Progression Of Hemophilic Arthropathy Research Articles

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

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. 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. 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. 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. 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.

Joint Dysfunction as a Cause of Spontaneous Subclinical Bleeding in Infants with Hemophilia.

Hemophilia is an inherited hemorrhagic disorder; its main clinical manifestations being bleeding in muscles and joints. Ankles, knees, and elbows are the most frequently affected joints, followed by shoulders and hips. The clinical signs of joint involvement are reduced mobility, swelling and walking difficulties. Bleeding episodes in patients with hemophilia are usually divided into traumatic and spontaneous, but we believe that the latter are not truly spontaneous but rather the result of joint stresses owing to motion actions that create dysfunctions starting from infancy. Pharmacological prophylaxis with factor replacement therapies or non-replacement drugs markedly reduces musculoskeletal hemorrhages. However, the onset of subclinical joint stress can be reduced only by associating this therapeutic approach with the accurate observation of the child motion patterns and restoring them if dysfunctional, thereby primarily preventing subclinical bleeding and ultimately the onset or progression of hemophilic arthropathy.

Subclinical synovial proliferation in patients with severe haemophilia A: The value of ultrasound screening and biochemical markers.

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. 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. This cohort consisted of 79 patients with a median age of 31years (range 16.5-50.8years) with 62/79 (78%) of the patients using continuous prophylaxis. The annualized joint bleeding rate over the last 5years 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. 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.

Clinical and radiological assessment of joints in people with haemophilia in Assam, Northeast India: a cross-sectional study

Abstract Background Despite the availability of factor replacement therapy, including prophylaxis, to treat and prevent bleeding, haemophilic arthropathy continues to be the most common complication of haemophilia and significantly impairs the quality of life in people with haemophilia (PwH). Regular periodic assessment of joint status in PwH is essential to identify early arthropathic changes and prevent the development or progression of haemophilic arthropathy. Kinematic and kinetic assessment are preferable and MRI is the gold standard for diagnosing haemophilic arthropathy, but availability is limited in developing countries. HJHS and ultrasound in conjunction with HEAD-US have been shown to effective in assessing changes indicating arthropathy. Aim This study is designed to identify which radiological assessment tool(s) works best when integrated with clinical assessment tools to examine joint health in PwH, with the aim of establishing a cheap, effective, multimodal approach to joint assessment in clinical practice in low resource settings which can then help to guide treatment. Methods A cross-sectional observational study was carried out among PwH attending a clinic in the department of medicine at Assam Medical College and Hospital, Northeast India, over a one-year time period. The elbow, knee and ankle joints of participants were assessed clinically and functionally using HJHS and FISH and radiologically by Pettersson (X-ray) and HEAD-US (ultrasound) scoring. The resulting data was analysed statistically to ascertain correlation between these parameters. Results Sixty-seven PwH were enrolled in the study, with a mean age of 21.69±8.24 years (median 21 years); 38 (57.72%) had severe factor deficiency. The majority (71.70%) presented with joint bleeds; 40 (59.70%) had the knee as a target joint, followed by the elbow (11; 16.41%) and ankle (6; 8.95%). Mean ABR (annual bleed rate), AJBR (annual joint bleed rate) and ATJBR (annual target joint bleed rate) values had a positive correlation with increased severity of factor deficiency (p <0.001). FISH score increased with factor activity level; HJHS, HEAD-US and Pettersson scores decreased with factor activity level. Significant positive correlation was established between Pettersson score, age and ABR. The degree of association was greatest between HJHS and HEAD-US at 60.62%; between HJHS and Pettersson it was 57.74%. Statistically significant negative correlation was established between FISH and HEAD-US. Conclusion A combined multimodal approach using the HJHS, FISH and HEAD-US scoring systems can provide a cheap, quick, more reliable and accurate option for assessing haemophilic joints, with minimal inter and intra observer reliability. This can support the optimisation of management of joint damage in PwH in resource-constrained settings.

Cost-effectiveness of emicizumab vs bypassing agents in the prevention of bleeding episodes in haemophilia A patients with anti-FVIII inhibitors in France.

