Post on 14-Mar-2018
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: rbissonnette@innovaderm.ca
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
aging did not rrrrrrreefeeeee
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eenenenenen vascuuuulaaaaar rrr r annannand d dd d sysysysysystststststemememememicicicicic infnfnfnn lall mmmmatatatatatioioiooion nnnn inininiin pppppsososososoriasasasasasisisisss.
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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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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
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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.
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22
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.
al uptake of FDFDDDDDDG
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Baseline Week 15C
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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.
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The online version of this article, along with updated information and services, is located on the
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