Unique transcriptome signatures and GM-CSF expression in lymphocytes from patients with spondyloarthritis.

Spondyloarthritis encompasses a group of common inflammatory diseases thought to be driven by IL-17A-secreting type-17 lymphocytes. Here we show increased numbers of GM-CSF-producing CD4 and CD8 lymphocytes in the blood and joints of patients with spondyloarthritis, and increased numbers of IL-17A+GM-CSF+ double-producing CD4, CD8, γδ and NK cells. GM-CSF production in CD4 T cells occurs both independently and in combination with classical Th1 and Th17 cytokines. Type 3 innate lymphoid cells producing predominantly GM-CSF are expanded in synovial tissues from patients with spondyloarthritis. GM-CSF+CD4+ cells, isolated using a triple cytokine capture approach, have a specific transcriptional signature. Both GM-CSF+ and IL-17A+GM-CSF+ double-producing CD4 T cells express increased levels of GPR65, a proton-sensing receptor associated with spondyloarthritis in genome-wide association studies and pathogenicity in murine inflammatory disease models. Silencing GPR65 in primary CD4 T cells reduces GM-CSF production. GM-CSF and GPR65 may thus serve as targets for therapeutic intervention of spondyloarthritis.

Functional outcome of debridement, antibiotics and implant retention in periprosthetic joint infection involving the hip: a case-control study.

AIMS: Advocates of debridement, antibiotics and implant retention (DAIR) in hip periprosthetic joint infection (PJI) argue that a procedure not disturbing a sound prosthesis-bone interface is likely to lead to better survival and functional outcome compared with revision. This case-control study aims were to compare outcome of DAIRs for infected primary total hip arthroplasty (THA) with outcomes following primary THA and two-stage revision of infected primary THAs. PATIENTS AND METHODS: We retrospectively reviewed all DAIRs, performed for confirmed infected primary hip arthropasty (n = 82) at out institution, between 1997 and 2013. Data recorded included full patient information and type of surgery. Outcome measures included complications, mortality, implant survivorship and functional outcome. Outcome was compared with two control groups matched for gender and age; a cohort of primary THAs (n = 120) and a cohort of two-stage revisions for infection (n = 66). RESULTS: Mean age at DAIR was 69 years (33 to 87) and mean follow-up was eight years (2 to 17; standard deviation (sd) 5). A total of 52 (63%) of DAIRs were for early PJI (less than six weeks). Greater success in the eradication of infection with DAIR was identified with early PJI, comprising an interval less than a week between onset of symptoms and exchange of modular components with the DAIR procedure. Eradication of infection, complications and re-operation rates were similar in the DAIR and two-stage revision groups. For hips with successful eradication of infection with DAIR, the five-year survival (98%; 95% confidence interval (CI) 94 to 100) was similar to the primary THA group (98%; 95% CI 95 to 100) (n = 43; p = 0.3). The DAIR group had inferior mean Oxford Hip Scores (OHS) (38; 12 to 48) compared with the primary THA group (42; 15 to 48) (p = 0.02) but a significantly better mean OHS compared with the two-stage revision group (31; 0 to 48) (p = 0.008). Patients who required only one DAIR for eradication of infection had a similar mean OHS (41; 20 to 48) to the primary THA group (p = 0.2). CONCLUSION: The DAIR procedure is associated with a similar complication rate and ability to eradicate infection as two-stage revision. This study emphasises the need for exchange of modular components for improved chances of eradication of infection. This is the first study showing that DAIR is better than a two-stage revision regarding functional outcome. Cite this article: Bone Joint J 2017;99-B:614-22.

Predictive outcomes of revision total hip replacement--a consecutive series of 1176 patients with a minimum 10-year follow-up.

