Category: Fibromyalgia

Unbiased immune profiling reveals a natural killer cell-peripheral nerve axis in fibromyalgia

Abstract:

The pathophysiology of fibromyalgia syndrome (FMS) remains elusive, leading to a lack of objective diagnostic criteria and targeted treatment. We globally evaluated immune system changes in FMS by conducting multiparametric flow cytometry analyses of peripheral blood mononuclear cells and identified a natural killer (NK) cell decrease in patients with FMS. Circulating NK cells in FMS were exhausted yet activated, evidenced by lower surface expression of CD16, CD96, and CD226 and more CD107a and TIGIT. These NK cells were hyperresponsive, with increased CCL4 production and expression of CD107a when co-cultured with human leukocyte antigen null target cells. Genetic and transcriptomic pathway analyses identified significant enrichment of cell activation pathways in FMS driven by NK cells. Skin biopsies showed increased expression of NK activation ligand, unique long 16-binding protein, on subepidermal nerves of patients FMS and the presence of NK cells near peripheral nerves. Collectively, our results suggest that chronic activation and redistribution of circulating NK cells to the peripheral nerves contribute to the immunopathology associated with FMS.

Source: Verma V, Drury GL, Parisien M, Özdağ Acarli AN, Al-Aubodah TA, Nijnik A, Wen X, Tugarinov N, Verner M, Klares R 3rd, Linton A, Krock E, Morado Urbina CE, Winsvold B, Fritsche LG, Fors EA, Piccirillo C, Khoutorsky A, Svensson CI, Fitzcharles MA, Ingelmo PM, Bernard NF, Dupuy FP, Üçeyler N, Sommer C, King IL, Meloto CB, Diatchenko L; HUNT-All In Pain. Unbiased immune profiling reveals a natural killer cell-peripheral nerve axis in fibromyalgia. Pain. 2021 Sep 24:10.1097/j.pain.0000000000002498. doi: 10.1097/j.pain.0000000000002498. Epub ahead of print. PMID: 34913882; PMCID: PMC8942876. https://pubmed.ncbi.nlm.nih.gov/34913882/

Gastric herpes simplex virus type 1 infection is associated with functional gastrointestinal disorders in the presence and absence of comorbid fibromyalgia: a pilot case-control study

Abstract:

Purpose: Animal studies have linked gastric herpesvirus infections to symptoms associated with functional gastrointestinal disorders (FGIDs). Herpesviruses have also been hypothesized to contribute to fibromyalgia (FM), a chronic pain syndrome frequently comorbid with FGIDs. The purpose of this study was to compare the prevalence of gastric herpesvirus infection in patients with FGIDs, with and without comorbid FM, to that of controls.

Methods: For this pilot case-control study, we enrolled 30 patients who met both the Rome IV diagnostic criteria for one or more FGIDs and the American College of Rheumatology 2010 criteria for FM, 15 patients with one or more FGIDs without comorbid FM, and 15 control patients. Following endoscopic examination, gastric biopsies were analyzed for herpesvirus DNA and protein, Helicobacter pylori infection, and histological evidence of gastritis. Importantly, the viral nonstructural protein ICP8 was used as a marker to differentiate cell-associated actively replicating virus from latent infection and/or free virus passing through the GI tract.

Results: Gastric herpes simplex virus type 1 (HSV-1) infection, as indicated by ICP8 presence, was significantly associated with FGIDs in the presence (OR 70.00, 95% CI 7.42-660.50; P < .001) and absence (OR 38.50, 95% CI 3.75-395.40; P < .001) of comorbid FM. Neither histological gastritis nor H. pylori infection were found to be associated with FGIDs or FM.

Conclusions: HSV-1 infection was identified in gastric mucosal biopsies from patients with diverse FGIDs, with and without comorbid FM. Larger, multi-center studies investigating the prevalence of this association are warranted.

