Haemophilic Arthropathy Patients Research Articles

Neutrophil-Dependent Immune Response Promotes Joint Damage in Hemophilia

Background: Hemophilic arthropathy (HA) is the predominant pathophysiology resulting from recurrent joint bleeding in individuals with hemophilia and leads to permanent joint damage, chronic pain and reduced quality of life. Although FVIII replacement therapy or FVIII mimetics like HEMLIBRA have significantly improved the disease outcome, joint bleeding continues to occur in severely hemophilic patients (FVIII<1%). HA starts at an early age and develops progressively over time, warranting the need for a therapy that can intervene the progression of HA. Unfortunately, such therapy does not exist and the etiological mechanism of HA remains poorly understood. Aim: To determine whether neutrophil Gasdermin-D (GSDMD)-dependent generation of neutrophil extracellular traps (NETs) in in the joint promotes HA. Methods: Knee joints in FVIII-total knockout (F8 TKO) or littermate WT male mice were injured using a needle . Scoring of the bleeding severity and histology of injured joints were conducted to assess the joint injury in mice.Imaging-flow-cytometry and ELISA assays were used to evaluate the number of circulating NETs in the blood samples of patients diagnosed with HA and mice with following knee injury. Neutrophils from HA patients, F8 TKO mice and matched controls were isolated, activation of GSDMD-pathway components was evaluated in neutrophils using qRT-PCR (gene expression) and western blotting (protein levels and cleavage). Results: F8 TKO but not control mice manifested unresolved joint injury and severe bleeding 5-days post knee injury. Circulating NETs (cNETs) and cNETs markers llike neutrophil elastase or citrulinated histones were significantly elevated in the plasma of hemophilia patients diagnosed with HA and injured F8 TKO mice but not plasma of control humans or injured WT mice or uninjured F8 TKO mice. Major genes (mRNA levels) associated with GSDMD-mediated NETs generation were significantly elevated in neutrophils of HA patients and injured F8 TKO mice compared to matched controls. Finally, western blot analysis revealed activation of GSDMD pathway in neutrophils isolated from HA patients and F8 TKO mice but not matched controls. Conclusions: These findings are the first to suggest that GSDMD-dependent generation of NETs contributes to the pathogenesis of HA

Ferroptosis: a new target for iron overload-induced hemophilic arthropathy synovitis.

Iron deposition is closely related to developing haemophilic arthropathy (HA). Studying the relationship between ferroptosis signal expression and iron overload in HA synovium facilitates understanding the pathogenesis of joint synovial hyperplasia in bloodborne arthritis and the development of new protective methods. The knee synovium was collected from HA and osteoarthritis (OA) patients, and pathological changes were analysed by HE and Prussian blue staining. Ferroptosis phenotypes were examined by immunohistochemistry and western blotting. Moreover, ferric ammonium citrate (FAC)-induced was used to construct an in vitro iron overload model to investigate the relationship between iron overload and ferroptosis in synovial fibroblasts (FLS). Furthermore, the factors influencing ferroptosis in FLS were explored. Iron deposition, cell proliferation, and vascular proliferation in the synovium of HA were more obvious. Ferroptosis in HA synovium appears to inhibit. FLS ferroptosis increased with iron accumulation, malondialdehyde (MDA) in cells, and glutathione (GSH) depletion. TNF-α plays a protective role in this process. Blocking the action of TNF-α and inducing ferroptosis significantly reduced synovial proliferation. TNF-α inhibitors combined with a ferroptosis inducer may be a new therapeutic method for HA synovitis.

Total Hip Arthroplasty in Patients with Hemophilia: What Do We know?

Total hip arthroplasty (THA) is the mainstay therapy for terminally hemophilic arthropathy patients. Hemophilic patients have distinguishing characteristics, including the increased likelihood of bleeding, younger age, restricted pre-operative joint motion, disrupted anatomy, and more post-operative side effects. The present study aimed to assess the THA sequels in hemophilic patients from various perspectives, including indications, challenges, factor replacement post-operative outcomes, and other complications.

ADAMTS-4 as a possible distinguishing indicator between osteoarthritis and haemophilic arthropathy.

