CME Article

Submitted: 5.11.2015 DOI: 10.1111/ddg.12957

Accepted: 30.12.2015
Conflict of interest
None.

Stressed skin? – a molecular

psychosomatic update on stress-causes
and effects in dermatologic diseases

Eva M.J. Peters1, 2 Summary

(1) Psychoneuroimmunology Laboratory,
Department of Psychosomatics
­Medicine and Psychotherapy, Justus
­Liebig University, Giessen, Germany
(2) Charité Center 12 (CC12) for
Internal Medicine and Dermatology,
Universitäts­medizin – Charité, Berlin,
­Germany
Section Editor
Prof. Dr. D. Nashan, Dortmund
A pathogenetically relevant link between stress, in terms of psychosocial stress, and
disease was first described in the 1970s, when it was proven that viral diseases of mu-
cous membranes (such as rhinovirus and Coxsackie virus infections) develop faster
and more severe after stress exposure. Since then, there has been an annual increase
in the number of publications which investigate this relationship and break it down
to the molecular level. Nevertheless, the evidences for the impact of psychosocial
stress on chronic inflammatory skin diseases and skin tumors are hardly known. In
the present review, we outline current insights into epidemiology, psychoneuroim-
munology, and molecular psychosomatics which demonstrate the manifold disea-
se-relevant interactions between the endocrine, nervous, and immune systems. The
focus is on stress-induced shifts in immune balance in exemplary disorders such as
atopic dermatitis, psoriasis, and malignant melanoma. The objective of this article is
to convey basic psychosomatic knowledge with respect to etiology, symptomatolo-
gy, and therapeutic options for chronic skin diseases. Particular attention is directed
towards the underlying molecular relationships, both from a somatic to mental as
well as a mental to somatic perspective.

Introduction
Inflammatory skin diseases are often accompanied by the unpleasant sensation
of pruritus. Scratching is the consequence, and the resulting excoriations visibly
exacerbate the skin lesions, causing considerable psychosocial stress. To a certain
extent, this is also true for tumors, as they may also present with slight pruritus.
Excoriation in a malignant tumor is easily misinterpreted as ulceration, and a poo-
rer prognosis is subsequently presumed. Insomnia and an impairment of general
well-being are further distressing sequelae of chronic skin disorders. Apart from
the clearly visible and vitaly perceptable health impairment, patients suffer from
the fact that it is often impossible to avoid the trigger factors, and that the disease
course, especially in inflammatory skin disorders, but also cutaneous malignan-
cies, is often chronic and marked by unpredictable flare-ups. This is subjectively
disconcerting, and prevents adaptation to having and living with the disease.

