Advances in Veterinary Dermatology, Volume 7 E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 1181

Veröffentlichungsjahr: 2013

Beschreibung

Representing the state of the art of veterinary dermatology around the globe, Advances in Veterinary Dermatology, Volume 7, presents selected scientific papers from the Seventh World Congress of Veterinary Dermatology.  The Congress, held in Vancouver, Canada in July 2012, was organized with the support of the World Association for Veterinary Dermatology (WAVD) and its affiliated societies.   A record number of delegates attended from over 50 countries to take advantage of the exceptional scientific program.  Cutting edge information was presented as review papers and original studies in the areas of:

• Allergy
• Immunology   
• Skin Biology   
• Therapy
• Infectious Diseases
• Oncology

These peer-reviewed and edited papers were published in the journal Veterinary Dermatology in volume 24, issue 1, and are included in this hardbound book volume of the conference proceedings.  Also included are 13 Workshop Reports which summarise sessions where experts presented topics in various areas providing a wonderful opportunity for colleagues to ask questions and exchange ideas in an informal atmosphere.

A vital resource for all practising veterinarians and researchers interested in the field of veterinary dermatology.

Leseprobe

Contents

Cover

Half Title page

Title page

Copyright page

Sponsors

Officers and Organizing Committees

Members of the Administrative Committee of the WAVD

Preface

Part 1: Allergy

Chapter 1.1: Epidemiology of human atopic dermatitis – seven areas of notable progress and seven areas of notable ignorance

Introduction

Seven areas of notable progress

Seven areas of notable ignorance

Reflections

References

Chapter 1.2: The genomics revolution: will canine atopic dermatitis be predictable and preventable?

Introduction

Investigating AD-associated genotypes

Genomic studies in canine AD

Conclusions

Glossary

References

Chapter 1.3: Serum anti-Staphylococcus pseudintermedius IgE and IgG antibodies in dogs with atopic dermatitis and nonatopic dogs

Introduction

Materials and methods

Results

Discussion

Acknowledgements

References

Chapter 1.4: Characterization of canine filaggrin: gene structure and protein expression in dog skin

Introduction

Materials and methods

Results

Discussion

Acknowledgements

References

Supporting Information

Part 2: Immunology

Chapter 2.1: Innate immune defense system of the skin

Introduction

Antimicrobial peptides

Cathelicidins

β-Defensins

Dermcidin

Psoriasin

Antimicrobial peptide production in atopic dermatitis

Conclusion

References

Chapter 2.2: Evaluation of canine antimicrobial peptides in infected and noninfected chronic atopic skin

Introduction

Material and methods

Results

Discussion

Acknowledgements

References

Chapter 2.3: Interleukin-31: its role in canine pruritus and naturally occurring canine atopic dermatitis

Introduction

Materials and methods

Results

Discussion

Acknowledgements

References

Supporting Information

Chapter 2.4: Expression of thymic stromal lymphopoietin in canine atopic dermatitis

Introduction

Materials and methods

Results

Discussion

References

Part 3: Skin Biology

Chapter 3.1: The stratum corneum: the rampart of the mammalian body

Introduction

Stratum corneum components crucial for barrier function

Cutaneous manifestations associated with the alteration of SC components in humans and other mammalian species

Implications and future perspectives for biological and clinical research

References

Chapter 3.2: Fixing the skin barrier: past, present and future - man and dog compared

What is known in human medicine

What is known in dogs

Concluding remarks

References

Chapter 3.3: Autosomal recessive ichthyosis in golden retriever dogs: distribution and frequency of the PNPLA1 mutant allele in different populations

Introduction

Materials and methods

Results

Discussion

Acknowledgements

References

Chapter 3.4: Epidermal structure created by canine hair follicle keratinocytes enriched with bulge cells in a three-dimensional skin equivalent model in vitro: implications for regenerative therapy of canine epidermis

Introduction

Materials and methods

Results

Discussion

Acknowledgements

References

Chapter 3.5: Skin lipid profiling in normal and seborrhoeic shih tzu dogs

Introduction

Material and methods

Results

Discussion

Acknowledgements

References

Part 4: Therapy

Chapter 4.1: Stem cell therapy in veterinary dermatology

Introduction

Sources and types of stem cells

Identification and characterization of the mesenchymal stem cell

Mechanisms of action of the mesenchymal stem cell

Engineered skin

Mesenchymal stem cell therapy of chronic nonhealing wounds

Mesenchymal stem cell therapy of immune-mediated skin diseases

Mesenchymal stem cell therapy of scar tissue

Mesenchymal stem cell therapy in alopecia

Bulge stem cell markers in oncology

US Food and Drug Administration (FDA) regulation of stem cell therapy in veterinary medicine

Future perspectives of stem cell therapy in veterinary dermatology

References

Chapter 4.2: A systematic review of randomized controlled trials for prevention or treatment of atopic dermatitis in dogs: 2008-2011 update

Introduction

Objectives

Methods

Results

Discussion

Conclusions

References

Chapter 4.3: The effect of ketoconazole on whole blood and skin ciclosporin concentrations in dogs

Introduction

Materials and methods

Results

Discussion

Acknowledgements

References

Chapter 4.4: In vitro antiseptic susceptibilities for Staphylococcus pseudintermedius isolated from canine superficial pyoderma in Japan

Introduction

Materials and methods

Results

Discussion

References

Supporting Information

Chapter 4.5: Photodynamic therapy for pythiosis

Introduction

Material and methods

Results

Discussion

References

Part 5: Infectious Diseases

Chapter 5.1: The canine and feline skin microbiome in health and disease

Introduction

Assessment of microbial populations

The human skin

The canine and feline skin bacterial microbiota: culture-dependent studies

The canine and feline skin microbiomes: culture-independent studies

Role of the skin microbiome in health and disease

Manipulation of the skin microbiome

Conclusion

References

Chapter 5.2: Ulcerated and nonulcerated nontuberculous cutaneous mycobacterial granulomas in cats and dogs

Introduction

Canine leproid granuloma (canine leprosy)

Feline leprosy syndromes

Treatment of canine leproid granuloma and feline leprosy syndrome

Localized infections due to Mycobacterium ulcerans

Zoonotic implications

Acknowledgements

References

Supporting information

Chapter 5.3: Prevalence of and risk factors for isolation of meticillin-resistant Staphylococcus spp. from dogs with pyoderma in northern California, USA

Introduction

Materials and methods

Results

Discussion

Acknowledgements

References

Chapter 5.4: Usefulness of cefovecin disk-diffusion test for predicting mecA gene-containing strains of Staphylococcus pseudintermedius and clinical efficacy of cefovecin in dogs with superficial pyoderma

Introduction

Materials and methods

Results

Discussion

Acknowledgements

References

Chapter 5.5: Small Demodex populations colonize most parts of the skin of healthy dogs

