Early infection risk in patients with systemic lupus erythematosus treated with rituximab or belimumab from the British Isles Lupus Assessment Group Biologics Register (BILAG-BR): a prospective longitudinal study

Background: Patients with systemic lupus erythematosus (SLE) are at an increased risk of infection relative to the general population. We aimed to describe the frequency and risk factors for serious infections in patients with moderate-to-severe SLE treated with rituximab, belimumab, and standard of care therapies in a large national observational cohort. Method(s): The British Isles Lupus Assessment Group Biologics Register (BILAG-BR) is a UK-based prospective register of patients with SLE. Patients were recruited by their treating physician as part of their scheduled care from 64 centres across the UK by use of a standardised case report form. Inclusion criteria for the BILAG-BR included age older than 5 years, ability to provide informed consent, a diagnosis of SLE, and starting a new biological therapy within the last 12 months or a new standard of care drug within the last month. The primary outcome for this study was the rate of serious infections within the first 12 months of therapy. Serious infections were defined as those requiring intravenous antibiotic treatment, hospital admission, or resulting in morbidity or death. Infection and mortality data were collected from study centres and further mortality data were collected from the UK Office for National Statistics. The relationship between serious infection and drug type was analysed using a multiple-failure Cox proportional hazards model. Finding(s): Between July 1, 2010, and Feb 23, 2021, 1383 individuals were recruited to the BILAG-BR. 335 patients were excluded from this analysis. The remaining 1048 participants contributed 1002.7 person-years of follow-up and included 746 (71%) participants on rituximab, 119 (11%) participants on belimumab, and 183 (17%) participants on standard of care. The median age of the cohort was 39 years (IQR 30-50), 942 (90%) of 1048 patients were women and 106 (10%) were men. Of the patients with available ethnicity data, 514 (56%) of 911 were White, 169 (19%) were Asian, 161 (18%) were Black, and 67 (7%) were of multiple-mixed or other ethnic backgrounds. 118 serious infections occurred in 76 individuals during the 12-month study period, which included 92 serious infections in 58 individuals on rituximab, eight serious infections in five individuals receiving belimumab, and 18 serious infections in 13 individuals on standard of care. The overall crude incidence rate of serious infection was 117.7 (95% CI 98.3-141.0) per 1000 person-years. Compared with standard of care, the serious infection risk was similar in the rituximab (adjusted hazard ratio [HR] 1.68 [0.60-4.68]) and belimumab groups (1.01 [0.21-4.80]). Across the whole cohort in multivariate analysis, serious infection risk was associated with prednisolone dose (>10 mg;2.38 [95%CI 1.47-3.84]), hypogammaglobulinaemia (<6 g/L;2.16 [1.38-3.37]), and multimorbidity (1.45 [1.17-1.80]). Additional concomitant immunosuppressive use appeared to be associated with a reduced risk (0.60 [0.41-0.90]). We found no significant safety signals regarding atypical infections. Six infection-related deaths occurred at a median of 121 days (IQR 60-151) days from cohort entry. Interpretation(s): In patients with moderate-to-severe SLE, rituximab, belimumab, and standard immunosuppressive therapy have similar serious infection risks. Key risk factors for serious infections included multimorbidity, hypogammaglobulinaemia, and increased glucocorticoid doses. When considering the risk of serious infection, we propose that immunosupppressives, rituximab, and belimumab should be prioritised as mainstay therapies to optimise SLE management and support proactive minimisation of glucocorticoid use. Funding(s): None.Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license

In-person versus virtual administration of the American College of Rheumatology gold standard cognitive battery in systemic lupus erythematosus: Are they interchangeable?