The burden of revision total hip replacement (THR) surgery is increasing. With an increasing life expectancy and younger age of primary surgery this trend is set to continue. There are few data on the long-term outcome of revision THR. This retrospective study of 1176 consecutive revision THRs with a minimum 10-year follow-up from a University Teaching Hospital was undertaken to review implant survival and patient reported outcomes. Mean follow-up was 11 years with implant survival at 10 years of 82% (CI: 80-85). Implant survival varied between 58% (unexplained pain) to 84% (aseptic loosening) depending on the indication for revision surgery. Positive predictors of survival were age greater than 70 at the time of surgery (p=0.011), revision for aseptic loosening (p<0.01) and revision of both components or just the acetabular component (p<0.01). At the last review, mean Oxford Hip Score (OHS) was 34 (SD: 11.3) and 92% of the living patients with unrevised hips were satisfied with the outcome of revision surgery. This long term study has demonstrated that positive predictors of survival and outcome of revision THR surgery are age greater than 70 years, revision for aseptic loosening and component revision. This should aid surgeons in their counselling of patients prior to surgery.

The ten-year survival of the Birmingham hip resurfacing: an independent series.

Recent events have highlighted the importance of implant design for survival and wear-related complications following metal-on-metal hip resurfacing arthroplasty. The mid-term survival of the most widely used implant, the Birmingham Hip Resurfacing (BHR), has been described by its designers. The aim of this study was to report the ten-year survival and patient-reported functional outcome of the BHR from an independent centre. In this cohort of 554 patients (646 BHRs) with a mean age of 51.9 years (16.5 to 81.5) followed for a mean of eight years (1 to 12), the survival and patient-reported functional outcome depended on gender and the size of the implant. In female hips (n = 267) the ten-year survival was 74% (95% confidence interval (CI) 83 to 91), the ten-year revision rate for pseudotumour was 7%, the mean Oxford hip score (OHS) was 43 (SD 8) and the mean UCLA activity score was 6.4 (SD 2). In male hips (n = 379) the ten-year survival was 95% (95% CI 92.0 to 97.4), the ten-year revision rate for pseudotumour was 1.7%, the mean OHS was 45 (SD 6) and the mean UCLA score was 7.6 (SD 2). In the most demanding subgroup, comprising male patients aged < 50 years treated for primary osteoarthritis, the survival was 99% (95% CI 97 to 100). This study supports the ongoing use of resurfacing in young active men, who are a subgroup of patients who tend to have problems with conventional THR. In contrast, the results in women have been poor and we do not recommend metal-on-metal resurfacing in women. Continuous follow-up is recommended because of the increasing incidence of pseudotumour with the passage of time.

Successful management of recalcitrant infection related to total hip replacement using pedicled rectus femoris or vastus lateralis muscle flaps.

Deep prosthetic joint infection remains an uncommon but serious complication of total hip replacement. We reviewed 24 patients with recalcitrant hip wounds following infected total hip replacement treated with either pedicled rectus femoris or vastus lateralis muscle flaps between 1998 and 2009. The mean age of the patients was 67.4 years (42 to 86) with ten men and 14 women. There had been a mean of four (1 to 8) previous attempts to close the wound. A total of 20 rectus femoris and five vastus lateralis flaps were used, with one of each type of flap failing and requiring further reconstruction. All patients had positive microbiology. At a mean follow-up of 47 months (9 to 128), 22 patients had a healed wound and two had a persistent sinus. The prosthesis had been retained in five patients. In the remainder it had been removed, and subsequently re-implanted in nine patients. Six patients continued to take antibiotics at final follow-up. This series demonstrates the effectiveness of pedicled muscle flaps in healing these infected wounds. The high number of previous debridements suggests that these flaps could have been used earlier.

Optimal acetabular orientation for hip resurfacing.

Pseudotumours are a rare complication of hip resurfacing. They are thought to be a response to metal debris which may be caused by edge loading due to poor orientation of the acetabular component. Our aim was to determine the optimal acetabular orientation to minimise the risk of pseudotumour formation. We matched 31 hip resurfacings revised for pseudotumour formation with 58 controls who had a satisfactory outcome from this procedure. The radiographic inclination and anteversion angles of the acetabular component were measured on anteroposterior radiographs of the pelvis using Einzel-Bild-Roentgen-Analyse software. The mean inclination angle (47 degrees, 10 degrees to 81 degrees) and anteversion angle (14 degrees, 4 degrees to 34 degrees) of the pseudotumour cases were the same (p = 0.8, p = 0.2) as the controls, 46 degrees (29 degrees to 60 degrees) and 16 degrees (4 degrees to 30 degrees) respectively, but the variation was greater. Assuming an accuracy of implantation of +/- 10 degrees about a target position, the optimal radiographic position was found to be approximately 45 degrees of inclination and 20 degrees of anteversion. The incidence of pseudotumours inside the zone was four times lower (p = 0.007) than outside the zone. In order to minimise the risk of pseudotumour formation we recommend that surgeons implant the acetabular component at an inclination of 45 degrees (+/- 10) and anteversion of 20 degrees (+/- 10) on post-operative radiographs. Because of differences between the radiographic and the operative angles, this may be best achieved by aiming for an inclination of 40 degrees and an anteversion of 25 degrees.

