Tag: Fluge

Gastric dysmotility and gastrointestinal symptoms in myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Background: Gastrointestinal symptoms are common in ME/CFS, but there is a knowledge gap in the literature concerning gastrointestinal motility features and detailed symptom description.

Objective: In this study, we aimed to characterize gastric motility and gastric symptoms in response to a liquid meal.

Methods: We included 20 patients with ME/CFS with abdominal complaints who were recruited to a double-blind randomized placebo-controlled trial of Rituximab. The patients of this sub study were examined with an ultrasound drink test, and gastrointestinal symptoms were evaluated using the Rome III questionnaire and Irritable Bowel Syndrome Symptom Severity Scale (IBS-SSS) questionnaire.

Results: We found that patients commonly reported fullness/bloating (75%), abdominal pain (45%) and nausea (35%). Ultrasound measurements revealed lower proximal measurements of the stomach after a meal (p < 0.01) and larger fasting antral area (p = 0.019) compared to healthy controls. The patients had a stronger symptomatic response to the liquid meal compared to healthy controls regarding epigastric pain, discomfort and nausea (p < 0.05). Ninety percent of the patients reported bowel movement frequencies within the normal range but scored high on bowel habit dissatisfaction and life disruption.

Conclusion: The patients presented with fullness/bloating, nausea and epigastric pain, showed signs of impaired gastric accommodation and visceral hypersensitivity, showing that the gastrointestinal symptoms of ME/CFS patients are similar to functional dyspepsia.

Key summary:

  • Gastrointestinal symptoms are common in ME/CFS, but there is a knowledge gap in the literature concerning gastrointestinal motility features and detailed symptom description.

  • In this study, patients with ME/CFS had signs of impaired gastric accommodation after a liquid meal.

  • Out of 20 patients, 15 patients reported fullness/bloating, 9 reported abdominal pain, and 7 reported nausea. The patients showed signs of visceral hypersensitivity on a drink test.

  • Our findings suggest that patients with ME/CFS share many similarities with patients with Functional Dyspepsia. The findings were not typical for Irritable Bowel Syndrome.

Source: Steinsvik EK, Hausken T, Fluge Ø, Mella O, Gilja OH. Gastric dysmotility and gastrointestinal symptoms in myalgic encephalomyelitis/chronic fatigue syndrome. Scand J Gastroenterol. 2023 Feb 2:1-8. doi: 10.1080/00365521.2023.2173533. Epub ahead of print. PMID: 36728717. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0280942 (Full text)

Endothelial dysfunction in ME/CFS patients

Abstract:

Objective: A few earlier studies have found impaired endothelial function in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). The present study investigated large-vessel and small-vessel endothelial function in patients with ME/CFS.

Study design: The study was a substudy of the RituxME trial, a national, multicenter, randomized, double-blind, placebo-controlled phase III study on the effect of rituximab vs. placebo in ME/CFS patients in Norway. Flow-mediated dilation (FMD) and post-occlusive reactive hyperemia (PORH) was measured at baseline and after 18 months of treatment in 39 patients and compared with healthy controls. Other outcome measures were symptom severity and various physical function measures.

Results: ME/CFS patients had markedly reduced FMD compared to healthy controls at baseline (5.1% vs. 8.2%, p< 0.0001, adjusted for arterial diameter and sex), and significantly lower microvascular regulation measured by PORH than healthy controls (1354 PU vs. 2208 PU, p = 0.002). There were no differences between the treatment and placebo groups in symptom changes or vascular measures. As a group, the ME/CSF patients experienced a slight, but significant improvement in clinical symptoms after 18 months. PORH, but not FMD, was similarly improved (1360 to 1834 PU, p = 0.028). There was no significant correlation between FMD and PORH. There were non-significant tendencies towards associations between symptom severity/physical function measures and lower FMD and PORH, and a significant correlation between PORH and steps per 24 hours at baseline.

Conclusions: ME/CFS patients had reduced macro- and microvascular endothelial function, indicating that vascular homeostasis may play a role in the clinical presentation of this disease.