OBJECTIVE: During the COVID-19 pandemic, many research studies were adapted, including our longitudinal study examining cognitive impairment (CI) in systemic lupus erythematosus (SLE). Cognitive testing was switched from in-person to virtual. This analysis aimed to determine if the administration method (in-person vs. virtual) of the ACR-neuropsychological battery (ACR-NB) affected participant cognitive performance and classification. METHODS: Data from our multi-visit, SLE CI study included demographic, clinical, and psychiatric characteristics, and the modified ACR-NB. Three analyses were undertaken for cognitive performance: (1) all visits, (2) non-CI group visits only and (3) intra-individual comparisons. A retrospective preferences questionnaire was given to participants who completed the ACR-NB both in-person and virtually. RESULTS: We analysed 328 SLE participants who had 801 visits (696 in-person and 105 virtual). Demographic, clinical, and psychiatric characteristics were comparable except for ethnicity, anxiety and disease-related damage. Across all three comparisons, six tests were consistently statistically significantly different. CI classification changed in 11/71 (15%) participants. 45% of participants preferred the virtual administration method and 33% preferred in-person. CONCLUSIONS: Of the 19 tests in the ACR-NB, we identified one or more problems with eight (42%) tests when moving from in-person to virtual administration. As the use of virtual cognitive testing will likely increase, these issues need to be addressed - potentially by validating a virtual version of the ACR-NB. Until then, caution must be taken when directly comparing virtual to in-person test results. If future studies use a mixed administration approach, this should be accounted for during analysis.

Antithrombin Iii (At3) in Covid-19: A Pilot Study Defining At3 Levels and Safety of Exogenous At3

INTRODUCTION: COVID pathogenesis involves a dysregulated inflammatory state and coagulopathy. Affected patients are at risk for thrombosis and bleeding as well as cytokine storming. Antithrombin 3 (AT3) has antiinflammatory and anti-coagulant properties but its role in COVID is unknown. The incidence of AT3 deficiency (< 80% activity) in COVID is unknown. We hypothesize that AT3 supplementation is safe in patients with COVID and AT3 deficiency. METHOD(S): Prospective randomized control trial of COVID, IRB approved at 2 centers from July 2021 to March 2022. Those with plasma AT3< 100% were randomized to either standard of care (SOC) or SOC+AT3 q48hr weight-based for a goal of 120% for up to 5 doses. An additional group with AT3>100% received SOC. Data are compared using ANOVA and Fisher's exact test. Enrollment was concluded early due to reduced COVID cases and reduced length of stay. RESULT(S): In 531 subjects assessed for eligibility, 324 did not meet inclusion criteria, 151 did not consent, 4 withdrew consent, and 52 subjects completed the study. Enrollment AT3 (M+/-SD) was 96+/-12%. AT3 levels were < 100% in 40 (77%) and < 80% in 11(21%). SOC+AT3, SOC only, and AT3>100% had a Disseminated Intravascular Coagulation (DIC) score change (M+/-SD) of 0.4+/-1.5, -0.13+/-1.85 and 0+/-1.2, respectively, (p=0.63). Hospital length of stay was 13.9+/-14.9, 9.1+/-8.4, and 13+/-0.5 days respectively, (p=0.39). Mortality occurred in 2 (10%), 3 (15%), and 3 (25%), respectively, (p=0.56). There was 1 bleeding event in a subject with AT3>100% and no bleeding events were observed with exogenous AT3. There were no observed drug-related adverse events. Of the 18 subjects assigned to receive AT3, 15 received a median of 2 doses (IQR 2) for a total of 38 doses with a median dose of 1825.5 IU (IQR 794). CONCLUSION(S): COVID is associated with a relative AT3 deficiency and was observed in 21% of this cohort with reports of .02% to .2% in the general population. Exogenous AT3 supplementation was safe with no bleeding complications or drug-related adverse events. There was no significant change in outcomes, likely due to under-dosing and sample size. Further studies should evaluate higher doses of exogenous AT3 and focus on higher risk groups.

While We Wait: understanding the impact of service wait times on GPs' treatment behaviour for youth patients with mental health problems

