AAV mediated repression of Neat1 lncRNA combined with F8 gene augmentation mitigates pathological mediators of joint disease in haemophilia.

Haemophilic arthropathy (HA), a common comorbidity in haemophilic patients leads to joint pain, deformity and reduced quality of life. We have recently demonstrated that a long non-coding RNA, Neat1 as a primary regulator of matrix metalloproteinase (MMP) 3 and MMP13 activity, and its induction in the target joint has a deteriorating effect on articular cartilage. In the present study, we administered an Adeno-associated virus (AAV) 5 vector carrying an short hairpin (sh)RNA to Neat1 via intra-articular injection alone or in conjunction with systemic administration of a capsid-modified AAV8 (K31Q) vector carrying F8 gene (F8-BDD-V3) to study its impact on HA. AAV8K31Q-F8 vector administration at low dose, led to an increase in FVIII activity (16%-28%) in treated mice. We further observed a significant knockdown of Neat1 (~40 fold vs. untreated injured joint, p = 0.005) in joint tissue of treated mice and a downregulation of chondrodegenerative enzymes, MMP3, MMP13 and the inflammatory mediator- cPLA2, in mice receiving combination therapy. These data demonstrate that AAV mediated Neat1 knockdown in combination with F8 gene augmentation can potentially impact mediators of haemophilic joint disease.

Randomized placebo-controlled, double-blind clinical trial of nanoemulsion curcumin in women with aromatase inhibitor-induced arthropathy: an Alliance/NCORP pilot trial.

PURPOSE: Aromatase inhibitor (AI) therapy reduces risk of recurrence and death for postmenopausal women with breast cancer (BC); however, AI-induced arthralgia (AIIA) can lead to discontinuation of treatment. Curcumin, a bioactive polyphenolic substance, may help ameliorate inflammation-related conditions including osteoarthritis and pain. METHODS: We conducted a multisite randomized placebo-controlled, double-blind pilot trial (Alliance A22_Pilot9) to evaluate the effects of nanoemulsion curcumin (NEC, 200 mg/day) in postmenopausal women experiencing AIIA for ≥ 3 months. The primary objective was to determine the feasibility of using Functional Assessment of Cancer Treatment-Endocrine Symptoms (FACT-ES) to detect changes from 0 (T0) to 3 months (T3) of NEC treatment in AI-induced symptoms and well-being; secondary objectives included evaluation of changes in Disabilities of the Shoulder, Arm, and Hand (DASH), Brief Pain Inventory-short form (BPI-SF), grip strength, and biomarkers at T0 and T3. RESULTS: Forty-two patients were randomized to NEC or placebo; 34 women completed the 3-month study. Patient-reported outcome measures (PROMs: FACT-ES, DASH, BPI-SF) and biospecimens were collected at T0-T3 in > 80% of participants. Adherence was ≥ 90% for both arms. PROMs and grip strength did not differ significantly by treatment arm. Plasma curcumin was detected only in NEC arm participants. Serum estradiol and estrone levels were below detection or low on study agent. Gastrointestinal adverse effects were commonly reported in both arms. CONCLUSION: NEC versus placebo in a multisite randomized trial is feasible and well-tolerated. Additional studies with larger sample size are needed to further evaluate the efficacy and safety of NEC in treatment of AIIA. CLINICALTRIALS: gov Identifier: NCT03865992, first posted March 7, 2019.

Shedding light on the effects of blood on meniscus tissue: the role of mononuclear leukocytes in mediating meniscus catabolism.

