Psychophysiology of Stress in Dermatology

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PSYCHOPHYSIOLOGY OF STRESS IN DERMATOLOGY

The Psychobiologic Pattern of Psychosomatics

Emiliano Panconesi, MD, and Giuseppe Hautmann, MD

In 1878, Bernard5 first recognized the physiologic response of animals to environmental stimuli when he described the "milieu in- terieur" of the animal, characterized by its constancy, and the external environment, characterized by its variability. Cannon'O later redefined this concept as "homeostasis," in which a steady state is obtained by the opti- mal interaction of counteracting processes within the host. He also defined the flight- fight reflex of animals exposed to undue stress and identified the potentially damaging effects of stress on the individual. The physiologic basis of the stress response was attributed to activation of endocrinologic factors involving the sympathetic adrenomedullary axis." Selye106 then described the response of laboratory animals experimentally exposed to noxious stimuli, which he classified as the "general adaptation syndrome." The syndrome was classified as having three distinct phases: (1) an alarm reaction, (2) a resistance phase, and (3) if stress was not dissipated, exhaustion of the biologic system. Because different noxious stimuli produced an apparently similar physiologic response, involving activation of the pituitary-adrenal-cortical axis, he concluded that the response to stress

was "nonspecific." This led to the widely held view that stress largely involved nonspecific production of corticosteroids, and it sub- sequently has led to the measurement of glu- cocorticosteroids as the primary indicator of stress and animal well-being. As the field of neuroendocrinology evolved, Selye's concept of the nonspecific response was refuted. Ma- son68 has shown that different types of stress such as fasting and heat shock produce dra- matically different corticosteroid levels in experimental monkeys. He showed characteristically different responses and produced characteristic responses to the different stressors. It now is accepted widely that there are unique but different endocrine responses to different physical, chemical, and psychological stressors and that these responses vary from one species of animals to another and from one individual to another within a species.

Stress currently can be defined as an abnormal or extreme adjustment in the physiology of an animal to cope with adverse effects of the environment and management. In this article the adverse effect is designated the stressor. The term stress has been qualified further by other workersz3, Io5 to include the

From the Department of Dermatology, University of Florence, Florence, Italy

DERMATOLOGIC CLINICS

VOLUME 14 - NUMBER 3 * JULY 1996 399

400 PANCONESI At HAUTMANN

term distress. This term is used to identify the extreme response to adverse stimuli that cause a damaging pathophysiologic reaction in the host, producing associative changes in behavior, physiology, and disease susceptibility. It also has been recognized that other forms of stimuli potentiate the physiologic responses of the host without producing any adverse effect, and such responses are said to involve eustres~.~~, lo5

There are two main types of host factors that can influence y2 They are genetics and perception.

GENETICS

Evolutionary changes have led to marked differences in the adaptative physiologic response of different species exposed to stress. This is reflected in variations in the endocrine response of species to individual stressors and in the variable effects of specific endocrine factors on the target cells in different animal species. Variations of response also are found within species and may be accentuated by selective breeding, age, sex, and conditioning.

PERCEPTION

The most important factor that influences stress is the individual’s perception of the challenge posed by the specific stimulus. Fac- tors that influence the individual’s perception of stress include bonding during rearing, the novelty or predictability of the stimulus, and training that frustrates the avoidance response and evokes a state of learned help- le~sness .~~ Conditioning to stimuli also may occur in which the association between an aversive chemical stimulus and an immunomodulating agent, given in combination, can evoke a conditioned state of immunosuppres- sion or immunoenhancement when the aversive stimulus is applied in the absence of the immunomodulating agent.

There are numerous types of stressors. Stressors include a variety of environmental stimuli that evoke significant homeostatic alterations in the host. They may result from

natural changes in the environment or from artificial changes imposed by management constraints or be caused by a range of experimental stimuli that have been used to study stress physiology. The effect produced by exposure to stress may be influenced by the severity of the stressor, the time of applica- tion (acute versus chronic), or whether the animal can escape the stressor if it is applied repeatedly (escapable versus inescapable).

Environmental

Natural exposure to extremes of heat or cold under climatic conditions or artificially in animal housing or holding facilities is among the most common stressors. Physical restraint associated with separation, treatment, or transport of animals is another important stressor. Environmental changes that produce strange or novel sounds, sights, odors, or tastes also can evoke stress. Drugs or chemicals used in the management or treatment of animals can act as stressors, and toxic products released by infectious agents, environmental pollutants, or inadequate ven- tilation can have a similar effect. Shearing, docking, and castration carried out during routine management also cause stress.

Behavioral

Overcrowding, hierarchic challenge, wean- ing, exposure to unfamiliar surroundings, or isolation can have a major behavioral impact on animals and evoke stress. Changes or re- strictions in diet also can act as stressors, alone or in combination with other stressors such as physical restraint.

Psychological

In animal species, the capture of wild subjects or the exposure of domesticated animals to restraint, transport, or management extremes may evoke adaptative stress in the host. In the context of Selye’s general adaptation syndrome, the response is recognizable initially as anxiety, which may progress to

PSYCHOPHYSIOLOGY OF STRESS IN DERMATOLOGY 401

fright or terror. Failure of the animal to express the flight-fight response results in the expression of anger or rage and, if the stimulus persists, frustration or helplessness. Be- cause stress results largely from the individual’s perception of the threat posed by a stimulus rather than its nature per se, a cognitive or psychological component is central to all stress.y2

The biologic response within the host that results from exposure to stress is outlined in Figure 1. This response produces an impact on many of the organs within the affected

Behavioral and psychological experiences involving stress, documented in animals, are what our patients propose to us every day. Overcrowding, hierarchic challenge, wean- ing, exposure to unfamiliar surroundings, isolation, anger and rage, frustration, and helplessness, even without the precise flight- fright response, seem to be a normal condition of life for modern humans. Isolation, deprivation, fasting, starvation, and religious and mystic passions can be proposed as eq~ivalents .~~

Because stress can be caused by environmental factors just as well as psychic re-elabo- ration, it is easy to perceive the relationship

y2

perception

activation CNS recognition

Autonomic nervous stimulation

Endocrine response

cardiovascular

multiorgan Flight-fight Systemic reactivity

immune system

Physiologic I -1 Conservation reactivity adaptation withdrawal

Pathologic Exhaustion reactivity

Figure 1. Organized multisystem response to stress. CNS = central nervous system.

between everyday stress and defense mechanisms and disease susceptibility, on one hand, and the involvement of the physical and psychological sphere on the other. The result is a unitary concept of human pathology, and the problem is to determine the entity of the emotional component in any disease. The body (soma) and the mind (psyche) constitute a single unit. Separating the two and treating them individually should be con- sidered only reductive necessity or abusive operative simplification for the investigator or doctor.

Psychosomatic medicines3, 92 proposes the examination of psyche and soma as a unit “in sickness and in health” and, in the former case, useful intervention in the attempt to reestablish equilibria that have been altered. The fortunate term psychosomatic by now has become a part of current medical terminology incorporated into everyday language, and it was inevitable that any organ (including the skin) and its diseases become the object of medical observation and interpretation from a psychosomatic point of view.83 Neverthe- less, in the American dermatologic literature the term psychosomatic is resisted (in the author’s opinion, unjustifiably) and the term psychocutaneous is preferred.