Introduction

Materials and methods

Results

Discussion

Acknowledgements

References

Part 6: Oncology

Chapter 6.1: Advances in the management of skin cancer

Introduction

Receptor tyrosine kinase inhibitors

Retinoids

Toll-like receptor agonists

Histone deacetylase inhibitors

BRAF inhibitors

Xenogeneic DNA vaccine for canine melanoma

Monoclonal antibodies

Monoclonal antibodies in the treatment of skin cancer

Identifying appropriate targets

The hurdles to clinical advancement

Conclusions

References

Chapter 6.2: Kinase dysfunction and kinase inhibitors

Protein kinases and normal cell biology

Resistance to therapy

Summary

References

Chapter 6.3: The contribution of stem cells to epidermal and hair follicle tumours in the dog

Introduction

Materials and methods

Results

Discussion

Acknowledgements

References

Supporting Information

Chapter 6.4: Epithelial-to-mesenchymal transition: immunohistochemical investigation of related molecules in canine cutaneous epithelial tumours

Introduction

Materials and methods

Results

Discussion

References

Chapter 6.5: Canine inflamed nonepitheliotropic cutaneous T-cell lymphoma: a diagnostic conundrum

Introduction

Materials and methods

Results

Discussion

Acknowledgements

References

Part 7: Equine Dermatology

Chapter 7.1: Comparison of hair follicle histology between horses with pituitary pars intermedia dysfunction and excessive hair growth and normal aged horses

Introduction

Materials and methods

Results

Discussion

Acknowledgements

References

Chapter 7.2: Equine sarcoidosis: clinical signs, diagnosis, treatment and outcome of 22 cases

Introduction

Materials and methods

Results

Discussion

Acknowledgements

References

Part 8: Workshop Reports

Chapter 8.1: Nonpruritic hair loss

Canine recurrent flank alopecia (CRFA) (S. Vandenabeele)

Alopecia in silver Labrador retrievers (V. Fadok and C. Vitale)

Description and characterization of a hair coat disorder in schipperkes (E.R. May)

Treatment of alopecia X with progesterone (L.A. Frank)

References

Chapter 8.2: Dietary management of skin disease: elimination diets and dietary approach to canine allergic disease

References

Chapter 8.3: Fun with lasers

Light, tissue and magic: a peek behind the curtain (G.M. Peavy)

New frontiers in structural and functional optical diagnostics (G.M. Peavy)

Chapter 8.4: Allergen-specific immunotherapy

Rush immunotherapy (A. Foust)

Early experiences in sublingual immunotherapy (V. Fadok)

How to utilize allergen cross-reactivity for formulation of immunotherapy (K. Lee)

References

Chapter 8.5: Pododermatitis: canine interdigital follicular cysts and feline plasma cell pododermatitis

Interdigital cysts (D. Duclos)

Medical therapy of interdigital furunculosis (J.C. Angus)

Feline plasma cell pododermatitis (B.E. Wildermuth)

Complicated plasma cell pododermatitis in a domestic medium-hair cat (S. Bartlett)

References

Chapter 8.6: Hot topics in zoonosis

Overview of zoonotic methicillin-resistant staphylococci (S. Weese)

Transmission of methicillin-resistant Staphylococcus (L. Frank)

Once infectious, always infectious. So what about persistence of MRS? (D. Lloyd)

Recommendations for management (V. Fadok)

References

Chapter 8.7: Responsible use of antimicrobials

The Swedish approach to prudent antimicrobial use (K.E. Bergvall)

Control of antimicrobial drug use in North America (A. Hillier)

Responsible use of topical antimicrobial agents (D.N. Carlotti)

Use of antimicrobial combinations in difficult infections (J.S. Weese)

References

Chapter 8.8: Refractory atopic dermatitis therapy

Antihistamines: ‘What percentage of atopic dermatitis (AD) cases respond to antihistamines?

Essential fatty acids: ‘How do you use EFAs?’

Pentoxifylline: ‘What percentage of AD cases respond to pentoxifylline?’

Glucocorticoids: ‘Which is the favourite steroid to use first?’

Ciclosporin: ‘Do you use the brand name Atopica® versus the generic ciclosporin?’

The audience was asked whether any change is noted when generic ciclosporins are used?

What kind of modification methods are used when the patients don’t respond to the usual ciclosporin 5 mg/kg every 24 hour dosing?

The audience was then asked: ‘When you use ketoconazole (KTZ) what dosage do you use?’

Interferon: ‘For those who do not use interferon, why do you not use interferon for atopic dermatitis?’

The participants who use interferon were then asked how they use it

Gabapentin: ‘How many use the drug and how effective is it?’

References

Chapter 8.9: Challenges in otitis

Developing an objective clinical score for canine otitis externa (T. Nuttall)

The management of Pseudomonas otitis (R. Rosychuk)

TrizEDTA significantly potentiates the bactericidal activity of silver sulfadiazine against multidrug-resistant Pseudomonas aeruginosa associated with chronic otitis (L. Buckley)

In vitro antimicrobial activity of Pseudomonas aeruginosa isolated from dogs with otitis externa (A. Vercelli)

BAER (brainstem auditory evoked response) testing in practice (S. Paterson)

Study to compare owners’ perceptions of their dogs’ hearing and brainstem auditory-evoked response findings in 45 dogs (C.L. Ball)

Myringotomy: when and how to perform; indications and complications (L. Cole)

Treatment of primary secretory otitis media (PSOM) with myringotomy in dogs with Chiari-like malformation: 21 dogs (28 bullae) with 24-month follow-up (D. Marino)

Reference

Chapter 8.10: Allergy testing revisited

Patch testing and IgE/IgG testing for canine adverse food reactions (R.S. Mueller)

Reliability of intradermal testing in atopic dogs (K. Beale)

Drug interference in intradermal testing and serology: an evidence-based review (M. Saridomichelakis)

Enzyme coupling methodology and its effects on mab specificity (J. Bexley)

Storage mites and serological reactivity in canine atopic dermatitis (CAD): have we underestimated its importance? (D.L. Wassom)

Intradermal testing (IDT) reactivity to dust mites and storage mites in the south-eastern USA (P. Hensel)

Individual allergen vs group testing in IgE serology (K.W. Lee)

References

Chapter 8.11: Epidermal barrier function

Antimicrobial skin barrier in canine atopic dermatitis: how much do we really know? (D. Santoro)

Changes in epidermal ceramides in canine atopic dermatitis (J.S. Yoon)

Looking at the stratum corneum barrier function through ichthyosis (E. Guaguere and C. Andre)

Changes in the profiles of genes associated with cutaneous barrier function in atopic beagles (R.S. Mueller)

Veterinary drugs affecting cutaneous barrier function in dogs (R. Marsella)

References

Chapter 8.12: The changing faces of parasite control

The use of permethrin spot-on formulations in dogs (M. Kietzmann)

