Biologics to Treat Atopic Dermatitis: Effectiveness, Safety, and Future Directions

Abstract

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases worldwide. The clinical presentation of AD is heterogeneous and is characterized by a relapsing and remitting course. Most patients suffer from mild AD while approximately 5% to 20% experience severe disease activity, which often requires systemic treatment. Before 2017, systemic treatment options were limited to broad immunosuppressants, which often had significant toxicity and limited effectiveness. Advances in understanding AD pathophysiology have led to the development of targeted biologic therapies, including dupilumab, tralokinumab, lebrikizumab, and nemolizumab. These monoclonal antibodies specifically block key pro-inflammatory cytokines involved in AD, improving disease control and symptom relief. Dupilumab, the first approved biologic, inhibits IL-4 and IL-13 signaling, while tralokinumab and lebrikizumab selectively block IL-13. Nemolizumab targets IL-31, which plays a crucial role in pruritus. This review summarizes primarily real-world data on the effectiveness and safety of these biologics, providing clinical guidance for their use and management of side effects. It also briefly discusses promising therapeutic targets currently in phase 3 trials.

Keywords: atopic dermatitis; biologics; dermatology.

FIGURE 1

Timeline of currently available T2‐targeting biologics for the treatment of moderate‐to‐severe atopic dermatitis, based on EMA approval dates. D, dupilumab; L, lebrikizumab; N, nemolizumab; T, tralokinumab; y, year. Figure created with Biorender.

FIGURE 2

Overview of the pathophysiology of atopic dermatitis (AD). AD is a chronic inflammatory skin disease characterized by epidermal barrier dysfunction, immune dysregulation, and Staphylococcus aureus colonization. In response to barrier disruption, keratinocytes release epithelial‐derived cytokines such as thymic stromal lymphopoietin (TSLP), interleukin (IL)‐25, and IL‐33, collectively known as alarmins, which further impair barrier integrity and initiate type 2 immune responses [18, 19, 20]. These cytokines activate type 2 innate lymphoid cells (ILC2s), leading to the production of IL‐5 and IL‐13, and promote the recruitment of Th2 cells that secrete IL‐4, IL‐5, IL‐13, and IL‐31. Immune cell trafficking is further regulated by chemokine receptors such as CCR4, CCR10, and the prostaglandin D receptor CRTH2. IL‐4, and to a lesser extent IL‐13, can drive B cell class switching to IgE, eosinophil recruitment, and mast cell activation. Chemokines produced by Langerhans cells and dermal dendritic cells such as TARC/CCL17 and PARC/CCL18 facilitate the migration of Th2 cells into the skin, amplifying inflammation. Keratinocyte‐derived TSLP and IL‐33 also activate sensory neurons that transmit itch (pruritus) signals to the central neurol system. This leads to the release of neuropeptides like Substance P, which recruits and activates immune cells such as T cells and mast cells, driving further secretion of IL‐4, IL‐13, and IL‐31, and amplifying the itch–inflammation cycle. Another key pathway is the OX40–OX40L signaling axis. OX40, expressed on activated T cells (including Th1, Th2, Th17, and regulatory T cells), interacts with OX40L, which is found on antigen presenting cells and ILC2s. This interaction supports T cell survival, proliferation, and memory, contributing to the chronic and relapsing nature of AD [18, 21, 22]. In later stages, persistent inflammation can lead to the involvement of Th1, Th22, and CD8 T cells, which produce cytokines such as IFN‐γ and IL‐22, contributing to keratinocyte hyperproliferation and epidermal thickening. Together, these pathways drive the chronic relapsing–remitting nature of AD, with therapeutic interventions targeting key pathways or mediators including IL‐4R (dupilumab, with the IL‐4R being widely expressed immune and nonimmune cells such as keratinocytes, sensory neurons and endothelial cells, with the highest expression on naive B cells, followed by monocytes, neutrophils, ILC2s, and Th2 cells), IL‐13 (tralokinumab, lebrikizumab), IL‐31 (nemolizumab), OX40 receptor (rocatinlimab), and OX40L (amlitelimab) to restore immune balance and barrier function [23]. Figure created with Biorender.

FIGURE 3

Current available clinical effectiveness outcomes for EASI, IGA, NRS pruritus, and CDLQI during treatment with T2 biologics. (A) After 16 weeks of treatment, (B) After 52 weeks of treatment. Outcomes defined by Treat to Target or commonly used in RCTs and RWE studies: EASI (i.e., EASI‐75 or EASI ≤ 7), IGA (i.e., IGA 0/1), NRS pruritus (i.e., ≥ 4 points improvement from baseline or NRS pruritus ≤ 4), DLQI (i.e., ≥ 4 points improvement from baseline or DLQI ≤ 5) [86]. M, month; y, year; EASI, eczema area and severity index; NRS, numeric rating scale. Figure created with Biorender [30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83].

FIGURE 4

Ocular surface disease in atopic dermatitis patients and the hypothesized effects of biological treatments on the ocular surface. AD, atopic dermatitis; GzmB, Granzyme B; IFN, interferon; IL, Interleukin; MUC5AC, mucin 5 AC; Th, T‐helper. Figure created in Biorender [97, 98, 99, 101, 102, 107, 108].

FIGURE 5

(A) Most common adverse events of T2 biologics and their potential effect on atopic comorbidities. (B) Possible treatment interventions based on available literature and expert opinion for T2‐induced biologic adverse events. *prescribed by an ophthalmologist. AE, adverse event; BID, twice a day; OSD, ocular surface disease; QD, once daily; TCI, topical calcineurin inhibitor. Figure created with Biorender.

FIGURE 6

Patient‐centered dosing regimen and experiences with dose tapering of dupilumab treatment. D, dupilumab; EASI, eczema Area and Severity Index; NRS, numeric Rating Scale; PARC, pulmonary and activation‐regulated chemokine; Q2W, every 2 weeks; Q3W, every 3 weeks; Q4W, every 4 weeks; Q6W, every 6 weeks; Q8W, every 8 weeks; TARC, thymus and activation‐regulated chemokine; Th, T helper; IL4Ra, interleukin‐4 receptor alpha. Figure created with Biorender.

FIGURE 7

Immunological effects of biologics on blood, skin, and microbiome. AD, atopic dermatitis; IgE, immunoglobulin E; LDH, lactate dehydrogenase; PARC/CCL18, pulmonary and activation‐regulated chemokine; TARC/CCL17, thymus and activation‐regulated chemokine; Th, T helper. Figure created with Biorender.

FIGURE 8

Suggested practical guide for prescribing biologics and Janus kinase inhibitors (JAKi) for the treatment of moderate‐to‐severe atopic dermatitis in adult patients. Bari, baricitinib; Dupi, dupilumab; Tralo, tralokinumab; Upa, upadacitinib; Lebri, lebrikizumab; VZV, varicella zoster virus. ^aEvidence regarding safety in humans is still limited. Baricitinib is not available in the US since it is not FDA approved. Figure created with Biorender.

FIGURE 9

Infection risk during biologic and JAK‐inhibitor treatment in patients with atopic dermatitis treated in the BioDay registry. (A) Mean cumulative infection rates for biologics and Janus kinase inhibitors. Results were determined by univariable Cox regression analysis for recurrent events. (B) Infection‐free survival probability for biologic and Janus kinase inhibitors. Results were determined by univariable Cox regression analysis for first events. TE, treatment episode. Figure adapted from Van der Gang et al. [185].