Andrew Gordon

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.

Insights into the genetic architecture of osteoarthritis from stage 1 of the arcOGEN study

Objectives The genetic aetiology of osteoarthritis has not yet been elucidated. To enable a well-powered genome-wide association study (GWAS) for osteoarthritis, the authors have formed the arcOGEN Consortium, a UK-wide collaborative effort aiming to scan genome-wide over 7500 osteoarthritis cases in a two-stage genome-wide association scan. Here the authors report the findings of the stage 1 interim analysis. Methods The authors have performed a genome-wide association scan for knee and hip osteoarthritis in 3177 cases and 4894 population-based controls from the UK. Replication of promising signals was carried out in silico in five further scans (44 449 individuals), and de novo in 14 534 independent samples, all of European descent. Results None of the association signals the authors identified reach genome-wide levels of statistical significance, therefore stressing the need for corroboration in sample sets of a larger size. Application of analytical approaches to examine the allelic architecture of disease to the stage 1 genome-wide association scan data suggests that osteoarthritis is a highly polygenic disease with multiple risk variants conferring small effects. Conclusions Identifying loci conferring susceptibility to osteoarthritis will require large-scale sample sizes and well-defined phenotypes to minimise heterogeneity.

Polymorphisms in the interleukin-1 receptor antagonist and interleukin-6 genes affect risk of osteolysis in patients with total hip arthroplasty.

OBJECTIVE To determine whether osteolysis after total hip arthroplasty (THA) is associated with common polymorphisms within the genes encoding the interleukin-1 (IL-1) family and IL-6, and to determine whether polymorphisms that are associated with osteolysis affect in vitro messenger RNA (mRNA) expression in human peripheral blood mononuclear cells (PBMCs) in response to wear particles. METHODS Unrelated white subjects of North European descent (n=612) were recruited a mean of 11 years after cemented THA for primary osteoarthritis. Of these subjects, 272 had previous osteolysis and 340 had no radiographic evidence of osteolysis (control group). Genomic DNA was genotyped for the following single-nucleotide polymorphisms (SNPs): IL1A +4845, IL1B +3954, IL1B -3737, IL1B -511, IL1RA +2018, IL6 -174, IL6 -572, and IL6 -597. In a subset of 60 subjects, PBMCs were extracted and stimulated with titanium particles and/or endotoxin, and cytokine mRNA expression was measured using quantitative real-time reverse transcriptase-polymerase chain reaction. RESULTS The odds ratio (OR) for osteolysis associated with carriage of the IL1RA +2018C allele was 0.66 (95% confidence interval [95% CI] 0.48-0.91) (P=0.012). The remaining SNPs were not individually associated with osteolysis. The uncommon IL6 haplotype -174G/-572G/-597A (osteolysis group frequency 2.4%, control group frequency 0.8%) was associated with osteolysis (P=0.02, calculated using Haploview software). The IL1RA +2018CC genotype was associated with increased mRNA expression compared with the +2018TT genotype in both unstimulated and stimulated PBMCs (P=0.01 by analysis of variance, after Bonferroni correction). CONCLUSION The IL1RA +2018C allele is associated with a decreased risk of osteolysis after THA and with increased IL-1 receptor antagonist mRNA expression in vitro. An uncommon haplotype within the promoter region of the gene for IL-6 is positively associated with osteolysis.

