WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by various disabling symptoms including exercise intolerance and is diagnosed in the absence of a specific cause, making its clinical management challenging. A better understanding of the molecular mechanism underlying this apparent bioenergetic deficiency state may reveal insights for developing targeted treatment strategies. We report that overexpression of Wiskott-Aldrich Syndrome Protein Family Member 3 (WASF3), here identified in a 38-y-old woman suffering from long-standing fatigue and exercise intolerance, can disrupt mitochondrial respiratory supercomplex formation and is associated with endoplasmic reticulum (ER) stress. Increased expression of WASF3 in transgenic mice markedly decreased their treadmill running capacity with concomitantly impaired respiratory supercomplex assembly and reduced complex IV levels in skeletal muscle mitochondria. WASF3 induction by ER stress using endotoxin, well known to be associated with fatigue in humans, also decreased skeletal muscle complex IV levels in mice, while decreasing WASF3 levels by pharmacologic inhibition of ER stress improved mitochondrial function in the cells of the patient with chronic fatigue. Expanding on our findings, skeletal muscle biopsy samples obtained from a cohort of patients with ME/CFS showed increased WASF3 protein levels and aberrant ER stress activation. In addition to revealing a potential mechanism for the bioenergetic deficiency in ME/CFS, our study may also provide insights into other disorders associated with fatigue such as rheumatic diseases and long COVID.

Parathyroid Hormone Resistance and Autoantibodies to the PTH1 Receptor.

We describe two cases of acquired parathyroid hormone (PTH) resistance consequent to the development of serum PTH type 1 receptor (PTH1R) autoantibodies, which block PTH binding and signaling. Both cases were associated with other autoimmune manifestations, and one case was associated with atypical membranous glomerulonephritis. In vitro binding and signaling assays identified the presence of PTH1R-blocking IgG autoantibodies, which were not present in serum samples from patients with other renal or autoimmune disorders. (Funded by the Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases and others.).

Inhibition of JAK-STAT pathway corrects salivary gland inflammation and interferon driven immune activation in Sjögren's disease.

OBJECTIVES: Inflammatory cytokines that signal through the Janus kinases-signal transducer and activator of transcription (JAK-STAT) pathway, especially interferons (IFNs), are implicated in Sjögren's disease (SjD). Although inhibition of JAKs is effective in other autoimmune diseases, a systematic investigation of IFN-JAK-STAT signalling and the effect of JAK inhibitor (JAKi) therapy in SjD-affected human tissues has not been fully investigated. METHODS: Human minor salivary glands (MSGs) and peripheral blood mononuclear cells (PBMCs) were investigated using bulk or single-cell (sc) RNA sequencing (RNAseq), immunofluorescence (IF) microscopy and flow cytometry. Ex vivo culture assays on PBMCs and primary salivary gland epithelial cell (pSGEC) lines were performed to model changes in target tissues before and after JAKi. RESULTS: RNAseq and IF showed activated JAK-STAT pathway in SjD MSGs. Elevated IFN-stimulated gene (ISGs) expression associated with clinical variables (eg, focus scores, anti-SSA positivity). scRNAseq of MSGs exhibited cell type-specific upregulation of JAK-STAT and ISGs; PBMCs showed similar trends, including markedly upregulated ISGs in monocytes. Ex vivo studies showed elevated basal pSTAT levels in SjD MSGs and PBMCs that were corrected with JAKi. SjD-derived pSGECs exhibited higher basal ISG expressions and exaggerated responses to IFN-ß, which were normalised by JAKi without cytotoxicity. CONCLUSIONS: SjD patients' tissues exhibit increased expression of ISGs and activation of the JAK-STAT pathway in a cell type-dependent manner. JAKi normalises this aberrant signalling at the tissue level and in PBMCs, suggesting a putative viable therapy for SjD, targeting both glandular and extraglandular symptoms. Predicated on these data, a phase Ib/IIa randomised controlled trial to treat SjD with tofacitinib was initiated.

Transcriptional derepression of CHD4/NuRD-regulated genes in the muscle of patients with dermatomyositis and anti-Mi2 autoantibodies.

OBJECTIVES: Myositis is a heterogeneous family of diseases including dermatomyositis (DM), immune-mediated necrotising myopathy (IMNM), antisynthetase syndrome (AS) and inclusion body myositis (IBM). Myositis-specific autoantibodies define different subtypes of myositis. For example, patients with anti-Mi2 autoantibodies targeting the chromodomain helicase DNA-binding protein 4 (CHD4)/NuRD complex (a transcriptional repressor) have more severe muscle disease than other DM patients. This study aimed to define the transcriptional profile of muscle biopsies from anti-Mi2-positive DM patients. METHODS: RNA sequencing was performed on muscle biopsies (n=171) from patients with anti-Mi2-positive DM (n=18), DM without anti-Mi2 autoantibodies (n=32), AS (n=18), IMNM (n=54) and IBM (n=16) as well as 33 normal muscle biopsies. Genes specifically upregulated in anti-Mi2-positive DM were identified. Muscle biopsies were stained for human immunoglobulin and protein products corresponding to genes specifically upregulated in anti-Mi2-positive muscle biopsies. RESULTS: A set of 135 genes, including SCRT1 and MADCAM1, was specifically overexpressed in anti-Mi2-positive DM muscle. This set was enriched for CHD4/NuRD-regulated genes and included genes that are not otherwise expressed in skeletal muscle. The expression levels of these genes correlated with anti-Mi2 autoantibody titres, markers of disease activity and with the other members of the gene set. In anti-Mi2-positive muscle biopsies, immunoglobulin was localised to the myonuclei, MAdCAM-1 protein was present in the cytoplasm of perifascicular fibres, and SCRT1 protein was localised to myofibre nuclei. CONCLUSIONS: Based on these findings, we hypothesise that anti-Mi2 autoantibodies could exert a pathogenic effect by entering damaged myofibres, inhibiting the CHD4/NuRD complex, and subsequently derepressing the unique set of genes defined in this study.

