Delgocitinib: A newer Janus kinase inhibitor for dermatologists

AD

Th2 cytokines such as interleukin (IL)-4, IL-13, and IL-31 play an important role in the pathogenesis of AD.^[8] Type 1 IL-4 receptor-mediated pathway activates JAK1 and JAK3 while type II IL-4 and IL-13 receptors activate JAK1 and TYK2.^[9] Topical JAK inhibitor like delgocitinib not only blocks these Th2-mediated cutaneous reactions but also improves skin barrier dysfunction and pruritus.^[10] Figure 1 demonstrates the mechanism of different JAK inhibitors at the molecular level. A study reported that delgocitinib improves skin barrier function by suppressing STAT3 activation, leading to increased levels of filaggrin and natural moisturizing factors.^[11] Delgocitinib did not cause any epidermal atrophy as reported by another author.^[12] A study reports a significant reduction in modified Eczema Area Severity Index score in both 0.25% delgocitinib ointment (54.2%) and 0.5% ointment group (61.8%) in comparison to the control group (4.8%).^[13] Another study compared delgocitinib ointment with topical corticosteroids (TCS) for proactive maintenance therapy.^[14] This study reports eczema flare-up in 32% versus 16% in delgocitinib and TCS group, respectively. However, stratum corneum hydration was maintained much better in the delgocitinib group. Application site irritation and contact dermatitis were the most common adverse events noted.^[15] There is a single report of delgocitinib-induced anti-LAD1 immunoglobulin G positive, anti-BP180 negative bullous pemphigoid in a patient of AD.^[16]

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Figure 1:

Demonstrates the mechanism of different Janus kinase (JAK) inhibitors at the molecular level. IL: Interleukin, STAT: Signal transducer and activator of transcription.

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CHE

At present, TCs are the first-line treatment option but their long-term use often leads to skin atrophy.^[17] A phase IIb trial showed the clinical efficacy of topical delgocitinib cream formulation applied twice daily for 16 weeks in mild-to-severe cases of CHE.^[18] Investigator’s Global Assessment (IGA)-CHE score of 0 (clear) or 1 (almost clear) with a ≥ 2-point improvement from baseline was considered a successful treatment.^[19] The study reported 21.2% (1 mg/g), 7.8% (3 mg/g), 36.5% (8 mg/g), and 37.7% (20 mg/g) clinical efficacy with variable formulations as mentioned.^[18] Nasopharyngitis, eczema, and headache were the common adverse events reported during the study.^[18]

Other skin conditions

Kurihara et al. reported the successful use of delgocitinib ointment in two cases of psoriasiform dermatitis arising secondary to dupilumab therapy.^[20] Another author reported 0.5% delgocitinib ointment to be efficacious in the treatment of a rare case of indeterminate cell histiocytosis.^[21] The ointment was applied once daily and continued for 12 months without any recurrence.^[21] In another randomized controlled trial, the authors used delgocitinib (30 mg/g) for treating alopecia areata but reported no significant improvement probably due to its inability to penetrate the scalp dermis.^[22] However, Senda et al. reported a case where they successfully used delgocitinib ointment in a case of alopecia areata with cytotoxic T lymphocyte antigen-4 haploinsufficiency.^[23] Topical delgocitinib has been successfully used for treating a case of subacute cutaneous lupus erythematosus.^[24] Similarly, there are case reports of successfully using topical delgocitinib ointment in cutaneous T-cell pseudolymphoma, lichen planus pigmentosus, and cutaneous sarcoidosis.^[25-27] Another author reports effective treatment of corticosteroid-resistant dermatitis in a Netherton syndrome patient with delgocitinib.^[28] Furthermore, two cases of vitiligo vulgaris were also successfully treated with delgocitinib as reported by Yagi et al.^[29]

Why delgocitinib over other biological agents?

• Delgocitinib acts at multiple pathways and blocks different cytokines and chemokines in diseases with complex pathogenesis such as AD and CHE.^[30-32]

• Topical formulations are easily acceptable to patients.

• No major adverse effect reported.

• Single agent can be widely used for various inflammatory skin conditions.