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Aim: Subclinical bleeding and inflammation play a role in progression of haemophilic arthropathy. Synovial proliferation is predictive of joint bleeding and its early detection may guide treatment changes and prevent arthropathy progression. This study evaluated the prevalence of active and inactive subclinical synovial proliferation and investigated potential biochemical blood/urine markers to identify patients with active subclinical synovial proliferation., Methods: This cross-sectional study included patients with severe haemophilia A born 1970-2006 who were evaluated during routine clinic visits. Patients with (a history of) inhibitors or recent joint bleeding were excluded. Elbows, knees and ankles were examined for subclinical synovial proliferation by ultrasound and physical examination. Active synovial proliferation was distinguished from inactive synovial proliferation using predefined criteria. Blood/urine biochemical markers (serum osteopontin, sVCAM-1, Coll2-1, COMP, CS846, TIMP, and urinary CTX-II) were compared individually and as combined indexes between patients with and without active synovial proliferation., Results: This cohort consisted of 79 patients with a median age of 31 years (range 16.5-50.8 years) with 62/79 (78%) of the patients using continuous prophylaxis. The annualized joint bleeding rate over the last 5 years was .6 (.2-1.1). Active (17/79, 22%) and inactive subclinical synovial proliferation (17/79, 22%) were both prevalent in this cohort. Biochemical markers were not correlated with active subclinical synovial proliferation., Conclusion: Subclinical synovial proliferation, both active and inactive, was prevalent in patients with severe haemophilia A with access to prophylaxis and would be overlooked without routinely performed ultrasounds. Biochemical markers were unable to identify patients with active subclinical synovial proliferation., (© 2023 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Aim: Haemophilia is characterized by recurrent joint bleeding caused by a lack of clotting factor VIII or IX. Due to repeated joint bleeding, end-stage arthropathy occurs in relatively young patients. A total knee replacement (TKR) can be a solution. However, TKR may be complicated by perioperative and postoperative bleeds despite clotting factor therapy. The aim of this study was to evaluate the prevalence of pre-operative synovial hyperaemia and the effects of Genicular Artery Embolization on synovial hyperaemia and 3-month postoperative joint bleeding., Methods: In this retrospective cohort study, all patients with haemophilia who underwent periarticular catheter angiography between 2009 and 2020 were evaluated after written informed consent. Synovial hyperaemia on angiography was scored by an interventional radiologist., Results: Thirty-three angiography procedures in 24 patients were evaluated. Median age was 54.4 years (IQR 48.4-65.9). Preoperative synovial hyperaemia was observed in 21/33 joints (64%). Moderate and severe synovial hyperaemia was observed in 10/33 joints (30%). Synovial hyperaemia decreased in 13/15 (87%) joints after embolization. Three-month postoperative joint bleeding occurred in 5/32 joints: in 2/18 joints (11%) without synovial hyperaemia and in 3/14 joints (21%) with mild synovial hypertrophy. Non-embolized and embolized joints did not differ regarding 3-month postoperative bleeding (P = .425). No complications were observed after embolization., Conclusion: One-third of patients with haemophilia requiring a TKR had moderate or severe synovial hyperaemia which can be reduced safely by Genicular Artery Embolization prior to TKR. Three-month postoperative bleeding appears to occur independently of the presence of residual mild synovial hyperaemia., (© 2023 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Introduction: Ankle joint distraction (AJD) is a promising treatment for patients with severe haemophilic ankle arthropathy (HAA). However, some patients showed no clinical improvement after AJD and these differences may be related to structural differences., Aim: Primarily to quantify the structural changes after AJD in patients with HAA by the use of 3D joint space width (JSW) measurements and biochemical markers and secondarily to correlate these findings with clinical pain/function., Methods: Patients with haemophilia A/B who underwent AJD were included for this study. Bone contours on MRI (performed before and 12 and 36 months after AJD) were drawn manually and percentage change in JSW was calculated. Blood/urine (before and 6, 12, 24 and 36 months after AJD) was collected for biomarker measurement (COMP, CS846, C10C, CALC2, PRO-C2, CTX-II) and combined indexes of markers were calculated. Mixed effects models were used for analyses on group level. Structural changes were compared with clinical parameters., Results: Eight patients were evaluated. On group level, percentage changes in JSW showed a slight decrease after 12 months followed by a non-statistically significant increase in JSW after 36 months compared to baseline. Biochemical marker collagen/cartilage formation also showed an initial decrease, followed by a trend towards net formation 12, 24 and 36 months after AJD. On individual patient level, no clear correlations between structural changes and clinical parameters were observed., Conclusion: Cartilage restoration activity on group level in patients with HAA after AJD was in concordance with clinical improvements. Correlating structural modifications with clinical parameters in the individual patient remains difficult., (© 2023 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Aim: Traditionally, recovery after a joint bleed in people with bleeding disorders is evaluated by clinical symptoms. Following a bleed, however, asymptomatic joints may still show synovial hypertrophy and effusion on ultrasound. We evaluated the duration of full recovery from a joint bleed. Additionally, we determined how recovery differed when assessed by physical examination and ultrasound., Methods: In this retrospective cohort study, we investigated joint bleeds in elbows, knees and ankles of people with haemophilia or Von Willebrand disease who attended the Van Creveldkliniek between 2016 and 2021. Physical examination (warmth, swelling, range of motion and gait) and ultrasound (effusion and synovial hypertrophy) were performed within 7 days after the onset of the bleed, 1 week after the first examination and monthly thereafter until patients had recovered fully. Joint bleeds were treated in line with the current international treatment guidelines., Results: We evaluated 30 joint bleeds in 26 patients. The median recovery time was 1 month (range 0.3-5 months). In 47% of the joint bleeds, the recovery took longer than 1 month. The moment of recovery based on physical examination and ultrasound differed in 27% of bleeds. Both persistent abnormalities at physical examination in joints with normalized ultrasounds and persistent ultrasound findings in clinically recovered joints occurred., Conclusion: Joint bleed recovery can take long and recovery times differed per bleed. Recovery differed when assessed by physical examination or ultrasound. Therefore, both should be used to closely monitor recovery of joint bleeds and offer personalized care., (© 2023 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Introduction: Ultrasound is increasingly used as addition to physical examination for detection of subclinical joint changes in haemophilia. However, the added value of ultrasound to physical examination for detecting synovial proliferation is not fully established., Aim: To determine the diagnostic accuracy of swelling at physical examination for ultrasound-detected synovial proliferation in haemophilia., Methods: PubMed and EMBASE were searched up to 2 August 2022. Studies reporting original data on occurrence of swelling at physical examination and synovial proliferation on ultrasound of index joints in persons with haemophilia were included. Risk of bias and applicability were assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool. Diagnostic accuracy parameters of swelling at physical examination for ultrasound-detected synovial proliferation were determined. Summary sensitivity and specificity were calculated using a bivariate random-effects model., Results: Fifteen studies reporting on swelling at physical examination and synovial proliferation on ultrasound in 2890 joints of 627 patients were included. Prevalence of subclinical synovial proliferation ranged between 0% and 55%. Sensitivity of swelling was low [summary estimate .34; 95% confidence interval (CI) .24-.46], while specificity was high (summary estimate .97; CI .92-.99). Predictive values varied widely due to inter-study differences in prevalence of synovial proliferation., Conclusion: Joint swelling has low sensitivity for presence of ultrasound-detected synovial proliferation in haemophilia, suggesting underestimation of synovial proliferation by physical examination alone. Consequently, ultrasound screening may generate important information on synovial changes which would otherwise remain undetected., (© 2022 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Introduction: Haemophilic ankle arthropathy (HAA) causes major morbidity. When conservative treatment fails, major surgical interventions are indicated. An alternative treatment to maintain joint mobility and postpone these interventions is desired., Aim: To gather prospective data on clinical/structural changes after ankle joint distraction (AJD) in HAA., Methods: This study includes patients with severe HAA insufficiently responding to conservative treatment. AJD was performed during 8-10 weeks by use of an external frame. Questionnaires, physical examination and radiology were used to evaluate pain, function and structural changes before and 6, 12, 24 and 36 months after distraction. Mixed effect models were used for analysis., Results: This study includes eight cases (21-53 years). The fixed effects estimates of the visual analogue score (0-10) improved from 7.5 at baseline to 3.4 (p = .023) 3 years after distraction. The Haemophilia Activities List (HAL, 0-100) for basic/complex lower extremities functions improved from respectively 29.6 and 31.5 to 54.3 (p = .015) and 50.7 (p = .031). Joint mobility was maintained. Magnetic resonance imaging (MRI) showed thickened cartilage and reduced bone marrow oedema and subchondral cysts. Pin tract infections (n = 6) were effectively treated and no adverse bleeding events occurred. At 3-year follow-up, in none of the patients the originally indicated arthrodesis was performed., Conclusion: This first prospective study showed that AJD in HAA results in decreased