Transcriptomic profiling reveals distinct subsets of immune checkpoint inhibitor induced myositis.

OBJECTIVES: Inflammatory myopathy or myositis is a heterogeneous family of immune-mediated diseases including dermatomyositis (DM), antisynthetase syndrome (AS), immune-mediated necrotising myopathy (IMNM) and inclusion body myositis (IBM). Immune checkpoint inhibitors (ICIs) can also cause myositis (ICI-myositis). This study was designed to define gene expression patterns in muscle biopsies from patients with ICI-myositis. METHODS: Bulk RNA sequencing was performed on 200 muscle biopsies (35 ICI-myositis, 44 DM, 18 AS, 54 IMNM, 16 IBM and 33 normal muscle biopsies) and single nuclei RNA sequencing was performed on 22 muscle biopsies (seven ICI-myositis, four DM, three AS, six IMNM and two IBM). RESULTS: Unsupervised clustering defined three distinct transcriptomic subsets of ICI-myositis: ICI-DM, ICI-MYO1 and ICI-MYO2. ICI-DM included patients with DM and anti-TIF1γ autoantibodies who, like DM patients, overexpressed type 1 interferon-inducible genes. ICI-MYO1 patients had highly inflammatory muscle biopsies and included all patients that developed coexisting myocarditis. ICI-MYO2 was composed of patients with predominant necrotising pathology and low levels of muscle inflammation. The type 2 interferon pathway was activated both in ICI-DM and ICI-MYO1. Unlike the other types of myositis, all three subsets of ICI-myositis patients overexpressed genes involved in the IL6 pathway. CONCLUSIONS: We identified three distinct types of ICI-myositis based on transcriptomic analyses. The IL6 pathway was overexpressed in all groups, the type I interferon pathway activation was specific for ICI-DM, the type 2 IFN pathway was overexpressed in both ICI-DM and ICI-MYO1 and only ICI-MYO1 patients developed myocarditis.

Effectiveness of Land- and Water-based Exercise on Fatigue and Sleep Quality in Women With Fibromyalgia: The al-Ándalus Quasi-Experimental Study.

OBJECTIVE: To assess the effectiveness of 24 weeks of land- and water-based exercise on fatigue and sleep quality in women with fibromyalgia, and the persistence of changes 12 weeks after exercise cessation. DESIGN: Quasi-experimental study. SETTING: University facilities and fibromyalgia associations. PARTICIPANTS: Women with fibromyalgia (N=250; 50.8±7.6 years old). INTERVENTIONS: Participants were assigned to land-based exercise (n=83), water-based exercise (n=85), or no exercise control (n=82) groups. The intervention groups engaged in a similar multicomponent exercise program for 24 weeks. MAIN OUTCOME MEASURES: The Multidimensional Fatigue Inventory and Pittsburgh Sleep Quality Index were used. RESULTS: Intention-to-treat analyses revealed that, compared with the control group, at week 24: (i) the land-based exercise group improved physical fatigue (mean difference -0.9 units; 95% confidence interval -1.7 to -0.1; Cohen's d=0.4) and (ii) the water-based exercise group improved general fatigue (-0.8; -1.4 to -0.1, d=0.4), and global sleep quality (-1.6; -2.7 to -0.6, d=0.6). Additionally, compared with the land-based exercise group, the water-based exercise group improved global sleep quality (-1.2; -2.2 to -0.1, d=0.4). Changes were generally not sustained at week 36. CONCLUSION: Land-based multicomponent exercise improved physical fatigue, whereas water-based exercise improved general fatigue and sleep quality. The magnitude of the changes was small-to-medium, and no benefits were maintained after exercise cessation.

The pathogenesis of neurologic symptoms of the postacute sequelae of severe acute respiratory syndrome coronavirus 2 infection.

PURPOSE OF REVIEW: The coronavirus disease 2019 (COVID) pandemic has resulted in significant mortality and morbidity globally. Patients who survive infection may develop continuing disease collectively known as the postacute sequelae of severe acute respiratory syndrome coronavirus 2 infection (PASC), which includes neurologic symptoms especially fatigue and cognitive impairment. The pathogenic mechanisms driving PASC are unknown although a postinfectious process, persistent infection, or lasting pathophysiological changes that occur during acute infection are all suspected to contribute. RECENT FINDINGS: Here we review the current evidence underlying potential pathogenic mechanisms of the neurological complications of PASC with particular emphasis on the evidence for postinfectious immune processes and viral persistence. SUMMARY: Immune dysregulation favoring persistent inflammation, including neuroinflammation and enhanced autoimmunity, are present in patients with COVID and likely contribute to the development of PASC. Limited evidence of viral persistence exists but may explain the ongoing inflammatory processes and affinity maturation observed in some patients recovering from COVID infections. No specific studies to date have tied persistent infection to PASC. CNS trauma, in particular hypoxic changes in the CNS, and psychiatric complications occur with greater frequency in patients with COVID and may contribute to the development of PASC. Future research is needed to fully understand the pathophysiological mechanisms driving PASC.

Attitudes and Perceptions Toward Authorized Deception: A Pilot Comparison of Healthy Controls and Fibromyalgia Patients.