Permethrin intoxication in cats (R. Malik)

Recent and potential future challenges for veterinary dermatologists arising from ‘benign’ topical flea preventatives (U. Oberkirchner)

Resistance of Sarcoptes mites to ivermectin (M. Nagata)

Clinical experience with the Leishmania vaccine (S. Viaud)

References

Chapter 8.13: Topical antimicrobial therapy

Antibacterial shampoos – can they relieve/reduce bacterial burden? (R. Mueller)

Antibacterial shampoos/washing and staphylococci (Nobuo Murayama)

The in vitro antimicrobial activity of a spot-on containing a mixture of essential oils and a plant extract against Staphylococcus pseudintermedius and Malassezia pachydermatis. (Lionel Fabriès)

Antimicrobial shampoos: efficacy against staphylococci, Pseudomonas and Malassezia (Tim Nuttall)

References

Index

Advances in Veterinary Dermatology

This edition first published 2013© 2013 The Authors. Journal compilation © 2013 ESVD and ACVD

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Sponsors of the Seventh World Congress of Veterinary Dermatology

Officers and Organizing Committees of the Seventh World Congress of Veterinary Dermatology

Officers

President: Dr Manon Paradis

Secretary: Dr Stephen White

Treasurer: Dr Rosario Cerundolo

Executive Organizing Committee

The Officers and:

Dr Douglas DeBoer, Fundraising

Dr Alan Hoey, Local Organizing Committee

Dr Chiara Noli, Programme

Dr Rusty Muse, Publicity

Dr Sheila Torres, Publications

Prof. Richard Halliwell, WAVD Representative

Dr Masahiko Nagata, Asia Representative

Committees

Fundraising Committee

Dr Douglas DeBoer (Chairperson)

Dr Wayne Rosenkrantz (Co-chairperson)

Local Organizing Committee

Dr Alan Hoey (Chairperson)

Dr Vincent Defalque (Co-chairperson)

Programme Committee

Dr Chiara Noli (Chairperson)

Sonya Bettenay (Co-chairperson)

Mona Boord (Co-chairperson)

Kerstin Bergvall

Valerie Fadok

Andy Hillier

Koji Nishifuji

David Robson

Manolis Saridomichelakis

Anthony Yu

Publications Committee

Dr Sheila Torres (Chairperson)

Dr Linda Frank

Dr Ann Hargis

Publicity Committee

Dr Rusty Muse (Chairperson)

Dr Mandy Burrows (Co-chairperson)

Dr Kinga Gortel

Dr Ian Spiegel

Dr Claudia Nett

Dr Masahiko Nagata

WAVD Representatives

Prof. Richard Halliwell (UK)

Dr Masahiko Nagata (Asia)

Members of the Administrative Committee of the WAVD

Kenneth Kwochka (USA)

President WAVD, Representative of ACVD

Didier Noel Carlotti (France)

Past President WAVD, President WCVD8

Amanda Burrows (Australia)

Secretary WAVD, Representative DCACVS

David Lloyd (UK)

Treasurer WAVD, President WCVD5

Phil Roudebush (USA)

Representative of AAVD

Luc Beco (Belgium)

Representative of ESVD

Emmanuel Bensignor (France)

Representative of ECVD

Manon Paradis (Canada)

Representative of CAVD, President WCVD7

Carmel Taylor (Hong Kong)

Representative of AiSVD

Claudia Nett-Mettler (Switzerland)

Member-at-Large

Wayne Rosenkrantz (USA)

Member-at-Large

Richard Halliwell (UK)

President WCVD1, Past President WAVD

Hans Koch (Germany)

President WCVD3

Peter Ihrke (US)

President WCVD4

Preface

The Seventh World Congress of Veterinary Dermatology, held in Vancouver, Canada, from July 24 to 28, was unquestionably a success! The Congress was organized with the support of the World Association for Veterinary Dermatology (WAVD) and its affiliated societies. A record number of more than 1600 delegates from over 50 countries participated, reflecting the worldwide interest in the Veterinary Dermatology specialty.

The scientific programme was exceptional and covered a broad range of topics. Speakers of six state of the art, six supporting review and 20 supporting original studies presented cutting edge information in the areas of allergy, immunology, skin biology, therapy, infectious diseases and oncology. The 69 free communications and 121 posters provided diverse high-quality research and reports of clinical cases catering to the broad interest of the audience. Moreover, there was an extensive and well-attended advance and comprehensive continuing education programme for veterinary practitioners, not to mention the programmes exclusively focused in equine, feline and exotic dermatology. Last but not least, 14 workshops, where experts presented topics in various areas, provided a wonderful opportunity for colleagues to ask questions and exchange ideas in an informal atmosphere. This large number of scientific presentations and the high calibre of the material delivered by colleagues from across the globe reflect, unquestionably, the worldwide advancement of the Veterinary Dermatology field and, for this, we should all be proud.

This hardbound volume, Advances in Veterinary Dermatology 7, contains the manuscripts published in the special issue in addition to the workshop reports. The memory of the other scientific presentations is preserved in the abstract issue of Veterinary Dermatology, Volume 23 Supplement 1, July 2012, and in the Proceedings of the Continuing Education Programme.

The success of this Congress is largely a result of the hard work of the officers and members of the various organizing committees who unpretentiously donate countless hours of their time to make this a memorable event. Moreover, without the kind support of the corporate sponsors this Congress would not be possible. On behalf of all participants, I would like to take this opportunity to thank all the sponsors of the Seventh World Congress of Veterinary Dermatology.

I hope you are already making plans for the Eighth World Congress of Veterinary Dermatology which will take place in Bordeaux, France, and promises to be as outstanding as this one.

Sheila TorresCollege of Veterinary Medicine, University of Minnesota, St Paul, Minnesota, USA

Part 1

ALLERGY

1.1 Epidemiology of human atopic dermatitis – seven areas of notable progress and seven areas of notable ignoranceHywel C. Williams

1.2 The genomics revolution: will canine atopic dermatitis be predictable and preventable?Tim Nuttall

1.3 Serum anti-Staphylococcus pseudintermedius IgE and IgG antibodies in dogs with atopic dermatitis and nonatopic dogsJennifer Bexley, Timothy J. Nuttall, Bruce Hammerberg, J. Ross Fitzgerald and Richard E. Halliwell

1.4 Characterization of canine filaggrin: gene structure and protein expression in dog skinSatoko Kanda, Takashi Sasaki, Aiko Shiohama, Koji Nishifuji, Masayuki Amagai, Toshiroh Iwasaki and Jun Kudoh

To cite this article, please use DOI: 10.1111/j.1365-3164.2012.01079.x

Chapter 1.1

Epidemiology of human atopic dermatitis – seven areas of notable progress and seven areas of notable ignorance

Hywel C. Williams

Centre of Evidence-Based Dermatology, Room A103, Lenton Lane, University of Nottingham King’s Meadow Campus, Nottingham NG7 2NR, UK

Correspondence: Hywel C. Williams, Centre of Evidence-Based Dermatology, Room A103, Lenton Lane, University of Nottingham King’s Meadow Campus, Nottingham NG7 2NR, UK. E-mail: [email protected]

Background – This narrative review highlights areas within the epidemiology of human atopic dermatitis (AD) where significant progress has been made and where considerable ignorance still exists. The review is supported by systematic reviews wherever possible, with the purpose of stimulating fresh approaches to human and veterinary research into AD.

