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The complement system regulator CD55 was initially found to carry the Cromer blood group system antigens, and its complete loss of function was subsequently revealed to cause a severe monogenic gastrointestinal syndrome characterized by protein-losing enteropathy and susceptibility to venous thrombosis. Here we present homozygosity to the CD55 c.596CT; p.Ser199Leu variant, which was previously described as the Cromer Dr(a-) genotype, in two Bukharan Jewish CD55-deficiency patients with variable disease severity. We confirm that this missense variant causes aberrant splicing and deletion of 44 bp in exon 5, leading to premature termination and low expression of the CD55 protein. Furthermore, Patient 1 exhibited a mildly abnormal B cell immunophenotyping profile. By population screening we established that this variant is highly prevalent in the Bukharan Jewish population, with a carrier frequency of 1:17, suggesting that many similar patients are un- or mis-diagnosed. The phenotypic variability, ranging from abdominal pain when eating a high-fat diet to the full CD55-deficiency phenotype, is likely related to modifiers affecting the proportion of the variant that is able to escape aberrant splicing. Establishing the diagnosis of CD55-deficiency in a timely manner, even in patients with milder symptoms, may have a critical effect on their management and quality-of-life since treatment with the complement inhibitor eculizumab is highly effective in ameliorating disease manifestations. Awareness of founder mutations within certain populations can further guide genetic testing and prevent a diagnostic odyssey, by placing this CD55 variant high on the differential diagnosis.

Background: A high Neutrophil to Lymphocyte Ratio (NLR) is considered an unfavorable prognostic factor in various diseases, including COVID-19. The prognostic value of NLR in other respiratory viral infections, such as Influenza, has not hitherto been extensively studied. We aimed to compare the prognostic value of NLR in COVID-19, Influenza and Respiratory Syncytial Virus infection (RSV).Method: A retrospective cohort of COVID-19, Influenza and RSV patients admitted to the Tel Aviv Medical Center from January 2010 to October 2020 was analyzed. Laboratory, demographic, and clinical parameters were collected. Two way analyses of variance (ANOVA) was used to compare the association between NLR values and poor outcomes among the three groups. ROC curve analyses for each virus was applied to test the discrimination ability of NLR. Results: 722 COVID-19, 2213 influenza and 482 RSV patients were included. Above the age of 50, NLR at admission was significantly lower among COVID-19 patients (PConclusions: NLR at admission is lower and has more prognostic value in COVID-19 patients, when compared to Influenza and RSV.

As members of a gender minority, transgender individuals face many challenges. Many experience distress, depression, anxiety and suicidal ideation related to gender non-conformity and transphobia. Stress and trauma may contribute to the development of fibromyalgia (FM) syndrome, characterised by widespread pain and fatigue. The prevalence of FM among transgenders is not known.Transgender participants were recruited at a specialised clinic. Questionnaires included the Widespread Pain Index (WPI), the Symptom Severity Score (SSS) and the SF-36. Data concerning hormonal treatment protocols was retrieved from charts. The current prevalence of FM was determined, as well as the prevalence before and after testosterone treatment among TM. Pearson correlations were calculated between all measures.115 participants were recruited, 62.6% transgender men (TM), 37.4% transgender women (TW). 17 individuals (14.8%) fulfilled the 2011 modified ACR FM criteria, for a rate of 19.4% among TM and 6.98% among TW. Among TM, FM was associated with younger age, smoking and SF-36 sub-scales related to physical functioning, role limitation due to physical pain, fatigue, pain and general health. Among TW, FM was associated with social status, employment, depression, existing medical treatment and substance abuse, as well as SF-36 subscales related to role limitations affected due to pain.Fibromyalgia symptoms are highly prevalent among Israeli transgender individuals and may be related to psychological distress and gender dysphoria. Healthcare professionals treating transgenders should remain vigilant for the occurrence of chronic pain, fatigue and other FM-related symptoms and be prepared to treat and/or refer such patients accordingly.

The coping mechanisms utilised by patients with the fibromyalgia syndrome (FM) pose a crucial focus of treatment. Previous research points to the positive effects of religiosity and spirituality (R/S) as tools for coping with illness. The role of these factors in coping with chronic pain in FM has not previously been studied. The aim of this study was to evaluate the link between R/S and FM outcomes.Fifty-five FM patients (ACR criteria) attending a tertiary rheumatology clinic completed a packet of questionnaires assessing demographic data, levels of religiosity and spirituality (SpREUK) and locus of control (LOC). These variables were then individually assessed for influence on FM outcome measures, using the Fibromyalgia Impact Questionnaire (FIQ), the SF-36, and the Beck Depression Index (BDI).A high score on SpREUK I (search for meaningful support) was negatively correlated with the Role-Physical (p=0.032) and Role-Emotional (p0.005) scales on SF-36. Secular patients scored higher on SF-36 domains of "Role limitation due to emotional health" and "General health" (p0.05). Employment demonstrated a positive correlation with the FIQ (p0.01), the BDI (p0.001), and the SF-36 (p0.05). Physical activity correlated positively with BDI scores (p=0.012) and better scores on SF-36: energy/fatigue (p=0.024), social-functioning (p=0.014) and physical-functioning (p0.01). No significant correlation was found between LOC (internal versus external) and FM outcomes. No significant correlation was found between SpREUK domains and the BDI.FM patients do not appear to benefit from high levels of R/S. Physicians should be aware of the impact of R/S on well-being in this population.

