Published in 2017

Bursitis efter vaccination i skulderregionen

Bliddal, H., Torp-Pedersen, S., Falk-Riecke, B. & Bartels, E. 23 okt. 2017 I : Ugeskrift for laeger. 179, 43, s. V05170423

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Shoulder pain may develop after vaccination in the deltoid area due to inadvertent injection of the vaccine into the subdeltoid bursa, which may be located close to the skin. As far as we know, such vaccination reactions occur more frequently than officially registered, and doctors may not be aware of the problem. We present two of these cases of a suspected inflammatory reaction in the shoulder bursa after vaccination. Injection of cortisone in the bursa may relieve the reaction to some extent, but chronic shoulder pain may develop.

Originalsprog Dansk
Tidsskrift Ugeskrift for laeger
Vol/bind 179
Tidsskriftsnummer 43
Sider (fra-til) V05170423
ISSN 0041-5782
Status Udgivet - 23 okt. 2017

C5a and C5aR are elevated in joints of rheumatoid and psoriatic arthritis patients, and C5aR blockade attenuates leukocyte migration to synovial fluid

Hornum, L., Hansen, A. J., Tornehave, D., Fjording, M. S., Colmenero, P., Wätjen, I. F., Søe Nielsen, N. H., Bliddal, H. & Bartels, E. M. 2017 I : P L o S One. 12, 12, s. e0189017

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Complement activation correlates to rheumatoid arthritis disease activity, and increased amounts of the complement split product C5a is observed in synovial fluids from rheumatoid arthritis patients. Blockade of C5a or its receptor (C5aR) is efficacious in several arthritis models. The aim of this study was to investigate the role of C5a and C5aR in human rheumatoid arthritis and psoriatic arthritis-both with respect to expression and function. Synovial fluid, blood and synovial samples were obtained from rheumatoid arthritis, psoriatic arthritis and osteoarthritis patients as a less inflammatory arthritis type, and blood from healthy subjects. Cells infiltrating synovial tissue were analysed by immunohistochemistry and flow cytometry. SF and blood were analysed for biomarkers by flow cytometry or ELISA. The effect of a blocking anti-human C5aR mAb on leukocyte migration was determined using a Boyden chamber. Appropriate statistical tests were applied for comparisons. C5aR+ cells were detected in most rheumatoid arthritis, in all psoriatic arthritis, but not in non-inflammatory control synovia. C5aR+ cells were primarily neutrophils and macrophages. C5aR+ macrophages were mainly found in lymphoid aggregates in close contact with T cells. C5a levels were increased in both rheumatoid arthritis and psoriatic arthritis synovial fluid compared to osteoarthritis, and in blood from rheumatoid arthritis compared to healthy subjects. Neutrophil and monocyte migration to rheumatoid arthritis synovial fluid was significantly inhibited by anti-C5aR. The data support that the C5a-C5aR axis may be driving the infiltration of inflammatory cells into the synovial fluid and synovium in both rheumatoid and psoriatic arthritis, and suggest that C5a or C5aR may be a promising treatment target in both diseases.

Originalsprog Engelsk
Tidsskrift P L o S One
Vol/bind 12
Tidsskriftsnummer 12
Sider (fra-til) e0189017
ISSN 1932-6203
DOI
Status Udgivet - 2017

Cancer risk in patients with spondyloarthritis treated with TNF inhibitors: a collaborative study from the ARTIS and DANBIO registers

Hellgren, K., Dreyer, L., Arkema, E. V., Glintborg, B., Jacobsson, L. T. H., Kristensen, L-E., Feltelius, N., Hetland, M. L., Askling, J. & ARTIS Study Group, For the DANBIO Study Group jan. 2017 I : Annals of the Rheumatic Diseases. 76, 1, s. 105-111 7 s.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

BACKGROUND: Safety data on cancer risks following tumour necrosis factor α inhibitors (TNFi) in patients with spondyloarthritis (SpA) (here defined as ankylosing spondylitis (AS), undifferentiated spondarthropaties (SpA UNS), psoriatic arthritis (PsA)) are scarce. Our objective was to assess risks for cancer overall and for common subtypes in patients with SpA treated with TNFi compared with TNFi-naïve patients with SpA and to the general population.

METHODS: From the Swedish (Anti-Rheumatic Therapy in Sweden (ARTIS)) and Danish (DANBIO) biologics registers, we assembled 8703 (ARTIS=5448, DANBIO=3255) patients with SpA initiating a first TNFi 2001-2011. From the Swedish National Patient and Population Registers we assembled a TNFi-naïve SpA cohort (n=28,164) and a Swedish age-matched and sex-matched general population comparator cohort (n=131 687). We identified incident cancers by linkage with the nationwide Swedish and Danish Cancer Registers 2001-2011, and calculated age-standardised and sex-standardised incidence ratios as measures of relative risk (RR).

RESULTS: Based on 1188 cancers among the TNFi-naïve patients with SpA, RR of cancer overall was 1.1 (95% CI 1.0 to 1.2). Based on 147 cancers among TNFi initiators with SpA, RR versus TNFi-naïve was 0.8 (95% CI 0.7 to 1.0) and results were similar for AS and PsA when analysed separately. Site-specific cancer RRs: prostate 0.5 (95% CI 0.3 to 0.8), lung 0.6 (95% CI 0.3 to 1.3), colorectal 1.0 (95% CI 0.5 to 2.0), breast 1.3 (95% CI 0.9 to 2.0), lymphoma 0.8 (95% CI 0.4 to 1.8) and melanoma 1.4 (95% CI 0.7 to 2.6).

CONCLUSIONS: In patients with SpA, treatment with TNFi was not associated with increased risks of cancer, neither overall nor for the six most common cancer types.

