Management of Primary Psychocutaneous Disorders: the role of inflammation in skin-psyche interactions

Introduction

Psychodermatology is a field that studies the relationship between the psychology and skin condition, including psychocutaneous disorders. Recent studies showed that psychological stress is closely related to the severity of skin diseases. Therefore, when treating skin diseases, clinicians should have a vast understanding not only of the biological factors, but also the psychological and social state of the patients to determine the most suitable approach [1]. Conversely, the skin condition could also affect the patient’s mental state in which the more severe the skin disease, the more severe the psychological stress, thus eventually affecting the patients’ quality of life [1, 2].
Up until now, studies have shown that there were three ways through which stress can affect the skin (fig. 1) [3].
The mechanism in which psychological stress might contribute to the worsening of skin diseases is not fully understood. One of the proposed theories is that mental stress might invoke the release of stress mediators, such as neuropeptides and proinflammatory cytokines through the hypothalamic–pituitary–adrenocortical (HPA) axis since the levels of such mediators were reported to be elevated in patients with major depression disorder and associated with the severity of skin diseases [3, 4].
In addition, the physiological human’s physiological response when exposed to stressors is the enhancement of the sympathetic activity, over-activation of the HPA axis, and the release of inflammatory markers, including C-reactive protein (CRP), interleukins 1β (IL-1β) and interleukins 6 (IL-6) and tumor necrosis factor a (TNF-a), thus aggravates the inflammatory skin diseases by promoting inflammation and keratinocyte proliferation [4].

Classification

Generally, there is no standard classification system of psychocutaneous disorders. However, in 2021, Ferreira and Jafferany managed to classify the disorders into three groups [5]:
● Group A: Primary psychodermatological diseases.
The psychological stress, psychological mechanism, and/or psychopathology act as the main contributing factors either by inducing or worsening primary dermatoses, e.g., atopic dermatitis, psoriasis, chronic spontaneous urticaria, alopecia areata (AA), acne vulgaris, seborrheic dermatitis, lichen simplex chronicus, and vitiligo.
● Group B: Primary psychodermatological illnesses.
In this type, there is no primary dermatosis lesion. However, the dermatological symptoms occurred with or without the self-induced skin lesions (such as excoriations), e.g., psychogenic pruritus, body dysmorphic disorder, delusional infestation, self-inflicted skin lesions, dysesthesias, and vulvodynia.
● Group C: Secondary psychodermatological disorders.
This group consists of the psychiatric complications of dermatology medications or dermatology side effects of psychotropic medications. This class is further divided into two, such as the secondary dermatologic diseases due to psychiatric medications, and secondary psychiatric conditions associated with dermatological treatment.

Pathophysiology

The central nervous system (CNS) and skin are connected due to their embryological origins (the ectoderm), thus there are similarities in the system’s hormones, neurotransmitters and receptors [6]. Skin can act both as the stress perceiver and as the target of stress responses. The brain-skin axis, HPA axis, plays an important role in the interaction of the skin and psychological stressors. When a human is exposed to stress, the hypothalamus responds by secreting corticotropin-releasing hormone (CRH), which then induces the pituitary gland to secrete various neuropeptides including adrenocorticotropin (ACTH). In the adrenal gland, ACTH stimulates the production of glucocorticoids including cortisol and corticosterone. Cortisol is the primary hormone that influences stress response in human body. In the skin, cortisol plays a major role in immune and inflammation system. In addition, cortisol has been found to increase DNA damage [7].
On the other hand, the HPA system also resides in the skin, in which CRH and ACTH are produced locally by epidermal and hair follicle keratinocytes, melanocytes, sebocytes and mast cells. These hormones are pro-inflammatory hormones and are released when the skin is exposed to stressors such as immune cytokines, UV irradiation, and cutaneous pathology. The major population of skin cells in the epidermis, dermis, and subcutis layers expresses the CRH receptors 1 (CRH-R1), while the CRH-R2 is expressed in the hair follicle keratinocytes and papilla fibroblasts. Therefore, the high production of CRH during stress also leads to the local ACTH and corticosterone production in the skin [7].
Another pathway in which psychocutaneous disorders might develop is through the sympathetic-adrenal-medullary (SAM) axis. During stress, the inner layer of adrenal medulla secretes epinephrine and norepinephrine, which causes blood vessel constriction, and eventually decreases skin blood flow and induces inflammation. In addition, the skin itself also has a peripheral system where epinephrine is produced in keratinocytes while the receptors are available in both keratinocytes and melanocytes. Therefore, when a patient had stressors either from psychological tension or directly in the skin, both HPA and SAM axes ultimately increase sympathetic activity, and release the proinflammatory cytokines, which can aggravate inflammatory dermatological diseases, as shown in figure 2 [2–4, 8].
In addition, patients with skin diseases often show maladaptive coping responses along with problems in body image, self-esteem, fear of stigma from society, and embarrassment regarding their appearance. Those kinds of stressors will then also contribute to the severity of the skin diseases [4].