© 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2016/1403 233
 CME Article 
Scientific work on the relationship bet-
ween psychosocial stress and dermato-
logical diseases is conducted within
the realm of psychoneuroimmunology
(PNI), molecular psychosomatics, and
psychodermatology (see also guide-
lines of the Association of the Scien-
tific Medical Societies [AWMF] or the
homepage of the Working Group for
Neuroendocrine Immunology [AKNEI]
of the German Society for Immunology
[DGFI] and of the Working Group for
Psychodermatology [APD] of the
German Society of Dermatology [DDG]).
Three possible interactions:
 stress → skin: for example, delusional
parasitosis, body dysmorphic
disorder, artifacts
 skin → stress: for example, reactive
depression, adjustment disorder,
anxiety disorder as a result of a skin
disease (such as cancer, chronic
inflammation)
 stress ↔ skin: for example, atopic
dermatitis, psoriasis, urticaria, acne,
effluvium, cancer
234 © 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2016/1403
It is therefore not surprising that psychosocial stress as a consequence of in-
flammatory skin disorders or skin cancer is a widely acknowledged fact. Many stu-
dies show that the intensity of chronic, debilitating skin symptoms such as pruritus
correlate with psychopathological conditions such as depression, anxiety, dysfun-
ctional coping behavior, dissociation, withdrawal, and helplessness [1–3]. Treat-
ment is required, but frequently the necessity to address the psychosocial distress of
chronically ill individuals is met by ill acceptance, a phenomenon that seems worth
changing both in the medical as well as in the social context. Especially against the
background of recent epidemiological and epigenetic studies, the question arises
whether a causal relationship between psychosocial stress and skin is possible, or
at least one that impacts disease severity.
Subject areas, protagonists, and goals of the
­molecular psychosomatic approach in dermatology
Scientific work on the relationship between psychosocial stress and skin diseases
is conducted within the research areas psychoneuroimmunology (PNI), molecular
psychosomatics, and psychodermatology (see also guidelines of the Association
of the Scientific Medical Societies [AWMF] http://www.awmf.org/leitlinien/detail/
ll/013-024.html or the homepage of the Working Group for Neuroendocrine Im-
munology [AKNEI] of the German Society for Immunology [DGFI] http://aknei.
com/ and of the Working Group for Psychodermatology [APD] of the German
Society of Dermatology [DDG] http://www.akpsychderm.de/). The central topic of
these research fields is the interdisciplinary scientific analysis of skin diseases in the
contex of the biopsychosocial concept and psychoneuroimmunological insights. In
general, three possible interactions exist:
 stress → skin: skin disorders which are caused by mental disease (such as de-
lusional parasitosis, body dysmorphic disorder, artifacts). Apart from psycho-
dermatology, workup and treatment of these disorders fall into the realm of
psychiatry.
 skin → stress: psychosocial stress/disorder (such as reactive depression, adjust-
ment disorder, anxiety disorder) is the result of a skin disease (including sever-
ely disfiguring diseases, malignancy, anaphylaxis). The skin symptoms are lea-
ding and psychosocial stress is merely a consequence which can be addressed
by adjuvant psychosomatic/psychotherapeutic treatment aimed at improving
patients’ quality of life.
 stress ↔ skin: genuine interrelation between psychosocial stress and somatic
aspects at the beginning and/or over the course of chronic skin diseases (such
as atopic dermatitis, psoriasis, urticaria, acne, effluvium). Understanding this
interrelation is critically relevant, not only to ensure a good quality of life of
affected patients but also for consistent therapeutic success. Close cooperation
between psychosomatic/psychotherapeutic and dermatological care is essenti-
al in order to improve both quality of life as well as disease course and severity.
The goal of the molecular psychosomatic approach is to understand the inter-
relation between stress and neuroendocrine-immune interactions from behavior to
the molecular level. If successful, diagnosis and treatment of dermatologic patients
can greatly profit from the integration of biological-somatic [4–6] and psychosoci-
al aspects [7, 8] into one unifying bio-psycho-social approach.
A physician for example, who can explain how pruritus is aggravated by
stress, which skin structures are involved, and which lifestyle factors may have an
CME Article 
The goal of this article is to improve
dermatological treatment and integrate
the bio-psycho-social approach into
routine care.
© 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2016/1403
effect on these structures, will be taken seriously by his or her patients. They will
feel part of the diagnosis and treatment process, which increases their compliance
and active contribution to the therapeutic success. This in turn improves work-­
satisfaction of their healthcare providers. A chronically ill patient who under-
stands his or her disease and learns how to cope with it, is a grateful, cooperative,
and returning patient, providing positive feed back and efficient interaction. In
other words: treatment - in the best sense of the word - takes place in the context of
the bio-psycho-social approach. The present review article discusses this treatment
approach. In the following, we will first extensively dilineate the short- and long-
term effects of stress on the release of stress mediators and present their effects on
the immune response. We will then apply this knowledge to specific disease patho-
logies and discuss the specific effects of stress in distinct neuroendocrine-immune
disease interactions.
Historical pitfalls which hamper productive
integration of molecular psychosomatic findings into
the diagnosis and treatment of skin diseases
Historically, the psychodermatological approach developed when it was disco-
vered that stress can cause increased inflammation – especially by viruses – at
the epithelial surfaces of the organism. In the 1970s, these findings initiated PNI
research. One could say that allready the first PNI experiments were ultimately
dermatological experiments. In the following decade, research activities predomi-
nantly focused on the idea that every chronic somatic disease is accompanied by
an underlying disease-specific personality structure. Accordingly, numerous pub-
lications demonstrated that psychosocail trauma (a severe loss or uncontrollable
threatening experience, such as the loss of a partner or child; experiencing severe
violence; and others) frequently occurres prior to the onset of atopic dermatitis,
psoriasis, or malignant melanoma. Also anxiety disorders and depression are often
associated with skin diseases. However, ultimately no specific disease personality
structures or specific interdependencies between one or the other mental disease
and a specific skin disease could be identified. Thus, researchers were unable to
identify an atopic dermatitis, psoriasis, or cancer personality, and interest in this
field subsided for the time being.
In the meantime, epidemiological studies have confirmed a high and rising
coincidence of psychopathological diagnoses and chronic skin disorders [9]. Among
other things, there is evidence that a low psychosocial status is associated with an
increased incidence of allergic diseases and cancer – in certain contexts even with
increased mortality. Research on psychosocial factors in skin disorders is therefo-
re once again picking up speed. This includes mental states such as anxiety and
depression, as well as more social and lifestyle factors such as low education, low
income, domestic or occupational stress, and health-damaging behavior (such as
sleep deprivation, high-calorie diet, smoking, drinking, lack of exercise) [9]. A cur-
rent systematic review of 16 publications links maternal psychosocial stress with
atopic disorders in the child [7]. Similarly, an age- and gender-adapted metaanalysis
(68,222 healthy participants of the Health Survey in England) shows that mental
strain correlates with a 41 % higher cancer mortality after 8.2 ± 3.4 years (overall
mortality: 1.2 %), including patients with malignant melanoma [10]. Here, using
a self-assessment tool (Global Health Questionnaire 12, GHQ 12), disstress was
measured at values between 6 and 12, thus indicating great mental stress. The mor-
tality in this group was compared to that of participants with lower GHQ12 score.
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 CME Article 
While there is no atopic dermatitis or
cancer personality, there is epidemiolo-
gical evidence for a high and increasing
coincidence of mental distress and
chronic skin diseases.
The stress reaction helps explain how
stress reaches the skin. Classic definiti-
on by Hans Selye: stress is a strain that
requires an adaptive response.
Stress activates the response systems
 Hypothalamus-pituitary-adrenal axis
(HPA)
 Sympathetic axis (SA)
 Cholinergic axis (CA)
 Neuropeptides and neurotrophins
Under acute stress fight or flight are
enabled by changes in memory perfor-
mance, blood flow, energy metabolism,
and many other features of the stress
response.
236 © 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2016/1403
Hence, epidemiological studies clearly show that psychosocial stress and the
development of chronic and malignant diseases of the skin are linked. It remains to
be determined how exactly stress and disease are linked in a specific context, that
is for a particular type of stress (such as acute vs. chronic stress) and a particular
skin disease (such as atopic dermatitis, psoriasis, melanoma), and which molecular
mechanisms can be made responsible.
In general, stress activates the endocrine system
and the nervous system to enable the organism’s
­adaptation to it
Various idioms in the German language illustrate the close link between psy-
chosocial distress and the state of the skin. I am “pale with fear” or “red with
shame”, it “does not give me itch” (meaning: does not bother me) or something
gets “under my skin”. These figurative idioms suggest specific neuroendocrine
activation and it’s interaction with the skin’s immune system: for example, regu-
lation of blood flow by adrenergic nerves or sensory stimulation with subsequent
neuropeptide release and mast cell activation, also known as neurogenic inflam-
mation. The attentive clinician will be able to confirm that thoroughly taking a
patient’s history frequently reveals a link between psychosocial stress situations
and a flare-up of symptoms such as pruritus (review [11]). A symptom hence pro-
vides an mint at neuroendocrine-immune processes involved that bring the stress
into the skin.
So what are the exact mechanisms involved that bring experienced the
stress into the body and, ultimately, under the skin? First, through its dense
innervation and network of blood vessels, the skin is directly linked to central
structures of the neuroendocrine stress response. These structures include the
classic stress response systems of the organism such as the endocrine system
and the nervous system, whose interactions have been intensively investigated
by PNI research for more than 40 years [12–14]. Stress thereby acts as the key
term which summarizes findings from many different fields. Since Hans Selye
it is defined as any challenge that requires an adaptive response. Hence, in its
original definition, the term does not differentiate between “good” and “bad”
stress [15].
Acute stress activates the stress response supersystems
coordinating the “fight” and “flight” response
Experimentally, an acute stress response can be triggered by skydiving or an exam
situation. The following components are involved in this response:
The endocrine system is considered the primary, efferent stress response system:
 The hypothalamus-pituitary-adrenal axis (HPA) with it’s mediators: cor-
tisol, corticotrophin-releasing hormone (CRH), and adrenocorticotropic
hormone (ACTH). Under acute stress, the HPA is responsible for cogni-
tive processes, which manifest the memory of the stress-generating situati-
on. At the same time, energy is mobilized by gluconeogenesis, lipolysis, and
insulin release; blood pressure rises and the perception of pain is suppres-
sed. Obvious cutaneous symptoms include the increase in skin temperature
due to an increase in metabolic rate as well as pain suppression under acute
stress.
CME Article 
Considering the differences between
acute and chronic stress, it is is import-
ant to note that different forms of stress
can act in different directions. Precise
understanding of protective and dest-
ructive aspects of the stress response in
a defined situation is therefore crucial
in order to appreciate the relevance of
stress for diseases such as atopic derma-
titis, psoriasis, or malignant melanoma,
and to integrate this understanding into
improved diagnostic proceedures and
treatment.
The immune system always co-reacts
when stress mediators are released.
Receptors for stress mediators can be
found on every cutaneous and skin-
infiltrating cell of the immune system.
© 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2016/1403
Along with the HPA, and mutually interacting with it, the autonomous nervous
system is activated:
 The sympathetic axis (SA) with its mediators adrenaline and noradrenaline
(NA) is responsible for the actual startle response, that is: for increased blood
pressure and heart rate; blood vessel dilation in heart, lungs, muscles; blood
vessel constriction in bowels, kidneys, skin; sweat secretion; and catabolic me-
tabolism with increased glycogenolysis, lipolysis, and protein metabolism. The
activation of this axis is easily visible on the skin by its turning pale.
Subsequently released acetylcholine exerts regulatory effects, and indicates the
­activation of another stress response system:
 The cholinergic axis (CA) with the mediator acetylcholine and its nicotinic and
muscarinic receptors regulates, for example, pulse frequency on the s­ ystemic
level and locally, body temperature through sweat secretion.
Thus, adaptive responses involving the entire organism enable fight or fight.
This reaches from a central response, which includes a “ready-to-fight mood”, to
local effects in peripheral organs such as the skin.
Chronic stress results in a switch to long-term
­adaptation: a vulnerable point
Adaptive responses to acute stress have to be distinguished from the events that occur
under chronic stress: here, adoption of a “ready-to-fight mood” is not usefull, as it is
too energy-consuming and leads to collateral damage. Instead, a change in the neuroen-
docrine profile is initiated. The release of cortisol in response to acute stressors for ex-
ample is reduced, instead, baseline secretion is increased. Hence, if a chronically stres-
sed organism encounters acute stressors, cortisol levels do not rise as much as otherwise
under acute conditions, nor do they decrease as much afterwards. At the same time, the
coupling of the SA and the HPA is lost. Under these conditions, the organism intends to
make room for long-term adaptive responses and remodelling – for example, through
neuronal plasticity – of the responsiveness of the HPA, SA, and CA to acute stress. In
a way, the stress response systems transgress to a higher level of stress responsiveness.
However, in case of very long-term stress exposure, without time for recovery
and regeneration of the responsiveness to stress, the adaptive capacity of the stress
response systems is lost. In the skin, the effects are complex and strongly affect
neuroanatomy and the immune response, as will be discussed in the following.
The immune system is reached by all stress mediators
and conveys detrimental and protective stress effects
to immune-mediated skin disorders
By now, the above-mentioned neuroendocrine stress response is well known, and
some cutaneous effects, for example through changes in energy metabolism or
circulation, are easy to comprehend. In order to understand the complex effects
of neuroendocrine stress responses in skin disorders, it is important to realize that
the immune system always co-reacts when stress mediators are released (Figure 1).
Receptors for stress mediators can be found on every cutaneous and skin-infiltra-
ting cell of the immune system. This includes the protagonists of innate immunity
such as mast cells, Langerhans cells, neutrophils, and eosinophils, as well as the
protagonists of specific adaptive immunity such as B and T cells [11, 13, 16–18].
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 CME Article 
Acute stress triggers innate and adap-
tive cellular immune responses. While
these adaptive responses effectively
eliminate new microbes and also tumor
cells, they are associated with potential
collateral damage and high energy
consumption.
238 © 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2016/1403
Figure 1  Summary of key stress response systems and their main effects on
the i­mmune response (Abbr.: SA, sympathetic axis; CA, cholinergic axis; HPAA,
­hypothalamus-pituitary-adrenal axis; NNA, neuropeptide-neurotrophin axis).
Acute stress activates the immune response
Acute psychosocial stress (such as anger) as well as short-term exposure to somatic/
physical stressors (such as physical activity, heat, cold) first results in activation of
HPA and SA (Figure 2). Getting up in the morning represents such an acute stress
exposure and raises for example cortisol levels with all the aforementioned conse-
quences. In addition, by redistributing immune cells from the blood and lymphatic
organs to peripheral organs such as the skin, the body also prepares for a “fight” on
the immunological level. Acutely elevated and then rapidly dropping cortisol levels,
which are readily detectable in sputum and serum [19], lead for example to the acti-
vation of natural killer cells, thus innate immune mechanisms, within minutes. Cy-
tokines of the T helper cell type 1 (Th1) response such as tumor necrosis factor al-
pha (TNF-alpha) or interferon-gamma (IFN-gamma) are released somewhat more
slowly but still within the first few hours. These mediators of acquired, adaptive
cellular immunity are also frequently referred to as pro-inflammatory cytokines.
This immunological set-up is supposed to ensure a rapid defense against acute
infections such as can be expected due to fight-related injuries, but is also condu-
cive to eliminating other damage-causing cells such as tumor cells. The successful
nonspecific defense against disruptive factors is thus the aim of an acute inflam-
matory response. Diseases associated with increased cellular immunity, however,
show exacerbation due to the immune system’s response to such stressors (for ex-
ample, psoriasis) (Figure 2).
Chronic stress alters the immune system’s response to
further stressors
Persistent stress over a long period of time causes changes to the stress response.
Morning cortisol rise declines and baseline secretion over the course of the day
increases as evidence of changes to the HPA under chronic stress. This altered
pattern induces changes in the response pattern of the immune response with the
CME Article 
Chronic stress causes humoral inflam-
matory responses supposed to replace
acute inflammatory responses. Howe-
ver, it has a proallergenic and proau-
toimmune effects.
© 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2016/1403
Figure 2  Acute versus chronic stress: neuroendocrine-immune interactions and
their effects on immunological health and dermatological diseases (Abbr. NK,
natural killer cells; MC, mast cells).
aim to enable adaptation to chronic stress (Figure 2). Now, cytokines are released
that suppress the initial, predominantly cellular immune response. The involved
cytokines interleukin 4 (IL-4) and IL-5 are therefor frequently referred to as an-
ti-inflammatory cytokines. Hence, immune cells are activated which recognize and
eliminate specific challenges to the immune system. These cells are part of the ad-
aptive immune response, especially of the humoral branch, which is responsible for
antibody production [13, 20] and permanently elevated endogenous cortisol levels
lead to a shift in the immune responds towards Th2 predominance.
Under chronic stress, there is a switch from innate nonspecific immunity and
an adaptive cellular, Th1-weighted response, to an adaptive Th2 profile and predo-
minance of humoral immune responses. This has advantages for the organism. An
acute inflammatory response has to be turned off again once the acute challenge
has been eliminated. In this situation, there is time to “clean up” and develop a
customized response to the – now known – stressor. This saves energy and avoids
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collateral damage caused by excessive inflammatory reactions. At the same time,

