Effects of IL17/23 Inhibitors on Markers of Subclinical Atherosclerosis in Patients With Psoriasis: an Observational Study
Conditions: Psoriasis, Cardiovascular Disease, Atherosclerosis
Sponsor: National and Kapodistrian University of Athens

NATIONAL AND KAPODISTRIAN UNIVERSITY OF ATHENS 
DEPARTMENT OF MEDICINE 
01 July 2021 
 
 
 
 
 
STUDY TITLE 
Eﬀects of IL17/23 inhibitors on markers of subclinical atherosclerosis in paOents with 
psoriasis: an observaOonal study 
 
 
 
 
 
 
STUDY PROTOCOL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

IntroducOon  
Plaque psoriasis is a chronic inﬂammatory disease characterized by the development 
of clearly demarcated, erythematous, pruriOc plaques on the skin of geneOcally 
predisposed individuals. It has a worldwide incidence of 0.5–11%, with over 50% of 
paOents developing the disease in the ﬁrst three decades of life. In recent years, 
increasing evidence supports that psoriasis is a systemic inﬂammatory disease that 
extends beyond the skin, as it is o_en associated with comorbidiOes, including 
psoriaOc arthriOs, cardiovascular disease, metabolic syndrome, and inﬂammatory 
bowel disease, greatly aﬀecOng the quality of life of paOents and mortality (1). 
The pathophysiology of psoriasis is complex and has been shown to be due to 
inﬂammatory mediators of the Th1 and Th17 immune response, such as tumor 
necrosis factor (TNF-a), interleukin (IL) 1, IL6, IL12, IL17A, IL17F and IL23. In fact, it has 
been shown that these pathways are shared between psoriasis and the 
aforemenOoned comorbidiOes and, thus, their selecOve inhibiOon with newer 
biological therapies posiOvely aﬀects this enOre disease spectrum beyond the skin (1). 
Regarding cardiovascular disease, current data support that psoriasis is an 
independent cardiovascular risk factor, as systemic inﬂammaOon can also aﬀect the 
vascular endothelium in addiOon to the skin (2). Therefore, understanding the 
common pathophysiological mechanisms between psoriasis and atherosclerosis as 
well as studying the eﬀect of newer biologic agents approved for the treatment of 
moderate/severe psoriasis on atherosclerosis may contribute to opOmal management 
of these paOents. The present study aims to highlight the eﬀect of IL23/IL17 pathway 
inhibiOon on subclinical atherosclerosis in paOents with moderate-to-severe psoriasis. 
 
Background 
Increasing evidence supports the importance of the Th17 immune response in the 
pathogenesis of psoriasis (3–5). Th17-diﬀerenOated T cells produce large amounts of 
IL17 (parOcularly the IL17A and IL17F isoforms), a cytokine that is signiﬁcantly involved 
in local skin immune mechanisms and the inﬂammatory process of psoriasis. It has 
been shown that Th17 (as well as Th1) cells are found in the dermis of psoriaOc lesions 
and produce IL17 and IL22, which in turn promote the secreOon of inﬂammatory and 
anOmicrobial molecules by keraOnocytes. Another important cytokine is IL23, which is 

responsible for the survival and expansion of Th17 cells and IL17 producOon (4). In 
combinaOon with the above, the development of new biological agents against IL17 
and IL23 for the treatment of psoriasis has highlighted in vivo the essenOal role of the 
IL23/Th17 axis in its pathogenesis (6). 
InteresOngly, the same axis has also been shown to play an important role in the 
pathophysiology of atherosclerosis (2,7). In one study, increased levels of IL23 and its 
receptor (IL23R) have been found in the blood and atheroscleroOc plaque of paOents 
with caroOd atherosclerosis compared with healthy volunteers. Another study showed 
that both psoriasis paOents and those with acute coronary syndrome have increased 
levels of Th17 immune response cytokines in the blood, including IL17A (8). The 
increased levels of IL17A in these paOents have been correlated with the degree of 
platelet aggregaOon measured in vitro, suggesOng that IL17A may promote platelet 
aggregaOon in acute coronary syndrome (9). 
Taking into account the above data, it has been hypothesized that inhibiOon of the 
IL23/Th17 axis may lead to simultaneous improvement of psoriaOc and concomitant 
atheroscleroOc disease (1). To date, isolated studies have shown this associaOon in 
paOents receiving IL17 inhibitors for moderate or severe psoriasis. Speciﬁcally, in one 
study, treatment of paOent for one year with an IL17 inhibitor (secukinumab) resulted 
in improvements in myocardial deformaOon, arterial elasOcity, and coronary artery 
funcOon, along with signiﬁcant reducOons in psoriasis acOvity and oxidaOve stress, 
ﬁndings that were not observed in paOents treated with cyclosporine or methotrexate 
(10). In contrast, another study of paOents with psoriasis did not demonstrate a 
signiﬁcant beneﬁt in terms of cardiovascular risk in paOents treated with IL23/Th17 
axis inhibitors (ustekinumab, secukinumab, ixekizumab), which was partly ahributed 
to the short duraOon of treatment and follow-up (6 months) (11). Finally, in another 
study, biological therapy with TNF-a, IL17, and IL12/23 inhibitors was associated with 
reduced coronary inﬂammaOon assessed by the perivascular fat ahenuaOon index 
(12). 
 
