Published in 2018

A systematic review of measurement properties of patient reported outcome measures in psoriatic arthritis: A GRAPPA-OMERACT initiative

Højgaard, P., Klokker, L., Orbai, A-M., Holmsted, K., Bartels, E. M., Leung, Y. Y., Goel, N., de Wit, M., Gladman, D. D., Mease, P., Dreyer, L., Kristensen, L. E., FitzGerald, O., Tillett, W., Gossec, L., Helliwell, P., Strand, V., Ogdie, A., Terwee, C. B. & Christensen, R. 2018 I : Seminars in Arthritis and Rheumatism.

Publikation: Bidrag til tidsskriftReview

BACKGROUND: An updated psoriatic arthritis (PsA) core outcome set (COS) for randomized controlled trials (RCTs) was endorsed at the Outcome Measures in Rheumatology (OMERACT) meeting in 2016.

OBJECTIVES: To synthesize the evidence on measurement properties of patient reported outcome measures (PROMs) for PsA and thereby contribute to development of a PsA core outcome measurement set (COMS) as described by the OMERACT Filter 2.0.

METHODS: A systematic literature search was performed in EMBASE, MEDLINE and PsycINFO on Jan 1, 2017 to identify full-text articles with an aim of assessing the measurement properties of PROMs in PsA. Two independent reviewers rated the quality of studies using the COnsensus based standards for the Selection of health Measurement INstruments (COSMIN) checklist, and performed a qualitative evidence synthesis.

RESULTS: Fifty-five studies were included in the systematic review. Forty-four instruments and a total of 89 scales were analyzed. PROMs measuring COS domains with at least fair quality evidence for good validity and reliability (and no evidence for poor properties) included the Stockerau Activity Score for PsA (German), Psoriasis Symptom Inventory, visual analogue scale for Patient Global, 36 Item Short Form Health Survey Physical Function subscale, Health Assessment Questionnaire Disability Index, Bath Ankylosing Spondylitis Functional Index, PsA Impact of Disease questionnaire, PsA Quality of Life questionnaire, VITACORA-19, Functional Assessment of Chronic Illness Therapy Fatigue scale and Social Role Participation Questionnaire.

CONCLUSIONS: At least one PROM with some evidence for aspects of validity and reliability was available for six of the eight mandatory domains of the PsA COS.

Originalsprog Engelsk
Tidsskrift Seminars in Arthritis and Rheumatism
ISSN 0049-0172
DOI
Status E-pub ahead of print - 2018

Bibliografisk note

COPECARE

Antibody-Mediated Neutralization of uPA Proteolytic Function Reduces Disease Progression in Mouse Arthritis Models

Almholt, K., Hebsgaard, J. B., Nansen, A., Andersson, C., Pass, J., Rønø, B., Thygesen, P., Pelzer, H., Loftager, M., Lund, I. K., Høyer-Hansen, G., Frisch, T., Jensen, C. H., Otte, K. S., Søe, N. H., Bartels, E. M., Andersen, M., Bliddal, H. & Usher, P. A. 1 feb. 2018 I : Journal of immunology (Baltimore, Md. : 1950). 200, 3, s. 957-965

Publikation: Bidrag til tidsskriftTidsskriftartikel

Genetic absence of the urokinase-type plasminogen activator (uPA) reduces arthritis progression in the collagen-induced arthritis (CIA) mouse model to an extent just shy of disease abrogation, but this remarkable observation has not been translated into therapeutic intervention. Our aim was to test the potential in mice of an Ab that blocks the proteolytic capacity of uPA in the CIA model and the delayed-type hypersensitivity arthritis model. A second aim was to determine the cellular origins of uPA and the uPA receptor (uPAR) in joint tissue from patients with rheumatoid arthritis. A mAb that neutralizes mouse uPA significantly reduced arthritis progression in the CIA and delayed-type hypersensitivity arthritis models. In the CIA model, the impact of anti-uPA treatment was on par with the effect of blocking TNF-α by etanercept. A pharmacokinetics evaluation of the therapeutic Ab revealed target-mediated drug disposition consistent with a high turnover of endogenous uPA. The cellular expression patterns of uPA and uPAR were characterized by double immunofluorescence in the inflamed synovium from patients with rheumatoid arthritis and compared with synovium from healthy donors. The arthritic synovium showed expression of uPA and uPAR in neutrophils, macrophages, and a fraction of endothelial cells, whereas there was little or no expression in synovium from healthy donors. The data from animal models and human material provide preclinical proof-of-principle that validates uPA as a novel therapeutic target in rheumatic diseases.

Originalsprog Engelsk
Tidsskrift Journal of immunology (Baltimore, Md. : 1950)
Vol/bind 200
Tidsskriftsnummer 3
Sider (fra-til) 957-965
ISSN 0022-1767
DOI
Status Udgivet - 1 feb. 2018

Association between NICE guidance on biologic therapies with rates of hip and knee replacement among rheumatoid arthritis patients in England and Wales: An interrupted time-series analysis

Hawley, S., Cordtz, R., Dreyer, L., Edwards, C. J., Arden, N. K., Delmestri, A., Silman, A., Cooper, C., Judge, A. & Prieto-Alhambra, D. 2018 I : Seminars in Arthritis and Rheumatism.

Publikation: Bidrag til tidsskriftTidsskriftartikel

OBJECTIVE: To estimate the impact of NICE approval of tumor necrosis factor inhibitor (TNFi) therapies on the incidence of total hip replacement (THR) and total knee replacement (TKR) among rheumatoid arthritis (RA) patients in England and Wales.