The endogenous stress response is
not to be confused with the effects
of pharmacological intervention with
­corticosteroids.
however, the innate nonspecific immune response is now suppressed, and the or-
ganism is blind to new microbes and tumor cells. Furthermore, errors occur in
the distinction between “foreign” and “self”, so that specific immune responses
are aimed at targets such as allergens or the bodies own proteins (autoimmunity),
which normally should not pose a threat to the organism. Thus, under chronic
stress, anti-inflammatory cytokines should rather be classified as pro-autoimmune
and pro-allergenic. This neuroendocrine-immune set-up is therefore relevant for all
chronic skin diseases which are predominantly characterized by an excessive hu-
moral immune response (for example, allergies, autoimmune diseases) (Figure 2).
With respect to this stress modulation of the HPA, it is important to under-
stand that the immunological changes caused by an endogeneous neuroendocrine
stress response are not the same as the immunosuppressive effects of therapeutic
corticosteroid dosages applied in dermatology, or of the HPA changes that result
from chronic, long-term stress exposure. Similar to the latter, high-dose corticos-
teroid therapy causes general immunosuppression (reduced lymphocyte prolifera-
tion, decreased antigen presentation) associated with a breakdown of the immune
defense. Both in the lay and specialist literature, stress is often only associated with
this extreme immunosuppressive effect of high doses of corticosteroids and HPA
alterations while it represents only the most severe form, and occurs rarely outside
treatment with corticosteroids or chronic exhaustion.
Recently, the hypothesis of the anti-inflammatory CA has attracted a lot of
attention. Indeed, acetylcholine is able to suppress the release of TNF-alpha from
different cells of the immune system [21, 22], and there is evidence that the CA
affects the barrier function of the skin under stress conditions. It is, however, still
unknown which role this observation plays with respect to the interaction between
stress and skin disorders.

Neurogenic inflammation is key to the damaging

­effects of stress

Apart from the described effects of the HPA, SA, and CA, mast cells seem to play
a key role in excessive immunological responses to stress. Already Hans Selye, who
coined the stress term, described mast cells as pivotal immune cells when it comes
to recognizing disturbances (microbes, toxins, physical stress) at the interface bet-
ween organism and environment. Only with the discovery of mediators released by
sensory nerve fibers did one realize however that mast cells are in close contact with
signaling nerve fibers, and thus may be activated also by psychosocial stress [23].
Until this discovery, it had been assumed that the only function of sensory
nerve fibers was to sense. The fact that these nerve fibers – through the release
of neuropeptides such as substance P (SP) – also assume efferent tasks revolutio-
nized the field of neuroendocrine-immune interactions. The existence of another
stress axis was proposed which includes neuropeptides (SP, calcitonin gene-related
peptide [CGRP]) and neurotrophins (nerve growth factor [NGF] or brain-derived
neurotrophic factor [BDNF]) as mediators.
Systemically, SP modifies the stress response by inhibiting the HPA; locally, by
increasing sensory perception and pruritus. In an animal model, stress leads to an
increased number of contacts between peptidergic nerve fibers and mast cells [24],
which subsequently results in increased mast cell degranulation. Stress-induced SP
release from nerve fibers sensitizes mast cells for further stimuli. Under the influ-
ence of SP, mast cell degranulation is significantly more pronounced in response

