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Gülen Arslan Lied,1 Anne Marita Milde,2 Kim Nylund,1,3 Maja Mujic,1 Tore Grimstad,1,4 Trygve Hausken,1,3 Odd Helge Gilja1,31Institute of Medicine, University of Bergen, Norway; 2Department of Biological and Medical Psychology, University of Bergen, Norway; 3National Centre for Ultrasound in Gastroenterology, Haukeland University Hospital, Bergen, Norway; 4Division of Gastroenterology, Stavanger University Hospital, Stavanger, NorwayAbstract: Experimentally induced colitis is used in animals to investigate pathophysiological mechanisms in inflammatory bowel disease. When following disease course and treatment effects, it should be possible to perform repeated measurements without harming the animals. This pilot study was performed to investigate whether transabdominal ultrasound using a clinical scanner could be used on rats to demonstrate bowel inflammation in an experimental colitis model. Colitis was induced by either 5% dextran sodium sulfate (DSS) in drinking water for 7 days or a single dose of intracolonic trinitrobenzene sulfonic acid (TNBS). Using ultrasonography, wall thickness of distal colon, cecum, and small bowel was recorded prior to and after DSS, and prior to, 2, and 7 days after TNBS. Blood (tumor necrosis factor [TNF]-alpha) and fecal samples (HemoFEC occult blood) were taken from each group on the same days as sonography. Thereafter, rats were killed and specimens for histology were taken. Wall thickness of distal colon, not of cecum or small bowel, increased significantly after 7 days of DSS, and wall thickness of both distal colon and small bowel increased on day 2 and 7 after TNBS. TNF-alpha increased after 7 days in the latter group only. There was a significant correlation between ultrasonographic measurements and combined histology score of distal colon in the DSS group. HemoFEC was also positive in accordance with sonographic and histological features. Increased intestinal wall thickness in response to both DSS- and TNBS-induced colitis was able to be visualized by transabdominal sonography. Moreover, ultrasound findings, occult blood sampling, and histological findings supported each other, indicating that ultrasonography can be used to assess inflammation in a rat experimental model.Keywords: transabdominal bowel sonography, inflammatory bowel disease, experimental colitis, dextran sodium sulfate, trinitrobenzene sulfonic acid

Objectives: The production of magnesium is a well known source of both aliphatic and aromatic chlorinated compounds, among others the polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs). The aim of this study was to establish whether increased concentrations of PCDDs and PCDFs could be found in the blood of workers in a magnesium plant.Methods: Blood plasma from 10 workers, employed at a magnesium plant for 10 to 36 years, and from a control group consisting of nine people who had no direct contact with the production were studied. Isomer specific analyses of PCDDs and PCDFs by means of high resolution gas chromatography/high resolution mass spectrometry (HRGC/HRMS) techniques were performed.Results: A significant increase was found in the concentrations of some of the congeners, mainly PCDFs, in the workers compared with the control group. Octachlorodibenzofuran (OCDF) is the congener that most strongly correlates with occupational exposure in the magnesium plant. Low concentrations of 1,2,3,4,6,8,9-heptachlorodibenzofuran were found in seven of the workers. Such isomers--that is, not 2,3,7,8-substituted--are rarely found in human samples.Conclusion: Due to the long biological half lives and lipid solubility of PCDDs and PCDFs, blood analyses may serve as an index of past cumulative occupational exposure and a means of assessing a person's exposure situation. [ABSTRACT FROM AUTHOR]

Long-COVID caused by SARS-CoV-2 infection has significant and increasing effects on human health worldwide. Although a unifying molecular or biological explanation is lacking, several pathophysiological mechanisms have been proposed. Involvement of mast cells-evolutionary old "multipurpose" innate immune cells-was reported recently in studies of acute infection and post-acute-COVID-19 syndrome. Mast cell activity has been suggested in long-COVID. In this case-control study, we compared data from 24 individuals with long-COVID (according to the NICE criteria) and 24 age- and sex-matched healthy individuals with a history of SARS-CoV-2 infection without developing sequelae. Serum levels of the proteases beta-tryptase (TPSB2) and carboxypeptidase (CPA3), which are mast cell specific, were measured using immunoassays. The values were compared between the two groups and correlated to measures of physical exertional intolerance. TPSB2 and CPA3 levels were median (range) 26.9 (2.0-1000) and 5.8 (1.5-14.0) ng/mL, respectively, in the long-COVID group. The corresponding values in the control group were 10.9 (2.0-1000) (p = 0.93) and 5.3 (3.5-12.9) ng/mL (p = 0.82). No significant correlations between TPSB2 or CPA3 levels and scores on the ten physical subscales of SF-36, 3.1-3.10 were revealed. We found no significant differences in the levels of mast cell activation markers TPSB2 and CPA3 between the long-COVID and control groups and no correlations with proxy markers of exercise intolerance. Mast cell activation does not appear to be part of long-term pathogenesis of long-COVID, at least in the majority of patients., (© 2024 The Author(s). Scandinavian Journal of Immunology published by John Wiley & Sons Ltd on behalf of The Scandinavian Foundation for Immunology.)

