Untangling Lupus Through Integrative Multi-Omics Approaches (ULTIMA)

Lupus is a complex autoimmune disease in which the immune system mistakenly attacks the body’s own tissues. Although many treatments are available, including recently developed targeted therapies, it is still difficult to predict which treatment will work best for which patient. One reason is that lupus varies greatly from one person to another: some patients experience long periods of stable disease, while others develop frequent flares or respond poorly to treatment. As a result, treatment decisions are often made by trial and error.

The goal of the ULTIMA project (Untangling Lupus Through Integrative Multi-Omics Approaches) is to understand the biological mechanisms behind these differences and to translate this knowledge into better tools for predicting disease course and treatment response.

To do this, ULTIMA will study several types of biological information from people living with lupus. These include proteins circulating in the blood, patterns of autoantibodies, regulatory mechanisms that control immune gene activity, and small regulatory molecules known as microRNAs. The project will also explore molecules present in exhaled breath and urine, which may provide a completely non-invasive way to monitor disease activity. By integrating these different types of biological information with detailed clinical data collected over time, the researchers aim to identify the molecular programs that shape how lupus develops, evolves, and responds to treatment in different patients.

ULTIMA focuses especially on two critical moments in lupus: what happens after treatment is started, and how stable disease can suddenly progress to a flare. Understanding these transitions may help identify early warning signs of worsening disease, and markers that predict whether a treatment is likely to work or not. Understanding of these mechanisms is required for the implementation of preventive strategies.

The project brings together an international team of experts in rheumatology, immunology, genomics, and computational biology. The team will work with large, well-characterized patient cohorts in which biological samples and clinical information have been collected at multiple time points.

Ultimately, ULTIMA aims to turn complex molecular findings into practical tools that doctors can use in everyday care. By identifying reliable biomarkers of disease activity, flare risk, and treatment response, the project seeks to move lupus care closer to precision medicine, where treatment decisions are guided by the biology of each patient’s disease. This could lead to earlier and better-targeted treatment, fewer flares, and more personalized care for people living with lupus.

Systemic lupus erythematosus (SLE) is characterized by profound clinical and molecular heterogeneity, resulting in highly variable disease trajectories and treatment responses. Despite major advances in immunology, clinicians remain unable to reliably predict which patients will respond to therapy, remain stable, or progress to disease flare. Although multiple molecular signatures have been described in lupus, including type I interferon activation, B-cell dysregulation, and inflammatory cytokine pathways, most studies rely on cross-sectional datasets and single molecular layers. Consequently, the regulatory mechanisms linking immune programs to disease evolution and treatment response remain poorly understood, representing a major barrier to precision medicine in lupus.

The long-term objective of ULTIMA (Untangling Lupus Through Integrative Multi-Omics Approaches) is to define the molecular programs that determine disease trajectories in lupus and translate these insights into biomarkers enabling biologically informed patient stratification. Our central hypothesis is that coordinated regulatory immune programs, centered on B-cell activation, type I interferon signaling, and stromal–myeloid immune interactions, drive distinct clinical trajectory classes in lupus. These programs leave measurable signatures across multiple molecular layers and can be identified through integrative analysis of multi-omics datasets combined with longitudinal clinical data.

ULTIMA focuses on two clinically critical transitions: (i) progression from active disease toward treatment response or refractoriness following therapy initiation, and (ii) transition from quiescent disease toward disease flare. The program leverages deeply phenotyped longitudinal lupus cohorts from the 3TR consortium, enabling integration of molecular profiling with detailed clinical trajectory analysis.

To address this hypothesis, ULTIMA is structured into five complementary research projects that interrogate distinct regulatory layers of lupus pathogenesis and collectively integrate molecular profiling, functional validation, and systems-level modeling across the consortium.

Project 1: Identify trajectory-linked autoantibody and liquid-biopsy biomarkers through serum autoantibody profiling and urine proteomics, and validate candidate biomarker panels for clinical translation.

Project 2: Define epigenomic regulatory mechanisms controlling immune gene expression and evaluate their functional relevance through ex vivo perturbation and targeted in vivo models.

Project 3: Characterize microRNA regulatory networks that coordinate immune signaling pathways and contribute to disease heterogeneity.

Project 4: Identify volatile metabolite signatures in exhaled breath as potential non-invasive biomarkers of lupus disease activity.

Project 5: Integrate multi-omics datasets across projects to reconstruct regulatory networks and develop predictive models of lupus disease trajectories.

By linking molecular immune programs to longitudinal disease evolution, ULTIMA will generate a systems-level understanding of lupus heterogeneity. The expected outcome is the identification of robust biomarkers that predict disease activity, flare risk, and therapeutic response. These discoveries will provide a foundation for biomarker validation studies and the development of clinically implementable tools enabling precision medicine strategies that improve treatment selection and outcomes for patients with lupus.