COMMENTARY

See related article on pg 326

Commentary on Dynamic Analysis of

Histamine-Mediated Attenuation of
Acetylcholine-Induced Sweating via
GSK3b Activation
Torsten Zuberbier1 and Margitta Worm1
Matsui et al. (2014) delineate a novel pathomechanism for attenuated sweating in
atopic dermatitis (AD). They provide evidence that acetylcholine-induced sweating can be inhibited via H1-receptor activation. This work suggests that H1
blockers may be useful in patients with AD.
Journal of Investigative Dermatology (2014) 134, 302303. doi:10.1038/jid.2013.436

The background

Atopic dermatitis (AD) is a frequent

chronic dermatological disease, with
high prevalence in northern countries,
such as those of Scandinavia, where up
to 1020% of adolescents have the disease (Ring et al., 2012a, b). Although
international treatment guidelines are
available (Ring et al., 2012a, b), AD is
a multifactorial disease and treatment is
often far from simple (Darsow et al.,
2013).
Difficulties in AD management arise
mainly from the huge heterogeneity in
disease-triggering factors (e.g., effects of
different allergens), but also from effects
of highly variable genetic backgrounds
among patients. Although genetic differences between normal individuals and
those with AD have come into focus in
recent decades and although there is
new understanding about filaggrin mutations in AD, these are useful features in
managing only a minority of patients.
On the other hand, on the basis
of the information cited above, unique
responses among subsets of patients
should now be included in the design
of clinical trials. Previously, most trials
in AD evaluated patient responses as
a simple mean of all responses instead
of identifying individual responders,

leading to potentially controversial data

and interpretations. One example has
been the debate on the usefulness of
antihistamines in treating AD. Although
many practicing dermatologists know of
patients who report good responses
to antihistamines, evidence derived
from controlled clinical studies is not
impressive. On the other hand, studies
of second-generation antihistamines
using small patient numbers did reveal
reduced SCORAD numbers and effects
on chemokine production (Furukawa
et al., 2004); the effects differed among
individual patients.
In this issue, the paper from the research
team at Osaka University, with co-workers
from Korea, may offer an explanation for unique individual responses.
The novel findings

On the basis of the observation that one

of the hallmarks of AD is dry skin with
attenuated sweating, Matsui et al.
(2014), using a novel approach, now
report a pathological mechanism that
leads to attenuated sweating.
Working with both mice and humans,
they provide evidence that acetylcholine-induced sweating can be inhibited
via H1-receptor activation. This research
is of high clinical interest, and it suggests

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

Correspondence: Torsten Zuberbier, Department of Dermatology and Allergy, Allergy-Centre-Charite,

ChariteUniversity Hospital Berlin, Schumannstrasse 20/21, Berlin D-10117, Germany.
E-mail: torsten.zuberbier@charite.de

302

Journal of Investigative Dermatology (2014), Volume 134

that histamine, most likely from mast

cells, is a major factor in AD. It has been
shown that patients with AD can have
increased histamine serum levels and
that exogenous histamine can, at least
in some patients, aggravate eczema.
The data from the present paper link
such findings, because data from
mouse models suggest clinical efficacy
for antihistamines (earlier H1- and more
recently H4) in AD (Akamatsu et al.,
2006; Maintz et al., 2006; Worm et al.,
2009).
Several publications from the 80s
have shown increased numbers of mast
cells in patients with AD, as well as
heterogeneous distributions and increased
numbers in patients with concomitant
other airway disease (Sugiura et al.,
1989). In addition, Damsgaard et al.
(1997) showed that mast cell numbers
were increased in lesional versus
nonlesional skin in AD, although there
were no correlations with severity.
Ashida and Denda (2003) reported that
a dry environment increases mast cell
numbers and histamine content in the
dermis of hairless mice. Interestingly,
both dryness and sweating have been
reported to increase itching in AD
(Chrostowska-Plak et al., 2009).
At first glance, this may seem contradictory to the results of Matsui et al.
(2014), but the opposite may be the
case. In general, AD is associated with
a reduced tendency for sweating, as
shown by Matsui et al. (2014), based
on H1 receptor activation. This may
lead to reduced insensible baseline
perspiration, which is one of the
mechanisms that keeps skin moisture
content in balance; this would add to
the well-known phenomenon of dry
skin in AD. Consequently, dry skin not
only increases the potential for itching,
but it also allows the skin to be more
prone to react to external irritants from
impaired epidermal barrier function. On
the other hand, when patients mention
that sweating increases itching, they
refer to visible amounts of sweat,
e.g., after exercise. This salty sweat
may very well induce itching merely
by irritating skin that already has
reduced barrier function. In sum, the
& 2014 The Society for Investigative Dermatology

