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1.  Progressive high-load strength training compared with general low-load exercises in patients with rotator cuff tendinopathy: study protocol for a randomised controlled trial 
Trials  2015;16:27.
Shoulder pain is the third most common musculoskeletal disorder, often affecting people’s daily living and work capacity. The most common shoulder disorder is the subacromial impingement syndrome (SIS) which, among other pathophysiological changes, is often characterised by rotator cuff tendinopathy. Exercise is often considered the primary treatment option for rotator cuff tendinopathy, but there is no consensus on which exercise strategy is the most effective. As eccentric and high-load strength training have been shown to have a positive effect on patella and Achilles tendinopathy, the aim of this trial is to compare the efficacy of progressive high-load exercises with traditional low-load exercises in patients with rotator cuff tendinopathy.
The current study is a randomised, participant- and assessor-blinded, controlled multicentre trial. A total of 260 patients with rotator cuff tendinopathy will be recruited from three outpatient shoulder departments in Denmark, and randomised to either 12 weeks of progressive high-load strength training or to general low-load exercises. Patients will receive six individually guided exercise sessions with a physiotherapist and perform home-based exercises three times a week. The primary outcome measure will be change from baseline to 12 weeks in the patient-reported outcome Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire.
Previous studies of exercise treatment for SIS have not differentiated between subgroups of SIS and have often had methodological flaws, making it difficult to specifically design target treatment for patients diagnosed with SIS. Therefore, it was considered important to focus on a subgroup such as tendinopathy, with a specific tailored intervention strategy based on evidence from other regions of the body, and to clearly describe the intervention in a methodologically strong study.
Trial registration
The trial was registered with (NCT01984203) on 31 October 2013.
PMCID: PMC4318133  PMID: 25622594
Shoulder; Impingement; Tendinopathy; Exercise; Rotator cuff
2.  The efficacy of motivational counseling and SMS-reminders on daily sitting time in patients with rheumatoid arthritis: protocol for a randomized controlled trial 
Trials  2015;16:23.
Patients with RA (Rheumatoid Arthritis) are more sedentary than the general population. Reduction of Sedentary Behaviour (SB) has been suggested as a mean for improvement of health in patients with chronic diseases and mobility problems. Short-term intervention studies have demonstrated that SB can be reduced by behavioural interventions in healthy populations. However, it remains unexplored whether it is valid for patients with RA also.
Therefore, the aim of this trial is to investigate the efficacy of an individually tailored, theory-based motivational counseling intervention on reducing daily sitting time in sedentary patients with RA. Additionally, to explore whether a reduction in daily sitting time is associated with reduced pain and fatigue, self-reported physical function, self-efficacy, improved health-related quality of life (HR-QoL) and cardiovascular biomarker levels, and finally to assess the cost-effectiveness of the intervention.
For this parallel group randomized trial, 150 patients with RA and at least 5 hours of sitting time per day, will be recruited from a rheumatology outpatient clinic, and block-randomized to the intervention group or the control group receiving usual care. The intervention includes: 1) individual motivational counseling (in total 3 sessions) on reduction of daily sitting time in combination with 2) individual Short Text Message Service (SMS) reminders over a 16-week intervention period. Primary outcome is change in daily sitting time (minutes) from baseline to 16 weeks measured objectively using an ActivPAL® Activity Monitor. Secondary outcomes include fatigue, pain, physical function, HR-QoL, self-efficacy, costs and cost-effectiveness. Furthermore, anthropometric measures will be included as well as measurement of blood pressure and serum lipids. All outcomes are assessed at baseline and repeated after 16 weeks. Follow-up assessments are made at 6 and 18 months post-intervention.
The intervention is simple, non-invasive and may be implemented at low costs. If the study confirms the positive results expected, the intervention might be implemented in clinical practice and potentially transferred to other clinical populations.
Trial registration registration number: NCT01969604. Date of registration: 17 October 2013.
PMCID: PMC4324661  PMID: 25623388
Sedentary behavior; Short text message service; Fatigue; Pain; Self-efficacy; ActivPAL; HR-QoL
3.  Validity and Agreement between the 28-Joint Disease Activity Score Based on C-Reactive Protein and Erythrocyte Sedimentation Rate in Patients with Rheumatoid Arthritis 
Arthritis  2015;2015:401690.
Objective. To validate the agreement between the 28-joint disease activity score based on erythrocyte sedimentation rate (DAS28-ESR) and the 28-joint disease activity score based on C-reactive protein (DAS28-CRP) in a group of Danish patients with rheumatoid arthritis (RA). Methods. Data from 109 Danish RA patients initiating biologic treatment were analysed at baseline and following one year of treatment. Participants were retrospectively enrolled from a previous cohort study and were considered eligible for this project if CRP and ESR were measured at baseline and at the follow-up visit. To assess the extent of agreement between the two DAS28 definitions, the “European League Against Rheumatism” (EULAR) response criteria based on each definition were calculated with cross-classification. Weighted Kappa (κ) coefficients were calculated, and Bland-Altman plots were used to illustrate degree of agreement between DAS28 definitions. Results. The 75 eligible patients were classified as EULAR good, moderate, and nonresponders with good agreement (61/75; 81%) between DAS28-CRP and DAS28-ESR (κ = 0.75 (95% CI: 0.63 to 0.88)). Conclusions. According to our findings, DAS28-CRP and DAS28-ESR are interchangeable when assessing RA patients and the two versions of DAS28 are comparable between studies.
PMCID: PMC4303021  PMID: 25632353
4.  The effect on knee-joint load of instruction in analgesic use compared with neuromuscular exercise in patients with knee osteoarthritis: study protocol for a randomized, single-blind, controlled trial (the EXERPHARMA trial) 
Trials  2014;15(1):444.
