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  • 1. Bottai, Matteo
    et al.
    Tjärnlund, Anna
    Santoni, Giola
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Werth, Victoria P.
    Pilkington, Clarissa
    de Visser, Marianne
    Alfredsson, Lars
    Amato, Anthony A.
    Barohn, Richard J.
    Liang, Matthew H.
    Singh, Jasvinder A.
    Aggarwal, Rohit
    Arnardottir, Snjolaug
    Chinoy, Hector
    Cooper, Robert G.
    Danko, Katalin
    Dimachkie, Mazen M.
    Feldman, Brian M.
    García-De La Torre, Ignacio
    Gordon, Patrick
    Hayashi, Taichi
    Katz, James D.
    Kohsaka, Hitoshi
    Lachenbruch, Peter A.
    Lang, Bianca A.
    Li, Yuhui
    Oddis, Chester V.
    Olesinka, Marzena
    Reed, Ann M.
    Rutkowska-Sak, Lidia
    Sanner, Helga
    Selva-O'Callaghan, Albert
    Song, Yeong Wook
    Vencovsky, Jiri
    Ytterberg, Steven R.
    Miller, Frederick W.
    Rider, Lisa G.
    Lundberg, Ingrid E.
    EULAR/ACR classification criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups: a methodology report2017In: RMD Open, E-ISSN 2056-5933, Vol. 3, no 2, article id e000507Article in journal (Refereed)
    Abstract [en]

    Objective To describe the methodology used to develop new classification criteria for adult and juvenile idiopathic inflammatory myopathies (IIMs) and their major subgroups.

    Methods An international, multidisciplinary group of myositis experts produced a set of 93 potentially relevant variables to be tested for inclusion in the criteria. Rheumatology, dermatology, neurology and paediatric clinics worldwide collected data on 976 IIM cases (74% adults, 26% children) and 624 non-IIM comparator cases with mimicking conditions (82% adults, 18% children). The participating clinicians classified each case as IIM or non-IIM. Generally, the classification of any given patient was based on few variables, leaving remaining variables unmeasured. We investigated the strength of the association between all variables and between these and the disease status as determined by the physician. We considered three approaches: (1) a probability-score approach, (2) a sum-of-items approach criteria and (3) a classification-tree approach.

    Results The approaches yielded several candidate models that were scrutinised with respect to statistical performance and clinical relevance. The probability-score approach showed superior statistical performance and clinical practicability and was therefore preferred over the others. We developed a classification tree for subclassification of patients with IIM. A calculator for electronic devices, such as computers and smartphones, facilitates the use of the European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria.

    Conclusions The new EULAR/ACR classification criteria provide a patient's probability of having IIM for use in clinical and research settings. The probability is based on a score obtained by summing the weights associated with a set of criteria items.

  • 2. Hedström, Anna Karin
    et al.
    Hössjer, Ola
    Stockholm University, Faculty of Science, Department of Mathematics.
    Klareskog, Lars
    Alfredsson, Lars
    Interplay between alcohol, smoking and HLA genes in RA aetiology2019In: RMD Open, E-ISSN 2056-5933, Vol. 5, no 1, article id e000893Article in journal (Refereed)
    Abstract [en]

    Objectives The relationship between alcohol consumption and risk for rheumatoid arthritis (RA) is incompletely understood. We aimed to determine the influence of alcohol on anticitrullinated protein antibody (ACPA) positive and ACPA-negative RA and investigate potential interactions between alcohol consumption, smoking and the presence of human leucocyte antigen (HLA)-DRB1-shared epitope (SE).

    Methods A Swedish population-based case-control study with incident cases of RA was used (3353 cases, 2836 matched controls). Subjects with different HLA-DRB1-SE status, smoking and alcohol consumption were compared regarding risk of ACPA-positive and ACPA-negative RA, by calculating OR with 95% CI employing logistic regression. Interaction on the additive scale between alcohol, HLA-DRB1-SE and smoking was estimated by calculating the attributable proportion (AP) due to interaction.