METHODS: Primary care data [Clinical Practice Research Datalink (CPRD)] for the study period (1995-2014) were used to identify incident adult RA patients. The age and sex-standardised 5-year incidence of THR and TKR was calculated separately for RA patients diagnosed in each six-months between 1995-2009. We took a natural experimental approach, using segmented linear regression to estimate changes in level and trend following the publication of NICE TA 36 in March 2002, incorporating a 1-year lag. Regression coefficients were used to calculate average change in rates, adjusted for prior level and trend.

RESULTS: We identified 17,505 incident RA patients of whom 465 and 650 underwent THR and TKR surgery, respectively. The modeled average incidence of THR and TKR over the biologic-era was 6.57/1000 person years (PYs) and 8.51/1000 PYs, respectively, with projected (had pre-NICE TA 36 level and trend continued uninterrupted) figures of 5.63/1000 PYs and 12.92 PYs, respectively. NICE guidance was associated with a significant average decrease in TKR incidence of -4.41/1000 PYs (95% C.I. -6.88 to -1.94), equating to a relative 34% reduction. Overall, no effect was seen on THR rates.

CONCLUSIONS: Among incident RA patients in England and Wales, NICE guidance on TNFi therapies for RA management was temporally associated with reduced rates of TKR but not THR.

Originalsprog Engelsk
Tidsskrift Seminars in Arthritis and Rheumatism
ISSN 0049-0172
DOI
Status E-pub ahead of print - 2018

Bibliografisk note

COPECARE

OBJECTIVE: Compare arthroscopic partial meniscectomy to a true sham intervention.

METHODS: Sham-controlled superiority trial performed in three county hospitals in Denmark comparing arthroscopic partial meniscectomy to skin incisions only in patients aged 35-55 years with persistent knee pain and an MRI-confirmed medial meniscus lesion. A computer-generated table of random numbers generated two comparison groups. Participants and outcome assessors were blinded to group allocation. Exclusions were locking knees, high-energy trauma or severe osteoarthritis. Outcomes were collected at baseline, 3 and 24 months. We hypothesised no difference between groups. The primary outcome was the between-group difference in change from baseline to 2 years in the mean score across all five normalised Knee injury and Osteoarthritis Outcome Score (KOOS) subscales (KOOS5).

RESULTS: Forty-four patients (of the estimated 72) underwent randomisation; 22 in each group. Sixteen participants (36%) were non-blinded and eight participants (36%) from the sham group crossed over to the surgery group prior to the 2-year follow-up. At 2 years, both groups reported clinically relevant improvements (surgery 21.8, skin incisions only 13.6), the mean difference between groups was 8.2 in favour of surgery, which is slightly less than the cut-off of 10 prespecified to represent a clinically relevant difference; judged by the 95% CI (-3.4 to 19.8), a possibility of clinically relevant difference could not be excluded. In total, nine participants experienced 11 adverse events; six in the surgery group and three in the skin-incisions-only group.

CONCLUSION: We found greater improvement from arthroscopic partial meniscectomy compared with skin incisions only at 2 years, with the statistical uncertainty of the between-group difference including what could be considered clinically relevant. Because of the study being underpowered, nearly half in the sham group being non-blinded and one-third crossing over to surgery, the results cannot be generalised to the greater patient population.

TRIAL REGISTRATION NUMBER: NCT01264991.

Originalsprog Engelsk
Tidsskrift BMJ Paediatrics Open
Vol/bind 8
Tidsskriftsnummer 2
Sider (fra-til) e019461
ISSN 2044-6055
DOI
Status Udgivet - 2 feb. 2018

Burden of rheumatoid arthritis in the Nordic region, 1990-2015: a comparative analysis using the Global Burden of Disease Study 2015

Kiadaliri, A. A., Kristensen, L-E. & Englund, M. mar. 2018 I : Scandinavian Journal of Rheumatology. 47, 2, s. 1-101 101 s.

Publikation: Bidrag til tidsskriftTidsskriftartikel

OBJECTIVE: To report mortality and disability due to rheumatoid arthritis (RA) in the Nordic region (Denmark, Finland, Greenland, Iceland, Norway, and Sweden) using data from the Global Burden of Disease Study (GBD) 2015.

METHOD: Using the results of GBD 2015, we present rates and trends in prevalence, mortality, years of life lost, years lived with disability (YLD), and disability-adjusted life-years (DALYs) of RA in the Nordic region during 1990-2015.

RESULTS: In 2015, the age-standardized prevalence of RA was higher in the Nordic region than the global level (0.44%, 95% uncertainty interval 0.40-0.48%, vs 0.35%, 0.32-0.38%). For women (men), DALYs increased by 2.4% (12.9%), from 29 263 (10 909) in 1990 to 29 966 (12 311) in 2015. The burden of RA as a proportion of total DALYs in women (men) increased from 0.90% (0.29%) in 1990 to 0.94% (0.36%) in 2015. Age-standardized DALY rates declined in all countries except Denmark and Greenland between 1990 and 2015. Of 315 conditions studied, RA was ranked as the 16th (37th) leading cause of YLD in women (men) in the region. Of 195 countries studied, Greenland, Finland, Denmark, Norway, Sweden, and Iceland had the 7th, 11th, 28th, 38th, 48th, and 78th highest age-standardized YLD rates for RA, respectively.

CONCLUSIONS: The prevalence of RA in the Nordic region is higher than the global average. Current trends in population growth and ageing suggest a potential increase in RA burden in the coming decades in the region that should be considered in healthcare resources allocation.