Knee osteoarthritis (OA) is a mechanically driven disease, and it is suggested that medial tibiofemoral knee-joint load increases with pharmacologic pain relief, indicating that pharmacologic pain relief may be positively associated with disease progression. Treatment modalities that can both relieve pain and reduce knee-joint load would be preferable. The knee-joint load is influenced by functional alignment of the trunk, pelvis, and lower-limb segments with respect to the knee, as well as the ground-reaction force generated during movement. Neuromuscular exercise can influence knee load and decrease knee pain. It includes exercises to improve balance, muscle activation, functional alignment, and functional knee stability. The primary objective of this randomized controlled trial (RCT) is to investigate the efficacy of a NEuroMuscular EXercise (NEMEX) therapy program, compared with optimized analgesics and antiinflammatory drug use, on the measures of knee-joint load in people with mild to moderate medial tibiofemoral knee osteoarthritis.
One hundred men and women with mild to moderate medial knee osteoarthritis will be recruited from general medical practices and randomly allocated (1:1) to one of two 8-week treatments, either (a) NEMEX therapy twice a week or (b) information on the recommended use of analgesics and antiinflammatory drugs (acetaminophen and oral NSAIDs) via a pamphlet and video materials. The primary outcome is change in knee load during walking (the Knee Index, a composite score of the first external peak total reaction moment on the knee joint from all three planes based on 3D movement analysis) after 8 weeks of intervention. Secondary outcomes include changes in the external peak knee-adduction moment and impulse and functional performance measures, in addition to changes in self-reported pain, function, health status, and quality of life.
These findings will help determine whether 8 weeks of neuromuscular exercise is superior to optimized use of analgesics and antiinflammatory drugs regarding knee-joint load, pain and physical function in people with mild to moderate knee osteoarthritis.
Trial registration Identifier: NCT01638962 (July 3, 2012).
PMCID: PMC4240848  PMID: 25399048
Osteoarthritis; Exercise; Gait; Joint load; Knee joint; Middle-aged; Knee; Pain management
5.  Can the painDETECT Questionnaire score and MRI help predict treatment outcome in rheumatoid arthritis: protocol for the Frederiksberg hospital's Rheumatoid Arthritis, pain assessment and Medical Evaluation (FRAME-cohort) study 
BMJ Open  2014;4(11):e006058.
Pain in rheumatoid arthritis (RA) is traditionally considered to be of inflammatory origin. Despite better control of inflammation, some patients still report pain as a significant concern, even when being in clinical remission. This suggests that RA may prompt central sensitisation—one aspect of chronic pain. In contrast, other patients report good treatment response, although imaging shows signs of inflammation, which could indicate a possible enhancement of descending pain inhibitory mechanisms.
When assessing disease activity in patients with central sensitisation, the commonly used disease activity scores (eg, DAS28-CRP (C reactive protein)) will yield constant high total scores due to high tender joint count and global health assessments, whereas MRI provides an isolated estimate of inflammation.
The objective of this study is, in patients with RA initiating anti-inflammatory treatment, to explore the prognostic value of a screening questionnaire for central sensitisation, hand inflammation assessed by conventional MRI, and the interaction between them regarding treatment outcome evaluated by clinical status (DAS28-CRP). For the purpose of further exploratory analyses, dynamic contrast-enhanced MRI (DCE-MRI) is performed.
Method and analysis
The painDETECT Questionnaire (PDQ), originally developed to screen for a neuropathic pain component, is applied to indicate the presence of central sensitisation. Adults diagnosed with RA are included when either (A) initiating disease-modifying antirheumatic drug treatment, or (B) initiating or switching to biological therapy.
We anticipate that 100 patients will be enrolled, tested and reassessed after 4 months of treatment.
Data collection includes
Clinical data, conventional MRI, DCE-MRI, blood samples and patient-reported outcomes.
Ethics and dissemination
This study aims at supporting rheumatologists to define strategies to reach optimal treatment outcomes in patients with RA based on chronic pain prognostics. The study has been approved by The Capital region of Denmark's Ethics Committee; identification number H-3-2013-049. The results will be published in international peer-reviewed journals.
PMCID: PMC4244416  PMID: 25394817
Rheumatoid Arthritis; Central sensitization; painDETECT Questionnaire; Prognostics
6.  Assessing bias in osteoarthritis trials included in Cochrane reviews: protocol for a meta-epidemiological study 
BMJ Open  2014;4(10):e005491.
The validity of systematic reviews and meta-analysis depends on methodological quality and unbiased dissemination of trials. Our objective is to evaluate the association of estimates of treatment effects with different bias-related study characteristics in meta-analyses of interventions used for treating pain in osteoarthritis (OA). From the findings, we hope to consolidate guidance on interpreting OA trials in systematic reviews based on empirical evidence from Cochrane reviews.
Methods and analysis
Only systematic reviews that compare experimental interventions with sham, placebo or no intervention control will be considered eligible. Bias will be assessed with the risk of bias tool, used according to the Cochrane Collaboration’s recommendations. Furthermore, center status, trial size and funding will be assessed. The primary outcome (pain) will be abstracted from the first appearing forest plot for overall pain in the Cochrane review. Treatment effect sizes will be expressed as standardised mean differences (SMDs), where the difference in mean values available from the forest plots is divided by the pooled SD. To empirically assess the risk of bias in treatment benefits, we will perform stratified analyses of the trials from the included meta-analyses and assess the interaction between trial characteristics and treatment effect. A relevant study-level covariate is defined as one that decreases the between-study variance (τ2, estimated as Tau-squared) as a consequence of inclusion in the mixed effects statistical model.
Ethics and dissemination
Meta-analyses and randomised controlled trials provide the most reliable basis for treatment of patients with OA, but the actual impact of bias is unclear. This study will systematically examine the methodological quality in OA Cochrane reviews and explore the effect estimates behind possible bias. Since our study does not collect primary data, no formal ethical assessment and informed consent are required.
