In an exploratory proteomics analysis of treatments for atopic dermatitis (AD), a JAK inhibitor and an anti-interleukin (IL)-4 monoclonal antibody produced different effects, supporting substantial mechanistic differences.

Relative to the anti-IL-4 targeted therapy, the JAK inhibitor “more broadly modulated the AD serum proteome,” reported Emma Guttman-Yassky, MD, PhD, chair in the Department of Dermatology in the Icahn School of Medicine at Mount Sinai in New York City.

The proteomic analysis was performed on blood samples from a subset of patients participating in the phase 3 placebo-controlled JADE COMPARE trial, the results were published in 2021. This was a placebo-controlled head-to-head comparison of the JAK inhibitor abrocitinib (Cibinqo) and the anti-IL-4 monoclonal antibody dupilumab (Dupixent).

The drugs performed similarly on the primary endpoint of that trial, but there were differences. For example, the higher 200-mg dose of abrocitinib (but not the lower 100-mg dose) was superior to dupilumab for control of itch by 2 weeks.

In this new proteomic analysis, abrocitinib, relative to dupilumab, “demonstrated broader clinical biomarker correlations with a greater number of serum protein changes significantly associated with clinical disease activity scores,” Guttman-Yassky said.

She presented the results of the proteomic analysis as a late breaker at the European Academy of Dermatology and Venereology (EADV) 2026 Congress in Vienna.

Abrocitinib is a JAK1-selective oral therapy that is known to inhibit activation of proinflammatory genes and downstream activation of inflammatory cytokines such as IL-4, IL-13, and IL-22. It also inhibits IL-31, which is implicated in triggering itch.

Dupilumab is an injectable monoclonal antibody that binds to IL-4 receptor-alpha, which inhibits IL-13 as well as IL-4. Additional anti-inflammatory effects are thought to be derived from blocking signaling pathways downstream of IL-4/IL-13 activation.

“The systemic molecular effects of these distinct mechanisms have not been directly compared in a large patient cohort, highlighting the need for proteomic characterization,” Guttman-Yassky explained.

Of the 838 patients who participated in JADE COMPARE, this analysis was restricted to blood samples from 352 patients participating in the proteomics substudy. Each treatment — 200 mg once-daily abrocitinib, 100 mg once-daily abrocitinib, 300 mg dupilumab administered every other week, and placebo — was represented by about 25% of the patient subset.

A multiplex platform was used to compare changes in the serum proteome at week 12 relative to baseline. At a threshold of a 1.3 fold change, the 200-mg dose of abrocitinib produced the largest number of statistically significant (P < .05) protein changes after controlling for the false discovery rate.

While there were no changes in either direction among patients randomized to placebo, the numbers of proteins upregulated and downregulated on the 200-mg dose of abrocitinib were 8 and 25, respectively. For dupilumab, the upregulated and downregulated numbers were 2 and 14, respectively. For the lower dose of abrocitinib, no proteins were significantly upregulated, but nine were downregulated.

Although both abrocitinib and dupilumab were associated with a significant downregulation of numerous key Th2, Th1, and Th17 markers, only abrocitinib downregulated Th1 markers, and it downregulated more Th17 markers. Comparing the two doses of abrocitinib, these changes appear to be dose related. Itch and fibrosis markers were also numerically modulated to a larger extent by abrocitinib 200 mg vs dupilumab.

The study provides evidence at the level of the genome that these drugs differ, according to Guttman-Yassky. Although some proteins associated with inflammation or itch were reduced by both drugs, they did not do so with the same degree of effect, she said.

As an example, when change in inflammatory proteins associated with greater disease activity, as measured with the Eczema Area and Severity Index (EASI), reductions were significant on abrocitinib and on dupilumab (P < .001 for each), but the Pearson correlation and the slope of the correlation was stronger with abrocitinib (r = 0.61; slope = 1.34) relative to dupilumab (r = 0.045; slope = 0.67).