Originalsprog Engelsk
Tidsskrift Scandinavian Journal of Rheumatology
Vol/bind 47
Tidsskriftsnummer 2
Sider (fra-til) 1-101
Antal sider 101
ISSN 0300-9742
DOI
Status Udgivet - mar. 2018

Changes in job strain and subsequent weight gain: a longitudinal study, based on the Danish Nurse Cohort

Vesterlund, G. K., Keller, A. C. & Heitmann, B. L. apr. 2018 I : Public Health Nutrition. 21, 6, s. 1131-1138 8 s.

Publikation: Bidrag til tidsskriftTidsskriftartikel

OBJECTIVE: Obesity as well as job strain is increasing, and job strain might contribute to weight gain. The objective of the current study was to examine associations between longitudinal alterations in the components of job strain and subsequent weight gain.

DESIGN: The study was designed as a prospective cohort study with three questionnaire surveys enabling measurement of job-strain alterations over 6 years and subsequent measurements of weight gain after further 10 years of follow-up. ANCOVA and trend analyses were conducted. Job demands were measured as job busyness and speed, and control as amount of influence.

SETTING: Employed nurses in Denmark.

SUBJECTS: We included a sub-sample of 6188 female nurses from the Danish Nurse Cohort, which consisted of the nurses who participated in surveys in 1993, 1999 and 2009.

RESULTS: A linear trend in weight gain was seen in nurses who were often busy in 1999 between those who were rarely v. sometimes v. often busy in 1993 (P=0·03), with the largest weight gain in individuals with sustained high busyness in both years. Loss of influence between 1993 and 1999 was associated with larger subsequent weight gain than sustained high influence (P=0·003) or sustained low influence (P=0·02). For speed, no associations were found.

CONCLUSIONS: Busyness, speed and influence differed in their relationship to subsequent weight gain. A decrease in job influence and a sustained burden of busyness were most strongly related to subsequent weight gain. Focus on job strain reduction and healthy diet is essential for public health.

Originalsprog Engelsk
Tidsskrift Public Health Nutrition
Vol/bind 21
Tidsskriftsnummer 6
Sider (fra-til) 1131-1138
Antal sider 8
ISSN 1368-9800
DOI
Status Udgivet - apr. 2018

Several genetic variants in Toll-like receptor (TLR) and nuclear factor (NF)-κB signalling pathways have been reported associated with responsiveness to tumour necrosis factor inhibitor (anti-TNF) treatment in rheumatoid arthritis (RA). The present study was undertaken to replicate these findings. In a retrospective case-case study including 1007 Danish anti-TNF-treated RA patients, we genotyped 7 previously reported associated single-nucleotide polymorphisms (SNPs) in these pathways. Furthermore, 5 SNPs previously reported by our group were genotyped in a subcohort (N=469). Primary analyses validated the IRAK3 rs11541076 variant as associated (odds ratio (OR)=1.33, 95% confidence interval (CI): 1.00-1.77, P-value=0.047) with a positive treatment response (EULAR (European League Against Rheumatism) good/moderate vs none response at 4±2 months), and found the NLRP3 rs461266 variant associated (OR=0.75, 95% CI: 0.60-0.94, P=0.014) with a negative treatment response. Meta-analyses combining data from previous studies suggested smaller effect sizes of associations between variant alleles of CHUK rs11591741, NFKBIB rs3136645 and rs9403 and a negative treatment response. In conclusion, this study validates rs11541076 in IRAK3, a negative regulator of TLR signalling, as a predictor of anti-TNF treatment response, and suggests true positive associations of previously reported SNPs within genes encoding activators/inhibitors of NF-κB (CHUK, MYD88, NFKBIB, and NLRP3).The Pharmacogenomics Journal advance online publication, 4 October 2016; doi:10.1038/tpj.2016.66.

Originalsprog Engelsk
Tidsskrift The pharmacogenomics journal
ISSN 1470-269X
DOI
Status E-pub ahead of print - 2018

Cross-sectional associations between maternal self-efficacy and dietary intake and physical activity in four-year-old children of first-time Swedish mothers

Rohde, J. F., Bohman, B., Berglind, D., Hansson, L. M., Frederiksen, P., Mortensen, E. L., Heitmann, B. L. & Rasmussen, F. 1 jun. 2018 I : Appetite. 125, s. 131-138 8 s.

Publikation: Bidrag til tidsskriftTidsskriftartikel

BACKGROUND: Healthy dietary and physical activity behaviours are established early in life where children learn by observing their parents. Therefore, parents can act as role models and influence their children toward a healthier lifestyle. Besides a strong association between parental and child health behaviours, parents also influence their children's health behaviours through socio-cognitive processes, where perceived self-efficacy is the central component. The objective was to examine if parental self-efficacy among Swedish mothers was associated with their four-year-old children's dietary and physical activity behaviours.

METHODS: This cross-sectional study was based on information from control participants that took part in the Swedish primary prevention trial of childhood obesity (PRIMROSE) (n = 420 mother-child pairs). Linear regression models were used to examine the associations between parental self-efficacy (Parental Self-Efficacy for Promoting Healthy Physical Activity and Dietary Behaviours in Children Scale) and children's dietary intake (parent reported) and levels of physical activity (accelerometer) with adjustments for potential confounders.

RESULTS: Mothers' efficacy beliefs in promoting healthy dietary or physical activity behaviours in their children were associated with a slightly higher consumption of fruit and vegetables among their children (β: 0.03 [95%CI: 0.01; 0.04] P < 0.001) and slightly higher levels of moderate-to-vigorous activity (β: 0.43 [95%CI: 0.05; 0.81] P = 0.03). Mothers' belief in their ability to limit unhealthy dietary and physical activity behaviours was inversely associated with children's intake of unhealthy snacks (β: -0.06 [95%CI: -0.10; -0.02] P < 0.01).