The development of an anti-FVIII inhibitor is the most serious complication of haemophilia A occurring in up to 30% of severe haemophilic patients. The current management of haemophilia A with inhibitor uses bypassing agents (BPA) and represents a significant therapeutic burden together with a limited adherence to prophylactic treatment. Emicizumab is the first monoclonal antibody developed in haemophilia A approved for the prevention of bleeding episodes in patients with anti-FVIII inhibitor. The purpose of this study is to evaluate the incremental cost-effectiveness ratio (ICER) of emicizumab versus BPAs. A Markov model was developed over a five-year time horizon to estimate the comparative costs and benefits of the different therapeutic approaches in this rare disease. Model inputs were clinical, including annual bleeding rate and quality of life, and economical including mainly costs of prophylaxis, bleeds and adverse events. Emicizumab treatment is dominant, ie lest costly and more effective, in the base-case analysis saving 234191 € for a gain of 0.88 QALY. This is confirmed by both the deterministic and probabilistic sensitivity analyses. The main limit of the study remains the absence of long-term clinical data allowing to relate treatment consumption to clinical benefit, especially in the progression of haemophilic arthropathy. Our results show that emicizumab is a cost-effective treatment allowing to consider an easy to implement prophylactic treatment for haemophilia A patients with anti-FVIII inhibitors.

The Progression of Hemophilic Arthropathy: The Role of Biomarkers.

Background: Hemophilia A and B are X-linked congenital bleeding disorders characterized by recurrent hemarthroses leading to specific changes in the synovium and cartilage, which finally result in the destruction of the joint: this process is called hemophilic arthropathy (HA). This review highlights the most prominent molecular biomarkers found in the literature to discuss their potential use in the clinical practice to monitor bleeding, to assess the progression of the HA and the effectiveness of treatments. Methods: A review of the literature was performed on PubMed and Embase, from 3 to 7 August 2020. Study selection and data extraction were achieved independently by two authors and the following inclusion criteria were determined a priori: English language, available full text and articles published in peer-reviewed journal. In addition, further articles were identified by checking the bibliography of relevant articles and searching for the studies cited in all the articles examined. Results: Eligible studies obtained at the end of the search and screen process were seventy-three (73). Conclusions: Despite the surge of interest in the clinical use of biomarkers, current literature underlines the lack of their standardization and their potential use in the clinical practice preserving the role of physical examination and imaging in early diagnosis.

ПРОФИЛАКТИКА И ЛЕЧЕНИЕ ГЕМОФИЛИЧЕСКОЙ АРТРОПАТИИ

Background. The main clinical manifestations of hemophilia are spontaneous hemarthrosis and haemophilic arthropathy. Currently (since 2009) two hemostatic therapy regimens are employed in Belarus – «on demand» and prophylactic ones. The purpose of this research was to clarify the influence of different types of hemostatic therapy on the development of hemophilic arthropathy and to determine the effectiveness of chemical synoviorthesis and total knee replacement (TKR). Material and methods. A retrospective analysis of the therapy and its results in 87 patients with severe hemophilia treated at the Belarusian Research and Practical Center of Traumatology and Orthopedic Surgery and Belarusian Research Center for Pediatric Oncology, Hematology and Immunology during 2009-2018 years was performed. Results. The obtained findings showed that prophylactic hemostatic therapy prevented the development of haemophilic arthropathy. In the patients treated "on demand" the progression of haemophilic arthropathy could be slowed down by chemical synoviorthesis; in the cases of its later stages the operation of choice was TKR.

Knee Fat Pad Volumes in Patients with Hemophilia and Their Relationship with Osteoarthritis.

Hemophilic arthropathy is a progressive, disabling condition with poorly understood pathobiology. Since there is an emerging interest to study the role of intra-articular fat pad size and biology in arthritic conditions, we explored fat pad volume changes in hemophilic arthropathy and to what extent they differed from osteoarthritis. We matched a cohort of 13 adult patients with hemophilic arthropathy of the knee with age- and gender-matched cohorts without osteoarthritis (“control cohort”) and with the same degree of radiographic osteoarthritis (“OA cohort”) in 1 : 2 fashion. Infrapatellar fat pad (IPFP) and suprapatellar fat pad (SPFP) volumes were calculated based on magnetic resonance imaging and differences in fat pad volumes, demographics, height, weight, and osteoarthritis scores were evaluated. Fat pad volumes were positively associated with body size parameters in all three cohorts but were unaffected by the degree of osteoarthritis. While IPFP volumes did not differ between cohorts, SPFP volumes expanded disproportionally with weight in hemophilia patients. Our observations indicate that IPFPs and SPFPs behave biologically differently in response to different arthritic stimuli. The exaggerated expansion of the SPFP in hemophilia patients highlights the importance of further studying the implications of fat pad biology for progression of hemophilic arthropathy.

