144 CHAPTER 7 disease. Although, this could be challenging, as sampling ST and SF is difficult when there is no arthritis. One might also speculate about investigating other bodily compartments where the adaptive immune system thrives, such as bone marrow and lymph nodes. Up till now only one study, from a Swedish group, has been performing single-cell sorting of B-cells from the bone marrow in comparison to peripheral blood in RA patients [3]. They showed sharing of clones between the bone marrow and blood. Furthermore, they showed the presence of heavy-chain so-called “public” bone marrow clones. As four out of five RA patients showed plasma cells in the bone marrow with identical heavy chains but different light chains, this may be indicative of clonal convergence or receptor editing. Studies investigating lymph nodes have been done more extensively [4]. However, it would be interesting to further elaborate on this, by using our quantitative, TCR and BCR repertoire analysis to test for comparability of the various compartments, linking this data to phenotyping, and see over time how the adaptive immune system evolves during disease progression. One might argue that harvesting these samples may be burdensome for patients. However, both ST and lymph node biopsies have been reported to be well tolerated [5–7]. Of note, patients would even be willing to undergo the lymph node procedure a second time, if necessary. In 2019, Humby et al. showed, using cellular and molecular analyses of synovial tissue in early RA, the presence of three so-called “pathotypes”: (1) Lympho-Myeloid, dominated by the presence of B-cells in addition to myeloid cells; (2) Diffuse-Myeloid, with myeloid lineage predominance but poor in B-cells, and (3) Fibroid-Pauci immune, characterized by scanty immune cells and prevalent stromal cells [8]. Elevation of myeloid- and lymphoid-associated gene expression strongly correlated with disease activity, acute phase reactants and DMARD response at 6 months. Furthermore, elevation of synovial lymphoid-associated genes correlated with autoantibody positivity and elevation of osteoclast-targeting genes predicting radiographic joint damage progression at 12 months. A higher proportion of patients classified as Lympho-Myeloid pathotype required biological therapy after 12-months of RA diagnosis [9]. Patients with predominant Fibroid-Pauci immune pathology showed less severe disease activity and radiographic progression [10]. However, this immunopathotype responds significantly less to TNF-blockade [11]. Consequently, a future prospect could be that, before starting anti-rheumatic treatment, a patient would initially undergo synovial tissue biopsy in order to define the pathotype, followed by the best suited treatment (e.g. TNF-blockade, rituximab, tocilizumab) given the most dominant pathotype or gene signature.
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