Source: Duffy C, Pridgen WL, Whitley RJ. Gastric herpes simplex virus type 1 infection is associated with functional gastrointestinal disorders in the presence and absence of comorbid fibromyalgia: a pilot case-control study. Infection. 2022 Apr 21. doi: 10.1007/s15010-022-01823-w. Epub ahead of print. PMID: 35445970.  https://link.springer.com/article/10.1007/s15010-022-01823-w (Full text)

Altered Pain in the Brainstem and Spinal Cord of Fibromyalgia Patients During the Anticipation and Experience of Experimental Pain

Abstract:

Chronic pain associated with fibromyalgia (FM) affects a large portion of the population but the underlying mechanisms leading to this altered pain are still poorly understood. Evidence suggests that FM involves altered neural processes in the central nervous system and neuroimaging methods such as functional magnetic resonance imaging (fMRI) are used to reveal these underlying alterations. While many fMRI studies of FM have been conducted in the brain, recent evidence shows that the changes in pain processing in FM may be linked to autonomic and homeostatic dysregulation, thus requiring further investigation in the brainstem and spinal cord.

Functional magnetic resonance imaging data from 15 women with FM and 15 healthy controls were obtained in the cervical spinal cord and brainstem at 3 tesla using previously established methods. In order to investigate differences in pain processing in these groups, participants underwent trials in which they anticipated and received a predictable painful stimulus, randomly interleaved with trials with no stimulus. Differences in functional connectivity between the groups were investigated by means of structural equation modeling.

The results demonstrate significant differences in brainstem/spinal cord network connectivity between the FM and control groups which also correlated with individual differences in pain responses. The regions involved in these differences in connectivity included the LC, hypothalamus, PAG, and PBN, which are known to be associated with autonomic homeostatic regulation, including fight or flight responses. This study extends our understanding of altered neural processes associated with FM and the important link between sensory and autonomic regulation systems in this disorder.

Source: Ioachim G, Warren HJM, Powers JM, Staud R, Pukall CF, Stroman PW. Altered Pain in the Brainstem and Spinal Cord of Fibromyalgia Patients During the Anticipation and Experience of Experimental Pain. Front Neurol. 2022 May 6;13:862976. doi: 10.3389/fneur.2022.862976. PMID: 35599729; PMCID: PMC9120571. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9120571/ (Full text)

The impact of Micro RNA-320a serum level on severity of symptoms and cerebral processing of pain in patients with fibromyalgia

Abstract:

Objectives: The aim of this work was to explore the expression of miR-320a level in fibromyalgia patients in comparison to healthy controls, and to clarify its impact on the severity of symptoms and the cerebral processing of pain assessed by middle latency somatosensory evoked potentials (SSEPs).

Design: Case-control study.

Setting: Rheumatology and Neurology outpatient clinics.

Subjects: Seventy-four fibromyalgia patients and seventy-four normal healthy controls.

Methods: The included patients were subjected to detailed history taking, assessment of severity of fibromyalgia symptoms using the Fibromyalgia Impact Questionnaire Revised (FIQR), assessment of pain intensity using the Neuropathic Pain Symptom Inventory (NPSI), measurement of the serum level of miR-320a in addition to of measurement peak latencies and amplitudes of middle latency SSEPs.

Results: Fibromyalgia patients had significantly higher micro-RNA-320a levels (0.907 ± 0.022) in comparison to controls (0.874 ± 0.015) (P-value < 0.001). The mean values of micro-RNA-320a levels were significantly higher in fibromyalgia patients with insomnia, chronic fatigue syndrome, persistent depressive disorder, and primary headache disorder than those without (P-value = 0.024, <0.001, 0.006, 0.036 respectively). There were statistically significant positive correlations between micro-RNA-320a levels, and disease duration, FIQR and NPSI total scores (P-value <0.001, 0.003, 0.002 respectively). There were no statistically significant correlations between micro-RNA-320a levels and middle latency SSEPs.

Discussion: Micro-RNA-320a level is significantly upregulated in fibromyalgia patient. It has a crucial impact on the severity of symptoms but not related to the cerebral processing of pain.