    Results Compared with non-drinking, low and moderate alcohol consumption was dose dependently associated with a reduced risk of ACPA-positive and ACPA-negative RA. Independent of smoking habits, non-drinking and the presence of HLA-DRB1-SE interacted to increase the risk of ACPA-positive RA. Among HLA-DRB1-SE positive subjects, there was also a significant interaction between non-drinking and smoking with regard to risk for ACPA-positive RA. A three-way interaction was observed between alcohol, smoking and HLA-DRB1-SE with regard to risk for ACPA-positive RA (AP 0.7, 95% CI 0.6 to 0.8) that remained significant when the influence from the two-way interactions was removed (AP 0.4, 95% CI 0.2 to 0.6).

    Conclusions Our findings emphasize the need to investigate complex interactions between several environmental and genetic factors in order to better understand the etiology of RA. Whereas of great interest in an aetiological perspective, the finding of a protective role of alcohol on risk for RA must, however, be interpreted with caution in a clinical and public health perspective.

  • 3. Karshikoff, B.
    et al.
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Olgart Höglund, C.
    Axelsson, J.
    Pain sensitivity during experimentally induced systemic inflammation in humans2013In: Brain, Behavior, and Immunity, 2013, Vol. 32, p. e32-Conference paper (Refereed)
  • 4.
    Lasselin, Julie
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden; University Hospital Essen, Germany.
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Axelsson, John
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Karshikoff, Bianka
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden; Stanford University School of Medicine, USA.
    Sex differences in how inflammation affects behavior: What we can learn from experimental inflammatory models in humans2018In: Frontiers in neuroendocrinology (Print), ISSN 0091-3022, E-ISSN 1095-6808, Vol. 50, p. 91-106Article, review/survey (Refereed)
    Abstract [en]

    Human models demonstrate that experimental activation of the innate immune system has profound effects on brain activation and behavior, inducing fatigue, worsened mood and pain sensitivity. It has been proposed that inflammation is a mechanism involved in the etiology and maintenance of depression, chronic pain and long-term fatigue. These diseases show a strong female overrepresentation, suggesting that a better understanding of sex differences in how inflammation drives behavior could help the development of individualized treatment interventions. For this purpose, we here review sex differences in studies using experimental inflammatory models to investigate changes in brain activity and behavior. We suggest a model in which inflammation accentuates sex differences in brain networks and pre-existing vulnerability factors. This effect could render women more vulnerable to the detrimental effects of immune-to-brain communication over time. We call for systematic and large scale investigations of vulnerability factors for women in the behavioral response to inflammation.

  • 5. Mork, P.J.
    et al.
    Nilsson, Johan
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Lorås, H.W.
    Riva, Roberto
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Lundberg, Ulf
    Stockholm University, Faculty of Social Sciences, Centre for Health Equity Studies (CHESS). Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Westgaard, R.H.
    Heart rate variability in fibromyalgia patients and healthy controls during non-REM and REM sleep: a case–control study2013In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 42, no 6, p. 505-508Article in journal (Refereed)
    Abstract [en]

    Objectives: To investigate heart rate variability (HRV) in fibromyalgia (FM) patients and healthy controls (HCs) during different sleep stages, and to examine the association of HRV with pain and sleep quality.

    Method: Polysomnography was recorded from 23 female FM patients and 22 age- and sex-matched HCs. HRV was recorded from bedtime until awakening including the standard deviation of normal-to-normal intervals (SDNN), the root mean square successive difference (RMSSD), and the low (LF; 0.04–0.15 Hz) and high (HF; 0.15–0.4 Hz) frequency power. Subjective scores of neck/shoulder pain and sleep quality were obtained at bedtime and awakening.