Trial registration number
PROSPERO (CRD42013006924).
PMCID: PMC4187994  PMID: 25280805
osteoarthritis; meta-analysis; meta-epidemiology; risk of bias
7.  Interpreting trial results following use of different intention-to-treat approaches for preventing attrition bias: a meta-epidemiological study protocol 
BMJ Open  2014;4(9):e005297.
When participants drop out of randomised clinical trials, as frequently happens, the intention-to-treat (ITT) principle does not apply, potentially leading to attrition bias. Data lost from patient dropout/lack of follow-up are statistically addressed by imputing, a procedure prone to bias. Deviations from the original definition of ITT are referred to as modified intention-to-treat (mITT). As yet, the impact of the potential bias associated with mITT has not been assessed. Our objective is to investigate potential bias and disadvantages of performing mITT and evaluate possible concerns when executing different mITT approaches in meta-analyses.
Methods and analysis
Using meta-epidemiology on randomised trials considered less prone to bias (ie, good internal validity) and assessing biological or targeted agents in patients with rheumatoid arthritis, we will meta-analyse data from 10 biological and targeted drugs based on collections of trials that would correspond to 10 individual meta-analyses.
Ethics and dissemination
This study will enhance transparency for evaluating mITT treatment effects described in meta-analyses. The intended audience will include healthcare researchers, policymakers and clinicians. Results of the study will be disseminated by peer-review publication.
Protocol registration
In PROSPERO CRD42013006702, 11. December 2013.
PMCID: PMC4179424  PMID: 25260368
8.  Effect of Combination Therapy on Joint Destruction in Rheumatoid Arthritis: A Network Meta-Analysis of Randomized Controlled Trials 
PLoS ONE  2014;9(9):e106408.
Despite significant cost differences, the comparative effect of combination treatments of disease modifying anti-rheumatic drugs (DMARDs) with and without biologic agents has rarely been examined. Thus we performed a network meta-analysis on the effect of combination therapies on progression of radiographic joint erosions in patients with rheumatoid arthritis (RA).
Methods and Findings
The following combination drug therapies compared versus single DMARD were investigated: Double DMARD: 2 DMARDs (methotrexate, sulfasalazine, leflunomide, injectable gold, cyclosporine, chloroquine, azathioprin, penicillamin) or 1 DMARD plus low dose glucocorticoid (LDGC); triple DMARD: 3 DMARDs or 2 DMARDs plus LDGC; biologic combination: 1 DMARD plus biologic agent (tumor necrosis factor α inhibitor (TNFi) or abatacept or tocilizumab or CD20 inhibitor (CD20i)). Randomized controlled trials were identified in a search of electronic archives of biomedical literature and included in a star-shaped network meta-analysis and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement protocol. Effects are reported as standardized mean differences (SMD). The effects of data from 39 trials published in the period 1989–2012 were as follows: Double DMARD: −0.32 SMD (CI: −0.42, −0.22); triple DMARD: −0.46 SMD (CI: −0.60, −0.31); 1 DMARD plus TNFi: −0.30 SMD (CI: −0.36, −0.25); 1 DMARD plus abatacept: −0.20 SMD (CI: −0.33, −0.07); 1 DMARD plus tocilizumab: −0.34 SMD (CI: −0.48, −0.20); 1 DMARD plus CD20i: −0.32 SMD (CI: −0.40, −0.24). The indirect comparisons showed similar effects between combination treatments apart from triple DMARD being significantly better than abatacept plus methotrexate (−0.26 SMD (CI: −0.45, −0.07)) and TNFi plus methotrexate (−0.16 SMD (CI: −0.31, −0.01)).
Combination treatment of a biologic agent with 1 DMARD is not superior to 2–3 DMARDs including or excluding LDGC in preventing structural joint damage. Future randomized studies of biologic agents should be compared versus a combination of DMARDs.
PMCID: PMC4171366  PMID: 25244021
9.  Is there a causal link between knee loading and knee osteoarthritis progression? A systematic review and meta-analysis of cohort studies and randomised trials 
BMJ Open  2014;4(7):e005368.
We performed a systematic review, meta-analysis and assessed the evidence supporting a causal link between knee joint loading during walking and structural knee osteoarthritis (OA) progression.
Systematic review, meta-analysis and application of Bradford Hill's considerations on causation.
Data sources
We searched MEDLINE, Scopus, AMED, CINAHL and SportsDiscus for prospective cohort studies and randomised controlled trials (RCTs) from 1950 through October 2013.
Study eligibility criteria
We selected cohort studies and RCTs in which estimates of knee joint loading during walking were used to predict structural knee OA progression assessed by X-ray or MRI.
Data analyses
Meta-analysis was performed to estimate the combined OR for structural disease progression with higher baseline loading. The likelihood of a causal link between knee joint loading and OA progression was assessed from cohort studies using the Bradford Hill guidelines to derive a 0–4 causation score based on four criteria and examined for confirmation in RCTs.
Of the 1078 potentially eligible articles, 5 prospective cohort studies were included. The studies included a total of 452 patients relating joint loading to disease progression over 12–72 months. There were very serious limitations associated with the methodological quality of the included studies. The combined OR for disease progression was 1.90 (95% CI 0.85 to 4.25; I2=77%) for each one-unit increment in baseline knee loading. The combined causation score was 0, indicating no causal association between knee loading and knee OA progression. No RCTs were found to confirm or refute the findings from the cohort studies.
There is very limited and low-quality evidence to support for a causal link between knee joint loading during walking and structural progression of knee OA.
Trial registration number
PMCID: PMC4120424  PMID: 25031196
10.  Synovial explant inflammatory mediator production corresponds to rheumatoid arthritis imaging hallmarks: a cross-sectional study 
Arthritis Research & Therapy  2014;16(3):R107.
