Dermatologic Clinics
Volume 14 • Number 3 • July 1996
Copyright © 1996 W. B. Saunders Company
From the Department of Dermatology, University of Florence,
Florence, Italy
Address reprint requests to Emiliano Panconesi, MD Department of Dermatology University of Florence 37, Via Alfani 50121 Florence Italy
In 1878, Bernard[5] first recognized the physiologic response of animals to environmental stimuli when he described the ''milieu interieur'' of the animal, characterized by its constancy, and the external environment, characterized by its variability. Cannon[10] later redefined this concept as ''homeostasis,'' in which a steady state is obtained by the optimal 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.[11] Selye[106] 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 subsequently 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. Mason[68] has shown that different types of stress such as fasting and heat shock produce dramatically 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 workers[23] ,[105] to include the 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 physiclogic responses of the host without producing any adverse effect, and such responses are said to involve eustress.[92] ,[105]
There are two main types of host factors that can influence stress.[76] ,[92] They are genetics and perception.
Evolutionary changes have led to marked differences in the adaptative physiclogic 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.
The most important factor that influences stress is the individual's perception of the challenge posed by the specific stimulus. Factors 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 helplessness.[76] Conditioning to stimuli also may occur in which the association between an aversive chemical stimulus and an immuno-modulating agent, given in combination, can evoke a conditioned state of immunosuppression 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 application (acute versus chronic), or whether the animal can escape the stressor if it is applied repeatedly (escapable versus inescapable).
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 ventilation can have a similar effect. Shearing, docking, and castration carried out during routine management also cause stress.
Overcrowding, hierarchic challenge, weaning, exposure to unfamiliar surroundings, or isolation can have a major behavioral impact on animals and evoke stress. Changes or restrictions in diet also can act as stressors, alone or in combination with other stressors such as physical restraint.
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 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. Because 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.[92]
Behavioral and psychological experiences involving stress, documented in animals, are what our patients propose to us every day. Overcrowding, hierarchic challenge, weaning, 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 equivalents.[92]
Because stress can be caused by environmental factors just as well as psychic re-elaboration, it is easy to perceive the relationship 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 considered only reductive necessity or abusive operative simplification for the investigator or doctor.
Psychosomatic medicine[83] ,[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] Nevertheless, 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 psychology, neuroendocrinology, and immunology into a new subspecialty called psychoneuroendocrinimmunology. Research in this multifaceted 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, neuro-peptides (NP), adrenocorticotrophin, catecholamines, corticosteroids, opioids, and cytokines, including lymphokines and monokines.[7] 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 similarities between the immune and neuroendocrine systems include the observation, in both systems, 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 smallest ones containing only two amino acids, with larger peptides consisting of 40 or more amino acids. In the nervous system, NPs fulfill many of the criteria of a neurotransmitter and neuromodulator. Many have been studied in other contexts as hormones, ''gut peptides,'' or growth factors.[46] ,[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 systems.[48] ,[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.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.
The skin and CNS are related embryologically 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.[6] This embryologic association between the skin and the CNS is the most likely basis for the finding 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 generous 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 unmy-elinated C fibers, including sensitive and au-tonomic fibers. It is well known that the skin is innervated by primary afferent sensory nerves, postganglionic cholinergic parasym-pathetic nerves, and postganglionic adrenergic 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 cord.[115] Ascending nerve tracts transmit this sensory information to the thalamus, which transmits it to higher cortical centers involved in processing cognitive information.[101] Descending pathways relay the sensory information back down the spinal cord, resulting in peripheral autonomic responses (e.g., vaso-dilation and sweating).[101]
Stimulation of cutaneous nociceptors by noxious stimuli (mechanical, thermal, or chemical injuries) influences nerve endings that are depolarized, and impulses are conveyed centrally and peripherally (antidromically). 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.[101] Stimulation of cutaneous nociceptors also causes activation of ascending pathways, resulting in enhanced electrical activity[102] and decreased levels of SP[31] 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. Activation of higher cortical areas during stress results in altered release of SP from the adre-nal gland by descending autonomic fibers.[111] Because some of these descending fibers innervate opioid interneurons in the dorsal horn[63] and these interneurons are connected anatomically to SP-containing nerves in the spinal cord, it is possible that descending au-tonomic nerves can trigger antidromic release of NPs in the skin. In addition to stress-induced alterations in SP levels in the CNS, increased concentrations have been reported also in serum 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 proposed.[60] ,[113]
The following lists review the main functions of SP, CGRP, VIP, and NPY.[48] ,[64] ,[91] Main Activities of SP:
Main Activities of CGRP:
Main ctivities of VIP:
Main Activities of NPY:
