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Fibromyalgia (FM), a musculoskeletal condition characterized by widespread pain and numerous associated symptoms, is a complex disorder with uncertain etiology and pathogenesis. Most of the patients suffering from this syndrome are undiagnosed due to a lack of standard diagnostic criteria. Recent studies have shown the involvement of immune dysfunction and various pro-inflammatory cytokines in FM. Since there is so much uncertainty regarding the pathogenesis of FM, treatment modalities are very limited and ineffective. This review aimed to analyze the immunological mechanisms behind FM, attempting to deepen the understanding of its pathogenesis. Additionally, the review elucidates FM's associations with autoimmune diseases, highlighting shared pathophysiological mechanisms and overlapping symptoms. We synthesized current literature available on Google Scholar, PubMed, Springer, and Web of Science, the review explored the intricate interactions between genetic predisposition, immune dysregulation, and environmental factors in FM pathogenesis. The inclusion criteria prioritized studies focusing on the immunological aspect of FM. In conclusion, immune dysfunction has a role to play in the pathogenesis of FM, and immunomodulatory therapies have proven to be beneficial in the treatment of FM. Genetic variants, epigenetic modifications, and gut microbiome alterations are potential triggers for immune system dysfunction, contributing to the manifestation and exaggeration of FM symptoms. This review provided a comprehensive resource for researchers and clinicians, a guide for future investigations and clinical management towards improved outcomes and enhanced quality of life for individuals with FM., (Copyright© by the Egyptian Association of Immunologists.)

Introduction: Post-Covid Syndrome, Sick Building Syndrome, Silicone Breast Syndrome, Choric Fatigue Syndrome, Fibromyalgia -Autoimmunity to the Autonomic Nervous System.

Fibromyalgia (FM) remains a condition with a pathogenesis that is not completely understood, affecting a significant portion of the global population. This article summarises the main advances in FM during the last year. Even in 2023, research on FM was notably active. From a clinimetric perspective, studies have been conducted to evaluate the possibilities of interchanging the primary indices of disease severity, primarily for studies with substantial case numbers. Regarding FM pathogenesis, ongoing research focuses on small fiber neuropathy: some studies have documented its association with central sensitisation, while others have revealed distinct sensory profiles in patients with FM and small fiber neuropathy compared to those solely with small fiber neuropathy. Dorsal root ganglia seem to play a crucial role in the pathogenesis of FM as they host satellite glial cells, which are targeted by pain-driving immunoglobulin G. These antibodies have been identified in a subset of patients exhibiting high symptom severity. An important study conducted on animal models confirmed the role of neuroinflammation at the level of dorsal root ganglia, in this case mediated by polymorphonuclear neutrophils. Mounting evidence underscores the link between COVID-19 and the persistence of FM symptoms after recovery. In identifying potential biomarkers aiding FM diagnosis, research has also concentrated on studying the expression of specific circulating microRNAs. Recent discoveries have unveiled novel therapeutic strategies for FM, especially focused in non-pharmacological interventions. This includes a focus on non-invasive brain stimulation and exercise programs, all directed towards relieving symptoms and improving functionality in individuals affected by the condition.

Fibromyalgia (FM) is a chronic disease characterized by widespread musculoskeletal pain of unknown etiology. The condition is commonly associated with other symptoms, including fatigue, sleep disturbances, cognitive impairment, and depression. For this reason, FM is also referred to as FM syndrome. The nature of the pain is defined as nociplastic according to the latest international classification and is characterized by altered nervous sensitization both centrally and peripherally. Psychosocial conditions have traditionally been considered critical in the genesis of FM. However, recent studies in animal models and humans have provided new evidence in favor of an inflammatory and/or autoimmune pathogenesis. In support of this hypothesis are epidemiological data of an increased female prevalence, similar to that of autoimmune diseases, and the frequent association with immune-mediated inflammatory disorders. In addition, the observation of an increased incidence of this condition during long COVID revived the hypothesis of an infectious pathogenesis. This narrative review will, therefore, discuss the evidence supporting the immune-mediated pathogenesis of FM in light of the most current data available in the literature.

Pain is a significant issue in rheumatoid arthritis (RA) and psoriatic arthritis (PSA) and can have a negative impact on patients' quality of life. Despite optimal control of inflammatory disease, residual chronic pain remains a major unmet medical need in RA. Pain in RA can be secondary to inflammation but can also generate neuroendocrine responses that initiate neurogenic inflammation and enhance cytokine release, leading to persistent hyperalgesia. In addition to well-known cytokines such as TNFα and IL-6, other cytokines and the JAK-STAT pathway play a role in pain modulation and inflammation. The development of chronic pain in RA involves processes beyond inflammation or structural damage. Residual pain is often observed in patients even after achieving remission or low disease activity, suggesting the involvement of non-inflammatory and central sensitization mechanisms. Moreover, fibromyalgia syndrome (FMS) is prevalent in RA patients and may contribute to persistent pain. Factors such as depression, sleep disturbance, and pro-inflammatory cytokines may contribute to the development of fibromyalgia in RA. It is essential to identify and diagnose concomitant FMS in RA patients to better manage their symptoms. Further research is needed to unravel the complexities of pain in RA. Finally, recent studies have shown that JAK inhibitors effectively reduce residual pain in RA patients, suggesting pain-reducing effects independent of their anti-inflammatory properties., Competing Interests: Declaration of competing interest None, (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The aetiology of fibromyalgia is unknown; its symptoms may be related to a T-lymphocyte-mediated response to infectious organisms., Objectives: First, to test the hypothesis that fibromyalgia is associated with increased interferon (IFN)-γ-secreting T-lymphocytes after stimulation with Anaplasmataceae-related major surface proteins (MSPs) and the macromolecular translocation type IV secretion system effector ankyrin repeat domain-containing protein A (AnkA). Second, to ascertain the relationship in fibromyalgia between (i) the IFN-γ-secreting T-lymphocyte response to stimulation with Anaplasmataceae-related MSPs and AnkA, and (ii) co-infection by Borrelia and Yersinia spp., and antinuclear antibodies., Methods: Using a case-control design, patients fulfilling the American College of Rheumatology revised criteria for fibromyalgia, and controls, underwent the following blinded assessments: (i) enzyme- linked immune absorbent spot (ELISpot) IFN-γ release assay of T-lymphocyte reactivity to Anaplasmataceae-related MSPs and AnkA; (ii) ELISpot IFN-γ release assays of T-lymphocyte reactivity to three Borrelia antigens, namely Borrelia burgdorferi full antigen (B31); peptide mix (from Borrelia burgdorferi sensu stricto, Borrelia afzelii, Borrelia garinii ); and Borrelia burgdorferi lymphocyte function-associated antigen-1; (iii) immunoglobulin (Ig) A assay by enzyme-linked immunosorbent assay (ELISA) of antibodies to Yersinia spp.; (iv) IgG (ELISA) antibodies to Yersinia spp.; (v) serum antinuclear antibodies (immunofluorescence)., Results: The groups were age- and sex-matched. The mean (standard error) value of IFN-γ release for the fibromyalgia group was 1.52 (0.26), compared with 1.00 (0.22) for the controls. Generalised linear modelling (p<0.001) of IFN-γ release in the fibromyalgia patients showed significant main effects of all three indices of Borrelia infection and of antinuclear antibodies., Conclusion: Anaplasmataceae may play an aetiological role in fibromyalgia., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: The impact of sex, age, body mass index (BMI) in fibromyalgia is still unclear. A systematic review was conducted to investigate whether sex, age and BMI influence the clinical outcomes and rate of adverse events., Methods: The present study was performed according to the PRISMA guidelines. The literature search was performed in February 2021. All the RCTs investigating pharmacological strategies for fibromyalgia were accessed., Results: Data from 51 RCTs (17,311 patients) were collected. Short Form 36 emotional, Social function and physical role subscales showed evidence of a negative association with BMI (P = 0.02, P = 0.002 and P = 0.0001, respectively). Depression and anxiety subscales of the Hospital Anxiety and Depression score demonstrated evidence of a positive association with age (P = 0.04 and P = 0.001, respectively) and sex (P = 0.00005 and P = 0.0001, respectively). Visual analog scale evidenced a positive association with BMI (P = 0.04). Clinical Global Impression Severity scale demonstrated evidence of a negative association with BMI (P = 0.02)., Conclusion: Irrespective from the pharmacological approach, a higher BMI is negatively associated with a favorable outcome in patients with fibromyalgia. The association with sex and age remains controversial., Level of Evidence: I, systematic review of RCTs.

