Page 12 - THE EVOLUTION OF EARLY ARTHRITIS AND CARDIOVASCULAR RISK Samina A. Turk

CHAPTER 1
PRECLINICAL PHASE OF RA 2221
Figure 1. Overview of the preclinical and earliest clinically apparent phases of rheumatoid arthritis. This figure was published in van Steenbergen et al.(8)
CARDIOVASCULAR DISEASE IN RHEUMATOID ARTHRITIS
Since RA is a systemic autoimmune disease, it also affects other tissues and organs in addition to the joints, leading to the so-called extra-articular manifestations. These
Figure 2. Overview of the preclinical phases of rheumatoid arthritis (RA) and the designs of the studies of the preclinical phases that have been manifestations are associated with an increased risk of premature death in RA patients.
performed. A, The six phases of preclinical and earliest clinically apparent RA, as defined by the European League Against Rheumatism study group This increased risk is especially due to the earlier development of cardiovascular (CV)
for risk factors for RA. B, Nested case–control study design. A predefined set of subjects (e.g., blood donors) is followed up. From this set of subjects, RA cases are identified and for each case, a specified number of matched controls who have not developed RA is selected. Biomarkers are compared
disease. Of the CV diseases, atherosclerotic disease is the leading cause of death in
between preclinically collected samples from these cases and the controls. C, Prospective cohort study design. Autoantibody-positive arthralgia RA. In the accelerated development of atherosclerosis, both traditional risk factors and
patients are identified and followed up prospectively.
RA-related factors play a role(28-30). The RA-related factor is the presence of systemic inflammation, which causes accelerated atherosclerosis by stimulating the accumulation
RA might be explained by environmental risk factors have been studied in the last few years. This has been
(phaosfelBip).idMsainytehnevirvoensmsenltawlarilslk.Bfaecstoidrsehsatvheebedeinrectedffoenectuosifnginmflaimnlymtwaotiodniffeornenthsetuvdyesdseesilgwnsa:lnl,ested
studied (details are available from the corresponding case–control studies and prospective cohort studies. As
inflammation is important in the initiation of atherosclerosis as well as in its further
author upon request), and smoking is the best replicated will be discussed, the design of the study determined the
development(30;31). Some traditional risk factors are common in the development of
environmental risk factor (14,15). Smoking predisposes sort of outcome that was obtained and the conclusions to RbAotphartRicAularnlydinCpVatdieinstesawsheo,claikrrey spmecoifkicinHgLaAn–d obtehsaittyca(n32be;3d3r)a.wAn. novel CV risk factor is an
unfavorable body composition, especially an excess of body fat and primarily fat on the
DRB1 alleles, e.g., smokers carrying two HLA–DRB1
alleles have a 21-fold increased risk of developing anti–
abdomen, which is associated with atherosclerosis(32;34). Compared to the general
citrullinated protein antibody (ACPA)–positive RA (16).
population, RA patients more often have a conditionStcuadlilesdassasorcioaptiengnicRoAbewsitihty,swystheimchic isauto-
Despite the high odds ratio in this subgroup, a large majodreitfiynoefdsmaoskearslodsosnotfdsekveleoptaRlAm.uWsecalekemriantsesr,-inthepresenceofastableorevenincreased
fat mass (especially on the abdomen) while maintaining a stable weight(35-38). Dual-
actions have also been demonstrated between other
genes and smoking (17). using a nested case–control study design (also called
energy X-ray absorptiometry (DXA) differentiates between skeletal mass and fat mass,
From RA back to pre-RA systemic autoimmunity
immune responses in the preclinical phase (phase C, with or without phase A and B) were mainly performed
The genetic and environmental risk factors con- case–control studies in a cohort) (Figure 2B). In this
andmightthereforebeamoreaccuratemeatsypuereomfestnutdya,sRaACVcasreiskwfearectiodrentthifaiendbwohdoywere ceptually constitute the earliest preclinical phases of
RA.mTahseseinridskexfac(tBoMrsIh)(a3ve9)a.lrIenadaydbdeietinoknotwonafothrerosmclemrboetirscodfaisperaedsefsin,esduddatdaesnet,cea.gr.d,aiaccohdoretaotfhblood some time, and an extensive discussion of these risk donors from whom blood samples were obtained at least
is two times more common in RA patients, mostly due to cardiac arrhythmias(40-42).
factors is beyond the scope of this review. once (11,18). For each RA patient, a specified number
The increased arrhythmia risk is partly due to systemic inflammation, which affects the
The next two preclinical phases, “developing systemyicocauatrodimiaml uenleitcytarsosopchiaytseidowloitghyR(4A1”;4(p3h;a4s4e)C. ) and “symptoms without clinical arthritis” (phase D),
of matched controls who had not developed RA was selected from the same data set. Consequently, blood samples from RA cases that were collected and stored
10