Two-stage revision for prosthetic joint infection: predictors of outcome and the role of reimplantation microbiology.

OBJECTIVES: We describe rates of success for two-stage revision of prosthetic joint infection (PJI), including data on reimplantation microbiology. METHODS: We retrospectively collected data from all the cases of PJI that were managed with two-stage revision over a 4 year period. Patients were managed with an antibiotic-free period before reimplantation, in order to confirm, clinically and microbiologically, that infection was successfully treated. RESULTS: One hundred and fifty-two cases were identified. The overall success rate (i.e. retention of the prosthesis over 5.75 years of follow-up) was 83%, but was 89% for first revisions and 73% for re-revisions [hazard ratio = 2.9, 95% confidence interval (CI) 1.2-7.4, P = 0.023]. Reimplantation microbiology was frequently positive (14%), but did not predict outcome (hazard ratio = 1.3, 95% CI 0.4-3.7, P = 0.6). Furthermore, most unplanned debridements following the first stage were carried out before antibiotics were stopped (25 versus 2 debridements). CONCLUSIONS: We did not identify evidence supporting the use of an antibiotic-free period before reimplantation and routine reimplantation microbiology. Re-revision was associated with a significantly worse outcome.

Hip resurfacings revised for inflammatory pseudotumour have a poor outcome.

Inflammatory pseudotumours occasionally occur after metal-on-metal hip resurfacing and often lead to revision. Our aim was to determine the severity of this complication by assessing the outcome of revision in these circumstances and by comparing this with the outcome of other metal-on-metal hip resurfacing revisions as well as that of matched primary total hip replacements. We identified 53 hips which had undergone metal-on-metal hip resurfacing and required revision at a mean of 1.59 years (0.01 to 6.69) after operation. Of these, 16 were revised for pseudotumours, 21 for fracture and 16 for other reasons. These were matched by age, gender and diagnosis with 103 patients undergoing primary total hip replacement with the Exeter implant. At a mean follow-up of three years (0.8 to 7.2) the outcome of metal-on-metal hip resurfacing revision for pseudotumour was poor with a mean Oxford hip score of 20.9 (sd 9.3) and was significantly worse (p < 0.001) than the outcome for fracture with a mean Oxford hip score of 40.2 (sd 9.2) or that for other causes with a mean Oxford hip score of 37.8 (sd 9.4). The clinical outcome of revision for pseudotumour was also significantly worse (p < 0.001) than the outcome of matched primary total hip replacements. By contrast, the outcome for fracture and other causes was not significantly different from that of matched primary total hip replacements (p = 0.065). After revision for pseudotumour there were three cases of recurrent dislocation, three of palsy of the femoral nerve, one of stenosis of the femoral artery and two of loosening of the component. Five hips required further revision. In three of these there was evidence of recurrent pseudotumour, and one is currently awaiting further revision. The incidence of major complications after revision for pseudotumour (50%) was significantly higher (p = 0.018) than that after revision for other causes (14%). The outcome of revision for pseudotumour is poor and consideration should be given to early revision to limit the extent of the soft-tissue destruction. The outcome of resurfacing revision for other causes is good.

One hundred and twelve infected arthroplasties treated with 'DAIR' (debridement, antibiotics and implant retention): antibiotic duration and outcome.

