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Impact of Biological Agents on Imaging and Biomarkers of Cardiovascular Disease in Patients with Psoriasis: A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials

Open ArchivePublished:April 20, 2021DOI:https://doi.org/10.1016/j.jid.2021.03.024

      Background

      The effect of biologics on the risk for cardiovascular disease in patients with psoriasis is still unclear despite their widespread use.

      Objective

      The objective of this study was to examine the impact of licensed biological therapies on imaging and biomarkers of cardiovascular disease risk in patients with psoriasis by a systematic review and meta-analysis of placebo-controlled trials.

      Methods

      A comprehensive search of studies published before 1 June 2020 was performed in Medline-Ovid, EMBASE, and CENTRAL using a predefined strategy to identify relevant articles.

      Results

      Five studies were included for the final examination, and two studies were included in the meta-analysis. We did not find a significant reduction in aortic vascular inflammation in patients treated with adalimumab compared with those who received placebo at weeks 12–16. There was no beneficial effect on imaging biomarkers (aortic vascular inflammation or flow-mediated dilatation) of cardiovascular disease risk in patients exposed to biological therapies (adalimumab and secukinumab) compared with those exposed to placebo, except for ustekinumab showing a reduction in aortic vascular inflammation at week 12 but not at week 52 after the open-label extension period. The strongest reduction in blood-based cardiometabolic risk biomarkers was observed with adalimumab (CRP, TNF-α, IL-6, and GlycA) and phototherapy (CRP and IL-6) compared with that observed with placebo.

      Conclusions

      Randomized controlled trials show that ustekinumab reduces aortic vascular inflammation and that TNF-α inhibitors and phototherapy reduce CRP and IL-6. These surrogate marker findings require randomized controlled trials evaluating cardiovascular events to inform clinical practice.

      Abbreviations:

      CV (cardiovascular), CVD (cardiovascular disease), FMD (flow-mediated dilatation), HDL (high-density lipoprotein), RCT (randomized controlled trial)

      Introduction

      Patients with psoriasis have an increased risk of cardiovascular (CV) morbidity and mortality. The risk of cardiometabolic disease increases with increasing psoriasis severity, is independent of traditional risk factors, and culminates in a lifespan reduction of approximately 5 years (
      • Abuabara K.
      • Azfar R.S.
      • Shin D.B.
      • Neimann A.L.
      • Troxel A.B.
      • Gelfand J.M.
      Cause-specific mortality in patients with severe psoriasis: a population-based cohort study in the U.K.
      ;
      • Gelfand J.M.
      • Troxel A.B.
      • Lewis J.D.
      • Kurd S.K.
      • Shin D.B.
      • Wang X.
      • et al.
      The risk of mortality in patients with psoriasis: results from a population-based study.
      ;
      • Noe M.H.
      • Shin D.B.
      • Wan M.T.
      • Gelfand J.M.
      Objective measures of psoriasis severity predict mortality: a prospective population-based cohort study.
      ). The biological mechanisms linking psoriasis to adverse cardiometabolic outcomes are multifactorial and complex. Irrespective of classical CV risk factors, the systemic inflammation characteristic of psoriasis is thought to play a pivotal role in increasing CV risk by accelerating atherosclerosis (
      • Harrington C.L.
      • Dey A.K.
      • Yunus R.
      • Joshi A.A.
      • Mehta N.N.
      Psoriasis as a human model of disease to study inflammatory atherogenesis.
      ). Thus, medications for psoriasis such as biological therapies, which have anti-inflammatory effects, could theoretically improve atherosclerosis and therefore modulate the risk of development of CV disease (CVD).
      Over the last decade, the therapeutic armamentarium against psoriasis has been enriched, including TNF-α inhibitors such as infliximab, etanercept, and adalimumab; an inhibitor of the p40 subunit common to IL-12 and IL-23, ustekinumab; inhibitors of IL-17A, secukinumab and ixekizumab; an inhibitor of the IL-17 receptor, brodalumab; and more recently, inhibitors of the p19 subunit of IL23, guselkumab, tildrakizumab, and risankizumab. Although biologics have revolutionized the treatment of psoriasis, their impact on CVD remains uncertain. Observational studies suggest that TNF-α inhibitors are associated with a decreased risk of CV events in patients with psoriasis (
      • Yang Z.S.
      • Lin N.N.
      • Li L.
      • Li Y.
      The effect of TNF inhibitors on cardiovascular events in psoriasis and psoriatic arthritis: an updated meta-analysis.
      ); however, gold-standard randomized placebo-controlled trials evaluating the impact of psoriasis biologics on CV events are not available. Therefore, the aim of this systematic review and meta-analysis of randomized placebo-controlled trials was to examine the impact of licensed biological therapies on biomarkers of CVD risk in adult patients with plaque psoriasis.

