Effects of the TNF alpha Antagonist Adalimumab on Arterial...

Effects of the TNF alpha Antagonist Adalimumab on Arterial Inflammation

Assessed by Positron Emission Tomography in Patients with Psoriasis:

Results of a Randomized Controlled Trial

Bissonnette et al: Adalimumab, Arterial Inflammation and Psoriasis

Robert Bissonnette, MD, FRCPC1; Jean-ClaudeTardif, MD2; François Harel, MD, PhD2;

Joséphine Pressacco, MD, PhD2; Chantal Bolduc, MD, FRCPC1; Marie-Claude Guertin, PhD3

1Innovaderm Research Inc, Department of Dermatology, Montreal, Quebec, Canada,

2Montreal Heart Institute Research Center, Université de Montréal; Montreal, Quebec, Canada;

3Montreal Heart Institute Coordinating Center (MHICC), Montreal, Quebec, Canada

Correspondence to Robert Bissonnette 1851 Sherbrooke Street East, Suite 502 Montreal, Quebec, H2K 4L5, Canada Fax: 514-906-0659 Phone: 514-521-4285 Email: [email protected]

DOI: 10.1161/CIRCIMAGING.112.975730

Journal Subject Codes: [30] CT and MRI, [112] Lipids, [32] Nuclear cardiology and PET, [118] Cardiovascular Pharmacology, [135] Risk factors, [150] Imaging

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Abstract

Background—Psoriasis is a chronic inflammatory disease associated with increased risks of

myocardial infarction and stroke. Systemic treatments for moderate to severe psoriasis can

reduce skin and joint inflammation; however their effects on vascular inflammation are

unknown.

Methods and Results—This randomized, controlled trial included 30 patients with moderate to

severe psoriasis and a history, or multiple risk factors, of coronary atherosclerosis. Patients were

randomized (2:1) to receive either adalimumab subcutaneously for four months or to control

non-systemic treatment (topical therapies or phototherapy). Vascular inflammation was

measured in the carotid artery and ascending aorta at baseline and week 15 by 18F-fluorodeoxyglucose uptake on positron emission tomography (PET). The change in target to

background ratio (TBR), in the vessel with highest baseline TBR (primary endpoint) was

significant at week 15 as compared to baseline for patients randomized to adalimumab (-0.23

[95% CI -0.39 to -0.08]; p=0.004) but not for the control group (-0.10 [95% CI -0.32 to 0.12];

p=0.35). The difference between study arms for this primary endpoint did not reach statistical

significance (-0.13 [95% CI -0.01 to 0.14]; p=0.32). The change in TBR at week 15 improved

with adalimumab compared to controls both in the ascending aorta (-0.26±0.11, p=0.021) and in

carotid arteries (-0.32±0.15, p=0.037) when analysed separately (secondary endpoints). Changes

in other PET indices also improved significantly with adalimumab compared to controls in the

ascending aorta and carotids. hs-CRP decreased by 51% at week 16 with adalimumab compared

to 5% in controls (p=0·002).

Conclusions—The study did not meet its primary endpoint as the change in TBR in patients

randomized to adalimumab was not different from controls. Although adalimumab may reduce

vascular inflammation in patients with moderate to severe psoriasis this effect is not large

enough to be demonstrated in a study with a small sample size.

Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier:

NTC00940862.

Key Words: aorta, atherosclerosis, carotid arteries, inflammation, inhibitors

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Psoriasis is a chronic immune-mediated disease affecting up to 3% of the population.1 Skin and

joint inflammation are the hallmarks of psoriasis and an increase in the number of T

lymphocytes, antigen presenting cells, macrophages and neutrophils is found in psoriatic

plaques.2 The complex interplay between inflammatory cells and keratinocytes induces

epidermal proliferation resulting in the typical indurated, scaly and erythematous plaques of

psoriasis.3 Psoriasis has been shown to increase the risk of myocardial infarction and stroke.4-7

Psoriasis treatments include topical corticosteroids, vitamin D analogues and phototherapy but

also systemic anti-inflammatory agents such as methotrexate, cyclosporin or biological agents

targeting tumor necrosis factor alpha (TNF- ) or interleukin-12/interleukin-23.8 These systemic

agents all have a profound effect on skin and/or joint inflammation.

