Rheumatoid Arthritis Disability and Absence Trends in the United States

Objectives: Employers increasingly focus on absence benefits and connections with employee health. United States absence benefits include Sick Leave (SL), Short- and Long-Term Disability (STD and LTD, respectively) for non-work-related injuries/illnesses, and Workers’ Compensation (WC) for work-related injuries/illnesses. This research explores all-cause absence (SL, STD, LTD, and WC) utilization and changes from baseline for eligible employees with rheumatoid arthritis to determine if the use a constant payment factor is appropriate for models. Study Design: Retrospective multi-year database analysis. Methods: The Workpartners database (1/1/2001-12/31/2019) was used to identify employees with rheumatoid arthritis with adjudicated medical claims. Annual prevalence, benefit utilization, mean days of leave, and median payments (as % of salary) were analyzed. Annual outcomes were calculated as a percent of baseline (2001). Results: Rheumatoid arthritis prevalence averaged 0.5% between 2001 and 2019. At baseline, the percent of eligible employees using STD = 15.5%, LTD = 0.7%, WC = 1.7%, SL = 61.7%. Mean absence days were 48.5, 367.5, 43.8 for STD, LTD, WC, respectively and median payments were 70.5%, 22.2%, 65.7% of salary for STD, LTD, WC, respectively. From 2002-2019: 11.7%-16.9% of eligible employees filed STD claims for 82.1%-995.9% of baseline days and 80.4%-125.9% median payments; 0.6%-2.9% of eligible employees filed LTD claims for 66.6%-114.7% of baseline days and 63.2%-254.8% median payments; 0.3%-1.6% of eligible employees filed WC claims for 44.0%-472.8% of baseline days and 70.4%-271.5% median payments. Median payments were highest in 2012, 2019, 2003 for STD, LTD, WC, respectively and the most absence days were used in 2017 for SL and LTD, 2008 for STD, and 2005 WC. Conclusion: Employees with rheumatoid arthritis used absence benefits at differing rates over time with varying leave-lengths and payments. Using a constant cost or salary replacement factor for absence costs over time and across benefits is not accurate.

Evaluation of mutagenic effects of pure hydroxyapatite doped with chromium (III) through the SMART Test in Drosophila melanogaster Meigen, 1830 (Diptera: Drosophilidae)

Hydroxyapatite (HAP) is a bioceramic used in the medical and dental areas as a bone replacement factor due to its chemical similarity to the mineral phase of bones and teeth. Its use in implants stimulate the growth of bone tissue, showing no toxicity or rejection of the host tissue. Its nanostructured form has been shown to be a viable alternative for photoprotection when doped with metal ions, such as trivalent chromium (Cr+³). Due to the reach of this form among the population, this work evaluated the mutagenic potential of pure nanostructured hydroxyapatite (HAP) and doped with trivalent chromium (Cr+³) (HCrIII) by means of the Somatic Mutation and Recombination Test (SMART Test) on Drosophila melanogaster Meigen, 1830 (Diptera: Drosophilidae) wings. Larvae resulting from standard crosses (ST) and high metabolic bioactivation (HB), treated with PAH and with HCrIII at concentrations 16.66 mg/mL, 8.33 mg/mL, and 4.16 mg/mL. As positive and negative controls, urethane and dodecyl sulfate sodium (SDS) were used, respectively. The frequencies of the different categories of mutant spots observed in offspring of HAP (HAP) and HCrIII treated crosses were not significantly different from those observed in the negative control. These data show that pure and chromium-doped (Cr+³) nanoestructured hydroxyapatite do not exhibit mutagenicity.