      Results

      Literature search

      The search strategy initially retrieved 3,057 records. No additional citations were added by a hand search of relevant article bibliographies. After screening titles and abstracts, a total of 2,237 studies were excluded because they were f duplicates, review articles, preclinical studies, or clinical studies dealing with the wrong population, intervention, or outcome. Among the remaining, five (
      • Bissonnette R.
      • Harel F.
      • Krueger J.G.
      • Guertin M.C.
      • Chabot-Blanchet M.
      • Gonzalez J.
      • et al.
      TNF-α antagonist and vascular inflammation in patients with psoriasis vulgaris: a randomized placebo-controlled study.
      ;
      • Gelfand J.M.
      • Shin D.B.
      • Alavi A.
      • Torigian D.A.
      • Werner T.
      • Papadopoulos M.
      • et al.
      A Phase IV, Randomized, Double-Blind, Placebo-Controlled Crossover Study of the Effects of Ustekinumab on Vascular Inflammation in Psoriasis (the VIP-U Trial).
      ,
      • Gelfand J.M.
      • Shin D.B.
      • Duffin K.C.
      • Armstrong A.W.
      • Blauvelt A.
      • Tyring S.K.
      • et al.
      A randomized placebo-controlled trial of secukinumab on aortic vascular inflammation in moderate-to-severe plaque psoriasis (VIP-S).
      ;
      • Mehta N.N.
      • Shin D.B.
      • Joshi A.A.
      • Dey A.K.
      • Armstrong A.W.
      • Duffin K.C.
      • et al.
      Effect of 2 psoriasis treatments on vascular inflammation and novel inflammatory cardiovascular biomarkers: a randomized placebo-controlled trial.
      ;
      • von Stebut E.
      • Reich K.
      • Thaçi D.
      • Koenig W.
      • Pinter A.
      • Körber A.
      • et al.
      Impact of secukinumab on endothelial dysfunction and other cardiovascular disease parameters in psoriasis patients over 52 weeks.
      ) studies were selected for a final examination, and two articles were included in the quantitative synthesis (meta-analysis) (Figure 1).
      Figure thumbnail gr1
      Figure 1PRISMA flow diagram of included studies for systematic review. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-analyses.