240 © 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2016/1403
CME Article 
Under stress, neurogenic inflammation
may take a visibly and perceptible more
severe course and aggravate respective
skin disorders.
© 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2016/1403
to immunological triggers such as IgE [25]. Stimulation with neuropeptides can
directly prompt mast cells to release their best known secretagogue: histamine.
Furthermore, neuropeptides very individually and specifically stimulate the release
of individual cytokines from mast cells (for example, SP induces TNF-alpha [26]),
and activates endothelial cells, with subsequent T-cell infiltration of the skin [27]).
Hence, mast cells interacting with peptidergic nerve fibers can trigger nons-
pecific inflammation in response to psychosocial stress, and initiate cellular im-
munity. Thereby, neurotrophins supervise the interaction between mast cells and
peptidergic nerve fibers under stress by regulating neuronal plasticity and contacts
between nerve fibers and mast cells [28, 29]. In case neurogenic inflammation is
activated by a stimulus that is actually harmless, severe adverse effects may ensue.
An impressive example of this are anaphylactoid reactions, which are marked by
an acute inflammatory response, potentially culminating in death.
In an animal model, stress also results in a greater number of contacts between
peptidergic nerve fibers and antigen-presenting cells, which is followed by increa-
sed migration of dendritic cells into skin draining lymph nodes [30]. Subsequent
neuroendocrine-immune interactions in organs of the lymphatic system (lymph
nodes, spleen) lead to additional cytokine production [IL-2, IL-10) and increased
antibody production, as well as T-cell proliferation and infiltration of inflamed
skin [31, 32]. Clinically, this manifests as pruritus, erythema, and edema of the
skin. In response to stimulus, neurogenic inflammation can thus take a visibly and
perceptibly more severe course, and through this effect play a role in skin disor-
ders, which are characterized by the respecitve symptoms.
Molecular basis for the interaction between stress/
psychological stress and impaired skin function:
skin and brain speak the same chemical language
Neurogenic inflammation illustrates quite impressively how stress mediators are
able to affect the skin. All other mediators of the aforementioned stress response
systems, including the transcription factors and their regulators (e.g. NF K B), epi-
genetic regulatory mechanisms (e.g. demethylases, histon deacetylases), as well as
activating (e.g. prohormone convertases) and deactivating enzymes (e.g. proteases)
are not only present in the central nervous system but also in the structural and
functional cells of the skin itself. By producing mediators, which are traditionally
exclusively attributed to the brain, keratinocytes, fibroblasts, sebocytes, melanocy-
tes, Merkel cells, and endothelial cells create their own local neuroendocrine mili-
eu. At the same time, these cells exhibit a broad spectrum of corresponding recep-
tors and signaling cascades.
It would be beyond the scope of this article to present the complete neuroen-
docrine repertoire for every structural cell of the skin; for detailed and still current
information, the reader is referred to other sources [11, 13, 33–42]. It is, however,
important to realize that the spectrum of possible responses to stress mediators is
very broad for any given skin inhabitating cell type. Not only are keratinocytes
able to produce CRH, ACTH, and cortisol but they also produce noradrenaline,
the neurotrophins NGF and BDNF, as well as numerous other stress mediators
such as the neuropeptide SP. At the same time, they also have receptors for all
of these stress mediators. The corticosteroid receptors on keratinocytes and skin-­
based cells of the immune system for example regulate proliferation and inflamma-
tion. Thus, by producing cortisol, keratinocytes can play a role in wound healing
[43] as well as in tumor growth and chronic inflammation, both in an autocrine
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The skin has its own local counterpart
to the central stress response.
Via cytokines and immune cells, inflam-
mation induces sickness behavior and
depression.
Psychological trauma frequently occurs
in the last six months prior to the onset
of a dermatological disease, and is
associated with high serum levels of
pro-inflammatory cytokines.
242 © 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2016/1403
and a paracrine fashion. In case of chronic cortisol exposure, however, the corti-
costeroid receptors may be epigenetically regulated by methylation, resulting in
cellular desensitization.
The systemic stress response is thus complemented by a local stress response.
Hence, both local and systemic stimuli converge in the skin, and there are likely
stress-induced changes of and effects on the immune response, which can become
pathogenetically relevant in skin disorders.
Peripheral inflammation has feedback effects on the brain
The above described neuroendocrine-immune set-up, which can be observed un-
der persistent psychosocial stress (e.g. such as long-term unemployment, home
care, burdensome conflicts and problems), corresponds to that seen in chronic
inflammation or under continuous somatic/physical stress. An analogous and
reciprocal, pathogenetically relevant relationship between chronic psychosocial
stress and chronic immunologically mediated diseases can therefor be assumed.
Stress-enhanced inflammation, in turn, can affect the brain, since neuroendocrine
mediators and cytokines released during inflammation cause a feeling of malaise
and sickness behavior (for example, interferon-alpha). First of all, such sickness
behavior resulting from chronic inflammation and characterized, for example, by
reduced physical and social activity, can be understood as an energy-saving adjust-
ment measure. It allows the body to perform specific adjustment (Th2 r­ esponse)
and repair measures (tissue regeneration) in an energy-efficient manner. In the
long run, however, it can barely be clinically distinguished from endogenous­
depression.
Various stress mediators mutually influence each others central effects. For
example, SP slows down the HPA response, which can accelerate the switch to-
wards a chronic stress response in the brain. Immunocytes matured in peripheral
lymphatic organs also contribute to the modification of the central stress response.
For example, peripherally derived monocytes which trigger anxiety behavior are
found in the brains of stressed mice [44]. Are the mice splenectomized, there are
neither monocytes in the brain nor do the animals exhibit anxiety-like behavior.
Thus, anxiety-inducing monocytes in the brain are primed in the periphery, in this
case in the spleen.
How can psychosocial stressors, which are able to
­exert neuroendocrine-immune effects, be identified?
The most common forms of disease-relevant psychosocial disstress certainly in-
clude traumatization, anxiety, and depression. Anamnestic assessment of patient’s
biographical history identifies traumatic life events, which show high coincidence
with atopic dermatitis, psoriasis, or skin tumors, and usually occur within appro-
ximately six months prior to the onset of the skin disease. Of note, several studies
have shown that there is a close neuroendocrine-immune relationship between
trauma and inflammation; high serum IL-6 levels at the time of an accident are
associated with posttraumatic stress disorder (PTSD). Vice versa, an intense expe-
rience of stress at the time of trauma predestines for high IL-6 levels six months
later. Thus, there is an interrelation between pro-inflammatory response and psy-
chosocial trauma and its consequences for mental health.
Patients with skin disorders sometimes exhibit feelings of stress and emotional
impairment that go far beyond the responses that can usually be expected, indicating
CME Article 
A dermatological diagnosis may have
traumatising effects independent of
disease severity and prognosis.
Anxiety is a frequent epiphenomenon
of chronic skin diseases, indicating a
hyperactive sympathetic axis.
Depression is common in dermatological
diseases, and indicates a chronically
altered HPA and immune imbalance.
© 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2016/1403
that the diagnosis itself can have traumatising effects. The consequences for social
functions and performance are drastic. Here, the patient’ own assessment can si-
gnificantly differ from that of the treating physicians [45]. What counts is always
the patients’ self-assessment. As doctors, we are prone to consider atopic dermatitis
a burdensome but rather harmless disease, since it is not life-threatening. By con-
trast, a diagnosis of “melanoma metastasis” is expected to entail a fatal outcome,
and great psychosocial stress is readily anticipated. Numerous studies, however,
have shown that the extent to which stress is experienced is independent of disease
severity and prognosis.
The term “anxiety disorders” subsumes a variety of psychological disorders.
Common to all of them, anxiety is the dominant symptom, as is the case in panic
disorder (triggered by specific psychological stress), social phobia, and trauma-
induced PTSD. Hightend anxiety however may also result from exposure to a
succession of mild psychosocial challenges (e.g personal conflicts, worries, anxi-
ous expectations), which by themselves do not impose great trouble but sum up
to constant distress, especially when enhanced by the presence of a chronic so-
matic disorder. Hence stress experiences are frequently enhanced by the presence
of dermatological diseases. From a neuroendocrine perspective, this is associated
with increased responsivity of the SA to stress; this results in an increased level
of arousal in response to an anxiety-inducing event, with immunological effects
initially similar to those of an acute stress response. If there is recurrent stress wi-
thout phases of recovery, the response eventually corresponds to a chronic stress
response.
Apart from addictive disorders, the resultant anxiety disorders are the most
frequent mental disorders observed in skin patients, with a prevalence of appro-
ximately 20 % [9]. Examples include panic attacks in response to anaphylactic
shock, or social phobia in case of disfigureing diseases such as atopic dermatitis
or cancer. Clinically, it is important to distinguish between neurotic anxiety and
phobic anxiety. The former is diffuse and felt “close to the body”. Patients are
prone to somatization. For example, in a stressful work situation, patients report
recurrent pruritus in varying skin regions and adamantly suspect allergens at the
work place to be the trigger, without being able to identify the occupational situ-
ation as culprit. The second type of anxiety is generally brought on by a specific
event; however, the anxiety response is disproportionate to the trigger. For examp-
le, following the excision of a melanoma which was ulcerated and slightly pruritic,
any future pruritic lesion is feared to be a melanoma, even if it is not pigmented or
oozing. Both types of anxiety lead to avoidance and safety strategies, which may
significantly impair functioning in daily life.
Depression primarily occurs in chronic, somatically stressful diseases such as
acne, psoriasis, atopic dermatitis, lupus erythematosus, cancer, chronic recurrent
urticaria, prurigo, and others. From a neuroendocrine-immune perspective, de-
pression is similar to chronic stress (see above). Interestingly, the neuroendocri-
ne-immune set-up in depression corresponds to that of chronic inflammation. This
is especially true with respect to cytokines and inflammatory cascades that induce
sickness behavior, such as IFN-gamma. Clinically, patients are characterized by a
depressed mood, pronounced fatigue, diminished motivation and activity, diminis-
hed interest and ability to concentrate, diminished ability to feel joy, diminished
ability to express changes in emotion, diminished self-esteem and self-confidence,
as well as feelings of guilt or thoughts about one’s own worthlessness, culmina-
ting in self-destructive thoughts (risk of suicide). In addition, there are associated
vegetative symptoms (such as trouble sleeping, agitation, anhedonia, digestive
­problems, paresthesia, unstable blood pressure, headache, dizziness, susceptibility
243
 CME Article 
Adaptation to acute stress is more suc-
cessful with good preparation: a good
night's sleep, physical fitness, a good
diet, avoidance of coffee, alcohol, and
cigarettes, and others. Situational and
mental preparation is also helpful.
In atopic dermatitis, stress exacerbates
Th2 response and neurogenic inflam-
mation, and consequently disease
severity.
244 © 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2016/1403
to infection, loss of libido a.o.), which can be easily inquired about, and frequently
help address hidden distress.
Specific examples of neuroendocrine-immune
­interactions: from successful adaptation to tumor
­development
Athletes are a good example of successful adaptation. If you do not want to flee
from an attacker but engage in the fight, you do not only need a “ready-to-fight
mood”, a rapidly pumping heart and readily available energy but also an immune
response that is able to effectively fight unknown pathogens in case of injury (see
remarks on acute stress above). One may prepare for such a situation with a good
night’s sleep, physical fitness, and a diet that is able to quickly release energy.
Although frequently used for stress regulation in our culture, substances such as
coffee, alcohol, cigarettes, – even though stimulating –also need to be avoided,
since they are full of side effects. Another important factor is mental training,
which helps enter a situation with great alertness and controlled fear. All these
measures are immunologically effective. Every athlete knows that permanent ten-
sion and poor preparation can be an obstacle to success, and also leads to injuries
and infections.
The immunopathogenesis of atopic dermatitis is predominantly characterized
by breakdown of the skin’s barrier, excessive Th2 immunity, and neurogenic in-
flammation. Under psychosocial stress, both of physical and psychosocial origin,
approximately 50 % of patients experience an exacerbation. Posttraumatic stress,
anxiety, and depression correlate with increased pruritus and elevated IgE levels.
In general, exacerbation of skin lesions after acute stress sets in within 24 hours.
This is the time required for the buildup of a Th2 response and neuronal plasticity
resulting in increased neurogenic inflammation. Moreover, stress exposure in utero
or during early development is associated with high IgE levels, Th2 cytokines, and
a higher incidence of atopic dermatitis symptoms [46]. Adults with atopic derma-
titis show an altered responsiveness of the HPA and SA to acute stress, correspon-
ding to that of healthy individuals under chronic stress: hyporeactivity of the HPA
and hyperreactivity of the SA [47]. This can further aggravate the Th2 imbalance.
Maladaptive coping strategies such as increased scratching (triggering of neuron-
al plasticity and neurogenic inflammation) and the use of addictive substances
(caffeine, nicotine, and others trigger the stimulation of the SA and CA) interfere
with these processes, and can further exacerbate the inflammation. In analogy
to this, it has therefore been inferred that stress and an “unhealthy” lifestyle can
exacerbate and possibly even cause atopic dermatitis [47].
Despite the amount of available data apparently supporting this hypothesis,
the question remains unresolved whether a mental disorder in atopic dermatitis
patients is cause or consequence of the skin disorder. Animals stressed by 24-hour
noise exposure exhibit a disturbed barrier function [48], and the sensitivity to
stress has been shown to be increased through an increased number of contacts
between peptidergic nerve fibers and mast cells and a higher likelihood of neuroge-
nic inflammatory responses. Similar to the events in healthy skin described above,
in this animal model, the increased neurogenic inflammation in response to stress
– especially in case of allergic inflammation–can even be detected in the serum
by elevated SP and NGF levels. At the same time, if stress and allergic inflamma-
tion coincide, the reaction is not stopped by mast cell proteases. Subsequently,
stress leads to endothelial fenestration and activation as well as eosinophilia. In an
CME Article 
In psoriasis, stress potentially enhances
proinflammatory cytokine release and
neurogenic inflammation.
With respect to skin cancer develop-
ment, a weak cellular immune response
and a strong T regulatory response, as
observed in chronic psychosocial stress,
are unfavorable.
© 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2016/1403
­animal model, this results in significant disease exacerbation, with an allergic in-
flammation approximately twice as severe as without stress exposure [27], as well
as in increased sensitivity to further stimuli [28].
Remarkably, clinical observation shows that atopic dermatitis patients can
also benefit from stressful periods in life. Following a major earthquake in Ja-
pan, the majority of patients with atopic dermatitis experienced not only stress but
also the expected exacerbation. However, one in ten showed clinical improvement.
How can that be explained? Here, again, animal models have yielded interesting
findings. When animals are repeatedly exposed to noise stress during the sensiti-
zation phase but are also allowed to recover from the exposure, peptidergic nerve
fibers increasingly make contact with antigen-presenting cells in the epidermis. If a
neuropeptide such as SP is repeatedly released in this context, these cells ensure an
increased number of T regulatory cells in the dermis, thereby significantly impro-
ving the allergic inflammation [49]. Thus, PNI provides evidence for the potential
efficiency of stress-training measures.
Immunopathologically, psoriasis is primarily characterized by chronic exces-
sive Th1/Th17 immunity and neurogenic inflammation. Frequently new onset of
psoriasis is preceeded by stress as well as stressful life events [50]. Characteristically,
psoriasis patients also show lower quality of life and a more frequent occurrence of
depression, especially in case of disease flare-ups. To date, whether there are neu-
roendocrine-immune effects of stress involved has not been studied in as much detail
as in atopic dermatitis. What is known is that there is an increased release of norad-
renaline under acute stress, thereby raising the number of CD4+ cells in peripheral
blood. Furthermore, psoriatic lesions exhibit an increased number of peptidergic
nerve fibers showing contacts with mast cells. Hence, neurogenic inflammation can
again be triggered by stress. It is therefore likely that acute stressors play a key role
in intervening in the predominant pathogenetic elements of psoriasis, TH1/TH17
immunity and neurogenic inflammation; however, there is as yet no definitive proof.
In malignancies, the immunological situation associated with more rapid di-
sease progression is different than in chronic inflammation. Thus, the checkpoints
at which stress can interfere with a tumor-controlling immune responses also dif-
fer. Tumor cells are not foreign to the organism. To identify them as dangerous
thus requires an immune response that reacts to disturbances in a nonspecific way.
Many publications on the association between cancer, stress (usually operationali-
zed as depression), and the immune response consequently show that natural killer
cells and an increase in cellular immune responses under acute stress may have
tumor-preventive effects [51, 52]. Increased numbers of regulatory T cells under
chronic stress, on the other hand, have tumor-permissive effects. Experiments in
which mice kept in standard conditions (small cage with litter, food, and water)
were compared to mice kept in an enriched environment, yielded instructive re-
sults. Under the latter conditions, mice had significantly more space and materi-
al for species-appropriate behavior. Under enriched environment conditions, the
stress level decreased, and the neurotrophin BDNF, a mediator showing low levels
in depressed patients, increased, while pulmonary metastases of injected melano-
ma cells were drastically reduced [53].
State of care: how frequent is the need for psychodermatological care?
Despite the strong evidence for their relevance, psychosomatic and psychosocial
aspects are rarely addressed by doctors and patients alike (lack of experience in
dealing with disstress, fear of stigmatization, lack institutional structures) [54].
However, dermatologists are frequently the first – and sometimes also the only
245
 CME Article 

