Clinical Dermatology: Research and Therapy Review Article Treatment of Atopic Dermatitis: What’s New? Defne Ozkoca, Zekayi Kutlubay* and Ozge Karakus Department of Dermatology, Istanbul University-Cerrahpasa, Turkey ARTICLE INFO ABSTRACT Atopic dermatitis is a common and chronic skin disorder among the children and Received Date: May 07, 2019 Accepted Date: June 28, 2019 adults. The treatment guideline that was recently accepted in Europe includes Published Date: July 05, 2019 dupilumab, a monoclonal antibody, along with the conventional treatment methods. In KEYWORDS addition to dupilumab, other monoclonal antibodies have been developed and their efficacies were evaluated with randomized controlled trials. These antibodies are Atopic nemolizumab, lebrikizumab, tralokinumab, fezakinumab, ustekinumab and Biologic Dermatitis tezepelumab. Small molecule inhibitors are also being developed and evaluated. Molecule These are tofacitinib, upadacitinib, baricitinib, PF-04965842, tradipitant and New crisaborole. Thus, the chronic and relapsing course of atopic dermatitis is a driving Treatment small force for the emergence of new drugs. INTRODUCTION Copyright: © 2019 Zekayi Kutlubay et Atopic dermatitis is a common and chronic skin disorder that has a prevalence of 17% al., Clinical Dermatology: Research and among the school-age children in the US. The disease usually precedes other allergic Therapy. This is an open access article distributed under the Creative disorders of the atopic march i.e., asthma and allergic rhinitis [1]. The pathogenesis of Commons Attribution License, which the disease includes altered skin microbiome, skin barrier defects and dysregulated permits unrestricted use, distribution, innate immune response along with the shift of the adaptive immune system towards and reproduction in any medium, provided the original work is properly the type-2 pathway. One of the risk factors for the disease is the gene mutations cited. leading to the decreased expression of filaggrin [2]. In addition to the genetic predisposition, environmental factors can also lead to decreased filaggrin expression, Citation for this article: Defne Ozkoca, Zekayi Kutlubay and Ozge Karakus. which is referred to as the “hygiene hypothesis”. As a result, atopic dermatitis has an Treatment of Atopic Dermatitis: What’s increasing prevalence among the adults along with the children [3]. The presentation New?. Clinical Dermatology: Research of atopic dermatitis can be acute, subacute or chronic. In the acute phase, erythema, and Therapy. 2019; 2(1):127 vesicles, bullae, weeping and crusting dominate the clinical picture. In the subacute phase, erosion, crusts, papules and scaly plaques are seen. The chronic phase is characterized by scaling, lichenified plaques and post lesional hypo/hyperpigmentation [2]. In the pediatric population, the disease typically manifest itself either with erythematous plaques or lichenification on the cheeks or flexural sites [1]. (Figure 1) shows one of the typical manifestations of the disease in children: desquamated erythematous plaques on the cheeks. In adults linear excoriations, excoriated papules and lichenified plaques either localized or Corresponding author: generalized is seen [1]. (Figure 2) shows an adult patient with widespread Zekayi Kutlubay, excoriations due to atopic dermatitis. (Figure 2a,2b,2c). In adult patients with chronic, Department of Dermatology, Istanbul University-Cerrahpasa, Turkey, severe atopic dermatitis, wide-spread lichenified and excoriated papules may be Tel: +00 90 212 414 3120; seen as in prurigo nodularis [1]. Email: [email protected] 01 Treatment of Atopic Dermatitis: What’s New?. Clinical Dermatology: Research and Therapy. 2019; 2(1):127. Clinical Dermatology: Research and Therapy Figure 1: Desquamated erythematous plaques on the cheeks of an infant. Figure 2a: Widespread excoriations due to atopic dermatitis in the abdominal area. 02 Treatment of Atopic Dermatitis: What’s New?. Clinical Dermatology: Research and Therapy. 2019; 2(1):127. Clinical Dermatology: Research and Therapy Figure 2b: Widespread excoriations due to atopic dermatitis in the antecubital region. Figure 2b: Widespread excoriations due to atopic dermatitis in the antecubital region. 03 Treatment of Atopic Dermatitis: What’s New?. Clinical Dermatology: Research and Therapy. 