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Concept: Osteoarthritis

444

Objective To characterise the determinants, time course, and risks of acute myocardial infarction associated with use of oral non-steroidal anti-inflammatory drugs (NSAIDs).Design Systematic review followed by a one stage bayesian individual patient data meta-analysis.Data sources Studies from Canadian and European healthcare databases.Review methods Eligible studies were sourced from computerised drug prescription or medical databases, conducted in the general or an elderly population, documented acute myocardial infarction as specific outcome, studied selective cyclo-oxygenase-2 inhibitors (including rofecoxib) and traditional NSAIDs, compared risk of acute myocardial infarction in NSAID users with non-users, allowed for time dependent analyses, and minimised effects of confounding and misclassification bias. Exposure and outcomes Drug exposure was modelled as an indicator variable incorporating the specific NSAID, its recency, duration of use, and dose. The outcome measures were the summary adjusted odds ratios of first acute myocardial infarction after study entry for each category of NSAID use at index date (date of acute myocardial infarction for cases, matched date for controls) versus non-use in the preceding year and the posterior probability of acute myocardial infarction.Results A cohort of 446 763 individuals including 61 460 with acute myocardial infarction was acquired. Taking any dose of NSAIDs for one week, one month, or more than a month was associated with an increased risk of myocardial infarction. With use for one to seven days the probability of increased myocardial infarction risk (posterior probability of odds ratio >1.0) was 92% for celecoxib, 97% for ibuprofen, and 99% for diclofenac, naproxen, and rofecoxib. The corresponding odds ratios (95% credible intervals) were 1.24 (0.91 to 1.82) for celecoxib, 1.48 (1.00 to 2.26) for ibuprofen, 1.50 (1.06 to 2.04) for diclofenac, 1.53 (1.07 to 2.33) for naproxen, and 1.58 (1.07 to 2.17) for rofecoxib. Greater risk of myocardial infarction was documented for higher dose of NSAIDs. With use for longer than one month, risks did not appear to exceed those associated with shorter durations.Conclusions All NSAIDs, including naproxen, were found to be associated with an increased risk of acute myocardial infarction. Risk of myocardial infarction with celecoxib was comparable to that of traditional NSAIDS and was lower than for rofecoxib. Risk was greatest during the first month of NSAID use and with higher doses.

Concepts: Cyclooxygenase, Osteoarthritis, Non-steroidal anti-inflammatory drug, Paracetamol, Ibuprofen, Aspirin, Celecoxib, Naproxen

404

Biological resurfacing of entire articular surfaces represents an important but challenging strategy for treatment of cartilage degeneration that occurs in osteoarthritis. Not only does this approach require anatomically sized and functional engineered cartilage, but the inflammatory environment within an arthritic joint may also inhibit chondrogenesis and induce degradation of native and engineered cartilage. The goal of this study was to use adult stem cells to engineer anatomically shaped, functional cartilage constructs capable of tunable and inducible expression of antiinflammatory molecules, specifically IL-1 receptor antagonist (IL-1Ra). Large (22-mm-diameter) hemispherical scaffolds were fabricated from 3D woven poly(ε-caprolactone) (PCL) fibers into two different configurations and seeded with human adipose-derived stem cells (ASCs). Doxycycline (dox)-inducible lentiviral vectors containing eGFP or IL-1Ra transgenes were immobilized to the PCL to transduce ASCs upon seeding, and constructs were cultured in chondrogenic conditions for 28 d. Constructs showed biomimetic cartilage properties and uniform tissue growth while maintaining their anatomic shape throughout culture. IL-1Ra-expressing constructs produced nearly 1 µg/mL of IL-1Ra upon controlled induction with dox. Treatment with IL-1 significantly increased matrix metalloprotease activity in the conditioned media of eGFP-expressing constructs but not in IL-1Ra-expressing constructs. Our findings show that advanced textile manufacturing combined with scaffold-mediated gene delivery can be used to tissue engineer large anatomically shaped cartilage constructs that possess controlled delivery of anticytokine therapy. Importantly, these cartilage constructs have the potential to provide mechanical functionality immediately upon implantation, as they will need to replace a majority, if not the entire joint surface to restore function.