New treatment options beyond immunosuppression have emerged in recent years for patients with Crohn´s disease (CD), a chronic systemic condition affecting primarily the gut with great impact in the quality of life. The cause of CD is largely unknown, and a curative treatment is not yet available. In addition, despite the growing therapeutic armamentarium in recent years almost half of the patients don´t achieve a sustained response over time. Thus, new therapeutic strategies are urgently needed. In this review, we discuss the current state of promising new "out of the box" possibilities to control chronic inflammation beyond current pharmacological treatments, including: exclusive enteral nutrition, specific diets, cell therapies using T regs, hyperbaric oxygen, fecal microbiota transplantation, phage therapy, helminths, cannabis and vagal nerve stimulation. The exploration of original and novel therapeutic modalities is key to address their potential as main or complementary treatments in selected CD populations in order to increase efficacy, minimize side effects and improve quality of life of patients.

Introduction: Fatigue is a frequent complaint in patients with celiac disease. A gluten-free diet is the only established treatment for celiac disease, but how this diet influences fatigue is uncertain. We aimed to investigate fatigue prevalence, severity, and associated factors in patients with celiac disease, at diagnosis and at 1 year after commencing a gluten-free diet., Methods: 78 patients with serologically and histologically verified celiac disease, 78 age- and sex-matched healthy subjects. Primary endpoints were Fatigue Visual Analog Scale (fVAS), Fatigue Severity Scale (FSS), and inverted Vitality subscale of the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36vs). Clinically relevant fatigue was defined as: FSS score ≥ 4, fVAS score ≥ 50 mm, or inverted SF-36vs score ≥ 65. Higher scores represented more fatigue., Results: Fatigue was reduced after a 12-month gluten-free diet. Median scores changed from 3.8 (interquartile range [IQR]: 2.2 to 4.8) to 1.9 (IQR: 1.4 to 3.5) for FSS, from 44.5 (IQR: 18.8 to 66.0) to 15.5 (IQR: 7.8 to 43.3) for fVAS, and from 65 (IQR: 40 to 75) to 35 (IQR: 25 to 55) for inverted SF-36vs ( p < 0.001 for all). Fatigue prevalence also declined after treatment. However, scores were significantly higher in patients compared to control subjects. Higher fatigue scores were associated with depression and pain, but not with signs of disease activity or nutritional deficiency., Conclusion: At diagnosis, patients with celiac disease frequently had severe fatigue. Fatigue declined after a gluten-free diet, but it remained higher than that observed in healthy subjects., Clinical Trial Registration: ClinicalTrials.gov, Identifier NCT01551563., 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 © 2023 Skjellerudsveen, Omdal, Hetta, Kvaløy, Aabakken, Skoie and Grimstad.)

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., (© 2023. The Author(s).)

Background: Endoscopic and histological activity scores in ulcerative colitis (UC) are associated with clinical outcomes and have become important targets of clinical trials. However, these endpoints have been scarcely investigated in patients receiving only conventional treatment., Objective: We aimed to assess the deep and complete remission rates after 3 months of conventional treatment in patients with newly diagnosed UC with moderate to severe endoscopic activity. We also aimed to investigate whether selected clinical and biochemical variables at baseline were associated with complete remission status after 3 months., Design: This was a prospective cohort study., Methods: Newly diagnosed patients with active UC commencing 5-aminosalicylate, corticosteroid, and/or azathioprine treatment were consecutively included. Clinical, biochemical, endoscopic, and histological data were collected at baseline and after 3 months. Rates of clinical remission (Partial Mayo Score ⩽ 2), mucosal healing (Mayo Endoscopic Score ⩽ 1), and histologic healing (Nancy Index ⩽ 1) were determined. Deep remission was assessed as clinical remission plus mucosal healing and complete remission as deep remission plus histologic healing. Predictors of complete remission were identified by logistic regression., Results: A total of 180 patients were included in the study. Deep remission and complete remission occurred in 62.8% and 42.2% of patients, respectively. Thus, of patients in deep remission one-third had persistent histologic activity. Histologic activity in mucosally healed patients was associated with higher symptom scores and faecal calprotectin levels. Of baseline variables, less endoscopic distribution and disease activity showed strongest association with achieving complete remission, and limited distribution in combination with moderate activity gave highest odds for complete remission (odds ratio: 4.1, 95% confidence interval: 7.69-2.18)., Conclusion: In patients with mucosal healing, persistent histologic activity was a common finding and was associated with increased disease activity. Pancolitis and severe inflammatory activity at baseline were associated with lower complete remission rates., Competing Interests: T.B.G. has served as a speaker for Ferring Pharmaceuticals, Takeda, and advisory board member for Takeda, Janssen-Cilag and Tillotts Pharma. A.C. has served as a speaker and advisory board member for Tillotts Pharma. The other authors report no conflicts of interest., (© The Author(s), 2022.)