Experimental studies done during the last 20 years have seen the marriage of psychol- ogy, neuroendocrinology, and immunology into a new subspecialty called psychoneuroen- docrinimmunology. Research in this multifac- eted system has identified and integrated the physiologic factors produced by the neurologic and immunologic systems. Soluble factors produced by the neurologic and immunologic tissues in normal or pathologic conditions include neurotransmitters, neuropeptides (NP), adrenocorticotrophin, catecholamines, corticosteroids, opioids, and cytokines, including lymphokines and mono- kine^.^ These bidirectional loops between the CNS and the immune system occur as a consequence of neurohormones acting on cells of the immune system, while cytokines or antibodies secreted by lymphocytes and mac- rophages influence neuroendocrine function. Nevertheless, the newly recognized similari- ties between the immune and neuroendocrine systems include the observation, in both sys-

402 PANCONESI & HAUTMANN

tems, of an increasing number of peptides and proteins that are used as intercellular messengers. These substances usually are called neuropeptides. These NPs represent a heterogeneous group of molecules; the small- est ones containing only two amino acids, with larger peptides consisting of 40 or more amino acids. In the nervous system, NPs ful- fill many of the criteria of a neurotransmitter and neuromodulator. Many have been studied in other contexts as hormones, "gut peptides," or growth 65, 85 Recent evidence strongly supports the notion that NPs are endogenous to the immune system and are used for intraimmune system regulation, as well as for bidirectional communication between the immune and neuroendocrine

64, 91 NPs may exert their regulatory influence in one or more of the following ways: (1) as components of the autonomic nervous system, acting locally at peripheral sites; (2) as brain peptides, acting on central regulatory centers; and (3) as neurohormones, reaching their target organs via the hypo- physial portal vessels (such as the releasing factors) or via the general circulation (such as oxytocin or vasopressin).

The number of NPs described exceeds 50, and most, if not all, alter behavior and mood states." Figure 2 shows a suggested schematic illustration of a possible NP-behavior relationship. Relationship A illustrates how an NP can regulate different behaviors by acting differently or at different neural loci. This statement is supported by the findings that many individual NPs are widespread in the nervous system, exercise multiple neural ac- tions, and are involved in the regulation of many different and often unrelated behaviors.

Relationship B in Figure 2 indicates that neurons mediating a given behavioral effect of an NP are distributed across anatomic boundaries in the CNS.

Different NPs act on the same population of neurons but through different cellular mechanisms to regulate a given mechanism. It is obvious that most of the behaviors are regulated by more than one NP.

They affect the same behavior through a similar neural locus, suggesting that different NPs act on the same population of neurons

to exert their effects on a behavior; moreover, in vitro studies suggest that some NPs act through modulation of neuronal responses, whereas other NPs probably act as stimula- tory or inhibitory neurotransmitters, as schematized in relationship C in Figure 2.

Finally, relationship D in Figure 2 shows that an NP that activates a behavior peripherally often also may serve as a neurotransmitter at each synapse in the central pathway mediating that behavior; thus, it has been suggested that a given behavior tends to be mediated by a pathway consisting of a chain of neurons containing the same NPs and that an NP could induce a given behavior at several neural loci. An infusion in the cerebral ventricles often would be more effective than a local microapplication for an NP to induce a given behavior.48

The skin and CNS are related embryologi- cally because the epidermis and neural plate derive from the embryonic ectoderm. The neural plate gives rise to the neural tube and neural crest, from which the central and peripheral nervous systems develop. The mela- nocytes and, possibly, the Merkel cells in the skin also originate from the neural crest.h This embryologic association between the skin and the CNS is the most likely basis for the find- ing that various neuroectodermal syndromes often are associated with CNS abnormalities such as mental retardation and seizures. The clinical implications of this embryologic association may be more far reaching because the skin and the CNS share various hormones, neurotransmitters, and receptors. The gener- ous primary sensory neuronal innervation of the superficial dermis should ensure a wide distribution of NPs in the skin. During the last decade, numerous studies have shown that many of these peptides, including substance P (SP), calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP), neuropeptide Y (NPY), neurokinin, and neu- rotensin A, are present in the skin, where they may play roles as neurotransmitters and trophins. Cutaneous NPs are contained in myelinated A-delta fibers and small unmyelinated C fibers, including sensitive and autonomic fibers. It is well known that the skin is innervated by primary afferent sensory nerves, postganglionic cholinergic parasym- pathetic nerves, and postganglionic adrener-


CNS Locus a + behavior a CNS Locus b + behavior b CNS Locus c

behavior c € mediating action

modulatory action - I CNS Locus d A CNS Locus e _.+ behavior d

A Neuropeptide a

CNS Locus a CNS Locus b behavior a CNS Locus c CNS Locus d

B Neuropeptide a

C

Neuropeptide c -

D Neuropeptide a + CNS - NPa + CNS - NPa + CNS - NPa - behavior a , (NPa) , , puss Locus b Y u s c ,

Neuropeptide a - (modulation) Neuropeptide b - (mediation)

Neuropeptide d - (mediation)

a single population of CNS neurons + behavior a

c periphery

.) CNS

Figure 2. A-D, Possible neuropeptide-behavior relationship.

gic and cholinergic sympathetic nerves.48, 64, 91

It must be emphasized that sensory nerves not only function as an afferent system to conduct stimuli from the skin to the CNS but also act in an efferent "neurosecretory" fashion throughout their branches. In addition to the classic role of the neuroendocrine and autonomic systems in the stress response, the sensory nervous system also plays a role in this response. Specialized cutaneous receptors (nociceptors) sense and transmit sensory signals, including noxious stimuli, by unmyelinated afferent C fibers to the dorsal root ganglia and the dorsal horn of the spinal

Ascending nerve tracts transmit this sensory information to the thalamus, which transmits it to higher cortical centers involved in processing cognitive information.101 De- scending pathways relay the sensory information back down the spinal cord, resulting in peripheral autonomic responses (e.g., vaso- dilation and sweating).'O'

Stimulation of cutaneous nociceptors by noxious stimuli (mechanical, thermal, or chemical injuries) influences nerve endings that are depolarized, and impulses are con- veyed centrally and peripherally (antidromi- cally). These peripheral effector functions provided by afferent sensory neurons under-

lie so-called neurogenic inflammation, which is based on the release of NPs, including SP, CGRP, and VIP, from collateral sensory nerve branches.'O' Stimulation of cutaneous nociceptors also causes activation of ascending pathways, resulting in enhanced electrical activity'02 and decreased levels of SP3I in several higher cortical CNS regions. Local release of NPs from sensory nerves in the skin, however, has not been measured in response to stressful stimuli in animals or humans. Acti- vation of higher cortical areas during stress results in altered release of SP from the adrenal gland by descending autonomic fibers."' Because some of these descending fibers in- nervate opioid interneurons in the dorsal horn63 and these interneurons are connected anatomically to SP-containing nerves in the spinal cord, it is possible that descending autonomic nerves can trigger antidromic release of NPs in the skin. In Figure 3 the authors present schematically the mechanism of axon reflex in neurogenic inflammation. Such a novel possible mechanism would explain the effects of emotional stress on skin physiology. Several experimental findings support this hypothesis.62, 82 In addition to stress-induced alterations in SP levels in the CNS, increased concentrations have been reported also in se-


Primary afferent neuron

Polymodal nociceptor

Mast cell

Figure 3. Axon reflex in neurogenic inflammation. H = histamine; NP = neuropeptides.

rum after emotional immobilization stress in rats.34 Circulating NPs might be generated by stimulated release from the adrenal or from nonneural peripheral cells and sensory nerves. SP is colocalized in adrenergic chro- maffin cells in the adrenal gland, and its role as an antistress peptide has been pro-

The following lists review the main functions of SP, CGRP, VIP, and NPY.48* 64, 91

Main 1.