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.

Data on the association between fibromyalgia syndrome (FMS) and psoriasis are scarce. We aimed to examine the association between FMS and psoriasis using a large-scale observational population-based study. This cross-sectional study analyzed data from a big computerized database to evaluate potential differences in the prevalence of psoriasis between patients with FMS and matched control subjects. The study included 18,598 patients with FMS and 36,985 controls. The prevalence of psoriasis was increased in patients with FMS as compared with control subjects (6.7% vs. 4.8%, respectively; OR, 1.4; 95% CI, 1.3-1.5; P < 0.001). This association was robust to multivariate analysis adjustment for sex, age, ancestry, socioeconomic status, and healthcare utilization (OR, 1.3; 95% CI, 1.2-1.4; P < 0.001). When compared with patients with only FMS, patients with a dual diagnosis of FMS and psoriasis presented with FMS at a significantly older age, had a higher mean BMI, and a higher frequency of smoking. To conclude, we found a significant association between FMS and psoriasis. More extensive cooperation between dermatologists and rheumatologists is suggested to enable early identification of their co-occurrence.

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.

Fibromyalgia is one of the most important "rheumatic" disorders, after osteoarthritis. The etiology of the disease is still not clear. At the moment, the most defined pathological mechanism is the alteration of central pain pathways, and emotional conditions can trigger or worsen symptoms. Increasing evidence supports the role of mast cells in maintaining pain conditions such as musculoskeletal pain and central sensitization. Importantly, mast cells can mediate microglia activation through the production of proinflammatory cytokines such as IL-1β, IL-6, and TNFα. In addition, levels of chemokines and proinflammatory cytokines are enhanced in serum and could contribute to inflammation at systemic level. Despite the well-characterized relationship between the nervous system and inflammation, the mechanism that links the different pathological features of fibromyalgia, including stress-related manifestations, central sensitization, and dysregulation of the innate and adaptive immune responses is largely unknown. This review aims to provide an overview of the current understanding of the role of adaptive immune cells, in particular T cells, in the physiopathology of fibromyalgia. It also aims at linking the latest advances emerging from basic science to envisage new perspectives to explain the role of T cells in interconnecting the psychological, neurological, and inflammatory symptoms of fibromyalgia., Competing Interests: The authors declare no conflict of interest.

Since the first discovery that the bioactive lipid, lysophosphatidic acid (LPA) and LPA 1 receptor signaling play a role in the initiation of neuropathic pain (NeuP), accumulated reports have supported the original findings and extended the study toward possible therapeutic applications. The present review describes beneficial roles of LPA receptor signaling in a variety of chronic pain, such as peripheral NeuP induced by nerve injury, chemotherapy and diabetes, central NeuP induced by cerebral ischemia with hemorrhage and spinal cord injury, and fibromyalgia-like wide spread pain induced by repeated cold, psychological and muscular acidic stress. Emerging mechanistic findings are the feed-forward amplification of LPA production through LPA 1 , LPA 3 and microglia and the evidence for maintenance of chronic pain by LPA receptor signaling.

Objective: Rheumatoid arthritis (RA) patients with concomitant fibromyalgia (FM) exhibit alterations in brain connectivity synonymous with central sensitization. This study was undertaken to investigate how peripheral inflammation, the principal nociceptive stimulus in RA, interacts with brain connectivity in RA patients with FM., Methods: RA patients with concomitant FM and those without FM (FM+ and FM-, respectively; n = 27 per group) underwent functional connectivity magnetic resonance imaging. Seed-to-whole-brain functional connectivity analyses were conducted using seeds from the left mid/posterior insula and left inferior parietal lobule (IPL), which are regions that have been previously linked to FM symptoms and inflammation, respectively. The association between functional connectivity and erythrocyte sedimentation rate (ESR) was assessed in each group separately, followed by post hoc analyses to test for interaction effects. Cluster-level, family-wise error (FWE) rates were considered significant if the P value was less than 0.05., Results: The group of RA patients with FM and those without FM did not differ by age, sex, or ESR (P > 0.2). In FM+ RA patients, increased functional connectivity of the insula-left IPL, left IPL-dorsal anterior cingulate, and left IPL-medial prefrontal cortex regions correlated with higher levels of ESR (all FWE-corrected P < 0.05). Post hoc interaction analyses largely confirmed the relationship between ESR and connectivity changes as FM scores increased., Conclusion: We report the first neurobiologic evidence that FM in RA may be linked to peripheral inflammation via pronociceptive patterns of brain connectivity. In patients with such "bottom-up" pain centralization, concomitant symptoms may partially respond to antiinflammatory treatments., (© 2019, American College of Rheumatology.)

Fibromyalgia (FM) is a disease characterized by chronic widespread pain, fatigue, aches, joint stiffness, depression, cognitive dysfunction, and nonrestorative sleep. In FM, neurotransmission and glial activation can occur with an increase in inflammatory cytokines and involvement of mast cells (MCs) in the skin. FM skin biopsies show an increase in the number of MCs, as well as the production of corticotropin releasing hormone and substance P (SP) by the neurons, which in turn activate MCs to release neurosensitizing proinflammatory substances, such as cytokines, secreted preformed mediators, and lipids, which can exacerbate low-grade inflammation. In fact, certain proinflammatory cytokines are higher in FM and mediate muscle pain, the mechanism of which is not yet clear. MC-derived tumor necrosis factor (TNF) induces nerve growth factor (NGF) and participates in nerve fiber elongation in skin hypersensitivity. IL-37 is an inhibitor of proinflammatory IL-1 family members, which are generated and released by MCs. The goal of this article is to demonstrate that inflammatory cytokines and MC products play a role in FM and that inflammation may be inhibited by IL-37. Here, we propose IL-37 as a cytokine that contributes to improve the pathogenesis of FM by blocking IL-1 family members., (© 2019 Wiley Periodicals, Inc.)

