ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 0816

Distinct Transcript and Protein Dysregulation Patterns in Dermatomyositis and Systemic Lupus Erythematosus

James Ward1, Mythri Ambatipudi2, Zerai Manna3, Michael Smith4, Melissa de los Reyes5, Adam Schiffenbauer6, Saifur Rahman7, Kamelia Zerrouki5, Fredrick Miller1, Mariana Kaplan8, Jian-Liang Li1, Kerry Casey9, Lisa Rider10 and Sarfaraz Hasni6, 1National Institute of Environmental Health Sciences, NIH, Durham, NC, 2Harvard Medical School, Boston, MA, 3NIH, Bethesda, MD, 4Horizon Therapeutics, Alexandria, VA, 5AstraZeneca, Gaithersburg, MD, 6NATIONAL INSTITUTES OF HEALTH, Bethesda, MD, 7AstraZeneca, Gaithersburg, 8NIAMS/NIH, Bethesda, MD, 9Regeneron Pharmaceuticals, Terrytown, NY, 10NIEHS, NIH, Garrett Park, MD

Meeting: ACR Convergence 2024

Keywords: , , ,

Session Information

Date: Saturday, November 16, 2024

Title: Abstracts: SLE – Diagnosis, Manifestations, & Outcomes I: Omics

Session Type: Abstract Session

Session Time: 1:00PM-2:30PM

Background/Purpose: Systemic lupus erythematosus (SLE) and dermatomyositis (DM) are hypothesized to be triggered by shared genetic and environmental factors leading to aberrant activation of innate immune pathways such as type I interferons and neutrophil extracellular trap (NET) formation. Despite these similarities in pathogenesis, SLE and DM are distinctive clinical phenotypes with variable responses to the same therapeutic agents. The present study addresses the shared and distinct dysregulated pathways between SLE and DM by comparing peripheral blood transcript and protein expression in a combined multi-enrichment analysis of pathway and ligand-receptor signaling.

Methods: 48 SLE patients were age- and gender-matched 3:1 to 16 adult DM patients. 58 whole blood samples from sex- and age- (±10 years) matched healthy donors (HD) were collected. Whole blood RNA and sera were analyzed for transcriptomics and proteomics (using SomaLogic and RBM platforms). Significant transcript and protein results were combined across platforms into one collective set of gene locus abundance changes per patient cohort for pathway enrichment. Multi-enrichment analysis was performed using the top 10 pathways. Pathways were clustered using each gene-pathway incidence matrix, then split into four sub-clusters for within-cohort analyses and five sub-clusters for cross-cohort analyses.

Results: After quality control, 41 SLE and 14 DM samples were analyzed for transcriptomics, and 34 SLE and 14 DM with matching HD were analyzed for proteomics. Baseline characteristics were similar, except DM patients were older, with shorter disease duration, and on higher doses of glucocorticoids (Table 1). SLE expression analysis produced 222 significantly dysregulated transcripts and 150 proteins. Twenty gene loci in SLE and 31 in DM were confirmed across platforms. Granulocyte Adhesion and Diapedesis, Glucocorticoid Receptor Signaling, Wound Healing Signaling, Hepatic Fibrosis, and Acute Phase Response Signaling pathways were significantly enriched in both SLE and DM, with 22% gene loci shared and 88% concordance in direction (Figure 1). SLE-specific pathways included Interferon, Hypercytokinemia in Pathogenesis of Influenza, and Atherosclerosis Signaling (Figure 2). DM-specific pathways included PI3K/AKT, IGF-1, coordinated lysosomal expression and regulation (CLEAR), and MSP-RON.

Conclusion: Our study revealed a moderate overlap in underlying pathogenic pathways between SLE and DM, with several pathways that were distinct for each. Both cohorts were also found to have unique, significantly enriched gene loci and proteins. These distinct dysregulated pathways may help explain differences in clinical phenotypes and responses to treatment.

Supporting image 1

Table 1. Demographic and Clinical Features of Dermatomyositis and Systemic Lupus Erythematosus Patients.

Supporting image 2

Figure 1. Multi-enrichment expression heatmaps. The central network displays enriched pathway clusters, connected to significant gene loci represented in each pathway cluster. Nodes are colored gold for significant changes in DM, purple for SLE, and gold/purple for both SLE and DM. Node outlines indicate direction of change, using red for up- and blue for down-regulation. Heatmaps beside each pathway cluster show expression changes for gene loci connected to each cluster, with four column groupings separated by patient cohort and platform. Heatmap rows are split by cohort(s) in which genes were significantly regulated, gold for DM alone, purple for SLE alone, and gold/purple for gene loci significant in both the DM and SLE patient cohorts.

Supporting image 3

Figure 2. Expression of gene loci in SLE-specific pathways. SLE-specific pathways included interferon Signaling, Hypercytokinemia in Pathogenesis of Influenza, and Caveolar-Mediated Endocytosis Signaling. Left bars indicate the direction of significant changes, red is up- and blue is down-regulated, white is not significantly changed, and grey is not tested by the platform. Expression is shown as log2 differences from respective healthy control mean expression, labeled as normal fold changes.
The majority of SLE patients (27 of 34, 80%) show very high (8- to over 16-fold) up-regulation of interferon-activated genes, while only a subset of DM patients (4 of 12, 33%) show moderate (2- to 4-fold) up-regulation.

Disclosures: J. Ward: None; M. Ambatipudi: None; Z. Manna: None; M. Smith: Amgen, 3; M. de los Reyes: AstraZeneca, 3, 11; A. Schiffenbauer: AstraZeneca, 11, Hope Pharmaceuticals, 5; S. Rahman: Sanofi, 3, 11; K. Zerrouki: None; F. Miller: None; M. Kaplan: Astra Zeneca, 5; J. Li: None; K. Casey: Astr, 3, 11, Regeneron, 3, 11; L. Rider: AstraZeneca, 5, Bristol-Myers Squibb(BMS), 5, Cabaletta Bio, 1, 12, no financial support, Cure JM Foundation, 1, 5, Hope Pharmaceuticals, 5, Horizon Therapeuetics, 1, 12, no financial support, Pfizer, 1, 12, no financial support; S. Hasni: None.

To cite this abstract in AMA style:

Ward J, Ambatipudi M, Manna Z, Smith M, de los Reyes M, Schiffenbauer A, Rahman S, Zerrouki K, Miller F, Kaplan M, Li J, Casey K, Rider L, Hasni S. Distinct Transcript and Protein Dysregulation Patterns in Dermatomyositis and Systemic Lupus Erythematosus [abstract]. Arthritis Rheumatol. 2024; 76 (suppl 9). https://acrabstracts.org/abstract/distinct-transcript-and-protein-dysregulation-patterns-in-dermatomyositis-and-systemic-lupus-erythematosus/. Accessed .

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