what is new in atopic dermatitis?


New topical agents for AD include phosphodiesterase 4 inhibitor, JAK (Januse kinase) inhibitors,
and commensal bacteria.
Systemic agents include targeted monoclonal antibodies, antagonizing TH2/ TH22/TH17-related cytokines,
and broad-acting systemic therapeutics, including JAK inhibitors and histamine 4 receptor

Topical therapy is an important component of AD care, even in these times of newly introduced highly
effective systemic drugs. The topical treatment is used for barrier repair and delivery of antiinflammatory
compounds, and the mainstay of disease management includes generous use of emollients and moisturizers. For many years, the only active topical agents used as an antiinflammatory were topical corticosteroids and calcineurin
inhibitors. As the treatment paradigm of AD expands, however, new topical drugs are also introduced.
The first drug to be licensed, crisaborole, is a phosphodiesterase (PDE) 4 antagonist. In AD,elevated PDE activity was found compared withnormal skin.21,22 PDE hydrolyzes cyclic adenosinemonophosphate (cAMP) and results in upregulationof inflammatory mediators. PDE antagonismacts in a broad, nonspecific mechanism,
because it elevates intracellular cAMP; thus,downstream inhibition of numerous proinflammatory
factors ensues.21Crisaborole 2% topical ointment is indicated inadults and children over 2 years of age with mildto-moderate AD.

Another promising group of topical agents, now in clinical trials for AD, are the Janus kinase (JAK)inhibitors. The JAKs, a family of tyrosine kinases(TYKs), including JAK1, JAK2, JAK3, and TYK2,phosphorylate the intracellular domain of severalcytokine receptors to facilitate the attachmentand stimulation of the signal transducer and activatorof transcription (STAT), which then enters the nucleus and effects transcription

A different possible topical therapy relies on another aspect of AD pathophysiology, the disruptedskin microbiome of AD patients. During flares,the diversity of the bacteria that normally reside onthe skin is reduced, and there is a shift towardStaphylococcus aureus colonization.28 S aureushas an important pathogenic role in AD, because
it perpetuates the inflammation, specifically TH2-related, and further compromises skin barrier.
Autologous microbiome transplant in 1 study andapplication of commensal gram-negative bacteria
in another led to decreased colonization of S aureus, with clinical improvement and reducedused of topical corticosteroids in the second study.

Dupilumab, Tralokinumab, and Lebrikizumab
Cytokine-targeted drugs currently are an important therapeutic tool in dermatology, and because AD is largely TH2/TH22 centered, antagonizing these axes have strong rationale for AD treatment


Interleukin 31 Blockers
Despite the suggested pivotal role of IL-4/IL-13 in AD, skin lesions of AD are characterized by robust up-regulations of various other TH2-related cytokines and chemokines, and these too have the potential
of being therapeutic targets

Inhibitors of the Thymic Stromal Lymphopoietin–OX40 Axis

The TH2 pathway also includes the thymic stromal lymphopoietin (TSLP)-OX40 axis, which is speculated to initiate the allergic response and is referred as the master switch of allergic inflammation. 42,43


In addition to common TH2 skewing across all AD subtypes, TH22-related genes are also overexpressed,
and the main cytokine in this axis, IL-22, plays a major role in barrier function disruption, by down-regulating terminal differentiation and tight junction products, and promotes epidermal hyperplasia resulting in acanthosis

As discussed previously, in addition to the common TH2/TH22 overexpression, some AD phenotypes
(including Asian AD, intrinsic AD, and pediatric AD) show higher TH17-related markers expression as well as histologic features that are also seen in psoriasis, which is TH17/TH1 driven.6

Janus Kinase Inhibitors
The JAK-STAT, as discussed previously, mediates TH2 polarization in addition to a range of otherintracellular immune dysregulations.78 Oral JAK inhibitorsare small molecules that block these intracellularsignaling and result in a potent, broad,inhibition of various inflammatory pathways aswell as antiproliferative activity.79
Currently, 3 JAK inhibitors are studied in clinicaltrials for AD: baricitinib, a JAK 1 and JAK 2 antagonist;
upadacitinib, a JAK1 antagonist; andPF-04965842 (abrocitinib), another specific JAK1inhibitor.


Histamine 4 Receptor Antihistamines
Other broad-acting, oral, small molecules, representing an additional promising treatment optionfor AD, are the histamine 4 receptor (H4R) antihistamines.Unlike the H1R-blocking antihistaminesthat traditionally are used as antipruritic agents,yet with effects in AD patients relying mostly ontheir sedative properties,83 H4R antihistamineshave implications relevant to AD pathogenesis

About Dr. Jayaprakash

Asst. Prof. of Pediatrics, ICH. Institute of Child Health. Gov. Medical College Kottayam. Kerala, India.

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