Background: Wait times for in-person mental health treatment are a national crisis for young people. Long wait times are associated with many negative consequences such as lower treatment satisfaction and discontinuation, symptom deterioration and relapse, and lower likelihood of future help-seeking. With the onset of COVID-19, wait times have become longer. General Practitioners (GPs) are the primary referrers to in-person mental health treatment, however, their ability to care for their youth patients' mental health is often negatively impacted by long wait times, often resulting in GPs engaging in significantly high levels of management, with little resources to do so. Brief, low-intensity digital interventions may provide accessible, evidence-based, and cost-effective care while young people await in-person mental health care. Aim/Objectives: This study aims to examine the impact of service wait times on GPs' treatment of mental health problems in youth patients and explore their openness to recommending digital interventions as support during this time. Method(s): A national cross-sectional survey conducted among 430 GPs (currently recruiting). Finding(s): This presentation will outline the survey results. Preliminary results (N=53) indicate that wait times impact GP decisions and management of young patients. Specifically, participants reported that due to long wait times, they often increase their care rather than refer patients to services (M=4.08, SD=.79) and often refer patients to different services than their preferred service (M=4.00, SD=.69), are very open to recommending mobile mental health apps to their patients (M=4.24, SD=.84), but are only somewhat confident in doing so (M=3.57, SD=1.27). Implications: This research is the first in Australia to examine mental health service wait times on GP treatment care and decisions specifically for youth. It will inform how young patients can be best supported and which interventions GPs consider to be most ideal for supporting young people while they await in-person mental health care.

Development of a Vascularised Cardiac Organoid Platform Reveals a Regulatory Role for Extracellular Matrix Environment on Muscle Functionality

Multicellular composition of the heart is important for regulating organ development and responses to injury, however the role of cardiac cell types in organ maturation is not well characterised. In this study we characterised a vascularised cardiac organoid model (vhCO) derived from human pluripotent stem cells to better understand cell-cell interactions in human heart tissue. We show that endothelial cells in vhCO increase organoid force of contraction and enhance the expression of mature sarcomeric proteins and extracellular matrix (ECM) components. Through proteomics, we identified LAMA5 as an important component of the ECM network that enhances force of contraction. Subsequent knockdown of LAMA5 specifically in endothelial cells down regulate force of contraction and reverts the ECM protein profile. We also show that endothelial cells are important for modelling cardiac dysfunction induced by cytokine storm following COVID-19 infection. This study identifies matrix regulatory functions of endothelial cells that govern cardiac maturation and also highlights the importance of organoid multicellularity for disease modelling.

RHEUMATOLOGY REFERRALS TO TERTIARY CARE HOSPITAL OVER A THREE MONTH PERIOD DURING COVID- 19 PANDEMIC: A QUALITY IMPROVEMENT PROJECT

Background/Aims During the COVID-19 pandemic, waiting times for routine new referrals to our tertiary rheumatology department was >20 weeks. Therefore, a quality improvement project (QIP) was undertaken to understand the nature of these referrals and develop an alternative option to rheumatology review. Our aim was to reduce waiting times and improve patient experience by better integrating primary, secondary and therapy services, as well as provide additional triage options. Methods We conducted a retrospective analysis of all routine referrals over a 3- month period (1st April to 30th June 2020). Urgent referrals including GCA, CTD and EIA were excluded. Results A total of 92/143 (64%) patients were referred, a more significant reduction than normal due to the pandemic. Median age [IQR] was 39.5 [28-66.25] years and most referrals (79%) were from primary care. Table 1 represents information included in the referrals. Thirty-one patients had previously undergone a rheumatology review, of which 11 (35%) were seen in our department. Of these, 18/31 (58%) patients had a diagnosis of Hypermobility Spectrum Disorder (HSD) or fibromyalgia. The commonest reason for re-referral was worsening of existing symptoms (n=11, 35%), with no suggestive of an alternative diagnosis. Conclusion Our QIP identified a variation in the quality of referrals and that a high proportion of referrals concerned HSD and fibromyalgia, with many rereferred due to exacerbation of their existing disease. Based on this, we conducted a regional GP trainee educational session and highlighted: i) key features in investigation and management of common rheumatological conditions ii) vital information to include in referrals based on presenting complaint(s) and working diagnosis. We developed a pathway for patients previously diagnosed with fibromyalgia or HSD in our department and re-referred with worsening symptoms, to be triaged into a newly set up weekly specialist MSK physiotherapy-led clinic with rheumatology supervision. Future work will involve re-assessing routine new-referral waiting times and evaluating pre- and post-physiotherapy intervention MSK and quality of life scores, with the aim of formulating a business case to conduct this clinic on a permanent basis. We hope incorporating this pathway will lead to improved patient outcomes and ease some departmental management decisions. (Table Presented).