Overall, nine proteins associated with a higher EASI score were significantly downregulated (P < .001 for all) on abrocitinib, Guttman-Yassky reported. Although seven were reduced on dupilumab, only two reached the same level of significance.

For the Numerical Rating Score for itch, dupilumab produced a significant change in one protein. This was related to Th22 (P = .019). Abrocitinib produced a significant change in seven, including those related to activation of T cells and of Th17. Abrocitinib also downregulated activity of the MMP12 gene, which is associated with general inflammation.

With proteins related to AD, “tighter and greater correlations were seen in clinical abrocitinib responders relative to nonresponders when compared to dupilumab,” Guttman-Yassky reported.

Comparison of therapies at the proteomic level have important implications for understanding therapeutic effects overall and how they might differ for specific AD phenotypes, the data suggest.

Although AD is classified as a chronic inflammatory skin disease, Guttman-Yassky pointed out that it involves “heterogeneous clinical and molecular phenotypes driven mainly by type 2 immunity but with variable contributions from Th1, Th17/Th22, and innate immune pathways.”

As proteomics provides insights into how drugs modify disease activity, Guttman-Yassky pointed to the potential for individualizing therapy.

The progress over the past two decades in tracking the pathophysiology of AD has not only led to more targeted therapies, but also it has revealed “the disease’s complexity, multiple underlying pathways, and resulting heterogeneity in both clinical presentation and treatment response,” said Anna De Benedetto, MD, associate professor of dermatology at the University of Rochester Medical Center in Rochester, New York.

De Benedetto was not involved in the studies by Guttman-Yassky and did not hear her presentation at the EADV 2026 Congress, but she was the senior author of a study published earlier this year that used machine learning to conduct serum-proteomic profiling of AD. The goal was to identify severity-linked signatures.

That study identified a proteomic footprint for severe AD that might, like Guttman-Yassky’s work, provide proteomic phenotypes to guide therapy.

“Emerging proteomic technologies enable large-scale protein profiling [that] offers a powerful approach to better define patient subgroups and potentially predict therapeutic outcomes,” De Benedetto told Medscape Medical News.

“In parallel, advances in machine learning and bioinformatics provide the tools needed to extract meaningful insights from these highly multidimensional datasets,” she added.

The work is promising but early, according to De Benedetto.

“Proteomic findings must be interpreted in their appropriate biological and clinical context, integrated with patient phenotypes and validated in independent cohorts before they can be translated into clinical practice,” she said.

Guttman-Yassky reported having financial relationships with AbbVie, Aclaris Therapeutics, Almirall, Alumis, Amgen, AnaptysBio, Apogee Therapeutics, Apollo Therapeutics, Arcutis, Artax Biopharma, Astria, Boehringer-Ingelheim, Bristol Myers Squibb, Celldex, Centrexion Therapeutics, Connect Biopharm, Coty, DBV, Eli Lilly, Enveda Biosciences, Escient Pharmaceuticals, Galderma, Gate Bio, GSK Immunology, Incyte, Inmagene, Janssen Biotech, Jasper Therapeutics, Kymera Therapeutics, Kyowa Kirin, Leo Pharma, Matchpoint Therapeutics, Merck, Nektar Therapeutics, Numab Therapeutics, Otsuka, Pfizer, Pharmaxis, Proteologix, RAPT, RayThera, Regeneron, RiBon Therapeutics, Sanofi, SATO, Schrödinger, Sitryx, Syntara, Sun Pharma, Takeda, Teva, TRex Bio, UCB, and VRG Therapeutics. De Benedetto reported having financial relationships with AbbVie, Allakos, AstraZeneca, Bambusa, Incyte Corporation, dMed Biopharmaceutical, Kiniksa, and Pfizer.

Ted Bosworth, a career medical writer based in New York City, has been covering advances in clinical medicine, including dermatology and oncology, for several decades.