B. Willem Schreurs

Identification of Small Heat Shock Protein B8 (HSP22) as a Novel TLR4 Ligand and Potential Involvement in the Pathogenesis of Rheumatoid Arthritis

Dendritic cells (DCs) are specialized APCs that can be activated upon pathogen recognition as well as recognition of endogenous ligands, which are released during inflammation and cell stress. The recognition of exogenous and endogenous ligands depends on TLRs, which are abundantly expressed in synovial tissue from rheumatoid arthritis (RA) patients. Furthermore TLR ligands are found to be present in RA serum and synovial fluid and are significantly increased, compared with serum and synovial fluid from healthy volunteers and patients with systemic sclerosis and systemic lupus erythematosus. Identification of novel endogenous TLR ligands might contribute to the elucidation of the role of TLRs in RA and other autoimmune diseases. In this study, we investigated whether five members of the small heat shock protein (HSP) family were involved in TLR4-mediated DC activation and whether these small HSPs were present in RA synovial tissue. In vitro, monocyte-derived DCs were stimulated with recombinant αA crystallin, αB crystallin, HSP20, HSPB8, and HSP27. Using flow cytometry and multiplex cytokine assays, we showed that both αA crystallin and HSPB8 were able to activate DCs and that this activation was TLR4 dependent. Furthermore, Western blot and immunohistochemistry showed that HSPB8 was abundantly expressed in synovial tissue from patients with RA. With these experiments, we identified sHSP αA crystallin and HSPB8 as two new endogenous TLR4 ligands from which HSPB8 is abundantly expressed in RA synovial tissue. These findings suggest a role for HSPB8 during the inflammatory process in autoimmune diseases such as RA.

Acetabular Reconstruction with Impaction Bone-Grafting and a Cemented Cup in Patients Younger Than Fifty Years Old

In a previous report, we presented our results of forty-two acetabular reconstructions, performed with use of impaction bone-grafting and a cemented polyethylene cup, in thirty-seven patients who were younger than fifty years and had a minimum of fifteen years of follow-up. The present update study shows the results after twenty to twenty-eight years. Eight additional cups had to be revised--four because of aseptic loosening, three because of wear, and one during a revision of the stem. Three additional cups were considered loose on radiographs. Survivorship of the acetabular reconstructions, with an end point of revision for any reason, was 73% after twenty years and 52% after twenty-five years. With revision for aseptic loosening as the end point, survival was 85% after twenty years and 77% after twenty-five years; for signs of loosening on radiographs, survival was 71% at twenty years and 62% at twenty-five years. In conclusion, our previous results have declined but the technique of using impacted morselized bone graft and a cemented cup is useful for the purpose of restoring bone stock in young patients whose acetabular defects require primary or revision total hip arthroplasty.

Particle size of bone graft and method of impaction affect initial stability of cemented cups: human cadaveric and synthetic pelvic specimen studies.

We determined the effect of bone graft particle size and impaction technique on the initial stability of cemented acetabular cups. First, acetabular reconstructions were performed in human cadaveric pelvic bones in which type 2 AAOS cavitary defects were created. Reconstructions were made with small bone grafts (average 2 mm) produced by a bone mill or large bone grafts (average 9 mm) produced by hand with a rongeur. All chips were made from freshly-frozen femoral heads. Impaction was done using acetabular impactors and a hammer. We did a loading experiment with a gradually increasing dynamic load up to 3000 N. We used radiostereometric analysis (RSA) to determine cup stability. The cups were more stable when large bone grafts were used. Because of limitations of the cadaver model, we developed a synthetic acetabular model. For validation of this model, we repeated the experiments using small and large bone grafts. The results with both models were similar. In the synthetic model, we compared impaction with hammer and impactors with the reversed reaming technique using manual compression on the reamer. The latter method resulted in more migration. We recommend firm impaction with a hammer of large bone grafts for optimal stability of the cup.

Favorable results of acetabular reconstruction with impacted morsellized bone grafts in patients younger than 50 years: A 10- to 18-year follow-up study of 34 cemented total hip arthroplasties

We report a long-term review of 41 acetabular reconstructions using impacted morsellized bone grafts and a cemented total hip arthroplasty (THA) in patients younger than 50 (22-49; average 38) years. Reconstruction was performed in 23 primary THA (19 patients) and 18 revision THA (17 patients). 3 patients were lost to follow-up and 3 (4 hips) died within 10 years of surgery; none had a revision. Thus, 34 hips (30 patients) were reviewed with an average follow-up of 13 (10-18) years. In 2 hips, a revision was performed for aseptic loosening of the acetabular component 7 and 11 years after surgery. One additional cup was revised after 12 years during a femoral stem revision due to wear and matching problems, but was well fixed. The survival rate of the acetabular reconstruction technique was 94% (95% CI: 90-98%).

