The use of arthroscopic biopsy for examination of rheumatoid arthritis (RA) synovial tissue (ST) for disease activity and prognostic indices is of major interest for improving patient outcome and for assessing clinical trial efficacy. Dendritic cells (DCs), the professional antigen-presenting cells of the immune system, have been proposed to play a central role in the initiation and perpetuation of the immune response in RA. We have previously demonstrated that differentiated DCs can be specifically identified in tissues by double immunohistochemical staining, which includes the identification of the NFκB family member, RelB, in the nucleus. Differentiated DCs were thus identified in the T cell areas of normal or reactive human lymph nodes and in a perivascular location in ST from patients with untreated active RA. Double immunohistochemical staining on 13 ST biopsies demonstrated that 88% of the nRelB+ cells present are differentiated dendritic cells, the remaining 12% comprising activated B cells, sub-lining monocytes, and occasional follicular DCs. To examine the relationship between the presence of differentiated DCs in the ST and disease activity, serial ST biopsies from seven patients with RA were obtained before and after either successful or unsuccessful therapy, as determined by the ACR response criteria. RA treatment-associated clinical improvement correlated with a reduction in infiltrating differentiated DCs, infiltrating lymphocytes, tissue vascularity, expression of TNF-α in the lining and sub-lining layers, and CD68+ lining layer cellularity. In contrast, IL-1β expression was not correlated. These data suggest that clinical joint inflammation, tissue vascularity, local TNF-α production, DC and lymphocyte infiltration, and lining-layer hypertrophy are interdependent events. Furthermore, taken together with published data, they suggest that the synovial immune response and joint destruction are linked pathogenetic processes.