High-Throughput Proteomic Profiling of Longitudinal Serum Samples to Predict Treatment Response in Lupus Nephritis

Benjamin Jones¹, Rufei Lu², Andrea Fava³, Peter Izmirly⁴, Jennifer Anolik⁵, Chaim Putterman⁶, David Wofsy⁷, Matthias Kretzler⁸, Celine Berthier⁹, E. Steven Woodle¹⁰, Michael Weisman¹¹, Mariko Ishimori¹², The Accelerating medicines Partnership: RA/SLE Network¹³, Betty Diamond¹⁴, Jill Buyon¹⁵, Michelle Petri¹⁶, Judith James¹³ and Joel Guthridge¹³, ¹Oklahoma State University, Oklahoma City, OK, ²University of California San Francisco, San Bruno, CA, ³Johns Hopkins University, Baltimore, MD, ⁴New York University Grossman School of Medicine, New York, NY, ⁵University of Rochester Medical Center, Rochester, NY, ⁶Albert Einstein College of Medicine, Safed, Israel, ⁷University of California San Francisco, SF, CA, ⁸University of Michigan, Ann Arbor, MI, USA, Ann Arbor, MI, ⁹University of Michigan, Ann Arbor, MI, ¹⁰University of Cincinnati College of Medicine, Cincinnati, OH, USA, Cinncinnati, OH, ¹¹Stanford University, Los Angeles, CA, ¹²Cedars-Sinai Health System, Los Angeles, CA, ¹³Oklahoma Medical Research Foundation, Oklahoma City, OK, ¹⁴The Feinstein Institutes for Medical Research, Manhasset, NY, ¹⁵NYU Grossman School of Medicine, New York, NY, ¹⁶Johns Hopkins University School of Medicine, Timonium, MD

Meeting: ACR Convergence 2024

Keywords: B-Lymphocyte, Biomarkers, immunology, Lupus nephritis, T Cell

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: Lupus nephritis (LN) can lead to severe morbidity and early mortality in SLE patients. While therapeutic options for LN have improved, they are not universally effective and can cause significant adverse effects. Thus, a robust panel of non-invasive biomarkers are needed to optimize and predict treatment response. Using high-throughput proteomics and machine learning, this study generated a prediction model of treatment response based on serum protein expression as part of the Accelerating Medicines Partnership RA/SLE Network.

Methods: Over 5,000 serum proteins were measured in serum of 158 LN patients at the time of diagnostic kidney biopsy (baseline) and 12 weeks post-biopsy using Olink Explore HT. Clinical response was determined at 52 weeks as complete (CR; n=25), partial (PR; n=22), or no response (NR; n=49). Multivariate logistic regression adjusting for age, gender, and genetic ancestry and machine learning algorithm approaches (Extreme Gradient Boosting) were used to generate a robust prediction model of treatment responsiveness.

Results: At baseline, patients with NR exhibited 515 (p-value < 0.05; 160 upregulated) dysregulated proteins within the innate immune system and platelet activation and aggregation pathways. In addition, 1227 (p-value < 0.05; 1180 upregulated) proteins involving the TGFb, IL-10, Th1/Th2 differentiation, platelet activation, and leukocyte transendothelial migration pathways at 12 weeks post-biopsy were differentially expressed in patients with NR compared to those with a CR. Proteins involved in T cell proliferation, Th17 cell differentiation, and TNF, Wnt, EGFR, and IL-10 signaling were persistently elevated at week 12 compared to baseline in CR. A model incorporating changes in 34 proteins from baseline to week 12 was more effective at predicting treatment response at 52 weeks (83.8% +/- 0.76%) compared to levels at baseline (67.3% +/- 6.3%) or 12 weeks (70.5% +/- 7.03%) (Figure 1A). In particular, patients with a CR had a significant reduction in CD27, IL-7, VSIG4, HIP1R, PDGFB, and WFDC1 from baseline to 12 weeks post-biopsy (Figure 1B). Gene regulatory network analyses of the top predictors demonstrated significantly down-regulated lymphocyte activation/differentiation (CD27, IL-7, IL-3, IL-16, CD83, and IL-10) and cellular migration pathways (NRP1, IL-16, PDGFB, CSF1, DDR1, FSTL1) in patients with a CR at week 12 (Figure 1C-D).

