Clinics in Dermatology (2013) 31, 707–711

Psychological factors in skin diseases: Stress and skin: Factsand controversiesEdith Orion, MDa,b,⁎, Ronni Wolf, MDa

aThe Dermatology Unit, Kaplan Medical Center, Rehovot, Israel, 76100bThe Psychodermatology Clinic, Kaplan Medical Center, Rehovot, Israel, 76100

Abstract Psychological stress (PS) has long been related to many common skin diseases and conditions,thought to be the cause of their onset or aggravation. Although clinical experience is often inconcordance with this notion, apparently scientific proof can sometimes be challenging rather thanstraight forward. Although many data have been published, it appears that not enough good statisticalevidence exists to support them. The difficulty in validating beyond a doubt the stress–skin interactionshas rendered some skepticism among physicians.

The gap between clinical expertise and problematic clinical research data has led scientists to bypassthe need to tackle the question directly by searching the evidence in basic science.© 2013 Elsevier Inc. All rights reserved.

Stress and skin: The paradigm

Skin diseases, especially the more common ones, such aspsoriasis, atopic dermatitis, and alopecia areata, are widelyassociated with psychosocial problems, such as mood andanxiety disorders, basically as a result of the skin conditionitself.1 Stress also is widely considered the most popularpsychological etiology for the onset, exacerbation, andreoccurrence of many skin conditions2 by lay people andpatients, as well as by physicians. Many patients report suchan association to their doctors, and as a result, many doctorsask directly for stress and stressful life events when takingtheir patients' disease history, thus anchoring this connectionin their patients' minds.

Despite this widespread belief that PS leads to disease, thebiomedical community remains skeptical of this conclusion.3

⁎ Corresponding author. Fax: +972 3 6436086.E-mail address: eorion@013.net (E. Orion).

0738-081X/$ – see front matter © 2013 Elsevier Inc. All rights reserved.http://dx.doi.org/10.1016/j.clindermatol.2013.05.006

What do we mean when we say“psychological stress”?

The presence of a force that threatens to disrupt theorganism's homeostasis is perceived as a stressor.4 PS occurswhen an individual perceives that environmental demandstax or exceed his or her adaptive capacity.3 PS is a physio-logic process. The human body and mind react to stress byactivating an array of physiologic and behavioral centralnervous system and peripheral adaptive responses, which, ifinadequate or excessive and/or prolonged, may affectpersonality development and behavior, and may haveadverse physiologic consequences.5,6 The principal effectorsof the stress system include corticotropin-releasing hormone,arginine vasopressin, and glucocorticoids, also known as thehypothalamic–pituitary–adrenal (HPA) axis, and the cata-cholamines norepinephrine and epinephrine.5 Cortisol, theprimary effector of HPA activation, regulates a broad rangeof physiologic processes, including anti-inflammatory re-sponses, carbohydrate metabolism, and gluconeogenesis.3

708 E. Orion, R. Wolf

The glucocorticoids and catecholamines affect majorimmune functions such as antigen presentation, leukocytesproliferation and traffic, secretion of cytokines and anti-bodies, and shifts between T-helper (Th)1 and Th2 re-sponses,5 thus having the potential to affect chronicinflammatory skin diseases.

When physicians and patients talk about stress in relationto skin diseases, they usually refer to “chronic PS,” which isknown to have adverse effects on health, favor progression ofinfections, and alter immunity.7

Stress and skin: Can the relationshipbe measured?

If the psychophysiologic relations between stress and skinconditions are so obvious in everyday clinical practice, it isnot surprising that the literature is packed with numerouscase reports, case series, and many studies trying to provethis connection,2,8 whereas new studies keep appearing inprint every other day.

How can one prove that what most patients and doctorsaccept and acknowledge is really true? If this stress–skinconnection is so obvious in clinical practice, why do we havesuch a large body of work that, at least in part, repeats itself?After all that is said and done, does research really prove thisconnection beyond a doubt? Unlike other areas in dermatol-ogy, where one can quantitatively measure, for example, theeffect of a drug or a procedure on a tissue, in the field ofpsychosomatic medicine other measuring tools are used.These research tools have their limits, thus opening the doorto skepticism among a vast majority of physicians who areused to rely on other standards of research.

