M. R. Reed

Identification of new susceptibility loci for osteoarthritis (arcOGEN): A genome-wide association study

Summary Background Osteoarthritis is the most common form of arthritis worldwide and is a major cause of pain and disability in elderly people. The health economic burden of osteoarthritis is increasing commensurate with obesity prevalence and longevity. Osteoarthritis has a strong genetic component but the success of previous genetic studies has been restricted due to insufficient sample sizes and phenotype heterogeneity. Methods We undertook a large genome-wide association study (GWAS) in 7410 unrelated and retrospectively and prospectively selected patients with severe osteoarthritis in the arcOGEN study, 80% of whom had undergone total joint replacement, and 11 009 unrelated controls from the UK. We replicated the most promising signals in an independent set of up to 7473 cases and 42 938 controls, from studies in Iceland, Estonia, the Netherlands, and the UK. All patients and controls were of European descent. Findings We identified five genome-wide significant loci (binomial test p≤5·0×10−8) for association with osteoarthritis and three loci just below this threshold. The strongest association was on chromosome 3 with rs6976 (odds ratio 1·12 [95% CI 1·08–1·16]; p=7·24×10−11), which is in perfect linkage disequilibrium with rs11177. This SNP encodes a missense polymorphism within the nucleostemin-encoding gene GNL3. Levels of nucleostemin were raised in chondrocytes from patients with osteoarthritis in functional studies. Other significant loci were on chromosome 9 close to ASTN2, chromosome 6 between FILIP1 and SENP6, chromosome 12 close to KLHDC5 and PTHLH, and in another region of chromosome 12 close to CHST11. One of the signals close to genome-wide significance was within the FTO gene, which is involved in regulation of bodyweight—a strong risk factor for osteoarthritis. All risk variants were common in frequency and exerted small effects. Interpretation Our findings provide insight into the genetics of arthritis and identify new pathways that might be amenable to future therapeutic intervention. Funding arcOGEN was funded by a special purpose grant from Arthritis Research UK.

Blood metal ion concentrations after hip resurfacing arthroplasty: A COMPARATIVE STUDY OF ARTICULAR SURFACE REPLACEMENT AND BIRMINGHAM HIP RESURFACING ARTHROPLASTIES

There have been no large comparative studies of the blood levels of metal ions after implantation of commercially available hip resurfacing devices which have taken into account the effects of femoral size and inclination and anteversion of the acetabular component. We present the results in 90 patients with unilateral articular surface replacement (ASR) hip resurfacings (mean time to blood sampling 26 months) and 70 patients with unilateral Birmingham Hip Resurfacing (BHR) implants (mean time 47 months). The whole blood and serum chromium (Cr) and cobalt (Co) concentrations were inversely related to the size of the femoral component in both groups (p < 0.05). Cr and Co were more strongly influenced by the position of the acetabular component in the case of the ASR, with an increase in metal ions observed at inclinations > 45 degrees and anteversion angles of < 10 degrees and > 20 degrees. These levels were only increased in the BHR group when the acetabular component was implanted with an inclination > 55 degrees. A significant relationship was identified between the anteversion of the BHR acetabular component and the levels of Cr and Co (p < 0.05 for Co), with an increase observed at anteversion angles < 10 degrees and > 20 degrees. The median whole blood and serum Cr concentrations of the male ASR patients were significantly lower than those of the BHR men (p < 0.001). This indicates that reduced diametral clearance may equate to a reduction in metal ion concentrations in larger joints with satisfactory orientation of the acetabular component.