CONCLUSION: Our cross-sectional study suggests weak positive correlations between maternal self-efficacy and healthy dietary and physical activity behaviours, and weak inverse associations between maternal self-efficacy and unhealthy dietary and physical activity behaviours among their children.

Originalsprog Engelsk
Tidsskrift Appetite
Vol/bind 125
Sider (fra-til) 131-138
Antal sider 8
ISSN 0195-6663
DOI
Status Udgivet - 1 jun. 2018

Effects of Lifestyle on Muscle Strength in a Healthy Danish Population

Bartels, E. M., Robertson, S., Danneskiold-Samsøe, B., Appleyard, M. & Stockmarr, A. jan. 2018 I : Journal of lifestyle medicine. 8, 1, s. 16-22 7 s.

Publikation: Bidrag til tidsskriftTidsskriftartikel

Background: Lifestyle is expected to influence muscle strength. This study aimed at assessing a possible relationship between smoking, alcohol intake and physical activity, and muscle strength in a healthy Danish population aged 20-79 years. Population study based on data collected from The Copenhagen City Heart Study (CCHS) and measurements of Isokinetic muscle strength from a sub-study of randomly selected healthy participants from CCHS.

Methods: 126 women and 63 men were studied. All participants completed a questionnaire regarding their lifestyle, including physical activity, alcohol intake and smoking habits. Isokinetic muscle strength was measured over the upper extremities (UE), trunk, and lower extremities (LE). Multivariate analyses including all of the variables were carried out.

Results: The level of daily physical activity during leisure was positively correlated to muscle strength in the lower extremities (p = 0.03) for women, and lower extremities (p = 0.03) and trunk (p = 0.007) for men. Alcohol Intake was in general not correlated to muscle strength. No clear effect of smoking was seen on muscle strength.

Conclusion: Our results show that physical activity during leisure is associated with a positive effect on muscle strength in both sexes. When keeping alcohol intake within the recommended limits, alcohol does not seem to affect muscle strength negatively. No effect of smoking on muscle strength was found in our group of healthy subjects. The findings are of importance when considering recommendation on life style when wishing to keeping fit with age to be able to carry out daily activities.

Originalsprog Engelsk
Tidsskrift Journal of lifestyle medicine
Vol/bind 8
Tidsskriftsnummer 1
Sider (fra-til) 16-22
Antal sider 7
ISSN 2234-8549
DOI
Status Udgivet - jan. 2018

Estimating the causal effect of body mass index on hay fever, asthma and lung function using Mendelian randomization

Skaaby, T., Taylor, A. E., Thuesen, B. H., Jacobsen, R. K., Friedrich, N., Møllehave, L. T., Hansen, S., Larsen, S. C., Völker, U., Nauck, M., Völzke, H., Hansen, T., Pedersen, O., Jørgensen, T., Paternoster, L., Munafò, M., Grarup, N. & Linneberg, A. 2018 I : Allergy. 73, 1, s. 153-64

Publikation: Bidrag til tidsskriftTidsskriftartikel

BACKGROUND: Observational studies have shown that body mass index (BMI) is positively associated with asthma. However, observational data are prone to confounding and reverse causation. In Mendelian randomization, genetic variants are used as unconfounded markers of exposures to examine causal effects. We examined the causal effect of BMI on asthma, hay fever, allergic sensitization, serum total immunoglobulin E (IgE), forced expiratory volume in one-second (FEV1) and forced vital capacity (FVC).

METHODS: We included 490 497 participants in the observational and 162 124 participants in the genetic analyses. A genetic risk score (GRS) was created using 26 BMI-associated single nucleotide polymorphisms (SNPs). Results were pooled in meta-analyses and expressed as odds ratios (ORs) or β-estimates with 95% confidence interval (CI).

RESULTS: The GRS was significantly associated with asthma (OR=1.009; 95% CI: 1.004, 1.013), but not with hay fever (OR= 0.998; 95% CI: 0.994, 1.002) or allergic sensitization (OR=0.999; 95% CI: 0.986, 1.012) per BMI-increasing allele. The GRS was significantly associated with decrease in FEV1: β=-0.0012 (95% CI: -0.0019, -0.0006) and FVC: β=-0.0022 (95% CI: -0.0031, -0.0014) per BMI-increasing allele. Effect sizes estimated by instrumental variable analyses were OR=1.07 (95% CI: 1.03, 1.10) for asthma, a 9 ml decrease in FEV1 (95% CI: 2.0-15 mL decrease) and a 16 ml decrease in FVC (95% CI: 7.0-24 mL decrease) per 1 kg/m(2) higher BMI.

CONCLUSIONS: The results support the conclusion that increasing BMI is causally related to higher prevalence of asthma and decreased lung function, but not with hay fever or biomarkers of allergy.

Originalsprog Engelsk
Tidsskrift Allergy
Vol/bind 73
Tidsskriftsnummer 1
Sider (fra-til) 153-64
ISSN 0105-4538
DOI
Status Udgivet - 2018

OBJECTIVE: To examine if fetal exposure to a small dosage of extra vitamin D from food fortification was associated with a decrease in the risk of pre-eclampsia later in life.

DESIGN: Cancellation of the mandatory vitamin D fortification of margarine in 1985 created a societal experiment, with entire adjacent birth cohorts exposed or unexposed to extra vitamin D during fetal development. The Danish national medical health registries allowed the identification of pre-eclampsia cases later in life among all exposed and unexposed female individuals.

