Category: Fibromyalgia

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/

A Thesis on Immune Differences in Chronic Fatigue Syndrome, Fibromyalgia and Healthy Controls

Abstract:

Background: Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM) are debilitating disorders that significantly affect the daily lives of those suffering from them, as well as their loved ones. Both conditions have overlapping clinical features that resemble inflammatory disorders, and overlapping symptoms, such as depression, suggest central nervous system (CNS) involvement. The role of the immune system’s soluble messengers in the pathogenesis of CFS and FM has been under investigation, but so far the results are inconclusive. In addition, there is growing evidence that the kynurenine pathway is involved in the pathology of diseases related to the CNS, yet the role of each metabolite is not clear. The relationship between kynurenine metabolism and CFS and FM has not been extensively explored. Few studies have simultaneously examined the immunological status in both CFS and FM, making this thesis the first to comprehensively evaluate the potential distinct immunological differences between the two disorders.

Objective: The objective of this study was to compare the CFS and FM with healthy controls, regarding the levels of several soluble blood markers related to the immune system. The markers chosen were:

  • The inflammatory marker high-sensitive CRP (hsCRP)
  • The following cytokines and chemokines: Interferon (IFN)-γ, Interleukin (IL)-1β, IL1ra, IL-4, IL-6, IL-8, IL-10, IL-17, Interferon gamma-induced protein (IP)-10, Monocyte Chemoattractant Protein (MCP)-1, Transforming Growth Factor (TGF)-β1, TGF-β2, TGF-β3 and Tumour Necrosis Factor (TNF)-α
  • The metabolites and their ratios of the kynurenine pathway: Tryptophan (Try), kynurenine (Kyn), kynurenic acid (KA), 3-hydroxykykynurenine (HK), anthranilic acid (AA), xanthurenic acid (XA), 3-hydroxyanthranilic acid (HAA), quinolinic acid (QA) and picolinic acid (Pic).

Method: The population consisted of three groups: CFS patients (n = 49), FM patients (n = 58), and healthy controls (n = 54). All participants were females aged 18–60. Patients were recruited from a specialised university hospital clinic and controls were recruited by advertisement among the staff and students at the hospital and university.

Plasma levels of hsCRP were analysed at the hospital. The cytokines and chemokines IFN-γ, IL-1β, IL-1ra, xii IL-4, IL-6, IL-8, IL-10, IL-17, IP-10, MCP-1, TGF-β1, TGF-β2, TGF-β3, and TNF-α were analysed by multiplex. Kynurenine metabolites were analysed by LC-MS/MS.

Linear regression models of log-transformed data for hsCRP and the kynurenine metabolites were conducted for comparison of the three groups CFS, FM and controls. The Kruskal-Wallis test was used to analyse differences of cytokines between the three groups. Main findings were controlled for age, body mass index (BMI), and symptoms of anxiety and depression.

Results: hsCRP levels were significantly higher for both the CFS and FM groups compared to healthy controls when adjusting for age and BMI (p = .006). There was no difference between the two patient groups. Level of hsCRP was affected by BMI (p < .001) but not age.

MCP-1 was significantly increased in both patient groups compared to healthy controls (p < .001). IL-1β, Il-4, IL-6, TNF-α, TGF-β1, TGF-β2, TGF-β3 (all p < .001), IL-10 (p = .003) and IL17 (p = .002) all were significantly lower in the patient groups compared to healthy controls. IFN-γ was significantly lower in the FM group (p < .001). For IL-8, IP-10 and IL1ra there were no significant difference.

QA differed between CFS and FM patients (p = .036) and was related to higher levels of BMI (p = .002). The KA/QA ratio was lower for CFS patients compared to healthy controls (p = .016). The KA/HK ratio was lower for FM patients compared to healthy controls, and this lower ratio was associated with increased symptoms of pain (p = .002). The kynurenine aminotransferase II (KAT II) enzymatic activity given by XA/HK was lower for FM patients compared to healthy controls (p = .013). In addition, BMI was negatively associated with enhanced KAT II enzymatic activity (p = .039).

