Cardiovascular Safety of Biologics Targeting Interleukin (IL)-12 and/or IL-23

What Does the Evidence Say?

Marianne de Brito; Zenas Z. N. Yiu

Disclosures

Am J Clin Dermatol. 2021;22(5):587-601. 

In This Article

Abstract and Introduction

Abstract

There is substantial evidence regarding the association between psoriasis and the elevated risk of cardiovascular (CV) disease. Many patients with psoriasis may also be concerned that their treatments may be associated with a further increase in the risk of CV disease. In this article, we summarize the data regarding the biological role of interleukin (IL)-12/23 in atherogenesis. We performed a literature search for currently known CV safety data from trials and observational studies of treatments targeting IL-12/23 in psoriasis, i.e. the p40 inhibitors ustekinumab and briakinumab, and the p19 inhibitors guselkumab, risankizumab, and tildrakizumab. On balance, extensive evidence supports the CV safety of ustekinumab, with over 14 years of follow-up data in multiple cohort studies and randomized controlled trials (RCTs). One self-controlled study concluded ustekinumab may precipitate short-term raised CV risk, but the study had limitations hindering interpretation. The safety evidence from RCTs on the p19 inhibitors are reassuring thus far, but these studies may not detect rare CV events in real-world patients. We concluded that the overall evidence does not show that ustekinumab is associated with an increase in the risk of CV disease in patients with psoriasis, but further data are awaited to assess the CV safety of p19 inhibitors for the treatment of psoriasis.

Introduction

There is substantial evidence for the association between having psoriasis and the development of cardiovascular (CV) events such as myocardial infarction and ischaemic Stroke.[1,2] The attributable risk from psoriasis is uncertain as related comorbidities are also highly associated with CV events.[3] According to multiple risk algorithms, psoriasis severity is associated with an increased risk of CV events.[4] Many patients with psoriasis will have elevated risk for developing CV events at baseline and may also be concerned about whether their treatment may be associated with any further increase in the risk of CV events.

Since reports emerged of major adverse cardiovascular events (MACE) during briakinumab and ustekinumab randomized controlled trials (RCTs), inhibitors of the shared p40 subunit of interleukin (IL)-12 and IL-23, there has been a question over the CV safety of these therapies.[5] This led to the withdrawal of briakinumab from further development, leaving ustekinumab as the only currently licensed p40 inhibitor. Since the introduction of ustekinumab in 2009, three further drugs inhibiting the p19 subunit unique to IL-23 have been licensed in psoriasis—guselkumab, tildrakizumab and risankizumab.[3]

The aim of this article was to summarize the evidence from basic science, translational, trial and observational data to understand the CV risk associated with the p40 and p19 inhibitors. We accessed the PubMed and Cochrane databases on 23 November 2020 and searched for publications using the search term 'psoriasis', Medical Subject Headings Major Topic and 'IL-12/23' or 'ustekinumab' or 'IL-23' and 'MACE' or 'cardiovascular' or 'safety'. Abstracts and titles were then screened for suitability. Overall, there were 506 results, and 67 references were included.

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