Psoriasis and Cardiovascular Disease: Novel Mechanisms and Evolving Therapeutics

Abstract

Purpose of Review:

Psoriasis is a chronic inflammatory skin condition that is associated with increased cardiovascular risk compared to those without psoriasis. This review will cover emerging mechanisms of cardiovascular risk, key pathways targeted with biologic therapies, and the current evidence on therapies to modulate this risk in patients with psoriasis.

Recent Findings;

Recent scientific work has highlighted mechanisms that contribute to this enhanced risk, including the role of vascular endothelial dysfunction, platelet activation, dyslipidemia, and increased cardiometabolic co-morbidities. Newer biologic and targeted synthetic therapies have transformed psoriasis treatment with high rates of clinical remission and durable skin disease control now possible. Epidemiological evidence suggests that many of these therapies may lower cardiovascular risk in psoriasis, although prospective interventional data is lacking (or mixed). Recently, caution has also been raised that some treatments may negatively affect cardiovascular risk

Summary:

Overall, the current data suggests a positive or neutral ability to reduce cardiovascular risk for TNF, IL-17A and IL-12/23p40 inhibitors, but current evidence remains conflicting for anti-IL-23/p19 and JAK inhibitors. More studies that include prospective cohorts, larger number of patients, treatment duration, and validated surrogate outcomes are needed to better evaluate the role of biologic therapies on cardiovascular risk in psoriasis.

Introduction:

Systemic, auto-immune inflammatory diseases, including psoriatic disease, rheumatoid arthritis, and systemic lupus erythematosus are associated with increased cardiovascular (CV) risk and CV disease is the leading cause of mortality and morbidity among these conditions (1–4). Plaque psoriasis (psoriasis vulgaris) is one such condition commonly presenting as thick, erythematous, and scaly plaques (5). Psoriasis impacts both men and women equally, affecting almost 2–3 % of all Americans (5). Approximately 30% of those with psoriasis have co-existing joint involvement, psoriatic arthritis, itself demonstrating a highly inflammatory systemic state. (5–7). The initiation of psoriatic skin disease includes a combination of genetic predisposition and environmental stimuli driving dysregulation of dendritic cells, T-cells, keratinocytes, and neutrophils (5, 8). Cytokines produced during this process include type I and II interferons, tumor necrosis factor (TNF)α, interleukin (IL)-6, and IL-1β (5, 9). Subsequent activation of myeloid dendritic cells produces IL-12/IL-23 leading to further T-cell differentiation with the production of IL-17 isoforms (5, 10). Inflammatory mediators and cross-talk between the innate and adaptive immune systems drive further keratinocyte activation and proliferation. A pro-inflammatory feed-back loop is generated (11–13) with breaking of the positive feedback loop a mainstay of therapies in psoriasis.

It has not gone unnoticed that key cytokine abnormalities pronounced in psoriasis share a link with atherosclerosis development (14). More than 50 years ago, the dermatology community noted higher than expected myocardial fibrosis and coronary atherosclerosis at autopsy in psoriasis patients (15) along with thinned and damaged vascular endothelium in both lesional and non-lesional skin (16). Epidemiologic evidence in the 1970s found an association between psoriasis and vascular disease, however these studies were small and in primarily hospitalized cohorts (17, 18). In 2006, a prospective registry from the United Kingdom described a 3-fold higher relative risk of myocardial infarction (MI) in young patients with severe psoriasis and an overall 50% elevated risk of MI in psoriasis when compared to matched controls (19). More recently, in those who experienced a first MI at 50 years of age or younger, a co-existing systemic inflammatory disease (the largest percentage of which was psoriasis) resulted in a 2.5-fold increase risk of mortality when compared to individuals without an inflammatory condition (20). In summary, while not all studies show a connection (21, 22), meta-analyses support an approximate 50% increased risk of cardiovascular (CV) disease in patients with psoriasis, while severe psoriasis confers a 40% increased risk of CV mortality (23).

