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TNF-α Antagonist and Vascular Inflammation in Patients with Psoriasis Vulgaris: A Randomized Placebo-Controlled Study

Open ArchivePublished:March 09, 2017DOI:https://doi.org/10.1016/j.jid.2017.02.977
      Vascular inflammation is increased in patients with psoriasis. This randomized, double-blind, multicenter study evaluated the effects of tumor necrosis factor-α antagonist adalimumab on vascular inflammation in patients with psoriasis. A total of 107 patients were randomized (1:1) to receive adalimumab for 52 weeks or placebo for 16 weeks followed by adalimumab for 52 weeks. Vascular inflammation was assessed with positron emission tomography-computed tomography. There were no differences in the change from baseline in vessel wall target-to-background ratio (TBR) from the ascending aorta (primary endpoint) (adalimumab: TBR = 0.002, 95% confidence interval [CI] = –0.048 to 0.053; placebo: TBR = –0.002, 95% CI = –0.053 to 0.049; P = 0.916) and the carotids (adalimumab: TBR = 0.031, 95% CI = –0.005 to 0.066; placebo: TBR = 0.018, 95% CI = –0.019 to 0.055; P = 0.629) at week 16 between adalimumab and placebo. After 52 weeks of treatment with adalimumab there was no significant change from start of treatment in TBR from the ascending aorta (TBR = –0.006, 95% CI = –0.049 to 0.038; P = 0.796), but there was an increase in TBR in carotids (TBR = 0.027, 95% CI = 0.000 to 0.054; P = 0.046). This study showed no difference over 16 weeks in vascular inflammation in patients treated with a tumor necrosis factor-α antagonist or placebo and a modest increase in vascular inflammation in carotids after 52 weeks of treatment with adalimumab.

      Abbreviations:

      18FDG (18-fluoro-2-deoxy-d-glucose), hs-CRP (high-sensitivity C-reactive protein), PASI (Psoriasis Area Severity Index), PET/CT (position emission tomography-computed tomography), TBR (target-to-background ratio), TNF-α (tumor necrosis factor alpha)

      Introduction

      Psoriasis is an immune-mediated skin disease with a reported prevalence as high as 2% in the North American and European populations (
      • Boehncke W.H.
      • Schon M.P.
      Psoriasis.
      ). Several studies have reported a higher risk of myocardial infarction and stroke in patients with psoriasis (
      • Gelfand J.M.
      • Neimann A.L.
      • Shin D.B.
      • Wang X.
      • Margolis D.J.
      • Troxel A.B.
      Risk of myocardial infarction in patients with psoriasis.
      ,
      • Horreau C.
      • Pouplard C.
      • Brenaut E.
      • Barnetche T.
      • Misery L.
      • Cribier B.
      • et al.
      Cardiovascular morbidity and mortality in psoriasis and psoriatic arthritis: a systematic literature review.
      ,
      • Levesque A.
      • Lachaine J.
      • Bissonnette R.
      Risk of myocardial infarction in canadian patients with psoriasis: a retrospective cohort study.
      ,
      • Samarasekera E.J.
      • Neilson J.M.
      • Warren R.B.
      • Parnham J.
      • Smith C.H.
      Incidence of cardiovascular disease in individuals with psoriasis: a systematic review and meta-analysis.
      ). In addition, some studies using data from registries and public or private public health organizations have suggested that treatment of psoriasis or rheumatoid arthritis with methotrexate or tumor necrosis factor-α (TNF-α) antagonists could reduce the risk of myocardial infarction (
      • Ahlehoff O.
      • Skov L.
      • Gislason G.
      • Gniadecki R.
      • Iversen L.
      • Bryld L.E.
      • et al.
      Cardiovascular outcomes and systemic anti-inflammatory drugs in patients with severe psoriasis: 5-year follow-up of a Danish nationwide cohort.
      ,
      • Hugh J.
      • Van Voorhees A.S.
      • Nijhawan R.I.
      • Bagel J.
      • Lebwohl M.
      • Blauvelt A.
      • et al.
      From the medical board of the National Psoriasis Foundation: the risk of cardiovascular disease in individuals with psoriasis and the potential impact of current therapies.
      ,
      • Wu J.J.
      • Poon K.Y.
      • Channual J.C.
      • Shen A.Y.
      Association between tumor necrosis factor inhibitor therapy and myocardial infarction risk in patients with psoriasis.
      ), whereas others have suggested no effect (
      • Abuabara K.
      • Lee H.
      • Kimball A.B.
      The effect of systemic psoriasis therapies on the incidence of myocardial infarction: a cohort study.
      ). The mechanisms involved in this putative decrease in incidence of myocardial infarction are currently unknown and should be further investigated.
      One possible explanation for the reported decrease in risks of myocardial infarction with methotrexate and TNF-α antagonist is an effect on vascular inflammation. Atherosclerosis is characterized by a significant increase in vascular wall infiltration by cells involved in innate and acquired immunity, including T cells and macrophages (
      • Libby P.
      • Ridker P.M.
      • Hansson G.K.
      Progress and challenges in translating the biology of atherosclerosis.
      ). An increase in proinflammatory cytokines, including IFN-γ and TNF-α, has also been reported in atheromatous plaques (
      • Libby P.
      • Ridker P.M.
      • Hansson G.K.
      Progress and challenges in translating the biology of atherosclerosis.
      ). TNF-α, one of the central cytokines in the pathophysiology of psoriasis, has important pro-atherosclerotic effects in hypercholesterolemic mice and is believed to play an important role in vascular inflammation (
      • Libby P.
      • Ridker P.M.
      • Hansson G.K.
      Progress and challenges in translating the biology of atherosclerosis.
      ).
      Position emission tomography-computed tomography (PET/CT) can be used to measure uptake of radiolabeled 18fluoro-2-deoxy-d-glucose (18FDG) as a possible reflection of vascular inflammation (
      • Emami H.
      • Tawakol A.
      Noninvasive imaging of arterial inflammation using FDG-PET/CT.
      ). We conducted a pilot study in which 30 patients with psoriasis were randomized (2:1) to adalimumab or a control group to study the effect of blocking TNF-α on vascular inflammation (
      • Bissonnette R.
      • Tardif J.C.
      • Harel F.
      • Pressacco J.
      • Bolduc C.
      • Guertin M.C.
      Effects of the tumor necrosis factor-alpha antagonist adalimumab on arterial inflammation assessed by positron emission tomography in patients with psoriasis: results of a randomized controlled trial.
      ). In that study, there was no difference in change from baseline in vascular inflammation present in the vessel (ascending aorta or carotid), with the highest baseline inflammation after 15 weeks of treatment as the primary endpoint. However, there was a significant decrease in vascular inflammation for patients randomized to adalimumab compared with those randomized to placebo when the ascending aorta and carotid arteries were analyzed separately. The main objective of this trial was to study the effects of blocking TNF-α with adalimumab on 18FDG uptake as a biomarker of vascular inflammation in patients with moderate to severe psoriasis vulgaris.