OBJECTIVE: Little is known about the perceptions and attitudes of participants who volunteer in studies involving authorized deception. Thus, this cross-sectional pilot study measured, for the first time, the perceptions about participation in an authorized-deception placebo analgesia study in chronic pain patients with fibromyalgia and assessed whether their perceptions differed from healthy controls. METHODS: An anonymous survey with questions about trust in research and willingness to participate in future research involving deception was mailed to participants in both groups after completion of the parent study. Statistical analyses were performed using the Mann-Whitney U and chi-square tests (31 controls and 16 fibromyalgia patients were included in the analyses). RESULTS: The majority of participants expressed little or no concern about the deception, still trusted the scientific process, and found the debriefing procedure helpful and worthwhile. Group differences were found in willingness to 1) participate in the parent study had the deceptive element been disclosed in advance (controls = definitely, fibromyalgia patients = probably, U = 341.5, P = 0.01) and 2) participate in future studies (controls = definitely, fibromyalgia patients = probably, U = 373, P < 0.001). CONCLUSIONS: Despite slightly less favorable responses of fibromyalgia patients and the relatively small size of the study, these findings suggest that attitudes and perceptions about participating in an authorized placebo study remain positive in both healthy and chronic pain populations.

Coffee and Tea Consumption in Relation to Risk of Rheumatoid Arthritis in the Women's Health Initiative Observational Cohort.

OBJECTIVE: The aim of this study was to evaluate whether tea or coffee consumption is associated with an increased risk of older-onset rheumatoid arthritis (RA) using the Women's Health Initiative Observational Study. METHODS: The Women's Health Initiative Observational Study is a longitudinal prospective cohort study conducted from 1993 to 1998. There were 76,853 women who completed a self-administered questionnaire about their daily consumption of tea and coffee. One hundred eighty-five women self-reported and validated incident cases of RA were observed after 3 years of observation. Multivariable Cox proportional hazards models were performed to assess the relationship between consumption habits and disease incidence. Trend tests were calculated using categorical variables modeled as a continuous variable without collapsing. RESULTS: There was no increase in the hazard ratio for incident RA in those participants who drank coffee compared with those who did not. The amount of coffee consumed and the method of preparation (caffeinated/decaffeinated; filtered/unfiltered) also did not alter the risk of incident RA. There was a positive association of incident RA and caffeinated tea consumption in the trend test (p = 0.03). When assessing any caffeinated tea consumption versus no tea consumption, the hazard ratio for incident RA was 1.40 (confidence interval, 1.01-1.93; p = 0.04). CONCLUSIONS: In a large prospective cohort of older women, there was no association between coffee consumption and incident RA. A small association between daily caffeinated, nonherbal tea consumption and incident RA was found.

Extraordinary Altruists Exhibit Enhanced Self-Other Overlap in Neural Responses to Distress.

Shared neural representations during experienced and observed distress are hypothesized to reflect empathic neural simulation, which may support altruism. But the correspondence between real-world altruism and shared neural representations has not been directly tested, and empathy's role in promoting altruism toward strangers has been questioned. Here, we show that individuals who have performed costly altruism (donating a kidney to a stranger; n = 25) exhibit greater self-other overlap than matched control participants ( n = 27) in neural representations of pain and threat (fearful anticipation) in anterior insula (AI) during an empathic-pain paradigm. Altruists exhibited greater self-other correspondence in pain-related activation in left AI, highlighting that group-level overlap was supported by individual-level associations between empathic pain and firsthand pain. Altruists exhibited enhanced functional coupling of left AI with left midinsula during empathic pain and threat. Results show that heightened neural instantiations of empathy correspond to real-world altruism and highlight limitations of self-report.

Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia.

