PERSEPT 3: A phase 3 clinical trial to evaluate the haemostatic efficacy of eptacog beta (recombinant human FVIIa) in perioperative care in subjects with haemophilia A or B with inhibitors.

INTRODUCTION: Surgical procedures in persons with haemophilia A or B with inhibitors (PwHABI) require the use of bypassing agents (BPA) and carry a high risk of complications. Historically, only two BPAs have been available; these are reported to have variable responses. AIM: To prospectively evaluate the efficacy and safety of a new bypassing agent, human recombinant factor VIIa (eptacog beta) in elective surgical procedures in PwHABI in a phase 3 clinical trial, PERSEPT 3. METHODS: Subjects were administered 200 µg/kg (major procedures) or 75 µg/kg eptacog beta (minor procedures) immediately prior to the initial surgical incision; subsequent 75 µg/kg doses were administered to achieve postoperative haemostasis and wound healing. Efficacy was assessed on a 4-point haemostatic scale during the intra- and postoperative periods. Anti-drug antibodies, thrombotic events and changes in clinical/laboratory parameters were monitored throughout the perioperative period. RESULTS: Twelve subjects underwent six major and six minor procedures. The primary efficacy endpoint success proportion was 100% (95% CI: 47.8%-100%) for minor procedures and 66.7% (95% CI: 22.3%-95.7%) for major procedures; 81.8% (95% CI: 48.2%-97.7%) of the procedures were considered successful using eptacog beta. There was one death due to bleeding from a nonsurgical site; this was assessed as unlikely related to eptacog beta. No thrombotic events or anti-eptacog beta antibodies were reported. CONCLUSION: Two eptacog beta dosing regimens in PwHABI undergoing major and minor surgical procedures were well-tolerated, and the majority of procedures were successful based on surgeon/investigator assessments. Eptacog beta offers clinicians a new potential therapeutic option for procedures in PwHABI.

The safety of activated eptacog beta in the management of bleeding episodes and perioperative haemostasis in adult and paediatric haemophilia patients with inhibitors.

INTRODUCTION: Haemophilia patients with inhibitors often require a bypassing agent (BPA) for bleeding episode management. Eptacog beta (EB) is a new FDA-approved recombinant activated human factor VII BPA for the treatment and control of bleeding in haemophilia A or B patients with inhibitors (≥12 years of age). We describe here the EB safety profile from the three prospective Phase 3 clinical trials performed to date. AIM: To assess EB safety, immunogenicity and thrombotic potential in children and adults who received EB for treatment of bleeding and perioperative care. METHODS: Using a randomized crossover design, 27 subjects in PERSEPT 1 (12-54 years) and 25 subjects in PERSEPT 2 (1-11 years) treated bleeding episodes with 75 or 225 µg/kg EB initially followed by 75 µg/kg dosing at predefined intervals as determined by clinical response. Twelve PERSEPT 3 subjects (2-56 years) received an initial preoperative infusion of 75 µg/kg (minor procedures) or 200 µg/kg EB (major surgeries) with subsequent 75 µg/kg doses administered intraoperatively and post-operatively as indicated. Descriptive statistics were used for data analyses. RESULTS: Sixty subjects who received 3388 EB doses in three trials were evaluated. EB was well tolerated, with no allergic, hypersensitivity, anaphylactic or thrombotic events reported and no neutralizing anti-EB antibodies detected. A death occurred during PERSEPT 3 and was determined to be unlikely related to EB treatment by the data monitoring committee. CONCLUSION: Results from all three Phase 3 trials establish an excellent safety profile of EB in haemophilia A or B patients with inhibitors for treatment of bleeding and perioperative use.

Vascular remodeling underlies rebleeding in hemophilic arthropathy.