2.

3.

4.

Activities of SP: SP is a potent vasodilator peptide and increases blood vessel permeability. SP induces microvascular endothelium to express endothelial leukocyte adhesion molecule 1 (ELAM-1). Intradermal injection of SP into human skin induces a flare and wheal reaction. SP is about 100 times more potent than histamine in producing these reactions. Skin injection of SP provokes an increased cutaneous fibrinolytic activity, mediated by t-PA. This increase seems

to be caused at least partially by histamine release from mast cells.

5. SP induces cutaneous mast cell secretion. .

6. SP increases the delivery and accumulation of many leukocytes in the tissue.

7. SP stimulates production of H,O, by human neutrophils in a dose-dependent manner.

8. SP increases phagocytosis by macro- phages and neutrophils.

9. SP can increase the in vitro production of IgA by lymphocytes from Peyer’s patches by as much as 300%.

10. SP significantly enhances DNA synthesis by lymphocytes from spleen and Peyer’s patches.

11. SP stimulates the mitogenesis of T cells. Helper T cells bind SP more than sup- pressor T cells.

12. SP may potentiate the activities of other mediators such as 5-HT, bradykinins, and prostaglandin El .

13. SP is a potent pharmacologic mediator of pruritus and is thought to play a key role in painful sensation.

Main Activities of CGRP:

1. CGRP dose dependently inhibits the proliferative response of lymph node cells and spleen cells stimulated by concanavalin A (Con-A) and phytohe- magglutinin.

2. Human CGRP releases histamine from mast cells in a dose-dependent manner.

3. CGRP injection sites present increased infiltration of polymorphonuclear leukocytes.

4. CGRP is chemotactic for T lymphocytes.

5. CGRP is a potent vasodilatative agent. 6. Intradermal injection of CGRP pro-

duces circular wheal and flare responses similar to those produced by SP.

7. CGRP induces rapid translocation of GMP140 from cytoplasmatic Weibel- Palade granules to plasma membrane of endothelial cells.

8. CGRP inhibits the antigen-presenting function of Langerhans’ cells.

Main Activities of VIP:

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.


life cycle. It long has been recognized that

VIP is a vasodilator agent on the small blood vessels. VIP has high affinity binding to human lymphoid cells through specific cell surface receptors for this neuropeptide. VIP inhibits the response of murine lymphocytes to Con-A and phytohemag- glutinin but not lipopolysaccharides. VIP inhibits natural killer activity of large granular lymphocytes. VIP increases IgA synthesis by Peyer’s patches. VIP stimulates histamine releases in rat peritoneal connective tissue mast cells. VIP activates mast cells in a IgE-inde- pendent pattern. Mast cells and eosinophils can release VIP. VIP enhances monocyte migration in chemotaxis chambers. VIP often is present in cholinergic neurons. In the skin, VIP has mitogenic proper- ties on keratinocytes, stimulating their proliferation. Intradermally injected VIP provokes a slight but statistically not significant re- duction in weal and flare reaction.

Main Activities of NPY:

1. NPY is one of the most potent vasoconstrictor agents.

2. NPY often is present in adrenergic neurons.

3. NPY produces vasoconstriction and increases blood pressure.

4. NPY evokes coronary vasoconstriction and has a negative inotropic effect in some species.

5. NPY decreases glomerular filtration and inhibits renin secretion.

6. NPY can modulate the release of CGRP.

7. NPY is one of the most abundant peptides found in the CNS in all mamma- lian species studied.

The skin occupies a powerful position as an organ of communication and plays an important role in socialization throughout the

psychosomatic factors play a role in dermatologic disease. In agreement with I ron~ide ,~~ the authors believe that an organ system is vulnerable to psychosomatic ailments when (1) several etiologic factors, including genetic and constitutional predisposition, are opera- ble, (2) emotional factors mediated by the CNS are in play, ( 3 ) intrapsychic processes such as self-concept, identity, or eroticism are involved, (4) the organ system is likely to be the object of ”conversion” and conditioning because of emotional arousal related to intrapsychic problems, and (5) social values and standards are linked with the organ system. Rook and Wilkins~n,’”~ in the well-known Textbook of Dermatology, open the chapter on ”Psychocutaneous Disorders” with the af- firmation that “the role of emotional factors on diseases of the skin is of such significance that if they are ignored the effective management of at least 40% of the patients attending departments of dermatology is impossible.” These percentages are even higher for the psycho-influenced dermatoses; Obermayer8I reported 66% and for Medansky and Hand- ler73 “almost 80% of dermatologic patients had a psychogenic overlay.” The patient may use the skin to communicate emotional distress, and there may be a full range of personal and family problems underlying the presenting dermatologic problem. For example, women whose complaint of hair loss seems disproportionate to the objective degree of alopecia have been reported to have marital difficulties and depression.’Y Patients with immature psychological coping mechanisms may not be able to obtain nurturing or attention from others by other means and therefore may derive secondary gain from a visible skin condition. Alternately, development of a cosmetically disfiguring condition can result in social disapproval and increased self-consciousness. This can result in social withdrawal, academic underachievement, and even serious psychological problems, especially when the skin disorder occurs during a developmentally critical period such as adolescence. In psoriasis, for example, the cos- metic disfigurement and consequent social stigma (real or imagined) can have a profoundly adverse effect on the patient’s quality


of life and result in significant disease-related stress. This disease-related stress may exacerbate the psoriasis and adversely affect the course of the disease.

Various clinical observations suggest that psychoneuroimmunologic factors may have important applications in dermatology. Psy- chological stress has been associated with increased CNS levels of opioid neuropeptides and also has been reported to exacerbate certain dermatologic conditions that have a psychosomatic and an immunologic component, such as chronic idiopathic urticaria, atopic dermatitis, and psoriasis.48, 64, 91, 92 These are only a few examples, because the authors believe that some stressing factor can be indi- viduated in almost all dermatoses, in major or minor degree.