OBJECTIVE: Traumatic meniscal injuries can cause acute pain, hemarthrosis (bleeding into the joint), joint immobility, and post-traumatic osteoarthritis (PTOA). However, the exact mechanism(s) by which PTOA develops following meniscal injuries is unknown. Since meniscus tears commonly coincide with hemarthrosis, investigating the direct effects of blood and its constituents on meniscus tissue is warranted. The goal of this study was to determine the direct effects of blood and blood components on meniscus tissue catabolism. METHODS: Porcine meniscus explants or primary meniscus cells were exposed to whole blood or various fractions of blood for 3 days to simulate blood exposure following injury. Explants were then washed and cultured for an additional 3 days prior to collection for biochemical analyses. RESULTS: Whole blood increased matrix metalloproteinase (MMP) activity. Fractionation experiments revealed blood-derived red blood cells did not affect meniscus catabolism. Conversely, viable mononuclear leukocytes induced MMP activity, nitric oxide (NO) production, and loss of tissue sulfated glycosaminoglycan (sGAG) content, suggesting that these cells are mediating meniscus catabolism. CONCLUSIONS: These findings highlight the potential challenges of meniscus healing in the presence of hemarthrosis and the need for further research to elucidate the in vivo effects of blood and blood-derived mononuclear leukocytes due to both hemarthrosis and blood-derived therapeutics.

Zoledronate alleviates subchondral bone collapse and articular cartilage degeneration in a rat model of rotator cuff tear arthropathy.

OBJECTIVE: To evaluate the humeral head bone volume of patients with cuff tear arthropathy (CTA) and examine the therapeutic effect of zoledronate in a rat modified model of CTA (mCTA). DESIGN: The bone mass in patients with CTA was measured using Hounsfield units from CT images. The mCTA was induced by transecting the rotator cuff, biceps brachii tendon, and superior half of the joint capsule in adult rat shoulders. A single subcutaneous injection of zoledronate was followed by bone histomorphometry and immunohistochemistry of the humeral head, as well as the Murine Shoulder Arthritis Score (MSAS) assessment. RESULTS: The humeral head bone volume was decreased in patients with CTA. In the mCTA model, M1 macrophages were increased in the synovium and were decreased by zoledronate treatment. The increased expressions of TNF-α, IL-1ß and IL-6 in mCTA synovium and articular cartilage were suppressed in the zoledronate-treated mCTA group. The expression of catabolic enzymes in the articular cartilage and MSAS showed similar results. The zoledronate-treated mCTA group showed a decreased subchondral bone collapse with a decreased RANKL/OPG expression ratio and a suppressed number of osteoclasts compared with the control mCTA group. The enhanced expressions of HMGB1 and S100A9 in the mCTA shoulders were eliminated in the zoledronate-treated mCTA group. CONCLUSIONS: The humeral head subchondral bone was decreased in patients with CTA. In the mCTA model, the collapse and osteoarthritic changes were prevented by zoledronate administration. Zoledronate seemed to suppress the number of M1 macrophages in the synovium and osteoclasts in the subchondral bone.

What is the rationale for mesenchymal stromal cells based therapies in the management of hemophilic arthropathies?

Hemophilia A and B are rare X-linked genetic bleeding disorders due to a complete or partial deficiency in the coagulation factors VIII or IX, respectively. The main treatment for hemophilia is prophylactic and based on coagulation factor replacement therapies. These treatments have significantly reduced bleeding and improved the patients' quality of life. Nevertheless, repeated joint bleedings (hemarthroses), even subclinical hemarthroses, can lead to hemophilic arthropathy (HA). This disabling condition is characterized by chronic pain due to synovial inflammation, cartilage and bone destruction requiring ultimately joint replacement. HA resembles to rheumatoid arthritis because of synovitis but HA is considered as having similarities with osteoarthritis as illustrated by the migration of immune cells, production of inflammatory cytokines, synovial hypertrophy and cartilage damage. Various drugs have been evaluated for the management of HA with limited success. The objective of the review is to discuss new therapeutic approaches with a special focus on the studies that have investigated the potential of using mesenchymal stromal cells (MSCs) in the management of HA. A systematic review of the literature has been made. Most of the studies have focused on the interest of MSCs for the delivery of missing factors VIII or IX but in some studies, more insight on the effect of MSC injection on synovial inflammation or cartilage structure were provided and put in perspective for possible clinical applications.

Monosodium urate crystals alter the circadian clock in macrophages leading to loss of NLRP3 inflammasome repression: Implications for timing of the gout flare.

