Insights into pathogenesis of AD define novel therapeutic targets

DOI
https://doi.org/10.1016/S0140-6736(20)31022-9
Conference
24th World Congress of Dermatology Milan 2019
Conference Date
10/06/2019

Novel insights into the pathogenesis of atopic dermatitis (AD) are leading to many new treatment options–both systemically and locally. Prof. Graham Ogg (Oxford University, United Kingdom) pointed out that AD pathogenesis is complex, encompassing both genetic and environmental risk factors [1]. In addition, different therapeutic targets might be required for different types of AD, e.g. acute vs chronic or Western vs Asian.

In 2007, a null inactivating mutation in the filaggrin gene was recognised as an important predisposition factor for childhood eczema and eczema-associated asthma. Filaggrin null alleles are also an indicator of poor prognosis in AD, predisposing to a form of eczema that starts in early infancy and persists into adulthood [2]. In addition, dysregulation of innate and adaptive immunity plays a key role [3]. A transcriptome study of nonlesional skin and acute and chronic lesions has shown that acute disease was associated with significant increases in gene expression levels of major T(H)22 and T(H)2 cytokines, whereas T(H)1 activation can be found in the chronic lesional stage [4]. Therefore, different cytokines are involved in different AD stages (see Figure) [5-7]. Type-2 cytokines also inhibit filaggrin expression [8]. The interplay between type-2 inflammation and microbiome leads to further skin barrier degradation and inflammation, and S. aureus binding and colonisation [9]. Clinical studies with broad and targeted therapeutics have helped to elucidate the contribution of various immune axes to the disease phenotype. Immune activation extends well beyond lesional AD because non-lesional skin and the blood component harbour AD-specific inflammatory changes [9]. This emphasises the necessity of systemic therapy in moderate to severe disease.

All AD subtypes share Th2 activation

Th2 activation is common in all AD subtypes. Yet, stratification of biomarkers specific to different AD phenotypes may be important for developing a personalised medicine approach for AD [10]. The importance of the type-2 immune response with the cytokines IL-4 and IL-13 explain the efficacy of the IL-4/IL-13 blocker dupilumab, which impacts both the inflammation and the barrier dysfunction of AD [10]. In the phase 3 SOLO1 and SOLO2 trials, 48% of patients reached the primary endpoint of improvement of the Eczema Area and Severity Index (EASI) by 75% [11]. “This research cements AD as a reversible, immune-driven disease, like psoriasis”, said As Prof. Emma Guttman-Yassky (Icahn School of Medicine at Mount Sinai Medical Center, USA). Results of a phase 2b study with the human IL-13 antibody tralokinumab showed that IL-13 inhibition is enough for controlling AD [12]. In this trial, tralokinumab significantly improved change from baseline in EASI score vs placebo (adjusted mean difference, -4.94) [12]. In another study with the IL-13 inhibitor lebrikizumab, 56.1% of patients treated with lebrikizumab every 4 weeks and 60.6% of patients treated with lebrikizumab every 2 weeks gained an EASI 75 response at week 16 [10].

Another interesting target is IL-31, commonly referred to as the “itch-cytokine”, which is highly expressed in AD lesions and correlates with disease severity. In a phase 2b trial, the combination of topical corticosteroids and the anti-IL-31 agent nemolizumab was assessed in adults with moderate to severe AD and severe pruritus. Nemolizumab showed good efficacy for pruritus, but only modest efficacy on AD severity [13].

OX40 pathway: A first step towards disease modification?

An interesting novel target is the OX40 pathway. Inhibition of this costimulatory OX40 molecule appears to have improvements on lesional skin pathology and clinical disease activity parameters in patients with moderate-to-severe AD, suggesting its therapeutic potential in AD. In a first proof-of-concept study, administration of 2 intravenous doses of the anti-OX40 antibody GBR 830 administered 4 weeks apart induced significant and progressive improvements in clinical severity scores and in the cutaneous molecular AD signature lasting until day 71. “OX40 antagonism may help not only suppress the atopic Th2 inflammation, but also increase T-regulatory cells and achieve tolerance, which could enable us to influence disease modification,” concluded Prof. Guttman-Yassky. Thus, GBR 830 may provide a novel therapeutic paradigm for patients with moderate-to-severe AD.

Figure: Pathogenesis of AD in different disease stages. Data derived from [5-7]

1 Ogg G. 24th World Congress of Dermatology, 10-15 June 2019, Milan, Italy.

2 Barker JN, et al. J Invest Dermatol 2007;127:564-7.

3 Tsakok T, et al. Br J Dermatol 2019;180:464-74.

4 Gittler JK, et al. J Allergy Clin Immunol 2012:130:1344-54.

5 Noda S, et al. J Allergy Clin Immunol 2015;135:324-36.

6 Gandhi NA, et al. Nat Rev Drug Discov 2016;15:35-50.

7 Wynn TA. Nat Rev Immunol 2015;15:271-82.

8 Howell MD, et al. J Allergy Clin Immunol 2007;120:150-5.

9 Brunner PM, et al. J Allergy Clin Immunol 2017;139 :S65-S76.

10 Guttman-Yassky E. 24th World Congress of Dermatology, 10-15 June 2019, Milan, Italy.

11 Ferandiz C. FC07.09, EADV 2017, 13-17 Sept 2017, Geneva, Switzerland.

12 Wollenberg A, et al. J Allergy Clin Immunol 2019;143:135-141.

13 Wollenberg A, et al. S034, AAD 2019, 1-5 March, Washington, USA.

14 Guttman-Yassky E, et al. J Allergy Clin Immunol 2019;144:482-93.

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