83 Prevention of rheumatoid arthritis to the point that this aspect might influence patients’ perspective on preventive treatment more than the efficacy of the intervention in preventing RA [72,74,75]. Discussion and future perspectives Preventive strategies focus on the prevention or delay of disease onset. While the concept of preventive therapies is not novel, no clear strategy has yet emerged for the prevention of RA. We systematically reviewed the literature for interventional studies in individuals with either high-risk of RA, UA or very early RA. In the past years, several clinical trials have investigated the safety and effectiveness of early (preventive) treatment in RA, focusing on individuals who were at high risk for disease without a clinical diagnosis (true prevention) and patients with very early disease (UA or early RA). These trials investigated a wide range of drugs, such as glucocorticoids, cs/bDMARDs and statins, some of which are used in clinical practice for disease management. Several of these trials showed that early treatment with csDMARDs and bDMARDs may transiently increase the likelihood of drug-free remission and reduce physical limitations in both arthralgia and UA or very early RA patients. Thus, while glucocorticoids did not have a significant effect on disease prevention, studies focusing on csDMARDs or bDMARDs were able to demonstrate some efficacy of treatment. An important aspect of preventive trials is their feasibility, both in terms of safety, efficacy, and willingness of patients to participate. At-risk individuals are less likely to participate in trials and to adhere to treatment when largely asymptomatic. Both the STAPRA study and the PRAIRI trial faced difficulties in patient recruitment, which led to early interruption of the study (STAPRA, only 62 participants included out of 175 found eligible), or a reduction in sample size (PRAIRI, 81 participants out of 90 patients planned, due to slow inclusion rate) [64,68]. This reduction in the number of participants poses a serious problem, because it may lead to loss of statistical significance (type 2 statistical error). Tailored educational strategies might be required to improve individuals’ awareness and their predisposition towards preventive studies as patients are more inclined to participate when well-informed and if the risk of RA is strongly reduced by an intervention with limited side effects. The involvement of general practitioner might help increase inclusion rates, since they could approach patients in the earliest stages of risk, even before arthralgia or UA manifest. Moreover, the establishment of a registry of at-risk individuals, such as the one created by the Rheuma Tolerance for Cure (RTCure) consortium, could help in the identification and inclusion of more patients in RCTs [76]. 4
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