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1.  Recommendations for standardization and phenotype definitions in genetic studies of osteoarthritis: the TREAT-OA consortium 
Objective
To address the need for standardization of osteoarthritis (OA) phenotypes by examining the effect of heterogeneity among symptomatic (SOA) and radiographic osteoarthritis (ROA) phenotypes.
Methods
Descriptions of OA phenotypes of the 28 studies involved in the TREAT-OA consortium were collected. To investigate whether different OA definitions result in different association results, we created hip OA definitions used within the consortium in the Rotterdam Study-I and tested the association of hip OA with gender, age and BMI using one-way ANOVA. For radiographic OA, we standardized the hip, knee and hand ROA definitions and calculated prevalence's of ROA before and after standardization in 9 cohort studies. This procedure could only be performed in cohort studies and standardization of SOA definitions was not feasible at this moment.
Results
In this consortium, all studies with symptomatic OA phenotypes (knee, hip and hand) used a different definition and/or assessment of OA status. For knee, hip and hand radiographic OA 5, 4 and 7 different definitions were used, respectively. Different hip OA definitions do lead to different association results. For example, we showed in the Rotterdam Study-I that hip OA defined as “at least definite JSN and one definite osteophyte” was not associated with gender (p=0.22), but defined as “at least one definite osteophyte” was significantly associated with gender (p=3×10−9). Therefore, a standardization process was undertaken for radiographic OA definitions. Before standardization a wide range of ROA prevalence's was observed in the 9 cohorts studied. After standardization the range in prevalence of knee and hip ROA was small. Standardization of SOA phenotypes was not possible due to the case-control design of the studies.
Conclusion
Phenotype definitions influence the prevalence of OA and association with clinical variables. ROA phenotypes within the TREAT-OA consortium were standardized to reduce heterogeneity and improve power in future genetics studies.
doi:10.1016/j.joca.2010.10.027
PMCID: PMC3236091  PMID: 21059398
2.  Disk degeneration of the upper lumbar disks is associated with hip pain 
European Spine Journal  2012;22(4):721-726.
Purpose
A possible cause of hip pain is the presence of radiating pain from the higher lumbar spine. Identification of factors associated with hip pain arising from the lumbar spine would aid the physician. The first step in identifying possible factors is to look at the association between hip pain and osteoarthritis of the lumbar spine.
Methods
In an open population based study of people 55 years and older (Rotterdam study), 2,819 lumbar radiographs were scored for the presence and severity of individual radiographic features of disk degeneration. Hip osteoarthritis was scored on anteroposterior pelvic radiographs, and questionnaires including self-reported hip pain were taken. Logistic regression adjusted for possible confounders was used to determine the association between self-reported hip pain and the individual radiographic features of lumbar disk degeneration.
Results
The presence of dis space narrowing grade ≥1 at level L1/L2 was significantly associated with hip pain in the last month (men OR = 2.0; 95 % CI 1.1–3.8 and women OR = 1.7; 95 % CI 1.1–2.5). The presence of disk space narrowing grade ≥1 at level L2/L3 was only significantly associated with hip pain in women. The strength of the associations increased for self-reported chronic hip pain, especially in men (L1/L2 OR = 2.5; 95 % CI 1.3–5.0). The presence of disk space narrowing at the lower levels (L3/L4/L5/S1) was not significantly associated with hip pain.
Conclusion
Our data provide evidence for an association between hip pain and disk space narrowing at disk level L1/L2 and L2/L3. In case of uncertainty of the cause of hip pain, evaluation of lumbar radiographs may help to identify those hip pain patients who might have pain arising from the lumbar spine.
doi:10.1007/s00586-012-2559-6
PMCID: PMC3631034  PMID: 23135791
Hip pain; Back pain; Lumbar disk degeneration
3.  Prevalence, characteristics, and management of childhood functional abdominal pain in general practice 
Abstract
Objective
To (i) describe the proportion of children presenting with abdominal pain diagnosed by the GP as functional abdominal pain (GPFAP); (ii) evaluate the association between patient and disease characteristics and GPFAP; (iii) describe diagnostic management by the GP in children presenting with abdominal pain, and (iv) evaluate whether children with GPFAP fulfill diagnostic criteria for functional abdominal pain (FAP) as described in current literature: chronic abdominal pain (CAP) and the Rome III criteria (PRC-III) for abdominal pain-related functional gastrointestinal disorders (FGID).
Design
Cross-sectional study.
Setting
General practices in the Netherlands.
Subjects
305 children aged 4–17 years consulting for abdominal pain.
Main outcome measures
GPFAP, CAP, FGIDs.