Progress – Areas of progress include valid and repeatable methods of disease definition, global documentation of disease prevalence and impact, clarification of the role of some genetic factors, such as filaggrin gene mutations, clear evidence that environmental factors are key, as demonstrated by the positive social class gradient and rising prevalence, a possible protective effect of infections in early life, documentation of comorbidities, such as a reduced risk of glioma, and mapping the evidence base through systematic reviews and an online global resource of clinical trials.

Ignorance – Areas where significant uncertainty still exists include the question of whether AD is more than one disease, the tendency for researchers to look at the same old risk factors, lack of specific environmental risk factors that are amenable to manipulation, inconsistencies in the hygiene hypothesis, sparse knowledge about adult AD, lack of evidence that eczema can be prevented, and little scientific work exploring what causes flares in people with established AD.

Introduction

Epidemiology is concerned with much more than simply documenting the prevalence of a disease such as atopic dermatitis.1 By observing cases with atopic dermatitis (AD) and contrasting them with those who do not have AD in relation to various genetic and environmental factors, critical information about potential risk factors for determining disease expression can be gleaned. Identification of such risk factors brings us one step closer to the dream of disease prevention, an important concept in a society so preoccupied with disease treatment. The beauty of epidemiology is that knowledge of pathophysiology and scientific mechanism is not a prerequisite to identifying important risk factors that can be acted upon. By simply counting diseased cases in relation to population denominators served by different water supplies, John Snow was able to deduce that some ‘morbid matter’ transmitted by water was responsible for the terrible cholera epidemics in London in the 1850s, and was able to halt the epidemics by appropriate action. These discoveries were made long before germ theory had demonstrated the responsible bacteria.2

It is not possible to summarize all knowledge relating to the distribution and determinants of human AD in one review article without reducing everything to superficial and potentially uninteresting summary statements. The author edited an entire textbook of 250 pages on the epidemiology of AD over 10 years ago,3 and inclusion of subsequent studies would now probably fill 500 pages. Instead, and with the readership of veterinary dermatologists in mind, who might be looking for ideas and parallels between human and animal AD, the author has chosen to highlight areas where significant progress has been made over the last 12 years, as well as to highlight some areas of notable ignorance, which may serve to stimulate new research. The selection of which seven areas of progress and seven areas of uncertainty to include is a personal choice of the author based upon 23 years researching the epidemiology of AD. The author has also become more aware of existing and missing evidence through evidence mapping in the form of systematic reviews in his previous work as dermatology lead for the UK National Electronic Library for Health, now called NHS Evidence.4

Seven areas of notable progress

Disease definition

In the 1970s, many synonyms for atopic dermatitis were in use over the world, and it is unclear whether they all referred to the same clinical concept. The Hanifin and Rajka consensus criteria marked an important development in listing the clinical features of AD, although their complexity and lack of validity and repeatability meant that they were unsuitable for epidemiological studies.5 This was the task of the UK Working Party, which refined the Hanifin and Rajka criteria to a minimum list of reliable discriminators that could be used in epidemiological studies (Table 1).6 An independent systematic review of diagnostic criteria for AD found 19 validation studies of the UK diagnostic criteria, which showed sensitivity and specificity ranging from 10 to 100 and from 89.3 to 99.1%, respectively.7 These criteria have now been used in many studies worldwide, although more validation in the very young and in adults is still needed. The criteria permit a more standardized approach towards defining the AD phenotype in a way that any researcher can understand and replicate. It is encouraging to note that a similar approach for developing diagnostic criteria for canine AD has been undertaken.8

Table 1. The UK refinement of the Hanifin and Rajka diagnostic criteria for atopic dermatitis (reproduced with permission of John Wiley & Sons, Ltd).6

To qualify as a case, the child must have:

An itchy skin

Plus three or more of:

Onset under age 2 years

History of rash in skin creases

Personal history of asthma or hay fever

A history of a generally dry skin

Visible flexural dermatitis

Advances have also been made with disease nomenclature. It should be pointed out that the term ‘atopic dermatitis’ or its synonymous term ‘atopic eczema’ should only be used when denoting those with the phenotype of eczema who also have evidence of allergen-specific circulating immunoglobulin E (IgE) antibodies, as demonstrated by serum or skin prick tests.9,10 Evidence from the International Study of Asthma and Allergies in Children (ISAAC) Phase Two, the largest sample of well-defined AD cases in the world, suggests that around 50% of examined AD cases in developed countries are, in fact, not atopic, and an even greater proportion in developing countries are not atopic.11 The study has concluded that any association between atopy and examined flexural eczema is weak and more variable than previously suggested, and that the strength of this association is positively linked to gross national income.11 Part of the misguided obsession with atopy resides in the fact that atopy is more common in people with more severe skin disease who typically characterize hospital-based populations that are easy to study.10 Indeed, some have even argued that raised serum IgE could be an epiphenomenon of disease severity.10 The World Allergy Organization (WAO) nomenclature committee has recommended that the term ‘eczema’ is used to denote what we typically refer to as the phenotype of atopic dermatitis, and that the prefix ‘atopic’ is used when defining a subset that is truly atopic.9 The WAO proposition makes good sense and it obviates the need for yet more sets of diagnostic criteria, such as the ‘millennium criteria’, which look remarkably like the original Hanifin and Rajka criteria, with IgE reactivity stuck on top as a necessary criterion.12 We will, however, continue to use the term atopic dermatitis (AD) throughout this article, simply for familiarity to the reader.

