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Abstract
The disease category of early rheumatoid arthritis (RA) has been limited with respect to clinical criteria. Pathological manifestations of synovitis in patients whose disease is clinically classified as early RA seem to be heterogeneous, with regular variations. To clarify the relation between the molecular and histopathological features of the synovitis, we analyzed gene-expression profiles in the synovial lining tissues to correlate them with histopathological features. Synovial tissues were obtained from knee joints of 12 patients with early RA by targeted biopsy under arthroscopy. Surgical specimens of long-standing RA (from four patients) were examined as positive controls. Each histopathological parameter characteristic of rheumatoid synovitis in synovial tissues was scored under light microscopy. Total RNAs from synovial lining tissues were obtained from the specimens selected by laser capture microdissection and the mRNAs were amplified by bacteriophage T7 RNA polymerase. Their cDNAs were analyzed in a cDNA microarray with 23,040 cDNAs, and the levels of gene expression in multilayered lining tissues, compared with those of normal-like lining tissues in specimens from the same person, were determined to estimate gene-expression profiles characteristic of the synovial proliferative lesions in each case. Based on cluster analysis of all cases, gene-expression profiles in the lesions in early RA fell into two groups. The groups had different expression levels of genes critical for proliferative inflammation, including those encoding cytokines, adhesion molecules, and extracellular matrices. One group resembled synovitis in long-standing RA and had high scores for some histopathological features – involving accumulations of lymphocytes and plasma cells – but not for other features. Possible differences in the histopathogenesis and prognosis of synovitis between the two groups are discussed in relation to the candidate genes and histopathology.
Highlights
Synovial lesions in rheumatoid arthritis (RA) show complex histopathological manifestations, involving several diagnostic hallmarks such as multilayered synovial lining tissues associated with a palisading structure of the intimal lining cells and the presence of non-foreign-body-type giant cells, formation of lymphoid follicles, and massive accumulation of plasma cells and macrophages [1]
We focused on the analysis of gene-expression profiles characteristic of proliferative lesions in the synovial lining tissues, which are one of the initial histopathological events of synovitis in early RA
Synovial specimens in early RA were obtained from knee joints by targeted biopsy under arthroscopy, and specimens from long-standing RA were obtained by total knee arthroplasty at the Center for Rheumatic Disease, Matsuyama Red Cross Hospital
Summary
Synovial lesions in rheumatoid arthritis (RA) show complex histopathological manifestations, involving several diagnostic hallmarks such as multilayered synovial lining tissues associated with a palisading structure of the intimal lining cells and the presence of non-foreign-body-type giant cells, formation of lymphoid follicles, and massive accumulation of plasma cells and macrophages [1]. Mesenchymoid transformation and fibrinoid degeneration are definite histopathological features of RA [2]. These lesions are specific to the synovium in the progression stage of RA and their developmental processes remain unclear. 'Early RA' is a clinical term referring to the early stage of RA used to predict the eventual progression stage of RA. The American College of Rheumatology (ACR) 1987 classification criteria for RA [3] have often been used as a diagnostic tool in patients with recent-onset arthritis.
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