Results
89.2% of children were diagnosed with GPFAP. Headaches and bloating were positively associated with GPFAP whereas fever and > 3 red flag symptoms were inversely associated. Additional diagnostic tests were performed in 26.8% of children. Less than 50% of all children with GPFAP fulfilled criteria for CAP and FGIDs; in 47.9% of patients the duration of symptoms at presentation was less than three months.
Conclusions
In almost 90% of children included in this study the GP suspected no organic cause for the abdominal pain. GPs diagnose FAP in children without alarm symptoms and order diagnostic testing in one out of four children presenting with abdominal pain. No difference was found in GPs’ management between children with a diagnosis of GPFAP and other diagnoses. Only about half of the children with a GP diagnosis of FAP fulfilled time-criteria of FAP as defined in the literature.
doi:10.3109/02813432.2013.844405
PMCID: PMC3860295  PMID: 24106821
Abdominal pain; adolescent; child; diagnosis; family practice; general practice; the Netherlands
4.  Delayed Gadolinium-Enhanced MRI of Cartilage (dGEMRIC) Shows No Change in Cartilage Structural Composition after Viscosupplementation in Patients with Early-Stage Knee Osteoarthritis 
PLoS ONE  2013;8(11):e79785.
Introduction
Viscosupplementation with hyaluronic acid (HA) of osteoarthritic (OA) knee joints has a well-established positive effect on clinical symptoms. This effect, however, is only temporary and the working mechanism of HA injections is not clear. It was suggested that HA might have disease modifying properties because of its beneficial effect on cartilage sulphated glycosaminoglycan (sGAG) content. Delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) is a highly reproducible, non-invasive surrogate measure for sGAG content and hence composition of cartilage. The aim of this study was to assess whether improvement in cartilage structural composition is detected using dGEMRIC 14 weeks after 3 weekly injections with HA in patients with early-stage knee OA.
Methods
In 20 early-stage knee OA patients (KLG I-II), 3D dGEMRIC at 3T was acquired before and 14 weeks after 3 weekly injections with HA. To evaluate patient symptoms, the knee injury and osteoarthritis outcome score (KOOS) and a numeric rating scale (NRS) for pain were recorded. To evaluate cartilage composition, six cartilage regions in the knee were analyzed on dGEMRIC. Outcomes of dGEMRIC, KOOS and NRS before and after HA were compared using paired t-testing. Since we performed multiple t-tests, we applied a Bonferroni-Holm correction to determine statistical significance for these analyses.
Results
All KOOS subscales (‘pain’, ‘symptoms’, ‘daily activities’, ‘sports’ and ’quality of life’) and the NRS pain improved significantly 14 weeks after Viscosupplementation with HA. Outcomes of dGEMRIC did not change significantly after HA compared to baseline in any of the cartilage regions analyzed in the knee.
Conclusions
Our results confirm previous findings reported in the literature, showing persisting improvement in symptomatic outcome measures in early-stage knee OA patients 14 weeks after Viscosupplementation. Outcomes of dGEMRIC, however, did not change after Viscosupplementation, indicating no change in cartilage structural composition as an explanation for the improvement of clinical symptoms.
doi:10.1371/journal.pone.0079785
PMCID: PMC3819245  PMID: 24223194
5.  Fibrates as therapy for osteoarthritis and rheumatoid arthritis? A systematic review 
Fibrates are used as lipid-lowering drugs to prevent cardiovascular pathology. Fibrates are ligands of peroxisome proliferator-activated receptor α (PPARα). Besides altering lipid metabolism, PPARα ligands exert anti-inflammatory effects on various cell types. In this study, we hypothesized that PPARα agonists exert beneficial effects on osteoarthritis (OA) and rheumatoid arthritis (RA) by their local anti-inflammatory effects, but also by their systemic influences.
A systematic literature search of Medline and EMBASE databases was performed up to August 2011. The main search items were osteoarthritis, rheumatoid arthritis, peroxisome proliferator-activated receptor alpha and fibrates. Inclusion criteria were in vivo or in vitro studies regarding humans or animals in which the effects of PPARα ligands were studied.
Six in vivo human studies, four in vivo animal studies and seven in vitro studies were included. The in vivo human studies showed all beneficial clinical effects of PPARα ligands, but studies were small and only four were randomized. Ligands for PPARα significantly reduced pain, swelling of the joints and decreased systemic inflammatory markers. In vitro and in vivo animal studies indicate that PPARα agonists inhibit bone resorption, and reduce inflammatory and destructive responses in cartilage and synovium.