PSORIASIS

Psoriasis is a frequent, chronic, erythema- tous dermatosis with squamous accumula- tions. It may be circumscribed or dissemin- ated with preferential sites (elbows, knees, scalp). It is presumed to be determined genet- ically, and it has typical histologic markers (capillary dilatation, sterile epidermal microabscesses, parakeratosis) and accelerated epidermal turnover. In the vessels of the dermal (”squirting”) papilla, Munro-Sabouraud epidermal microabscesses (formed by polymorphonuclear cells squirted out from the vessels), and accelerated turnover of keratinocytes, the authors hypothetically identify the key points of the disease influenced or influ- enceable by acute or chronic emotional stress. Arnetz et a12 studied psychoendocrine and metabolic reactions during standardized stressor exposure (color-word conflict test and forced mental arithmetics) in psoriatic patients and in matched healthy subjects. Un- der resting conditions, the groups were similar with regard to psychological and biochem- ical variables, whereas during stressor exposure, the psoriatic group reported significantly higher strain levels. Blood pressure, pulse rate, plasma glucose, and urinary adrenaline excretion increased in both groups during exposure, with more pronounced increases in the latter two in the psoriatic

group.2 Serum cortisol, prolactin, progester- one, and urinary cortisol decreased in both groups during stressor exposure. The de- crease in serum cortisol was more pronounced in the psoriatic group. In contrast, during standardized stressor exposure, psoriatic subjects reported higher levels of strain, which was accompanied by higher levels of urinary adrenaline and lower levels of plasma cortisol, suggesting the hypothesis that psoriatic patients perceive certain challenging situations as more stressful than do nonpsoriatic control subjects and react accordingly in their different psychoendocrine reaction pattern.2 Because in 60% of patients psoriasis starts before the age of 30 years, the nature of the skin disease (its visibility and the need for consistent care) becomes a crucial factor in these persons’ psychological development. Updike,Il2 one of the most important contem- porary American writers, writes of his feelings about his psoriasis: “One hates one’s abnormal, erupting skin. . . . The skin was my enemy . . . ,” and he refers to his mother, who had psoriasis, and her protec- tiveness of her ”defective cub. . . . Strategies of concealment ramify, and self-examination is endless.” Many studies have specifically indicated that feelings of being stigmatized by psoriasis are important in how patients perceive themselves. Jowett and Ryan55 reported that the majority of psoriatic patients indicated that the worst thing about their disease was the appearance and consequent embarrassment; 89% reported shame and embarrassment, 50% anxiety, 42% lack of con- fidence, and 24% depression. Twenty-six per- cent said that psoriasis caused family friction. Almost half curtailed athletic activities, especially ~wimming.’~, 52, 55, h1

Several studies support the importance of psychosocial factors in the onset or exacerba- tion of psoriatic symptoms in 39% to 80% of patientsz4 It also has been suggested that there is a subset of psoriasis patients characterized as high stress reactors who suffer more clinically disfiguring lesions and more frequent disease flare.43

Although there is evidence that heredity has a recognized role (probably multifactorial inheritance with a polygenic mechanism) in the case of psoriasis, it also has been shown


by studies on monozygotic that environmental factors are important in triggering the disease. Vast amounts of the literature and our personal experience allow‘us to include acute and chronic emotional stimuli in the general group of environmental factors. There is a great diversity of exogenous and endogenous factors that can trigger the onset of psoriasis, possibly via the strategically located tumor necrosis factor-alpha producing dermal dendrocyte. Koebner’s phenomenon refers to the development of psoriatic lesions in traumatized skin, whereas endogenous factors that may precipitate psoriasis include certain drugs and bacterial and viral infections.

The importance of emotional shock was at the base of historic observations by Hardy, Leloir, Brocq, Bodin, and Andry, mentioned by Bolgert et a1,8 who answer affirmatively to the question posed in the title of their work: ”Le psoriasis est-il une psycho-dermatose?” (Is psoriasis a psychodermatosis?). Other authors are more cautious in affirming the relationship between emotional events and psoriasis, but, with time, psychosomatic research has passed from reference to ”significant” an- amnestic episodes (the ”anedoctal” period) to reference to “personality profile” held to be specific for the various dermato~es.~, 297 99 Nu- merous studies have attempted to identify a specific personality profile, but have failed to show any reproducible personality type; however, several emotional features and reactions have been identified in samples of psoriasis patients. They have been found to have increased levels of anxiety and depre~sion,2~ increased tendencies for obsessiveness,M and increased expression of aggre~sion.~~ Feelings of stigmatization and other emotional se- quelae have been suggested as well.36 Despite these and other studies, it remains unclear whether these emotions precede and precipitate psoriatic flares or whether they are a consequence of having a chronic, sympto- matic, disfiguring illness. It is the authors’ opinion that hereditary factors constitute in all likelihood the fundamental predisposing condition on which various stressors, not the least of which psychosocial (psychobiologic) ones, activate the emotional stress mechanism, provoking onset or exacerbating the

disease. Much significance recently has been attributed to an understanding of the psycho- neuroimmunology of psoriasis.28 Neuropep- tides have been suggested to be of pathogenic importance in psoriasis,28, 4R, 64, 91 as a neuro- modulatory factor underlying psoriasis flare or responsible for the maintenance of psoriatic lesions. According to this theory, the oc- currence of a psoriasis flare after stress is related to the release of certain neuropeptides, and the symmetry of psoriatic lesions would be caused by bilateral distribution of cutaneous peripheral nerves.2R There is a significant increase in SP-containing nerves in psoriatic skin, and psoriatic lesions are innervated more densely.

An abundance of neuropeptides such as SP and VIP has been shown in psoriatic lesions. The neuropeptides locally released, such as SP, VIP, and CGRP, can act as a neurotransmitter in neurogenic inflammation mediated by antidromic pathways. SP interacts in vitro with the functions of most dermal and epidermal cells, including keratinocyte proliferation.ls, 25, 27, 787 96 SP can influence inflammatory response by stimulating lymphomononuclear cells, altering endothelial cells, and degranu- lating mast cells.22, 95 VIP also can stimulate proliferation of keratinocytes. This effect is accentuated in the presence of leukotriene B4.98 Keratinocyte proliferation, a hallmark of psoriasis, can be triggered by SP and VIP. SP-induced lymphocytic proliferation may be responsible for the altered cell-mediated immune response in patients with psoriasis. In- duction of ELAM-1 on endothelium by SP and even more so by CGRP and VIP, could explain the initiation and maintenance of the lesional infiltrate.’O

Therapeutic efficacy of neuropeptide-modulating drugs is more indirect evidence that supports the role of neuropeptides in psoriasis. Capsaicin, an SP-depleter, has been reported to improve psoriasis partially, and peptide T, a VIP analogue, recently has been observed to be effective in the treatment of psoriasis. All these findings are consistent with the hypothesis that cutaneous nerves to- gether with their neuropeptides play a key role in the pathogenesis of psoriasis.47, 48 Con- sidering the influence of the previously mentioned neuropeptides on the mechanisms of


inflammation and immunity, as well as their trophic and stimulating effects on cell growth, certain pathogenetic mechanisms in psoriasis might indicate neuropeptide action in this disease.