      Results

      A total of 107 patients were randomized in the study. Patient disposition is presented in Figure 1, and baseline demographics are presented in Table 1. There was no difference in the change from baseline in target-to-background ratio (TBR) from the ascending aorta (TBR = 0.004; P = 0.916) and the mean of carotid arteries (TBR = 0.013; P = 0.629) at week 16 between patients randomized to adalimumab and placebo (Table 2). There was no significant change from the start of treatment in TBR from the ascending aorta after 52 weeks of continuous treatment with adalimumab (TBR = –0.006; P = 0.796), but there was an increase in TBR in carotid arteries after 52 weeks of treatment with adalimumab (TBR = 0.027; P = 0.046) (Table 2). There was no difference in the change from baseline in carotid wall area with atherosclerosis at week 16 between patients randomized to adalimumab and placebo (P = 0.680) (Table 2). At week 16, in the per-protocol population, there was an increase in carotid wall area of 0.86% for patients randomized to placebo and a decrease of 2.70% for patients randomized to adalimumab, but the difference between the two groups was not statistically significant (P = 0.157). The correlation coefficient (r) between the change from baseline in carotid wall area and the change from baseline in Psoriasis Area and Severity Index (PASI) was 0.08 (P = 0.785) for the placebo group and 0.31 (P = 0.183) for the adalimumab group at week 16. There was no significant change from the start of treatment in carotid wall area after 52 weeks of continuous treatment with adalimumab (–2.02%, P = 0.232) (Table 2).
      Figure 1
      Figure 1CONSORT diagram. SAE, serious adverse event.
      Table 1Baseline demographics and clinical characteristics
      CharacteristicPlaceboAdalimumab
      Baseline demographicsn = 53n = 54
       Age in years, mean ± standard deviation50.5 ± 12.448.9 ± 11.6
      Sex, n (%)
       Female16 (30.2)13 (24.1)
       Male37 (69.8)41 (75.9)
      Race, n (%)
       Asian1 (1.9)0 (0.0)
       Black2 (3.8)3 (5.6)
       White50 (94.3)49 (90.7)
       Other0 (0.0)2 (3.7)
      Ethnicity, n (%)
       Hispanic0 (0.0)1 (1.9)
       Non-Hispanic53 (100.0)53 (98.1)
      Weight in kg, mean ± standard deviation93.63 ± 22.1495.05 ± 21.09
      Psoriasis severityn = 53n = 54
       PASI, mean ± standard deviation9.54 ± 4.7810.12 ± 4.47
       PGA, n (%)
      22 (3.8)3 (5.6)
      333 (62.3)34 (63.0)
      417 (32.1)17 (31.5)
      51 (1.9)0 (0.0)
      Body surface area with psoriasis, mean ± standard deviation9.93 ± 9.9511.14 ± 10.93
      Baseline cardiovascular characteristics
       Baseline PET/CT values, mean ± standard deviation
      MeanMax TBR, # of ascending aortan = 53n = 54
      1.893 ± 0.2601.902 ± 0.193
      MeanMax TBR, # of carotid arteriesn = 46n = 50
      1.594 ± 0.2261.571 ± 0.182
       Carotid wall area in mm2, mean ± standard deviation (geometric mean)n = 15n = 20
      32.01 ± 10.11 (30.66)34.93 ± 10.70 (33.50)
       hs-CRP in mg/L, mean ± standard deviation (geometric mean)n = 53n = 54
      5.32 ± 6.27 (3.16)2.72 ± 2.75 (1.80)
      Abbreviations: hs-CRP, high-sensitivity C-reactive protein; MeanMax, mean of maximum values; PASI, Psoriasis Area Severity Index; PET/CT, positron emission tomography-computed tomography; PGA, Physician Global Assessment; TBR, target-to-background ratio.
      Table 2Changes from baseline in imaging endpoints and hs-CRP
      PET/CT EndpointsWeek 16
      Mean change or geometric mean percentage change with (95% confidence interval), adjusted for baseline value and randomization group. P-value for the group comparison.
      52 Weeks after First Dose of Adalimumab
      Mean change or geometric mean percentage change with (95% confidence interval), adjusted for randomization group. P-value for the change.
      PlaceboAdalimumabAll patients
      Change from baseline in MeanMax TBR from the ascending aortan = 53n = 54n = 103
      –0.002 (–0.053 to 0.049)0.002 (–0.048 to 0.053)–0.006 (–0.049 to 0.038)
      P = 0.916P = 0.796
      Change from baseline in MeanMax TBR of carotid arteriesn = 46n = 50n = 93
      0.018 (–0.019 to 0.055)0.031 (–0.005 to 0.066)0.027 (0.000 to 0.054)
      P = 0.629P = 0.046
      Percentage change from baseline in carotid wall area
      Based on log-transformed data.
      n = 15n = 20n = 35
      –0.27 (–4.10 to 3.71)–1.33 (–4.62 to 2.07)–2.02 (–5.29 to 1.38)
      P = 0.680P = 0.232
      Percentage change from baseline in hs-CRP
      Based on log-transformed data.
      n = 53n = 54n = 103
      1.09 (–16.30 to 22.10)–28.67 (–40.83 to –14.01)–33.535 (–44.522 to –20.373)
      P = 0.012P < 0.001
      Abbreviations: hs-CRP, high-sensitivity C-reactive protein; MeanMax, mean of maximum values; PET/CT, positron emission tomography-computed tomography; TBR, target-to-background ratio.
      1 Mean change or geometric mean percentage change with (95% confidence interval), adjusted for baseline value and randomization group. P-value for the group comparison.
      2 Mean change or geometric mean percentage change with (95% confidence interval), adjusted for randomization group. P-value for the change.
      3 Based on log-transformed data.
      There was a decrease in high-sensitivity C-reactive protein (hs-CRP) levels of 28.7% at week 16 for patients randomized to adalimumab and a slight increase of 1.1% for patients randomized to placebo. The difference between adalimumab and placebo in change from baseline in hs-CRP at week 16 was statistically significant (P = 0.012). There was no significant difference between the two groups in changes in low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride levels at week 16 (not shown).
      There was a positive correlation between baseline PASI and serum levels of TNF-α (P = 0.023), IL-17A (P = 0.026), and S100A9 (P = 0.009), a trend toward a positive correlation between PASI and IL-22 (P = 0.057), but no trend between PASI and IL-6 serum levels (P = 0.712) (Figure 2). There was no significant correlation between baseline TBR and baseline levels of TNF-α, IL-17A, IL-22, S100A9, IL-6, IL-8, and IL-10. There was no significant correlation between the change from the start of treatment in TBR in the ascending aorta and the change from baseline in PASI at week 52 (r = 0.1017, P = 0.307). There was no correlation between change from baseline in PASI at week 16 and change from baseline in hs-CRP in the placebo (r = –0.1351, P = 0.335) and adalimumab groups (r = –0.0226, P = 0.871).
      Figure 2
      Figure 2Association between PASI at baseline and baseline cytokines levels. There was a significant positive correlation between PASI and serum levels of TNF-α, IL-17A, and S100A9 and a trend with IL-22. There was no significant correlation between PASI and serum levels of IL-6. PASI, Psoriasis Area and Severity Index.
      Adalimumab was on average well tolerated. There were six serious adverse events that all occurred while patients were taking adalimumab. Three were determined to be at least possibly related to adalimumab by the investigator (viral syndrome with bronchitis and neutropenia, pneumonia, and cellulitis), and three were evaluated as nonrelated to adalimumab (sciatalgia, Legionnaire’s disease, and ureteral cancer).

