MRI-Derived Radiomics of Hemophilic Arthropathy Is Associated with Severity of Joint Disease

Introduction Joint bleeding resulting in synovial hypertrophy and articular cartilage damage are the hallmarks of hemophilic arthropathy. Early prophylaxis with extended half-life factor products and non-factor replacement therapies reduce joint bleeds but do not provide complete protection from development of arthropathy. MRI is the gold standard imaging technique to diagnose and monitor arthropathy in hemophilia. MRI changes that are associated with joint bleeding and development of arthropathy, however, are not sensitive enough to detect early changes in the synovial membranes after sub-clinical bleeding. Radiomics, the computerized extraction of sub-visual attributes from imaging scans can detect early changes of hemophilic arthropathy and help in more accurate characterizations of severe joint disease. The goal of this project was to develop and compare MRI radiomics with the International Prophylaxis Study Group (IPSG) score, an established MRI joint disease scale, in assessing the severity of joint disease. Methods After IRB approval, knee MRI scans of 17 hemophilia patients with a history of joint bleeding and 12 age-matched healthy controls were included in this study. Manual annotations were performed in consensus by a board-certified musculoskeletal radiologist to include the prefemoral fat, suprapatellar fat pad and bursa . To ensure that the signal intensities from different cases were in tissue-specific correspondence, a landmark-based histogram transformation was used to align MRI signal intensity distributions across all cases. 560 radiomic features capturing MRI pixels texture heterogeneity (Gabor wavelets, Laws texture, Haralick and GoLIAGe co-occurrence patterns) were subsequently extracted on all MRI slices with ROI for all the cases. Top 2 radiomic features (F 2) for differentiating between abnormal joint changes and control were selected by Minimum Redundancy Maximum Relevance (mRMR) algorithm with 100 iterations of 3-fold cross-validation. Consensus hierarchical clustering was then applied on F 2, from which two patient clusters were generated. A disease severity score was calculated based on historical lifetime bleed events in the joint, designation of target joint status, and history of surgical synovectomy. A previously described 17-point MRI IPSG score was also calculated by 2 independent reviewers. Both the IPSG score and the F 2 were then fit into a linear regression model separately as predictors whereas the disease severity score was set to be the response variable. The Akaike's Information Criteria (AIC) and the root mean square error (RMSE) were used to evaluate the model fitness and the likelihood ratio (LR) test was applied for model comparison. Results The dataset consisted of 17 males with moderate and severe hemophilia ranging in age from 10-55 years. The median disease severity score was 2 (0-11) and the median IPSG MRI Score was 2 (0-11). The top 2 radiomic features F 2, a Gabor wavelet feature and a Lawshc texture feature, yielded an AUC of 0.94 and an accuracy of 0.9 for differentiating between hemophilic joint changes and healthy control patients. Unsupervised clustering demonstrated good separation between the two classes (Fig panel A and B). The radiomic-based linear regression model (AIC: 86.67; RMSE: 2.86) was significantly better than the IPSG score-based model (AIC: 94.24; RMSE: 3.66) in joint disease severity characterizations (LR, p = 0.0083, Fig panel C). Conclusions Radiomic analysis of knee MRI in hemophilia patients with history of joint bleeding is correlated with the severity of joint disease. Our study demonstrates the feasibility of developing and utilizing a radiomics based tool to detect the severity of joint damage in a small population of knee joint hemophilic arthropathy. We plan to perform an Independent validation of the radiomics signature in a larger dataset of hemophilia joint MRI scans Figure 1 Figure 1. Disclosures Madabhushi: Astrazeneca: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers-Squibb: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; Caris: Consultancy; Aiforia: Consultancy; Philips: Research Funding; AstraZeneca: Research Funding; Boehringer-Ingelheim: Research Funding; Bristol Meyers-Squibb: Research Funding. Ahuja: Sanofi: Membership on an entity's Board of Directors or advisory committees; XaTek, Inc: Patents & Royalties; Genentech: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: DSMB member .