In a previous study, we showed that the subjective item assessing cognitive impairment (SSS-Cog) for fibromyalgia (FM) did not correlate with the objective cognitive measures. In the current study, we describe two modifications designed to enhance this correlation: extending the SSS-cog scale from 0-3 to 1-5, and administration of a new questionnaire that specifically targets the cognitive impairments associated with FM.Sixty-two FM patients underwent a computerised cognitive assessment battery. FM symptoms were assessed on the Fibromyalgia Impact Questionnaire (FIQ); the Widespread Pain Index (WPI); the Symptom Severity Scale (SSS), the new SSS-Cog scale ranging from 1 to 5, the Beck Depression Inventory (BDI) and the new cognitive questionnaire developed by the authors.Significant correlations were found between the new SSS-Cog, the global cognitive score and all indices [Global Score r=-0.532, p=0.00; Indices: Memory r=-0.305, p=.01; Executive function r=-0.514, p=0.00; Attention r=-0.471, p=0.00; Processing Speed r=-0.468, p=0.00; Motor Skills r=-0.495, p=.00]. Significant correlations were found between the new questionnaire and the global cognitive score and all indices except the memory index [Global Score r=-0.522, p=0.00; Indices: Memory r=-0.163, p=0.212; Executive function r=-0.477, p=0.00; Attention r=-0.439, p=0.00; Processing Speed r=-0.496, p=0.00; Motor Skills r=-0.532, p=0.00].Given the simplicity involved in extending the scale, we suggest incorporating this modification into the FM diagnostic criteria of the American College of Rheumatology (ACR).

Objective To study the prevalence of fibromyalgia (FM) in the general population according to a 2016 modification of the American College of Rheumatology criteria (FM 2016) and the Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks-American Pain Society pain taxonomy criteria (AAPT), and to compare diagnostic and clinical variables between the criteria sets. Methods We studied 2,531 randomly selected subjects from the German general population in 2019. Pain regions from the Michigan Body Map were fitted to the FM 2016 and the AAPT criteria, and criteria symptom items were derived from validated questionnaires assessing somatic and psychological symptom burden and disability. We determined FM criteria prevalence and criteria-related scales including widespread and multisite pain (MSP) and symptom scales, and measured symptom burden and disability. Results According to the FM 2016 criteria, the prevalence of FM was 3.4% (n = 75 subjects; 95% confidence interval [95% CI] 2.7, 4.3) compared with 5.7% (n = 130 subjects; 95% CI 4.8, 6.8) for the AAPT criteria; κ = 0.65. Compared with AAPT-positive subjects, FM 2016-positive subjects had higher MSP, Widespread Pain Index score, Polysymptomatic Distress Scale scores, Symptom Severity Scores, and psychological symptom burden. Physician-diagnosed FM was reported by 1.1% of the subjects. Of these, 44.0% met the FM 2016 criteria, and 47.5% met the AAPT criteria. Conclusion The prevalence of FM in the German general population is 73% greater using the AAPT criteria than the FM 2016 criteria. The AAPT criteria select individuals with less symptom severity and fewer pain sites. The FM 2016 criteria, but not the AAPT criteria, provide a general severity measure for FM.

Purpose Studies of the relation of fibromyalgia (FM) and widespread pain (WSP) to mortality have differed as to the presence or absence of an association and the extent of cause-specific mortality. However, no studies have investigated which definitions of FM and WSP associate with mortality, nor of FM mortality in other diseases. We investigated these issues and the meaning of mortality in patients with FM. Methods We used Cox regression to study 35,248 rheumatic disease patients with up to 16 years of mortality follow-up in all patients and separately in those with diagnoses of rheumatoid arthritis (RA) (N = 26,458), non-inflammatory rheumatic disorders (NIRMD) (N = 5,167) and clinically diagnosed FM (N = 3,659). We applied 2016 FM criteria and other FM and WSP criteria to models adjusted for age and sex as well as to models that included a full range of covariates, including comorbid disease and functional status. We estimated the degree of explained of variance (R2) as a measure of predictive ability. Results We found positive associations between al`l definitions of FM and WSP and all-cause mortality, with relative risks (RR)s ranging from 1.19 (95%CI 1.15–1.24) for American College of Rheumatology (ACR) 1990 WSP to 1.38 (1.31–1.46) in age and sex adjusted revised 2016 criteria (FM 2016). However, in full covariate models the FM 2016 RR reduced further to 1.15 (1.09–1.22). The association with mortality was noted with RA (1.52 (1.43–1.61)), NIRMD (1.43 (1.24–1.66)) and clinical FM (1.41 (1.14–1.75) - where 37% of FM diagnosed patients did not satisfy FM 2016 criteria. In the all-patient analyses, the age and sex explained variation (R2) was 0.255, increasing to 0.264 (4.4%) when FM 2016 criteria were added, and to 0.378 in a full covariate model. Death causes related to FM 2016 status included accidents, 1.45 (1.11–1.91); diabetes 1.78 (1.16–2,71); suicide, 3.01 (1.55–5.84) and hypertensive related disorders, 3.01 (1.55–5.84). Cancer deaths were less common 0.77 (0.68–0.88). Conclusions FM is weakly associated with mortality within all criteria definitions of FM and WSP examined (3.4% of explained variance), and across all diseases (RA, NIRMD, clinical FM) equally. Clinical and criteria-defined FM had different mortality outcomes. We found no evidence for a positive association of cancer and FM or WSP.