      Discussion

      PET/CT imaging after injection of 18FDG is increasingly used as a potential measure of vascular inflammation (
      • Emami H.
      • Tawakol A.
      Noninvasive imaging of arterial inflammation using FDG-PET/CT.
      ,
      • Joshi N.V.
      • Vesey A.
      • Newby D.E.
      • Dweck M.R.
      Will 18F-sodium fluoride PET-CT imaging be the magic bullet for identifying vulnerable coronary atherosclerotic plaques?.
      ). 18FDG uptake correlates positively with inflammation in carotid arteries at the histological level and has been shown to be predictive of occlusive arterial events in a cohort of 932 oncology patients followed up over time (
      • Rominger A.
      • Saam T.
      • Wolpers S.
      • Cyran C.C.
      • Schmidt M.
      • Foerster S.
      • et al.
      18F-FDG PET/CT identifies patients at risk for future vascular events in an otherwise asymptomatic cohort with neoplastic disease.
      ,
      • Tawakol A.
      • Fayad Z.A.
      • Mogg R.
      • Alon A.
      • Klimas M.T.
      • Dansky H.
      • et al.
      Intensification of statin therapy results in a rapid reduction in atherosclerotic inflammation: results of a multicenter fluorodeoxyglucose-positron emission tomography/computed tomography feasibility study.
      ). Statins, which are known to decrease the risk of myocardial infarction even in patients with normal cholesterol levels, have been shown to decrease vascular inflammation (
      • Tahara N.
      • Kai H.
      • Ishibashi M.
      • Nakaura H.
      • Kaida H.
      • Baba K.
      • et al.
      Simvastatin attenuates plaque inflammation: evaluation by fluorodeoxyglucose positron emission tomography.
      ,
      • Tawakol A.
      • Fayad Z.A.
      • Mogg R.
      • Alon A.
      • Klimas M.T.
      • Dansky H.
      • et al.
      Intensification of statin therapy results in a rapid reduction in atherosclerotic inflammation: results of a multicenter fluorodeoxyglucose-positron emission tomography/computed tomography feasibility study.
      ,
      • Watanabe T.
      • Kawasaki M.
      • Tanaka R.
      • Ono K.
      • Kako N.
      • Saeki M.
      • et al.
      Anti-inflammatory and morphologic effects of pitavastatin on carotid arteries and thoracic aorta evaluated by integrated backscatter trans-esophageal ultrasound and PET/CT: a prospective randomized comparative study with pravastatin (EPICENTRE study).
      ,
      • Wu Y.W.
      • Kao H.L.
      • Huang C.L.
      • Chen M.F.
      • Lin L.Y.
      • Wang Y.C.
      • et al.
      The effects of 3-month atorvastatin therapy on arterial inflammation, calcification, abdominal adipose tissue and circulating biomarkers.
      ). In one of these studies, 43 patients who underwent 18FDG PET/CT for cancer screening were randomized to simvastatin or dietary management. In that study, vascular inflammation was significantly decreased after 12 weeks in the simvastatin group but not in the control group (
      • Tahara N.
      • Kai H.
      • Ishibashi M.
      • Nakaura H.
      • Kaida H.
      • Baba K.
      • et al.
      Simvastatin attenuates plaque inflammation: evaluation by fluorodeoxyglucose positron emission tomography.
      ). A decrease in TBR of 0.2 has been observed with statins and is likely to be clinically meaningful (
      • Singh P.
      • Emami H.
      • Subramanian S.
      • Maurovich-Horvat P.
      • Marincheva-Savcheva G.
      • Medina H.M.
      • et al.
      Coronary plaque morphology and the anti-inflammatory impact of atorvastatin: a multicenter 18F-fluorodeoxyglucose positron emission tomographic/computed tomographic study.
      ). Intensive statin therapy with atorvastatin at 80 mg daily has also been shown to both improve cardiovascular outcomes and reduce TBR better than lower-dose treatment with atorvastatin at 10 mg daily (
      • Tawakol A.
      • Fayad Z.A.
      • Mogg R.
      • Alon A.
      • Klimas M.T.
      • Dansky H.
      • et al.
      Intensification of statin therapy results in a rapid reduction in atherosclerotic inflammation: results of a multicenter fluorodeoxyglucose-positron emission tomography/computed tomography feasibility study.
      ). Recent advances in the understanding of 18FDG uptake have shown that the marker is also taken up by endothelial and smooth muscle cells, suggesting that its accumulation is dependent not only on vascular inflammation (
      • Brammen L.
      • Steiner S.
      • Berent R.
      • Sinzinger H.
      Molecular imaging of atherosclerotic lesions by positron emission tomography—can it meet the expectations?.
      ).
      Studies using 18FDG PET/CT have shown that vascular inflammation is increased in patients with psoriasis compared with age- and comorbidity-matched control subjects (
      • Mehta N.N.
      • Yu Y.
      • Saboury B.
      • Foroughi N.
      • Krishnamoorthy P.
      • Raper A.
      • et al.
      Systemic and vascular inflammation in patients with moderate to severe psoriasis as measured by [18F]-fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET/CT): a pilot study.
      ,
      • Naik H.B.
      • Natarajan B.
      • Stansky E.
      • Ahlman M.A.
      • Teague H.
      • Salahuddin T.
      • et al.
      Severity of psoriasis associates with aortic vascular inflammation detected by FDG PET/CT and neutrophil activation in a prospective observational study.
      ,
      • Rose S.
      • Sheth N.H.
      • Baker J.F.
      • Ogdie A.
      • Raper A.
      • Saboury B.
      • et al.
      A comparison of vascular inflammation in psoriasis, rheumatoid arthritis, and healthy subjects by FDG-PET/CT: a pilot study.
      ). This increase in vascular inflammation is present even in patients with milder psoriasis (
      • Rose S.
      • Sheth N.H.
      • Baker J.F.
      • Ogdie A.
      • Raper A.
      • Saboury B.
      • et al.
      A comparison of vascular inflammation in psoriasis, rheumatoid arthritis, and healthy subjects by FDG-PET/CT: a pilot study.
      ,
      • Youn S.W.
      • Kang S.Y.
      • Kim S.A.
      • Park G.Y.
      • Lee W.W.
      Subclinical systemic and vascular inflammation detected by (18) F-fluorodeoxyglucose positron emission tomography/computed tomography in patients with mild psoriasis.
      ). A 18FDG PET/CT study performed in Korea comparing 10 patients with mild psoriasis (defined as having a body surface area involved of less than 5%) to 10 sex- and age-matched control subjects without psoriasis showed that vascular inflammation was higher in patients with mild psoriasis (
      • Youn S.W.
      • Kang S.Y.
      • Kim S.A.
      • Park G.Y.
      • Lee W.W.
      Subclinical systemic and vascular inflammation detected by (18) F-fluorodeoxyglucose positron emission tomography/computed tomography in patients with mild psoriasis.
      ). This study suggests that the increase in vascular inflammation is not restricted to psoriatic patients with severe skin involvement.
      Few studies have investigated the effects of blocking TNF-α on vascular inflammation. In a 30-patient study in which patients with moderate to severe psoriasis were randomized (2:1) to adalimumab or placebo, we observed no significant difference in vascular inflammation when the vessel with the highest baseline TBR was selected for analysis (primary endpoint) (
      • Bissonnette R.
      • Tardif J.C.
      • Harel F.
      • Pressacco J.
      • Bolduc C.
      • Guertin M.C.
      Effects of the tumor necrosis factor-alpha antagonist adalimumab on arterial inflammation assessed by positron emission tomography in patients with psoriasis: results of a randomized controlled trial.
      ). However, there was a decrease in vascular inflammation in patients randomized to adalimumab when inflammation in the ascending aorta and carotid arteries was studied in each vessel individually. An open-label study of 17 patients with rheumatoid arthritis treated with either adalimumab or etanercept showed a decrease in vascular inflammation after 8 weeks of therapy compared with baseline (
      • Maki-Petaja K.M.
      • Elkhawad M.
      • Cheriyan J.
      • Joshi F.R.
      • Ostor A.J.
      • Hall F.C.
      • et al.
      Anti-tumor necrosis factor-alpha therapy reduces aortic inflammation and stiffness in patients with rheumatoid arthritis.
      ). However, this study did not include a placebo or control group. In addition, a number of studies looking at measuring the effect of various treatments on vascular inflammation in patients with psoriasis are currently ongoing.
