Abstract:
Tag: fibromyalgia
Myalgic encephalomyelitis/chronic fatigue syndrome and fibromyalgia are indistinguishable by their cerebrospinal fluid proteomes
Abstract:
Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and fibromyalgia have overlapping neurologic symptoms particularly disabling fatigue. This has given rise to the question whether they are distinct central nervous system (CNS) entities or is one an extension of the other.
Material and methods: To investigate this, we used unbiased quantitative mass spectrometry-based proteomics to examine the most proximal fluid to the brain, cerebrospinal fluid (CSF). This was to ascertain if the proteome profile of one was the same or different from the other. We examined two separate groups of ME/CFS, one with (n = 15) and one without (n = 15) fibromyalgia.
Results: We quantified a total of 2083 proteins using immunoaffinity depletion, tandem mass tag isobaric labelling and offline two-dimensional liquid chromatography coupled to tandem mass spectrometry, including 1789 that were quantified in all the CSF samples. ANOVA analysis did not yield any proteins with an adjusted p value <.05.
Conclusion: This supports the notion that ME/CFS and fibromyalgia as currently defined are not distinct entities.
Key message: ME/CFS and fibromyalgia as currently defined are not distinct entities. Unbiased quantitative mass spectrometry-based proteomics can be used to discover cerebrospinal fluid proteins that are biomarkers for a condition such as we are studying.
Source: Schutzer SE, Liu T, Tsai CF, Petyuk VA, Schepmoes AA, Wang YT, Weitz KK, Bergquist J, Smith RD, Natelson BH. Myalgic encephalomyelitis/chronic fatigue syndrome and fibromyalgia are indistinguishable by their cerebrospinal fluid proteomes. Ann Med. 2023 Dec;55(1):2208372. doi: 10.1080/07853890.2023.2208372. Epub 2023 Sep 18. PMID: 37722890. https://www.tandfonline.com/doi/full/10.1080/07853890.2023.2208372 (Full text)
Increased gut permeability and bacterial translocation are associated with fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome: implications for disease-related biomarker discovery
Abstract:
Background: There is growing evidence of the significance of gastrointestinal complaints in the impairment of the intestinal mucosal barrier function and inflammation in fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome. However, data on intestinal permeability and gut barrier dysfunction in FM and ME/CFS are still limited with conflicting results. This study aimed to assess circulating biomarkers potentially related to intestinal barrier dysfunction and bacterial translocation and their association with self-reported symptoms in these conditions.
Methods: A pilot multicentre, cross-sectional cohort study with consecutive enrolment of 22 patients with FM, 30 with ME/CFS, and 26 matched healthy controls. Plasma levels of anti-beta-lactoglobulin antibodies (IgG anti-beta-LGB), zonulin-1 (ZO-1), LPS, sCD14, and IL-1β) were assayed using ELISA. Demographic and clinical characteristics of the participants were recorded using validated self-reported outcome measures. The diagnostic accuracy of each biomarker was assessed using the ROC curve analysis.
Results: FM patients had significantly higher levels of anti-β-LGB, ZO-1, LPS, and sCD14 than healthy controls (all P < 0.0001). In ME/CFS patients, levels of anti-β-LGB, ZO-1, LPS, and sCD14 were significantly higher than controls, but lower than in FM (all P < 0.01), while there was no significant difference in IL-1β level. In the FM and ME/CFS cohorts, both anti-β-LGB and ZO-1 correlated significantly with LPS and sCD14 (P < 0.001 for both). In the FM group, both anti-beta-LGB and ZO-1 were correlated significantly with physical and mental health components on the SF-36 scale (P < 0.05); whereas IL-1beta negatively correlated with the COMPASS-31 score (P < 0.05). In the ME/CFS cohort, ZO-1 was positively correlated with the COMPASS-31 score (P < 0.05). The ROC curve analysis indicated a strong ability of anti-β-LGB, ZO-1, LPS, and sCD14 to predictively distinguish between FM and ME/CFS from healthy controls (P < 0.0001).
Conclusions: Biomarkers of intestinal barrier function and inflammation were associated with autonomic dysfunction assessed by COMPASS-31 scores in FM and ME/CFS respectively. Anti-β-LGB antibodies, ZO-1, LPS, and sCD14 may be putative predictors of intestinal barrier dysfunction in these cohorts. Further studies are needed to assess whether these findings are causal and can therefore be applied in clinical practice.