BACKGROUND: Fibromyalgia is a clinically defined chronic condition of unknown etiology characterized by chronic widespread pain that often co-exists with sleep disturbances, cognitive dysfunction and fatigue. People with fibromyalgia often report high disability levels and poor quality of life. Drug therapy, for example, with serotonin and noradrenaline reuptake inhibitors (SNRIs), focuses on reducing key symptoms and improving quality of life. This review updates and extends the 2013 version of this systematic review. OBJECTIVES: To assess the efficacy, tolerability and safety of serotonin and noradrenaline reuptake inhibitors (SNRIs) compared with placebo or other active drug(s) in the treatment of fibromyalgia in adults. SEARCH METHODS: For this update we searched CENTRAL, MEDLINE, Embase, the US National Institutes of Health and the World Health Organization (WHO) International Clinical Trials Registry Platform for published and ongoing trials and examined the reference lists of reviewed articles, to 8 August 2017. SELECTION CRITERIA: We selected randomized, controlled trials of any formulation of SNRIs against placebo or any other active treatment of fibromyalgia in adults. DATA COLLECTION AND ANALYSIS: Three review authors independently extracted data, examined study quality, and assessed risk of bias. For efficacy, we calculated the number needed to treat for an additional beneficial outcome (NNTB) for pain relief of 50% or greater and of 30% or greater, patient's global impression to be much or very much improved, dropout rates due to lack of efficacy, and the standardized mean differences (SMD) for fatigue, sleep problems, health-related quality of life, mean pain intensity, depression, anxiety, disability, sexual function, cognitive disturbances and tenderness. For tolerability we calculated number needed to treat for an additional harmful outcome (NNTH) for withdrawals due to adverse events and for nausea, insomnia and somnolence as specific adverse events. For safety we calculated NNTH for serious adverse events. We undertook meta-analysis using a random-effects model. We assessed the evidence using GRADE and created a 'Summary of findings' table. MAIN RESULTS: We added eight new studies with 1979 participants for a total of 18 included studies with 7903 participants. Seven studies investigated duloxetine and nine studies investigated milnacipran against placebo. One study compared desvenlafaxine with placebo and pregabalin. One study compared duloxetine with L-carnitine. The majority of studies were at unclear or high risk of bias in three to five domains.The quality of evidence of all comparisons of desvenlafaxine, duloxetine and milnacipran versus placebo in studies with a parallel design was low due to concerns about publication bias and indirectness, and very low for serious adverse events due to concerns about publication bias, imprecision and indirectness. The quality of evidence of all comparisons of duloxetine and desvenlafaxine with other active drugs was very low due to concerns about publication bias, imprecision and indirectness.Duloxetine and milnacipran had no clinically relevant benefit over placebo for pain relief of 50% or greater: 1274 of 4104 (31%) on duloxetine and milnacipran reported pain relief of 50% or greater compared to 591 of 2814 (21%) participants on placebo (risk difference (RD) 0.09, 95% confidence interval (CI) 0.07 to 0.11; NNTB 11, 95% CI 9 to 14). Duloxetine and milnacipran had a clinically relevant benefit over placebo in patient's global impression to be much or very much improved: 888 of 1710 (52%) on duloxetine and milnacipran (RD 0.19, 95% CI 0.12 to 0.26; NNTB 5, 95% CI 4 to 8) reported to be much or very much improved compared to 354 of 1208 (29%) of participants on placebo. Duloxetine and milnacipran had a clinically relevant benefit compared to placebo for pain relief of 30% or greater. RD was 0.10; 95% CI 0.08 to 0.12; NNTB 10, 95% CI 8 to 12. Duloxetine and milnacipran had no clinically relevant benefit for fatigue (SMD -0.13, 95% CI -0.18 to -0.08; NNTB 18, 95% CI 12 to 29), compared to placebo. There were no differences between either duloxetine or milnacipran and placebo in reducing sleep problems (SMD -0.07; 95 % CI -0.15 to 0.01). Duloxetine and milnacipran had no clinically relevant benefit compared to placebo in improving health-related quality of life (SMD -0.20, 95% CI -0.25 to -0.15; NNTB 11, 95% CI 8 to 14).There were 794 of 4166 (19%) participants on SNRIs who dropped out due to adverse events compared to 292 of 2863 (10%) of participants on placebo (RD 0.07, 95% CI 0.04 to 0.10; NNTH 14, 95% CI 10 to 25). There was no difference in serious adverse events between either duloxetine, milnacipran or desvenlafaxine and placebo (RD -0.00, 95% CI -0.01 to 0.00).There was no difference between desvenlafaxine and placebo in efficacy, tolerability and safety in one small trial.There was no difference between duloxetine and desvenlafaxine in efficacy, tolerability and safety in two trials with active comparators (L-carnitine, pregabalin). AUTHORS' CONCLUSIONS: The update did not change the major findings of the previous review. Based on low- to very low-quality evidence, the SNRIs duloxetine and milnacipran provided no clinically relevant benefit over placebo in the frequency of pain relief of 50% or greater, but for patient's global impression to be much or very much improved and in the frequency of pain relief of 30% or greater there was a clinically relevant benefit. The SNRIs duloxetine and milnacipran provided no clinically relevant benefit over placebo in improving health-related quality of life and in reducing fatigue. Duloxetine and milnacipran did not significantly differ from placebo in reducing sleep problems. The dropout rates due to adverse events were higher for duloxetine and milnacipran than for placebo. On average, the potential benefits of duloxetine and milnacipran in fibromyalgia were outweighed by their potential harms. However, a minority of people with fibromyalgia might experience substantial symptom relief without clinically relevant adverse events with duloxetine or milnacipran.We did not find placebo-controlled studies with other SNRIs than desvenlafaxine, duloxetine and milnacipran.

Human Leukocyte Antigen Shared Epitope and Inflammation, Cardiovascular Disease, Cancer, and Mortality Among Postmenopausal Women in the Women's Health Initiative Rheumatoid Arthritis Study.

Specific alleles of the human leukocyte antigen (HLA)-DRB1 gene (HLA-DRB1) encode a "shared epitope" (SE) associated with rheumatoid arthritis (RA), especially more severe cyclic-citrullinated peptide antibody-positive (anti-CCP+) RA. We evaluated associations of number of SE alleles (0, 1, or 2) with total and cardiovascular disease (CVD) mortality and incident coronary heart disease (CHD), CVD, and cancer over a mean 8.9 (standard deviation, 3.5) years of follow-up, stratifying by baseline anti-CCP status (positive (+) vs. negative (-)). A longitudinal study, the Women's Health Initiative RA Study (1993-2010), sampled postmenopausal women who reported RA at baseline (1993-1998) or follow-up in the Women's Health Initiative, classified as anti-CCP+ RA (n = 556) or anti-CCP- non-RA (n = 1,070). Among anti-CCP+ RA women, SE alleles were not related to age-adjusted risks of CHD, CVD, or cancer or to total or CVD mortality. Among anti-CCP- non-RA women, age-adjusted hazard ratios for 1 and 2 SE alleles versus 0 SE alleles were 0.41 (95% confidence interval (CI): 0.34, 0.50) and 0.44 (95% CI: 0.27, 0.72), respectively, for CVD; 0.43 (95% CI: 0.37, 0.53) and 0.30 (95% CI: 0.16, 0.64), respectively, for CHD; and 0.62 (95% CI: 0.53, 0.73) and 0.52 (95% CI: 0.33, 0.83), respectively, for cancer. Associations persisted after adjustment for CVD risk factors, joint pain, rheumatoid factor positivity, and inflammatory markers (white blood cell count or cytokine level). In future studies, investigators should evaluate SE associations among anti-CCP- adults without RA and potential mechanisms.