      With a total of 107 patients, this study is, to our knowledge, the largest published placebo-controlled trial investigating the effects of a TNF-α antagonist on vascular inflammation. The study showed no difference between adalimumab and placebo in change from baseline vascular inflammation in the aorta and carotid arteries after 16 weeks of treatment with adalimumab, no change from start of treatment after 52 weeks of treatment with adalimumab in the ascending aorta, and a modest increase in vascular inflammation in carotids after 52 weeks of treatment with adalimumab. There was a significant effect of adalimumab on hs-CRP levels, suggesting that adalimumab has an effect on systemic inflammation. These results suggest that adalimumab does not decrease vascular inflammation in patients with psoriasis. Moreover, the increase in carotid vascular inflammation observed after 52 weeks of treatment suggests that adalimumab cannot completely prevent the natural progression of carotid wall atherosclerosis in patients with psoriasis. The 16-week placebo-controlled phase of the current study prevented us from comparing long-term treatments of adalimumab and placebo on vascular inflammation. Based on studies showing no decrease in carotid atherosclerosis after long-term treatment with a TNF-α antagonist, future studies using an active comparator should assess the effect of blocking TNF-α on the natural progression of atherosclerosis (
      • Ramonda R.
      • Puato M.
      • Punzi L.
      • Rattazzi M.
      • Zanon M.
      • Balbi G.
      • et al.
      Atherosclerosis progression in psoriatic arthritis patients despite the treatment with tumor necrosis factor-alpha blockers: a two-year prospective observational study.
      ,
      • van Sijl A.M.
      • van Eijk I.C.
      • Peters M.J.
      • Serne E.H.
      • van der Horst-Bruinsma I.E.
      • Smulders Y.M.
      • et al.
      Tumour necrosis factor blocking agents and progression of subclinical atherosclerosis in patients with ankylosing spondylitis.
      ). Further long-term studies with an active comparator should explore this hypothesis. Another limitation of our study is that there was a statistically significant difference in baseline hs-CRP between the two groups, with levels being more than 1.75 times higher in the placebo group (P = 0.003), although groups were well balanced in terms of baseline PASI, body surface area, physician global assessment, and TBR. The impact of this difference on vascular inflammation response to TNF-α blockade is unknown, but statistical analysis was adjusted to take these differences into account. Based on a mean PASI of 9.8 at baseline, most patients included in this study had moderate psoriasis. It is possible that adalimumab may have a different effect on vascular inflammation in patients with psoriasis who have a more severe and extensive disease. Only 10.3% of patients enrolled in this study had a history of psoriatic arthritis. Gene expression of peripheral blood mononuclear cells of patients with psoriatic arthritis is different from patients who have only skin psoriasis (
      • Pollock R.A.
      • Abji F.
      • Liang K.
      • Chandran V.
      • Pellett F.J.
      • Virtanen C.
      • et al.
      Gene expression differences between psoriasis patients with and without inflammatory arthritis.
      ). In addition, the presence of sacroiliitis has been shown to be associated with increased vascular inflammation in patients with psoriatic arthritis (
      • Rose S.
      • Dave J.
      • Millo C.
      • Naik H.B.
      • Siegel E.L.
      • Mehta N.N.
      Psoriatic arthritis and sacroiliitis are associated with increased vascular inflammation by 18-fluorodeoxyglucose positron emission tomography computed tomography: baseline report from the Psoriasis Atherosclerosis and Cardiometabolic Disease Initiative.
      ). IL-6 levels, which are known to be elevated in patients with psoriatic arthritis and have been shown to correlate with vascular inflammation (
      • Alenius G.M.
      • Eriksson C.
      • Rantapaa Dahlqvist S.
      Interleukin-6 and soluble interleukin-2 receptor alpha-markers of inflammation in patients with psoriatic arthritis?.
      ,
      • Mani V.
      • Woodward M.
      • Samber D.
      • Bucerius J.
      • Tawakol A.
      • Kallend D.
      • et al.
      Predictors of change in carotid atherosclerotic plaque inflammation and burden as measured by 18-FDG-PET and MRI, respectively, in the dal-PLAQUE study.
      ), were generally low at baseline in our patient population. This suggests that vascular inflammation may be quantitatively and qualitatively different in patients with psoriatic arthritis and that the effect of blocking vascular inflammation on this patient population should be specifically investigated.
      The effect of TNF-α antagonists on carotid atherosclerosis is not well known. In a series of 16 patients with psoriasis treated for 6 months with a TNF-α antagonist, a decrease in carotid intima media thickness was observed (
      • Jokai H.
      • Szakonyi J.
      • Kontar O.
      • Marschalko M.
      • Szalai K.
      • Karpati S.
      • et al.
      Impact of effective tumor necrosis factor-alfa inhibitor treatment on arterial intima-media thickness in psoriasis: results of a pilot study.
      ). However, in another study of 32 patients with psoriatic arthritis treated with different TNF-α antagonists for a period of 2 years, an increase in carotid intima media thickness was observed with ultrasonography (
      • Ramonda R.
      • Puato M.
      • Punzi L.
      • Rattazzi M.
      • Zanon M.
      • Balbi G.
      • et al.
      Atherosclerosis progression in psoriatic arthritis patients despite the treatment with tumor necrosis factor-alpha blockers: a two-year prospective observational study.
      ). In a different series of 67 patients with ankylosing spondylitis who were using TNF-α antagonists and were followed up for 4.9 years, no change in carotid atherosclerosis was seen in patients treated continuously with a TNF-α antagonist, but progression of carotid atherosclerosis was seen in patients who stopped taking the TNF-α antagonist (
      • van Sijl A.M.
      • van Eijk I.C.
      • Peters M.J.
      • Serne E.H.
      • van der Horst-Bruinsma I.E.
      • Smulders Y.M.
      • et al.
      Tumour necrosis factor blocking agents and progression of subclinical atherosclerosis in patients with ankylosing spondylitis.
      ). These studies suggest that blocking TNF-α antagonist may slow down, but not reverse, the progression of carotid atherosclerosis. These results are similar to our observations on carotid atherosclerosis in patients with psoriasis treated with adalimumab for a period of 1 year.
      Correlation analysis between TBR and circulating levels of various cytokines was performed to identify potential therapeutic targets to improve vascular inflammation. However, there was no significant correlation between levels of all cytokines studied, including TNF-α, and vascular inflammation. There were positive correlations between PASI and circulating levels of TNF-α, IL-17A, S100A9, and IL-22, which have been reported before in patients with psoriasis (
      • Benoit S.
      • Toksoy A.
      • Ahlmann M.
      • Schmidt M.
      • Sunderkötter C.
      • Foell D.
      • et al.
      Elevated serum levels of calcium-binding S100 proteins A8 and A9 reflect disease activity and abnormal differentiation of keratinocytes in psoriasis.
      ,
      • Lo Y.H.
      • Torii K.
      • Saito C.
      • Furuhashi T.
      • Maeda A.
      • Morita A.
      Serum IL-22 correlates with psoriatic severity and serum IL-6 correlates with susceptibility to phototherapy.
      ,
      • Mussi A.
      • Bonifati C.
      • Carducci M.
      • D'Agosto G.
      • Pimpinelli F.
      • D'Urso D.
      • et al.
      Serum TNF-α levels correlate with disease severity and are reduced by effective therapy in plaque-type psoriasis.
      ,
      • Yilmaz S.B.
      • Cicek N.
      • Coskun M.
      • Yegin O.
      • Alpsoy E.
      Serum and tissue levels of IL-17 in different clinical subtypes of psoriasis.
      ). Serum levels of IL-6 have been shown to correlate with vascular inflammation in previous studies (
      • Mani V.
      • Woodward M.
      • Samber D.
      • Bucerius J.
      • Tawakol A.
      • Kallend D.
      • et al.
      Predictors of change in carotid atherosclerotic plaque inflammation and burden as measured by 18-FDG-PET and MRI, respectively, in the dal-PLAQUE study.
      ). Serum levels of IL-6 were low in our patient population, possibly because of the small proportion of patients with psoriatic arthritis.
      In conclusion, this study showed no difference in vascular inflammation after 16 weeks in patients treated with the TNF-α antagonist adalimumab compared with those treated with placebo. Future studies on the effect of blocking TNF-α on vascular inflammation should involve patients with more extensive skin psoriasis and patients with psoriatic arthritis and should compare the long-term treatment with a TNF-α antagonist to another non–TNF-α–blocking active treatment.

