78 CHAPTER 4 MRI during treatment and up to a year after treatment was stopped (mean difference of -1.4 points). Moreover, patients treated with methotrexate had reduced disease-related symptoms (pain=-8 on 1-100 scale in treatment vs- placebo, morning stiffness=-12, and functional impairment), less physical limitations and less loss of work productivity, regardless of their autoantibody status. High risk participants, who had a risk of developing RA higher than 70% at baseline, also had a delay in RA onset during treatment, although disease frequency was similar at 2 years after treatment initiation (67% in both groups) [54,55]. Interestingly, most beneficial effects occurred in the first 4 months and were sustained throughout the rest of the study despite a moderate target dose treatment adherence of 53% at 52 weeks in the methotrexate group. Hydroxychloroquine Hydroxychloroquine is a weak basic that has been used for centauries as antimalarial drug. Hydroxycloroquine accumulates in the lysosome, interfering with its activity and autophagy, preventing immune cell activation and cytokine production. On T cells, hydroxychloroquine also causes reduction of CD154 expression [56]. The StopRA study is currently being conducted and focuses on first degree relatives of RA patients with serum levels of anti-cyclic citrullinated peptide (anti-CCP3) two or more times higher than normal, but without clinical joint inflammation. The study aims to recruit 114 participants, who are randomized to either receive 200-400 mg/ daily hydroxychloroquine (based on ideal body weight) or placebo, for 12 months and followed for 2 additional years. The primary endpoint is the number of patients who progress to clinically apparent RA, defined by ACR/EULAR 2010 classification criteria. Secondary outcomes include changes in disease activity defined by joint pain, swelling, stiffness, and fatigue at 12 and 36 months, as well as self-reported Physical, Mental and Social Health Quality of Life Measures. Results should be available after the primary completion date by the end of 2022 [40]. Biological DMARDs Abatacept Abatacept is a human fusion protein of CTLA-4 and the Fc portion of IgG that targets CD80 and CD86 on antigen presenting cells, thereby preventing binding to CD28 expressed on T cells and subsequent activation of these cells via downstream signaling pathways [57].
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