Background/Purpose:  In rheumatoid arthritis (RA), synovial fibroblasts (SF) expand and undergo phenotypic changes that contribute to chronic inflammation and joint destruction. Podoplanin (Pdp) is a transmembrane glycoprotein normally expressed by lymphatic endothelium and stromal cells of the T-cell zone in lymph nodes. Recent studies have shown that Pdp is inducible by TNF-α in SF and its expression is increased in RA synovium. Pdp-deficient mice have defective development of both lymphoid organ and ectopic inflammation-associated lymphoid follicles. The aim of this study was to investigate the clinical and pathological significance of increased podoplanin expression in RA patients with particular focus on ectopic lymphoid neogenesis (LN).

Methods: Pdp expression was quantified by immunohistochemistry with specific anti-human podoplanin antibody (clone D2-40) in synovial arthroscopic biopsies from RA patients with active knee arthritis and variable disease characteristics (n=39) and healthy synovial tissues (n=6). Pdp expression was quantified as the fractional immunostained area using ImageJ software. Variation in Pdp expression was analyzed regarding the presence of LN (defined as large grade 2-3 T/B aggregates with MECA79+ high endothelial venules), pathological data including CD68, CD3, CD20 and CD31 cell density, and clinical variables such as disease duration and severity or activity variables. Changes in Pdp expression in a subgroup of 16 patients that underwent a second arthroscopic biopsy after anti-TNF-α therapy were also analyzed. Correlation between Pdp expression and other quantitative variables was analyzed by Spearman’s test and changes in Pdp expression in different patient groups by Mann Whitney U-test.

Results: Pdp was abundantly expressed by lining cells of all RA synovial tissues whereas it was undetectable in healthy synovial tissues. In 54% of the patients, Pdp expression extended to sublining fibroblasts and reticular stromal cells within lymphoid aggregates of LN structures. Pdp expression was significantly increased in the group of patients (64%) with ectopic LN (13.7±2.4% vs 21.9±1.7%, mean±SEM, p=0.006). We also found significantly increased Pdp expression in the groups of patients with rheumatoid factor (14.6±2.3% vs 23.2±2.5%, p=0.02) or ACPA autoantibodies (10.7±1.9% vs 21.8±2.1%, p=0.01). No other clinical or pathological correlations were found. Therapy with TNF-α antagonists induced a significant reduction in Pdp expression (18.6±2.4% to 6.8±1.5%, p=0.0002).

Conclusion: Pdp is ectopically expressed by stromal cells of the lining and sublining in RA tissues, a phenomenon partially reversed by anti-TNF-α therapy. A higher level of Pdp expression is present in the subgroup of patients with LN providing a potential mechanistic link between stromal cell changes and LN.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/podoplanin-expression-in-rheumatoid-stroma-correlates-with-lymphoid-neogenesis-and-is-downregulated-by-anti-tnf-%ce%b1-therapy/