WITHDRAWN: Anticonvulsants for fibromyalgia.

BACKGROUND: Fibromyalgia (FM) is a clinically well-defined chronic condition of unknown aetiology characterised by chronic widespread pain that often co-exists with sleep problems and fatigue. People often report high disability levels and poor health-related quality of life (HRQoL). Drug therapy focuses on reducing key symptoms and disability, and improving HRQoL. Anticonvulsants (antiepileptic drugs) are drugs frequently used for the treatment of chronic pain syndromes. OBJECTIVES: To assess the benefits and harms of anticonvulsants for treating FM symptoms. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 8, 2013), MEDLINE (1966 to August 2013), PsycINFO (1966 to August 2013), SCOPUS (1980 to August 2013) and the reference lists of reviewed articles for published studies and www.clinicaltrials.gov (to August 2013) for unpublished trials. SELECTION CRITERIA: We selected randomised controlled trials of any formulation of anticonvulsants used for the treatment of people with FM of any age. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted the data of all included studies and assessed the risks of bias of the studies. We resolved discrepancies by discussion. MAIN RESULTS: We included eight studies: five with pregabalin and one study each with gabapentin, lacosamide and levetiracetam. A total of 2480 people were included into anticonvulsants groups and 1099 people in placebo groups. The median therapy phase of the studies was 13 weeks. The amount and quality of evidence were insufficient to draw definite conclusions on the efficacy and safety of gabapentin, lacosamide and levetiracetam in FM. The amount and quality of evidence was sufficient to draw definite conclusions on the efficacy and safety of pregabalin in FM. Therefore, we focused on our interpretation of the evidence for pregabalin due to our greater certainty about its effects and its greater relevance to clinical practice. All pregabalin studies had a low risk of bias. Reporting a 50% or greater reduction in pain was more frequent with pregabalin use than with a placebo (risk ratio (RR) 1.59; 95% confidence interval (CI) 1.33 to 1.90; number needed to treat for an additional beneficial outcome (NNTB) 12; 95% CI 9 to 21). The number of people who reported being 'much' or 'very much' improved was higher with pregabalin than with placebo (RR 1.38; 95% CI 1.23 to 1.55; NNTB 9; 95% CI 7 to 15). Pregabalin did not substantially reduce fatigue (SMD -0.17; 95% CI -0.25 to -0.09; 2.7% absolute improvement on a 1 to 50 scale) compared with placebo. Pregabalin had a small benefit over placebo in reducing sleep problems by 6.2% fewer points on a scale of 0 to 100 (standardised mean difference (SMD) -0.35; 95% CI -0.43 to -0.27). The dropout rate due to adverse events was higher with pregabalin use than with placebo use (RR 1.68; 95% CI 1.36 to 2.07; number needed to treat for an additional harmful outcome (NNTH) 13; 95% CI 9 to 23). There was no significant difference in serious adverse events between pregabalin and placebo use (RR 1.03; 95% CI 0.71 to 1.49). Dizziness was reported as an adverse event more frequently with pregabalin use than with placebo use (RR 3.77; 95% CI 3.06 to 4.63; NNTH 4; 95% CI 3 to 5). AUTHORS' CONCLUSIONS: The anticonvulsant, pregabalin, demonstrated a small benefit over placebo in reducing pain and sleep problems. Pregabalin use was shown not to substantially reduce fatigue compared with placebo. Study dropout rates due to adverse events were higher with pregabalin use compared with placebo. Dizziness was a particularly frequent adverse event seen with pregabalin use. At the time of writing this review, pregabalin is the only anticonvulsant drug approved for treating FM in the US and in 25 other non-European countries. However, pregabalin has not been approved for treating FM in Europe. The amount and quality of evidence were insufficient to draw definite conclusions on the efficacy and safety of gabapentin, lacosamide and levetiracetam in FM.

Quantifying the influence of child abuse history on the cardinal symptoms of fibromyalgia.

OBJECTIVES: To quantify the influence of abuse, particularly in childhood, with pain sensitivity and other adverse symptoms experienced by women with fibromyalgia (FM). METHODS: Subjects with FM completed a detailed abuse interview, dolorimetry, and questionnaire-based assessments of fatigue, cognitive self-appraisal, and depression. Student's t- and chi-square tests were used to analyse differences in FM symptoms between those with and without a history of childhood abuse. Linear regression was used to evaluate the relationship between abuse and symptom severity, adjusting for possible confounders. RESULTS: In 111 women with FM, physical abuse during childhood demonstrated a clinically modest, yet statistically significant, association with increased tenderness as measured by pain pressure thresholds (ß=-0.25, p=0.011) and tender points (ß=0.23, p=.022). Physical child abuse was also associated with cognitive language impairment after adjusting for depression (ß=0.27, p=0.001). While emotional child abuse was associated with fatigue, the association did not persist after adjustment for depressive symptoms. CONCLUSIONS: Group differences are of small magnitude and might not directly impact clinical practice, however, the experience of child abuse is associated with FM symptom severity and may shape the biological development of interoception in ways that predispose to pain and polysymptomatic distress.

Antipsychotics for fibromyalgia in adults.

