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Does Treatment of Psoriasis Reduce Cardiovascular Comorbidities?

  • Mark Lebwohl
    Correspondence
    Correspondence: Mark Lebwohl, 5 East 98th Street, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
    Affiliations
    Icahn School of Medicine at Mount Sinai, New York, New York, USA
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      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. Longer and larger studies are needed to explain why tumor necrosis factor-α blockade appears to reduce cardiovascular events in patients with severe psoriasis.
      • Severe psoriasis has been associated with an increase in myocardial infarctions.
      • In many registries, the use of TNF-α blockers is associated with a large reduction in the frequency of myocardial infarctions in patients with severe psoriasis.
      • A 52-week study of adalimumab in patients with psoriasis failed to show a reduction in cardiovascular inflammation.
      An association between psoriasis and myocardial infarctions has been observed for decades. Over 30 years ago, the associations between psoriasis and cardiovascular risk factors such as diabetes and hyperlipidemia were noted, and some of those publications suggested that psoriasis was not an independent risk factor for heart disease (
      • Török L.
      • Tóth E.
      • Bruncsák A.
      Untersuchungen uber die beziehungen zwischen psoriasis und kardio-vaskularen erkrankungen.
      ). It was a highly cited study by Gelfand et al. in 2006 that convincingly linked severe psoriasis as an independent risk factor to an increase in myocardial infarctions, particularly in young patients. Using prospective data collected from general practitioners in the United Kingdom using the General Practice Research Database from 1987–2002, adjustments for hypertension, diabetes, history of previous myocardial infarction, hyperlipidemia, cigarette smoking, age, sex, and body mass index were made. Over 500,000 control patients were compared with approximately 127,000 patients with mild psoriasis and 3,837 patients with severe psoriasis. The adjusted relative risk for myocardial infarction in a 30-year-old patient with mild psoriasis was 1.29 (95% confidence interval [CI] = 1.14–1.46), and for a 30-year-old with severe psoriasis, the adjusted relative risk was 3.10 (95% CI = 1.98–4.86) (
      • 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.
      ). The relative risk remained elevated, but less so, as older age groups were examined because the frequency of myocardial infarctions in the general population increases with age.
      Increases in cardiovascular risk factors such as smoking, hypertension, diabetes, obesity, and metabolic syndrome have all been shown in psoriasis (
      • Shapiro J.
      • Cohen A.D.
      • David M.
      • Hodak E.
      • Chodik G.
      • Viner A.
      • Kremer E.
      • Heymann A.
      The association between psoriasis, diabetes mellitus, and atherosclerosis in Israel: a case-control study.
      ). Comorbidities like stroke and peripheral vascular disease are also increased in patients with psoriasis and can be directly related to severity of the disease (
      • Kaye J.A.
      • Li L.
      • Jick S.S.
      Incidence of risk factors for myocardial infarction and other vascular diseases in patients with psoriasis.
      ). Increases in inflammatory proteins and markers including C-reactive protein, osteopontin, leptin, and others have been shown in patients with psoriasis, suggesting that inflammation contributes to both diseases (
      • Gisondi P.
      • Girolomoni G.
      Psoriasis and atherothrombotic diseases: disease-specific and non-disease-specific risk factors.
      ).
      Not every study shows an increase in heart disease in patients with psoriasis.
      • Dowlatshahi E.A.
      • Kavousi M.
      • Nijsten T.
      • Ikram M.A.
      • Hofman A.
      • Franco O.H.
      • Wakkee M.
      Psoriasis is not associated with atherosclerosis and incident cardiovascular events: the Rotterdam Study.
      showed that psoriasis patients smoked more and had higher blood pressure and body mass index levels, but the adjusted carotid intima-media thickness was the same for psoriasis as for reference subjects. Ankle-brachial indexes, pulse wave velocities, and coronary artery calcium scores were also similar, as was the risk of incident cardiovascular disease, including coronary heart disease, stroke, and heart failure. That study, however, predominately looked at patients with mild psoriasis (
      • Dowlatshahi E.A.
      • Kavousi M.
      • Nijsten T.
      • Ikram M.A.
      • Hofman A.
      • Franco O.H.
      • Wakkee M.
      Psoriasis is not associated with atherosclerosis and incident cardiovascular events: the Rotterdam Study.
      ). Similarly, in a study by
      • Egeberg A.
      • Thyssen J.P.
      • Jensen P.
      • Gislason G.H.
      • Skov L.
      Risk of myocardial infarction in patients with psoriasis and psoriatic arthritis: a nationwide cohort study.
      , all residents of Denmark older than 18 years were included. Adjusted hazard ratios for mild psoriasis did not show an increase in the risk of myocardial infarction (hazard ratio = 1.02, 95% CI = 0.96–1.09), and the risk in patients with severe psoriasis was only modestly increased (hazard ratio = 1.21, CI = 1.07–1.37) (
      • Egeberg A.
      • Thyssen J.P.
      • Jensen P.
      • Gislason G.H.
      • Skov L.
      Risk of myocardial infarction in patients with psoriasis and psoriatic arthritis: a nationwide cohort study.
