Advances in Integrative Dermatology

An authoritative overview of contemporary approaches to integrative skin health

The popularity of integrative medical treatment of skin disorders has increased significantly in recent years—requiring practicing clinicians to keep pace with continuingdevelopments in dermatological research and methods. Advances in Integrative Dermatology offers a comprehensive survey of this dynamic field, providing up-to-date information on both preventative and therapeutic approaches to skin health. Combining clinical medicine with complimentary treatment plans, integrative dermatology provides an innovative perspective to individual patient care.

This essential text explores new research in areas including the effects of stress and pollution on the skin, the importance of high-quality sleep, complementary methods of averting skin conditions, and more. Recognizing the impact skin disorders have on physiological, psychological, and emotional health, editors Katlein França and Torello Lotti illustrate key components of inclusive skin health strategies, such as therapeutic diets and nutritional supplements, topical botanicals, and other complementary therapies. Filling a significant gap in current literature on integrative dermatology, this valuable resource: 

• Answers the common questions asked by patients in real-world dermatology practices
• Addresses pervasive misconceptions of integrative dermatological methods and principles with evidence-based review of current practices
• Examines contemporary research in the diagnosis and treatment of dermatological disorders
• Presents comprehensive treatment options for a wide range of conditions such as rosacea, melanoma, and psoriasis

Advances in Integrative Dermatology is an indispensable volume for physicians seeking to incorporate holistic techniques into their practices, expand their knowledge of integrative medicine, and provide the best possible care for their patients. 

• Language: English
• Publisher: Wiley
• Release date: Jan 22, 2019
• ISBN: 9781119475880

Book preview

1

Advances in Integrative Dermatology: Modifying the Concepts from the Past to Change the Future of Dermatology

Katlein França1,2 and Torello Lotti1

¹ Centro Studi per la Ricerca Multidisciplinare e Rigenerativa, Università degli Studi Guglielmo Marconi, Rome, Italy

² Department of Dermatology & Cutaneous Surgery; Department of Psychiatry & Behavioral Sciences; Institute for Bioethics & Health Policy, University of Miami Miller School of Medicine, Miami, FL, USA

Every writer creates his own precursors. His work modifies our conception of the past, as it will modify the future.

Jorge Luis Borges

Introduction

Medical practices that reside outside the mainstream medical structures have existed for centuries. [1] The origins of medicine are deeply rooted in civilization's cultural beliefs, experiences, and observations, and those practicing medicine believed that the body and the mind were not two separate entities. In the 1600s Rene Descartes, in an attempt to protect the body from spirits, separated the body from the mind. This was the beginning of evidence‐based medicine where the understanding of parts would lead to an understanding of the whole [2]. Subsequent developments such as antibiotics, other pharmaceuticals, anesthetics, and sterile surgical procedures gave a different perspective to medicine [3]. In particular, the discovery of antibiotics in 1928 boosted the pharmaceutical model we have today which emphasizes drugs as a primary means to treat disease. In Western civilizations, complementary and alternative medicines (CAMs) only began to re‐emerge after the 1960s with the awareness that chronic diseases were replacing acute diseases as the predominant health problem, and that a reductionist pharmaceutical model alone could not be sufficient for the prevention or treatment of these chronic diseases [4].

Different concepts and terms were given to describe the Integrative Medicine field: holistic medicine, alternative or complementary medicine, and then complementary and alternative medicine(CAM) [5]. The authors of this chapter understand that Integrative Medicine encompasses the coordination of conventional medicine with complementary therapies. The same concept applies to the Integrative Dermatology field. The skin is the largest organ of the human body interacting with other organs and responding to psychological, endocrines, and nervous stimuli through the Psycho‐Neuro‐Endocrine‐Immune system [6]. The integrative approach consists of a comprehensive evaluation of the physical, biological, psychological, social, and environmental overlapping aspects that affect the patient's life, offering them conventional and complementary therapies with scientific basis. The integrative approach is based on the concept that every human being has a diffuse brain that commands a cross‐talk of messengers (cytokines, neuropeptides, hormones, grow factors, etc.) involved in the Psycho‐Neuro‐Endocrine‐Immune system.

This book explores a new kind of dermatological healthcare. It is patient centered, and considers the physical, biological, psychological, social, and environmental aspects of the patient's life. It is based on dermatological healthcare promotion and skin diseases prevention, and embraces evidence‐based conventional and complementary therapies.

Integrative Dermatology: Conventional and Complementary Dermatology

Conventional Dermatology

Also called allopathic dermatology, mainstream dermatology, orthodox dermatology, or Western dermatology, this healthcare model of dermatology is generally taught in traditional medical schools and dermatology specialization programs. It uses evidence‐based knowledge and uses drugs, surgery, and minimally invasive procedures as a form of treatment.

Complementary Dermatology

Complementary dermatology refers to a group of diagnostic and therapeutic disciplines that are used together with conventional dermatology. Complementary dermatology is different from alternative dermatology. Whereas complementary dermatology is used together with conventional dermatology, alternative dermatology is used in place of conventional dermatology [7, 8] (Figures 1.1 and 1.2).

A circle labeled conventional dermatology added to a circle labeled complementary dermatology equal to a circle labeled integrative dermatology.

Figure 1.1 Integrative dermatology: combination of conventional dermatology and complementary dermatology.

Top: continuous cycle from physical to biological to psychological to social to environmental. Bottom: flow from dermatological health promotion and diseases prevention to incorporation of concepts of quality….

Figure 1.2 Pillars and principles of integrative dermatology by França and Lotti.

Pillars of the Integrative Approach

Physical Findings

What does the patient present, and is visible to the physician?

Greeting the patient is the first step to establish rapport between the healthcare provider and the patient. In general, a handshake seems to be the most appropriate way to start a consultation. However, religious and cultural aspects may interfere in this process, so the healthcare professional should remain sensitive to nonverbal cues that might indicate whether patients are open to this behavior. The physicians should introduce themselves using their first and last names and also call the patients by their first and last names, at least in the initial contact, following the national patient safety recommendations concerning patient identification. [9, 10]

The physician should ask the reason for the visit. The interview should address the duration and location of the patient's cutaneous diseases (if any), other diseases, family medical history, use of and allergy to medications, sun exposure, current and previous skincare regimens, daily habits including exercise and diet, and the patient's emotional state [11]. More questions should be asked during the physical examination as needed.