Originalsprog Engelsk
Tidsskrift Annals of the Rheumatic Diseases
Vol/bind 76
Tidsskriftsnummer 1
Sider (fra-til) 105-111
Antal sider 7
ISSN 0003-4967
DOI
Status Udgivet - jan. 2017

Clinical characteristics of importance to outcome in patients with axial spondyloarthritis: protocol for a prospective descriptive and exploratory cohort study

Andreasen, R. A., Kristensen, L. E., Ellingsen, T., Christensen, R., Baraliakos, X., Wied, J., Aalykke, C., Ulstrup, T., Schiøttz-Christensen, B., Horn, H. C., Emamifar, A., Duerlund, B., Fischer, L. & Hansen, I. M. J. 10 jul. 2017 I : BMJ Paediatrics Open . 7, 7, s. e015536

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INTRODUCTION: Spondyloarthritis (SpA) is a heterogeneous spectrum of rheumatic diseases with either predominantly axial inflammatory symptoms of the spine and sacroiliac joints or predominantly peripheral arthritis. The two main entities of axial SpA (axSpA) are ankylosing spondylitis or non-radiographic axSpA (nr-axSpA). Tumour necrosis factor-α inhibitors have revolutionised the treatment of patients with axSpA who failed to respond to non-steroidal anti-inflammatory drugs and physical therapy. Chronic pain is common in patients with SpA and may still persist despite the lack of signs of inflammation. This has led researchers to hypothesise that central pain sensitisation may play a role in the generation of chronic pain in SpA. The painDETECT Questionnaire (PDQ) is a screening tool developed to detect neuropathic pain components. The primary objective is to explore the prognostic value of the PDQ regarding treatment response in patients with axSpA 3 months after initiating a biological agent. Secondary aim is to evaluate the impact of extra-articular manifestations, comorbidities and patient-reported outcomes and elucidate if these factors influence treatment response.

METHOD AND ANALYSIS: We will include 60 participants (≥18 years of age) diagnosed with axSpA independent of main entity, who initiate or switch treatment of a biologic. Data will be collected at baseline and at endpoint following Danish clinical practice (≥3 months) of treatment with biologics. We will explore whether the PDQ and other phenotypical patient characteristics are prognostically important for response to biological therapy according to established response criteria like 50% improvement in the Bath Ankylosing Spondylitis Disease Activity Index (50%) and Ankylosing Spondylitis Disease Activity Score.

ETHICS AND DISSEMINATION: The study is approved by the Region of Southern Denmark's Ethics committee (S-20160094) and has been designed in cooperation with patient representatives. The study is registered at clinicaltrials.gov (NCT02948608, pre-results). Dissemination will occur through publication(s) in international peer-reviewed journal(s).

Originalsprog Engelsk
Tidsskrift BMJ Paediatrics Open
Vol/bind 7
Tidsskriftsnummer 7
Sider (fra-til) e015536
ISSN 2044-6055
DOI
Status Udgivet - 10 jul. 2017

Coffee Drinking and Mortality in 10 European Countries: A Multinational Cohort Study

Gunter, M. J., Murphy, N., Cross, A. J., Dossus, L., Dartois, L., Fagherazzi, G., Kaaks, R., Kühn, T., Boeing, H., Aleksandrova, K., Tjønneland, A., Olsen, A., Overvad, K., Larsen, S. C., Redondo Cornejo, M. L., Agudo, A., Sánchez Pérez, M. J., Altzibar, J. M., Navarro, C., Ardanaz, E., Khaw, K-T., Butterworth, A., Bradbury, K. E., Trichopoulou, A., Lagiou, P., Trichopoulos, D., Palli, D., Grioni, S., Vineis, P., Panico, S., Tumino, R., Bueno-de-Mesquita, B., Siersema, P., Leenders, M., Beulens, J. W. J., Uiterwaal, C. U., Wallström, P., Nilsson, L. M., Landberg, R., Weiderpass, E., Skeie, G., Braaten, T., Brennan, P., Licaj, I., Muller, D. C., Sinha, R., Wareham, N. & Riboli, E. 15 aug. 2017 I : Annals of internal medicine. 167, 4, s. 236-247 12 s.

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Background: The relationship between coffee consumption and mortality in diverse European populations with variable coffee preparation methods is unclear.

Objective: To examine whether coffee consumption is associated with all-cause and cause-specific mortality.

Design: Prospective cohort study.

Setting: 10 European countries.

Participants: 521 330 persons enrolled in EPIC (European Prospective Investigation into Cancer and Nutrition).

Measurements: Hazard ratios (HRs) and 95% CIs estimated using multivariable Cox proportional hazards models. The association of coffee consumption with serum biomarkers of liver function, inflammation, and metabolic health was evaluated in the EPIC Biomarkers subcohort (n = 14 800).

Results: During a mean follow-up of 16.4 years, 41 693 deaths occurred. Compared with nonconsumers, participants in the highest quartile of coffee consumption had statistically significantly lower all-cause mortality (men: HR, 0.88 [95% CI, 0.82 to 0.95]; P for trend < 0.001; women: HR, 0.93 [CI, 0.87 to 0.98]; P for trend = 0.009). Inverse associations were also observed for digestive disease mortality for men (HR, 0.41 [CI, 0.32 to 0.54]; P for trend < 0.001) and women (HR, 0.60 [CI, 0.46 to 0.78]; P for trend < 0.001). Among women, there was a statistically significant inverse association of coffee drinking with circulatory disease mortality (HR, 0.78 [CI, 0.68 to 0.90]; P for trend < 0.001) and cerebrovascular disease mortality (HR, 0.70 [CI, 0.55 to 0.90]; P for trend = 0.002) and a positive association with ovarian cancer mortality (HR, 1.31 [CI, 1.07 to 1.61]; P for trend = 0.015). In the EPIC Biomarkers subcohort, higher coffee consumption was associated with lower serum alkaline phosphatase; alanine aminotransferase; aspartate aminotransferase; γ-glutamyltransferase; and, in women, C-reactive protein, lipoprotein(a), and glycated hemoglobin levels.

Limitations: Reverse causality may have biased the findings; however, results did not differ after exclusion of participants who died within 8 years of baseline. Coffee-drinking habits were assessed only once.

Conclusion: Coffee drinking was associated with reduced risk for death from various causes. This relationship did not vary by country.