Vascular Dysfunction and Atherosclerosis Burden in Psoriasis

Atherosclerosis development involves a complex interplay between the endothelium, circulating lipids, platelets and the immune system, each of which are dysregulated in psoriasis (24). The endothelium provides a permeability barrier for the vasculature, maintains a non-thrombogenic surface, regulates vascular tone and tissue flow, and inhibits vascular smooth muscle cell growth. In psoriasis, the endothelium exhibits a pro-inflammatory phenotype, including upregulation of chemotactic and vascular adhesion molecules such as VCAM1, CXCL10, and IL-1β (25, 26). While many pro-atherogenic cytokines are upregulated in psoriasis, IL-6 (27) and a synergistic component of IFNƔ, TNFα and the IL-17 family of cytokines play a dominant role in endothelial dysfunction and atherosclerosis development (25, 28). Impaired vascular nitric oxide production is also present leading to coronary microvascular dysfunction (via doppler assessed reduced left anterior descending [LAD] coronary artery flow reserve) associated with severe psoriasis (odds ratio [OR] 3.1, p=0.03), psoriatic arthritis (OR 2.9, p=0.03), and prolonged duration of psoriasis exposure > 6 years (OR 1.9, p=0.03) (29).

Immune mediated mechanisms to explain the link between psoriasis and atherosclerosis comprise an abnormal myeloid cell response and direct cytokine induced vascular injury. Macrophages in a murine model of psoriasis prone to atherosclerosis exhibit increased lipid uptake and foam cell formation (5). The neutrophil subtype, low-density granulocytes, associate with non-calcified coronary plaque and induces in vitro endothelial damage (30). The downstream consequences of immune system activation include vascular arterial inflammation with a correlation between psoriasis disease severity and vascular inflammation (β=0.41, p<0.01) (30, 31). In the epicardial coronary arteries, prior studies reported higher coronary artery calcium deposits (coronary artery calcium > 0) in psoriasis compared to non-psoriasis (OR 2.3) patients; however, recent research suggests a predominantly higher non-calcified burden (32, 33). Psoriasis patients have a 15% higher non-calcified plaque burden than matched controls and a similar burden of high-risk coronary plaque compared to a high CV risk non-psoriasis patient (34). Finally, the degree of non-calcified plaque in psoriasis correlates with the degree of disease severity after adjustment for traditional CV risk factors and high sensitivity C-reactive protein (hsCRP).

Use of Imaging in CV disease risk stratification

Expanding on the potential contribution of both epicardial and microvascular processes to CV risk and atherosclerosis in psoriasis, recent work has utilized positron emission tomography (PET) myocardial perfusion imaging to assess coronary flow reserve (CFR) which is an integrative measure of the fluid dynamic effects of epicardial coronary artery disease, diffuse atherosclerosis, and vessel remodeling, and microvascular dysfunction on myocardial tissue perfusion across the entire coronary circulation. Among patients referred for cardiac PET perfusion imaging for symptom assessment (chest pain and/or dyspnea), those with psoriasis had a higher prevalence of coronary microvasculature dysfunction (defined as CFR <2) (61.7% vs 38.7%, p=0.004) than matched controls (35). Prognostically, a single-center retrospective study evaluated the value of impaired CFR (via cardiac PET) in patients with systemic inflammatory diseases [n=198] including psoriasis (32%), rheumatoid arthritis (47%) and systemic lupus erythematosus (21%). Patients in the lowest tertile of CFR (CFR<1.65) had higher all-cause mortality compared to those in the highest tertile (HR 2.4 95% CI 1.1–5.4 p=0.04) and lower cardiovascular event free survival (HR 3.6; 95% CI 1.7–7.6 p=0.001) (36). These results support the potential utility of CFR as a marker of CV risk in patients with psoriasis and as a potential non-invasive intermediate endpoint for assessing treatment efficacy in clinical trials.

Dyslipidemia in Psoriasis:

