145 General discussion and future perspectives Part II Treatment options in early stages of rheumatoid arthritis In the second part of this thesis, we focus on the earliest phases of RA. In Chapter 4 we provide a systematic literature review of all preventive strategies explored in at-risk individuals. Several of these preventive strategies have been shown to delay RA onset when applied in the early stages of the disease. Consequently, these therapies decrease disease burden at least temporarily. Unfortunately, to date, true prevention has not (yet) been achieved. In the past years, several clinical trials have investigated the safety and effectiveness of early treatment in RA, focusing on individuals who were at high risk for disease without a clinical diagnosis and patients with very early disease (undifferentiated arthritis (UA) or early RA). The studies described investigate a variety of treatments, such as glucocorticoids, conventional synthetic DMARDs (csDMARDs), bDMARDs, and statins. Some of these therapies are also used in clinical practice for disease management. While glucocorticoids and statins did not have a significant effect on disease prevention, studies focusing on csDMARDs or bDMARDs were able to demonstrate some efficacy of treatment [12–18]. In the TREAT-EARLIER study treatment with methotrexate showed delayed development of RA in individuals with prior high risk of developing RA at 1 year [12]. The PROMPT study, in individuals with UA, showed that this was only in ACPA-positive, but not ACPA-negative [13,14]. Abatacept therapy delayed onset of full-blown RA and showed radiographical improvement and delay of progression, in both at-risk individuals and those with UA [19,20]. The PRAIRI study, in RA-risk individuals, showed that treatment with rituximab resulted in a 12 month delay of RA development [21]. These studies show that early treatment with csDMARDs and bDMARDs could potentially give a transient period of drug-free remission/prevention and reduce physical limitations in both arthralgia, UA, and very early RA patients. In the meantime, the interim result of the StopRA trial with hydroxychloroquine were published: in at-risk individuals one year of hydroxychloroquine is not superior to placebo in preventing or delaying the development of arthritis and classified RA at 3 years. Thus, the study was halted due to futility [22]. Also, the preliminary results from the APIPPRA study with abatacept were published: during the RA at-risk phase, therapeutic intervention with abatacept for 52 weeks showed a reduction in the development of RA over a two years period [23]. Obviously, further evidence is needed to determine if other disease-modifying therapies can truly prevent or also delay the onset of RA. In the United Kingdom, Emery et al. are currently recruiting those at risk of developing RA to participate in a therapeutic intervention study with baricitinib, a selective Janus Kinase inhibitor, to determine if it reduces the incidence of RA [24]. 7
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