Allergy
EDITORIAL
Atopic dermatitis revisited DOI:10.1111/all.12359
At the beginning of this new year, we would like to wrap up current knowledge on atopic dermatitis (AD) and highlight key advances of the past few years. Therefore, both front-line researchers and clinicians have provided original research and review articles on this important disease for the current issue of Allergy. Together, these articles allow state-of-the art insights into the field. Beyond that, they impressively demonstrate how heterogeneous and complex the disease is in terms of clinical picture, course, pathophysiological mechanisms and therapy. Although it is quite obvious from epidemiological studies that the global prevalence of AD has considerably increased over the past decades and constitutes a major public health problem (1), accurate estimates and cross-data source comparisons of prevalence are challenging because of different designs, assessment instruments and outcome definitions. Flohr and Mann (2) provide a comprehensive review on the epidemiology of childhood AD, showing that over 20% of children in most developed countries are affected by AD, that AD continues to increase in prevalence in particular in low-income countries, and that epidemiology has identified a number of well-established risk factors as well as protective factors. Based on the frequent co-occurrence of atopic diseases and the well-known association of early AD with later asthma and/or rhinitis (3, 4), the concept of the ‘atopic march’ has been developed, which, however, is a highly and controversially debated theory. In this issue, Dharmage and colleagues (5) present a critical reflection of the available data in favour of and against the atopic march hypothesis and the possible explanations thereof. Deckert et al. (6) shed some light on comorbidities of AD apart from asthma and rhinitis. Their overview of systematic reviews on this topic indicates that AD might affect the risk of different types of cancer, auto-inflammatory conditions and psychiatric diseases, and demonstrates the need for further studies on AD comorbidities. Recently published results from a US population-based study of almost 100 000 children in addition indicate an increased susceptibility for epilepsy (7). AD is among the complex diseases with the highest heritability estimates, and the discovery of filaggrin (FLG) null mutations as major risk factors constituted a major breakthrough in allergy genetics. Findings from molecular genetics support the notion that a primary skin barrier deficiency is central for the initiation and progress of AD at least in subgroups of patients. The renewed interest in the epidermal barrier has stimulated fresh approaches of prevention, which so far have been mostly focused on allergen avoidance, dietary measures and immunoregulation (8–10). However, the results have not produced consistently effective interventions, as
reviewed by Flohr and Mann (11). The accumulating knowledge on the genetic architecture of AD is also increasingly being translated into clinical questions, e.g. AD subclassification and stratified therapy (12–14). However, it is unlikely that single factors and markers will be sufficient to achieve this, since multiple genetic and environmental factors are involved in the complex AD pathogenesis. These factors affect both the epidermal (15, 16) and immunological phenotype (17, 18), to which also Th17 cells contribute, as shown by Simon et al. (19). Of note, epidermal and immunological mechanisms are closely entangled, as e.g. demonstrated by in vitro studies showing the impact of immune cell mediators such as histamine on keratinocyte differentiation (20). It is thus conceivable that the individual predisposition and environmental exposures in combination affect multiple different pathophysiological pathways with varying degrees of skin barrier failure and immune dysregulation (21), opening out in rather uniform, yet distinguishable clinical presentations if closely looked at as shown by Garmhausen and colleagues for AD (22), and Amelink and colleagues for asthma (23). It is likely that the results of molecular studies will be of great nosological significance, enabling a classification of AD based on the underlying mechanisms rather than on hypothetical concepts and clinical symptoms as is the case today. They will also help to identify biomarkers from different molecular levels and sources for different purposes, e.g. gene variants like FLG mutations (24) and STAT6 polymorphisms (25), vitamin D pathway genes (26), protein profiles in vernix (27) or vitamin levels in serum (28, 29) for risk prediction, and to allocate available approved and off-label therapies in a more targeted fashion (14, 30, 31). All of these recent advances in biomedical research have contributed to an altered view of how AD is initiated, triggered and maintained. A major challenge of the next years, including this year, will be to translate more of this knowledge into the clinic and to achieve improved diagnosis, preventive measures and therapeutic approaches. Conflicts of interest None. S. Weidinger1 and N. Novak2 Department of Dermatology, Venerology and Allergy, University Hospital Schleswig-Holstein, Campus Kiel, 2 Department of Dermatology and Allergy, University of Bonn, Germany E-mail: [email protected]
Allergy 69 (2014) 1–2 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
1
1
Editorial
References 1. De Monchy JG, Demoly P, Akdis CA, Cardona V, Papadopoulos NG, Schmid-Grendelmeier P et al. Allergology in Europe, the blueprint. Allergy 2013;68:1211–1218. 2. Flohr C, Mann J. New insights into the epidemiology of childhood atopic dermatitis. Allergy 2014;69:3–16. 3. Ballardini N, Kull I, Lind T, Hallner E, € Almqvist C, Ostblom E et al. Development and comorbidity of eczema, asthma and rhinitis to age 12 – data from the BAMSE birth cohort. Allergy 2012;67:537–544. 4. Ranciere F, Nikasinovic L, Bousquet J, Momas I. Onset and persistence of respiratory/ allergic symptoms in preschoolers: new insights from the PARIS birth cohort. Allergy 2013;68:1158–1167. 5. Dharmage SC, Lowe AJ, Matheson MC, Burgess JA, Allen KJ, Abramson MJ. Atopic dermatitis and the atopic march revisited. Allergy 2014;69:17–27. 6. Deckert S, Kopkow C, Schmitt J. Nonallergic comorbidities of atopic eczema: an overview of systematic reviews. Allergy 2014;69:37–45. 7. Silverberg JI, Joks R, Durkin HG. Allergic disease is associated with epilepsy in childhood: a US population-based study. Allergy 2014;69:95–103. 8. Nwaru BI, Takkinen H-M, Niemel O, Kaila M, Erkkola M, Ahonen S et al. Introduction of complementary foods in infancy and atopic sensitization at the age of 5 years: timing and food diversity in a Finnish birth cohort. Allergy 2013;68:507–516. 9. Palmer DJ, Sullivan T, Gold MS, Prescott SL, Heddle R, Gibson RA et al. Randomized controlled trial of fish oil supplementation in pregnancy on childhood allergies. Allergy 2013;68:1370–1376. 10. West CE, Hammarstr€ om M-L, Hernell O. Probiotics in primary prevention of allergic disease – follow-up at 8–9 years of age. Allergy 2013;68:1015–1020. 11. Flohr C, Mann J. New approaches to the prevention of childhood atopic dermatitis. Allergy 2014;69:56–61.
2
12. Bieber T. Atopic dermatitis 2.0: from the clinical phenotype to the molecular taxonomy and stratified medicine. Allergy 2012;67:1475–1482. 13. Lazic N, Roberts G, Custovic A, Belgrave D, Bishop CM, Winn J et al. Multiple atopy phenotypes and their associations with asthma: similar findings from two birth cohorts. Allergy 2013;68:764–770. 14. Hotze M, Baurecht H, Rodrıguez E, Chapman-Rothe N, Ollert M, F€ olster-Holst R et al. Increased efficacy of omalizumab in atopic dermatitis patients with wild-type filaggrin status and higher serum levels of phosphatidylcholines. Allergy 2014;69:132– 135. 15. Jungersted JM, Scheer H, Mempel M, Baurecht H, Cifuentes L, Høgh JK et al. Stratum corneum lipids, skin barrier function and filaggrin mutations in patients with atopic eczema. Allergy 2010;65:911–918. 16. Kezic S, O’Regan GM, Yau N, Sandilands A, Chen H, Campbell LE et al. Levels of filaggrin degradation products are influenced by both filaggrin genotype and atopic dermatitis severity. Allergy 2011;66:934–940. 17. Novak N, Peng WM, Bieber T, Akdis C. FceRI stimulation promotes the differentiation of histamine receptor 1-expressing inflammatory macrophages. Allergy 2013;68:454–461. 18. von Gunten S, Marsland BJ, von Garnier C, Simon D. Update in clinical allergy and immunology. Allergy 2012;67:1491–1500. 19. Simon D, Aeberhard C, Erdemoglu Y, Simon H-U. Th17 cells and tissue remodeling in atopic and contact dermatitis. Allergy 2014;69:125–131. 20. Gschwandtner M, Mildner M, Mlitz V, Gruber F, Eckhart L, Werfel T et al. Histamine suppresses epidermal keratinocyte differentiation and impairs skin barrier function in a human skin model. Allergy 2013;68:37–47. 21. Bieber T. Many ways lead to Rome: a glance at the multiple immunological pathways underlying atopic dermatitis. Allergy 2013;68:957–958.