Enhanced recovery program for hip and knee replacement reduces death rate

Background and purpose Multimodal techniques can aid early rehabilitation and discharge of patients following primary joint replacement. We hypothesized that this not only reduces the economic burden of joint replacement by reducing length of stay, but also helps in reduction of early complications. Patients and methods We evaluated 4,500 consecutive unselected total hip replacements and total knee replacements regarding length of hospital stay, mortality, and perioperative complications. The first 3,000 underwent a traditional protocol while the other 1,500 underwent an enhanced recovery protocol involving behavioral, pharmacological, and procedural modifications. Results There was a reduction in 30-day death rate (0.5% to 0.1%, p = 0.02) and 90-day death rate (0.8% to 0.2%, p = 0.01). The median length of stay decreased from 6 days to 3 days (p < 0.001), resulting in a saving of 5,418 bed days. Requirement for blood transfusion was reduced (23% to 9.8%, p < 0.001). There was a trend of a reduced rate of 30-day myocardial infarction (0.8% to 0.5%. p = 0 .2) and stroke (0.5% to 0.2%, p = 0.2). The 60-day deep vein thrombosis figures (0.8% to 0.6%, p = 0.5) and pulmonary embolism figures (1.2% to 1.1%, p = 0.9) were similar. Re-admission rate remained unchanged during the period of the study (4.7% to 4.8%, p = 0.8). Interpretation This large observational study of unselected consecutive hip and knee arthroplasty patients shows a substantial reduction in death rate, reduced length of stay, and reduced transfusion requirements after the introduction of a multimodal enhanced recovery protocol.

Lower rates of dislocation with increased femoral head size after primary total hip replacement: A FIVE-YEAR ANALYSIS OF NHS PATIENTS IN ENGLAND

Increased femoral head size may reduce dislocation rates following total hip replacement. The National Joint Registry for England and Wales has highlighted a statistically significant increase in the use of femoral heads ≥ 36 mm in diameter from 5% in 2005 to 26% in 2009, together with an increase in the use of the posterior approach. The aim of this study was to determine whether rates of dislocation have fallen over the same period. National data for England for 247 546 procedures were analysed in order to determine trends in the rate of dislocation at three, six, 12 and 18 months after operation during this time. The 18-month revision rates were also examined. Between 2005 and 2009 there were significant decreases in cumulative dislocations at three months (1.12% to 0.86%), six months (1.25% to 0.96%) and 12 months (1.42% to 1.11%) (all p < 0.001), and at 18 months (1.56% to 1.31%) for the period 2005 to 2008 (p < 0.001). The 18-month revision rates did not significantly change during the study period (1.26% to 1.39%, odds ratio 1.10 (95% confidence interval 0.98 to 1.24), p = 0.118). There was no evidence of changes in the coding of dislocations during this time. These data have revealed a significant reduction in dislocations associated with the use of large femoral head sizes, with no change in the 18-month revision rate.

Efficacy of a single ultrasound-guided injection for the treatment of hip osteoarthritis

Background Intra-articular injection is effective for osteoarthritis, but the best single injection strategy is not known, nor are there established predictors of response. The objectives of this study were to assess and predict response to a single ultrasound-guided injection in moderate to severe hip osteoarthritis. Methods 77 hip osteoarthritis patients entered a prospective, randomised controlled trial, randomised to one of four groups: standard care (no injection); normal saline; non-animal stabilised hyaluronic acid (durolane) or methylprednisolone acetate (depomedrone). Main Outcome Measures Numerical rating scale (NRS 0–10) ‘worst pain’, Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain/function. Potential predictors of response (including radiographic severity, ultrasound synovitis and baseline symptom severity) were examined using univariate logistic regression analysis and Fishers exact test. Results NRS pain, WOMAC pain and function improved significantly for the steroid arm alone. Effect sizes at week 1 were striking: NRS pain 1.5, WOMAC pain 1.9 and WOMAC function 1.3. Outcome Measures in Rheumatoid Arthritis Clinical Trials—Osteoarthritis Research Society responder criteria identified 22 responders (intention-to-treat): steroid 14 (74%; number needed to treat, two); saline, four (21%); durolane, two (11%); and no injection, two (10%; χ2 test between groups, p<0.001). Corticosteroid arm response was maintained over 8 weeks (summary measures analysis of variance, p<0.002 for NRS pain). Synovitis was a significant predictor of response at weeks 4 and 8 (p<0.05, Fishers exact test; week 4 OR 16.7, 95% CI 1.4 to 204). Conclusions Ultrasound-guided corticosteroid injections are highly efficacious; furthermore synovitis on ultrasound is a biomarker of response to injection.

