point and C-reactive protein as surrogate parameter, the “well-known marker of systemic inflammation” . The authors of the study concluded that “methotrexate at low doses, such those used for maintenance therapy of RA, predicted a decreased risk of CVE” .
Given the uncertainties inherent in observational trials, Ridker et al (2013) have mounted a randomized, double-blind, placebo-controlled trial of low-dose methotrexate or matching placebo in 4786 patients with previous myocardial infarction or multivessel coronary disease who additionally had either type 2 diabetes or the metabolic syndrome―the CIRT Trial . This trial set out to test the changes in CRP as well as in interleukin-1β and interleukin-6 compared to baseline.
After 2.3 years the trial was stopped by the Data Safety Monitoring Board (DSMB). The primary endpoint occurred equally in those treated with MTX (n = 201) or placebo (n = 207) (hazard ratio, 0.96; 95% confidence interval [CI], 0.79 to 1.16). Compared with placebo, MTX treated patients had more liver enzyme elevations, leukopenia, higher MCV values, more anemia and non-basal-cell skin cancers. MTX patients also had more oral ulcers and unintended weight loss. Additionally, MTX did not significantly lower interleukin-1β, interleukin-6, or C-reactive protein levels than placebo .
The CANTOS trial was supposed to validate the inflammation hypothesis in atherosclerosis, a landmark trial to test whether blocking IL-1β, a component of the inflammatory cascade, might translate into improved outcome in the context of secondary prevention of cardiovascular events in patients who have sustained a myocardial infarction    .
Patients on the 150 mg dose regimen of canakinumab experienced a 15% relative risk reduction of a composite of MACE (i.e., nonfatal heart attacks, nonfatal strokes and cardiovascular death). Responses were particularly beneficial for patients whose levels of hsCRP, viewed as a risk factor for heart disease, fell below 2 mg/L during the trial. Late last year, however, the US Food and Drug Administration issued a complete response letter to Novartis, essentially rejecting the application on the grounds that the submitted data were insufficient to support the company’s proposed indication. In Europe, Novartis opted to close the file on the cardiovascular indication when it withdrew from the approval process without addressing questions from regulators. Understandably, the FDA rejection and European withdrawal seem in stark contrast to the enthusiastic reception of CANTOS received in 2017. At the time, financial analysts pegged the anti-inflammatory agent canakinumab as a potential blockbuster, with future sales estimates in the billions, despite the known price tag for 150 mg dose used in CANTOS costing approximately $73,000 per year, translating into one quality-adjusted life-year (QALY/year)adding up to $6.4 million    .
In the scientific community, on the other side, there is a widespread agreement that CANTOS is an important “proof of principle” for the inflammatory hypothesis in atherosclerosis, at best.
A currently ongoing trial is testing the anti-inflammatory effects of colchicine and spironolactone since February 2017 (Colchicine and Spironolactone in Patients with STEMI/SYNERGY Stent Registry (CLEAR-SYNERGY) (Clinical Trials.gov Identifier: NCT03048825). The CLEAR SYNERGY trial will study the long-term effects of treatments following PCI to treat ST elevation myocardial infarction. These treatments address both the culprit artery (PCI with SYNERGY Stent) as well as the non-culprit arteries (randomization to routine colchicine and spironolactone).
Another trial to determine the effect of psoriasis treatment (adalimumab, phototherapy, and placebo) oncardiometabolic disease, the vascular inflammation in psoriasis (VIP) trial, tested the hypothesis that psoriasis therapy would improve cardiometabolic biomarkers. Patientshad PASI 12 and BSA10 and were washed out of psoriasis treatments. 97 patients were randomized to adalimumab, nbUVB phototherapy, or placeboin a 1:1:1 ratio and treated for 12 weeks; patients then entered an open-label extension (VIP-E, NCT01866592) so that all received adalimumab for 52 weeks. The primary outcome was FDGPET/CT derived aortic inflammation measured as target-to-background ratio and secondary outcomes were cardiometabolic biomarkers including a novel marker of inflammation, GlycA. There was no difference in change in aortic inflammation at week 12 in the adalimumab group or the nbUVB group or after 52 weeks of adalimumab treatment. Analysis within groups demonstrated a significant reduction in aortic inflammation by 4.09% (95% CI-7.78%, −0.39%) in the nbUVB arm only. Neither treatment had impact on metabolic markers (insulin, adiponectin, leptin) whereas only nbUVB increased HDLat12 weeks. Despite no change in aortic inflammation and minimal impact on lipids and insulin resistance, adalimumab reduced GlycA levels, a biomarker predictive of coronary disease .