Gout is caused by monosodium urate (MSU) crystal deposition within joints. This leads to acute episodes of inflammation ("gout flares") driven by NLRP3 inflammasome activation in macrophages. Gout flares are frequently present during late night/early morning. The reason for this timing is unclear. Recent evidence suggests the NLRP3 inflammasome is under circadian control. The purpose of this study was to determine whether MSU crystals cause changes in the circadian clock in macrophages leading to time-of-day differences in NLRP3 inflammasome activation. Levels of circadian clock components were measured in undifferentiated "monocytic" and PMA-differentiated "macrophagic" THP-1 cells cultured with/without MSU crystals. Caspase-1 activity was measured to assess NLRP3 inflammasome activity. MSU crystal exposure resulted in minimal effects on clock genes in THP-1 monocytes but BMAL1, CRY1, PER2, and REV-ERBα showed altered expression with reduced protein levels of BMAL1 and REV-ERBα in THP-1 macrophages. REV-ERBα activation or BMAL1 over-expression resulted in reduced MSU crystal-induced caspase-1 activity. BMAL1 knockdown resulted in a further increase in MSU crystal-induced caspase-1 activity, but only at times of day when BMAL1 levels were naturally high. MSU crystal-induced NLRP3 inflammasome activation was greatest at the time of day when BMAL1 levels were naturally low. MSU crystals alter the expression of circadian clock components in THP-1 macrophages leading to loss of BMAL1 and REV-ERBα-mediated repression of NLRP3 inflammasome activity and time-of-day differences in susceptibility to inflammasome activation. Our findings suggest that the nocturnal risk of gout flare is at least partially a consequence of altered circadian control of immune cell function.

Resistance to chicken amyloid arthropathy is associated with a dysfunctional mutation in serum amyloid A.

Chicken amyloid arthropathy is a debilitating disease with a major impact on animal welfare. Since the disease is triggered by bacterial infection, preventative treatment also contributes to the widespread overuse of antibiotics. Bacterial infection initiates an acute phase response including increased serum amyloid A (SAA) production by the liver. SAA accumulates at sites of infection and in particular in large joints of affected birds. Interestingly, white egg-laying chickens (WL) are resistant to the disease whilst brown egg-laying chickens (BL) are most affected. Disease susceptibility has an immunological basis but the possible contribution of underlying genetic risk factors is not understood. Using a whole genome sequencing approach, we discovered a novel variant in the SAA gene in WL, which is predicted to result in an arginine to serine substitution at position 90 (SAA.R90S). Surprisingly, when overexpressed in chicken hepatocellular carcinoma cells, SAA.R90S was expressed at a higher rate and secreted to a greater degree than the wild-type SAA protein. Moreover, RNASeq analysis showed that the R90S mutant exerted a differential effect on the expression of core transcription factors linked to cell fate determination and cell differentiation. Comparative analysis of gene expression in murine CD4 T-cells stimulated with IL-6/SAA, suggests that SAA.R90S might block an induced cell fate change toward pro-inflammatory T helper 17 cells, which are required for immunological protection against pathogenic bacteria during an acute phase response. Our results provide first mechanistic insights into the genetic resistance of WL to amyloid arthropathy and could be applied to commercial layer breeding programs to improve animal welfare and reduce the negative effects of the overuse of antibiotics.

A single-centre experience of 29 total ankle replacement in haemophiliac patients: Therapeutic management, factor consumption and cost.

INTRODUCTION: In patients with haemophilia, repeated bleeding in large joints leads to chronic haemophilic arthropathy, a rare disease that can be managed surgically with ankle arthrodesis or with total ankle replacement (TAR). TAR has been reported to provide good surgical results in the medium/long-term and allow preservation of joint mobility but the medical therapeutic management of the patients has not been described. AIM: To describe the medical therapeutic management of TAR. METHODS: All patients with haemophilia A/B, with haemophilic ankle arthropathy, and who underwent TAR between April 2006 and October 2019 were retrospectively included. Factor consumption, perioperative and early complications, volume of blood lost, and orthopaedic data were collected. RESULTS: A total of 25 patients underwent 29 TAR (mean age was 44.7 years [range: 26-65]). In the 17 patients with HA without history of anti-FVIII inhibitor, the mean ± SD consumption the day of surgery was 116 ± 16 UI/kg when clotting factors were administered by continuous infusion, 106 ± 13 UI/kg when SHL factors were administered by bolus infusion, and 75 ± 22 UI/kg when EHL factors were administered by bolus infusion. During hospitalisation, the mean factor cost was €38,073 (83.7% of the total cost of surgery). Mean blood loss was significantly lower in patients treated with tranexamic acid (164 mL, range: 40-300) than in those not (300 mL, range: 70-800; p = .01). Six patients had haematoma. The 10-year survival free of any prosthesis removal/arthrodesis was estimated to be 92.2% (95% CI [83; 100]). CONCLUSION: The medical therapeutic management of TAR is complex, carried out by a multidisciplinary team but effective in avoiding the occurrence of complications.