Assessing Protection from Intracranial Hemorrhage in Clinical Studies for Investigational Agents in Patients with Hemophilia

Background: Intracranial hemorrhage (ICH) is a serious complication for patients with Hemophilia. In the Universal Data Collection (UDC) program (Witmer C et al., 2011), the rate of ICH in patients with hemophilia (PWH) was 3.9 per 1000 patient-years, with the majority of events (74.4%) taking place in patients with severe hemophilia. The incidence of mortality for hemophilia patients experiencing ICH approaches 20%. Prophylaxis with replacement factor remains the standard of care for PWH and is efficacious in reducing the incidence of ICH by 48% in HIV-negative, severe hemophilia patients and by 50% in severe hemophilia patients with inhibitors. Multiple investigational non-factor products are currently undergoing clinical evaluation for the treatment of Hemophilia. Given their different mechanisms of action, it is unknown if they will provide the same level of protection from ICH as the current standard of care. Aims: We aimed to estimate the sample size needed to power a clinical study adequately to detect a reduction in the risk of ICH in PWH using a hypothetical investigational agent compared to the rates of ICH observed in the UDC Hemophilia cohort. Methods: We conducted a simulated power analysis to quantify the number of patients needed to detect a reduction in risk of ICH in PWH exposed to a hypothetical investigational agent compared to the risk of ICH observed in the UDC cohort. Based on published data, we assumed an overall ICH risk of 1.9% over a 10-year follow-up (average follow-up 5 years). We assumed a risk of ICH of 1.7% over an average of 5 years in patients prescribed prophylaxis with replacement factor and a risk of mortality due to ICH within patients with hemophilia of 0.4%. We used a two-sided Z test with pooled variance and targeted the significance level of the test at 0.05 and the power at 0.8. Results: A sample size of 11,595 patients per group followed for 1 year is required to achieve 80% power to detect a 2-fold reduction in ICH risk for patients receiving investigational treatment compared to the overall observed risk in PWH receiving treatment at federally funded HTCs. Sample sizes of 13,650 would be required per group, to demonstrate a 2-fold reduction in ICH risk for patients receiving investigational treatment vs. patients prescribed prophylaxis with replacement factor. Additionally, sample sizes of 11,737 per group, would be required to achieve 80% power to detect a 2-fold reduction in the risk of ICH mortality in a population of patients treated with an investigational agent vs. patients with hemophilia under the current standard of care. Conclusions: The relatively high mortality associated with incidence of ICH, highlights a need to determine how efficacious investigational agents are in protecting from these events. However, the relatively infrequent incidence of ICH represents an obstacle for current clinical studies to adequately evaluate protection against these types of events. These analyses demonstrate that clinical trials of investigational non-factor products would require extremely large samples sizes in order to demonstrate a level of protection that is comparable or superior to that observed with the current standard of care. Additional clinical and scientific strategies will be required in order to thoroughly assess the efficacy of non-factor agents in protecting from ICH. Disclosures Gallo: Shire: Employment. Chiuve:Shire: Employment. Rowan:Baxalta: Consultancy. Valentino:Shire: Employment.

As patients get older, we should be aware of salt levels in factor products

Hypertension is a well-known risk factor for ischaemic heart disease and cerebrovascular events. Globally, there is a drive to try to reduce salt intake. In an older population, where hypertension is likely to have a high prevalence, are health care professionals aware of the sodium content in replacement factor?

Thromboelastography for Monitoring of Hemostatic Changes Following Factor Administration