A complete skin examination is essential in the assessment of patients. All healthcare professionals should have a fundamental knowledge of the structures and functions of the skin in order to assess any changes to normal skin [12]. The ideal physical examination includes a systematic exam of the entire skin and its appendages. It is important to examine the skin for lesions that are directly related to the chief complaint as well as for incidental findings, especially for lesions that may be skin cancer [13].

A study published in the British Journal of Dermatology showed that in a nine‐month period, in a sample of 483 new patients, three patients (0.6%) had potentially lethal skin malignancies identified that would not have been diagnosed without a complete skin examination. Sixteen (3.3%) patients had basal cell carcinomas that would have been missed without a complete skin examination. This study confirms the traditional teaching that complete skin examination has the potential to reduce morbidity and mortality from cutaneous malignancy [14].

Dermatological equipment should be available during the physical examination, including: magnifying lens, dermatoscope, Wood's light, a microscope, and a camera to document the findings. França performed a study in Brazil with 307 patients and found that 57% of that sample considered that the use of devices (magnifying lens, dermatoscope) by the physician during the physical examination would be fundamental for the correct diagnosis of the disease. Although not always true, these patients may believe that the technology helps their physician to make their diagnosis [15].

This physical findings session emphasizes the need for a complete physical assessment to find the physical manifestations of the disease or complaint, and the findings that are visible to the physician.

Biological Factors: The Psycho‐Neuro‐Endocrine‐Immune System

What is the identity of the patient?

Biological factors refer to anything that could affect the function and behavior of a living organism. These factors could be physiological, chemical, neurological, endocrinological, and immunological, or a genetic condition which causes a psychological effect. Biological factors are seen as the primary determinants of human behavior [16]. The psychobiological concept involving the Psycho‐Neuro‐Endocrine‐Immune System is particularly useful for the study of dermatological diseases. The Psycho‐Neuro‐Endocrine‐Immunology (PNEI) is a scientific field of study that investigates the link between multidirectional communications among the nervous system, the endocrine system, and the immune system, and the correlations of this cross‐talk with physical health of the skin. The authors emphasize that this innovative medical approach represents a paradigm shift from a strictly biomedical view of health and disease taken as hermetically sealed compartments to a more interdisciplinary and integrative one [17].

Psychological Aspects: Psychodermatology and Quality of Life

How does the patient think, feel, and behave?

Exploring the psychological aspects and emotional state of patients with skin disorders is one of the bases of the integrative approach. The skin is a visible organ and any disease affecting this important organ can cause psychological distress. On the other hand, psychological distress can also trigger certain dermatologic diseases [18]. This vicious cycle should be kept in mind when assisting a patient in the integrative dermatology clinic. Medical care can be significantly improved when the physician pays more attention to the psychological aspects of medical assessment and treatment [19].

A good doctor–patient relationship, as well as empathy, is fundamental for a successful conversation between the doctor and the patient and disease management. The patient's background, previous traumas, current feelings, and coping strategies should be explored during the consultation [19]. Skin diseases can affect the psychological state and quality of life of patients, affecting the health in general and the progression of the disease, as well as the patient's response to therapy [20]. Different dermatology‐specific measures are available such as the Dermatology Life Quality Index (DLQI), the Dermatology Quality of Life Scales (DQOLSs), the Dermatology Specific Quality of Life (DSQL), and Skindex. Other disease‐specific measures such as the Psoriasis Disability Index (PDI), the Psoriasis Life Stress Inventory (PLSI), and the Acne Disability Index (ADI) can be also useful in the clinical practice. There are instruments used for measuring QOL in the pediatric population such as the Children's Dermatology Life Quality Index (CDLQI) and for measuring the impact of atopic dermatitis on the families of affected children (the Dermatitis Family Impact [DFI] questionnaire). New versions of the current measurements and development of new ones are in process [21]. Chen explains that the improvement of health‐related quality of life (HRQoL) is a major goal of dermatology. Important targets in clinical dermatology include the identification of how the skin condition affects lives, quantifying this burden, and using this information to improve patients' lives on an individual basis [22].

Balance is often mentioned in personal development and well‐being circles. The concept and idea of a balanced life should be incorporated into the dermatology practice and discussed with patients. Bloom et al. define the domains for a balanced life and the list includes: health, family, spirituality, learning, primary relationship, sexuality, play, creative expression, emotional well‐being, career, finances, friendship, home, and service [23].

Social Perspective: Social Interactions that Worsen or Improve Patient's Lives

How does the condition affect the patient's social life? How can social interactions improve or worsen the patient's condition?

In 1934, Dr. George Minot wrote "a considerable fraction of the successful care and treatment of patients and, undoubtedly, the prevention of much illness is to be identified with the proper consideration of sociologic factors. The case of every patient who consults a physician has a medical social aspect. This social component of medicine may vary widely in importance, but frequently it plays a major role in diagnosis, prognosis, and treatment and in the prevention of disease and unhappiness." [24] There is a cycle where social behavior influences the disease, and the disease influences the social behavior [25]. More than a cosmetic problem, skin diseases can cause stigma and disfigurement that could lead to bullying and social isolation [26, 27]. Stigmatization is defined as having a discrediting mark that leads to social discrimination and alienation [28].

One of the most stigmatizing diseases affecting the skin is leprosy. For many centuries, this disease has been responsible for social segregation, depression, and anxiety. Over the years with the advancement of treatments and education of patients and the community, this situation has improved. However, it still poses a challenge for many cultures [29]. Psoriasis, a chronic, autoimmune and inflammatory skin disorder, is another challenging disease that causes rejection and stigma. Despite the fact that is not a contagious disease, it has a serious impact on the patients' lives and well‐being [30]. It is important for the dermatologist to ask the patient about their social relationships and how the disease is affecting their social life. A questionnaire named The Sociotype Questionnaire (SOCQ) containing 16 items that evaluate the quality of relationships through the dimensions of family, friends, acquaintances, and study/work colleagues (including four questions for each dimension) was developed to explore both structural and dynamic aspects of social networking. The SOCQ is pending publication [31].