A post hoc comparative real-world analysis of HEAD-US score for joint health assessment of patients with severe haemophilia A and B in Spain.

AIM: Joint damage due to haemarthrosis can be effectively monitored with point-of care ultrasound using the Haemophilia Early Arthropathy Detection with US (HEAD-US) scoring system. A post hoc comparative analysis of the joint status of patients with severe haemophilia A (HA) or B (HB) was performed. METHODS: The databases of two observational, cross-sectional studies that recruited patients with HA or HB from 12 Spanish centres were analysed to compare the status of the elbows, knees and ankles in patients with severe disease according to treatment modality. The HEAD-US score was calculated in both studies by the same trained operators. RESULTS: Overall, 95 HA and 41 HB severe patients were included, with a mean age of 35.2 ± 11.8 and 32.7 ± 14.2 years, respectively. The percentage of patients who received prophylaxis, over on-demand (OD) treatment, was much higher in HA (91.6%) than in HB (65.8%) patients. With a similar number of target joints, the HEAD-US score was zero in 6.3% HA and 22.0% HB patients (p < .01), respectively. The HA population showed significantly worse HEAD-US scores. Whilst osteochondral damage occurred more frequently in patients OD or tertiary prophylaxis, our data suggest that articular damage is less prominent in primary/secondary prophylaxis, regardless of the type of haemophilia. These latter treatment modalities were also associated with a lower prevalence of synovial hypertrophy, particularly in HB patients. CONCLUSION: This post hoc analysis indicates that joint status seems to be significantly influenced by haemophilia type (HA or HB) and treatment modality in these severe Spanish populations with severe disease. Continuing HEAD-US monitoring for the early detection and management of intra-articular abnormalities, as well as more efficiently tailored therapies should be warranted.

Arthroscopic ankle surgery in people with haemophilia.

INTRODUCTION: People with haemophilia (PWH) not administered primary haematological prophylaxis since childhood, that is, those treated haematologically on demand or not treated at all, often experience the degeneration of the ankles, leading to pain and functional impairment. AIM: To analyse the outcomes and complications of arthroscopic ankle surgery performed on PWH. METHODS: For this narrative review of the literature, a search was conducted in PubMed on 2, December 2023, using the keywords "haemophilia", "ankle" and "arthroscopy". Of the 29 articles identified, 15 specifically related to ankle arthroscopy in PWH were selected (inclusion criterion). The remaining articles did not meet this requirement (exclusion criterion) and were therefore eliminated. RESULTS: Arthroscopic procedures (arthroscopic synovectomy, debridement and arthrodesis of the ankle) are increasingly used in the surgical treatment of haemophilic ankle arthropathy. Although arthroscopic ankle surgery offers good outcomes in patients with haemophilia, the procedure is not free of complications, which range from 7.9% for arthroscopic ankle debridement to 13.1% in arthroscopic ankle synovectomy and 17.8% in arthroscopic ankle arthrodesis, respectively. The non-union rate of arthroscopic ankle arthrodesis is 7.1% (2/28). CONCLUSION: Although arthroscopic interventions in the haemophilic ankle (synovectomy, debridement, arthrodesis) offer good functional outcomes, they are associated with a non-negligible rate of complications. Arthroscopic ankle surgery in PWH is major surgery and should be treated as such.

Physical activity and factor VIII levels in patients with haemophilia: A real-world prospective observational study.