Background: Chronic fatigue is common in patients with psoriasis, and heat-shock proteins (HSPs) have been suggested to influence fatigue., Aim: To evaluate gene expression patterns of selected HSPs in patients with psoriasis with high vs. low fatigue., Methods: Fatigue was assessed using the fatigue Visual Analogue Scale, and disease activity by the Psoriasis Area and Severity Index. Peripheral blood transcriptional profiling was performed using RNA sequencing (RNA-seq) of HSP genes from 10 patients with high fatigue, and compared with 10 patients with low fatigue. HSPB11, HSPBAP1, HSPA14, HSPA9P1, HSP90B1 and HSP90AB1 contributed most to separation of the two groups in a principal components analysis. Four of these genes (HSPB11, HSPA14, HSP90B1 and HSP90AB1) were further investigated by real-time reverse transcription quantitative PCR (RT-qPCR) in 20 patients with high- and 20 patients with low-fatigue scores., Results: Both RNA-seq and RT-qPCR analyses revealed a tendency to higher expression levels of HSPB11 and lower expression of HSP90B1 in the high- vs. the low-fatigue group. Psoriasis disease activity had no influence on the expression levels of the studied HSP genes., Conclusion: Overall, the results suggest that some HSPs are involved in generation of fatigue in psoriasis, supporting the hypothesis that downregulatory innate immune responses influence fatigue., (© 2022 British Association of Dermatologists.)

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., (© 2022. The Author(s).)

Objective: The relationship between the disease activity of ulcerative colitis and fatigue is unclear. We investigated how reaching deep remission versus remaining in active disease influenced the severity of fatigue., Materials and Methods: We included 149 consecutive patients in a longitudinal study. Patients were re-examined after 3 months of conventional treatment and dichotomized into A: Active disease or B: Deep remission. The Partial Mayo Score (PMS) was recorded in all patients. Fatigue was rated using the fatigue visual analog scale (fVAS), Fatigue Severity Scale (FSS), and Short Form-36 Vitality Subscale (SF-36vs). A control group of 22 age and sex-matched healthy subjects were included as controls for patients reaching deep remission., Results: After 3 months there were no significant differences in fVAS, FSS and SF-36vs scores in patients with active disease compared to patients reaching deep remission, when adjusting for baseline fatigue scores. Patients in remission based on MES-UC scores had no significant reduction in fatigue scores, whereas patients in remission based on PMS had all three fatigue scores reduced. However, patients reaching deep remission still had higher fVAS and lower SF-36vs scores compared to healthy control subjects., Conclusions: After 3 months of conventional treatment there were no differences in fatigue severity in patients reaching deep remission compared with patients still having active disease. Fatigue was more pronounced in patients in deep remission than in healthy subjects, and was associated with subjective and not objective measures of disease activity. This indicates that other potent factors than inflammation influence fatigue in UC.

Objectives: To evaluate the psychometric properties of the Norwegian version of the multidimensional fatigue inventory (MFI-20) in patients with inflammatory bowel disease., Methods: Participants were recruited from nine hospitals in the southeastern and western parts of Norway. Clinical and sociodemographic data were collected, and participants completed the MFI-20, as well as the Fatigue Questionnaire (FQ). In addition to a confirmatory factor analysis, validity, reliability, test-retest and responsiveness were evaluated., Results: In total, 410 patients were included. The Norwegian MFI-20 had an acceptable model fit when compared to the original five-dimensional structure. A positive correlation was observed between the dimensions of MFI-20 and the FQ. MFI-20 scores increased according to subjective disease activity, but no differences were observed when using a calprotectin cut-off < or > =250 µg/g mg/kg. All MFI-20 dimensions except 'reduced motivation' in both ulcerative colitis (UC) and Crohn's disease (CD) patients had alpha Cronbach alpha values ≥70, and test-retest reliability revealed good to excellent values. Merely one dimension (Reduced activity) in UC patients reporting improvement did not reach the threshold for acceptable responsiveness according to Guyatt statistics., Conclusions: The Norwegian version of MFI-20 is valid, reliable and responsive. The instrument can safely be used in studies using fatigue as an endpoint.

Fatigue is common in all chronic inflammatory and autoimmune diseases. A conceptual model for understanding the biological basis of fatigue describes it as being a part of the sickness behaviour response generated by pro-inflammatory cytokines and other mediators. We hypothesised that the pro-inflammatory high mobility group box 1 (HMGB1) protein is a fatigue-inducing molecule and that auto-Abs against HMGB1 reduce fatigue. We measured Abs against disulphide (ds) HMGB1 and fully reduced (fr) HMGB1 in plasma from 57 patients with Crohn's disease. Fatigue was rated using the fatigue visual analogue scale (fVAS) and disease activity with faecal calprotectin, C-reactive protein and the Simple Endoscopic Score for Crohn's disease. Multivariable regression models identified anti-dsHMGB1 and anti-frHMGB1 Abs as the strongest contributing factors for fVAS scores ( B  = -29.10 ( P  = 0.01), R 2  = 0.17, and B  = -17.77 ( P  = 0.01), R 2  = 0.17, respectively). Results indicate that anti-HMGB1 auto-Abs alleviate fatigue possibly by down-regulating HMGB1-induced sickness behaviour.

