Abstract
Precision medicine in immune-mediated inflammatory diseases (IMIDs) requires an understanding of how cellular networks change following therapy. We describe a therapeutic atlas for Crohn’s disease (CD) and ulcerative colitis (UC) following anti-tumour necrosis factor (TNF) therapy. We generated ~1 million single-cell transcriptomes, organised into 109 cell states, from 216 gut biopsies from 38 patients and three controls, revealing disease- and therapy-specific differences. A systems-biology analysis identified distinct spatially-resolved cellular microenvironments: granuloma signatures in CD and interferon (IFN)-response signatures localising to T-cell aggregates and epithelial damage in CD and UC. Longitudinal comparisons demonstrated that disease progression in non-responders associated with myeloid and stromal cell perturbations in CD and increased multi-cellular IFN signalling in UC. IFN signalling was also observed in rheumatoid arthritis (RA) synovium with a lymphoid pathotype. Our therapeutic atlas informs drug positioning across IMIDs, and suggests a rationale for the use of janus kinase (JAK) inhibition following anti-TNF resistance.
Competing Interest Statement
TT has received research support from Celsius Therapeutics, and consulting fees from Abbvie and ZuraBio. DA is an employee and shareholder of Novartis Pharma AG. This article reflects the authors' personal opinions and not that of their employer. RP is employed by Scorpion Therapeutics and holds equity in Celsius Therapeutics. FMP received research support from Roche and Janssen, and consulting fees from GSK, Novartis and Genentech. H.H.U. received research support or consultancy fees from Janssen, Eli Lilly, UCB Pharma, BMS/Celgene, MiroBio, Mestag and OMass. HHU received research support or consultancy fees from Janssen, Eli Lilly, UCB Pharma, BMS/Celgene, MiroBio, Mestag and OMass. AF has consulted for Janssen and Sonoma, and has received research funding from: BMS, Roche, UCB, Nascient, Mestag, GSK and Janssen. ST has received grants and research support, from AbbVie, Buhlmann, Celgene, Celsius, ECCO, Helmsley Trust, IOIBD, Janssen, Lilly, Pfizer, Takeda, UKIERI, Vifor, and Norman Collisson Foundation; consulting fees from: AbbVie, ai4gi, Allergan, Amgen, Apexian, Arcturis, Arena, AstraZeneca, Bioclinica, Biogen, BMS, Buhlmann, Celgene, ChemoCentryx, Clario, Cosmo, Dynavax, Endpoint Health, Enterome, EQrX, Equillium, Ferring, Galapagos, Genentech/Roche, Gilead, GSK, Immunocore, Indigo, Janssen, Lilly, Mestag, Microbiotica, Novartis, Pfizer, Phesi, Protagonist, Sanofi, Satisfai, Sensyne Health, Sorriso, Syndermix, Takeda, Theravance, Topivert, UCB Pharma, VHsquared, Vifor and speaker fees from AbbVie, Amgen, Biogen, BMS, Falk, Ferring, Janssen, Lilly, Pfizer, Takeda. CDB, MB, MC and SR are founders of Mestag Therapeutics. All other authors declare no competing interests.