INTRODUCTION: Regular physical activity (PA) is recommended for patients with haemophilia (PwH). For PwH it is crucial to ensure a sufficient factor level to prevent PA-induced bleedings. However, there is a gap in the literature dealing with specific factor levels, which are needed when performing specific types of PA. AIM: To provide data on factor VIII (FVIII) levels at the start of PA performed by PwH. METHODS: In this prospective 12-month real-world observational study, 23 PwH recorded every PA they performed and the FVIII levels at the start of the PA using a pharmacokinetic application. PA types were clustered according to the collision and injury risk into three categories (Cat I = low, Cat II = medium, Cat III = high risk). Haemophilia Joint Health Scores (HJHS) were performed at baseline, after 6 and 12 months. RESULTS: 795 PA sessions of Cat I, 193 of Cat II, and 23 of Cat III were documented. FVIII levels at the start of PA were different between categories (Cat I: 29.8 ± 32.1%, Cat II: 38.3 ± 33.4%, Cat III: 86.6 ± 29.2%). Out of all PA sessions, 145 (14%) were performed at a factor level of ≤3%. Three PA-induced bleeding occurred. Baseline HJHS was 14.5 ± 13.6 points and did not change throughout the study. CONCLUSION: This study provides real-life data on FVIII levels at the start of 1011 PA sessions. PwH are mainly active in low-risk sports with higher FVIII levels observed in Cat II and III, respectively. Only three PA-induced bleeding occurred, even though several PA were started with low FVIII levels.

Accuracy and clinical role of digital templating for total knee arthroplasty performed on haemophilic knees.

INTRODUCTION: In total knee arthroplasty (TKA), choosing the correct implant size is important. There is lack of data on accuracy of templating on haemophilic knees. Our aim was to test the accuracy of 2D digital templating for TKA on haemophilic arthropathy (HA) of knee. MATERIALS AND METHODS: TKAs performed on HA between January 2011 and January 2022 were screened. Osteoarthritis (OA) group was created as control group by a one-to-one matching regarding type of implant used. Intra- and interobserver correlations were measured in HA, then correlation between templated and implanted sizes was investigated in four assessments (femur AP, femur lateral, tibia AP, tibia lateral), then compared with OA group. Fifty-eight knees in each group included. RESULTS: Regarding intraobserver correlation in HA, there was excellent correlation for femur AP [.93 (.73-.98)], femur lateral [.98 (.91-.99)], and tibia AP (1.0) templating. Regarding interobserver correlation in HA, excellent correlation was observed for femur lateral [.93 (.74-.98)] and tibia AP templating [.90 (.65-.97)]. Regarding correlation of templated and applied sizes in HA; tibia AP, tibia lateral and femur lateral templating showed good correlation [.81 (.70-.89), .86 (.77-.91), .79 (.67-.87) while femur AP templating showed moderate correlation [.67 (.50-.79)]. Comparing HA and OA, there was no difference in correlation levels regarding femur AP, femur lateral, tibia AP and tibia lateral templating (p = .056, p = .781, p = .761, p = .083, respectively). CONCLUSION: Although 2D digital templating shows comparable correlation in HA and OA, clinical applicability of templating on HA appears to be limited in its current state.

Effects of resistance training on muscle strength in adults with haemophilia: A systematic review and meta-analysis.

INTRODUCTION: Although resistance training is frequently prescribed for people with haemophilia (PWH), no previous meta-analyses have quantified the effect of this intervention on muscle strength, nor the implications of the intervention's modality and duration. AIM: (1) To determine the effects of resistance training on muscle strength in adults with haemophilia; (2) To determine the most effective duration and modality among the exercise protocols. METHODS: A systematic search from inception until 28 November 2023 was conducted in PubMed, Embase, Web of Science, CENTRAL and CINAHL databases. We included randomised controlled trials or before-after studies that involved resistance training without other physiotherapy co-interventions. Study selection, data extraction and risk of bias assessment were independently performed by two reviewers. Disagreements were resolved in consultation with a third author. The level of evidence was determined according to the GRADE methodology. RESULTS: Seven studies were included. Measurements of knee extensor strength and elbow extensor strength were included in the meta-analysis. Subgroup analysis showed significant effects for both elastic resistance protocols (SMD: 0.54; 95% CI: 0.02-1.07) and conventional training (isometric and weight-based equipment) (SMD: 0.88; 95% CI: 0.50-1.25), demonstrating small and moderate effect sizes respectively. Additionally, both protocols of duration 5-7 weeks (SMD: 1.16, 95% CI: 0.63-1.69) as well as those of duration ≥8 weeks (SMD: 0.57, 95% CI: 0.20-0.94) showed a significant difference. CONCLUSION: Resistance training is effective in improving muscle strength of the knee and elbow extensors in PWH. Both elastic resistance and conventional training show benefits.