Primary Funding Source: European Commission Directorate-General for Health and Consumers and International Agency for Research on Cancer.

Originalsprog Engelsk
Tidsskrift Annals of internal medicine
Vol/bind 167
Tidsskriftsnummer 4
Sider (fra-til) 236-247
Antal sider 12
ISSN 0003-4819
DOI
Status Udgivet - 15 aug. 2017
Originalsprog Engelsk
Tidsskrift Annals of the Rheumatic Diseases
Vol/bind 76
Tidsskriftsnummer Suppl 2
Sider (fra-til) 456-457
Antal sider 2
ISSN 0003-4967
Status Udgivet - 2017

Content and Construct Validity, Reliability, and Responsiveness of the Rheumatoid Arthritis Flare Questionnaire: OMERACT 2016 Workshop Report

Bartlett, S. J., Barbic, S. P., Bykerk, V. P., Choy, E. H., Alten, R., Christensen, R., den Broeder, A., Fautrel, B., Furst, D. E., Guillemin, F., Hewlett, S., Leong, A. L., Lyddiatt, A., March, L., Montie, P., Pohl, C., Scholte Voshaar, M., Woodworth, T. G. & Bingham, C. O. okt. 2017 I : Journal of Rheumatology. 44, 10, s. 1536-1543 8 s.

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OBJECTIVE: The Outcome Measures in Rheumatology (OMERACT) Rheumatoid Arthritis (RA) Flare Group was established to develop a reliable way to identify and measure RA flares in randomized controlled trials (RCT). Here, we summarized the development and field testing of the RA Flare Questionnaire (RA-FQ), and the voting results at OMERACT 2016.

METHODS: Classic and modern psychometric methods were used to assess reliability, validity, sensitivity, factor structure, scoring, and thresholds. Interviews with patients and clinicians also assessed content validity, utility, and meaningfulness of RA-FQ scores.

RESULTS: People with RA in observational trials in Canada (n = 896) and France (n = 138), and an RCT in the Netherlands (n = 178) completed 5 items (11-point numerical rating scale) representing RA Flare core domains. There was moderate to high evidence of reliability, content and construct validity, and responsiveness. Factor analysis supported unidimensionality. Rasch analysis showed acceptable fit to the Rasch model, with items and people covering a broad measurement continuum and evidence of appropriate targeting of items to people, ordered thresholds, minimal differential item functioning by language, sex, or age. A summative score across items is defensible, yielding an interval score (0-50) where higher scores reflect worsening flare. The RA-FQ received endorsement from 88% of attendees that it passed the OMERACT Filter 2.0 "Eyeball Test" for instrument selection.

CONCLUSION: The RA-FQ has been developed to identify and measure RA flares. Its review through OMERACT Filter 2.0 shows evidence of reliability, content and construct validity, and responsiveness. These properties merit its further validation as an outcome for clinical trials.

Originalsprog Engelsk
Tidsskrift Journal of Rheumatology
Vol/bind 44
Tidsskriftsnummer 10
Sider (fra-til) 1536-1543
Antal sider 8
ISSN 0315-162X
DOI
Status Udgivet - okt. 2017

STUDY DESIGN: Cross-sectional study.

OBJECTIVE: To investigate if adding a lumbar pillow in supine position during magnetic resonance imaging (MRI) is superior to standing positional MRI for diagnosing lumbar spinal stenosis (LSS).

SUMMARY OF BACKGROUND DATA: The upright standing position and especially extension of the lumbar spine seem to worsening symptoms of LSS. However, it is unclear whether a forced lumbar extension by a pillow in the lower back during conventional supine MRI may improve the diagnostics of LSS compared with standing MRI.

METHODS: Patients suspected for LSS and referred to conventional MRI were included to an additional positional MRI scan (0.25T G-Scan) performed in: (1) conventional supine, (2) standing, (3) supine with a lumbar pillow in the lower back. LSS was evaluated for each position in consensus on a 0 to 3 semi-quantitative grading scale. Independently, L2-S1 lordosis angle, spinal cross-sectional diameter (SCSD), dural cross-sectional diameter (DCSD), and dural cross-sectional diameter (DCSA) were measured. The smallest dural diameter was defined as stenosis level and the largest control level for comparison.

RESULTS: Twenty-seven patients (60.6 years; ±9.4) were included. The lordosis angle increased significantly from supine to standing (3.2° CI: 1.2-5.2) and with the lumbar pillow (12.8° CI: 10.3-15.3). One-way analysis of variance (ANOVA) showed significant differences between positions (P < 0.001). When compared with the supine position, pairwise comparisons showed decreased SCSD, DCSD, DCSA, and increasing semi-quantitative grading, during both standing and supine with the lumbar pillow. A difference in the semi-quantitative grades was only found between standing and supine with a lumbar pillow, and the scan with a lumbar pillow was significantly more painful.

CONCLUSION: Standing MRI and supine MRI with a lumbar pillow resulted in equal changes in the lumbar spine, although standing MRI may be more sensitive in the assessment of patients suspected for LSS.

LEVEL OF EVIDENCE: 2.

Originalsprog Engelsk
Tidsskrift Spine
Vol/bind 42
Tidsskriftsnummer 9
Sider (fra-til) 662-669
Antal sider 8
ISSN 0362-2436
DOI
Status Udgivet - 1 maj 2017

Correction to: Adaptation of the 2015 American College of Rheumatology treatment guideline for rheumatoid arthritis for the Eastern Mediterranean Region: an exemplar of the GRADE Adolopment

Darzi, A., Harfouche, M., Arayssi, T., Alemadi, S., Alnaqbi, K. A., Badsha, H., Al Balushi, F., Elzorkany, B., Halabi, H., Hamoudeh, M., Hazer, W., Masri, B., Omair, M. A., Uthman, I., Ziade, N., Singh, J. A., Christensen, R. D. K., Tugwell, P., Schünemann, H. J. & Akl, E. A. 26 okt. 2017 I : Health and Quality of Life Outcomes. 15, 1, s. 214

