic Review and Meta-analysis

Background: Fatigue is a frequent complaint in patients with inflammatory bowel disease. Biological drugs have demonstrated beneficial effects on some extraintestinal manifestations, but the effect on fatigue is not clear. Objective: This study investigated the effects of biological and small molecule drugs approved for inflammatory bowel disease on fatigue. Methods: We performed a systematic review and meta-analysis of randomized, placebo-controlled trials reporting Federal Drug Agency (FDA)-approved biological and small molecule drugs for use in ulcerative colitis and Crohn’s disease in which measures of fatigue were recorded before and after treatment. Only induction studies were included. Maintenance studies were excluded. We searched Embase (Ovid), Medline (Ovid), PsycINFO (Ovid), Cinahl (EBSCOhost), Web of Science Core Collection, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov in May 2022. Risk of bias was analyzed using the Cochrane risk-of-bias tool. Standardized mean difference was used to measure the treatment effect. Results: A total of seven randomized controlled trials composed of 3835 patients were included in the meta-analysis. All of the studies included patients with moderately to severely active ulcerative colitis or Crohn’s disease. The studies used three different generic fatigue instruments: the Functional Assessment of Chronic Illness Therapy-Fatigue and the Short Form 36 Health Survey Vitality Subscale versions 1 and 2. Overall treatment with biological or small molecule agents showed a beneficial effect compared with placebo, with a standardized mean difference of 0.25 (95% confidence interval 0.15–0.34, p < 0.001). The effect was independent of type of drug or subtype of inflammatory bowel disease. Discussion: The risk of bias was considered to be low for all domains except for missing outcome data. Even though the included studies were of high methodological quality, the review is limited by the small number of studies included and that the available studies were not designed to evaluate fatigue specifically. Conclusion: Biological and small molecule drugs used in inflammatory bowel disease have a consistent, though small, beneficial effect on fatigue.publishedVersio

High mobility group box 1 and a network of other biomolecules influence fatigue in patients with Crohn’s disease

Background Fatigue is common in patients with chronic inflammatory and autoimmune diseases, often with a severe impact on the patient’s daily life. From a biological point of view, fatigue can be regarded as an element of the sickness behavior response, a coordinated set of responses induced by pathogens to enhance survival during an infection and immunological danger. The mechanisms are not fully understood but involve activation of the innate immune system, with pro-inflammatory cytokines, in particular interleukin (IL)-1β, acting on cerebral neurons. These mechanisms are also active during chronic inflammatory conditions. High mobility group box 1 (HMGB1) protein has interleukin-1 like properties and is a strong inducer of innate immune responses. Its role in generation of fatigue is not clarified. Emerging evidence indicates that also other biomolecules may influence sickness behavior. We aimed to elucidate how HMGB1 influences fatigue in patients with Crohn’s disease, and how the protein interacts with other candidate biomarkers of fatigue. Methods In 56 patients with newly diagnosed Crohn’s disease, fatigue was evaluated using three different fatigue instruments: the fatigue visual analog scale (fVAS), Fatigue Severity Scale (FSS), and the vitality subscale of Medical Outcomes Study Short-Form Health Survey (SF-36vs). The biochemical markers IL-1 receptor antagonist (RA), soluble IL-1 receptor type 2 (sIL-RII), heat shock protein 90 alpha (HSP90α), HMGB1, anti-fully reduced (fr)HMGB1 antibodies (abs), hemopexin (HPX), and pigment epithelium-derived factor (PEDF) were measured in plasma. Multivariable regression and principal component analyses (PCA) were applied. Results Multivariable regression analyses revealed significant contributions to fatigue severity for HMGB1 in the FSS model, HSP90α in the fVAS model and IL-1RA in the SF-36vs model. Depression and pain scores contributed to all three models. In PCA, two components described 53.3% of the variation. The “inflammation and cellular stress dimension” was dominated by IL-1RA, sIL-1RII, HSP90α, HPX, and PEDF scores, where the “HMGB1 dimension” was dominated by HMGB1, anti-frHMGB1 abs, and fVAS scores. Conclusion This study supports the hypothesis that HMGB1 and a network of other biomolecules influence fatigue severity in chronic inflammatory conditions. The well-known association with depression and pain is also acknowledged.publishedVersio

Interleukin-1-related activity and hypocretin-1 in cerebrospinal fluid contribute to fatigue in primary Sjögren’s syndrome

Background Fatigue is a common and sometimes debilitating phenomenon in primary Sjögren’s syndrome (pSS) and other chronic inflammatory diseases. We aimed to investigate how IL-1 β-related molecules and the neuropeptide hypocretin-1 (Hcrt1), a regulator of wakefulness, influence fatigue. Methods Hcrt1 was measured by radioimmunoassay (RIA) in cerebrospinal fluid (CSF) from 49 patients with pSS. Interleukin-1 receptor antagonist (IL-1Ra), IL-1 receptor type 2 (IL-1RII), IL-6, and S100B protein were measured by enzyme-linked immunosorbent assay (ELISA). Fatigue was rated by the fatigue visual analog scale (fVAS). Results Simple univariate regression and multiple regression analyses with fatigue as a dependent variable revealed that depression, pain, and the biochemical variable IL-1Ra had a significant association with fatigue. In PCA, two significant components were revealed. The first component (PC1) was dominated by variables related to IL-1β activity (IL-1Ra, IL-1RII, and S100B). PC2 showed a negative association between IL-6 and Hcrt1. fVAS was then introduced as an additional variable. This new model demonstrated that fatigue had a higher association with the IL-1β-related PC1 than to PC2. Additionally, a third component (PC3) became significant between low Hcrt1 concentrations and fVAS scores. Conclusions The main findings of this study indicate a functional network in which several IL-1β-related molecules in CSF influence fatigue in addition to the classical clinical factors of depression and pain. The neuropeptide Hcrt1 seems to participate in fatigue generation, but likely not through the IL-1 pathway.publishedVersio