Assessing joint health in haemophilia patients: The combined value of physical examination and ultrasound imaging.

INTRODUCTION: Early diagnosis of joint damage is pivotal in haemophilia to prevent the occurrence and progression of haemophilic arthropathy thus providing optimal personalised management. The haemophilia joint health score version 2.1 (HJHS) is based on a physical examination of the mainly affected joints. Musculoskeletal ultrasound has demonstrated the capability to detect early changes in terms of synovitis and osteochondral damage. The haemophilia early detection with ultrasound (HEAD-US) score has been proposed as a simple and reliable evaluation tool. AIM: This study aims to investigate the correlation between the HJHS and the HEAD-US scores performed by two independent operators (physical therapist and musculoskeletal ultrasound expert) for the evaluation of the joint health status of patients with haemophilia. METHODS: Consecutive adult patients independent of the severity degree were included. Elbows, knees and ankles were evaluated by a physical therapist by HJHS and by a musculoskeletal ultrasound expert following the HEAD-US protocol. RESULTS: We observed a good positive correlation between HJHS and HEAD-US (Spearman's rho 0.72). The main discrepancy in conceptually similar domains was found between the HJHS swelling and the HEAD-US synovitis (rho 0.17), as ultrasound was able to detect even mild synovitis when HJHS swelling was scored 0 in up to 40% of cases. CONCLUSIONS: The HJHS and HEAD-US correlate well even when performed by two independent operators. Musculoskeletal ultrasound is particularly useful for the early detection of synovitis. The routine assessment of both scores helps clinicians define the stage and extension of joint involvement and set up a personalised treatment.

Benefits of physical activity self-monitoring in patients with haemophilia: a prospective study with one-year follow-up.

INTRODUCTION: Activity wristbands have been shown to be effective in relation to self-monitoring activity levels and increasing exercise adherence. However, previous reports have been based on short-term follow-ups in people with haemophilia (PWH). AIM: (1) To evaluate compliance with physical activity (PA) recommendations in PWH during a 1-year follow-up period using activity wristbands to record daily steps and intensity; (2) To determine the effect of PA self-monitoring on clinical outcomes. METHODS: A prospective observational study was conducted in 27 adults with severe haemophilia undergoing prophylactic treatment. The Fitbit Charge HR was used to track daily PA for an entire year. The participants were encouraged to try to reach a goal of 10,000 steps/day and to track their progress. The pre- and post-evaluation included quality of life (A36 Hemophilia-QoL Questionnaire), joint health (Haemophilia Joint Health Score), functionality (Timed Up and Go test), and muscle strength. RESULTS: A total of 323.63 (95%CI: 194-364) valid days (i.e., > 2000 steps) were recorded. The annual average number of steps per day taken by participants was 10,379. Sixteen (59%) PWH reached 10,000 steps/day at baseline and 17 (63%) at 1 year follow-up, with no significant differences (x2 = .33; p = .56). A statistically significant improvement was observed in daily moderate activity time (p = .012) and in the 'physical health' quality of life subscale (mean difference: 2.15 points; 95%CI: .64-3.65; p = .007). CONCLUSION: Our results suggest that patients with severe haemophilia who self-managed their PA can improve their long-term quality of life in the domain of physical health and also the daily time spent in moderate-intensity PA.

Haemophilic arthropathy: Diagnosis, management, and aging patient considerations.