Background: Fatigue is a common symptom of systemic autoimmune rheumatic disease (SARD). Patients with SARD have a protracted pre-clinical phase during which progressive immunologic derangements occur culminating in disease. In this study, we sought to determine when fatigue develops and whether its presence correlates with inflammatory factors or predicts disease progression., Methods: Anti-nuclear antibody (ANA)-negative healthy controls (HCs) and ANA-positive participants with no criteria, at least one clinical criteria (undifferentiated connective tissue disease, UCTD), or meeting SARD classification criteria were recruited. Fatigue was assessed using a modified version of the FACIT-F questionnaire and the presence of fibromyalgia determined using a questionnaire based on the modified 2010 ACR criteria. Peripheral blood expression of five IFN-induced genes was quantified by NanoString and the levels of IL-1β, IL-6, or TNF-α by ELISA., Results: Fatigue was as prevalent and severe in individuals lacking SARD criteria as it was in UCTD and SARD. Overall, ~ 1/3 of ANA + subjects met fibromyalgia criteria, with no differences between sub-groups. Although fatigue was more severe in these individuals, those lacking fibromyalgia remained significantly more fatigued than ANA - HC. However, even in these subjects, fatigue correlated with the widespread pain index and symptom severity scores on the fibromyalgia questionnaire. Fatigue was not associated with elevated cytokine levels in any of the ANA + sub-groups and did not predict imminent disease progression., Conclusions: Fatigue is common in ANA + individuals lacking sufficient criteria for a SARD diagnosis, correlates with fibromyalgia-related symptoms, and is not associated with inflammation or predictive of disease progression.

Fibromyalgia (FM) is a chronic syndrome characterized by widespread musculoskeletal pain, and physical and emotional symptoms. Although its pathophysiology is largely unknown, immune-inflammatory pathways may be involved. We examined serum interleukin (IL)-6, high sensitivity C-reactive protein (hs-CRP), CXCL-8, and IL-10 in 67 female FM patients and 35 healthy women while adjusting for age, body mass index (BMI), and comorbid disorders. We scored the Fibromyalgia Severity Score, Widespread Pain Index (WPI), Symptom Severity Scale (SSS), Hospital Anxiety (HADS-A), and Depression Scale and the Perceived Stress Scale (PSS-10). Clinical rating scales were significantly higher in FM patients than in controls. After adjusting for covariates, IL-6, IL-10, and CXCL-8 were lower in FM than in HC, whereas hs-CRP did not show any difference. Binary regression analyses showed that the diagnosis FM was associated with lowered IL-10, quality of sleep, aerobic activities, and increased HADS-A and comorbidities. Neural networks showed that WPI was best predicted by quality of sleep, PSS-10, HADS-A, and the cytokines, while SSS was best predicted by PSS-10, HADS-A, and IL-10. Lowered levels of cytokines are associated with FM independently from confounders. Lowered IL-6 and IL-10 signaling may play a role in the pathophysiology of FM.

Fibromyalgia (FM) is a highly prevalent and disabling syndrome characterized by chronic widespread musculoskeletal pain and a broad range of cognitive and affective symptoms. Up to now, the pathogenesis of FM is unknown although a peripheral and central sensitization involving an imbalance on immune biomarkers appears to have a relevant role in its aetiology. The aim of this study was to extend previous clinical findings of Mindfulness-Based Stress Reduction (MBSR) to both its impact on clinical symptomatology and immune biomarkers (IL-6, CXCL8, IL-10 and hs-CRP), and also to explore the role of biomarkers as predictors of efficacy., Methods: A total of 70 female patients with FM were randomly assigned to two treatment modalities, namely Treatment as Usual (TAU) plus MBSR (n = 35) or TAU alone (n = 35). This study is embedded within a larger RCT (n = 225) that includes three study arms (TAU; TAU plus MBSR; and TAU plus the psychoeducative intervention FibroQoL), and a 12-month follow-up (clinical trial registration: NCT02561416). Blood cytokine assays and clinical assessment were conducted at baseline and post-treatment. Treatment effects were analysed using linear mixed models with intention to treat and per protocol analyses. In order to evaluate the balance between pro- and anti-inflammatory pathways, ratios of pro-inflammatory IL-6, CXCL8 and hs-CRP with the anti-inflammatory cytokine IL-10 were calculated (i.e. IL-6/IL-10, CXCL8/IL10 and hs-CRP/IL-10)., Results: The results show that MBSR is an efficacious intervention to reduce clinical severity of patients with FM. MBSR also prevents the tendency of IL-10 to decrease as observed in the TAU group. Higher levels of baseline CXCL8 levels attenuate the beneficial effect of MBSR practice on clinical symptomatology, including pain, energy, stiffness or quality of sleep. Furthermore, higher baseline IL-6/IL-10 and CXCL8/IL-10 ratios were associated with less improvement in psychological inflexibility following MBSR treatment., Discussion: Our results show that mindfulness training has clinical efficacy in patients with FM. The results suggest that MBSR has significant immune regulatory effects in FM patients, while immune-inflammatory pathways may in part predict the clinical efficacy of MBSR. These cytokines and chemokines may be adequate biomarkers to monitor responsivity to MBSR., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Fibromyalgia is a multifaceted disease. The clinical picture of fibromyalgia covers numerous comorbidities. Each comorbidity stands as a distinct condition. However, common pathophysiologic factors are occupied in their background. Along with the genetic, environmental and neuro-hormonal factors, inflammation has been supposed to have role in the pathogenesis of fibromyalgia. The aim of the present article was to review the current literature regarding the potential role of inflammation in the pathogenesis and treatment of fibromyalgia. A literature search was conducted through PubMed/MEDLINE and Web of Science databases using relevant keywords. Recent evidence on this highly studied topic indicates that fibromyalgia has an immunological background. Cytokines/chemokines, lipid mediators, oxidative stress and several plasma-derived factors underlie the inflammatory state in fibromyalgia. There are potential new therapeutic options targeting inflammatory pathways in fibromyalgia patients. In conclusion, there is evidence to support the inflammation-driven pathways in the pathogenesis of fibromyalgia. However, further research is required to fully understand the network of inflammation and its possible role in diagnosis and/or treatment of fibromyalgia.

