The combination of DMARDs and drugs that target fibroblast-like synoviocytes (FLS) has been proposed as an approach to improve therapeutic response in rheumatoid arthritis (RA), but agents that selectively target FLS are currently lacking. New research suggests that receptor-type tyrosine-protein phosphatase S (PTPRS), which is highly expressed on FLS, could be leveraged to develop an FLS-targeted agent for use in combination therapy for RA.
The researchers had previously shown that targeting PTPRS on FLS using the decoy protein immunoglobulin-like domains 1 and 2 (Ig1&2), which activates the phosphatase, impaired FLS invasiveness into cartilage and reduced the development of FLS-mediated inflammatory arthritis in mice. The current work explored whether the mechanism of action of Ig1&2 in arthritis is mediated through suppression of immune cell function and also evaluated the effects of using Ig1&2 in the context of TNF inhibition.
“We discovered that PTPRS is enriched in synovial lining layer RA FLS, a population identified as critical for RA pannus invasiveness,” reports Mattias Svensson, first author of the study published in Science Advances. Notably, they showed that Ig1&2 inhibited the motility of RA FLS but not osteoarthritis FLS.
The researchers next showed that the anti-arthritic effect of Ig1&2 in mice with K/B × N serum transfer-induced arthritis or collagen-induced arthritis (CIA) is not mediated through inhibition of adaptive or innate immune cells.
“We unexpectedly found that TNF reduces the expression of PTPRS in RA FLS,” says corresponding author Nunzio Bottini. “This discovery led us to a finding that in our opinion is very exciting, which is a therapeutic synergy between suboptimal doses of Ig1&2 and of anti-TNF therapy in reversing arthritis in the CIA model.” As well as reversing clinical disease, the combination therapy also protected against bone erosion and cartilage loss, whereas these effects were not seen with either agent administered as monotherapy at suboptimal doses.
“the anti-arthritic effect of Ig1&2 … is not mediated through inhibition of adaptive or innate immune cells”
The researchers are planning further studies to better understand how activation of PTPRS on FLS leads to substantial anti-inflammatory effects in arthritic joints and to further establish the in vivo safety of Ig1&2 and potentially of other approaches to activate PTPRS.
Svensson, M. N. D. et al. Synoviocyte-targeted therapy synergizes with TNF inhibition in arthritis reversal. Sci. Adv. 6, eaba4353 (2020)
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Onuora, S. Therapies targeting FLS and TNF can have synergistic effects. Nat Rev Rheumatol 16, 473 (2020). https://doi.org/10.1038/s41584-020-0487-0