Source: Hussein M, Fathy W, Abdelaleem EA, Nasser M, Yehia A, Elanwar R. The impact of Micro RNA-320a serum level on severity of symptoms and cerebral processing of pain in patients with fibromyalgia. Pain Med. 2022 May 19:pnac076. doi: 10.1093/pm/pnac076. Epub ahead of print. PMID: 35587745. https://pubmed.ncbi.nlm.nih.gov/35587745/

Intimate partner violence and women living with episodic disabilities: a scoping review protocol

Abstract:

Background: Violence towards women with disabilities is most commonly perpetrated by current or former intimate partners and more than half of disabled women experience intimate partner violence in their lifetime. Disabilities differ by presence, type, and complexity, yet are commonly researched collectively. A more nuanced understanding of the relationship between intimate partner violence and episodic disability is required to better support women living with these concurrent challenges. The objective of this scoping review is to investigate and synthesize the literature reporting on intimate partner violence for women living with an episodic disability to identify key concepts and knowledge gaps on this topic. Ultimately, this review aims to improve health services for this stigmatized group of women with episodic disabilities.

Methods: This scoping review will consider all studies that focus on women (18 years of age or older) who have experienced intimate partner violence and have an episodic disability. Episodic disabilities will include multiple sclerosis, chronic fatigue syndrome, fibromyalgia, lupus, or rheumatoid arthritis. The broad review question is what is known about intimate partner violence within the context of women living with an episodic disability? Databases to be searched include MEDLINE (OVID), CINAHL, Embase, PsychInfo, and Scopus with no limits on language or time frame. Joanna Briggs Institute methodology will guide this scoping review to address the review questions outlined in the protocol. For papers that meet the inclusion criteria, data will be extracted, and findings will be presented in tables and narrative form. A PRISMA table will be included to enhance the transparency of the process. A descriptive qualitative approach to analysis will be conducted following Braun and Clarke’s reflexive thematic analysis. The findings of the scoping review will be presented through a thematic narrative.

Discussion: Findings from this review will be used to identify important priorities for future research based on knowledge gaps and inform both health care practices and health and social interventions for women living with intimate partner violence and episodic disabilities.

Source: Campbell KA, Ford-Gilboe M, Stanley M, MacKinnon K. Intimate partner violence and women living with episodic disabilities: a scoping review protocol. Syst Rev. 2022 May 18;11(1):97. doi: 10.1186/s13643-022-01972-x. PMID: 35585642. https://systematicreviewsjournal.biomedcentral.com/articles/10.1186/s13643-022-01972-x  (Full text)

Pain Burden in Post-COVID-19 Syndrome following Mild COVID-19 Infection

Abstract:

The global pandemic of SARS-CoV-2 has affected several hundred million people, and many infected people have suffered from a milder initial infection but have never fully recovered. This observational study investigates the pain burden in sufferers of post-COVID-19 syndrome after a milder initial infection.

One hundred post-COVID-19 patients filled out questionnaires regarding sociodemographic data, previous comorbidities, present pharmacological treatment, pain intensity and pain localisation. Health-related quality of life, fatigue, emotional status, and insomnia were measured by validated questionnaires. Multiple post-COVID-19 symptoms, including post-exertional malaise, were evaluated by a symptom questionnaire. Among the 100 participants (mean age 44.5 years), 82% were women, 61% had higher education, and 56% were working full or part time. Nine participants reported previous pain or inflammatory conditions. Among the most painful sites were the head/face, chest, lower extremities, and migrating sites. Generalised pain was self-reported by 75 participants and was estimated in 50 participants. Diagnosis of fibromyalgia according to the 2016 criteria was suspected in 40 participants. Subgroup analyses indicated that comorbidities might play a role in the development of pain.

In conclusion, a major part of sufferers from post-COVID-19 syndrome develop pain, and in addition to its many disabling symptoms, there is an urgent need for pain management in post-COVID-19 syndrome.