Psychocutaneous disorders and treatments

Treatment of psychocutaneous disorders should address both the patient’s skin conditions and their mental state. Thus, a multidisciplinary approach is preferable, and the therapeutic team should include a dermatologist, a psychiatrist, and a psychologist to provide high-quality care. The purpose of treatment is to allow patients to have an uninterrupted social life while also controlling their cutaneous symptoms, allowing them to improve their quality of life [9, 10].

General approach

Managing any psychocutaneous disorder needs patience and time. In addition, maintaining a good rapport and comfortable relationship with the patients is crucial. Identifying the psychological stressor should be performed slowly, and any sensitive information such as the relationship with the spouse or other family members, the feelings of humiliation, guilt, shame about skin diseases should be asked at the end of the session or be kept for the next visit. However, any possibility of organic causes of the skin conditions must be ruled out first before considering the psychological stress as the primary cause [11]. In addition, including psychotherapy in treating patients with psychocutaneous disorders might also be beneficial. One study showed that a cognitive behavioral therapy reduced depression, anxiety, and stress caused by dermatological conditions including psoriasis [12].
In pediatric population, psychological disorders come in a range of symptoms. Symptoms of various skin conditions such as atopic dermatitis and psoriasis might be worsened by stress. In addition, scratching may also increase and the child might learn to use it as a tool for seeking attention from the parents. Therefore, managing psychocutaneous disorders in children is more challenging. The prognosis is better for the patients when the parents understand the nature of their children’s condition, including the management, prognosis and are able to explain it to the children in an age-appropriate manner [11].
Recently, Eckardt et al. performed a randomized controlled trial studying a technique for reducing the symptoms of psychocutaneous disorders particularly psoriasis. The technique involved directing the patients’ mind and attention to the present moment in a purposeful and non-judgmental manner. This action was called mindfulness and can be trained through interventions such as mindfulness-based stress reduction (MBSR) or mindfulness-based cognitive therapy (MBCT). The study showed that there were positive effects of the mindfulness intervention in patients with psoriasis. However, further studies are still needed to confirm the exact usefulness of this therapy [13].