Early Findings on the Use of Motion Capture during Simulated Sports Activities to Better Understand Hemophilic Arthropathy

Many persons with hemophilia (PwH) have joint bleeding despite prophylaxis. We hypothesize that movement biomechanics play a significant and largely unexplored role in joint bleeding, which could be exploited to develop personalized rehabilitation programs. We have designed a clinical study to test this hypothesis. Here we show data from the first 3 enrollees as case studies of what could potentially be learned. Data were collected from 3 participants with hemophilia A, ages 10-30 years, on prophylaxis with emicizumab, with at least 1 joint bleed in the lower extremity in the past year, using motion capture techniques with force plates and reflective markers collected through a Vicon system. Motion lab activities were designed to simulate sports activities and included walking (barefoot and shod), squatting (double and single leg), hopping on one foot, and jumping from a 30-cm box. Two patients (B and C) routinely take additional factor VIII prophylaxis prior to physical activity and did so before coming to the motion lab. Hemophilia Joint Health Score (HJHS) was obtained by an experienced physical therapist prior to motion lab collection to gauge degree of hemophilic arthropathy by physical exam. A subset of participants and activities are shown graphically. Participant A (not shown) had a higher HJHS in the right knee than left (3 vs 0) and had HJHS of 4 in bilateral ankles, with most recent bleed in the right ankle 8 months prior; primary physical activity was walking. This participant showed subtle differences between the right and left in all activities, including less weight on the right leg during double leg squat, and right single leg hop lower than the left. Participant B had a higher HJHS in the right knee than the left (3 vs 0) and in the right ankle than the left (7 vs 6), and he had had multiple episodes of knee pain but no change in HJHS since 2 years prior. Knee MRIs performed outside of the study were consistent with tendinosis of bilateral quadriceps rather than bleeding. Primary sports were basketball, hiking, biking, and skiing. Participant B had subtle differences between the right and left side that seemed to protect the right, including mildly decreased right knee flexion with weight acceptance during walking (more pronounced when wearing shoes), lower power generation by the right ankle than the left in walking, and lower peak ground reaction force (GRF) on the right than left in forward hopping. Some motions seemed to protect the left side more, with less power generation and absorption by the ankle (double and single leg squats) and hip (single leg squat only), right single leg squat somewhat deeper than the left, and slower time to step onto the left foot than the right. Participant C had a higher HJHS in the right knee than left (2 vs 1) and in the right ankle than left (5 vs 3) but had had worsening HJHS in bilateral ankles compared to his previous scores, with bleeds in both knees in the past year. Primary physical activities were baseball (pitching), basketball, biking, skiing, and golf. He had recently been diagnosed with Osgood Schlatter (patellar tendon/tibial tuberosity inflammation) of the left knee, which had been causing pain for several months, but no bleeding in that knee. Movement analysis reflected left knee pain, including very little flexion with weight acceptance when walking; very little power absorption or generation from the knee in walking, hopping, and squatting; shallower squats and lower hops on the left; and lower ground reaction force on the left than the right with walking. Perhaps related to the left knee protection, both ankles were consistently more plantarflexed in walking, and there was increased power generation in the right ankle compared to the left. These findings suggest the presence of subtle asymmetry related to hemophilic arthropathy and previous bleeding, which were more pronounced in more strenuous activities than with walking. The results of participant C could suggest that pain, even if unrelated to hemophilia, could cause compensatory movement mechanisms that could lead to increased bleeding risk in other lower extremity joints. Ongoing analysis will include tracking of bleeding over 1 year following motion analysis, enrollment of additional participants, comparison with controls, and performing detailed statistical analysis to determine which movement parameters correlate best with HJHS and lower extremity bleeding risk. Figure 1 Figure 1. Disclosures Warren: Novo Nordisk: Consultancy; Hema Biologics: Consultancy; Bayer: Research Funding; CSL Behring: Research Funding; Genentech: Research Funding. Funk: Biomarin: Consultancy; Sanofi Genzyme: Speakers Bureau; Toronto Sick Kids Hospital: Patents & Royalties: Hemophilia Joint Health Score Royalties; Partners: Honoraria.

Assessment of TRM-201 (Rofecoxib) Efficacy and Safety for Chronic Pain in Hemophilic Arthropathy: The Rofecoxib Efficacy and Safety Evaluation Trial in Hemophilic Arthropathy (RESET-HA), a Randomized, Double-Blind Placebo-Controlled Phase III Clinical Trial