22. Garmhausen D, Hagemann T, Bieber T, Dimitriou I, Fimmers R, Diepgen T et al. Characterization of different courses of atopic dermatitis in adolescent and adult patients. Allergy 2013;68:498–506. 23. Amelink M, de Nijs SB, de Groot JC, van Tilburg PMB, van Spiegel PI, Krouwels FH et al. Three phenotypes of adult-onset asthma. Allergy 2013;68: 674–680. 24. Thyssen JP, Linneberg A, Johansen JD, Carlsen BC, Zachariae C, Meldgaard M et al. Atopic diseases by filaggrin mutations and birth year. Allergy 2012;67:705–708. 25. Casaca VI, Illi S, Klucker E, Ballenberger N, Schedel M, vonMutius E et al. STAT6 polymorphisms are associated with neonatal regulatory T cells and cytokines and atopic diseases at 3 years. Allergy 2013;68:1249– 1258. 26. Wang SS, Hon KL, Kong APS, Tang MF, Sy HY, Chan JCN et al. Eczema phenotypes are associated with multiple vitamin D pathway genes in Chinese children. Allergy 2014;69:118–124. 27. Holm T, Rutishauser D, Kai-Larsen Y, Lyutvinskiy Y, Stenius F, Zubarev RA et al. Protein biomarkers in vernix with potential to predict the development of atopic eczema in early childhood. Allergy 2014;69:104–112. 28. Nwaru BI, Virtanen SM, Alfthan G, Karvonen AM, Genuneit J, Lauener RP et al. Serum vitamin E concentrations at 1 year and risk of atopy, atopic dermatitis, wheezing, and asthma in childhood: the PASTURE study. Allergy 2014;69:87–94. 29. Heimbeck I, Wjst M, Apfelbacher CJ. Low vitamin D serum level is inversely associated with eczema in children and adolescents in Germany. Allergy 2013;68:906–910. 30. Novak N, Simon D. Atopic dermatitis – from new pathophysiologic insights to individualized therapy. Allergy 2011;66: 830–839. 31. Simon D, Bieber T. Systemic therapy for atopic dermatitis. Allergy 2014;69: 46–55.
Allergy 69 (2014) 1–2 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
EDITORIAL
Atopic dermatitis revisited DOI:10.1111/all.12359
At the beginning of this new year, we would like to wrap up current knowledge on atopic dermatitis (AD) and highlight key advances of the past few years. Therefore, both front-line researchers and clinicians have provided original research and review articles on this important disease for the current issue of Allergy. Together, these articles allow state-of-the art insights into the field. Beyond that, they impressively demonstrate how heterogeneous and complex the disease is in terms of clinical picture, course, pathophysiological mechanisms and therapy. Although it is quite obvious from epidemiological studies that the global prevalence of AD has considerably increased over the past decades and constitutes a major public health problem (1), accurate estimates and cross-data source comparisons of prevalence are challenging because of different designs, assessment instruments and outcome definitions. Flohr and Mann (2) provide a comprehensive review on the epidemiology of childhood AD, showing that over 20% of children in most developed countries are affected by AD, that AD continues to increase in prevalence in particular in low-income countries, and that epidemiology has identified a number of well-established risk factors as well as protective factors. Based on the frequent co-occurrence of atopic diseases and the well-known association of early AD with later asthma and/or rhinitis (3, 4), the concept of the ‘atopic march’ has been developed, which, however, is a highly and controversially debated theory. In this issue, Dharmage and colleagues (5) present a critical reflection of the available data in favour of and against the atopic march hypothesis and the possible explanations thereof. Deckert et al. (6) shed some light on comorbidities of AD apart from asthma and rhinitis. Their overview of systematic reviews on this topic indicates that AD might affect the risk of different types of cancer, auto-inflammatory conditions and psychiatric diseases, and demonstrates the need for further studies on AD comorbidities. Recently published results from a US population-based study of almost 100 000 children in addition indicate an increased susceptibility for epilepsy (7). AD is among the complex diseases with the highest heritability estimates, and the discovery of filaggrin (FLG) null mutations as major risk factors constituted a major breakthrough in allergy genetics. Findings from molecular genetics support the notion that a primary skin barrier deficiency is central for the initiation and progress of AD at least in subgroups of patients. The renewed interest in the epidermal barrier has stimulated fresh approaches of prevention, which so far have been mostly focused on allergen avoidance, dietary measures and immunoregulation (8–10). However, the results have not produced consistently effective interventions, as