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Originalsprog Engelsk
Tidsskrift Health and Quality of Life Outcomes
Vol/bind 15
Tidsskriftsnummer 1
Sider (fra-til) 214
ISSN 1477-7525
DOI
Status Udgivet - 26 okt. 2017

Critical Outcomes in Longitudinal Observational Studies and Registries in Patients with Rheumatoid Arthritis: An OMERACT Special Interest Group Report

Zamora, N. V., Christensen, R., Goel, N., Klokker, L., Lopez-Olivo, M. A., Kristensen, L. E., Carmona, L., Strand, V., Curtis, J. R. & Suarez-Almazor, M. E. 15 jun. 2017 I : Journal of Rheumatology.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

OBJECTIVE: Outcomes important to patients are those that are relevant to their well-being, including quality of life, morbid endpoints, and death. These outcomes often occur over the longterm and can be identified in prospective longitudinal observational studies (PLOS). There are no standards for which outcome domains should be considered. Our overarching goal is to identify critical longterm outcome domains for patients with rheumatic diseases, and to develop a conceptual framework to measure and classify them within the scope of OMERACT Filter 2.0.

METHODS: The steps of this initiative primarily concern rheumatoid arthritis (RA) and include (1) performing a systematic review of RA patient registries and cohorts to identify previously collected and reported outcome domains and measurement instruments; (2) developing a conceptual framework and taxonomy for identification and classification of outcome domains; (3) conducting focus groups to identify domains considered critical by patients with RA; and (4) surveying patients, providers, and researchers to identify critical outcomes that can be evaluated through the OMERACT filter.

RESULTS: In our initial evaluation of databases and registries across countries, we found both commonalities and differences, with no clear standardization. At the initial group meeting, participants agreed that additional work is needed to identify which critical outcomes should be collected in PLOS, and suggested several: death, independence, and participation, among others. An operational strategy for the next 2 years was proposed.

CONCLUSION: Participants endorsed the need for an initiative to identify and evaluate critical outcome domains and measurement instruments for data collection in PLOS.

Originalsprog Engelsk
Tidsskrift Journal of Rheumatology
ISSN 0315-162X
DOI
Status Udgivet - 15 jun. 2017

Defining the optimal biological monotherapy in rheumatoid arthritis: A systematic review and meta-analysis of randomised trials

Tarp, S., Furst, D. E., Dossing, A., Østergaard, M., Lorenzen, T., Hansen, M. S., Singh, J. A., Choy, E. H., Boers, M., Suarez-Almazor, M. E., Kristensen, L. E., Bliddal, H. & Christensen, R. jun. 2017 I : Seminars in Arthritis and Rheumatism. 46, 6, s. 699-708 10 s.

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OBJECTIVES: To summarize and compare the benefits and harms of biological agents used as monotherapy for rheumatoid arthritis (RA) in order to inform decisions for patients who are intolerant to conventional DMARD therapy.

METHODS: We searched MEDLINE, EMBASE, CENTRAL, and other sources for randomised trials that compared biological monotherapy with methotrexate, placebo, or other biological monotherapies. Primary outcomes were ACR50 and the number of patients who discontinued due to adverse events. Our network meta-analysis was based on mixed-effects logistic regression, including both direct and indirect comparisons of the treatment effects, while preserving the randomised comparisons within each trial. PROSPERO identifier: CRD42012002800.

RESULTS: The analysis comprises 28 trials (8602 patients), including all nine biological agents approved for RA. Eight trials included "DMARD-naïve", and 20 "DMARD-Inadequate responder" (DMARD-IR) patients. All agents except anakinra and infliximab were superior (p < 0.05) to placebo (i.e., no DMARD treatment) with regard to ACR50. Etanercept and rituximab were superior to anakinra (p = 0.018 and p = 0.049, respectively). Tocilizumab was superior to adalimumab (p = 0.0082), anakinra (p = 0.0083), certolizumab (p = 0.037), and golimumab (p = 0.049). No differences among etanercept, tocilizumab, and rituximab were found (p > 0.52). However, because rituximab was evaluated in just 40 patients, our confidence in the estimates is limited. When including only DMARD-IR trials, the same statistical pattern emerged; in addition etanercept and tocilizumab were superior to abatacept. At recommended doses, both etanercept and tocilizumab were superior to adalimumab and certolizumab. No statistically significant differences among biological agents were found with respect to discontinuation due to adverse events (p > 0.068).

CONCLUSIONS: Evidence from randomised trials suggests that most biological agents are effective as monotherapy. Although our confidence in the estimates is limited, etanercept or tocilizumab may be the optimal choice for most patients who need treatment with biological monotherapy. However, given our limited confidence in the estimates including possibility of bias, it is appropriate to strongly weight patients׳ preferences and values in the final treatment choice.

Originalsprog Engelsk
Tidsskrift Seminars in Arthritis and Rheumatism
Vol/bind 46
Tidsskriftsnummer 6
Sider (fra-til) 699-708
Antal sider 10
ISSN 0049-0172
DOI
Status Udgivet - jun. 2017

Definition and Standardization of Inflammatory Pathology in Hand Osteoarthritis Assessed By Ultrasound: Results from a Delphi Process and Reliability Testing in the Omeract Ultrasonographer Group in Hand Osteoarthritis

Mathiessen, A., Hammer, H. B., Terslev, L., Bruyn, G. A. W., D'Agostino, M. A., Filippou, G., Filippucci, E., Haugen, I. K., Kortekaas, M., Mancarella, L., Mandl, P., Moller, I., Mortada, . M. A., Naredo, E., Sedie, A. D., Wittoek, R., Iagnocco, A. & Ellegaard, K. 2017 I : Arthritis & Rheumatology. 69, S10, 2020

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Originalsprog Engelsk
Artikelnummer 2020
Tidsskrift Arthritis & Rheumatology
Vol/bind 69
Tidsskriftsnummer S10
ISSN 1537-2960
Status Udgivet - 2017

Dynamic contrast-enhanced magnetic resonance imaging in a randomized placebo-controlled rheumatoid arthritis trial – impact of applying joint coverage quality criteria

Axelsen, M. B., Bliddal, H., Jacobssen, L. T. H., Hansen, M. S., Dudek, A., Rell-Bakalarska, M., Boesen, M., Stefanek, J., Sundman-Engberg, B. & Østergaard, M. 2017 I : Annals of the Rheumatic Diseases. 76, Suppl 2, s. 1419 1 s.