Individual Susceptibility to Periprosthetic Osteolysis Is Associated with Altered Patterns of Innate Immune Gene Expression in Response to Pro-Inflammatory Stimuli

Susceptibility to osteolysis after total hip arthroplasty (THA) varies between individuals. We examined whether patients susceptible to osteolysis (group I, n = 34 subjects) after cemented Charnley THA have quantitatively different innate immune responses to pro‐inflammatory stimuli versus patients without this susceptibility (group II, n = 28 subjects) at a mean of 14 years after primary surgery. Extracted peripheral blood mononuclear cells were stimulated for 3 h using endotoxin (lipopolysaccharide—LPS, 100 ng/mL), endotoxin‐stripped titanium particles (Ti) or endotoxin‐stripped particles with adherent LPS added‐back (TI + LPS). Subjects returned 1 week later and the experimental protocol was repeated. Assays for mRNA induction for interleukin (IL)‐1α, IL‐1β, IL‐1Ra, IL‐6, IL‐10, IL‐18, and tumor necrosis factor (TNF) were made using quantitative real‐time PCR. Although baseline levels of mRNA expression were slightly lower in group I, inducibility of mRNA expression was markedly greater in group I versus group II for all cytokines in response to LPS or Ti + LPS, and for IL‐1α in response to Ti (P < 0.05). LPS or Ti + LPS stimulation also resulted in an increase in the IL‐1/IL‐1Ra mRNA ratio in group I versus group II (P < 0.05). mRNA induction was highly reproducible between subject visits (r > 0.7, P < 0.001). Osteolysis‐susceptible patients show repeatable, quantitatively different patterns of innate cytokine gene expression in response to pro‐inflammatory stimuli versus THA patients who do not display this susceptibility. These innate immune differences may contribute to the variation in osteolysis‐susceptibility observed clinically between individuals.

Genetic variation in inflammatory and bone turnover pathways and risk of osteolytic responses to prosthetic materials

Wear particle‐induced inflammatory bone loss (osteolysis) is the leading cause of total hip arthroplasty (THA) failure. Individual susceptibility to osteolysis is modulated by genetic variation. In this 2‐stage case‐control association study we examined whether variation within candidate genes in inflammatory and bone turnover signaling pathways associates with susceptibility to osteolysis and time to prosthesis failure. We examined two cohorts, comprising 758 (347 male) Caucasian subjects who had undergone THA with a metal on polyethylene bearing couple; 315 of whom had developed osteolysis. Key genes within inflammatory, bone resorption, and bone formation pathways were screened for common variants by pairwise‐SNP tagging using a 2‐stage association analysis approach. In the discovery cohort four SNPs within RANK, and one each within KREMEN2, OPG, SFRP1, and TIRAP (p < 0.05) were associated with osteolysis susceptibility. Two SNPs within LRP6, and one each within LRP5, NOD2, SOST, SQSTM1, TIRAP, and TRAM associated with time to implant failure (p < 0.05). Meta‐analysis of the two cohorts identified four SNPs within RANK, and one each within KREMEN2, OPG, SFRP1, and TIRAP associated with osteolysis susceptibility (p < 0.05). Genetic variation within inflammatory signaling and bone turnover pathways may play a role in susceptibility to osteolysis.

Risk Factors for Aseptic Loosening Following Total Hip Arthroplasty

Total hip arthroplasty (THA) is one of the most successful orthopaedic procedures and has relieved pain and improved hip function in millions of patients worldwide. Despite the success of modern prosthetic designs and bearing surfaces, around 10% of THA prostheses still fail within 10 years1. Improvements in surgical technique and prosthesis design have decreased the incidence of deep sepsis, dislocation and fracture, however aseptic loosening, the clinical end point of osteolysis, remains the most frequent complication and in the UK accounts for 63% of all revision surgery (Table 1)2. Prosthesis loosening results in pain and disability, requiring revision surgery. Revision THA is associated with a 3 to 8-fold greater in-hospital mortality, poorer functional outcome, longer hospital stay, and higher cost than primary surgery1,3-5. The problem of osteolysis has been recognized in Judet’s acrylic hemiarthroplasty introduced in the 1940s. Prosthesis loosening complicating THA in the 1950’s and 1960’s was poorly understood and attributed to unconfirmed sepsis6 and prosthesis motion7. In the 1980’s loosening was thought to be the result of “cement disease”8, arising due to a foreign body reaction to methyl methacrylate. When the development of cementless prostheses