Atherosclerosis is also an inflammatory disease.9 We hypothesized that treatment-induced

reduction in the local inflammatory process in patients with psoriasis would be associated with

decreased vascular inflammation as assessed by positron emission tomography – computed

tomography (PET/CT).

Methods

Study design and patients

This was an investigator-initiated, single-centre, single-blind (cardiologist and all staff involved

in vascular imaging and analysis were blinded to treatment assignment), randomized, parallel

group and active-controlled study (clinicaltrials.gov NTC00940862). Declaration of Helsinki

protocols were followed, the study protocol was approved by the Montreal Heart Institute

institutional review board, and written informed consent was obtained from each patient. Eligible

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patients were 18 to 80 years of age with chronic, moderate to severe plaque type psoriasis

covering a minimum of 5% of the body surface area who were candidates for systemic therapy.

In addition, patients had to have either a history of coronary atherosclerosis (defined as having at

least one narrowing of the diameter of the arterial lumen of 50% on coronary angiography,

previous myocardial infarction, previous coronary revascularization, abnormal radionuclide

myocardial perfusion scan or abnormal stress echocardiogram) or a minimum of three risk

factors among the following: hypertension, active smoking, diabetes mellitus, dyslipidemia,

obesity, microalbuminuria, age above 55 years, and first-degree relative with evidence of

coronary atherosclerosis before 65 years. Patients were also required to show a carotid artery or

ascending aorta TBR of 1.6 as determined by 18F-FDG uptake measured by PET as evidence of

atherosclerotic plaque inflammation. Patients taking medications for angina, hypertension,

dyslipidemia or other agents that could have an effect on inflammation must have been on a

stable dose for 8 weeks before baseline. Patients were excluded if they had a myocardial

infarction or hospitalization for a cardiac condition within 12 weeks of baseline, if they had used

non-biological systemic therapy for the treatment of psoriasis less than 30 days before Day 0,

biological therapy for the treatment of psoriasis less than 90 days before Day 0, phototherapy or

topical treatment for psoriasis within the last 2 weeks prior to baseline.

Patients were seen at the dermatology research clinic from May 2009 to June 2011 and were

randomized (2:1) to either the TNF- antagonist adalimumab10 or the control group using a

concealed computer-generated code created by the sponsor. Adalimumab was administered

subcutaneously with a loading dose of 80 mg followed by 40 mg one week later and every other

week thereafter up to and including Week 15. Patients in the control group could use any topical

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psoriasis treatment, ultraviolet B (UVB) phototherapy or no treatment. Psoriasis severity was

evaluated at each visit using the PASI.11 Fasting serum lipids and hs-CRP were analysed at a

local laboratory (CDL laboratories, Montreal, Canada).

PET/CT image acquisition

Details of imaging procedures and analyses have been published previously.12 PET/CT imaging

was performed at the Montreal Heart Institute after an overnight fast using a GE Healthcare

(Milwaukee, Wisconsin) Discovery DST PET/CT scanner. Fasting serum glucose levels were

checked by fingerstick to assure glucose levels lower than 11.1 mmol/l before FDG

administration. FDG-PET/CT scans of the carotid arteries and ascending thoracic aorta were

performed approximately ten days before baseline and at Week 15. Subjects were injected with

10mCi of 18F-FDG. Care was taken to ensure that imaging was performed at the same time

interval (two hours) after FDG injection for serial scans, in order to limit variability in FDG

accumulation and background activity. After a 30-second scout CT scan was acquired (140kV,

80mA, 4.25 mm slice thickness) for co-registration and attenuation correction, a 2D chest PET

scan was performed from the aortic arch to the diaphragm. The scan was reconstructed using the

OSEM algorithm with corrections applied for normalization, dead time, random events, scatter,

attenuation and sensitivity. A 3D PET/CT scan of the neck was acquired after stabilizing the

neck in a holder to minimize movement and after setting the upper landmark to the superior

portion of the auditory meatus in the scout view. This scan was reconstructed using the FORE-IT

algorithm with standard parameters.

