Category: Fibromyalgia

Systemic Hyperalgesia in Females with Gulf War Illness, Chronic Fatigue Syndrome and Fibromyalgia

Abstract:

Pain is a diagnostic criterion for Gulf War Illness (GWI), Chronic Fatigue Syndrome (CFS), and fibromyalgia (FM). The physical sign of systemic hyperalgesia (tenderness) was assessed in 920 women who were stratified by 2000 Kansas GWI, 1994 CFS, and 1990 FM criteria.

Pressure was applied by dolorimetry at 18 traditional tender points and the average pressure causing pain determined. GWI women were the most tender (2.9 ± 1.6 kg, mean ± SD, n = 70), followed by CFS/FM (3.1 ± 1.4 kg, n = 196), FM (3.9 ± 1.4 kg, n = 56), and CFS (5.8 ± 2.1 kg, n = 170) compared to controls (7.2 ± 2.4 kg, significantly highest by Mann-Whitney tests p < 0.0001, n = 428). Receiver operating characteristics set pressure thresholds of 4.0 kg to define GWI and CFS/FM (specificity 0.85, sensitivities 0.80 and 0.83, respectively), 4.5 kg for FM, and 6.0 kg for CFS.

Pain, fatigue, quality of life, and CFS symptoms were equivalent for GWI, CFS/FM and CFS. Dolorimetry correlated with symptoms in GWI but not CFS or FM. Therefore, women with GWI, CFS and FM have systemic hyperalgesia compared to sedentary controls.

The physical sign of tenderness may complement the symptoms of the Kansas criteria as a diagnostic criterion for GWI females, and aid in the diagnosis of CFS. Molecular mechanisms of systemic hyperalgesia may provide new insights into the neuropathology and treatments of these nociceptive, interoceptive and fatiguing illnesses.

Source: Surian AA, Baraniuk JN. Systemic Hyperalgesia in Females with Gulf War Illness, Chronic Fatigue Syndrome and Fibromyalgia. Sci Rep. 2020 Apr 1;10(1):5751. doi: 10.1038/s41598-020-62771-9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113257/ (Full text)

Characterization of Cortisol Dysregulation in Fibromyalgia and Chronic Fatigue Syndromes: A State-Space Approach

Abstract:

OBJECTIVE: Fibromyalgia syndrome (FMS) and chronic fatigue syndrome (CFS) are complicated medical disorders, with little known etiologies. The purpose of this research is to characterize FMS and CFS by studying the variations in cortisol secretion patterns, timings, amplitudes, the number of underlying pulses, as well as infusion and clearance rates of cortisol.

METHODS: Using a physiological state-space model with plausible constraints, we estimate the hormonal secretory events and the physiological system parameters (i.e., infusion and clearance rates).

RESULTS: Our results show that the clearance rate of cortisol is lower in FMS patients as compared to their matched healthy individuals based on a simplified cortisol secretion model. Moreover, the number, magnitude, and energy of hormonal secretory events are lower in FMS patients. During early morning hours, the magnitude and energy of the hormonal secretory events are higher in CFS patients.

CONCLUSION: Due to lower cortisol clearance rate, there is a higher accumulation of cortisol in FMS patients as compared to their matched healthy subjects. As the FMS patient accumulates higher cortisol residues, internal inhibitory feedback regulates the hormonal secretory events. Therefore, the FMS patients show a lower number, magnitude, and energy of hormonal secretory events. Though CFS patients have the same number of secretory events, they secrete lower quantities during early morning hours. When we compare the results for CFS patients against FMS patients, we observe different cortisol alteration patterns.

SIGNIFICANCE: Characterizing CFS and FMS based on the cortisol alteration will help us to develop novel methods for treating these disorders.

Source: Pednekar DD, Amin MR, Fekri Azgomi H, Aschbacher K, Crofford LJ, Faghih RT. Characterization of Cortisol Dysregulation in Fibromyalgia and Chronic Fatigue Syndromes: A State-Space Approach. IEEE Trans Biomed Eng. 2020 Mar 5. doi: 10.1109/TBME.2020.2978801. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/32149617

Activation of Transposable Elements in Immune Cells of Fibromyalgia Patients

Abstract:

Advancements in nucleic acid sequencing technology combined with an unprecedented availability of metadata have revealed that 45% of the human genome constituted by transposable elements (TEs) is not only transcriptionally active but also physiologically necessary. Dysregulation of TEs, including human retroviral endogenous sequences (HERVs) has been shown to associate with several neurologic and autoimmune diseases, including Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). However, no study has yet addressed whether abnormal expression of these sequences correlates with fibromyalgia (FM), a disease frequently comorbid with ME/CFS.