Despite the widespread use of magnetic resonance imaging (MRI) and Doppler ultrasound for the detection of rheumatoid arthritis (RA) disease activity, little is known regarding the association of imaging-detected activity and synovial pathology. The purpose of this study was to compare site-specific release of inflammatory mediators and evaluate the corresponding anatomical sites by examining colour Doppler ultrasound (CDUS) and MRI scans.
RA patients were evaluated on the basis of CDUS and 3-T MRI scans and subsequently underwent synovectomy using a needle arthroscopic procedure of the hand joints. The synovial tissue specimens were incubated for 72 hours, and spontaneous release of monocyte chemoattractant protein 1 (MCP-1), interleukin 6 (IL-6), macrophage inflammatory protein 1β (MIP-1β) and IL-8 was measured by performing multiplex immunoassays. Bone marrow oedema (BME), synovitis and erosion scores were estimated on the basis of the rheumatoid arthritis magnetic resonance imaging score (RAMRIS). Mixed models were used for the statistical analyses. Parsimony was achieved by omitting covariates with P > 0.1 from the statistical model.
Tissue samples from 58 synovial sites were obtained from 25 patients. MCP-1 was associated with CDUS activity (P = 0.009, approximate Spearman’s ρ = 0.41), RAMRIS BME score (P = 0.01, approximate Spearman’s ρ = 0.42) and RAMRIS erosion score (P = 0.03, approximate Spearman’s ρ = 0.31). IL-6 was associated with RAMRIS synovitis score (P = 0.04, approximate Spearman’s ρ = 0.50), BME score (P = 0.04, approximate Spearman’s ρ = 0.31) and RAMRIS erosion score (P = 0.03, approximate Spearman’s ρ = 0.35). MIP-1β was associated with CDUS activity (P = 0.02, approximate Spearman’s ρ = 0.38) and RAMRIS synovitis scores (P = 0.02, approximate Spearman’s ρ = 0.63). IL-8 associations with imaging outcome measures did not reach statistical significance.
The association between imaging activity and synovial inflammatory mediators underscores the high sensitivity of CDUS and MRI in the evaluation of RA disease activity. The associations found in our present study have different implications for synovial mediator releases and corresponding imaging signs. For example, MCP-1 and IL-6 were associated with both general inflammation and bone destruction, in contrast to MIP-1β, which was involved solely in general synovitis. The lack of association of IL-8 with synovitis was likely underestimated because of a large proportion of samples above assay detection limits among the patients with the highest synovitis scores.
PMCID: PMC4078218  PMID: 24886513
11.  Effect of physical therapy on breast cancer related lymphedema: protocol for a multicenter, randomized, single-blind, equivalence trial 
BMC Cancer  2014;14:239.
Physical therapy treatment of patients with lymphedema includes treatment based on the principles of ‘Complete Decongestive Therapy’ (CDT). CDT consists of the following components; skin care, manual lymphatic drainage, bandaging and exercises. The scientific evidence regarding what type of treatment is most effective is sparse. The objective of this study is to investigate whether CDT is equally effective if it includes manual lymphatic drainage or not in the treatment of arm lymphedema among patients with breast cancer.
A randomized, single-blind, equivalence trial. A total of 160 breast cancer patients with arm lymphedema will be recruited from 3 hospitals and randomized into one of two treatment groups A: Complete Decongestive Therapy including manual drainage or B: Complete Decongestive Therapy without manual lymphatic drainage. The intervention period will be approximately 4 weeks followed by a 6 month follow-up period (7 months from baseline). Primary outcome variable: the percentage volume reduction of lymphedema (%) from baseline to 7 months. Secondary outcome variables: Differences from baseline to week 4 and from week 4 to month 7 in circumference of the arm (cm), body weight (kg), patient sensation of heaviness (scale range: 0–10), patient sensation of tension (scale range: 0–10), and quality of life (EQ-5D-5 L-questionnaire).
All measurements are standardized and will be performed before randomization, after 4 weeks and after 7 months.
This randomized controlled study seeks to provide data on an effective treatment for patients with breast cancer related arm lymphedema and which at the same time causes minimal patient inconvenience.
Trial registration Identifier NCT02015897
PMCID: PMC3978135  PMID: 24708851
Manual lymphatic drainage; Complete Decongestive Therapy; Breast cancer
12.  Effect of phenylephrine vs. ephedrine on frontal lobe oxygenation during caesarean section with spinal anesthesia: an open label randomized controlled trial 
Background: During caesarean section spinal anesthesia may provoke maternal hypotension that we prevent by administration of phenylephrine and/or ephedrine. Phenylephrine is however reported to reduce the near infrared spectroscopy-determined frontal lobe oxygenation (ScO2) but whether that is the case for patients exposed to spinal anesthesia is not known.
Objectives: To evaluate the impact of phenylephrine vs. ephedrine on ScO2during caesarean section with spinal anesthesia in a single center, open-label parallel-group study with balanced randomization of 24 women (1:1). Secondary aims were to compare the effect of the two drugs on maternal hemodynamics and fetal heart rate.
Intervention: Ephedrine (0.8–3.3 mg/min) vs. phenylephrine infusion (0.02–0.07 mg/min).
Results: For the duration of surgery, administration of ephedrine maintained ScO2 (compared to baseline +2.1 ± 2.8%; mean ± SE, while phenylephrine reduced ScO2 (−8.6 ± 2.8%; p = 0.005) with a 10.7% difference in ScO2between groups (p = 0.0106). Also maternal heart rate was maintained with ephedrine (+3 ± 3 bpm) but decreased with phenylephrine (−11 ± 3 bpm); difference 14 bpm (p = 0.0053), but no significant difference in mean arterial pressure (p = 0.1904) or CO (p = 0.0683) was observed between groups. The two drugs also elicited an equal increase in fetal heart rate (by 19 ± 3 vs. 18 ± 3 bpm; p = 0.744).