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PET/CT image analysis

Image analysis was performed using ITKsnap version 2.2.0 (GNU General public licence) and

in-house software developed using MATLAB 2010a (Natick, MA). An experienced reader

(F.H.) analyzed all scans. All PET/CT measurements were performed at the end of the study,

with core laboratory personnel and physician blinded to the randomization assignment. Using the

CT images for co-registration, areas of interest were identified on PET scan images of the

ascending aorta, right and left carotid arteries. Arterial FDG uptake was quantified by drawing a

region of interest (ROI) around each artery on every slice of the co-registered PET/CT images.

The maximal arterial standardized uptake value (SUV) was then calculated as the maximal pixel

activity within the ROI of every slice of the vessel. The mean SUV was also calculated for every

slice. The maximum and mean SUVs were measured along the carotid arteries and ascending

aorta at approximately five mm intervals, in axial orientation. The SUV is calculated as a time-

corrected concentration of tissue radioactivity in kilobecquerels per mL, adjusted for the injected

FDG dose and the body weight of the patient, and is a widely used method for quantification of

FDG-PET data. The maximal and mean arterial TBR were then calculated by dividing the

maximum and mean arterial SUVs by the blood (background) SUV, the latter estimated from the

superior vena cavae (for the ascending aorta TBR) and jugular veins (for carotid artery TBR) to

produce a blood (background)-corrected artery SUV. This is considered to be a reflection of

arterial FDG uptake. For evaluation of the mean FDG blood pool uptake, at least six three- to

four-mm ROIs were placed in consecutive slices of both jugular veins and superior vena cavae

and averaged.

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Study Outcomes

The primary endpoint was the change in the average of maximum target to background ratio

values (MeanMAX TBR) of carotid arteries and ascending aorta from baseline to Week 15,

analyzed in the vessel with highest baseline TBR. Secondary endpoints included the change in

the average of the mean TBR values (MeanMEAN TBR) and the change in the most diseased

segment (MDS TBR) from baseline to Week 15 in the vessel with the highest baseline value.

MDS TBR was defined as the 1.5 cm segment that demonstrated the highest PET/CT activity at

baseline and was calculated as the MeanMax TBR values derived from three contiguous axial

segments. The changes in TBR values were also analyzed separately in the carotid arteries and in

the ascending aorta.

Changes in hs-CRP and serum lipids (total cholesterol, low density lipoprotein (LDL)-

cholesterol, high density lipoprotein (HDL)-cholesterol, triglycerides), which were all secondary

endpoints, were calculated from baseline to Week 16. The proportion of patients reaching 75%

improvement in psoriasis area and severity index (PASI 75) at Week 16 was also evaluated.

Statistical Methods

Due to the exploratory nature of this study, the sample size of 30 patients was not based on

formal power calculations. Changes from baseline in PET/CT endpoints were studied using an

analysis of covariance model adjusting for the baseline value of the endpoint. Changes from

baseline are presented as least square mean estimates and standard error. A repeated measures

analysis of covariance adjusting for baseline was used for the secondary endpoints of hs-CRP

and lipid values. The proportion of patients reaching PASI 75 was compared using a chi-square

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test. For all endpoints, the analysis was conducted on the ITT population and the last observation

carried forward method for missing data was used except for the PASI 75 endpoint where a non-

responder imputation method was used. Sensitivity analyses were also performed on the ITT

population with complete cases (for the primary endpoint) and a per-protocol (PP) population

(for primary and secondary endpoints). All analyses were performed using SAS version 9.2

(Cary, NC) with a significance level of 0.05 and pre-specified in the statistical analysis plan.

Results

Patient disposition and baseline characteristics

Thirty patients were enrolled in this study and included in the intent to treat (ITT) analysis

(Figure 1). Baseline characteristics of patients are shown in Table 1. All patients completed the

study except one who died of a myocardial infarction after Week 8. Seven patients were

excluded from the per-protocol analysis: 4 started a new medication and 3 had a dose change in a

medication that could influence vascular inflammation.

PET/CT vascular results

For the primary endpoint of change at Week 15 in MeanMAX TBR in the vessel with the highest

baseline TBR, the change was significant in the adalimumab group (-0.23±0.07, p=0.004) but not

in the control group (-0.10±0.11, p=0.35). The difference of least square means among groups

did not reach statistical significance (-0.13±0.13, p=0.32). The same conclusion was reached

when the analysis was performed using the Wilcoxon rank sum test (p=0.695). Sensitivity

analyses performed on the PP population and the ITT population with complete cases supported

the primary analysis of the ITT population (not shown).