IntroductionOsteoarthritis (OA) and haemophilic arthropathy (HA) are clinically similar, but pathologically distinct conditions which result in joint pain and loss of function. Distinguishing their disease mechanisms is therefore a key step in the development of curative therapy, as opposed to current symptomatic treatments. A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) 4 is a metzincin‐family member proteoglycan with known local involvement in OA pathogenesis.AimTo investigate the potential differences and discriminatory potential of ADAMTS‐4 between OA and HA patients.MethodsWe determined ADAMTS‐4 plasma concentrations by ELISA in patients with HA and OA. This pilot cross‐sectional study included N = 40 male participants equally divided across four subgroups: haemophilia patients with severe or mild HA and control subjects with severe or mild/no OA.ResultsOur study showed a striking elevation in plasma ADAMTS‐4 expression levels in HA patients as compared to OA, as well as an increase in patients with severe as compared to mild HA. By performing the binomial logistical analysis and fitting the receiver–operator curve (ROC) (cut‐off probability .5), ADAMTS‐4 had a sensitivity of 95% and specificity of 50% in discriminating between HA and OA among our study participants.ConclusionUncovering the marked differences in plasma levels of ADAMTS‐4 in patients with HA versus OA potentially sheds new light on the mechanisms of HA pathogenesis and could foster more research into the roles ADAMTS‐4 and other matrix metalloproteinases (MMPs) play in HA versus OA.

Therapy Response of the Yttrium-90 (Y-90) Colloid and Rhenium-186 (Re-186) Sulphur Colloid Radiosynovectomy in Hemophilic Arthropathy

Introduction Radiosynovectomy (also known as radiosynoviorthesis) is a local form of radiotherapy that is used in chronic hemophilic synovitis in the absence of radiological evidence of extensive joint damage and in patients that have failed conservative therapy with clotting factor replacement and physiotherapy. Objectives To evaluate the effectiveness of the Yttrium-90 (Y-90) colloid and Rhenium-186 (Re-186) sulphur colloid radiosynovectomy in hemophilic arthropathy in terms of bleeding frequency, pain score, range of motion and performance score. Methodology This was a prospective cohort trial. A total of 68 hemophilic arthropathy patients who had been treated with radiosynovectomy for knee, ankle, elbow and hip joint were included in this study. Patients were followed up to assess their bleeding frequency, pain score, range of motion of the affected joint and Karnofsky or Lansky performance scale at pre and 6 months post therapy. Result A marked decrease (80–100%) in bleeding frequency was seen in 66.2% of patients, 14.7% of patients had moderate decrease (51–79%) and mild decrease (30–50%) was seen in 14.7% of patients. The frequency of intraarticular bleeding and pain score were significantly reduced at 6 months follow up ( p<0.005). The Karnofsky and Lansky performance scales were also improved at 6 months follow up ( p<0.005). There was no significant difference between percentage of range of motion measured before and after the therapy ( p>0.005). Conclusion Radiosynovectomy is a safe and effective procedure in limiting bleeding frequency, reducing pain and increasing performance scale.

Artificial Intelligence Algorithm-Based Magnetic Resonance Imaging to Evaluate the Effect of Radiation Synovectomy for Hemophilic Arthropathy.

This study aimed to discuss magnetic resonance imaging (MRI) based on artificial intelligence (AI) algorithm to evaluate the effect of radiation synovectomy for hemophilic arthropathy (HA). MRI based on the Canny algorithm was applied and compared with conventional MRI to evaluate its application effects according to the PSNR and SSIM. Sixty patients diagnosed with HA were selected as the research subjects. According to the detection method, the patients were divided into group A (pathological detection after radiation synovectomy), group B (conventional MRI detection), and group C (MRI detection based on the Canny algorithm). The application value of MRI based on the Canny algorithm was judged by comparing the differences between the two detection methods and pathological results. The results displayed that the reconstruction effect of the Canny algorithm was remarkably better than that of the traditional algorithm regarding the peak signal-to-noise ratio (PSNR) and structural similarity (SSIM), which showed a clearer synovial contour. The results of the IPSG score of joint effusion and hemorrhage showed that there was a difference in the detection rate of joints between conventional MRI and pathological results on the score of 1 and 2 (P < 0.05); and there was no significant difference between the MRI and pathological results based on the Canny algorithm (P > 0.05). The results of the IPSG score of synovial hyperplasia showed that the detection rate of conventional MRI was different from pathological results on the score of 1 and 2 (P < 0.05); and there was no significant difference between the MRI and pathological results based on the Canny algorithm (P > 0.05). The results of the IPSG score of hemosiderin deposition showed that the detection rate of conventional MRI was different from the pathological results on the score of 1 and 2 (P < 0.05); and there was no significant difference between the MRI and pathological results based on the Canny algorithm (P > 0.05). The synovial volume of patients after surgery was reduced compared with that before surgery. One-factor variance was used to analyze the clinical hemorrhage frequency before and after surgery, and the results showed that the differences were statistically significant (P < 0.05). Therefore, MRI on account of AI algorithm made it easier to detect synovial contour, which was helpful to evaluate the efficacy of polygenic risk scores (PRS) surgery in HA patients. MRI based on the Canny algorithm had less differences between the score of hemophilic arthropathy and pathological results, which could replace conventional MRI examination and have clinical application value.

