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Introduction: Poor adherence to factor replacement therapy among patients with haemophilia can lead to joint bleeding and eventual disability. Aim: The aim of this study was to determine patient-related characteristics associated with adherence to factor replacement in adults with haemophilia. Methods: Adults with haemophilia were recruited to participate in this cross-sectional study. Adherence was measured using either the Validated Hemophilia Regimen Treatment Adherence Scale (VERITAS)-Pro or the VERITAS-PRN questionnaire. Simple and multiple regression analyses that controlled for confounding were performed to determine the association between patient-related characteristics and adherence to factor replacement therapy. Results: Of the 99 subjects enrolled, all were men; 91% had haemophilia A and 78% had severe disease. Age ranged from 18 to 62 years. Most (95%) had functional health literacy; but only 23% were numerate. Mean adherence scores were 45.6 (SD 18) and 51.0 (SD 15) for those on a prophylactic and those on an episodic regimen, respectively, with a lower score indicating better adherence. On multivariable analysis, being on any chronic medication, longer duration followed at our haemophilia treatment centre, higher physician trust and better quality of life were associated with higher adherence. A history of depression was associated with lower adherence. Conclusion: Two potentially modifiable characteristics, physician trust and depression, were identified as motivator and barrier to adherence to factor replacement therapy. Promoting a high level of trust between the patient and the healthcare team as well as identifying and treating depression may impact adherence to factor replacement therapy and accordingly reduce joint destruction.

Although persons with nonsevere hemophilia A (NSHA) account for about one-half of the hemophilia A population, epidemiological data in this subset of individuals are scarce. We set out to describe the clinical characteristics of persons with NSHA with inhibitors, and to determine mortality rates, predictors of mortality, and primary causes of death in persons with NSHA in the United States over a 9-year period (2010-2018). We queried the American Thrombosis and Hemostasis Network dataset (ATHNdataset) for information on demographics, inhibitor status, and date and cause of death. A total of 6624 persons with NSHA (86.0% men; 14.0% women) were observed for an average of 8.5 years; total 56 119 person-years. The prevalence of inhibitors was 2.6% (n = 171), occurring at a median age of 13 years. At the end of follow-up, 136 persons died at a median age of 63 years; an age-adjusted mortality rate of 3.3 deaths per 1000 person-years. Three deaths occurred in inhibitor participants. Presence of inhibitors was not associated with increased mortality risk (hazard ratio [HR], 0.7, 95% confidence interval [CI], 0.2-2.3). Factors independently associated with increased risk of death (HR, 95% CI) were the following: age (10-year increase) (2.1, 2.0-2.4); male (2.6, 1.0-6.4); hepatitis C (2.2, 1.5-3.1); and HIV (3.6, 2.2-6.0). The most common primary cause of death was malignancy (n - 27, 20.0%). In persons with NSHA, the development of inhibitors occurred at an early age and was not associated with increased mortality.

Background: Immune tolerance induction (ITI) in patients with congenital hemophilia A is successful in up to 70%. Although there is growing understanding of predictors of response to ITI, the probability and predictors of inhibitor recurrence following successful ITI are not well understood. Objectives: To determine the association of clinical characteristics, particularly adherence to FVIII prophylaxis following ITI, with inhibitor recurrence in patients with hemophilia A who were considered tolerant following ITI. Methods: In this multicenter retrospective cohort study, 64 subjects with FVIII level <2% who were considered successfully tolerant following ITI were analyzed to estimate the cumulative probability of inhibitor recurrence using the Kaplan-Meier method. The association of clinical characteristics with inhibitor recurrence was assessed using logistic regression. Results: A recurrent inhibitor titer ≥ 0.6 BU/ml occurred at least once in 19 (29.7%) and more than once in 12 (18.8%). The probability of any recurrent inhibitor at 1 and 5 years was 12.8% and 32.5% respectively. Having a recurrent inhibitor was associated with having received immune modulation during ITI (OR 3.8, 95% CI: 1.2-22.4) and FVIII recovery of <85% at the end of ITI (OR 2.6, 95% CI: 1.3-5.9), but was not associated with adherence to post-ITI prophylactic FVIII infusion (OR=0.5, 95% CI: 0.06-4.3). Conclusions: The use of immune modulation therapy during ITI and lower FVIII recovery at the end of ITI appear to be associated with an increased risk of inhibitor recurrence following successful ITI. Adherence to post-ITI prophylactic FVIII infusions is not a major determinant of recurrence.