SETTING: Denmark.

SUBJECTS: Women born between June 1983 and August 1988, who gave birth to their first child at age 14·5-27·5 years (n 32 621).

RESULTS: OR (95 % CI) for pre-eclampsia among women exposed v. unexposed to extra vitamin D from fortification during fetal development was 0·86 (0·76, 0·97). Exposure to extra vitamin D was associated with further reduced odds of pre-eclampsia (0·49 (0·34, 0·72)) among current smokers, but not among former smokers and non-smokers.

CONCLUSIONS: Additional vitamin D in fetal life from food fortification seems to reduce the risk of pre-eclampsia later in life. The risk reduction may be particularly strong among women who smoke during pregnancy.

Originalsprog Engelsk
Tidsskrift Public Health Nutrition
Vol/bind 21
Tidsskriftsnummer 4
Sider (fra-til) 721-731
Antal sider 11
ISSN 1368-9800
DOI
Status Udgivet - 24 mar. 2018

Extra vitamin D from fortification and the risk of preeclampsia: The D-tect Study

Stougaard, M., Damm, P., Frederiksen, P., Jacobsen, R. & Heitmann, B. L. 25 jan. 2018 I : P L o S One. 13, 1, s. e0191288

Publikation: Bidrag til tidsskriftTidsskriftartikel

The objective of the study was to examine if exposure to extra vitamin D from food fortification was associated with a decrease in the risk of preeclampsia. The study was based on a natural experiment exploring the effect of the abolition of the Danish mandatory vitamin D fortification of margarine in 1985. The effect of the extra vitamin D (1.25μg vitamin D/100 g margarine) was examined by comparing preeclampsia risk in women who have been exposed or unexposed to extra vitamin D from the fortified margarine during pregnancy, and who gave birth in the period from June 1983 to August 1988. The Danish National Patient Registry allowed the identification of pregnancies complicated by preeclampsia. The study included 73,237 women who gave birth during 1983-1988. We found no association between exposure to vitamin D fortification during pregnancy and the risk of any of the pregnancy related hypertensive disorders, including preeclampsia: Odds ratios (OR, 95%) for all hypertensive pregnancy related disorders among exposed vs. unexposed women was (OR 1.04, 95%CI: 0.98,1.10). In conclusion, the extra vitamin D from the mandatory vitamin D fortification did not influence the risk of preeclampsia.

Originalsprog Engelsk
Tidsskrift P L o S One
Vol/bind 13
Tidsskriftsnummer 1
Sider (fra-til) e0191288
ISSN 1932-6203
DOI
Status Udgivet - 25 jan. 2018

Genetically determined high activity of IL-12 and IL-18 in ulcerative colitis and TLR5 in Crohns disease were associated with non-response to anti-TNF therapy

Bank, S., Andersen, P. S., Burisch, J., Pedersen, N., Roug, S., Galsgaard, J., Turino, S. Y., Brodersen, J. B., Rashid, S., Rasmussen, B. K., Avlund, S., Olesen, T. B., Hoffmann, H. J., Nexø, B. A., Sode, J., Vogel, U. & Andersen, V. 2018 I : The pharmacogenomics journal. 18, 1, s. 87-97

Publikation: Bidrag til tidsskriftTidsskriftartikel

Anti-tumour necrosis factor-α (TNF-α) is used for treatment of severe cases of inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). However, one-third of the patients do not respond to the treatment. A recent study indicated that genetically determined high activity of pro-inflammatory cytokines, including interleukin-1β (IL-1β), IL-6 and interferon gamma (IFN-γ), are associated with non-response to anti-TNF therapy. Using a candidate gene approach, 21 functional single-nucleotide polymorphisms (SNPs) in 14 genes in the Toll-like receptors, the inflammasome and the IFNG pathways were assessed in 482 and 256 prior anti-TNF naïve Danish patients with CD and UC, respectively. The results were analysed using logistic regression (adjusted for age and gender). Eight functional SNPs were associated with anti-TNF response either among patients with CD (TLR5 (rs5744174) and IFNGR2 (rs8126756)), UC (IL12B (rs3212217), IL18 (rs1946518), IFNGR1 (rs2234711), TBX21 (rs17250932) and JAK2 (rs12343867)) or in the combined cohort of patient with CD and UC (IBD) (NLRP3 (rs10754558), IL12B (rs3212217) and IFNGR1 (rs2234711)) (P<0.05). Only the association with heterozygous genotype of IL12B (rs3212217) (OR: 0.24, 95% CI: 0.11-0.53, P=0.008) among patients with UC withstood Bonferroni correction for multiple testing. In conclusion, Our results suggest that SNPs associated with genetically determined high activity of TLR5 among patients with CD and genetically determined high IL-12 and IL-18 levels among patients with UC were associated with non-response. Further studies will evaluate whether these genes may help stratifying patients according to the expected response to anti-TNF treatment.The Pharmacogenomics Journal advance online publication, 31 January 2017; doi:10.1038/tpj.2016.84.

Originalsprog Engelsk
Tidsskrift The pharmacogenomics journal
Vol/bind 18
Tidsskriftsnummer 1
Sider (fra-til) 87-97
ISSN 1470-269X
DOI
Status Udgivet - 2018

Group for Research and Assessment of Psoriasis and Psoriatic Arthritis/Outcome Measures in Rheumatology Consensus-Based Recommendations and Research Agenda for Use of Composite Measures and Treatment Targets in Psoriatic Arthritis

Coates, L. C., FitzGerald, O., Merola, J. F., Smolen, J., van Mens, L. J. J., Bertheussen, H., Boehncke, W-H., Callis Duffin, K., Campbell, W., de Wit, M., Gladman, D., Gottlieb, A., James, J., Kavanaugh, A., Kristensen, L. E., Kvien, T. K., Luger, T., McHugh, N., Mease, P., Nash, P., Ogdie, A., Rosen, C. F., Strand, V., Tillett, W., Veale, D. J. & Helliwell, P. S. mar. 2018 I : Arthritis & rheumatology (Hoboken, N.J.). 70, 3, s. 345-355 11 s.