Unique Inflammatory Signature in Hemophilic Arthropathy: Epigenetic Changes Due to Interaction between Blood and Fibroblast-like Synoviocytes

Context: Hemophilic patients bleeding occur mainly into large joints such as knee, elbow or ankle. Severe recurrence of hemarthrosis leads to irreversible arthropathy called hemophilic arthropathy (HA) characterized by a progressive complete destruction of the joint with permanent pain, musculoskeletal disability and poor quality of life. Physiopathology of blood joint disease remains unclear. Some data suggest that HA and rheumatoid arthritis (RA) may share similar pathogenicity including elevation of inflammatory cytokines, chronic proliferative synovitis and cartilage destruction. However, in these two diseases the origin of inflammation differs and is linked to autoimmunity in RA and bleeding in HA. HA is the unique model of arthropathy in which resident cells like fibroblasts-like synoviocytes (FLS) are directly in contact with blood. Therefore, we hypothesized that FLS in HA could have a unique inflammatory signature as a consequence of contact with blood.Materials and methods: Human FLS were isolated from synovial tissues from five different HA patients and two non-HA patients at the time of knee or ankle joint arthroscopic synovectomy after informed consent were obtained from patients. Experiments with FLS cultures were performed between the third and the ninth passage. During that time, cultures were constituted of a homogeneous population of fibroblastic cells. THP-1 cells line has been used as a control.Results: FLS from hemophilic patients have a singular inflammatory cytokines profile- FLS (5x105 cells) were activated or not (medium) with LPS from Salmonella abortus equi (1 µg/ml) for 6 h and activated-cells supernatants were analyzed by ELISA. ELISPOT were performed with a panel of 105 different cytokines. After LPS stimulation, HA FLS expressed a unique profile of cytokines secretion, which differs from non-HA FLS and THP-1 cell line including IL-1α, IL-6 and IL-8 involved in innate immunity, IFN-γ, IL-5, IL-17A and IL-22 involved in adaptive immunity and MCP-1, M-CSF, MIF and MIP-3α involved in macrophages polarization.- Constitutive expression of IL-1 and IL-6 mRNA was detectable in all cells, but in contrast, as shown previously in normal FLS, no TNF-α mRNA was detectable. To investigate mechanisms responsible for the lack of IL-1 protein synthesis in LPS-activated HA FLS, cells were incubated with LPS for 3 h and then with 5 µg/ml actinomycin D. After 2h of actinomycin D treatment, IL-1 mRNA became lower in LPS-activated HA FLS versus LPS-activated non-HA FLS and THP-1 cells. These results indicate that de novo synthesized IL-1 mRNA has a short half-life in LPS-activated HA FLS.- Since cytokines mRNA seems to be unstable, we then investigated microRNA involvement in the regulation of cytokines. A miRNOME (Transcriptome Profiling miRNA, AFFYMETRIX) analysis showed that miRNAs expression was different between HA and nonHA FLS. Five have a very high difference in expression (hsa-miR664b-5p, hsa-miR4516, hsa-miR4289, hsa-miR6719-3p, hsa-miR675-5p), which potentially target mRNA involved in inflammatory pathways (NFKB, MAPK, Wnt/beta-catenin).In conclusion our study demonstrates for the first time that the presence of blood in contact with FLS may induce durable epigenetic changes that may participate to the pathophysiology of hemophilic arthropathy. DisclosuresMignot:Shire: Research Funding. Delarue:Roche: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Frenzel:Shire: Research Funding.