Symptoms of anxiety and depression were not associated with any of the immune markers studied.

Conclusion: In our material hsCRP and MCP-1 are increased in patients both with CFS and with FM, while several other cytokines are either similar or significantly lower in patients than controls. Our study also indicates associations between kynurenine metabolism and CFS and FM. Kynurenine also is associated with single symptoms such as fatigue and pain. Forthcoming studies indicating interactions and causative effects, or restoration of the inflammatory status, may place cytokines and kynurenine metabolites as a target for treatment as well as prevention of these conditions in the future.

Source: Groven, Nina. A Thesis on Immune Differences in Chronic Fatigue Syndrome, Fibromyalgia and Healthy Controls. PhD Thesis [Norwegian University of Science and Technology] https://ntnuopen.ntnu.no/ntnu-xmlui/handle/11250/3072207 (Full text available as PDF file)

A comparison of pain, fatigue, and function between post–COVID-19 condition, fibromyalgia, and chronic fatigue syndrome: a survey study

Abstract

A growing number of individuals report prolonged symptoms following acute COVID-19 infection, known as post-COVID-19 condition (post-COVID-19).

While studies have emerged investigating the symptom sequelae of post-COVID-19, there has been limited investigation into the characterization of pain, fatigue, and function in these individuals, despite initial reports of a clinical phenotype similar to fibromyalgia (FMS) and chronic fatigue syndrome/myalgic encephalomyelitis (CFS).

This study aimed to characterize multiple symptom domains in individuals reporting post-COVID-19 and compare its clinical phenotype to those with FMS and CFS.

A total of 707 individuals with a single or comorbid diagnosis of post-COVID-19, FMS, and/or CFS completed multiple surveys assessing self-reported pain, fatigue, physical and cognitive function, catastrophizing, kinesiophobia, anxiety, depression, dyspnea, and sleep quality. In all three diagnoses, elevated pain, fatigue, anxiety, depression, catastrophizing, and kinesiophobia were reported.

Physical and cognitive function were similarly impacted among individuals with post-COVID-19, FMS, and CFS; however, individuals with post-COVID-19 reported lower pain and fatigue than FMS and CFS.

The comorbid diagnosis of post-COVID-19 with FMS and/or CFS further exacerbated pain, fatigue, and psychological domains when compared to post-COVID-19 alone.

In summary, individuals with post-COVID-19 report a symptom phenotype similar to FMS and CFS, negatively impacting cognitive and physical function, but with less severe pain and fatigue overall. These findings may help direct future investigations of the benefit of a biopsychosocial approach to the clinical management of post-COVID-19.

Source: Haider S, Janowski AJ, Lesnak JB, Hayashi K, Dailey DL, Chimenti R, Frey-Law LA, Sluka KA, Berardi G. A comparison of pain, fatigue, and function between post-COVID-19 condition, fibromyalgia, and chronic fatigue syndrome: a survey study. Pain. 2023 Feb 1;164(2):385-401. doi: 10.1097/j.pain.0000000000002711. Epub 2022 Jun 29. PMID: 36006296; PMCID: PMC9797623.  https://pubmed.ncbi.nlm.nih.gov/36006296/

Clinical overlap between fibromyalgia and myalgic encephalomyelitis. A systematic review and meta-analysis

Abstract:

Introduction: Myalgic encephalomyelitis is an illness characterized by profound malaise after mental or physical effort occurring in patients already suffering from constant fatigue. On the other hand, widespread pain and widespread allodynia are the core fibromyalgia clinical features.

There is controversy on these two syndromes alikeness. Through the years, different diagnostic and/or classification criteria have been put forward to appraise both fibromyalgia and myalgic encephalomyelitis.

