Baseline Innate Immunity Transcriptional Signatures Act as Predictors of Response to Immunosuppressive and Biologic Treatments in Systemic Lupus Erythematosus While Disturbances Linked to p53-signaling Define “Resistant” Disease

Panagiotis garantziotis¹, Georgia-Savina Moysidou², stavros doumas³, Dionysis nikolopoulos², Sofia Flouda⁴, Noemin kapsala², Anastasia Filia², George Sentis², Antonis Fanouriakis², George Bertsias⁵ and Boumpas Dimitrios⁶, ¹Department of Internal Medicine 3-Rheumatology and Immunology, Friedrich Alexander University Erlangen-Nuremberg and Universitätsklinikum Erlangen, Erlangen, Germany, ²School of Medicine, National and Kapodistrian University of Athens, Athens, Greece, ³Department of Medicine, MedStar Georgetown University Hospital, Washington, DC, ⁴Unit of Attikon University Hospital, Athens, Greece, ⁵Rheumatology, Clinical Immunology and Allergy Department, Medical School, University of Crete, Greece; Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology Hellas (FORTH), Heraklion, Greece, ⁶National and Kapodistrian University of Athens, Athens, Greece

Meeting: ACR Convergence 2023

Keywords: Biologicals, Gene Expression, immunology

Session Information

Date: Sunday, November 12, 2023

Title: (0582–0608) SLE – Treatment Poster I

Session Type: Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose: Despite recent advances, the current state of SLE therapeutics remains largely empirical with existing immunosuppressive treatments failing to induce remission in over 40% of patients. There is currently a paucity of tools that would predict response to treatment and guide therapeutic choices.

Methods: Whole blood transcriptome samples were obtained from 95 patients with moderate to severe SLE at baseline, 1 month and 6 months after initiation of treatment with cytotoxic agents (cyclophosphamide, mycophenolate mofetil), mycophenolate mofetil/anti-CD40 antibody, rituximab or belimumab. Disease activity was assessed using the SLEDAI-2K. Response to treatment was defined as achievement of Low Disease Activity State (LLDAS) or remission at 6 months. Differentially expressed genes (DEGs) were identified using the DEseq2. Weighted correlation network analysis (WGCNA) was applied to detect modules of co-expressed transcripts. Abundances of cell types were assessed by CIBERSORTx.

Results: Out of 95 patients the majority were women (93.7%) with a mean [SD] age at SLE diagnosis of 42.9 [13.6] years and a mean disease duration [SD] at sampling of 5.1 [7.2] years. At baseline, mean SLEDAI [SD] was 9.4 [5.7] and active lupus nephritis (LN) was the most common treatment indication (24%), followed by active neuropsychiatric SLE (NPSLE) (20%). Cyclophosphamide was the most frequently used immunosuppressive agent (n=46), followed by belimumab (n=24) and rituximab (n=21). Forty-three patients responded to treatment. WGCNA-generated modules (Figure 1.) that positively correlated with response to treatment at 6 months (p = 0.005, p = 0.04) were enriched in biological processes that included type I interferon, pattern recognition receptor signaling, and neutrophil degranulation. Unsupervised clustering of the baseline samples, based on the module eigengene, revealed a respondent rich patient subset (Cluster 2), which was characterized by high prevalence of active LN (Figure 2.). The transcriptional landscape of “resistant” disease was dominated by disturbances related to p53-signaling pathway. Upregulation of pathways linked to neutrophil degranulation, Th17 responses, IL6 mediated responses, TGF-beta, PPARA, and NOTCH signaling differentiated the one-month-transcriptional profile of responders compared to non-responders (Figure 3.).

Conclusion: Baseline molecular fingerprints related to innate immunity correlated with 6-month response to treatment in SLE. Aberrances linked to p53-signaling decisively shaped the transcriptional signature of “resistant” disease.

Figure 1. WGCNA module eigengene (ME) correlations to clinical features uncover the brown and green gene modules which are associated with 6 month-response to treatment. Severity_sampling: Presence of moderate or severe disease at sampling timepoint as defined by BILAG Glossary Definition combined with expert physician judgement (DB, GB); Response_6mo: Response to treatment 6 months after treatment initiation; Acute.CLE: Presence of acute cutaneous SLE at any time during the disease course; Renal: Presence of renal manifestations, as defined in the EULAR/ACR SLE classification criteria, at any time during the course of the disease; CNS: Presence of neurological features, as defined in the EULAR/ACR SLE classification criteria, at any time during the course of the disease; Serositis: Presence of polyserositis, as defined in the EULAR/ACR SLE classification criteria, at any time during the course of the disease; Immunological: Presence of immunological disturbances, as defined in the EULAR/ACR SLE classification criteria, at any time during the course of the disease; APS: Antiphospholipid Syndrome. * p-value < 0.05.

Figure 2. K-means clustering of the baseline samples based on module eigengene (ME) defined the cluster 2, enriched for responders. aLN: Active LN; aMajor_Organ: Active major organ involvement other than LN or NPSLE; aNon_Major_Organ: Active non-major organ involvement; aNPSLE: Active NPSLE; iLN: Inactive LN; iMajor_Organ: Inactive major organ involvement other than LN or NPSLE; iNon_Major_Organ: Inactive non-major orgen involvement; iNPSLE: Inactive NPSLE.

Figure 3. Functional enrichment analysis of the upregulated DEGs resulting from the comparison of responders versus non-responders 1 month after treatment initiation.

Disclosures: P. garantziotis: None; G. Moysidou: None; s. doumas: None; D. nikolopoulos: None; S. Flouda: None; N. kapsala: None; A. Filia: None; G. Sentis: None; A. Fanouriakis: None; G. Bertsias: None; B. Dimitrios: None.

To cite this abstract in AMA style:

garantziotis P, Moysidou G, doumas s, nikolopoulos D, Flouda S, kapsala N, Filia A, Sentis G, Fanouriakis A, Bertsias G, Dimitrios B. Baseline Innate Immunity Transcriptional Signatures Act as Predictors of Response to Immunosuppressive and Biologic Treatments in Systemic Lupus Erythematosus While Disturbances Linked to p53-signaling Define “Resistant” Disease [abstract]. Arthritis Rheumatol. 2023; 75 (suppl 9). https://acrabstracts.org/abstract/baseline-innate-immunity-transcriptional-signatures-act-as-predictors-of-response-to-immunosuppressive-and-biologic-treatments-in-systemic-lupus-erythematosus-while-disturbances-linked-to-p53-signalin/. Accessed .

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