reviewed by Flohr and Mann (11). The accumulating knowledge on the genetic architecture of AD is also increasingly being translated into clinical questions, e.g. AD subclassification and stratified therapy (12–14). However, it is unlikely that single factors and markers will be sufficient to achieve this, since multiple genetic and environmental factors are involved in the complex AD pathogenesis. These factors affect both the epidermal (15, 16) and immunological phenotype (17, 18), to which also Th17 cells contribute, as shown by Simon et al. (19). Of note, epidermal and immunological mechanisms are closely entangled, as e.g. demonstrated by in vitro studies showing the impact of immune cell mediators such as histamine on keratinocyte differentiation (20). It is thus conceivable that the individual predisposition and environmental exposures in combination affect multiple different pathophysiological pathways with varying degrees of skin barrier failure and immune dysregulation (21), opening out in rather uniform, yet distinguishable clinical presentations if closely looked at as shown by Garmhausen and colleagues for AD (22), and Amelink and colleagues for asthma (23). It is likely that the results of molecular studies will be of great nosological significance, enabling a classification of AD based on the underlying mechanisms rather than on hypothetical concepts and clinical symptoms as is the case today. They will also help to identify biomarkers from different molecular levels and sources for different purposes, e.g. gene variants like FLG mutations (24) and STAT6 polymorphisms (25), vitamin D pathway genes (26), protein profiles in vernix (27) or vitamin levels in serum (28, 29) for risk prediction, and to allocate available approved and off-label therapies in a more targeted fashion (14, 30, 31). All of these recent advances in biomedical research have contributed to an altered view of how AD is initiated, triggered and maintained. A major challenge of the next years, including this year, will be to translate more of this knowledge into the clinic and to achieve improved diagnosis, preventive measures and therapeutic approaches. Conflicts of interest None. S. Weidinger1 and N. Novak2 Department of Dermatology, Venerology and Allergy, University Hospital Schleswig-Holstein, Campus Kiel, 2 Department of Dermatology and Allergy, University of Bonn, Germany E-mail: [email protected]
Allergy 69 (2014) 1–2 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
1
1
Editorial
References 1. De Monchy JG, Demoly P, Akdis CA, Cardona V, Papadopoulos NG, Schmid-Grendelmeier P et al. Allergology in Europe, the blueprint. Allergy 2013;68:1211–1218. 2. Flohr C, Mann J. New insights into the epidemiology of childhood atopic dermatitis. Allergy 2014;69:3–16. 3. Ballardini N, Kull I, Lind T, Hallner E, € Almqvist C, Ostblom E et al. Development and comorbidity of eczema, asthma and rhinitis to age 12 – data from the BAMSE birth cohort. Allergy 2012;67:537–544. 4. Ranciere F, Nikasinovic L, Bousquet J, Momas I. Onset and persistence of respiratory/ allergic symptoms in preschoolers: new insights from the PARIS birth cohort. Allergy 2013;68:1158–1167. 5. Dharmage SC, Lowe AJ, Matheson MC, Burgess JA, Allen KJ, Abramson MJ. Atopic dermatitis and the atopic march revisited. Allergy 2014;69:17–27. 6. Deckert S, Kopkow C, Schmitt J. Nonallergic comorbidities of atopic eczema: an overview of systematic reviews. Allergy 2014;69:37–45. 7. Silverberg JI, Joks R, Durkin HG. Allergic disease is associated with epilepsy in childhood: a US population-based study. Allergy 2014;69:95–103. 8. Nwaru BI, Takkinen H-M, Niemel O, Kaila M, Erkkola M, Ahonen S et al. Introduction of complementary foods in infancy and atopic sensitization at the age of 5 years: timing and food diversity in a Finnish birth cohort. Allergy 2013;68:507–516. 9. Palmer DJ, Sullivan T, Gold MS, Prescott SL, Heddle R, Gibson RA et al. Randomized controlled trial of fish oil supplementation in pregnancy on childhood allergies. Allergy 2013;68:1370–1376. 10. West CE, Hammarstr€ om M-L, Hernell O. Probiotics in primary prevention of allergic disease – follow-up at 8–9 years of age. Allergy 2013;68:1015–1020. 11. Flohr C, Mann J. New approaches to the prevention of childhood atopic dermatitis. Allergy 2014;69:56–61.