OBJECTIVES: We describe treatment failure rates by antibiotic duration for prosthetic joint infection (PJI) managed with debridement, antibiotics and implant retention (DAIR). METHODS: We retrospectively collected data from all the cases of PJI that were managed with DAIR over a 5 year period. Surgical debridement, microbiological sampling, early intravenous antibiotics and prolonged oral follow-on antibiotics were used. RESULTS: One hundred and twelve cases of PJI were identified. Twenty infections (18%) recurred during a mean follow-up of 2.3 years. The mean duration of antibiotic use was 1.5 years. Failure was more common after arthroscopic debridement, for previously revised joints and for Staphylococcus aureus infection. There were 12 failures after stopping antibiotics and 8 while on antibiotics [hazard ratio (HR) = 4.3, 95% confidence interval (CI) 1.4-12.8, P = 0.01]. However, during the first 3 months of follow-up, there were eight failures after stopping antibiotics and two while on antibiotics (HR = 7.0, 95% CI 1.5-33, P = 0.015). The duration of antibiotic therapy prior to stopping did not predict outcome. CONCLUSIONS: PJI may be managed by DAIR. The risk of failure with this strategy rises after stopping oral antibiotics, but lengthening antibiotic therapy may simply postpone, rather than prevent, failure.

Pseudotumours associated with metal-on-metal hip resurfacings.

We report 17 patients (20 hips) in whom metal-on-metal resurfacing had been performed and who presented with various symptoms and a soft-tissue mass which we termed a pseudotumour. Each patient underwent plain radiography and in some, CT, MRI and ultrasonography were also performed. In addition, histological examination of available samples was undertaken. All the patients were women and their presentation was variable. The most common symptom was discomfort in the region of the hip. Other symptoms included spontaneous dislocation, nerve palsy, a noticeable mass or a rash. The common histological features were extensive necrosis and lymphocytic infiltration. To date, 13 of the 20 hips have required revision to a conventional hip replacement. Two are awaiting revision. We estimate that approximately 1% of patients who have a metal-on-metal resurfacing develop a pseudotumour within five years. The cause is unknown and is probably multifactorial. There may be a toxic reaction to an excess of particulate metal wear debris or a hypersensitivity reaction to a normal amount of metal debris. We are concerned that with time the incidence of these pseudotumours may increase. Further investigation is required to define their cause.

The five-year results of the Birmingham Hip Resurfacing arthroplasty: an independent series.

Few independent studies have reported the outcome of resurfacing arthroplasty of the hip. The aim of this study was to report the five-year clinical outcome and seven-year survival of an independent series. A total of 610 Birmingham Hip Resurfacing arthroplasties were performed in 532 patients with a mean age of 51.8 years (16.5 to 81.6). They were followed for between two and eight years; 107 patients (120 hips) had been followed up for more than five years. Two patients were lost to follow-up. At a minimum of five years' follow-up, 79 of 85 hips (93%) had an excellent or good outcome according to the Harris hip score. The mean Oxford hip score was 16.1 points (sd 7.7) and the mean University of California Los Angeles activity score was 6.6 points (sd 1.9). There were no patients with definite radiological evidence of loosening or of narrowing of the femoral neck exceeding 10% of its width. There were 23 revisions (3.8%), giving an overall survival of 95% (95% confidence interval 85.3 to 99.2) at seven years. Fractured neck of femur in 12 hips was the most common indication for revision, followed by aseptic loosening in four. In three hips (three patients) (0.5%), failure was possibly related to metal debris. Considering that these patients are young and active these results are good, and support the use of resurfacing. Further study is needed to address the early failures, particularly those related to fracture and metal debris.

Osteonecrosis in retrieved femoral heads after failed resurfacing arthroplasty of the hip.

We present the histological findings of bone retrieved from beneath the femoral components of failed metal-on-metal hip resurfacing arthroplasties. Of a total of 377 patients who underwent resurfacing arthroplasty, 13 required revision; for fracture of the femoral neck in eight, loosening of a component in three and for other reasons in two. None of these cases had shown histological evidence of osteonecrosis in the femoral bone at the time of the initial implantation. Bone from the remnant of the femoral head showed changes of osteonecrosis in all but one case at revision. In two cases of fracture which occurred within a week of implantation, the changes were compatible with early necrosis of the edge of the fracture. In the remaining six fractures, there were changes of established osteonecrosis. In all but one of the non-fracture cases, patchy osteonecrosis was seen. We conclude that histological evidence of osteonecrosis is a common finding in failed resurfaced hips. Given that osteonecrosis is extensive in resurfaced femoral heads which fail by fracture, it is likely to play a role in the causation of these fractures.