Ultrasound for Early Detection of Joint Disease in Patients with Hemophilic Arthropathy

Joint bleeding represents the most commonly reported type of hemorrhage in patients affected by hemophilia. Although the widespread use of prophylaxis has been able to significantly reduce the onset of arthropathy, it has been shown that a non-negligible percentage of patients develop degenerative changes in their joints despite this type of treatment. Thus, periodic monitoring of the joint status in hemophilia patients has been recommended to identify early arthropathic changes and prevent the development or progression of hemophilic arthropathy. Ultrasound (US) has proven able to detect and quantify the most relevant biomarkers of disease activity (i.e., joint effusion and synovial hypertrophy) and degenerative damages (i.e., osteo-chondral changes) by means of scoring scales of increasing disease severity. In the present review, we have detailed major literature evidence about the use of US to assess joint status in hemophilia patients, focusing on signs of disease activity and degenerative damages. In particular, we have discussed recent evidence about “point-of-care” use patients with hemophilia.

Progression of haemophilic arthropathy in children: a Lithuanian – Danish comparative study

Recurrent bleeding into joints initiates a sequence of events leading to a progressive joint damage in people with severe haemophilia. This is a continuous process during childhood and adolescence, therefore joint abnormalities may be minimal on physical examination in very young children - even those receiving on-demand treatment. The aim of our study was to quantify the burden of arthropathy in Lithuanian patients who had been treated exclusively by on-demand substitution and compare their physical joint health with age-matched Danish patients who received prophylaxis from an early age. Boys, aged 4-17years, with severe haemophilia and no signs of inhibitors were included in the study. Joint outcome based on the Haemophilia Joint Health Score (HJHS) was analysed in two different treatment groups and compared within the matched pairs. In total, 32 (16 in each treatment group) patients were enroled. A total of 192 joints were evaluated. Joint status according to treatment strategy was strikingly different: 27.4 for on-demand vs. 3.3 for prophylaxis (<0.001) group. Significance of the difference in joint status comparing different treatment strategies was equally strong both in younger (4-9years) and older (10-17years) patient groups: 2.2 vs. 12.5 (P= 0.0002) and 3.9 vs. 36.3 (P<0.0001) respectively. The results further demonstrate the unequivocal effect of prophylaxis on joint status and give an insight into early and late manifestations of joint impairment based on the HJHS in haemophilia patients with treatment on-demand compared with joint changes that may develop over the time with the preventative treatment.

Arthroscopic synovectomies combined with reduced weight‐bearing using patella tendon‐bearing braces were very effective for progressed haemophilic ankle arthropathy in three paediatric patients