Acetabular Revision with Impacted Morselized Cancellous Bone Graft and a Cemented Cup in Patients with Rheumatoid Arthritis A Concise Follow-up, at Eight to Nineteen Years, of a Previous Report*

Background: Acetabular revision in patients with rheumatoid arthritis is often difficult because of the poor quality and quantity of the acetabular bone stock. The purpose of this study was to evaluate the midterm clinical and radiographic outcomes of acetabular revision with use of an impaction bone-grafting technique and a cemented polyethylene cup.Methods: Thirty-five consecutive acetabular revisions were performed with impaction bone-grafting and use of a cemented cup in twenty-eight patients with rheumatoid arthritis. The average age at the revision was fifty-seven years. The minimum duration of follow-up of all reconstructions that were still functioning or that were followed until the time of death was three years (mean, 7.5 years; range, three to fourteen years). No patient was lost to follow-up, but five patients (six hips) died before the time of the review. The acetabular bone defects were classified as cavitary in twelve hips and as combined segmental-cavitary in twenty-three.Results: The five patients (six hips) who died had been doing well at the time of their latest follow-up. Of the remaining patients, six (six hips) had a repeat revision. The average Harris hip score of the living patients with a surviving implant at the time of follow-up was 82 points, and there was no or only mild pain in twenty-one of the twenty-three hips. Radiographic analysis of all twenty-nine hips that had not been revised showed loosening in one hip and a nonprogressive radiolucent line in one zone in two others. Kaplan-Meier analysis demonstrated a prosthetic survival rate, with aseptic loosening as the end point, of 90% at eight years.Conclusion: Acetabular revision with impaction bone-grafting and a cemented cup in patients with rheumatoid arthritis had acceptable results at an average of 7.5 years postoperatively.Level of Evidence: Therapeutic study, Level IV (case series [no, or historical, control group]). See Instructions to Authors for a complete description of levels of evidence.

Revisions of extensive acetabular defects with impaction grafting and a cement cup.

BackgroundLoosening of acetabular components often leads to bony defects. Management of extensive acetabular bone loss in hip revision arthroplasty can be a tremendous challenge.Questions/purposesWe asked whether a reconstruction with impacted bone grafts will provide a durable and pain-free function in extensive acetabular defects. We specifically determined the (1) survival rates with the end point of revision for any reason, aseptic revision, and radiographic loosening; (2) visual analog scale (VAS) pain score, Harris hip score (HHS), and the Oxford Hip Questionnaire score (OHQS); (3) number of repeat revisions; (4) complications; and (5) radiographic loosening, wear, and radiolucencies.Patients and MethodsWe retrospectively followed 25 patients (27 hips) with extensive acetabular defects. No patient was lost to followup. Two patients died during followup. Minimum followup was 3xa0years (mean, 8.8xa0years; range, 3–14.1xa0years).ResultsThree patients (three hips) underwent repeat revision surgery and another two patients (two hips) had radiographically loose hips. The 10-year survival rate was 88% (95% confidence interval, 74.2%–100%) with the end point acetabular revision for any reason and 95% (95% confidence interval, 86.0%–100%) with the end point acetabular revision for aseptic loosening. The mean HHSs were 55 points before surgery and 72 points postoperatively.ConclusionsAcetabular reconstruction with impaction bone grafting and a cemented cup is a reliable technique with a 10-year survival rate of 88% in patients with extensive acetabular deficiencies.Level of EvidenceLevel IV, case series. See the Guidelines for Authors for a complete description of levels of evidence.

Novel insights in the regulation of CCL18 secretion by monocytes and dendritic cells via cytokines, Toll-like receptors and rheumatoid synovial fluid

BackgroundThe T cell attracting chemokine CCL18 is produced by antigen presenting cells and a role for CCL18 has been suggested in the pathogenesis of a variety of diseases. Rheumatoid arthritis (RA) is one of these conditions, in which abundant CCL18 production is present. Although Th2 cytokines and IL-10 are known to have an effect on CCL18 production, there are several gaps in our knowledge regarding the exact regulation of CCL18 secretion, both in general and in RA. In this study we provide new insights in the regulation of CCL18 secretion by monocytes and dendritic cells.ResultsIn contrast to a large panel of pro-inflammatory stimuli (IL-1β, TNF-α, IL-10, IL-13, IL-15, IL-17, IL-18, IFN-γ), T cell mimicking molecules (RANKL, CD40L) or TLR driven maturation, the anti-inflammatory IL-10 strongly stimulated DC to secrete CCL18. On freshly isolated monocytes, CCL18 secretion was induced by IL-4 and IL-13, in strong synergy with IL-10. This synergistic effect could already be observed after only 24 hours, indicating that not only macrophages and dendritic cells, but also monocytes secrete CCL18 under these stimulatory conditions. A high CCL18 expression was detected in RA synovial tissue and incubation of monocytes with synovial fluid from RA patients clearly enhanced the effects of IL-4, IL-13 and IL-10. Surprisingly, the effect of synovial fluid was not driven by IL-10 of IL-13, suggesting the presence of another CCL18 inducing factor in synovial fluid.ConclusionIn summary, IL-10 synergistically induces CCL18 secretion in combination with IL-4 of IL-13 on monocytes and monocyte derived cells. The effects of IL-14, IL-13 and IL-10 are strongly enhanced by synovial fluid. This synergy may contribute to the high CCL18 expression in RA.