BACKGROUND: Studies of COVID-19 have shown that African Americans have been affected by the virus at a higher rate compared to other races. This cohort study investigated comorbidities and clinical outcomes by race among COVID-19 patients admitted to the intensive care unit. METHODS: This is a case series of critically ill patients admitted with COVID-19 to an academic healthcare system in Atlanta, Georgia. The study included all critically ill hospitalized patients between March 6, 2020, and May 5, 2020. Clinical outcomes during hospitalization included mechanical ventilation, renal replacement therapy, and mortality stratified by race. RESULTS: Of 288 patients included (mean age, 63 ± 16 years; 45% female), 210 (73%) were African American. African Americans had significantly higher rates of comorbidities compared to other races, including hypertension (80% vs 59%, P = 0.001), diabetes (49% vs 34%, P = 0.026), and mean BMI (33 kg/m2 vs 28 kg/m2, P < 0.001). Despite African Americans requiring continuous renal replacement therapy during hospitalization at higher rates than other races (27% vs 13%, P = 0.011), rates of intubation, intensive care unit length of stay, and overall mortality (30% vs 24%, P = 0.307) were similar. CONCLUSION: This racially diverse series of critically ill COVID-19 patients shows that despite higher rates of comorbidities at hospital admission in African Americans compared with other races, there was no significant difference in mortality.

Background: The Pain, Functional Impairment, and Quality of Life study was an observational, cross-sectional assessment of the impact of pain on functional impairment and quality of life in adult people with hemophilia (PWH) of any severity in the USA who experience joint pain and/or bleeding. Objective: To assess internal consistency (IC) and item-total correlation (ITC) of assessment tools used in the Pain, Functional Impairment, and Quality of Life study. Methods: Participants completed 5 patient-reported outcome instruments (EQ-5D-5L with visual analog scale, Brief Pain Inventory v2 Short Form [BPI], International Physical Activity Questionnaire [IPAQ] , Short Form 36 Health Survey v2 [SF-36v2], and Hemophilia Activities List [HAL] ) and underwent an optional physiotherapist-administered musculoskeletal exam (Hemophilia Joint Health Score v2.1) during routine visits. Reliability assessment included IC and ITC of each instrument. Results: A total of 381 adult PWH (median age, 34 years) were enrolled. Participants were predominantly white/non-Hispanic (69.2%); 75% had congenital hemophilia A, and 70.5% had severe hemophilia. A total of 310 subjects reported bleeding within the past 6 months (mean [SD] number of bleeds, 7.1 [13.00] ). IC was generally high across the instruments employed (Cronbach’s alpha 0.79-0.98) with the exception of HAL use of transportation (0.58) and IPAQ total physical activity (0.51). ITC was high (Pearson’s product-moment correlation coefficient.0.20) for all items except the “vigorous intensity activities” item of IPAQ, which was applicable to less than one-third of participants. The ITCs were generally highest in domains/scores that measured the functional consequences of hemophilic arthropathy on mobility and pain. Conclusion: The demonstrated reliability (IC/ITC) of the patient-reported outcome instruments and Hemophilia Joint Health Score v2.1 support a role for these instruments in evaluating adult PWH in US clinical and research settings.

Development of anti-factor VIII (FVIII) inhibitory antibodies (inhibitors) is the most significant treatment complication of hemophilia A. Characteristics of the interaction between major histocompatibility complex (MHC) class II and FVIII peptides may influence FVIII antigen presentation to T cells and subsequent inhibitor development. We analyzed predicted HLA-DRB1, a subset of MHC class II, and FVIII peptide binding and its association with inhibitor development among subjects with nonsevere hemophilia A, including 20 cases (inhibitor titer ≥ 1.0 BU/mL on 2 occasions or on 1 occasion with subsequent immune tolerance induction) and 37 controls (who had received FVIII infusions and did not develop inhibitor). Using the MHC-II Binding Predictions Tool (https://www.iedb.org), the binding affinity and core binding were determined for endogenous FVIII (eFVIII) and treatment FVIII (tFVIII). A tFVIII peptide was considered novel if it was predicted to bind and present a surface to the T-cell receptor that was unique from that presented by eFVIII. Having >10 novel HLA-DRB1 allele-tFVIII peptide combinations was associated with inhibitor development (adjusted odds ratio, 4.1; 95% confidence interval, 1.1-15.0). Cases and controls with p.Arg612Cys and p.Arg2169His demonstrated a high level of novel HLA-DRB1-tFVIII peptide combinations. Assessing the likelihood that tFVIII is presented to T cells in a novel fashion may be useful for understanding and ultimately reducing the risk for inhibitor development among patients with nonsevere hemophilia, particularly those with F8 mutations other than p.Arg612Cys and p.Arg2169His.