Publikation: Bidrag til tidsskriftKonferenceabstrakt i tidsskriftForskningpeer review

Originalsprog Engelsk
Tidsskrift Annals of the Rheumatic Diseases
Vol/bind 76
Tidsskriftsnummer Suppl 2
Sider (fra-til) 1419
Antal sider 1
ISSN 0003-4967
Status Udgivet - 2017

Early menarche, nulliparity and the risk for premature and early natural menopause

Mishra, G. D., Pandeya, N., Dobson, A. J., Chung, H-F., Anderson, D., Kuh, D., Sandin, S., Giles, G., Bruinsma, F., Hayashi, K., Lee, J. S., Mizunuma, H., Cade, J. E., Burley, V., Greenwood, D. C., Goodman, A., Simonsen, M. K., Adami, H-O., Demakakos, P. & Weiderpass, E. 1 mar. 2017 I : Human reproduction (Oxford, England). 32, 3, s. 679-686 8 s.

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STUDY QUESTION: Are parity and the timing of menarche associated with premature and early natural menopause?

SUMMARY ANSWER: Early menarche (≤11 years) is a risk factor for both premature menopause (final menstrual period, FMP <40 years) and early menopause (FMP 40-44 years), a risk that is amplified for nulliparous women.

WHAT IS KNOWN ALREADY: Women with either premature or early menopause face an increased risk of chronic conditions in later life and of early death. Findings from some studies suggest that early menarche and nulliparity are associated with early menopause, however overall the evidence is mixed. Much of the evidence for a direct relationship is hampered by a lack of comparability across studies, failure to adjust for confounding factors and inadequate statistical power.

STUDY DESIGN, SIZE, DURATION: This pooled study comprises 51 450 postmenopausal women from nine observational studies in the UK, Scandinavia, Australia and Japan that contribute to the International collaboration for a Life course Approach to reproductive health and Chronic disease Events (InterLACE).

PARTICIPANTS/MATERIALS, SETTING, METHODS: Age at menarche (categorized as ≤11, 12, 13, 14 and 15 or more years) and parity (categorized as no children, one child and two or more children) were exposures of interest. Age at FMP was confirmed by at least 12 months of cessation of menses where this was not the result of an intervention (such as surgical menopause due to bilateral oophorectomy or hysterectomy) and categorized as premature menopause (FMP before age 40), early menopause (FMP 40-44 years), 45-49 years, 50-51 years, 52-53 years and 54 or more years. We used multivariate multinomial logistic regression models to estimate relative risk ratio (RRR) and 95% CI for associations between menarche, parity and age at FMP adjusting for within-study correlation.

MAIN RESULTS AND THE ROLE OF CHANCE: The median age at FMP was 50 years (interquartile range 48-53 years), with 2% of the women experiencing premature menopause and 7.6% early menopause. Women with early menarche (≤11 years, compared with 12-13 years) were at higher risk of premature menopause (RRR 1.80, 95% CI 1.53-2.12) and early menopause (1.31, 1.19-1.44). Nulliparity was associated with increased risk of premature menopause (2.26, 1.84-2.77) and early menopause (1.32, 1.09-1.59). Women having early menarche and nulliparity were at over 5-fold increased risk of premature menopause (5.64, 4.04-7.87) and 2-fold increased risk of early menopause (2.16, 1.48-3.15) compared with women who had menarche at ≥12 years and two or more children.

LIMITATIONS, REASONS FOR CAUTION: Most of the studies (except the birth cohorts) relied on retrospectively reported age at menarche, which may have led to some degree of recall bias.

WIDER IMPLICATIONS OF THE FINDINGS: Our findings support early monitoring of women with early menarche, especially those who have no children, for preventive health interventions aimed at mitigating the risk of adverse health outcomes associated with early menopause.

STUDY FUNDING/COMPETING INTEREST(S): InterLACE project is funded by the Australian National Health and Medical Research Council project grant (APP1027196). G.D.M. is supported by Australian Research Council Future Fellowship (FT120100812). There are no competing interests.

Originalsprog Engelsk
Tidsskrift Human reproduction (Oxford, England)
Vol/bind 32
Tidsskriftsnummer 3
Sider (fra-til) 679-686
Antal sider 8
ISSN 0268-1161
DOI
Status Udgivet - 1 mar. 2017

Importance: It is unclear whether a lifestyle intervention can maintain glycemic control in patients with type 2 diabetes.

Objective: To test whether an intensive lifestyle intervention results in equivalent glycemic control compared with standard care and, secondarily, leads to a reduction in glucose-lowering medication in participants with type 2 diabetes.

Design, Setting, and Participants: Randomized, assessor-blinded, single-center study within Region Zealand and the Capital Region of Denmark (April 2015-August 2016). Ninety-eight adult participants with non-insulin-dependent type 2 diabetes who were diagnosed for less than 10 years were included. Participants were randomly assigned (2:1; stratified by sex) to the lifestyle group (n = 64) or the standard care group (n = 34).

Interventions: All participants received standard care with individual counseling and standardized, blinded, target-driven medical therapy. Additionally, the lifestyle intervention included 5 to 6 weekly aerobic training sessions (duration 30-60 minutes), of which 2 to 3 sessions were combined with resistance training. The lifestyle participants received dietary plans aiming for a body mass index of 25 or less. Participants were followed up for 12 months.

Main Outcomes and Measures: Primary outcome was change in hemoglobin A1c (HbA1c) from baseline to 12-month follow-up, and equivalence was prespecified by a CI margin of ±0.4% based on the intention-to-treat population. Superiority analysis was performed on the secondary outcome reductions in glucose-lowering medication.