Background/aims: Fibromyalgia (FM) is a common rheumatologic disease characterized by chronic widespread pain, along with various clinical manifestations including atypical autoimmune characteristics. Despite its high prevalence, there remain no approved laboratory tests to identify specific manifestations of FM, or to rule out FM from other rheumatic diseases. Anti-dense fine speckled 70 (anti-DFS70) antibodies were initially identified as a form of anti-nuclear antibodies in a patient with interstitial cystitis. Anti-DFS70 antibodies are found in ≤ 10% of healthy individuals, but have suggestive negative association with autoimmune diseases; however, the clinical significance of these autoantibodies in FM patients remains poorly understood., Methods: We examined 39 patients with FM, along with 17 patients with systemic lupus erythematosus (SLE), and 19 healthy individuals (HI). Patients were compared based on physical measurements, disease duration, tender point counts, FM Impact Questionnaire (FIQ) scores, visual analog scale (VAS) for pain, somatic symptoms, and anti-DFS70 antibodies., Results: Levels of anti-DFS70 antibodies were significantly higher in the FM and HI groups than in those with SLE. Both anti-DFS70 antibodies and VAS scores were positively correlated with FM. Within the FM group, patients with arthralgia had higher anti-DFS70 antibody values compared to those without arthralgia (p = 0.024); antibody levels were also higher in patients with sleep disturbances relative to those without sleep issues (p = 0.024). In contrast, there were no correlations between anti-DFS70 antibodies and age, body mass index, disease duration, tender point counts, FIQ, short-form health survey results, or other clinical manifestations., Conclusion: Anti-DFS70 antibodies may represent a useful biomarker for differentiating between FM and other autoimmune diseases. The levels of anti-DFS70 antibodies were also significantly higher among patients with arthralgia and sleep disturbances. Further investigations are necessary to evaluate the relationships between anti-DFS70 antibodies and other cytokines as a predictive marker for pain.

Introduction: A significant proportion of patients with fibromyalgia (FM) complain of dry eyes and mouth. Many Sjögren's syndrome (SS) patients also complain of FM symptoms, and there is literature that suggests that there is interplay between these two disorders. Recently, the presence of novel tissue specific autoantibodies (TSAs), SP-1, CA6, and PSP, has been observed in the early stages of SS. These early markers present themselves before the classic autoantibodies, such as SS-A/Ro, SS-B/La, ANA, and RF., Objective: This study aims to examine the relationship between SS and FM by testing patients with FM who also complain of xerostomia and sicca symptoms, for SS- related biomarkers., Methods: A cohort of 185 patients who met both the 1990 and 2010 preliminary diagnostic criteria for FM and who admitted to symptoms of sicca and/or xerostomia were selected for this study. Serum from 151 study patients was sent to a tertiary lab, Immco Diagnostics, for testing of the classic autoantibodies (SS-A/Ro, SS-B/La, ANA and RF) and TSAs (SP-1, CA6, PSP), while the rest (34 patients) were tested for TSAs only., Results: Of the 151 patients who were evaluated for both the early and classic SS markers, 49 (32%) tested positive for SS autoantibodies. Of those, 4 (3%) tested positive for the classic SS markers only, 40 (26%) of the patients tested positive for the early SS markers only, and 5 (3%) tested positive for both the early and classic SS markers. Of the 34 patients who were tested for early SS markers only, 10 (29%) tested positive and 24 (71%) tested negative. Further analysis of all the patients that tested positive for the TSAs (n = 55), found 83.6% (46) were positive for SP-1, 12.7% (7) were positive for CA6 and 20.0% (11) were positive for PSP. 85.5% (47) of these patients were positive for only one of the TSAs and 14.5% (8) were positive for more than one TSA., Conclusion: Approximately 1/3 of FM patients that were tested for both the TSAs and classic Sjögren's markers tested positive for a SS biomarker, and the majority of those patients tested positive for one or more of the TSAs. This suggests that autoimmunity, specifically early- stage Sjögren's syndrome, may be involved in the pathophysiology of fibromyalgia., (Copyright © 2018. Published by Elsevier B.V.)

Objectives: Hyperbaric oxygen therapy (HBOT) has been used as treatment for different clinical conditions, including fibromyalgia (FM). HBOT modulates brain activity, ameliorates chronic pain and modifies the ratio of immune cells. Clinical studies have provided evidence that FM is associated with immune system dysregulation. In the present study we aimed to evaluate the effect of HBOT on immune system and on the quality of life-style of FM patients., Methods: Patients with primary FM and controls were treated with HBOT. Physical, emotional and social assessment, quality of sleep, tender points, intensity score, WPI and symptom severity were evaluated before and after HBOT. Furthermore, a characterisation of CD4 T lymphocytes and their cytokine production was performed by flow cytometry. The expression of TNF-α, IFN-γ, IL-17, IL-9 and IL-22 was also assessed by RT-PCR. Finally, the serum levels of serotonin were evaluated by ELISA., Results: Our results confirm the participation of immune system in the pathogenesis of FM and highlight the impact of HBOT treatment, with particular regard to the changes on proinflammatory cytokines production by CD4 T cells subsets., Conclusions: FM patients show a Th1 signature and the activation of this subset is modulated by HBOT.

Evidence suggests that the gut microbiota might play an important role in fibromyalgia syndrome (FMS) and chronic fatigue syndrome (CFS). Our goal is to systematically review the reported effect of probiotic treatments in patients diagnosed with FMS or CFS. A systematic review was carried out using 14 databases (PubMed, Cochrane Library, Scopus, PsycINFO, and others) in February 2016 to search for randomised controlled trials (RCTs) and pilot studies of CFS or FMS patient, published in the last ten years (from 2006 to 2016). The Jadad scale was used to asseverate the quality of the clinical trials considered. Two studies (n=83) met the inclusion criteria, which were performed in CFS patients and both studies were considered as a 'High range of quality score'. The administration of Lactobacillus casei strain Shirota in CFS patients, over the course of 8 weeks, reduced anxiety scores. Likewise, this probiotic changed the faecal composition following 8 weeks of treatment. Additionally, the treatment with Bifidobacterium infantis 35624 in CFS patients, during the same period, reduced inflammatory biomarkers. The evidence about the usefulness of probiotics in CFS and FMS patients remains limited. The studied strains of probiotics have demonstrated a significant effect on modulating the anxiety and inflammatory processes in CFS patients. However, more experimental research, focusing mainly on the symptoms of the pathologies studied, is needed.

