Atopic dermatitis (AD), a pruritic, inflammatory chronic disease with multifactorial pathogenesis, has been a therapeutic challenge. Novel target treatments aim to reduce not only the immunologic dysfunction and microbiome dysbiosis but also the recovery of the damaged skin barrier. The current review focuses on the interleukin 31 (IL-31) pathway and AD and offers an overview of the current clinical studies with monoclonal antibodies blocking this cascade. Pruritus, the key symptom of AD, has substantial participation of the IL-31 complex and activation of relevant signaling pathways. Epidermal keratinocytes, inflammatory cells, and cutaneous peripheral nerves express the interleukin-31 receptor α-chain (IL-31RA), upregulated by Staphylococcus aureus toxins or Th2 cytokines involved in AD. Nemolizumab is a humanized monoclonal antibody that antagonizes IL-31RA, inhibiting the IL-31 cascade and therefore contributing to reducing the pruritus and inflammation and recovering the damaged skin barrier in AD patients. Phases 2 and 3 clinical trials with nemolizumab in AD show a suitable safety profile, with a fast, efficient, and sustained reduction of pruritus and severity scores, especially when associated with topical treatment. Deciphering the full interplay of the IL-31 pathway and AD may expand the potential of nemolizumab as a targeted therapy for AD and other pruritic conditions.

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Blockage of the IL-31 Pathway as a Potential Target Therapy for Atopic Dermatitis

Patients who completed the originating studies, BREEZE-AD1 (NCT03334396), BREEZE-AD2 (NCT03334422), and BREEZE-AD7 (NCT03733301), were eligible for enrolment in the multicentre, phase 3, long-term extension study BREEZE-AD3 (NCT03334435). At week 52, responders and partial responders to baricitinib 4 mg were re-randomized (1:1) into the sub-study to dose continuation (4 mg, N = 84), or dose down-titration (2 mg, N = 84).Maintenance of response was assessed from week 52 to 104 of BREEZE-AD3. Physician-rated outcomes included vIGA-AD (0,1), EASI75, and mean change from baseline in EASI. Patient-reported outcomes included DLQI, POEM total score, HADS, and from baseline: WPAI (presenteeism, absenteeism, overall work impairment, daily activity impairment) and change from baseline in SCORAD itch and sleep loss.With continuous treatment with baricitinib 4 mg, efficacy was maintained up to week 104 in vIGA-AD (0,1), EASI75, EASI mean change from baseline, SCORAD itch, SCORAD sleep loss, DLQI, POEM, HADS, and WPAI (all scores). Patients down-titrated to 2 mg maintained most of their improvements in each of these measures.The sub-study of BREEZE AD3 supports flexibility in baricitinib dosing regimens. Patients who continued treatment with baricitinib 4 mg and down-titrated to 2 mg maintained improvements in skin, itch, sleep, and quality of life for up to 104 weeks.

Maintained Improvement in Physician- and Patient-Reported Outcomes with Baricitinib in Adults with Moderate-to-Severe Atopic Dermatitis who were Treated for up to 104 Weeks in a Randomized Trial.

BACKGROUND: Atopic dermatitis is a chronic, relapsing and severely itchy dermatitis that usually occurs in childhood and has a characteristic age-related distribution. Atopic dermatitis is relatively frequent, affecting 1020% of children in developed countries. Atopic dermatitis in children associated with poor school performance, low self-esteem and family problems. Recent studies show importance in atopic dermatitis pathogenesis of protein filaggrin and modulation of its activity may be a promising direction in the pathogenic therapy of atopic dermatitis. 
AIM: to study the effect of a cream for dry, sensitive and atopic skin with a modulator of filaggrin activity on the course of mild and moderate atopic dermatitis. 
MATERIAL AND METHODS: An open, prospective, multicentre, non-comparative, single-group clinical trial was organized to test the effectiveness of a cream with a filaggrin activity modulator. The study was on outpatients in the participated centers and included 5 visits with a screening visit 1, and 5th visit ― therapy completion. Cream was used for 12 weeks. In total, the study involved 60 children aged 3 to 18 years with diagnoses of atopic dermatitis of mild and moderate severity. The severity of atopic dermatitis was measured with the SCORAD, EASI, IGA scales, also measured was skin pH and transepidermal water loss (TEWL), as well as the severity of xerosis according to visual analogue scale. 
RESULTS: The severity of atopic dermatitis in children whose therapy regimens included Admera cream decreased by 19.6 points according to the SCORAD index, including in children who did not receive mometasone furoate in the therapy schemes, the SCORAD index decreased statistically significantly compared to the baseline data (p 0.001). The overall decline in the EASI index ― by 3.0 points, the IGA global assessment index ― by 2.0 points, the severity of xerosis decreased by 3 points (in all cases, p 0.001). Transepidermal water loss decreased (by 4.5 g/m2 per hour, p 0.001); Skin pH did not change (difference 0.02, p=0.34). The smell was rated as "excellent" by 86.7% (95% CI 75.494.1), the consistency ― by 83.3% (95% CI 71.591.7) of the respondents, and overall satisfaction was noted by ― 88.3% (95% CI 77.495.2) of the respondents. 
CONCLUSION: Сream for dry and sensitive skin with a modulator of filaggrin activity during the study showed good efficacy and tolerability and can be used in atopic dermatitis treatment regimens as a basic care product, both during exacerbation and remission.

Influence of the cream with filaggrin activity modulator for dry and sensitive skin in children with mild to moderate severity atopic dermatitis on objective indicators of skin barrier function and disease severity indices

The latest findings regarding AD pathogenesis point to an impaired function of the epidermal barrier, changed immune response, colonization of the skin by microorganisms, and certain psychological factors among other causes/triggers. The inflammatory response of AD patients is mainly associated with the activation of T cells (Th2 cells predominate), dendritic cells, macrophages, keratinocytes, mast cells, and eosinophils. Therapy usually involves medical evaluations and adequate management including treatment of concomitant diseases (e.g., allergies and infections), patient education and nursing care, psychological support, and nutritional consultations, which are organized through specific programs and structured educational groups. Systemic AD therapy includes conventional systemic treatment (cyclosporine, methotrexate, azathioprine) and new, specific drugs, interleukin inhibitors (e.g., dupilumab) and JAK inhibitors (baricitinib, abrocitinib, upadacitinib, etc.). Since many AD patients are affected by various psychological factors and comorbidities, they should be assessed and managed through a multidisciplinary approach, involving different professions (psychologists, ear–nose–throat specialists, pulmonologists, allergologists, immunologists, nutritionists, pediatricians, gastroenterologists, psychiatrists (when necessary), and others). A multidisciplinary approach provides better coping strategies and improves control over the disease, patient adherence to therapy, and quality of life. It also has a positive influence on family quality of life while at the same time making more efficient use of dermatology healthcare resources, reducing the economic burden on both patients and society.

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Atopic Dermatitis: Disease Features, Therapeutic Options, and a Multidisciplinary Approach

Quantifying Inflammatory Response and Drug-Aided Resolution in an Atopic Dermatitis model with Deep Learning.

Atopic dermatitis is a chronic inflammatory skin condition that affects approximately 18 million people in the United States. Assessing the extent and severity of atopic dermatitis is critical for determining baseline disease burden and treatment effectiveness for both investigators and clinicians. Considerable efforts over the past several decades have been made in developing a highly validated instrument called the Eczema Area and Severity Index (EASI). Although several guides exist for the EASI, questions continue to arise regarding its use and interpretation. This review was developed to serve as the definitive guide for the EASI and to address commonly asked questions. 

Jue Huang

Papers

The Eczema Area and Severity Index—A Practical Guide