Prevalence and impact

Although scores of ad hoc prevalence studies have documented the burden of AD to a variable extent, such studies are not truly comparable because of the different diagnostic criteria and sampling methods used and age groups studied. The advent of the ISAAC has opened up the global map of AD by using identical methods in over a million children in over 100 countries worldwide.13 The latest ISAAC Phase Three world map of AD symptoms shows that for 385,853 children aged 6–7 years from 143 centres in 60 countries, the prevalence of AD ranged from 0.9% in India to 22.5% in Ecuador, with new data showing high values in Asia and Latin America.14 For the 663,256 aged 13–14 years from 230 centres in 96 countries, AD prevalences ranged from 0.2% in China to 24.6% in Columbia, with the highest values in Africa and Latin America.14 Current eczema was lower for boys than girls (odds ratio, 0.94 and 0.72 at ages 6–7 and 13–14 years, respectively). The ISAAC data have shown that AD is now a common problem in cities in developing countries that are undergoing rapid demographic transition, as well as in developed countries. Phase Two of the ISAAC study also included physical examination of 28,591 randomly selected children aged 8–12 years and skin prick testing, enabling much firmer exploration of the link between AD and atopy across the world.11 Point prevalences of flexural eczema by skin examination ranged between 0.4% in Kintampo, Ghana to 14.2% in Östersund, Sweden.11 The association between atopy and examined flexural eczema was weak, especially in nonaffluent countries.1

One limitation of the ISAAC study was low participation from the USA, for reasons that are unclear. That lack of information has been filled by a recent analysis of a nationally representative sample of 102,353 children aged 17 years and under who took part in the 2003 National Survey of Children’s Health.15,16 The survey showed that the prevalence of AD diagnosis ranged from 8.7 to 18.1% between states and districts, with the highest prevalence reported in East Coast states. Metropolitan living, black ethnicity and high educational level in the household were all associated with increased AD prevalence.15,16

Four systematic reviews have summarized the impact of AD.17–20 Sleep loss seems to be the dominant problem, which affects the entire family as well as the child with AD.19 Depression, anxiety and quality-of-life impairment may also occur, and morbidity is comparable to other ‘important’ noncommunicable diseases.21,22 The direct and indirect financial costs of AD can be significant. A review of 59 US studies estimated that national annual AD costs in 2008 could be as large as $3.8 billion US dollars.20

Role of genetic factors

A strong familial component has always been a feature of AD, and twin studies pointed to a strong influence of genetic factors.23 While earlier work on the genetics of AD focused on immunological phenomena with mixed findings,24 significant breakthroughs into understanding the role of genetics in AD occurred following the discovery of filaggrin gene mutations responsible for the dry skin seen in eczema.25 Filaggrin is a skin protein that appears to be essential for maintaining the integrity of skin barrier function, which is important in AD and other dry skin conditions, including ichthyosis vulgaris.25 Profilaggrin gene mutations resulting in loss of function are present in around 10% of western European and North American populations.26 In addition, such mutations predict AD severity, disease persistence and allergic sensitization and may be involved in the progression of AD to other allergic diseases, such as allergic rhinitis and asthma.27,28 The chronology of the discovery of the filaggrin gene and its subsequent association has been documented in a recent review by Brown and McLean.25 The remaining challenge in AD is to establish whether other genes responsible for barrier integrity are also important and to explore whether filaggrin mutations have important therapeutic applications, including disease prevention. The author’s group is involved in developing a national study to see whether barrier enhancement of babies born to parents with atopic disease can reduce the incidence and severity of AD.29 Many immunological and skin barrier similarities between human and canine AD have emerged, such as increased transepidermal water loss, abnormal lipid lamellae, decreased ceramides and reduced filaggrin protein expression, and these are summarized comprehensively by Marsella et al.30

Key role for the environment

While the breakthroughs associated with filaggrin gene mutations have been illuminating and helpful in refocusing interest on the outside skin barrier rather than on immune cells within the body, the environment must also play a key role.31 Thus, it is difficult to find a genetic explanation for the observation that AD is more common in wealthier and more educated families,15,32 or in smaller families,33 or in those ethnic groups migrating from a country of low prevalence to a country of high prevalence.34 The ISAAC study has provided convincing evidence that eczema symptom prevalence has increased substantially over a 5–10 year time span (Figure 1), especially in younger children.35 Such rapid increases in disease prevalence cannot be explained by genetics, nor can they be explained by our current knowledge of risk factors for AD, such as exposure to allergens. While there is little doubt that allergic factors are important in AD, especially in severe disease, their role has been overemphasized, perhaps because there has been little else, such as filaggrin gene mutations, to look at until recently. The concept that allergic sensitization is a risk factor for AD has been challenged,10,11 and it is possible that increasing exposure to allergens at a critical time of immune development to induce tolerance may be more fruitful than trying to reduce ubiquitous allergens, such as house dust mite.36

Figure 1. (a, b) World maps from the International Study of Asthma and Allergies in Childhood depicting flexural eczema symptoms in the last year, showing changes in the prevalence of eczema symptoms for 13–14 and 6–7 year olds in consecutive prevalence surveys conducted 5–10 years apart. SE, standard error

(reproduced with permission of Elsevier).35

Protective effect of infections in early life

The observation that AD is more common in smaller families and in younger rather than older siblings led to the hygiene hypothesis.37 In other words, AD may become manifest when a developing immune system is deprived of the obligatory stimulation from certain microbial antigens. Such a protective effect on AD development that could be mediated by microbial stimulation is also observed with increased endotoxin exposure, infant day care attendance, consumption of unpasteurized farm milk,38 and even being raised with a dog during early life.39 In a recent updated systematic review of the hygiene hypothesis in relation to AD, Flohr and Yeo conclude that the protective effects seen with early day care, endotoxin, unpasteurized farm milk and animal exposure are likely to be due to a general increase in exposure to nonpathogenic microbes, a hypothesis which might also explain the increase in risk of AD by the use of broad-spectrum antibiotics.40 Loss of exposure to gut helminths may also predispose to more atopy and AD,41,42 suggesting that increased allergic disease may be one of the prices to pay for the benefits of deworming. The picture is far from clear, and research is now needed to improve understanding of the interaction between genetic factors, such as defective skin barrier, and environmental microbial stimulation at critical times of early life.

Comorbidities

Several studies have evaluated possible disease associations with AD, and most have been inconclusive. Three areas have progressed in the last 10 years. The first is quantifying the risk of subsequent asthma in a child who has AD. A systematic review of 13 cohort studies by van der Hulst and co-workers in 2007 confirmed that although there is an increased risk of developing asthma after AD in early childhood, only one in every three such children developed asthma.27 This is much lower than previously assumed. Another cohort study, of 1314 German children followed from birth to age 7 years, found a clear association between early AD and asthma at school age.43 Yet, in many of these asthmatic children, wheezing manifested itself before or with the onset of AD, suggesting a distinct phenotype of early wheezers rather than a progressive development from AD to asthma.43 There is little doubt about the strong association between asthma and AD, but it may not be a straightforward progression of events, as the simplistic notion of an ‘atopic march’ suggests.44

One systematic review has suggested an inverse relationship between atopic disorders and childhood leukaemia.45 Another systematic review, of 10 case–control and two cohort studies involving 61,090 patients, suggested that the risk of glioma was substantially reduced in those with asthma, AD and hay fever, with odds ratios of 0.70 (95% confidence interval 0.62–0.79, P < 0.001), 0.69 (95% confidence interval 0.62–0.78, P < 0.001), and 0.78 (95% confidence interval 0.70–0.87, P < 0.001), respectively.46 Reasons for such a protective effect, although suspected for a long time,47 remain unclear.

