146 CHAPTER 7 An important aspect of preventive trials is their feasibility, both in terms of safety, efficacy, and willingness of patients to participate. In this phase, treating individuals has its ethical challenges. At-risk individuals might feel uncertain about the risk of developing disease, as they are still largely asymptomatic, and have to balance an uncertain potential personal benefit in the future against a fear for (potentially) severe side-effects. But also socially, the benefit in terms of cost-effectiveness can be discussed, as some of these treatments are very costly and true prevention has not been achieved yet [25]. On the other hand, a recent extensive survey in three countries showed that at-risk individuals, with an assumed 60% risk of developing RA, are willing to participate in a preventive trial, with treatment efficacy as the most important determinant [26]. Mild side effects were shown to be the least important and the method of treatment administration gave varying results [26,27]. Nevertheless, both the STAPRA study and the PRAIRI trial faced difficulties in patient recruitment, which led to early interruption of the study and a reduction in sample size, respectively [21,28]. 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, about RA, personal risk, trial aim, and trial medication, 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 [25]. Possible options for these educations could be visual overviews showing the study aim, study mechanism, expected benefits, and risks. Furthermore, actively addressing misconceptions and concerns in both treated individuals and aiding physicians. Also, during study design researchers should try and limit study burden as much as possible. The involvement of primary care, through general practitioners (GPs), might help increase inclusion rates. Effectively, GPs see much more patients eligible for inclusion in these trials. Furthermore, GPs could approach individuals at risk of developing RA in the earliest stages, during very early arthralgia or even before UA manifests. Additionally, GPs could identify first degree relatives of RA patients more easily. Patients with early RA on average consult with their GPs four times before being referred to a rheumatologist [29,30]. By then, patients are often not eligible anymore to enroll in a preclinical or early RA study. However, early disease can be challenging to identify in primary care, especially given the fact that RA makes up a small proportion of the non-specific musculoskeletal conditions that account for one in seven GP appointments [31]. For this reason, the establishment of an European registry of at-risk individuals could be of great help to identify and include more patients in RCTs [32].
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