Source: Franz Martin, Manuel Blanco Suárez2 Paola Zambrano, Óscar Cáceres Calle, Miriam Almirall, Jose Alegre-Martín, Beatriz Lobo, Ana María Gonzalez-Castro, Javier Santos, Joan Carles Domingo, Joanna Jurek, Jesús Castro-Marrero. Increased gut permeability and bacterial translocation are associated with fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome: implications for disease-related biomarker discovery. Front. Immunol., Sec. Mucosal Immunity, Volume 14 – 2023 | doi: 10.3389/fimmu.2023.1253121 https://www.frontiersin.org/articles/10.3389/fimmu.2023.1253121/abstract
DNA methylation signatures of functional somatic syndromes: Systematic review
Abstract:
Objective: Functional somatic syndromes (FSS) are highly prevalent across all levels of healthcare. The fact that they are characterised by medically unexplained symptoms, such as fatigue and pain, raises the important question of their underlying pathophysiology. Psychosocial stress represents a significant factor in the development of FSS and can induce long-term modifications at the epigenetic level. The aim of this review was to systematically review, for the first time, whether individuals with FSS are characterised by specific alterations in DNA methylation.
Methods: MEDLINE and PsycINFO were searched from the first available date until September 2022. The inclusion criteria were: 1) adults fulfilling research diagnostic criteria for chronic fatigue syndrome, fibromyalgia syndrome, and/or irritable bowel syndrome, 2) healthy control group, and 3) candidate-gene or genome-wide study of DNA methylation.
Results: Sixteen studies (N = 957) were included. In candidate-gene studies, specific sites within NR3C1 were identified, which were hypomethylated in individuals with chronic fatigue syndrome compared to healthy controls. In genome-wide studies in chronic fatigue syndrome, a hypomethylated site located to LY86 and hypermethylated sites within HLA-DQB1 were found. In genome-wide studies in fibromyalgia syndrome, differential methylation in sites related to HDAC4 , TMEM44 , KCNQ1 , SLC17A9 , PRKG1 , ALPK3 , TFAP2A , and LY6G5C was found.
Conclusions: Individuals with chronic fatigue syndrome and fibromyalgia syndrome appear to be characterised by altered DNA methylation of genes regulating cellular signalling and immune functioning. In chronic fatigue syndrome, there is preliminary evidence for these to be implicated in key pathophysiological alterations, such as hypocortisolism and low-grade inflammation, and to contribute to the debilitating symptoms these individuals experience.
Preregistration PROSPERO identifier: CRD42022364720.
Source: Fischer S, Kleinstäuber M, Fiori LM, Turecki G, Wagner J, von Känel R. DNA methylation signatures of functional somatic syndromes: Systematic review. Psychosom Med. 2023 Aug 21. doi: 10.1097/PSY.0000000000001237. Epub ahead of print. PMID: 37531610. https://pubmed.ncbi.nlm.nih.gov/37531610/
In severe first episode major depressive disorder, psychosomatic, chronic fatigue syndrome, and fibromyalgia symptoms are driven by immune activation and increased immune-associated neurotoxicity.
Abstract:
Background: Major depressive disorder (MDD) is accompanied by activated neuro-immune pathways, increased physiosomatic and chronic fatigue-fibromyalgia (FF) symptoms. The most severe MDD phenotype, namely major dysmood disorder (MDMD), is associated with adverse childhood experiences (ACEs) and negative life events (NLEs) which induce cytokines/chemokines/growth factors.
Aims: To delineate the impact of ACE+NLEs on physiosomatic and FF symptoms in first episode (FE)-MDMD, and examine whether these effects are mediated by immune profiles.
Methods: ACEs, NLEs, physiosomatic and FF symptoms, and 48 cytokines/chemokines/growth factors were measured in 64 FE-MDMD patients and 32 normal controls.
Results: Physiosomatic, FF and gastro-intestinal symptoms belong to the same factor as depression, anxiety, melancholia, and insomnia. The first factor extracted from these seven domains is labeled the physio-affective phenome of depression. A part (59.0%) of the variance in physiosomatic symptoms is explained by the independent effects of interleukin (IL)-16 and IL-8 (positively), CCL3 and IL-1 receptor antagonist (inversely correlated). A part (46.5%) of the variance in physiosomatic (59.0%) symptoms is explained by the independent effects of interleukin (IL)-16, TNF-related apoptosis-inducing ligand (TRAIL) (positively) and combined activities of negative immunoregulatory cytokines (inversely associated).
Partial Least Squares analysis shows that ACE+NLEs exert a substantial influence on the physio-affective phenome which are partly mediated by an immune network composed of interleukin-16, CCL27, TRAIL, macrophage-colony stimulating factor, and stem cell growth factor.
Conclusions: The physiosomatic and FF symptoms of FE-MDMD are partly caused by immuneassociated neurotoxicity due to Th-1 polarization, T helper-1, and M1 macrophage activation and relative lowered compensatory immunoregulatory protection.