Results: Among 98 randomized participants (mean age, 54.6 years [SD, 8.9]; women, 47 [48%]; mean baseline HbA1c, 6.7%), 93 participants completed the trial. From baseline to 12-month follow-up, the mean HbA1c level changed from 6.65% to 6.34% in the lifestyle group and from 6.74% to 6.66% in the standard care group (mean between-group difference in change of -0.26% [95% CI, -0.52% to -0.01%]), not meeting the criteria for equivalence (P = .15). Reduction in glucose-lowering medications occurred in 47 participants (73.5%) in the lifestyle group and 9 participants (26.4%) in the standard care group (difference, 47.1 percentage points [95% CI, 28.6-65.3]). There were 32 adverse events (most commonly musculoskeletal pain or discomfort and mild hypoglycemia) in the lifestyle group and 5 in the standard care group.

Conclusions and Relevance: Among adults with type 2 diabetes diagnosed for less than 10 years, a lifestyle intervention compared with standard care resulted in a change in glycemic control that did not reach the criterion for equivalence, but was in a direction consistent with benefit. Further research is needed to assess superiority, as well as generalizability and durability of findings.

Trial Registration: clinicaltrials.gov Identifier: NCT02417012.

Originalsprog Engelsk
Tidsskrift JAMA - Journal of the American Medical Association
Vol/bind 318
Tidsskriftsnummer 7
Sider (fra-til) 637-646
Antal sider 10
ISSN 0002-9955
DOI
Status Udgivet - 15 aug. 2017

Effect of specific exercise-based football injury prevention programmes on the overall injury rate in football: a systematic review and meta-analysis of the FIFA 11 and 11+ programmes

Thorborg, K., Krommes, K. K., Esteve, E., Clausen, M. B., Bartels, E. M. & Rathleff, M. S. 1 maj 2017 I : British Journal of Sports Medicine. 51, 7, s. 562-571

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

OBJECTIVE: To investigate the effect of FIFA injury prevention programmes in football (FIFA 11 and FIFA 11+).

DESIGN: Systematic review and meta-analysis.

ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials comparing the FIFA injury prevention programmes with a control (no or sham intervention) among football players.

DATA SOURCES: MEDLINE via PubMed, EMBASE via OVID, CINAHL via Ebsco, Web of Science, SportDiscus and Cochrane Central Register of Controlled Trials, from 2004 to 14 March 2016.

RESULTS: 6 cluster-randomised controlled trials had assessed the effect of FIFA injury prevention programmes compared with controls on the overall football injury incidence in recreational/subelite football. These studies included 2 specific exercise-based injury prevention programmes: FIFA 11 (2 studies) and FIFA 11+ (4 studies). The primary analysis showed a reduction in the overall injury risk ratio of 0.75 (95% CI 0.57 to 0.98), p=0.04, in favour of the FIFA injury prevention programmes. Secondary analyses revealed that when pooling the 4 studies applying the FIFA 11+ prevention programme, a reduction in the overall injury risk ratio (incidence rate ratio (IRR) 0.61; 95% CI 0.48 to 0.77, p<0.001) was present in favour of the FIFA 11+ prevention programme. No reduction was present when pooling the 2 studies including the FIFA 11 prevention programme (IRR 0.99; 95% CI 0.80 to 1.23, p=0.940).

CONCLUSIONS: An injury-preventing effect of the FIFA injury prevention programmes compared with controls was shown in football. This effect was induced by the FIFA 11+ prevention programme which has a substantial injury-preventing effect by reducing football injuries by 39%, whereas a preventive effect of the FIFA 11 prevention programme could not be documented.

TRIAL REGISTRATION NUMBER: PROSPERO CRD42015024120.

Originalsprog Engelsk
Tidsskrift British Journal of Sports Medicine
Vol/bind 51
Tidsskriftsnummer 7
Sider (fra-til) 562-571
ISSN 0306-3674
DOI
Status Udgivet - 1 maj 2017

OBJECTIVE: The study aimed to evaluate the impact of a 15-month intervention on dietary intake conducted among obesity-prone normal-weight pre-school children.

DESIGN: Information on dietary intake was obtained using a 4 d diet record. A diet quality index was adapted to assess how well children's diet complied with the Danish national guidelines. Linear regression per protocol and intention-to-treat analyses of differences in intakes of energy, macronutrients, fruit, vegetables, fish, sugar-sweetened beverages and diet quality index between the two groups were conducted.

SETTING: The Healthy Start study was conducted during 2009-2011, focusing on changing diet, physical activity, sleep and stress management to prevent excessive weight gain among Danish children.

SUBJECTS: From a population of 635 Danish pre-school children, who had a high birth weight (≥4000 g), high maternal pre-pregnancy BMI (≥28·0 kg/m2) or low maternal educational level (<10 years of schooling), 285 children completed the intervention and had complete information on dietary intake.

RESULTS: Children in the intervention group had a lower energy intake after the 15-month intervention (group means: 5·29 v. 5·59 MJ, P=0·02) compared with the control group. We observed lower intakes of carbohydrates and added sugar in the intervention group compared with the control group after the intervention (P=0·002, P=0·01).

CONCLUSIONS: The intervention resulted in a lower energy intake, particularly from carbohydrates and added sugar after 15 months of intervention, suggesting that dietary intake can be changed in a healthier direction in children predisposed to obesity.

Originalsprog Engelsk
Tidsskrift Public Health Nutrition
Vol/bind 20
Tidsskriftsnummer 16
Sider (fra-til) 2988-2997
Antal sider 10
ISSN 1368-9800
DOI
Status Udgivet - nov. 2017

BACKGROUND: There is limited evidence to support the effectiveness of primary interventions aiming to prevent excess weight gain among young children. Evaluating behavioral changes, such as physical activity (PA), may add to future development of efficient interventions. The objective was to evaluate the effect on PA outcomes of the 15 month Healthy Start intervention that focused on changing diet, PA, sleep and stress management among normal weight but obesity-prone preschool children. Children were defined as obesity-prone if they had a birth weight > 4,000 g, mothers with a pre-pregnancy body mass index of > 28 kg/m2, or mothers with ≤ 10 years of schooling.