Hemophilic arthropathy is a debilitating condition that can develop as a consequence of frequent joint bleeding despite adequate clotting factor replacement. The mechanisms leading to repeated spontaneous bleeding are unknown. We investigated synovial, vascular, stromal, and cartilage changes in response to a single induced hemarthrosis in the FVIII-deficient mouse. We found soft-tissue hyperproliferation with marked induction of neoangiogenesis and evolving abnormal vascular architecture. While soft-tissue changes were rapidly reversible, abnormal vascularity persisted for months and, surprisingly, was also seen in uninjured joints. Vascular changes in FVIII-deficient mice involved pronounced remodeling with expression of α-Smooth Muscle Actin (SMA), Endoglin (CD105), and vascular endothelial growth factor, as well as alterations of joint perfusion as determined by in vivo imaging. Vascular architecture changes and pronounced expression of α-SMA appeared unique to hemophilia, as these were not found in joint tissue obtained from mouse models of rheumatoid arthritis and osteoarthritis and from patients with the same conditions. Evidence that vascular changes in hemophilia were significantly associated with bleeding and joint deterioration was obtained prospectively by dynamic in vivo imaging with musculoskeletal ultrasound and power Doppler of 156 joints (elbows, knees, and ankles) in a cohort of 26 patients with hemophilia at baseline and during painful episodes. These observations support the hypothesis that vascular remodeling contributes significantly to bleed propagation and development of hemophilic arthropathy. Based on these findings, the development of molecular targets for angiogenesis inhibition may be considered in this disease.

A comprehensive meta-analysis of association between genetic variants of GDF5 and osteoarthritis of the knee, hip and hand.

OBJECTIVE: A number of studies have reported an association of GDF5 with osteoarthritis (OA) but have produced some divergent findings and their interpretation may not be straightforward. METHODS: We investigated the association between GDF5 and OA using meta-analytic techniques, combining all published data up to Nov 2014. 16 independent samples from 11 research teams contributed data on SNP rs143383 (located in the 5'-UTR of GDF5) and knee, hip, and hand OA. The total number of cases and controls for this marker was 7,965 and 12,747 for knee OA, 6,363 and 9,727 for hip OA, and 4,335 and 5,991 for hand OA, respectively. The ORs for each OA phenotype were synthesized using random-effects models or fixed-effects models depending on the test of between-study heterogeneity. RESULTS: Using a random-effect model, a significant difference was identified between patients with knee OA and controls for the T-allele of rs143383 (Subtotal OR = 1.18, 95 % CI=1.10-1.27, P=1.84 × 10(-6)). For hand OA, a moderate association was also observed (Subtotal OR = 1.09, 95 % CI = 1.02-1.16, P = 0.01) for SNP rs143383 in the combined population. However, non-statistically significant summary OR of hip OA was found in both combined studies (Subtotal OR = 1.22, 95 % CI = 0.97-1.53, P = 0.09) and European studies (Subtotal OR = 1.16, 95 % CI = 0.91-1.48, P = 0.23). CONCLUSIONS: Our results demonstrate that SNP rs143383 of GDF5 is a compelling risk factor for both knee and hand OA, and provide further support for GDF5 in the etiology of OA. Further efforts to identify functional variants of GDF5 in in vitro and in vivo will be required.

Revisiting the concept of inflammatory cell-induced corrosion.

A peculiar type of surface pitting damage to revised joint replacement implant metal surfaces has been attributed to cellular activity and termed "inflammatory cell-induced-corrosion." We visually examined 1859 explanted metal implants to document the presence and extent of these features. The data was used to examine correlations between these features and the implant material, and modularity as well as clinical variables. The features were observed in approximately 77% of modular and 30% of monobloc hip implants in a variety of metals, as well as to some degree in various other implants. To test the possibility that these features were an artefact of electrocautery damage during revision surgery, a cleaned, flat, polished, CoCr disk was exposed to a variety of electrocautery interactions. This led to the production of pits and markings comparable to the published damage and to the damage found on the explants we examined. It is concluded that electrocautery damage rather than cellular activity is the cause of these features. Although rarely reported, this damage may be associated with femoral neck fracture. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1148-1155, 2018.

Radial head excision and synovectomy in patients with hemophilia.