The skin occupies a powerful position as an organ of communication and plays an important role in socialization throughout the life cycle. It long has been recognlzecl that psychosomatic factors play a role in dermatologic disease. In agreement with Ironside,[51] the authors believe that an organ system is vulnerable to psychosomatic ailments when (1) several etiologic factors, including genetic and constitutional predisposition, are operable, (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 intra-psychic problems, and (5) social values and standards are linked with the organ system. Rook and Wilkinson,[104] in the well-known Textbook of Dermatology, open the chapter on ''Psychocutaneous Disorders'' with the affirmation 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; Obermayer[81] reported 66% and for Medansky and Handler[73] ''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.[19] 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 cosmetic 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. Psychological stress has been associated with increased CNS levels of opioid neuropeptides and also has been reported to exacerbate certain dermatologic conditions that have a psy-chosomatic 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 is a frequent, chronic, erythema-tous dermatosis with squamous accumulations. It may be circumscribed or disseminated with preferential sites (elbows, knees, scalp). It is presumed to be determined genetically, and it has typical histologic markers (capillary dilatation, sterile epidermal mi-croabscesses, parakeratosis) and accelerated epidermal turnover. In the vessels of the der-mal (''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 influenceable by acute or chronic emotional stress. Arnetz et al[2] 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. Under resting conditions, the groups were similar with regard to psychological and biochemical 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, progesterone, and urinary cortisol decreased in both groups during stressor exposure. The decrease 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,[112] one of the most important contemporary 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 protectiveness 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 Ryan[55] 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 confidence, and 24% depression. Twenty-six percent said that psoriasis caused family friction. Almost half curtailed athletic activities, especially swimming.[14] ,[52] ,[55] ,[61]
Several studies support the importance of psychosocial factors in the onset or exacerbation of psoriatic symptoms in 39% to 80% of patients.[24] 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 twins[25] 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 al,[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 psori-asis, but, with time, psychosomatic research has passed from reference to ''significant'' anamnestic episodes (the ''anedoctal'' period) to reference to ''personality profile'' held to be specific for the various dermatoses.[3] ,[29] ,[99] Numerous 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 depression,[29] increased tendencies for obsessiveness,[44] and increased expression of aggression.[71] Feelings of stigmatization and other emotional sequelae 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, symptomatic, 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 psychoneuroimmunology of psoriasis.[28] Neuropeptides have been suggested to be of pathogenic importance in psoriasis,[28] ,[48] ,[64] ,[91] as a neuromodulatory factor underlying psoriasis flare or responsible for the maintenance of psoriatic lesions. According to this theory, the occurrence 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.[28] 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.[18] ,[25] ,[27] ,[78] ,[96] SP can influence inflammatory response by stimulating lymphomononuclear cells, altering endothelial cells, and degranulating 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. Induction 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.[70]
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 together with their neuropeptides play a key role in the pathogenesis of psoriasis.[47] ,[48] Considering 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, macrophages (Langerhans' cells and dermal dendrocytes), and the overlying hyperplastic keratinocytes. Such a complex and reciprocal interaction between keratinocytes and immunocytes 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-controlled interactions between TNF-alphaproducing 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 hyperplasia 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 reactions[41] because anatomically it is situated 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. Derreal 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 derreal 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.[70] 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 membranes[114] 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 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 cascade 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 production[42] ; the cyclosporine-induced improvement of psoriasis is probably caused by the property of this drug to inhibit TNF-alpha production.[100]
Atopic dermatitis (AD) is a common disease characterized by chronic or chronically recurrent lesions, with severe itching and scratchmarks, and eczematous papulovesicular 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 hyperkeratosis and parakeratosis, and perivascular infiltration of lymphocytes and histiocytes with exocytosis. The lichenified areas of the epidermis are thickened, and the papillary body is hypertrophic, permeated by inflammatory cells (lymphocytes and histiocytes). Moreover, 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 unusually 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 extend to many other areas and, on occasion, become diffuse. The disease becomes chronic. The periods of remission, practically nonexistent 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, localizing 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 Scandinavia, seems to emphasize that this strange affection comports also a strange and suspicious 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 continuation.[46] ,[49] , [65] ,[85] [86] [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 preweaned 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 maturation.[94] It has been shown that human preterm neonates who received tactile and kinesthetic stimulation gained weight more rapidly and exhibited more mature neurologic reflexes than did controls; they were also more alert.