Background : Pain and vitamin D deficiency are common in inflammatory bowel disease (IBD). Disease activity, fatigue, frequent relapses, prior surgery and psychological factors all seem to influence the experience of pain in IBD. Vitamin D deficiency has been associated with muscle and skeletal pain. This study aimed to determine whether there is an association between vitamin D deficiency and severity of pain in patients with IBD, and to investigate the influence of other socio-demographic and psychological variables on the experience of pain. Methods : Patients with IBD were recruited from nine hospitals in Norway in a multicenter cross-sectional study. The Brief Pain Inventory (BPI) questionnaire was used to measure pain. Disease activity was assessed using clinical disease activity indices, C-reactive protein (CRP) and fecal calprotectin. Regression models were fitted to explore a possible association between 25-hydroxyvitamin D and pain severity. Results : Of 407 patients included in the analyses, 229 (56%) had Crohn's disease (CD) and 178 (44%) had ulcerative colitis (UC). Vitamin D deficiency was present in half (203/407) of patients. Presence of pain was reported by 76% (309/407). More severe pain was associated with female gender and increased disease activity scores, but not with increased CRP or fecal calprotectin. In CD, patients without prior intra-abdominal surgery reported more severe pain. In multivariate analyses, there was no association between 25-hydroxyvitamin D and pain severity. Conclusions : In this study, no significant association between pain severity and vitamin D deficiency was revealed in patients with IBD., Competing Interests: Frigstad SO reports a research grant from Pharmacosmos AS, during the conduct of the study; personal fees from Tillotts Pharma, Pharmacosmos AS, Janssen-Cilag, Pfizer, Takeda, Intercept Pharma, and Abbvie, outside the submitted work. Høivik ML reports personal fees from MSD, Tillotts Pharma, Abbvie, Takeda and MEDA, outside the submitted work, and investigator initiated research grants, outside the submitted work. Jelsness-Jørgensen LP reports an unrestricted research grant from Tillotts Pharma, during the conduct of the study. The other authors state no conflicts of interest.

Background and Aim: Adalimumab is administered and dosed using a standardized treatment regimen. Although therapeutic drug monitoring (TDM) may help optimize treatment efficacy, the lower cut-off concentration of adalimumab needed to retain disease remission has not been established. This cross-sectional study of patients with Crohn's disease on stable medication aimed to determine a lower therapeutic drug concentration threshold of adalimumab associated with biochemical disease remission., Methods: C-reactive protein (CRP) and fecal calprotectin were used as established markers and albumin as an explorative marker of disease activity. Time since introduction, treatment interval, drug dosage, serum drug concentration and antidrug antibodies, disease duration, age, and sex were recorded., Results: The study included 101 patients who were divided into "active disease" and "remission" groups for inflammatory markers based on cut-off levels of 5 mg/L for CRP and 50 mg/kg for fecal calprotectin. Cut-off levels for albumin of 36.5 and 41.5 g/L were also added as further indicatives of remission. Receiver operating characteristic analysis found optimal thresholds for adalimumab associated with remission at 6.8-7.0 mg/L for the combination of CRP and fecal calprotectin and when combining CRP, fecal calprotectin, and albumin., Conclusions: In patients with Crohn's disease, serum adalimumab of at least 6.8 mg/L was associated with biochemical disease remission based on CRP and fecal calprotectin, supporting the use of TDM to ensure disease control. Albumin should be further tested in this setting., (© 2019 The Authors. JGH Open: An open access journal of gastroenterology and hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Fatigue is increasingly recognized as a significant problem in patients with chronic inflammatory and autoimmune diseases. In celiac disease, a chronic immune-mediated disease triggered by dietary gluten, conflicting opinions exist regarding both the size of the problem and the effect of a gluten-free diet (GFD) on fatigue. We reviewed the existing literature regarding fatigue in celiac disease. We conducted a systematic search in the Embase, Ovid Medline, and Cochrane databases using subject terms from controlled vocabularies. Articles were reviewed based on language, type of article, title, and abstract or full text. Eighteen articles were finally selected for review. Fatigue was significantly greater in patients with celiac disease compared to healthy control subjects. Fatigue prevalence ranged from 8 to 100%. Fatigue severity was assessed in six studies. The fatigue visual analogue scale was the most frequently used fatigue instrument with scores from 57 to 79 prior to starting a GFD and from 39 to 59 in patients on a GFD. Seven studies investigated the effect of a GFD on fatigue, including five studies that reported less fatigue while on the diet and two studies that showed no significant difference. This review concludes that fatigue is a substantial complaint in patients with celiac disease. A GFD seems to reduce fatigue, but existing data are limited.