Objective To compare the concordance of the three diagnostic criteria, respectively the 2011 ACR criteria (ACR 2011 Cr), the ACR 2016 criteria (ACR 2016 Cr) and the Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks (ACTTION)-APS Pain Taxonomy criteria (AAPT Cr), and to explore the performance of an additional set of criteria, the modified Fibromyalgia Assessment Status (FAS 2019 modCr), in the diagnosis of FM syndrome. Methods Consecutive patients with chronic widespread pain, referred by the primary care setting, underwent rheumatologic assessment that established the presence or not of FM and were investigated through the four sets of proposed criteria. For the FAS 2019 modCr, discriminant validity to distinguish patients with FM and non-FM was assessed with receiver operating characteristic curve analysis. Results A total of 732 (405 with FM and 327 with other common chronic pain problems) patients were evaluated. Against the clinical diagnosis of FM, the sensitivity, specificity and correct classification were, respectively: 79.8, 91.7 and 85.1% for ACR 2011 Cr; 78, 90.5 and 83.6% for the ACR 2016 Cr; and 73.8, 91.7 and 81.8% for the AAPT Cr. The alternative set, proposed on the FAS 2019 modCr, provided a maximal diagnostic accuracy with a score ≥20 (Youden’s index), with a sensitivity of 84.2%, specificity 89.0% and positive likelihood ratio 7.65. Conclusion There is a considerable agreement between criteria-based diagnoses of FM, although the AAPT Cr perform least well in terms of percentage of correct classification. The FAS 2019 modCr had comparable characteristics.

Fibromyalgia (FM) is a common disorder characterised by heterogeneous symptoms often leading to decreased functioning, work productivity and quality of life. Although a multimodal approach is used to treat FM, a significant proportion of patients show low satisfaction with perceived care, potentially resulting in an inefficient use of health care resources. The aim of the present review is to summarize the available evidence about the economic impact of FM and the specific cost drivers of health care expenditure for the syndrome.MedLine and Web of Science databases were searched to identify eligible articles. Studies reporting direct medical and non-medical costs and/or indirect costs of FM were included. Annual costs per person were extrapolated from each study and converted to United States Dollars ($) after adjusting the local currency for inflation in year 2019.The 36 studies included in the final synthesis differed considerably in their design and in the cost categories analysed. Overall risk of bias was high. Estimates for the total annual direct costs per patient ranged from $ 1750 to $ 35,920 in the USA and from $ 1250 to $ 8504 in Europe. In most included studies, medications were the major contributor to overall expenditures.Fibromyalgia represents a substantial economic burden to health care systems and society. A better understanding of this complex disorder may not only improve quality of life of FM patients, but also have a significant impact on direct and indirect costs associated with the syndrome.

Research into the neurobiological and psychosocial mechanisms involved in fibromyalgia has progressed remarkably in recent years. Despite this, current accounts of fibromyalgia fail to capture the complex, dynamic, and mutual crosstalk between neurophysiological and psychosocial domains. We conducted a comprehensive review of the existing literature in order to: a) synthesize current knowledge on fibromyalgia; b) explore and highlight multi-level links and pathways between different systems; and c) build bridges connecting disparate perspectives. An extensive panel of international experts in neurophysiological and psychosocial aspects of fibromyalgia discussed the collected evidence and progressively refined and conceptualized its interpretation. This work constitutes an essential step towards the development of a model capable of integrating the main factors implicated in fibromyalgia into a single, unified construct which appears indispensable to foster the understanding, assessment, and intervention for fibromyalgia.

Cognitive dysfunction is one of the criteria for the diagnosis of fibromyalgia (FM) and is typically based on self-report questionnaires such as the Symptom Severity Scale. However, recent studies have shown that there is no correlation between these subjective measures of cognitive dysfunction and more lengthy objective measures of cognitive functioning. This points to the need for a briefer valid evaluation tool for cognitive dysfunction in FM. The aim of this study is to examine whether the Montreal Cognitive Assessment (MoCA) test is a valid measure of cognitive assessment in FM patients, by comparing it to a comprehensive computerised cognitive assessment battery.Sixty-two FM patients (55 women, 7 men, mean age = 46.17 years, sd=12.56) were administered the MoCA and a computerised cognitive assessment battery. FM symptoms were assessed on the Fibromyalgia Impact Questionnaire (FIQ), the Widespread Pain Index (WPI), the Symptom Severity Scale (SSS), and the Beck Depression Inventory (BDI-2). Patient effort was controlled on the TOMM (Test of Memory Malingering).Moderate positive correlations were found between the MoCA and the computerised cognitive scores as follows: Global Cognitive Score (r=0.493**, p=0.00), Memory Index Score (r= 0.384**, p=0.002), Executive Function Index Score (r=0.461**, p=0.00), Attention Index Score (r=0.310*, p=0.016), Information Processing Speed Index Score (r=0.435**, p=0.001), and Motor Skills (r=0.406**, p=0.002).The MoCA is an acceptable cognitive screening test for the cognitive evaluation of FM patients.