The work presented here shows, for the first time, that, in fact, HERVs of the H, K and W types are overexpressed in immune cells of FM patients with or without comorbid ME/CFS. Patients with increased HERV expression (N = 14) presented increased levels of interferon (INF-β and INF-γ) but unchanged levels of TNF-α. The findings reported in this study could explain the flu-like symptoms FM patients present with in clinical practice, in the absence of concomitant infections. Future work aimed at identifying specific genomic loci differentially affected in FM and/or ME/CFS is warranted.

Source: Ovejero T, Sadones O, Sánchez-Fito T, Almenar-Pérez E, Espejo JA, Martín-Martínez E, Nathanson L, Oltra E. Activation of Transposable Elements in Immune Cells of Fibromyalgia Patients. Int J Mol Sci. 2020 Feb 18;21(4). pii: E1366. doi: 10.3390/ijms21041366. https://www.mdpi.com/1422-0067/21/4/1366 (Full text)

A System Theoretic Investigation of Cortisol Dysregulation in Fibromyalgia Patients with Chronic Fatigue

Abstract:

Fibromyalgia Syndrome (FMS) and Chronic Fatigue Syndrome (CFS) are complex medical conditions with similar symptoms such as anxiety, fatigue, depression, headaches, muscle aches and joint pain. The etiology of both these syndromes is unknown. The objective of this study is to characterize FMS, both in the presence and in the absence of CFS, by analyzing variations in cortisol secretion patterns, timings, amplitudes, and the number of the underlying pulses as well as infusion and clearance rates.

The comparison is performed against matched healthy control subjects. We estimate the hormonal secretory events by deconvolving cortisol data using a two-step coordinate descent approach. The first step implements a sparse recovery approach to infer the amplitudes and the timings of the cortisol secretion events from limited cortisol hormone data. The main advantage of this method is estimating the cortisol secretory events using a system theoretic approach. The second step is to estimate the physiological system parameters (i.e. infusion and clearance rates). This approach has been verified on healthy individuals previously.

Our results show that the clearance rate of cortisol by the liver is relatively lower in patients as compared to the matched healthy individuals. This suggests that there is a relatively higher accumulation of serum cortisol in patients when compared to matched healthy subjects.

Source: Pednekar DD, Amin MR, Azgomi HF, Aschbacher K, Crofford LJ, Faghih RT. A System Theoretic Investigation of Cortisol Dysregulation in Fibromyalgia Patients with Chronic Fatigue. Conf Proc IEEE Eng Med Biol Soc. 2019 Jul;2019:6896-6901. doi: 10.1109/EMBC.2019.8857427. https://www.ncbi.nlm.nih.gov/pubmed/31947425

Intimate Partner Violence and the Risk of Developing Fibromyalgia and Chronic Fatigue Syndrome

Abstract:

Intimate partner violence (IPV) is a global public health issue with a variety of ill health consequences associated with exposure. Due to the stimulation of chronic stress and inflammatory pathways, childhood abuse has been associated with the subsequent development of functional syndromes such as fibromyalgia and chronic fatigue syndrome (CFS). Although IPV in women appears to elicit similar biochemical responses, this association has not been tested thoroughly in IPV survivors. These functional syndromes are complex in etiology and any indication of their risk factors would benefit health care professionals managing this population. Therefore, we aimed to investigate the association between exposure to IPV with functional syndromes: fibromyalgia and CFS.

We conducted a retrospective open cohort study using “The Heath Improvement Network” database between January 1, 1995 and December 1, 2017. A total of 18,547 women who were exposed to IPV were each matched by age to four controls who were not exposed (n = 74,188). The main outcome measures were the risk of developing fibromyalgia and CFS. These were presented as adjusted incidence rate ratios (aIRR) with 95% confidence intervals (CIs).

We found that 97 women in the exposed group developed fibromyalgia (incidence rate [IR] = 1.63 per 1,000 person-years) compared to 239 women in the unexposed group (IR = 0.83 per 1,000 person-years). Following adjustment, this translated to an IRR of 1.73 (95% CI = [1.36, 2.22]). Similarly, 19 women developed CFS in the exposed group (IR = 0.32 per 1,000 person-years), compared to 53 in the unexposed group (0.18 per 1,000 person-years), which translates to an aIRR of 1.92 (95% CI = [1.11, 3.33]).