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The change (differences of least square means among groups) at Week 15 in MeanMAX TBR

improved with adalimumab compared to the control group both in the ascending aorta

(-0.26±0.11, p=0.021 versus control, Figure 2A) and in carotid arteries (-0.32±0.15, p=0.037

versus control, Figure 2B). The changes in MeanMEAN TBR and the change in MDS TBR also

improved with adalimumab compared to the control group in the ascending aorta and in carotid

arteries, as shown in Table 2 (p=0.010, 0.011, 0.030, and 0.080 respectively). Representative

PET/CT images of changes over time in patients of the adalimumab and control groups are

shown in Figure 3.

Psoriasis evaluation

The proportion of patients who had at least a 75% improvement in psoriasis area and severity

index (PASI 75) at Week 16 was 70% for patients randomized to adalimumab as compared to

20% for patients in the control group (p=0.01). This difference was also statistically significant

when analyzed with Fisher’s exact test (not shown).

High sensitivity C-reactive protein (hs-CRP) and serum lipids

hs-CRP levels were significantly decreased in patients randomized to adalimumab compared to

those in patients randomized to the control group at Days 28, 56, and 112 (p=0.013, 0.008, and

0.002 respectively; Figure 4). The results were supported by those in the per-protocol population

(not shown). There were no statistically significant changes over time in serum lipids (Figure 5).

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Safety

There were two serious adverse events reported, one death due to myocardial infarction, and one

incidence of lithium toxicity. Both occurred in patients randomized to adalimumab and were

deemed to be not related to the study drug by the investigator.

Discussion

This study showed that patients with moderate to severe psoriasis both in the active treatment

and control arms had a change in MeanMAX TBR from baseline and the difference across

groups was not significant for the primary endpoint. However, patients treated for 15 weeks with

adalimumab had a statistically significant decrease in vascular inflammation as measured by the

change in MeanMAX TBR in the vessel with the highest baseline TBR whereas the reduction

was not significant in the control group (local therapy). The differences between adalimumab

and control for MeanMAX TBR, MDS TBR, and MeanMEAN TBR were significant both in the

carotid arteries and the ascending aorta when evaluated separately (secondary endpoints). The

small sample size of 30, with only 10 patients in the control group, combined with the choice of

vessel with highest TBR as primary endpoint may be responsible for the fact that the primary

endpoint was not met. Selection of the vessel with the highest baseline inflammation may

partially explain the non-significant decrease observed in the control group as higher baseline

values usually tend to regress to the mean. Using the observed distribution, the measured change

from baseline in TBR and the 2:1 randomisation scheme used in the current trial, a sample size

of 306 patients would have been required to detect a statistically significant difference for the

primary endpoint. Adalimumab also resulted in a reduction of plasma levels of hs-CRP as early

as 4 weeks after initiation of treatment and the effect lasted until the end of the study at 16

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weeks. Finally, patients treated with adalimumab had a substantial improvement in psoriasis. The

response rate is almost identical to what has been observed in the pivotal phase III study with

adalimumab where 71% of patients achieved PASI 75.10

Atherosclerosis is an inflammatory disease13-19 and patients with different clinical atherosclerotic

manifestations are faced with persistent vascular risk despite our current armamentarium. Anti-

inflammatory therapies are presently being assessed to reduce further the risk of myocardial

infarction and stroke of patients with established vascular disease. Inflammatory diseases such as

psoriasis and rheumatoid arthritis are now known to expose patients to an increased risk of

myocardial infarction and stroke.4-7 Psoriasis is a complex multi-systemic disease influenced by

environmental and genetic factors. It is characterized by expansion of Th1, Th17, and Th22 cells

resulting in significant inflammation at the skin and joint levels.2 The expression of several

cytokines, including TNF- , interferon gamma, IL-17, IL-22, IL-23 is increased in the skin of

patients with psoriasis. Inflammation is a hallmark of psoriasis and cardiovascular risks have

been shown to be higher in patients with more severe cutaneous disease.7 Systemic inflammation

is also increased in patients with psoriasis as shown by elevated levels of hs-CRP but correlation

between hsCRP and myocardial infarction has not been well studied in this patient population.

