Commentary on ‘‘Dynamic Analysis ofHistamine-Mediated Attenuation ofAcetylcholine-Induced Sweating viaGSK3b Activation’’Torsten Zuberbier1 and Margitta Worm1

Matsui et al. (2014) delineate a novel pathomechanism for attenuated sweating inatopic dermatitis (AD). They provide evidence that acetylcholine-induced sweat-ing can be inhibited via H1-receptor activation. This work suggests that H1blockers may be useful in patients with AD.

Journal of Investigative Dermatology (2014) 134, 302–303. doi:10.1038/jid.2013.436

The background

Atopic dermatitis (AD) is a frequentchronic dermatological disease, withhigh prevalence in northern countries,such as those of Scandinavia, where upto 10–20% of adolescents have the dis-ease (Ring et al., 2012a, b). Althoughinternational treatment guidelines areavailable (Ring et al., 2012a, b), AD isa multifactorial disease and treatment isoften far from simple (Darsow et al.,2013).

Difficulties in AD management arisemainly from the huge heterogeneity indisease-triggering factors (e.g., effects ofdifferent allergens), but also from effectsof highly variable genetic backgroundsamong patients. Although genetic differ-ences between normal individuals andthose with AD have come into focus inrecent decades and although there isnew understanding about filaggrin muta-tions in AD, these are useful features inmanaging only a minority of patients.

On the other hand, on the basisof the information cited above, uniqueresponses among subsets of patientsshould now be included in the designof clinical trials. Previously, most trialsin AD evaluated patient responses asa simple mean of all responses insteadof identifying individual responders,

leading to potentially controversial dataand interpretations. One example hasbeen the debate on the usefulness ofantihistamines in treating AD. Althoughmany practicing dermatologists know ofpatients who report good responsesto antihistamines, evidence derivedfrom controlled clinical studies is notimpressive. On the other hand, studiesof second-generation antihistaminesusing small patient numbers did revealreduced SCORAD numbers and effectson chemokine production (Furukawaet al., 2004); the effects differed amongindividual patients.

In this issue, the paper from the researchteam at Osaka University, with co-workersfrom Korea, may offer an expla-nation for unique individual responses.

The novel findings

On the basis of the observation that oneof the hallmarks of AD is dry skin withattenuated sweating, Matsui et al.(2014), using a novel approach, nowreport a pathological mechanism thatleads to attenuated sweating.

Working with both mice and humans,they provide evidence that acetylcho-line-induced sweating can be inhibitedvia H1-receptor activation. This researchis of high clinical interest, and it suggests

that histamine, most likely from mastcells, is a major factor in AD. It has beenshown that patients with AD can haveincreased histamine serum levels andthat exogenous histamine can, at leastin some patients, aggravate eczema.The data from the present paper linksuch findings, because data frommouse models suggest clinical efficacyfor antihistamines (earlier H1- and morerecently H4) in AD (Akamatsu et al.,2006; Maintz et al., 2006; Worm et al.,2009).

Several publications from the 80shave shown increased numbers of mastcells in patients with AD, as well asheterogeneous distributions and increasednumbers in patients with concomitantother airway disease (Sugiura et al.,1989). In addition, Damsgaard et al.(1997) showed that mast cell numberswere increased in lesional versusnonlesional skin in AD, although therewere no correlations with severity.Ashida and Denda (2003) reported thata dry environment increases mast cellnumbers and histamine content in thedermis of hairless mice. Interestingly,both dryness and sweating have beenreported to increase itching in AD(Chrostowska-Plak et al., 2009).

At first glance, this may seem contra-dictory to the results of Matsui et al.(2014), but the opposite may be thecase. In general, AD is associated witha reduced tendency for sweating, asshown by Matsui et al. (2014), basedon H1 receptor activation. This maylead to reduced insensible baselineperspiration, which is one of themechanisms that keeps skin moisturecontent in balance; this would add tothe well-known phenomenon of dryskin in AD. Consequently, dry skin notonly increases the potential for itching,but it also allows the skin to be moreprone to react to external irritants fromimpaired epidermal barrier function. Onthe other hand, when patients mentionthat sweating increases itching, theyrefer to ‘‘visible’’ amounts of sweat,e.g., after exercise. This salty sweatmay very well induce itching merelyby irritating skin that already hasreduced barrier function. In sum, the

See related article on pg 326COMMENTARY

1Department of Dermatology and Allergy, Allergy-Centre-Charite, Charite—University Hospital Berlin,Berlin, Germany

Correspondence: Torsten Zuberbier, Department of Dermatology and Allergy, Allergy-Centre-Charite,Charite—University Hospital Berlin, Schumannstrasse 20/21, Berlin D-10117, Germany.E-mail: torsten.zuberbier@charite.de

302 Journal of Investigative Dermatology (2014), Volume 134 & 2014 The Society for Investigative Dermatology

work of Matsui et al. (2014) now allowsa rather compelling picture to fall intoplace.

The learning points

For clinicians, this paper shows that H1blockers may be useful in AD, but onlyas an ‘‘add on’’, with close monitoring ofresponses. The second-generation anti-histamines would be more useful thanfirst-generation antihistamines, whichare associated with a number of unde-sired effects, most importantly changesin REM sleep patterns and reducedcognitive function (Church et al., 2010).

