Patients with inborn errors of immunity (IEI) harbour mutations in critical immune signalling and differentiation pathways. These mutations can lead to immune dysregulation, resulting in recurrent infections, autoimmunity, inflammation, and cancer. It is crucial to establish a timely diagnosis and treatment initiation as soon as possible. Over 450 genes have been identified as causing IEI, with some impacting crucial inflammatory regulatory circuits. These genes constitute a good reference for genetically complex autoimmune and inflammatory diseases. The strong pressure to treat patients with monogenic IEI led to developing pathway-oriented personalized medicine approaches. The goal of PROMISE is to extend these approaches to patients with non-monogenic, genetically complex chronic inflammatory and autoimmune disease. Patients will be categorized based on comprehensive omics signatures, using monogenic patients as a reference. Based on biological similarity of the multi-omics data, personalized treatments through mechanism-based repurposing of immune-modulating drugs will be introduced to patients with complex immune-mediated inflammatory conditions. PROMISE brings together clinical scientists, epigeneticists, bioinformaticians, data scientists, and a molecular diagnostic SME. Our consortium manages over 1000 invaluable IEI patients. We have vast clinical expertise and have generated hundreds of omics datasets including transcriptomic, epigenomic, and proteomic datasets from patients with monogenic IEI. PROMISE will use existing data from members of the consortium and generate new single-cell omics datasets from a longitudinal cohort of patients with monogenic IEI to identify disease signatures, determine omics responses to targeted treatments, and evaluate specific targeted therapies that can provide a personalized treatment approach to patients with complex inflammatory diseases.