PMU4 Healthcare System IMPACT of High-Cost Disease Metrics in Colombia

The Colombian High-Cost Disease Fund (CHCDF) is a non-governmental technical organization created by the Ministry of Treasury and the Ministry of Health. All the insurers are required to report information on patients diagnosed with cancer, HIV, hemophilia, RA, CKD, hypertension, and diabetes mellitus. Through the SISCAC platform, CHCDF obtains such information and reports standardized metrics that allow stakeholders to improve the quality of health care and the delivery of health services. Record the selection and adoption of high-cost disease metrics by insurers and health service providers in Colombia. A development group was convened, consisting of two members of the CHCDF and two physician specialists; and a panel of independent experts, consisting of five sectors of the healthcare Colombian system. The search criteria were established to perform a systematic review of the literature and the preliminary indicators were selected by the development group. Between 2012 and 2019, a total of 13 evidence-based consensuses were held in which 267 metrics were established. In the last consensus, representativeness from the five sectors was obtained. The percentage of controlled diabetic patients increased from 33.0% in 2015 to 52.4% in 2018; 46.2% of hemophilic arthropathy patients received prophylaxis in 2015 and 60.2% in 2019; the percentage of maternal-infant transmission studies conducted on children under 6 months exposed to HIV increased from 23.5% in 2012 to 73.0% in 2018; the average waiting time for confirmation of the diagnosis in stomach cancer decreased from 42 days in 2016 to 29 days in 2018, and the percentage of patients with rheumatoid arthritis with acute phase reactants in the diagnostic process increased from 36.1% in 2016 to 93.4% in 2018. The assessment of high-cost disease metrics showed improvements in the quality of care. Measuring compliance with best practices is a good strategy for directing efforts towards achieving goals.

The Efficacy of Platelet-Rich Plasma in the Treatment of Hemophilic Arthropathy

Background: The most clinical manifestation of hemophilia, as a congenital bleeding disorder, is the Intra-articular hemorrhage. The treatment of acute hemarthrosis with a sufficient amount of factor replacement will return the joint to the normal status. Objectives: This study aimed to evaluate the efficacy of platelet-rich plasma in the treatment of hemophilic arthropathy patients to reduce and improve their pain and physical function. Methods: Consecutive patients with hemophilic arthropathy were included in a self-control open-label trial in Mofid Children’s Hospital, Tehran, Iran. All participants received three platelet-rich plasma injections given two weeks apart. Also, the seriate self-reported and objective clinical outcomes were evaluated before and three months after the treatment. Results: A total of 11 patients with hemophilic arthropathy involving 14 joints received three injections of platelet-rich plasma at 2-week intervals, at our center. All patients were evaluated with a visual analog scale, the hemophilia joint health score, and the range of motion, and bleeding events, before and after the treatment. Finally, 9 boys (81.8%) and 2 girls (18.2%) completed the study. The mean age of the participants was 14.7 years (range, 9-19 years). In all patients, statistically significant improvements were noted on all evaluated measures. Conclusion: Platelet-rich plasma therapy is a reasonable and minimally invasive procedure that includes beneficial chondro-regenerative properties.

Complications of total knee arthroplasty in patients with haemophilia compared with osteoarthritis and rheumatoid arthritis: A 20-year single-surgeon cohort.

Patients with haemophilia are prone to haemophilic arthropathy (HA). For end-stage HA, total knee arthroplasty (TKA) is an effective procedure. However, limited data were available regarding complications of TKA in HA patients. To provide comprehensive comparisons of TKA complications among patients with osteoarthritis (OA), rheumatoid arthritis (RA) or HA. The present study was a single-surgeon cohort study including patients who underwent TKAs for OA, HA or RA from January 1997 to December 2017. The information of patients was extracted from medical records and follow-up database. The primary outcome was complications. Potential risk factors of complications in HA patients were also evaluated. A total of 1515 patients with 2083 TKAs were selected following the criteria. The overall complication rate in the HA group was 21.79%, which was much higher than the OA or RA group (7.08% and 8.70%, respectively, P<.05). The dominate complications were prosthetic loosening and wound dehiscence. For HA, more complications occurred in the period more than 1year after TKA when compared with OA (33.33% vs 11.43%, P=.028). Among the potential risk factors, patients with haemophilia B and severe haemophilia had significantly higher complication rates (P<.05 for both). When compared with OA or RA, HA patients had different characteristics on complications, including the higher complication rate, different complication distribution and later occurring time. In HA patients who underwent TKA, haemophilia B and severe haemophilia were risk factors of complications which should be paid more attention to.

Non-Canonical MYD88/TIRAP-Dependent Anti-Inflammatory Function of Pro-Coagulant Factor VIII