      Study characteristics

      All the selected studies evaluated one or more aspects of vascular characterization using surrogate measures of vascular inflammation (fluorodeoxyglucose-positron emission tomography with computer-assisted tomography) or endothelial dysfunction. Two randomized controlled trials (RCTs) compared adalimumab (
      • Bissonnette R.
      • Harel F.
      • Krueger J.G.
      • Guertin M.C.
      • Chabot-Blanchet M.
      • Gonzalez J.
      • et al.
      TNF-α antagonist and vascular inflammation in patients with psoriasis vulgaris: a randomized placebo-controlled study.
      ;
      • Mehta N.N.
      • Shin D.B.
      • Joshi A.A.
      • Dey A.K.
      • Armstrong A.W.
      • Duffin K.C.
      • et al.
      Effect of 2 psoriasis treatments on vascular inflammation and novel inflammatory cardiovascular biomarkers: a randomized placebo-controlled trial.
      ) with placebo, assessing aortic vascular inflammation as a primary endpoint; one of these RCTs (
      • Mehta N.N.
      • Shin D.B.
      • Joshi A.A.
      • Dey A.K.
      • Armstrong A.W.
      • Duffin K.C.
      • et al.
      Effect of 2 psoriasis treatments on vascular inflammation and novel inflammatory cardiovascular biomarkers: a randomized placebo-controlled trial.
      ) included a phototherapy arm. One study compared ustekinumab with placebo, with vascular inflammation as a primary endpoint. Finally, two studies compared secukinumab with placebo, one with vascular inflammation as a primary endpoint and one with endothelial dysfunction as the endpoint. These trials involved a total of 489 patients with plaque psoriasis. The five RCTs were double-blind studies. The length of the randomized placebo-controlled phase ranged from 12 to 16 (median = 12) weeks. The included studies involved from 43 to 151 patients with plaque psoriasis, with the percentage of male patients ranging from 57.4 % to 77.1%, with mean age range being 39.45–55.5 years, mean duration of psoriasis range being 11–20.8, and mean PASI range being 9.54–22.5 (Table 1). Other descriptive features of selected articles are outlined in Table 1, whereas the main primary and secondary endpoints findings in randomized placebo-controlled trials included in the systematic review are summarized in Tables 2 and 3. Among the included studies, only ustekinumab showed a reduction in the primary imaging endpoint (aortic vascular inflammation) compared with placebo. A reduction in inflammation with adalimumab compared with placebo was observed for CRP, TNF-α, IL-6, and GlycA. An increase in high-density lipoprotein (HDL) particles was observed with phototherapy, whereas it reduced CRP and IL-6. Secukinumab showed a reduction in adiponectin and triglycerides in one study, whereas an increase in low-density lipoprotein particles was observed in another study. Finally, ustekinumab showed a reduction in VCAM-1 and IL-2RA, whereas it increased low-density lipoprotein particles (Table 3).
      Table 1Characteristics of Included Randomized Controlled Trials
      Authors, yMaskingRandomized Placebo-Controlled Phase (wk)Interventions during Randomized Controlled-PhaseNo. of Participants Receiving TreatmentMean Age ± SD (Median) yMale, n (%)Mean BMI ± SDMean Duration of Psoriasis ± SD (Median) yMean Psoriasis Area and Severity Index Score ± SD (Median)Mean Body Surface Area ± SD (Median) (%)Psoriatic Arthritis, n (%)Primary OutcomeSecondary Outcome
      • Bissonnette R.
      • Harel F.
      • Krueger J.G.
      • Guertin M.C.
      • Chabot-Blanchet M.
      • Gonzalez J.
      • et al.
      TNF-α antagonist and vascular inflammation in patients with psoriasis vulgaris: a randomized placebo-controlled study.
      Double blind16Adalimumab was given—80 mg SC at wk 0, followed by 40 mg SC EOW starting at wk 1.5355.5 ± 12.437 (69.8)NRNR10.12 ± 4.4711.14 ± 10.93NRChange from baseline in TBR from the ascending aortaChange from baseline in hsCRP and serum lipids
      Placebo at wk 0 then EOW starting at wk 1.5448.9 ± 11.641 (75.9)NRNR9.54 ± 4.789.93 ± 9.95NR
      • Mehta N.N.
      • Shin D.B.
      • Joshi A.A.
      • Dey A.K.
      • Armstrong A.W.
      • Duffin K.C.
      • et al.
      Effect of 2 psoriasis treatments on vascular inflammation and novel inflammatory cardiovascular biomarkers: a randomized placebo-controlled trial.
      (VIP)
      Double blind12Adalimumab was given— 80 mg followed by 40 mg at wk 1 and then 40 mg EOW.3344.15 ± 13.9724 (72.7)30.93 ± 7.4211 (2–22)17.4 (15.4–22.0)18 (15–25)4 (12.90)Change from baseline TBR from the aortaBiomarkers of inflammation, insulin resistance, and lipoproteins.
      NB-UVB phototherapy three times per wk, according to the Fitzpatrick scale for skin types.3341.97 ± 13.9723 (69.7)32.61 ± 8.6612 (7–17)16.8 (14.5–21.0)19.5 (15–26)3 (9.68)
      Placebo at wk 0 then EOW starting at wk 1.3144.32 ± 14.5020 (64.5)31.95 ± 7.7420 (7–29)15.0 (13.3–20.6)21 (16–33)2 (6.45)
      • Gelfand J.M.
      • Shin D.B.
      • Alavi A.
      • Torigian D.A.
      • Werner T.
      • Papadopoulos M.
      • et al.
      A Phase IV, Randomized, Double-Blind, Placebo-Controlled Crossover Study of the Effects of Ustekinumab on Vascular Inflammation in Psoriasis (the VIP-U Trial).
      ) (VIP-U)
      Double blind12Ustekinumab was given—45 mg (if the person’s weight is 100 kg or less) or 90 mg (if the person’s weight is >100 kg) at d 0 and wk 4, followed by every 12-wk dosing thereafter.2239.45 ± 13.616 (72.73)33.24 ± 7.9516.45 ± 11.0220.03 ± 7.4726.18 ± 17.511 (4.55)Change from baseline TBR from the aortaBiomarkers of inflammation, lipid, and glucose metabolism
      Placebo SC (same dose and schedule as the active comparator until wk 12)2145.33 ± 12.7614 (66.67)33.32 ± 6.2920.29 ± 14.4119.82 ± 7.6423.71 ± 15.586 (28.57)
      • von Stebut E.
      • Reich K.
      • Thaçi D.
      • Koenig W.
      • Pinter A.
      • Körber A.
      • et al.
      Impact of secukinumab on endothelial dysfunction and other cardiovascular disease parameters in psoriasis patients over 52 weeks.
      (CARIMA)
      Double blind12Secukinumab was given—300 mg SC every wk for 4 wks, followed by 300 mg every 4 wks.4844.2 ± 12.937 (77.1)27.820.6 ± 12.719.3 ± 7.9NR12 (25.0)Change from baseline FMDbiomarkers of inflammation and metabolism
      Secukinumab was given—150 mg SC every wk for 4 wks, followed by 150 mg every 4 wks5446.0 ± 14.431 (57.4)28.120.8 ± 13.321.7 ± 10.5NR15 (27.8)
      Placebo SC, followed by 300 mg secukinumab after wk 12.2643.7 ± 11.418 (69.2)30.118.9 ± 11.717.5 ± 4.2NR4 (15.4)
      Placebo SC, followed by 150 mg secukinumab after wk 12.2346.8 ± 13.116 (69.6)29.720.3 ± 11.719.5 ± 6.1NR4 (17.4)
      • Gelfand J.M.
      • Shin D.B.
      • Duffin K.C.
      • Armstrong A.W.
      • Blauvelt A.
      • Tyring S.K.
      • et al.
      A randomized placebo-controlled trial of secukinumab on aortic vascular inflammation in moderate-to-severe plaque psoriasis (VIP-S).
      (VIP-S)
      Double blind12Secukinumab was given—300 mg SC every wk, for 4 wks followed by 300 mg every 4 wks.4647.9 ± 12.733 (71.7)31.09 ± 6.816.3 ± 12.322.5 ± 12.027.6 ± 19.36 (13.0)Change from baseline TBR from the aortaBlood-based cardiometabolic biomarkers
      Placebo SC (same dose and schedule as the active comparator until wk 12)4547.0 ± 14.728 (62.2)32.75 ± 7.815.4 ± 12.521.4 ± 9.930.1 ± 18.711 (24.4)
      Abbreviations: BMI, body mass index; EOW, every other week; FMD, flow- mediated dilation; hsCRP, high sensitivity C-reactive protein; NB-UVB, narrow band UVB; NR, nonreported; SC, subcutaneous; TBR, target-to-background ratio.
      Table 2Imaging Cardiovascular Biomarkers Findings of the Included Randomized Placebo-Controlled Trials
      Imaging Cardiovascular BiomarkersIntervention (Authors, y)
      Adalimumab Versus Placebo (
      • Bissonnette R.
      • Harel F.
      • Krueger J.G.
      • Guertin M.C.
      • Chabot-Blanchet M.
      • Gonzalez J.
      • et al.
      TNF-α antagonist and vascular inflammation in patients with psoriasis vulgaris: a randomized placebo-controlled study.
      )
      Adalimumab Versus Placebo (
      • Mehta N.N.
      • Shin D.B.
      • Joshi A.A.
      • Dey A.K.
      • Armstrong A.W.
      • Duffin K.C.
      • et al.
      Effect of 2 psoriasis treatments on vascular inflammation and novel inflammatory cardiovascular biomarkers: a randomized placebo-controlled trial.
      )