      Methods

      Participants

      This multicenter study was conducted at four centers in Canada from December 2012 through September 2015. Patients were 18–80 years of age with moderate to severe psoriasis, defined as having involved body surface area of at least 5%. Patients using medication to control angina, hypertension, or lipids had to be receiving a stable dosage for at least 8 weeks before baseline. The main exclusion criteria were pregnancy; active infections; use of a biologic within 12 weeks of day 0; use of an oral medication to treat psoriasis within 4 weeks of day 0; use of a topical treatment or UVB phototherapy for psoriasis within 2 weeks of day 0; or a history of myocardial infarction, acute coronary syndrome, or percutaneous coronary intervention, stent installation, or carotid revascularization within 12 weeks of day 0. This study was conducted in compliance with the declaration of Helsinki, was approved by an ethics committee (IRB Services, Aurora, ON), and written informed consent was obtained from each patient. This study was registered on ClinicalTrial.gov (NCT01722214) before patient recruitment began.

      Assignment

      Patients were randomized (1:1) to receive adalimumab 80 mg followed by 40 mg at week 1 and 40 mg every other week for 52 weeks or to receive placebo for 16 weeks followed by adalimumab 80 mg at week 16, 40 mg at week 17, and 40 mg every other week thereafter, for a total of 52 weeks of adalimumab treatment for each of the two cohorts. A computer-generated randomization list stratified by centers with block size of two prepared by AbbVie (Lake County, IL; previously Abbott Laboratories) was used to allocate patients to therapy.

      Masking

      Each center received blinded medication kits to be used sequentially in ascending order, starting with the lowest number received. The investigator, patient, and study staff were blinded until a patient approached the week 52 visit, when unblinding was required to determine if the patient had to end the study at week 52 visit or continue until week 68. The patient was unblinded along with the patient randomized in his/her block of two, thereby ensuring that the week 16 data were cleaned and locked.