This study shows the lack of correlation between CRP and IL-6 with aortic inflammation as assessed by FDGPET/CT at 12 and 52 weeks for adalimumab treatment.
Concerns about venous thromboembolic events (VTE) had also been raised during the premarketing trials of another JAK inhibitor, baricitinib (Olumiant), and that drug had been approved only for use in a low dose .
A few of the examples above, perhaps the ones that mostly attracted both attention and hope as potential breakthrough the rapiesmerit closer appraisal.
Overall, widespread primary and secondary prevention of CVD treatment by lowering of plasma low-density lipoprotein (LDL) is known to prevent subendothelial retention of lipoproteins and thereby decrease inflammatory atherosclerotic disease . However, despite decades of such treatment applied early and bringing LDL to quite low levels, the goal to eliminate atherosclerosis with lipid lowering treatment has not yet been achieved.
The initial hope related to Canakinumab’s inflammatory effect was related to findings from mice indicating that neutralization of IL-1β could diminish the atherosclerotic lesion in animals (ignoring the associated finding that deletion of IL-1α/β receptors was worsening plaque stability in a mouse model of advanced atherosclerosis through effects on the extracellular matrix)  . Besides,
Reproduced after Stephen Chu-Sung Hu, Int. J. Mol. Sci. 2017.
the potential benefit of long-term use of canakinumab in humans at high risk for atherosclerotic vascular disease might need to be substantial enough to counter its high price and the increased risk of infection, which was 67% in a 2-yearcryopyrin-associated periodic syndromes (CAPS)trial vs. 25% for placebo .
Finally, low-dose MTX is known to be a relatively safe and well-tolerated drug; it has, however, several mild and usually self-limited side effects, including nausea, stomatitis, and fatigue, but long-term use has rarely been associated with more important adverse effects, such as hepatotoxicity, pulmonary disease, and infection . However, if low-dose MTX were effective in atherosclerosis but would require long-term use, these side effects might become more important. Moreover, the risk of liver injury and infection is increased in subjects with type 2 diabetes   , which represents a sizable percentage of the high-risk CAD population that would be considered for this drug.
The atherosclerotic plaque is considered the culprit of a series of sequential events taking place upfront (angina pectoris, unstable angina/acute pulmonary oedema), culminating with an acute myocardial infarction and followed by different degrees of heart failure, cardiorenal syndrome, etc. .
Inflammation of the vessel wall is involved in all stages of the course of atherothrombotic disease, from the development of early lesions to the occurrence of clinical events. Significant advances in recent years have largely improved our understanding of this phenomenon and of its influence not only on atherogenesis, but also on other intimately related disorders such as arterial hypertension or the metabolic syndrome. Emerging imaging technologies (e.g., the FDGPET/CT  ) as well as measurement of serum concentrations of novel biomarkers (TNFα, ILs, e.g., GlycA (nuclear magnetic resonance signal)  and high mobility group box (HMGB1  )) offer the possibility to monitor and quantify the degree of chronic vascular inflammation in vivo, as well as to test new therapeutic options, especially in the field of inflammation signaling.
The risk for major cardiovascular events as well as vascular inflammation increases with psoriasis severity and its duration independent of traditional CV risk factors    - .
Inflammation as a hallmark of both PsO/PsA and atherosclerosis implies common pathogenic features, including local and systemic immunologic processes, inflammatory cytokine/chemokine profiles, and inflammatory markers (Figure 1)   .
Lymphocytes expressing CD4+ receptor on the surface, also known as T helper cells (Th) have fundamental role in the adaptive immune response. They are commonly classified into Th1, Th2, Th17, and T-reg subsets based on the effector cytokines released, with a prevalence of IL-12 and IFN-γ in Th1, IL-4, and IL-13 in Th2, IL-17, and IL-23 in Th17, and finally IL-10 and TGF-β in T-regs . These cytokines are then involved in mounting a particular type of inflammatory response     as indicated in Figure 2. The Th17 lineage produces IL-17A, IL-17F, IL-22 and IL-21.
