Alterations of synovial tissue and their potential role in the deposition of β₂-microglobulin-associated amyloid

Background. Beta-2-microglobulin-associated amyloidosis (AB2M) is a frequent complication of long-term dialysis treatment. Uraemic retention of beta-2-microglobulin (β₂M) apparently constitutes the basis for AB2M. However, it is unclear why clinical manifestations are largely confined to osteoarticular tissues. It has been speculated that synovial inflammatory changes, induced by uraemia and/or dialysis therapy could predispose this tissue to amyloid deposition. Methods. We investigated which local synovial alterations preceded or paralleled amyloid deposition. Using immunohistology we evaluated synovial leukocyte infiltration (B and T lymphocytes, monocytes/macro phages), cell proliferation, fibroblast activation (de novo expression of α-smooth-muscle actin), the expression of extracellular matrix components (heparan sulphate proteoglycan, collagen types I, III, IV), and advanced glycation end-products (AGEs). Results. Synovial AB2M was detected in 20 of 36 chronic peritoneal and haemodialysis patients and none of eight non-uraemic controls. Notably, non-AB2M synovial amyloid was present in six additional dialysis and three control patients. Cellular infiltration was largely restricted to patients with advanced AB2M deposits. The infiltrates consisted mainly of macrophages and progressed with increasing degrees of AB2M deposition. In advanced cases they exhibited characteristics of a foreign-body reaction. Other infiltrating leukocyte types, altered cell proliferation, or fibroblast activation were absent or uncommon in periarticular tissue of dialysis patients with and without AB2M. Neither dialysis treatment nor the presence of AB2M deposits appreciably altered the qualitative matrix composition in periarticular tissue. AGEs were present in AB2M deposits, the extracellular synovial matrix of dialysis patients (of both, patients with and without AB2M) and, to a lesser degree, in synovia of controls. Conclusions. These data suggest that, except for AGE formation, alterations of none of the parameters assessed, and in particular no inflammatory tissue alterations, precede periarticular AB2M. Rather synovial tissue, possibly modified by AGEs, seems to have an intrinsic propensity for amyloid deposition and inflammatory changes appear to only arise secondary to amyloid deposition.