Source: Sandvik MK, Sørland K, Leirgul E, Rekeland IG, Stavland CS, Mella O, Fluge Ø. Endothelial dysfunction in ME/CFS patients. PLoS One. 2023 Feb 2;18(2):e0280942. doi: 10.1371/journal.pone.0280942. PMID: 36730360; PMCID: PMC9894436. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9894436/ (Full text)

Activity monitoring and patient-reported outcome measures in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients

Abstract:

Introduction: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease with no validated specific and sensitive biomarker, and no standard approved treatment. In this observational study with no intervention, participants used a Fitbit activity tracker. The aims were to explore natural symptom variation, feasibility of continuous activity monitoring, and to compare activity data with patient reported outcome measures (PROMs).

Materials and methods: In this pilot study, 27 patients with mild to severe ME/CFS, of mean age 42.3 years, used the Fitbit Charge 3 continuously for six months. Patients wore a SenseWear activity bracelet for 7 days at baseline, at 3 and 6 months. At baseline and follow-up they completed the Short Form 36 Health Survey (SF-36) and the DePaul Symptom Questionnaire-Short Form (DSQ-SF).

Results: The mean number of steps per day decreased with increasing ME/CFS severity; mild 5566, moderate 4991 and severe 1998. The day-by-day variation was mean 47% (range 25%-79%). Mean steps per day increased from the first to the second three-month period, 4341 vs 4781 steps, p = 0.022. The maximum differences in outcome measures between 4-week periods (highest vs lowest), were more evident in a group of eight patients with milder disease (baseline SF-36 PF > 50 or DSQ-SF < 55) as compared to 19 patients with higher symptom burden (SF-36 PF < 50 and DSQ-SF > 55), for SF-36 PF raw scores: 16.9 vs 3.4 points, and for steps per day: 958 versus 479 steps. The correlations between steps per day and self-reported SF-36 Physical function, SF-36 Social function, and DSQ-SF were significant. Fitbit recorded significantly higher number of steps than SenseWear. Resting heart rates were stable during six months.

Conclusion: Continuous activity registration with Fitbit Charge 3 trackers is feasible and useful in studies with ME/CFS patients to monitor steps and resting heart rate, in addition to self-reported outcome measures.

Source: Rekeland IG, Sørland K, Bruland O, Risa K, Alme K, Dahl O, Tronstad KJ, Mella O, Fluge Ø. Activity monitoring and patient-reported outcome measures in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients. PLoS One. 2022 Sep 19;17(9):e0274472. doi: 10.1371/journal.pone.0274472. PMID: 36121803. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0274472 (Full text)

No replication of previously reported association with genetic variants in the T cell receptor alpha (TRA) locus for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease with a variety of symptoms such as post-exertional malaise, fatigue, and pain, but where aetiology and pathogenesis are unknown. An increasing number of studies have implicated the involvement of the immune system in ME/CFS. Furthermore, a hereditary component is suggested by the reported increased risk for disease in relatives, and genetic association studies are being performed to identify potential risk variants.

We recently reported an association with the immunologically important human leucocyte antigen (HLA) genes HLA-C and HLA-DQB1 in ME/CFS. Furthermore, a genome-wide genetic association study in 42 ME/CFS patients reported significant association signals with two variants in the T cell receptor alpha (TRA) locus (P value <5 × 10-8). As the T cell receptors interact with the HLA molecules, we aimed to replicate the previously reported findings in the TRA locus using a large Norwegian ME/CFS cohort (409 cases and 810 controls) and data from the UK biobank (2105 cases and 4786 controls).

We investigated numerous SNPs in the TRA locus, including the two previously ME/CFS-associated variants, rs11157573 and rs17255510. No associations were observed in the Norwegian cohort, and there was no significant association with the two previously reported SNPs in any of the cohorts. However, other SNPs showed signs of association (P value <0.05) in the UK Biobank cohort and meta-analyses of Norwegian and UK biobank cohorts, but none survived correction for multiple testing. Hence, our research did not identify any reliable associations with variants in the TRA locus.

Source: Ueland M, Hajdarevic R, Mella O, Strand EB, Sosa DD, Saugstad OD, Fluge Ø, Lie BA, Viken MK. No replication of previously reported association with genetic variants in the T cell receptor alpha (TRA) locus for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Transl Psychiatry. 2022 Jul 11;12(1):277. doi: 10.1038/s41398-022-02046-1. PMID: 35821115. https://www.nature.com/articles/s41398-022-02046-1 (Full text)

Genetic association study in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) identifies several potential risk loci

Highlights:

• Largest ME/CFS genetic study to date.