Gene therapy and universal use of safer, more effective, and personalised prophylactic regimens (factor, and nonfactor) are expected to prevent joint bleeding and promote joint health in persons with haemophilia (PwH). Growing evidence suggests that subclinical bleeding, with active and inactive synovial proliferation, continues and haemophilic arthropathy remains a major morbidity in PwH despite early institution of joint prophylaxis. Joint health assessment is evolving with physical examination scores complementing imaging scores. Point-of-care ultrasound is emerging as a safe, cost-effective, and readily available tool for acute determination of musculoskeletal abnormalities, serial evaluation of joints for sonographic markers of haemophilic arthropathy, and in providing objective insight into the efficacy of new therapies. In acute haemarthrosis, arthrocentesis expedites recovery and prevent the vicious cycle of bleed-synovitis-rebleed. When synovial proliferation develops, a multidisciplinary team approach is critical with haematology, orthopaedics, and physiotherapy involvement. Synovectomy is considered for patients with chronic synovitis that fail conservative management. Non-surgical and minimally invasive procedures should always be offered and considered first. Careful patient selection, screening and early intervention increase the success of these interventions in reducing bleeding, pain, and improving joint function and quality of life. Chemical synovectomy is practical in developing countries, but radioactive synovectomy appears to be more effective. When surgical synovectomy is considered, arthroscopic/minimally invasive approach should be attempted first. In advanced haemophilic arthropathy, joint replacement and arthrodesis can be considered. While excited about the future of haemophilia management, navigating musculoskeletal challenges in the aging haemophilia population is equally important.

Structural alterations and pain perception at the ankle joint in patients with haemophilia.

BACKGROUND: Patients with haemophilia (PwH) suffer from chronic pain due to joint alterations induced by recurring haemorrhage. OBJECTIVES: This study aimed to investigate the relationship between structural alterations and pain perception at the ankle joint in PwH. PATIENTS/METHODS: Ankle joints of 79 PwH and 57 healthy controls (Con) underwent ultrasound examination (US) and assessment of pain sensitivity via pressure pain thresholds (PPT). US discriminated between joint activity (synovitis) and joint damage (cartilage and/or bone degeneration) applying the HEAD-US protocol. Based on US-findings, five subgroups were built: PwH with activity/damage, PwH with activity/no damage, PwH with no activity/no damage, controls with activity/no damage and controls with no activity/no damage. RESULTS: Joint activity and joint damage were significantly increased in ankles of PwH compared to Con (p ≤.001). Subgroup analysis revealed that structural alterations negatively impact pain perception. This is particularly evident when comparing PwH with both activity/damage to PwH with no activity/no damage at the tibiotalar joint (p = .001). At the fibulotalar joint, no significant differences were observed between PwH subgroups. Further analysis showed that both joint activity and joint damage result in an increase in pain sensitivity (p ≤.001). CONCLUSION: The data suggest a relation between joint activity, joint damage and pain perception in PwH. Even minor changes due to synovitis appear to affect pain perception, with the effect not intensifying at higher levels of inflammation. In terms of joint damage, severe degeneration leads to a sensitised pain state most robustly, whereas initial changes do not seem to significantly affect pain perception.

Health-related quality of life and physical activity in Nordic patients with moderate haemophilia A and B (the MoHem study).