The major goals of synovectomy for haemophilic arthropathy are considered to be reduction of bleeding and maintenance of joint function [1]. Synovectomy is generally thought to retard, but not halt, the progression of haemophilic arthropathy. It is thus not typically indicated for advanced haemophilic arthropathy. Rodriguez-Merchan [1] stated that the best solution for advanced arthropathy of the ankle is ankle arthrodesis. Although arthrodesis represents the gold standard for progressed ankle arthropathy, we prefer to avoid this option, particularly for paediatric patients. We therefore devised a treatment to reduce weight-bearing using a patella tendon-bearing (PTB) brace after synovectomy. The purpose of the present study was to report the clinical results of this procedure in three paediatric patients. Arthroscopic synovectomy was performed through anteromedial, anterolateral and posterolateral portals with non-invasive mechanical distraction (Achflex; Smith & Nephew, Tokyo, Japan). A 2.7mm, 30 arthroscope was used. Full-radius shaves and an electrothermal bipolar vapor system (Mitek, Westwood, MA, USA) were used for synovectomy. Defective cartilage areas were treated using a bone marrow stimulation technique with drilling. Drilling was performed with a 1.8-mm diameter Kirschner wire through anteromedial and anterolateral portals and across the medial malleolus. A below-the-knee cast was applied for 5 days. Immediately after removing the cast, the PTB brace was applied and range-of-motion exercises were initiated. Use of the PTB brace was continued for 1 year (Fig. 1). Preoperative factor levels were raised to nearly 100 U dL in all patients. Secondary prophylaxis was performed postoperatively. Three male paediatric haemophilic patients (11, 5 and 8 years) with progressed ankle arthropathy were treated (Table 1). Case 1 was diagnosed as having moderately severe haemophilia B at 24 months of age, where as case 2 and 3 were diagnosed as severe haemophilia A at 8 and 7 months, respectively. In case 3, an inhibitor was detected for the first time at 15 months (the maximum inhibitor level: 12 Bethesda U mL). At the age of seven, immune tolerance induction (ITI) was attempted. Three months after ITI was commenced, the inhibitor disappeared and the recovery rate of factor VIII: C after the administration of factor VIII concentrates was normalized. Contralateral side of the ankle and the other joints were unaffected in all patients. Frequent bleeding was observed in the affected ankle and severe or moderate pain was reported during walking. The three patients were followed for a mean duration of 30 months (range, 24–40 months). Two patients showed no intra-articular bleeding after treatment (Table 2). The other patient experienced only one episode of bleeding at 18 months after surgery and a cast was applied for one week. No recurrent bleeding occurred thereafter. Clinical results were evaluated using the American Orthopaedic Foot and Ankle Society (AOFAS) ankle and hindfoot scale, which includes scores for pain (40 points), function (50 points) and alignment (10 points). Mean AOFAS score improved from 41 points preoperatively to 96 points at follow-up. Dorsiflexion of the all ankles were improved Correspondence: Yasuhito Tanaka, MD, Department of Orthopaedic Surgery, Nara Medical University, Kashihara, Nara 6348522, Japan. Tel.: +81 74 429 8873; fax: +81 74 425 6449; e-mail: yatanaka@naramed-u.ac.jp

Extravascular Clotting Factor Activity within Joint Tissues Protects Against Progression of Hemophilic Arthropathy.

Hemophilic arthropathy is the major morbidity of congenital factor VIII and IX deficiency. Therapies localized to hemophilic joints could provide adjunctive protection, in addition to that provided by systemic factor replacement. However, the ability of extravascular clotting factors to contribute to hemostatic protection within joint tissue is unknown. We hypothesized that replacing deficient factor VIII or IX within the injured joint capsule of mice with hemophilia A (FVIII −/ −) or hemophilia B (FIX −/ −), respectively, would decrease the progression of synovitis. We developed a bleeding model consisting of a unilateral knee joint capsule needle puncture to induce hemorrhage in hemophilic mice. Pathology of the joint at two weeks after the injury is graded 0 to 10 using a murine hemophilic synovitis grading system (Valentino, Hakobyan. Haemophilia, 2006). Hemostatically normal mice do not develop synovitis following this injury, but > 95% of FIX −/ − mice develop bleeding and synovitis with a mean grade of 3–4 or greater. Coincident with needle puncture, recombinant human coagulation factor doses ranging from 0 to 20 IU/kg body weight of factor IX or 0 to 25 IU/kg of factor VIII were instilled intraarticularly (I.A.). Comparison groups received the same injury and intravenous (I.V.) factor IX or VIII doses of 25 IU/kg to 100 IU/kg (n= 4–7 mice per study group). Joint bleeding phenotype of the two strains of mice was similar. Mice receiving only saline injection at the time of needle puncture developed mean synovitis scores of 5 ±0.5 in the FVIII −/ − mice and 6 ±0.5 in the FIX −/ − mice. Protection by human clotting factor in the mouse coagulation system was incomplete; mice receiving 100 IU/kg I.V. of factor VIII or factor IX developed synovitis scores of 2.6 ± 1.7 and 2.1 ± 0.2, respectively. In contrast, pathology grade of FVIII −/ − mice dosed with 25 IU/kg I.A. was 0.67 ± 0.3 (p = 0.05 for comparison of 25 IU/kg I.A. with 100 IU/kg IV); FIX−/ − mice receiving 20 IU/kg I.A. had synovitis scores of 0.45 ± 0.58 (p < 0.01 for comparison of 25 IU/kg I.A. with 100 IU/kg I.V.). We next ruled out the possibility that I.A. factor was entering the circulation, and via that route resulting in joint protection, either through technical error at the time of injection, or from a depot effect in the joint with late equilibration into the circulation. Additional groups of mice received factor VIII or IX intravenously at 100 IU/kg, or intraarticularly at 4 times the doses used in the hemarthrosis challenge (80 IU/kg FIX or 100 IU/kg FVIII), and factor activity assays were performed at 1, 4, 12, 24, and 48 hours. Expected circulation kinetics were seen following I.V. dosing; no increase in circulating factor VIII or IX activity were seen in the intraarticular dosing groups at any timepoint. In considering the potential immunogenicity of an intraarticular therapy approach for hemophilic joint therapy, factor VIII −/ − mice were treated with three doses of human factor VIII 100 IU/kg at five day intervals either I.V. or I.A. At two weeks after exposure, 5/5 I.V.-treated mice developed inhibitor antibodies with titers ranging 0.8–7.2 BU; 2/5 I.A.-treated mice had detectable low-titer antibodies (1.3 BU), indicating no greater immunogenicity in the I.A. model. Extravascular factor VIII and factor IX can contribute to protection against blood-induced joint deterioration; enhancing local tissue hemostasis with protein or gene therapy may prove a useful adjunct to systemic replacement.