Objective.To investigate the relation of physical (non-psychological) comorbidity and multimorbidity to quantitative measures of fibromyalgia (FM) and musculoskeletal pain.Methods.We studied 12,215 patients in a research databank with quantitative measures of FM-related variables (FMV) that included binary determinations of FM and widespread pain (WSP), and constituent variables of FM diagnosis that included the WSP index (WPI), the symptom severity score (SSS), and the polysymptomatic distress scale (PSD). We assessed self-reported comorbid conditions and covariates that included age, sex, body mass index, hypertension, smoking history, and total household income. We used nearest-neighbor matching and regression adjustment treatment effects models to measure the effect of comorbidities on FMV.Results.We found a positive association between FMV and the probability of having each comorbid condition. Patients with ≥ 1 comorbidities had PSD, WPI, and SSS increases of 3.0 (95% CI 2.7–3.3), 1.8 (95% CI 1.6–2.0), and 1.2 (95% CI 1.1–1.3) units, respectively, and an increase in FM prevalence from 20.4% to 32.6%. As the number of comorbid conditions present increased from 1 to 4 or more, PSD, WPI, SSS, and FM percent increased stepwise. For patients with ≥ 4 conditions, the predicted prevalence of FM was 55.2%.Conclusion.FM and FMV are associated with an increase in the number of comorbidities, and the association can be measured quantitatively. However, the association of WSP and FM may be an effect of definitions of WSP and FM, because comorbidity increases are also present with subsyndromal levels of both conditions.

Coronavirus disease-19 (COVID-19) patients are prone to thrombotic complications that may increase morbidity and mortality. These complications are thought to be driven by endothelial activation and tissue damage promoted by the systemic hyperinflammation associated with COVID-19. However, the exact mechanisms contributing to these complications are still unknown. To identify additional mechanisms contributing to the aberrant clotting observed in COVID-19 patients, we analyzed platelets from COVID-19 patients compared to those from controls using mass spectrometry. We identified increased serum amyloid A (SAA) levels, an acute-phase protein, on COVID-19 patients’ platelets. In addition, using an in vitro adhesion assay, we showed that healthy platelets adhered more strongly to wells coated with COVID-19 patient serum than to wells coated with control serum. Furthermore, inhibitors of integrin aIIbβ3 receptors, a mediator of platelet–SAA binding, reduced platelet adhesion to recombinant SAA and to wells coated with COVID-19 patient serum. Our results suggest that SAA may contribute to the increased platelet adhesion observed in serum from COVID-19 patients. Thus, reducing SAA levels by decreasing inflammation or inhibiting SAA platelet-binding activity might be a valid approach to abrogate COVID-19-associated thrombotic complications.

none 8 si Background: Fibromyalgia (FM) is a complex syndrome incorporating many features associated with poor outcome in orthopaedic surgery. Aim of the present review was to comprehensively characterize the available evidence on the consequences of pre-existent FM on the outcomes of orthopaedic surgery. Methods: We performed a systematic search in MedLine and Web of Science (WOS) to identify studies evaluating the effect of FM on patient-centred outcomes, opioids consumption and postoperative complications. Results: The search strategy identified 519 records in PubMed and 507 in WOS. A total of 27 articles were deemed eligible for inclusion in qualitative synthesis. Based on quality assessment, 10 studies were rated as good quality, 10 as fair quality and 7 as poor quality. Studies reporting the prevalence of FM in consecutive patients undergoing orthopaedic surgery (n = 19) were included in quantitative synthesis. The pooled prevalence of FM in patients undergoing orthopaedic surgery was 4.1% (95% CI: 2.4-6.8) in those receiving hip or knee surgery, 10.1% (95% CI: 5.7-17.2) in those receiving shoulder or elbow surgery and 21.0% (95% CI: 18.5-23.7) in those receiving spinal surgery. The results of our systematic review consistently report FM as a significant risk factor for less satisfaction, higher pain, worse functional outcome, increased risk for postoperative opioids prescription and higher rate of medical and surgical complications following orthopaedic surgery. Conclusion: Identifying pre-existing FM in patients scheduled for elective orthopaedic surgery may help to better assess the benefit/risk ratio, improve patients' awareness and minimize any discrepancy between expectancy and results. none D'Onghia, Martina; Ciaffi, Jacopo; McVeigh, Joseph G; Di Martino, Alberto; Faldini, Cesare; Ablin, Jacob N; Meliconi, Riccardo; Ursini, Francesco D'Onghia, Martina; Ciaffi, Jacopo; McVeigh, Joseph G; Di Martino, Alberto; Faldini, Cesare; Ablin, Jacob N; Meliconi, Riccardo; Ursini, Francesco

Acute or chronic stress may trigger or aggravate symptoms of fibromyalgia (FM). We aimed to evaluate the physical and mental health of fibromyalgia patients during the COVID 19 outbreak and identify protective/risk factors.An online survey was published in May 2020, following two months of lockdown due to the COVID 19 outbreak, including questionnaires regarding demographic characteristics, access to medical services, anxiety, depression, life approach, coping strategies, perception of social support, widespread pain index (WPI) and symptoms severity scale (SSS), insomnia severity index (ISI) and patient global assessment.Of the 233 patients included in the study, 98% were forced to discontinue complementary or alternative treatments during lockdown. Up to 30% of responders who had been treated with medical cannabis had to stop due to logistic difficulties and this was associated with significantly higher scores of WPI/SSS (p=0.024). Higher levels of anxiety and depression were significantly correlated with higher levels of pain, sleep disorders and subjective perception of deterioration (p=0.00). Higher scores of social support and positive life approach were correlated with less anxiety and depression (p0.01), lower levels of pain (p0.05) and less sleep disturbances (p0.01). Avoidant coping style was strongly associated to higher levels of pain, sleep disturbances, anxiety, depression, and subjective perception of worsening (p0.01).Fibromyalgia patients reported adverse mental and physical outcomes during the COVID-19 outbreak. Factors such as stopping current treatments may play a central role. Social support and a positive life approach appear to be protective.