    Results: Both patients and HCs showed high incidence of arousals per hour (FM: 16 ± 9.7; HCs: 17 ± 11). RMSSD was lower in patients than HCs during non-rapid eye movement (non-REM) stage 2 (N2) sleep (mean ± SD; 30 ± 12 ms vs. 42 ± 13 ms, p < 0.002) and during REM sleep (23 ± 11 ms vs. 37 ± 16 ms, p < 0.003). HRV did not differ between groups during N3 sleep (p > 0.19 for all comparisons). In patients, SDNN, RMSSD, and HF power showed modest positive correlations with sleep quality (HF power during N3 sleep showed the highest correlation; Spearman’s ρ = 0.54) and modest negative correlations with neck/shoulder pain (RMSSD during N3 sleep showed the highest correlation with pain at bedtime; Spearman’s ρ = –0.51).

    Conclusions: RMSSD, indicative of parasympathetic predominance, is attenuated in FM patients compared to HCs during N2 sleep and REM sleep. This difference was not present for the HF component. HRV during sleep in FM patients is moderately and positively associated with sleep quality and moderately and negatively associated with neck/shoulder pain

  • 6. Onder, Graziano
    et al.
    Vetrano, Davide L.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Marengoni, Alessandra
    Bell, J. Simon
    Johnell, Kristina
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Palmer, Katie
    Accounting for frailty when treating chronic diseases2018In: European journal of internal medicine, ISSN 0953-6205, E-ISSN 1879-0828, Vol. 56, p. 49-52Article, review/survey (Refereed)
    Abstract [en]

    Chronic diseases are considered to be major determinants of frailty and it could be hypothesized that their treatment may counteract the development of frailty. However, the hypothesis that intensive treatment of chronic diseases might reduce the progression of frailty is poorly supported by existing studies. In contrast, some evidence suggests that intensive treatment of chronic diseases may increase negative health outcomes in frail older adults. In particular, if treatment of symptoms related to chronic diseases (i.e. pain in osteoarthritis, dyspnoea in respiratory disease, motor symptoms in Parkinson disease) might potentially reverse frailty, the benefits related to preventive pharmacological treatment of chronic diseases (i.e. antihypertensive treatment) in patients with prevalent frailty is not certain. In particular, several factors might alter the risk/benefit ratio of a given treatment in persons with frailty. These include: exclusion of frail persons from clinical studies, reduced life expectancy in frail persons, increased susceptibility to iatrogenic events, and functional deficits associated with frailty. Therefore, frailty acts as an effect modifier, by modifying the risks and benefits of chronic disease treatments. This hypothesis must be considered and tested in future clinical intervention studies and clinical guidelines should provide specific recommendations for the treatment of frail people, underlining the pros and the cons of pharmacological treatment and possible targets for therapy in this population. Meanwhile, in older patients, the prescribing process should be individualized and flexible.

  • 7. Schultz, Nina
    et al.
    Brännström, Kristoffer
    Byman, Elin
    Moussaud, Simon
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Nielsen, Henrietta M.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Olofsson, Anders
    Wennström, Malin
    Amyloid-beta 1-40 is associated with alterations in NG2+pericyte population exvivo and invitro2018In: Aging Cell, ISSN 1474-9718, E-ISSN 1474-9726, Vol. 17, no 3, article id e12728Article in journal (Refereed)
    Abstract [en]

    The population of brain pericytes, a cell type important for vessel stability and blood brain barrier function, has recently been shown altered in patients with Alzheimer's disease (AD). The underlying reason for this alteration is not fully understood, but progressive accumulation of the AD characteristic peptide amyloid-beta (A beta) has been suggested as a potential culprit. In the current study, we show reduced number of hippocampal NG2+ pericytes and an association between NG2+ pericyte numbers and A1-40 levels in AD patients. We further demonstrate, using invitro studies, an aggregation-dependent impact of A beta 1-40 on human NG2+ pericytes. Fibril-EP A beta 1-40 exposure reduced pericyte viability and proliferation and increased caspase 3/7 activity. Monomer A beta 1-40 had quite the opposite effect: increased pericyte viability and proliferation and reduced caspase 3/7 activity. Oligomer-EP A beta 1-40 had no impact on either of the cellular events. Our findings add to the growing number of studies suggesting a significant impact on pericytes in the brains of AD patients and suggest different aggregation forms of A beta 1-40 as potential key regulators of the brain pericyte population size.