COMMENTARY

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 patients

with AD.

work of Matsui et al. (2014) now allows

a rather compelling picture to fall into
place.
The learning points

For clinicians, this paper shows that H1

blockers may be useful in AD, but only
as an add on, with close monitoring of
responses. The second-generation antihistamines would be more useful than
first-generation antihistamines, which
are associated with a number of undesired effects, most importantly changes
in REM sleep patterns and reduced
cognitive function (Church et al., 2010).
This paper also shows that we need
better clinical trials in diseases such as
AD, which have heterogeneous population bases. Individual treatment responses
may be quite important. For investigators, the message is simple: apparently
simple minor features of a disease may
lead to novel findings; congratulations
go to Matsui et al. (2014).
CONFLICT OF INTEREST

The authors state no conflict of interest.

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Ashida Y, Denda M (2003) Dry environment
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content in dermis in hairless mice. Br J
Dermatol 149:2407
Chrostowska-Plak D, Salomon J, Reich A et al.
(2009) Clinical aspects of itch in adult atopic
dermatitis patients. Acta Derm Venereol
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Church MK, Maurer M, Simons FE et al.N. Asthma
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Damsgaard TE, Olesen AB, Sorensen FB et al.
(1997) Mast cells and atopic dermatitis.
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Darsow U, Wollenberg A, Simon D et al. E. E. T. F.
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Matsui S, Murota H, Takahashi A et al. (2014)

Dynamic analysis of histamine-mediated
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(2013) Difficult to control atopic dermatitis.

World Allergy Organ J 6:6

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Guidelines for treatment of atopic eczema
(atopic dermatitis) Part II. J Eur Acad Dermatol
Venereol 26:117693

Furukawa H, Takahashi M, Nakamura K et al. (2004)

Effect of an antiallergic drug (Olopatadine
hydrochloride) on TARC/CCL17 and MDC/
CCL22 production by PBMCs from patients with
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Sugiura H, Hirota Y, Uehara M (1989)

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Evidence for a reduced histamine degradation
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Acta Derm Venereol 89:526

See related article on pg 345

Alternative Models of Comorbidity: A

Framework for the Interpretation of
Epidemiological Association Studies
Jochen Schmitt1 and Stephan Weidinger2
Relationships between chronic diseases have emerged as major clinical, public
health and research issues. Consequently, clinical and epidemiological research
on comorbidities of skin diseases is increasingly recognized as an important tool
to understand their etiologies more fully and to capture their morbidities and
burdens. In this issue, Flohr and colleagues report a cross-sectional analysis on the
complex associations among atopic dermatitis, filaggrin loss-of-function mutations, skin barrier function, and food sensitization in exclusively breastfed infants.
When interpreting this and other association studies, various alternative models of
comorbidity should be considered as suggested by Neale and Kendler.
Journal of Investigative Dermatology (2014) 134, 303307. doi:10.1038/jid.2013.527

Comorbidity studies in dermatology

With increasing life expectancy, the

simultaneous presence of multiple pathological conditions in the form of comorbidity and multimorbidity has become
common. The term comorbidity was

coined initially to describe the occurrence of an independent medical condition in addition to an index disease
(Feinstein, 1970). In a broader understanding, the term has been used interchangeably with multimorbidity to

Center for Evidence-Based Healthcare, University Hospital Carl Gustav Carus, Technical University
Dresden, Dresden, Germany and 2Department of Dermatology, Venerology and Allergy, Excellence
Cluster Inflammation at Interfaces, University Hospital Schleswig-Holstein, Christian-AlbrechtsUniversity, Kiel, Germany
Correspondence: Jochen Schmitt, Center for Evidence-Based Healthcare, University Hospital Carl Gustav
Carus, Technical University Dresden, Fetscherstr. 74, Dresden D-01307, Germany.
E-mail: jochen.schmitt@uniklinikum-dresden.de

www.jidonline.org

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