Striking familial aggregation is found in fibromyalgia (FM) as well as in other chronic pain conditions, leading to the assumption that a genetic component plays an important role in the pathogenesis of this condition. However, as in other complex conditions involving the central nervous system, a polygenic background is most likely. Studies into the genetics of FM initially focused on candidate genes, thus identifying some important markers including genes related to the autonomic nervous system and to neurotransmitters involved in pain processing. Subsequent progress in genetic technology such as the application of genome-wide association studies (GWAS) has added additional insight into the complex genetics of FM.

The story of fibromyalgia is lengthy, intricate, often frustrating—but always fascinating. Starting from early nineteenth-century conceptions about the entity of “neurasthenia,” moving on into early twentieth-century coining of the presumably inflammatory condition of “fibrositis” and on through the multiple definitions, redefinitions, and ever-changing classifications and sets of diagnostic criteria developed over recent decades, the syndrome of fibromyalgia serves as a paradigm for complex disorders affecting the central as well as the autonomic and peripheral nervous systems, and as an intriguing example for the way in which future insight into medical complexity calls for the most eclectic and multidisciplinary of approaches.

Research into the neurobiological and psychosocial mechanisms involved in fibromyalgia (FM) has progressed remarkably in recent years. Despite this, currents accounts of FM fail to capture the complex, dynamic and mutual crosstalk between neurophysiological and psychosocial domains. We conducted a comprehensive review of the existing literature in order to synthesise current knowledge on FM, explore and highlight multi-level links and pathways among different systems and build bridges between existing approaches. An extensive panel of international experts in neurophysiology and psychosocial aspects of FM discussed the collected evidence and progressively refined and conceptualized its interpretation. Fibromyalgia is a complex condition resulting from the dynamic interplay between multiple systems and processes. We provided an updated overview of the most relevant observations in FM to date as well as the potential pathways by which they exert they are related and exert their mutual influence, to produce the manifestations commonly associated with FM. This review constituted the first step towards and supported the development of a much needed model capable of integrating the main factors implicated in FM into a single, unified model that may prove valuable in understanding and managing FM.

Rheumatoid arthritis (RA) and fibromyalgia syndrome (FM) are common diagnoses encountered in rheumatology practice, but do not enjoy the same status. We aimed to examine physician's illness perceptions regarding these two rheumatologic disorders and to evaluate how they correlate with their relationship with these patients.Forty-five rheumatologists were enrolled in the study. Demographic data were registered. Measures collected included the Brief Illness Perception Questionnaire (BIPQ) and the Difficult Doctor- Patient Relation Questionnaire (DDPRQ-10). Both were recorded twice, related to FM and RA. Empathy and burnout were also assessed.Of 45 physicians included in the study, only 53% were willing to accept FM patients. FM was considered a more severe disease than RA (FM-BIPQ mean score 54, SD 5.5 versus RA-BIPQ mean 45.6 SD 6.5, p0.00) in terms of treatment control, understanding and emotional response generated by the disease. Doctor-patient relationship was perceived more difficult with FM patients compared to RA patients (FM-DDPRQ mean score 35.1, SD 9.2 versus RA-DDPRQ mean 19.6, SD 7.1, p0.00), and was significantly correlated to the patient's concern about the illness (p0.034) and patient's emotional response (p0.036). Resistance to accept FM patients was largely influenced by difficult doctor-patient relationship. Higher levels of empathy were found in physicians experiencing less difficulty with FM patients.FM patients were perceived as more difficult than RA patients, with a high level of concern and emotional response. A high proportion of physicians were reluctant to accept them because they feel emotional/psychological difficulties meeting and coping with these patients.

Background There are interrelationships between the autonomic nervous system and pain. This study aims to explore the effect of different autonomic manipulations on pain perception and modulation. Methods Twenty healthy subjects (10 men and 10 women, mean age 25±3) participate in this single-blinded, semi-randomized, controlled study, which included 2 study visits. Warm and heat pain thresholds, conditioned pain modulation and pain adaptation were tested before and after administration of phenylephrine, clonidine, yohimbine and saline. Results Changes in heart rate and blood pressure were found after all the pharmacological interventions. The only effect on pain measures was that yohimbine enhanced pain adaptation capacity while phenylephrine reduced it (p=0.032). Several significant correlations were found between autonomic and pain parameters; greater decreases in heart rate after phenylephrine were associated with reduced pain ratings (r2= 0.288, p=0.018). In addition, enhanced pain adaptation was associated with higher total vascular resistance (r2=0.442, p=0.01). Conclusions Different effects of acute autonomic manipulations on experimental pain were found; an increase in sympathetic tone induced by yohimbine led to reduced pain sensitivity; a decrease in sympathetic tone with no effect on vagal-parasympathetic tone induced by phenylephrine led to reduction in pain adaptation capacity; and a decrease in sympathetic tone and increase in vagal parasympathetic tone by clonidine led to no change in pain adaptation capacity. While increased sympathetic outflow does facilitate pain adaptation, activation of either the sympathetic or parasympathetic limbs of the autonomic nervous system does not affect pain thresholds or CPM. Finally, a correlation exists between nociception and cardiovascular parameters only due to baroreflex activation. This article is protected by copyright. All rights reserved.

