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IL-13 Inhibitors for AD CT
Expert Commentary on the Use of IL-13 Inhibition in Treating Moderate to Severe Atopic Dermatitis

Released: May 19, 2023

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Key Takeaways
  • Interleukin (IL)-13 inhibitors are subcutaneous injections given every 2 to 4 weeks, offering a novel mechanism among the biologic agents to optimize outcomes in those with moderate to severe atopic dermatitis (AD).
  • Recent data suggest that IL-13 is likely the most impactful cytokine involved in the pathophysiology of AD.
  • Approved and investigational IL-13 inhibitors have demonstrated a durable efficacy and clean safety profile.

In this commentary, Dr Jonathan Silverberg discusses novel agents targeting interleukin (IL)-13 cytokines in the management of atopic dermatitis (AD), which was covered in the recently released on-demand webcast titled “Targeting IL-13 in Moderate to Severe Atopic Dermatitis: Forging a New Path to Improved Disease and Patient Outcomes” Watch the webcast here and download the slides here. 

The Role of IL-13 in AD Pathology
TLR2 cells are the primary effector cells that we know of that contribute to AD pathophysiology. They produce prototypical cytokines which contribute to this cascade, including IL-13, IL-4, and some other cytokines like IL-31. The issue of which of these cytokines is more impactful for the pathology of AD has been highly debated over the years. However, more and more, we are starting to recognize that it is probably IL-13 that matters the most, if not fully, and much more so than IL-4. When we look at the pathologic schema of AD, the expression is at the IL-13 level, whereas we find minimal, if any, detection of IL-4. Although IL-4 technically can do similar things in terms of leading to barrier disruption and more skin inflammation, it leads to more Th2 differentiation. Both IL-4 and IL-13 play a role in immunoglobulin E (IgE) class switching and upregulation of other inflammatory cell types. In addition, they both have receptors on peripheral nerves that they can amplify; although this doesn’t trigger AD, it can increase the signals for itch.

Targeting IL-13 in AD Management
When interleukins binds to receptors on cell membranes, particularly IL-13, extracellular signals are going to set off enzymatic cascades to transduce intracellular signals. This occurs through the JAK-STAT pathway, ultimately impacting gene transcription. The result is an increased IL-13 expression and activity in the skin of those with AD that translates to decreased skin barrier, protein expression, transepidermal water loss, and xerosis, as well as decreased epidermal lipids and antimicrobial peptides, which might increase the susceptibility to skin and even systemic infections. There are some suggestions of IL-13 having profibrotic effects, which may be less important in AD, but could certainly be relevant in other dermatologic conditions and the amplification of itch that occurs.  

Today we have 2 targeted IL-13 blockers that are either approved or in development. Tralokinumab was the first of the monoclonal antibodies to bind to the free IL-13 cytokine. It is currently approved in the United States and many other countries around the world for the treatment of moderate to severe AD. Lebrikizumab is also a monoclonal antibody targeting IL-13; it is currently in development with a hopeful FDA approval in the upcoming months. There are some nuanced differences in terms of how these 2 bind. Although they both bind to the cytokine, not the receptors, they do have differences that impact a so-called “decoy receptor.” We don't know what the decoy receptor does with respect to the function or clinical presentation of AD, so we aren’t sure how important it really is, but there certainly are differences in terms of pharmacokinetics, binding affinity, and how long these medications will last. There are some data from which we can glean there may be some clinical implications of this difference; however, we need more time to know for sure.

Incorporating IL-13 Inhbitors Into Clinical Practice for AD
Tralokinumab, which, again, is FDA approved for adults with moderate to severe AD, can be used with a single subcutaneous (SC) loading dose of 600 mg (4 injections) and a maintenance dose of 300 mg (2 injections) every other week. There is an option to extend the maintenance dosing to every 4 weeks in patients who are responding well after the initial 16 weeks of therapy. As a SC agent, tralokinumab can be self-administered or given with the help of a caregiver; injection sites should be rotated through various areas of subcutaenous fat with each dose. Approval for use in adolescents 12 years and older is under review and we are hopeful that will come to fruition in the next few months.

Lebrikizumab, which is currently under FDA review for use in AD, has had several recently published phase III trials (ADvocate 1, ADvocate 2, and ADhere) demonstrating a similar efficacy and safety profile to tralokinumab. If approved, after two 2-shot loading doses, this agent may require fewer maintenance injections per dose with 1 shot every other week. Of interest, in the ADvocate trials, there is no indication of an efficacy plateau at the 16-week mark, which could suggest there is more efficacy to be gained thereafter.

This class has demonstrated a relatively clean safety profile, which is similar to what we have seen in trials and practice with dupilumab therapy (an IL-4 α-subunit receptor antagonist). The most common adverse events seen in trials include conjunctivitis, keratitis, and dry eyes. Overall, the IL-13 inhibiting agents offer significant benefits in the treatment armamentarium for AD.

Your Thoughts?
What are your thoughts and questions on best practices in using novel agents like the IL-13 inhibitors for managing moderate to severe AD? Please answer the polling question and join the conversation by posting a comment in the discussion section below.

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When would you consider incorporating an IL-13 inhibitor into the therapeutic plan for patients with moderate to severe AD in your practice?

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