BACKGROUND: This review is one of a series on drugs used to treat fibromyalgia. Fibromyalgia is a clinically well-defined chronic condition of unknown aetiology characterised by chronic widespread pain that often co-exists with sleep problems and fatigue. It affects approximately 2% of the general population. Up to 70% of patients with fibromyalgia meet the criteria for a depressive or anxiety disorder. People often report high disability levels and poor health-related quality of life. Drug therapy focuses on reducing key symptoms and disability, and improving health-related quality of life. Antipsychotics might reduce fibromyalgia and associated mental health symptoms. OBJECTIVES: To assess the efficacy, tolerability and safety of antipsychotics in fibromyalgia in adults. SEARCH METHODS: We searched CENTRAL (2016, Issue 4), MEDLINE and EMBASE to 20 May 2016, together with reference lists of retrieved papers and reviews and two clinical trial registries. We also contacted trial authors. SELECTION CRITERIA: We selected controlled trials of at least four weeks duration of any formulation of antipsychotics used for the treatment of fibromyalgia in adults. DATA COLLECTION AND ANALYSIS: We extracted the data from all included studies and two review authors independently assessed study risks of bias. We resolved discrepancies by discussion. We performed analysis using three tiers of evidence. We derived first tier evidence from data meeting current best standards and subject to minimal risk of bias (outcome equivalent to substantial pain intensity reduction, intention-to-treat analysis without imputation for drop-outs, at least 200 participants in the comparison, eight to 12 weeks duration, parallel design), second tier evidence from data that failed to meet one or more of these criteria and that we considered at some risk of bias but with adequate numbers in the comparison, and third tier evidence from data involving small numbers of participants that we considered very likely to be biased or used outcomes of limited clinical utility, or both. We rated the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: We included a total of four studies with 296 participants.Three studies with 206 participants compared quetiapine, an atypical (second-generation) antipsychotic, with placebo. One study used a cross-over design and two studies a parallel-group design. Study duration was eight or 12 weeks. Quetiapine was used in all studies with a bedtime dosage between 50 and 300 mg/day. All studies had one or more sources of potential major bias and we judged them to be at moderate risk of bias overall. The primary outcomes in this review were participant-reported pain relief of 50% or greater, Patient Global Impression of Change (PGIC) much or very much improved, withdrawal due to adverse events (tolerability) and serious adverse events (safety).Second tier evidence indicated that quetiapine was not statistically superior to placebo in the number of participants with a 50% or more pain reduction (very low quality evidence). No study reported data on PGIC. A greater proportion of participants on quetiapine reported a 30% or more pain reduction (risk difference (RD) 0.12, 95% confidence interval (CI) 0.00 to 0.23; number needed to treat for an additional benefit (NNTB) 8, 95% CI 5 to 100) (very low quality evidence). A greater proportion of participants on quetiapine reported a clinically relevant improvement of health-related quality of life compared to placebo ( RD 0.18, 95% CI 0.05 to 0.31; NNTB 5, 95% CI 3 to 20) (very low quality evidence). Quetiapine was statistically superior to placebo in reducing sleep problems (standardised mean difference (SMD) -0.67, 95% CI -1.10 to -0.23), depression (SMD -0.39, 95% CI -0.74 to -0.04) and anxiety (SMD -0.40, 95% CI -0.69 to -0.11) (very low quality evidence). Quetiapine was statistically superior to placebo in reducing the risk of withdrawing from the study due to a lack of efficacy (RD -0.14, 95% CI -0.23 to -0.05) (very low quality evidence). There was no statistically significant difference between quetiapine and placebo in the proportion of participants withdrawing due to adverse events (tolerability) (very low quality evidence), in the frequency of serious adverse events (safety) (very low quality evidence) and in the proportion of participants reporting dizziness and somnolence as an adverse event (very low quality evidence). In more participants in the quetiapine group a substantial weight gain was noted (RD 0.08, 95% CI 0.02 to 0.15; number needed to treat for an additional harm (NNTH) 12, 95% CI 6 to 50) (very low quality evidence). We downgraded the quality of evidence by three levels to a very low quality rating because of limitations of study design, indirectness (patients with major medical diseases and mental disorders were excluded) and imprecision (fewer than 400 patients were analysed).One parallel design study with 90 participants compared quetiapine (50 to 300 mg/day flexible at bedtime) to amitriptyline (10 to 75 mg/day flexible at bedtime). The study had three major risks of bias and we judged it to be at moderate risk of bias overall. We downgraded the quality of evidence by two levels to a low quality rating because of indirectness (patients with major medical diseases and mental disorders were excluded) and imprecision (fewer than 400 patients were analysed). Third tier evidence indicated no statistically significant differences between the two drugs. Both drugs did not statistically significantly differ in the reduction of average scores for pain, fatigue, sleep problems, depression, anxiety and for limitations of health-related quality of life and in the proportion of participants reporting dizziness, somnolence and weight gain as a side effect (low quality evidence). Compared to amitriptyline, more participants left the study due to adverse events (low quality evidence). No serious adverse events were reported (low quality evidence).We found no relevant study with other antipsychotics than quetiapine in fibromyalgia. AUTHORS' CONCLUSIONS: Very low quality evidence suggests that quetiapine may be considered for a time-limited trial (4 to 12 weeks) to reduce pain, sleep problems, depression and anxiety in fibromyalgia patients with major depression. Potential side effects such as weight gain should be balanced against the potential benefits in shared decision making with the patient.

Cannabinoids for fibromyalgia.

