During a session at the 2025 American Academy of Dermatology (AAD) Annual Meeting, Jonathan I. Silverberg, MD, PhD, MPH, and colleagues reviewed several immune pathways that are involved in the pathogenesis of atopic dermatitis (AD) and the clinical role of the biologics that target these pathways.

Following this presentation, featured expert Jonathan I. Silverberg, MD, PhD, MPH, was interviewed by Conference Reporter Medical Director Lauren Weinand, MD. Clinical perspectives from Dr Silverberg on these findings are presented here.

Several immune signaling pathways have been implicated in the pathogenesis of AD, as discussed during our session at the recent 2025 AAD Annual Meeting titled, “Clarifying Pathways in the Treatment of Atopic Dermatitis With Biologics.” At this stage, we believe that the most critical pathways are signaling by the type 2 cytokines IL-4, IL-13, and IL-31. IL-4 and IL-13 have multiple redundant functions with respect to epidermal barrier disruption. While they do not directly trigger the itch signal, they can amplify it, and they have feed-forward loops that can increase inflammation in the skin. IL-31 is often referred to as the “itch cytokine,” as it is a major driver of itch, but it is also implicated in epidermal barrier disruption, inflammation, and fibrosis.

There are 4 US Food and Drug Administration (FDA)–approved biologics for AD. The first to be approved was dupilumab, which binds to IL‐4Rα and thereby blocks IL‐4 and IL‐13 signaling. Lebrikizumab and tralokinumab block IL-13 signaling by binding to soluble IL-13 with high affinity but have different downstream effects. Lebrikizumab prevents IL‐4Rα/IL‐13Rα1 heterodimerization, while tralokinumab prevents the interaction of IL-13 with IL-13Rα1. Finally, nemolizumab binds to IL-31Rα, blocking IL-31 signaling.

Through cross-trial comparisons using network meta-analyses, we have found that high doses of oral JAK inhibitors may be the most effective therapies for AD. Dupilumab and lebrikizumab appear to have similar efficacy, and the next most effective therapies are lower-dose JAK inhibitors followed by tralokinumab. Without head-to-head studies, this gives us a hierarchy that we can consider when choosing treatment for patients with AD. All of these treatments have data showing a maintenance of response overall, which is very reassuring and important for us when counseling patients about long-term use.

We have the longest track record of safety with dupilumab, but lebrikizumab and tralokinumab have both had encouraging safety data too. An issue to be aware of with the use of biologics is the potential for patients to develop ocular surface diseases, including conjunctivitis, blepharitis, dry eyes, and, more rarely, keratitis. This seems to be a class-wide effect; we see ocular surface disease develop with lebrikizumab use to a similar extent as with dupilumab use, and with tralokinumab use to a slightly lesser extent. An adverse effect that has not been reported in clinical trials with these biologics but is seen in the real world is facial erythema. In addition, through monitoring from the World Health Organization (WHO) global pharmacovigilance database, there was a signal found for arthralgias and Th17-mediated autoimmune disorders as complications associated with dupilumab use. These may be due to a paradoxical immune shifting. Fortunately, these complications are rare, and they may also be a class-wide effect.

Nemolizumab has had an overall clean safety profile as well. Despite some initial concerns, no asthma safety signals were observed in the phase 3 ARCADIA 1 and ARCADIA 2 clinical trials, and it is no longer considered an adverse event of special interest. Notably, no conjunctivitis issues were seen with nemolizumab use.