  • 8. Thålin, Charlotte
    et al.
    Daleskog, Maud
    Paues Göransson, Sophie
    Schatzberg, Daphne
    Lasselin, Julie
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Laska, Ann-Charlotte
    Kallner, Anders
    Helleday, Thomas
    Wallén, Håkan
    Demers, Mélanie
    Validation of an enzyme-linked immunosorbent assay for the quantification of citrullinated histone H3 as a marker for neutrophil extracellular traps in human plasma2017In: Immunologic research, ISSN 0257-277X, E-ISSN 1559-0755, Vol. 65, no 3, p. 706-712Article in journal (Refereed)
    Abstract [en]

    There is an emerging interest in the diverse functions of neutrophil extracellular traps (NETs) in a variety of disease settings. However, data on circulating NETs rely largely upon surrogate NET markers such as cell-free DNA, nucleosomes, and NET-associated enzymes. Citrullination of histone H3 by peptidyl arginine deiminase 4 (PAD4) is central for NET formation, and citrullinated histone H3 (H3Cit) is considered a NET-specific biomarker. We therefore aimed to optimize and validate a new enzyme-linked immunosorbent assay (ELISA) to quantify the levels of H3Cit in human plasma. A standard curve made of in vitro PAD4-citrullinated histones H3 allows for the quantification of H3Cit in plasma using an anti-histone antibody as capture antibody and an anti-histone H3 citrulline antibody for detection. The assay was evaluated for linearity, stability, specificity, and precision on plasma samples obtained from a human model of inflammation before and after lipopolysaccharide injection. The results revealed linearity and high specificity demonstrated by the inability of detecting non-citrullinated histone H3. Coefficients of variation for intra- and inter-assay variability ranged from 2.1 to 5.1% and from 5.8 to 13.5%, respectively, allowing for a high precision. Furthermore, our results support an inflammatory induction of a systemic NET burden by showing, for the first time, clear intra-individual elevations of plasma H3Cit in a human model of lipopolysaccharide-induced inflammation. Taken together, our work demonstrates the development of a new method for the quantification of H3Cit by ELISA that can reliably be used for the detection of NETs in human plasma.

  • 9. Wändell, P.
    et al.
    Andreasson, Anna
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Hagström, H.
    Kapetanovic, M. C.
    Carlsson, A. C.
    The use of anthropometric measures in the prediction of incident gout: results from a Swedish community-based cohort study2019In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 48, no 4, p. 294-299Article in journal (Refereed)
    Abstract [en]

    Objectives: To study associations between different anthropometric measures and incident gout, and to find the best predictive measure.

    Method: We used the baseline investigation from the Malmo Diet and Cancer study, excluding cases of prevalent gout (n = 28 081). Cox regression for each anthropometric measurement was calculated per standard deviation increment for men and women, with hazard ratios (HRs) and 95% confidence intervals (CIs), using a hospital diagnosis of incident gout (M10) during follow-up as the outcome. Incremental C-statistics for each anthropometric measure were used to determine the measure with the best predictive capacity, in models adjusted for age, socio-economic data, lifestyle factors, comorbidities, and antihypertensive medications.

    Results: The study population included 11 049 men and 17 032 women, with 633 incident gout cases, 393 in men (3.6%) and 240 in women (1.4%). For both men and women, the five anthropometric measurements with highest C-statistics were weight, body mass index (BMI), waist circumference (WC), hip circumference, and waist-to-height ratio; in men, the measurement with the highest C-statistic was BMI (0.7361; fully adjusted HR 1.52, 95% CI 1.39-1.68), and in women WC (0.8085; fully adjusted HR 1.62, 95% CI 1.46-1.81). The increment in C-statistic with anthropometric measures was good, around 0.035. Waist-to-hip ratio, waist-to-hip-to-height ratio, body fat percentages, and especially A Body Shape Index had lower C-statistics.

    Conclusions: Both BMI and WC showed good predictive ability for incident gout. The clinically used cut-offs for BMI and WC appeared to be relevant in the assessment of increased risk of gout.

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