Therefore, we have identified an association between a history of IPV in women and the development of these functional syndromes, which may provide more information to inform the biopsychosocial pathway precipitating the development of fibromyalgia and CFS.

Source: Chandan JS, Thomas T, Raza K, Bradbury-Jones C, Taylor J, Bandyopadhyay S1, Nirantharakumar K. Intimate Partner Violence and the Risk of Developing Fibromyalgia and Chronic Fatigue Syndrome. J Interpers Violence. 2019 Dec 6:886260519888515. doi: 10.1177/0886260519888515. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/31805821

Neuroimmunology: What Role for Autoimmunity, Neuroinflammation, and Small Fiber Neuropathy in Fibromyalgia, Chronic Fatigue Syndrome, and Adverse Events after Human Papillomavirus Vaccination?

Abstract:

Fibromyalgia is a disorder characterized by chronic widespread pain and non-pain symptoms, such as fatigue, dysautonomia, and cognitive and sleep disturbances. Its pathogenesis and treatment continue to be the subject of debate. We highlight the role of three mechanisms-autoimmunity, neuroinflammation, and small fiber neuropathy in the pathogenesis of the disease. These mechanisms are shown to be closely interlinked (also on a molecular level), and the review considers the implementation of this relationship in the search for therapeutic options.

We also pay attention to chronic fatigue syndrome, which overlaps with fibromyalgia, and propose a concept of “autoimmune hypothalamopathy” for its pathogenesis. Finally, we analyze the molecular mechanisms underlying the neuroinflammatory background in the development of adverse events following HPV vaccination and suggesting neuroinflammation, which could exacerbate the development of symptoms following HPV vaccination (though this is hotly debated), as a model for fibromyalgia pathogenesis.

Source: Ryabkova VA, Churilov LP, Shoenfeld Y. Neuroimmunology: What Role for Autoimmunity, Neuroinflammation, and Small Fiber Neuropathy in Fibromyalgia, Chronic Fatigue Syndrome, and Adverse Events after Human Papillomavirus Vaccination? Int J Mol Sci. 2019 Oct 18;20(20). pii: E5164. doi: 10.3390/ijms20205164. https://www.mdpi.com/1422-0067/20/20/5164 (Full article)

Scientific Advances in and Clinical Approaches to Small-Fiber Polyneuropathy: A Review

Abstract:

IMPORTANCE: Small-fiber polyneuropathy involves preferential damage to the thinly myelinated A-delta fibers, unmyelinated C sensory fibers, or autonomic or trophic fibers. Although this condition is common, most patients still remain undiagnosed and untreated because of lagging medical and public awareness of research advances. Chronic bilateral neuropathic pain, fatigue, and nausea are cardinal symptoms that can cause disability and dependence, including pain medication dependence.

OBSERVATIONS: Biomarker confirmation is recommended, given the nonspecificity of symptoms. The standard test involves measuring epidermal neurite density within a 3-mm protein gene product 9.5 (PGP9.5)-immunolabeled lower-leg skin biopsy. Biopsies and autonomic function testing confirm that small-fiber neuropathy not uncommonly affects otherwise healthy children and young adults, in whom it is often associated with inflammation or dysimmunity. A recent meta-analysis concluded that small-fiber neuropathy underlies 49% of illnesses labeled as fibromyalgia. Initially, patients with idiopathic small-fiber disorders should be screened by medical history and blood tests for potentially treatable causes, which are identifiable in one-third to one-half of patients. Then, secondary genetic testing is particularly important for familial and childhood cases. Treatable genetic causes include Fabry disease, transthyretin and primary systemic amyloidosis, hereditary sensory autonomic neuropathy-1, and ion-channel mutations. Immunohistopathologic evidence suggests that small-fiber dysfunction and denervation, especially of blood vessels, contributes to diverse symptoms, including postexertional malaise, postural orthostatic tachycardia, and functional gastrointestinal distress. Preliminary evidence implicates acute or chronic autoreactivity in some cases, particularly in female patients and otherwise healthy children and young adults. Different temporal patterns akin to Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy have been described; here, corticosteroids and immunoglobulins, which are often efficacious for inflammatory neuropathic conditions, are increasingly considered.