BACKGROUND: Chronic hemophilic synovitis of the elbow usually leads to enlargement and erosion of the radial head, resulting in mechanical blockage of forearm rotation, synovial impingement, recurrent hemarthrosis, and pain. The purpose of the present study was to evaluate the intermediate-term results of radial head excision and synovectomy in a large group of patients with hemophilia who had been managed at a single institution. METHODS: Information on forty radial head excision and synovectomy procedures that had been performed at our institution from 1969 to 2004 was retrospectively collected. All but one of the operations had been performed in patients with severe hemophilia. The mean age of the patients at the time of the procedure was thirty-three years. Pain, limited range of motion, and bleeding were the indications for surgery. The mean duration of follow-up was 7.7 years. RESULTS: Only one postoperative complication was observed: a posterior interosseous nerve palsy that fully resolved by six months. No additional surgical intervention for bleeding was required in sixteen of the nineteen elbows in which bleeding was one of the indications for surgery. Of the forty elbows, seven required a secondary surgical procedure at a mean of five years after the excision of the radial head. Examination of the mean range of motion at the time of the latest follow-up demonstrated a 63 degrees increase in the pronation-supination arc (p < 0.00001) but only a 2 degrees increase in the flexion arc. CONCLUSIONS: Radial head excision in patients with hemophilia is an effective procedure for improving forearm rotation and reducing pain and bleeding frequency, with a low risk of complications.

Long-term results of primary total knee replacement in patients with hemophilia.

BACKGROUND: The outcome of total knee replacement in patients with hemophilia has been variable. Several authors have suggested a relationship between high rates of late infection following total knee replacement in patients with hemophilia and a positive HIV status. The objective of this study was to evaluate the results of primary total knee replacements performed in a large group of hemophilic patients at a single institution by the same primary surgeon. METHODS: The results of ninety primary total knee replacements performed in sixty-eight hemophilic patients between 1975 and 2001 were reviewed retrospectively. The HIV status and the CD4 count at the time of the surgery were recorded for fifty-three patients (seventy-one knees). Knee Society clinical and functional scores were determined for twenty-nine patients (thirty-eight knees) who were available for follow-up. Prosthetic survival was calculated with use of Kaplan-Meier survivorship analysis. RESULTS: The overall prevalence of infection was 16%. Twelve knees required removal of components, and the reason for the removal was late infection in nine of them. The prevalence of infection in HIV-positive and HIV-negative patients was 17% and 13%, respectively (p = 0.5). When component removal for any reason, survival free of infection at any point, and mechanical failure were considered to be the end points, the ten-year survival rates were 83%, 77%, and 96%, respectively. The Knee Society clinical score was excellent or good for 80% of the knees, and the Knee Society functional score was excellent or good for 97% of the knees. CONCLUSIONS: Despite the anatomical challenges, the mechanical survival of total knee replacements in patients with hemophilia is quite good. However, the prevalence of infection after the total knee replacements was high. The prevention of late infection would substantially improve the long-term outcome of total knee replacements in this patient population.

Orthopedic surgery fellowships: the effects of interviewing and how residents establish a rank list.

The Orthopaedic Fellowship Match was established in 2008 to streamline and improve the process of matching residents and fellowships. The purpose of this study was to quantify the factors that affect the application process and to determine how residents establish a rank list. The Orthopaedic Fellowship Match has improved the ability of residents and programs to consider their options more carefully and to focus on finding the best match. However, this process introduces new factors for all parties involved to consider. The costs of the interview process and time away from service for residents may be larger than anticipated. Ultimately, residents value operative experience and staff members at a fellowship more than all other factors when selecting a fellowship.

Advances in radionuclide therapeutics in orthopaedics.

Radiopharmaceuticals not only are used for diagnostic purposes but also increasingly in the treatment of many orthopaedic-related disorders. With the development of specific bone-seeking radiopharmaceuticals, the side effects of treatment are minimized, therapeutic effects are sustained, and concomitant use with other modalities may have synergistic effects. These new radiopharmaceuticals, such as strontium 89 and samarium 153-ethylene diamine tetramethylene phosphate, have been used as palliative treatment for patients with bone pain from osseous metastases. Excellent clinical responses with acceptable hematologic toxicity have been observed, and clinical results rival those of external beam radiation therapy. Radiosynovectomy has become a procedure of choice at many institutions to treat recurrent hemarthrosis and chronic synovitis in patients whose hemophilia is poorly controlled with medical management. Radiosynovectomy also remains a viable option to treat chronic synovitis secondary to inflammatory arthropathies, particularly rheumatoid arthritis.