Finally, some interest has been shown in a possible association between attention deficit hyperactivity disorder and AD.48 As most studies are cross-sectional, it is difficult to say which came first, but it is an area worthy of further study.

Knowledge mapping

Knowing what research has been done and collating reliable evidence in one place has been undertaken by the Centre of Evidence-Based Dermatology at Nottingham.49 When the Centre was part of the National Electronic Library for Health, annual searches were conducted for new evidence regarding AD in the form of systematic reviews with accompanying detailed critical commentaries on the relevance and reliability of the evidence.50,51 Every systematic review on AD identified through these annual updates has been mapped into a central resource at the Centre, which is freely available in the public domain.49 Each systematic review is catalogued under epidemiology (27), prevention (44), topical treatments (68), systemic treatments (47), phototherapy (15), dietary approaches (15), psychological and educational interventions (8), physical therapies (10), complementary and alternative therapies (18) and other interventions (13). Each category is further subdivided into more specific topics; for example, epidemiology is divided into ‘risk factors, definition, impact, et cetera’, and each review is hyperlinked to the original abstract. The comprehensive mapping of AD systematic reviews is a useful resource for researchers, clinicians and the public, and is currently undergoing a further update, which will be available later in 2012.

For all randomized controlled trials of AD, the Centre has created an international collection called the GREAT (Global Resource of EczemA Trials) database, which is updated annually.52 This mapping exercise of randomized controlled trials is also free in the public domain.53

The purpose behind these mapping exercises is to reduce research wastage, which is a significant problem in human medicine.54 Research is often undertaken in a vacuum rather than being informed by a systematic review of all relevant studies to date. The creation of an international repository of systematic reviews and randomized controlled trials of AD will hopefully reduce efforts in locating essential evidence and unnecessary duplication of exhaustive searches.

Seven areas of notable ignorance

Is AD more than one disease?

Reference has already been made to the revised nomenclature for eczema, and of its division into ‘atopic’ (or extrinsic) and ‘nonatopic’ (or intrinsic or atopiform) eczema.9 The author is sceptical of the utility of such a division, given that atopy may be a marker of disease severity rather than a distinct phenotype.10 If true, then it means that studies making claim that intrinsic and extrinsic eczema behave in different ways should ideally measure IgE responsiveness repeatedly over time, or at least adjust for disease severity when making comparisons. Differentiating into those with enhanced barrier defects caused by filaggrin gene defects may make more sense in predicting the natural history of disease.28 Other patterns of eczema associated with AD in children, such as the discoid (nummular) pattern, may represent aberrant responses to Staphylococcus aureus infections. Perhaps there is a distinct form of AD associated with respiratory disease,43 and other suggestions may emerge as new discoveries are made. The division of AD into subtypes should not occur lightly, but should be preceded by studies that demonstrate that division into subtypes is clinically or scientifically worthwhile, for example by explaining or predicting responsiveness to treatment or suggesting that a particular strategy, such as allergen tolerance or reduction, will be worthwhile in that group.

Looking at the same old risk factors

A search on the epidemiology of AD in April 2012 revealed 2197 studies. While encouraging, many of the identified citations were found not to be true epidemiological studies and those that were tended to be rather similar, with a few notable exceptions. Two patterns seemed to emerge. The first is a ‘fishing’ expedition type of study that includes less than 1000 children, which finds yet more evidence that only family history of atopic disease is a strong risk factor for AD. The second type of study revisits a well-explored intervention, such as breastfeeding and AD, using the same design and limitations, such as inadequate consideration of confounding, as previous studies, which unsurprisingly comes to the same inconclusive results as others.55 What is needed is a fresh approach that identifies new areas for research by exploring the interfaces between AD and other areas of medicine. This could entail learning from other chronic relapsing and remitting diseases, or by working with other branches of science that might, at first, appear to have little to do with AD. For example, our previous work with medical geographers showed that AD was more common in geographic regions with hard water.56 The finding led to a randomized controlled trial of ion-exchange water softeners in AD.57 Although the trial showed that water softeners were not helpful in AD, the study nevertheless visited a new and plausible hypothesis that may still turn out to be important.

Lack of risk factors that are amenable to manipulation

There is a need to progress from documenting how attributes such as age, sex and social class explain some of the differences in AD prevalence to drilling down into exploring the specific components of such attributes. It is difficult to act on the knowledge that AD seems to improve during adolescence in many children, but if such an observation opens up new insights, such as an association between hormonally induced sebum production in puberty with enhanced skin barrier function, more specific interventions can then be developed to prevent or ameliorate existing disease.

Inconsistencies in the hygiene hypothesis

The author has deliberately mentioned the hygiene hypothesis in the progress and ignorance section. While it has been an exciting hypothesis that has explained some of the epidemiological findings, such as decreased risk of AD in younger siblings, large family size and living on a farm, the topic is far more complex and is studded with inconsistent findings in different countries. The type of microbial or parasitic exposure, the timing of exposure, the intensity of exposure and whether specific or broad exposures are required for disease risk reduction are still unclear.40

Sparse knowledge about adult AD

It is not surprising that most epidemiological studies of AD have been done in children because AD is more common in childhood, the effects of the disease may be critical in early life and school children make an easily accessible population for research. However, as Herd et al. point out,58 adults over 16 years still constitute around one-third of the total AD cases in a given community. Such adults often suffer from more severe and chronic disease than children, and the effects of AD on their employment and leisure activities may be considerable. Virtually nothing is known about the epidemiology of AD in adults except that it probably affects at least 3% of adults,59 and it tends to be persistent.60 We know little about the validity of diagnostic criteria in adults,61 the natural history of disease, and whether risk factors for disease persistence are similar to those for childhood AD.

Not enough research on eczema prevention

Although at least 44 systematic reviews relating to AD prevention have been published,49 a recent overview of seven systematic reviews (covering 39 relevant trials with 11,897 participants) of prevention strategies for AD failed to find any convincing evidence that any were effective in unselected infants.62 There was some evidence to suggest that exclusive breastfeeding for at least 6 months and prebiotics might reduce eczema incidence in high-risk participants, although the studies supporting these assertions were scant and had methodological shortcomings. Such an absence of evidence cannot be equated as evidence of no effect due to the limitations in design, size and refinement of the intervention, and further studies that evaluate hydrolysed formulae, prebiotics and probiotics, as well as enhancement of the skin barrier are worthwhile.62

What causes atopic dermatitis to flare?