Dyslipidemia (of any variety) is up to 5-fold higher in those psoriasis with severe skin manifestations (37, 38). Psoriasis patients have lower HDL and reduced HDL efflux capacity (39), increased LDL particle concentration, decreased LDL size, and elevation of circulating PCSK9 when compared to non-psoriasis (40, 41). Liquid chromatography-tandem mass spectrometry of psoriatic lesional skin reveals an interplay between pro-inflammatory and resolving fatty acids including elevations in oxidized and non-modified arachidonic acid derived prostanoids, linoleic acid pathways, and omega-3 and 6 fatty acids (42, 43). A suggested mechanism in psoriasis includes neutrophil derived myeloperoxidase driving lipoprotein oxidation and promoting damage both locally (at the skin level) and systemically (44). Supporting this concept, psoriasis patients have up to a 30% higher oxidized lipoprotein(a) and a 15% higher oxidized HDL when compared to non-psoriasis. The degree of oxidized LDL and oxidized HDL (rather than the non-modified forms) each correlate to the degree of non-calcified plaque (45). Finally, circulating soluble lectin-like oxidized low density lipoprotein receptor (LOX-1, a scavenger receptor for oxidized modified lipoproteins) is 1.5-fold higher in psoriasis than non-psoriasis and associated with non-calcified plaque (46). These data highlight the powerful role circulating lipids and lipid oxidization may play to potentiate CV risk in psoriasis, and how traditional cholesterol metrics, may not adequately capture that risk.

Activated Platelet Phenotype in Psoriasis

Recent investigations have begun to shed light on the connection between psoriasis and platelet activation (47). Both human psoriasis and murine models corroborate that platelets are preferentially found in lesional psoriatic skin (48, 49). Circulating markers of platelet activation including platelet derived microparticles and soluble p-selectin are elevated in those with psoriasis (50). Platelet-lymphocyte aggregates and platelet-neutrophil aggregates are approximately 30% and 40% higher in psoriasis when compared to non-psoriatic patients, respectively (48). In psoriasis, platelets augment IL-17 secretion from CD4⁺ lymphocytes, while the neutrophil subtype, low-density granulocytes, co-localize with platelets, and induce in vitro endothelial damage and apoptosis through neutrophil extracellular traps (termed NETosis) (31, 51). Independently, platelets isolated from psoriasis patients (when compared to controls) induce endothelial cell activation with up to a 20-fold increase in endothelial derived cytokines such as IL-1β and IL-8. Mechanistic studies dating back to the early 1990s, identified platelet cyclooxygenase activity as elevated in those with psoriasis with platelet RNA sequencing confirming higher platelet gene expression of cyclooxygenase-1 (48, 52) and suggesting that cyclooxygenase-1 inhibition (with aspirin) may improve vascular inflammation. Finally, in a pro-thrombotic murine psoriatic model, blockade of key psoriatic cytokines IL-23 or IL-17A, reduced circulating neutrophils, IL-6, and thrombotic events (27, 53). These studies suggest the contribution of platelets to psoriatic lesional skin and endothelial dysfunction and highlight the utility of targeting platelet activation to reduce atherothrombosis in psoriasis (52).

Cardiometabolic Comorbidities in Psoriasis:

The odds of obesity in psoriasis range from 1.46 for mild and 2.23 for severe psoriasis (54). Adipose tissue deposits comprise elevated expression of the adipokines leptin and resistin while visceral adiposity (β=0.55, p<0.001), but not subcutaneous adiposity, associated with vascular aortic inflammation in obese psoriasis (55–57) thus suggesting a further driver of enhanced CV risk. Cells of the innate and adaptive immune system co-localize with adipocytes producing cytokines including IL6, TNF, and MCP-1 to potentiate the pro-atherosclerotic inflammatory milieu of psoriasis (12, 14). Dietary free fatty acids in psoriasis may also play a role as they amplify the pro-inflammatory phenotype and skin inflammation in psoriasis including enhanced inflammasome production of IL-1β and IL-18 (58).

In addition to a higher rate of adiposity, co-existing diabetes and metabolic syndrome are also highly prevalent in psoriasis. In meta-analysis, the pooled odds ratio assessing the prevalence of diabetes in psoriasis is 1.53 for mild and 1.97 for severe psoriasis (59). Importantly, psoriasis patients with diabetes have a higher hazard ratio for both micro and macrovascular events when compared to diabetics without psoriasis (60). Small studies suggest insulin resistance linked to both impaired endothelial function, vascular inflammation and coronary atherosclerosis burden in psoriasis (61–63). The diagnosis of metabolic syndrome in psoriasis, is independently linked to non-calcified coronary plaque burden compared to psoriasis patients without metabolic syndrome (β=0.21, p<0.001) (64). Collectively, metabolically active visceral adipocytes potentiate the insulin-resistant phenotype and represent a key link between psoriasis, obesity, metabolic syndrome and CV disease (57, 65, 66).