Hemophilic arthropathy.

The most common clinical manifestation of hemophilia is arthropathy secondary to recurrent hemarthroses and chronic synovitis. Joint-surface erosions secondary to chronic synovitis often occur in early childhood and progress to advanced arthropathy by late adolescence. The knee, elbow, ankle, hip, and shoulder are the most commonly involved joints. Management of hemophilic arthropathy has advanced with the development of purified clotting factor concentrates and procedures to prevent chronic synovitis. Radiosynovectomy using beta particle-emitting radiocolloids has been effective in dramatically reducing the frequency of hemarthroses and resolving chronic synovitis. The most common surgical procedures used to manage hemophilic arthropathy are synovectomy, joint debridement, fusion, and joint arthroplasty. Late infection and arthrofibrosis complicate joint arthroplasty more often in these patients than in patients with other forms of arthritis. The high incidence of late infection may relate to frequent intravenous self-infusion of clotting factor combined with immune suppression. Despite the medical and surgical complexities of hemophilic arthropathy, orthopaedic procedures have a high incidence of patient satisfaction.

Radial head excision and synovectomy in patients with hemophilia. Surgical technique.

BACKGROUND: Chronic hemophilic synovitis of the elbow usually leads to enlargement and erosion of the radial head, resulting in mechanical blockage of forearm rotation, synovial impingement, recurrent hemarthrosis, and pain. The purpose of the present study was to evaluate the intermediate-term results of radial head excision and synovectomy in a large group of patients with hemophilia who had been managed at a single institution. METHODS: Information on forty radial head excision and synovectomy procedures that had been performed at our institution from 1969 to 2004 was retrospectively collected. All but one of the operations had been performed in patients with severe hemophilia. The mean age of the patients at the time of the procedure was thirty-three years. Pain, limited range of motion, and bleeding were the indications for surgery. The mean duration of follow-up was 7.7 years. RESULTS: Only one postoperative complication was observed: a posterior interosseous nerve palsy that fully resolved by six months. No additional surgical intervention for bleeding was required in sixteen of the nineteen elbows in which bleeding was one of the indications for surgery. Of the forty elbows, seven required a secondary surgical procedure at a mean of five years after the excision of the radial head. Examination of the mean range of motion at the time of the latest follow-up demonstrated a 63 degrees increase in the pronation-supination arc (p < 0.00001) but only a 2 degrees increase in the flexion arc. CONCLUSIONS: Radial head excision in patients with hemophilia is an effective procedure for improving forearm rotation and reducing pain and bleeding frequency, with a low risk of complications.

Repair of steps and gaps in articular fracture models.

To examine the healing of surface defects in articular fractures, gaps measuring 0.5 mm wide and 2 mm deep were created in 0.5-mm coronal step-offs on the medial femoral condyles of 16 rabbits, and identical gaps without step-offs were created in another set of 13 rabbits. Evaluation of repair was done 6, 12, and 24 weeks postoperatively. Histologically, subchondral bone restoration of gaps in step-offs was complete by 24 weeks, whereas restoration was incomplete in most gap-only lesions. Bone density measured by peripheral quantitative computed tomography was normal in gaps in step-offs by 24 weeks, but values were less than in controls in the gap-only group. A moderate degree of degeneration was detected only at the high sides of step-off + gap lesions. The joint surface was restored by fibrous cartilage that showed gradually improving maturity in all defects, however, real integration with adjacent original cartilage did not occur. Immunohistologic examination showed decreasing collagen Type I and increasing Type II staining intensity in repair tissue of both types of lesions. These observations suggest that minor surface gaps and steps of articular fractures may regenerate without inducing severe early joint degeneration. However, certain repair features make the long-term outcome of these defects uncertain.