Biomarkers in atopic dermatitis: it is time to stratify
Authors: M.R. Ardern-Jones, T. Bieber
Journal: British Journal of Dermatology (2014)

The year 2014 marks the 20th anniversary of the publication in this journal of the U.K. Working Party's Diagnostic Criteria for Atopic Dermatitis (AD).1 These were a refinement of the extensive 1980 criteria of Hanifin and Rajka,2 whose aim was to develop a validated definition of AD for population and clinical studies. Over this period, our understanding of the pathogenesis of AD has altered immeasurably. Serum IgE, found to be high in approximately 80% of patients with AD, was one of the earliest molecules tested as a biomarker in AD; however, interestingly, differences in the skin such as eosinophilic infiltration and T helper (Th)2 responses are seen equally in IgE low (intrinsic) and IgE high (extrinsic) AD,3 suggesting that both have a Th2 pathogenesis. It has been shown that the skewed induction towards Th2 inflammation is due to altered regulation by the skin in individuals with AD,4 which is likely to be mediated to a large degree by keratinocyte thymic stromal lymphopoietin (TSLP) regulation of skin dendritic cell responses.5 Such Th2 overactivation has been shown to provide further barrier dysfunction by impairing filaggrin expression.6 Interleukin (IL)-227 and IL-33 also seem to be important in mediating the characteristic AD 'Th2' cytokine milieu of allergen-specific inflammation,8, 9 and the newly discovered T-cell-derived cytokine IL-31, which is produced predominantly by Th2 cells, regulates itch in AD by binding to its receptor on neurons.10 Furthermore, the finding that a genetically mediated keratinocyte deficiency of filaggrin is strongly associated with an increased risk of developing AD and other allergic 'Th2' conditions, including asthma, demonstrates that skin barrier (dys)function in AD is critical for regulating the exposure threshold for induction of the characteristic dysregulated Th2 inflammation. Over the same time frame, apart from the introduction of topical calcineurin inhibitors, little has changed in the therapeutic area. While mild and moderate forms of AD can be effectively controlled by proactive management, more severe AD still remains a disease that is hard to treat because of the paucity of approved and effective systemic therapies.11 However, with this new understanding of the pathogenesis, the development of targeted therapies in AD is exciting, and it seems likely that interesting times are ahead for AD therapy. Monoclonal antibody therapy has proved revolutionary in psoriasis, but this area has so far been disappointing in AD. Initial efforts to target the Th2/atopy pathway have shown some exciting case series, and the great hope was anti-IgE therapy (omalizumab), but so far two randomized placebo-controlled studies in patients with AD have failed to show benefit.12, 13 Perhaps it is not surprising that anti-IgE therapy has not shown strong evidence of benefit given the consensus for a minimal role of IgE in disease pathogenesis. In view of the importance attached to the Th2 pathway, it is therefore possibly no surprise that blocking the IL-4 receptor (thus inhibiting IL-4 and IL-13 signalling) has shown exciting early positive results, with 71% of adults with severe AD (n = 67) showing > 50% reduction in disease severity after 1 month of treatment.14 Dupilumab therapy is more advanced in the clinical trial pipeline for treatment of asthma, where it has shown an 87% reduction in asthma exacerbations.15 Importantly, following previous failures of anti-IL-13 and anti-IgE agents in unselected asthmatics, these studies were undertaken in patients with 'Th2' dominant asthma using the surrogate biomarker of hypereosinophilia.15 This immunophenotypic screening is now seen as a standard approach to asthma clinical trials and demonstrates that subtleties in immunopathogenesis in individuals can be important. Other Th2 pathway inhibitors are also in the clinical phase of development for AD, including inhibitors of CRTH2 (chemokine receptor homologous molecule expressed on Th2 lymphocytes). It is likely that biomarker-based stratification including immunological characterization of patients with AD will, beside the clinical phenotype, lead to some kind of molecular taxonomy,16 and similarly prove critical for future clinical trials in AD. Indeed, substantial changes in the design of clinical trials are expected with the option of so-called adaptive trial designs and other prospective–retrospective approaches.17 Periostin has been shown to have a pathogenic role in asthma by inducing subepithelial thickening in bronchial airways. High levels reflect the individual's Th2 airway inflammation18 and predict response to therapeutic inhibitors of the Th2 pathway. In this issue of BJD, Kou et al. show that serum periostin levels correlate with AD severity and with eosinophil count. Although no correlation was found with total IgE, as in asthma, periostin levels were shown to correlate with 'Th2 overdrive' and were higher in the atopic group; however, no correlation with disease severity was found in the nonatopic group.19 The data show that periostin levels fall with treatment, but more data are required to confirm this. Importantly, raised periostin levels were not seen in patients with psoriasis or healthy controls, in contrast to some previously reported biomarkers such as serum IL-2 receptor.20 Work so far confined to mice suggests that periostin induces TSLP synthesis by keratinocytes, thus defining a pathway whereby Th2 inflammation further enhances disease persistence in AD.21 This suggests that periostin may be not only a valuable disease-specific, Th2-driven severity biomarker, but also potentially a therapeutic target in AD. Nevertheless, it can be clearly seen from the work of Kou et al. that not all individuals with AD have high periostin levels, reflecting individual variation. Other AD-specific serum biomarkers have previously been reported to correlate with disease severity, including chemokine (C–C motif) ligand (CCL)17/thymus and activation-regulated chemokine, CCL22/macrophage-derived chemokine, CCL26/eotaxin-3, CCL27/cutaneous T-cell-attracting chemokine and IL-31, but not all apply in all cases.22 This is also the case for filaggrin mutations, which are found in only 30% of patients with AD,23 but which strongly predict a worse prognosis.24 Therefore, further work is needed for complete stratification of AD into relevant groups based on biomarker analyses. These molecular differences between individuals are likely to represent important characteristics underlying differences in response to treatment. This concept of personalized medicine is not new and is likely to be important for reanalysis of treatment response to existing therapies such as methotrexate and ciclosporin, but is especially relevant for new targeted therapies in development. Although the U.K. Working Party's Criteria for Diagnosis of AD have served us well, the next decade will show the importance of attaching molecular analyses to our clinical criteria so that markers of prognosis and response to treatment can become part of the dermatologist's approach to managing AD. It seems that the binary 'intrinsic' vs. 'extrinsic' IgE paradigm is too simplistic, and forthcoming clinical trials in AD must add modern key markers of disease pathogenesis, at least including filaggrin status and measurements of the Th2 pathway, to define important differentiating biomarkers. We must be prepared to power future studies for analyses of these important subgroups. None declared.