Atopic dermatitis treatments: Latest advances and emerging therapies

Atopic dermatitis (AD) is a chronic, inflammatory cutaneous disease characterised by xerosis, scaly skin changes, and pruritus. AD has the highest disease burden among all cutaneous diseases, as measured by disability-adjusted life years, with disease prevalence being particularly high in Western Europe, Australia, and Scandinavia. There is also an increasing incidence in developing countries. Furthermore, there is great geographic influence on disease presentation, with papular lichenoid lesions being more commonly reported in people with African ancestry and exudative lesions being more common in those with Southeast Asian heritage.

Epidermal barrier function is disrupted in AD patients, driven by a T-helper 2 (Th2) inflammatory response and microbiome dysfunction, both of which are affected by environmental factors. There is a well-established connection between AD and loss-of-function mutations of the filaggrin gene, which is essential for skin barrier formation. Environmental influences can also induce epigenetic changes and regulate gene expression through heritable methods, such as CpG island formation, contributing to the over- or under-expression of specific genes. The impaired function of crucial epidermal proteins, such as filaggrin, transglutaminases, keratins, and intercellular proteins, all increase allergen and microbial invasion into the skin and possibly contribute to the development of AD. The management of AD with systemic therapies relies on the regulation of immune pathways.

Conventional treatments

Clinical management of AD depends on presenting disease severity, the body-surface area affected, and the presence of comorbidities. Furthermore, there are variations in regional guidelines, patient preference, and patient-specific circumstances.

Treatment follows a stepped-care approach, starting with patient education, the avoidance of identified irritants and triggers, and topical therapy use. Although most cases of AD can be treated with emollients, topical treatment, and phototherapy, a small percentage of patients with moderate to severe disease require systemic immuno-suppressive treatment to induce and maintain control. Cyclosporin (CyA) and methotrexate (MTX) are the main conventional systemic treatments for AD. CyA is a calcineurin inhibitor that decreases production of inflammatory cytokines associated with AD and inhibits T-cell activation, while methotrexate is a folic acid antagonist that modulates immune system activity by hindering cell division, DNA and RNA synthesis and repair, and protein synthesis.

The TREatment of severe Atopic dermatitis Trial (TREAT) was a multicentre, parallel-group, assessor-blinded randomised controlled trial (RCT) that compared effectiveness, speed of onset, side-effect profiles, flare reduction, and cost-effectiveness of ciclosporin and methotrexate in children with severe AD.^1,2 The results showed that while CyA induced a slightly more rapid response to treatment, MTX induced more sustained disease control after discontinuation. 

Targeted treatments

Targeted systemic AD treatments, including biologics and small molecule Janus kinase (JAK) inhibitors, are increasingly used to treat AD in high-income countries.

The biologic therapies dupilumab, tralokinumab, and lebrikizumab target the key Th2 immune pathways that drive AD pathogenesis. Dupilumab, the first biologic therapy to enter clinical practice, blocks the interleukin-4 receptor alpha (IL-4Rα) subunit, and inhibits IL-4 and IL-13 cytokine-induced responses. Tralokinumab and lebrikizumab inhibit IL-13 by binding to soluble IL-13 and disrupting activation of the IL-13Rα1/IL-4Rα complex. The efficacy and safety of these therapies has been well-demonstrated through RCTs, with similar incidence rates of adverse events across placebo and treatment groups.^3-5 The main side-effects associated with these treatments are eye-related disorders including conjunctivitis and injection site reactions.

Abrocitinib, baricitinib, and upadacitinib target the Janus kinase 1 (JAK1) signalling pathway, which is a component of the canonical JAK-STAT pathways activated by IL-4 and IL-13 through engagement of the IL-4Rα receptor and is also used by several other cytokines.⁶ Baricitinib additionally targets the Janus kinase 2 (JAK2) signalling pathway. JAK inhibitors specifically block pro-inflammatory pathways by preventing the phosphorylation and activation of signal transducer and activator of transcription (STAT) factors. The efficacy and safety of these therapies has been investigated through RCTs.^7-9 The main treatment-emergent adverse events associated with these treatments are upper respiratory tract infections, nasopharyngitis, herpes simplex infections, acne, and nausea.