• Three different cohorts totaling >2500 patients.

• First Immunochip study in ME/CFS.

• Possible implication of TPPP genetic region.

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease of unknown etiology and pathogenesis, which manifests in a variety of symptoms like post-exertional malaise, brain fog, fatigue and pain. Hereditability is suggested by an increased disease risk in relatives, however, genome-wide association studies in ME/CFS have been limited by small sample sizes and broad diagnostic criteria, therefore no established risk loci exist to date.

In this study, we have analyzed three ME/CFS cohorts: a Norwegian discovery cohort (N = 427), a Danish replication cohort (N = 460) and a replication dataset from the UK biobank (N = 2105). To the best of our knowledge, this is the first ME/CFS genome-wide association study of this magnitude incorporating 2532 patients for the genome-wide analyses and 460 patients for a targeted analysis. Even so, we did not find any ME/CFS risk loci displaying genome-wide significance.

In the Norwegian discovery cohort, the TPPP gene region showed the most significant association (rs115523291, P = 8.5 × 10−7), but we could not replicate the top SNP. However, several other SNPs in the TPPP gene identified in the Norwegian discovery cohort showed modest association signals in the self-reported UK biobank CFS cohort, which was also present in the combined analysis of the Norwegian and UK biobank cohorts, TPPP (rs139264145; P = 0.00004). Interestingly, TPPP is expressed in brain tissues, hence it will be interesting to see whether this association, with time, will be verified in even larger cohorts. Taken together our study, despite being the largest to date, could not establish any ME/CFS risk loci, but comprises data for future studies to accumulate the power needed to reach genome-wide significance.

Source: Hajdarevic R, Lande A, Mehlsen J, Rydland A, Sosa DD, Strand EB, Mella O, Pociot F, Fluge Ø, Lie BA, Viken MK. Genetic association study in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) identifies several potential risk loci. Brain Behav Immun. 2022 Mar 19:S0889-1591(22)00078-2. doi: 10.1016/j.bbi.2022.03.010. Epub ahead of print. PMID: 35318112. https://www.sciencedirect.com/science/article/pii/S0889159122000782 (Full study)

A map of metabolic phenotypes in patients with myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease usually presenting after infection. Emerging evidence supports that energy metabolism is affected in ME/CFS, but a unifying metabolic phenotype has not been firmly established. We performed global metabolomics, lipidomics, and hormone measurements, and we used exploratory data analyses to compare serum from 83 patients with ME/CFS and 35 healthy controls.

Some changes were common in the patient group, and these were compatible with effects of elevated energy strain and altered utilization of fatty acids and amino acids as catabolic fuels. In addition, a set of heterogeneous effects reflected specific changes in 3 subsets of patients, and 2 of these expressed characteristic contexts of deregulated energy metabolism. The biological relevance of these metabolic phenotypes (metabotypes) was supported by clinical data and independent blood analyses.

In summary, we report a map of common and context-dependent metabolic changes in ME/CFS, and some of them presented possible associations with clinical patient profiles. We suggest that elevated energy strain may result from exertion-triggered tissue hypoxia and lead to systemic metabolic adaptation and compensation. Through various mechanisms, such metabolic dysfunction represents a likely mediator of key symptoms in ME/CFS and possibly a target for supportive intervention.

Source: Hoel F, Hoel A, Pettersen IK, Rekeland IG, Risa K, Alme K, Sørland K, Fosså A, Lien K, Herder I, Thürmer HL, Gotaas ME, Schäfer C, Berge RK, Sommerfelt K, Marti HP, Dahl O, Mella O, Fluge Ø, Tronstad KJ. A map of metabolic phenotypes in patients with myalgic encephalomyelitis/chronic fatigue syndrome. JCI Insight. 2021 Aug 23;6(16):149217. doi: 10.1172/jci.insight.149217. PMID: 34423789. https://pubmed.ncbi.nlm.nih.gov/34423789/

