Reviewing Multiple Subtypes of CHE and Delgocitinib as a Pan-JAK Inhibitor

“My personal experience has been, however, that the patients who suffer the most in terms of their quality of life detriment are those that experience those deep, painful fissures on the hands, particularly on the fingers, and that's usually accompanied by swelling,” said Christopher Bunick, MD, PhD, in an interview with Dermatology Times on recent chronic hand eczema (CHE) and delgocitinib cream updates.

Bunick, associate professor of dermatology and translational biomedicine at the Yale University School of Medicine in New Haven, Connecticut, and Dermatology Times’ 2024 Winter Editor in Chief, reviewed 2 posters presented at the 2024 European Academy of Dermatology and Venerology (EADV) Congress in Amsterdam, Netherlands, on the multifactorial and heterogenous nature of CHE and delgocitinib’s (LEO Pharma) ability to restore the molecular signature of lesional skin in patients with CHE.

In his interview, Bunick discussed the diagnostic challenges of CHE, emphasizing its overlapping subtypes and varied immune signatures, all linked by the JAK/STAT pathway.¹ He highlighted the efficacy of delgocitinib, a pan-JAK inhibitor, in addressing inflammation and skin barrier dysfunction across CHE subtypes, noting its safety due to negligible systemic absorption. Additionally, he explained the clinical implications of differential gene expression in severe versus mild CHE.²

The Multifactorial and Heterogeneous Nature of CHE

Bunick first highlighted the diagnostic challenges posed by the multifactorial and heterogeneous nature of CHE. Data from the CARPE registry revealed that over 50% of patients present with more than one active subtype of CHE, emphasizing the prevalence of mixed or overlapping forms. The European 2022 guidelines categorize CHE into etiological subtypes, including irritant contact dermatitis, atopic hand eczema, allergic contact dermatitis, and protein contact dermatitis/contact urticaria, as well as clinical subtypes such as hyperkeratotic eczema, vesicular eczema, nummular eczema, and pulpitis.

Recent findings, presented in a 2024 EADV poster, revealed that 75% of CHE patients show 3 or more overlapping signs and symptoms—such as erythema, itching, scaling, fissures, lichenification, hyperkeratosis, pain, vesicles, or edema. This overlap complicates clinical diagnosis. Bunick emphasized that although CHE subtypes have distinct immune signatures (eg, Th1/Th17 profiles in irritant contact dermatitis versus Th2/Th22 profiles in atopic eczema), all subtypes share a common underlying JAK/STAT signaling pathway. This makes pan-JAK inhibitors, such as delgocitinib, broadly effective in managing CHE.

Signs and Symptoms of CHE Progression

While discussing the progression of CHE symptoms, Bunick emphasized that the condition’s heterogeneity means no single presentation signals severity. Severe CHE can manifest on the fingers, palms, back of the hands, or wrists, with various combinations of signs and symptoms. However, he noted that fissures of the fingers accompanied by swelling are particularly debilitating and often result in significant quality of life impairments for patients.

The Role of Delgocitinib in CHE Treatment

Bunick reviewed delgocitinib’s mechanism of action, which effectively targets the molecular drivers of CHE. He explained that CHE subtypes, despite their varied immune profiles, share aberrant JAK/STAT signaling as a common pathway connecting inflammation and skin barrier dysfunction. Delgocitinib inhibits JAK1, JAK2, JAK3, and TYK2, making it a true pan-JAK inhibitor. Delgocitinib’s comprehensive inhibition targets multiple cytokines and signaling pathways involved in CHE, addressing both immunoinflammatory responses and skin barrier repair.

According to Bunick, a significant advantage of delgocitinib is its negligible systemic absorption, which ensures safety while delivering efficacy across diverse CHE subtypes. By modulating the JAK/STAT pathway, delgocitinib restores the molecular signature of lesional skin, reducing inflammation and improving skin barrier function.

Clinical Implications of Gene Expression Changes

Data presented at EADV 2024 demonstrated that gene expression varies between severe and mild CHE. Severe CHE is associated with upregulation of S100A9, a calcium-binding protein linked to inflammation, and downregulation of LOR and FLG2, genes crucial for skin barrier homeostasis. The findings show the interplay between inflammation and barrier dysfunction in CHE pathogenesis. Bunick explained how this "trigger cycle" of inflammation and barrier impairment exacerbates CHE severity.

Delgocitinib’s ability to disrupt this cycle makes it a potent therapeutic option. By targeting multiple cytokines through JAK/STAT inhibition, it breaks the inflammation-barrier dysfunction loop, providing relief for patients with severe CHE and restoring skin integrity across subtypes.

Click here to watch Bunick’s part 1 interview on the burden and unmet need of CHE.

References

1. Fargnoli MC, Molin S, Bewley A, et al. The multifactorial and heterogenous nature of Chronic Hand Eczema in clinical practice: Results from the RWEAL study. Poster presented at: 2024 EADV Congress; September 25-28, 2024; Amsterdam, Netherlands
2. Worm M, Jiang L, Litman T, et al. Topical pan-JAK inhibition with delgocitinib restores the molecular signature of lesional skin in patients with chronic hand eczema: insights from a phase 2a study. Poster presented at: 2024 EADV Congress; September 25-28, 2024; Amsterdam, Netherlands