In addition to confirming that features of inflammatory dyslipidemia are present in patients with axSpA, in the present study we assessed for the first time PCSK9 in these patients. Although PCSK9 is downregulated in axSpA, a link between disease activity and PCSK9 levels was found.
Previous reports revealed a disrupted lipid profile in axSpA. However, most studies focused on the prevalence of hyperlipidemia in patients with axSpA and only a few compared a full lipid panel between patients and controls assessed in real-life clinical practice. In this regard, studies derived from the ASAS-COMOSPA cohort (28–30) defined the presence of dyslipidemia based on the presence of hypercholesterolemia or cholesterol-lowering therapy or on an LDL cholesterol level above target according to country recommendations. However, as neither a complete lipid profile was not assessed nor was a comparison with controls performed, no association analyses were carried out in a multivariate way. Interestingly, in a recent report on the CARMA project (a 10-year prospective cohort study designed to determine the CV mortality risk in patients with chronic inflammatory rheumatic diseases) (31), patients with axSpA were more likely to have hyperlipoproteinemia (a) than controls after adjusting for age and sex. This association was not found in our cohort.
Lipid profile differences between patients and controls found in our report are in accordance with the ‘lipid paradox’ (32) described in other inflammatory diseases such as rheumatoid arthritis (17, 33, 34) or systemic lupus erythematosus (35). This means that individuals with untreated inflammatory diseases or those with these conditions who have high disease activity exhibit lower levels of total cholesterol and LDL cholesterol, and it is believed that this may be due to the lipid-lowering effects of systemic inflammation. The large sample size assessed in the present study allowed us to perform a multivariate analysis. For this reason, we believe that our findings regarding lipid profile modifications in axSpA are robust enough to be considered conclusive.
The downregulation of PCSK9 in axSpA patients found in our study is in agreement with a previous report of our group that showed similar findings in in patients with rheumatoid arthritis (17). PCSK9 serum concentrations were lower in axSpA and rheumatoid arthritis patients than in controls. However, the exact mechanisms of PCSK9 downregulation are not yet understood. One explanation could be that PSCK9 levels are downregulated as a compensatory mechanism in the context of heightened cardiovascular disease risk to reduce the accelerated atherosclerosis of these diseases. On the other hand, although higher levels of plasma PCSK9 have been independently associated with major systemic inflammatory markers in patients with acute coronary syndrome and coronary artery disease (36), it is possible that the presence of a persistently elevated chronic proinflammatory state in patients with chronic inflammatory disease would promote PCSK9 downregulation. This would be in agreement with the increased metabolic clearance of total cholesterol and LDL cholesterol observed in these conditions.
Although the effect of glucocorticoids over PCSK9 had not previously been explored, in our study we observed that PCSK9 was related to prednisone intake, being higher in patients treated with glucocorticoids. Therefore, we cannot exclude the possibility that some deleterious effects of glucocorticoids on cardiovascular disease and dyslipidemia might be mediated by this molecule. In contrast, anti-TNF therapies showed a negative association with PCSK9. This result may be of potential interest since the effect of anti-TNF therapy on PCSK9 has not previously been studied. This finding was not observed in a series of 27 patients with rheumatoid arthritis treated with tocilizumab during one year (37). However, in this series, variations in LDL cholesterol over the year of study correlated directly with changes in PCSK9 serum concentration.
In our series, statin use was associated with higher PCSK9 serum levels in patients and controls. This upregulation effect has been previously described in a recent meta-analysis in which statin therapy was shown to increase plasma PCSK9 concentrations, an effect that has been correlated to the magnitude of reduction that statins exert over plasma LDL cholesterol (38).
In our report, PCSK9 was associated with carotid plaques, but not with the cIMT. However, the relation between carotid plaques and PCSK9 was lost after multivariable analysis. It is well established that carotid plaque and cIMT are biologically and genetically distinct entities, representing different phenotypes of atherosclerosis (39). cIMT is thought to represent a mainly hypertensive medial hypertrophy, while carotid plaque is more strongly associated with traditional risk factors and coronary artery disease than is cIMT. Although extensive evidence suggests that there is a significant correlation between PCSK9 levels and future CV risk, scarce data exist about the relationship between PCSK9 levels and vascular biomarkers such as carotid plaque. We believe that the fact that PCSK9 was associated with carotid plaque, though univariately, points to the validity of this molecule as a potential future target in the treatment of atherosclerosis in axSpA patients.
PCSK9 was downregulated in axSpA patients. Nevertheless, it was positively related to some disease-specific factors such as disease duration and ASDAS-CRP and BASFI scores. As previously discussed, we believe that although PCSK9 may be reduced due to the presence of a chronic inflammatory state, the absolute levels of this molecule indicate an increased risk of CV disease in the subgroup of patients with more severe disease. With respect to this, ASDAS-CRP was positively associated with total cholesterol, LDL cholesterol, LDL: HDL ratio, non-HDL cholesterol, lipoprotein (a) and atherogenic index in the univariate assessment. Interestingly, the relationships of ASDAS-CRP with total cholesterol, apolipoprotein A1 and PCSK9 remained significant in the multivariate regression analysis. Therefore, these three molecules were related to ASDAS-CRP regardless of other changes that the disease activity might exert over the lipid profile. Additional analysis showed that the effect of disease activity on PCSK9 was not mediated by the influence that the disease activity could exert over cholesterol or apolipoprotein A1. Therefore, while disease activity seems to affect PCSK9, changes in this molecule are not the consequence of other modifications in the lipid panel produced by the disease.
We acknowledge the limitation that controls were not sex-matched. This was because we were preferentially interested in matching for statins intake due to its potential effect over lipid patterns and the effect on PCSK9 serum levels. On the other hand, it is important to highlight that all the analyses in our study were performed by adjusting for important confounders such as age, sex and lipid profile. Nevertheless, identical results have been found irrespective of matching or not matching when multivariable regression analysis was applied in epidemiological cross-sectional or case-control studies (40). We believe, therefore, that the multivariable analysis performed in the present study was capable of handling confounding situations in our analysis regarding sex non-matched controls.