Objective To evaluate the prevalence of sacroiliitis, the radiographic hallmark of inflammatory spondyloarthropathy, among patients diagnosed with fibromyalgia syndrome (FMS), using the current Assessment of SpondyloArthritis International Society (ASAS) criteria and magnetic resonance imaging. Methods Patients experiencing FMS (American College of Rheumatology 1990 criteria) were interviewed regarding the presence of spondyloarthritis (SpA) features and underwent HLA–B27 testing, C-reactive protein (CRP) level measurement, and magnetic resonance imaging examinations of the sacroiliac joints. FMS severity was assessed by the Fibromyalgia Impact Questionnaire and the Short Form 36 health survey. SpA severity was assessed by the Bath Ankylosing Spondylitis Disease Activity Index. Results Sacroiliitis was demonstrated among 8 patients (8.1%) and ASAS criteria for diagnosis of axial SpA were met in 10 patients (10.2%). Imaging changes suggestive of inflammatory involvement (e.g., erosions and subchondral sclerosis) were demonstrated in 15 patients (17%) and 22 patients (25%), respectively. The diagnosis of axial SpA was positively correlated with increased CRP level and with physical role limitation at recruitment. Conclusion Imaging changes suggestive of axial SpA were common among patients with a diagnosis of FMS. These findings suggest that FMS may mask an underlying axial SpA, a diagnosis with important therapeutic implications. Physicians involved in the management of FMS should remain vigilant to the possibility of underlying inflammatory disorders and actively search for such comorbidities.

Introduction. Fibromyalgia syndrome (FMS) is a pain disorder with an estimated prevalence of 1–5%. It is associated with a variety of somatic and psychological disorders. Its exact pathogenesis is still unclear but is involved with neural oversensitization and decreased conditioned pain modulation (CPM), combined with cognitive dysfunction, memory impairment, and altered information processing. Connectivity between brain areas involved in pain processing, alertness, and cognition is increased in the syndrome, making its pharmacologic therapy complex. Only three drugs, pregabalin, duloxetine, and milnacipran are currently FDA-approved for FM treatment, but many other agents have been tested over the years, with varying efficacy. Areas Covered. The purpose of this review is to summarize current clinical experience with different pharmacologic treatments used for fibromyalgia and introduce future perspectives in developing therapies. Expert Opinion. Future insights into the fields of cannabinoid and opioid research, as well as an integrative approach towards the incorporation of genetics and functional imaging combined with additional fields of research relevant towards the study of complex CNS disorders, are likely to lead to new developments of novel tailor-made treatments for FMS patients.

Bartonellaspecies are fastidious, Gram-negative aerobic rods and a well-recognised pathogen responsible for culture-negative endocarditis. The histopathological appearance of glomerulonephritis (GN) caused byBartonellaendocarditis may include a pauci-immune GN similar to that usually seen in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Herein, we present an unusual case report ofBartonellaendocarditis masquerading as ANCA-positive vasculitis, with crescentic GN. A 66-year-old woman, who had undergone aortic valve replacement 2 years prior to admission, presented with confusion and loss of vision in her right nasal field. Following an extensive diagnostic evaluation, the main findings were right central retinal artery occlusion, ground-glass appearance on chest CT and ANCA-positive, anti PR-3 negative, rapidly progressive GN. The patient was scheduled to start treatment with rituximab for presumed ANCA-positive GN, when a positive serological test forBartonella henselaewas received. In view of this result, a diagnosis of endocarditis was made, based on fulfilment of five Duke minor criteria, namely fever, predisposition, arterial emboli, immunological phenomena and serological evidence of active infection with an organism consistent with infective endocarditis. Immunosuppressive treatment was withheld and antibiotic treatment initiated. This case report emphasises the need for maintaining a high index of suspicion regarding the diagnosis ofBartonellainfection, which might mimic ANCA-associated GN.

Medical cannabis is being increasingly used in the treatment of rheumatic diseases because, despite the paucity of evidence regarding its safety and efficacy, a growing number of countries are legalising its use for medical purposes in response to social pressure. Cannabinoids may be useful in the management of rheumatic disorders for two broad reasons: their anti-inflammatory and immunomodulatory activity, and their effects on pain and associated symptoms. It is interesting to note that, although a wide range of medications are available for the treatment of inflammation, including an ever-lengthening list of biological medications, the same is not true of the treatment of chronic pain, a cardinal symptom of many rheumatological disorders. The publication of systematic reviews (SR) concerning the use of cannabis-based medicines for chronic pain (with and without meta-analyses) is outpacing that of randomised controlled trials. Furthermore, narrative reviews of public institution are largely based on these SRs, which often reach different conclusions regarding the efficacy and safety of cannabis-based medicines because of the lack of high-quality evidence of efficacy and the presence of indications that they may be harmful for patients. Societal safety concerns about medical cannabis (e.g. driving risks, workplace safety and pediatric intoxication) must always be borne in mind, and will probably not be addressed by clinical studies. Medical cannabis and cannabis-based medicines have often been legalised as therapeutic products by legislative bodies without going through the usual process of regulatory approval founded on the results of traditional evidence-based studies. This review discusses the advantages and limitations of using cannabis to treat rheumatic conditions.