Midterm outcome of the plasma cup in total hip arthroplasty

One hundred and twenty eight primary total hip arthroplasties (THA) in 104 patients were reviewed to assess mid-term survivorship and clinical outcome of the Plasma cup. Outcome was evaluated clinically, radiographically, and by self-administered questionnaires. Patient mean age at surgery was 51 years, and 52 THAs (41%) were performed for secondary arthritis. Prior to surgery the median Merle DAubigne score was 8. At 59 (standard deviation 18) months this score had improved to 17, and the median Harris hip score was 85. The mean annual polyethylene wear rate was 0.14mm/year. There were no instances of aseptic loosening but 2 cups had small, focal osteolytic lesions at the site of screw holes. Three cups were revised, two for recurrent dislocations, and one for infection. Cup survivorship at 5 years was 97% (Kaplan-Meier).This data suggests that the Plasma cup performs well in the mid-term and may be used safely in a young population with a high incidence of secondary osteoarthritis. (Hip International 2002; 2: 119-25).

Stay Short or Go Long? Can a Standard Cemented Femoral Prosthesis Be Used at Second-Stage Total Hip Arthroplasty Revision for Infection Following an Extended Trochanteric Osteotomy?

BACKGROUND The aim of this study was to review the results of the use of a cemented, standard length, taper-slip femoral component at second stage following an extended trochanteric osteotomy (ETO). METHODS We reviewed prospectively collected data from the hospital arthroplasty database, identifying and reviewing all patients who had undergone an ETO at first-stage revision for infection, who had subsequently undergone second-stage reimplantation. RESULTS Over 17 years, 99 patients underwent 102 2-stage procedures with ETO at first stage, with a mean follow-up of 5.5 years; 70 of 102 patients received a standard prosthesis following ETO union and 32 of 102 patients received a long-stem prosthesis at second stage because of deficiencies in proximal femoral bone stock. There was a significant difference in the Paprosky classification between the 2 groups (P < .0001); 77% of the standard group and 52% of the long-stem group had no complications. A significant complication (infection, fracture, or dislocation) was observed in 12% patients in the standard group and 16% patients in the long-stem group. A number of radiographs were independently reviewed to assess for ETO union and complications and an intraclass correlation of 0.84 (P < .0001) was observed. CONCLUSION A standard femoral prosthesis can be implanted at second stage following ETO union for Paprosky type I and some type II femora. There is no greater risk of complications, and distal bone stock is preserved for potential revision surgery in the future.

Hip and Knee Arthroplasty in the Patient with Inflammatory Arthritis

The term inflammatory arthritis refers to an inflammatory arthropathy in patients suffering from one of a number of chronic inflammatory conditions including rheumatoid arthritis (RA), and the seronegative spondyloarthropathies of ankylosing spondylitis (AS), psoriatic arthritis (PsA), spondyloarthritis associated with inflammatory bowel disease and undifferentiated spondyloarthritis. This chapter will focus on a review of the surgical management of patients with RA, AS, and PsA, as these represent the most common of the inflammatory arthropathies.

EBRA-Digital release 2003 versus 1998: A comparison of instrument repeatability for measuring implant migration and wear

EBRA-Digital is an established method for measuring implant migration after total hip arthroplasty using digitized radiographs that has recently undergone a change in the software platform that may influence its precision. We assessed the precision of EBRA-Digital 2003 release and compared it to the previous 1998 release using consecutive, standardized, plain radiographic examinations made on the same day after repositioning in 29 patients. The precision of implant migration and wear measurements was similar between the two software releases, although analysis times were quicker using the 2003 release (p<0.01). Image file compression at a ratio of 30 resulted in poorer measurement precision for some variables. The EBRA 2003 software platform has similar precision to the previous release and allows faster measurement of implant migration and wear. The level of image file compression that is used affects the precision of these measurements. (Hip International 2005; 15: 226-9).