High-Throughput Proteomic Profiling of Sera as a Non-Invasive Method for Identifying Lupus Nephritis Subtypes

Rufei Lu¹, Andrea Fava², Benjamin Jones³, Peter Izmirly⁴, Jennifer Anolik⁵, Chaim Putterman⁶, David Wofsy⁷, Matthias Kretzler⁸, Celine Berthier⁹, E. Steve Woodle¹⁰, Michael Weisman¹¹, Mariko Ishimori¹², The Accelerating medicines Partnership: RA/SLE Network¹³, Betty Diamond¹⁴, Jill Buyon¹⁵, Michelle Petri¹⁶, Richard Furie¹⁷, Judith James¹³ and Joel Guthridge¹³, ¹University of California San Francisco, San Bruno, CA, ²Divison of Rheumatology, Johns Hopkins University, Baltimore, MD, ³Oklahoma State University, Oklahoma City, OK, 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, ¹⁷Northwell Health, Manhasset, NY

Meeting: ACR Convergence 2024

Keywords: B-Lymphocyte, Biomarkers, Lupus nephritis, Systemic lupus erythematosus (SLE), Tumor necrosis factor (TNF)

Session Information

Date: Sunday, November 17, 2024

Title: Genetics, Genomics & Proteomics Poster

Session Type: Poster Session B

Session Time: 10:30AM-12:30PM

Background/Purpose: Lupus nephritis (LN) treatment decisions are typically informed using histopathological classification based on the International Society of Nephrology/Renal Pathology Society (ISN/RPS) and NIH activity and chronicity indices. LN class and activity can change over time, which often requires changes in treatment. However, serial kidney biopsies are invasive and impractical; thus, noninvasive biomarkers of LN classification are needed to help guide treatment decisions. Here, we investigated serum proteomic profiles to define noninvasive biomarkers of histological class and activity and chronicity indices.

Methods: SLE patients with LN (n=184) were recruited for this study as part of the Accelerating Medicines Partnership RA/SLE network. Kidney biopsies were evaluated by a renal pathologist according to ISN/RPS classification and NIH activity and chronicity indices. Serum samples were collected at the time of kidney biopsy, and protein expression was measured using the Olink Explore HT. Multivariate logistic regression, adjusting for age, gender, and genetic ancestry, and random forest algorithms were used to identify biomarkers of LN class and activity and chronicity indices.

Results: Compared to healthy controls, LN patients upregulated multiple pathways related to the innate and adaptive immune systems, including TNF, IL-10, efferocytosis, and antigen processing and presentation pathways (Figure 1A). Patients with pure proliferative LN (class III/IV) showed further upregulation in B cell receptor signaling, Th1/Th2 differentiation, neutrophil degranulation, Th17 differentiation, and leukocyte chemotaxis pathways compared to those with minimal disease (class I/II), membranous (V), or mixed proliferative (III/IV+V) LN (Figure 1A). Machine learning models achieved high accuracy for distinguishing healthy controls (95.3% [86.9%-99%]) and LN patients (99.5%, [97% – 100%]) but were only able to distinguish pure proliferative (84.5% [75.8%, 91.1%]) from the other LN subclasses (Figure 1B). In addition, the expression of 398 and 2252 proteins was associated with the NIH activity and chronicity indices, respectively (Figure 1C). Specifically, proteins involved in IL-18, TNF, and IL-1 pathways and intracellular proteins from multiple organ systems with prominent enrichment in immune cells positively correlated with the activity index (Figure 1D). Interestingly, proteins enriched in interferon, growth factor, and neurotrophin receptor pathways and intracellular proteins from multiple organ systems, particularly the nervous system, correlated with the chronicity index (Figure 1D).

Conclusion: Serum protein expression pathways may serve as noninvasive biomarkers of LN class and activity and chronicity indices, helping to direct therapeutic decisions.

Figure 1. (A) Canonical pathway analyses cross-comparing healthy controls, SLE patients with the minimal disease (class I/II), membranous (V), pure proliferative (III or IV), and mixed proliferative (III/IV+V) LN. (B) Proximity plot from a random forest machine learning algorithm permuted 500 times and the important predictors for each LN classification. Variable importance is measured by the mean accuracy decrease after permutation. Open diamonds denote the predictors with p<0.05 for each LN classification. (C) Volcano plots showing the proteins correlated with the NIH activity and chronicity indices (c). (d) Significant enriched functional pathways and tissues from StingDB enrichment analysis. +correlation coefficients are estimates from regression model adjusted for age, gender, and race.

Disclosures: R. Lu: None; A. Fava: Arctiva, 2, AstraZeneca, 2, Exagen, 5, Novartis, 6, UCB, 2; B. Jones: None; 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; R. Furie: AstraZeneca, 1, 2, 6; 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:

Lu R, Fava A, Jones B, 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, Furie R, James J, Guthridge J. High-Throughput Proteomic Profiling of Sera as a Non-Invasive Method for Identifying Lupus Nephritis Subtypes [abstract]. Arthritis Rheumatol. 2024; 76 (suppl 9). https://acrabstracts.org/abstract/high-throughput-proteomic-profiling-of-sera-as-a-non-invasive-method-for-identifying-lupus-nephritis-subtypes/. Accessed .

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