PPARα agonists such as fibrates should be considered as potential therapeutic strategy for RA. There is no clinical evidence for their use in OA, although in vitro studies indicate that PPARα agonists demonstrate different joint-protective effects locally, and systemic effects on inflammation, serum lipid levels and vascular pathology. Animal studies should be performed and after confirmation of the protective effects of PPARα, large randomized controlled trials could investigate fibrates in OA and RA.
doi:10.1177/1759720X12468659
PMCID: PMC3582306  PMID: 23515070
fibrates; osteoarthritis; peroxisome proliferator activated receptor α; rheumatoid arthritis
6.  Determinants of the intention for using a lumbar support among home care workers with recurrent low back pain 
European Spine Journal  2010;19(9):1502-1507.
In most effectiveness studies on lumbar supports for patients with low back pain, insufficient data are reported about adherence. In a secondary preventive RCT, we found beneficial effects and a good adherence among home care workers with low back pain. To target the use of lumbar supports on those patients who can benefit optimally from usage, we need to know why people are adherent. We used the attitude, social support and self-efficacy model to identify determinants for prolonged adherence to wearing a lumbar support. The strongest predictor for intending sustained use of a lumbar support was a positive attitude towards lumbar supports, explaining 41% of the variance (B = 1.31; p < 0.001). Social support and self-efficacy played a minor role. The intention for prolonged use of a lumbar support for workers with recurrent back pain was mainly explained by a positive attitude. The discomfort of a lumbar support was outweighed by perceived benefit.
Electronic supplementary material
The online version of this article (doi:10.1007/s00586-010-1399-5) contains supplementary material, which is available to authorized users.
doi:10.1007/s00586-010-1399-5
PMCID: PMC2989292  PMID: 20490876
Low back pain; Lumbar supports; Behaviour; Adherence; ASE-model
7.  Predictive factors for new onset or progression of knee osteoarthritis one year after trauma: MRI follow-up in general practice 
European Radiology  2011;21(7):1509-1516.
Objective
To prospectively evaluate prognostic factors for new onset or progression of degenerative change on follow-up MRI one year after knee trauma and the association with clinical outcome.
Methods
Within a prospective observational cohort study in general practice, we studied a subgroup of 117 patients with acute knee trauma (mean age 41 years, 43% women). Degenerative change was scored on MRI at baseline and after one year follow-up. Multivariate logistic regression analysis was performed to evaluate prognostic factors for new onset or progressive degenerative change on follow-up MRI. Association between new or progressive degeneration and clinical outcome after one year was assessed.
Results
On follow-up MRI 15% of patients with pre-existing knee osteoarthritis showed progression and 26% of patients demonstrated new degenerative change. The only statistically significant prognostic variable in the multivariate analysis was bone marrow oedema on initial MRI (OR 5.29 (95% CI 1.64–17.1), p = 0.005). A significant association between new or progressive degenerative change and clinical outcome was found (p = 0.003).
Conclusion
Bone marrow oedema on MRI for acute knee injury is strongly predictive of new onset or progression of degenerative change of the femorotibial joint on follow-up MRI one year after trauma, which is reflected in clinical outcome.
doi:10.1007/s00330-011-2089-3
PMCID: PMC3101345  PMID: 21380741
Knee injury; Osteoarthritis; MRI; Follow-up; Clinical outcome
8.  Effectiveness of additional supervised exercises compared with conventional treatment alone in patients with acute lateral ankle sprains: systematic review 
Objective To summarise the effectiveness of adding supervised exercises to conventional treatment compared with conventional treatment alone in patients with acute lateral ankle sprains.
Design Systematic review.
Data sources Medline, Embase, Cochrane Central Register of Controlled Trials, Cinahl, and reference screening.
Study selection Included studies were randomised controlled trials, quasi-randomised controlled trials, or clinical trials. Patients were adolescents or adults with an acute lateral ankle sprain. The treatment options were conventional treatment alone or conventional treatment combined with supervised exercises. Two reviewers independently assessed the risk of bias, and one reviewer extracted data. Because of clinical heterogeneity we analysed the data using a best evidence synthesis. Follow-up was classified as short term (up to two weeks), intermediate (two weeks to three months), and long term (more than three months).
Results 11 studies were included. There was limited to moderate evidence to suggest that the addition of supervised exercises to conventional treatment leads to faster and better recovery and a faster return to sport at short term follow-up than conventional treatment alone. In specific populations (athletes, soldiers, and patients with severe injuries) this evidence was restricted to a faster return to work and sport only. There was no strong evidence of effectiveness for any of the outcome measures. Most of the included studies had a high risk of bias, with few having adequate statistical power to detect clinically relevant differences.