Whether treating patients with moderate to severe psoriasis with an anti-inflammatory biological

agent could reduce vascular inflammation and future vascular events (myocardial infarctions and

strokes) is not known. Some studies based on claims databases or registries have suggested that

treatment of rheumatoid arthritis or psoriasis with methotrexate or TNF- antagonists could

decrease the risks of myocardial infarction and/or stroke whereas others have not been able to

detect a significant risk difference.20-26 In contrast, a non-statistically significant increase in

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major cardiovascular events was observed when patients with psoriasis were treated with

antibodies targeting IL-12 and IL-23 compared to placebo.27 Before assessing the value of a

TNF- antagonist such as adalimumab on hard vascular events in a large prospective

randomized placebo-controlled study, we first evaluated its effects on vascular inflammation as

assessed with 18F-radiolabeled fluorodeoxyglucose (18F-FDG) uptake on PET/CT imaging in a

study with a positive control arm.

FDG-PET is a sensitive and reproducible non-invasive technique to measure inflammation based

on the accumulation of 18F-FDG in inflamed atherosclerotic plaques.15, 28-30 18F-FDG has been

used to image metabolically active macrophages and inflammation. The uptake of 18F-FDG has

been shown to correlate with the extent of macrophage infiltration in carotid plaques of patients

scheduled for carotid endarterectomy.31 Carotid inflammation as detected by FDG-PET has been

shown to be associated with cardiovascular risk factors.32 FDG-PET has shown a reduction in

plaque metabolic activity in large arteries following statin therapy in a small cohort of patients

that were not preselected for the presence of vascular disease.33 More recently, FDG-PET

imaging was also used to evaluate the effects on vascular inflammation of the HDL-raising drug

dalcetrapib in patients with atherosclerosis.12

In the current study, patients in the control group could be treated with any topical medication or

UVB. There was a numerical decrease in the primary endpoint (MeanMAX TBR in the vessel

with the highest baseline TBR) in the control group. Of note, the patient who had the largest and

most prominent decrease in TBR (0.87) for the primary endpoint was treated with a super-potent

topical corticosteroid and had a 97% decrease in PASI (almost complete skin response). It has

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been suggested that inflammation in the skin may increase inflammation in atherosclerotic

plaques by the release from skin of activated T cells and cytokines such as IL-1, IL-6 and TNF-

in circulation.2 This raises the intriguing and testable hypothesis that reduction of cutaneous

inflammation using a local treatment such as a very potent topical corticosteroid or UVB may

decrease vascular inflammation.

The PET/CT results obtained with adalimumab are concordant with reduced hs-CRP levels as

well as the improvement of skin lesions observed in this study group. We however did not

observe significant correlations between PET/CT findings and hs-CRP levels or PASI

improvement (results not shown). The decrease in hs-CRP level was 51% at end of study for

patients randomized to adalimumab as compared to 5% for patients in the control group. Higher

hs-CRP levels have previously been shown to be associated with a higher risk of myocardial

infarction and stroke.34, 35 A study where psoriatic patients with an unsatisfactory response to

other agents were switched to adalimumab reported a decrease of hs-CRP from 2.1 to 0.3 mg/L

but did not include a control group, did not report statistical analysis on hs-CRP data and

included patients who had recently been treated with systemic agents for psoriasis.36

Vascular FDG-PET imaging used in this study did not reflect major changes in systemic

inflammation (hs-CRP) or clinical improvement (PASI) in psoriasis treated with the TNF-alpha

antagonist adalimumab. Possible explanations for this discrepancy include the small study size,

the relatively short study duration (four months), the lack of prospective power calculation and

the potential that vascular inflammation measured by FDG uptake may differ from systemic

inflammation in psoriasis. The clinical significance of reduced vascular inflammation on

s-CRP levels ororororororor

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PET/CT imaging and hs-CRP levels is uncertain and would need to be determined in a large

randomized trial evaluating the effects of adalimumab on cardiovascular clinical outcomes.