Objective: The aim of the study was to investigate whether heat shock protein (HSP)90α plasma concentrations were associated with disease activity in patients with Crohn's disease., Materials and Methods: This cross-sectional study included 53 patients who were newly diagnosed with Crohn's disease. Demographic data and disease distribution were recorded, and disease activity was rated using the Simple Endoscopic Score for Crohn's Disease (SES-CD) and the Harvey Bradshaw Index (HBI). Faecal calprotectin and plasma concentrations of CRP and HSP90α were measured., Results: The median SES-CD was 7, and the median HSP90α level was 17.2 ng/mL. The HSP90α level was significantly correlated with SES-CD, CRP, and faecal calprotectin, but not with HBI. Linear regression analysis revealed that HSP90α was significantly associated with SES-CD (r 2 = 0.27, p < .001) and with CRP (r 2 = 0.18, p = .002). HSP90α concentrations were significantly higher in the 10 patients with the highest SES-CD scores compared to the 10 patients with the lowest SES-CD scores., Conclusions: Objective measures of disease activity and inflammation in Crohn's disease - SES-CD and CRP - were closely associated with HSP90α concentrations in plasma, suggesting that HSP90α may be a biomarker of Crohn's disease.

Aim: To investigate if vitamin D deficiency is associated with fatigue in patients with inflammatory bowel disease (IBD)., Methods: IBD patients were recruited from nine hospitals in the southeastern and western regions of Norway to participate in a multicenter cross-sectional study lasting from March 2013 to April 2014. Data were collected by interviews, from medical records and laboratory tests. The Fatigue Questionnaire (FQ) was used to measure fatigue. Linear and logistic regression models were applied to explore the possible association between vitamin D deficiency and total fatigue scores and chronic fatigue, respectively. The analyses were adjusted for age, gender, disease activity, depressive symptoms and sleep disturbance., Results: In total, 405 patients were included in the analyses, of which 227 (56%) had Crohn's disease (CD) and 178 (44%) had ulcerative colitis (UC). Vitamin D deficiency (< 50 nmol/L) was present in half (203/405) of the patients. Chronic fatigue was reported by 116 (29%) of all included patients with substantial fatigue reported by 194 (48%). Vitamin D levels were neither associated with total fatigue nor with chronic fatigue. Higher total fatigue scores and chronic fatigue were both associated with increased disease activity scores in patients with UC and CD, but not with increased CRP or fecal calprotectin. In UC patients, female gender was associated with fatigue in the univariate analysis, but no such difference was found when adjusted for elevated disease activity scores. Sleep disturbance and more depressive symptoms were associated with total fatigue scores in both UC and CD patients, but with chronic fatigue only in CD patients., Conclusion: In this study, no significant association between fatigue and vitamin D deficiency in IBD patients was revealed., Competing Interests: Conflict-of-interest statement: The authors declare no conflicts of interest.

Background: Low anti-tumor necrosis factor α (TNFα) serum concentrations may result in lack of treatment response in patients with inflammatory bowel disease. We determined the anti-TNFα drug concentrations in patients with inflammatory bowel disease and investigated whether or not subtherapeutic drug concentrations were associated with increased levels of disease activity., Methods: In a single-center cross-sectional study, we included patients with ulcerative colitis or Crohn's disease who were receiving infliximab or adalimumab maintenance therapy. Demographic data, disease activity symptom scores (Partial Mayo Score, Harvey Bradshaw Index), inflammatory markers [C-reactive protein (CRP), fecal calprotectin], antidrug antibodies and serum drug concentrations were recorded. Therapeutic drug concentrations were defined as 3-8 mg/liter for infliximab and 5-12 mg/liter for adalimumab., Results: Of 210 patients included, 137 (65.2%) had Crohn's disease. In the adalimumab group, subtherapeutic drug concentrations were measured in 16.7% of patients with ulcerative colitis and in 27.7% of patients with Crohn's disease. In the infliximab group, subtherapeutic drug concentrations were found in 23% (ulcerative colitis) and 30.3% (Crohn's disease) of patients. In Crohn's disease, subtherapeutic adalimumab concentrations were associated with higher fecal calprotectin and CRP concentrations compared with therapeutic concentrations. Subtherapeutic infliximab concentrations in patients with Crohn's disease were also associated with higher CRP concentrations compared with therapeutic concentrations., Conclusions: The prevalence of subtherapeutic drug levels ranged from 17% to 30%. In patients with Crohn's disease, subtherapeutic serum drug concentrations were associated with significantly higher disease activity with both anti-TNFα agents. These findings were not observed in patients with ulcerative colitis. Clinicaltrials.gov identifier [NCT02134054] ., Competing Interests: Conflict of interest statement: Arne Carlsen has served as speaker for Takeda AS and Tillotts Pharma AB. Knut Lundin has served as speaker for Takeda AS and MSD. Tore Grimstad has served as speaker for Ferring Pharmaceuticals, served as consultant for Takeda AS and Janssen, and has received unrestricted research grants from AbbVie AS and Tillotts Pharma AB. All other authors declare that there is no conflict of interests.

