Background: Belimumab, has a putative disease-modifying effect such as reduction of disease activity, risk of flares and organ damage accrual in systemic lupus erythematosus (SLE).

Objectives: To characterize proteome changes upon belimumab treatment and their potential role in mediate these clinical outcomes.

Methods: A total of 10 paired serum samples out of 45 from a transcriptomic study using Belimumab [1] were collected before treatment (M0) and at 6 months after belimumab (M6), from patients with active SLE. Active SLE was defined as Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) ≥6 and Physician Global Assessment (PGA)≥1.5. Attainment of lupus low disease activity state (LLDAS) 6 months after treatment initiation (M6) was recorded. The Olink Explore 384 Inflammation I panel was used to quantify the levels of 368 proteins in the cohort. Gene Set Enrichment Analysis (GSEA) was performed to identify proteome changes upon treatment. Correlation of the proteomics data with the previously published data is in progress.

Results: Six patients achieved LLDAS at M6 (LLDAS patients), while four had only partial response (non-LLDAS patients) (Table 1). At baseline (M0), LLDAS patients exhibited increased expression of the IRAK1 and IRAK4 kinases involved in innate immune responses, and IFN-γ known to correlate with SLE disease activity [2]. In contrast to LLDAS achievers, at M0 non-LLDAS patients exhibited increased expression of ITGA6 (related to PI3K-AKT signaling pathway), KYNU and CCL26. At the 6-months follow-up (M6) both LLDAS and non-LLDAS patients exhibited upregulation of the apoptosis and IFN-α response pathways, and downregulation of the IFN-γ and the mTOR pathway, the latest involved in Treg cell dysfunction and apoptosis in SLE patients [3]. At M6, non-LLDAS patients exhibited the most pronounced upregulation of the IFN-α pathway, suggesting that, may correlate with attenuated response to belimumab.

Conclusion: In SLE patients, belimumab, leads to a reconstitution of the apoptosis and Treg pathways which may account-at least in part- for its disease modifying effects. Proteins related to innate immunity may influence clinical response to belimumab.

REFERENCES: [1] Moysidou GS, Garantziotis P, Sentis G, Nikoleri D, Malissovas N, Nikoloudaki M, Stergioti EM, Polia S, Paschalidis N, Filia A, Grigoriou M, Nikolopoulos D, Kapsala N, Katechis S, Fanouriakis A, Bertsias G, Boumpas DT. Molecular basis for the disease-modifying effects of belimumab in systemic lupus erythematosus and molecular predictors of early response: blood transcriptome analysis implicates the innate immunity and DNA damage response pathways. Ann Rheum Dis. 2024 Nov 13:ard-2024-226051. doi: 10.1136/ard-2024-226051.

[2] Theofilopoulos AN, Koundouris S, Kono DH, Lawson BR. The role of IFN-gamma in systemic lupus erythematosus: a challenge to the Th1/Th2 paradigm in autoimmunity. Arthritis Res. 2001;3(3):136-41. doi: 10.1186/ar290.

[3] Zhao X, Wang S, Wang S, Xie J, Cui D. mTOR signaling: A pivotal player in Treg cell dysfunction in systemic lupus erythematosus. Clin Immunol. 2022 Dec;245:109153. doi: 10.1016/j.clim.2022.109153.

Acknowledgements: G-S Moysidou and M Grigoriou contributed equally to the abstract.

Disclosure of Interests: None declared.

© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.