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Abstract
Objective Current therapeutic management of lupus nephritis (LN) fails to induce long-term remission in over 50% of patients, highlighting the urgent need for more effective drugs. The aim of this study was to investigate the LN transcriptome in depth to gain insights into underlying molecular mechanisms and to identify new potential drug targets for LN.
Methods We analysed differentially expressed genes in peripheral blood from active LN (n=41) and active non-renal lupus (n=62) patients versus healthy controls (n=497) from the European PRECISESADS project (NTC02890121) and dysregulated gene modules in a discovery (n=26) and a replication (n=15) set of active LN cases. Replicated gene modules qualified for correlation analyses with serological markers, and regulatory network and druggability analysis.
Results Unsupervised co-expression network analysis revealed 20 dysregulated gene modules; seven showed prominent dysregulation in three distinct subgroups of LN patients (figure 1A). These subgroups were classified based on the ‘interferon’ (IFN) gene module upregulation into low, intermediate, and high IFN subgroups and showed differential dysregulation of the ‘B cell’ and ‘plasma cells/immunoglobulins’ modules. Drugs annotated to the IFN network included CC-motif chemokine receptor 1 inhibitors, programmed death-ligand 1 inhibitors, and irinotecan, while the anti-CD38 daratumumab and proteasome inhibitor bortezomib showed potential for counteracting the transcriptomic signature associated with the ‘plasma cells/immunoglobulins’ module. In silico analysis demonstrated that the low-IFN subgroup may benefit from calcineurin inhibitors while the intermediate-IFN subgroup may benefit from B cell targeted therapies (figure 1B). High-IFN patients exhibited greater anticipated response to anifrolumab while the intermediate-IFN and high-IFN subgroups displayed greater anticipated response to daratumumab.
Conclusion Interferon upregulation and B and plasma cell gene dysregulation patterns revealed three distinct LN patient subgroups, providing a conceptual framework for precision medicine in LN.
Conflicts of Interest IP has received research funding and/or honoraria from Amgen, AstraZeneca, Aurinia, Bristol Myers Squibb, Elli Lilly, Gilead, GlaxoSmithKline, Janssen, Novartis, Otsuka, and Roche. The other authors declare that they have no conflicts of interest related to this work. The funders had no role in the design of the study, the analyses or interpretation of data, or the writing of the manuscript.
Interferon (IFN) upregulation and B and plasma cell gene dysregulation patterns reveal three distinct lupus nephritis subgroups with differential anticipated response to targeted therapies. (A) Heatmap displaying the most discriminative gene modules, grouping the patients into low-IFN, intermediate-IFN, and high-IFN. Red and blue colours denote higher and lower gene dysregulation, as measured by z-scores, compared to healthy controls, respectively. (B) Bars depicting proportions of patients with an anticipated benefit from inhibition of selected drug targets across lupus nephritis patient subgroups
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