Context : FVIII is involved in the coagulation pathway. In the model developed by Hoffman in 1995, FVIII (with FIX) is at the center of coagulation. FVIII deficiency leads to a disease called hemophilia A. A deficiency of FVIII leads to inadequate coagulation and increases the risk of bleeding. Bleeding in hemophilic patient occurs mainly into large joints such as knee, elbow or ankle. Severe recurrence of hemarthrosis leads to irreversible arthropathy called hemophilic arthropathy (HA) characterized by a progressive complete destruction of the joint with permanent pain, musculoskeletal disability and poor quality of life. These patients have an increased inflammatory pattern. Prophylactic treatment of hemophilia A patients with the FVIII protein efficiently prevents bleeding events and preserves joint function. Recently, evidence for novel functions for FVIII across multiple systems, including the cardiovascular system, angiogenesis and maintenance of bone health has emerged. However, no study has shown the involvement of FVIII in inflammation. Here, we demonstrate that FVIII has an anti-inflammatory role and impacts the NF-κB pathway, independently from coagulation pathway. Materials and methods : Human fibroblast-like synoviocytes (FLS) were isolated from synovial tissues from five different HA patients and two non-HA patients at the time of knee or ankle joint arthroscopic synovectomy after informed consent. Primary FLS were used between the third and the ninth passage. We also used commercial normal and rheumatoid arthritis FLS, as well as THP-1. In particular, THP1-Blue NK-κB cells allow monitoring the NF-κB signaling transduction pathway. Different commercial recombinant FVIII were tested following dialysis. We are also tested recombinant FIX and vWF. FLS (5x105 cells) and THP1 (1x107 cells) were activated or not (medium) with LPS from Salmonella abortus equi (1 µg/mL) in the presence or absence of FVIII for 6 hr. Alternatively, THP1-Blue (5x105 cells) were activated or not (medium) with different PRR (Pattern Recognition Receptors) agonists for 24 hours: TLR2 (peptidoglycans), TLR4 (LPS) and TLR5 (flagellin). Cell supernatants were analyzed by ELISA and an ELISPOT were performed with a panel of 105 different cytokines. Results : Anti-inflammatory effect of FVIII After LPS stimulation and incubation with FVIII, cells expressed a unique profile of cytokine secretion, with a decrease in pro-inflammatory cytokines IL-1, IL-6 and TNF-alpha. This anti-inflammatory effect was not found when other coagulation factors, in particular vWF and FIX, were tested. A transcriptome analysis was performed on FLS from 3 different patients, normal FLS and THP1 cells and incubated alone or with FVIII. Transcriptomic results correlated with the inflammatory protein expression pattern, irrespective of the cell type. FVIII is involved in the NF- κ B signaling pathway through MYD88/TIRAP interaction Incubation of THP1 cells with the different TLR agonists resulted in an increase in the NF-KB signaling pathway. In the presence of FVIII, a decrease in NF-KB signaling was observed with TLR-2 and TLR-4 agonists but not with the TLR-5 agonist. NF-KB translocation in the nucleus, performed by AMNIS, was decreased when cells were incubated with FVIII (but not with vWF or FIX) after TLR-2/TLR-4 activation. Analysis of differences between TLR-2/TLR-4 and TLR-5 pathways showed that TIRAP is required only in TLR-2/TLR-4 to interact with MyD88 while TLR-5 pathway is required only for MyD88 activation. After silencing TIRAP by specific siRNA approach, no anti-inflammatory effect on NF-kB pathways was observed after FVIII incubation and TLR2/4 activation. Silencing TIRAP using specific siRNA abrogated the inhibitory effect of FVIII on TLR2/4-triggered NF-kB signaling. The results suggest that FVIII blocks the interaction between TIRAP and MyD88 and impairs the NF-kB pathway. In conclusion, our study suggests a new potential role for FVIII in the control of inflammation through the NF-kB pathway. Further investigations are ongoing with animal models to confirm these data and clinical study will be performed. Disclosures Hermine: AB science: Consultancy, Equity Ownership, Honoraria, Research Funding; Celgene: Research Funding; Novartis: Research Funding.

TNF-α/TNF-R System May Represent a Crucial Mediator of Proliferative Synovitis in Hemophilia A.