In everyday practice, there is a large
discrepancy between the need for
psychosocial support and its detecti-
on. These aspects should be openly
­addressed.
– medical professionals contacted by patients with chronic skin diseases. The res-
ponsibility to identify relevant psychosocial distress and refer affected patients to
specialized care as soon as possible is therefor often in their hands only. Timely
referral is essential for therapeutic success, especially in order to prevent potential
chronification of mental symptoms (e.g. PTSD after a cancer diagnosis).

The diagnosis of skin diseases initially

­includes a ­medical history aimed at detecting
­psychoimmunologically relevant distress
Further psychosomatic workup in skin patients including molecular and cellular
mechanisms involved, always starts with a medical history, which suggests an in-
teraction between psychosocial stress, neuroendocrine-immune disturbance, and
skin disorder. Thus, taking a general dermatological history always includes the
assessment of psychosocial distress (such as living and partnership situation, occu-
pational and financial situation, personal and occupational conflicts, psychologi-
Psychosocial case history in cal trauma etc.), including their temporal relationship to onset and exacerbation of
­dermatological patients: the skin disease. In detail, this includes:
 
factors accompanying the  taking an exact history of the development and course of the skin lesions
­development of skin lesions, (when and in which situation were lesions first noticed; what was the situation
  
placement of the disease course in the like; what were the reactions of the social environment; when did flare-ups
biographical context of the patient, occur?),
  
inferring a possible pathogenic inter-  placing the disease course in a biographical context (do biographical events
action between stress and symptoms or chronic life-stress exposures coincide with disease exacerbations; under
with the PNI concept in mind, which everyday stresses can exacerbations or improvements of disease activi-
  
ruling out other somatic causes. ty be observed; what are the consequences of beiing diseased for the patient’s
living conditions; which measures taken by the patient him- or herself are
helpful?),
 derivation of potential pathogenetically relevant interactions between symp-
toms and stress with the PNI concept in mind (e.g. “More severe pruritus
precedes the exacerbation of your atopic dermatitis skin lesions, every time
you are exposed to this kind of stress. It is possible that stress-induced neuro-
genic inflammation is responsible for this.”),
 ruling out other somatic causes,