The Association Between Body Mass Index and the Outcomes of Total Knee Arthroplasty

BACKGROUND In the United Kingdom, organizations involved in health-care commissioning have recently introduced legislation limiting access to total knee arthroplasty through the introduction of arbitrary thresholds unsupported by the literature and based on body mass index. This study aimed to establish the relationship between body mass index and patient-reported specific and general outcomes on total knee arthroplasty. METHODS Using national patient-reported outcome measures (PROMs) linked to the National Joint Registry, we identified 13,673 primary total knee arthroplasties performed for the treatment of osteoarthritis. The PROMs project involves the collection of condition-specific and general health outcomes before and at six months following total knee arthroplasty. The relationships between body mass index and the Oxford Knee Score, EuroQol 5D index, and EuroQol 5D Visual Analogue Scale were assessed with use of scatterplots and linear regression. The improvement in these measures was compared for three distinct groups based on body mass index (Group I [15 to 24.9 kg/m(2)], Group II [25 to 39.9 kg/m(2)], and Group III [40 to 60 kg/m(2)]) with use of multiple regression analysis to adjust for differences in age, sex, American Society of Anesthesiologists grade, general health rating, and number of comorbidities. RESULTS The preoperative and postoperative patient-reported outcome measures declined to a similar extent with increasing body mass index. The gradient of the linear regression equation relating to the change in scores was positive in all cases, indicating that there was a tendency for scores to improve to a greater extent as body mass index increased. After adjustment, the changes in patient-reported outcome measures in Group I and Group III were equivalent for the Oxford Knee Score (mean difference, 0.5 point [95% confidence interval, -0.5 to 1.5 points]; p = 0.78), the EuroQol 5D index (mean difference, 0.014 point [95% confidence interval, -0.021 to 0.048 point]; p = 1.00), and the EuroQol 5D Visual Analogue Scale (mean difference, 1.9 points [95% confidence interval, -0.4 to 4.1 points]; p = 0.13). Wound complications were significantly higher (p < 0.001) at a rate of 17% (168 of 1018 patients) in Group III compared with 9% (121 of 1292 patients) in Group I. CONCLUSIONS The improvements in patient-reported outcome measures experienced by patients were similar, irrespective of body mass index. Health policy should be based on the overall improvements in function and general health gained through surgery. Obese patients should not be excluded from the benefit of total knee arthroplasty, given that their overall improvements were equivalent to those of patients with a lower body mass index.

Return to theatre following total hip and knee replacement, before and after the introduction of rivaroxaban: a retrospective cohort study.

Rivaroxaban has been recommended for routine use as a thromboprophylactic agent in patients undergoing lower-limb arthroplasty. However, trials supporting its use have not fully evaluated the risks of wound complications. This study of 1048 total hip/knee replacements records the rates of return to theatre and infection before and after the change from a low molecular weight heparin (tinzaparin) to rivaroxaban as the agent of chemical thromboprophylaxis in patients undergoing lower-limb arthroplasty. During a period of 13 months, 489 consecutive patients undergoing lower-limb arthroplasty received tinzaparin and the next 559 consecutive patients received rivaroxaban as thromboprophylaxis. Nine patients in the control (tinzaparin) group (1.8%, 95% confidence interval 0.9 to 3.5) returned to theatre with wound complications within 30 days, compared with 22 patients in the rivaroxaban group (3.94%, 95% confidence interval 2.6 to 5.9). This increase was statistically significant (p = 0.046). The proportion of patients who returned to theatre and became infected remained similar (p = 0.10). Our study demonstrates the need for further randomised controlled clinical trials to be conducted to assess the safety and efficacy of rivaroxaban in clinical practice, focusing on the surgical complications as well as the potential prevention of venous thromboembolism.