Publikation: Bidrag til tidsskriftTidsskriftartikel

OBJECTIVE: A meeting was convened by the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) and Outcome Measures in Rheumatology (OMERACT) to further the development of consensus among physicians and patients regarding composite disease activity measures and targets in psoriatic arthritis (PsA).

METHODS: Prior to the meeting, physicians and patients completed surveys on outcome measures. A consensus meeting of 26 rheumatologists, dermatologists, and patient research partners reviewed evidence on composite measures and potential treatment targets plus results of the surveys. The meeting consisted of plenary presentations, breakout sessions, and group discussions. International experts including members of GRAPPA and OMERACT were invited to the meeting, including the developers of all of the measures discussed. After discussions, participants voted on proposals for use, and consensus was established in a second survey.

RESULTS: Survey results from 128 health care professionals and 139 patients were analyzed alongside a systematic literature review summarizing evidence. A weighted vote was cast for composite measures. For randomized controlled trials, the most popular measures were the PsA disease activity score (40 votes) and the GRAPPA composite index (28 votes). For clinical practice, the most popular measures were an average of scores on 3 visual analog scales (45 votes) and the disease activity in PsA score (26 votes). After discussion, there was no consensus on a composite measure. The group agreed that several composite measures could be used and that future studies should allow further validation and comparison. The group unanimously agreed that remission should be the ideal target, with minimal disease activity (MDA)/low disease activity as a feasible alternative. The target should include assessment of musculoskeletal disease, skin disease, and health-related quality of life. The group recommended a treatment target of very low disease activity (VLDA) or MDA.

CONCLUSION: Consensus was not reached on a continuous measure of disease activity. In the interim, the group recommended several composites. Consensus was reached on a treatment target of VLDA/MDA. An extensive research agenda was composed and recommends that data on all PsA clinical domains be collected in ongoing studies.

Originalsprog Engelsk
Tidsskrift Arthritis & rheumatology (Hoboken, N.J.)
Vol/bind 70
Tidsskriftsnummer 3
Sider (fra-til) 345-355
Antal sider 11
ISSN 2326-5191
DOI
Status Udgivet - mar. 2018

Harm, benefit and costs associated with low-dose glucocorticoids added to the treatment strategies for rheumatoid arthritis in elderly patients (GLORIA trial): study protocol for a randomised controlled trial

Hartman, L., Rasch, L. A., Klausch, T., Bijlsma, H. W. J., Christensen, R., Smulders, Y. M., Ralston, S. H., Buttgereit, F., Cutolo, M., Da Silva, J. A. P., Opris, D., Rovenský, J., Szamosi, S., Middelink, L. M., Lems, W. F. & Boers, M. 25 jan. 2018 I : Trials. 19, 1, s. 67

Publikation: Bidrag til tidsskriftTidsskriftartikel

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory disease of the joints affecting 1% of the world population. It has major impact on patients through disability and associated comorbidities. Current treatment strategies have considerably improved the prognosis, but recent innovations (especially biologic drugs and the new class of so-called "JAK/STAT inhibitors") have important safety issues and are very costly. Glucocorticoids (GCs) are highly effective in RA, and could reduce the need for expensive treatment with biologic agents. However, despite more than 65 years of clinical experience, there is a lack of studies large enough to adequately document the benefit/harm balance. The result is inappropriate treatment strategies, i.e. both under-use and over-use of GCs, and consequently suboptimal treatment of RA.

METHODS: The GLORIA study is a pragmatic multicentre, 2-year, randomised, double-blind, clinical trial to assess the safety and effectiveness of a daily dose of 5 mg prednisolone or matching placebo added to standard of care in elderly patients with RA. Eligible participants are diagnosed with RA, have inadequate disease control (disease activity score, DAS28 ≥ 2.6), and are ≥ 65 years. The primary outcome measures are the time-averaged mean value of the DAS28 and the occurrence of serious adverse events or adverse events of special interest. During the trial, change in antirheumatic therapy is permitted as clinically indicated, except for GCs. Cost-effectiveness and cost-utility are secondary outcomes. The main challenge is the interpretation of the trial result with two primary endpoints and the pragmatic trial design that allows co-interventions. Another challenge is the definition of safety and the relative lack of power to detect differences between treatment groups. We have chosen to define safety as the number of patients experiencing at least one serious adverse event. We also specify a decision tree to guide our conclusion on the balance of benefit and harm, and our methodology to combat potential confounding caused by co-interventions.

DISCUSSION: Pragmatic trials minimise impact on daily practice and maximise clinical relevance of the results, but analysis and interpretation of the results is challenging. We expect that the results of this trial are of importance for all rheumatologists who treat elderly patients with RA.

TRIAL REGISTRATION: ClinicalTrials.gov, NCT02585258 . Registered on 20 October 2015.

Originalsprog Engelsk
Tidsskrift Trials
Vol/bind 19
Tidsskriftsnummer 1
Sider (fra-til) 67
ISSN 1745-6215
DOI
Status Udgivet - 25 jan. 2018

OBJECTIVE: To investigate the impact of patient-reported flares on radiographic damage and disability in rheumatoid arthritis (RA).