We aimed to investigate the changes in the objective and subjective sleep variables during painful episodes of fibromyalgia and post-episode period, and to evaluate the impact of the sleep variables on the current clinical, psychological, and immunologic parameters. Thirty-one consecutive patients who were referred to the Erenköy Physical Therapy and Rehabilitation Polyclinic with a diagnosis of fibromyalgia were evaluated before and in the sixth week of the acute pain treatment. The sleep variables were measured by polysomnography, Pittsburgh Sleep Quality Index, and Epworth Sleepiness Scale. The clinical and psychiatric assessment of patients was performed by using Fibromyalgia Impact Questionnaire; Patient Health Questionnaire-Somatic, Anxiety, and Depressive Symptoms; and Visual Analog Scale. Serum pro-inflammatory molecules were measured to evaluate the immunological status. The pain treatment significantly affected subjective sleep variables, psychiatric variables, clinical variables, and IL-6 levels. The subjective sleep parameters, clinical and psychiatric variables, and IL-6 levels were improved with pain treatment in fibromyalgia. The objective sleep variables, IL-1 and TNF-alpha levels were not significantly improved with the pain treatment, and they were not related to clinical presentation of patients with fibromyalgia. Subjective variability of sleep contributes to the clinical presentation, suggesting that the objective structure is trait-specific with IL-1 and TNF-alpha., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The aims of this study were to compare circulating cytokines between FM and healthy controls and to investigate the effect on cytokine levels by 15 weeks of progressive resistance exercise or relaxation therapy in FM. Baseline plasma cytokine levels and clinical data were analyzed in 125 women with FM and 130 age-matched healthy women. The FM women were then randomized to progressive resistance exercise ( n = 49) or relaxation ( n = 43). Baseline IL-2, IL-6, TNF- α , IP-10, and eotaxin were higher in FM than in healthy controls ( P < 0.041), whereas IL-1 β was lower ( P < 0.001). There were weak correlations between cytokine levels and clinical variables. After both interventions, IL-1ra had increased ( P = 0.004), while IL-1 β had increased in the relaxation group ( P = 0.002). Changes of IFN- γ , IL-2, IL-4, IL-6, IL-8, and IL-17A were weakly correlated with changes of PPT, but there were no significant correlations between changes of cytokine and changes in other clinical variables. The elevated plasma levels of several cytokines supports the hypothesis that chronic systemic inflammation may underlie the pathophysiology of FM even if the relation to clinical variables was weak. However, 15 weeks of resistance exercise, as performed in this study, did not show any anti-inflammatory effect on neither FM symptoms nor clinical and functional variables. This trial is registered with ClinicalTrials.gov NCT01226784, registered October 21, 2010. The first patient was recruited October 28, 2010.

Objective: In patients with fibromyalgia (FM), exercise is indicated for symptomatic treatment. However, little is known about the inflammatory response to acute exercise in these patients. This study examines the acute effects of exercise on the inflammatory response in patients with FM., Methods: A systematic review was conducted using PubMed, PsycINFO, Web of Science, SportDiscus, Scopus, Virtual Health Library (VHL), and Cochrane Library databases., Results: Six studies that met the inclusion criteria were included in the analysis; three of them evaluated the effects of resistive exercise, while three evaluated the effects of aerobic exercise. Several studies evaluated pro-inflammatory (interleukin [IL]-6, IL-8, IL-1β, IL-18, tumor necrosis factor-α) and anti-inflammatory cytokine levels (IL-10) and stress (Hsp72) protein levels before and after the intervention with exercise. Studies found a low-grade baseline chronic inflammatory state in patients with FM, demonstrated by the alteration of one or more of the studied markers., Conclusions: We suggest that patients with FM probably have low-grade chronic inflammation, because studies found higher concentrations of IL-8 and TNF-α and high expression of IL-10 in these patients; however, the effects of exercise on the inflammatory markers in these patients are unclear. Although more research is needed on the effect of exercise on inflammation, none of the studies reported worsening of symptoms with exercise recommended as treatment., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: The exact mechanism of arterial stiffness in fibromyalgia (FM) remains unclear. The present study aimed to evaluate the association between thyroid function and markers of arterial function in postmenopausal FM patients., Methods: This study included 163 postmenopausal FM patients without any known cardiovascular diseases and within a normal reference range of thyroid-stimulating hormone (TSH) level. Clinical parameters including the Fibromyalgia Impact Questionnaire (FIQ), the pain visual analogical scale (VAS) and tender point counts were measured. Vascular function was assessed by brachial-ankle pulse wave velocity (baPWV) and flow-mediated dilation (FMD). We evaluated the associations between arterial markers and serum TSH, free thyroxin, as well as serum thyroidperoxidase autoantibody (TPO Ab)., Results: Patients with a high baPWV (≥ 1490 cm/s) showed more positive TPO Ab (65% vs. 10%, P = 0.006) than those with a normal baPWV. Additionally, the baPWV values of patients with positive TPO Ab were significantly different from those with negative TPO Ab. Age, FIQ and TPO Ab were significantly correlated with baPWV and FMD (all P < 0.05). Multiple linear regression analysis revealed that the only significant predictors of baPWV were age, FIQ and the presence of TPO Ab after adjustment for traditional risk factors. A significant association was also found between FMD and positive TPO Ab., Conclusion: Age, functional status and presence of TPO Ab were significantly associated with increased arterial stiffness in postmenopausal FM patients. Given the combined thyroid autoimmunity in FM patients, a re-evaluation of the effects on the vasculature may be necessary., (© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.)

Aim: Fibromyalgia syndrome (FMS) is defined as chronic widespread pain that cannot be accounted for by any other medical disorder. Our aim was to explore the prevalence of thyroid autoimmunity in patients with FMS., Methods: For determining thyroid function in 207 FMS patients, we tested for the titers of free tri-iodothyronine, free thyroxine, thyroid-stimulating hormone (TSH), anti-thyroid peroxidase antibody (TPOAb), anti-thyroglobulin antibody (TgAb) and anti-TSH receptor antibody (TRAb)., Results: Twenty-five patients who had either subclinical hyper- or hypothyroidism, or overt hypothyroidism were excluded. Sixty-nine FMS patients with autoimmune thyroid diseases (AITD) (37.9%, 69/182) were identified. The prevalence of positivity for TRAb, TgAb and TPOAb was 20.3% (n = 37), 16.5% (n = 30) and 13.2% (n = 24), respectively. Compared to control populations in previous studies, the prevalence of TRAb positivity was high, and titers of TRAb were low (1.0-1.5 IU/L). The prevalence of TPOAb and TgAb positivity was not significantly higher than that reported in FMS patients in previous studies. Clinical symptom profiles were identical for FMS patients with and without AITD., Conclusion: We found a high prevalence of AITD among 207 patients with clinically defined FMS, with TRAb being especially prominent among these patients. Further study is needed to evaluate changes in thyroid function among FMS patients with AITD., (© 2016 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Objectives: The high concordance between systemic lupus erythematosus (SLE) and fibromyalgia (FM) suggests common underlying mechanisms related to pain and distress in both patient groups. Increasing evidence indicates that N-methyl-D-aspartate receptors (NMDARs) play a major role in the induction and maintenance of central sensitisation with chronic pain. In this study, we evaluated the role of anti-NMDAR antibodies in the development of FM in patients with SLE., Methods: Sera from 104 patients with SLE, 112 patients with FM, and 110 healthy controls were analysed to detect antibodies to the N-terminus of the 2B subunit of NMDARs (GluN2B). Subjects underwent clinical examination and neuropsychiatric evaluation, and completed a questionnaire regarding FM and neuropsychiatric symptoms., Results: Of the 104 patients with SLE, 18 (17.3%) had FM. The anti-GluN2B antibody titer was significantly higher in patients with SLE (p<0.001). Among patients with SLE, those with concomitant FM had higher anti-GluN2B antibody titers (p<0.05). The anti-GluN2B antibody titer was associated positively with the tender point count (p=0.016) and the widespread pain index (p=0.005), but not with other symptom measurements. Anti-GluN2B antibody-positive patients with SLE were more likely to have neuropsychiatric systemic lupus erythematosus (NPSLE) and concomitant FM (p<0.05). Multivariate analysis showed that the anti-GluN2B antibody was an independent predictor of concomitant FM and NPSLE., Conclusions: To our knowledge, this report is the first to suggest that anti-NMDAR antibodies are associated with the pathogenesis of FM with SLE.