Pandemic precarity and everyday disparity: gendered housing needs in North America

We identify key issues for housing researchers, practitioners, and advocates working in the United States and Canada to consider, both during the COVID-19 pandemic and far beyond. First, we draw upon feminist and intersectional literatures on gendered inequalities and social structures, which provide the often forgotten or overlooked context for women’s experiences in housing. This includes the broader insight that too frequently, women have not been involved in shaping the policy and planning climate around housing, even as they disproportionately are affected by them. Second, we describe women’s housing-related precarity and some of its implications, grounding this research in a political economic critique of the way that housing and resources are allocated and the neoliberal climate that values profit over people and that has induced instability for many women in so many communities. We conclude by offering examples of organizations and initiatives that work to address the disparities identified herein. Throughout the paper, we emphasize the need for intersectional and interdisciplinary collaborations (for example, among queer, anti-racist, feminist, political economic, and other scholars) that engage with complexity and orient toward equity and justice. © 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

RUXCOVID: A phase 3, randomized, placebo-controlled study evaluating the efficacy andsafety of ruxolitinib in patients with COVID-19-associatedcytokine storm

Background: Severe COVID-19 can result in pneumonia, with many patients (pts) requiring hospitalization andoxygen support. Severe COVID-19 may also be complicated by acute respiratory distress syndrome, sepsis andseptic shock, and/or multiorgan failure. Many of these pts have features consistent with cytokine release syndrome(CRS) and its associated hyperinflammation. Given their immunomodulatory effects, Janus kinase (JAK) inhibitorshave been suggested as a potential therapeutic option in pts with severe COVID-19. Ruxolitinib-a potentJAK1/JAK2 inhibitor approved for treating myelofibrosis, polycythemia vera, and steroid-refractory acute graft-vs.-host disease (GvHD;US only)-has been associated with reduced levels of inflammatory cytokines in disorderswhere cytokine dysregulation plays a role, including GvHD and secondary hemophagocytic lymphohistiocytosis.Additionally, findings from a small, randomized, phase 2 study (N = 43;Cao Y et al., J Allergy Clin Immunol 2020)showed that treatment with ruxolitinib plus standard of care (SOC) reduced CRS-associated hyperinflammation inpts with severe COVID-19 vs placebo plus SOC, with significant improvement seen in chest computed tomography(CT) features. Although no statistically significant differences were observed, ruxolitinib-treated pts also had anumerically shorter median time to clinical improvement, a lower proportion requiring intensive care/mechanicalventilation, and reduced mortality, with ruxolitinib having a favorable safety profile. Methods: RUXCOVID ( NCT04362137 ) is a global, randomized (2:1), double-blind, placebo-controlled, 29-day, phase 3 study evaluating the efficacy and safety of ruxolitinib plus SOC compared with placebo plus SOC in pts withCOVID-19. Pts are eligible for the study if they are ≥ 12 years old, have confirmed COVID-19, are hospitalized, andmeet ≥ 1 of the following: pulmonary infiltrates (by chest x-ray or CT scan), respiratory frequency ≥ 30 breaths/min, requirement of supplemental oxygen, oxygen saturation (SpO ) ≤ 94% on room air, or arterial oxygen partialpressure (PaO )/fraction of inspired oxygen (FiO ) < 300 mm Hg (1 mm Hg = 0.133 kPa). Pts with a need forintensive care or intubation are not eligible. Pts will be randomized to ruxolitinib 5 mg twice daily or placebo andtreated for 14 days. Pts may be treated for an additional 14 days if no improvement occurs and the potential benefitoutweighs the potential risk per investigator assessment. The primary endpoint is the proportion of pts who die, develop respiratory failure (require mechanical ventilation), or require intensive care by day 29. Secondaryendpoints include improvement in clinical status, in-hospital outcomes, change in National Early Warning Score, change in SpO :FiO ratio, mortality rate, change in inflammatory biomarkers, and safety. Target enrollment is 402pts. Sponsored by Novartis Pharmaceuticals and Incyte.