The pro-inflammatory cytokine IL-23, composed by the two subunits p19 and p40, is mainly produced by inflammatory Dendritic Cells (DCs) within the inflamed skin  , with the additional contribution of macrophages and keratinocytes  . IL-23 induces the expansion and the maintenance of the Th 17 subsets of T cells.
The Th17 lymphocytes are characterised by the expression of the transcription factor Retinoic acid receptor-Related Orphan receptor-t (ROR-γt) and the signalling pathway Janus Kinase (JAK)-Signal Transducer and Activator of Transcription (STAT). They differentiate from naïve T cells in the presence of three potential combinations of cytokines: 1) IL-6 and Transforming Growth Factor-β (TGFβ), with the additional potentiating effect of IL-1β and TNFα; 2) IL-21 and TGFβ; and 3) IL-6, IL-1β and IL-23 . The IL-17 family includes six members, namely IL-17A, B, C, D, E and F. Of these, IL-17A is the principal effector
of the IL-17-related inflammatory activity in PsO/PsA and atherosclerosis. IL-17 can exert its effects by binding members of the IL-17-Receptors (IL-17R) family (i.e., IL-17RA, RB, RC, RD and RE).
Functionally, the Th17 cells can be categorised into host protective cells or pathogenic inflammatory cells. What role they exercise depends on the type of cytokines promoting their differentiation. Commonly, IL-23-activated Th17 cells trigger autoimmunity and chronic inflammation; conversely, TGFβ and IL-6 promote pathogenic Th17 cells important in tissue defence and integrity . As such, concomitant increase in IL-17 and IL-10 levels and reduction in IFN-γ is likely to limit lesion development and to promote plaque stability, whereas simultaneous production of IL-17 and IFN-γ is seems to promote lesion progression and plaque instability .
Upon activation, Th17 cells release effector molecules able to trigger a variety of target cells such as osteoclasts, B-cells and macrophages, which are responsible for the disease-specific inflammatory response (Figure 3) .
Overall, IL-17 stimulation can increase keratinocytes proliferation, neo-angiogenesis, recruitment and activation of mast cells, neutrophils and macrophages, while reducing the expression of adhesion molecules thus favouring the disruption of the skin barrier and arterial plaque instability.
In a recent publication, Schüler et al.  describe ground-breaking findings from having analysed three murine models with varying severity of psoriasis-like skin disease and their associated vascular function and inflammation:
・ K14-IL-17Aind/+ mice with keratinocyte-specific IL-17A over expression and an early onset severe psoriasis-like phenotype,
・ homozygous CD11c-IL-17Aind/ind and heterozygous CD11c-IL-17Aind/+mice over expressing IL-17A in CD11c+ cells leading to a delayed onset of moderate psoriasis-like skin disease, and
・ the acute model of imiquimod-induced psoriasis-like skin inflammation (IMQ).
Their data demonstrate a direct link between systemic IL-17A levels and the severity of skin disease and vascular inflammation/dysfunction and confirm previous theory extended by Wohn et al.  indicating that a certain threshold of systemic IL-17A must be exceeded for vascular dysfunction to develop. These findings are aligned with those coming from two other research groups   suggesting a link between the severity of skin disease and the amount of cutaneous and systemic IL-17A with the level of peripheral oxidative stress and vascular dysfunction. Further on, the IMQ model  with moderate to severe psoriatic skin lesion displayed only early signs of vascular inflammation and peripheral oxidative stress, very much in line with the natural course of psoriatic skin disease leading to only moderately up-regulated IL-17A levels in the skin and peripheral blood .
Saleh et al.  showed that arterial thrombus formation was attenuated in a mouse model of psoriasis under IL-17A inhibition (Li et al., 2018), indicating
that targeting cytokines that mediate psoriatic inflammation may indeed improve cardiovascular comorbidities.
Perhaps the most compelling piece of experimental research in this area comes from the group of Li-Hao Huang et al.  from Washington University School of Medicine in St. Louis. The researchers managed to narrow down the common inflammatory pathway of the psoriasis-affected skin lesions and vascular stiffness in atherosclerosis caused by the thickening of the collagenous matrix. The thickening is known to be caused by an excess of collagen in the skin and blood vessel, respectively. By use of a light-sensitive form of high-density lipoprotein (HDL) that fluoresces when hit with a laser, the researchers could see that HDL cholesterol was delayed in getting out of the bloodstream in the mice that received the compound, a phenomenon present in both the skin and the internal arteries near the heart. In addition, the skin and blood vessels were more densely interlaced with collagen and more resistant to stretching. Further, when the researchers fed mice a high-cholesterol diet for three weeks, the mice in the experimental psoriasis group developed significantly larger cholesterol deposits in their blood vessels.
