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

Adjusted D-dimer to Exclude Concurrent Pulmonary Embolism in Patients with COVID-19

Objectives: To determine if elevated D-dimers in Severe Acute Respiratory Syndrome Coronavirus-2 (COVID-19) positive patients were predictive of concurrent pulmonary embolism (PE), and what, if any, adjusted D-dimer cutoff would be predictive of PE in COVID-19 patients. Background(s): COVID-19 has led to over 500,000 death the United States. COVID-19 has been linked to a prothrombotic state, increasing the affected individual's propensity to form blood clots which is reflected in elevated D-dimers levels. While elevated D-dimers have been associated with 28-day mortality (making them useful in tracking the disease), it is difficult, in the acute setting, to determine if an elevated D-dimer is due to COVID-19, a pulmonary embolism (PE), or both conditions simultaneously. Method(s): This was a retrospective chart review of emergency department patients who underwent a computed tomography pulmonary angiogram (CTPA) who had documented COVID-19 infections between March and December of 2020. Charts were ed for COVID-19 polymerase chain reaction (PCR) results, D-dimers levels, and CTPA results. Kruskal-Wallis rank sum one-way analysis of variance and sensitivity analyses were completed via the software R. Result(s): Of 346 COVID-19 positive patients by nasal swab PCR, 24 (6.9%) had a PE on CTPA. The average D-dimer in the subset was 22,768 ng/dL vs 3,620 ng/dL in COVID-19 positive but PE negative patients (p=.034). As a screening test for concurrent PE, a D-dimer cut off of 1,000ng/dL or, for those over 50, [age in years]*20 ng/dL, had a sensitivity of 96%, specificity of 48% and negative predictive value (NPV) of 99.4%. A cut off of 1,000ng/dL had a sensitivity of 100%, specificity of 44% and NPV of 100%. Conclusion(s): Emergency department patients with COVID-19 and a PE have a significantly higher elevation in their D-dimer when compared to COVID-19 positive patients without a PE. A flat cut off of 1000ng/dL or a two tiered cut off of 1,000ng/dL for those <50 years old and [age in years]*20 ng/dL for those >50 years old proved to be reasonable screening tests for concurrent PE in COVID-19 positive patients.Copyright © 2023

Type I interferons and their autoantibodies in the context of systemic lupus erythematosus

PurposeType I IFNs and their autoantibodies are implicated in the pathogenesis of Systemic lupus erythematosus (SLE), but their incidence and importance is still unclear. Neutralizing autoantibodies against IFNα have been previously reported in patients with autoimmune polyendocrinopathy syndrome type I (APS-1), rheumatoid arthritis, thymoma and more recently life-threatening COVID-19 patients. We hypothesized that autoantibodies towards type I IFNs, that develop in some patients with SLE, are neutralizing and may interfere with the course of the disease.MethodsLuciferase immunoprecipitation (LIPS) analysis was used to screen 474 SLE patient and 312 control serum samples for the presence of IFNα binding autoantibodies and determine their subclasses. Type I IFN neutralizing capacity was tested using a reporter cell line. Circulating levels of IFNα were measured with Single Molecule Array (Simoa).Results14% of SLE patients were positive for anti-IFNα and 13% were positive for anti-IFNω. The autoantibodies against IFNα were predominantly of IgG1 subclass and neutralized IFNα bioactivity in approximately one half of the positive cases. Once developed, anti-IFNα autoantibodies were present throughout the disease course. IFNα2 and -α8 were targeted first in two informative follow-up cases. The reactivity broadened to other IFNα subtypes and IFNω within several months. Serum levels of IFNα correlated negatively with anti-IFNα neutralizing titers. Patients with high levels of autoantibodies against IFNα had significantly lower levels of circulating IFNα compared to anti-IFNα negative patients. Interestingly, patients with high IFNα neutralizing capacity displayed significantly lower disease activity than patients without these autoantibodies.ConclusionsBased on our results we suggest that autoantibodies that are able to neutralize the circulating levels of all IFNα subtypes may have a beneficial effect to SLE disease course.

Sex differences in autoimmune disease susceptibility;A multi-omic approach

Background: Males and females have altered immune responses resulting in variation in autoimmune and cardiovascular disease risk (CVR). Recently, these differences have played a role in the inflammatory response to COVID-19. Sex differences exist in the frequency and activity of immune-cell subsets but mechanisms underlying sexual dimorphism remain unknown. Juvenile-onset systemic lupus erythematosus (JSLE) is an autoimmune disorder that commonly emerges during puberty, has a strong female prevalence (female:male ratio, 4.5:1) and results in an increased CVR. JSLE is characterised by chronic inflammation and dyslipidaemia, where cardiovascular disease is a leading cause of mortality for patients. Our previous work identified a link between immune cell function and lipid metabolism in adult-onset SLE. We hypothesised that sex hormones could influence both lipid metabolism and immune cell function and this could determine sex-specific susceptibility to JSLE and associated CVR. Objectives: We investigated the role of sex hormones in modifying systemic lipid metabolism and inflammation. Methods: Nuclear magnetic resonance spectroscopy based serum metabolomics measuring over 130 lipoproteins (14-subsets with lipid compositions), flow cytometry measuring immune-cells, and RNA-sequencing were used to assess the metabolic and immune profile in young, pre/post-pubertal males (n=10/17) and females (n=10/23) and in individuals with gender-dysphoria (GD) under cross-hormone treatment (trans-male/female, n=26/25). This analysis was also performed on a cohort of post-pubertal male (n=12) and female (n=23) JSLE patients. Data was analysed by logistic regression, balanced random forest machine learning (BRF-ML), differential gene expression (DEG) and pathway analysis. Results: Post-pubertal males had significantly reduced cardio-protective high-density lipoprotein (HDL) subsets (p<0.0001) and increased cardio-pathogenic very-low-density lipoprotein subsets (p<0.0001) compared to females. These differences were not observed pre-puberty and were reversed significantly by cross-hormone treatment in GD individuals, suggesting that sex hormones regulate lipid metabolism in-vivo. BRF-ML (28 immune-cell subsets) identified an increased frequency of anti-inflammatory regulatory T-cells (Tregs) in post-pubertal males compared to females (p=0.0097). These Tregs were also more suppressive in males compared to females. Differences in Treg frequency were seen pre-puberty and were not altered by sex hormone treatment in GD individuals. However, Treg DEGs and functional transcriptomic pathways altered between post-pubertal males and females, including those involved in inflammatory signalling, overlapped with those altered by hormones in GD, suggesting hormones may also drive Treg functional changes. In addition, HDL metabolites modified by hormones showed differential associations with Treg phenotypes between post-pubertal males and females. Strikingly, sex differences in lipoproteins and Tregs were lost in JSLE, suggesting hormone signalling could be dysregulated in the pathogenesis of autoimmunity and could increase CVR for patients. Conclusion: Sex hormones drive altered lipoprotein metabolism and functional transcriptomic pathways in Tregs. Males have a lipoprotein profile associated with increased CVR, but a more anti-inflammatory immune profile compared to females. Together, this could explain sex differences in inflammatory disease susceptibilities and inform future sex-specific therapeutic strategies for the management of both JSLE and CVR.