Source: Michael Maes, Abbas F Almulla, Bo Zhou, Ali Abbas Abo Algon, Pimpayao Sodsai. In severe first episode major depressive disorder, psychosomatic, chronic fatigue syndrome, and fibromyalgia symptoms are driven by immune activation and increased immune-associated neurotoxicity. ResearchGate [Preprint] https://www.researchgate.net/publication/372940821_In_severe_first_episode_major_depressive_disorder_psychosomatic_chronic_fatigue_syndrome_and_fibromyalgia_symptoms_are_driven_by_immune_activation_and_increased_immune-associated_neurotoxicity (Full text)
Tryptophan catabolites, inflammation, and insulin resistance as determinants of chronic fatigue syndrome and affective symptoms in long COVID
Abstract:
Critical COVID-19 disease is accompanied by depletion of plasma tryptophan (TRY) and increases in indoleamine-dioxygenase (IDO)-stimulated production of neuroactive tryptophan catabolites (TRYCATs), including kynurenine (KYN). The TRYCAT pathway has not been studied extensively in association with the physiosomatic and affective symptoms of Long COVID.
In the present study, we measured serum TRY, TRYCATs, insulin resistance (using the Homeostatic Model Assessment Index 2-insulin resistance, HOMA2-IR), C-reactive protein (CRP), physiosomatic, depression, and anxiety symptoms in 90 Long COVID patients, 3–10 months after remission of acute infection.
We were able to construct an endophenotypic class of severe Long COVID (22% of the patients) with very low TRY and oxygen saturation (SpO2, during acute infection), increased kynurenine, KYN/TRY ratio, CRP, and very high ratings on all symptom domains. One factor could be extracted from physiosomatic symptoms (including chronic fatigue-fibromyalgia), depression, and anxiety symptoms, indicating that all domains are manifestations of the common physio-affective phenome.
Three Long COVID biomarkers (CRP, KYN/TRY, and IR) explained around 40% of the variance in the physio-affective phenome. The latter and the KYN/TRY ratio were significantly predicted by peak body temperature (PBT) and lowered SpO2 during acute infection. One validated latent vector could be extracted from the three symptom domains and a composite based on CRP, KYN/TRY, and IR (Long COVID), and PBT and SpO2 (acute COVID-19).
In conclusion, the physio-affective phenome of Long COVID is a manifestation of inflammatory responses during acute and Long COVID, and lowered plasma tryptophan and increased kynurenine may contribute to these effects.
Source: Al-Hakeim HK, Khairi Abed A, Rouf Moustafa S, Almulla AF, Maes M. Tryptophan catabolites, inflammation, and insulin resistance as determinants of chronic fatigue syndrome and affective symptoms in long COVID. Front Mol Neurosci. 2023 Jun 2;16:1194769. doi: 10.3389/fnmol.2023.1194769. PMID: 37333619; PMCID: PMC10272345. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10272345/ (Full text)
Evidence of neuroinflammation in fibromyalgia syndrome: a [18F]DPA-714 positron emission tomography study
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Inflammation-induced pain and fatigue in fibromyalgia and ME/CFS and role of variant connective tissue
Abstract:
Background: Fibromyalgia and ME/CFS are multifaceted conditions with overlapping symptoms(1); the pathophysiological mechanisms are under debate. It remains unclear whether dysregulated inflammation, induced either by an exogenous stimulus (eg a virus or other stressor), or autoimmunity, is of prime importance [2].
Objectives: 1. To determine in a novel human model the effects of an in vivo inflammatory challenge in the induction of pain and fatigue in fibromyalgia and ME/CFS compared to controls. 2. Explore potential mediators and moderators involved.
Methods: Data were available for 48 patients with confirmed diagnoses of Fibromyalgia and/ or ME/CFS and 22 matched controls, who had undergone a placebo controlled inflammatory challenge (typhoid vaccination) as part of ISRCTN78820481. Participants underwent full research diagnostic evaluation including a hypermobility assessment. Subjective pain and fatigue were assessed after saline injection and typhoid vaccination (VAS). Linear regression models were used to explore predictors, with adjustment for potential confounders (age/gender) and baseline levels as appropriate.
Mediation analyses (looking for mechanistic effects) were conducted according to the method of Hayes (3) and mediation considered significant if bootstrapped confidence intervals of the estimated indirect effect did not cross zero. In these mediation analyses predictor variable was group membership (patient or control), outcome variable was change in 1) pain and 2) fatigue induced by challenge and mediators/moderators included change in IL-6 induced by inflammatory challenge and hypermobility features.
Results: Being a patient rather than control significantly predicted inflammation-induced fatigue (B=14.89 (95%CI 3.29-26.50), t=2.56, p=0.013) and pain (B=12.88 (95%CI 0.65-25.10), t=2.11, p=0.039) after adjusting for levels induced by placebo.
