Cardiovascular disease in psoriatic arthritis: facts and unmet needs

Editorial on: Risk of major adverse cardiovascular events in patients initiating biologics/apremilast for psoriatic arthritis: a nationwide cohort study (Laura Pina Vegas et al. doi: 10.1093/rheumatology/keab522). Cardiovascular disease (CVD) imposes a considerable burden on morbidity of autoimmune rheumatic diseases. In PsA, although patients display an increased prevalence of traditional cardiovascular (CV) risk factors, subclinical atherosclerosis exists, even without their presence. It seems that systematic inflammation triggers endothelial dysfunction, which in turn induces atherosclerosis and CV sequalae [1]. There is accumulating evidence supporting a beneficial effect of TNF inhibitors (TNFi) on CVD surrogate markers. Di Minno et al. showed that PsA patients on TNFi therapy, compared with those receiving conventional DMARDs, had lower carotid intima-media thickness (cIMT) and fewer of them had carotid plaques. Notably, treatment duration was inversely related to cIMT, implying an accruing impact of treatment on vascular injury (reviewed in [1]). Similarly, Eder et al. showed that treatment with TNFi had a favourable effect in atherosclerosis in males with PsA and reported an improvement in vascular inflammation regardless of the gender and CV risk factors (reviewed in [1]). Interestingly, Ortolan et al. enrolling 32 PsA patients starting anti-TNF therapy noted a mild deterioration of IMT during the first 2 years, becoming stable, however, in a follow-up period of 5 years [2]. The association of apremilast with CVD is still ambiguous. In a prospective study by Ferguson et al., apremilast treatment did not affect vascular function in PsA patients. However, small sample size and relatively short follow-up period should be taken into account in the interpretation of these findings [3]. In the same direction, active inflammation is deemed to drive atherogenic lipoprotein alterations. In general, PsA patients present lower levels of total cholesterol (TC), high-density lipoprotein (HDL) and low-density lipoprotein (LDL), but higher levels of triglycerides. Of note, it was demonstrated that 5-year treatment with etanercept increased TC, LDL and HDL leaving, however, the TC/HDL ratio stable (reviewed in [1]). The effect of DMARDs in CV surrogate markers is reflected in clinical outcomes. Studies regarding this should be interpreted with caution for three reasons: (i) differences in the reported outcomes; (ii) different types of inflammatory arthritis (IA) are occasionally examined as one group; and (iii) different comparator groups. It appears that in IA, risk for CV events is lower for patients using biologic DMARDs (bDMARDs) but not for those who have stopped treatment (reviewed in [1]), while a recent meta-analysis showed that the short-term risk of major adverse cardiovascular events (MACEs) in PsA/psoriasis patients starting bDMARDs was comparable to placebo [4]. In a real-world study [5], Pina Vegas et al. examined the incidence of myocardial infarction and stroke in PsA patients commencing therapy with bDMARDs or apremilast. They used data from the national database, including 9510 bDMARD and 1885 apremilast new users, without CVD history. The overall risk for MACE was low [crude incidence rate (IR) 3.4 per 1000 patient-years]. Risk was significantly elevated with IL-12/23 and IL-17 inhibitors against TNFi [weighted hazard ratio (HRw) 2.0, 95% CI 1.3, 3.0; and HRw 1.9, 95% CI 1.2, 3.0, respectively], but not with apremilast (HRw 1.3, 95% CI 0.8, 2.2). In a sub-analysis in patients without CV risk factors, MACEs occurred more frequently with IL-17 inhibitors (HRw 1.6, 95% CI 1.1, 2.8) than with TNFi. It is debatable whether this is down to a protective role of TNFi or to a harmful effect of IL-17 and IL-12/23 inhibitors. It seems that TNF-α overexpression promotes endothelial dysfunction, vascular inflammation and thus CV risk (reviewed in [1]). In contrast, it seems that IL-17 may acts concurrently in favour of and against plaque stability [6]. Possible beneficial effects of TNFi in CVD outcomes in PsA have been recognized. On the other hand, a study examining data from an insurance database suggested that immune-mediated disease patients with a high cardiovascular risk are more susceptible to severe cardiovascular events (CVE) in the first 6 months under ustekinumab treatment [7]. It remains unclear whether there is indeed a difference in the impact of various DMARDs in CVE in PsA. A recent study observed that the comparative risk for MACEs in PsA was not increased in patients receiving only apremilast compared with other treatments [8]. Additionally, results from a registry, including 60 028 patients with psoriasis or PsA, support that the incidence of MACEs does not differ between IL-12/23 inhibitor and TNFi initiators [9]. Finally, another study examining IA patients having an initial CVE showed that class of bDMARD had no effect in the occurrence of a subsequent CVE [10]. The study by Pina Vegas et al. has certain strengths. Data were obtained from a large public health insurance database, linked with a hospital discharge system. Therefore, selection bias that could be related with registry-based studies is likely avoided. Furthermore, recognizing the important role of extra-articular manifestations and of comorbidities in the disease course and outcomes of PsA, the authors have incorporated them into their analysis. Importantly, French deprivation index was also taken into account. This is related to the increasingly recognized concept of ‘syndemics’, which encompasses socioeconomic determinants in the treatment of these patients [11]. Notably, these features are related to comorbidities, frequently encountered in PsA. This study has also some limitations. First, given the nature of the study (observational-database), channelling bias cannot be excluded. Therefore, findings should be interpreted with caution awaiting confirmation by randomized controlled trials. Second, no data were available for disease activity/features. Thus, it cannot be excluded that patients with more severe skin involvement, for example, were preferably treated with anti-IL-17 or anti-IL-12/23 regimes. Besides, severity of skin involvement (at least for psoriasis) has been associated with CVD [1]. Third, as discussed by the authors, drugs administered are recorded based on their reimbursement. However, this does not ensure that the medication was indeed used by the patients. Finally, newer therapeutic regimes (i.e. tofacitinib) were not examined as it was only recently marketed in France. However, all the other bDMARDs (except from ixekizumab) and apremilast were available for at least 5 years, and therefore the exposure time was adequate. In conclusion, in PsA there is a gap in the research on the effect of bDMARDs in CVD. Given that PsA is a clinical entity with cardiometabolic burden, studies that would examine possible differential effect of DMARDs in the CVD-related parameters and outcomes are eagerly awaited. Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article. Disclosure statement: The authors have declared no conflicts of interest.