2019; 2(1):127. Clinical Dermatology: Research and Therapy PATHOGENESIS NEW TREATMENT MODALITIES The inflammation of atopic dermatitis directed by the homing Biologic agents and incoming cells of the skin; and the cytokines, chemokines The chronic and relapsing course of the disease has led and immunoglobulins produced by these cells. Interleukin (IL) 4 physicians to the search of newer and more effective treatment and 13 are two of the most important of these factors with modalities for atopic dermatitis. The monoclonal antibodies that multiple effects on innate and adaptive immune systems. were previously used for other diseases were tried in the Together with Tumor Necrosis Factor-Alpha (TNF-alpha), IL4 treatment of atopic dermatitis as well; however, none of these and IL13 induce the keratinocytes to produce Thymic Stromal were successful in treating the disease [6]. These agents Lymphopoeitin (TSLP) and increase the activity of T-helper 2 include: omalizumab (anti-IgE), infliximab (anti-TNF), pathway. IL4 and IL13 also decrease the synthesis of filaggrin, efalizumab and alefacept (anti-T-cell), pitrakinra (anti- involucrin and loricrin which are structural barrier proteins of IL(interleukin)4/13), mepolizumab (anti-IL5) and rituximab the skin; thus leading to barrier dysfunction. IL-13, IL-31, IL-17 (anti-CD20) [7]. Newer biologic agents are being developed and IL-22 are other important mediators of this ongoing for atopic dermatitis [6]. Currently, only Dupilumab, a inflammation of atopic dermatitis. Janus Kinase (JAK) inhibitors, monoclonal antibody against IL-4R-alpha, is approved for antimicrobial peptides, Phosphodiesterase (PDE)-4, Aryl atopic dermatitis in Europe and US [8]. Hydrocarbon Receptor (AhR) and Transient Receptor Potential Dupilumab: Dupilumab is a monoclonal antibody which has an Vanilloid Member 1 (TRPV1) are the other members of this affinity towards the alpha chains of IL-4 and IL-13, both of inflammatory pathway [4]. which have a role in inducing the activation of T-helper 2 cells CONVENTIONAL TREATMENT and production of cytokines [8]. Thus, dupilumab has a double According to the Atopic Dermatitis 2018 treatment guideline action in the inhibition of inflammatory pathways of atopic accepted in Europe, the baseline therapeutic interventions dermatitis [9]. In a study performed by Beck et al., compared include avoidance of clinically relevant allergens, application to the patients treated with placebo, patients treated with of emollients and bath oils. For mild disease, with a SCORAD dupilumab had a significantly higher reduction in the Eczema (Scoring Atopic Dermatitis) less than 25, class 2 topical Area And Severity Index (EASI) scores, significantly higher corticosteroids, topical calcineurin inhibitors and topical near-clearance rate according to the investigator’s global antiseptics are recommended. For patients with recurrent assessment scores and a significantly decreased pruritus scores. disease and/or SCORAD between 25 and 50, class 2 or 3 Furthermore, skin infections were found to be more frequent in topical corticosteroids, topical calcineurin inhibitors (proactive, the placebo group, whereas nasopharyngitis and headache twice-weekly use), wet-wrap therapy, phototherapy and were more common with dupilumab [10]. Simpson et al., have psychological counselling are recommended. For patients with conducted two independent phase 3 studies, enrolling over a severe disease, SCORAD greater than 50 and/or persistent thousand patients, evaluating the efficacy of dupilumab in dermatitis, systemic immunosuppression with or without patients with moderate to severe atopic dermatitis: SOLO 1 hospitalization, is recommended. Cyclosporine, methotrexate, and SOLO 2. They have concluded that, dupilumab was more azathioprine and mycophenolate mofetil can be used both in efficacious in clearing atopic dermatitis according to the children and adults. On the other hand, oral corticosteroids are investigator’s global assessment index with a p-value less than only recommended for adults and it should only be used during 0.001 in both studies; the improvement in EASI score was flares for a short period of time. Dupilumab, which is also a significantly higher with dupilumab in both studies and newly emerging therapeutic option for atopic dermatitis, is also dupilumab was more successful in reducing of pruritus, anxiety included in the guideline, however, it is only recommended for and depression compared to placebo in both studies. The most adults with severe disease. It is important to note that many of frequently encountered side effects of dupilumab were the systemic drugs are not licensed for atopic dermatitis and injection site reactions and conjunctivitis [11]. Food and Drug are used off-label in many countries [5]. Association (FDA) has approved dupilumab in the treatment of 04 Treatment of Atopic Dermatitis: What’s New?. Clinical Dermatology: Research and Therapy. 2019; 2(1):127. Clinical Dermatology: Research and Therapy atopic dermatitis in the year 2017, as a result of these studies lebrikizumab with a randomized, placebo controlled phase-two [5]. In a meta-analysis about the adverse effects of dupilumab, trial