Skin disorders can affect not only the patient's quality of life but also that of partners and other family members in very diverse ways. Basra and Finlay proposed the term the greater patient to determine the secondary impact of a patient's skin disease on the patient's family or partner. The ‘Greater Patient' concept describes the immediate close social group affected by a person having skin disease [32].

The concept of Social Medicine emerged in the nineteenth century and aims to understand how social and economic conditions impact health, disease, and the practice of medicine, and to foster conditions in which this understanding can lead to a healthier society [33]. Social support is necessary for the optimal management of certain skin conditions. Education and involvement of family members in the management of disease, or support groups with the presence of other patients and healthcare professionals, can help the patient to cope with their own condition and help others suffering from a similar disease. This helps the patient's empowerment process.

Environmental Overview: The Ecology and the Skin

How do the external and internal environments contribute to the development, exacerbation, or improvement of the skin condition?

Environment is defined as the circumstances, objects, or conditions by which one is surrounded [34]. The environment plays an important role in the skin's health. Exposures to smoke, pollution, ultraviolet radiation, different temperatures, toxic chemicals, or prolonged/repeated exposure to water are environmental stressors [35]. It is the level of exposure that determines if damage to the organism will result. Diseases such as contact dermatitis, halogen acne, chemical depigmentation, connective tissue diseases, and skin cancer, etc. have the influence of the environment in their etiology [29]. The effects of environmental stressors on the skin were described by França et al. These authors defined the concept of Environmental Psychodermatology as a developing area that studies the interaction between environmental and psychological stressors and the skin [36]. On the other hand, the environment can contribute to the improvement of certain skin conditions. For example, some patients with psoriasis may improve during summertime due to the exposure to UV rays. As part of the integrative approach, it is important to explore and understand the environment surrounding the patient and how this can affect the skin.

Another way of exploring the environmental perspective is considering the internal environment. The microbiota are an important part of the internal environment and understanding how these bacteria interact with the innate immune cells to generate immune tolerance, as well as how they interact with the brain through the gut‐brain connection, may open up opportunities for development of new therapeutic strategies in dermatology. [37, 38] (Table 1.1)

Table 1.1 Integrative dermatology healthcare model: key questions‐ by França and Lotti.

Conclusion

Integrative dermatology is an upcoming field of study that encompasses the coordination of conventional dermatology with evidence‐based complementary therapies. The integrative dermatology approach considers the physical, biological, psychological, social, and environmental aspects of the patient's life.

References

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2 Petri, R.P. Jr., Delgado, R.E., and McConnell, K. (2015). Med. Acupuncture.27 (5): 309–317. https://doi.org/10.1089/acu.2015.1120.

3 Sierpina, V. (2006). The history of complementary and integrative medicine. South. Med. J.99 (8): 906–907.

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5 Dattner, A. (2014). The history, research, education, and future of integrative dermatology. In: Integrative Dermatology (ed. R.A. Norman, P.D. Shenefelt and R.N. Rupani). Oxford, UK: Oxford University Press Retrieved 29 Sep. 2017, from http://oxfordmedicine.com/view/10.1093/med/9780199907922.001.0001/med‐9780199907922‐chapter‐30.

6 Lotti, T., Hercogova, J., Wollina, U. et al. (2015). Treating skin diseases according to the low dose medicine principles. Data and hypotheses. J. Biol. Regul. Homeost. Agents.29 (1 Suppl): 47–51.

7 Complementary Medicine: Available at: https://www.medicinenet.com/script/main/art.asp?articlekey=31077. Accessed on 11.29.2017

8 França, K. and Lotti, T. (2017). Complementary medicine and the role of integrative dermatology for the treatment of atopic dermatitis. Dermatol. Ther.30: e12469. https://doi.org/10.1111/dth.12469.

9 Laird, J.E., Tolentino, J.C., and Gray, C. (2013). Patient greeting preferences for themselves and their providers in a military family medicine clinic. Mil. Med.178 (10): 1111–1114. https://doi.org/10.7205/MILMED‐D‐12‐00360.

10 Makoul, G., Zick, A., and Green, M. (2007). An evidence‐based perspective on greetings in medical encounters. Arch. Intern. Med.167 (11): 1172–1176.

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13 Soutor, C. History and physical examination of the skin, hair, and nails. In: Clinical Dermatology (ed. C. Soutor and M.K. Hordinsky). New York, NY: McGraw‐Hill http://accessmedicine.mhmedical.com/content.aspx?bookid=2184§ionid=165458551.

14 Moran, B., McDonald, I., Wall, D. et al. (2011). Complete skin examination is essential in the assessment of dermatology patients: findings from 483 patients. Br. J. Dermatol.165 (5): 1124–1126. https://doi.org/10.1111/j.1365‐2133.2011.10483.x.

15 França, K. A dermatologia e o relacionamento medico‐paciente: aspectos psicosociais e bioéticos. Ed Juruá, 2012 Brazil.

16 Psychology dictionary: biological factor. Available at: https://psychologydictionary.org/biological‐factor Access on December 5th, 2018

17 França, K. and Lotti., T. (2017). Psycho‐neuro‐endocrine‐immunology: a psychobiological concept. Adv. Exp. Med. Biol.996: 123–134. https://doi.org/10.1007/978‐3‐319‐56017‐5_11.

18 França, K., Castillo, D.E., Roccia, M.G. et al. (2017). Psychoneurocutaneous medicine: past, present and future. Wien. Med. Wochenschr.https://doi.org/10.1007/s10354‐017‐0573‐3.

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21 Finlay, A.Y. (1998). Quality of life assessments in dermatology. Semin. Cutan. Med. Surg.17 (4): 291–296.

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23 Bloom, L. and Bloom, C. How to Rebalance and Out‐of‐balanced life. Available at: https://www.psychologytoday.com/blog/stronger‐the‐broken‐places/201509/how‐rebalance‐out‐balanced‐life

24Minot, G. (1934). Medical social aspects In practice. Arch. Intern. Med. (Chic).54 (1): 1–10. https://doi.org/10.1001/archinte.1934.00160130004001.