BACKGROUND: This review is one of a series on drugs used to treat fibromyalgia. Fibromyalgia is a clinically well-defined chronic condition of unknown aetiology characterised by chronic widespread pain that often co-exists with sleep problems and fatigue affecting approximately 2% of the general population. People often report high disability levels and poor health-related quality of life (HRQoL). Drug therapy focuses on reducing key symptoms and disability, and improving HRQoL. Cannabis has been used for millennia to reduce pain and other somatic and psychological symptoms. OBJECTIVES: To assess the efficacy, tolerability and safety of cannabinoids for fibromyalgia symptoms in adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE to April 2016, together with reference lists of retrieved papers and reviews, three clinical trial registries, and contact with trial authors. SELECTION CRITERIA: We selected randomised controlled trials of at least four weeks' duration of any formulation of cannabis products used for the treatment of adults with fibromyalgia. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted the data of all included studies and assessed risk of bias. We resolved discrepancies by discussion. We performed analysis using three tiers of evidence. First tier evidence was derived from data meeting current best standards and subject to minimal risk of bias (outcome equivalent to substantial pain intensity reduction, intention-to-treat analysis without imputation for drop-outs; at least 200 participants in the comparison, eight to 12 weeks' duration, parallel design), second tier evidence from data that did not meet one or more of these criteria and were considered at some risk of bias but with adequate numbers (i.e. data from at least 200 participants) in the comparison, and third tier evidence from data involving small numbers of participants that were considered very likely to be biased or used outcomes of limited clinical utility, or both. We assessed the evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation). MAIN RESULTS: We included two studies with 72 participants. Overall, the two studies were at moderate risk of bias. The evidence was derived from group mean data and completer analysis (very low quality evidence overall). We rated the quality of all outcomes according to GRADE as very low due to indirectness, imprecision and potential reporting bias.The primary outcomes in our review were participant-reported pain relief of 50% or greater, Patient Global Impression of Change (PGIC) much or very much improved, withdrawal due to adverse events (tolerability) and serious adverse events (safety). Nabilone was compared to placebo and to amitriptyline in one study each. Study sizes were 32 and 40 participants. One study used a cross-over design and one used a parallel group design; study duration was four or six weeks. Both studies used nabilone, a synthetic cannabinoid, with a bedtime dosage of 1 mg/day. No study reported the proportion of participants experiencing at least 30% or 50% pain relief or who were very much improved. No study provided first or second tier (high to moderate quality) evidence for an outcome of efficacy, tolerability and safety. Third tier (very low quality) evidence indicated greater reduction of pain and limitations of HRQoL compared to placebo in one study. There were no significant differences to placebo noted for fatigue and depression (very low quality evidence). Third tier evidence indicated better effects of nabilone on sleep than amitriptyline (very low quality evidence). There were no significant differences between the two drugs noted for pain, mood and HRQoL (very low quality evidence). More participants dropped out due to adverse events in the nabilone groups (4/52 participants) than in the control groups (1/20 in placebo and 0/32 in amitriptyline group). The most frequent adverse events were dizziness, nausea, dry mouth and drowsiness (six participants with nabilone). Neither study reported serious adverse events during the period of both studies. We planned to create a GRADE 'Summary of findings' table, but due to the scarcity of data we were unable to do this. We found no relevant study with herbal cannabis, plant-based cannabinoids or synthetic cannabinoids other than nabilone in fibromyalgia. AUTHORS' CONCLUSIONS: We found no convincing, unbiased, high quality evidence suggesting that nabilone is of value in treating people with fibromyalgia. The tolerability of nabilone was low in people with fibromyalgia.

Chemobrain: a critical review and causal hypothesis of link between cytokines and epigenetic reprogramming associated with chemotherapy.

One consequence of modern cancer therapy is chemotherapy related cognitive dysfunction or "chemobrain", the subjective experience of cognitive deficits at any point during or following chemotherapy. Chemobrain, a well-established clinical syndrome, has become an increasing concern because the number of long-term cancer survivors is growing dramatically. There is strong evidence that correlates changes in peripheral cytokines with the development of chemobrain in commonly used chemotherapeutic drugs for different types of cancer. However, the mechanisms by which these cytokines elicit change in the central nervous system are still unclear. In this review, we hypothesize that the administration of chemotherapy agents initiates a cascade of biological changes, with short-lived alterations in the cytokine milieu inducing persistent epigenetic alterations. These epigenetic changes lead to changes in gene expression, alterations in metabolic activity and neuronal transmission that are responsible for generating the subjective experience of cognition. This speculative but testable hypothesis should help to gain a comprehensive understanding of the mechanism underlying cognitive dysfunction in cancer patients. Such knowledge is critical to identify pharmaceutical targets with the potential to prevent and treat cancer-treatment related cognitive dysfunction and similar disorders.

Self-reported childhood maltreatment, lifelong traumatic events and mental disorders in fibromyalgia syndrome: a comparison of US and German outpatients.

OBJECTIVES: The robustness of findings on retrospective self-reports of childhood maltreatment and lifetime traumatic experiences of adults with fibromyalgia syndrome (FMS) has not been demonstrated by transcultural studies. This is the first transcultural study to focus on the associations between FMS, childhood maltreatment, lifetime psychological traumas, and potential differences between countries adjusting for psychological distress. METHODS: 71 age-and sex-matched US and German FMS outpatients were compared. Childhood maltreatment were assessed by the Childhood Trauma Questionnaire and potential, traumatic experiences by the trauma list of the Munich Composite International Diagnostic Interview. Potential posttraumatic stress disorder (PTSD) was diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders IV-TR symptom criteria by the Posttraumatic Diagnostic Scale. Potential depressive and anxiety disorder were assessed by the Patient Health Questionnaire PHQ 4. RESULTS: US and German patients did not significantly differ in the amount of self-reported childhood maltreatment (emotional, physical and sexual abuse or neglect) or in the frequency of lifetime traumatic experiences. No differences in the frequency of potential anxiety, depression, and PTSD were seen. Psychological distress fully accounted for group differences in emotional and sexual abuse and emotional and physical neglect. CONCLUSIONS: The study demonstrated the transcultural robustness of findings on the association of adult FMS with self-reports of childhood maltreatment and lifelong traumatic experiences. These associations are mainly explained by current psychological distress.