Conclusion: In the choice between phenylephrine and ephedrine for maintenance of blood pressure during caesarean section with spinal anesthesia, ephedrine maintains frontal lobe oxygenation and maternal heart rate with a similar increase in fetal heart rate as elicited by phenylephrine.
Trial registration: Clinical trials NCT 01509521 and EudraCT 2001 006103 35.
PMCID: PMC3940064  PMID: 24624090
cerebral autoregulation; drug effect; heart rate; fetal; near infrared spectroscopy; vasoconstrictor agents
13.  Temporal summation of pain and ultrasound Doppler activity as predictors of treatment response in patients with rheumatoid arthritis: protocol for the Frederiksberg hospitals Rheumatoid Arthritis, pain assessment and Medical Evaluation (FRAME-cohort) study 
BMJ Open  2014;4(1):e004313.
Chronic pain is common in rheumatoid arthritis (RA) and may still persist despite regression of objective signs of inflammation. This has led researchers to hypothesise that central pain sensitisation may play a role in the generation of chronic pain in RA. Application of the disease activity score DAS28 can classify some patients with active RA solely based on a high tender joint count and poor patient global health score. In such cases, intensified treatment with anti-inflammatory drugs would be expected to yield poorer results than in cases with DAS28 elevation due to a high score for swollen joints and C reactive protein (CRP). Evaluation of central pain sensitisation in patients with few inflammatory indices may be a predictive tool regarding the effect of anti-inflammatory treatment. Computerised pneumatic cuff pressure algometry (CPA) is a method for assessing temporal summation (ie, degree of central sensitisation). The main objective of this study was to examine the prognostic values of pressure pain-induced temporal summation, ultrasound Doppler activity and the interaction between them in relation to treatment response (DAS28-CRP change) in patients with RA initiating any anti-inflammatory therapy.
Method and analysis
120 participants ≥18 years of age will be recruited. Furthermore, they must be either (1) diagnosed with RA, untreated with disease-modifying antirheumatic drugs for at least 6 months and about to initiate disease-modifying antirheumatic drug treatment or (2) about to begin or switch treatment with any biological drug for their RA. Data (clinical, imaging, blood samples, patient reported outcomes and CPA measurements) will be collected from each participant at baseline and after 4 months of anti-inflammatory treatment.
Ethics and dissemination
This study has been approved by the ethics committee for the Copenhagen region (H-4-2013-007). Dissemination will occur through presentations and publication in international peer-reviewed journals.
PMCID: PMC3902530  PMID: 24390385
rheumatoid arthritis; central nervous system sensitization; pain measurement; ultrasound doppler; inflammation
14.  Thermic effect of a meal and appetite in adults: an individual participant data meta-analysis of meal-test trials 
Food & Nutrition Research  2013;57:10.3402/fnr.v57i0.19676.
Thermic effect of a meal (TEF) has previously been suggested to influence appetite.
The aim of this study was to assess whether there is an association between appetite and TEF. Second, to examine whether protein intake is associated with TEF or appetite.
Individual participant data (IPD) meta-analysis on studies were performed at the Department of Nutrition, Exercise and Sports, University of Copenhagen, Denmark. Five randomized meal-test studies, with 111 participants, were included. The included studies measured energy expenditure (EE) in respiration chambers and pre- and postprandial appetite sensations using Visual Analog Scales (VAS). The primary meta-analysis was based on a generic-inverse variance random-effects model, pooling individual study Spearman's correlation coefficients, resulting in a combined r-value with 95% confidence interval (95% CI). The I 2 value quantifies the proportion (%) of the variation in point estimates due to among-study differences.
The IPD meta-analysis found no association between satiety and TEF expressed as the incremental area under the curve (TEFiAUC) (r=0.06 [95% CI −0.16 to 0.28], P=0.58; I 2=15.8%). Similarly, Composite Appetite Score (CAS) was not associated with TEFiAUC (r=0.08 [95% CI −0.12 to 0.28], P=0.45; I 2=0%). Posthoc analyses showed no association between satiety or CAS and TEF expressed as a percentage of energy intake (EI) (P>0.49) or TEF expressed as a percentage of baseline EE (P>0.17). When adjusting for covariates, TEFiAUC was associated with protein intake (P=0.0085).
This IPD meta-analysis found no evidence supporting an association between satiety or CAS and TEF at protein intakes ∼15 E% (range 11–30 E%).
PMCID: PMC3873760  PMID: 24376394
thermic effect of a meal; diet-induced thermogenesis; appetite; energy expenditure; satiety; Composite Appetite Score
15.  Knee Arthroscopy Cohort Southern Denmark (KACS): protocol for a prospective cohort study 
BMJ Open  2013;3(10):e003399.
Meniscus surgery is a high-volume surgery carried out on 1 million patients annually in the USA. The procedure is conducted on an outpatient basis and the patients leave the hospital a few hours after surgery. A critical oversight of previous studies is their failure to account for the type of meniscal tears. Meniscus tears can be categorised as traumatic or non-traumatic. Traumatic tears (TT) are usually observed in younger, more active individuals in an otherwise ‘healthy’ meniscus and joint. Non-traumatic tears (NTT) (ie, degenerative tears) are typically observed in the middle-aged (35–55 years) and older population but the aetiology is largely unclear. Knowledge about the potential difference of the effect of arthroscopic meniscus surgery on patient symptoms between patients with traumatic and NTT is sparse. Furthermore, little is known about the natural time course of patient perceived pain, function and quality of life after meniscus surgery and factors affecting these outcomes. The aim of this prospective cohort study is to investigate the natural time course of patient-reported outcomes in patients undergoing meniscus surgery, with particular emphasis on the role of type of symptom onset.