Source: Bileviciute-Ljungar I, Norrefalk JR, Borg K. Pain Burden in Post-COVID-19 Syndrome following Mild COVID-19 Infection. J Clin Med. 2022 Jan 31;11(3):771. doi: 10.3390/jcm11030771. PMID: 35160223; PMCID: PMC8836662. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8836662/ (Full text)

An Open-Label, Pilot Trial of HRG80™ Red Ginseng in Chronic Fatigue Syndrome, Fibromyalgia, and Post-Viral Fatigue

Abstract:

Chronic fatigue syndrome and fibromyalgia (CFS/FMS) affect 2.1% of the world’s population and ~10–25% of people who have had COVID-19. Previous clinical data suggested that a unique Panax ginseng (C.A. Meyer, family Araliaceae) root extract (HRG80™ Red Ginseng) often resulted in marked improvement. We aimed to study this hydroponic form of red ginseng root, containing high levels of rare ginsenosides, for improving energy, cognition, and stamina. This open-label prospective study included participants with severe CFS/FMS who took a daily supplement of HRG80 capsules (200–400 mg) or tablets (100–200 mg) for one month.
A total of 188 subject patients completed the one-month treatment trial. Of these, 60.1% rated themselves as improved, with 13.3% rating themselves as being much better. In this group, the mean composite score improved from 11.9 to 18.8 (p < 0.001), with a 67% average increase in energy, 44% average increase in overall well-being, 48% average improvement in mental clarity, 58% average composite improvement in the previous three measurements (primary outcome measure), 46% average improvement in sleep, 33% average decrease in pain, and 72% average increase in stamina. Our study showed that HRG80 red ginseng root powder resulted in a marked improvement in people with CFS and fibromyalgia. This included the subgroup with post-viral CFS/FMS.
Source: Teitelbaum J, Goudie S. An Open-Label, Pilot Trial of HRG80™ Red Ginseng in Chronic Fatigue Syndrome, Fibromyalgia, and Post-Viral Fatigue. Pharmaceuticals. 2022; 15(1):43. https://doi.org/10.3390/ph15010043 (Full text)

Induced pluripotent stem cells as suitable sensors for fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome Monzón-Nomdedeu MB, Morten KJ, Oltra E. Induced pluripotent stem cells as suitable sensors for fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

BACKGROUND: Fibromyalgia (FM) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are devastating metabolic neuroimmune diseases that are difficult to diagnose because of the presence of numerous symptoms and a lack of specific biomarkers. Despite patient heterogeneity linked to patient subgroups and variation in disease severity, anomalies are found in the blood and plasma of these patients when compared with healthy control groups. The seeming specificity of these “plasma factors”, as recently reported by Ron Davis and his group at Stanford University, CA, United States, and observations by our group, have led to the proposal that induced pluripotent stem cells (iPSCs) may be used as metabolic sensors for FM and ME/CFS, a hypothesis that is the basis for this in-depth review.

AIM: To identify metabolic signatures in FM and/or ME/CFS supporting the existence of disease-associated plasma factors to be sensed by iPSCs.

METHODS: A PRISMA (Preferred Reported Items for Systematic Reviews and Meta-analysis)-based systematic review of the literature was used to select original studies evaluating the metabolite profiles of FM and ME/CFS body fluids. The MeSH terms “metabolomic” or “metabolites” in combination with FM and ME/CFS disease terms were screened against the PubMed database. Only original studies applying omics technologies, published in English, were included. The data obtained were tabulated according to the disease and type of body fluid analyzed. Coincidences across studies were searched and P-values reported by the original studies were gathered to document significant differences found in the disease groups.

RESULTS: Eighteen previous studies show that some metabolites are commonly altered in ME/CFS and FM body fluids. In vitro cell-based assays have the potential to be developed as screening platforms, providing evidence for the existence of factors in patient body fluids capable of altering morphology, differentiation state and/or growth patterns. Moreover, they can be further developed using approaches aimed at blocking or reversing the effects of specific plasma/serum factors seen in patients. The documented high sensitivity and effective responses of iPSCs to environmental cues suggests that these pluripotent cells could form robust, reproducible reporter systems of metabolic diseases, including ME/CFS and FM. Furthermore, culturing iPSCs, or their mesenchymal stem cell counterparts, in patient-conditioned medium may provide valuable information to predict individual outcomes to stem-cell therapy in the context of precision medicine studies.