Fibromyalgia syndrome (FMS) is a chronic disorder characterized by widespread pain and tenderness, accompanied by disturbed sleep, chronic fatigue and multiple additional functional symptoms. FMS continues to pose an unmet need regarding pharmacological treatment and many patients fail to achieve sufficient relief from existing treatments. As FMS is considered to be a condition in which pain amplification occurs within the CNS, therapeutic interventions, both pharmacological and otherwise, have revolved around attempts to influence pain processing in the CNS. In the current review, we present an update on novel targets in the search for effective treatment of FMS.

OBJECTIVE To compare the concordance of the three diagnostic criteria, respectively the 2011 ACR criteria (ACR 2011 Cr), the ACR 2016 criteria (ACR 2016 Cr) and the Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks (ACTTION)-APS Pain Taxonomy criteria (AAPT Cr), and to explore the performance of an additional set of criteria, the modified Fibromyalgia Assessment Status (FAS 2019 modCr), in the diagnosis of FM syndrome. METHODS Consecutive patients with chronic widespread pain, referred by the primary care setting, underwent rheumatologic assessment that established the presence or not of FM and were investigated through the four sets of proposed criteria. For the FAS 2019 modCr, discriminant validity to distinguish patients with FM and non-FM was assessed with receiver operating characteristic curve analysis. RESULTS A total of 732 (405 with FM and 327 with other common chronic pain problems) patients were evaluated. Against the clinical diagnosis of FM, the sensitivity, specificity and correct classification were, respectively: 79.8, 91.7 and 85.1% for ACR 2011 Cr; 78, 90.5 and 83.6% for the ACR 2016 Cr; and 73.8, 91.7 and 81.8% for the AAPT Cr. The alternative set, proposed on the FAS 2019 modCr, provided a maximal diagnostic accuracy with a score ≥20 (Youden's index), with a sensitivity of 84.2%, specificity 89.0% and positive likelihood ratio 7.65. CONCLUSION There is a considerable agreement between criteria-based diagnoses of FM, although the AAPT Cr perform least well in terms of percentage of correct classification. The FAS 2019 modCr had comparable characteristics.

Introduction: The premenstrual syndrome (PMS) is a constellation of somatic and psychogenic symptoms that appear during late luteal (LL) phase of the menstrual cycle. Since many symptoms could be related to the autonomic nervous system, we hypothesized that the sympathetic nervous system is perturbed in PMS. Methods: The cardiovascular autonomic profile of nine women with PMS (30.4 ± 2.5 years) were compared to that of nine healthy controls (30 ± 2.5 years) during their early follicular (EF) and LL phases of the menstrual cycle. Plasma norepinephrine (NE) concentrations, power spectral analysis of heart rate and systolic blood pressure (BP), and baroreflex sensitivity (BRS) were assessed during recumbency and a head-up tilt (HUT). Cardiovascular responsiveness to α1- and β-adrenoreceptor agonists (phenylephrine and isoproterenol, respectively) were also assessed. Results: In the LL phase, the plasma NE concentrations in women with PMS during recumbency and a HUT were lower than those in women without PMS [180 ± 30 vs. 320 ± 50 pg/ml; p = 0.04 (recumbent), and 480 ± 70 vs. 940 ± 180 pg/ml: p = 0.02 (HUT)]. In the LL phase, the dose of phenylephrine required to increase systolic BP by 15 mmHg in women with PMS was significantly greater than that in women without PMS (202 ± 30 μg vs. 138 ± 20 μg; p = 0.02). Sympathetic and vagal cardiac control indices were comparable in the two groups in the menstrual phases. In women with PMS, the value of LF SBP in the LL phase was lower than that in the EF phase (0.98 ± 0.2 vs. 1.77 ± 0.4 mmHg2, p = 0.04). The increase in LF SBP in women with PMS in the LL phase during HUT was greater than that in the controls, 5.2 ± 0.9 vs. 3.1 ± 0.5 mmHg2, p = 0.045, and this increase was associated with a significant decrease in BRS. Conclusion: In women with PMS without psychogenic symptoms, the sympathetic control of their circulation is not dominant during the LL phase of their menstrual cycle.

We investigated whether the central pain symptoms in fibromyalgia syndrome (FM) are related to defective top-down sensorimotor regulation. The pain matrix was activated in a top-down manner by presenting pictures of painful situations while recording brain activity using magnetoencephalography (MEG). We investigated alpha desynchronisation in FM patients and healthy controls in response to pictures depicting pain.19 FM patients and 14 age-matched healthy controls (age 20-60) were recruited. Participants were shown photographs of right hands and feet in situations depicting pain or of control situations with no depiction of pain. MEG was recorded in a whole-head 248-sensor system as subjects laid supine.In healthy controls exposure to pictures depicting painful situations elicited a decrease in alpha activity (10Hz) at 100-500ms post-stimulus, which was significantly more pronounced than the one elicited by non-painful content mostly on sensors above the right sensorimotor cortex. However, FM patients did not show significant differences in alpha activity between responses to pain and no-pain pictures.Consistent with previous findings, healthy participants displayed stronger alpha desynchronisation for pain pictures, indicating automatic disinhibition of the sensorimotor cortices in response to the observation of pain in others. We found evidence for a deficient modulation of sensorimotor cortex in FM patients. The lack of differential response suggests that they perceived relatively neutral pictures as potentially painful, at least in this setting. Our findings suggest that defective top-down regulation may play a role in the pathogenesis of FM.