Heterotopic bone formation following hip arthroplasty in Paget's disease.

Heterotopic bone formation in soft tissues occurs commonly in Paget's disease patients following a primary total hip arthroplasty (THA). The nature of this heterotopic bone has not been documented. In this report, we show that the heterotopic bone removed 14 years after primary THA in a case of Paget's disease was sclerotic, contained prominent mosaic cement lines and showed increased remodelling activity on the bone surface. In addition to these typically Pagetic histological features, it was noted ultrastructurally that the osteoclasts contained characteristic intranuclear viral-like inclusions. In contrast, the foreign body macrophages found in the joint pseudocapsule and pseudomembrane, which are a population of mononuclear precursor cells from which osteoclasts can be formed, did not contain viral-like inclusions. These findings are of interest regarding the pathogenesis of heterotopic bone formation following hip arthroplasty and the ontogeny of Pagetic osteoclasts.

A correlative study of clinical and histological findings of revision hip arthroplasty for rheumatoid arthritis and inflammatory joint disease.

OBJECTIVE: Primary hip arthroplasty in rheumatoid arthritis (RA) and other forms of inflammatory joint disease (IJD) is generally thought to be associated with a less favourable outcome in terms of implant survival and other complications. Whether the duration of implant survival correlates with the degree of rheumatoid-like inflammatory changes in periprosthetic tissues is uncertain. METHODS: Histopathological changes in periprosthetic tissues obtained following revision surgery of 34 total hip replacements on 27 patients with IJD (RA 18 cases: ankylosing spondylitis three cases; juvenile chronic arthritis six cases) were examined. RESULTS: A heavy diffuse lymphocyte and plasma cell infiltrate +/- lymphoid aggregates was noted in 29% of cases in whom the mean implant survival was 5.6 years (range: 2-8 years). Where little or no lymphocytic infiltrate was noted in periprosthetic tissues, the mean implant survival was 8.6 years (range: 1-17 years). Revision arthroplasty was not undertaken for early or late infection of a primary hip replacement. CONCLUSIONS: Our findings indicate that implant survival is less in those cases where there is a heavy lymphocyte and plasma-cell infiltrate in periprosthetic tissues. These findings suggest that the presence of a heavy chronic inflammatory-cell infiltrate in periprosthetic tissues is likely to be a contributory factor in causing early implant failure in RA.

Synovial macrophage-osteoclast differentiation in inflammatory arthritis.

BACKGROUND: Pathological bone resorption (marginal erosions and juxta-articular osteoporosis) by osteoclasts commonly occurs in rheumatoid arthritis (RA). OBJECTIVES: To define the nature of the mononuclear precursor cells from which osteoclasts are formed in inflamed synovial tissues and to determine the cellular and humoral factors which influence osteoclast differentiation. METHOD: Macrophage (CD14+), non-macrophage (CD14-), and unsorted (CD14+/CD14-) synovial cell populations from RA and inflammatory/non-inflammatory osteoarthritis (OA) synovium were cultured in the presence of receptor activator for nuclear factor kappaB ligand (RANKL) and monocyte-colony stimulating factor (M-CSF; in the presence/absence of prostaglandin E(2) (PGE(2)), interleukin 1beta (IL1beta), tumour necrosis factor alpha (TNFalpha), and IL6). Osteoclast differentiation was assessed by expression of tartrate resistant acid phosphatase (TRAP), vitronectin receptor (VNR), and lacunar resorption. RESULTS: TRAP+ and VNR+ multinucleated cells capable of lacunar resorption were only formed in cultures of CD14+-containing synovial cell populations (that is, CD14+ and CD14+/CD14- cells). No difference in the extent of osteoclast formation was noted in cultures of CD14+ cells isolated from RA, inflammatory OA, and non-inflammatory OA synovium. However, more TRAP+/VNR+ cells and more lacunar resorption was noted in CD14+/CD14- cells from RA and inflammatory OA synovial tissues. The addition of PGE(2), IL1beta, TNFalpha, and IL6 did not increase RANKL/M-CSF-induced osteoclast formation and lacunar resorption of both CD14+/CD14- and CD14+ synovial cell populations. CONCLUSIONS: Osteoclast precursors in synovial tissues are CD14+ monocyte/macrophages. The increase in osteoclast formation in cultures of CD14+/CD14- compared with CD14+ synovial cells in RA and inflammatory OA points to a role for CD14- cells in promoting osteoclast differentiation and bone resorption in inflamed synovial tissues by a mechanism which does not involve a direct effect of proinflammatory cytokines/prostaglandins on RANKL-induced macrophage-osteoclast differentiation.