      Analysis

      A PET/CT scan was performed after injection of 18FDG at baseline, week 16, and week 52/week 68. Details of imaging procedures and analyses have been published previously (
      • Bissonnette R.
      • Tardif J.C.
      • Harel F.
      • Pressacco J.
      • Bolduc C.
      • Guertin M.C.
      Effects of the tumor necrosis factor-alpha antagonist adalimumab on arterial inflammation assessed by positron emission tomography in patients with psoriasis: results of a randomized controlled trial.
      ). PET/CT imaging was performed at different centers, but all images were analyzed by the Montreal Heart Institute core laboratory. PET/CT scan facilities had to run a test PET/CT with a phantom to be qualified for the study. Fasting serum glucose levels were checked by glucometer to ensure glucose levels of less than 11.1 mmol/L before 18FDG administration. Subjects were injected with 10 millicuries of 18FDG. Care was taken to ensure that imaging was performed at the same time interval (within 2 hours) after 18FDG injection for a given subject. CT scan was acquired (140 kV, 80 mA, 3.2-mm slice thickness) for co-registration and attenuation correction. A chest PET scan was performed from the aortic arch to the diaphragm, which was reconstructed using the ordered subset expectation maximization algorithm with corrections applied for normalization, dead time, random events, scatter, attenuation, and sensitivity. A 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 also reconstructed using the ordered subset expectation maximization iterative algorithm. To be eligible, patients had to have a TBR of at least 1.6.
      High-resolution magnetic resonance imaging of the carotid arteries was performed at baseline, week 16, and week 52/week 68 in a subset of patients seen at the Montreal center using a 3 Tesla MRI Scanner (Magneton Skyra A-Tim-Dot, Siemens, Germany). The carotid wall area was measured with the MRI Plaque view software (VP diagnostic, Seattle, WA).
      Psoriasis severity was assessed with the PASI (
      • Fredriksson T.
      • Pettersson U.
      Severe psoriasis—oral therapy with a new retinoid.
      ), a six-scale physician global assessment (

      Ko H-S. Clinical design for psoriasis. Presented at: Dermatologic and Ophthalmic Drugs Advisory Committee 49th Meeting Open Session (Volume II). 20 March 1998; Gaithersburg, MD.

      ), and by evaluating the body surface area involved with psoriasis. The primary endpoint was the change from baseline in the TBR from the ascending aorta at week 16. Secondary endpoints included change from baseline in the mean TBR from the carotid arteries and in hs-CRP levels at week 16, change from the start of treatment in TBR from the ascending aorta and in TBR from the mean of carotid arteries 52 weeks after the first dose of adalimumab, change from baseline in carotid wall area at week 16 as measured by magnetic resonance imaging, and change from start of treatment in carotid wall area as measured by magnetic resonance imaging 52 weeks after the first dose of adalimumab. Levels of IL-17 and IL-22 were measured at baseline using the Singulex immunoassay platform (Singulex, Alameda, CA). Baseline serum levels of TNF-α, IL-6, and S100A9 were measured by multiplex ELISA.

      Statistical analysis

      A sample size of 106 had a power of 0.80 to detect a difference of 0.2 or more of change from baseline in TBR from the ascending aorta at week 16 between patients randomized to adalimumab and placebo, assuming a common standard deviation of 0.35, a two-sided alpha level of 0.05, and a dropout rate of 5%. For missing follow-up data, the last observation carried forward approach was used. Baseline demographics and psoriasis severity are presented as mean ± standard deviation or count and proportion (n [%]). Baseline cardiovascular characteristics are presented as mean ± standard deviation and geometric mean, where appropriate. Changes in TBR (mean of maximum values) from the ascending aorta at week 16 were analyzed using an analysis of covariance model that included a term for randomization group (placebo and adalimumab) and for the baseline value of TBR (mean of maximum values) from the ascending aorta. A similar model was also used to analyze change from baseline in TBR (mean of maximum values) from the mean of the carotid arteries, in carotid wall area, in hs-CRP, and in lipid levels at week 16. Changes from start of treatment to 52 weeks after the first dose of adalimumab were analyzed using an analysis of variance model including a term for the randomization group. Of note, for the analyses of endpoints 52 weeks after the first dose of adalimumab, week 16 values served as the baseline for subjects randomized to placebo. Changes from baseline are presented as adjusted means with 95% confidence intervals. Before analyses, a logarithmic transformation was applied to hs-CRP and carotid wall area. Adjusted geometric mean percentage changes are presented for these parameters. The relationships between TBR and PASI, carotid wall area and PASI, baseline PASI and baseline cytokine levels, and PASI and hs-CRP were analyzed using the Pearson correlation except for the correlation between baseline PASI and baseline IL-17A, for which the Spearman rho coefficient was used because of the presence of outlier values. All analyses were conducted on the intent-to-treat population. Sensitivity analyses were also performed on a per-protocol population for the primary and secondary endpoints. Reported results are for the intent-to-treat population unless mentioned otherwise. All statistical tests were two-sided and were performed at a significance level of 0.05. Analyses were performed using SAS version 9.4 (SAS Institute, Inc., Cary, NC) or SPSS version 22 (for correlation analyses; IBM, Amonk, NY).

      Conflict of Interest

      Robert Bissonnette has received grants and research support, served as a consultant, or received honoraria from Abbvie, Amgen, ApoPharma, Boehringer Ingelheim, Celgene, Dermira, Eli Lilly, Galderma, GSK-Stiefel, Merck, Incyte, Janssen, Kineta, Leo Pharma, Novartis, Pfizer, Tribute, and Xenoport. James G. Krueger reports grants paid to his Institution from Novartis, Pfizer, Janssen, Lilly, Kadmon, Dermira, Boehringer, BMS, Paraxel, Kineta, Leo Pharma, Amgen, Innovaderm Research, Vitae, Provectus, and Kyowa and personal fees from Novartis, Pfizer, Janssen, Lilly, Kadmon, Dermira, Boehringer, BMS, Kineta, Merck, Serono, Biogen ldec, Delenex, AbbVie, Sanofi, Baxter, and Xenoport. Catherine Maari has received grants and research support, served as a consultant or received honoraria from Abbvie, Amgen, ApoPharma, Boehringer Ingelheim, Celgene, Dermira, Eli Lilly, Galderma, GSK-Stiefel, Merck, Incyte, Janssen, Kineta, Leo Pharma, Novartis, and Pfizer. Isabelle Delorme has received grants and research support, served as a speaker or consultant, or received honoraria from Abbvie, Actelion, Amgen, Celgene, Dermira, Dignity Science, Eli Lilly, Innovaderm Research, Janssen, Kineta, Leo Pharma, Novartis, Regeneron, Vitae, Moberg Pharma, Cutanea, and Galderma. Charles W. Lynde served as principal investigator, a speaker, or a consultant for AbbVie, Amgen, Merck, BI, Eli Lilly, Novartis, Valeant, and Pfizer. Jean-Claude Tardif has received research support from Amarin, AstraZeneca, DalCor, Eli Lilly, Hoffmann-LaRoche, Merck, Pfizer, Sanofi, and Servier; honoraria from DalCor, Hoffmann-LaRoche, Pfizer, and Servier; and has equity in DalCor. The other authors state no conflict of interest.