Psoriasis

Psoriasis is a chronic proliferative and inflammatory condition of the skin. The lesion associated with this condition is erythematous plaque usually covered with thick and silvery scales [4, 6]. It usually appears on visible areas and joints, thus giving major impacts on quality of life and increases the psychological stress and body dissatisfaction [14]. In addition, the treatment of psoriasis is already a source of stress since the patients usually are prevented from doing things they might enjoy. Bulat et al. concluded that psoriasis has a strong impact on patients’ life as it influences the working habits, poses a significant financial burden, and significantly impairs their quality of life and psychological status [14].
Psoriasis patients’ skin responds to psychological stress by oversecretion of cytokines (e.g., IL-6, IL-1, interferon-γ (IL-γ)), corticosteroid production, and activation of skin peripheral (CRH, proopiomelanocortin (POMC)-derived adrenocorticotropic hormone (ACTH), melanocyte-stimulating hormones (MSH) [4].
The European Academy of Dermatology and Venereology (EADV)’s consensus on psoriasis treatment recommended the conventional systemic therapy for plaque-type psoriasis, including acitretin, cyclosporine, fumarates, and methotrexate (fig. 3) [6].
However, psychological stress had not been included as an important factor that needs to be analyzed in the EADV’s recommendations. Instead, the Dermatology Life Quality Index (DLQI) score was used to define a successful treatment along with the Psoriasis Area and Severity Index (PASI). A cut-off improvement value in PASI score of only 50% but with a DLQI score of equal to or lower than 5 was enough to be considered as a success, whereas a DLQI score above 5 was considered as treatment failure [6]. Among all DLQI variables, a study by Suryawati et al. observed that two variables (“symptoms and feelings” and “daily activities”) were found to have a positive correlation with stress [15].
Although there is no specific guideline in targeting the psychological stress in treating psoriasis, lifestyle modification to reduce stress has been proven effective in alleviating the symptoms of psoriasis. The study observed that dietary modification along with exercise reduced the severity of psoriasis. Lifestyle changes that showed the possibility of improvement in psoriasis included a low-calorie-diet, alcohol abstinence, smoking cessation, and exercise [16].

Atopic dermatitis

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases with significant pruritus and phases of exacerbation and remission. It is usually associated with other manifestations of atopy, such as allergic rhinitis and asthma. All of these signs may appear simultaneously or at different times, with AD as the starting step of the so-called “atopic march” [17].
The pathogenesis of AD includes epidermal barrier dysfunction, changes in cell-mediated immune responses, IgE-mediated hypersensitivity, and environmental variables. The clinical symptoms of AD are associated with an increased risk of developing mental disorders such as depression, anxiety, and suicidal ideation [17].
In patients with AD, psychological stress can also exacerbate the AD symptoms. Therefore, the consensus-based European guidelines for treatment of atopic dermatitis in adults and children showed that AD should be treated in both medical and psychosomatic aspects (fig. 4) [18].
Research showed that dietary modification was also helpful in treating AD. Nutritional balance is important, including the balance of fatty acids, probiotics, and vitamins. In addition, avoiding allergens in daily food plays a pivotal role in reducing symptoms of AD. Patients may also need to consult a nutritionist for personalized dietary recommendations [19].

Acne vulgaris

Acne vulgaris (AV) is a multifactorial inflammatory dermatosis affecting the pilosebaceous unit. It is characterized by the development of comedones, either open or closed (blackheads and whiteheads, respectively) along with other inflammatory lesions such as papules, pustules, nodules, or cysts. AV is primarily reported in adolescents or young adults. However, it can also occur during adulthood. AV is associated with reduced self-esteem, depression, and social impairment, ultimately reducing the quality of life. Several factors are involved in the pathogenesis of acne, including stress, which activates the HPA axis, causing an increased level of CRH which stimulates the activity of the sebaceous gland and steroidogenesis, along with the production of IL-6 and IL-11 in keratinocytes. These mechanisms induce inflammation and aggravate acne development [5, 20].
In addition, exposure to stressors causes the peripheral nerves to release the neuropeptide substance P or vasointestinal peptide which stimulates the proliferation and differentiation of sebaceous glands and increases lipid synthesis in sebaceous cells. Psychological stress is also known to impact the skin barrier function and risk of particular bacterial infection on the skin, as well as delayed wound healing by up to 40%, thus impairing the repair of acne lesions [5, 20].
Current guidelines of the American Academy of Dermatology (AAD) on AV treatment stated that in AV the initial severity assessment should include not only the severity of the acne itself, but also the patients’ satisfaction with appearance and the impact on quality of life. In these guidelines, the first-line recommendation for mild acne consists of topical therapy of benzoyl peroxide (BP), topical retinoid, or antibiotics, all of which can be combined if necessary. In moderate-to-severe acne, systemic antibiotics might be considered. Other options include oral contraceptives, spironolactone, intralesional corticosteroids or isotretinoin, with the latter recommended especially for patients with psychosocial burden or scarring [21]. In addition, having a normal body mass index, balanced diet, and adequate sleep play important roles in decreasing the risk of acne development and its severity [22].
Another interesting study also recommended additional therapy in moderate-to-severe AV with Lactium, a biomolecule that possesses anxiolytic-like properties. It works by binding to g-aminobutyric acid (GABA-A)-A receptors in the central nervous system, decreasing neurotransmission and regulating anxiety and stress without sedative effects. The effects of Lactium include lowering serum cortisol levels, improving the quality and efficiency of sleep, reducing anxiety, general fatigue, and stress symptoms. Treatment with Lactium combined with standard acne management resulted in a decrease in inflammation, the number of acne lesions, and acne severity along with the improvement in the quality of life [23].