The epidemiology of these two illnesses, and their overlap, may vary accordingly to the used definition. The most recent Wolfe et al. 2016 fibromyalgia diagnostic criteria incorporates three myalgic encephalomyelitis features including fatigue, waking unrefreshed and dyscognition. The objective of this meta-analysis was to define the clinical overlap between fibromyalgia and myalgic encephalomyelitis based on a systematic literature review.

Methods: PubMed, Embase, Lilacs, and Cochrane data bases were searched on January 25, 2021 linking the medical subject heading “Fibromyalgia” to the following terms “chronic fatigue syndrome”, “myalgic encephalomyelitis” and “systemic exertion intolerance disease”.

Our review included all original articles in which the clinical overlap between fibromyalgia and myalgic encephalomyelitis could be quantified based on recognized diagnostic or classification criteria. Articles scrutiny and selection followed the PRISMA guidelines. Each study quality was assessed according to GRADE recommendations. The global clinical overlap was calculated using a fixed effect model with inverse variance-weighted average method.

Results: Twenty one publications were included in the meta-analysis. Reviewed studies were highly dissimilar in their design, objectives, sample size, diagnostic criteria, and/or outcomes yielding a 98% heterogeneity index.

Nevertheless, the clinical overlap between fibromyalgia and myalgic encephalomyelitis was a well defined outcome that could be reliably calculated despite the high heterogeneity value.

All reviewed publications had moderate GRADE evidence level. Most evaluated articles used the old 1990 Wolfe et al. fibromyalgia diagnostic criteria. Myalgic encephalomyelitis and fibromyalgia diagnoses overlapped in 47.3% (95% CI: 45.97-48.63) of the reported cases.

Conclusion: This meta-analysis found prominent clinical overlap between fibromyalgia and myalgic encephalomyelitis. It seems likely that this concordance would be even higher when using the most recent Wolfe et al. 2016 fibromyalgia diagnostic criteria.

Source: Ramírez-Morales R, Bermúdez-Benítez E, Martínez-Martínez LA, Martínez-Lavín M. Clinical overlap between fibromyalgia and myalgic encephalomyelitis. A systematic review and meta-analysis. Autoimmun Rev. 2022 Aug;21(8):103129. doi: 10.1016/j.autrev.2022.103129. Epub 2022 Jun 9. PMID: 35690247. https://www.sciencedirect.com/science/article/abs/pii/S1568997222000994?via%3Dihub

Evidence of neuroinflammation in fibromyalgia syndrome: a [18F]DPA-714 positron emission tomography study

Abstract:

This observational study aimed to determine whether individuals with fibromyalgia (FM) exhibit higher levels of neuroinflammation than healthy controls (HCs), as measured with positron emission tomography using [18F]DPA-714, a second-generation radioligand for the translocator protein (TSPO).
Fifteen women with FM and 10 HCs underwent neuroimaging. Distribution volume (VT) was calculated for in 28 regions of interest (ROIs) using Logan graphical analysis and compared between groups using multiple linear regressions. Group (FM vs HC) was the main predictor of interest and TSPO binding status (high- vs mixed-affinity) was added as a covariate. The FM group had higher VT in the right postcentral gyrus (b = 0.477, P = 0.033), right occipital gray matter (GM; b = 0.438, P = 0.039), and the right temporal GM (b = 0.466, P = 0.042). The FM group also had lower VT than HCs in the left isthmus of the cingulate gyrus (b = −0.553, P = 0.014).
In the subgroup of high-affinity binders, the FM group had higher VT in the bilateral precuneus, postcentral gyrus, parietal GM, occipital GM, and supramarginal gyrus. Group differences in the right parietal GM were associated with decreased quality of life, higher pain severity and interference, and cognitive problems.
In support of our hypothesis, we found increased radioligand binding (VT) in the FM group compared with HCs in several brain regions regardless of participants’ TSPO binding status. The ROIs overlapped with prior reports of increased TSPO binding in FM. Overall, increasing evidence supports the hypothesis that FM involves microglia-mediated neuroinflammation in the brain.
Source: Mueller C, Fang YD, Jones C, McConathy JE, Raman F, Lapi SE, Younger JW. Evidence of neuroinflammation in fibromyalgia syndrome: a [18F]DPA-714 positron emission tomography study. Pain. 2023 Jun 15. doi: 10.1097/j.pain.0000000000002927. Epub ahead of print. PMID: 37326674. https://pubmed.ncbi.nlm.nih.gov/37326674/