Volitional neural modulation using neurofeedback has been indicated as a potential treatment for chronic conditions that involve peripheral and central neural dysregulation. Here we utilized neurofeedback in patients suffering from Fibromyalgia - a chronic pain syndrome that involves sleep disturbance and emotion dysregulation. These ancillary symptoms, which have an amplification effect on pain, are known to be mediated by heightened limbic activity. In order to reliably probe limbic activity in a scalable manner fit for EEG-neurofeedback training, we utilized an Electrical Finger Print (EFP) model of amygdala-BOLD signal (termed Amyg-EFP), that has been successfully validated in our lab in the context of volitional neuromodulation. We anticipated that Amyg-EFP-neurofeedback training aimed at limbic down modulation should improve chronic pain in patients suffering from Fibromyalgia, by balancing disturbed indices for sleep and affect. We further expected that improved clinical status would correspond to successful training as indicated by improved down modulation of the Amygdala-EFP signal. Thirty-Four Fibromyalgia patients (31F; age 35.6 ± 11.82) participated in a randomized placebo-controlled trial with biweekly Amyg-EFP-neurofeedback sessions and placebo of sham neurofeedback (n = 9) for a total duration of five consecutive weeks. Following training, participants in the Real-neurofeedback group were divided into good (n = 13) or poor (n = 12) modulators according to their success in the neurofeedback training. Before and after treatment, self-reports on pain, depression, anxiety, fatigue and sleep quality were obtained, as well as objective sleep Indices. Long-term clinical follow-up was made available, within up to three years of the neurofeedback training completion. REM latency and objective sleep quality index were robustly improved following the treatment course only in the Real-neurofeedback group (both time × group p < 0.05) and to a greater extent among good modulators (both time*sub-group p < 0.05). In contrast, self-report measures did not reveal a treatment-specific response at the end of the treatment. However, the follow-up assessment revealed a delayed improvement in chronic pain and subjective sleep experience, evident only in the Real-neurofeedback group (both time × group p < 0.05). Moderation analysis showed that the enduring clinical effects on pain evident in the follow-up assessment were predicted by the immediate improvements following training in objective sleep and subjective affect measures. Our findings suggest that Amyg-EFP- neurofeedback that specifically targets limbic activity down modulation offers a successful principled approach for volitional EEG based neuromodulation training in Fibromyalgia patients. Importantly, it seems that via its immediate sleep improving effect, the neurofeedback training induced a delayed reduction in the target subjective symptom of chronic pain, far and beyond the immediate placebo effect. This indirect approach to chronic pain management reflects the necessary link between somatic and affective dysregulation that can be successfully targeted using neurofeedback.

Fibromyalgia syndrome (FM), characterised by widespread pain and fatigue, has frequently been associated with stress in various models, including workplace related stress. In the current study we have evaluated the prevalence of FM symptoms among Israeli school teachers and have attempted to correlate such symptoms with work-related stress.Individuals, all currently employed as school teachers in Israel, were recruited to the study. Participants were asked to answer a questionnaire evaluating symptoms of FM, based on the current diagnostic criteria, which include the widespread pain index (WPI) and the symptom severity scale (SSS). Participants were further questioned regarding stressful experiences during their work and about post-traumatic symptoms as well as regarding work performance and motivation.321 participants were recruited (79.4% female, 20.6 male). 30 individuals (9.3%) of the sample fulfilled current criteria for a diagnosis of FM, with a rate of 11.4% among females and 1.5% among males. While specific symptoms such as fatigue and irritable bowel symptoms were negatively correlated with work performance, no significant difference was found between teachers with or without fibromyalgia regarding work attendance and performance. FM symptoms were strongly correlated with work-related stress and were strongly correlated with post-traumatic stress disorder (PTSD) related symptoms. Motivation to work was significantly lower among teachers fulfilling FM criteria, but other performance-related parameters did not differ between teachers fulfilling or not fulfilling FM criteria.Fibromyalgia symptoms are highly prevalent among Israeli school teachers, and may be related to stress encountered in the classroom. These results are relevant both for physicians treating individuals involved in educational careers as well as for educators and decision-makers involved in planning and managing educational strategies.

The current provisional diagnostic criteria for the fibromyalgia syndrome (FM) include a cognitive index score (SSS-Cog), which constitutes a part of the Symptom Severity Scale (SSS). The current study aimed at assessing the validity of the cognitive index score, by comparing this subjective measure of cognitive impairment with an objective measure of cognitive functioning, collected through comprehensive computerised cognitive testing and assessment.50 FM patients underwent a computerised cognitive assessment battery, including testing in domains of memory, executive function, attention and information processing speed (NeuroTraxCorp.). Age and education standardised scores were computed. FM symptoms were assessed by the Fibromyalgia Impact Questionnaire (FIQ), Widespread Pain Index (WPI) and Symptom Severity Scale (SSS), a Visual Analog Scale (VAS) of clinical pain and the Beck Depression inventory (BDI-II).The index score for subjective assessment of cognitive decline (SSS-Cog) was not correlated with any of the objective cognitive measures. However, a positive correlation was found between the SSS-Cog and the FIQ, the WPI and the VAS measures, all reflecting subjective overall functional ability.No significant relationship was found between FM patients' subjective appraisal of cognitive deficit and objective cognitive scores on all computerised subtests. However, subjective appraisal of cognitive impairment was found to be strongly and significantly related to patients' functional ability. Therefore, we suggest reconsidering the definition of this index score (SSS-Cog) and propose developing novel and more accurately defined tools in order to measure cognitive impairment in FM patients, for both diagnostic and epidemiological purposes.