Much confusion can arise if those studying AD do not at least consider separating the risk factors for disease occurrence, risk factors for disease flares and risk factors for disease perpetuation, because they may not necessarily be the same. Although textbooks about AD typically cite a long list of factors that may exacerbate established AD, very few of these are based on scientific studies. A previous systematic review of studies that explored factors that may cause eczema flares showed that only four of 28 studies were of a longitudinal design, an arguably essential design in order to separate the temporal relationship between cause and effect.63 One panel study from Germany suggested (post hoc) that there may be a summer and winter type of AD,64 which was not confirmed in a larger subsequent study.65 That later study by Langan et al. evaluated 60 children aged 1–15 years intensively for up to 9 months using electronic diaries and additional meteorological information. Autoregressive moving average models were used to study the impact of exposures on AD severity for individuals over time. Nylon clothing, dust, unfamiliar pets, sweating and shampoos were shown to play a role in worsening AD in children.65 Interestingly, the study found that combinations of exposures may be acting in concert. In other words, a putative exacerbating factor, such as dust, may not cause a child’s AD to worsen on one day, but it would on another day if that child was also tired and had been sweating. Further work in exploring such a multiple component hypothesis is worthwhile, although the length and intensity of follow-up is challenging. Even defining what is meant by a flare is not straightforward, because it is relative to each individual. Simple definitions, such as escalation of treatment or seeking additional healthcare, may be as good as more numerically exact sounding but clinically meaningless methods.66

Reflections

This review has illustrated the considerable progress that has been made over the last 12 years in understanding the epidemiology of human AD. The tree of AD research (Figure 2) is no longer as bent over by the imbalance of basic science as it has been, and basic scientists and epidemiologists are finally discovering the value of working together, as exemplified by the field of skin barrier genes,26 and exploring the possible role of autoimmunity.67 This review is not intended to condemn well-intentioned efforts of the past, but to stimulate more research in those areas that need it most, with the ultimate aim of reducing human (and animal) suffering from this common disease. More effort needs to be made into conducting much larger and well-designed studies that focus on testing new and existing clearly defined hypotheses, and such studies need to be much more clearly reported according to STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) criteria so that others can understand exactly what was done and replicate the research if necessary.68 More international research should be undertaken in order to explore new exposures and the intensity of those exposures that may vary within and across different countries, as has been exemplified by the ISAAC group.69 Cross-disciplinary research, such as working across the human and small animal divide, may be key in eliciting new ideas about disease causes. Such research is a two-way process. Some ideas, such as skin barrier genes and the role of allergy and gut helminths, are worth exploring in more detail, for example, in canine AD. Some areas in veterinary dermatology, such as Malassezia sensitivity and the role of essential fatty acids in canine and feline AD, need revisiting for human AD. And so the constructive dialogue continues….

Figure 2. Depiction of how research into atopic dermatitis has been imbalanced by basic science in the past. Abbreviations: AD, atopic dermatitis; IgE, immunoglobulin E; and Th2, T helper 2

(reproduced with permission by Cambridge University Press).3

References

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29. Centre of Evidence-Based Dermatology Barrier Enhancement Eczema Prevention (BEEP) Pilot Study. Available at: http://www.nottingham.ac.uk/scs/divisions/evidencebaseddermatology/research/nihrprogrammegrant/barrierenhancementeczemaprevention(beep)feasibilitystudy.aspx. Accessed May 28, 2012.

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33. Williams HC, Hay RH, Strachan D. Eczema and family size. J Invest Dermatol 1992; 98: 601.

34. Burrell-Morris C, Williams HC. Atopic dermatitis in migrant populations. In: Williams HC, ed. Atopic Dermatitis. Cambridge: Cambridge University Press, 2000; 169–182.

35. Williams H, Stewart A, von Mutius E et al. Is eczema really on the increase worldwide? J Allergy Clin Immunol 2008; 121: 947–954.

36. Williams HC. Perspective: acting on the evidence. Nature 2011; 479: S16.

37. Strachan DP. Hay fever, hygiene, and household size. BMJ 1989; 299: 1259–1260.

38. Flohr C, Pascoe D, Williams HC. Atopic dermatitis and the ‘hygiene hypothesis’: too clean to be true? Br J Dermatol 2005; 152: 202–216.

39. Langan S, Flohr C, Williams HC. The role of furry pets in eczema: a systematic review. Arch Dermatol 2007; 143: 1570–1577.

40. Flohr C, Yeo L. Atopic dermatitis and the hygiene hypothesis revisited. Curr Probl Dermatol 2011; 41: 1–34.

41. Flohr C, Tuyen LN, Quinnell RJ et al. Reduced helminth burden increases allergen skin sensitization but not clinical allergy: a randomized, double-blind, placebo-controlled trial in Vietnam. Clin Exp Allergy 2010; 40: 131–142.

42. Mpairwe H, Webb EL, Muhangi L et al. Anthelminthic treatment during pregnancy is associated with increased risk of infantile eczema: randomised-controlled trial results. Pediatr Allergy Immunol 2011; 22: 305–312.

43. Illi S, von Mutius E, Lau S et al. The natural course of atopic dermatitis from birth to age 7 years and the association with asthma. J Allergy Clin Immunol 2004; 113:925–931.

44. Williams H, Flohr C. How epidemiology has challenged 3 prevailing concepts about atopic dermatitis. J Allergy Clin Immunol 2006; 118: 209–213.

45. Linabery AM, Jurek AM, Duval S et al. The association between atopy and childhood/adolescent leukemia: a meta-analysis. Am J Epidemiol 2010; 171: 749–764.

46. Chen C, Xu T, Chen J et al. Allergy and risk of glioma: a meta-analysis. Eur J Neurol 2011; 18:387–395.

47. Wang H, Diepgen TL. Is atopy a protective or a risk factor for cancer? A review of epidemiological studies Allergy 2005; 60: 1098–1111.

48. Schmitt J, Buske-Kirschbaum A, Roessner V. Is atopic disease a risk factor for attention-deficit/hyperactivity disorder? A systematic review Allergy 2010; 65: 1506–1524.

49. Centre of Evidence-Based Dermatology website. Maps of systematic review on atopic eczema. Available at: http://www.nottingham.ac.uk/scs/documents/documentsdivisions/documentsdermatology/methodologicalresources/mapsofsystematicreviewsonatopiceczema.pdf. Accessed April 16, 2012.

50. Centre of Evidence-Based Dermatology website, Batchelor J, Williams HC. “What’s new?” — a tour of the 2009 Annual Evidence Update on Atopic Eczema with the busy clinician in mind. Available at: http://www.nottingham.ac.uk/scs/documents/documentsdivisions/documentsdermatology/methodologicalresources/2009-annual-evidence-update-on-atopic-eczema.pdf. Accessed April 16, 2012.

51. Centre of Evidence-Based Dermatology website, Shams K, Williams HC. “What’s new?” — a tour of the 2010 Annual Evidence Update on Atopic Eczema with the busy clinician in mind. Available at: http://www.nottingham.ac.uk/scs/documents/documentsdivisions/documentsdermatology/methodologicalresources/2010-annual-evidence-update-on-atopic-eczema.pdf. Accessed April 17, 2012.