Conclusion Additional supervised exercises compared with conventional treatment alone have some benefit for recovery and return to sport in patients with ankle sprain, though the evidence is limited or moderate and many studies are subject to bias.
doi:10.1136/bmj.c5688
PMCID: PMC2965125  PMID: 20978065
9.  Medial Knee Osteoarthritis Treated by Insoles or Braces: A Randomized Trial 
Background
There is controversial evidence regarding whether foot orthoses or knee braces improve pain and function or correct malalignment in selected patients with osteoarthritis (OA) of the medial knee compartment. However, insoles are safe and less costly than knee bracing if they relieve pain or improve function.
Questions/purposes
We therefore asked whether laterally wedged insoles or valgus braces would reduce pain, enhance functional scores, and correct varus malalignment comparable to knee braces.
Patients and Methods
We prospectively enrolled 91 patients with symptomatic medial compartmental knee OA and randomized to treatment with either a 10-mm laterally wedged insole (index group, n = 45) or a valgus brace (control group, n = 46). All patients were assessed at 6 months. The primary outcome measure was pain severity as measured on a visual analog scale. Secondary outcome measures were knee function score using WOMAC and correction of varus alignment on AP whole-leg radiographs taken with the patient in the standing position. Additionally, we compared the percentage of responders according to the OMERACT-OARSI criteria for both groups.
Results
We observed no differences in pain or WOMAC scores between the two groups. Neither device achieved correction of knee varus malalignment in the frontal plane. According to the OMERACT-OARSI criteria, 17% of our patients responded to the allocated intervention. Patients in the insole group complied better with their intervention. Although subgroup analysis results should be translated into practice cautiously, we observed a slightly higher percentage of responders for the insole compared with bracing for patients with mild medial OA.
Conclusions
Our data suggest a laterally wedged insole may be an alternative to valgus bracing for noninvasively treating symptoms of medial knee OA.
Level of Evidence
Level I, therapeutic study. See the Guidelines for Authors for a complete description of level of evidence.
doi:10.1007/s11999-010-1274-z
PMCID: PMC2881986  PMID: 20177839
10.  Medial Knee Osteoarthritis Treated by Insoles or Braces: A Randomized Trial 
Background
There is controversial evidence regarding whether foot orthoses or knee braces improve pain and function or correct malalignment in selected patients with osteoarthritis (OA) of the medial knee compartment. However, insoles are safe and less costly than knee bracing if they relieve pain or improve function.
Questions/purposes
We therefore asked whether laterally wedged insoles or valgus braces would reduce pain, enhance functional scores, and correct varus malalignment comparable to knee braces.
Patients and Methods
We prospectively enrolled 91 patients with symptomatic medial compartmental knee OA and randomized to treatment with either a 10-mm laterally wedged insole (index group, n = 45) or a valgus brace (control group, n = 46). All patients were assessed at 6 months. The primary outcome measure was pain severity as measured on a visual analog scale. Secondary outcome measures were knee function score using WOMAC and correction of varus alignment on AP whole-leg radiographs taken with the patient in the standing position. Additionally, we compared the percentage of responders according to the OMERACT-OARSI criteria for both groups.
Results
We observed no differences in pain or WOMAC scores between the two groups. Neither device achieved correction of knee varus malalignment in the frontal plane. According to the OMERACT-OARSI criteria, 17% of our patients responded to the allocated intervention. Patients in the insole group complied better with their intervention. Although subgroup analysis results should be translated into practice cautiously, we observed a slightly higher percentage of responders for the insole compared with bracing for patients with mild medial OA.
Conclusions
Our data suggest a laterally wedged insole may be an alternative to valgus bracing for noninvasively treating symptoms of medial knee OA.
Level of Evidence
Level I, therapeutic study. See the Guidelines for Authors for a complete description of level of evidence.
doi:10.1007/s11999-010-1274-z
PMCID: PMC2881986  PMID: 20177839
11.  MRI follow-up of conservatively treated meniscal knee lesions in general practice 
European Radiology  2009;20(5):1242-1250.
Objective
To evaluate meniscal status change on follow-up MRI after 1 year, prognostic factors and association with clinical outcome in patients with conservatively treated knee injury.
Methods
We analysed 403 meniscal horns in 101 conservatively treated patients (59 male; mean age 40 years) in general practice who underwent initial knee MRI within 5 weeks of trauma. We performed ordinal logistic regression analysis to analyse prognostic factors for meniscal change on follow-up MRI after 1 year, and we assessed the association with clinical outcome.
