0594: 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

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.








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.