Background: Intra-articular bleeding (hemarthrosis) accounts for 80-90% (Roosendaal, et. al. Semin Thromb Hemost . 2003;29:37) of all bleeds and more than 90% of serious bleeding events in patients with severe hemophilia (Valentino. J Thromb Haemost . 2010;8:1895). Recurrent hemarthroses result in progressive joint damage and the development of hemophilic arthropathy (HA) in up to 50% of adults with hemophilia (Forsyth, et al. Haemophilia . 2014;20:44). Acetaminophen is commonly prescribed for pain due to HA yet has limited efficacy at therapeutic doses (Rodriguez-Merchan. Blood Rev. 2018;32:116). Traditional non-steroidal anti-inflammatory drugs (tNSAIDs) inhibit platelet function and cause gastrointestinal (GI) complications including bleeding, both of which can be harmful in patients with hemophilia (Rodriguez-Merchan. Blood Rev. 2018;32:116; Brooks, et al. Rheumatology . 1999;38(8):779). Opioids are prescribed in over 60% of patients with HA(Witkop, et al. Haemophilia. 2012;18:e115) despite dependence, potential for abuse, and an increased risk of falls and other opioid-related injury (Rodriguez-Merchan. Blood Rev. 2018;32:116). Given an unmet need in pain management for HA, alternate approaches are needed. TRM-201 (rofecoxib) is a cyclooxygenase-2 (COX-2) selective NSAID with no impact on platelet function and a lower GI risk than tNSAIDs (Vioxx (rofecoxib) package insert. Merck & Co. I, ed. Whitehouse Station, NJ, 2004). The RESET-HA study is designed to evaluate the efficacy and safety of rofecoxib for HA pain management. Methods/Design: RESET-HA is a multi-national, randomized, double-blind study to evaluate the efficacy and safety of rofecoxib in hemophilia A or B patients with diagnosed HA, aged 12 to 75 years and is based on a previous pilot study (Tsoukas, et al. Blood, 2006;107:1785). Patients must have a history of joint bleeding, and chronic symptomatic pain in one or more joint(s) on 20 of the 30 days prior to screening. Exclusion criteria include use of opioids for greater than 4 days/week, or opioid transdermal patches in the 30 days prior to screening, history of GI perforation, ulcer or bleeding, peptic ulcer disease and major cardiac ischemic symptoms or events. Randomized patients (n=80 per arm) are washed out of analgesics prior to daily administration of TRM-201 (17.5 mg/day) or placebo for 12 weeks (Part I) during which acetaminophen (Stage-1) and acetaminophen plus codeine (Stage-2) are available as rescue medication (where available and acceptable to the patient and study doctor). The patient assessment of hemophilic arthropathy pain, a 0- to 10-point numeric rating scale validated for the assessment of pain across many disease states, is recorded daily. The primary endpoint is the placebo adjusted change from baseline in weekly average of patient assessment of daily HA pain score at Week 12. Key secondary endpoints include patient assessments using the PROMIS physical function instrument and pain interference from the Brief Pain Inventory. Sleep disturbance is also measured using the PROMIS instrument. The study explores the efficacy of rofecoxib on the number of suspected joint bleeds and on the amount of rescue medication used. Following Part I, all study patients (regardless of original randomization arm) receive rofecoxib 17.5 mg once daily for up to 12 additional months (Part II). During Part II of the study, only acetaminophen will be provided as rescue medication. Discussion: The RESET-HA study is intended to evaluate the efficacy and safety of TRM-201 in patients with HA and is the first Phase III trial ever conducted to assess a treatment for HA pain. Pain management in HA requires analgesic anti-inflammatory treatment that does not exacerbate bleeding. Rofecoxib has been shown to have no effect on platelet function, even at supratherapeutic doses(Vioxx (rofecoxib) package insert. Merck & Co. Whitehouse Station, NJ, 2004), a decreased risk of GI side effects, including GI bleeding compared with tNSAIDs, and no greater cardiovascular risk than equipotent doses of COX-2 selective and tNSAIDs (U.S. Food and Drug Administration. J Pain Palliat Care Pharmacother. 2005;19:83). TRM-201 is anticipated to provide analgesic efficacy, with an acceptable tolerability and safety profile, and could become a new treatment option that may possibly facilitate the avoidance of opioid use in patients with HA. (NCT04684511) Disclosures Boice: Tremeau Pharmaceuticals Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Buckner: Novo Nordisk: Honoraria; American Thrombosis: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria; Genetech: Honoraria; Spark: Honoraria; Sanofi: Honoraria; Bayer: Honoraria; Pfizer: Honoraria; Takeda: Honoraria; Tremeau Pharmaceuticals: Consultancy, Honoraria; uniQure: Consultancy, Honoraria; BioMarin: Consultancy, Honoraria; Hemostasis Network: Membership on an entity's Board of Directors or advisory committees. Croteau: Tremeau Pharmaceuticals,Inc: Consultancy. Katz: Tremeau Pharmaceuticals,Inc: Consultancy. Sidonio: Takeda: Consultancy, Research Funding; Octapharma: Consultancy, Research Funding; Catalyst: Consultancy; Guardian Therapeutics: Consultancy; Bayer: Consultancy; Novo Nordisk: Consultancy; Biomarin: Consultancy; Pfizer: Consultancy; Genentech: Consultancy, Research Funding. Bolognese: Tremeau Pharmaceuticals,Inc: Consultancy. Garfield: Tremeau Pharmaceuticals,Inc: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Corrigon: Tremeau Pharmaceuticals,Inc: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Walsh: Genentech: Consultancy; Biomarin: Consultancy; Takeda: Consultancy; Novo Nordisk: Consultancy; Tremeau: Consultancy.