Stress measurements

The effect of stress on skin conditions and diseases hasbeen mentioned numerous times in the medical literature inthe form of case reports and case series,9 but an objectiveresearch tool was needed in order to prove this alleged effect.As stress is a key concept in psychosomatic medicine,measurements of stress were much investigated and muchdebated.10 Apparently, there is no consensus as to how itshould be measured. Over time, measuring stress wasdeveloped in basically two major “pathways”: (1) measuringexternal stressors in terms of environmental “objective”conditions and life events, and (2) measuring the person'sown reaction to stress, the individual's sense of control, andcoping ability.10

The “environmental pathway,” which historically devel-oped first, focuses on more specific external events orexperiences that are commonly associated with considerableadaptive demands from the individual, with an emphasis onthe objective stressfulness of such events.10 The secondpathway focuses on the psychology of the individum:

individual's subjective stress experiences and his or herevaluation of his or her own ability to cope with theperceived stress posed by the events or experiences.8,10

The tools by which stress is measured are questionnairesand interviews; therefore, their limitations (bias, culturaldifferences, etc.) are inherent. Many questionnaires weredeveloped over the past decades in an attempt to measurestress. Each “pathway” or “tradition” has its own researchquestionnaire that was changed and evolved over the years tomake them better and more accurate10; nevertheless, eachtype of stress measurement has its own drawbacks asresearch tools in psychosomatic medicine,11 thus giving riseto skepticism and disparagement by some clinicians andresearchers.

The environmental pathway records stress exposure bygiving the participants lists of critical life events; they areasked to report whether they have experienced any of theevents during a defined period. For each change, a score isassigned based on population studies, and a total unit sumcan be calculated.12 The life events structured interviewswere later introduced allowing the understanding of thecontext in which life events occur.10 By using these tools,stress research has shown an inconsistent picture of theeffects of life events or daily hassles on health.

Empirical studies have shownmany examples in which anexperience of accumulated or chronic stress led to physicalhealth problems, whereas others could not predict illness tothe same extent10; moreover, in addition to life events, othersources of stress such as daily hassles, as well as enduringeconomic, work, health, or family problems, are not includedin the checklist of life event questionnaires or interviews, andthey require a specific measurement instrument. Also, bydefinition, not all possible life events can be included in aquestionnaire. That is, in part, the reason why, historically,stress definitions have become more strongly focused on thesubjective reactions to external events or demands ratherthan on objective events, and new questionnaires weredeveloped to measure “perceived stress.” These question-naires aimed at putting the focus on the individual'ssubjective perception and emotional response,11,13 and theyfocus on a more cognitive appraisal of stress and theindividual's perceived control and coping capabilities.

Also, of interest is the fact that most research connectingstress and skin diseases (basically psoriasis and atopicdermatitis, but also some other skin conditions), was doneretrospectively, thus is prone to biased recall. Evidence fora prospective relationship between stressors and diseaseoutcome was only scarcely investigated, and in a very limitedextent.14,15 Although biased recall may not be a problem inthe format of prospective studies, suggestibility of patientstoward their symptoms may well be, so theoreticallyimperfections can be an integral part also in prospectivestudies.

Picardi et al,8 in their eye-opening concise criticaloverview on stress measurements in skin diseases state that“although a great number of papers on this subject have been

709Psychological factors in skin diseases: Stress and skin: Facts and controversies

published, unfortunately there appears to be a paucity ofcontrolled studies adopting standardized methods formeasuring stress.” We believe that although this is a trueproblem, even in the best of hands, implementing the mostmeticulous study design, there always will be drawbacks andpitfalls inherent to the tools used. Picardi et al8 also statedthat after critically reviewing all data, the role of stressfulevents in psoriasis, alopecia areata, atopic dermatitis, andurticaria is probably confirmed.

Apparently, there are limits to clinical research in this field,as probably exist in other fields of psychosomatic medicine aswell. These limits, as well as the technical problems inconducting perfect clinical trials measuring stress (or otherparameters in psychodermatology), should be acknowledged.Obviously, when conducting such a trial, attention should begiven to every aspect in the patient's life (eg, skin condition,general health, stressful events, protective and vulnerabilityfactors, etc.),8 as well as to the setting in which the study isconducted, the interaction with researchers, and so on.Countless parameters should be taken into consideration,thus making such a perfect trial almost impossible to perform.In our opinion, these difficulties and limitations should notdiscredit the large body of research that was done and will bedone in years to come, but rather encourage us to judge itwith adifferent perspective than we are used to.