Comparing treatment efficacy and safety

With the growing number of novel therapies available for the treatment of AD, studies comparing their effectiveness, safety profiles, and long-term disease control capabilities are greatly needed. For instance, the Heads Up trial directly compared oral upadacitinib and dupilumab in adults with moderate to severe AD. The study found that the proportion of patients achieving a clinically meaningful improvement was higher in the upadacitinib arm compared to the dupilumab arm.¹⁰ However, this was a short-term study over 16 weeks of treatment and did not include other systemic treatments. The first platform trial comparing conventional and
novel systemic medications for AD is now underway in the UK (BEACON; www.beacontrial.org/).

In the current absence of direct head-to-head RCT data, alternative study methods can help to compare systemic AD therapies. A living systematic review and network meta-analysis (NMA) provides regular updates on reported measures of efficacy and the safety profiles of treatments for AD,¹¹ with the living updates also available through a decision-making tool for physicians and patients (www.eczematherapies.com). NMAs use published RCT data to simultaneously compare three or more interventions through the combination of direct and indirect evidence across studies. A recent update, which included 98 trials and 24,707 patients, showed that lebrikizumab displayed no important difference in change of Eczema Area and Severity Index (EASI), Patient Oriented Eczema Measure (POEM), Dermatology Life Quality Index (DLQI), or Peak Pruritus Numerical Rating Scale (PP-NRS) compared to dupilumab in adults with AD, but that dupilumab was associated with higher odds of efficacy in binary outcomes. The most recent iteration of the analysis also reported that high dose upadacitinib (30mg daily) and abrocitinib (200mg daily) demonstrated the highest relative efficacy and better scores than dupilumab (600mg then 300mg every two weeks), as measured by EASI-50, -75, and -90. Upadacitinib (15mg daily) performed similarly to dupilumab while abrocitinib (100mg daily), baricitinib (4mg and 2mg daily), and tralokinumab (600mg then 300mg every two weeks) reduced EASI slightly less than dupilumab. The NMA update results for EASI reduction are shown in Figure 1.

Real-world studies

Real-world data has proven to be a crucial source of information for monitoring treatment outcomes and safety in the long-term, which RCTs are less able to provide due to their restrictive inclusion criteria and often short-term and placebo-controlled study design. Register-based studies also provide evidence to support regulatory decision-marking, real-world treatment costs, and optimisation of therapeutic regimens through direct comparisons between agents.

This is the gap that AD registers, such as the UK-Irish Atopic Dermatitis Eczema Systemic Therapy Register (A-STAR, https://astar-register.org/), TREATgermany (https://treatgermany.org/), TREAT NL/BE (Netherlands and Belgium, https://treatregister.nl/), Severe and ChRonic Atopic deramtitis Treatment CoHort (SCRATCH, Denmark, https://naed.zitelab.eu/), and CorEvitas (US and Canada, www.corevitas.com/registry/atopic-dermatitis/) address, providing databases of real-world data on treatment effectiveness and safety of therapies from which future comparative analyses can be completed. A-STAR UK, A-STAR Ireland, TREATgermany, TREAT NL/BE, and SCRATCH are also working together in a larger consortium (DREAM TO TREAT AD), which aggregates data across country borders on the use of abrocitinib and other systemic treatments.

A recent real-world comparison of the effectiveness and safety of CyA, dupilumab, and MTX in adult and paediatric AD from the A-STAR register found that patients treated with dupilumab and CyA experience a greater reduction in EASI, POEM, and itch compared to those treated with MTX.¹² There was a similar incidence of adverse events with all three medications over the one-year study period. The CyA group had a shorter duration of treatment than the MTX and dupilumab groups, reflecting the real-world clinical preference for CyA as short-term and fast-acting rescue treatment, which is often stopped within a year to prevent adverse events.