      Phototherapy Versus Placebo (
      • Mehta N.N.
      • Shin D.B.
      • Joshi A.A.
      • Dey A.K.
      • Armstrong A.W.
      • Duffin K.C.
      • et al.
      Effect of 2 psoriasis treatments on vascular inflammation and novel inflammatory cardiovascular biomarkers: a randomized placebo-controlled trial.
      )
      Ustekinumab Versus Placebo (
      • Gelfand J.M.
      • Shin D.B.
      • Alavi A.
      • Torigian D.A.
      • Werner T.
      • Papadopoulos M.
      • et al.
      A Phase IV, Randomized, Double-Blind, Placebo-Controlled Crossover Study of the Effects of Ustekinumab on Vascular Inflammation in Psoriasis (the VIP-U Trial).
      )
      Secukinumab Versus Placebo (
      • von Stebut E.
      • Reich K.
      • Thaçi D.
      • Koenig W.
      • Pinter A.
      • Körber A.
      • et al.
      Impact of secukinumab on endothelial dysfunction and other cardiovascular disease parameters in psoriasis patients over 52 weeks.
      )
      Secukinumab Versus Placebo (
      • Gelfand J.M.
      • Shin D.B.
      • Duffin K.C.
      • Armstrong A.W.
      • Blauvelt A.
      • Tyring S.K.
      • et al.
      A randomized placebo-controlled trial of secukinumab on aortic vascular inflammation in moderate-to-severe plaque psoriasis (VIP-S).
      )
      Aortic vascular inflammation by 18-FDG-PET/CT0.004−0.0150.027−0.246 (P < 0.001)NR−0.053
      Flow-mediated dilatationNRNRNRNR+1.2%
      300-mg group.
      /+0.76%
      150-mg group.
      NR
      Abbreviations: 18-FDG-PET/CT, 18-fluorodeoxyglucose-positron emission tomography with computer-assisted tomography scans; NR, nonreported.
      1 300-mg group.
      2 150-mg group.
      Table 3Serological Cardiometabolic Biomarkers Findings of the Included Randomized Placebo-Controlled Trials
      Serological BiomarkersIntervention (Authors, y)
      Adalimumab Versus Placebo (
      • Bissonnette R.
      • Harel F.
      • Krueger J.G.
      • Guertin M.C.
      • Chabot-Blanchet M.
      • Gonzalez J.
      • et al.
      TNF-α antagonist and vascular inflammation in patients with psoriasis vulgaris: a randomized placebo-controlled study.
      )
      Adalimumab Versus Placebo (
      • Mehta N.N.
      • Shin D.B.
      • Joshi A.A.
      • Dey A.K.
      • Armstrong A.W.
      • Duffin K.C.
      • et al.
      Effect of 2 psoriasis treatments on vascular inflammation and novel inflammatory cardiovascular biomarkers: a randomized placebo-controlled trial.
      )
      Phototherapy Versus Placebo (
      • Mehta N.N.
      • Shin D.B.
      • Joshi A.A.
      • Dey A.K.
      • Armstrong A.W.
      • Duffin K.C.
      • et al.
      Effect of 2 psoriasis treatments on vascular inflammation and novel inflammatory cardiovascular biomarkers: a randomized placebo-controlled trial.
      )
      Ustekinumab Versus Placebo (
      • Gelfand J.M.
      • Shin D.B.
      • Alavi A.
      • Torigian D.A.
      • Werner T.
      • Papadopoulos M.
      • et al.
      A Phase IV, Randomized, Double-Blind, Placebo-Controlled Crossover Study of the Effects of Ustekinumab on Vascular Inflammation in Psoriasis (the VIP-U Trial).
      )
      Secukinumab Versus Placebo (
      • von Stebut E.
      • Reich K.
      • Thaçi D.
      • Koenig W.
      • Pinter A.
      • Körber A.
      • et al.
      Impact of secukinumab on endothelial dysfunction and other cardiovascular disease parameters in psoriasis patients over 52 weeks.
      )
      Secukinumab Versus Placebo (
      • Gelfand J.M.
      • Shin D.B.
      • Duffin K.C.
      • Armstrong A.W.
      • Blauvelt A.
      • Tyring S.K.
      • et al.
      A randomized placebo-controlled trial of secukinumab on aortic vascular inflammation in moderate-to-severe plaque psoriasis (VIP-S).
      )
      Advanced lipoprotein characterization
       Cholesterol (mg/dl)NR6.4818.15419.20 (P < 0.05)−0.819.2 (P < 0.05)
       HDL cholesterol (mg/dl)NRNRNR3.66−0.80.8
       HDL function (cholesterol efflux)NR0.0460.0350.06NR0.05
       HDL-particle total (μmol/l)NR2.5583.319 (P < 0.05)1.25NR0.2
       HDL Size (nm)NRNRNR−0.11NR0.05
       IDL particle total (nmol/l)NRNRNR152.65 (P < 0.01)NR46.2
       LDL cholesterol (mg/dl)NRNRNR21.37 (P < 0.01)0.216.3 (P < 0.05)
       LDL particle total (nmol/l)NR9.19352.320230.77 (P < 0.01)NR206.7 (P < 0.05)
       LDL size (nm)NRNRNR0.04NR−0.1
       Triglycerides (mg/dl)NRNRNR2.06−24 (P < 0.05)20.4
       VLDL particle total (nmol/l)NRNRNR−16.74 (P < 0.05)NR−0.7
       VLDL size (nm)NRNRNR3.14NR1.2
      Inflammation
       TNF-α (pg/ml)NR−0.411 (P < 0.001)−0.177−0.90NR0.3
       IL-6 (pg/ml)NRNRNR−0.47NR4.1
       CRP (mg/l)Reduction (P = 0.012)−0.883 (P < 0.05)−0.752 (P < 0.05)−3,027.210.04−3.1
       GlycANR−41.165 (P < 0.05)−7.199−4.14NR−6.6
       IL-12/23NRNRNR191.49 (P < 0.001)NRNR
       IL-17aNRNRNR−2.63 (P < 0.05)NRNR
       IL-6NR−0.764 (P < 0.05)−0.683 (P < 0.05)−0.47NRNR
       IL-8NRNRNR−16.87NRNR
       ICAM-1NRNRNR−64.97NRNR
       VCAM-1NRNRNR−80.89 (P < 0.05)NRNR
       SAANRNRNR−7,884.29NRNR
       IFN-γNRNRNR−0.07NRNR
       MCP-1NRNRNR−14.79NRNR
       IL-1bNRNRNR−0.52NRNR
       S100B proteinNRNRNRNR−0.02 (P < 0.005)NR
      Adiposity
       Leptin (pg/ml)NR−0.0860.0503,320.580.3−643.3
       Adiponectin total (ng/ml)NR−0.142−0.151−0.28−0.9 (P < 0.05)2,505.2
      Insulin Resistance
       HOMA-IRNRNRNR−0.49−0.21.2
      Predictive of diabetes
       Apolipoprotein A1, mg/dlNRNRNRNR0.5NR
       Apolipoprotein B (ng/ml)NRNRNR0.15−0.02−0.001
       Ferritin (ng/ml)NRNRNR20.66NR7.5
       IL-2 receptor A (pg/ml)NRNRNR−70.76 (P < 0.05)NR−1.0
       IL-18 (pg/ml)NRNRNR−155.31NR36,688.3
       HbA1C absolute (mmol/mol Hb)NRNRNRNR0.5NR
       SHBG (nmol/l)NRNRNRNR−3.7NR
       Fetuin A (ng/ml)NRNRNR48.43NR−22,505
      Abbreviations: Hb, hemoglobulin; HDL, high-density lipoprotein; HOMA-IR, homeostatic model assessment of insulin resistance; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; MCP-1, monocyte chemoattractant protein-1; NR, nonreported; SAA, serum amyloid A; VLDL, very-low-density lipoprotein.