Introduction: The Joint Outcome Study (JOS) demonstrated that previously untreated children with severe hemophilia A treated with prophylactic factor VIII (FVIII) concentrate had superior joint outcomes at age six years compared to those children treated episodically for bleeding. However, variation in joint outcome within each treatment arm was not well-explained. Aim: In this study, we sought to better understand variation in joint outcomes at age 6 years in participants of the JOS. Methods: We evaluated the influence of FVIII half-life, treatment adherence, constitutional coagulant and anticoagulant proteins, and global assays on joint outcomes (number of joint bleeds, total number of bleeds, total MRI score, and joint physical exam score). Logistic regression was used to evaluate the association of variables with joint failure status on MRI, defined as presence of subchondral cyst, surface erosion, or joint-space narrowing. Each parameter was also correlated with each joint outcome using Spearman correlations. Results: Prophylaxis treatment arm and FVIII trough were each found to reduce risk of joint failure on univariate logistic regression analysis. When controlling for treatment arm, FVIII trough was no longer significant, likely because of the high level of covariation between these variables. We found no consistent correlation between any laboratory assay performed and any joint outcome parameter measured. Conclusion: In the JOS, the effect of prescribed prophylactic FVIII infusions on joint outcome overshadowed the contribution of treatment adherence, FVIII half-life, global assays of coagulation, and constitutional coagulation proteins. (ClinicalTrials.gov number, NCT00207597)

Background: The Pain, Functional Impairment, and Quality of Life (P-FiQ) study was an observational, cross-sectional assessment of the impact of pain on functional impairment and quality of life in adults with hemophilia in the United States who experience joint pain or bleeding. Objective: To describe known-groups validity of assessment tools used in the P-FiQ study. Patients and methods: Participants completed 5 patient-reported outcome (PRO) instruments (5-level EuroQoL 5-dimensional questionnaire [EQ-5D-5L] with visual analog scale [VAS] , Brief Pain Inventory v2 Short Form [BPI], International Physical Activity Questionnaire [IPAQ] , Short-Form Health Survey [SF-36v2], and Hemophilia Activities List [HAL] ) and underwent a musculoskeletal examination (Hemophilia Joint Health Score [HJHS]) during a routine clinical visit. Results: P-FiQ enrolled 381 adults with hemophilia (median age, 34 years). Participants were predominantly white/non-Hispanic (69.2%), 75% had congenital hemophilia A, and 70.5% had severe hemophilia. Most (n=310) reported bleeding within the past 6 months (mean [SD] number of bleeds, 7.1 [13.00]). All instruments discriminated between relevant known (site-or self-reported) participant groups. Domains related to pain on EQ-5D-5L, BPI, and SF-36v2 discriminated self-reported pain (acute/chronic/both; P,0.05), domains related to functional impairment on IPAQ, SF-36v2, and HAL discriminated self-reported functional impairment (restricted/unrestricted; P,0.05), and domains related to mental health on the EQ-5D-5L and SF-36v2 discriminated self-reported anxiety/depression (yes/no; P,0.01). HJHS ankle and global gait domains and global score discriminated self-reported arthritis/bone/joint problems, percentage of lifetime on prophylaxis, current treatment regimen, and hemophilia severity (P,0.01); knee and elbow domains discriminated all of these (P,0.01) except for current treatment regimen. Conclusion: All assessment tools demonstrated known-group validity and may have practical applicability in evaluating adults with hemophilia in clinical and research settings in the United States.

Background: Hemophilia is marked by frequent joint bleeding, resulting in pain and functional impairment. Objective: This study aimed to assess the reliability of five patient-reported outcome (PRO) instruments in people with hemophilia (PWH) in a non-bleeding state. Methods: Adult male PWH of any severity and inhibitor status, with a history of joint pain or bleeding, completed a pain history and five PRO instruments (EQ-5D-5L, Brief Pain Inventory v2 [BPI], International Physical Activity Questionnaire [IPAQ] , Short Form 36 Health Survey v2 [SF-36v2], and Hemophilia Activities List [HAL] ) during their routine comprehensive care visit. Patients were approached to complete the PRO instruments again at the end of their visit while in a similar non-bleeding state. Concordance of individual questionnaire items and correlation between domain scores were assessed using intra-class correlation coefficient (ICC). Results: Participants completing the retest (n=164) had a median age of 33.9 years. Median time for completion of the initial survey with PRO instruments was 36.0 minutes and for the five PRO instruments, median retest time was 21.0 minutes. The majority of participants had hemophilia A (74.4%), were white and non-Hispanic (72.6%), and self-reported arthritis/bone/joint problems (61%). Median/mean test-retest concordance was EQ-5D-5L 80.0%/79.1%, BPI 54.5%/58.9%, IPAQ 100%/100%, SF-36v2 77.8%/76.4%, and HAL 77.4%/75.9%. ICCs for test-retest reliability were EQ-5D-5L index 0.890; BPI - severity 0.950; BPI - interference 0.920; IPAQ total activity 0.940; SF-36v2 overall health 0.910; HAL total score 0.970. Conclusion: All five PRO scales showed acceptable test-retest reliability in adult PWH. Therefore, the choice of instrument to be used for research or clinical care should be driven by instrument characteristics other than reliability.