This prospective cohort study enrol patients assigned for meniscus surgery. At the baseline (PRE surgery), patient characteristics are assessed using an email-based questionnaire also comprising several validated questionnaires assessing general health, knee-specific characteristics and patient's expectations of the surgery. Follow-up will be conducted at 12 and 52 weeks after meniscus surgery. The major outcomes will be differences in changes, from before to 52 weeks after surgery, in each of the five domains on the Knee injury and Osteoarthritis Outcome Score (KOOS) between patients undergoing surgery for traumatic compared with non-traumatic meniscus tears.
The study findings will be disseminated in peer-reviewed journals and presented at national and international conferences.
Trial registration number Identifier: NCT01871272.
PMCID: PMC3808767  PMID: 24127057
Cohort study; Arthroscopy; Meniscus; Prospective study
16.  Enhancing the reporting and transparency of rheumatology research: a guide to reporting guidelines 
Manuscripts and abstracts from biomedical journals frequently do not contain proper information for meeting required standards and serving the multiple needs of their end users. Reporting guidelines and checklists help researchers to meet those standards by providing rules or principles for specific research areas. Rheumatology research includes a broad range of heterogeneous research areas, each with its own requirements, producing several distinct categories of articles. Our objectives with this article are to raise awareness of the existence and importance of reporting guidelines, to present a structured overview of reporting guidelines that rheumatology journals could apply, and to encourage their use by journal authors, editors, and reviewers, including those of Arthritis Research & Therapy. Internationally recognized reporting guidelines exist for a diversity of research areas. We encourage colleagues to consult the 'Enhancing the QUAlity and Transparency Of health Research' (EQUATOR) network when writing scientific papers. EQUATOR is an international initiative that seeks to improve the reliability and value of biomedical research literature by promoting transparent and accurate reporting of studies. We propose specific reporting guidelines for a number of study designs: animal research, randomized trials, reliability and agreement studies, systematic reviews with and without meta-analyses, diagnostic test accuracy studies, and also observational research including cross-sectional, cohort, and case-control studies. We encourage authors, editors, and reviewers to adhere to and enforce the use of the appropriate guidelines when writing, reading, and reviewing scientific papers.
PMCID: PMC3672749  PMID: 23448311
17.  Changes in bone marrow lesions in response to weight-loss in obese knee osteoarthritis patients: a prospective cohort study 
Patients are susceptible for knee osteoarthritis (KOA) with increasing age and obesity and KOA is expected to become a major disabling disease in the future. An important feature of KOA on magnetic resonance imaging (MRI) is changes in the subchondral bone, bone marrow lesions (BMLs), which are related to the future degeneration of the knee joint as well as prevalent clinical symptoms. The aim of this study was to investigate the changes in BMLs after a 16-week weight-loss period in obese subjects with KOA and relate changes in BMLs to the effects of weight-loss on clinical symptoms.
This prospective cohort study included patients with a body mass index ≥ 30 kg/m2, an age ≥ 50 years and primary KOA. Patients underwent a 16 weeks supervised diet program which included formula products and dietetic counselling ( NCT00655941). BMLs in tibia and femur were assessed on MRI before and after the weight-loss using the Boston-Leeds Osteoarthritis Knee Score. Response to weight-loss in BML scores was dichotomised to patients experiencing a decrease in BML scores (responders) and patients who did not (non-responders). The association of BMLs to weight-loss was assessed by logistic regressions and correlation analyses.
39 patients (23%) were classified as responders in the sum of all BML size scores whereas 130 patients (77%) deteriorated or remained stable and were categorized as non-responders. Logistic regression analyses revealed no association between weight-loss < or ≥ 10% and response in BMLs in the most affected compartment (OR 1.86 [CI 0.66 to 5.26, p=0.24]). There was no association between weight-loss and response in maximum BML score (OR 1.13 [CI 0.39 to 3.28, p=0.81]). The relationship between changes in BMLs and clinical symptoms revealed that an equal proportion of patients classified as BML responders and non-responders experienced an OMERACT-OARSI response (69 vs. 71%, p=0.86).
Weight-loss did not improve the sum of tibiofemoral BML size scores or the maximum tibiofemoral BML score, suggesting that BMLs do not respond to a rapidly decreased body weight. The missing relationship between clinical symptoms and BMLs calls for further investigation.
PMCID: PMC3618315  PMID: 23522337
MRI; Knee osteoarthritis; Bone marrow lesions; Weight-loss; Obesity
18.  Development of a Danish Language Version of the Manchester Foot Pain and Disability Index: Reproducibility and Construct Validity Testing 
Pain Research and Treatment  2013;2013:284903.
Introduction. The Manchester Foot Pain and Disability Index (MFPDI) is a 19-item questionnaire for the assessment of disability caused by foot pain. The aim was to develop a Danish language version of the MFPDI (MFPDI-DK) and evaluate its reproducibility and construct validity. Methods. A Danish version was created, following a forward-backward translation procedure. A sample of 84 adult patients with foot pain was recruited. Participants completed two copies of the MFPDI-DK within a 24- to 48-hour interval, along with the Medical Outcomes Study Short Form 36 (SF-36), and a pain Visual Analog Scale (VAS). Reproducibility was assessed using the intraclass correlation coefficient (ICC) and 95% limits of agreement (Bland-Altman plot). Construct validity was evaluated with Pearson's Rho, using a priori hypothesized correlations with SF-36 subscales and VASmean. Results. The MFPDI-DK showed very good reliability with an ICC of 0.92 (0.88–0.95). The 95% limits of agreement ranged from −6.03 to 6.03 points. Construct validity was supported by moderate to very strong correlations with the SF-36 physical subscales and VASmean. Conclusion. The MFPDI-DK appears to be a valid and reproducible instrument in evaluating foot-pain-related disability in Danish adult patients in cross-sectional samples. Further research is needed to test the responsiveness of the MFPDI-DK.