Results
On follow-up MRI 49 meniscal horns had deteriorated and 18 had improved. Age (odds ratio [OR] 1.3/decade), body weight (OR 1.2/10 kg), total anterior cruciate ligament (ACL) rupture on initial MRI (OR 2.4), location in the posterior horn of the medial meniscus (OR 3.0) and an initial meniscal lesion (OR 0.3) were statistically significant predictors of meniscal MRI appearance change after 1 year, which was not associated with clinical outcome.
Conclusion
In conservatively treated patients, meniscal deterioration on follow-up MRI 1 year after trauma is predicted by higher age and body weight, initial total ACL rupture, and location in the medial posterior horn. Change in MRI appearance is not associated with clinical outcome.
doi:10.1007/s00330-009-1648-3
PMCID: PMC2850528  PMID: 19921201
Knee; Trauma; Meniscus; Magnetic resonance imaging; Conservative treatment; Follow-up
12.  Management in non-traumatic arm, neck and shoulder complaints: differences between diagnostic groups 
European Spine Journal  2008;17(9):1218-1229.
Arm, neck and/or shoulder complaints are common in western societies. In the Netherlands, general practice guidelines are issued on shoulder pain and epicondylitis only. Little is known about actual management of the total range of diagnoses. The objectives of the study are: to determine management in patients consulting the GP with a new episode of non-traumatic arm neck and shoulder complaints up to 6 months after the first consultation. To evaluate differences in management between patients with specific diagnoses versus non-specific diagnoses and between specific diagnostic groups. In a prospective cohort study in general practice. We recruited 682 eligible patients. Data on diagnosis, management, patient- and complaint-characteristics were collected. Co-occurrence of treatment options was presented in scaled rectangles. After 6 months, additional diagnostic tests had been performed in 18% of the patients, mainly radiographic examination (14%). Further, 49% had been referred for physiotherapy and 12% to the medical specialist. Patients with specific diagnoses were more frequently referred for specialist treatment, and patients with non-specific diagnoses for physiotherapy. Corticosteroid injections (17%) were mainly applied specific diagnoses (e.g. impingement syndrome, frozen shoulder, carpal tunnel and M. Quervain). Frequencies of prescribed medication (51%) did not differ between specific and non-specific diagnoses. In 19% of the patients no referral, prescribed analgesics or injection was applied. Braces (4%) were mainly prescribed in epicondylitis. Overall, management most frequently consisted of prescribed analgesics and referral for physiotherapy. Specific and non-specific diagnostic subgroups differed in the frequency corticosteroid injections were applied, and referrals to physiotherapy and to a medical specialist.
doi:10.1007/s00586-008-0710-1
PMCID: PMC2527426  PMID: 18607647
Arm; Neck; Shoulder; Treatment; General practice
13.  Knee disorders in primary care: design and patient selection of the HONEUR knee cohort 
Background
Knee complaints are a frequent reason for consultation in general practice. These patients constitute a specific population compared to secondary care patients. However, information to base treatment decisions on is generally derived from specialistic settings. Our cohort study is aimed at collecting knowledge about prognosis and prognostic factors of knee complaints presented in a primary care setting. This paper describes the methods used for data collection, and discusses potential selectiveness of patient recruitment.
Methods
This is a descriptive prospective cohort study with one-year follow-up. 40 Dutch GPs recruited consecutive patients with incident knee complaints aged 12 years and above from October 2001 to October 2003. Patients were assessed with questionnaires and standardised physical examinations. Additional measurements of subgroups included MRI for recent knee traumas and device assessed function measurements for non-traumatic patients.
After the inclusion period we retrospectively searched the computerized medical files of participating GPs to obtain a sample to determine possible selective recruitment. We assessed differences in proportions of gender, traumatic onset of injury and age groups between participants and non-participants using Odds Ratios (OR) and 95% confidence intervals.
Results
We recruited 1068 patients. In a sample of 310 patients visiting the GP, we detected some selective recruitment, indicating an underrepresentation of patients aged 12 to 35 years (OR 1.70; 1.15–2.77), especially among men (OR 2.16; 1.12–4.18). The underrepresentation of patients with traumatic onset of injury was not statistically significant.
Conclusion
This cohort is unique in its size, setting, and its range of both age and type of knee complaints. We believe the detected selective recruitment is unlikely to introduce significant bias, as the cohort will be divided into subgroups according to age group or traumatic onset of injury for future analyses. However, the underrepresentation of men in the age group of 12 to 35 years of age warrants caution. Based on the available data, we believe our cohort is an acceptable representation of patients with new knee complaints consulting the GP, and we expect no problems with extrapolation of the results to the general Dutch population.
doi:10.1186/1471-2474-6-45
PMCID: PMC1208897  PMID: 16117830

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