25 Russell, W.M. and Russell, C. (1983). Evolutionary and social aspects of disease. Ecol. Dis.2 (2): 95–106.

26 Barankin, B. and DeKoven, J. (2002). Psychosocial effect of common skin diseases. Can. Family Phys.48: 712–716.

27 Roosta, N., Black, D.S., Peng, D., and Riley, L.W. (2010). Skin disease and stigma in emerging adulthood: impact on healthy development. J. Cutan. Med. Surg.14 (6): 285–290. https://doi.org/10.2310/7750.2010.09053.

28 Hrehorów, E., Salomon, J., Matusiak, L. et al. (2012). Patients with psoriasis feel stigmatized. Acta Derm. Venereol.92 (1): 67–72. https://doi.org/10.2340/00015555‐1193.

29 Couto Dal Secco, R.G., França, K., Castillo, D. et al. (2017). Wien. Med. Wochenschr167 (Suppl 1): 27. https://doi.org/10.1007/s10354‐017‐0590‐2.

30 Łakuta, P., Marcinkiewicz, K., Bergler‐Czop, B., and Brzezińska‐Wcisło, L. (2017). How does stigma affect people with psoriasis? Adv. Dermatol. Allergol. Poste¸py Dermatologii i Alergologii.34 (1): 36–41. https://doi.org/10.5114/pdia.2016.62286.

31 Marron, S.E., Del Moral, R., Navarro, J. et al. (2018). The Sociotype in Dermatology. J. Eur. Acad. Dermatol. Venereol.32 (5): e188–e190.

32 Basra, M.K.A. and Finlay, A.Y. (2007). The family impact of skin diseases: the Greater Patient concept. Br. J. Dermatol.156: 929–937. https://doi.org/10.1111/j.1365‐2133.2007.07794.x.

33 McKeown, T. and Lowe, C.R. (1966). An Introduction to Social Medicine. Oxford and Edinburgh: Blackwell Scientific Publications.

34 Merriam‐Webster Dictionary Online: Access: https://www.merriam‐webster.com/dictionary/environment on November 16th, 2017.

35 English, J.S., Dawe, R.S., and Ferguson, J. (2003). Environmental effects and skin disease. Br. Med. Bull.68: 129–142.

36 França, K., França, A., and França, R. (2016). Environmental psychodermatology: stress, environment and skin. In: Stress and Skin Disorders: Basic and Clinical Aspects (ed. K. França and M. Jafferany). London: Springer.

37 Hu, Y., Wong, F.S., and Wen, L. (2017). Antibiotics, gut microbiota, environment in early life and type 1 diabetes. Pharmacol. Res.119: 219–226. https://doi.org/10.1016/j.phrs.2017.01.034.

38 França, K. and Lotti, T. (2017). The gut‐brain connection and the use of probiotics for the treatment of depression, anxiety and obsessive‐compulsive disorders in dermatology. Dermatol. Ther.30 (5): https://doi.org/10.1111/dth.12506.

2

Psycho‐Neuro‐Endocrine‐Immunology: A Psychobiological Concept

Torello Lotti1 and Katlein França1,2

¹ Centro Studi per la Ricerca Multidisciplinare e Rigenerativa , Università degli Studi Guglielmo Marconi, Rome, Italy

² Department of Dermatology & Cutaneous Surgery, Department of Psychiatry & Behavioral Sciences, Institute for Bioethics & Health Policy, University of Miami Miller School of Medicine, Miami, FL, USA

In the field of experimental psychology applied to medicine, the second half of the 1980s is characterized by Dr. Rober Ader and his colleagues. They theorized and divulged the principles of Psycho‐Neuro‐Endocrine‐Immunology (PNEI), the scientific field of study that investigates the link between bidirectional communications among the nervous system, the endocrine system, and the immune system, and the correlations of this cross‐talk with physical health.

The sentence For this is the great error of our day that the physicians separate the soul from the body (Hippocrates, sixth century BCE) clearly represents the primum movens of Dr. Ader's studies against the traditional scotomized medical view which is described, for example, by the assertion that the immune system is autonomous, with its self‐regulatory and functions separate and independent from the rest of the body.

Dr. Ader's initial research in the 1970s on the conditioning of the immune system by psychosocial factors become a cornerstone for studies that described the vast communications network among immune cells, hormones, and neurotransmitters; Ader's early observations were also confirmed by Ader himself and other researchers at Harvard University during the 1980s.

Thanks to Dr. Ader's work devoted to the postulation and the development of the new science of PNEI, these old views become less legitimate and, nowadays, the PNEI concepts guide the scientific community to a unified vision of the biological functions of the body [1–4]. The PNEI innovative medical approach represents a paradigm shift from a strictly biomedical view of health and disease taken as hermetically sealed compartments to a more interdisciplinary one. After years of ostracism and diffidence, mind–body interactions are now well recognized, deeply studied in the medical literature, and taught at most important medical schools.

In 1983 Dr. Ader wrote: Converging data from a variety of disciplines suggest that the immune system is integrated with other physiological systems and, like all such systems operating in the interests of homeostasis, is sensitive to regulation or modulation by the brain. Thus, the immune system stands as a potential mediator of a variety of psychophysiologic effects [5]. The concept of cross‐talk between PNEI system components and the pivotal role of the immune system clearly appear in these sentences.

More than 30 years have passed since Ader's pioneering observations and the PNEI concept is now well established and accepted, despite the initial resistances. An example of a modern, full, integrated medical approach to reduce job‐related distress symptoms (e.g. in healthcare workers) and adrenocortical activity is represented by Psycho‐Neuro‐Endocrino‐Immunology‐based meditation (PNEIMED) an innovative approach that combines the teaching of philosophy and meditation practice with biomedical analysis from a systemic and integrative perspective [6]. Moreover, from the biochemical point of view, the advances in the fields of molecular biology and physiopathology identified hormones, neuropeptides, cytokines, and growth factors as the signaling molecules involved in both physiological and pathological biological processes, are in clear accordance with the principles of PNEI

Bidirectional PNEI Cross‐talk in Dermatology: The Gut–Brain–Skin Axis

The key element of PNEI approach is represented by the concept of bidirectional cross‐talk [7] between the psychoneuroendocrine and immune systems (Figure 2.1).