Evidence for the validity of a patient-based instrument for assessment of outcome after revision hip replacement.

The Oxford hip score (OHS) is a patient-based instrument for assessment of outcome which is often used after total hip replacement, and the EuroQol 5D (EQ5D) is a patient-based generic questionnaire for health assessment. In an analysis of the outcome at one year of 609 revision hip replacements (RHRs), we compared the OHS and EQ5D scores, postoperative patient satisfaction and change in pain. About 25% of the operations were repeat RHRs. At one year, 57% of patients were very pleased with their operation. The correlation between preoperative and postoperative scores and change scores for the OHS and EQ5D was high. For both instruments the effect sizes were large, but the greater effect size of the OHS suggests that it is particularly sensitive to improvements after RHR. The effect scores of the OHS declined with the number of previous RHRs, while those for the EQ5D seemed less sensitive. Our results confirm the value of the OHS in assessing outcome after RHR.

Issues relating to long-term follow-up in hip arthroplasty surgery: a review of 598 cases at 7 years comparing 2 prostheses using revision rates, survival analysis, and patient-based measures.

We reviewed 598 cemented Charnley and Hi-nek total hip arthroplasties at 7 years. Data were obtained from general practitioners, hospital medical notes, microfilm, and patient questionnaires. Outcome measures were revision rates, survival analysis, 12-item Oxford Hip Score, and satisfaction ratings. There were 471 Charnley (79%) and 127 Hi-nek (21%) total hip arthroplasties; 139 deaths (23%) occurred, and 5 (<1%) were lost to follow-up. Characteristics of the Charnley and Hi-nek patient groups were similar, with more information missing for Charnley cases. Revision rates were Charnley, 37 (8%), and Hi-nek, 6 (5%) (not significant). Survival analysis revealed no difference between the 2 groups (P = .23). The patients' median Oxford Hip Score was low/good (19), slightly worse for the Hi-nek group (not significant). Taking all evidence together, neither implant was outperforming the other at 7 years.

Human bone-derived cells support formation of human osteoclasts from arthroplasty-derived cells in vitro.

Mononuclear osteoclast precursors are present in the wear-particle-associated macrophage infiltrate found in the membrane surrounding loose implants. These cells are capable of differentiating into osteoclastic bone-resorbing cells when co-cultured with the rat osteoblast-like cell line, UMR 106, in the presence of 1,25(OH)2 vitamin D3. In order to develop an in vitro model of osteoclast differentiation which more closely parallels the cellular microenvironment at the bone-implant interface in situ, we determined whether osteoblast-like human bone-derived cells were capable of supporting the differentiation of osteoclasts from arthroplasty-derived cells and analysed the humoral conditions required for this to occur. Long-term co-culture of arthroplasty-derived cells and human trabecular-bone-derived cells (HBDCs) resulted in the formation of numerous tartrate-resistant-acid-phosphatase (TRAP) and vitronectin-receptor (VNR)-positive multinucleated cells capable of extensive resorption of lacunar bone. The addition of 1,25(OH)2 vitamin D3 was not required for the formation of osteoclasts and bone resorption. During the formation there was release of substantial levels of M-CSF and PGE2. Exogenous PGE2 (10(-8) to 10(-6) M) was found to stimulate strongly the resorption of osteoclastic bone. Our study has shown that HBDCs are capable of supporting the formation of osteoclasts from mononuclear phagocyte precursors present in the periprosthetic tissues surrounding a loose implant. The release of M-CSF and PGE2 by activated cells at the bone-implant interface may be important for the formation of osteoclasts at sites of pathological bone resorption associated with aseptic loosening.