Reviews and feature article
The atopic march and atopic multimorbidity: Many trajectories, many pathways

https://doi.org/10.1016/j.jaci.2018.11.006Get rights and content

The atopic march recognizes the increased occurrence of asthma, allergic rhinitis, or both after atopic dermatitis (AD) onset. Mechanisms for developing atopic comorbidities after AD onset are poorly understood but can involve the impaired cutaneous barrier, which facilitates cutaneous sensitization. The association can also be driven or amplified in susceptible subjects by a systemic TH2-dominant immune response to cutaneous inflammation. However, these associations might merely involve shared genetic loci and environmental triggers, including microbiome dysregulation, with the temporal sequence reflecting tissue-specific peak time of occurrence of each disease, suggesting more of a clustering of disorders than a march. Prospective longitudinal cohort studies provide an opportunity to explore the relationships between postdermatitis development of atopic disorders and potential predictive phenotypic, genotypic, and environmental factors. Recent investigations implicate disease severity and persistence, age of onset, parental atopic history, filaggrin (FLG) mutations, polysensitization, and the nonrural environment among risk factors for development of multiple atopic comorbidities in young children with AD. Early intervention studies to repair the epidermal barrier or alter exposure to the microbiome or allergens might elucidate the relative roles of barrier defects, genetic locus alterations, and environmental exposures in the risk and sequence of occurrence of TH2 activation disorders.

Section snippets

Association of AD and allergen-specific TH2-driven disorders: The atopic march

The earlier mean onset of AD than formally diagnosed asthma and AR has suggested a causal relationship between the occurrence of AD and the development of other comorbidities. The atopic march was originally defined 15 years ago as the natural history of atopic manifestations characterized by a typical sequence of progression of clinical signs of atopic disease, with some signs becoming more prominent while others subside. In general, the clinical signs of AD predate the development of asthma

Potential trajectories from AD to TH2-dominant comorbidities

Longitudinal prospective cohort studies beginning at birth or early during childhood have allowed more refined study of the potential trajectories of children after AD development and suggest that the atopic march, even with its broader definition, does not occur in approximately 50% of children with AD (Table I).3, 10, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 Furthermore, the majority of atopic children do not have early AD, and AD occurrence is not a risk factor for asthma development in adults.

Mechanisms of atopic multimorbidity with or without prior AD

Given the number of possible multimorbid disease trajectories reviewed above, several distinct pathways and mechanisms are likely to be involved, some of which are common to all atopic/TH2-dominant disease and others of which are disease specific. It is important to recognize that asthma occurring in the context of atopy (atopic asthma) is itself an asthma endotype most commonly seen for the first time in childhood.28 A full understanding of these mechanisms will require analyses of

Treatment to prevent the development of atopic comorbidities

Interventions to prevent the atopic march/atopic multimorbidity could theoretically be introduced during pregnancy, shortly after birth, or early after AD onset. The fetus during pregnancy is capable of mounting a T-cell response to antigenic exposure when allergens are presented in amniotic fluid,49 and umbilical cord blood mononuclear cells are able to proliferate in response to antigens to express TH2 cytokines.50 However, changes in maternal diet in several studies have not altered the

Conclusions

Several endotypes that increase the risk of having other TH2-driven disorders after AD onset have been identified: early AD onset, greater severity, disease persistence, having an FLG mutation, polysensitization, and parental atopy. Ultimately, investigations will require better classification of the phenotypes and endotypes of AD to track how these subgroups relate to the development of other comorbidities after AD. Longitudinal cohort studies are the ideal tool to identify those at greatest

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    Disclosure of potential conflict of interest: A. S. Paller is an investigator without personal compensation for AbbVie, Anaptysbio, Eli Lilly, Galderma, Incyte, Leo, Janssen, Novartis, and Sanofi-Regeneron and a consultant with honorarium for AbbVie, Amgen, Asana, Dermavant, Dermira, Galderma, Eli Lilly, Forte, Leo, Matrisys, Menlo, Morphosys/Galapagos, Novartis, Pfizer, and Sanofi-Regeneron. J. M. Spergel is an investigator for Pfizer and a consultant with honorarium for Regeneron. P. Mina-Osorio is an employee and shareholder of Regeneron Pharmaceuticals; however, she participated in this manuscript as an independent researcher, and the opinions expressed here do not necessarily represent the views of the company. A. D. Irvine is an investigator for Pfizer and a consultant with honorarium for AbbVie, Benevolent AI, Dermavant, Regeneron, and Sanofi.

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