      Meta-analysis

      Our meta-analysis comprised a total of two RCTs comparing adalimumab with placebo (87 adalimumab; 84 placeboes). We did not find a significant reduction in aortic vascular inflammation measured as the change from baseline in mean maximum target-to-background ratio from the ascending aorta (mean difference = 0.00, 95% confidence interval = −0.01 to 0.01), compared with placebo at weeks 12–16. These results, in addition to individual RCT mean differences, standard deviations, number of patients, P-values, I2 statistics, and forest plot, are shown in Figure 2.
      Figure thumbnail gr2
      Figure 2Meta-analyses of aortic vascular inflammation in patients with psoriasis treated with adalimumab. CI, confidence interval; MD, mean difference.

      Risk of bias assessment

      Our risk of bias assessment found that the five RCTs showed a low risk of bias (Figure 3) in the six categories included in the Cochrane quality assessment tool for RCTs (RoB2) (
      • Sterne J.A.C.
      • Savović J.
      • Page M.J.
      • Elbers R.G.
      • Blencowe N.S.
      • Boutron I.
      • et al.
      RoB 2: a revised tool for assessing risk of bias in randomised trials.
      ) for the outcomes of interest. No significant heterogeneity was observed between the studies with respect to the clinical characteristics of the patients or to the methodological aspects.
      Figure thumbnail gr3
      Figure 3Risk of bias assessment for randomized controlled trials. ID, identification.