Hemophilic arthropathy (HA) typically begins with proliferative synovitis that shares some similarities with inflammatory arthritides, in which the proinflammatory cytokine tumor necrosis factor (TNF)-α has a crucial pathogenetic role. Inappropriate release of TNF-α was shown to contribute to arthropathy development following intra-articular bleeding in hemophilic mice. Here, we were interested in determining whether systemic levels of TNF-α and synovial tissue expression of the TNF-α/TNF receptor (TNF-R) system could be increased and related to joint damage in hemophilia A patients with severe HA. Serum levels of TNF-α measured by quantitative enzyme-linked immunosorbent assay (ELISA) were significantly increased in HA patients (n = 67) compared to healthy controls (n = 20). In HA patients, elevated TNF-α levels were significantly associated with the number of hemarthroses, the grade of synovial hypertrophy, and both the clinical World Federation of Hemophilia score and ultrasound score. The expression of TNF-α, TNF-R1, and TNF-R2 was strongly increased in HA synovium (n = 10) compared to the non-inflamed osteoarthritis control synovium (n = 8), as assessed by both immunohistochemistry and Western blotting. Increased protein levels of TNF-α, TNF-R1, and TNF-R2 were retained in vitro by HA fibroblast-like synoviocytes (n = 6) with respect to osteoarthritis control fibroblast-like synoviocytes (n = 6). Stimulation with TNF-α resulted in a significant increase in HA fibroblast-like synoviocyte proliferation quantified by the water-soluble tetrazolium (WST)-1 assay, while it had no relevant effect on osteoarthritis fibroblast-like synoviocytes. Quantification of active/cleaved caspase-3 by ELISA demonstrated that TNF-α did not induce apoptosis either in HA or in osteoarthritis fibroblast-like synoviocytes. The TNF-α/TNF-R system may represent a crucial mediator of proliferative synovitis and, therefore, a new attractive target for the prevention and treatment of joint damage in HA patients. Our findings provide the groundwork for further clinical investigation of anti-TNF-α therapeutic feasibility in hemophiliacs.

Using synovial volume measurement by MRI to evaluate the effect of 32P Radiation synovectomy on hemophilic arthropathy patients.

To evaluate the potential of synovial membrane volume measurement by MRI in monitoring the effect of radiation synovectomy on patients of Hemophilic Arthropathy (HA). We studied 63 diseased joints of 42 HA patients who received hospitalized services at the Hemophilia Diagnosis and Treatment Center of Henan Provincial People's Hospital from May 2011 to January 2015. Unenhanced and enhanced MR scanning of each diseased joint was performed simultaneously. The volumes of synovial membrane of 21 joints from 16 patients before and after being treated with 32P radiation synovectomy (PRS) were measured and compared using image post-processing software and workstation. Two sample matching t test was conducted to analyze the synovial membrane volumes of the same joint measured by unenhanced and enhanced MR, as well as change of MR enhancement ratio after treatments. The synovial membrane volumes measured by unenhanced versus enhanced MR scanning showed no statistical significance. Significant reduction (t = 7.831, p < 0.001) of the synovial membrane volume after treatment (2479.45±46.48 mm3 versus 2983.30±42.87 mm3 before treatment) was observed. MR enhancement ratio of synovial membrane decreased after treatment (0.92±0.06 after vs 1.17±0.07 before treatment) with statistical significance. The synovial membrane volume and MR enhancement ratio can be used to monitor patient response to PRS treatment.

Increased serum levels of progranulin (PGRN) in patients with haemophilic arthropathy.

Haemophilia A and B are rarely occurring X chromosome-linked congenital coagulation disorders dominated by spontaneous joint bleedings and chronic synovitis, leading to development of haemophilic arthropathy (HA). Progranulin (PGRN) is a growth factor with anti-inflammatory and immunomodulatory properties. PGRN is an important molecule in the pathogenesis of osteoarthritis (OA) and rheumatological disorders. This study was aimed at investigating the potential role of PGRN in the mechanisms underlying the pathogenesis of HA. The serum levels of PGRN were measured by enzyme-linked immunosorbent assay (ELISA) in patients with end-stage knee joint HA (n=20) and end-stage primary knee joint OA (n=20) who met the inclusion and exclusion criteria. The clinical and radiological assessment of disease severity was evaluated by the Knee Society Score (KSS) and Kellgren-Lawrence scale. Median PGRN levels in HA patients was 349.1ng/mL (232.8-415.6ng/mL) and in OA patients 148.3ng/mL (112.1-275.3ng/mL) with statistically significant differences between both groups (P<0.015). Further analysis revealed no correlation between PGRN levels and any of the patient demographics and clinical parameters. This study demonstrates increased PGRN serum levels in patients with HA and provides new insights into the mechanisms underlying the pathogenesis of HA indicating a new potential target for therapeutic intervention.