A plausible immunopathogenetic mechanism for psoriasis involves the reciprocal interactions between mononuclear cells within the dermis, including activated T cells, mac- rophages (Langerhans’ cells and dermal dendrocytes), and the overlying hyperplastic keratinocytes. Such a complex and reciprocal interaction between keratinocytes and immu- nocytes probably includes the cytokines interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-alpha), and the adhesion molecule ICAM-1.80 The results of in vivo studies, combined with others in vitro, delineate important spatially coordinated cytokine-con- trolled interactions between TNF-alpha-producing dermal dendrocytes and overlying keratinocytes, which have increased IL-8, ICAM-1, and transforming growth factor- alpha (TGF-alpha) expression. IL-8 is known as a potent T-cell chemotactic factor, and keratinocyte-drived ICAM-1 is able to mediate the recruitment and retention of T cells, as characteristically observed in the squirting papilla zone of the psoriatic epidermis. The increased keratinocyte production of TGF- alpha induced by TNF-alpha may be an important contribution to keratinocyte hyper- plasia because TGF-alpha is a potent mitogen for keratinocytes.21 It also has been suggested that the dermal dendrocyte plays an important central role in cutaneous inflammatory reactions4I because anatomically it is sit- uated immediately between the basal keratinocyte layer of the epidermis and adjacent to the endothelial cells, permitting the monitoring of the external and internal microenvironmental milieu. Dermal mast cells, although increased in psoriatic lesions, do not appear to produce TNF-alpha or IL-8. The dermal mast cells, however, are associated intimately with TNF-alpha-containing dendrocytes. This close association may have functional significance because stimulation of dermal mast cells in short-term skin cultures has been observed to induce TNF-alpha- mediated adhesion molecule expression on endothelial cells.57

It has been shown that SP stimulates mast

cell degranulation in foreskin cultures, which is associated with rapid induction of ELAM-1 on adjacent postcapillary venular endothelial cells.” The mast-cell inhibition blocks the ability of SP to induce ELAM-1. The dermal microvasculature is associated intimately with small, predominantly unmyelinated fibers and mast cells in the immediate perivascular space, and frequently axons are in direct proximity to mast cell membrane^."^ These associations raise the possibility that neurogenic triggering of mast cells might be important physiologically and in certain pathologic settings such as psoriasis. The cytokine network in psoriasis involves production of TNF-alpha and IL-8 and expression of ICAM- 1 by resident and recruited cells. These data may explain several clinical and pathologic observations involving psoriasis, including that many different exogenous and endogenous stimuli can trigger the onset of psoriasis (Koebner phenomenon), possibly via the strategically located TNF-alpha-producing dermal dendrocyte. The stimuli illustrated in Fig- ure 4 (modified from 80) include exogenous factors that affect the skin directly, such as trauma, which may damage the increased numbers of sensory nerve fibers in psoriatic skin, leading to the release of SP. SP contained within dermal nerve fibers also may represent a critical initial mediator of a cas- cade of cellular events involving mast cell degranulation, with subsequent induction of ELAM-1 on adjacent venular endothelium. This would facilitate the local accumulation of blood leukocytes during early, vascular phases of the inflammatory reaction. This neuropeptide also may be produced by increased stress or during intrapsychic conflicts, then interact with the mast cells, and via the dermal dendrocyte, produce TNF-alpha. Other than stress, endogenous stimuli, that is, indirect stimuli delivered to the skin from the blood stream, capable of inducing psoriasis, include HIV, which would stimulate the dermal dendrocyte via CD4, ICAM-1 cell surface molecules, lithium, which can potentiate the effects of macrophage-derived TNF-alpha, and immune complexes, perhaps formed by streptococcal antigen-antibody interaction. In psoriatic plaques, there are elevated levels of interleukin-6 (IL-6) because TNF-alpha induces its p rod~ct ion~~; the cyclosporine-in-


Stress Emotior Psychic

Figure 4. Exogenous and endogenous stimuli can trigger the onset of psoriasis. TNFa = tumor necrosis factor-alpha; IL-8 = interleukin-8; CAM-1 = intercellular .adhesion molecule-1; DD =

dendrocyte; L i t+ = lithium salts: TGF-a = transforming growth factor-alpha; Ag = antigen; LC = Langerhans’ cell.

duced improvement of psoriasis is probably caused by the property of this drug to inhibit TNF-alpha production.’00

ATOPIC DERMATITIS

Atopic dermatitis (AD) is a common disease characterized by chronic or chronically recurrent lesions, with severe itching and scratchmarks, and eczematous papulovesicu- lar lesions, with crusting and lichenification. In early childhood, exudative-eczematous lesions usually predominate, whereas in school-aged children and adults, pruritus, pruriginous lichenoid papules, and lichenification are prominent. The microscopic picture depends on the clinical morphology of the disease. The more exudative lesions present spongiotic vesicles, acanthosis with hyperker- atosis and parakeratosis, and perivascular infiltration of lymphocytes and histiocytes with exocytosis. The lichenified areas of the epider-

mis are thickened, and the papillary body is hypertrophic, permeated by inflammatory cells (lymphocytes and histiocytes). More- over, there are a large number of mast cells that also explain the increased histamine content of chronically lichenified foci. A brief, perhaps superfluous, account in story form might be the following. A family, not unusu- ally with signs of atopy (allergic asthma, hay fever, eczema in bottle-fed babies, or “cradle cap”), has a child who, at the age of about 3 months, presents with acute, often exudative and intensely itchy eczema on the face (cheeks and forehead) and perhaps also on the forearms, diaper area, and the flexural regions in general. Sometimes the lesions ex- tend to many other areas and, on occasion, become diffuse. The disease becomes chronic. The periods of remission, practically nonexis- tent in severe cases, alternate with periods of relapse or improvement or aggravation. In about 50% of the cases, the most fortunate ones, the dermatitis pretty much disappears


when the child is just older than one year old. There may be minor signs of delicate or dry skin and some itching or redness in flexural areas. In the other 50%, the less fortunate cases, the dermatosis boldly persists, localiz- ing almost anywhere but preferentially on the face (eyebrows, eyelids, around the mouth), the backs of the hands, and the cervical and malleolar regions. As the years of childhood and adolescence go by, the youngster lives with the torment of lichenified dermatitis. The skin generally is pale, grayish, cold, dry, and anhydrotic with raised, keratotic follicles. When this child becomes an adult, the characteristics are similar to those described previously, but with more evident signs of lichenification in the most severely affected areas, in particular the flexural areas, face, and hands.

Important dermatologists of the past associated the AD with neuropsychic factors, as is evidenced by the use of the term neurodermatitis in the nineteenth century, whereas the term prurigo of Besnier, still used in Scandina- via, seems to emphasize that this strange affection comports also a strange and suspi- cious persistence of the itching, which is the most ambiguous and the most psychosomatic of all symptoms. Moreover, the itch appears to be the leitmotif of the disease, perhaps the cause of its continuati~n.~~. 4y, 65, 85-87

Cutaneous stimulation during infancy appears to be an important factor for cell growth and differentiation and CNS maturation.30, 94

In the rat model, handling and cutaneous stroking in early life also appear to enhance humoral immunity in later life.30 In pre- weaned rats, temporary interruption of active tactile stimulation or maternal deprivation is associated with reduced ornithine decarboxylase activity, which is a sensitive index of cell growth and differentiation and CNS mat- ration.^^ It has been shown that human preterm neonates who received tactile and kinesthetic stimulation gained weight more rapidly and exhibited more mature neurologic re- flexes than did controls; they were also more alert.'O' in a series of famous experi- ments involving monkeys, showed that deprivation of touch, or contact comfort, in early life results in the development of inappropri- ately aggressive behaviors and other psychological problems. All these findings underline

the relevance of cutaneous perception and stimulation in physical and psychological development. The awareness of the psychobiologic unity of the human being and of the impossibility to consider the child's development separated from the environment obliges us to evaluate not only items concerning the child but also items of the parent-child system with the goal of creating interactive se- meiotics. This means that the operators try to bring out the most positive, significant, and functional choices of the child and family in that particular environment and moment.