Pathomechanisms and possible interventions in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease with unknown etiology, no validated specific and sensitive biomarker, and no standard approved effective treatment. ME/CFS has a profound impact on the quality of life of both patients and caregivers and entails high costs for society. The severity varies among patients who are able to participate to some extent in social life (mild), those who are mainly housebound (moderate) or bedridden (severe), and the very severely ill who are completely dependent on assistance for all daily living tasks, such as feeding or turning around in bed.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) often starts in previously healthy individuals after an infection, the most common being infectious mononucleosis (EBV). It is more frequent in women and influenced by genetic predisposition. The main symptoms are postexertional malaise (PEM), fatigue, orthostatic intolerance, cognitive disturbances, sleep problems with inadequate restitution after rest, sensory hypersensitivity with pain, and symptoms related to autonomic and immune dysfunction. The prevalence is 0.1% to 0.8%, and ME/CFS must be distinguished from general fatigue, which is much more common in the population.

Historically, there has been limited scientific interest in ME/CFS. However, research efforts have increased in the last decade. Although this has led to different hypotheses, a firmly established pathomechanism is lacking.

Herein, we suggest a framework model for the initiation and maintenance of ME/CFS consisting of three principal steps: (a) an initial aberrant immune response; (b) an effector system for symptom generation and maintenance; and (c) compensatory adaptations.

Source: Fluge Ø, Tronstad KJ, Mella O. Pathomechanisms and possible interventions in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). J Clin Invest. 2021 Jul 15;131(14):150377. doi: 10.1172/JCI150377. PMID: 34263741. https://www.jci.org/articles/view/150377 (Full article)

Reduced Endothelial Function in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-Results From Open-Label Cyclophosphamide Intervention Study

Abstract:

Introduction: Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) present with a range of symptoms including post-exertional malaise (PEM), orthostatic intolerance, and autonomic dysfunction. Dysfunction of the blood vessel endothelium could be an underlying biological mechanism, resulting in inability to fine-tune regulation of blood flow according to the metabolic demands of tissues. The objectives of the present study were to investigate endothelial function in ME/CFS patients compared to healthy individuals, and assess possible changes in endothelial function after intervention with IV cyclophosphamide.

Methods: This substudy to the open-label phase II trial “Cyclophosphamide in ME/CFS” included 40 patients with mild-moderate to severe ME/CFS according to Canadian consensus criteria, aged 18-65 years. Endothelial function was measured by Flow-mediated dilation (FMD) and Post-occlusive reactive hyperemia (PORH) at baseline and repeated after 12 months. Endothelial function at baseline was compared with two cohorts of healthy controls (N = 66 and N = 30) from previous studies. Changes in endothelial function after 12 months were assessed and correlated with clinical response to cyclophosphamide. Biological markers for endothelial function were measured in serum at baseline and compared with healthy controls (N = 30).

Results: Baseline FMD was significantly reduced in patients (median FMD 5.9%, range 0.5-13.1, n = 35) compared to healthy individuals (median FMD 7.7%, range 0.7-21, n = 66) (p = 0.005), as was PORH with patient score median 1,331 p.u. (range 343-4,334) vs. healthy individuals 1,886 p.u. (range 808-8,158) (p = 0.003). No significant associations were found between clinical response to cyclophosphamide intervention (reported in 55% of patients) and changes in FMD/PORH from baseline to 12 months. Serum levels of metabolites associated with endothelial dysfunction showed no significant differences between ME/CFS patients and healthy controls.

Conclusions: Patients with ME/CFS had reduced endothelial function affecting both large and small vessels compared to healthy controls. Changes in endothelial function did not follow clinical responses during follow-up after cyclophosphamide IV intervention.

Source: Sørland K, Sandvik MK, Rekeland IG, Ribu L, Småstuen MC, Mella O, Fluge Ø. Reduced Endothelial Function in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-Results From Open-Label Cyclophosphamide Intervention Study. Front Med (Lausanne). 2021 Mar 22;8:642710. doi: 10.3389/fmed.2021.642710. PMID: 33829023; PMCID: PMC8019750. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019750/ (Full text)

Intravenous Cyclophosphamide in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. An Open-Label Phase II Study

Abstract:

Introduction: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease with high symptom burden, of unknown etiology, with no established treatment. We observed patients with long-standing ME/CFS who got cancer, and who reported improvement of ME/CFS symptoms after chemotherapy including cyclophosphamide, forming the basis for this prospective trial.