Simultaneous bilateral total knee arthroplasty in patients with end-stage hemophilic arthropathy: a mean follow-up of 6 years

To investigate the safety, cost-effectiveness, and clinical outcomes of simultaneous bilateral total knee arthroplasty (TKA) in hemophilic arthropathy (HA), the requirements for transfusions, complications, costs, hospital stays, Hospital for Special Surgery (HSS) knee scores, knee range of motion (ROM) and revision rates were compared between simultaneous bilateral and unilateral TKA in HA patients. A total of 36 patients and 54 knees were included. Compared to the unilateral group, the bilateral group did not require more transfusions (2.39 ± 3.13 vs 0.83 ± 1.38 units of RBCs, p > 0.05) or consumption of coagulation factors (50091.67 ± 25168.5 vs 46477.78 ± 11348.32 IU, p > 0.05), complications rate (13/36 vs 6/18, p > 0.05), hospital stay (32.39 ± 19.77 vs 29.11 ± 12.67 days, p > 0.05), or costs excluding prostheses (14945.41 ± 6634.35 vs 14742.12 ± 5746.78 US dollars, p > 0.05). Additionally, the two groups exhibited similar medium-term knee HSS scores (83.67 ± 7.11 vs 81.00 ± 10.35, p > 0.05) and ROM (89.39° ± 13.66° vs 88.91° ± 12.90°, p > 0.05). Our data indicate that bilateral TKA is a safe and cost-effective treatment for HA with similar medium-term results compared to unilateral TKA.

Sensory strategies of postural sway during quiet stance in patients with haemophilic arthropathy.

The sensory strategies of postural control in adult haemophilic arthropathy patients are still poorly understood. To determine sensorial posture-control strategies through postural sway frequency analysis when in a bipedal quiet stance with and without visual stimulus deprivation in healthy subjects and patients with haemophilic arthropathy. Secondarily, to determine the irregularity of postural balance control through sample entropy (SampEn). A triaxial accelerometer attached at the L3 level determined the displacement and acceleration of the centre of mass (DCoM and ACoM, respectively) under open- and closed-eyes conditions. Sensorial strategies were studied by spectral analysis of the DCoM signal, divided into low, medium and high frequencies for visual/vestibular, cerebellum and somatosensory strategies respectively. DCoM irregularity was also analysed by SampEn. Fifteen young, healthy subjects and fifteen young, haemophilia patients were included. The mediolateal DCoM and anteroposterior ACoM differed between groups. During the open-eyes condition, haemophiliacs presented limited high and medium frequencies, and more low frequency bands as compared to non-haemophiliacs (P<.05). In the closed-eyes condition, haemophiliacs had a minor percentage of high frequencies but an elevated percentage of low frequencies as compared to non-haemophiliacs (P<.05). Non-haemophiliacs had higher SampEn than haemophiliacs in the mediolateral axis with open- and closed-eyes (P<.05 and <.001, respectively). The presented results indicate that patients with haemophilic arthropathy, as compared to healthy subjects, have less postural control irregularity and poor somatosensory system contributions that are compensated by more vestibular inputs.

Joint lavage followed by viscosupplementation and triamcinolone in patients with severe haemophilic arthropathy: objective functional results.

Viscosupplementation can improve function in haemophilia patients. Viscosupplementation results can be improved by prior joint lavage and triamcinolone administration. To objectively assess whether viscosupplementation and associated triamcinolone use in patients with severe haemophilic arthropathy following joint lavage improves force and balance and reduces bleeding events. Fourteen patients with haemophilic knee arthritis with and without the involvement of other joints underwent joint lavage and subsequent injections of Hylan G-F20 and triamcinolone into all affected joints. Patients were evaluated with NeuroCom® force and balance platforms using the step-up-and-over task (STP), sit-to-stand test (STS), one-leg stance (UNI) and weight-bearing squat (WBS) at baseline and at 1, 3, 6 and 12 months after the procedure. Bleeding events in the year prior to and the year after the procedure were analysed. Sixteen knees, 15 ankles, eight elbows and one shoulder were treated. The STP results indicated improvements in the lift-up indices (right leg) at all time points evaluated (P = 0.03). The STS results revealed coupled improvement in weight transfer and the rising index for up to a year (P = 0.02). Balance (UNI) with eyes open or closed improved in all evaluations. The WBS results revealed improvements at all degrees of flexion (0, P = 0.003; 30°, P = 0.001; 60°, P < 0.001 and 90°, P < 0.001). The numbers of total and traumatic bleeding events were reduced (P = 0.04). Joint lavage followed by injections of triamcinolone and Hylan G-F20 improved balance, function and bleeding events in severe haemophilic arthropathy patients.