Long‐term major joint outcomes in young adults with haemophilia: interim data from the HGDS

A study of major joint outcomes, specifically range of motion and synovitis, was conducted with data from a subset of adolescents enrolled in the prospective Hemophilia Growth and Development Study (HGDS). Clinical observations were carried out over a 7-year period from 1989 to 1996. A secondary aim was to gain insight into factors that might influence decisions regarding maintaining or discontinuing prophylaxis during early adulthood. Twenty-nine participants (median age 17.4 at entry) were included. Median follow-up was 7 years (range: 4.8-7.7). Range of motion (ROM) and synovitis in six major joints (knees, elbows and ankles), were evaluated by physical examination every 6-12 months. At the baseline observation, 73.6% of joints showed no ROM abnormalities or synovitis, and all joints were normal in 11 patients. Of the 11 participants, 54.5% developed abnormalities and 28.1% of normal joints at baseline became abnormal during the follow-up. Ankles were the most severely affected and had persistent progression during late adolescence and adulthood. Elbows and knees did not show progression after the first few years of the follow-up. The progression of haemophilic arthropathy in adolescents and young adults varies from individual to individual and also in the site of affected joints. In view of this, the decision regarding discontinuation of prophylaxis in patients with haemophilia should be individualized.

Orthopedic interventions in patients with hemophilia

Patients with severe hemophilia A or B and von Willebrand Syndrome have recurrent joint bleedings, which can occur spontaneously or as a result of trauma. Resorption of intraarticular blood induces an inflammation of the synovium and cartilage damage, finally leading to severe changes of the joint with complete destruction. This process is called hemophilic arthropathy. After failure of substitution and intensive conservative therapy after 3 to 6 months, a synovectomy or a synoviorthesis are indicated. In some cases the progression of hemophilic arthropathy cannot be stopped and requires total joint arthroplasty. In some cases joint motion cannot be saved and requires arthrodesis. This paper presents methods and results of different operation concepts in patients (n = 39) with hemophilia or von-Willebrand-syndrome. Especially by implanting total knee (n = 17) and total hip joints (n = 6) we obtained very good functional results after an average follow-up period of 33.3 respectively 56.3 months. In a series of synovectomie of the knee performed before 1990 (n = 7) and followed after an average period of 21.4 years the progression of hemophilic arthropathy could not be stopped. In a second series of synovectomy of the knee performed after 1990 (n = 5) and follow after an average period of 5.6 years, at least the mobility of the knee could be saved. Only one patient of a series of supra- and infracondylar osteotomie (n = 9) achieved the wanted result. Further we performed 6 operations on the hindfoot with satisfying results.