Obermayer;' one of the fathers of psychosomatic dermatology, in reviewing the ample series studied by Gruber and Sanford, emphasized that many babies were separated early from their mother's breast, a truly trau- matizing event in the psychological development of the child and one that can cause severe damage to emotional stability. Many investigators have studied psychodynamics and the mother-child relationship, so often altered in the case of a child with AD. The extreme is the mother who rejects the atopic child, even refusing to touch him or her, with consequent anger, anxiety, or hostility of the child toward the mother herself or mother substitutes. In 1950, it was reported that up to 98% of children with AD had rejecting mothers, whereas few children in a control group without AD suffered maternal rejec- t i~n. '~, 85* 86 In some instances, the maternal rejection is a reaction to the child's dermatitis, that is, once the skin condition erupts, the mother tends to reject the ~ h i l d . ~ ~ , ~ ~ ~ The dis- turbed parent-child relationship aggravates the existing dermatosi~.~~ With scratching and self-excoriation the child makes himself or herself ugly and unlovable, unworthy of love; the excoriations modify the self-image, and they are also the results of disobeying the regular request not to scratch. As reported by Slany,lo8 children with AD frequently are in conflict with an unattentive, unaffectionate, and inadequate mother; this results in an un- conscious triggering of the psychosomatic mechanism, leading to onset of the disease. This model would work as follows: a small child or infant is unable to defend himself or herself from a psychic conflict except by removal, which provokes internal tension,


leading to anguish, depression, and hostility followed by conversion and regression. It has been hypothesized that in the phase of de- tachment from the mother, the subject with AD does not invent or find a transitional object and that the dermatitis substitutes the object; thus, the child's difficulty or inability to progress along the normal path of development is expressed in the form of a somatic cutaneous pathology.84, 86

It has been noted in general that patients with AD experience more emotional upsets than normal subjects. Parental separations, psychiatric illness, and skin disorders frequently are noted in the family history. Pa- tients with AD also tend to be more irritable, resentful, guilt ridden, and hostile than persons who do not have eczema.54

There have been many reports that refer specifically to the personality of the infant with AD. He or she is typically irritable, de- manding, and unhappy and needs more cud- dling and skin contact than the average baby. The parents' pride and joy in their offspring becomes compromised by the persistent and highly visible eczematous eruption. When the need to follow a complicated medical regi- men is compounded by the child being difficult and unattractive, some degree of parental resentment, embarrassment, and withdrawal occurs. A bad fit (difficult interpersonal relationship between parent and child and subse- quently with the rest of the world) begins, and the infant responds to unmet needs with self-stimulation and abusive ~cratching.~~ A vicious cycle is created in which anxiety provokes itching, and itching and scratching ag- gravate the patient's anxiety.

As the child grows older, the problems associated with AD increase. Other persons tend to avoid the child, seemingly fearful of contamination (the leper effect), and devel- oping peer relationships suffer. School problems include increased absenteeism, impaired performance because of sleep deprivation, and decreased ability to concentrate as self- consciousness intrudes on learning ability.32

A subject with cutaneous atopy often is found to be tense, insecure, and aggressive and to have most or all of the following characteristics: feelings of inferiority and inade- quacy, repressed hostility toward parental

figures, affective hypersensitivity, emotional instability, sexual difficulties with masochistic tendencies and cutaneous eroticism, and a fairly high level of intelligence."" No constant, specific personality type, however, was found in patients with AD.77 What has been noted throughout all the investigations is that most patients with AD display some form of emotional disturbance?, 81 They usually are repressed persons who internalize their problems and express their anxious and hostile emotional conflicts by scratching.56* 72 Whit- lock116 and Champion and ParishI2 have indicated that atopic subjects have "conflicting" personality profiles.

Atopic subjects are more likely than others to respond with itching and scratching to fairly minor signals and stimuli, and some of those signals are more profoundly significant in psychodynamic terms than would appear on the surface.56 Excitability and arousal of the CNS from an emotional upset can inten- sify the vasomotor and sweat responses in the skin and lead to the itch-scratch response. This is compatible with the observation that many patients experience an emotionally dis- turbing event before an attack of AD.116 The emotional upset lowers the itch threshold and triggers the scratch res~onse .~

Excessive anxiety is known to correlate with ease of conditioning, and patients with AD are conditioned more readily to scratch responses than are their matched control counterpart^.^^, 53 It is probably relevant that in moments of frustration or embarrassment many normal persons also tend to scratch at sites that are typically affected by AD.

AD also alters the personality. Because of the unsightly skin changes, difficulties en- countered in personal relationship are under- standable. The patient is judged unfairly because of an unsightly appearance, which can be an emotional threat. Nighttime awakening because of violent itching also takes its toll on the patient's disposition and per~onality.~~

The pathway from the emotional phenom- ena, which the authors have tried to describe, to the triggering of the various phases of the disease phenomenon typical of AD still remains to be clarified fully. There may be glimpses of the basic structure in the experimental acquisitions of modern psychoneu-


-1- (scratching) 4

roendocrinimmunology; its multifactorial pathogenesis makes AD a good model for the preparation of an integrated hypothesis of biological psychos~matics.~~~ 48, 49* 85, 86

A further essential step toward specifica- tion of the relays between psyche-emotion- stress (simplistically summarizing in this term the complex psyche-emotion factors characteristic of the psychological evolution of the patient with AD) and peripheral response was mastered with the findings of experimental studies on neuropeptides and their receptors, specifically their identification and involvement in the CNS and peripheral organs, including the 84-86

The most significant findings regarding AD in this field are presented in Figures 5 through 9. Figure 5 shows a hypothetic outline of the pathogenesis of AD correlated with the possible influence of emotional stress (dotted lines) that was presented in 1984.84 Figure 6 illustrates the presumed influence of SP in the pathogenesis of AD (see also previous lists for functions of SP, CGRP, VIP, and NPY). SP has been shown in lichenoid infiltrate in the perivascular papillary dermis of

PRURITUS

AD subjects. Figure 7 shows the presumed influence of CGRP on the pathogenesis of this disease. CGRP-like immunoreactivity consis- tently is observed as free endings in the papillary dermis close to the dermoepidermal junction, with the same pattern and staining intensity in patients with AD and control subjects. A presumed influence of VIP on the pathogenesis of AD is presented in Figure 8. Levels of VIP are increased in lesional skin of patients with AD. Figure 9 presents a presumed influence of NPY on the pathogenesis of AD. NPY-like immunoreactivity has been detected in Langerhans’ cells in 6 of 11 patients with AD but not in normal control subjects; this NP is one of the most potent vasoconstrictor peptides (arteries and arteri- oles but not venous vessels) identified up to

Other peptides presumably involved, but without experimental evidence, in AD are the endorphins and somatostatin. Endorphins exercise various effects in different phases of the hypothetic outline shown in Figure 5, and

now.35, 37. 97

. . the endogenous opioids also represent neuropeptidergic system involved - in

the the

Figure 5. Hypothetic outline of the pathogenesis of AD correlated with the possible influence of emotional stress (dotted lines). CMI = cell-mediated immunity; H, = type 2 receptors for histamine; PGE = prostaglandin E.


