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Title: Macro- and microvascular endothelial dysfunction in young patients with rheumatoid arthritis and axial spondyloarthropathy without classical cardiovascular risk factors : patient phenotype and factors influencing the development of endothelial dysfunction
Abstract:
Rheumatoid arthritis (RA) is an autoimmune systemic inflammatory disease that manifests mainly in the synovial joints. It is the most common autoimmune arthritis in humans that leads to disability and premature death. Patients with RA live on average 7 years less than the general population and the single largest cause of mortality in this group are cardiovascular events. In RA patients, cardiovascular risk is 50% higher than in the general population, which makes it an independent risk factor of relevance comparable to diabetes mellitus. Endothelial dysfunction plays a key role in the pathogenesis of atherosclerosis, which can be present even during the first years of the disease. Classic calculators used to assess cardiovascular risk do not provide reliable results in patients with RA. Axial spondyloarthritis (axSpA) is an umbrella term for the group of inflammatory spondyloarthropathies that affect the sacroiliac and spinal joints with ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA) as its two main subtypes. AxSpA patients also have higher rates of cardiovascular comorbidity compared to the general population and an increased risk of cardiovascular events explained by the accelerated atherosclerosis and endothelial dysfunction found in this subset of patients. However, there are conflicting data on the prevalence and risk factors for endot ; helial dysfunction in RA and axSpA. It is still unknown why there are young patients with short-duration rheumatoid arthritis who have microvascular endothelial dysfunction and older patients with long-term disease who do not. Classical cardiovascular risk factors (i.e. older age, smoking, hypertension, dyslipidaemia, diabetes) do not completely explain the presence of endothelial dysfunction in patients with RA and axSpA, but there is research that did not exclude patients with those factors. As a consequence, certain studies could identify endothelial dysfunction caused by traditional cardiovascular risk factors and not only RA or axSpA itself. The results of the studies suggest that neither the duration nor activity of the disease is sufficient, however, in specific cases it might be necessary to induce endothelial dysfunction. In particular, it remains unexplained to what extent endothelial dysfunction is due to a specific inflammatory burden linked to chronic inflammatory arthropathies or to comorbidities known to represent cardiovascular risk. These uncertainties are related to the design of previous studies detecting endothelial dysfunction in patients with inflammatory rheumatic diseases, which often involved heterogeneous groups, long-term pathophysiological progression, and the use of drugs that can affect the endothelium, such as glucocorticoids and non-steroid anti- ; inflammatory drugs. Research objectives The aim of this study, was to verify whether young patients with RA and axSpA strictly controlled for not having classical cardiovascular risk factors with relatively short duration of disease, effective treatment and mostly moderate disease activity, would show endothelial dysfunction and to answer the question what are the factors contributing to their potential occurrence, with a focus on clinical, laboratory and therapeutic data. Methods This was a case-control study conducted in 129 young (18-50 years old) patients with inflammatory arthropathies (64 with RA, 65 with axSpA) without classical cardiovascular risk factors (hypertension, diabetes, hyperlipidemia, smoking, obesity, family history of cardiovascular diseases) treated according to the international recommendations and 60 age and sex-matched healthy controls adjusted for treatment confounders (nonsteroidal anti-inflammatory drugs and glucocorticoids). Patients with RA and axSpA were treated according to international recommendations and routinely monitored in the outpatient clinic. We obtained a complete set of clinical data and laboratory tests. Macrovascular endothelial function was evaluated in brachial artery by Flow Mediated Dilation (FMD), while microvascular endothelial function was assessed with Peripheral Arterial Tonometry (PAT, Endo-PAT®, expressed as Reactive ; Hyperemia Index [RHI]) and Flow-Mediated Skin Fluorescence (FMSF). Multiple parameters were used to comprehensively quantify functional endothelial responses in FMD, PAT, and FMSF. Results The mean (SD) age of the patients was 35 (9) years, the mean duration of the disease was 6.97 (6.37) years and average disease activity was moderate or low: DAS28-ESR 3.53 (1.5), DAS28-CRP 3.3 (3.2), BASDAI 3.5 (2.1), ASDAS 1.98 (0.96). FMD [%], RHI, or HR index were neither altered in patients with RA and axSpA compared to the healthy control group. Other parameters characterizing FMD, PAT or FMSF (e.g., Time to FMD Peak, Shear Stress, Shear Rate, Hypoxia Sensitivity, Power Spectral Density Ratio) were also not changed. However, in 54 patients with inflammatory arthropathies (RA and axSpA) who had endothelial dysfunction of conduit arteries (FMD < 7%), higher total cholesterol (TC) levels were detected, 4.86 (0.79) mmol/l, and higher low-density lipoprotein (LDL) concentration, 2.85 (0.79) mmol/L. On the contrary, the subgroup with higher C-reactive protein (CRP >2 mg/L) had higher FMD [%] than the subgroup with a cut-off value of CRP lower than 2 mg/L (FMD 9.52 ((4.25)) vs 7.64 ((4.63)), p=0.03). In contrast to FMD, neither PAT (RHI) nor FMSF (HR index) discriminated patients with higher and lower cholesterol or CRP. Interestingly, the HR index was lower in a subset of patients with axSpA ; with lower disease activity (BASDAI 1.74((0.4)) and ASDAS 1.1 ((0.25)), p=0.001 respectively). However, no differences were detected in the comparison of subgroups of axSpA (AS and nr-axSpA). Conclusions This study found that young patients with RA and axSpA without classical cardiovascular risk factors with moderate disease activity have largely preserved macro- and microvascular endothelial function compared to healthy controls. Disease activity, duration of the disease, mode of therapy, presence of RA-specific antibodies or subtype of axSpA (AS or nr-axSpA) where not related to endothelial function. However, in a subset of patients with higher TC and LDL, but still within the range that would not require pharmacological intervention, endothelial dysfunction was detected in the conduit artery, suggesting a permissive role of subclinical lipid disturbances in the development of endothelial dysfunction. Furthermore, in the subset of patients with elevated CRP and ESR, higher parameters of FMD [%] and shear rate were detected, suggesting an early endothelial compensatory response to systemic inflammation in young patients with RA and axSpA. However, neither effect was related to disease activity. In a subset of patients with axSpA, microvascular endothelial dysfunction was also detected in FMFS and again could not be related to the increased disease activity expressed as BA ; SDAI or ASDAS. Taken together, these results show that combined endothelial assessment methods that include shear rate correction provide detailed information on heterogeneous susceptibility to the development of endothelial dysfunction in young patients with inflammatory rheumatic diseases, indicating the need for an individualized endothelial-guided risk assessment. Importantly, the presence of macrovascular endothelial dysfunction in the context of increased TC and LDL in young otherwise healthy patients with RA and axSpA calls for a reevaluation of the lipid profile norms in patients with inflammatory arthropathies that show an increased cardiovascular risk, similar to what was done for diabetic patients.
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Rada Dyscypliny Nauki medyczne
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Jul 16, 2024
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Jul 16, 2024
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http://dl.cm-uj.krakow.pl:8080/publication/5143
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| Edition name | Date |
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| UJCM78bbc23ee34747ad8232584150f00c65 | Jul 16, 2024 |
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