Hypertension

While controversy remains as to the strength of the association (37), meta-analysis suggests a 30% and 50% higher risk of hypertension in mild and severe psoriasis, respectively (67). A dose-response relationship exists between uncontrolled hypertension and psoriasis severity further supporting the relationship between psoriasis and hypertension (68). Upregulation of the renin-angiotensin system and higher expression of circulating endothelin 1 are present in psoriasis (68). Recent work focuses on the contribution of TNFα, interferon signaling, and critically IL-17A to this process (69). For example, murine overproduction of IL-17A promotes hypertension and left ventricular hypertrophy (26) while treatment with IL-17A inhibitors alleviates this phenotype thus highlighting IL-17A as a contributing factor to hypertension in psoriasis (70).

Psoriasis Treatments and Cardiovascular Risk

Biologic treatments that target specific pathways involved in the pathogenesis of psoriasis are now highly efficacious and psoriasis skin remission approaching 100% is now possible (71, 72). Conversely, psoriatic arthritis, which affects up to 30% of patients with psoriasis, is complicated by a heterogeneity in the presentation of joint disease and the overall treatment efficacy and ability to induce remission are not as robust as those seen with skin manifestations alone. For example, during biologic therapy, a clinical response of ACR70 (70% improvement in joint disease) in no more than a third of patients is usually seen (73, 74). The main classes of therapy for moderate-severe disease psoriatic disease includes TNF inhibitors, IL-12/IL-23(p40), IL-23(p19), and IL-17 inhibitors. These same classes of therapy are also approved for psoriatic arthritis, as well as JAK inhibitors. In addition, other disease modifying medications, in particular methotrexate and the oral small molecule, apremilast, are used frequently in psoriatic disease prior to initiation of the targeted biologic therapy. While nuances remain in the decision of overall therapy, these therapies are well tolerated and if used appropriately, exhibit a minimal risk of serious infections (75). However, the data on CV risk, including both benefit and possible harm, remains an area of active investigation.

TNFα Inhibitors:

TNFα inhibitors commonly used in psoriatic disease include infliximab, etanercept, certolizumab and adalimumab. Similar to rheumatoid arthritis, epidemiological evidence suggests that treatment with TNFα inhibitors is associated with a reduction in the incidence of cardiovascular disease. In a systemic meta-analysis, TNFα inhibitors were associated with a significant lower risk of cardiovascular events compared to topical treatment/phototherapy (relative risk,, 0.58; 95 % CI, 0.43 to 0.77; P < 0.001) and methotrexate (relative risk, 0.67; 95 % CI, 0.52 to 0.88; P = 0.003) (76, 77). Prior studies have demonstrated a decrease risk of MI in psoriasis patients treated with TNFα inhibitors compared to those who received topical therapy (78) and methotrexate (79). The duration of therapy has furthermore been shown to be associated with a greater risk reduction, over a 2-year median follow-up, TNFα inhibitor therapy was associated with a 11% CV event risk reduction for every 6 months of cumulative exposure (78). One caveat with these epidemiologic studies is the inherent flaw in the study design with confounding by indication, such that the patients that require TNFα inhibition have more active disease at baseline than patients prescribed topical treatment and thus may derive a greater benefit from anti-inflammatory medications.

As such, prospective, including randomized placebo-controlled studies of TNFα inhibition to improve biomarkers of CV risk display conflicting results. TNFα inhibition is shown to improve microvascular function assessed by doppler echocardiography of the LAD (80), carotid artery stiffness based on pulse wave velocity, and improve endothelial indices of brachial artery reactivity (81). In psoriatic arthritis patients, TNFα inhibition compared to other disease modifying agents reduced the development of carotid atherosclerotic plaques which was identified in 15.8% of psoriasis patients treated with anti-TNFα versus 40.4% of patients receiving other (non-biologic) disease modifying agents after 4 years of treatment. Conversely, a large NIH-funded randomized controlled trial, Vascular Inflammation in Psoriasis trial (VIP), assessed the impact of anti-TNFα therapy on vascular inflammation by comparing adalimumab to UVB phototherapy and placebo and measuring the impact of aortic inflammation via 18F-FDG-PET/CT. At the study end-point of 12 weeks, there was no impact of TNFα inhibition on vascular inflammation measured by aortic FDG uptake (82). In addition to potential CV disease benefit, it is important to consider the effects of anti-TNFα on cardiovascular risk factors. TNFα inhibitors may also improve insulin sensitivity in non-diabetic patients (81) with psoriasis and suppress leptin levels. Conversely, some studies have suggested an increase in weight in psoriasis patient which could be due to neutralization of the cachectic properties of TNFα (83–85). Furthermore, anti-TNFα agents in psoriasis are shown to be less effective in obese patients compared to the non-obese (86, 87). Lastly, given the association of adverse outcomes in patients with heart failure and anti-TNFα therapy in the general population, TNFα therapy is not currently recommended in psoriatic patients whom have a known history of heart failure (37).