Schematic representation of homeostatic control systems within the PNEI network, with P and N for central nervous system and neurovegetative systems, E for endocrine system, and I for immune system.

Figure 2.1 Schematic representation of homeostatic control systems within the PNEI network.

The psychoneuroendocrine system can influence the immune response and, therefore, the capacity of the organism to react against diseases; conversely, the immune system can influence the neuroendocrine functions of the whole body. Such cross‐talk among systems is carefully trimmed by feedback loops that simultaneously act in order to maintain the homeostatic equilibrium.

This complex interplay is mediated by a wide network of cytokines, hormones, growth factors, neuropeptides, and other intermediate molecules collectively named signaling (or messenger) molecules. These molecules are the ABC, the fundamental language of physiological cross‐talk which efficiently regulates cellular responses to both endogenous and exogenous stimuli.

The state of health or disease of a whole body can be depicted by the fluctuations of signaling molecules circulating levels: if the fluctuations are outside the homeostatic range (upper or lower than the physiological limits) we consider this status as a pathologic one.

Gut and skin roles and relations with other organs and tissues are paradigmatic examples of the PNEI logic. Gut and skin are crucial contact organs through which the mammalian body communicates with the environment. They share some important characteristics: they are richly vascularized and innervated, and they are also heavily colonized by specific microbial strains [8, 9]. Gut and skin can be considered as complex immune and neuroendocrine organs integrated into the whole immune–endocrine system and their correct functioning is crucial to guarantee the homeostasis and, consequently, the survival of the entire organism [10].

All the PNEI axes, such as the Gut–Brain Axis and the Gut–Skin Axis, are multi‐level networks; they are continuously physiologically modulated by the cellular signaling exchange driven by cytokines, neuropeptides, neurohormones, and other messenger molecules. In physiological conditions, this continuous cross‐talk maintains the PNEI homeostasis of the axes. Recently, the concept of Gut–Brain–Skin Axis has been discussed by Petra Arck and colleagues [11].

In 2009 the researchers observed for the first time the connection between the well‐known Gut–Brain Axis and Gut–Skin Axis and, through experimental data (in vivo mice model), described the effectiveness of a probiotic‐based treatment for the reduction of stress‐induced neurogenic skin inflammation and hair growth inhibition. These evidences are in line with the observations of John H. Stokes and Donald M. Pillsbury who first theorized the Gut–Brain–Skin unifying vision in 1930 [12] (a clear example of PNEI approach application ante litteram).

Arck and colleagues validated the unifying model Gut–Brain–Skin Axis in order to highlight the idea that beneficial effects on skin homoeostasis and skin inflammation can be achieved by the consumption of the right kind of probiotics.

The complexity of the Gut–Brain–Skin Axis induces a deep reflection on its regulation, with particular emphasis on the role of the signaling molecule involved in this network. The imbalance of the signaling molecule at skin level is linked with the majority of inflammation‐related and autoimmune skin diseases (Figure 2.2).

Image described by caption.

Figure 2.2 Schematic representation of the action of proinflammatory triggers on Gut‐Brain‐Skin‐Axis.

The Gut–Brain–Skin Axis is a PNEI microcosm that acts as a homeostatic controller not only of its own systems but of the whole organism. Both the intestinal mucosa and the skin have in fact nervous (are able to secrete neuropeptides and neurohormones), endocrine (are able to secrete hormones), and immune (are able to secrete cytokines) competence, and they are in intimate connection with other organs, systems and apparatuses. By virtue of these interactions it appears that the presence of a state of physiological inflammation represents a normal phenomenon both in the intestine and at skin level. The intestinal mucosa and skin are constantly exposed to a heavy antigenic charge, mainly represented by bacterial flora. The tolerance of the microbiota is the key physiological inflammation.

These PNEI concepts also offer the opportunity and the tools to study the inflammatory phenomenon in all its complexity, and to identify the homeostatic mechanisms governing all stages of the inflammatory phenomenon, from its onset to its resolution.

From a PNEI point of view, inflammation is such an essential physiological process, and it can be

homeostatically controlled to trigger, develop, and stop. The healthy status of an organism coincides with the condition of homeostasis, in which the vital parameters (pH, temperature, glycemia, and oxygen's partial pressure) are maintained within a precise and defined range, and whose deviation up or down is identified with the pathological state. Inflammation is fully embedded in the physiological functions of homeostatic control; there is thus a level of physiological inflammation that falls within the parameters of normality[13].

In the intestine, some physiologically controlled inflammation is necessary for immunological function, as regulatory immune cells are triggered by intestinal microbiota and food constituents in order to regulate pro‐inflammatory pathways and maintain the correct immunocompetence.

Phlogogenic events such as epithelial barrier disruptions, sudden changes of microbiota composition, altered immune balance, and, finally, homeostatic balance disruption can however contribute to disease onset. Physiological inflammation is overcome by a low‐intensity chronic inflammatory condition called Low Grade Chronic Inflammation (LGCI) [14–16].

LGCI and quali/quantitative alterations of the microbiota may contribute to the onset of local diseases characterized by alterations in the permeability of the intestinal mucosa (IBD [Inflammatory Bowel Disease], IBS [Irritable Bowel Syndrome], gluten sensitivity, and leaky gut syndrome).

Systemic diseases such as autistic spectrum disorders, the anxious‐depressive syndromes, Alzheimer's disease, type II diabetes, obesity, psoriasis, rheumatoid arthritis, BPCO (Bronco‐Pulmonary‐Chronic‐Obstructive pulmonary disease) and RRI (Recurrent Respiratory Infections) are also linked with inflammatory conditions and PNEI homeostasis alterations. Interestingly, skin microbial changes and loss of physiological immunocompetence are also related to some local and systemic diseases such as acne vulgaris, vitiligo, and atopic dermatitis (AD) [9, 12, 17].