In conclusion, the study did not meet its primary endpoint as the change in TBR in patients

randomized to adalimumab was not different from controls. Although adalimumab may reduce

vascular inflammation in patients with moderate to severe psoriasis this effect is not large

enough to be demonstrated in a study with a small sample size.. The differences between

adalimumab and control for secondary PET/CT endpoints however were significant both in the

carotid arteries and the ascending aorta. Vascular FDG-PET imaging did not reflect major

changes in hs-CRP levels with adalimumab, which may have been due to the small study size or

to differences between vascular and systemic inflammation in psoriasis.

Acknowledgements.

The authors wish to thank Annik Fortier with her help with statistical analysis and Philippe

Marchessault with his assistance in manuscript production.

Sources of Funding

This study was funded and medication was provided by an investigator grant from Abbott

Laboratories.

Disclosures

Dr Bissonnette and Dr Bolduc have been investigators, advisors and/or consultants and received

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grants and/or honoraria from Abbott, Amgen, Astellas, Novartis, Janssen Ortho, Pfizer, Celgene

and Tribute. Drs Tardif, Harel, Pressacco, and Guertin have no conflicts of interest to declare.

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e in n n n n papapapapatititititienenenenentststststs with psoriasis. J Innnnnvevevvv st Dermatoooool.l.ll.l. 2009; 129:241GGGGGisisssslason nnn GHGHGHGHGH,,, LiLiLiLiLindndndndndhahahahahardrdrdrdrdseseseses n nnn J,J,JJ,J OOleeseeeeen nnnn JBJBJBJBJB,, ChChChhCharaarara looooot t t t t M,M,M,M,M SSSSSkokokokokov v v vv L,LLLLRRRRR. PrPPPP ognossisss fofofollowowowowing gggg ffirrrst-tttimemee mmmmmyoyoyoyoy cacardrddiall innnnffafarcttitt onoono inn pppa

Dannnnnisisisisish hhhh nannnn tititiiionononwiwiwiwiwidedd cccccohohohohohortttt t stststststudududududy.yyyy JJ JJJ InInInInInteteteteternrnrnrnrn MMMMMededededed. 2020202001111111111;;; ; 27272727270:00:0:0 23232323237Neimann AAAAAL,L,L,L,L, SSSShihihihihin n DBDBDBDBDB, ,, , , WaWaWaWaWangngngngng X,X,X,X,X, MMMMMarararrgogogogogolililililisssss DJDJDJDJDJ, TrTTTT oxel AB.nfnfnfarararctctctioioion n n ininin papapapp tititienenentststs wwwititith h h pspspspp orororiaiaiasisisis.ss. JAJAJAJJ MAMAMA.. 20220202 060606;;; 2929296:6:6:171717353535 11-1

KaKaKaplplananan DDDHHH BBBarararkekkek rrr JJJ PPPsososoriiriiasasasisisii NNN EnEnEnglgllll JJJ MMMeddeddd 202020090909;;; 3636361:1:1:494949666



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gyyyy BBBBBioioioiololololologigggg cscscscscs Register. Arthritis sss s RhRRRR eum. 20077777; ;;;; 56:2905-2912chahahahahaud KKKK. ThThThThThe e e riririririsksksksksk ooooof ffff mymymymymyocooo araarara didd alall infnfnfnfnfarararararctctctctctioioioioion nn ananananand phphphphpharararararmamamamamacococococololololologolllllogogogogogic myoocccardrdrdiallll iiini farcctiiionn preedddictctctctctorororoo ss in nn rheueuumammm toidididdid aarrthrhrritcontntntntntrororororol llll anananaa alalaaa ysysysisisisisi . Arrrrrthththththririririritis ssss RhRhRhRhRheueueueueum.mmmm 20202020200808080808;;;;; 5858585858:2:2:2:2:261616166 2-2-2-2-2-26262626262121212121. rnatsky S, HHHHHudududududsososososonnnn n M.M.M.M.M AAAAAntntntntntiririririrhehehehheumumummmatatatataticii dddddrurururugg g gg ususususu ee ananananand dddd the risk ofnfnfnfarararctctctioioion.n.n. ArArArthththririritititisss RhRhRheueueum.m.m. 202020060606; ; ; ;; 55555555:5:5:5313131-5-5-53636363 . LeLeLeeee HHH KKKimiimi babbabb llllll AAAAABBB TTThehheh eeeffffffffffecececttt ofoff sssysysystetetemimiiiccc pspspsorororiaiiai sisiiiisss ththerererapapapfffff