Seborrheic dermatitis

Seborrheic dermatitis (SD) presents with erythematous skin, pruritus, and skin scaling. The pathogenesis of SD is not fully understood. However, there are three hypothesized predisposition factors in SD development such as Malassezia colonization, lipid secretion by sebaceous glands and an underlying immune system susceptibility. In addition to these, stress is also involved in SD development by affecting the immune system (fig. 5) [24].
A study in Turkey by Gül et al. observed that SD is a psychosomatic disorder that requires a multi-disciplinary approach. The study showed that many psychiatric symptoms are considerably frequent in patients with SD and there were statistically significant higher rates of depression and anxiety in SD patients compared with the control group [25]. As mentioned above, psychological stress can induce the secretion of pro-inflammatory cytokines, thus increasing the SD severity. However, up until recently, psychological stress management has not been included in the consensus for SD. Regarding the management, there are numerous topical agents recommended for SD. The treatment of choice depends on the affected area (scalp or non-scalp area) and is summarized in figure 6 [26]. Moreover, a case-control study by Alshaebi et al. showed that dietary control might improve SD. Spicy food, sweets, fried food, and dairy products were shown to be the disease aggravators [27].

Lichen simplex chronicus

Lichen simplex chronicus (LSC), also referred to as neurodermatitis, is distinguished by the presence of a plaque with lichenification and a heavy scratch-caused itch cycle. A specific anatomical region, such as the posterior aspect of the neck, elbows, extensor, scrotum, vulva, ankles, and legs are usually affected. Predisposing variables include several illnesses, such as atopy, stasis dermatitis, as well as non-dermatologic conditions including anxiety, obsessive-compulsive disorder, depression, and sleep problems [28]. The study showed that 30% of dysthymic disorders and depressive disorders are the most common cause of LSC [9]. The pathophysiology of LSC includes HPA axis and autonomic nervous system that was activated by the CNS in response to psychological stress and later manifests as LSC. In addition, the study showed that there was an increase in the substance called neuro growth factor (NGF) in LSC. This factor would activate the immune mediator that eventually caused symptoms in the skin [28]. On the other hand, the patients’ quality of life was also further affected by the lack of sleep disturbance and pruritus caused by LSC [10].
The treatment of LSC is included in the guidelines for chronic pruritus in the European Dermatology Forum (EDF) and the EADV of 2019. The approach is arranged in combined, with each step also a step-by-step manner either consecutive or includes concomitant therapy such as antidepressants, psychosomatic care, and lifestyle modification through the behavioral therapy, as seen in table 1 [29].

Conclusions

It is clear that both psychological and dermatological conditions affect each other. A treatment approach that only addresses one aspect might not be effective. Clinicians should be aware that non-pharmacology managements such as behavioral therapy, lifestyle modification, dietary rearrangement, and mindfulness intervention are important and on some occasions are beneficial when applied before giving any medication, especially at the early stage of the disease. Therefore, both the mental state and any environmental factors of the patients with skin conditions need to be thoroughly evaluated. Thus, the authors of this study recommend a comprehensive, holistic, and multidisciplinary approach when facing patients with any dermatological conditions.

Funding

No external funding.

Ethical approval

Not applicable.

Conflict of interest

The authors declare no conflict of interest.

References