Editor’s Pick: Recent Advances in Understanding the Endophenotypes of Osteoarthritis

This narrative mini-review defines the concept of clinical phenotypes, molecular endotypes, and therapeutic subtypes (theratypes) in osteoarthritis (OA) and explores the conceptual transition from a disease that was incorrectly considered homogeneous in the recent past, to a more heterogeneous disorder with broadly defined clinical phenotypes, which are observable traits like malalignment, joint instability, or metabolic dysfunction, to molecular endotypes that represent the specific biological pathways driving disease pathogenesis. Studies that incorporate neo-epitope biomarkers of disease activity, multiplex measurements of pro-inflammatory cytokines, and ‘omics’ technologies into large datasets are not a currently applied gold standard, but, if widely implemented, they will allow increased use of machine learning to cluster large OA populations into subgroups with common endotype drivers. This approach is essential for exploring the underlying molecular pathways and developing future digital biomarkers and algorithms that can be used to identify distinct therapeutic subtypes characterised by specific, predictable treatment responses that may even be modelled in silico. Identifying these molecular drivers within phenotypic clusters is important for advancing OA clinical trials, because it allows for phenotypic enrichment in clinical studies of drugs and biological agents with well-known mechanisms of action, increasing the likelihood of demonstrating efficacy for future disease modifying interventions.