A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip

Objectives Osteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects. Methods We performed a two-stage meta-analysis on more than 78 000 participants. In stage 1, we synthesised data from eight GWAS whereas data from 10 centres were used for ‘in silico’ or ‘de novo’ replication. Besides the main analysis, a stratified by sex analysis was performed to detect possible sex-specific signals. Meta-analysis was performed using inverse-variance fixed effects models. A random effects approach was also used. Results We accumulated 11 277 cases of radiographic and symptomatic hip OA. We prioritised eight single nucleotide polymorphism (SNPs) for follow-up in the discovery stage (4349 OA cases); five from the combined analysis, two male specific and one female specific. One locus, at 20q13, represented by rs6094710 (minor allele frequency (MAF) 4%) near the NCOA3 (nuclear receptor coactivator 3) gene, reached genome-wide significance level with p=7.9×10−9 and OR=1.28 (95% CI 1.18 to 1.39) in the combined analysis of discovery (p=5.6×10−8) and follow-up studies (p=7.3×10−4). We showed that this gene is expressed in articular cartilage and its expression was significantly reduced in OA-affected cartilage. Moreover, two loci remained suggestive associated; rs5009270 at 7q31 (MAF 30%, p=9.9×10−7, OR=1.10) and rs3757837 at 7p13 (MAF 6%, p=2.2×10−6, OR=1.27 in male specific analysis). Conclusions Novel genetic loci for hip OA were found in this meta-analysis of GWAS.

Extramedullary or intramedullary tibial alignment guides: a randomised, prospective trial of radiological alignment

We undertook a prospective, randomised study of 135 total knee arthroplasties to determine the most accurate and reliable technique for alignment of the tibial prosthesis. Tibial resection was guided by either intramedullary or extramedullary alignment jigs. Of the 135 knees, standardised postoperative radiographs suitable for assessment were available in 100. Correct tibial alignment was found in 85% of the intramedullary group compared with 65% of the extramedullary group (p = 0.019). We conclude that intramedullary guides are superior to extramedullary instruments for alignment of the tibial prosthesis.

Reduced short-term complications and mortality following Enhanced Recovery primary hip and knee arthroplasty: results from 6,000 consecutive procedures.

Background and purpose Enhanced Recovery (ER) is a well-established multidisciplinary strategy in lower limb arthroplasty and was introduced in our department in May 2008. This retrospective study reviews short-term outcomes in a consecutive unselected series of 3,000 procedures (the “ER” group), and compares them to a numerically comparable cohort that had been operated on previously using a traditional protocol (the “Trad” group). Methods Prospectively collected data on surgical endpoints (length of stay (LOS), return to theater (RTT), re-admission, and 30- and 90-day mortality) and medical complications (stroke, gastrointestinal bleeding, myocardial infarction, and pneumonia within 30 days; deep vein thrombosis and pulmonary embolism within 60 days) were compared. Results ER included 1,256 THR patients and 1,744 TKR patients (1,369 THRs and 1,631 TKRs in Trad). The median LOS in the ER group was reduced (3 days vs. 6 days; p = 0.01). Blood transfusion rate was also reduced (7.6% vs. 23%; p < 0.001), as was RTT rate (p = 0.05). The 30-day incidence of myocardial infarction declined (0.4% vs. 0.9%; p = 0.03) while that of stroke, gastrointestinal bleeding, pneumonia, deep vein thrombosis, and pulmonary embolism was not statistically significantly different. Mortality at 30 days and at 90 days was 0.1% and 0.5%, respectively, as compared to 0.5% and 0.8% using the traditional protocol (p = 0.03 and p = 0.1, respectively). Interpretation This is the largest study of ER arthroplasty, and provides safety data on a consecutive unselected series. The program has achieved a statistically significant reduction in LOS and in cardiac ischemic events for our patients, with a near-significant decrease in return to theater and in mortality rates.