      Discussion

      We conducted a systematic literature review and meta-analysis of published randomized placebo-controlled trials assessing the impact of licensed biological therapies on imaging and blood biomarkers of CVD risk in adult patients with plaque psoriasis. We found that there was a neutral effect on imaging biomarkers (aortic vascular inflammation or flow-mediated dilatation [FMD]) of CVD risk in patients with psoriasis exposed to biological therapies (adalimumab and secukinumab) compared with those exposed to the placeboes, with the exception of ustekinumab, which was associated with a reduction in aortic vascular inflammation at week 12.
      The majority of the included RCTs had aortic vascular inflammation as the primary endpoint except for one, which included FMD. Vascular inflammation assessed by fluorodeoxyglucose-positron emission tomography with computed tomography is a marker of subclinical vascular disease, which although not a direct marker of coronary heart disease, is known to be predictive of future major CV events and improves rapidly (i.e., within 4–12 weeks), with interventions (i.e., statins) proven to prevent CVD and therefore being a surrogate marker for early trials of novel therapies for CVDs (
      • Figueroa A.L.
      • Abdelbaky A.
      • Truong Q.A.
      • Corsini E.
      • MacNabb M.H.
      • Lavender Z.R.
      • et al.
      Measurement of arterial activity on routine FDG PET/CT images improves prediction of risk of future CV events.
      ;
      • Mehta N.N.
      • Torigian D.A.
      • Gelfand J.M.
      • Saboury B.
      • Alavi A.
      Quantification of atherosclerotic plaque activity and vascular inflammation using [18-F] fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT).
      ;
      • 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.
      ). On the other hand, FMD—a measure of endothelium-dependent control of vascular tone—is a parameter of vascular endothelial function and an early predictor of CV prognosis. FMD has been proposed as a marker of early subclinical atherosclerosis, and previous studies showed that a 1% increase in FMD correlates with an approximately 13% decrease in relative CV risk (
      • Inaba Y.
      • Chen J.A.
      • Bergmann S.R.
      Prediction of future cardiovascular outcomes by flow-mediated vasodilatation of brachial artery: a meta-analysis.
      ).
      Previous observational studies have suggested that TNF inhibitors have a beneficial effect on CV risk in patients with psoriasis. One of these observational studies associated anti‒TNF-α therapy with a 50% reduction in myocardial infarction risk compared with the risk with treatment with topical agents; however, these analyses are limited by the healthy user effect, incomplete measurement of confounding factors, and a lack of inclusion of CV mortality (
      • Gelfand J.M.
      Commentary: does biologic treatment of psoriasis lower the risk of cardiovascular events and mortality?: a critical question that we are only just beginning to answer.
      ;
      • Wu J.J.
      • Poon K.Y.T.
      • Channual J.C.
      • Shen A.Y.J.
      Association between tumor necrosis factor inhibitor therapy and myocardial infarction risk in patients with psoriasis.
      ). Our analyses included two RCTs assessing the effect of biologics that target TNF (adalimumab) on aortic vascular inflammation, both showing a neutral effect compared with placebo (change from baseline in mean maximum target-to-background ratio from the ascending aorta compared with placebo = 0.00, 95% confidence interval = −0.01 to 0.01). One of these studies provided a comprehensive assessment of indices of subclinical and clinical atherosclerosis, showing that anti-TNF therapy had no impact on glucose metabolism, with potentially adverse effects on reverse cholesterol transport (a function of HDL) and HDL-particle size (
      • Mehta N.N.
      • Shin D.B.
      • Joshi A.A.
      • Dey A.K.
      • Armstrong A.W.
      • Duffin K.C.
      • et al.
      Effect of 2 psoriasis treatments on vascular inflammation and novel inflammatory cardiovascular biomarkers: a randomized placebo-controlled trial.
      ). By contrast, an observational study showed a reduction in vascular inflammation by positron emission tomography, with a similar effect of low-dose statin treatment in patients treated with anti-TNF therapy (
      • Dey A.K.
      • Joshi A.A.
      • Chaturvedi A.
      • Lerman J.B.
      • Aberra T.M.
      • Rodante J.A.
      • et al.
      Association between skin and aortic vascular inflammation in patients with psoriasis: a case-cohort study using positron emission tomography/computed tomography.
      ); however, the study differed with respect to study population and had a paucity of CV risk factors and was not placebo controlled. However, in one RCT (
      • Mehta N.N.
      • Shin D.B.
      • Joshi A.A.
      • Dey A.K.
      • Armstrong A.W.
      • Duffin K.C.
      • et al.
      Effect of 2 psoriasis treatments on vascular inflammation and novel inflammatory cardiovascular biomarkers: a randomized placebo-controlled trial.
      ), there was a reduction in inflammatory CVD markers such as GlycA, IL6, CRP, and TNF-α, suggesting perhaps a protective effect of TNF-α inhibition on CV events that is independent of the effect on aortic vascular inflammation. Longer-term studies (5 years) are greatly needed to better understand the durable effects on vascular inflammation after biological therapy in psoriasis.
      Preclinical, murine studies in psoriasis have shown that anti–IL-17 therapy has positive effects on peripheral oxidative stress levels, proinflammatory cytokines, and vascular inflammation (
      • Schüler R.
      • Brand A.
      • Klebow S.
      • Wild J.
      • Veras F.P.
      • Ullmann E.
      • et al.
      Antagonization of IL-17A attenuates skin inflammation and vascular dysfunction in mouse models of psoriasis.
      ). Two studies included in this systematic review evaluated the effect of secukinumab compared with that of placebo on CV risk biomarkers. One study found that secukinumab had minimal but no significant effect on FMD compared with placebo at week 12 (
      • von Stebut E.
      • Reich K.
      • Thaçi D.
      • Koenig W.
      • Pinter A.
      • Körber A.
      • et al.
      Impact of secukinumab on endothelial dysfunction and other cardiovascular disease parameters in psoriasis patients over 52 weeks.