Conclusion: Early downregulation of specific immune pathways upon treatment precedes future clinical response in LN. Changes in serum protein expression 12 weeks post-biopsy may serve as noninvasive biomarkers of 52-week treatment response in LN patients.

Figure 1. Changes in serum protein expression predict treatment response in LN patients. (A) UMAP of SLE patients with a complete response (CR) and no response (NR) based on 34 top predictors using an elbow finding method. (B) UMAP plots with the top 6 key predictors of responsiveness based on changes from week 0 to week 12. (C) Pathway analyses of the protein level changes from baseline to week 12 that differed based on treatment response. (D) Gene regulatory network analyses of all important predictors (importance value >0) for patients with complete or no response to treatment.

Disclosures: B. Jones: None; R. Lu: None; A. Fava: Annexionbio, 2, Arctiva, 2, AstraZeneca, 2, Exagen, 5, Novartis, 6, UCB, 2; P. Izmirly: Hansoh Bio, 2; J. Anolik: None; C. Putterman: Equillium, 2, Progentec, 2; D. Wofsy: Amgen, 2, Novartis, 2; M. Kretzler: None; C. Berthier: None; E. Woodle: None; M. Weisman: None; M. Ishimori: None; T. Accelerating medicines Partnership: RA/SLE Network: None; B. Diamond: adicet, 2, alpine, 12, dsmb, atara, 2, DBV, 2, icell, 2, sail, 2; J. Buyon: Artiva Biotherapeutics, 1, Bristol-Myers Squibb(BMS), 1, 2, Equillium, 1, GlaxoSmithKlein(GSK), 1, 2, Otsuka Pharmaceuticals, 1, Related Sciences, 1, 2; M. Petri: Amgen, 2, AnaptysBio, 2, Annexon Bio, 2, Arthros-FocusMedEd, 6, AstraZeneca, 2, 5, Atara Biosciences, 2, Aurinia, 5, 6, Autolus, 2, Avoro Ventures, 2, Biocryst, 2, Boxer Capital, 2, Cabaletto Bio, 2, Caribou Biosciences, 2, CTI, 1, CVS Health, 1, Eli Lilly, 2, 5, Emergent Biosolutions, 1, Ermiium, 2, Escient Pharmaceuticals, 2, Exagen, 5, Exo Therapeutics, 2, Gentibio, 2, GlaxoSmithKlein(GSK), 2, 5, iCell Gene Therapeutics, 2, Innovaderm Research, 2, IQVIA, 1, Janssen, 5, Kira Pharmaceuticals, 2, Merck/EMD Serono, 1, Nexstone Immunology, 2, Nimbus Lakshmi, 2, Novartis, 2, PPD Development, 2, Precision Biosciences, 2, Proviant, 2, Regeneron Pharmaceuticals, 2, Sanofi, 2, Seismic Therapeutic, 2, Senti Bioscienes, 2, Sinomab Biosciences, 2, Takeda, 2, Tenet Medicines Inc, 2, TG Therapeutics, 2, UCB, 2, Vertex Pharmaceuticals, 2, Worldwide Clinical Trials, 1, Zydus, 2; J. James: GlaxoSmithKlein(GSK), 1, Progentec Diagnostics, Inc., 5, 10; J. Guthridge: AstraZeneca, 5, Bristol-Myers Squibb(BMS), 5.

To cite this abstract in AMA style:

Jones B, Lu R, Fava A, Izmirly P, Anolik J, Putterman C, Wofsy D, Kretzler M, Berthier C, Woodle E, Weisman M, Ishimori M, Accelerating medicines Partnership: RA/SLE Network T, Diamond B, Buyon J, Petri M, James J, Guthridge J. High-Throughput Proteomic Profiling of Longitudinal Serum Samples to Predict Treatment Response in Lupus Nephritis [abstract]. Arthritis Rheumatol. 2024; 76 (suppl 9). https://acrabstracts.org/abstract/high-throughput-proteomic-profiling-of-longitudinal-serum-samples-to-predict-treatment-response-in-lupus-nephritis/. Accessed .

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