[109] Harlow,[45] in a series of famous experiments involving monkeys, showed that deprivation of touch, or contact comfort, in early life results in the development of inappropriately 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 semeiotics. 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,[81] 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 traumatizing 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 rejection.[75] ,[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 child.[56] ,[108] The disturbed parent-child relationship aggravates the existing dermatosis.[56] 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,[108] children with AD frequently are in conflict with an unattentive, unaffectionate, and inadequate mother; this results in an unconscious 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 detachment 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. Patients 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, demanding, and unhappy and needs more cuddling 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 regimen 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 subsequently with the rest of the world) begins, and the infant responds to unmet needs with self-stimulation and abusive scratching[56] A vicious cycle is created in which anxiety provokes itching, and itching and scratching aggravate 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 developing 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 inadequacy, repressed hostility toward parental figures, affective hypersensitivity, emotional instability, sexual difficulties with masochistic tendencies and cutaneous eroticism, and a fairly high level of intelligence.[110] 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.[9] ,[81] They usually are repressed persons who internalize their problems and express their anxious and hostile emotional conflicts by scratching.[56] ,[72] Whit-lock[116] and Champion and Parish[12] 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 intensify 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 disturbing event before an attack of AD.[116] The emotional upset lowers the itch threshold and triggers the scratch response.[4]
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 counterparts.[33] ,[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 encountered in personal relationship are understandable. 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 personality.[56]
The pathway from the emotional phenomena, 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 psychoneuroendocrinimmunology; its multifactorial pathogenesis makes AD a good model for the preparation of an integrated hypothesis of biological psychosomatics.[46] ,[49] ,[85] ,[86]
A further essential step toward specification 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 skin.[46] [47] [48] ,[84] [85] [86]
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 the endogenous opioids also represent the neuropeptidergic system involved in the 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 explaining and understanding the biologic psychosomatics of AD.
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 centrifugal extension. In the majority of cases, the affection tends to heal spontaneously, but in some it leads to total alopecia, sometimes definitive, 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 demonstration: the psychosomatic genesis and the autoimmune genesis. Greenberg[38] investigated 45 patients with AA and found psychoneurotic disturbances in 72%, psychotic structure in 9%, and schizophrenia in another 9%. Only three of his patients had no mental affections. Masters[69] 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 II. Anderson[1] 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 Tauschke[20] 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.[20] Colon and coworkers[15] recently administered the structured Diagnostic 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 (39%).[15] Koo et al[59] 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 re-suits of psychodiagnostic tests, above all the Rorschach test.[87] ,[88]
To the contrary, Cipriani and coworkers[13] 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 alexithymia was coined by Sifneos[107] to denote a cluster of cognitive and affective characteristics, including marked difficulty describing subjective feelings, impoverished fantasy, and a cognitive style that is literal, utilitarian, and externally oriented. As the early empiric findings and observational 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 (completed 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 (PTCO2 ) 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 vasospasm 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 PTCO2 , 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. 10).[66] ,[67] ,[74] ,[89]
As Rook states, urticaria is ''a disease which has suffered more than most from facile thought-sparing generalizations.''[103] 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 everyone 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.[116] The observations then became so numerous that they cannot all be referred. They are described by Obermayer,[81] who places urticaria with the ''dermatoses in which emotional factors usually contribute an important element.'' Wittkower and Russel[117] 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 authors[117] also reported the most frequent psychopathologic facts regarding their urticaria patients: ''repressed aggressiveness, masochism, repressed exhibitionism, and regressive revival of infantile skin erotism. Instead of hurting, scratching, and attacking their love-denying objects these individuals scratch themselves and develop ''attacks'' of urticaria. Urticarial wheals seem to represent a compromise between an unconscious 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-confidence[84] 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 symbolic value that the wheals seem to assume 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 explosiveness 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 ''letting 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 urticarial eruption seems to acquire the value of a means for avoiding strongly anxiety-provoking situations. Griesemer and Nadelson[39] 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 evidenced[40] 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. 11), 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 microvasculature.48
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