      Acknowledgments

      We want to thank Miguel Chagnon for statistical analysis of cytokine levels. This study was funded and medication was provided by an investigator grant from AbbVie Corporation.

      References

        • Abuabara K.
        • Lee H.
        • Kimball A.B.
        The effect of systemic psoriasis therapies on the incidence of myocardial infarction: a cohort study.
        Br J Dermatol. 2011; 165: 1066-1073
        • Ahlehoff O.
        • Skov L.
        • Gislason G.
        • Gniadecki R.
        • Iversen L.
        • Bryld L.E.
        • et al.
        Cardiovascular outcomes and systemic anti-inflammatory drugs in patients with severe psoriasis: 5-year follow-up of a Danish nationwide cohort.
        J Eur Acad Dermatol Venereol. 2015; 29: 1128-1134
        • Alenius G.M.
        • Eriksson C.
        • Rantapaa Dahlqvist S.
        Interleukin-6 and soluble interleukin-2 receptor alpha-markers of inflammation in patients with psoriatic arthritis?.
        Clin Exp Rheumatol. 2009; 27: 120-123
        • Benoit S.
        • Toksoy A.
        • Ahlmann M.
        • Schmidt M.
        • Sunderkötter C.
        • Foell D.
        • et al.
        Elevated serum levels of calcium-binding S100 proteins A8 and A9 reflect disease activity and abnormal differentiation of keratinocytes in psoriasis.
        Br J Dermatol. 2006; 155: 62-66
        • Bissonnette R.
        • Tardif J.C.
        • Harel F.
        • Pressacco J.
        • Bolduc C.
        • Guertin M.C.
        Effects of the tumor necrosis factor-alpha antagonist adalimumab on arterial inflammation assessed by positron emission tomography in patients with psoriasis: results of a randomized controlled trial.
        Circ Cardiovasc Imaging. 2013; 6: 83-90
        • Boehncke W.H.
        • Schon M.P.
        Psoriasis.
        Lancet. 2015; 386: 983-994
        • Brammen L.
        • Steiner S.
        • Berent R.
        • Sinzinger H.
        Molecular imaging of atherosclerotic lesions by positron emission tomography—can it meet the expectations?.
        VASA. 2016; 45: 125-132
        • Emami H.
        • Tawakol A.
        Noninvasive imaging of arterial inflammation using FDG-PET/CT.
        Curr Opin Lipidol. 2014; 25: 431-437
        • Fredriksson T.
        • Pettersson U.
        Severe psoriasis—oral therapy with a new retinoid.
        Dermatologica. 1978; 157: 238-244
        • Gelfand J.M.
        • Neimann A.L.
        • Shin D.B.
        • Wang X.
        • Margolis D.J.
        • Troxel A.B.
        Risk of myocardial infarction in patients with psoriasis.
        JAMA. 2006; 296: 1735-1741
        • Horreau C.
        • Pouplard C.
        • Brenaut E.
        • Barnetche T.
        • Misery L.
        • Cribier B.
        • et al.
        Cardiovascular morbidity and mortality in psoriasis and psoriatic arthritis: a systematic literature review.
        J Eur Acad Dermatol Venereol. 2013; 27: 12-29
        • Hugh J.
        • Van Voorhees A.S.
        • Nijhawan R.I.
        • Bagel J.
        • Lebwohl M.
        • Blauvelt A.
        • et al.
        From the medical board of the National Psoriasis Foundation: the risk of cardiovascular disease in individuals with psoriasis and the potential impact of current therapies.
        J Am Acad Dermatol. 2014; 70: 168-177
        • Jokai H.
        • Szakonyi J.
        • Kontar O.
        • Marschalko M.
        • Szalai K.
        • Karpati S.
        • et al.
        Impact of effective tumor necrosis factor-alfa inhibitor treatment on arterial intima-media thickness in psoriasis: results of a pilot study.
        J Am Acad Dermatol. 2013; 69: 523-529
        • Joshi N.V.
        • Vesey A.
        • Newby D.E.
        • Dweck M.R.
        Will 18F-sodium fluoride PET-CT imaging be the magic bullet for identifying vulnerable coronary atherosclerotic plaques?.
        Curr Cardiol Rep. 2014; 16: 521
      1. Ko H-S. Clinical design for psoriasis. Presented at: Dermatologic and Ophthalmic Drugs Advisory Committee 49th Meeting Open Session (Volume II). 20 March 1998; Gaithersburg, MD.