Chronic fatigue is a common phenomenon in inflammatory and autoimmune conditions, in cancer, and in neurodegenerative diseases. Although pain and psychological factors influence fatigue, there is an increasing understanding that there is a genetic basis, and that activation of the innate immune system is an essential generator of fatigue. Mast cells are important actors in innate immunity and serve specialized defense responses against parasites and other pathogens. They are also major effector cells in allergic reactions. Primary disorders causing constitutively hyperactivity of mast cells are called mastocytosis and are frequently due to a gain-of-function mutation of the KIT gene encoding the transmembrane tyrosine kinase receptor. It is a clinical experience that patients with mast cell disorders suffer from fatigue, but there is a lack of scientific literature on the phenomenon. We performed a controlled study of fatigue in mastocytosis patients and document a 54% prevalence of clinical significant fatigue.

Background: Pain has been associated with fatigue in many chronic diseases, but data are not available for inflammatory bowel disease (IBD). The aim of this study was to investigate whether fatigue is associated with pain in IBD after adjusting for the relevant covariates., Methods: Participants were recruited from nine hospitals in the south-eastern and western part of Norway. Socio-demographic variables were self-reported by patients. Disease activity was assessed by disease activity indices and faecal calprotectin. Patient-reported outcomes (PROs) were collected using the Fatigue Questionnaire (FQ), Brief Pain Inventory (BPI), Hospital Anxiety and Depression Scale (HADS) and Basic Nordic Sleep Questionnaire., Results: From a total of 452 invited patients, 414 (91.6%) provided written informed consent. After excluding any missing data, 408 total patients were included in the analyses (ulcerative colitis = 180 and Crohn's disease = 228). In the crude analysis, substantial and chronic fatigue were associated with increased pain intensity regardless of the diagnosis. However, when controlling for relevant covariates in the ANCOVA, the differences in pain intensity among patients with and without substantial or chronic fatigue were insignificant. The Cohen's d effect size was small to moderate (>0.20) in patients with chronic fatigue., Conclusions: Despite a tendency of elevated pain intensity scores among patients with fatigue, these differences were insignificant after controlling for the relevant covariates. However, based on Cohen's effect size, these differences may be of clinical importance in a subset of patients.

Objective: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) may be involved in the pathogenesis of inflammatory bowel disease. The aim was to investigate if TWEAK may reflect disease activity in inflammatory bowel disease., Materials and Methods: In this cohort study, 139 consecutive patients with newly diagnosed and previously untreated inflammatory bowel disease - 95 with ulcerative colitis (UC) and 44 with Crohn's disease (CD) - underwent colonoscopy. Disease activity was assessed by the Mayo score and the Mayo endoscopic score (MES) for UC, or the Simple Endoscopic Score (SES) for CD. Serum C-reactive protein (CRP) and fecal calprotectin were measured in IBD patients, as were plasma TWEAK levels in patients and 85 healthy subjects. Associations between TWEAK levels and disease activity markers were explored., Results: In the total IBD group, the median (interquartile range) TWEAK level was 430 pg/ml (109-6570), in UC 502 pg/ml (109-4547) and in CD patients 352 pg/ml (101-9179), respectively. Healthy subjects had a median (IQR) TWEAK of 307 pg/ml (63-3492). There were no significant differences in TWEAK levels between the total IBD group and healthy control subjects, nor between UC and CD, or between UC/CD and healthy subjects. Furthermore, we found no significant associations between Mayo scores, MES-UC, SES-CD, CRP, and fecal calprotectin with plasma TWEAK levels., Conclusions: Plasma TWEAK levels do not reflect disease activity or the grade of inflammation in patients with newly diagnosed inflammatory bowel disease. NCT01551563.

Introduction: The pathophysiology of chronic rhinosinusitis (CRS) is unclear. It has been discussed for decades whether gastro-oesophageal reflux (GOR) may be a contributing factor for some patients. The aim of the present study was to evaluate the level of GOR in an unselected group of patients with CRS using multichannel impedance-pH monitoring., Methods: Consecutive patients with CRS diagnosed using the EPOS2012 criteria, completed questionnaires on GOR symptoms and were offered 24-h multichannel intraluminal impedance (MII)-pH monitoring. The results were compared with a group of healthy controls., Results: Forty-six patients completed MII-pH-monitoring and were compared with 45 control subjects, with comparable age and gender distributions. The median number of reflux episodes in the patients was 56.5 compared with 33 in controls, while, the numbers of proximal reflux episodes was 27.5 versus 3, respectively. Thirty nine patients had abnormal pH-impedance recordings compared with five controls., Conclusion: The CRS patients had significantly higher incidences of gastro-oesophageal reflux compared with asymptomatic controls. The results of this study suggest that GOR may be a causative or contributing factor of CRS.