CONCLUSIONS AND RELEVANCE: Because small fibers normally grow throughout life, improving contributory conditions may permit regrowth, slow progression, and prevent permanent damage. The prognosis is often hopeful for improving quality of life and sometimes for abatement or resolution, particularly in the young and otherwise healthy individuals. Examples include diabetic, infectious, toxic, genetic, and inflammatory causes. The current standard of care requires prompt diagnosis and treatment, particularly in children and young adults, to restore life trajectory. Consensus diagnostic and tracking metrics should be established to facilitate treatment trials.

Source: Oaklander AL, Nolano M. Scientific Advances in and Clinical Approaches to Small-Fiber Polyneuropathy: A Review. JAMA Neurol. 2019 Sep 9. doi: 10.1001/jamaneurol.2019.2917. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/31498378

General theory of inflammation: patient self-administration of hydrocortisone safely achieves superior control of hydrocortisone-responding disorders by matching dosage with symptom intensity

Abstract:

Objective: To determine if patient self-administration of hydrocortisone will safely achieve superior symptom control for all hydrocortisone-responding disorders as it does for Addison’s disease and rheumatoid arthritis.

Methods: Two thousand four hundred and twenty-eight participants with hydrocortisone-responding disorders were brought to a minimum symptom state using daily administered hydrocortisone tablets in a 24-week, open study. Thereafter, participants used 5-day, low-dose hydrocortisone regimens to quench subsequent disorder exacerbations (flares) to maintain the minimum symptom state. Stressors such as emotional traumas, infections, allergies, and injuries were minimized to reduce disorder intensity, hydrocortisone consumption, and participant discomfort.

Results: Two thousand fifteen participants, 601 with fibromyalgia, 579 with osteoarthritis, 246 with rheumatoid arthritis, 226 with undifferentiated arthritis, 75 with back pain, 51 with Parkinson’s disease, 44 with polymyalgia rheumatica, 25 with neuropathy, 25 with chronic fatigue syndrome, 25 with dementia, 21 with migraine headache, 19 with multiple sclerosis, and 78 with other disorders completed the 24-week study to achieve a composite average symptom improvement of 76% with equal response rates. The participants averaged ingesting 12 mg of hydrocortisone per day. No significant adverse reactions were observed.

Conclusions: Patient self-administration of hydrocortisone safely achieves superior symptom control for 38 hydrocortisone-responding disorders at equal rates and symptom improvements to confirm and amplify an earlier double-blind study finding on rheumatoid arthritis. These results are consistent with the body having an inflammation control system and chronic inflammation being a disorder unto itself with differing symptoms sets dependent on its location.

Clinical Trials Government Identifier: NCT03558971.

Source: Irwin JB, Baldwin AL, Stenberg VI. General theory of inflammation: patient self-administration of hydrocortisone safely achieves superior control of hydrocortisone-responding disorders by matching dosage with symptom intensity. J Inflamm Res. 2019 Jun 13;12:161-166. doi: 10.2147/JIR.S195165. eCollection 2019. https://www.dovepress.com/general-theory-of-inflammation-patient-self-administration-of-hydrocor-peer-reviewed-article-JIR (Full article)

Gut bacteria associated with chronic pain for first time

Press Release:

Scientists have found a correlation between a disease involving chronic pain and alterations in the gut microbiome.

Fibromyalgia affects 2-4 percent of the population and has no known cure. Symptoms include fatigue, impaired sleep and cognitive difficulties, but the disease is most clearly characterized by widespread chronic pain. In a paper published today in the journal Pain, a Montreal-based research team has shown, for the first time, that there are alterations in the bacteria in the gastrointestinal tracts of people with fibromyalgia. Approximately 20 different species of bacteria were found in either greater or are lesser quantities in the microbiomes of participants suffering from the disease than in the healthy control group.

Greater presence or absence of certain species of bacteria

“We used a range of techniques, including Artificial Intelligence, to confirm that the changes we saw in the microbiomes of fibromyalgia patients were not caused by factors such as diet, medication, physical activity, age, and so on, which are known to affect the microbiome,” says Dr. Amir Minerbi, from the Alan Edwards Pain Management Unit at the McGill University Health Centre (MUHC), and first author on the paper. The team also included researchers from McGill University and Université de Montréal as well as others from the Research Institute of the MUHC.

Dr. Minerbi adds, “We found that fibromyalgia and the symptoms of fibromyalgia – pain, fatigue and cognitive difficulties – contribute more than any of the other factors to the variations we see in the microbiomes of those with the disease. We also saw that the severity of a patient’s symptoms was directly correlated with an increased presence or a more pronounced absence of certain bacteria – something which has never been reported before.”

Are bacteria simply the markers of the disease?