Generalized pain with tender points in specific areas accompanied by systemic symptoms such as fatigue and stiffness is characteristic of fibromyalgia (FM) syndrome. The genesis of FM is still being investigated with conflicting data on factors including autonomic dysfunction, neurotransmitters, and hormones often in combination with external stressful events. However, recent research is starting to suggest that there is a previously underappreciated subtype of fibromyalgia called inflammatory Fibromyalgia (iFM). Recent studies have described cytokines, inflammatory markers, sleep disorders, hyperalgesia, cognitive dysfunction, serum leptin levels and other inflammatory indicators as potential markers for iFM. This article will; 1) review the inflammatory markers and abnormal levels of other laboratory indicators that can help to identify the subgroup of patients that fall into the new category of Inflammatory Fibromyalgia [1-5] and 2) review all completed trials that were focused on treating this new category of disease. Through this review it is hoped that and further understanding of the complexity of the etiology of fibromyalgia can be explored., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Introduction: Fibromyalgia (FM) is a common, complex chronic widespread pain condition is characterized by fatigue, sleep disturbance and cognitive dysfunction. Treatment of FM is difficult, requiring both pharmacological and non-pharmacological approaches, with an empiric approach to drug therapy focused toward individual symptoms, particularly pain. The effectiveness of current medications is limited with many patients discontinuing use., Areas Covered: A systemic database search has identified 26 molecular entities as potential emerging drug therapies. Advances in the understanding of the pathophysiology of FM provides clues to targets for new medications. Investigation of bioamine modulation and α2δ ligands and novel targets such as dopamine receptors, NMDA receptors, cannabinoid receptors, melatonin receptors and potassium channels has identified potential drug therapies., Expert Opinion: Modest improvement of health status in patients with FM has been observed with drugs targeting a diverse range of molecular mechanisms. No single drug, however, offered substantial efficacy against all the symptoms characteristic of FM. Identification of new and improved therapies for FM needs to address the heterogeneity of the condition, which suggests existence of patient subgroups, the relationship of central and peripheral aspects of the pathophysiology and a requirement of combination therapy with drugs targeting multiple molecular mechanisms.

Background: This study aimed at investigating the effect of a resistance exercise intervention on the interstitial muscle levels of pro-inflammatory cytokines in fibromyalgia (FMS) and healthy controls (CON)., Methods: Twenty-four female patients with FMS (54 ± 8 years) and 27 female CON (54 ± 9 years) were subjected to intramuscular microdialysis of the most painful vastus lateralis muscle before and after 15 weeks of progressive resistance exercise twice per week. Baseline dialysates were sampled in the resting muscle 140 min after insertion of the microdialysis catheter. The participants then performed repetitive dynamic contractions (knee extension) for 20 min, followed by 60 min rest. Pain intensity was assessed with a 0-100 mm visual analogue scale (VAS), and fatigue was assessed with Borg's RPE throughout microdialysis. Dialysates were sampled every 20 min and analyzed with Luminex for interleukin (IL)-1β, tumor necrosis factor (TNF) alpha, IL-6, and IL-8., Results: At both sessions and for both groups the dynamic contractions increased pain (P < 0.012) and fatigue (P < 0.001). The levels of TNF were lower in the FMS group than the CON group at both sessions (P < 0.05), but none of the other cytokines differed between the groups. IL-6 and IL-8 increased after the dynamic contractions in both groups (P < 0.010), while TNF increased only in CON (P < 0.05) and IL-1β did not change. Overall pain intensity was reduced after the 15 weeks of resistance exercise in FMS (P < 0.05), but there was no changes in fatigue or cytokine levels., Conclusion: Progressive resistance exercise for 15 weeks did not affect the interstitial levels of IL-1β, TNF, IL-6, and IL-8 in the vastus lateralis muscle of FMS patients or CON., Trial Registration: Clinicaltrials.gov NCT01226784 , registered 21 October 2010.

Fibromyalgia (FM) is a prevalent disorder defined by the presence of chronic widespread pain in association with fatigue, sleep disturbances and cognitive dysfunction. Recent studies indicate that bipolar spectrum disorders frequently co-occur in individuals with FM. Furthermore, shared pathophysiological mechanisms anticipate remarkable phenomenological similarities between FM and BD. A comprehensive search of the English literature was carried out in the Pubmed/MEDLINE database through May 10th, 2015 to identify unique references pertaining to the epidemiology and shared pathophysiology between FM and bipolar disorder (BD). Overlapping neural circuits may underpin parallel clinical manifestations of both disorders. Fibromyalgia and BD are both characterized by functional abnormalities in the hypothalamic-pituitary-adrenal axis, higher levels of inflammatory mediators, oxidative and nitrosative stress as well as mitochondrial dysfunction. An over-activation of the kynurenine pathway in both illnesses drives tryptophan away from the production of serotonin and melatonin, leading to affective symptoms, circadian rhythm disturbances and abnormalities in pain processing. In addition, both disorders are associated with impaired neuroplasticity (e.g., altered brain-derived neurotrophic factor signaling). The recognition of the symptomatic and pathophysiological overlapping between FM and bipolar spectrum disorders has relevant etiological, clinical and therapeutic implications that deserve future research consideration.

To investigate how autoimmune thyroiditis (ATD) affects the clinical presentation of established rheumatoid arthritis (RA) with particular reference to fibromyalgia and chronic widespread pain (CWP). A cohort of 204 patients with RA for whom the presence or absence of autoimmune thyroid antibodies was documented was examined for the relationships between thyroid autoantibodies and fibromyalgia or CWP. We identified 29 % who tested positive for antithyroid peroxidase antibodies (TPOAb). The anti-thyroglobulin antibody (TgAb) was found in 24 %. Among the thyroid autoantibody-positive patients, 40 % had a diagnosis of fibromyalgia or CWP versus 17 % for antibody negative patients. Logistic regression analyses (adjusted by age, sex, diabetes and BMI) indicated that TPOAb-positive patients were more likely to have fibromyalgia or CWP, with an odds ratio (OR) of 4.641, 95 % confidence interval (CI) (2.110-10.207) P < .001. Adjusting for spinal degenerative disc disease did not change the association with fibromyalgia, OR 4.458, 95 % CI (1.950-10.191), P < .001. The OR between TgAb and fibromyalgia was not significant (P > .05). Additional logistic regression analyses (adjusted by age, sex and BMI) indicated a significant relationship between TPOAb and fibromyalgia or CWP in patients without diabetes and those without hypothyroidism (OR of 4.873, 95 % CI (1.877-12.653), P = .001 and OR of 4.615 95 % CI (1.810-11.770), P = .001, respectively). There may be a positive association between the ATD antibody TPOAb, and fibromyalgia syndrome and CWP in patients with established RA.