In the psychodermatological
consultation, attitude is important:
nonjudgmental, neutral, open.
The patients should have the opportunity to describe the symptoms in their
own words. Often, the way a patient describes his or her pruritus illustrates what
role it plays in the patients suffering and offers a starting point for a discussion
as to whether the pruritus also has a function other than drawing attention to a
somatic disorder. The aim is to engage in a conversation based on facts, not to
convict the patient of potential psychosocial implications of their skin disease.
If psychosocial triggering or aggravating psychosocial factors appear present or
great psychosocial burden is caused by the skin disease, this should be directly
addressed. This should be done without judgment and by summarizing the facts,
for example: “I have noticed that these events and the increased pruritus occurred
at the same time.” or by posing an open question such as: “Is it possible that you
are experiencing the diagnosis as a great burden?”. The patient’s resources should
also be inquired, for example: “Is there a person you trust and with whom you
can discuss the diagnosis?” The following steps can be placed into the hands of
experts who can initiate and carry out specialist treatment (such as a psycho-
somatic consultant, psychosomatic outpatient clinics etc.). However, one of the

246 © 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2016/1403
CME Article 
Preparation for the discussion of
­important news include:
  creating a value and undisturbed
situation
  meeting the patient on same level
  inviting the patient to bring a confident
 inform, that “bad news” will be
­discussed.
© 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2016/1403
objectives of primary somatic care is to first ascertain whether these interventions
are required.
Note: the consultation itself signifies stress
What remains to be considered, is that each patient consultation itself generates
stress. Let us consider skin patients, for example cancer patients, confronted with
a new diagnosis. This corresponds to an acute psychosocial stress situation. A
short and clearly structured time period until the diagnosis is being told and a
well-prepared manner of informing the patient about the diagnosis in an approp-
riate environment enable the patient to maintain a certain amount of control over
the situation and reduce anxious waiting. These measures significantly improve the
patient’s subsequent dealing with his or her disease [52]. Respective preparation
include: making an appointment for the communication of the diagnosis; seeking
out a quiet, undisturbed room that possibly allows for a view out of the window;
creating a situation that suggests equality of the participating partners in dialog
for example by not placing a table between physician and patient; inviting the
patient to bring a trusted person; making the announcement that unpleasant news
are going to be communicated, and much more [55]. With regard to preparation
for and organization of the communication of “bad news”, it is easy to compre-
hend why creating an appropriate environment can improve the disease experience.
It increases the capacity to absorb the news, and prevents the development of a
posttraumatic disorder. With regard to the neuroendocrine-immune level, this also
favors an adaptive response with profound consequences. A rapid rise and drop in
stress mediators such as adrenaline/noradrenaline and cortisol, as common to an
adaptive stress response, can be expected. On the level of the immune response,
this is associated with a transient activation of the innate immune system – thus,
the immune response that eliminates tumor cells; however, the development of a
detrimental chronified stress response does not take place.
Psychometric methods can be used to objectify the
psychsocial stress leads taken from the patient’s
­history, and initiate the discussion about them
While methods such as screening for psychosocial needs with the help of stan-
dardized queastionairs can be helpful in uncovering the need for psychosocial
care, they cannot replace addressing this need and dealing with stress on a pro-
fessional level. In order to objectify psychosocial stress and find a starting point
to address it, self-report test instruments can be used in addition to taking to the
patient and taking a detailed patient history. The use of these instruments is also
helpful in documenting the disease course and the effects of its treatment. They
allow to better document triggering factors and to illustrate therapeutic success
with respect to its psychosocial effectiveness. In this context, it is helpful to
graduate in primary psychosomatic care both with respect to ones personal ad-
vancement as a doctor and with respect to getting good and appropriately payed
work done. Moreover, it pays off having an active working relationship with ne-
arby psychosocial care providers who routinely use such diagnostic instruments
(for example, paper-pencil or computer-adapted questionairs for psychooncolo-
gic need screening, quality of life, pathologic anxiety, symptoms of depression
etc.). Both questionaires specifically developed for dermatologic patients and ge-
neral test instruments for self-assessment of mental health and stress can be used
247
 CME Article 
Diagnostic measures in psychoder-
matology may include self-assessment
questionnaires addressing mental
health and distress.
In psychodermatology, the entire
spectrum of psychotherapeutic
procedures, relaxation techniques, and
psychoeducative methods is available.
248 © 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2016/1403
for these purposes. In addition, there are questionairs developed for physicians
which are helpful, to document for example the assessement of a psycho-­
oncological need suspected in a patient in a structured way. Here we list a
­number of frequently used questionnaires:
 The Dermatological Quality of Life Index [DLQI] is well validated in Ger-
man-speaking countries. With ten questions it evaluates to what extent the
skin disorder has had an impact on the patient’s quality of life within the past
seven days.
 The Standardized Questionnaire on Quality of Life (SF-12) assesses physical
and mental health.
 The Symptom Checklist (SCL-90-R) is widely used and very well validated. By
means of 90 items, it assesses somatic as well as mental symptoms within the
past seven days on as the dimensions compulsiveness, insecurity social cont-
acts, depression, anxiety, aggressiveness/hostility, phobias, paranoid thinking,
and psychoticism.
 The Beck Depression Inventory (BDI) is aimed at the severity of depressive
symptoms.
 The State-Trait Anxiety Inventory (STAI) assesses anxiety as a trait and as a
state.
 In order to determine the need for psycho-oncological care, the Hornheider
Questionnaire and the Questionnaire for Cancer Patients (FBK-R10) can be
employed. The former has a very low threshold in determining general psycho-
social need; the latter also assesses the fear of disease progression.
 With regard to experiencing and handling stress, the stress handling questi-
onnaire (SVF 120) and the Patient Health Questionnaire (PHQ) Stress can be
recomended.
All these questionnaires are available from the respective authors or distribu-
ting publishers, and include instructions for their evaluation and interpretation.
Therapeutically, the entire spectrum of psychosocial
and psychotherapeutic methods is available
Dermatologists are frequently the first and only professionals addressed by severely
psychosocially stressed patients, both if the skin disorder causes stress, or if the
skin disorder coincides with other sources of stress but is the only problem for
which the patient is seeking help. In this context, it is vital to not only treat the skin
disorder as best as possible but also to recognize and address the distress so that
affected patients can be timely refered to competent experts. Not only does this
spare patients from a lot of distress, it also helps increase the number of satisfied
patients in the physician’s practice and lower the frequently high costs associated
with unrecognized mental comorbidities and their delayed treatment. If there is a
consulting and liaison service under the same roof with the pacticing dermatolo-
gist’s office, referral is simple. Discussing these comorbidities with colleagues is
uncomplicated, and patients do not have to go to a specialized institution and be
exposed to stigmatization. If there is no liaison service, the nearest psychosomatic
outpatient clinic is a good contact point. They generally provide expeditious access
to a first consultation to determine the nature of the distress and to explore poten-
tial therapeutic options.
In case stress-associated symptoms are suspected, health insurance companies
frequently offer helpful services for first intervention, which include lists of approved
CME Article 

relaxation courses. If patients require more than just an initial p ­ sychosomatic

consultation or relaxation techniques, they may seek probative psychothera-
peutic consultation from one or more office-based psychotherapists. Health in-
surance companies in Germany currently pay for five probative sessions before
an ­application for reimbursement of psychotherapy has to be filed. Searching a
therapist on the Internet, for example, using information provided by Medical As-
sociations or Associations of Statutory Health Insurance Physicians is useful in
finding a suitable therapist in this narrow market.
The following information can aid in making a decision on which therapeutic
method is suitable for subsequent treatment:
 Psychoanalysis is a therapeutic method aimed at uncovering dysfunctional
psychological development in early childhood and it’s effects on the current
psychodynamics of the patient. This type of therapy is considered the most
effective, but often takes years and sometimes uncovers conflicts that cannot
be resolved.
 Psychodynamic psychotherapy is the most frequently recommended form of
psychotherapy. In a conversation-based setting, current psychological constel-
lations and their development are discussed in order to find new perspectives
and restore the patient’s ability to act.
 In behavioral therapy, the most commonly practiced form of psychotherapy,
specific fear-provoking situations are sought out. By learning to tolerate these
situations for example with the help of relaxation methods, the anxiety is dis-
connected from it’s triggers, and alternative responses are trained. Classically,
among other things, a fear hierarchy is established and subsequently used for
desensitization (by moving up the hierarchy, beginning with the least fear-pro-
voking situation). Cognitive behavioral therapy is characterized by the modi-
fication of negative interpretations. It is especially helpful in the treatment of
scratching disorders, body dysmorphic and somatoform disorders, maladapti-
ve coping behavior, and others.
 Psychoeducation and disease-specific training programs impart information
and knowledge of the disease and their associated social, psychological, so-
matic, and neuroendocrine-immune aspects.
 Pharmacotherapy should always be left to experts. However, it is important to
note that psychotherapy, for example in depression, is usually more effective
than pharmacotherapy.