The findings suggest that psoriasis-affected skin lesions program interleukin-17-producing T cells in draining lymph nodes to distal skin and later to arteries. There, these cells mediate thickening of the collagenous matrix, such that larger molecules including lipoproteins become entrapped. HDL transit can be rescued by depleting CD4+ T cells or by neutralizing interleukin-17. Thus, interleukin-17 can reduce lipoprotein trafficking and increase vascular stiffness by, at least in part, remodeling collagen, the researchers concluded .
In parallel with, as well as following the animal experimental studies, many observational studies in patients with a variety of different inflammatory diseases have brought about evidence about IL-17 being a potent inflammatory factor with a key role in the pathogenetic mechanisms of these disease entities.
In particular, convincing evidence indicates that IL-17 is key player in multiple stages of the atherosclerotic coronary artery disease by promoting arterial wall inflammation, platelet aggregation, accelerated thrombosis and plaque vulnerability. All these changes translate into increased risk of all-cause and cardiovascular death in patients in whom there is a clustering of classical risk factors and particular inflammatory diseases such as PsO, PsA, RA, etc.     .
Most recently, a study by Mehta et al.  brings additional data in support of the role IL-17 has in patients with psoriasis and associated cardiovascular risk factors. Patients in the study, known with moderate to severe psoriasis were biologic-naïve at baseline and with low cardiovascular risk based on Framingham scores.
Most of these patients were treated with biologics, while those who declined biologics were treated with topicals and/or light therapy (the latter group served as the reference group for the study). A total of 89 patients received treatment with a TNF-alpha inhibitor (etanercept or adalimumab), interleukin (IL)-12/23 inhibitor (ustekinumab), or interleukin-17 inhibitor (ixekizumab or secukinumab), while the non-biologic group included 32 patients.
At one-year follow-up, the biologic-treated patient had significant improvements in coronary artery plaque as measured by coronary computed tomography angiography with no appreciable impact on lipids, glucose, or body mass index. This was associated with a reduction at one-year in total coronary plaque burden by 5% (P = 0.009) and driven mainly by a reduction in non-calcified plaque burden (P = 0.005), fibrofatty burden, and the size of the necrotic core. There was a significant decrease in non-calcified plaque burden favouring biologic over non-biologic treatment.
By contrast, there was a significant increase in fibrofatty plaque burden, amounting to a 38% increase (P = 0.004), and a non-significant 33% increase in necrotic burden, according to the report in those not treated with biologic therapy for their severe psoriasis.
Patients treated with biologics had a significant reduction in high sensitivity C-reactive protein (hsCRP), while patients treated with topicals and/or light therapy did not.
Unexpectedly (or perhaps not), exposure to the three different class of biologics revealed that after a year of treatment with anti-IL-17 there was a significantly greater reduction in coronary plaque burden versus both IL-12/23 treatment and no biologic treatment. For anti-TNF therapy, the reduction in non-calcified coronary plaque burden was only significant versus non-biologic treated patients, though Mehta et al.  emphasized the observational nature of their study and thereby the limitations of the study findings.
Another recent article by Zhang et al.  explored behaviour of cytokines belonging to the Th1, Th2 and Th17 lymphocytes in patients with acute myocardial infarction (AMI―19 cases), unstable angina (UA―25 cases), stable angina (SA―21 cases) and 20 healthy controls. Serum levels of IL-17 and IFNγ in the AMI and UA groups were statistically significantly higher than those in the control and SA group.
GlycA by FDG-PET/CT is a novel, relatively recently validated assay that quantifies the nuclear magnetic resonance signal from N-acetylglucosamine and N-acetylgalactosamine moieties of plasma glycoproteins. It has been proposed as an alternative to C-reactive protein (CRP) as a newer biomarker of systemic inflammation . FDG-PET/CT enables measurement of in vivo whole-body inflammation, including high sensitivity for macrophage activity in the early, subclinical inflammation of atherosclerosis . FDG is taken up by cells in proportion to their metabolic activity and quantifies vascular inflammation as a standardized uptake value. The measurement of vascular inflammation by FDG-PET/CT has evolved as an acceptable surrogate inflammatory marker that can be modulated with therapy and may prognosticate stroke and myocardial infarction .