Fibromyalgia syndrome (FMS) is characterized by chronic widespread pain and additional associated symptoms, such as fatigue, sleep disturbances and depressive moods. The pathophysiology of pain in FMS is unclear. In recent years, an involvement of the thinly myelinated A-delta and the unmyelinated C-nerve fibers has been reported in FMS patients. Independent research groups published consistent objective and multidimensional findings of damage to these small nerve fibers, such as disturbances of fiber function, electrical properties and morphological changes. All these alterations are not specific for FMS; however, they were described for the first time in subgroups of FMS patients. While the reasons for this small fiber pathology and its contribution to FMS pain are still unclear, a new research field has now been opened that will focus on uncovering the underlying pathophysiology. This review article summarizes these new findings and discusses the significance for the understanding of FMS.

Making a correct diagnosis is pivotal in the practice of clinical rheumatology. Occasionally, the consultation fails to provide desired clarity in making labeling an individual as having fibromyalgia (FM), systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA). A chemokine and cytokine multiplex assay was developed and tested with the goal of improving and achieving an accurate differential diagnosis. 160 patients with FM, 98 with RA and 100 with SLE fulfilling accepted criteria were recruited and compared to 119 controls. Supernatant cytokine concentrations for IL-6, IL-8, MIP-1 alpha and MIP-1 beta were determined using the Luminex multiplex immunoassay bead array technology after mitogenic stimulation of cultured peripheral blood mononuclear cells. Each patient's profile was scored using a logistical regression model to achieve statistically determined weighting for each chemokine and cytokine. Among the 477 patients evaluated, the mean scores for FM (1.7 ± 1.2; 1.52-1.89), controls (-3.56 ± 5.7; -4.59 to -2.54), RA (-0.68 ± 2.26; -1.12 to -0.23) and SLE (-1.45 ± 3.34, -2.1 to -0.79). Ninety-three percent with FM scored positive compared to only 11% of healthy controls, 69% RA or 71% SLE patients had negative scores. The sensitivity, specificity, positive predictive and negative predictive value for having FM compared to controls was 93, 89, 92 and 91%, respectively (p < 2.2 × 10(-16)). Evaluating cytokine and chemokine profiles in stimulated cells reveals patterns that are uniquely present in patients with FM. This assay can be a useful tool in assisting clinicians in differentiating systemic inflammatory autoimmune processes from FM and its related syndromes and healthy individuals.

Background: Fibromyalgia (FM) is defined as a widely distributed pain. While many rheumatologists and pain physicians have considered it to be a pain disorder, psychiatry, psychology, and general medicine have deemed it to be a syndrome (FMS) or psychosomatic disorder. The lack of concrete structural and/or pathological evidence has made patients suffer prejudice that FMS is a medically unexplained symptom, implying inauthenticity. Furthermore, FMS often exhibits comorbidity with rheumatoid arthritis (RA) or spondyloarthritis (SpA), both of which show similar indications. In this study, disease specific biomarkers were sought in blood samples from patients to facilitate objective diagnoses of FMS, and distinguish it from RA and SpA., Methods: Peripheral blood mononuclear cells (PBMCs) from patients and healthy donors (HD) were subjected to multicolor flow cytometric analysis. The percentage of mucosal-associated invariant T (MAIT) cells in PBMCs and the mean fluorescent intensity (MFI) of cell surface antigen expression in MAIT cells were analyzed., Results: There was a decrease in the MAIT cell population in FMS, RA, and SpA compared with HD. Among the cell surface antigens in MAIT cells, three chemokine receptors, CCR4, CCR7, and CXCR1, a natural killer (NK) receptor, NKp80, a signaling lymphocyte associated molecule (SLAM) family, CD150, a degrunulation marker, CD107a, and a coreceptor, CD8β emerged as potential biomarkers for FMS to distinguish from HD. Additionally, a memory marker, CD44 and an inflammatory chemokine receptor, CXCR1 appeared possible markers for RA, while a homeostatic chemokine receptor, CXCR4 deserved for SpA to differentiate from FMS. Furthermore, the drug treatment interruption resulted in alternation of the expression of CCR4, CCR5, CXCR4, CD27, CD28, inducible costimulatory molecule (ICOS), CD127 (IL-7 receptor α), CD94, NKp80, an activation marker, CD69, an integrin family member, CD49d, and a dipeptidase, CD26, in FMS., Conclusions: Combined with the currently available diagnostic procedures and criteria, analysis of MAIT cells offers a more objective standard for the diagnosis of FMS, RA, and SpA, which exhibit multifaceted and confusingly similar clinical manifestations.

There is an increasing interest in understanding the biological mechanism underpinning fibromyalgia (FM) and chronic fatigue syndrome (CFS). Despite the presence of mixed findings in this area, a few biological systems have been consistently involved, and the increasing number of studies in the field is encouraging. This chapter will focus on inflammatory and oxidative stress pathways and on the neuroendocrine system, which have been more commonly examined. Chronic inflammation, together with raised levels of oxidative stress and mitochondrial dysfunction, has been increasingly associated with the manifestation of symptoms such as pain, fatigue, impaired memory, and depression, which largely characterise at least some patients suffering from CFS and FM. Furthermore, the presence of blunted hypothalamic-pituitary-adrenal axis activity, with reduced cortisol secretion both at baseline and in response to stimulation tests, suggests a role for the hypothalamic-pituitary-adrenal axis and cortisol in the pathogenesis of these syndromes. However, to what extent these systems' abnormalities could be considered as primary or secondary factors causing FM and CFS has yet to be clarified., (© 2015 S. Karger AG, Basel.)

Objectives: The present paper aimed at reviewing literature data on the inflammatory hypothesis of mood spectrum, as well as the overlapping features with some chronic rheumatologic disorders, in particular fibromyalgia and chronic fatigue syndrome., Methods: A literature search was carried out for English papers published in the years 2000-2014, while using the following words: mood spectrum, depression, bipolar disorders, fibromyalgia, chronic fatigue syndrome, neurotransmitters, inflammation, neuroinflammation, cytokines., Results: Overlapping features were highlighted between mood spectrum, fibromyalgia and chronic fatigue syndrome suggesting common underlying mechanisms at pathophysiological level involving both central nervous and the immune systems., Conclusions: Taken together, the literature would suggest that the borders between different medical domains should be reconsidered in the light of common processes linking them.