Conclusion
Not only does a chronic somatic disease imply psychosocial stress with its own
dynamics, psychosocial stress also manifests itself in the form of somatic symp-
toms. The psychosocial and somatic dimensions are therefore equivalent in their
pathogenetic relevance, and should accordingly be both included in dermatolo-
gic disease models and respective therapeutic approaches. Here we summarize the
mounting evidence that stress in the sense of psychosocial stress alters the ability of
the skin – through neuroendocrine and immune changes – to respond to environ-
mental challenges. Especially in case of skin damage, due for example to a chronic
disease such as atopic dermatitis, there is a more rapid and severe exacerbation of
the skin disease under psychosocial stress. It therefore seems obvious: Anything
that reduces stress must also reduce inflammation. This possibly also plays a role
in the development of skin tumors. An adequate stress response can be trained and
allows for a rapid and efficient rise and drop of its mediators. With this in mind: A
small stressor a day keeps the therapist away.

© 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2016/1403 249
 CME Article 

Correspondence to References
1 Schut C, Mollanazar NK, Kupfer J et al. Psychological Interventions in the Treatment of
PD Dr. med. Eva Peters Chronic Itch. Acta Derm Venereol. 2015 Jun 15. [Epub ahead of print].
Psychoneuroimmunology 2 Kuo CL, Chen CY, Huang HL et al. Increased risk of major depression subsequent to a
­L aboratory first-attack and non-infection caused urticaria in adolescence: a nationwide popula-
Department of Psychosomatic tion-based study. BMC Pediatr 2014; 14: 181.
­Medicine and Psychotherapy 3 Metz M, Grundmann S, Stander S. Pruritus: an overview of current concepts. Vet
­Dermatol 2011; 22: 121–31.
University Hospital Giessen and
4 Brehler R, Stocker B, Grundmann S. Allergy – current insights into prevention and
Marburg GmbH
diagnostic workup of immediate-type allergy and treatment of allergic rhinoconjunc-
Aulweg 123 tivitis. J Dtsch Dermatol Ges 2015; 13: 747–62; quiz 63–4.
35385 Giessen 5 Bonnelykke K, Sparks R, Waage J, Milner JD. Genetics of allergy and allergic
­sensitization: common variants, rare mutations. Curr Opin Immunol 2015; 36: 115–26.
Germany
6 Bousquet J, Anto JM, Wickman M et al. Are allergic multimorbidities and IgE
E-mail: eva.peters@eva-peters.com ­polysensitization associated with the persistence or re-occurrence of fetal type 2
­signaling? The MeDALL hypothesis. Allergy 2015; 70: 1062–78.
7 Andersson NW, Hansen MV, Larsen AD et al. Prenatal maternal stress and atopic
­diseases in the child: a systematic review of observational human studies. Allergy
2016; 71(1): 15–26.
8 Kolves K, Barker E, De Leo D. Allergies and suicidal behaviors: A systematic literature
review. Allergy Asthma Proc 2015; 36: 433–8.
9 Dalgard FJ, Gieler U, Tomas-Aragones L et al. The psychological burden of skin dis-
eases: a cross-sectional multicenter study among dermatological out-patients in 13
European countries. J Invest Dermatol 2015; 135: 984–91.
10 Russ TC, Stamatakis E, Hamer M et al. Association between psychological distress and
mortality: individual participant pooled analysis of 10 prospective cohort studies. BMJ
2012; 345: e4933.
11 Peters EM, Liezmann C, Klapp BF, Kruse J. The neuroimmune connection interferes
with tissue regeneration and chronic inflammatory disease in the skin. Ann N Y Acad
Sci 2012; 1262: 118–26.
12 Rohleder N. Acute and chronic stress induced changes in sensitivity of peripheral
inflammatory pathways to the signals of multiple stress systems – 2011 Curt Richter
Award Winner. Psychoneuroendocrinology 2012; 37: 307–16.
13 Dhabhar FS. Psychological stress and immunoprotection versus immunopathology in
the skin. Clin Dermatol 2013; 31: 18–30.
14 Peters EM. Stress and the molecular basis of psychosomatics. Hautarzt 2013; 64: 402–9.
15 Selye H. The Physiology and Pathology of Exposure to STRESS. ACTA. INC. Medical
Publishers, Montreal, 1950.
16 Madva EN, Granstein RD. Nerve-derived transmitters including peptides influence
­cutaneous immunology. Brain Behav Immun 2013; 34: 1–10.
17 Theoharides TC, Alysandratos KD, Angelidou A et al. Mast cells and inflammation.
­Biochim Biophys Acta 2012; 1822: 21–33.
18 Suarez AL, Feramisco JD, Koo J, Steinhoff M. Psychoneuroimmunology of psychologi-
cal stress and atopic dermatitis: pathophysiologic and therapeutic updates. Acta
Derm Venereol 2012; 92: 7–15.
19 Staufenbiel SM, Penninx BW, Spijker AT et al. Hair cortisol, stress exposure, and mental
health in humans: a systematic review. Psychoneuroendocrinology 2013; 38: 1220–35.
20 Cox SS, Speaker KJ, Beninson LA et al. Adrenergic and glucocorticoid modulation of
the sterile inflammatory response. Brain Behav Immun 2014; 36: 183–92.
21 Huston JM, Tracey KJ. The pulse of inflammation: heart rate variability, the choliner-
gic anti-inflammatory pathway and implications for therapy. J Intern Med 2011; 269:
45–53.
22 Yamamoto T, Kodama T, Lee J et al. Anti-allergic role of cholinergic neuronal pathway
via alpha7 nicotinic ACh receptors on mucosal mast cells in a murine food allergy
model. PLoS One 2014; 9: e85888.
23 Singh LK, Pang X, Alexacos N et al. Acute immobilization stress triggers skin mast cell
degranulation via corticotropin releasing hormone, neurotensin, and substance P: A
link to neurogenic skin disorders. Brain Behav Immun 1999; 13: 225–39.