        • Levesque A.
        • Lachaine J.
        • Bissonnette R.
        Risk of myocardial infarction in canadian patients with psoriasis: a retrospective cohort study.
        J Cutan Med Surg. 2013; 17: 398-403
        • Libby P.
        • Ridker P.M.
        • Hansson G.K.
        Progress and challenges in translating the biology of atherosclerosis.
        Nature. 2011; 473: 317-325
        • Lo Y.H.
        • Torii K.
        • Saito C.
        • Furuhashi T.
        • Maeda A.
        • Morita A.
        Serum IL-22 correlates with psoriatic severity and serum IL-6 correlates with susceptibility to phototherapy.
        J Dermatol Sci. 2010; 58: 225-227
        • Maki-Petaja K.M.
        • Elkhawad M.
        • Cheriyan J.
        • Joshi F.R.
        • Ostor A.J.
        • Hall F.C.
        • et al.
        Anti-tumor necrosis factor-alpha therapy reduces aortic inflammation and stiffness in patients with rheumatoid arthritis.
        Circulation. 2012; 126: 2473-2480
        • Mani V.
        • Woodward M.
        • Samber D.
        • Bucerius J.
        • Tawakol A.
        • Kallend D.
        • et al.
        Predictors of change in carotid atherosclerotic plaque inflammation and burden as measured by 18-FDG-PET and MRI, respectively, in the dal-PLAQUE study.
        Int J Cardiovasc Imaging. 2014; 30: 571-582
        • Mehta N.N.
        • Yu Y.
        • Saboury B.
        • Foroughi N.
        • Krishnamoorthy P.
        • Raper A.
        • et al.
        Systemic and vascular inflammation in patients with moderate to severe psoriasis as measured by [18F]-fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET/CT): a pilot study.
        Arch Dermatol. 2011; 147: 1031-1039
        • Mussi A.
        • Bonifati C.
        • Carducci M.
        • D'Agosto G.
        • Pimpinelli F.
        • D'Urso D.
        • et al.
        Serum TNF-α levels correlate with disease severity and are reduced by effective therapy in plaque-type psoriasis.
        J Biol Regul Homeost Agents. 1997; 11: 115-118
        • Naik H.B.
        • Natarajan B.
        • Stansky E.
        • Ahlman M.A.
        • Teague H.
        • Salahuddin T.
        • et al.
        Severity of psoriasis associates with aortic vascular inflammation detected by FDG PET/CT and neutrophil activation in a prospective observational study.
        Arterioscler Thromb Vasc Biol. 2015; 35: 2667-2676
        • Pollock R.A.
        • Abji F.
        • Liang K.
        • Chandran V.
        • Pellett F.J.
        • Virtanen C.
        • et al.
        Gene expression differences between psoriasis patients with and without inflammatory arthritis.
        J Invest Dermatol. 2015; 135: 620-623
        • Ramonda R.
        • Puato M.
        • Punzi L.
        • Rattazzi M.
        • Zanon M.
        • Balbi G.
        • et al.
        Atherosclerosis progression in psoriatic arthritis patients despite the treatment with tumor necrosis factor-alpha blockers: a two-year prospective observational study.
        Rev Rhum Engl Ed. 2014; 81: 421-425
        • Rominger A.
        • Saam T.
        • Wolpers S.
        • Cyran C.C.
        • Schmidt M.
        • Foerster S.
        • et al.
        18F-FDG PET/CT identifies patients at risk for future vascular events in an otherwise asymptomatic cohort with neoplastic disease.
        J Nucl Med. 2009; 50: 1611-1620
        • Rose S.
        • Sheth N.H.
        • Baker J.F.
        • Ogdie A.
        • Raper A.
        • Saboury B.
        • et al.
        A comparison of vascular inflammation in psoriasis, rheumatoid arthritis, and healthy subjects by FDG-PET/CT: a pilot study.
        Am J Cardiovasc Dis. 2013; 3: 273-278
        • Rose S.
        • Dave J.
        • Millo C.
        • Naik H.B.
        • Siegel E.L.
        • Mehta N.N.
        Psoriatic arthritis and sacroiliitis are associated with increased vascular inflammation by 18-fluorodeoxyglucose positron emission tomography computed tomography: baseline report from the Psoriasis Atherosclerosis and Cardiometabolic Disease Initiative.
        Arthritis Res Ther. 2014; 16: R161
        • Samarasekera E.J.
        • Neilson J.M.
        • Warren R.B.
        • Parnham J.
        • Smith C.H.
        Incidence of cardiovascular disease in individuals with psoriasis: a systematic review and meta-analysis.
        J Invest Dermatol. 2013; 133: 2340-2346
        • Singh P.
        • Emami H.
        • Subramanian S.
        • Maurovich-Horvat P.
        • Marincheva-Savcheva G.
        • Medina H.M.
        • et al.
        Coronary plaque morphology and the anti-inflammatory impact of atorvastatin: a multicenter 18F-fluorodeoxyglucose positron emission tomographic/computed tomographic study.
        Circ Cardiovasc Imaging. 2016; 9
        • Tahara N.
        • Kai H.
        • Ishibashi M.
        • Nakaura H.
        • Kaida H.
        • Baba K.
        • et al.
        Simvastatin attenuates plaque inflammation: evaluation by fluorodeoxyglucose positron emission tomography.
        J Am Acad Cardiol. 2006; 48: 1825-1831
        • Tawakol A.
        • Fayad Z.A.
        • Mogg R.
        • Alon A.
        • Klimas M.T.
        • Dansky H.
        • et al.
        Intensification of statin therapy results in a rapid reduction in atherosclerotic inflammation: results of a multicenter fluorodeoxyglucose-positron emission tomography/computed tomography feasibility study.
        J Am Acad Cardiol. 2013; 62: 909-917
        • van Sijl A.M.
        • van Eijk I.C.
        • Peters M.J.
        • Serne E.H.
        • van der Horst-Bruinsma I.E.
        • Smulders Y.M.
        • et al.
        Tumour necrosis factor blocking agents and progression of subclinical atherosclerosis in patients with ankylosing spondylitis.
        Ann Rheum Dis. 2015; 74: 119-123
        • Watanabe T.
        • Kawasaki M.
        • Tanaka R.
        • Ono K.
        • Kako N.
        • Saeki M.
        • et al.
        Anti-inflammatory and morphologic effects of pitavastatin on carotid arteries and thoracic aorta evaluated by integrated backscatter trans-esophageal ultrasound and PET/CT: a prospective randomized comparative study with pravastatin (EPICENTRE study).
        Cardiovasc Ultrasound. 2015; 13: 17
        • Wu J.J.
        • Poon K.Y.
        • Channual J.C.
        • Shen A.Y.
        Association between tumor necrosis factor inhibitor therapy and myocardial infarction risk in patients with psoriasis.
        Arch Dermatol. 2012; 148: 1244-1250
        • Wu Y.W.
        • Kao H.L.
        • Huang C.L.
        • Chen M.F.
        • Lin L.Y.
        • Wang Y.C.
        • et al.
        The effects of 3-month atorvastatin therapy on arterial inflammation, calcification, abdominal adipose tissue and circulating biomarkers.
        Eur J Nucl Med Mol Imaging. 2012; 39: 399-407
        • Yilmaz S.B.
        • Cicek N.
        • Coskun M.
        • Yegin O.
        • Alpsoy E.
        Serum and tissue levels of IL-17 in different clinical subtypes of psoriasis.
        Arch Dermatol Res. 2012; 304: 465-469
        • Youn S.W.
        • Kang S.Y.
        • Kim S.A.
        • Park G.Y.
        • Lee W.W.
        Subclinical systemic and vascular inflammation detected by (18) F-fluorodeoxyglucose positron emission tomography/computed tomography in patients with mild psoriasis.
        J Dermatol. 2015; 42: 559-566

      Linked Article

      • Does Treatment of Psoriasis Reduce Cardiovascular Comorbidities?
        Journal of Investigative DermatologyVol. 137Issue 8
        • Preview
          Psoriasis has been associated with an increase in myocardial infarctions. Several registries have shown reductions in major adverse cardiovascular events in psoriasis patients and rheumatoid arthritis patients treated with tumor necrosis factor-α antagonists. Many assume that the reduction in cardiovascular events can be attributed to the anti-inflammatory effect of tumor necrosis factor blockers, but a 52-week study conducted by Bissonnette and coworkers failed to show a reduction in cardiovascular inflammation in psoriasis patients treated with adalimumab.
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