Background and Aim: Vitamin D deficiency is common in inflammatory bowel disease (IBD). The aims of the present study were to determine the prevalence of vitamin D deficiency and to identify clinical and epidemiological variables associated with vitamin D deficiency in an outpatient population with IBD., Methods: Participants were recruited from nine hospitals in the southeastern and western regions of Norway as part of an observational, multicentre study from March 2013 to April 2014. Clinical and epidemiological data were collected by interview and from medical records. All analyses of serum 25-hydroxyvitamin D (25-OH-D) were performed in the same laboratory., Results: In total, 49% (200/408) of the patients had a 25-OH-D concentration <50 nmol/L, including 53% (122/230) of the Crohn's disease (CD) patients and 44% (78/178) of the ulcerative colitis (UC) patients. In CD patients, disease activity, measured as the HBI, was inversely associated with vitamin D deficiency. No such association was observed with the Simple Clinical Colitis Activity Index (SCCAI) scores in UC, but in UC patients, vitamin D deficiency was associated with elevated faecal calprotectin >100 mg/kg. In patients with CD, there were significantly more relapses during the previous year in patients with vitamin D deficiency., Conclusions: Vitamin D deficiency was common, especially in CD, and was associated with increased disease activity, a relapsing disease course and higher inflammatory activity.

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.

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.

Background and Aims. No patient-reported outcome measures targeting pain have yet been validated for use in IBD patients. Consequently, the aim of this study was to test the psychometrical properties of the brief pain inventory (BPI) in an outpatient population with IBD. Methods. Participants were recruited from nine hospitals in the southeastern and western parts of Norway. Clinical and sociodemographic data were collected, and participants completed the BPI, as well as the Short-Form 36 (SF-36). Results. In total, 410 patients were included. The BPI displayed high correlations with the bodily pain dimension of the SF-36, as well as moderate correlations with disease activity indices. The BPI also displayed excellent internal consistency (Cronbach's alpha value of 0.91, regardless of diagnosis) and good to excellent test-retest values (intraclass correlation coefficient (ICC) 0.84-0.90 and Kappa values > .70). In UC, calculation of responsiveness revealed that only BPI interference in patients reporting improvement reached the threshold of 0.2. In CD, Cohen's d ranged from 0.26 to 0.68. Conclusions. The BPI may serve as an important supplement in patient-reported outcome measurement in IBD. There is need to confirm responsiveness in future studies. Moreover, responsiveness should ideally be investigated using changes in objective markers of inflammation.

Background: In the period 2000 – 2011, chronic hepatitis C virus infection (HCV infection) was primarily treated with a combination of pegylated interferon and ribavirin. New antiviral drugs, which are effective but very expensive, are in the process of replacing this regimen. We have investigated the results pegylated interferon and ribavirin have yielded in ordinary clinical practice and examined the part this treatment may play in the near future., Material and Method: We included in this retrospective study HCV-RNA-positive, treatment-naive patients at Stavanger University Hospital, Akershus University Hospital and Østfold Hospital who received at least one dose of pegylated interferon in combination with ribavirin in the period 2000 – 2011. The primary endpoint was sustained virologic response (SVR). Predictors for SVR were identified by means of logistic regression analysis., Results: Of 588 included patients, 69.6% (409/588) achieved SVR, 14.3% (84/588) suffered relapse and 16.1% (95/588) showed non-response. In a multivariate analysis, genotypes 2 or 3 and low age at treatment start were independent predictors of SVR. A total of 85.4% of patients aged ≤ 40 years with genotype 2 or 3 had SVR., Interpretation: We found good results for treatment of young patients with genotype 2 or 3 with pegylated interferon and ribavirin. Low age and viral genotype were predictors of sustained virologic response (SVR).

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.)

Background and Study Aims: Polyethylene glycol-based electrolyte solutions (PEG-ELS) and the combination of sodium picosulfate/magnesium citrate (SPMC) are commonly used bowel preparation agents. The aim of the present study was to compare the two agents with regard to cleansing efficacy and tolerance among individuals scheduled for outpatient colonoscopy., Materials and Methods: The 368 colonoscopy outpatients at three Norwegian hospitals were randomized to bowel lavage with either PEG-ELS or SPMC. Compliance and patient tolerance were evaluated using a patient questionnaire. Bowel cleansing was evaluated using the Ottawa Bowel Preparation Quality Scale (OBPS), a validated scoring system with scores between 0 (best) and 14., Results: There was no difference in the cleansing quality between the PEG-ELS and SPMC groups (median OBPS 5.0 in both groups). The group that received SPMC reported better overall patient tolerance than the PEG-ELS group (72.6 % vs 59.0 % reporting no or slight discomfort, P < 0.01). Compliance with the recommended total fluid intake (4 L) was better in the SPMC group than in the PEG-ELS group (94.2 % vs 81.2 % respectively, P < 0.01); moreover, the polyp detection rate was superior (34.3 % vs 23.3 %, P = 0.02)., Conclusion: PEG-ELS and SPMC are equally effective in cleansing efficacy, but SPMC was better tolerated by patients and resulted in superior patient compliance and polyp detection rate., Clinical Trial Registration: NCT01624454.