250 © 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2016/1403
CME Article 

24 Peters EM, Kuhlmei A, Tobin DJ et al. Stress exposure modulates peptidergic

­innervation and degranulates mast cells in murine skin. Brain Behav Immun 2005; 19:
252–62.
25 Church MK, Okayama Y, el-Lati S. Mediator secretion from human skin mast cells
­provoked by immunological and non-immunological stimulation. Skin Pharmacol
1991; 4(Suppl 1): 15–24.
26 Okabe T, Hide M, Koro O, Yamamoto S. Substance P induces tumor necrosis factor-
alpha release from human skin via mitogen-activated protein kinase. Eur J Pharmacol
2000; 398: 309–15.
27 Pavlovic S, Daniltchenko M, Tobin DJ et al. Further exploring the brain-skin connec-
tion: stress worsens dermatitis via substance P-dependent neurogenic inflammation
in mice. J Invest Dermatol 2008; 128: 434–46.
28 Peters EM, Michenko A, Kupfer J et al. Mental stress in atopic dermatitis – neuronal
plasticity and the cholinergic system are affected in atopic dermatitis and in response
to acute experimental mental stress in a randomized controlled pilot study. PLoS One
2014; 9: e113552.
29 Peters EM, Liezmann C, Spatz K et al. Nerve growth factor partially recovers inflamed
skin from stress-induced worsening in allergic inflammation. J Invest Dermatol 2011;
131: 735–43.
30 Joachim RA, Handjiski B, Blois SM et al. Stress-induced neurogenic inflammation in
murine skin skews dendritic cells towards maturation and migration: key role of inter-
cellular adhesion molecule-1/leukocyte function-associated antigen interactions. Am J
Pathol 2008; 173: 1379–88.
31 del Rey A, Besedovsky HO. Sympathetic nervous system-immune interactions in auto-
immune lymphoproliferative diseases. Neuroimmunomodulation 2008; 15: 29–36.
32 Liezmann C, Stock D, Peters EM. Stress induced neuroendocrine-immune plasticity: A
role for the spleen in peripheral inflammatory disease and inflammaging? Dermatoen-
docrinol 2012; 4: 271–9.
33 Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES. The sympathetic nerve – an integrative in-
terface between two supersystems: the brain and the immune system. Pharmacol Rev
2000; 52: 595–638.
34 Black PH. Stress and the inflammatory response: a review of neurogenic inflammation.
Brain Behav Immun 2002; 16: 622–53.
35 Seiffert K, Granstein RD. Neuroendocrine regulation of skin dendritic cells. Ann N Y
Acad Sci 2006; 1088: 195–206.
36 Arck PC, Slominski A, Theoharides TC et al. Neuroimmunology of stress: skin takes
center stage. J Invest Dermatol 2006; 126: 1697–704.
37 Botchkarev VA, Yaar M, Peters EM et al. Neurotrophins in skin biology and pathology.
J Invest Dermatol 2006; 126: 1719–27.
38 Grando SA, Pittelkow MR, Schallreuter KU. Adrenergic and cholinergic control in the
biology of epidermis: physiological and clinical significance. J Invest Dermatol 2006;
126: 1948–65.
39 Cevikbas F, Steinhoff A, Homey B, Steinhoff M. Neuroimmune interactions in allergic
skin diseases. Curr Opin Allergy Clin Immunol 2007; 7: 365–73.
40 Harvima IT, Nilsson G, Naukkarinen A. Role of mast cells and sensory nerves in skin
inflammation. G Ital Dermatol Venereol 2010; 145: 195–204.
41 Zmijewski MA, Slominski AT. Neuroendocrinology of the skin: An overview and selec-
tive analysis. Dermatoendocrinol 2011; 3: 3–10.
42 Dhabhar FS, Malarkey WB, Neri E, McEwen BS. Stress-induced redistribution of im-
mune cells – from barracks to boulevards to battlefields: a tale of three hormones –
Curt Richter Award winner. Psychoneuroendocrinology 2012; 37: 1345–68.
43 Cirillo N, Prime SS. Keratinocytes synthesize and activate cortisol. Journal of cellular
biochemistry 2011; 112: 1499–505.
44 Wohleb ES, McKim DB, Shea DT et al. Re-establishment of anxiety in stress-sensitized
mice is caused by monocyte trafficking from the spleen to the brain. Biol Psychiatry
2014; 75: 970–81.
45 Nolte S, van der Mei SH, Strehl-Schwarz K et al. Comparison of patient-reported need
of psycho-oncologic support and the doctor’s perspective: how do they relate to

© 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2016/1403 251
 CME Article 

disease severity in melanoma patients? Psychooncology 2015 Dec 3. [Epub ahead

of print].
46 Pincus M, Arck P. Developmental programming of allergic diseases. Chem Immunol
Allergy 2012; 98: 70–84.
47 Buske-Kirschbaum A, Ebrecht M, Hellhammer DH. Blunted HPA axis responsiveness to
stress in atopic patients is associated with the acuity and severeness of allergic inflam-
mation. Brain Behav Immun 2010; 24: 1347–53.
48 Curtis BJ, Plichta JK, Blatt H et al. Nicotinic acetylcholine receptor stimulation impairs
epidermal permeability barrier function and recovery and modulates cornified enve-
lope proteins. Life Sci 2012; 91: 1070–6.
49 Pavlovic S, Liezmann C, Blois SM et al. Substance P is a key mediator of stress-induced
protection from allergic sensitization via modified antigen presentation. J Immunol
2011; 186: 848–55.
50 Hunter HJ, Griffiths CE, Kleyn CE. Does psychosocial stress play a role in the exacerba-
tion of psoriasis? Br J Dermatol 2013; 169: 965–74.
51 Dhabhar FS, Saul AN, Daugherty C et al. Short-term stress enhances cellular immunity
and increases early resistance to squamous cell carcinoma. Brain Behav Immun 2010;
24: 127–37.
52 Peters EM. Psychological support of skin cancer patients. Br J Dermatol 2012;
167(Suppl 2): 105–10.
53 Cao L, Liu X, Lin EJ et al. Environmental and genetic activation of a brain-adipocyte
BDNF/leptin axis causes cancer remission and inhibition. Cell 2010; 142: 52–64.
54 Gieler U, Niemeier V, Kupfer J et al. Psychosomatic dermatology in Germany: a survey
of 69 dermatologic clinics. Hautarzt 2001; 52: 104–10.
55 Kaplan M. SPIKES: a framework for breaking bad news to patients with cancer. Clin J
Oncol Nurs 2010; 14: 514–6.

252 © 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2016/1403
CME Article 

Fragen zur Zertifizierung durch die DDA

1. Welche Antwort ist korrekt? Psychi- c) Anpassungsreaktion mit dem c) paternal, direktiv.
sche Belastung bei dermatologischer Ziel, die Homöostase wieder d) beratend, lösungsorientiert.
Erkrankung tritt vorwiegend auf … ­herzustellen. e) geschlossen, fokussiert, effizient.
a) bei atopischer Dermatitis. d) Reaktion des Organismus auf
b) bei Akne. eine Anforderung, die eine
c) bei Psoriasis. ­Anpassungsreaktion erforderlich 9. Zu den Selbstauskunftsfragebögen,
d) bei Melanom. macht. die zur Erfassung von psychosozialer
e) bei allen Dermatosen mit chroni- e) eine akute Schreckreaktion. Belastung bei dermatologischen
schem, unvorhersehbarem Verlauf. Erkrankungen eingesetzt werden
­können, zählen nicht:
5. Zu den neuroendokrinen a) der DLQI und der SF-12
2. Welche Antwort ist korrekt? ­Veränderungen bei akutem Stress b) die SCL-90-R
­Häufige psychische Erkrankungen bei ­zählen nicht: c) der BDI
dermatologischen Erkrankungen sind … a) Immunosuppression d) der TAS
a) Angsterkrankungen. b) rascher Cortisol-Anstieg e) der FBK-R10
b) Erkrankungen des depressiven c) rascher Cortisol-Abfall
­Formenkreises. d) Noradrenalin-Ausschüttung
c) posttraumatische Belastungs­ e) Substanz-P-Ausschüttung 10. Zu den möglichen
störung. ­Therapieoptionen krankheitsrele-
d) Stress im täglichen Leben. vanter psychosozialer Belastung bei
e) alle oben genannten Punkte. 6. Zu den immunologischen ­dermatologischen Erkrankungen
­Veränderungen bei chronischem Stress ­gehört nicht:
zählen nicht: a) Schulungsprogramme
3. Welche Antwort ist korrekt? Die a) TH2-Antwort b) Wait-and-See-Strategie
Ursache für die häufige Assoziation b) neurogene Entzündung c) Erlernen und Praktizieren von
zwischen chronischen Dermatosen c) Immunosuppression ­Entspannungstechniken
und psychosozialer Belastung sind … d) humorale Immunantwort d) Gesprächstherapie
a) wechselseitig, d. h. in beide Richtun- e) Dominanz von Zytokinen wie IL-4 e) Verhaltenstherapie
gen, von der somatischen Belastung und IL-5
auf psychosozialen Belastung wir-
kend und umgekehrt, möglich.
b) ausschließlich hohe psycho- 7. Zur Basisdiagnostik dermatologi-
soziale Belastungen durch die scher Patienten gehört nicht:
­Hauterkrankung. a) die genaue Anamnese der
c) ausschließlich hohe somatische ­Entstehung der Hautläsionen
Liebe Leserinnen und Leser,
Belastung durch die Hauterkrankung. b) eine körperliche Untersuchung
der Einsendeschluss an die DDA für
d) vor allem Stigmatisierung der c) die Einordnung des
­Krankheitsverlaufs in den diese Ausgabe ist der 18. April 2016.
­Patienten.
­biographischen Kontext Die richtige Lösung zum Thema
e) vor allem Unverständnis im Umfeld
der Patienten. d) eine Zuschreibung psychosozialer „Systemic therapy of metastatic
Ursachen ­melanoma“ in Heft 12 ­(December 2015)
e) die Feststellung hinreichender und ist: (1a, 2c, 3e, 4c, 5b, 6e, 7d, 8e, 9c, 10d).
4. Welche Antwort ist korrekt? weiterer somatischer Ursachen Bitte verwenden Sie für Ihre Einsen-
Die Stressreaktion ist nach Hans Selye dung das aktuelle Formblatt auf der
definiert als … folgenden Seite oder aber geben Sie
a) Reaktion auf eine hohe Überlastung. 8. Welche Antwort ist korrekt? Die Ihre Lösung online unter http://jddg.
b) Anpassung des internen Milieus ärztlichen Haltung in der Anamnese ist … akademie-dda.de ein.
an eine sich ständig verändernde a) symptomorientiert, somatisch.
Umwelt. b) offen, wertfrei, neutral.

© 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2016/1403 253