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36. Strober BE, Poulin Y, Kerdel FA, Langley RG, Gu Y, Gupta SR, Okun MM, Papp KA. Switching to adalimumab for psoriasis patients with a suboptimal response to etanercept, methotrexate, or phototherapy: efficacy and safety results from an open-label study. J Am Acad Dermatol. 2011; 64:671-681.

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Table 1. Baseline demographics and clinical characteristics

Adalimumab

n = 20

Control

n = 10

Age, years* 56.05 ± 10.95 57.40 ± 7.60

Male Sex† 17 (85) 6 (60)

Weight, kg* 95.09 ± 11.53 94.78 ± 17.56

Caucasian† 20 (100) 10 (100)

PASI‡* 11.58 ± 5.27 13.13 ± 5.68

Body Surface Area with psoriasis* 12.15 ± 10.16 13.30 ± 8.10

Coronary atherosclerosis and risks factors†

Known coronary atherosclerosis 4 (20) 3 (30)

Hypertension 13 (65) 6 (60)

Active smoking 5 (25) 4 (40)

Diabetes mellitus 4 (20) 2 (20)

Dyslipidemia 14 (70) 6 (60)

Obesity 19 (95) 10 (100)

Age above 55 years 12 (60) 8 (80)

First degree relative with myocardial infarction before age

65 years 12 (60) 3 (30)

Baseline PET/CT§ values*

MeanMAX|| TBR# of vessel with highest baseline TBR# 1.96 ± 0.26 2.18 ± 0.44

MeanMAX|| TBR# of carotid arteries 1.65 ± 0.25 1.84 ± 0.29

10101010101010.1.1.1.1.1.116 6 66666 13131313131313..

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Adalimumab

n = 20

Control

n = 10

MeanMAX|| TBR# of ascending aorta 1.86 ± 0.35 2.04 ± 0.51

Baseline lipid values* (mmol/L) and hs-CRP** (mg/L)

Total Cholesterol, mmol/L 4.60 ± 0.97 4.68 ± 1.14

HDL††-Cholesterol, mmol/L 1.08 ± 0.32 1.05 ± 0.21

LDL‡‡-Cholesterol, mmol/L 2.74 ± 0.79 2.84 ± 0.86

Triglycerides, mmol/L 1.69 ± 0.80 2.33 ± 1.72

hs-CRP**, mg/L 4.22 ± 3.66 4.28 ± 2.65

There was no statistically significant difference between the two groups. *mean ± SD, †n (%), ‡PASI:

psoriasis area severity index, §PET/CT: positron emission tomography – computed tomography,

||MeanMAX: average of maximum values; #TBR: target-to-background ratio, **hs-CRP: high-sensitivity

c-reactive protein, ††HDL: high density lipoprotein, ‡‡LDL: low density lipoprotein

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Table 2. Changes in target-to-background ratio on PET/CT imaging of ascending aorta and carotid

arteries.

PET/CT*

endpoints

Adalimumab†

(n=20)

Control†

(n=10)

Differences of

LSM †

95% Confidence

Interval

Primary: Change

in MeanMAX‡

TBR§ in vessel

with highest

baseline TBR§

-0.23 ± 0.07

p=0.004

-0.10 ± 0.11

p=0.35

-0.13 ± 0.13

p=0.32 (-0.40 to 0.14)

Change in

MeanMAX‡

TBR§ of carotid

arteries

-0.08 ± 0.08

p=0.33

0.24 ± 0.12

p=0.050

-0.32 ± 0.15

p=0.037 (-0.63 to -0.02)

Change in

MeanMAX‡

TBR§ of

ascending aorta

-0.17 ± 0.06

p=0.011

0.10 ± 0.09

p=0.28

-0.26 ± 0.11

p=0.021 (-0.48 to -0.04)