METHOD: Patients with low-active (Disease Activity Score based on 28-joint count with C-reactive protein < 3.2) RA were followed for 2 years. Based on annual questionnaires about incidence of flares, three 'flare phenotypes' were distinguished: no flares (NF), transient flares (TF), and a mixed category reporting persistent joint complaints (PJC) in at least one year. Baseline and 2 year radiographs of hands and feet were evaluated according to the Sharp/van der Heijde method. Major outcomes were change from baseline in Total Sharp Score (ΔTSS) and functional impairment, expressed by the Health Assessment Questionnaire (ΔHAQ). Their association with flare phenotype was analysed by logistic regression.

RESULTS: The study included 268 RA patients (70% female; 73% immunoglobulin M rheumatoid factor positive), with a median age (interquartile range) of 63 (55-70) years, and 7 (4-13) years' disease duration. Flares were recalled as NF (n = 77), TF (n = 141), and PJC (n = 50). ΔTSS > 0 was observed in 35%, 37%, and 46%, respectively (p = 0.42), but statistically significantly (p = 0.01) more patients progressed in the TF (10%) and PJC (14%) compared to NF (0%), based on the smallest detectable change (> 4.4 ΔTSS unit). ΔHAQ above the minimal clinically important difference (> 0.22) was seen in 13% (NF), 21% (TF), and 40% (PJC) (p = 0.0015), with PJC being associated with statistically significant impairment in function (odds ratio 4.47, 95% confidence interval 1.87-10.69) compared to NF.

CONCLUSION: In RA patients with low disease activity, the incidence of radiographic progression and functional impairment was higher in patients with flares and persistent complaints, compared to those without flares.

Originalsprog Engelsk
Tidsskrift Scandinavian Journal of Rheumatology
Vol/bind 47
Tidsskriftsnummer 2
Sider (fra-til) 87-94
Antal sider 8
ISSN 0300-9742
DOI
Status Udgivet - mar. 2018

Impact of red and processed meat and fibre intake on treatment outcomes among patients with chronic inflammatory diseases: protocol for a prospective cohort study of prognostic factors and personalised medicine

Christensen, R., Heitmann, B. L., Andersen, K. W., Nielsen, O. H., Sørensen, S. B., Jawhara, M., Bygum, A., Hvid, L., Grauslund, J., Wied, J., Glerup, H., Fredberg, U., Villadsen, J. A., Kjær, S. G., Fallingborg, J., Moghadd, S. A. G. R., Knudsen, T., Brodersen, J., Frøjk, J., Dahlerup, J. F., Bojesen, A. B., Sorensen, G. L., Thiel, S., Færgeman, N. J., Brandslund, I., Bennike, T. B., Stensballe, A., Schmidt, E. B., Franke, A., Ellinghaus, D., Rosenstiel, P., Raes, J., Boye, M., Werner, L., Nielsen, C. L., Munk, H. L., Nexøe, A. B., Ellingsen, T., Holmskov, U., Kjeldsen, J. & Andersen, V. 8 feb. 2018 I : BMJ Paediatrics Open . 8, 2, s. e018166

Publikation: Bidrag til tidsskriftTidsskriftartikel

INTRODUCTION: Chronic inflammatory diseases (CIDs) are frequently treated with biological medications, specifically tumour necrosis factor inhibitors (TNFi)). These medications inhibit the pro-inflammatory molecule TNF alpha, which has been strongly implicated in the aetiology of these diseases. Up to one-third of patients do not, however, respond to biologics, and lifestyle factors are assumed to affect treatment outcomes. Little is known about the effects of dietary lifestyle as a prognostic factor that may enable personalised medicine. The primary outcome of this multidisciplinary collaborative study will be to identify dietary lifestyle factors that support optimal treatment outcomes.

METHODS AND ANALYSIS: This prospective cohort study will enrol 320 patients with CID who are prescribed a TNFi between June 2017 and March 2019. Included among the patients with CID will be patients with inflammatory bowel disease (Crohn's disease and ulcerative colitis), rheumatic disorders (rheumatoid arthritis, axial spondyloarthritis, psoriatic arthritis), inflammatory skin diseases (psoriasis, hidradenitis suppurativa) and non-infectious uveitis. At baseline (pretreatment), patient characteristics will be assessed using patient-reported outcome measures, clinical assessments of disease activity, quality of life and lifestyle, in addition to registry data on comorbidity and concomitant medication(s). In accordance with current Danish standards, follow-up will be conducted 14-16 weeks after treatment initiation. For each disease, evaluation of successful treatment response will be based on established primary and secondary endpoints, including disease-specific core outcome sets. The major outcome of the analyses will be to detect variability in treatment effectiveness between patients with different lifestyle characteristics.

ETHICS AND DISSEMINATION: The principle goal of this project is to improve the quality of life of patients suffering from CID by providing evidence to support dietary and other lifestyle recommendations that may improve clinical outcomes. The study is approved by the Ethics Committee (S-20160124) and the Danish Data Protecting Agency (2008-58-035). Study findings will be disseminated through peer-reviewed journals, patient associations and presentations at international conferences.

TRIAL REGISTRATION NUMBER: NCT03173144; Pre-results.

Originalsprog Engelsk
Tidsskrift BMJ Paediatrics Open
Vol/bind 8
Tidsskriftsnummer 2
Sider (fra-til) e018166
ISSN 2044-6055
DOI
Status Udgivet - 8 feb. 2018

OBJECTIVES: To study the impact of the introduction of biological disease-modifying anti-rheumatic drugs (bDMARDs) and associated rheumatoid arthritis (RA) management guidelines on the incidence of total hip (THR) and knee replacements (TKR) in Denmark.