IL12/23p40 Inhibition

IL-12/23 inhibition is achieved through targeting p40, a subunit shared by IL-12 and IL-23. IL-12 typically induces Th1 responses whereas IL-23 is required for the Th17 response. IL-23 is required for the maintenance but not the commitment to the Th17 lineage (88). Levels of IL-12 and IL-23 are elevated in psoriasis patients and genetic studies demonstrate that polymorphisms in IL-23 and IL-12 are associated with an increased risk of psoriatic disease in addition to CV disease. Thus, targeting the IL-12/23 pathway could not only benefit and control skin disease but improve CV risk. A prospective study examined the role of ustekinumab (IL-12/23 inhibitor) in comparison with TNFα inhibition or cyclosporine therapy in 150 subjects with moderate psoriasis and measured their effects on left ventricular remodeling, the coronary microcirculation (CFR by LAD doppler echocardiography), arterial stiffness, and biomarkers of oxidative stress and inflammation. Despite successful resolution of psoriatic skin manifestations in all agents, IL-12/23 inhibition displayed a greater improvement in left ventricular strain, arterial stiffness and Doppler assessed LAD CFR (89). Furthermore, in the VIP-U (ustekinumab) assessed vascular inflammation by FDG-PET in a total of 43 patients were randomized to ustekinumab versus. At week 12, there was a modest reduction in the aortic vascular inflammation (−6.58% [95% CI = −13.64% to 0.47%]) and a decrease in inflammatory biomarkers. However, at week 52, there was no change in aortic vascular inflammation from baseline while inflammatory markers remained reduced (90).

In addition to potential benefit, safety concerns have also been raised after phase III studies revealed a possible higher rate of major adverse cardiovascular events (MACE) compared to placebo. Briakinumab (an IL-12/23 inhibitor) never came to market due to safety concerns after one of the four clinical trials reported an increase in MACE events (91, 92). For ustekinumab, among the phase II and III placebo-controlled studies, there was 1582 patients enrolled in the ustekinumab-arm and 732 placebo treated patients. A total of 5 MACE events occurred which were all in the ustekinumab-arm and there was no clustering with standardized incidence ratios at a rate lower than that estimated for the general population. Furthermore, the 5 MACE events occurred in patients with at least three established CV risk factors. Longer term data up to 4 years have confirmed that events remain low although the absence of a control group precludes definitive assessment (93, 94). Encompassing these studies, meta-analysis has been performed that incorporates nine independent double-blind, randomized, clinical trials to further assess an association of MACE with psoriatic treatment which did not reveal any significant observed differences (95, 96).

IL-23p19 inhibition:

IL-23 is a member of the IL-12 family and consists of 2 subunits: IL-12p40 and IL-23p19. Newer biologic therapy (which are now becoming the norm for psoriasis treatment) are specific for IL-23 target p19 as opposed to IL12/23 inhibition and can achieve psoriasis disease improvement up to-100% (97, 98). Suggesting a possible CV connection, in a study that assessed atherosclerotic plaque from mice and humans, immunostaining demonstrated IL-23 colocalization to plaque macrophages (99). However, basic scientific studies involving mouse models have yielded conflicted results on IL-23. For instance, in LDL receptor deficient⁻ mice, IL-23 deficiency did not demonstrate any differences on atherosclerotic development (100). Yet another study has proposed that IL-23 is protective against atherosclerosis by maintaining intestinal barrier and regulating gut dysbiosis (101).