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)

Rheumatology and Long COVID: lessons from the study of fibromyalgia

Abstract:

Rheumatology, such as other subspecialties, has both a unique perspective to offer as well as an evolving role to play in the global COVID-19 pandemic. Our field has already contributed meaningfully to the development and repurposing of many of the immune-based therapeutics which are now standard treatments for severe forms of the disease as well as to the understanding of the epidemiology, risk factors and natural history of COVID-19 in immune-mediated inflammatory diseases. Still in evolution is our potential to contribute to burgeoning research efforts in the next phase of the pandemic: the syndrome of postacute sequelae of COVID-19 or Long COVID. While our field brings many assets to the study of Long COVID including our expertise in the investigation of chronic inflammation and autoimmunity, our Viewpoint focuses on the strong similarities between fibromyalgia (FM) and Long COVID. While one can speculate on how embracing and confident practising rheumatologists already are regarding these interrelationships, we assert that in the emerging field of Long COVID the potential lessons from the field of fibromyalgia care and research have been underappreciated and marginalised and most importantly now deserve a critical appraisal.

Source: Clauw DJ, Calabrese L. Rheumatology and Long COVID: lessons from the study of fibromyalgia. Ann Rheum Dis. 2023 May 25:ard-2023-224250. doi: 10.1136/ard-2023-224250. Epub ahead of print. PMID: 37230736. https://ard.bmj.com/content/early/2023/05/24/ard-2023-224250 (Full text)

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

Influence of Chronic Fatigue Syndrome Codiagnosis on the Relationship between Perceived and Objective Psychoneuro-Immunoendocrine Disorders in Women with Fibromyalgia

Abstract:

Although the predominant symptom in fibromyalgia (FM) is muscle pain, and fatigue in chronic fatigue syndrome (CFS), differential diagnosis is very difficult. This research investigates the psychoneuroimmunoendocrine disorders of FM patients and ascertains whether a previous CFS diagnosis affected them.

Through accelerometry objective parameters, physical activity/sedentarism levels in relation to fatigue are studied, as well as whether perceived levels of stress, anxiety, and pain correspond to objective biomarkers, all of these with respect to a reference group (RG) of women without FM.

FM patients have a worse psychological state and perceived quality of life than those with RG. These perceived outcomes are consistent with impaired objective levels of a sedentary lifestyle, higher systemic levels of cortisol and noradrenaline, and lower levels of serotonin.

However, FM patients with a previous CFS diagnosis had lower systemic levels of IL-8, cortisol, oxytocin, and higher levels of adrenaline and serotonin than FM patients without diagnosed CFS.

In conclusion, while perceived health parameters do not detect differences, when objective neuroimmunoendocrine parameters related to stress, inflammation, pain, and fatigue are used, people with CFS could be overdiagnosed with FM. This reinforces the need for objective biomarker assessment of these patients for better diagnostic discrimination between both syndromes.

Source: Otero E, Gálvez I, Ortega E, Hinchado MD. Influence of Chronic Fatigue Syndrome Codiagnosis on the Relationship between Perceived and Objective Psychoneuro-Immunoendocrine Disorders in Women with Fibromyalgia. Biomedicines. 2023; 11(5):1488. https://doi.org/10.3390/biomedicines11051488 https://www.mdpi.com/2227-9059/11/5/1488 (Full text)