      ). A few other studies also question the increase in myocardial infarctions, but the vast majority of population-based studies, registries, and databases show an increase in myocardial infarctions, particularly in patients with severe disease.
      With the growing body of information pointing to increases in myocardial infarction and risk factors for cardiovascular disease in patients with psoriasis, the question that has been asked by many is Can we prevent heart attacks and other cardiovascular comorbidities of psoriasis by treating the psoriasis? Observational studies involving numerous registries have reported reductions in myocardial infarctions in patients treated with tumor necrosis factor (TNF)-α antagonists. Many of those studies showing reduced cardiovascular events have come from registries of patients treated for rheumatoid arthritis. However,
      • Wu J.J.
      • Poon K.Y.
      Tumor necrosis factor inhibitor therapy and myocardial infarction risk in patients with psoriasis, psoriatic arthritis, or both.
      recently showed that treatment of psoriasis with TNF-α inhibitors is associated with reduced frequency of myocardial infarctions. In a retrospective cohort study of over 1,500 patients with psoriasis or psoriatic arthritis, the hazard ratio for myocardial infarction for those psoriasis patients treated with TNF-α inhibitors compared with those not treated with TNF-α inhibitors was 0.26 (95% CI = 0.12–0.56) (
      • Wu J.J.
      • Poon K.Y.
      Tumor necrosis factor inhibitor therapy and myocardial infarction risk in patients with psoriasis, psoriatic arthritis, or both.
      ). The presumed explanation was a reduction in inflammation as manifested by clearing of psoriasis. Presumably, the accompanying reduction in inflammatory cytokines resulted in a reduction in atherosclerosis and cardiovascular disease.
      In an earlier 30-patient pilot study published by
      • Bissonnette R.
      • Tardif J.C.
      • Harel F.
      • Pressacco J.
      • Bolduc C.
      • Guertin M.C.
      Effects of the tumor necrosis factor-α antagonist adalimumab on arterial inflammation assessed by positron emission tomography in patients with psoriasis: results of a randomized controlled trial.
      looking at vascular inflammation in the ascending aorta and carotid arteries, decreases in vascular inflammation were shown in psoriasis patients treated with adalimumab compared with placebo when data for the ascending aorta and carotid arteries were analyzed separately at 15 weeks (
      • Bissonnette R.
      • Tardif J.C.
      • Harel F.
      • Pressacco J.
      • Bolduc C.
      • Guertin M.C.
      Effects of the tumor necrosis factor-α antagonist adalimumab on arterial inflammation assessed by positron emission tomography in patients with psoriasis: results of a randomized controlled trial.
      ). It was therefore with great anticipation that we awaited the results of the longer-term studies of cardiovascular inflammation, expecting further proof that the TNF-α antagonist, adalimumab, would result in reduction of cardiovascular inflammation over 52 weeks. The 52-week study by
      • 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.
      was a double-blind, placebo-controlled psoriasis trial of adalimumab that examined vascular inflammation using positron emission tomography-computed tomography to measure uptake of fluoro-2-deoxy-d-glucose in the ascending aorta and carotid arteries. This study, however, failed to show reduced vascular inflammation despite a reduction in high-sensitivity C-reactive protein in the adalimumab-treated patients (
      • 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.
      ).
      There are a number of reasons why this study may not have shown the anticipated reduction in cardiovascular inflammation. The registries showing reductions in cardiovascular disease have looked at thousands of patients treated for up to 10 years, and this study may be too small or of insufficient duration to show an effect. Moreover, even if we assume that the technology used to study vascular inflammation was sufficiently sensitive and specific to do so, it was the carotid arteries and ascending aorta that were studied, not the coronary arteries. Finally, we undoubtedly know less than we think about the factors linking cardiovascular inflammation, atherosclerosis, and coronary artery thrombosis, and undoubtedly TNF-α is not the only factor to be considered.
      Despite the negative results in this study, we cannot ignore the studies of registries that have reported reductions in myocardial infarctions and deaths from cardiovascular disease in patients treated with TNF-α antagonists both for psoriasis and for rheumatoid and psoriatic arthritis. In patients with cardiovascular risk factors, TNF-α antagonists have been the medications we turn to for severe psoriasis, for good reasons. More data will be needed to show a definite effect, but existing observational data suggest that TNF-α blockers are likely to prove to be cardioprotective in this population.

      Conflict of Interest

      Mark Lebwohl is an employee of the Mount Sinai Medical Center, which receives research funds from AbbVie, Amgen, Boehringer Ingleheim, Celgene, Eli Lilly, Janssen Research & Development, LLC, Kadmon, LEO Pharma, Novartis, Pfizer, and ViDac.

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      Linked Article

      • TNF-α Antagonist and Vascular Inflammation in Patients with Psoriasis Vulgaris: A Randomized Placebo-Controlled Study
        Journal of Investigative DermatologyVol. 137Issue 8
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          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.
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