Alteration of PNEI Homeostasis, Inflammation, and Dermatologic Diseases

Focusing the attention on skin compartment, it is important to remember that the skin's defense system is composed of three main levels: the skin's mechanical barrier, innate immunity, and acquired immunity [18, 19]. These levels play specific roles to react against external and internal inflammatory triggers. An example of the intercellular cross‐talk at the cutaneous level is the complex of signaling pathways that regulate the functional interactions between keratinocytes and melanocytes, fundamental for skin pigmentation. Keratinocytes produce growth factors and other signaling molecules which can drive melanocytes' migration, differentiation, and melanin synthesis. Keratinocyte‐melanocyte cross‐talk represents a small PNEI network at the epidermal level: the psychoneuro component is guaranteed by the embryologic origin of melanocytes which derive from the same embryonic layer that originates some neuronal cell lines, the neural crest [20]. The intercellular cross‐talk between keratinocytes and melanocytes is homeostatically regulated by growth factors and cytokines of endocrine origin. The immune function is linked with and represented by the involvement of melanocytes in the anti‐oxidative stress protective mechanisms mediated by keratinocyte‐derived b‐FGF (basic‐Fibroblast Growth Factor) (Figure 2.3).

Image described by caption and surrounding text.

Figure 2.3 Schematic representation of the keratinocytes‐melanocytes cross‐talk mediated by keratinocytes‐derived signaling molecules (ET; SCF; b‐FGF).

These observations highlight the pivotal role of PNEI homeostatic mechanisms in the maintenance of healthy skin conditions.

An alteration of skin structure (due to infection or mechanical/chemical injuries) and/or the loss of immune skin homeostasis contributes to the pathogenesis of inflammatory skin diseases that are characterized by the breakdown of the homeostatic cross‐talk. The role played by the immune system in the context of the PNEI network within the skin system is crucial for the maintenance of physiological inflammation.

The physiological inflammatory process is supported by a panel of Th1‐related cytokines which comprise IL‐1, TNF‐α, and IL‐6 that exert their role in a precise chronobiology. Within 72–96 hours after the proinflammatory stimulus, the response is managed by a sequence of cytokine activation and deactivation: IL‐1 and TNF‐α (primary inflammatory cytokines) induce the production of adhesive molecules, chemokines, growth factors, and lipid mediators such as prostaglandins and nitric oxide (NO). These mediators stimulate leukocyte recruitment at the site of inflammation by amplifying the innate immune mechanisms. Then, IL‐6 acts as secondary mediator, responsible for maintaining the inflammatory response, and stimulates the production of acute phase proteins in the liver. This chronobiology reflects the temporal scan triggering mechanisms and maintenance of the acute inflammatory phenomenon, which is followed by the progressive decrease in the levels of IL‐1, TNF‐α, and IL‐6 and increased levels of IL‐10, the most important Th2 anti‐inflammatory cytokine, typical of the phase of inflammation resolution [21, 22].

In the presence of LGCI, the two phases of inflammation maintenance and resolution coexist. The inflammation is continuously enhanced without an effective restitutio ad integrum; the phases of sequential release of cytokines are altered, and IL‐1, TNF‐α, and IL‐6 levels are about three to four times higher than baseline. Contextually, we do not assist the up‐regulation of IL‐10 anti‐inflammatory. Inflammation persists over time, like a fire smoldering under the ashes.

The persistence of an altered immune response to pro‐inflammatory triggers leads to the instauration of a chronic inflammatory process characterized by the absence of the typical signs and symptoms, the LGCI. A relevant number of dermatologic diseases include within their etiologic factors the presence of a shift of the immunological balance, which reflects an imbalance between the cytokines expressed by Th1/Th17 and Treg/Th2 lymphocyte subpopulations [23, 24].

The so called Th1/Th2 shift paradigm is supported by the evidence that Th1 cytokine hyper‐production is strictly linked with inflammatory and autoimmune skin diseases such as psoriasis, vitiligo, and alopecia areata.

An example of the complexity of the skin PNEI cross‐talk is given by the deep analysis of the inflammatory mechanism at skin level. In 1999, Caroline Robert and Thomas S. Kupper published on The New England of Medicine[25] an exhaustive review on immune imbalance related to inflammatory skin diseases. The authors highlighted the fundamental role of T cell‐mediated immune surveillance in both physiological and pathological skin conditions, pointing out the central role of a class of memory T cells characterized by the presence of the Cutaneous Lymphocyte Antigen (CLA) on their surface and responsible for skin‐homing T cell.

CLA‐positive T cells are generated in the draining lymph nodes and recruited back to the skin during inflammation. The presence of LGCI is a potent trigger for CLA+ T cells and their continuous activation is linked with the inappropriate immune surveillance which characterizes, for example, psoriasis, allergic contact dermatitis, and AD. Also, in vitiligo, CLA+ T cells contribute to the massive death of melanocytes driving the skin‐homing (mainly near disappearing melanocytes) of CD8+ T cells at perilesional level. The increased in situ presence of a CLA+/CD8+ T cells is responsible of the destruction of melanocytes, with consequent skin depigmentation [26].

LGCI is one of the most important etiopathogenetic factors of the most dramatic dermatologic chronic inflammatory autoimmune diseases, and consequently a therapeutic target.

At present, there are no classical therapeutic opportunities to treat LGCI because the chronic use of anti‐inflammatory active principles studied for the management of acute phenomena shows an unfavorable efficacy/adverse effects balance; in particular, chronic nonsteroidal anti‐inflammatory drug (NSAID) use is connected to an increased incidence of chronic diseases such as heart failure and hypertension [27].

In the 1990s, anti‐cytokine therapy was proposed and tested for the treatment of inflammatory and autoimmune diseases mainly counteracting the expression of Th1 proinflammatory cytokines such IL‐1 and TNF‐α. Moreover, the therapeutic use of Th2 cytokines (e.g. IL‐10) and specific antibodies was applied for alopecia areata, psoriasis, and AD treatment.

However, side effects due to high dosages normally used for these molecules have slowed down the development of possible new drugs [28]. The most important and limiting pitfalls connected with the use of high‐dosage cytokines and other signal molecules are:

the need for high doses of active molecules in order to reach the therapeutic goal

the low compliance of systemic administration performed by injective routes.

An innovative approach to the treatment of LGCI based on new therapeutic tools and concepts is needed. Low‐Dose Medicine (LDM) fulfills these specifications.