      ). Another study showed that treatment of moderate-to-severe psoriasis with secukinumab had a neutral effect on aortic vascular inflammation and biomarkers of cardiometabolic disease compared with treatment with placebo at week 12 (
      • Gelfand J.M.
      • Shin D.B.
      • Duffin K.C.
      • Armstrong A.W.
      • Blauvelt A.
      • Tyring S.K.
      • et al.
      A randomized placebo-controlled trial of secukinumab on aortic vascular inflammation in moderate-to-severe plaque psoriasis (VIP-S).
      ).
      We also included in our analysis an RCT evaluating the effect of ustekinumab on aortic vascular inflammation. At week 12, ustekinumab-treated patients had a reduction in aortic vascular inflammation, a reduction in inflammatory biomarkers, and an increase in apolipoprotein B lipoproteins compared with those who were placebo treated. However, in this study, placebo patients were crossed over at week 12 such that all patients received ustekinumab for 52 weeks. At the end of 52 weeks of ustekinumab treatment, there was no change in vascular inflammation compared with the baseline, inflammatory markers were reduced, and there were increases in selected measures of lipids and leptin, suggesting that blockade of IL-12 and/or IL-23 may transiently reduce aortic vascular inflammation, with a more durable reduction in inflammatory cytokines associated with CVD.
      Interestingly, one of the RCTs (
      • Mehta N.N.
      • Shin D.B.
      • Joshi A.A.
      • Dey A.K.
      • Armstrong A.W.
      • Duffin K.C.
      • et al.
      Effect of 2 psoriasis treatments on vascular inflammation and novel inflammatory cardiovascular biomarkers: a randomized placebo-controlled trial.
      ) included a phototherapy arm to analyze the effect of an established skin-directed treatment modality on CV and inflammatory markers. In this study, phototherapy showed a trend toward improvement in aortic vascular inflammation, but this was not statistically different from that associated with the placebo. However, there was a reduction in inflammatory CVD markers, such as CRP and IL-6, and an improvement in HDL particle, suggesting potential systemic benefits of this treatment modality.
      In our analysis, we included trials that include surrogate endpoints. Despite the potential advantages and efficiency, the use of surrogate outcomes for testing strategies is accompanied by concern for lack of efficacy on clinical outcomes because of lack of causal relationship between the surrogates and clinically important outcomes or because of coexisting but unexpected consequences that health interventions may have on pathways other than those of the surrogate outcome. Interestingly, trials with an imaging-related primary endpoint are more frequently followed by a clinical outcome trial than those with clinical biomarkers (
      • Bikdeli B.
      • Punnanithinont N.
      • Akram Y.
      • Lee I.
      • Desai N.R.
      • Ross J.S.
      • et al.
      Two decades of cardiovascular trials with primary surrogate endpoints: 1990–2011.
      ). Regarding clinical biomarkers, in our analysis, adalimumab and phototherapy showed a reduction in CRP and IL-6 compared with placebo. In this context, the systemic inflammatory marker CRP has long been used as a clinical marker of CV risk, and IL-6 has been established as a causal risk factor in CVD (
      • Bonaterra G.A.
      • Zügel S.
      • Kinscherf R.
      Novel systemic cardiovascular disease biomarkers.
      ), and both of these markers are elevated with psoriasis (
      • Boehncke W.H.
      Systemic inflammation and cardiovascular comorbidity in psoriasis patients: causes and consequences.
      ).
      This analysis was limited by several factors. First, the possibility that pertinent studies were not identified because of inherent limitations in database literature searches. Second, despite the mounting published evidence of an increased CV risk in patients with psoriasis, few randomized placebo-controlled trials with a relatively small sample size and a short duration of the randomized controlled phase of treatment have investigated biologics-based therapeutic strategies to reduce this risk. We were only able to find five RCTs adequately powered to assess the effect of psoriasis therapy CV imaging and biomarkers, all of which showed a low risk of bias, similar designs, similar baseline clinical characteristics of the included patients, and consistency in their findings. Furthermore, only two RCTs were finally included in the meta-analysis. Third, it is possible that fluorodeoxyglucose uptake in the aorta may capture processes differentially from other imaging modalities that have shown benefit after anti-inflammatory treatment (
      • Elnabawi Y.A.
      • Dey A.K.
      • Goyal A.
      • Groenendyk J.W.
      • Chung J.H.
      • Belur A.D.
      • et al.
      Coronary artery plaque characteristics and treatment with biologic therapy in severe psoriasis: results from a prospective observational study.
      ,
      • Elnabawi Y.A.
      • Oikonomou E.K.
      • Dey A.K.
      • Mancio J.
      • Rodante J.A.
      • Aksentijevich M.
      • et al.
      Association of biologic therapy with coronary inflammation in patients with psoriasis as assessed by perivascular fat attenuation index.
      ). Fourth, although the primary goal of our meta-analysis was to evaluate the effect of biologics on CV biomarkers, we also report the findings of UVB phototherapy that were evaluated in one of the placebo-controlled trials for completeness. We have since done a posthoc search of the literature and found no additional RCTs of phototherapy for psoriasis and CV biomarkers.
      In conclusion, RCTs show that ustekinumab reduces aortic vascular inflammation and TNF-α inhibitor and that phototherapy reduces CRP and IL-6, with only phototherapy improving lipid profile through HDL particle. Considering that observational studies of biomarkers and imaging are hypothesis generating, well-designed RCTs that involve larger numbers of patients and longer durations of treatment exposure evaluating major adverse CV events and direct measures of coronary artery disease or peripheral atherosclerosis (
      • Gonzalez-Cantero A.
      • Gonzalez-Cantero J.
      • Sanchez-Moya A.I.
      • Perez-Hortet C.
      • Arias-Santiago S.
      • Schoendorff-Ortega C.
      • et al.
      Subclinical atherosclerosis in psoriasis. Usefulness of femoral artery ultrasound for the diagnosis, and analysis of its relationship with insulin resistance.
      ) are required to better examine the effect of biological therapies on the risk of CVD in patients with psoriasis.