2
12. Bieber T. Atopic dermatitis 2.0: from the clinical phenotype to the molecular taxonomy and stratified medicine. Allergy 2012;67:1475–1482. 13. Lazic N, Roberts G, Custovic A, Belgrave D, Bishop CM, Winn J et al. Multiple atopy phenotypes and their associations with asthma: similar findings from two birth cohorts. Allergy 2013;68:764–770. 14. Hotze M, Baurecht H, Rodrıguez E, Chapman-Rothe N, Ollert M, F€ olster-Holst R et al. Increased efficacy of omalizumab in atopic dermatitis patients with wild-type filaggrin status and higher serum levels of phosphatidylcholines. Allergy 2014;69:132– 135. 15. Jungersted JM, Scheer H, Mempel M, Baurecht H, Cifuentes L, Høgh JK et al. Stratum corneum lipids, skin barrier function and filaggrin mutations in patients with atopic eczema. Allergy 2010;65:911–918. 16. Kezic S, O’Regan GM, Yau N, Sandilands A, Chen H, Campbell LE et al. Levels of filaggrin degradation products are influenced by both filaggrin genotype and atopic dermatitis severity. Allergy 2011;66:934–940. 17. Novak N, Peng WM, Bieber T, Akdis C. FceRI stimulation promotes the differentiation of histamine receptor 1-expressing inflammatory macrophages. Allergy 2013;68:454–461. 18. von Gunten S, Marsland BJ, von Garnier C, Simon D. Update in clinical allergy and immunology. Allergy 2012;67:1491–1500. 19. Simon D, Aeberhard C, Erdemoglu Y, Simon H-U. Th17 cells and tissue remodeling in atopic and contact dermatitis. Allergy 2014;69:125–131. 20. Gschwandtner M, Mildner M, Mlitz V, Gruber F, Eckhart L, Werfel T et al. Histamine suppresses epidermal keratinocyte differentiation and impairs skin barrier function in a human skin model. Allergy 2013;68:37–47. 21. Bieber T. Many ways lead to Rome: a glance at the multiple immunological pathways underlying atopic dermatitis. Allergy 2013;68:957–958.
22. Garmhausen D, Hagemann T, Bieber T, Dimitriou I, Fimmers R, Diepgen T et al. Characterization of different courses of atopic dermatitis in adolescent and adult patients. Allergy 2013;68:498–506. 23. Amelink M, de Nijs SB, de Groot JC, van Tilburg PMB, van Spiegel PI, Krouwels FH et al. Three phenotypes of adult-onset asthma. Allergy 2013;68: 674–680. 24. Thyssen JP, Linneberg A, Johansen JD, Carlsen BC, Zachariae C, Meldgaard M et al. Atopic diseases by filaggrin mutations and birth year. Allergy 2012;67:705–708. 25. Casaca VI, Illi S, Klucker E, Ballenberger N, Schedel M, vonMutius E et al. STAT6 polymorphisms are associated with neonatal regulatory T cells and cytokines and atopic diseases at 3 years. Allergy 2013;68:1249– 1258. 26. Wang SS, Hon KL, Kong APS, Tang MF, Sy HY, Chan JCN et al. Eczema phenotypes are associated with multiple vitamin D pathway genes in Chinese children. Allergy 2014;69:118–124. 27. Holm T, Rutishauser D, Kai-Larsen Y, Lyutvinskiy Y, Stenius F, Zubarev RA et al. Protein biomarkers in vernix with potential to predict the development of atopic eczema in early childhood. Allergy 2014;69:104–112. 28. Nwaru BI, Virtanen SM, Alfthan G, Karvonen AM, Genuneit J, Lauener RP et al. Serum vitamin E concentrations at 1 year and risk of atopy, atopic dermatitis, wheezing, and asthma in childhood: the PASTURE study. Allergy 2014;69:87–94. 29. Heimbeck I, Wjst M, Apfelbacher CJ. Low vitamin D serum level is inversely associated with eczema in children and adolescents in Germany. Allergy 2013;68:906–910. 30. Novak N, Simon D. Atopic dermatitis – from new pathophysiologic insights to individualized therapy. Allergy 2011;66: 830–839. 31. Simon D, Bieber T. Systemic therapy for atopic dermatitis. Allergy 2014;69: 46–55.
Allergy 69 (2014) 1–2 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
