Introduction

Atopic dermatitis (AD) is a multifactorial, chronic and inflammatory skin disorder [1]. The abnormality is characterised by epidermal barrier dysfunction, immune dysregulation leading to triggered immune responses, neuro-immune modulation, gut dysbiosis, and mutations of genes such as filaggrin (FLG), or can be triggered by environmental factors [2]. It causes dry eczematous skin, itch, rashes, and blisters. The disease features include relapsing or recurrent clinical heterogeneity, concerning the onset of disease, lesion morphology, distribution, and severity of lesions, as well as their long-term persistence [3]. There are three distinct phases of AD: acute, subacute, and chronic, with symptoms ranging from vesicular eruptions to lichenification of the skin due to persistent itching [4]. It typically affects flexures, neck, eyelids, and extremities [5]. The disease prevalence is higher in children, at about 15–20% compared to 7–10% among adults [6]. The eczematous skin condition develops due to defects in the skin barrier’s integrity, often resulting from reduced lipid production, which leads to trans-epidermal water loss, making the skin easily permeable to microbes [7]. Staphylococcus aureus (S. aureus) plays a crucial role; its toxins exacerbate inflammation, disrupt keratinocyte function, and accelerate barrier breakdown [7]. Conversely, an exaggerated type 2 helper T (Th2) cell response drives the production of pro-inflammatory cytokines, including interleukin (IL)-4, IL-13, and IL-31, which intensify itch and further compromise the barrier [8]. The NF-κB pathway plays a significant role in increasing inflammation in AD. The transmembrane protein 79 (Tmem79) gene, also referred to as matrin, and the FLG gene, encode proteins that play a central role in protecting epidermal barrier integrity. The mutations in these genes further weaken the immune defence, increasing susceptibility to allergic diseases and asthmatic conditions later in life [9, 10]. Several studies have also reported that AD has a negative impact on the quality of life, causing self-consciousness, sleep disturbances, concentration issues, and affecting development in children [11].

Reducing pruritus is one of the most critical goals in patient care, thereby improving the quality of life for individuals affected by AD. Conventional therapy options include topical corticosteroids (TCS) and antihistamines, which temporarily relieve itching, as AD is a non-histamine-triggered condition [12]. With the advancement of understanding of the pathogenesis, small-molecule inhibitors and targeted biologics have emerged as newer options for treating AD [13]. Current treatment guidelines for mild AD include basic skin care, such as moisturising the skin with moisturiser or emollients to prevent the intensity and frequency of flares. Emollients, such as collagen and shea butter, fill the gaps between the cracked corneocytes and smooth the skin texture [14]. Usage of TCS, topical calcineurin inhibitors (TCIs), or topical phosphodiesterase 4 (PDE4) inhibitors is the main treatment option for patients suffering from mild to moderate AD. Crisaborole 2% ointment is a PDE4 inhibitor formulation approved for use in patients 3 months or older [15]. For patients with widespread or severe AD, several other treatment options are considered. One of these is systemic therapeutic agents, such as corticosteroids, immunosuppressants, and anti-metabolites, which are administered orally or in injectable biologics or immunomodulators [16]. Ultraviolet (UV)-based phototherapies are also recommended, depending on availability and disease severity [17]. In this review, we focus on covering the pathology of AD and various treatment modalities.

Pathology of AD

Barrier dysfunction

One of the key characteristics of AD is the compromised integrity of the skin barrier. The outermost layer of the skin, known as the epidermis, is rich in lipids, including cholesterol, cholesterol esters, ceramides, acyl ceramides, and free fatty acids. The outermost section of the epidermis, called the stratum corneum, consists of 15 to 25 layers of corneocytes. In this layer, surface proteins are cross-linked to ω-hydroxy ceramide, creating a lipid envelope around the cells. Beneath this, the stratum granulosum is the innermost layer of the epidermis. It contains secretory lamellar granules that release sphingomyelin, phospholipids, and glucosylceramides, which are then transported to other layers of the epidermis [18]. The skin’s stratum corneum typically contains ceramides, cholesterol, and free fatty acids. With a decrease in ceramide and lipid levels, the epidermal layer is weakened, and the transepidermal water loss (TEWL) increases [19]. Alterations in FLG and other structural proteins, such as loricrin, involucrin, keratins, desmoglein, and desmocollins, further disrupt the epidermal layer, as illustrated in Figure 1 [20]. The FLG gene, a crucial component in skin health, consists of two introns and three exons. A loss-of-function nonsense mutation in the FLG gene, located in the third exon, has a profound impact on the FLG protein. This mutation results in a reduction in the number of FLG protein copies, depending on whether the mutation is homozygous or heterozygous. The severity of the resulting phenotype is influenced by the position of the gene on the third exon and the number of copies of tandem repeats encoding the FLG protein [10]. A frameshift nonsense mutation in the Tmem79 gene disrupted the lamellar granule secretion process, leading to alterations in stratum corneum formation and a spontaneous dermatitis phenotype. This damaged barrier allows allergens, microbes, and irritants to enter, triggering an immune response [9].