Serum cartilage oligomeric matrix protein reflects radiological damage and functional status in hemophilic arthropathy patients

Aim of the workThe objective of our study was to determine the utility of serum cartilage oligomeric matrix protein (COMP) as a serum biomarker for hemophilic arthropathy and to evaluate the degree of joint damage radiologically using plain X-ray and functionally using functional independence score of hemophilia (FISH) and to study their relation with COMP. Patients and methodsThe study was carried out on 30 boys with hemophilic arthropathy (group I) and 20 healthy boys as control (group II). All hemophiliacs patients were scored for FISH and radiological changes (Pettersson’s score). Factor activity level was measured in group I while COMP was measured in both groups. ResultsThe patients’ age ranged from 6 to 16years (mean 10.6±2.7years). The knee was the most commonly affected joint (83.3%). Fifteen patients (50%) had severe hemophilia, 7 had moderate and 8 had mild hemophilia. Mean serum levels of COMP in hemophilic patients (529±288.1ng/ml) were significantly higher than in control (285±63.2ng/ml) (p=0.014). The COMP level was significantly higher in patients with severe hemophilia compared to those with moderate or mild disease (p<0.001). The serum COMP significantly correlated with joint space narrowing (r=0.64, p<0.001) and with the total Pettersson score (r=0.42, p=0.02) and negatively with the FISH score (r=−0.44, p=0.016). ConclusionsSerum COMP level is indicative of the amount of joint damage in patients with hemophilic arthropathy. The combined scoring of functional independence and Pettersson score in addition to serum levels of COMP give a good overview of the degree of hemophilic arthropathy.

Inflammatory focal bone destruction in femoral heads with end-stage haemophilic arthropathy: a study on clinic samples with micro-CT and histological analyses.

Focal bone destruction has a high prevalence in haemophilic arthropathy (HA) affected joints, but the mechanism remains unclear. We undertook this study on clinic samples to explore the focal bone destruction in femoral heads suffered with end-stage HA. Twenty-one femoral heads from HA patients and 19 femoral heads from rheumatoid arthritis (RA) patients were scanned by micro-CT. Histological analysis, including TRAP staining of subchondral bone were performed to evaluate the bone destruction and osteoclasts activity. RANKL, OPG as well as pro-inflammatory cytokines, such as TNF-α and IL-1β in subchondral bone were detected by immunohistochemistry (IHC) method. Severe focal lesion was observed in all the HA and RA femoral heads by micro-CT imaging and histological analysis. The mean percentage of lesion volume to total volume of the femoral heads from HA patients was significantly higher than those from RA patients. There was no significant difference in osteoclasts numbers in subchondral bone between HA and RA groups. By IHC analysis, high expression of RANKL, TNF-α, IL-1β and low expression of OPG and RANK were observed in subchondral bone, and there were no significant differences in the expression of RANKL, OPG, RANK, TNF-α and IL-1β in femoral heads derived from HA and RA patients. Our findings demonstrated the focal bone destruction coupled with inflammatory osteoclastogenesis at subchondral bone in femoral heads from patients with end-stage HA, and that was similar to the changes in the femoral heads of RA patients.

Agonistic anti‐human Fas monoclonal antibody induces fibroblast‐like synoviocyte apoptosis in haemophilic arthropathy: potential therapeutic implications

Haemophilic arthropathy (HA) is characterized by chronic proliferative synovitis leading to cartilage destruction and shares some pathological features with rheumatoid arthritis (RA). Apoptosis has been implicated in RA pathogenesis, and an agonistic anti-Fas monoclonal antibody (mAb) was found to induce RA fibroblast-like synoviocyte (FLS) apoptosis and suppress synovial hyperplasia in animal models of RA. The aim of this study was to evaluate the effect of anti-Fas mAb on HA-FLS. FLS were isolated from knee synovial biopsies from six HA patients, six RA patients and six healthy subjects. The expression of Fas in synovial biopsies was investigated by immunohistochemistry. FLS were stimulated with anti-Fas mAb at different concentrations, alone or in combination with tumour necrosis factor-α (TNF-α) and basic fibroblast growth factor (bFGF). Fas expression in FLS was assessed by Western blot. Cell viability was studied with the WST-1 assay. Active caspase-3 levels were measured using ELISA and Western blot. A strong Fas-immunoreactivity was observed in different cells of HA synovium, including FLS, inflammatory cells and endothelial cells. Fas antigen was constitutively overexpressed in cultured HA-FLS. Anti-Fas mAb had a significant cytotoxicity on HA-FLS in a dose-dependent manner, either alone or in combination with TNF-α and bFGF. These cytotoxic effects were due to the ability of anti-Fas to induce HA-FLS apoptosis, as shown by the increased active caspase-3 levels. Anti-Fas mAb exhibited a more pronounced pro-apoptotic effect on HA-FLS than RA-FLS. Fas antigen is highly expressed on HA-FLS and its stimulation by anti-Fas mAb may be an effective strategy to induce HA-FLS apoptosis.