Effect of stress on skin: Laboratory research

The “biological pathway” is a third way to prove the effectof stress on the skin. It focuses on the activation of certainphysiologic systems in response to PS, with an emphasis onthe mechanism by which environmental demands may betranslated into biological changes in the body.8 Surprisingly,rather little research was done using the physiologicmediators of stress (ie, cortisol and catacholamines), althoughseveral studies tested serum cortisol levels as possible stressmarkers in psoriasis, and low basal cortisol levels weremeasured in patients with severe atopic dermatitis.16,17

Instead of measuring the stress hormone levels in patientswith skin diseases, there is a growing tendency to understandthis potential effect through laboratory basic research.Understanding the damage that stress implies on the skinin some skin diseases can help us understand the extent andthrough what mechanisms this psychological, somewhatelusive term, acts. The effect of psychological stress on theepidermal barrier integrity is in the focus of research in thepast several years. These studies can prove that stress indeedaffects the skin by bypassing the need to use the “imperfect”tools of psychosomatic research.

Stress can affect skin permeability in animals. Studies inrodents, for example, found that imposition of differentforms of PS provoked an abnormality barrier homeostasis,18

thus leading the way to studies in humans. Later, it wasproved that stress can affect skin permeability in humans as

well. Acute PS can inhibit recovery of skin barrier functionin humans, as physiologic stress does,19 as well as affect skinpermeability homeostasis, and so on.8 Stress also can affectthe antimicrobial properties of the epidermal barrier.18

Sustained PS compromises host defenses against bacterialand viral infections in humans and in experimentalanimals.20,21 The implications of all these findings areobvious considering psoriatic or atopic skin.

Although serious research is being done in this field, manykey issues of understanding the exact mechanisms of theeffect of stress on epidermal barrier still need to be elucidated;nevertheless, it reinforces the validation of “skin–mind”connection, using another perspective on the issue, byimplying research tools that are more familiar to cliniciansthat are less “comfortable” with psychosomatic medicine.

Understanding vulnerability to stress: Who is asusceptible to stress?

In recent years, more studies are done focusing on thenext obvious questions: Can we understand why somepatients are more resilient to stress than others? Can we mapthe major “roads” that lead to stress susceptibility?14,22,23

Can we find the common psychosocial denominators amongpatients developing specific skin conditions?

Indeed, these questions reflect the simple fact thatscientists already have accepted the assumption that stressis a true factor in the development and progression of someskin conditions, and based on that established knowledge,progression of research is on its way.

Basically, stressful events are thought to influence thepathogenesis of a physical disease by causing negativeaffective states (eg, feeling of anxiety and stress, as well asdepression), which in turn exert direct effects on biologicalprocesses and/or behavioral patterns that influence disease.24

Exposure to chronic stress is considered themost toxic becauseit is most likely to result in long-term or permanent changes inthe emotional, physiologic, and behavioral responses that caninfluence susceptibility to disease development and course.24

A number of factors have been implied so far to affect theindividual psychological vulnerability to disease. Early lifeevents may theoretically render the individual morevulnerable to the effects of stress in later life,25 as wasshown in animal models. Traumatic psychological eventshave consistently resulted in development of physiologicvulnerability such as increased HPA axis activation.25 Thispathway was not explored much in dermatologic patients,although some preliminary trials were done among patientswith psoriasis and atopy.22,26

Mapping vulnerability rendered, for example, a correla-tion between high levels of worrying and scratching and theeffect of stressors on the skin disease in psoriatic patients14;validation of the role of family dysfunction in the onset or theexacerbation of psoriasis, alopecia, and atopic dermatitis23;

710 E. Orion, R. Wolf

alexithymia, insecure attachment, and poor social supportwere found to increase susceptibility to vitiligo, possiblythrough deficits in emotion regulation or reduced ability tocope effectively with stress.27 Also, children and adolescentswith alopecia areata were found more often to be members ofa single-parent family and perceive less expressivenesswithin their family.28

Evidence-based medicineand psychodermatology

The evidence-based medicine (EBM) movement aroseout of concern that many patients were receiving ineffectivetreatments that were grounded in conventional practices,clinical intuitions, or practitioner idiosyncrasies rather thanscientific evidence.29 This concern is still prevalent amongmany dermatologists when discussing psychodermatologybecause many believe that some aspects in psychodermatol-ogy (stress-related diseases, being one of them) have notbeen investigated properly.

Sackett et al have defined EBM as the conscientious,explicit, and judicious use of current best evidence in makingdecisions about the care of individual patients. The practiceof EBM means integrating individual clinical expertise withthe best available external clinical evidence from systematicresearch.30

Clinical practice relies on EBM for the production ofpractice guidelines and the adoption of specific therapeuticinterventions.29 In other words, EBM deals with treatmentsrather than with etiology (although the connection of the twois obvious). Apparently, EBM is not the appropriate term tobe used by “psychodermatology-deniers” when arguingstress' role in skin conditions.