 
Outcomes 

The primary outcome is the assessment of the eﬀect of treatment with an IL17 or an 
IL23 inhibitor on arterial sOﬀness in paOents with moderate-to-severe psoriasis, by 
evaluaOng the pulse wave velocity (PWV) and the augmentaOon index normalized to 
75 beats/min (AIx75) at baseline, a_er 24 and 52 weeks of treatment. Secondary 
outcomes were the comparison of change in PWV and AIx75 between the study groups 
and the assessment of change in psoriasis disease severity scores and in ankle-brachial 
index (ABI) 
 
PaOents 
This observaOonal cohort study was performed between September 2021 and 
September 2024. ConsecuOve paOents with plaque psoriasis with or without psoriaOc 
arthriOs, who were monitored in the outpaOent department of a terOary academic 
hospital for skin diseases were included in the study if they fulﬁlled all of the following 
inclusion criteria: 1. Age ≥ 18 years; 2. Clinical diagnosis of moderate-to-severe 
psoriasis (Psoriasis Area Severity Index (PASI) score > 10 or Body Surface Area (BSA) 
>10 or Dermatology Life Quality Index (DLQI) >10) ; 3. Treatment with an IL17 inhibitor 
[secukinumab (CosentyxÒ), ixekizumab (TaltzÒ), brodalumab (KyntheumÒ)] or an IL23 
inhibitor [risankizumab (SkyriziÒ), guselkumab (TremfyaÒ)] or a convenOonal systemic 
agent (e.g. methotrexate, cyclosporine) or a small molecule [apremilast (OtezlaÒ)] as 
monotherapy for a total of 52 weeks. The exact agent was chosen from the treatment 
physician of each paOent, based on disease characterisOcs and comorbidiOes. PaOents 
who did not receive biologic therapy served as a control group. PaOents were not 
included in the if they fulﬁlled any of the following criteria: 1. Prior therapy with an 
IL17 or IL23 inhibitor; 2. Prior therapy with an TNFa-inhibitor for up to 3 months before 
entering the study; 3. Chronic or severe acute infecOons, malignancy, pregnancy or 
lactaOon 
 
 
Study locaOon 
The study will be conducted at the First University Dermatology Clinic of the NaOonal 
and Kapodistrian University of Athens, at the "Andreas Syggros" Hospital of Athens, in 

collaboraOon with the First University Cardiology Clinic of the NaOonal and 
Kapodistrian University of Athens, at the "HippokraOo" Hospital of Athens. 
 
Materials and Methods 
The enrollment of paOents who will parOcipate in the study will be carried out at the 
psoriasis clinic of the “Andreas Syggros” Hospital in Athens. All paOents will provide 
wrihen informed consent prior to enrollment in the study. The selecOon and 
administraOon of the biological agent will be done according to the usual pracOces of 
the psoriasis clinic based on the characterisOcs of the paOent/disease and the 
internaOonal guidelines for the administraOon of each drug. Assessment of psoriaOc 
disease and evaluaOon response will take place before the start of treatment, at week 
24 and 52. 
 
Monitoring of psoriasis 
Psoriasis assessment scores including Psoriasis Area Severity Index (PASI), physician 
global assessment (PGA), Body Surface Area (BSA) and Dermatology Life Quality Index 
(DLQI) were assessed at baseline, a_er 24 and 52 weeks of treatment. 
 
Monitoring of cardiovascular parameters 
All paOents will undergo measurement of caroOd-femoral PWV, AIx75 and right and 
le_ ABI at baseline, a_er 24 and 52 weeks of treatment. 
 
 
StaOsOcal analysis 
StaOsOcal analysis will be performed using StaOsOcal Package for the Social Sciences 
for iOS (version 29.0.2.2 IBM Corb: Armonk, NY, USA). DescripOve staOsOcs will be used 
to present the paOents’ characterisOcs. Variables with normal distribuOon will be 
reported as mean ± standard deviaOon (SD), while not normally distributed outcomes 
will be reported as median values and range. Categorical variables will be presented 
as frequencies and percentages. Between-group analysis will be performed using the 
Kruskal-Wallis Test and Student’s t-test or one-way ANOVA test. StaOsOcal signiﬁcance 
is determined at a two-tailed p value of 5% (0.05). 