Background: This study examined whether fecal calprotectin can be used in daily practice as a marker to monitor patients with ulcerative colitis (UC) receiving infliximab maintenance therapy., Methods: This prospective multicenter study enrolled adult patients with UC in clinical remission under infliximab maintenance therapy. Fecal calprotectin levels were measured every 4 weeks. Sigmoidoscopies were performed at inclusion and at study end. Relapse was defined as a clinical need for change in treatment or an endoscopic Mayo subscore of ≥2 at week 52. Sustained deep remission was defined as a partial Mayo score <3 at all points and an endoscopic Mayo score 0 at week 52., Results: Full analysis was possible for 87 of 113 included patients with UC (77%). Of these patients, 30 (34.4%) were considered to be in sustained deep remission and 13 (14.9%) to have relapsed. Calprotectin levels in patients with sustained deep remission remained very low (median < 40 mg/kg at all time points). Patients who flared had significantly higher calprotectin levels (median > 300 mg/kg) already 3 months before the flare. Further receiver operator curve analysis suggested that a calprotectin level >300 mg/kg had a reasonable sensitivity (58.3%) and specificity (93.3%) to model flare. Two consecutive calprotectin measurements of >300 mg/kg with 1-month interval were identified as the best predictor of flare (61.5% sensitivity and 100% specificity)., Conclusions: Fecal calprotectin can be used in daily practice to monitor patients with UC receiving infliximab maintenance therapy. Two consecutive measurements >300 mg/kg is more specific than a single measurement for predicting relapse.

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.

Background: The fatty acid analogue tetradecylthioacetic acid (TTA) is a moderate pan-activator of peroxisome proliferator-activated receptors (PPARs), and has in previous studies showed potential as an antioxidant and anti-inflammatory agent, both through PPAR and non-PPAR mediated mechanisms., Aims: This study aimed to determine whether TTA could alleviate dextran sulfate sodium (DSS)-induced colitis in rats., Methods: Male Wistar rats were fed a control diet (control- and DSS-group) or a diet supplemented with 0.4 % TTA (TTA + DSS-group) for 30 days, and DSS was added to the drinking water the last 7 days. Ultrasound measurements were performed at day 29. At day 30, rats were sacrificed and the distal colon was removed for histological evaluation and measurement of cytokine levels, oxidative damage, and gene expression., Results: The disease activity index was not improved in the TTA + DSS-group compared to the DSS-group. However, ultrasound measurements showed a significantly reduced colonic wall thickening in the TTA + DSS-group. TNF-α, IL-1β, and IL-6 were reduced at the protein and mRNA level in the TTA + DSS-group. Moreover, TTA-treated rats demonstrated reduced colonic oxidative damage, while inducible nitric oxide synthase 2 mRNA expression was elevated in both the DSS- and TTA + DSS-groups. PPARγ signaling may be involved in the anti-inflammatory response to TTA, as Pparg mRNA expression was significantly upregulated in colon., Conclusions: This study demonstrated that the pan-PPAR agonist TTA reduced colonic oxidative damage and cytokine levels in a rat model of colitis, and its potential to ameliorate colitis should be further explored.

Objective: To evaluate the effects of krill oil (KO) on inflammation and redox status in dextran sulfate sodium (DSS)-induced colitis in rats., Materials and Methods: Thirty male Wistar rats were divided into three groups: Control, DSS, and DSS + KO 5% in a 4-week diet study. Colitis was induced by 5% DSS in the drinking water the last week of the experiment. Weight and disease activity index (DAI), colon length, histological combined score (HCS), colon levels of selected cytokines and prostaglandins, markers of protein oxidative damage, fatty acid profile, and expression of selected genes were measured., Results: Rats in the DSS group increased their DAI and HCS compared with healthy controls. The colon length was significantly preserved after KO diet. Tumor necrosis factor (TNF)-α and interleukin (IL)-1β were elevated in the DSS group compared with controls. Cytokines and HCS were nonsignificantly lower in the KO versus the DSS group. Prostaglandin (PG)E(3) increased significantly in the KO versus the other groups. Peroxisome proliferator-activated receptor (PPAR)-γ expression was nonsignificantly increased while PPAR-γ coactivator 1α (Pparg1α) expression increased significantly after KO. The levels of protein oxidation markers decreased significantly., Conclusions: KO showed protective potential against DSS colitis based on the preservation of colon length, reduction of oxidative markers and the consistent beneficial changes of HCS, cytokine, and (PG)E(3) levels, as well as PPAR-γ and Pparg1α expression compared with DSS alone. These findings indicate an anti-inflammatory and a protein antioxidant effect of KO.