As another example, the CorEvitas registry found notable improvements in outcomes after six-month persistent use of tralokinumab, supporting the potential use of this treatment in AD patients.¹³ Improvements in both clinician-assessed and patient-reported outcomes were seen, with strong reductions in Validated Investigator Global Assessment Scale for Atopic Dermatitis (vIGA-AD), EASI, and DLQI from baseline to the six-month follow up.

Future directions

Further promising systemic therapeutic options, such as nemolizumab, OX40-ligand pathway inhibitors, and novel topical treatments, are currently being tested in clinical trials or pending approval by regulatory bodies. Nemolizumab is an IL-31 receptor subunit α antagonist that inhibits itch and skin inflammation in patients with AD. The ARCADIA 1 and ARCADIA 2 phase 3 trials found that patients treated with nemolizumab combined with topical corticosteroids with or without topical calcineurin inhibitors displayed statistically and clinically significant improvement in itch and inflammation, with a similar safety profile to the placebo arm.¹⁴ The drug is currently pending approval from the European Medicines Agency and was approved to treat nodular prurigo by the US Food and Drug Administration in August.

The OX40-ligand pathway inhibitors, rocatinlimab and amlitelimab, are in phase 2 clinical trials to determine effectiveness, with promising results. OX40 stimulates the pro-inflammatory T-cell response that plays a role in atopic dermatitis pathogenesis – the binding of OX40 to its ligand, OX40L, advances the expansion, differentiation, and survival of memory T-cells during AD pathogenesis. Rocatinlimab is a cell depleting anti-OX40 antibody that showed promising results in a phase 2b study, with greater reduction in EASI compared to placebo.¹⁵ Amlitelimab also produced a significant reduction in EASI mean percentage in the treatment arm compared to control.¹⁶ Both drugs were well-tolerated and are promising future options for moderate to severe AD.

There has also been an increase in the development of novel topical treatments for AD, such as the JAK inhibitors ruxolitinib and delgocitinib, the PDE4 inhibitors crisaborole and roflumilast and the aryl hydrocarbon receptor agonist tapinarof tapinarof, which is approved for psoriasis and currently in phase 3 trials for  AD. A network meta-analysis assessing topical anti-inflammatory agents for AD found that potent topical corticosteroids, JAK inhibitors, and tacrolimus 0.1 per cent were the most effective AD treatments based on patient- and physician-reported outcomes and investigator global assessment (IGA).¹⁷

As novel treatments are approved by regulatory bodies, there is greater need for sufficiently powered RCTs comparing these therapies to conventional systemic treatment and for head-to-head studies comparing novel treatments to each other. These RCTs will better inform clinical decisions and improve guidelines for AD management in addition to continuing to contribute to the findings of network meta-analyses. The RCT findings should be supported by real-world data that includes JAK inhibitors and long-term safety profiles of novel treatments. Furthermore, it is crucial to pair this clinical information with our scientific understanding of treatment efficacy in different AD phenotypes and skin types. Future RCTs also need to more accurately reflect the racial distribution of AD.

Lastly, there is still a need for research on the biomarkers regulating the pathogenesis and development of AD. A fuller understanding of the genetic component of AD will provide greater insight into the disease biology and assist in the development of new therapies. For instance, there may be a role for microbiome-modulating therapies if predictive biomarkers of treatment response can be identified.

While novel targeted treatments have revolutionised the treatment of AD over the last decade, conventional treatments remain an effective option and are essential in low resource settings. As further new treatments are developed and our understanding of the mechanisms underlying the disease pathogenesis increases, the outlook for patients with AD will improve further with better treatment outcomes and more personalised treatment pathways.

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