Change in MDS||

TBR§ in vessel

with highest

baseline TBR§

-0.37 ± 0.11

p=0.003

-0.21 ± 0.16

p=0.18

-0.15 ± 0.20

p=0.44 (-0.55 to 0.25)

Change in MDS||

TBR§ of carotid

arteries

-0.15 ± 0.08

p=0.065

0.10 ± 0.11

p=0.35

-0.25 ± 0.13

p=0.080 (-0.52 to 0.03)

± 0 15555555

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PET/CT*

endpoints

Adalimumab†

(n=20)

Control†

(n=10)

Differences of

LSM †

95% Confidence

Interval

Change in MDS||

TBR§ of

ascending aorta

-0.20 ± 0.07

p=0.009

0.08 ± 0.10

p=0.42

-0.29 ± 0.12

p=0.030 (-0.54 to -0.03)

Change in

MeanMEAN#

TBR§ in vessel

with highest

baseline TBR§

-0.18 ± 0.06

p=0.004

-0.09 ± 0.08

p=0.26

-0.09 ± 0.10

p=0.37 (-0.28 to 0.11)

Change in

MeanMEAN#

TBR§ of carotid

arteries

-0.11 ± 0.06

p=0.08

0.19 ± 0.09

p=0.042

-0.30 ± 0.11

p=0.011 (-0.52 to -0.08)

Change in

MeanMEAN#

TBR§ of

ascending aorta

-0.08 ± 0.04

p=0.067

0.12 ± 0.06

p=0.049

-0.19 ± 0.07

p=0.010 (-0.34 to 0.05)

*PET/CT: positron emission tomography – computed tomography, †LSM: least square means estimates ± SEM: standard error of the mean, ‡MeanMAX: average of maximum values; §TBR: target-to-background ratio, ||MDS: most diseased segment, #MeanMEAN: average of mean values.

0

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Figure Legends

Figure 1. Patient disposition in the study

Figure 2. Change from baseline in MeanMAX TBR in the vessel with the highest baseline TBR

(A) and ascending aorta (B) at Week 15. Box-plot representation with median, upper and lower

quartile and minimum and maximum value.

Figure 3. Representative examples of changes over time in arterial uptake of FDG on PET/CT

images from patients in the control group (A) and adalimumab group (B). Arrows indicate the

carotid artery.

Figure 4. High-sensitivity C-reactive protein (hs-CRP) levels at each visit for patients

randomized to adalimumab (square) and control (diamond). Geometric means ± SE and p-values

between groups are reported at each time point.

Figure 5. Mean serum concentration of HDL-cholesterol, LDL-cholesterol, total cholesterol and

triglycerides at each visit – adalimumab (A) and control (B). There were no significant changes

among groups for lipid values.

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Marie-Claude GuertinRobert Bissonnette, Jean-Claude Tardif, François Harel, Joséphine Pressacco, Chantal Bolduc and

TrialPositron Emission Tomography in Patients with Psoriasis: Results of a Randomized Controlled

Effects of the TNF alpha Antagonist Adalimumab on Arterial Inflammation Assessed by

Print ISSN: 1941-9651. Online ISSN: 1942-0080 Copyright © 2012 American Heart Association, Inc. All rights reserved.

TX 75231is published by the American Heart Association, 7272 Greenville Avenue, Dallas,Circulation: Cardiovascular Imaging

published online November 30, 2012;Circ Cardiovasc Imaging.

http://circimaging.ahajournals.org/content/early/2012/11/30/CIRCIMAGING.112.975730World Wide Web at:

The online version of this article, along with updated information and services, is located on the

http://circimaging.ahajournals.org//subscriptions/

is online at: Circulation: Cardiovascular Imaging Information about subscribing to Subscriptions:

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document. Permissions and Rights Question and Answer this process is available in the

located, click Request Permissions in the middle column of the Web page under Services. Further information aboutnot the Editorial Office. Once the online version of the published article for which permission is being requested is

can be obtained via RightsLink, a service of the Copyright Clearance Center,Circulation: Cardiovascular Imaging Requests for permissions to reproduce figures, tables, or portions of articles originally published inPermissions:



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http://circimaging.ahajournals.org/content/early/2012/11/30/CIRCIMAGING.112.975730

http://www.ahajournals.org/site/rights/

http://www.lww.com/reprints

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