PMCID: PMC3606795  PMID: 23533748
19.  Arthroscopic partial meniscectomy in middle-aged patients with mild or no knee osteoarthritis: a protocol for a double-blind, randomized sham-controlled multi-centre trial 
Arthroscopic partial meniscectomy has been shown to be of no benefit to patients with concomitant knee osteoarthritis, but the optimal treatment of a degenerative meniscus tear in patients with mild or no knee osteoarthritis is unknown. This article describes the rationale and methodology of a randomized sham-controlled trial to assess the benefit of arthroscopic partial meniscectomy of a medial meniscus tear in patients with mild or no knee osteoarthritis. The objective of the study is to test whether the benefit from arthroscopic partial meniscectomy in patients with knee pain, medial meniscus lesion and mild/no knee osteoarthritis, is greater after arthroscopic partial meniscectomy than following sham surgery.
We will conduct a randomized controlled trial of treatment for degenerative meniscus tears in middle-aged patients (aged 35–55 years) with an MRI-verified medial meniscus lesion and mild or no knee radiographic osteoarthritis (grade 0–2 on the Kellgren & Lawrence scale). Patients will be randomized to receive either conventional arthroscopic partial meniscectomy or a sham surgery procedure. The primary outcome will be the KOOS5 derived from the ‘Knee Injury and Osteoarthritis Outcome Score’ at 2 years follow-up. Secondary outcomes at 2 years will include all five individual subscales of the KOOS, a global perceived effect score, the Short-Form-36 health status score, EQ-5D for economic appraisal and objective tests of muscle strength and physical function. Radiographic knee osteoarthritis will be evaluated at 5 years.
Demonstration of no additional benefit from arthroscopic partial meniscectomy on pain and function should lead to a change in clinical care of patients with a degenerative meniscus tear. The results of this study will provide empirical evidence for the potential benefit/harm of arthroscopic partial meniscectomy compared to a masked sham-therapeutics intervention.
Trial registration
PMCID: PMC3599063  PMID: 23442554
In the design of scientific studies it is essential to decide on which scientific questions one aims to answer, just as it is important to decide on the correct statistical methods to use to answer these questions. The correct use of statistical methods is crucial in all aspects of research to quantify relationships in data. Despite an increased focus on statistical content and complexity of biomedical research these topics remain difficult for most researchers. Statistical methods enable researchers to condense large spreadsheets with data into means, proportions, and difference between means, risk differences, and other quantities that convey information. One of the goals in biomedical research is to develop parsimonious models ‐ meaning as simple as possible. This approach is valid if the subsequent research report (the article) is written independent of whether the results are “statistically significant” or not. In the present paper we outline the considerations and suggestions on how to build a trial protocol, with an emphasis on having a rigorous protocol stage, always leading to a full article manuscript, independent of statistical findings. We conclude that authors, who find (rigorous) protocol writing too troublesome, will realize that they have already written the first half of the final paper if they follow these recommendations; authors simply need to change the protocols future tense into past tense. Thus, the aim of this clinical commentary is to describe and explain the statistical principles for trial protocols in terms of design, analysis, and reporting of findings.
PMCID: PMC3474307  PMID: 23091782
analysis; research design; statistics
21.  A Hierarchy of Patient-Reported Outcomes for Meta-Analysis of Knee Osteoarthritis Trials: Empirical Evidence from a Survey of High Impact Journals 
Arthritis  2012;2012:136245.
Objectives. To develop a prioritised list based on responsiveness for extracting patient-reported outcomes (PROs) measuring pain and disability for performing meta-analyses in knee osteoarthritis (OA). Methods. A systematic search was conducted in 20 highest impact factor general and rheumatology journals chosen a priori. Eligible studies were randomised controlled trials, using two or more PROs measuring pain and/or disability. Results. A literature search identified 402 publications and 38 trials were included, resulting in 54 randomised comparisons. Thirty-five trials had sufficient data on pain and 15 trials on disability. The WOMAC “pain” and “function” subscales were the most responsive composite scores. The following list was developed. Pain: (1) WOMAC “pain” subscale, (2) pain during activity (VAS), (3) pain during walking (VAS), (4) general knee pain (VAS), (5) pain at rest (VAS), (6) other composite pain scales, and (7) other single item measures. Disability: (1) WOMAC “function” subscale, (2) SF-36 “physical function” subscale, (3) SF-36 (Physical composite score), and (4) Other composite disability scores. Conclusions. As choosing the PRO most favourable for the intervention from individual trials can lead to biased estimates, using a prioritised list as developed in this study is recommended to reduce risk of biased selection of PROs in meta-analyses.
PMCID: PMC3389647  PMID: 22792458
22.  Feasibility of a standardized ultrasound examination in patients with rheumatoid arthritis: a quality improvement among rheumatologists cohort 
Quality improvement is important to facilitate valid patient outcomes. Standardized examination procedures may improve the validity of US.
The aim of this study was to investigate the learning progress for rheumatologists during training of US examination of the hand in patients with rheumatoid arthritis (RA).
Rheumatologists with varying degrees of experience in US were instructed by skilled tutors. The program consisted of two days with hands-on training followed by personal US examinations performed in their individual clinics. Examinations were sent to the tutors for quality control. The US examinations were evaluated according to a scoring sheet containing 144 items. An acceptable examination was defined as > 80% correct scores.
Thirteen rheumatologists participated in the study. They included a total of 104 patients with RA. Only few of the initial examinations were scored below 80%, and as experience increased, the scores improved (p = 0.0004). A few participants displayed decreasing scores.
The mean time spent performing the standardized examination procedure decreased from 34 min to less than 10 minutes (p = 0.0001).
With systematic hands-on training, a rheumatologist can achieve a high level of proficiency in the conduction of US examinations of the joints of the hand in patients with RA. With experience, examination time decreases, while the level of correctness is maintained. The results indicate that US may be applied as a valid measurement tool suitable for clinical practice and in both single- and multi-centre trials.
