New Therapeutic Options in Light of Current Knowledge on the Pathogenesis of Atopic Dermatitis
Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by intense itching and recurrent eczematous lesions. AD is diagnosed in 2 out of 10 children and often persists into adulthood. In developed countries, it is the most common skin disease with a lifetime prevalence exceeding 15%. However, it is also very diverse due to a wide range of clinical phenotypes reflecting various pathophysiological mechanisms and interactions between genetics, the immune system, and the environment. So, what have we learned about atopic dermatitis from recent research, and how has this translated into advances in its treatment?
Impaired Epidermal Barrier and Microbiome in AD
An important component of the barrier between the body and the environment is the protein filaggrin (regulated by the FLG gene), whose deficiency is associated with the early onset of AD, a more severe course of the disease, and more frequent infections. A mutation in the FLG gene is present in up to 50% of patients; approximately 40% of carriers of the mutation do not develop AD. Dysfunction of the skin barrier in AD patients is further caused by low levels of ceramides and barriers in tight junctions.
The skin of AD patients is characterized by low microbiome diversity (dysbiosis), which is related to the severity of the disease. Disruption of the epidermal barrier increases the risk of secondary viral, bacterial, or yeast infections, which further worsen the dysfunction of the skin barrier. The skin microbiome is likely involved in regulating the immune response. In a mouse model, the amount of Staphylococcus aureus, a common pathogen also in AD patients, directly correlates with increased expression of interleukins and cytokines associated with AD. A normal skin microbiome helps suppress colonization by S. aureus and can prevent the onset of AD in infants. Yeast communities on the skin of AD patients differ from those of healthy individuals, and yeast imbalance is associated with changes in skin physiology and immune response. Understanding the role of microbial colonization in AD patients helps in choosing the optimal treatment approach.
The Role of JAK Signaling in the Pathogenesis of AD
Several signaling pathways are upregulated in atopic dermatitis. It appears that the dysregulation of the JAK-STAT pathway, which regulates subsequent signaling of inflammatory cytokines and several growth factors, plays a key role. Upon ligand binding to cytokine receptors, the JAK isoforms auto-phosphorylate and activate STAT transcription factors, which are translocated to the nucleus where they influence the expression of target genes.
All four members of the JAK family, i.e., Janus kinases (JAK1–3, TYK2), are involved in the pathogenic processes associated with AD. Complete blockade of all JAK isoforms, however, is not suitable as it would lead to severe immunodeficiency. The key to therapeutic success is the ability to specifically block only selected JAK isoforms.
Targeted Treatment of AD
The goal of atopic dermatitis treatment is to set and maintain control over its symptoms so that patients are not limited by the disease. Currently, patients with more severe forms of AD are candidates for systemic therapy, which specifically affects regulatory processes and has an immunosuppressive effect.
Baricitinib was the first JAK inhibitor indicated for the treatment of moderate to severe AD in adult patients suitable for systemic therapy, approved by the European Medicines Agency (EMA). It is an oral potent selective and reversible inhibitor of JAK1 and JAK2. In these patients, it led (alone or in combination with topical treatment) to significant and clinically meaningful improvements in overall AD severity, pruritus, skin pain, sleep disorders, and health-related quality of life (HRQoL) over 16 weeks. The onset of action was rapid and lasted long-term (treatment duration was up to 68 weeks). In AD patients, no new safety signals were observed that had not already been reported in patients with rheumatoid arthritis (RA) treated with the same active substance.
Conclusion
A more detailed understanding of the events leading to the onset of atopic dermatitis is key to selecting and deploying optimal treatment. Currently, based on this knowledge, one of the suitable modalities of targeted systemic therapy for moderate to severe AD is baricitinib.
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Sources:
1. Weidinger S., Novak N. Atopic dermatitis. Lancet 2016; 387 (10023): 1109–1122, doi:10.1016/S0140-6736(15)00149-X.
2. Bieber T., Paller A. S., Kabashima K. et al. Atopic dermatitis: pathomechanisms and lessons learned from novel systemic therapeutic options. J Eur Acad Dermatol Venereol 2022; 36 (9): 1432–1449, doi: 10.1111/jdv.18225.
3. Hoy S. M. Baricitinib: a review in moderate to severe atopic dermatitis. Am J Clin Dermatol 2022; 23 (3): 409–420, doi:10.1007/s40257-022-00684-1.
4. SPC Olumiant. Available at: www.ema.europa.eu/en/documents/product-information/olumiant-epar-product-information_cs.pdf
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