Materials and methods: This open-label phase II trial included 40 patients with ME/CFS diagnosed by Canadian criteria. Treatment consisted of six intravenous infusions of cyclophosphamide, 600-700 mg/m2, given at four-week intervals with follow-up for 18 months, extended to 4 years. Response was defined by self-reported improvements in symptoms by Fatigue score, supported by Short Form 36 (SF-36) scores, physical activity measures and other instruments. Repeated measures of outcome variables were assessed by General linear models. Responses were correlated with specific Human Leukocyte Antigen (HLA) alleles.

Results: The overall response rate by Fatigue score was 55.0% (22 of 40 patients). Fatigue score and other outcome variables showed significant improvements compared to baseline. The SF-36 Physical Function score increased from mean 33.0 at baseline to 51.5 at 18 months (all patients), and from mean 35.0 to 69.5 among responders. Mean steps per 24 h increased from mean 3,199 at baseline to 4,347 at 18 months (all patients), and from 3,622 to 5,589 among responders. At extended follow-up to 4 years 68% (15 of 22 responders) were still in remission. Patients positive for HLA-DQB1*03:03 and/or HLA-C*07:04 (n = 12) had significantly higher response rate compared to patients negative for these alleles (n = 28), 83 vs. 43%, respectively. Nausea and constipation were common grade 1-2 adverse events. There were one suspected unexpected serious adverse reaction (aggravated POTS) and 11 serious adverse events in eight patients.

Conclusion: Intravenous cyclophosphamide treatment was feasible for ME/CFS patients and associated with an acceptable toxicity profile. More than half of the patients responded and with prolonged follow-up, a considerable proportion of patients reported ongoing remission. Without a placebo group, clinical response data must be interpreted with caution. We nevertheless believe a future randomized trial is warranted. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT02444091.

Copyright © 2020 Rekeland, Fosså, Lande, Ktoridou-Valen, Sørland, Holsen, Tronstad, Risa, Alme, Viken, Lie, Dahl, Mella and Fluge.

Source: Rekeland IG, Fosså A, Lande A, Ktoridou-Valen I, Sørland K, Holsen M, Tronstad KJ, Risa K, Alme K, Viken MK, Lie BA, Dahl O, Mella O, Fluge Ø. Intravenous Cyclophosphamide in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. An Open-Label Phase II Study. Front Med (Lausanne). 2020 Apr 29;7:162. doi: 10.3389/fmed.2020.00162. eCollection 2020. https://www.frontiersin.org/articles/10.3389/fmed.2020.00162/full (Full text)

Human Leukocyte Antigen alleles associated with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract:

The etiology and pathogenesis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) are unknown, and autoimmunity is one of many proposed underlying mechanisms. Human Leukocyte Antigen (HLA) associations are hallmarks of autoimmune disease, and have not been thoroughly investigated in a large ME/CFS patient cohort.

We performed high resolution HLA -A, -B, -C, -DRB1, -DQB1 and -DPB1 genotyping by next generation sequencing in 426 adult, Norwegian ME/CFS patients, diagnosed according to the Canadian Consensus Criteria. HLA associations were assessed by comparing to 4511 healthy and ethnically matched controls. Clinical information was collected through questionnaires completed by patients or relatives.

We discovered two independent HLA associations, tagged by the alleles HLA-C*07:04 (OR 2.1 [95% CI 1.4-3.1]) and HLA-DQB1*03:03 (OR 1.5 [95% CI 1.1-2.0]). These alleles were carried by 7.7% and 12.7% of ME/CFS patients, respectively. The proportion of individuals carrying one or both of these alleles was 19.2% in the patient group and 12.2% in the control group (OR 1.7 [95% CI 1.3-2.2], pnc = 0.00003). ME/CFS is a complex disease, potentially with a substantial heterogeneity. We report novel HLA associations pointing toward the involvement of the immune system in ME/CFS pathogenesis.

Source: Lande A, Fluge Ø, Strand EB, Flåm ST, Sosa DD, Mella O, Egeland T, Saugstad OD, Lie BA, Viken MK. Human Leukocyte Antigen alleles associated with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Sci Rep. 2020 Mar 24;10(1):5267. doi: 10.1038/s41598-020-62157-x. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093502/ (Full text)