Axial spondyloarthritis (axSpA) is a chronic rheumatic disease characterised by inflammation predominantly involving the spine and the sacroiliac joints. In some patients, axial inflammation leads to irreversible structural damage that in the spine is usually quantified by the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). Available therapeutic options include biological disease-modifying antirheumatic drugs (bDMARDs), which have been proven effective in suppressing inflammation in several randomised controlled trials (RCT), the gold standard for evaluating causal treatment effects. RCTs are, however, unfeasible for testing structural effects in axSpA mainly due to the low sensitivity to change of the mSASSS. The available literature therefore mainly includes observational research, which poses serious challenges to the determination of causality. Here, we review the studies testing the effect of bDMARDs on spinal radiographic progression, making use of the principles of causal inference. By exploring the assumptions of causality under counterfactual reasoning (exchangeability, positivity and consistency), we distinguish between studies that likely have reported confounded treatment effects and studies that, on the basis of their design, have more likely reported causal treatment effects. We conclude that bDMARDs might, indirectly, interfere with spinal radiographic progression in axSpA by their effect on inflammation. Innovations in imaging are expected, so that placebo-controlled trials can in the future become a reality. In the meantime, causal inference analysis using observational data may contribute to a better understanding of whether disease modification is possible in axSpA.

https://rmdopen.bmj.com/content/rmdopen/7/2/e001654.full.pdf

Biological DMARDs and disease modification in axial spondyloarthritis: a review through the lens of causal inference

This research in vivo assessed the impact of the ethanolic extract of Annona muricata (A. muricata) on the histopathology, immunohistochemistry, and biochemistry of thioacetamide (TAA)-induced liver cirrhosis in Sprague Dawley rats. The rats, gavaged precisely with two doses of A. muricata (250 mg/kg and 500 mg/kg) with TAA, presented a substantial reduction in the liver index and hepatocyte propagation, with much lower cell injury. These groups showed meaningfully down-regulated proliferating cell nuclear antigen (PCNA) in the liver and spleen, α-smooth muscle actin (α-SMA), and transforming growth factor-beta 1 (TGF-β1) in liver parenchymal tissue. The liver homogenate displayed enhanced antioxidant enzymes, superoxide dismutase (SOD) and catalase (CAT) activity, along with a decrease in malondialdehyde (MDA) levels. The serum levels of bilirubin, total protein, albumin, and liver enzymes alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were returned to normal and were similar to that of the normal control and silymarin with TAA-treated groups. Oral acute toxicity revealed no evidence of any toxic symbols or mortality in rats, indicating the safety of A. muricata. Therefore, the normal microanatomy of hepatocytes, the clampdown of PCNA, α-SMA, TGF-β, improved antioxidant enzymes (SOD and CAT), and condensed MDA with repairs of liver biomarkers validate the hepatoprotective effect of A. muricata.

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Histopathological Evaluation of Annona muricata in TAA-Induced Liver Injury in Rats

Research elucidating the pathogenesis of systemic lupus erythematosus (SLE) has defined two critical families of mediators, type I interferon (IFN-I) and autoantibodies targeting nucleic acids and nucleic acid-binding proteins, as fundamental contributors to the disease. On the fertile background of significant genetic risk, a triggering stimulus, perhaps microbial, induces IFN-I, autoantibody production or most likely both. When innate and adaptive immune system cells are engaged and collaborate in the autoimmune response, clinical SLE can develop. This review describes recent data from genetic analyses of patients with SLE, along with current studies of innate and adaptive immune function that contribute to sustained IFN-I pathway activation, immune activation and autoantibody production, generation of inflammatory mediators and tissue damage. The goal of these studies is to understand disease mechanisms, identify therapeutic targets and stimulate development of therapeutics that can achieve improved outcomes for patients.

Pathogenesis of systemic lupus erythematosus: risks, mechanisms and therapeutic targets