METHOD: From a baseline study population of 635 normal weight 2-6 year old preschool children from the greater Copenhagen area, parents of 307 children had given information on PA at both the baseline and follow-up examinations. PA was obtained from a 7 days recording in the Children's Physical Activity Questionnaire. Time used for sport activities were combined with outdoor playing time to achieve a proxy of total PA level of moderate to vigorous intensity.

RESULTS: Linear regression analyses revealed that at follow-up the intervention group spent more time on sports and outdoor activities combined per week than the control group (ITT analyses: intervention: 400 min/week; 95% confidence interval (CI): 341, 459 versus control: 321 min/week; 95% CI: 277, 366; p = 0.02), although no significant intervention effects were seen for each of the subcategories, e.g. sports participation, outdoor activities, screen time, or commuting frequency.

CONCLUSION: Our results suggest that the overall time spent on sports and outdoor activities combined was increased at follow-up among normal weight obesity-prone children, as a result of the Healthy Start intervention.

TRIAL REGISTRATION: ClinicalTrials.gov NCT01583335.

Originalsprog Engelsk
Tidsskrift P L o S One
Vol/bind 12
Tidsskriftsnummer 10
Sider (fra-til) e0185266
ISSN 1932-6203
DOI
Status Udgivet - 2017

Emollients and moisturisers for eczema

van Zuuren, E. J., Fedorowicz, Z., Christensen, R., Lavrijsen, A. & Arents, B. WM. 6 feb. 2017 I : Cochrane Database of Systematic Reviews. 2, s. CD012119

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

BACKGROUND: Eczema is a chronic skin disease characterised by dry skin, intense itching, inflammatory skin lesions, and a considerable impact on quality of life. Moisturisation is an integral part of treatment, but it is unclear if moisturisers are effective.

OBJECTIVES: To assess the effects of moisturisers for eczema.

SEARCH METHODS: We searched the following databases to December 2015: Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, LILACS, the GREAT database. We searched five trials registers and checked references of included and excluded studies for further relevant trials.

SELECTION CRITERIA: Randomised controlled trials in people with eczema.

DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures.

MAIN RESULTS: We included 77 studies (6603 participants, mean age: 18.6 years, mean duration: 6.7 weeks). We assessed 36 studies as at a high risk of bias, 34 at unclear risk, and seven at low risk. Twenty-four studies assessed our primary outcome 'participant-assessed disease severity', 13 assessed 'satisfaction', and 41 assessed 'adverse events'. Secondary outcomes included investigator-assessed disease severity (addressed in 65 studies), skin barrier function (29), flare prevention (16), quality of life (10), and corticosteroid use (eight). Adverse events reporting was limited (smarting, stinging, pruritus, erythema, folliculitis).Six studies evaluated moisturiser versus no moisturiser. 'Participant-assessed disease severity' and 'satisfaction' were not assessed. Moisturiser use yielded lower SCORAD than no moisturiser (three studies, 276 participants, mean difference (MD) -2.42, 95% confidence interval (CI) -4.55 to -0.28), but the minimal important difference (MID) (8.7) was unmet. There were fewer flares with moisturisers (two studies, 87 participants, RR 0.40, 95% CI 0.23 to 0.70), time to flare was prolonged (median: 180 versus 30 days), and less topical corticosteroids were needed (two studies, 222 participants, MD -9.30 g, 95% CI -15.3 to -3.27). There was no statistically significant difference in adverse events (one study, 173 participants, risk ratio (RR) 15.34, 95% CI 0.90 to 261.64). Evidence for these outcomes was low quality.With Atopiclair (three studies), 174/232 participants experienced improvement in participant-assessed disease severity versus 27/158 allocated to vehicle (RR 4.51, 95% CI 2.19 to 9.29). Atopiclair decreased itching (four studies, 396 participants, MD -2.65, 95% CI -4.21 to -1.09) and achieved more frequent satisfaction (two studies, 248 participants, RR 2.14, 95% CI 1.58 to 2.89), fewer flares (three studies, 397 participants, RR 0.18, 95% CI 0.11 to 0.31), and lower EASI (four studies, 426 participants, MD -4.0, 95% CI -5.42 to -2.57), but MID (6.6) was unmet. The number of participants reporting adverse events was not statistically different (four studies, 430 participants, RR 1.03, 95% CI 0.79 to 1.33). Evidence for these outcomes was moderate quality.Participants reported skin improvement more frequently with urea-containing cream than placebo (one study, 129 participants, RR 1.28, 95% CI 1.06 to 1.53; low-quality evidence), with equal satisfaction between the two groups (one study, 38 participants, low-quality evidence). Urea-containing cream improved dryness (investigator-assessed) more frequently (one study, 128 participants, RR 1.40, 95% CI 1.14 to 1.71; moderate-quality evidence) with fewer flares (one study, 44 participants, RR 0.47, 95% CI 0.24 to 0.92; low-quality evidence), but more participants in this group reported adverse events (one study, 129 participants, RR 1.65, 95% CI 1.16 to 2.34; moderate-quality evidence).Three studies assessed glycerol-containing moisturiser versus vehicle or placebo. More participants in the glycerol group noticed skin improvement (one study, 134 participants, RR 1.22, 95% CI 1.01 to 1.48; moderate-quality evidence), and this group saw improved investigator-assessed SCORAD (one study, 249 participants, MD -2.20, 95% CI -3.44 to -0.96; high-quality evidence), but MID was unmet. Participant satisfaction was not addressed. The number of participants reporting adverse events was not statistically significant (two studies, 385 participants, RR 0.90, 95% CI 0.68 to 1.19; moderate-quality evidence).Four studies investigated oat-containing moisturisers versus no treatment or vehicle. No significant differences between groups were reported for participant-assessed disease severity (one study, 50 participants, RR 1.11, 95% CI 0.84 to 1.46; low-quality evidence), satisfaction (one study, 50 participants, RR 1.06, 95% CI 0.74 to 1.52; very low-quality evidence), and investigator-assessed disease severity (three studies, 272 participants, standardised mean difference (SMD) -0.23, 95% CI -0.66 to 0.21; low-quality evidence). In the oat group, there were fewer flares (one study, 43 participants, RR 0.31, 95% CI 0.12 to 0.7; low-quality evidence) and less topical corticosteroids needed (two studies, 222 participants, MD -9.30g, 95% CI 15.3 to -3.27; low-quality evidence), but more adverse events were reported (one study, 173 participants; Peto odds ratio (OR) 7.26, 95% CI 1.76 to 29.92; low-quality evidence).All moisturisers above were compared to placebo, vehicle, or no moisturiser. Participants considered moisturisers more effective in reducing eczema (five studies, 572 participants, RR 2.46, 95% CI 1.16 to 5.23; low-quality evidence) and itch (seven studies, 749 participants, SMD -1.10, 95% CI -1.83 to -0.38) than control. Participants in both treatment arms reported comparable satisfaction (three studies, 296 participants, RR 1.35, 95% CI 0.77 to 2.26; low-quality evidence). Moisturisers led to lower investigator-assessed disease severity (12 studies, 1281 participants, SMD -1.04, 95% CI -1.57 to -0.51; high-quality evidence) and fewer flares (six studies, 607 participants, RR 0.33, 95% CI 0.17 to 0.62; moderate-quality evidence), but there was no difference in adverse events (10 studies, 1275 participants, RR 1.03, 95% CI 0.82 to 1.30; moderate-quality evidence).Topical active treatment combined with moisturiser was more effective than active treatment alone in reducing investigator-assessed disease severity (three studies, 192 participants, SMD -0.87, 95% CI -1.17 to -0.57; moderate-quality evidence) and flares (one study, 105 participants, RR 0.43, 95% CI 0.20 to 0.93), and was preferred by participants (both low-quality evidence). There was no statistically significant difference in number of adverse events (one study, 125 participants, RR 0.39, 95% CI 0.13 to 1.19; very low-quality evidence). Participant-assessed disease severity was not addressed.