PMCID: PMC3414749  PMID: 22410241
Ultrasonography; Rheumatoid Arthritis; Wrist
23.  Abatacept with methotrexate versus other biologic agents in treatment of patients with active rheumatoid arthritis despite methotrexate: a network meta-analysis 
Arthritis Research & Therapy  2011;13(6):R204.
The goal of this study was to compare the efficacy in terms of Health Assessment Questionnaire change from baseline (HAQ CFB), 50% improvement in American College of Rheumatology criterion (ACR-50) and Disease Activity Score in 28 joints (DAS28) defined remission (< 2.6) between abatacept and other biologic disease modifying anti-rheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA) who have inadequate response to methotrexate (MTX-IR).
A systematic literature review identified controlled trials investigating the efficacy of abatacept (three studies), etanercept (two studies), infliximab (two), adalimumab (two), certolizumab pegol (two) ritixumab (three), and tocilizumab (two) in MTX-IR patients with RA. The clinical trials included in this analysis were similar with respect to trial design, baseline patient characteristics and background therapy (MTX). The key clinical endpoints of interest were HAQ CFB, ACR-50 and DAS28 < 2.6 measured at 24 and 52 weeks. The results were analysed using network meta-analysis methods that enabled calculation of an estimate for expected relative effect of comparative treatments. Analysis results were expressed as the difference in HAQ CFB score and odds ratio (OR) of achieving an ACR-50 and DAS28 response and associated 95% credible intervals (CrI).
The analysis of HAQ CFB at 24 weeks and 52 weeks showed that abatacept in combination with MTX is expected to be more efficacious than MTX monotherapy and is expected to show a comparable efficacy relative to other biologic DMARDs in combination with MTX. Further, abatacept showed comparable ACR-50 and DAS28 < 2.6 response rates with other biologic DMARDs at 24 and 52 weeks, except for ACR-50 compared to certolizumab pegol at 52 weeks and for DAS28 < 2.6 compared to tocilizumab at 24 weeks. Sensitivity analyses confirmed the robustness of the findings.
Abatacept in combination with MTX is expected to result in a comparable change from baseline in HAQ score and comparable ACR-50 and DAS28 < 2.6 response rates in MTX-IR patients compared to other approved biologic agents.
PMCID: PMC3334657  PMID: 22151924
abatacept; rheumatoid arthritis; biologic DMARDs; network meta-analysis; health assessment questionnaire
24.  Neck exercises, physical and cognitive behavioural-graded activity as a treatment for adult whiplash patients with chronic neck pain: Design of a randomised controlled trial 
Many patients suffer from chronic neck pain following a whiplash injury. A combination of cognitive, behavioural therapy with physiotherapy interventions has been indicated to be effective in the management of patients with chronic whiplash-associated disorders. The objective is to present the design of a randomised controlled trial (RCT) aimed at evaluating the effectiveness of a combined individual physical and cognitive behavioural-graded activity program on self-reported general physical function, in addition to neck function, pain, disability and quality of life in patients with chronic neck pain following whiplash injury compared with a matched control group measured at baseline and 4 and 12 months after baseline.
The design is a two-centre, RCT-study with a parallel group design. Included are whiplash patients with chronic neck pain for more than 6 months, recruited from physiotherapy clinics and an out-patient hospital department in Denmark. Patients will be randomised to either a pain management (control) group or a combined pain management and training (intervention)group. The control group will receive four educational sessions on pain management, whereas the intervention group will receive the same educational sessions on pain management plus 8 individual training sessions for 4 months, including guidance in specific neck exercises and an aerobic training programme. Patients and physiotherapists are aware of the allocation and the treatment, while outcome assessors and data analysts are blinded. The primary outcome measures will be Medical Outcomes Study Short Form 36 (SF36), Physical Component Summary (PCS). Secondary outcomes will be Global Perceived Effect (-5 to +5), Neck Disability Index (0-50), Patient Specific Functioning Scale (0-10), numeric rating scale for pain bothersomeness (0-10), SF-36 Mental Component Summary (MCS), TAMPA scale of Kinesiophobia (17-68), Impact of Event Scale (0-45), EuroQol (0-1), craniocervical flexion test (22 mmHg - 30 mmHg), joint position error test and cervical range of movement. The SF36 scales are scored using norm-based methods with PCS and MCS having a mean score of 50 with a standard deviation of 10.
The perspectives of this study are discussed, in addition to the strengths and weaknesses.
Trial registration
The study is registered in identifier NCT01431261.
PMCID: PMC3266656  PMID: 22136113
25.  Test-retest of computerized health status questionnaires frequently used in the monitoring of knee osteoarthritis: a randomized crossover trial 
To compare data based on touch screen to data based on traditional paper versions of questionnaires frequently used to examine patient reported outcomes in knee osteoarthritis patients and to examine the impact of patient characteristics on this comparison
Participants were recruited from an ongoing trial (http://ClinicalTrials.Gov Identifier: NCT00655941). 20 female participants, mean age 67 (SD 7), completed KOOS, VAS pain, function and patient global, SF-36, Physical Activity Scale, painDETECT, and the ADL Taxonomy. Patients were randomly assigned to one of two subgroups, completing either the paper or touch screen version first. Mean, mean differences (95% CI), median, median differences and Intraclass Correlation Coefficients (ICCs) were calculated for all questionnaires.
ICCs between data based on computerized and paper versions ranged from 0.86 to 0.99. Analysis revealed a statistically significant difference between versions of the ADL Taxonomy, but not for the remaining questionnaires. Age, computer experience or education-level had no significant impact on the results. The computerized questionnaires were reported to be easier to use.
The computerized questionnaires gave comparable results to answers given on paper. Patient characteristics did not influence results and implementation was feasible.
PMCID: PMC3176488  PMID: 21851618

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