Concepts: Biology, Extracellular matrix, Receptor, Cellular differentiation, Histology, Osteoarthritis, Engineering, Adult stem cell

358

Knee osteoarthritis (OA) is believed to be highly prevalent today because of recent increases in life expectancy and body mass index (BMI), but this assumption has not been tested using long-term historical or evolutionary data. We analyzed long-term trends in knee OA prevalence in the United States using cadaver-derived skeletons of people aged ≥50 y whose BMI at death was documented and who lived during the early industrial era (1800s to early 1900s; n = 1,581) and the modern postindustrial era (late 1900s to early 2000s; n = 819). Knee OA among individuals estimated to be ≥50 y old was also assessed in archeologically derived skeletons of prehistoric hunter-gatherers and early farmers (6000-300 B.P.; n = 176). OA was diagnosed based on the presence of eburnation (polish from bone-on-bone contact). Overall, knee OA prevalence was found to be 16% among the postindustrial sample but only 6% and 8% among the early industrial and prehistoric samples, respectively. After controlling for age, BMI, and other variables, knee OA prevalence was 2.1-fold higher (95% confidence interval, 1.5-3.1) in the postindustrial sample than in the early industrial sample. Our results indicate that increases in longevity and BMI are insufficient to explain the approximate doubling of knee OA prevalence that has occurred in the United States since the mid-20th century. Knee OA is thus more preventable than is commonly assumed, but prevention will require research on additional independent risk factors that either arose or have become amplified in the postindustrial era.

Concepts: Medical statistics, United States, Industrial Revolution, Osteoarthritis, Body mass index, United Kingdom, Gerontology, Life expectancy

179

BACKGROUND: Musculoskeletal conditions (MSCs) are widely prevalent in present-day society, with resultant high healthcare costs and substantial negative effects on patient health and quality of life. The main aim of this overview was to synthesize evidence from systematic reviews on the effects of exercise therapy (ET) on pain and physical function for patients with MSCs. In addition, the evidence for the effect of ET on disease pathogenesis, and whether particular components of exercise programs are associated with the size of the treatment effects, was also explored. METHODS: We included four common conditions: fibromyalgia (FM), low back pain (LBP), neck pain (NP), and shoulder pain (SP), and four specific musculoskeletal diseases: osteoarthritis (OA), rheumatoid arthritis (RA), ankylosing spondylitis (AS), and osteoporosis (OP). We first included Cochrane reviews with the most recent update being January 2007 or later, and then searched for non-Cochrane reviews published after this date. Pain and physical functioning were selected as primary outcomes. RESULTS: We identified 9 reviews, comprising a total of 224 trials and 24,059 patients. In addition, one review addressing the effect of exercise on pathogenesis was included. Overall, we found solid evidence supporting ET in the management of MSCs, but there were substantial differences in the level of research evidence between the included diagnostic groups. The standardized mean differences for knee OA, LBP, FM, and SP varied between 0.30 and 0.65 and were significantly in favor of exercise for both pain and function. For NP, hip OA, RA, and AS, the effect estimates were generally smaller and not always significant. There was little or no evidence that ET can influence disease pathogenesis. The only exception was for osteoporosis, where there was evidence that ET increases bone mineral density in postmenopausal women, but no significant effects were found for clinically relevant outcomes (fractures). For LBP and knee OA, there was evidence suggesting that the treatment effect increases with the number of exercise sessions. CONCLUSIONS: There is empirical evidence that ET has beneficial clinical effects for most MSCs. Except for osteoporosis, there seems to be a gap in the understanding of the ways in which ET influences disease mechanisms.