Three monoclonal antibodies that selectively inhibit the IL-23p19 subunit are approved for the treatment of moderate to severe psoriasis which include guselkumab, tildrakizumab, and risankizumab. Much of the CV data available thus far is for ustekinumab and to our knowledge no specific studies have specifically assesed IL23 inhibition compared to other biologic therapies on CV risk reduction and MACE. In a phase 2 trial that compared risankizumab to ustekinumab, better skin clearance outcomes were observed in terms of selective blockade of IL-23 with risankizumab, but the trial was not able to assess CV risks given the sample size and duration (102).

IL-17 Inhibitors

Several anti-IL-17 inhibitors have been developed and are approved for moderate-severe psoriasis. These include anti-IL17A monoclonal antibodies, secukinumab, ixekizumab, and anti-IL17 receptor monoclonal antibody, brodalimab. In head-to-head trials with other biologics, such as ustekinumab and etanercept, IL-17 inhibitors show superiority for improvement in psoriatic skin disease. In fact these trials have shown clearance rates up to 100% clinical improvement in skin disease (71).

In basic scientific studies of CV disease, using atherogenic mouse models, IL-17A is pro-atherogenic and functional blockade of IL-17A reduced plaque vulnerability and inflammatory cellular infiltration and cytokine expression(26, 103, 104). Conversely, IL-17 has also been proposed in other models to have anti-atherogenic roles(105–107). Overall, these basic scientific studies suggest that IL-17 is context-dependent and can vary according to the cytokine profile and microenvironment where IL-17 operates (108). Despite these contradictory results, the current clinical data at least suggests no harm. This includes a sub-study from the VIP trial, VIP-secukinumab, in which secukinumab exhibited a neutral impact on aortic vascular inflammation assessed by FDG-PET and cardiometabolic disease biomarkers after 52 weeks of treatment (109). These findings highlight the need for further work to clarify the role of the Th17 pathway in human mechanistic clinical trials. Given the key role of Th17 pathway in psoriatic pathogenesis, the multiple biologics that target the Th17 pathway and result in a reduction in inflammation, and the Th17 contribution to atherosclerosis, we believe that future studies should further investigate whether the Th17 pathway/IL-17A is a mechanistic link between psoriasis and CV disease.

Overall, the current evidence suggests that use of TNFa, IL12/23p40, IL23p19, and IL-17 inhibitors to treat underlying psoriasis/psoriatic arthritis likely leans toward a CV benefit; however, work still remains to rigorously address this hypothesis. These mixed findings are likely the result of the different measured surrogate endpoints, small sample size, study interval, and heterogeneity of the patient inclusion criteria. Larger trials that incorporate the use of non-invasive cardiovascular modalities that are linked clearly to cardiovascular outcomes, including cardiac PET and coronary computed tomography angiography, should be performed in the future to assess the relationship with specific inhibition of inflammatory pathways with each class of biologics and the overall effect on coronary vascular health.

JAK Inhibitors

Janus kinase (JAK) is a family of non-receptor tyrosine kinases and includes JAK1, JAK2, JAK3 and TYK2 (tyrosine kinase 2) which transmits signals through the signal transducer and activator of transcription (STAT). There are three JAK inhibitors approved for use in autoimmune diseases: tofacitinib, baricitinib, and upadacitinib. JAK-STAT kinase system is activated in psoriatic disease and upstream of cytokines implicated in psoriatic inflammation including IL-17 and IL-23 (110). While only tofacitinib is approved in psoriatic arthritis, ongoing studies are investigating the efficacy of JAK inhibition in psoriasis (111). In general, the cardiovascular risk associated with these drugs are unknown. Some evidence suggests that tofacitinib improves the risk of cardiovascular disease (112); however increasing evident points to adverse effects of JAK inhibitors on cardiovascular risk and CV risk factors including an increase in lipid levels (55, 113, 114) and thrombosis.