PREDISPOSING GENETIC FACTORS

transitory deficit of

I

chemotactic deficit

9. abnormal response of membrane receptors - (P-adrenergic, HP, PGE)

4 abnormal cutaneous vasomotor response - cutaneous lesion - (scratching)

Figure 6. SP and AD. The possible points where SP may play a role are marked in black.

f t STRESS PREDISPOSING GENETIC FACTORS

(“POLYGENIC INHERITANCE)

transitory deficit of secretory IgA

defect in CD4

system - CD8 - T- lymphocyte - I 4 . .

chemotactic deficit I

I abnormal response of membrane receptors (B-adrenergic, H2, PGE)

I I -~ I

4 abnormal cutaneous vasomotor response

cutaneous lesion 7 (scratching) <

Figure 7. CGRP and AD. The possible points where CGRP may play a role are marked in black.

414 I'ANCONESI & HAUTMANN

- abnormal response of membrane receptors (P-adrenergic, HP, PGE)


defect in A CD4 - T-lymphocyte System - CD8

cutaneous lesion

I

chemotactic deficit

- (scratching) PRURITUS

Figure 8. VIP and AD. The possible points where VIP may play a role are marked in black.


transitory deficit of secretory IgA

defect in CD4 - T-lymphocyte System - CD8 -

increased release of mediators by mastocytes

++ abnormal response of membrane receptors - (P-adrenergic, HP, PGE) A I

abnormal cutaneous vasomotor response

cutaneous lesion -(scratching) 4 PRURITUS

Figure 9. NPY and AD. The possible points where NPY may play a role are marked in black.


emotion-related pleasure/pain axis, fundamental to survival.

One can foresee that further biologic acquisitions in this field will fill in the dotted lines of the diagram in Figure 5, but further research is necessary. The activities of NPs presented here constitute a first step in ex- plaining and understanding the biologic psychosomatics of AD.

ALOPECIA AREATA

Alopecia areata (AA) is a fairly common form, often but not always reversible, characterized by the appearance of one or more hairless patches on the scalp or beard region (or even other body areas), with clearly defined margins, without clinical signs of inflammation, and with a tendency to centrifu- gal extension. In the majority of cases, the affection tends to heal spontaneously, but in some it leads to total alopecia, sometimes de- finitive, especially in cases with prepuberal onset. This disease is believed to be characterized by the sudden precipitation of anagen stage hair follicle into early catagen. The cause of this affection is unknown, but two pathogenetic aspects await conclusive dem- onstration: the psychosomatic genesis and the autoimmune genesis. Greenbe~-g~~ investi- gated 45 patients with AA and found psycho- neurotic disturbances in 72%, psychotic structure in 970, and schizophrenia in another 9%. Only three of his patients had no mental af- fections. mentioned a dramatic increase in the number of AA patients during the last weeks before the Allied invasion in the summer of 1944 during World War 11. Anderson' reported that 23% of his patients with AA had a shock or another acute anxiety experience in their personal history and that an additional 22% suffered from mental disturbances. More recently, there have been reports of increased incidence of relevant life events in relation to AA.50 After a review of the literature on psychiatric events in AA, Egele and TauschkeZ0 identified three groups of patients: (1) those with an ongoing feeling of loss, (2) those with life events and anxious, reserved, and depressive behavior, and (3) those with personality changes caused by life

events in connection with rejecting or over- protective mothers. Furthermore, the authors tried to relate psychiatric life events to immunologic T-cell disturbances with subsequent immunodeficiency.*" Colon and coworkers'5 recently administered the structured Diag- nostic Interview Schedule to AA patients. They determined that 74% of the 31 patients under evaluation had one or more lifetime psychiatric diagnoses. Also noteworthy were the high prevalence rates of major depression (39%) and generalized anxiety disorder (39Y0).'~ Koo et alS9 have recently observed prevalence rates of psychiatric disorders associated with AA to be higher than those in the general population, confirming that AA patients may indeed be at higher risk for development of a major depressive episode, generalized anxiety disorder, social phobia, or paranoid disorder at some point during their clinical course.

The authors also found (40 years ago) in patients with AA a high incidence of signs of neurosis and psychic "disreactivity," true mental diseases, abnormal reactions to events and stressors, and states of hypermotivity and anxiety. Findings of acute (37% of the cases) and protracted (52%) psychic trauma were based mainly on interviews and the results of psychodiagnostic tests, above all the Rorschach test.87,

To the contrary, Cipriani and coworkers'3 reported no statistically significant differences between 48 patients with AA, 30 with common baldness, and 30 with fungal infections, in regard to incidence of neurotic symptoms, suggesting that there is no correlation between AA and neurotic symptoms.

The authors recently focused their attention on the alexithymic component in patients with AA. The term ulexithymiu was coined by S i f n e o ~ ' ~ ~ to denote a cluster of cognitive and affective characteristics, including marked difficulty describing subjective feelings, im- poverished fantasy, and a cognitive style that is literal, utilitarian, and externally oriented. As the early empiric findings and observa- tional reports converged, the construct of alexithymia was formulated to include the following salient features: (1) difficulty in identifying and describing feelings, (2) difficulty in distinguishing between feelings and


the bodily sensations of emotional arousal, (3) constricted imaginative processes, as evidenced by a paucity of fantasies and, (4) an externally oriented cognitive style.79 In the authors’ research, they found that the majority of patients with AA unresponsive to each type of treatment were alexithymic.16, 17, 66. 67, 74

Moreover, their previous studies (com- pleted in 1955) evidenced an altered cutaneous reactivity to various vasoactive substances in circumscribed alopecic areas, leading to the hypothesis of local alterations of enzymatic activity, such that fewer of the catecholamines released by emotional stress were destroyed, leaving a larger quantity free to act.93 They studied 72 subjects with AA specifically for (1) evaluation of bleeding time in lesional and apparently noninvolved scalp, (2) analysis of the perivascular and peribulbar infiltrate for phenotyping and adhesion molecule expression, (3) endothelial and peribulbar related plasminogen activator activity, (4) ultrastructural study of the infiltrate and microvessel alterations, (5) visualization of neuropeptidergic cutaneous fibers, and (6) local transcutaneous oxygen tension (PTCO,) before and after apposition of a heated (42°C) Clark polarographic oxygen sensor. The authors’ findings allow them to hypothesize that microvessel alterations represent an important step in the pathogenesis of the disease, as shown by the reduced bleeding time in affected scalp and the ultrastructural abnormalities of the microvessels. The vaso- spasm documented may be related to the relative lack of neuropeptidergic fibers containing the vasodilating peptides (SP, CGRP, and VIP) and the persistence of the vasoconstrictor NPY neuropeptide. The vasoconstrictor and intraperivascular deposits of fibrin account for the reduced PTC02, which could play a role in the sudden precipitation of the anagen stage follicle into early catagen. The expulsion of the hair could be related to the release of proteinase (namely, urokinase), presumably released from the peribulbar infiltrate with consequent activation of latent tissue collagenases and elastases. Finally, in the authors’ experience, immunologic alterations seem to play an important role only in the early phase of the disease, whereas in the

late phase, extraimmunologic factors (mainly thickening of the basal membrane of microvessels) appear to be involved primarily in maintaining the disease (Fig. 67, 74, 89