      Materials and Methods

      The Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were followed for the registration of the protocol of this study, for trial identification, for data collection and integrity, and for assessment of bias. The Preferred Reporting Items for Systematic Reviews and Meta-analyses checklist is available in Supplementary Appendix S1 (see Supporting Information). The protocol was registered with the International Prospective Register of Systematic Reviews (CRD42020189551). Ethical committee approval was not required because the study did not include any intervention or alter the established care of the patients. The need for informed consent was waived because of the retrospective nature of the study and the use of deidentified data.

      Eligibility criteria

      We included RCTs that evaluated the effect of biologics, compared with that of placeboes, on CV risk biomarkers (i.e. vascular inflammation, FMD, biomarkers of inflammation, insulin resistance, lipoproteins, etc.) in adult patients with plaque psoriasis. If outcomes were reported at multiple follow-up points, data from the longest randomized follow-up were selected provided that there was a continuation of the control arm. The dosing regimen of biological therapies and conventional systemic therapies had to be approved by the U.S. Food and Drug Administration, the European Medicine Agency, or any European country. We considered RCTs with parallel groups, cluster-randomized trials, cross-over trials, and multiple intervention groups.

      Study identification and data collection

      Medline-Ovid, EMBASE, and CENTRAL (The Cochrane Library) were independently searched without language restrictions from their inception dates to 1 June 2020. The search term sets, which consisted of psoriasis, biological therapies (individual drug names, trade names, and drug classes), and study design, were tailored for each database. An example search strategy is available in Supplementary Appendix S2 (see Supporting Information). Both Medical Subject Headings and free text terms were used to identify relevant trials. In addition, the U.S. Food and Drug Administration, European Medicines Agency, five trial registries (the U.S. National Institutes of Health Ongoing Trials Register [www.clinicaltrials.gov], the EU Clinical Trials Register [www.clinicaltrialsregister.eu/], the World Health Organization International Clinical Trials Registry Platform [http://apps.who.int/trialsearch/], the Australian and New Zealand Clinical Trials Registry [www.anzctr.org.au], and the International Standard Randomised Controlled Trial Number registry [www.isrctn.com]), and pharmaceutical company websites (AbbVie [North Chicago, IL] marketing Humira_ [adalimumab], Pfizer [New York, NY] marketing Enbrel_ [etanercept], Janssen [Beerse, Belgium], Merck [Darmstadt, Germany] marketing Remicade_ [infliximab], Janssen marketing Stelara_ [ustekinumab], Eli Lilly and Company [Indianapolis, IN] marketing Taltz_ [ixekizumab], and Novartis Pharmaceutical [Basel, Switzerland] marketing Cosentyx_ [secukinumab]) were searched for additional details of clinical trials. Furthermore, we screened the reference lists of all included studies to determine whether they mentioned any other eligible trials and established contact with study authors to identify additional studies. The results of the literature search were collected and exported to Parsifal for the screening process.

      Study process

      Two reviewers (AGC and DOQ) independently screened the titles and abstracts of the retrieved records for inclusion in the systematic review. After the screening phase, the same two reviewers independently evaluated the remaining articles to determine eligibility according to the inclusion and exclusion criteria. Disagreements among the reviewers were resolved by discussion with a third senior reviewer until reaching a final consensus. All the data related to the evaluation of the effect of treatment on measures of CV risk biomarkers (e.g., vascular inflammation, FMD…) were recorded. A detailed flowchart of the study selection process is depicted in Figure 1.

      Data extraction and quality assessment

      Information on the description of interventions (regimens of biological therapies or placebo), participants (age, sex, body mass index, duration of psoriasis, PASI score, and percentage of the body surface area affected by psoriasis), outcome measures (vascular inflammation or FMD), and methodological quality was extracted with the aid of a standardized form tailored for this systematic review.
      Version 2 of The Cochrane Risk of bias tool for RCTs (RoB2) (
      • Sterne J.A.C.
      • Savović J.
      • Page M.J.
      • Elbers R.G.
      • Blencowe N.S.
      • Boutron I.
      • et al.
      RoB 2: a revised tool for assessing risk of bias in randomised trials.
      ) was used for assessing the risk of bias of each included trial. This was done independently by two review authors (AGC and DOQ). Five domains, including randomization process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selection of the reported result, were considered to calculate the overall risk of bias for each outcome.

      Data analysis

      We performed a pairwise meta-analysis for each direct comparison. Because the available number of studies is insufficient to estimate between-study variance (only two studies), we performed a fixed-effect meta-analysis. For each continuous outcome (i.e. maximum target-to-background ratio), we analyzed data using mean differences with their respective 95% confidence interval. We explored the variability between studies, analyzing the different sources of clinical and methodological heterogeneity. We described trial population characteristics across the included trials and assessed the presence of clinical or methodological heterogeneity by comparing their characteristics. For our pair-wise analyses, we used R software (version 3.6.2). We used the chi-square test to perform an evaluation of the chance to explain the variability, with heterogeneity occurring if a P-value was < 0.1. In addition, we used the I2 to quantify the heterogeneity through a description of the variability in effect estimates that is due to heterogeneity.

      Data availability statement

      Available data are posted on the International Prospective Register of Systematic Reviews (CRD42020189551). For further questions regarding the data, please contact the primary/corresponding author.

      Conflict of Interest

      AGC has served as a consultant for AbbVie, Janssen, Novartis Pharmaceutical, Almirall, Celgene, and LEO Pharma receiving grants and/or other payments, outside the submitted work. NNM is a full-time United States government employee and has received research grants from AbbVie, Janssen, Novartis Pharmaceutical, and Celgene, outside the submitted work. JMG served as a consultant for Bristol-Myers Squibb, Boehringer Ingelheim, GlaxoSmithKline, Janssen Biologics, Novartis Pharmaceutical, Regeneron, UCB (Data Safety and Monitoring Board), Sanofi, and Pfizer, receiving honoraria; in addition, he receives research grants (to the Trustees of the University of Pennsylvania, Philadelphia) from AbbVie, Janssen, Novartis Pharmaceutical, Sanofi, Celgene, OrthoDermatologics, and Pfizer. In addition, JMG is a deputy editor for the Journal of Investigative Dermatology, receiving honoraria from the Society for Investigative Dermatology. The remaining authors state no conflict of interest.

      Author Contributions

      Conceptualization: JMG, AGC, DOQ; Data Curation: JMG, AGC, DOQ, NAD; Formal Analysis: JMG, AGC, DOQ, DBS; Investigation: JMG, AGC, DOQ, JLGC, JG-C, NJG, AB, PJ, MGB; Methodology: JMG, DBS, AGC, DOQ, NAD; Project Administration: AGC; Resources: JMG, AGC, DOQ, NAD; Software: DOQ; Supervision: JMG, AGC; Validation: DBS; Visualization: DBS, AGC, DOQ; Writing - Original Draft Preparation: JMG, AGC, DOQ, JLGC, JG-C, NJG, AB, PJ, MGB; Writing – Review and Editing: JMG, AGC, DOQ, JLGC, NAD, JG-C, NJG, AB, PJ, MGB, NNM

      Supplementary Material

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      Linked Article

      • Estimating Cardiovascular Impacts of Drugs for Psoriatic Disease: A Long Way to Go
        Journal of Investigative DermatologyVol. 141Issue 10
        • Preview
          Patients with psoriasis and psoriatic arthritis are at an increased risk of cardiovascular (CV) events. A recent systematic review and meta-analysis by González Cantero et al. (2021) evaluated the effects of biologics on CV imaging and biomarkers in patients with psoriasis. In this commentary, we discuss the clinical and management implications of these and the related results for patients with psoriatic disease and the need for further pharmacoepidemiological research.
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