AUTHORS' CONCLUSIONS: Most moisturisers showed some beneficial effects, producing better results when used with active treatment, prolonging time to flare, and reducing the number of flares and amount of topical corticosteroids needed to achieve similar reductions in eczema severity. We did not find reliable evidence that one moisturiser is better than another.

Originalsprog Engelsk
Tidsskrift Cochrane Database of Systematic Reviews
Vol/bind 2
Sider (fra-til) CD012119
ISSN 1361-6137
DOI
Status Udgivet - 6 feb. 2017

EQ-5D utility, response and drug survival in rheumatoid arthritis patients on biologic monotherapy: A prospective observational study of patients registered in the south Swedish SSATG registry

Jørgensen, T. S., Turesson, C., Kapetanovic, M. C., Englund, M., Turkiewicz, A., Christensen, R., Bliddal, H., Geborek, P. & Kristensen, L. E. 2017 I : P L o S One. 12, 2, s. e0169946

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

OBJECTIVES: Biologic agents have dramatically changed treatment of rheumatoid arthritis (RA). To date only scarce head-to-head data exist especially when the biological therapies are given as monotherapy without concomitant disease modifying drugs (DMARDs). Thus the objective of the current study is to evaluate treatment response of all available biological therapies with special focus on utility (EQ-5D-3L) and drug survival of biologic DMARDs (bDMARDs) prescribed as monotherapy in RA patients in southern Sweden.

MATERIALS AND METHODS: All RA patients registered in a regional database as initiating bDMARD as monotherapy, i.e. without concomitant conventional synthetic DMARDs (csDMARDs), from 1st of January 2006 through 31st of December 2012, were included. Patients were followed from initiation of the first dose of bDMARD monotherapy treatment until withdrawal from treatment, loss of follow-up or 31st of December 2012. Descriptive statistics for utility (EQ-5D-3L), effectiveness, and drug survival of bDMARD monotherapy were calculated.

RESULTS: During the study period, a total of 554 patients were registered in SSATG as initiating bDMARD monotherapy. Most of the patients were women (81%), with a mean age of 57 years. The average disease duration was more than 12 years, and on average the patients had previously been treated with approximately four different csDMARDs. Fifty-five percent of the patients were initiating their first bDMARD, 26% their second, and 19% their third or more. At baseline the average EQ-5D-3L was 0.34. Most patients had moderate to high disease activity, with a mean DAS28 of 5.0, and were substantially disabled, with an average HAQ score of 1.4. At 6 months´ follow-up, the EQ-5D-3L in patients still on the biologic drug had increased by mean 0.23 (SD 0.4) with no differences between type of bDMARD (p = 0.49). The mean change in EQ-5D-3L ranged from 0.11 (rituximab and infliximab) to 0.42 (tocilizumab). Although the changes were numerically different, no distinct pattern favored any particular bDMARD for EQ-5D-3L (p = 0.49) or other clinical outcomes. Overall, DAS28 defined remission and low disease activity were achieved in 20% and 43% of patients, respectively. Drug survival rates were statistically significantly different between bDMARDs (p = 0.01), with the highest rates observed for rituximab, followed by etanercept. After failing first course of anti-TNF, patients switching to another mode of action had significantly higher drug survival than those switching to a second course of anti-TNF therapy (p = 0.02).

CONCLUSIONS: Utility (EQ-5D-3L) increased after 6 months of all bDMARD treatments in monotherapy, indicating improvement of patients' quality of life. After failure of anti-TNF treatment in monotherapy, switching to another mode of action may be associated with better drug survival than starting a second TNF-inhibitor.

Originalsprog Engelsk
Tidsskrift P L o S One
Vol/bind 12
Tidsskriftsnummer 2
Sider (fra-til) e0169946
ISSN 1932-6203
DOI
Status Udgivet - 2017

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