URTICARIA

As Rook states, urticaria is “a disease which has suffered more than most from fac- ile thought-sparing generalization^."'^^ The first of these is certainly the equation of urticaria with allergy: the common, well-known urticaria is allergic, that is, immunologically induced, in only a minority of cases, whereas it sometimes may be an emotional allergy (see following discussion). A large series of the same effectors that act as vasodilator- vasopermeabilizer agents cause extra-allergic urticarias (the majority of urticarias), among which we find those caused by physical agents such as trauma, pressure, cold, heat, sun, and even contact with water. As far as psychosomatics is concerned, the forms that stand out are factitious urticaria and so-called cholinergic urticaria, in both of which every- one seems to admit an emotional component.84

References to urticaria caused by psychic disturbances began long ago. Wilson observed that urticaria could be “caused by mental excitement, anxiety, and nervous debility,”84 as did Hebra, Tilbury Fox and, successively, Stokes, who in the 1930s, spoke of the action of psychic factors in 79% of all case of urticaria.’16 The observations then became so numerous that they cannot all be referred. They are described by Obermayer?’ who places urticaria with the “dermatoses in which emotional factors usually contribute an important element.” Wittkower and proposed an interesting interpretation based on the investigation of 35 “unselected patients” who submitted to personality studies: two thirds ”stated spontaneously that they missed parental and especially maternal affection as children” when, they emphasized, they had a frequent ”need of love.” Within limits, these findings are a suggestive reminder of those regarding AD and, more generally, atopy, which seem to include at least a part of the urticaria cases. These au-


Reduced storage of vasodilatant neuropeptides

(SP, CGRP, VIP) and persistence of NPY Reduced catabolism

of vasoactive amines

Induction of endothelial

release of t-PA

Antigen CD6 expression on bulbar keratinocytes

Vasoconstriction

Reduced transcutaneous passage of oxygen

and Langerhans’ cells

1 Release of IL-1 *-

I I Auto-maintenance of the disease J.

Lymphocytic activation

1 Release of

lymphokines (./-IFN, TNF-a)

I ’ HLA-DR expression

on keratinocytes

.). Trafficking of lymphocytes

toward bulbar region

1 Release of

lymphokines and urokinase by lymphocytes

1 Intraperivascular fibrin deposits

Activation of elastases and collagenases

1 I I Reduced transcutaneous I

Figure 10. A hypothesis of pathogenesis of alopecia areata.

thors117 also reported the most frequent psy- chopathologic facts regarding their urticaria patients: ”repressed aggressiveness, maso- chism, repressed exhibitionism, and regres- sive revival of infantile skin erotism. Instead of hurting, scratching, and attacking their love-denying objects these individuals scratch themselves and develop ”attacks” of urticaria. Urticaria1 wheals seem to represent a compromise between an tinconscious desire to draw the observer’s attention to the sufferer’s skin on the one hand, and feeling of guilt and need for self-punishment for these wishes on the other.” The authors’ experience

shows that urticaria subjects as a group have constant personality characteristics: marked hyperemotivity and anxiety, frequent and extreme states of worry, sensitivity, basic sense of insecurity, and little self-~onfidence.~~ In the authors’ experience, urticaria seems to have the least somatopsychic impact of all the cutaneous eruptions: only the severe forms have any significant impact, usually for fear that eruption will spread or because of the danger of anaphylactic shock or edema of the larynx in those cases in which the patient knows of these possibilities.

Another aspect is possible in urticaria: the


Eliciting Factors Modulating Factors Exogenous Endogenous

1

environment, temperature, foods, hormones, stress

(Neuropeptides)

IgE, C activation I I \ \ I

H Lymphocytes 1

Cytokines HRFs

Histamine-releasing Substances

Physical Stimuli temperature, water, trauma, vibration, physical exercise

Inflammatory Factors

eosinophil cationic proteins histamine, PGs, LTs, LTB4, PGs, 02, enzymes -

Psychic Conflicts

Figure 11. Urticaria angioedema: pathogenetic mechanisms. PGs = prostaglandins; LTs = leuko- trienes; NPs = nucleoprotein; K mins = kinins; HRFs = hormone-releasing factors; LTB, = leukotriene B,; 0, = oxygen. (Data from Mathews KP: A current view of urticaria. Med Clin North Am 58:188, 1974.)

symbolic value that the wheals seem to as- sume because, at least in psychosomatic urticaria, they emphasize the biologic mechanism. This mechanism proposes the following peculiar characteristic of a wheal: (1) sudden, lightning quick appearance (like emotion); (2) representational qualities, sudden redness and swelling, which almost signify the explo- siveness of an emotive-affective reaction, such as resentment, anger, and aggressiveness (as well as their equivalents on the skin because they are unexpressed and the skin is the only or the preferred path of expression); (3) presence of pruritus (and burning sensation), sometimes extreme, and with consequent scratching (even compulsive), signifying anger, tension, and aggressiveness (and "let- ting it out" through the skin), as well as embarrassment and shame; and (4) the sudden disappearance of the reaction, which seems to represent "relaxation by falling" similar to (or caused by) the exhaustion of the emotional tension.84

Life stressor events often act as triggering elements, and in many cases, the urticaria1 eruption seems to acquire the value of a means for avoiding strongly anxiety-provoking situations. Griesemer and N a d e l ~ o n ~ ~ place urticaria among the dermatoses with the highest incidence of emotional triggering, 68% of cases, and give it a minimal biologic incubation interval of only minutes. In the authors' experience, however, there are two paradigmatic forms of psychogenic urticaria, an acute emotional form that follows specific events in a clear cause-and-effect relationship and a chronic-recurrent form that seems to be structured deeply on a psychodynamic basis as a psychosomatic disease. In both forms, hyperemotive-anxiety traits have been evi- d e r f ~ e d . ~ ~ Urticaria is more an emotional "allergy," more an emotional and psychic allergy than a real "allergic" disease. In specific immunologic tests, immunoglogulin E-dependent induction is evident in only a minority of cases (< 20%). Emotional stress can


stimulate mast cells and IgE activity and influence release of vasoactive substances, the protagonists of urticaria, with the involvement of certain neuropeptides such as SP, CGRP, and VIP. In the schematized pathogenesis of urticaria-angioedema (Fig. ll), the relevance of neuropeptides is seen; they could be endogenous-modulating factors acting directly on mast cells and eliciting factors released from sensory nerve endings acting on micro~asculature.~~

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Psychophysiology of Stress in Dermatology

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