INTRODUCTION: The impact of moderate haemophilia on health-related quality of life (HRQoL) and physical activity (PA) is not well known. In previous studies, persons with factor VIII/factor IX activity (FVIII/FIX:C) below 3 IU/dL were associated with a more severe bleeding phenotype than predicted. AIM: To explore HRQoL and PA in patients with moderate haemophilia A (MHA) and B (MHB). METHODS: A cross-sectional, multicentre study covering patients with MHA and MHB in Sweden, Finland, and Norway. HRQoL was assessed with the EuroQoL 5-Dimensions (EQ-5D) form and PA with the International Physical Activity Questionnaire among participants aged ≥15 years. RESULTS: We report on 104 patients aged 15-84 years from the MoHem study. Overall, EQ-5D utility was .85 (median) (Q1-Q3 0.73-1.0) with corresponding visual analogue scale (VAS) 80 (70-90), which were similar regardless of treatment modality, FVIII/FIX:C, and MHA or MHB. Pain and mobility were most frequently affected dimensions. Utility (r = -.54), VAS (r = -.42), and PA (r = -.32) correlated negatively with arthropathy (HJHS). Only patients aged 41-50 years displayed lower utility (p = .02) and VAS (p < .01) than the Norwegian population norm. Patients on prophylaxis aged 35-54 years reported higher PA than those treated on-demand (p = .01). CONCLUSION: Haemophilic arthropathy had negative impact on HRQoL and PA in Nordic patients with moderate haemophilia. Middle-aged patients captured lower utility and VAS than observed in the general population. Tailored prophylaxis and improved joint health may influence positively on HRQoL and PA also in moderate haemophilia.

Functional clinical motor performance tests to assess potential fall risks in patients with haemophilia: A case-control study.

INTRODUCTION: Patients with haemophilia (PwH) are at increased risk of falls due to haemophilic arthropathy. Yet, studies on clinical tests associated with the risk of falling are scarce in PwH. AIMS: (1) To evaluate the feasibility of different clinical motor performance tests associated with the risk of falling in PwH; (2) to evaluate PwH's performance of these tests compared to a control group; (3) to identify possible influencing factors that affect performance. METHODS: Twenty-nine severe and moderate PwH (57.0 years, IQR: 48.0-61.5) and 29 healthy age- and BMI-matched control participants (CG) performed 13 different clinical tests (SPPB, timed up and go, push and release, functional reach, single-leg stance, knee and grip strength). Haemophilia joint health score (HJHS), kinesiophobia (TSK-11), subjective physical performance (HEP-Test-Q), falls efficiency (FES-I) and falls were assessed. RESULTS: No adverse events occurred. PwH showed impaired performance in all clinical tests, a lower falls efficiency and a higher HJHS than CG. PwH with higher HJHS, lower HEP-Test-Q and higher TSK-11 scores showed higher deficits. Largest discrepancies were observed in the single-leg stance with eyes open and knee extensor strength, where orthopaedically majorly affected PwH showed worse performance compared to minorly affected PwH and the CG, respectively. The prevalence of ≥1 fall in the last year was 27.6% (PwH) and 10.3% (CG). CONCLUSION: These clinical tests are feasible in PwH. Impaired joint status, a high kinesiophobia and low physical performance impair performance. These tests can be used by clinicians for gaining specific information on functional motor abilities of patients.

A qualitative study on the perioperative experiences and demands of haemophilic arthropathy patients undergoing total joint replacement.

INTRODUCTION: Total joint replacement is the optimal treatment option for patients with severe haemophilic arthritis. Current research emphasizes patient-reported outcomes as a vital measure for evaluating surgical outcomes and patient satisfaction. Nevertheless, very limited information about the subjective experience of perioperative haemophiliacs in the literature, highlighting the need for exploration in this area. AIM: To investigate the psychological experiences and health demands of haemophilic arthropathy patients during the perioperative period of total joint replacement. DESIGN: Qualitative descriptive research with semistructured individual interviews. METHODS: From June to September 2023, nine patients with severe haemophilic arthropathy who underwent total joint replacement at a Haemophilia Diagnosis and Treatment Centre in China were interviewed for average 37 min per person. Data were analysed using the traditional content analysis method and reported following the consolidated criteria for reporting qualitative research. The study is reported according to the COREQ checklist. RESULTS: Interviews described two main themes: (1) emotional decline which involves preoperative overoptimism, early postoperative anxiety and disease uncertainty during the early independent rehabilitation. (2) wellness aspiration which includes rehabilitation support and spiritual healing. CONCLUSION: This study reveals the patients' significant psychological changes and their well-being aspiration, particularly out-of-hospital rehabilitation needs. Strengthening communication between multidisciplinary teams and patients, enhancing the involvement of nurses, broadening the scope of functions at primary Haemophilia Treatment Centres, and developing telerehabilitation, these concerted efforts may improve the overall treatment experience for patients.