CONCLUSION: This opinion review explains our hypothesis that iPSCs could be developed as a screening platform to provide evidence of a metabolic imbalance in FM and ME/CFS.

Source: Monzón-Nomdedeu MB, Morten KJ, Oltra E. Induced pluripotent stem cells as suitable sensors for fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome. World J Stem Cells 2021; 13(8): 1134-1150 [DOI: 10.4252/wjsc.v13.i8.1134]  https://www.wjgnet.com/1948-0210/full/v13/i8/1134.htm (Full study)

Passive transfer of fibromyalgia symptoms from patients to mice

Abstract:

Fibromyalgia syndrome (FMS) is characterized by widespread pain and tenderness, and patients typically experience fatigue and emotional distress. The etiology and pathophysiology of fibromyalgia are not fully explained and there are no effective drug treatments. Here we show that IgG from FMS patients produced sensory hypersensitivity by sensitizing nociceptive neurons. Mice treated with IgG from FMS patients displayed increased sensitivity to noxious mechanical and cold stimulation, and nociceptive fibers in skin-nerve preparations from mice treated with FMS IgG displayed an increased responsiveness to cold and mechanical stimulation.

These mice also displayed reduced locomotor activity, reduced paw grip strength, and a loss of intraepidermal innervation. In contrast, transfer of IgG-depleted serum from FMS patients or IgG from healthy control subjects had no effect. Patient IgG did not activate naive sensory neurons directly. IgG from FMS patients labeled satellite glial cells and neurons in vivo and in vitro, as well as myelinated fiber tracts and a small number of macrophages and endothelial cells in mouse dorsal root ganglia (DRG), but no cells in the spinal cord. Furthermore, FMS IgG bound to human DRG. Our results demonstrate that IgG from FMS patients produces painful sensory hypersensitivities by sensitizing peripheral nociceptive afferents and suggest that therapies reducing patient IgG titers may be effective for fibromyalgia.

Source: Andreas Goebel, … , Camilla I. Svensson, David A. Andersson. Passive transfer of fibromyalgia symptoms from patients to mice. J Clin Invest. 2021;131(13):e144201. https://doi.org/10.1172/JCI144201. Published July 1, 2021 https://www.jci.org/articles/view/144201?key=51bf6d85e305f6b62f87 (Full text)

Central Sensitivity and Fibromyalgia

Abstract:

Fibromyalgia presents with symptoms of widespread pain, fatigue, sleeping and cognitive disturbances as well as other somatic symptoms. It often overlaps with other conditions termed ‘central sensitivity syndromes’ such as irritable bowel syndrome, chronic fatigue syndrome and temporomandibular disorder. Central sensitisation, mediated by amplified processing in the central nervous system, has been identified as the key pathogenic mechanism in these disorders. The term ‘central sensitivity’ can be used to collectively describe the clinical presentation of these disorders.

Fibromyalgia is highly prevalent in most rheumatic diseases as well as non-rheumatic chronic diseases and if unrecognised results in high morbidity. It is diagnosed clinically after excluding important differential diagnoses. Diagnostic criteria have been developed as tools to help identify and diagnose fibromyalgia. Such tools can fulfill an important need when managing patients with rheumatic disease and other chronic diseases as a way to identify fibromyalgia and improve patient outcomes. Treatment involves an integrated approach including education, exercise, stress reduction and pharmacological therapies targeting the central nervous system. This approach is suitable for all presentations of central sensitivity and some central sensitivity syndromes have additional treatment options specific to the clinical presentation.

Source: Mezhov V, Guymer E, Littlejohn G. Central Sensitivity and Fibromyalgia. Intern Med J. 2021 Jun 17. doi: 10.1111/imj.15430. Epub ahead of print. PMID: 34139045. https://pubmed.ncbi.nlm.nih.gov/34139045/