Role of Musculoskeletal Ultrasound in Detection of Hemophilic Arthropathy

Background Hemophilia is an X-linked congenital bleeding disorder, with hemophilia A comprising the majority of cases and hemophilia B. Von Willebrand disease (VWD) is a bleeding disorder of variable severity, caused by deficiency of von Willebrand factor (VWF) especially type III. The severe form of the bleeding disorders is characterized by spontaneous hemoarthrosis which occurs mainly in large synovial joints and results in hemophilic arthropathy (HA) that is characterized by soft tissue changes such as synovial hypertrophy and effusion as well as cartilage and bony damage., MRI is the gold standard, however ultrasound (US) was proven to be a sensitive tool in detecting synovial hypertrophy with results comparable to MRI, as well as differentiate between hemoarthrosis and arthritis-metiated joint pain, together with having more advantage to the MRI, making it an excellent tool in assessing disease activity. Objective To describe the value of MSK ultrasound in assessment of intra-articular findings in hemophilic arthropathy (HA) in the pediatric age group. Methods A descriptive, cross-sectional study that included 120 joints in 20 patients with bleeding disorders, (moderate or severe hemophilia A/B or vWD). Evaluated joints included elbows, knees and ankle joints on both sides for every patient. One additional patient was evaluated for a hip joint affection. The abnormal US findings among the involved joints were compared to the sonographically-normal contralateral side. We excluded patients with recent joint surgeries, those who have any other rheumatological disease. Results Out of the 120 joints examined, 28 joints showed US abnormal findings. The knee was the most common involved joint (75%), followed by the ankle (30%) then the elbow (15%). The most frequent US lesion was synovial hypertrophy (82%), followed by joint effusion (78.6%), synovial hyperemia (53%) and lastly comes the ostochondral lesions (7.1%). Other juxta-articular findings were reported as myositis, tenosynovitis and intra-/intermuscular hematoma. Hemoarthrosis was found in 6 out of 16 knee joints, 2 out of 7 ankles, yet no elbow nor hip joint bleedings were reported. There was a significant correlation between the incidence of synovial thickening, bone and cartlage damage and bleeding incidence and increasing age. A high statistical significant difference was found between the normal and abnormal joints (by US) and especially the knee and ankle joints. Conclusion MSK US has now emerged as a promising imaging modality for the early detection and management of HA, and for the evaluation of hemarthrosis and painful MSK episodes in hemophilic patients. It has a high efficacy in assessment of the soft tissue abnormalities such as synovial hypertrophy, vascularity and joint effusion, as well as late-onset degenerative changes. Global standardization of the different US scoring systems and clear definitions of the US pathologies in HA are needed with high-level MSK US training practice as well, for accurate assessment of HA using US.

Hemosiderin deposition evaluation in hemophilic ankle joints: association between US finding and gradient-recalled echo MR imaging sequence

Background Repeated bleeding in hemophilic arthropathy (HA) may result in severe degenerative changes and joint destruction. The gradient-recalled echo (GRE) sequence MR is proved to be the best method to detect hemosiderin deposition. However, MR is not widely available in developing countries, including Indonesia. Some studies have proposed ultrasonography (US) as an alternative tool in evaluating hemophilic joint. However, there is still some disagreement on the ability of US to detect hemosiderin deposition. Objective To evaluate the association between US and GRE-sequence MR imaging in detecting hemosiderin deposition in hemophilic ankle joint. Material and methods A total of 102 sites from 17 ankle joints of 11 boys with severe hemophilia A underwent US examination using a high-frequency linear array transducer. GRE-sequence MR examination was performed in sagittal view consistent with the sites scanned by US. Both examinations were performed on the same day, but MR interpretation was performed blindly at different times. The association between US and GRE-sequences in detecting hemosiderin deposition was analyzed using McNemar’s test. Results Statistical analysis showed a significant association (p value < 0.001) between US and GRE MR in detecting hemosiderin deposition, but the association is weak (R = 0.26). Sensitivity and specificity of US for detecting hemosiderin deposition were 46.84% (95%CI: 35.51–58.40) and 95.65% (95%CI: 78.05–99.89), respectively, with positive predictive value 97.37% (95%CI: 84.29–99.61), negative predictive value 34.38% (95%CI: 29.50–39.60) and accuracy 57.84% (95%CI: 47.66–67.56). Conclusion There was a weak association between US and GRE-sequences in detecting hemosiderin deposition of hemophilic ankle joint. ​​