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 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. 
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. 
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. 
Phase 3 studies are underway for dupilumab in paediatric atopic dermatitis.
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. 
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. 
However, the results on this trial are limited by its small size and lack of assessment with Eczema Area and Severity Index.
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. 
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
The results of topical treatment with tofacitinib have been examined in a phase 2 trial. 
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 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. 
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 is a phosphodiesterase 4 inhibitor that has been investigated in two phase 3 studies in atopic dermatitis in an ointment formulation. 
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.
Blauvelt A, de Bruin-Weller M, Gooderham M, et al. Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomised, double-blinded, placebo-controlled, phase 3 trial. Lancet. 2017 Jun 10;389(10086):2287-303.
Aszodi N, Thurau, S, Seegraber, et al. Management der Dupilumab‐assoziierten Konjunktivitis beim atopischen Ekzem, JDDG. 2019:17(5):488-92.
Simpson EL, Flohr C, Eichenfield LF, et al. Efficacy and safety of lebrikizumab (an anti-IL-13 monoclonal antibody) in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical corticosteroids: A randomized, placebo-controlled phase II trial (TREBLE). J Am Acad Dermatol. 2018 May;78(5):863-71.
Guttman-Yassky E, Brunner PM, Neumann AU, et al. Efficacy and safety of fezakinumab (an IL-22 monoclonal antibody) in adults with moderate-to-severe atopic dermatitis inadequately controlled by conventional treatments: A randomized, double-blind, phase 2a trial. J Am Acad Dermatol. 2018 May;78(5):872-81.
Guttman-Yassky E, Silverberg JI, Nemoto O, et al. Baricitinib in adult patients with moderate-to-severe atopic dermatitis: A phase 2 parallel, double-blinded, randomized placebo-controlled multiple-dose study. J Am Acad Dermatol. 2019 Apr;80(4):913-21.
Paller AS, Tom WL, Lebwohl MG, et al. Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. J Am Acad Dermatol. 2016 Sep;75(3):494-503.
Presenter disclosure information: D Simon: None disclosed.
Presented by: Prof. Kristian Reich, Translational Research in Inflammatory Skin Diseases, Institute for Health Services Research in Dermatology and Nursing, University Medical Center Hamburg-Eppendorf, and Skinflammation® Center, Hamburg, Germany