Background Type I interferons (IFN-I) contribute to a broad range of rheumatic and musculoskeletal diseases (RMDs). Compelling evidence suggests that the measurement of IFN-I pathway activation may have clinical value. Although several IFN-I pathway assays have been proposed, the exact clinical applications are unclear. We summarise the evidence on the potential clinical utility of assays measuring IFN-I pathway activation. Methods A systematic literature review was conducted across three databases to evaluate the use of IFN-I assays in diagnosis and monitor disease activity, prognosis, response to treatment and responsiveness to change in several RMDs. Results Of 366 screened, 276 studies were selected that reported the use of assays reflecting IFN-I pathway activation for disease diagnosis (n=188), assessment of disease activity (n=122), prognosis (n=20), response to treatment (n=23) and assay responsiveness (n=59). Immunoassays, quantitative PCR (qPCR) and microarrays were reported most frequently, while systemic lupus erythematosus (SLE), rheumatoid arthritis, myositis, systemic sclerosis and primary Sjögren’s syndrome were the most studied RMDs. The literature demonstrated significant heterogeneity in techniques, analytical conditions, risk of bias and application in diseases. Inadequate study designs and technical heterogeneity were the main limitations. IFN-I pathway activation was associated with disease activity and flare occurrence in SLE, but their incremental value was uncertain. IFN-I pathway activation may predict response to IFN-I targeting therapies and may predict response to different treatments. Conclusions Evidence indicates potential clinical value of assays measuring IFN-I pathway activation in several RMDs, but assay harmonisation and clinical validation are urged. This review informs the EULAR points to consider for the measurement and reporting of IFN-I pathway assays.

https://rmdopen.bmj.com/content/rmdopen/9/1/e002864.full.pdf

Association between type I interferon pathway activation and clinical outcomes in rheumatic and musculoskeletal diseases: a systematic literature review informing EULAR points to consider

276 I CUTIS WWW.MDEDGE.COM/DERMATOLOGY Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease that can have devastating effects on many organs. Despite the considerable morbidity and mortality associated with SLE, treatment options have been largely unchanged since the 1950s.1 It was not until the last decade that a new biologic medication was approved, and several other promising treatments currently are being evaluated in clinical trials. Dermatologists are most likely to encounter cutaneous lupus erythematosus (CLE) with or without SLE, which can present with a variety of skin manifestations. Cutaneous lupus erythematosus can have devastating effects on quality of life and can be a visible sign of the internal activity and damage of SLE.2,3 Although many trials have been completed evaluating SLE treatments, few medications have been evaluated specifically for CLE despite the availability of validated measures of CLE skin activity.4 There is a recent shortage of antimalarial medications, the current first-line therapy for CLE, due to both an import alert in the United States on quinacrine placed in 2019 as well as the use of hydroxychloroquine and chloroquine in treating coronavirus disease 2019.5,6 Due to this shortage, the need for new and effective treatments is more critical than ever, as alternatives to first-line therapy frequently require immunosuppression. We review recent drug approvals for SLE and their efficacy in CLE. We also provide an update on new agents currently being studied to treat this disease.

Emerging therapies for cutaneous lupus erythematosus.

Liver transplantation is the ultimate method for treating end-stage liver disease. With the increasing prevalence of obesity, the number of patients with non-alcoholic fatty liver, a common cause of chronic liver disease, is on the rise and may become the main cause of liver transplantation in the future. With the increasing gap between the number of donor livers and patients waiting for liver transplantation and the increasing prevalence of non-alcoholic fatty liver, the proportion of steatosis livers among non-standard donor organs is also increasing. Ischemia-reperfusion injury has historically been the focus of attention in the liver transplantation process, and severe ischemia-reperfusion injury leads to adverse outcomes of liver transplantation. Studies have shown that the production of reactive oxygen species and subsequent oxidative stress play a key role in the pathogenesis of hepatic ischemia and reperfusion injury and non-alcoholic fatty liver. Furthermore, the sensitivity of fatty liver transplantation to ischemia-reperfusion injury has been suggested to be related to the production of reactive oxygen species (ROS) and oxidative stress. In ischemia-reperfusion injury, Kupffer cell and macrophage activation along with mitochondrial damage and the xanthine/xanthine oxidase system promote marked reactive oxygen species production and the inflammatory response and apoptosis, resulting in liver tissue injury. The increased levels of ROS and lipid peroxidation products, vicious circle of ROS and oxidative stress along with mitochondrial dysfunction promoted the progress of non-alcoholic fatty liver. In contrast to the non-fatty liver, a non-alcoholic fatty liver produces more reactive oxygen species and suffers more serious oxidative stress when subjected to ischemia-reperfusion injury. We herein review the effects of reactive oxygen species on ischemia-reperfusion injury and non-alcoholic fatty liver injury as well as highlight several treatment approaches.

