Key histological features of RA including synovial lining layer hypertrophy, sublining infiltration with mononuclear cells, increased vascularity and fibrin deposition are seen in patients reporting as little as 6 weeks or less of symptoms and in the unaffected joints of patients with active synovitis [3
], whereas organized lymphoid follicles and pannus tissue are features generally associated with established RA synovium (Fig.
). As previously described, abnormalities of the synovial lining layer may be a very early feature of synovitis. Even in early clinical disease, the surface of the lining layer is often covered with fibrin deposits generated from the activation of the fibrinolytic system by synovial fluid. Indeed, the lining layer may be completely replaced by a fibrin cap, and in highly inflamed tissues this fibrin can extend deep into the sublining layers. In very early disease the sublining infiltrates may be minimal or modest [27
]. At this stage, macrophages [3
], and an infiltration by natural killer cells has been described [40
]. Diffuse mononuclear infiltrates and small lymphoid aggregates are seen in both early and late RA. However, as discussed in detail below, aggregates resembling lymphoid follicles with germinal centers are typically seen only in well established disease. The synovium obtained from ACPA positive RA patients tends to have more ectopic germinal centers and reduced fibrosis compared to synovium from ACPA negative patients, regardless of disease duration [41
], although other studies could not confirm these observations [43
]. Pannus, the highly destructive tissue present at the interface between synovium, cartilage, and bone is a characteristic feature of erosive RA and contains large numbers of macrophages and fibroblasts that express high levels of proteases. Osteoclasts derived from pannus tissue can be detected at the interface of bone and cartilage (Fig.
Histopathology of RA synovitis. (A) lymphoid aggregate; (B) Diffuse lymphocytes infiltrate; (C) Hyperplasia of the lining layer; (D) Fibrin cap replacing a denuded lining layer.
Interface between pannus tissue and bone in a patient with RA. (A) the synovial lesion is invading the adjacent bone. (B) Staining for tartrate resistant acid phosphatase in the circled area demonstrates the presence of osteoclasts.
Vascular patterns are also established early in disease and may serve to distinguish RA from other non-RA arthropathies [46
]. In established RA, vascular structures are prominent especially in the deep sublining areas presumably related to increased angiogenesis. Immature blood vessels can be found early in disease but are even more numerous in patients with erosive disease of longer duration indicating ongoing angiogenesis [48
]. Despite evidence of angiogenesis, morphometric studies indicate there are relatively fewer blood vessels in sites adjacent to the expanded lining layer which when combined with the increased metabolic demands of the highly cellular structures, suggests relative hypoxia [49
]. Hypoxia is a potent stimulus for the production of VEGF and other angiogenesis mediators which are highly expressed in inflamed RA synovium [50
]. The vascular endothelium is activated by pro-inflammatory mediators to express adhesion molecules such as E-selectin, P-selectin, and ICAM1 that are involved in the recruitment of inflammatory cells. Synoviocytes also express adhesion molecules including VCAM1, VLA4, PECAM1 and ICAM1. These molecules are expressed equally in synovium from patients with early (<1 year symptoms) and late RA [53
]. It is likely that adhesion molecules play a role in initiating and maintaining synovial infiltrates by recruiting inflammatory cells through the endothelium and then retaining inflammatory cells in the synovium through adherence to matrix cells and other synovial structures.
Histological comparisons of synovial tissue obtained from patients that have been matched for disease activity and treatment have shown no difference in cellular infiltration between those with early (<1 year) or late (>5 years) disease [54
]. Similarly, cytokine expression [56
] and adhesion molecule expression [53
] is similar between early and late disease. This supports the hypothesis that the earliest synovial pathology is subclinical, the duration of subclinical disease may be variable and that at the time of symptom onset, clinical assessment and subsequent tissue biopsy, the synovitis is already in a chronic stage [57
]. In the absence of serial sampling of joints that progress from asymptomatic to minimally symptomatic to definite clinical synovitis to erosive synovitis it is difficult to assess the true histological progression of disease. Such studies are difficult to perform.