METHODS: Nationwide register-based cohort and interrupted time-series analysis. Patients with incident RA between 1996 and 2011 were identified in the Danish National Patient Register. Patients with RA were matched on age, sex and municipality with up to 10 general population comparators (GPCs). Standardised 5-year incidence rates of THR and TKR per 1000 person-years were calculated for patients with RA and GPCs in 6-month periods. Levels and trends in the pre-bDMARD (1996-2001) were compared with the bDMARD era (2003-2016) using segmented linear regression interrupted by a 1-year lag period (2002).

RESULTS: We identified 30 404 patients with incident RA and 297 916 GPCs. In 1996, the incidence rate of THR and TKR was 8.72 and 5.87, respectively, among patients with RA, and 2.89 and 0.42 in GPCs. From 1996 to 2016, the incidence rate of THR decreased among patients with RA, but increased among GPCs. Among patients with RA, the incidence rate of TKR increased from 1996 to 2001, but started to decrease from 2003 and throughout the bDMARD era. The incidence of TKR increased among GPCs from 1996 to 2016.

CONCLUSION: We report that the incidence rate of THR and TKR was 3-fold and 14-fold higher, respectively among patients with RA compared with GPCs in 1996. In patients with RA, introduction of bDMARDs was associated with a decreasing incidence rate of TKR, whereas the incidence of THR had started to decrease before bDMARD introduction.

Originalsprog Engelsk
Tidsskrift Annals of the Rheumatic Diseases
ISSN 0003-4967
DOI
Status E-pub ahead of print - 2018

Increased Suicide Risk in Patients with Hidradenitis Suppurativa

Thorlacius, L., Cohen, A. D., Gislason, G. H., Jemec, G. B. E. & Egeberg, A. jan. 2018 I : The Journal of investigative dermatology. 138, 1, s. 52-57 6 s.

Publikation: Bidrag til tidsskriftTidsskriftartikel

Patients with skin disorders are considered at a higher risk of depression and anxiety than the background population. Patients with hidradenitis suppurativa (HS) may be particularly affected. We explored the association between HS and depression, anxiety, and completed suicides in the Danish national registries, expanding to include data on suicidal behavior, using both a cross-sectional and a cohort study design. Both designs included 7,732 patients with HS and a background population of 4,354,137. The cohort study revealed that HS patients had an increased risk of completed suicide after adjustment for confounding factors (11 per 7,732 vs. 2,904 per 4,354,137) (hazard ratio [95% confidence interval] = 2.42 [1.07-5.45]; P = 0.0334) and an increased risk of antidepressant drug use (1.30 [1.17-1.45]; P < 0.0001). In contrast to previous studies, the cross-sectional baseline data revealed nonsignificant association with depression (odds ratio [95% confidence interval] = 1.13; 0.87-1.47]; P = 0.36 and hospitalization due to depression (1.32 [0.94-1.85]; P = 0.1083). To the best of our knowledge, no previous studies have reported on the increased risk of completed suicide among HS patients. The increased risk of completed suicide is not solely explained by lifestyle and demographic differences and the results highlight the profound impact HS has on the lives of patients with this often devastating disease.

Originalsprog Engelsk
Tidsskrift The Journal of investigative dermatology
Vol/bind 138
Tidsskriftsnummer 1
Sider (fra-til) 52-57
Antal sider 6
ISSN 0022-202X
DOI
Status Udgivet - jan. 2018

Kind of blue: A systematic review and meta-analysis of music interventions in cancer treatment

Bro, M. L., Jespersen, K. V., Hansen, J. B., Vuust, P., Abildgaard, N., Gram, J. & Johansen, C. 2018 I : Psycho-Oncology. 27, 2, s. 386-400

Publikation: Bidrag til tidsskriftReview

OBJECTIVES: Music may be a valuable and low-cost coping strategy for cancer patients. We conducted a systematic review and meta-analysis to identify the psychological and physical effects of music interventions in cancer treatment.

METHODS: We included randomized, controlled trials with adult patients in active cancer treatment exposed to different music interventions versus control conditions. Qualitative studies and systematic reviews were excluded. We identified a total of 2624 records through 2 systematic searches (June 2015 and September 2016) in PubMed, Scopus, EMBASE, Cinahl, Web of Science, Cochrane, and PsycINFO and used Risk of Bias Assessment, GRADE and Checklist for Reporting Music-Based Interventions to evaluate the music applied and quality of the studies. We conducted meta-analyses using Review Manager (version 5.3). PROSPERO reg. no. CRD42015026024.

RESULTS: We included 25 RCT's (N = 1784) of which 20 were eligible for the meta-analysis (N = 1565). Music reduced anxiety (SMD -0·80 [95% CI, -1.35 to -0.25]), pain (SMD -0.88 [95% CI -1.45 to -0.32]), and improved mood (SMD -0.55 [95% CI, -0.98 to -0.13]). However, studies were hampered by heterogeneity with I2 varying between 54% and 96%. Quality of the studies ranged from very low to low. The most effective mode of music intervention appeared to be passive listening to self-selected, recorded music in a single session design.

CONCLUSIONS: Music may be a tool in reducing anxiety, pain, and improving mood among patients with cancer in active treatment. However, methodological limitations in the studies conducted so far prevent firm conclusions.

Originalsprog Engelsk
Tidsskrift Psycho-Oncology
Vol/bind 27
Tidsskriftsnummer 2
Sider (fra-til) 386-400
ISSN 1057-9249
DOI
Status Udgivet - 2018

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