This paper also shows that we needbetter clinical trials in diseases such asAD, which have heterogeneous popula-tion bases. Individual treatment responsesmay be quite important. For investiga-tors, the message is simple: apparentlysimple minor features of a disease maylead to novel findings; congratulationsgo to Matsui et al. (2014).

CONFLICT OF INTERESTThe authors state no conflict of interest.

REFERENCES

Akamatsu H, Makiura M, Yamamoto N et al.(2006) The effect of fexofenadine on pruritusin a mouse model (HR-ADf) of atopic derma-titis. J Int Med Res 34:495–504

Ashida Y, Denda M (2003) Dry environmentincreases mast cell number and histaminecontent in dermis in hairless mice. Br JDermatol 149:240–7

Chrostowska-Plak D, Salomon J, Reich A et al.(2009) Clinical aspects of itch in adult atopicdermatitis patients. Acta Derm Venereol89:379–83

Church MK, Maurer M, Simons FE et al.N. AsthmaEuropean (2010) Risk of first-generation H(1)-antihistamines: a GA(2)LEN position paper.Allergy 65:459–66

Damsgaard TE, Olesen AB, Sorensen FB et al.(1997) Mast cells and atopic dermatitis.Stereological quantification of mast cells inatopic dermatitis and normal human skin.Arch Dermatol Res 289:256–60

Darsow U, Wollenberg A, Simon D et al. E. E. T. F.European Task Force on Atopic Dermatitis

(2013) Difficult to control atopic dermatitis.World Allergy Organ J 6:6

Furukawa H, Takahashi M, Nakamura K et al. (2004)Effect of an antiallergic drug (Olopatadinehydrochloride) on TARC/CCL17 and MDC/CCL22 production by PBMCs from patients withatopic dermatitis. J Dermatol Sci 36:165–72

Maintz L, Benfadal S, Allam JP et al. (2006)Evidence for a reduced histamine degradationcapacity in a subgroup of patients with atopiceczema. J Allergy Clin Immunol 117:1106–12

Matsui S, Murota H, Takahashi A et al. (2014)Dynamic analysis of histamine-mediatedattenuation of acetylcholine-induced sweat-ing via GSK3b activation. J Invest Dermatol134:326–34

Ring J, Alomar A, Bieber T et al. (2012a)Guidelines for treatment of atopic eczema(atopic dermatitis) part I. J Eur Acad DermatolVenereol 26:1045–60

Ring J, Alomar A, Bieber T et al. (2012b)Guidelines for treatment of atopic eczema(atopic dermatitis) Part II. J Eur Acad DermatolVenereol 26:1176–93

Sugiura H, Hirota Y, Uehara M (1989)Heterogeneous distribution of mast cellsin lichenified lesions of atopic dermatitis.Acta Derm Venereol Suppl (Stockh) 144:115–8

Worm M, Fiedler EM, Dolle S et al. (2009)Exogenous histamine aggravates eczema in asubgroup of patients with atopic dermatitis.Acta Derm Venereol 89:52–6

Clinical Implications� A novel pathomechanism is proposed for the attenuated sweating found

in patients with atopic dermatitis (AD).

� Sweating can be inhibited via H1-receptor activation.

� The use of H1 blockers is a novel approach to treating some patientswith AD.

Alternative Models of Comorbidity: AFramework for the Interpretation ofEpidemiological Association StudiesJochen Schmitt1 and Stephan Weidinger2

Relationships between chronic diseases have emerged as major clinical, publichealth and research issues. Consequently, clinical and epidemiological researchon comorbidities of skin diseases is increasingly recognized as an important toolto understand their etiologies more fully and to capture their morbidities andburdens. In this issue, Flohr and colleagues report a cross-sectional analysis on thecomplex associations among atopic dermatitis, filaggrin loss-of-function muta-tions, skin barrier function, and food sensitization in exclusively breastfed infants.When interpreting this and other association studies, various alternative models ofcomorbidity should be considered as suggested by Neale and Kendler.

Journal of Investigative Dermatology (2014) 134, 303–307. doi:10.1038/jid.2013.527

Comorbidity studies in dermatology

With increasing life expectancy, thesimultaneous presence of multiple patho-logical conditions in the form of comor-bidity and multimorbidity has becomecommon. The term ‘‘comorbidity’’ was

coined initially to describe the occur-rence of an independent medical con-dition in addition to an index disease(Feinstein, 1970). In a broader under-standing, the term has been used inter-changeably with ‘‘multimorbidity’’ to

See related article on pg 345

1Center for Evidence-Based Healthcare, University Hospital Carl Gustav Carus, Technical UniversityDresden, Dresden, Germany and 2Department of Dermatology, Venerology and Allergy, ExcellenceCluster ‘Inflammation at Interfaces’, University Hospital Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany

Correspondence: Jochen Schmitt, Center for Evidence-Based Healthcare, University Hospital Carl GustavCarus, Technical University Dresden, Fetscherstr. 74, Dresden D-01307, Germany.E-mail: jochen.schmitt@uniklinikum-dresden.de

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