To critically appraise the literature related to the pathophysiology of rheumatoid arthritis (RA) focusing on the contribution of synovial tissue pathology (synovitis) in determining diverse clinical outcome/therapeutic response.

RA synovitis is highly heterogeneous with diverse cellular and molecular signatures (pathotypes) emerging as potential taxonomic classifiers of disease phenotypes.The challenge is to understand mechanistically the sophisticated interplay between systemic disease 'initiators' and joint-specific 'localizing/perpetuating' factors leading to disparate coupling of inflammation/tissue-destructive pathways and disease outcome. Synovial tissue analysis has been instrumental in enhancing understanding of R0A pathogenesis and developing targeted DMARD-biologic therapies. The next step is to elucidate the relationship of different synovial pathotypes/molecular signatures with therapeutic response/resistance in randomized clinical trials in order to develop effective therapies for 'resistant' patients. The development of ultrasound-guided synovial biopsy as a rapid, safe and well tolerated procedure that enables synovial tissue collection from most joints/patients will facilitate such studies.

RA is a heterogeneous clinical and pathobiological entity. Specific pathways within synovial tissues are emerging as associated with diverse clinical evolution and therapeutic response/resistance that, if confirmed in randomized clinical trials, may lead to the development of synovial tissue analysis as a potential clinical tool for patient stratification.