With an increasing prevalence during the past decades, atopic dermatitis is a chronically relapsing inflammatory skin condition. Although not completely understood, its pathogenesis is complex and seems to result from a combination of genetic and environmental factors that include skin barrier dysfunction, cutaneous and systemic immune dysregulation, skin microbiota dysbiosis and a strong genetic influence. Not unexpectedly, atopic dermatitis is burdensome for individuals with the disease, their families and society.

• Management of AD must consider the individual clinical variability of the disease.
• The aims of therapy are to reduce pruritus and establishing persistent disease control that is sufficient to enable patients to be fully functional.
• Hence, a multistep approach with interventions aimed at avoiding relevant triggers, improving the skin barrier, normalising skin dysbiosis and reducing inflammation, is mandatory.
• Therapy is chosen based on disease severity.
• Basic therapy consists of educational programs, emollients, bath oils and avoidance of clinically relevant triggers.
• Mild and moderate disease is treated with anti-inflammatory topical therapy, while the latter also consists of proactive therapy with the addition of topical tacrolimus or glucocorticosteroids in many cases.
• Systemic therapy is reserved for severe cases.
• In any approach undertaken, it is of utmost importance to make every effort to ensure patient compliance to therapy, while individualising treatment according to the profile and needs of each patient.

• The pathophysiology of atopic dermatitis is complex and multifactorial, involving elements of barrier dysfunction, alterations in cell mediated immune responses, IgE mediated hypersensitivity and environmental factors.
• Recent improvements in the understanding of atopic dermatitis have allowed for more rational utilisation of several targeted agents in therapy.
• Many biologics and small molecule antagonists are in phase 2 and phase 3 trials targeting different pathways, including Th2 immune response, JAK signalling and itch mediators, among others.

Dupilumab

• Dupilumab targets the IL-4/IL-13 receptor, and the results of two phase 3 trials of dupilumab vs. placebo have shown that it leads to significant improvement of the clinical symptoms of atopic dermatitis, as well as significant improvement in the quality of life. [1]
• More recently, the long-term efficacy and safety of dupilumab with medium-potency topical corticosteroids versus placebo with topical corticosteroids in adults with moderate-to-severe atopic dermatitis has been evaluated. [2]
• Importantly, week 52 results were similar to those at week 16, indicating that the treatment is long-lasting in patients with response to therapy.
• The safety profile was also acceptable, although treatment-associated conjunctivitis is seen in about 25-30% of patients. [3]
• Phase 3 studies are underway for dupilumab in paediatric atopic dermatitis.

Lebrikizumab

• Lebrikizumab and tralokinumab are two new targeted agents that block the activity of IL-13.
• Recent studies with both these agents have reported promising results, with improvements in disease severity and favourable safety profiles. [4]
• In considering blockage of other interleukins, the antibody fezakinumab blocks the activity of IL-22, which promotes epidermal hyperplasia and inhibits skin barrier function.
• This agent has been studied in a phase 2 trial, which documented significant improvement in SCORAD that was particularly relevant in those with severe disease. [5]
• However, the results on this trial are limited by its small size and lack of assessment with Eczema Area and Severity Index.

Nemolizumab

• The efficacy and safety of nemolizumab, a humanised antibody against IL-31 receptor A, have also been assessed in a recent phase 2 trial for treatment of atopic dermatitis. [6]
• At week 12, among the patients who received nemolizumab every 4 weeks, changes on the pruritus visual-analogue scale were -43.7% in the 0.1-mg group, -59.8% in the 0.5-mg group and -63.1% in the 2.0-mg group, versus -20.9% in the placebo group (P <0.01 for all comparisons).
• Changes in the EASI were -23.0%, -42.3% and -40.9%, respectively, in the nemolizumab groups, versus -26.6% in the placebo group.
• Thus, nemolizumab at all monthly doses significantly improved pruritus in patients with moderate-to-severe atopic dermatitis, which showed the efficacy of targeting IL-31 receptor A.
• Of note, nemolizumab was also associated with improvements in sleep disturbance.

• Several JAK inhibitors are in development as oral therapies for moderate-to-severe atopic dermatitis or as topical treatments for mild-to-moderate atopic dermatitis.
• JAK inhibitors block a range of cytokines, growth factors and/or hormone receptor signalling pathways depending on their relative specificity

Tofacitinib

• The results of topical treatment with tofacitinib have been examined in a phase 2 trial. [7]
• The mean percentage change from baseline at week 4 in EASI score was significantly greater for tofacitinib (-81.7%) vs. vehicle (-29.9%).
• Patients treated with tofacitinib showed significant improvements vs. vehicle across all prespecified efficacy end points and for pruritus at week 4.
• Significant improvements in EASI, PGA and BSA were observed by week 1 and improvements in pruritus were observed by day 2.

Baricitinib

• Baricitinib is a JAK1/2 inhibitor that has shown efficacy in atopic dermatitis in phase 2 trial where significantly more patients who received baricitinib, 4 mg, achieved EASI-50 than did patients receiving placebo (61% vs 37%) at 16 weeks. [8]
• One limitation of this trial was that topical corticosteroids were applied before baricitinib, limiting the ability to compare results with those of baricitinib monotherapy.

Crisaborole

• Crisaborole is a phosphodiesterase 4 inhibitor that has been investigated in two phase 3 studies in atopic dermatitis in an ointment formulation. [9]
• After 28 days of treatment, more crisaborole- than vehicle-treated patients achieved ISGA score success (clear/almost clear with ≥2-grade improvement; AD-301: 32.8% vs 25.4%, P = 0.038; AD-302: 31.4% vs 18.0%, P <0.001), with a greater percentage with clear/almost clear (51.7% vs 40.6%, P = 0.005; 48.5% vs 29.7%, P <0.001).
• Crisaborole has now been approved by the EMA and FDA for moderate atopic dermatitis in patients >2 years of age.

• Targeted therapies have provided new insights in the pathogenesis of AD.
• JAK inhibition through topical delivery is potentially a promising therapeutic target for AD.