Concepts: Osteoporosis, Back pain, Rheumatoid arthritis, Osteoarthritis, Acupuncture, Arthritis, Ankylosing spondylitis, Musculoskeletal disorders

173

To ascertain whether the use of oral glucosamine influences symptoms or functional outcomes in patients with chronic low back pain (LBP) thought to be related to spinal osteoarthritis (OA).

Concepts: Low back pain, Back pain, Symptoms, Osteoarthritis, Acupuncture

171

BACKGROUND: Research involving more representative samples is needed to extend our understanding of the broader impact of obesity in hip or knee joint disease (arthritis and OA) beyond clinical settings. Although population-based research has been conducted in the United States, how these findings translate to other countries is unclear. Using a national approach, this study explored associations between obesity and the burden of hip and knee joint disease in Australia (in terms of prevalence, pain, stiffness, function, Health-Related Quality of Life (HRQoL) and disease severity). METHODS: A random sample of 5000 Australians (>=39 years) from the federal electoral roll was invited to complete a mailed questionnaire to identify doctor-diagnosed hip arthritis, hip OA, knee arthritis and knee OA and evaluate the burden of these conditions. Validated questionnaires included the WOMAC Index, Assessment of Quality of Life instrument and Multi-Attribute Prioritisation Tool. Body Mass Index (BMI) was classified into underweight/normal weight (<=24.99 kg/m2), overweight (25--29.99) or obese (>=30). Multiple logistic regression was used to estimate odds of arthritis and OA, with demographic and socioeconomic variables included in the models. Associations between BMI and other variables were investigated using analysis of covariance, with adjustment for age and sex. RESULTS: Data were available from 1,157 participants (23%). Overweight participants had increased odds of knee arthritis (adjusted OR (AOR) 1.87, 95%CI 1.14-3.07) and knee OA (AOR 2.11, 95%CI 1.07-4.15). Obesity was associated with higher prevalence of hip arthritis (AOR 2.18, 95%CI 1.17-4.06), knee arthritis (AOR 5.47, 95%CI 3.35-8.95) and knee OA (AOR 7.35, 95%CI 3.85-14.02). Of those with arthritis or OA, obese individuals reported more pain (for hip arthritis, hip OA and knee OA), greater stiffness (for hip arthritis, knee arthritis and knee OA), worse function (all diagnoses), lower HRQoL (for hip arthritis and hip OA) and greater disease severity (all diagnoses). CONCLUSIONS: This national study has demonstrated that the odds of arthritis and OA was up to 7 times higher for obese individuals, compared with those classified as underweight/normal weight. Concurrent obesity and joint disease had a marked impact on several key aspects of wellbeing, highlighting the need for public health interventions.

Concepts: Cancer, Obesity, Quality of life, Osteoarthritis, Body mass index, Gout, Waist-hip ratio, Body shape

171

Spinal ligaments, such as the ligamentum flavum (LF), are prone to degeneration and iatrogenic injury that can lead to back pain and nerve dysfunction. Repair and regeneration strategies for these tissues are lacking, perhaps due to limited understanding of spinal ligament formation, the elaboration of its elastic fibers, maturation and homeostasis. Using immunohistochemistry and histology, we investigated murine LF elastogenesis and tissue formation from embryonic to mature postnatal stages. We characterized the spatiotemporal distribution of the key elastogenic proteins tropoelastin, fibrillin-1, fibulin-4 and lysyl oxidase. We found that elastogenesis begins in utero with the microfibril constituent fibrillin-1 staining intensely just before birth. Elastic fibers were first detected histologically at postnatal day (P) 7, the earliest stage at which tropoelastin and fibulin-4 stained intensely. From P7 to P28, elastic fibers grew in diameter and became straighter along the axis. The growth of elastic fibers coincided with intense staining of tropoelastin and fibulin-4 staining, possibly supporting a chaperone role for fibulin-4. These expression patterns correlated with reported skeletal and behavioral changes during murine development. This immunohistochemical characterization of elastogenesis of the LF will be useful for future studies investigating mechanisms for elastogenesis and developing new strategies for treatment or regeneration of spinal ligaments and other highly elastic tissues.

