13 General introduction and outline highly expanded clones. Simply said; the larger the clone, the higher the frequency of the cells that have the same TCR/BCR. Arbitrarily, we marked a clone larger than 0.5% of the total TCR/BCR repertoire as expanded (Figure 3). Figure 3 | Next-generation sequencing technology to identify expanded TCR- or BCR-clones During the first step TCR/BCR mRNA is isolated from a patient sample (i.e. blood, synovial fluid or tissue). From there the next-generation sequencing (NGS) pipeline is started with cDNA synthesis, linear amplification, and sequencing. During bioinformatic analysis unique clones are identified, characterized by fingerprints of their TCR/BCR. In the last step of the bioinformatic process counting of the unique fingerprints yields an estimate of the frequency of each clone. Expanded clones can be identified as a deviation in the repertoire, also known as dominant clones or highly expanded clones (i.e. a clone larger than 0.5% of the total repertoire). Window of opportunity In recent years, substantial advances in the treatment of RA have been seen, including the introduction of several new classes of drugs, including biologic Disease-Modifying Antirheumatic Drugs (DMARDs), such as anti-TNF, and targeted synthetic DMARDs (i.e. JAK/STAT-inhibitors). Targeting the adaptive immune response using these targeted therapies, for instance with abatacept (CTLA4-Ig) or rituximab, have been proven to be of clinical benefit in RA patients [24,33]. However, these new therapies are as yet not curative, only effective in 60% of RA patients, and often only induce a partial clinical response [34]. At the moment, no formal treatment recommendations exist for individuals in the pre-clinical stage of RA after presenting with arthralgia; patients are usually monitored over time, but as a rule, they do not receive any (DMARD) treatment until clinical signs of arthritis or a formal diagnosis of RA is established. 1
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