pain, improved function and decreased arthropathy-related MRI findings in the majority of patients for prolonged time. Although the study population is small and follow-up is relatively short, AJD may be promising to postpone invalidating interventions and might be a breakthrough treatment., (© 2022 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Introduction: Recurrent joint bleeding is the hallmark of haemophilia. Synovial hypertrophy observed with Magnetic Resonance Imaging (MRI) is associated with an increased risk of future joint bleeding., Aim: The aim of this study was to investigate whether point-of-care ultrasound (POC-US) is an accurate alternative for MRI for the detection of early joint changes., Methods: In this single centre diagnostic accuracy study, bilateral knees and ankles of haemophilia patients with no or minimal arthropathy on X-rays were scanned using POC-US and 3 Tesla MRI. POC-US was performed by 1 medical doctor, blinded for MRI, according to the "Haemophilia Early Arthropathy Detection with Ultrasound" (HEAD-US) protocol. MRIs were independently scored by 2 radiologists, blinded for clinical data and ultrasound results. Diagnostic accuracy parameters were calculated with 95% confidence intervals (CI)., Results: Knees and ankles of 24 haemophilia patients (96 joints), aged 18-34, were studied. Synovial hypertrophy on MRI was observed in 20% of joints. POC-US for synovial tissue was correct (overall accuracy) in 97% (CI: 91-99) with a positive predictive value of 94% (CI: 73-100) and a negative predictive value of 97% (CI: 91-100). The overall accuracy of POC-US for cartilage abnormalities was 91% (CI: 83-96) and for bone surface irregularities 97% (CI: 91-99)., Conclusion: POC-US could accurately assess synovial hypertrophy, bone surface irregularities and cartilage abnormalities in haemophilia patients with limited joint disease. As POC-US is an accurate and available alternative for MRI, it can be used for routine evaluation of early joint changes., (© 2018 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Introduction: Early initiation of prophylaxis in severe haemophilia is critical for effective prevention of arthropathy. However, the optimum time for starting prophylaxis has not been established yet., Aim: This study assessed long-term effects of age at starting prophylaxis and joint bleeding before prophylaxis on haemophilic arthropathy., Methods: In patients with severe haemophilia (FVIII/IX <0.01 IU mL -1 ), born between 1965 and 2000, haemophilic arthropathy was evaluated on X-rays. Patient groups were compared by multivariable regression analysis, adjusted for bleeding phenotype and lifetime intensity of prophylaxis., Results: One hundred and twenty-four patients were evaluated at a median age of 22 years. When comparing patients according to age at starting prophylaxis, starting before age 6 years was significantly better than starting later (P < 0.01), but no additional benefit of starting before age 3 years was demonstrated. The number of joint bleeds before prophylaxis had a stronger association with arthropathy than age at starting prophylaxis. Starting prophylaxis before the onset of joint bleeding resulted in the best long-term outcome (P ≤ 0.02); starting after one joint bleed appeared to have acceptable long-term outcome. The difference between starting after 0-1 and 2-5 joint bleeds was notable, but statistical significance was not reached (P = 0.15)., Conclusion: Future research with more patients on early prophylaxis will have to clarify whether starting prophylaxis before joint bleeding is superior., (© 2016 John Wiley & Sons Ltd.)

Introduction: Patients with haemophilia tend to bleed in large joints even during prophylactic replacement therapy. Detection of early blood-induced joint changes may improve monitoring of treatment. The aim of this study was to explore the value of routine ultrasound in detecting early joint abnormalities in children with haemophilia on prophylaxis., Methods: Sixty-four joints in 32 children with haemophilia were examined by one operator using the Haemophilia Early Arthropathy Detection with UltraSound protocol during annual multidisciplinary follow-up. Based on reported bleeding, the joint with the highest risk of blood-induced joint damage and the contralateral joint were examined. At the same day, clinical function was assessed according to the Haemophilia Joint Health Score (HJHS)., Results: Median age was 11.5 years (range = 5.5-16.4). Out of the 64 examined joints, one ankle was excluded because of previous surgery. Median lifetime joint bleeds/joint was three (interquartile ranges = 1-5). Clinical function of most joints was perfect: only 7/49 joints with reported bleeds scored positive due to swelling, muscle atrophy and/or range of motion loss (HJHS range = 1-2 points). Ultrasound showed abnormalities in 5/49 joints with reported bleeding, and 4/5 showed positive HJHS scores. Ultrasound abnormalities were present in 1/56 joints (1.8%, CI: 0.1-9.6%) without loss of clinical function., Conclusion: Ultrasound abnormalities were found during routine evaluation of joints in children with haemophilia on prophylaxis. Most joints with ultrasound abnormalities showed low HJHS scores too. Ultrasound could be used to evaluate whether minimal losses of clinical function might be caused by anatomical changes., (© 2015 John Wiley & Sons Ltd.)