Selective serotonin reuptake inhibitors for fibromyalgia syndrome.

BACKGROUND: Fibromyalgia is a clinically well-defined chronic condition with a biopsychosocial aetiology. Fibromyalgia is characterized by chronic widespread musculoskeletal pain, sleep problems, cognitive dysfunction, and fatigue. Patients often report high disability levels and poor quality of life. Since there is no specific treatment that alters the pathogenesis of fibromyalgia, drug therapy focuses on pain reduction and improvement of other aversive symptoms. OBJECTIVES: The objective was to assess the benefits and harms of selective serotonin reuptake inhibitors (SSRIs) in the treatment of fibromyalgia. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 5), MEDLINE (1966 to June 2014), EMBASE (1946 to June 2014), and the reference lists of reviewed articles. SELECTION CRITERIA: We selected all randomized, double-blind trials of SSRIs used for the treatment of fibromyalgia symptoms in adult participants. We considered the following SSRIs in this review: citalopram, fluoxetine, escitalopram, fluvoxamine, paroxetine, and sertraline. DATA COLLECTION AND ANALYSIS: Three authors extracted the data of all included studies and assessed the risks of bias of the studies. We resolved discrepancies by discussion. MAIN RESULTS: The quality of evidence was very low for each outcome. We downgraded the quality of evidence to very low due to concerns about risk of bias and studies with few participants. We included seven placebo-controlled studies, two with citalopram, three with fluoxetine and two with paroxetine, with a median study duration of eight weeks (4 to 16 weeks) and 383 participants, who were pooled together.All studies had one or more sources of potential major bias. There was a small (10%) difference in patients who reported a 30% pain reduction between SSRIs (56/172 (32.6%)) and placebo (39/171 (22.8%)) risk difference (RD) 0.10, 95% confidence interval (CI) 0.01 to 0.20; number needed to treat for an additional beneficial outcome (NNTB) 10, 95% CI 5 to 100; and in global improvement (proportion of patients who reported to be much or very much improved: 50/168 (29.8%) of patients with SSRIs and 26/162 (16.0%) of patients with placebo) RD 0.14, 95% CI 0.06 to 0.23; NNTB 7, 95% CI 4 to 17.SSRIs did not statistically, or clinically, significantly reduce fatigue: standard mean difference (SMD) -0.26, 95% CI -0.55 to 0.03; 7.0% absolute improvement on a 0 to 10 scale, 95% CI 14.6% relative improvement to 0.8% relative deterioration; nor sleep problems: SMD 0.03, 95 % CI -0.26 to 0.31; 0.8 % absolute deterioration on a 0 to 100 scale, 95% CI 8.3% relative deterioration to 6.9% relative improvement.SSRIs were superior to placebo in the reduction of depression: SMD -0.39, 95% CI -0.65 to -0.14; 7.6% absolute improvement on a 0 to 10 scale, 95% CI 2.7% to 13.8% relative improvement; NNTB 13, 95% CI 7 to 37. The dropout rate due to adverse events was not higher with SSRI use than with placebo use (23/146 (15.8%) of patients with SSRIs and 14/138 (10.1%) of patients with placebo) RD 0.04, 95% CI -0.06 to 0.14. There was no statistically or clinically significant difference in serious adverse events with SSRI use and placebo use (3/84 (3.6%) in patients with SSRIs and 4/84 (4.8%) and patients with placebo) RD -0.01, 95% CI -0.07 to 0.05. AUTHORS' CONCLUSIONS: There is no unbiased evidence that SSRIs are superior to placebo in treating the key symptoms of fibromyalgia, namely pain, fatigue and sleep problems. SSRIs might be considered for treating depression in people with fibromyalgia. The black box warning for increased suicidal tendency in young adults aged 18 to 24, with major depressive disorder, who have taken SSRIs, should be considered when appropriate.

Rheumatoid arthritis in the Women's Health Initiative: methods and baseline evaluation.

Second-generation assays for anti-cyclic citrullinated peptide (anti-CCP), a highly sensitive and specific marker for rheumatoid arthritis (RA), have redefined the epidemiology of RA. In the Women's Health Initiative (WHI) RA study (2009-2011), we evaluated the prevalence of anti-CCP positivity among 15,691 (10.2% of 161,808) WHI participants aged 50-79 years who reported RA. Using stored baseline specimens, we measured serum anti-CCP, rheumatoid factor (RF), and antinuclear antibody in a defined sample of 9,988 of black, white, and Hispanic women. In a subset of women, we measured plasma cytokine levels and number of copies of the human leukocyte antigen (HLA)-DRB1 (HLA-DRB1) shared epitope in DNA by means of Luminex polymerase chain reaction typing (Luminex Corporation, Austin, Texas). We validated classification of probable clinical RA in 2 clinics as anti-CCP positivity or self-reported validated use of disease-modifying antirheumatic drugs (DMARDs). The prevalence of anti-CCP positivity was 8.1%, and the prevalence of RF positivity was approximately 16.0%. DMARD use including prednisone was reported by 1,140 (11.4%) participants (841 excluding prednisone) but by 57.5% of anti-CCP-positive women. The prevalence of 2 shared epitopes was also much higher for anti-CCP-positive women (18.2%, as opposed to only 5.5% for women with anti-CCP-negative DMARD-positive RA and 6.6% for anti-CCP-negative, RF-negative DMARD nonusers). Median cytokine levels were much higher for anti-CCP-positive/RF-positive women. Women with anti-CCP-positive RA and anti-CCP-negative RA had different characteristics with regard to HLA shared epitope, cigarette smoking, and inflammation (cytokines).