Low‐Dose Medicine (LDM): Theoretical, Physiological, and Biochemical Bases

LDM is an innovative therapeutic approach based on the most advanced knowledge in molecular biology, PNEI, and research results in the field of low‐dose pharmacology.

LDM has deep roots within the fundamental PNEI principles based in the centrality of the human mind–body entity. Each patient is considered as a unique identity; this assumption guides the study of a specific therapeutic approach for a particular disease.

The primary outcome of the LDM approach is the restoration and preservation of the homeostatic equilibrium; the oral administration of the appropriate biological signaling molecules, which are selected after identification of the altered PNEI networks, is the therapeutic tool that allows the patient to reach the expected outcome.

The use of biological molecules to control and drive the intercellular cross‐talk in order to restore physiological homeostasis is the innovative core of LDM. The main characterizing points of the LDM approach are:

oral administration of signaling molecules

systemic and synergistic activity of the orally administered molecules

accurate modulating action of specific signaling pathways exerted by the orally administered molecules.

The most representative aspect of LDM is the efficacy of orally administered low‐dose signaling molecules. From a biochemical point of view, cytokines, hormones, neuropeptides, and growth factors are oligo‐peptides and small proteic sequences. Oligo‐peptides and small fragments of proteins reach the intestinal tract and here exert their biological actions [29].

The proposed action mechanism for orally delivered signaling molecules involves the intestinal M cells which act as a carrier, signaling to T cells in Peyer's patches lymph nodes [30]. The interaction between delivered signaling molecules and M cells is the key event that underlays the effectiveness of this administration route [31–33].

The critical issue of the oral administration route is the low bioavailability (within 1% and 2%) of signaling molecules and oligo‐peptides in general [34]; to overcome this critical pitfall an effective drug delivery system is needed.

The SKA (Sequential Kinetic Activation) technology, codified and standardized by GUNA S.p.a. Italy, allows the low doses of signaling molecules to be active even below the minimum dose classically considered as effective. SKA technology also permits low‐dose molecules to be as effective as classic recombinant peptides administered at higher concentrations, overcoming the high dose‐related adverse effects.

The action mechanism of SKA low‐dose signaling molecules takes advantage of the activation of some units of cellular (or plasmatic) receptors in their low concentration. Low‐dose SKA signaling molecules are administered in agreement with their physiological working levels (between 10−6 [micromolar] for hormones [35] and 10−12 [picomolar] for other messenger molecules [36]) (Figure 2.4).

Biological concentration‐dependent effects of signaling molecules, with toxic concentration, pharmacological concentrations, and physiological concentrations, etc.

Figure 2.4 Biological concentration‐dependent effects of signaling molecules.

A demonstration of the effectiveness of low doses of signaling molecules is made possible by referring to the effects demonstrable in accordance with Arndt‐Schultz experiments [37, 38]. W. H. Hauss observed and explained the effects of Arndt‐Schultz's Law on mesenchymal non‐specific reaction [39]. Recently, the research of Edward J. Calabrese on the phenomenon called hormesis, which means different behavior of the same substance at different doses, [37, 40] further elucidated Arndt‐Schultz's observations. Furthermore, the pharmacological importance of low doses is recognized by both regulatory bureaus and industries in the pharmacological field [41–43].

The biological response to low doses of signaling molecules is also linked with the characteristic of specific ligand/receptor binding. Receptors for both class‐I and class‐II helical signaling molecules [44, 45] undergo ligand‐induced receptor homo‐ or hetero‐oligomerization laws [46], which can explain the dose‐dependent mixed agonist/antagonist activity of some cytokines and oligo‐peptides [46, 47], a characteristic linked with low dose response [41].

The peculiar ligand/receptor interactions exerted by low‐dose SKA molecules induce the activation and fine regulation of a great number of intercellular signaling pathways, contributing to the restoration and/or protection of the biological function of the entire PNEI network.

Low‐dose SKA molecules can activate (or reactivate) the PNEI self‐tuning intra‐ and intercellular pathways, representing the innovative and highly effective tools of LDM as highlighted in a relevant number of in vitro/ex vivo, in vivo and clinical studies [48–64] (Table 2.1).

Table 2.1 List of the major published works in the field of Low‐Dose Medicine (2009–2018).

Low‐Dose Medicine and Skin Diseases: Preclinical Studies

As previously described, the skin diseases etiology is complex, and the alteration of both innate and adaptive immune responses occupies a relevant role in disease onset and maintenance.

From a biological point of view, the importance of LGCI in both psoriasis onset and progression, and the efficacy of low‐dose SKA molecules in the reduction of its negative impact, were recently evaluated by V. Barygina and colleagues.

A panel of in vitro experiments were performed on fibroblasts obtained from lesional skin of psoriatic patients [54] evaluating the oxidative stress level as marker of an inflammatory condition.

Extracellular Reactive Oxygen Species (ROS), over‐expressed by fibroblasts, exert a pro‐inflammatory action in psoriatic lesional skin; the effectiveness of low‐dose SKA interleukin‐4; 10, b‐FGF, and β‐Endorphin (IL‐4, IL‐10, b‐FGF, and b‐End – 10 fg ml−1) in the reduction of ROS production by lesional fibroblasts highlights one possible LDM medicine's action mechanism against LGCI, a crucial etiologic component of psoriasis onset and progression.

V. Barygina and colleagues also designed and performed a basic preclinical in vitro study [58] in order to evaluate the effects of low‐dose SKA IL‐4, IL‐10, b‐FGF, and β‐End (10 fg ml−1) in the modulation of intra‐ and extra‐cellular oxidative stress, and on the proliferation of human perilesional keratinocytes (PL) from the skin of vitiligo patients (in vitro study on cells obtained from lesion skin biopsies). Vitiligo, a highly psychologically disabling skin disorder characterized by a progressive depigmentation, is another example of a dermatologic disease characterized by the presence of LGCI and related excessive oxidative stress.

Obtained results showed that low‐dose SKA IL‐4, IL‐10, and b‐FGF are effective in significantly reducing the intra‐cellular oxidative stress rates. Furthermore, low‐dose SKA IL‐4 and b‐FGF are also able to reduce the extra‐cellular oxidative stress.