52. Nankervis H, Maplethorpe A, Williams HC. Mapping randomised controlled trials of treatments for eczema - The GREAT database (the Global Resource of EczemA Trials: a collection of key data on randomized controlled trials of treatments for eczema from 2000 to 2010). BMC Dermatol 2011; 11: 10.

53. Centre of Evidence-Based Dermatology website, Nankervis H, Williams HC. Global Resource of Eczema Trials. GREAT Database. 2000–2011.Centre of Evidence-Based Dermatology, University of Nottingham. Available at: http://www.greatdatabase.org.uk/. Accessed April 16, 2012.

54. Chalmers I, Glasziou P. Avoidable waste in the production and reporting of research evidence. Lancet 2009; 374: 86–89.

55. Yang YW, Tsai CL, Lu CY. Exclusive breastfeeding and incident atopic dermatitis in childhood: a systematic review and meta-analysis of prospective cohort studies. Br J Dermatol 2009; 161: 373–383.

56. McNally NJ, Williams HC, Phillips DR et al. Atopic eczema and domestic water hardness. Lancet 1998; 352: 527–531.

57. Thomas K, Koller K, Dean T et al. A multicentre randomised controlled trial and economic evaluation of ion-exchange water softeners for the treatment of eczema in children: the Softened Water Eczema Trial (SWET). Health Technol Assess 2011; 15: 1–156.

58. Herd RM, Tidman MJ, Prescott RJ et al. Prevalence of atopic eczema in the community: the Lothian atopic dermatitis study. Br J Dermatol 1996; 135: 18–19.

59. Muto T, Hsieh SD, Sakurai Y et al. Prevalence of atopic dermatitis in Japanese adults. Br J Dermatol 2003; 148: 117–121.

60. Sandström Falk MH, Faergemann J. Atopic dermatitis in adults: does it disappear with age? Acta Derm Venereol 2006; 86: 135–139.

61. Lan CC, Lee CH, Lu YW et al. Prevalence of adult atopic dermatitis among nursing staff in a Taiwanese medical center: a pilot study on validation of diagnostic questionnaires. J Am Acad Dermatol 2009; 61: 806–812.

62. Foisy M, Boyle RJ, Chalmers JR et al. The prevention of eczema in infants and children: an overview of Cochrane and non-Cochrane reviews. Evid Based Child Health 2011; 6: 1322–1339.

63. Langan SM, Williams HC. What causes worsening of eczema? A systematic review Br J Dermatol 2006; 155: 504–514.

64. Krämer U, Weidinger S, Darsow U et al. Seasonality in symptom severity influenced by temperature or grass pollen: results of a panel study in children with eczema. J Invest Dermatol 2005; 124: 514–523.

65. Langan S, Silcocks P, Williams HC. What causes flares of eczema in children? Br J Dermatol 2009; 161: 640–646.

66. Langan SM, Thomas K, Williams HC. What is meant by a “flare” in atopic dermatitis? A systematic review and proposal Arch Dermatol 2006; 142: 1190–1196.

67. Tang TS, Bieber T, Williams HC. Does “autoreactivity” play a role in eczema? - a systematic review J Allergy Clin Immunol 2012; 129: 1209–1215.

68. Langan SM, Schmitt J, Coenraads PJ et al. STROBE and reporting observational studies in dermatology. Br J Dermatol 2011; 164: 1–3.

69. Beasley R, Clayton T, Crane J et al. Association between paracetamol use in infancy and childhood, and risk of asthma, rhino-conjunctivitis, and eczema in children aged 6–7 years: analysis from Phase Three of the ISAAC programme. Lancet 2008; 372: 1039–1048.

Accepted 30 May 2012Sources of Funding: University of Nottingham.Conflict of Interest: No conflicts of interest have been declared.

To cite this article, please use DOI: 10.1111/j.1365-3164.2012.01094.x

Chapter 1.2

The genomics revolution: will canine atopic dermatitis be predictable and preventable?

Tim Nuttall

The University of Liverpool School of Veterinary Science, Leahurst Campus, Neston, UK

Correspondence: Tim Nuttall, The University of Liverpool School of Veterinary Science, Leahurst Campus, Chester High Road, Neston, Cheshire CH64 7TE, UK. E-mail: [email protected]

Background – Heritability studies suggest that atopic dermatitis (AD) involves multiple genes and interactions with environmental factors. Advances in genomics have given us powerful techniques to study the genetics of AD.

Objective – To review the application of these techniques to canine AD.

Results – Candidate genes can be studied using quantitative PCR and genomic techniques, but these are hypothesis-dependent techniques and may miss novel genes. Hypothesis-free techniques avoid this limitation. Microarrays quantify expression of large numbers of genes, although false-positive associations are common. In the future, expression profiling could be used to produce a complete tissue transcriptome. Genome-wide linkage studies can detect AD-associated loci if enough affected dogs and unaffected relatives are recruited. Genome-wide association studies can be used to discover AD-associated single nucleotide polymorphisms without relying on related dogs. Genomic studies in dogs have implicated numerous genes in the pathogenesis of AD, including those involved in innate and adaptive immunity, inflammation, cell cycle, apoptosis, skin barrier formation and transcription regulation. These findings, however, have been inconsistent, and problems include low case numbers, inappropriate controls, inconsistent diagnosis, incomplete genome coverage, low-penetrance mutations and environmental factors.

Conclusions – Canine AD has a complex genotype that varies between breeds and gene pools. Breeding programmes to eliminate AD are therefore unlikely to succeed, but this complexity could explain variations in clinical phenotype and response to treatment. Genotyping of affected dogs will identify novel target molecules and enable better targeting of treatment and management options. However, we must avoid misuse of genomic data.

Introduction

Human and canine AD

Canine atopic dermatitis (AD) is very similar to human AD;1–4 both are inflammatory dermatoses with characteristic clinical features. They are complex diseases involving immune dysregulation, allergic sensitization, skin barrier defects, microbial colonization and environmental factors. Human and canine AD are very common conditions, affecting up to one-third of children in Western societies and 10% of all dogs.1,5–8

It’s in the genes

Both the human and canine conditions have a genetic component. Family history is a major risk factor for human AD.1–3 Strong breed predispositions, with high prevalences in some dog breeds (e.g. up to 25% in West Highland white terrier dogs), suggest that this is also true in canine AD.9–11 In British guide dogs (mostly Labrador and golden retriever cross-bred dogs) the mean heritability is 0.47 (range 0.13–0.81), suggesting that the genetic background accounts for almost 50% of the risk of developing AD.12 Experimental laboratory colonies of dogs with conditions that mimic clinical AD have also been established.4,13–15

It’s not all genetic – environmental factors in AD

The risk of developing AD, the severity and the response to treatment are highly variable. This may be explained by complex genotypes, but it is also likely that environmental influences are important.8 Environmental factors that influence the development of canine AD are listed in Table 1.10,16,17