Display full size

Figure 1. Mechanistic overview of atopic dermatitis. Various factors, such as loss-of-function mutations of filaggrin, Tmem79, or other structural proteins, a decrease in lipid and ceramide levels, and microbial colonisations, trigger immune activation, leading to the itch-scratch cycle. Tmem79: transmembrane protein 79; TEWL: transepidermal water loss; IL: interleukin. Created in BioRender. Arumugam, S. (2025) https://BioRender.com/iodrcxa.

Immune dysregulation

During the early stages of AD, Th2-mediated cytokines, such as thymic stromal lymphopoietin (TSLP), IL-4, IL-5, IL-13, and IL-31, are elevated. As the disease progresses, acute lesions appear on the skin, resulting in an increased secretion of chemokines, including C-C motif ligand (CCL)-17 and CCL-22 [2]. These regulate and increase the production of IL-25 and IL-33, which are members of the IL-1 family. They further activate the ILC-2 and Th2 cells, where ILC-2 cells secrete IL-5 and IL-13, and the Th2 cells secrete the TSLP, IL-4, IL-5, IL-13 and IL-31 [21]. The cytokine superfamily, a key regulator of immune responses, governs various interactions between immune and non-immune cells, including keratinocytes, skin fibroblasts, and other cell types. Alarmins, a subset of cytokines, act as cytokine mediators or signalling molecules that activate immune responses by secreting TSLP, IL-33, and IL-25. Therefore, they act as central regulators of cutaneous immunity [22]. Children with AD show elevated oxidative stress markers, suggesting a disruption in the balance between oxygen and nitrogen radicals. Environmental pollutants, such as tobacco smoke and particulate matter, contribute to oxidative stress, causing inflammation and immune dysregulation. Oxidative stress activates the NF-κB pathway, which upregulates antioxidant enzymes but also induces proinflammatory cytokines (IL-6, IL-8, IL-9, and IL-33), thereby increasing dermal inflammation and worsening AD symptoms [23]. Fibroblasts, when the canonical NF-κB pathway is blocked by Ikkb gene deletion, exhibit a skin phenotype that closely resembles human AD-like skin lesions. These lesions are characterised by eosinophilia and a high number of type 2 immune cells. Our research reveals that skin fibroblasts, in addition to their traditional role in skin repair, play a critical regulatory role in immune homeostasis during early perinatal growth. They achieve this by modulating the activity of type 2 immune cells, a function regulated by Ikkb under normal physiological conditions [24]. These mechanisms have been illustrated in Figure 2. In the later stages of chronic AD, Th17 and Th22 cells are activated, suppressing the FLG expression, thus creating a disrupted skin barrier. The IL-4 and IL-13 also lead to the suppression of anti-microbial peptide formation, allowing microbes to enter the system. Both Th17 and Th22 cells actively secrete IL-22, which induces epidermal thickening, resulting in acanthosis, parakeratosis, and inflammation [25].

Display full size

Figure 2. Cellular crosstalk in atopic dermatitis. Schematic representation of the complex cellular interactions in atopic dermatitis skin. The keratinocyte-immune-neuro crosstalk sustains pain, inflammation and itch. The gene mutations also create a self-perpetuating loop of barrier dysfunction, infection, inflammation and chronic pruritus. TSLP: thymic stromal lymphopoietin; IL: interleukin; TEWL: transepidermal water loss; S. aureus: Staphylococcus aureus. Created in BioRender. Arumugam, S. (2025) https://BioRender.com/iodrcxa.

Treatment modalities

Various treatment modalities for AD are discussed below, as illustrated in Figure 3.

Display full size

Figure 3. Various treatment modalities for AD. AD: atopic dermatitis; PDE4: phosphodiesterase 4; SOD: superoxide dismutase; UVA: ultraviolet A; PUVA: psoralen plus UVA; FDA: Food and Drug Administration; JAK: Janus kinase; LECT2: leukocyte cell-derived chemotaxin 2. Created in BioRender. Arumugam, S. (2025) https://BioRender.com/iodrcxa.

Conclusions

AD is a complex condition; a universal strategy is ineffective. The frequency of AD in pediatric patients is a challenge for management and rescue. The correct kind of rapid diagnosis remains a challenge. As our understanding of disease pathophysiology has improved, several therapy options have emerged [40]. Systemic corticosteroids are one of the therapy options; however, long-term use might have adverse effects. Flares relapse after short-term use. Targeted biologics are not affordable to all patients [41]. Phototherapy is a second-line treatment to explore, and its dangers and benefits have yet to be investigated in significant numbers in clinical settings. Dual cytokine blockades in antibody therapy would help control the disease’s severity. Reports suggest that bivalent antibodies are currently being tested for AD. Several studies have demonstrated that restoring skin microbial diversity would help manage AD. Pro-biotic creams and bacterial lysates are being examined for their efficacy in inhibiting the growth of S. aureus colonies and balancing the skin microbiota flora [19]. Novel formulations, such as nanoparticles carrying ceramides or natural molecules like flavonoids, are being tested in vitro to understand their potency. Flavonoids such as quercetin and chrysin are naturally anti-inflammatory, antioxidant and have anti-allergic properties [42]. Nanocarriers containing natural lipid moieties are also screened. In cases of gene mutations, the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas system can be tested to improve disease outcomes in individuals with very severe AD. Lastly, individualised treatment according to disease severity should be tailored to each patient to achieve the full benefit of the treatment modality [10].