Low‐dose SKA IL‐10, b‐FGF, and β‐End induce a significant increase of keratinocyte viability compared to untreated perilesional cells. IL‐4, IL‐10, β‐End, and b‐FGF show a positive effect on both redox mechanism effectiveness and cell viability without interfering with the keratinocyte's cell cycle.

Low‐Dose Medicine and Skin Diseases: Clinical Results

In 2014, the first study conducted on a dermatologic disease (psoriasis vulgaris) in order to test the LDM approach of oral administration of low‐dose SKA activated cytokines was published.

Roberti and colleagues designed and performed a multicenter double‐blind placebo‐controlled clinical study [52] in order to test the efficacy of low‐dose SKA interleukin‐4, interleukin‐10, and interleukin‐11 (IL‐4, IL‐10, IL‐11 at the concentration of 10 fg ml−1) for the therapy of psoriasis vulgaris.

The main outcomes chosen for the evaluation of the treatment with low‐dose SKA interleukins were

presence and extension of psoriatic plaques evaluated in agreement with PASI (Psoriasis Area Severity Index) scale.

improvement of the quality of life parameters evaluated in agreement with DLQI (Dermatology Life Quality Index) rating scales.

The results of the study revealed the efficacy (and safety) of oral‐administered low‐dose SKA interleukins in the reduction of both evaluated scores. The study also highlighted the long‐lasting efficacy of the proposed treatment, opening the way to formulating a treatment protocol for psoriasis and other dermatologic chronic diseases characterized by an immune imbalance with the presence of a LGCI status.

In 2015, another interesting study in the field of LDM applied to the treatment of psoriasis was published by Lotti and colleagues [57]. The results of a spontaneous retrospective observational clinical study were collected and evaluated.

The clinical outcomes of the most up‐to‐date therapeutic approach for psoriasis treatment, based on UV‐A‐1 phototherapy combined with low‐dose SKA cytokine therapy, were evaluated. It was revealed that the combination of UV‐A‐1 phototherapy with laser plus low‐dose SKA interleukin‐4 and interleukin‐10 and low‐dose SKA antibodies anti IL‐1α/β was more effective than UV‐A‐1 phototherapy alone and also equally safe. The combination of phototherapy and LDM represents an innovative strategy for the treatment of inflammatory skin diseases such as psoriasis vulgaris.

Lotti and colleagues also performed a retrospective spontaneous clinical study comparing the effectiveness of current vitiligo treatments with LDM therapy [55].

In this study, some groups of patients treated in accordance with standard and experimental therapeutic protocols were evaluated; two groups, treated respectively with orally administered low‐dose SKA IL‐4, IL‐10, Anti‐IL‐1 antibodies, and low‐dose SKA b‐FGF were evaluated and compared with other groups of patients who received topical treatments with a cortisone cream (alone or in combined associations with both groups of low‐dose SKA molecules) and phototherapy (narrow‐band UV‐B radiation) alone or in combined associations with the low‐dose SKA molecules. Two groups of subjects treated with natural sunlight exposure and systemic oral intake of Gingko biloba extract were evaluated as control groups.

An inclusion criterion applicable for all current vitiligo treatments is that the skin surface presenting vitiliginous lesion is not exceeding the 15% of the total skin surface.

The study highlighted that the low‐dose SKA treatment effectively reduces the depigmented skin areas and stops the spread of the vitiliginous lesions, in particular when co‐administered with UV‐B phototherapy, with a significant reduction of the depigmented areas. The effectiveness of the association of low‐dose SKA treatments with the topical UV‐B treatment opens new scenarios for the combined use of phototherapy and LDM.

In the pediatric field, Carello and colleagues [62] evaluated the efficacy of a low‐dose SKA cytokine treatment (IL‐12 and IFN‐γ at a concentration of 10 fg ml−1) in association with a low‐dose multicomponent medication (exerting connective drainage action) in a pediatric population presenting chronic AD.

This randomized, controlled double‐blind two‐stage clinical study has been conducted to evaluate the effects of a long‐term treatment with LDM. The clinical trial included children with low‐medium grade AD in acute phase. The evaluation was based on the SCORAD [Scoring Atopic Dermatitis] index, which should not exceed a score of 40 (minimum score: 6) with a recurrence rate of ≥4 per year and with skin lesions occurring for at least six months after the enrollment.

The primary outcome, the reduction in the severity of AD, was evaluated through the SCORAD index; the elongation of the disease‐free interval was assumed as a secondary outcome. Tolerability and compliance of the treatment and management of adverse events was also evaluated. The results showed that the LDM group had a final decrease in SCORAD score of 54%; this trend was maintained during the follow‐up period, with an improvement of the SCORAD index to 64%. In the same observation period, the treated group showed a significant reduction in the consumption of drugs for symptomatic control (antihistamines and topical corticosteroids). The study also showed an improvement in the quality of life (reduction of both itching and night‐time disturbances) of subjects treated with the LDM protocol.

Conclusion

Many dermatologic diseases have a complex pathogenesis; the inflammatory phenomenon is one of the most important etiological components, and it is driven by the imbalance between Th1/Th17 and Th2/Treg responses and induces a profound alteration in immune response homeostasis. The consequent disruption of the PNEI equilibrium has not only local but also systemic negative outcomes that compromises the whole body's health condition.

An effective therapeutic action exerting a rebalancing action of the immune inflammatory response, not adequately managed with currently available therapies, is needed.

Today, the LDM is one of the most promising approaches, allowing researchers to design innovative therapeutic strategies for the treatment of skin diseases based on the rebalance of the immune response.

The availability of low‐dose SKA signaling molecules is the cardinal point of LDM. The effective and safe oral administration of low‐dose SKA signaling molecules represents the innovative core of the entire strategy for the treatment of dermatological diseases characterized by an immune imbalance and LGCI such as in psoriasis vulgaris, vitiligo, and AD.

Preclinical and clinical results confirm the effectiveness of the LDM approach and give the physician the therapeutic tools and theoretic basis for a fine tuning of the immune system in order to restore its homeostatic equilibrium in accordance with PNEI principles.

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