Fatigue: a frequent and biologically based phenomenon in newly diagnosed celiac disease

Fatigue is increasingly recognized as a major complaint in patients with chronic inflammatory and autoimmune diseases. Although fatigue is assumed to represent a significant problem in celiac disease, existing knowledge is scarce, and opinions are conflicting. This study aimed to investigate the prevalence and severity of fatigue in patients with newly diagnosed celiac disease and compare it with healthy control subjects. Ninety patients with newly diagnosed celiac disease were compared with 90 age- and sex-matched healthy subjects. The primary endpoints were fatigue severity as measured by: the fatigue Visual Analog Scale (fVAS), the Fatigue Severity Scale (FSS), and the inverted Vitality subscale of the MOS36 (SF-36vs). Higher scores indicate more severe fatigue. Clinically relevant fatigue was determined using predefined cut-off values. Secondary endpoints were the associations between fatigue, and sex, age, depression, pain, and selected biochemical variables. The median (IQR) fVAS-scores were 43.0 (18.0–64.5) in patients, and 9.0 (2.0–16.0) in the control group (p < 0.001); and the FSS scores 3.8 (2.0–4.8) in patients, and 1.4 (1.0–1.9) in control subjects (p < 0.001). Inverted SF-36vs scores had a mean (SD) value of 58.8 (23.6) in patients, and 29.7 (14.3) in healthy subjects (p < 0.001). The presence of clinically relevant fatigue ranged from 41 to 50% in patients. Increased fatigue severity was associated with female sex, younger age, and elevated pain and depression scores, but not with levels of selected biochemical variables, including hemoglobin. Fatigue is a severe and frequent phenomenon in patients with untreated celiac disease.publishedVersio

A salmon peptide diet alleviates experimental colitis as compared with fish oil

Fish oil (FO) has been shown to have anti-inflammatory properties in animal models of inflammatory bowel disease, but how fish peptides (FP) influence intestinal inflammation has been less studied. Male Wistar rats, divided into five groups, were included in a 4-week dietary intervention study. Of the groups, four were exposed in the fourth week to 5 % dextran sulfate sodium (DSS) to induce colitis, while one group was unexposed. The diets were: (1) control, (2) control + DSS, (3) FO (5 %) + DSS, (4) FP (3·5 %) + DSS, (5) FO + FP + DSS. Following DSS intake, weight and disease activity index (DAI) were assessed, and histological combined score (HCS), selected colonic PG, cytokines, oxidative damage markers and mRNA levels were measured. FP reduced HCS, tended to lower DAI (P = 0·07) and reduced keratinocyte chemoattractant/growth-regulated oncogene levels, as compared with the FO diet. FP also reduced mRNA levels of Il-6 and Cxcl1, although not significantly. FO intake increased the DAI as compared with DSS alone. PGE3 levels increased after the FO diet, and even more following FO + FP intake. The FP diet seems to have a protective effect in DSS-induced colitis as compared with FO. A number of beneficial, but non-significant, changes also occurred after FP v. DSS. A combined FO + FP diet may influence PG synthesis, as PGE3 levels were higher after the combined diet than after FO alone

A salmon peptide diet alleviates experimental colitis as compared with fish oil

Fish oil (FO) has been shown to have anti-inflammatory properties in animal models of inflammatory bowel disease, but how fish peptides (FP) influence intestinal inflammation has been less studied. Male Wistar rats, divided into five groups, were included in a 4-week dietary intervention study. Of the groups, four were exposed in the fourth week to 5 % dextran sulfate sodium (DSS) to induce colitis, while one group was unexposed. The diets were: (1) control, (2) control + DSS, (3) FO (5 %) + DSS, (4) FP (3·5 %) + DSS, (5) FO + FP + DSS. Following DSS intake, weight and disease activity index (DAI) were assessed, and histological combined score (HCS), selected colonic PG, cytokines, oxidative damage markers and mRNA levels were measured. FP reduced HCS, tended to lower DAI (P = 0·07) and reduced keratinocyte chemoattractant/growth-regulated oncogene levels, as compared with the FO diet. FP also reduced mRNA levels of Il-6 and Cxcl1, although not significantly. FO intake increased the DAI as compared with DSS alone. PGE3 levels increased after the FO diet, and even more following FO + FP intake. The FP diet seems to have a protective effect in DSS-induced colitis as compared with FO. A number of beneficial, but non-significant, changes also occurred after FP v. DSS. A combined FO + FP diet may influence PG synthesis, as PGE3 levels were higher after the combined diet than after FO alone.publishedVersio

Genetic and clinical basis for two distinct subtypes of primary Sjögren's syndrome

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.publishedVersio

Complement C4 Copy Number Variation is Linked to SSA/Ro and SSB/La Autoantibodies in Systemic Inflammatory Autoimmune Diseases

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.publishedVersio