This review considers the association between RA and PAD, coupled with their concomitant impact on HRQOL and FC. Four retrospective cohort studies investigating the association between RA and PAD were of a high-quality design [24, 35, 37, 40]. Moreover, four articles were cross-sectional, three of which demonstrated a high-quality design [24–31, 33, 39, 41], while a single article was of moderate quality [30]. Investigated articles isolating PAD in their analysis were in agreement of an increased PAD incidence or prevalence amongst patients with RA [24, 35–37]. One exception to the former persisted denoting no increase in prevalence between the RA and controls[33]. Grech et al. [31] questioned the validity of ABPI as a PAD diagnostic method in RA, suggesting that PAD remains substantially underdiagnosed. The examined literature determined that PAD incidence is associated with either extra-articular RA disease manifestations, the prevalence of comorbidities, or RA disease severity marked by CRP or ESR concentrations and joint deformity counts [35–38]. These findings suggested that disease manifestations of greater severity and chronicity would increase an RA patient’s susceptibility to PAD development. CVD risk factors at the time of RA diagnosis, including smoking history, are significantly associated with PAD development but are not independently responsible for its incidence [35]. The former ideation was echoed by other meta-analyses and systematic reviews concerning the association between RA and vascular morbidities [42–44]. These included venous thromboembolism (VTEs) [43] and CAD [42–44].
A grade “I” level of evidence was demonstrated concerning the positive association between ABPI and RA, suggesting RA as an independent risk factor for arterial obstruction or incompressibility [38]. One high-quality study presented the necessary “prospective cohort” and “single-centred” criterion proposed by the ASPS to award the noted gradation [38]. Two studies of a high-quality cross-sectional design noted an increased prevalence of reduced ABPI in patients with RA [29, 32]. This remained true when individuals diagnosed with PAD were excluded [32]. ABPI acts as a valid marker of generalized atherosclerotic changes concerning the peripheral [21, 45], carotid [43] and coronary [45] arterial beds. The association noted in this review may further validate ABPI as a marker of atherosclerosis in RA.
Articles addressing the impact of conjoint RA and PAD manifestations on HRQOL and FC measures were not eligible for a level of evidence gradation, despite a robust high-quality design [24, 29, 33]. Evidence appraised suggested diminished HRQOL and FC in concomitant disease manifestations [24]. This finding is independent of the reduced FC demonstrated by RA alone [39]. Detriments to HRQOL and FC more accurately correlated with RA severity and joint deformity, rather than the prevalence of PAD in concomitant manifestations [24]. The concomitance of RA and reduced ABPI was correlated with reduced FC in an RA population with non-significant disease activity [33]. No discussion ensued of the potential impact of symptomatic PAD on FC, HRQOL or perceived disease burden, despite denoting a 7.5% prevalence of IC amongst the RA population examined in one study [24]. Symptomatic PAD carries may reduce a patient’s HRQOL and FC as it often presents with pain on movement. Previously symptomatic patients with PAD demonstrated greater detriments to their HRQOL and FC when compared to non-symptomatic PAD counterparts, and were at risk of disease progression-related mobility loss [18, 46]. Investigating the impact of symptomatic PAD in RA remains paramount in improving patients’ prognostic outlook.