/pdf/reactive-oxygen-species-induce-fatty-liver-and-ischemia-8a3i98e3.pdf

Reactive Oxygen Species Induce Fatty Liver and Ischemia-Reperfusion Injury by Promoting Inflammation and Cell Death

Objectives Iberdomide is a high-affinity cereblon ligand that promotes proteasomal degradation of transcription factors Ikaros (IKZF1) and Aiolos (IKZF3). Pharmacodynamics and pharmacokinetics of oral iberdomide were evaluated in a phase 2b study of patients with active systemic lupus erythematosus (SLE). Methods Adults with autoantibody-positive SLE were randomised to placebo (n=83) or once daily iberdomide 0.15 mg (n=42), 0.3 mg (n=82) or 0.45 mg (n=81). Pharmacodynamic changes in whole blood leucocytes were measured by flow cytometry, regulatory T cells (Tregs) by epigenetic assay, plasma cytokines by ultrasensitive cytokine assay and gene expression by Modular Immune Profiling. Results Iberdomide exhibited linear pharmacokinetics and dose-dependently modulated leucocytes and cytokines. Compared with placebo at week 24, iberdomide 0.45 mg significantly (p<0.001) reduced B cells, including those expressing CD268 (TNFRSF13C) (−58.3%), and plasmacytoid dendritic cells (−73.9%), and increased Tregs (+104.9%) and interleukin 2 (IL-2) (+144.1%). Clinical efficacy was previously reported in patients with high IKZF3 expression and high type I interferon (IFN) signature at baseline and confirmed here in those with an especially high IFN signature. Iberdomide decreased the type I IFN gene signature only in patients with high expression at baseline (−81.5%; p<0.001) but decreased other gene signatures in all patients. Conclusion Iberdomide significantly reduced activity of type I IFN and B cell pathways, and increased IL-2 and Tregs, suggesting a selective rebalancing of immune abnormalities in SLE. Clinical efficacy corresponded to reduction of the type I IFN gene signature. Trial registration number NCT03161483.

https://ard.bmj.com/content/annrheumdis/81/8/1136.full.pdf

Biological impact of iberdomide in patients with active systemic lupus erythematosus

Background: We created a high dimensionality healthy human Immunome atlas by interrogating the peripheral blood mononuclear cells (PBMC) of >200 healthy subjects (cord blood to adult) with 63 unique mechanistic and phenotypic markers per cell by mass cytometry (CyTOF). This database is built with an open source, web-based bioinformatics toolkit, enabling its mining and uploading of datasets for comparison with the EPIC healthy database. Objectives: Here, we demonstrate the platform’s ability to identify the immunological differences of mechanistically important cell subsets in the uploaded data in comparison with EPIC. Methods: CyTOF data from 37 healthy elderly (>60 years old) was uploaded onto the EPIC Discovery tool where down-sampling, normalising and FlowSOM (Flow analysis with Self-Organising Maps) clustering were done with the EPIC database for comparison. Online visualisation outputs include cluster frequency boxplots, correspondence analysis (CA) plot and markers expression heat-map. The CA 2-dimensional plot depicts the global differences in immune cells composition between subjects with proximity between points (subjects) denoting similarity. Kruskal-Wallis test was done to identify age groups differences. Results: Increasing distances on the CA plot with age were observed with the elderly being farthest from the new-borns. Notably, we observed significant changes in naive CD4+ IL8+ T cells (p Conclusion: With EPIC, we have created an online tool enabling data uploading for comparison to a healthy database, allowing the holistic characterisation of immunological changes in different clinical scenarios. Using it, we were able to identify mechanistically important differences in immune cells composition in a distinct clinical cohort (elderly) compared to the younger ages. Translationally, the EPIC platform can be utilised similarly to catalyse the discovery process in auto-immune diseases interrogated with the EPIC antibody panels. References: [1]Fasching P, Stradner M, Graninger W, Dejaco C, Fessler J. Therapeutic Potential of Targeting the Th17/Treg Axis in Autoimmune Disorders. Molecules. 2017 Jan 14;22(1). pii: E134. [2]Klose CS, Artis D. Innate lymphoid cells as regulators of immunity, inflammation and tissue homeostasis. Nat Immunol. 2016 Jun 21; 17(7): 765-74. Disclosure of Interests: None declared

https://ard.bmj.com/content/annrheumdis/79/Suppl_1/1327.1.full.pdf

S. P. Tang

Papers

Reactive Oxygen Species Induce Fatty Liver and Ischemia-Reperfusion Injury by Promoting Inflammation and Cell Death

Biological impact of iberdomide in patients with active systemic lupus erythematosus

Ab0050 extended polydimensional immunome characterisation (epic) platform as a tool for translational research