Induced pain was independently predicted by level of IL-6 induced by inflammatory challenge (B=23.44 (95%CI 5.15-41.72),t=2.57, p=0.013) as was induced fatigue (B=10.63 (95%CI 2.84-18.41), t=2.73, p=0.008) Mediated moderation analyses suggested the link to induced pain and fatigue through induced inflammation was associated with hypermobility features (Index of mediated moderation 11.02 (95%CI 1.45-22.73) and 6.20 (95%CI 0.07-13.64) respectively))
Conclusion: To our knowledge this is the first human study to evaluate directly the effect of an exogenous inflammatory challenge (typhoid vaccination) in a combined group of Fibromyalgia and ME/CFS patients. Il-6 was shown to be a critical mediator. This work strongly supports the hypothesis that inflammation is key to the pathophysiology of ME/CFS. We are evaluating associated CNS inflammation in the model, as well as other associations, such as autonomic dysfunction and hypermobility. Further understanding the mediators involved in the condition should in future open the way to testing targeted anti-inflammatory therapy.
Source: Eccles J, Amato M, Themelis K, et alOP0194 INFLAMMATION-INDUCED PAIN AND FATIGUE IN FIBROMYALGIA AND ME/CFS AND ROLE OF VARIANT CONNECTIVE TISSUEAnnals of the Rheumatic Diseases 2023;82:129. https://ard.bmj.com/content/82/Suppl_1/129.2 (Full text)
Altered Lipid, Energy Metabolism and Oxidative Stress Are Common Features in a Range of Chronic Conditions
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Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), Gulf War Syndrome (GWS) and Fibromyalgia are chronic illnesses that, despite their prevalence in society, are still of unknown aetiology. All three conditions present similar clinical symptoms and are difficult to diagnose due to a lack of appropriate biomarkers. Currently, diagnosis consists of satisfying clinical criteria and eliminating other conditions, a lengthy and often costly process for patients. The discovery of biomarkers would significantly speed up patient diagnosis and allow the development of pharmacological therapies that target the underlying metabolic causes of these diseases.
Metabolomics is an emerging research area used to characterise the metabolites present within biological specimens. Developments within this field now allow the analysis of thousands of metabolites within different samples and model systems, and have the potential to aid in unravelling the metabolic phenotypes that underpin complex metabolic diseases. ME/CFS, GWS and Fibromyalgia are three conditions that could benefit from a plasma/tissue metabolomics analysis, allowing a greater understanding of their aetiology and identify common pathways. An analysis of the literature in these conditions reveals alterations within pathways associated with energy and lipid metabolism with alterations in key metabolites associated with elevated oxidative stress. Understanding what might drive the elevated oxidative stress within all three illnesses will not only be important in future research but could also be a potential therapeutic target for antioxidant medications which could be implemented to reduce the symptom burden in these illnesses.
Source: MORTEN, Karl Jonathan and Davis, Leah and Lodge, Tiffany A. and Strong, James and Espejo-Oltra, José Andrés and Zalewski, Pawel and Pretorius, Etheresia, Altered Lipid, Energy Metabolism and Oxidative Stress Are Common Features in a Range of Chronic Conditions. Available at SSRN: https://ssrn.com/abstract=4455366 or http://dx.doi.org/10.2139/ssrn.4455366 (Full text available as PDF file)
Identifying Demographic Trends in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients Presenting with Fibromyalgia as a Comorbidity in the Nationwide Inpatient Sample Database
Abstract
This retrospective observational study investigates the demographic differences between Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients with and without Fibromyalgia as a comorbidity using the Nationwide Inpatient Sample database.
Results reveal significant differences in demographics, including a higher proportion of females and a younger mean age in the Fibromyalgia group. Additionally, the Fibromyalgia group had lower in-hospital mortality, higher proportion of patients discharged home or to short-term hospitals, shorter lengths of stay, and lower hospital charges.
Despite having lower Elixhauser comorbidity scores, ME/CFS patients with Fibromyalgia had higher prevalence of certain conditions.
Limitations include missing data, and further research is warranted to refine ME/CFS definitions and develop personalized treatment plans. The study highlights the need for better understanding of ME/CFS mechanisms, correlations with comorbidities like Fibromyalgia, and potential predictors to improve diagnosis and treatment.
Source: Arvind Vishnu Murali. Identifying Demographic Trends in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients Presenting with Fibromyalgia as a Comorbidity in the Nationwide Inpatient Sample Database. Icahn School of Medicine at Mount Sinai ProQuest Dissertations Publishing, 2023. 30494377. https://www.proquest.com/openview/12cb80c96056a220f9e1d8bd7ea5fecc/1?pq-origsite=gscholar&cbl=18750&diss=y