At this point, it’s not clear whether the changes in gut bacteria seen in patients with fibromyalgia are simply markers of the disease or whether they play a role in causing it. Because the disease involves a cluster of symptoms, and not simply pain, the next step in the research will be to investigate whether there are similar changes in the gut microbiome in other conditions involving chronic pain, such as lower back pain, headaches and neuropathic pain.

The researchers are also interested in exploring whether bacteria play a causal role in the development of pain and fibromyalgia. And whether their presence could, eventually, help in finding a cure, as well as speed up the process of diagnosis.

Confirming a diagnosis and next steps towards finding a cure

Fibromyalgia is a disease that has proved difficult to diagnose. Patients can wait as long as 4 to 5 years to get a final diagnosis. But this may be about to change.

“We sorted through large amounts of data, identifying 19 species that were either increased or decreased in individuals with fibromyalgia,” says Emmanuel Gonzalez, from the Canadian Center for Computational Genomics and the Department of Human Genetics at McGill University. “By using machine learning, our computer was able to make a diagnosis of fibromyalgia, based only on the composition of the microbiome, with an accuracy of 87 per cent. As we build on this first discovery with more research, we hope to improve upon this accuracy, potentially creating a step-change in diagnosis.”

“People with fibromyalgia suffer not only from the symptoms of their disease but also from the difficulty of family, friends and medical teams to comprehend their symptoms,” says Yoram Shir, the senior author on the paper who is the Director of the Alan Edwards Pain Management Unit at the MUHC and an Associate Investigator from the BRaiN Program of the RI-MUHC. “As pain physicians, we are frustrated by our inability to help, and this frustration is a good fuel for research. This is the first evidence, at least in humans, that the microbiome could have an effect on diffuse pain, and we really need new ways to look at chronic pain.”

How the research was done

The research was based on a cohort of 156 individuals in the Montreal area, 77 of whom suffer from fibromyalgia. Participants in the study were interviewed and gave stool, blood, saliva and urine samples, which were then compared with those of healthy control subjects, some of whom lived in the same house as the fibromyalgia patients or were their parents, offspring or siblings.

The researchers’ next steps will be to see whether they get similar results in another cohort, perhaps in a different part of the world, and to do studies in animals to discover whether changes in bacteria play a role in the development of the disease.

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To read the article, “Altered microbiome composition in individuals with fibromyalgia” by Amir Minerbi et al in Pain: https://journals.lww.com/pain/Abstract/publishahead/Altered_microbiome_composition_in_individuals_with.98647.aspx

The research was funded by the Louise and Alan Edwards Foundation and the Israeli Society for Musculoskeletal Medicine.

Contact:

Julie Robert
Communications (Research)
McGill University Health Centre
T : 514 934-1934 ext. 71381
C : 514 971-4747
julie.robert@muhc.mcgill.ca
muhc.ca I rimuhc.ca

Altered microbiome composition in individuals with fibromyalgia

Abstract:

Fibromyalgia (FM) is a prevalent syndrome, characterised by chronic widespread pain, fatigue and impaired sleep, that is challenging to diagnose and difficult to treat. The microbiomes of 77 women with FM and that of 79 control participants were compared using 16S rRNA gene amplification and whole genome sequencing.

When comparing FM patients to unrelated controls using differential abundance analysis, significant differences were revealed in several bacterial taxa. Variance in the composition of the microbiomes was explained by FM-related variables more than by any other innate or environmental variable and correlated with clinical indices of FM. In line with observed alteration in butyrate metabolising species, targeted serum metabolite analysis verified differences in the serum levels of butyrate and propionate in FM patients.

Using machine learning algorithms, the microbiome composition alone allowed for the classification of patients and controls (ROC AUC 87.8%). To the best of our knowledge, this is the first demonstration of gut microbiome alteration in non-visceral pain. This observation paves the way for further studies, elucidating the pathophysiology of FM, developing diagnostic aids and possibly allowing for new treatment modalities to be explored.

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Source: Minerbi, Amir; Gonzalez, Emmanuel; Brereton, Nicholas J.B.; Anjarkouchian, Abraham; Dewar, Ken; Fitzcharles, Mary-Ann; Chevalier, Stéphanie; Shir, Yoram. Altered microbiome composition in individuals with fibromyalgia. PAIN: June 18, 2019 – Volume Articles in Press doi: 10.1097/j.pain.0000000000001640 https://journals.lww.com/pain/Abstract/publishahead/Altered_microbiome_composition_in_individuals_with.98647.aspx