Abstract 3373 Introduction: Monitoring therapy in children with hemophilia receiving factor replacement products is a major challenge. Measurement of factor levels following treatment is time consuming and not available in time to make changes to the treatment regimen. This study evaluates the use of thromboelastography (TEG), in monitoring the treatment with factor replacement products in children with severe hemophilia without inhibitors. Because of limitations of standard coagulation assays that test specific isolated end points of coagulation, thromboelastography has been used to assess hemostasis as a global process and can assess thrombin/fibrin generation potential of the whole blood. Materials and Methods: This is an ongoing study that has been approved by our University IRB. The aim of this study is to evaluate the haemostatic changes as demonstrated by TEG, following the administration of a single dose of replacement factor in pediatric patients with severe hemophilia A (SHA) or B (SHB) without inhibitors. Patients on prophylaxis or on-demand therapy, who had not received any replacement factor for a minimum of 72 hours were included on study. A baseline TEG and FVIII/IX activity was obtained in the non-bleeding state at the time of enrollment and subsequent samples were obtained at 15mins, 1, 4, 8, 24 and 48 hours post factor replacement. Results: 24 patients with SHA (n=21) or SHB (n=3) have been enrolled to date. 1 patient had to be eliminated from the study as he was noted to have an inhibitor on the day of study enrolment. The mean age of our patients on study was 12.2 years with the range of 2–24 years. The mean factor activity at the time of enrollment was 1.2%. 3 patients who had FVIII or IX levels >2% at the time of enrollment were excluded from the analysis; 2 with SHB on prophylaxis 2–3 times per week (FIX activity= 2.44% and 5.12%); 1 with SHA on twice weekly prophylaxis (FVIII=13.9). This may be related to FIX having a longer half life, or non-compliance with 72 hour washout period. The mean Factor level prior to factor administration, after elimination of these subjects was 0.42%. The mean Factor level and R time at each time point of the study are presented in Table 1. The calculated half life of FVIII (t1/2) ranged from 5.89 to 14.52 hours. There was no significant difference in factor t1/2 for children below or above 10 years of age. The rate of rise in the R time at 8 hours and 48 hours correlated with the drop in factor activity following infusion of a single dose of factor and was statistically significant (p=0.05, shown in table 1). This indicates that a prolonged R time at 8 or 48 hours is associated with a significantly shorter t1/2. Conclusion: Thromboelastography has been used for monitoring the factor therapy in children with hemophilia. Our study indicates that this may be a potentially useful tool to predict the half life of Factor with a single blood draw at 8 hours. This is extremely important given the variability in half life seen from patient to patient in everyday practice and the difficulty in conducting a PK analysis at several time points especially in children. The TEG is a quick (less than 3 hours) and easy method to monitor and make necessary changes to ongoing therapy. Larger multicenter studies may help define the use of TEG parameters for this purpose more accurately. The small sample size was a major limitation of our study, and hence we were unable to make clinical correlations to bleeding rates. Disclosures: No relevant conflicts of interest to declare.

Variability of In Vivo Recovery of Factor IX after Infusion of Monoclonal Antibody Purified Factor IX Concentrates in Patients with Hemophilia B

SummaryMonoclonal antibody purified factor IX concentrate, Mononine® (Armour Pharmaceutical Company, Kankakee, Illinois, USA), is a recently developed replacement factor concentrate for the treatment of patients with hemophilia B. The pharmacokinetic properties of monoclonal antibody purified factor IX concentrate (MAb Factor IX concentrate) have been evaluated in only small samples of patients, and little is known about those factors that might influence in vivo recovery of factor IX after infusion in a larger patient population. In vivo recovery of factor IX was therefore evaluated for 80 different indications in 72 patients who received MAb Factor IX concentrate for the management of spontaneous or trauma-induced bleeding, or as prophylaxis with surgery. The average recovery after infusions for presurgical pharmacokinetic analysis (mean ± standard deviation) was 1.28 ± 0.56 U/dl rise per U/kg infused (range 0.41-2.80), and the average recovery after all infusions for treatment was 1.23 ± 0.49 U/dl rise per U/kg infused (range -0.35-2.92). Recovery values for multiple MAb Factor IX doses in a given patient were also variable; the average recovery was 1.22 ± 0.53 U/dl rise per U/kg given, and standard deviations ranged from 0.03 to 1.26. Patient age, weight, and MAb Factor IX concentrate dose minimally but significantly influenced factor IX recovery. There was no significant effect of either race, history of previous thrombotic complications during treatment with other replacement factor concentrates, or bleeding state on recovery. All of the patients treated with this preparation experienced excellent hemostasis, and no thrombotic complications were observed.