Early clinical trials comparing high (10mg) and low (5mg) twice daily of tofacitinib in rheumatoid arthritis suggested a higher rate of venous thromboembolism leading to an FDA warning in 2019 and discontinuation of the 10mg dose in rheumatoid arthritis patients. An FDA mandated post-marketing safety study, termed the ORAL Surveillance study was therefore conducted over 5 years comparing tofacitinib to TNF inhibitor in rheumatoid arthritis patients great than 50 years of age with 1 or more CV risk factor with the co-primary endpoint MACE and malignancies. In 4,362 subjects after 5 years of follow-up the hazard ratio of the primary comparison of the combined tofacitinib doses to TNFi was 1.33 (0.91, 1.94) and the non-inferiority criteria of 1.8 was not met (115). Following this, FDA warnings were released informing providers of an increased risk of venous thromboembolism and death with the higher doses as well as increased risk of serious heart-related problems and malignancy in both doses of tofacitinib compared to TNFα inhibitor treated rheumatoid arthritis patients (115, 116). We still await the published results of this trial. It is not yet known if JAK1 specific inhibitors (such as upadacitinib and filgotinib) will have lower safety risk profiles compared to the pan-JAK inhibitors (117).

Non-biologic psoriasis therapies and evolving therapeutics:

The most commonly used non-biologic therapies in psoriasis includes apremilast, methotrexate, cyclosporine and acitretin (72). Nonbiologic systemic therapies may be effective but can be associated with significant short-term and long-term toxicities which includes hypertension, dyslipidemia, hepatotoxicity and nephrotoxicity (118, 119). Phototherapy, is an additional treatment option; however this requires strict compliance and long term toxicity can include photocarcinogenesis (72). Methotrexate is frequently used for moderate-severe psoriasis and psoriatic arthritis (120). The use of methotrexate was associated with a reduced incidence of CV disease in patients with psoriasis in some studies (121), but not in others (122, 123). One study evaluated patients with psoriasis enrolled in the U.S. Medicare program which allowed assessment of a large population to determine the incidence rate of cardiovascular events and assess the event rate associated with use of systemic treatments compared to biologics. There were 8,878 initiations of psoriasis treatments. Rates of MI were found to be highest for methotrexate (10.32/1000 patient-years, 95%CI 8.55–12.46) and lower for biologics, although this was not significant after multivariable adjustment. Similar patterns were observed for stroke and composite CV outcome between systemic therapy and biologics (124). Approved by the FDA in 2014 for psoriasis, apremilast, which inhibits phosphodiesterase-4, is one of few oral non-biologic drugs. It is recommended for moderate-severe psoriasis and limited data has suggested a benefit on CV risk (125). Apremilast is currently being studied in another sub-study of VIP that will assess the effects of apremilast on cardiovascular biomarkers and aortic inflammation by FDG PET (NCT03082729).

Conclusion

Psoriasis is a common and chronic inflammatory skin disorder which affects 2 – 3% of the population. The link between psoriasis and cardiovascular is clearly established although the precise mechanisms of this increased risk are not entirely known although is likely due to a heightened presence of traditional CV risk factors combined with psoriatic specific systemic inflammation. Recent evidence has highlighted the role of vascular endothelial dysfunction, activated platelets, dyslipidemia, and excess cardiovascular co-morbidities as key factors that may mediate this increased risk. Given that systemic inflammation is currently considered a key contributor to this enhanced cardiovascular risk, an important question remains as to whether the current biological therapies that treat the cutaneous manifestations will also improve cardiovascular risk. Epidemiological data overall suggests a positive or neutral impact on cardiovascular health for TNFi, IL-17A and IL-12/23p40, but current evidence remains conflicting for anti-IL-23/p19 and JAK inhibitors. More studies that include prospective cohorts, larger number of patients and treatment duration are needed to better evaluate the role of biologic therapies on CV risk. Furthermore, given the advancements of cardiovascular imaging that can serve as a surrogate measure for CV outcomes and the acceleration of immune and vascular phenotyping, future studies that incorporate these aspects will provide mechanistic insight into the relationship between psoriasis and cardiovascular health to improve patient outcomes.

Abbreviations:

CFR

Coronary flow reserve

CV

Cardiovascular

HDL

high density lipoprotein

hsCRP

high sensitivity C-reactive protein

IL

Interleukin

JAK

Janus kinase

LAD

left anterior descending

LDL

Low density lipoprotein

MACE

major adverse cardiovascular events

MI

Myocardial infarction

OR

Odds ratio

PET

Positron emission tomography

TNF

Tumor necrosis factor

VIP

Vascular inflammation in psoriasis