Background Systemic Lupus Erythematosus (SLE) is a complex autoimmune disease that leads to significant worsening of quality of life and mortality. The enormous molecular heterogeneity of SLE is reflected in different clinical manifestations, disease progression and also in a different drug efficacy across patients.1Lupus nephritis (LN) is the most severe SLE manifestation with the potential of rapidly evolving into irreversible chronic kidney disease. Mycophenolate mofetil (MMF) is the most widely used first-line treatment for LN, being ineffective in 15–30 percent of the patients.2 Reasons for non-response are still unknown and low or moderate drug efficacy may lead to aggravation of the disease. The development of new, more effective therapies to treat LN is an urgent unmet need.3 The objective of this work is to define the cellular and molecular immune landscape behind non-response to MMF to finally apply this knowledge within routine clinical practice.
Methods A longitudinal cohort comprising gene-expression and clinical data of 97 MMF responder and 28 non-responder samples was retrospectively analyzed (table 1). Differential gene expression across different clinical scenarios and functional analysis were performed. Response rate was measured based on blood cell proportions. Single-cell RNA sequencing data was analyzed to identify the cell subtypes influencing non-response and their contributing genes and regulatory mechanisms.
Results A robust signature comprising 41 differentially expressed genes defined non-response to MMF and cellular profiles that favor the response to the drug in the patients were revealed (figure 1). The response rate to MMF increases the lower the B cell/T cell ratio. Single-cell RNA sequencing showed that overexpression of the IFITM-family of genes in age-associated B cells, plasma cells, myeloid dendritic cells and macrophages was behind the non-response signature.
Conclusions Blood cell subtypes and genes mediating non-response to MMF were revealed, opening a new scenario for the development of new therapeutic strategies for LN.
Toro-Domínguez D, Martorell-Marugán J, Martinez-Bueno M, López-Domínguez R, Carnero-Montoro E, Barturen G, et al. Scoring personalized molecular portraits identify systemic lupus erythematosus subtypes and predict individualized drug responses, symptomatology and disease progression. Brief Bioinform. 2022 Sep 20;23(5):bbac332.
Chan TM, Li FK, Tang CSO, Wong RWS, Fang GX, Ji YL, et al. Efficacy of Mycophenolate Mofetil in Patients with Diffuse Proliferative Lupus Nephritis. N Engl J Med. 2000 Oct 19;343(16):1156–62.
Guthridge JM, Wagner CA, James JA. The promise of precision medicine in rheumatology. Nat Med. 2022 Jul;28(7):1363–71.
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