Magnetic resonance imaging (MRI) scores for haemophilic arthropathy are useful for evaluation of early and moderate arthropathy. The most recent additive International Prophylaxis Study Group (IPSG) MRI scale for haemophilic arthropathy includes joint effusion. However, it is unknown whether joint effusion is haemophilia specific. Correct interpretation of joint effusion is needed for outcome assessment of prophylactic therapies in haemophilia care. The aim of this study was to compare joint effusion on MRI between young adults with haemophilia and healthy controls. MRI's of both knees and ankles of 26 haemophilic patients (104 joints) and 30 healthy active men (120 joints) were assessed. Scans in both groups were performed in 2009/2010 and 2012 respectively. Joint effusion was measured and scored according to the MRI atlas referred by the IPSG MRI scale for haemophilic arthropathy. Median age of haemophilic patients and healthy controls was 21 and 24 years respectively. In haemophilic patients 23% of knees and 22% of ankles showed joint effusion. Healthy controls had significantly more positive scores for knee effusion (67%, P < 0.01) and a comparable scores for effusion in the ankle (17%). Joint effusion according to criteria of the IPSG MRI scale was observed significantly more often in knees of healthy controls, while findings in ankles were similar. These data suggest that joint effusion in knees and ankles is not haemophilia specific. Inclusion of joint effusion in the MRI scale is expected to reduce its specificity for haemophilic arthropathy., (© 2014 John Wiley & Sons Ltd.)

To evaluate outcome of prophylactic clotting factor replacement in children with haemophilia, the Haemophilia Joint Health Score (HJHS) was developed aiming at scoring early joint changes in children aged 4-18. The HJHS has been used for adults on long-term prophylaxis but interpretation of small changes remains difficult. Some changes in these patients may be due to sports-related injuries. Evaluation of HJHS score in healthy adults playing sports could improve the interpretation of this score in haemophilic patients. The aim of this study was to evaluate the HJHS scores in a cohort of young, healthy men participating in sports. Concomitant with a project collecting MRI images of ankles and knees in normal young adults, HJHS scores were assessed in 30 healthy men aged 18-26, participating in sports one to three times per week. One physiotherapist assessed their clinical function using the HJHS 2.1. History of joint injuries was documented. MRI images were scored by a single radiologist, using the International Prophylaxis Study Group additive MRI score. Median age of the study group was 24.3 years (range 19.0-26.4) and median frequency of sports activities was three times per week (range 1-4). Six joints (five knees, one ankle) had a history of sports-related injury. The median overall HJHS score was 0 out of 124 (range 0-3), with 60% of subjects showing no abnormalities on HJHS. All joints were normal on MRI. These results suggest that frequent sports participation and related injuries are not related with abnormalities in HJHS scores., (© 2013 John Wiley & Sons Ltd.)

Magnetic resonance imaging (MRI) is the most sensitive imaging modality to assess joint lesions, but the clinical relevance of subtle joint changes in haemophilic patients playing sports is unknown. A haemophilia specific MRI score is available, but was never evaluated in physically active healthy controls. It is not known if unexpected MRI changes in young active haemophilic patients are due to sports participation. The aim of this study was to evaluate knees and ankles in a cohort of young active healthy men using a haemophilia specific MRI score to provide context for joint evaluation by MRI in young haemophilic patients. Three Tesla MRI of knees and ankles were performed in 30 healthy men aged 18-26 years, regularly active in sports. MR images were scored by a single independent radiologist, using the International Prophylaxis Study Group additive MRI score. One physiotherapist assessed clinical function using the Haemophilia joint health scores (HJHS). History of complaints or injuries affecting knees and/or ankles, very intensive sports and current sports activities were documented. Median age was 24.3 years (range 19.0-26.4) and median number of sports activities per week was 3 (range 1-4). Six joints (five knees, one ankle) had a history of a sports-related injury. The median HJHS per joint was 0 out of 20 (range 0-1). All joints had a MRI score of 0. These results suggest that regular sports participation or very low HJHS scores are not associated with haemophilia specific MRI changes in knees and ankles., (© 2013 John Wiley & Sons Ltd.)