 
 
Funding 
The biological agents that will be administered are approved for the treatment of 
moderate/severe psoriasis in Greece, so the cost of treatment will be covered by each 
paOent's insurance a_er electronic prescripOon of each drug. The laboratory test that 
will be performed is part of the usual pracOce of monitoring treatment with biological 
agents, so the costs will be covered by the paOent's insurance, a_er electronic 
prescripOon. There will be no external funding for the study. 
 
Principal invesOgator 
Aikaterini Tsiogka 
 
SubinvesOgators 
Prof. Dimitrios Rigopoulos 
Prof. Alexander StraOgos 
Prof. Charalampos Vlachopoulos 
Stergios Soulaidopoulos 
Prof. StamaOos Gregoriou 
Natalia RompoO 
Pantelis Panagakis 
Marina Papoutsaki 
PanagioOs Kostakis 
George Kontochristopoulos 
Prof. KonstanOnos Tsiouﬁs 
 
 
 
References 
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Psoriasis and Its IntersecOon With Cardio-Metabolic ComorbidiOes. Front 
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2.  
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3.  
Schön MP, Erpenbeck L. The interleukin-23/interleukin-17 axis links adapOve 
and innate immunity in psoriasis. Front Immunol. 2018;9(JUN):1–13.  
4.  
Bugaut H, AracOngi S. Major Role of the IL17/23 Axis in Psoriasis Supports the 
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2021;12(February):1–8.  
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von Stebut E, Boehncke WH, Ghoreschi K, Gori T, Kaya Z, Thaci D, et al. IL-17A in 
Psoriasis and Beyond: Cardiovascular and Metabolic ImplicaOons. Front 
Immunol. 2020;10(January):1–15.  
6.  
Hawkes J. Discovery of the IL-23/IL-17 Signaling Pathway and the Treatment of 
Psoriasis. J Immunol. 2018;201(6): 1605–1613 
7.  
Egeberg A, Gisondi P, Carrascosa JM, Warren RB, Mrowietz U. The role of the 
interleukin-23/Th17 pathway in cardiometabolic comorbidity associated with 
psoriasis. J Eur Acad Dermatol Venereol. 2020;34(8):1695–706.  
8.  
Cheng X, Yu X, Ding Y jun, Fu Q qing, Xie J jiao, Tang T Ong, et al. The Th17/Treg 
imbalance in paOents with acute coronary syndrome. Clin Immunol. 
2008;127(1):89–97.  
9.  
Zhang S, Yuan J, Yu M, Fan H, Guo ZQ, Yang R, et al. IL-17A facilitates platelet 
funcOon through the ERK2 signaling pathway in paOents with acute coronary 
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Makavos G, Ikonomidis I, Andreadou I, Varoudi M, Kapniari I, Loukeri E, et al. 
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PATIENT CONSENT FORM 
 
for parOcipaOon in the scienOﬁc study enOtled: 
 
“Eﬀects of IL17/23 inhibitors on markers of subclinical atherosclerosis in paOents 
with psoriasis: an observaOonal study” 
 
General informaOon: Plaque psoriasis is a chronic inﬂammatory disease characterized 
by the development of red plaques covered with scales and can aﬀect any area of the 
skin. Today we know that this disease is not limited to the skin, but can also aﬀect 
other systems of the body, such as the joints, the vascular wall and the heart. 
Speciﬁcally, it has been shown that paOents with severe psoriasis are twice as likely to 
develop metabolic syndrome as well as cardiovascular disease, with subsequent 
complicaOons such as angina, myocardial infarcOon, heart failure and stroke compared 
to the healthy populaOon. The newest drugs against psoriasis have proven to be very 
eﬀecOve in treaOng skin lesions and improving the quality of life of paOents. At the 
same Ome, there are indicaOons that they can also improve the accompanying 
diseases menOoned above, including cardiovascular risk. 
 
Aim of the study: To study the impact of systemic treatment of plaque psoriasis on 
subclinical atherosclerosis in paOents who are going to receive an interleukin 17 or 23 
inhibitor compared to those who will receive a non-biological agent. 
 
Study design: In addiOon to the predeﬁned dermatological examinaOons at the “A. 
Syggros” paOents who will parOcipate in the study will undergo a cardiological 
examinaOon before the start, a_er 24 and 52 weeks. This examinaOon will be carried 
out at the university clinic of the “Hippokrateio” Hospital of Athens, will be free of 
charge and will include non-invasive examinaOons. The results of the examinaOons will 
be used anonymously and only for the purposes of this scienOﬁc research. 
 
ParOcipaOon and withdrawal: Your consent to parOcipate in the study is voluntary and 
does not deprive you of the right to withdraw it at any Ome you wish without any 
consequences for your subsequent treatment by your treaOng physician. 
 
I have read the above and agree to parOcipate in this scienOﬁc study. 
 
PaOent details 
Name 
Date 
Signature 
 
Physician’s details 
Name 
Date 
Signature