Has psychodermatology research evaluated the effective-ness of stress reduction in the management of skin diseases?Surprisingly, it appears that researchers show more enthu-siasm in proving psychological difficulties to be an etiologicfactor in the onset, exacerbation, or reoccurrence of skindiseases, but much less enthusiasm in finding whetherpsychological therapies can ameliorate them.

Searching the medical literature, one can find only limiteddata concerning psychotherapy or psychopharmacologyinterventions in skin conditions; most of it is preliminaryreports and case series. To date, we still do not know enoughabout how to deal with this issue, although ironically this isthe most important and practical question.

Psychosomatic medicine and psychodermatology:The clinician's angle

Psychosomatic medicine is a specialty field that cutsacross many specialties and is concerned with assessment

and treatment of psychosocial variables in the setting ofmedical disease. Psychosomatic medicine has evolved somuch, that it can now appreciate a wider spectrum of factorsaffecting individual vulnerability to all types of disease:recent and early life events, chronic stress and allostatic load,personality, psychological well-being, health attitudes, andbehaviors.31 It provides a comprehensive framework for amore “holistic” consideration of patient care. Psychoderma-tology, a division of the latter, also has evolved tremendouslyand can now offer a wider view and understanding of thepatient suffering from skin disease. Psychodermatology nolonger deals with mere “stress,” but acknowledges a broaderrange of factors such as family dysfunction,23 self-efficacy,32

and so on, affecting exacerbations and reoccurrences of skindiseases and conditions. The fact that dermatologists do notknow or are interested in or appreciate the advances thatpsychodermatology offers,33 especially in the field offactors, which have effects on disease/therapy outcome,may have a negative effect on patient management, andtherefore on patients' lives.

We believe that PS should not be reduced any more bydermatologists to a generic term but rather be appreciated asan elaborate term encompassing within it an array of factorscontributing to the development, exacerbations and to theoutcomes of many common skin diseases.

Conclusions

“If it walks like a duck, quacks like a duck, looks like aduck, it must be a duck.”

Stress is a key topic in dermatology because the onset and/orexacerbations of many skin conditions are traditionally relatedto stress. A huge effort wasmade to prove the effect of stress onseveral common skin diseases. Problems such as inherent flawsof the research tools (questionnaires) and paucity of controlledstudies adopting standardized methods for measuring stresshave led to difficulties of some dermatologists to accept thisrelationship as “legitimate.” Use of other research pathways,such as exploring the neuroimmunocutaneous reactions to PS,allows bypassing the need to rely solely on psychosomaticresearch tools that are less familiar to dermatologists. Newstudies that focus on the roots of stress vulnerability providemore information of the whole picture of stress–skinconnections but at the same time accept and validate thenotion that PS do have an effect on the skin.

References

1. Picardi A, Pasquini P, Abeni D, Fassone G, Mazzotti E, Fava GA.Psychosomatic assessment of skin diseases in clinical practice.Psychother Psychosom 2005;74:315-22.

711Psychological factors in skin diseases: Stress and skin: Facts and controversies

2. Pavlovsky L, Friedman A. Pathogenesis of stress-associated skindisorders: Exploring the brain-skin axis. Curr Prob Dermatol 2007;35:136-45.

3. Cohen S, Janicki-Deverts D, Miller GE. Psychological stress anddisease. JAMA 2007;298:1685-7.

4. Habib KE, Gold PW, Chrousos GP. Neuroendocrinology of stress.Endocrinol Metab Clin North Am 2001;30:695-728.

5. Elenkov IJ, Chrousos GP. Stress system- organization, physiology andimmunoregulation. Neuroimmunomodulation 2006;13:257-67.

6. Papadimitriou A, Priftis KN. Regulation of the hypothalamic-pituitary-adrenal axis. Neuroimmunomodulation 2009;16:265-71.

7. Tausk FA, Nousari H. Stress and the skin. Arch Dermatol 2001;137:78-82.

8. Picardi A, Abeni D. Stressful life events and skin diseases:Disentangling evidence from myth. Psychother Psychosom 2001;70:118-36.

9. Kimyai-Asadi A, Usman A. The role of psychological stress in skindisease. J Cutan Med Surg 2001;5:140-5.

10. Fliege H, Rose M, Arck P, et al. The Perceived Stress Questionnaire(PSQ) reconsidered: validation and reference values from differentclinical and healthy adult samples. Psychosom Med 2005;67:78-88.