Concepts: Liver, Anatomical pathology, Histology, Osteoarthritis, Immunohistochemistry, Staining, Ligament, Microtome

169

PurposeIn this retrospective study we investigated the clinical and radiological outcome after operative treatment of acute Rockwood III-V injuries of the AC-joint using two acromioclavicular (AC) cerclages and one coracoclavicular (CC) cerclage with resorbable sutures. METHODS: Between 2007 and 2009 a total of 39 patients fit the inclusion criteria after operative treatment of acute AC joint dislocation. All patients underwent open reduction and anatomic reconstruction of the AC and CC-ligaments using PDS® sutures (Polydioxane, Ethicon, Norderstedt, Germany). Thirty-three patients could be investigated at a mean follow up of 32+/-9 months (range 24–56 months). RESULTS: The mean Constant score was 94.3+/-7.1 (range 73–100) with an age and gender correlated score of 104.2%+/-6.9 (88-123%). The DASH score (mean 3.46+/-6.6 points), the ASES score (94.6+/-9.7points) and the Visual Analogue Scale (mean 0.5+/-0,6) revealed a good to excellent clinical outcome. The difference in the coracoclavicular distance compared to the contralateral side was <5 mm for 28 patients, between 5-10 mm for 4 patients, and more than 10 mm for another patient. In the axial view, the anterior border of the clavicle was within 1 cm (ventral-dorsal direction) of the anterior rim of the acromion in 28 patients (85%). Re-dislocations occured in three patients (9%). CONCLUSION: Open AC joint reconstruction using AC and CC PDS cerclages provides good to excellent clinical results in the majority of cases. However, radiographically, the CC distance increased significantly at final follow up, but neither the amount of re-dislocation nor calcifications of the CC ligaments or osteoarthritis of the AC joint had significant influence on the outcome.Level of evidenceCase series, Level IV.

Concepts: Osteoarthritis, Joint, Joints, Ligament, Joint dislocation, Clavicle, Acromioclavicular joint, Acromion

168

Hand pain is a relatively common complaint, and careful anamnesis and clinical examination may reveal its aetiology. Multiple joint involvement suggests either osteoarthritis or inflammatory arthritis. In the returning traveller, a more exotic explanation might be the case. A 31 year old woman was referred to our outpatient clinic for evaluation due to peripheral joint arthralgia. The symptoms started six months earlier, on the same day she returned from a three-week holiday in India. There were no signs of inflammatory arthritis or osteoarthritis. Blood tests were normal. Chikungunya virus serology was positive. The patient received symptomatic treatment with nonsteroid anti-inflammatory drugs and improved over a period of months. We describe the first case of Chikungunya fever diagnosed in our hospital.

Concepts: Inflammation, Hospital, Rheumatoid arthritis, Greek loanwords, Osteoarthritis, Non-steroidal anti-inflammatory drug, Arthralgia, Chikungunya

167

Objective. To study the role of different imaging modalities, ultrasonography, conventional radiography (CR) and CT, in visualization of chondrocalcinosis of the knees in patients with CPDD.Methods. Twenty-five patients (14 males and 11 females) with CPDD were enrolled in the study. Diagnosis was made according to D.J. McCarty classification criteria. All patients had arthritis of the knee and underwent aspiration of SF from the knee and microscopic investigation of SF samples. Diagnosis of CPDD was crystal proven. Three imaging methods were performed in patients: CR, CT and US of the knees.Results. CR of the knee confirmed cartilage calcification (CC) in 13 patients, CT in 18 patients and US in 25 patients. No difference in age or disease duration between patients with CC detected by different imaging methods was found.Conclusion. US appeared to be a helpful tool, possibly better than CR or CT, in revealing CC in patients with CPDD. Informativity of CT and CR in the detection of CC is almost equal.

Concepts: Medical imaging, Cartilage, Osteoarthritis, Knee, Difference