Background: The multiple symptoms of chronic fatigue syndrome (CFS) and fibromyalgia resemble those described in patients suffering from autoimmune/inflammatory syndrome induced by adjuvants (ASIA). It has been suggested that chronic metal-induced inflammation might play a role both in CFS and fibromyalgia as well as in ASIA. Humans are exposed to metals mainly through the release of metal ions from corroding dental restorations and orthopedic implants, food, vaccines and jewelry. Metals readily bind to sulphur and other groups in the mitochondria, enzymes and cell proteins. Metal-bound proteins are recognized by the immune system of susceptible subjects and might trigger an abnormal immune response, including allergy and autoimmunity., Objectives: To study three subjects with CFS and two with fibromyalgia, all of whom suspected metal exposure as a trigger for their ill health., Methods: We measured delayed-type hypersensitivity to metals (metal allergy) using a validated lymphocyte transformation test, LTT-MELISA. All patients except one were sensitized to metals present in their dental restorations. The remaining patient reacted to metals in his skull implant. The removal of sensitizing metals resulted in long-term health improvement. Nine healthy controls matched for gender and age showed only marginal reactivity to the metals tested., Conclusions: Patients with CFS and fibromyalgia are frequently sensitized to metals found in the environment or used in dentistry and surgery. This allergy to metals might initiate or aggravate non-specific symptoms in metal-sensitized patients.

Background and Objectives: The association between attachment style and subjective pain is controversially discussed and the influence of attachment styles on cytokine levels in chronic pain has received little attention in research. In this prospective longitudinal clinical study, we evaluated the relationship between cytokines, attachment style and subjective pain intensity as well as pain-related functioning in patients with fibromyalgia (FM) who underwent a 4-week multidisciplinary pain therapy., Materials and Methods: The attachment style was determined in 43 patients with FM using the relationship questionnaire (RQ-2) and subjective pain with the German version of the West Haven-Yale multidimensional pain inventory. Serum levels of the proinflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin 8 (IL-8) and the anti-inflammatory cytokines IL-4 and IL-10 were assessed before and after treatment and additionally once only in 18 healthy controls (Bio-Plex system)., Results: Patients with FM syndrome were significantly more often insecurely attached than healthy controls (p = 0.001). Serum levels of TNF-α (p = 0.001) and IL-10 (p = 0.039) were significantly higher in FM patients compared to controls. Attachment was unrelated to IL-4, IL-8, and IL-10 levels. Insecurely attached FM patients had significantly higher levels of TNF-α (p = 0.002). than securely attached patients. Insecurely and securely attached patients did not differ in subjective levels of pain severity, activity or functional interference. Cytokine levels were not correlated with subjective levels of pain severity or functional interference. Multidisciplinary pain therapy significantly reduced cytokine levels, pain severity, anxiety and depression independent of attachment style.

Fibromyalgia is a common chronic pain syndrome characterized by widespread pains and characteristic somatic symptoms. Current evidence suggests that cytokines and especially chemokines may have a role in the pathogenesis of this syndrome. Cytokines are small soluble factors that work as immune system messengers. They can be classified as pro-inflammatory and anti-inflammatory cytokines. Chemokines are a special kind of pro-inflammatory cytokines that guide the movement of circulating mononuclear cells to the injured side. Some pro-inflammatory cytokine levels (i.e. IL-1RA, IL-6, and IL-8) and, recently, some chemokines' levels have been found to be increased in patients with fibromyalgia. Thus, herein we review the current knowledge regarding the role of cytokines in fibromyalgia patients and their possible clinical relevance., (Copyright © 2014. Published by Elsevier B.V.)

Objective: A subset of patients with fibromyalgia (FM) exhibit a large fiber demyelinating peripheral polyneuropathy akin to that seen in chronic inflammatory demyelinating polyneuropathy (CIDP). It has been suggested that this demyelinating process is likely to be immune mediated. Because it is known that similar large fiber neuropathic lesions may be associated with a cutaneous small fiber neuropathy, we sought to determine the prevalence of small fiber neuropathy, as measured by epidermal nerve fiber density (ENFD), in a series of patients with FM and clinically healthy control subjects., Methods: Forty-one consecutive patients with FM and 47 control subjects underwent a 3-mm punch skin biopsy at the proximal thigh and distal leg near the ankle, for analysis of the ENFD. Patients with FM who had clinical evidence of a disorder known to be associated with small fiber neuropathy were excluded. The patients with FM also underwent pinwheel testing and vibratory testing for hypesthesia and serologic testing for a series of cytokine, circulating immune complex, and complement measurements., Results: All patients with FM had evidence of stocking hypesthesia. The ENFD of patients with FM was lower than that of control subjects at both the calf (mean ± SD 5.8 ± 2.8 versus 7.4 ± 1.9; P = 0.0002) and thigh (9.3 ± 3.2 versus 11.3 ± 2.0; P = 0.0007). There was an inverse correlation between calf ENFD and age at the time of skin biopsy in patients with FM (r = -0.29, P = 0.03) but not in control subjects; however, analysis of covariance showed that this relationship could not be explained by aging alone. Serologic evaluation showed an inverse correlation between calf ENFD in patients with FM and the interleukin-2 receptor (IL-2R) level (r = -0.28, P = 0.04). However, an inverse correlation between thigh ENFD and serum IL-2R levels did not reach significance (P = 0.08). Analysis of thigh-to-calf ENFD ratios suggested that the ENFD decline in FM is affected by both a diffuse and a length-dependent process., Conclusion: The calf and thigh ENFD in patients with FM is significantly diminished compared with that in control subjects. Advancing age alone cannot explain this finding. Calf ENFD was inversely correlated, although weakly, with serum levels of IL-2R. These findings suggest that small fiber neuropathy is likely to contribute to the pain symptoms of FM; that pain in this disorder arises, in part, from a peripheral immune-mediated process; and that measurement of ENFD may be a useful clinical tool in FM., (Copyright © 2014 by the American College of Rheumatology.)

Mast cell (MC) activation disorders present with multiple symptoms including flushing, pruritus, hypotension, gastrointestinal complaints, irritability, headaches, concentration/memory loss and neuropsychiatric issues. These disorders are classified as: cutaneous and systemic mastocytosis with a c-kit mutation and clonal MC activation disorder, allergies, urticarias and inflammatory disorders and mast cell activation syndrome (MCAS), idiopathic urticaria and angioedema. MCs are activated by IgE, but also by cytokines, environmental, food, infectious, drug and stress triggers, leading to secretion of multiple mediators. The symptom profile and comorbidities associated with these disorders, such as chronic fatigue syndrome and fibromyalgia, are confusing. We propose the use of the term 'spectrum' and highlight the main symptoms, useful diagnostic tests and treatment approaches.