Change from baseline in vessel wall target-to-background ratio is the variable looked at for assessing aorta inflammation .
In a pilot study of six patients with moderate to severe psoriasis versus controls, FDG-PET/CT demonstrated increased metabolic activity in the liver, increased clinical and subclinical joint inflammation, and increased aortic inflammation even after adjustment for cardiovascular risk factors. Inflammation observed in the aorta suggested that aortas of patients with psoriasis were aged ten years compared to their age-matched control cohorts .
Coronary CT angiography (CCTA) is used to investigate coronary atherosclerosis, enabling identification of rupture-prone plaques, and has been proposed as an independent predictor of cardiovascular events .
Coronary artery calcification, as detected by CT, has been found to be more prevalent in patients with psoriasis compared to controls    . Coronary artery calcium increases in patients with psoriasis in a similar manner to that of patients with type 2 diabetes after adjustment for body mass index . Excessive quantity of epicardial adipose tissue, a risk factor for coronary artery disease, has also been found to be increased in CT studies of psoriasis patients in comparison to controls  .
A huge amount of critical information that has been accrued during more than a decade might well enable translation of basic research into properly designed and powered, global randomized clinical trials, to substantiate the therapeutic potential of monoclonal antibodies and/or innovative small molecules targeting cytokines belonging to the IL-17 class. Available evidence suggests that the therapeutic potential covers not only psoriasis/psoriatic arthritis but also atherosclerosis, hypertension, liver and kidney disease, multiple sclerosis and many other inflammatory disease entities  - . Such a scenario would certainly need to imply that overall increased circulatory IL-17 levels would trigger inflammation in specific tissues/organs in the absence of psoriatic skin lesions. This concept is however not proven yet, leaving open the axiom that blocking IL-17 signaling pathways might prove to have preventive or therapeutic effects in patients with PsO/PsA and associated cardiovascular comorbidities (CV risk factors and/or established clinical entities).
Secukinumab and Ixekizumab are both IL-17A neutralizing while brodalumab blocks the IL-17RA receptor subunit. Over the coming years, UCB is expected to launch its IL-17A/IL-17F agent―bimekizumab. These are all monoclonal antibodies however, more recently there has also been focus on the small molecule oral therapeutics (Bristol-Myers Squibb’s BMS-986195  , Can-Fite Biopharma’s piclidenoson  and ABY-035, a very small protein drug that is undergoing ph 2 study in PsO-Affibody AB, Stockholm  ).
Other than the monoclonal antibodies, highly specific and potent inhibitors targeting Th17 specific transcription factor RORγt have been identified and found to be highly effective .
Finally, a highly innovative IL-17 blocking agent may come from Nuevolution AB (Copenhagen). Nuevolution’s small molecules may offer access to both topical (e.g. cream based) treatment as well as safe tablet-based treatment .
Recent results from the VIP-S80 study evaluating cardiovascular outcomes in patients with psoriasis treated with secukinumab are far from meeting expectations . Further on, potential anti-inflammatory effect of secukinumab is tested currently in the ObePso-S92 study  by evaluating changes in adipose tissue in patients with psoriasis treated with secukinumab. Likewise, real-world data derived from the Corrona Psoriasis Registry might provide valuable data on the topic .
One may wonder, how come that secukinumab, highly efficacious in treating the psoriasis and psoriatic arthritis symptoms, fails to show a meaningful effect on inflammation. There is obviously no straightforward answer to this question other than assuming that the great heterogeneity encountered in the natural course of disease intricacies (i.e., PsO/PsA/CV comorbidities), compounded by the complexity of physiopathological and immunological mechanisms playing in require out-of-the box thinking, thorough selection of the population segments to be explored as well as ingenious study designs and carefully selected endpoints.
Taken together, currently available clinical and experimental data do lend strong translational knowledge to key study design elements and enable highly focused clinical development strategy for any IL-17 inhibitor agent targeting PsO/PsA and the clinical cardiovascular burden simultaneously. In particular, such a strategy would have to focus on appropriate selection of patient population to be targeted, timing of 1st efficacy analysis, endpoints and, nonetheless, careful dose finding/dose regimen considerations (along with suitable monitoring of safety/tolerability/immunogenicity aspects of such an undertaking).
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