Metal ion interpretation in resurfacing versus conventional hip arthroplasty and in whole blood versus serum. How should we interpret metal ion data

Metal ions generated from joint replacements are a cause for concern. There is no consensus on the best surrogate measure of metal ion exposure, and both serum and whole blood measurements are used in clinical practice. This study provides a guideline for interpretation of metal ion analysis in clinical practice. In a prospective trial comparing hip resurfacing (HR) with a conventional metal-on-metal (MoM) total hip arthroplasty (THA) cobalt and chromium levels were determined for whole blood and serum in 343 paired samples at regular intervals up to 24 months postoperatively. Cobalt whole blood and serum levels increased significantly after both procedures. Cobalt concentrations were significantly higher for the HR group compared to the THA group, at 3, 6 and 12 months, for whole blood and serum. At 24 months cobalt levels decreased and differences between HR and THA were no longer significant. In contrast, chromium whole blood levels remained significantly higher for HR until 24 months. Whole blood and serum levels could not be used interchangeably. The mean differences for cobalt and chromium between blood and serum values were +0.13 μg/L and –0.91 μg/L respectively. Regression analysis provided a formula for conversion from serum to blood of 0.34+[0.88*Co serum] for cobalt and 0.14+[0.58*Cr serum] for chromium, with an acceptable prediction error below ±1.0 μg/L. Cobalt and chromium levels were significantly higher for HR versus THA, especially during the run-in phase of one year. Overall, the metal ion levels were well below 5 μg/L. We cannot recommend the use of whole blood over serum measurements or vice versa. The provided conversion formula between whole blood and serum in combination with the presented practical guidelines may be useful for clinical practice.

Favorable Survival of Acetabular Reconstruction With Bone Impaction Grafting in Dysplastic Hips

Acetabular bone loss hampers implantation of a total hip arthroplasty in patients with developmental dysplasia of the hip. The bone impaction grafting technique in combination with a cemented total hip can restore the bone stock in these patients, but do these reconstructions yield satisfying long-term results? We used this technique in 28 hips (22 consecutive patients). The degree of dislocation was graded preoperatively as Crowe I in five hips, Crowe II in eight hips, Crowe III in nine hips, and Crowe IV in four hips. We present the long-term results of this bone impaction grafting technique a minimum of 10xa0years after surgery. Two patients died before the minimum followup of 10xa0years, leaving 20 patients (26 hips). Two cups were revised, one cup for a sciatic nerve palsy (at 2xa0years) and the other for aseptic loosening after 12xa0years. The cumulative survival of the cup with revision for any reason as the end point was 96% at 10xa0years and 84% at 15xa0years. There were no femoral revisions during followup. The bone impaction grafting technique in combination with a cemented cup is an effective technique for developmental dysplasia of the hip with favorable long-term results.Level of Evidence: Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.

Similar effects of rofecoxib and indomethacin on the incidence of heterotopic ossification after hip arthroplasty

Backgroundu2003Although indomethacin is effective in preventing heterotopic ossification (HO) after primary total hip arthroplasty, side effects are frequently observed. In the last decade a new class of drugs—the COX-2 selective nonsteroidal anti-inflammatory drugs—has been developed. To investigate the effect of these COX-2 selective NSAIDs on heterotopic ossification (HO) after primary total hip arthroplasty (THA), we conducted a randomized controlled trial using either indomethacin or rofecoxib for 7 days. Methodsu2003186 patients received either indomethacin 3 times daily, or rofecoxib twice, and 1 placebo, daily for 7 days. HO was graded according to the 1-year postoperative radiographs according to the Brooker classification. Resultsu200312 of the 186 patients included discontinued their medication before the end of the trial due to side effects. The remaining 174 patients were included in the analysis. In the indomethacin group (n = 89), 77 patients (87%) showed no HO, 9 showed HO of grade 1 and 3 showed HO of grade 2 according to the Brooker classification. In the rofecoxib group (n = 85) 73 patients (86%) showed no ossification, 9 showed grade 1, and 3 showed grade 2. Interpretationu2003The prophylactic effect of rofecoxib for 7 days in preventing heteropic ossification after primary total hip arthroplasty is comparable to the effect of indomethacin given for 7 days. These results indicate that the development of HO follows a COX-2 pathway.