Individual study appraisal scores were determined using the CCAT, with all included studies demonstrating a robust design, carrying minimal potential for bias. Some studies, however, were subject to selection bias, limiting validity [30, 32]. Kim et al. [30] and Tehan et al.[33] for instance recruited RA patients with mild disease severity. Previous studies have denoted RA disease severity as a propagator of atherosclerotic changes[24, 31, 32, 34–37], suggesting the findings of Kim et al. [30] and Tehan et al [33] lack generalizability. Fan et al. [32] recruited healthy controls from the risk evaluation clinic of Baker IDI Heart and Diabetes Institute, rather than from the community. This may have reduced the significance of their findings given that data derived from the control group may be subject to Berkson’s Bias [47]. Other studies derived their samples from a predominately ethnically homogenous population, reducing the potential implication of their findings on ethnically diverse groups [29, 34, 36]. Despite a degree of methodological homogeneity, evident heterogeneity was present regarding ABPI acquisition. Notably, studies either implemented manual doppler [24, 30, 33, 38] or sphygmomanometric methods [29] in deriving ABPI scores. Manual methodological approaches in ascertaining ABPI posit a degree of observer bias [48]. ABPI score inaccuracies may have been present since the observer must measure ankle and brachial pressures successively rather than simultaneously [48]. Automated oscillometry was implemented in two studies [30, 31]. Despite reducing the risk of observer bias, no evidence was found validating automated oscillometry in an RA population.
RA has been previously documented as a novel CVD risk factor, with disease-associated cardiovascular event incidence similar to coronary heart disease (CHD) [49]. The presence of other CVD risk factors in RA have been demonstrated to accentuate vascular event risk [49]. The former premise has been validated by the studies included in this review, where-by inclusion of CVD risk factors in individual studies perpetuated PAD incidence risk [24, 34–36]. All pertinent studies controlled for most noted CVD risk factors through exclusion or adjustment. However, 90% of reviewed studies neglected to control for physical activity levels, further limiting their respective internal validity [24, 30–32, 34–38]. The evidence suggests that patients with RA tend to exhibit more sedentary behaviour when compared with population-based controls [50]. Despite this being likely due to pain, joint deformity and the prevalence of comorbidities, it may independently act to exaggerate PAD incidence within the population, affecting the internal validity and generalizability of appraised studies. This view is validated by Kumeda et al. [29], denoting that a lack of physical activity in the population perpetuates the multi-factorial incidence of arterial wall thickening, propagating atherosclerotic change.
This review has some limitations that warrant consideration. Available Journals were restricted to free-access organizations and those provided by Glasgow Caledonian University (GCU) access. This may have diminished the search strategy’s validity. Included studies consisted of peer-reviewed literature written in English exclusively, which may have acted to omit pertinent non-English literature. The appraisal and levels of evidence processes were conducted by a single researcher. CCAT and ASPS results may have been either attenuated or accentuated due to human error, limiting the validity of the results.
The implementation of exercise in the management of RA has been demonstrated to increase patient self-efficacy and reduce joint morning stiffness [21]. This benefit was best enabled when mild to moderate aerobic exercise was implemented [21]. The noted exercise intensity has been shown to combat disease-related muscle wasting and diminished fitness levels, which may improve HRQOL and act to attenuate morbidity [21]. Considering PAD, exercise therapy acts as a gold-standard first-line approach to treatment [22]. It is paramount in alleviating the risk of symptomatic disease or reducing the impact of symptomatic manifestations [22]. Exercise may be prominent in combating the HRQOL and FC hindrances that are likely present in conjoined RA and symptomatic/asymptomatic PAD manifestations [51]. Individualized exercise regimes have demonstrated improvements in endothelial function amongst patients with RA [52].
Future research would benefit from stratifying for physical activity levels and investigate the impact of symptomatic PAD on the relevant outcomes. Studies appraised did not implement exercise as a risk factor due to logistic difficulty, the subjectivity of self-reported measures and the inadequacy of medical databases used. No cohort or case-control studies produced by the search strategy implemented discussed the impact of conjoined RA and PAD on HRQOL and FC. Undertaking prognostic cohort studies to improve the level of evidence pertaining to the subject is necessary in perpetuating the appropriate guideline revisions.
To conclude, the evidence presented in this review demonstrated an association between RA and PAD. Multi-morbid patient presentations act to accentuate the incidence risk of PAD in RA. Little evidence was found articulating the impact of conjoined disease manifestations on HRQOL and FC. Future studies will benefit from controlling for exercise as a prominent PAD risk factor and establish the impact of symptomatic PAD on HRQOL and FC in the RA population.