11. Levenstein S, Prantera C, Varvo V, et al. Development of the PerceivedStress Questionnaire: a new tool for psychosomatic research. JPsychosom Res 1993;37:19-32.

12. Theorell T. Evaluating life events and chronic stressors in relation tohealth: Stressors and health in clinical work. In: Fava GA, Sonino N,Wise TN, editors. The psychosomatic assessment. Strategies to improveclinical practice. Karger Publishing; 2012. p. 58-71.

13. Cohen S, Kamarck T, Mermelstein R. A global measure of perceivedstress. J Health Soc Behav 1983;24:385-96.

14. Verhoeven EW, Kraaimaat FW, de Jong EM, Schalkwijk J, van deKerkhof PC, Evers AW. Individual differences in the effect of dailystressors on psoriasis: a prospective study. Br J Dermatol 2009;161:295-9.

15. King RM, Wilson GV. Use of a diary technique to investigatepsychosomatic relations in atopic dermatitis. J Psychosom Res 1991;35:697-706.

16. Evers AWM, Verhoeven EWM, Kraaimaat FW, et al. How stress getsunder the skin: cortisol and stress reactivity in psoriasis. Br J Dermatol2012;163:986-91.

17. Haeck IM, Timmer-de Mik L, Lentjes EG, et al. Low basal serumcortisol in patients with severe atopic dermatitis: potent topicalcorticosteroids wrongfully accused. Br J Dermatol 2007;156:979-85.

18. Orion E, Wolf R. Psychological stress and epidermal barrier function.Clin Dermatol 2012;30:280-5.

19. Altemus M, Rao B, Dhabhar FS, DingW, Granstein RD. Stress inducedchanges in skin barrier function in healthy women. J Invest Dermatol2001;117:309-17.

20. Rein M. Stress and genital herpes recurrences in women. JAMA2000;283:1394.

21. Hunzeker J, Padgett DA, Sheridan PA, Dhabhar FS, Sheridan JF.Modulation of natural killer cell activity by restraint stress during aninfluenza A/PR8 infection in mice. Brain Behav Immun 2004;18:526-35.

22. Simonić E, Kaštelan M, Peternel S, et al. Childhood and adulthoodtraumatic experiences in patients with psoriasis. J Dermatol 2010;37:793-800.

23. Poot F, Antoine E, Gravellier M, et al. A case–control study on familydysfunction in patients with alopecia areata, psoriasis and atopicdermatitis. Acta Dermatol Venereol 2011;91:415-21.

24. Cohen S, Kessler RC, Gordon UL. Strategies for measuring stress instudies of psychiatric and physical disorder. In: Cohen S, Kessler RC,Gordon UL, editors. Measuring Stress: A Guide for Health and SocialScientist. New York, NY: Oxford University Press; 1995. p. 3-26.

25. Plotsky PM, Meaney MJ. Early, postnatal experience alters hypotha-lamic corticotropin-releasing factor (CRF) in RNA, median eminenceCRF content and stress-induced release in adult rats. Brain Res MolBrain Res 1993;8:195-200.

26. Bockelbrink A, Heinrich J, Schäfer I, et al. Atopic eczema in children:another harmful sequel of divorce. Allergy 2006;61:1397-402.

27. Picardi A, Pasquini P, Cattaruzza MS, et al. Stressful life events, socialsupport, attachment security and alexithymia in vitiligo. A case–controlstudy. Psychother Psychosom 2003;72:150-8.

28. Diaz-Atienza F, Gurpegui M. Environmental stress but not subjectivedistress in children with alopecia areata. J Psychosom Res 2011;71:102-7.

29. Whitley R, Rousseau C, Carpenter-Song E, Kirmayer LJ. Evidence-based medicine: Opportunities and challenges in diverse society. Can JPsychiatr 2011;56:514-22.

30. Sackett DL, Rosenberg WM, Gray JA, Haynes RB, Richardson WS.Evidence based medicine: what it is and what it isn't. BMJ 1996;312:71-2.

31. Fava GA, Sonini N. Psychosomatic medicine: emerging trends andperspectives. Psychother Psychosom 2000;69:184-97.

32. Dalgard F, Stern R, Lien L, Hauser S. Itch, stress and self-efficacyamong 18-year-old boys and girls: a Norwegian population-basedcross-sectional study. Acta Derm Venereol 2012 [Epub 2012 Feb 15].

33. Jafferany M, Vander Stoep A, Dumitrescu A, Hornung RL. Theknowledge, awareness, and practice patterns of dermatologists towardpsychocutaneous disorders: results of a survey study. Int J Dermatol2010;49:784-9.