1.                  Introduction

Acne Vulgaris (AV) is a common skin disease, affecting over 90% of male adolescent and about 80% of female adolescent in all ethnic groups [1]. It causes both physical and psychological disorders. It has multifactorial pathophysiology, involves some main processes: hormonal imbalance, increased sebum production, and bacterial colonization [2,3]. Acne vulgaris is a visible skin disease and commonly occurs in adolescent, therefore it is relevant to understand AV correlation with psychosocial and psychoneuroimmunology factors. Due to adolescent is a significant and vulnerable phase of life to the various stressor, it is also transition time from the immaturity of childhood into the maturity and independent of adulthood [2].

Acne vulgaris is a common disorder encountered on the face and upper chest, and it affects nearly teenagers each day. Furthermore, it is interesting and substantial to study deeper the contributing factors of etiology of AV [4].

2.      Epidemiology

Acne vulgaris is an epidemic skin disease in developed countries, with its prevalence of 85% in adolescent. In the United States, AV persistent in teenagers and frequently continues into 30s in both men and women. These findings suggest that there are environment factors inducing AV after puberty, and it is found to be an independent factor from hormonal factor during puberty [5].Acne vulgaris affect more in adolescent, approximately 90% of male adolescent and 80% of female adolescent in all ethnic groups. It significantly causes physical and psychosocial disorders. Its pathophysiology is multifactorial interplay of hormonal, sebum production, and bacterial colonization that play an important role. Psychological stress may have in AV exacerbations [4].Green and Sinclair conducted on 215 graduating medical students showed that 67% of students believed that stress plays a role in acne exacerbations [6]. Chiu et al. conclude that patients with acne may experience worsening of the disease during examinations with increasing stress level [7]. Kilkenny et al. showed in their study of 2525 Australian students and conclude that students reporting moderate acne were more likely to report psychiatric symptoms of depression and anxiety [8].Smithard et al. observed 317 comprehensive school students with range of age 14-16 years old in the Nottingham, and they found that there was correlation between AV severity and emotional or behavioral symptoms [9].

Acne vulgaris is generally recognized as a skin disorder of adolescents, however a significant number of patients experience acne in patients between the ages of 35-44 years [10]. A study of 200 patients with post-adolescent acne revealed that 50% of patients had a first-degree relative suffering acne in family history [11]. Based on gender, AV is increasingly seen in women than men [12].By recognizing AV as a chronic disease similar to eczema, early and aggressive treatment can be started to avoid the psychological sequela that can result from active AV and acne scars [13].

3.      Clinical Manifestations

The active AV lesions appears similar in various ethnic patients. Acne vulgaris lesions in dark-skinned patients as in African Americans can develop inflammatory papules, pustules, nodules and cysts, and these inflammatory lesions can promote the development of Post Inflammatory Hyperpigmentation (PIH), acne scars and keloids. Inflammatory papules in lighter-skinned patients characteristically have an erythema; however, these lesions can develop an overlying hyperpigmentation and mimicking PIH, but the distinction is made upon palpation. Nodulocystic acne is less common in African Americans than Caucasians based on a study by Wilkins et al. Rates of nodulocystic acne lesions were significantly lower in dark-skinned patients. On the other hand, in Hispanics and Asians have similar prevalence rates of nodulocystic acne as Caucasians, although supporting evidence is lacking [14,15].

4.                  Pathophysiology

6.1.              Conventional View/Theory

The pathophysiology of AV is multifactorial process involving both endogenous and exogenous factors. Acne begins with the retention of desquamated keratinocytes within the pilosebaceous unit leading to follicular plugging (microcomedo), the microcomedo wall eventually ruptures and leading to inflammation process.Propionibacterium acnes(P.acnes), an anaerobic/microaerophilic, Gram-positive rod, resides within the sebaceous follicle and also incites an inflammatory response by acting on Toll-Like Receptor(TLR)-2, which may stimulate the secretion of cytokines, such as Interleukin (IL)-6 and IL-8 by follicular keratinocytes and IL-8 and IL-12 in macrophages [16,17]. Other contributing factors include hormonal influences from estrogen and androgens, such as De Hydro Epi Androsterone Sulfate (DHEAS), which has been shown to increase sebum production in adolescent leading to AV [18]. Genetic factors may also play a role in the development of AV [19,20]. He et al published a study in 2006 showing a possible association between the CYP17-34T/C polymorphism and the development of severe AV in Chinese patients [21]. However, further studies are required to evaluate the exact roles played by hormones, particularly estrogen, and genetics in the development of AV. Some AV lesions may progress to become visibly inflamed, appearing as papules, pustules, and/or nodules. As each follicle goes through its own independent pathophysiologic “life cycle”, most patients present at any given point in time with a mixture of AV lesions in various stages [22].

6.2.  Psychodermatology View/Theory

6.2.1.         Neuro-Immuno-Cutaneous System (NICS)

Understanding the psychosocial and occupational context of skin disease is critical for the optimal management of psychocutaneous disorders. The correlation between psychiatric and dermatological disorders exists due to more than a fact, that the brain, as the center of psychological functions, and the skin has the same ectodermal origin. Connecting the two disciplines is a complex interplay between neuroendocrine and immune systems that has been described as the Neuro- Immuno-Cutaneous System (NICS) [23].

The concept of NICS means narrow interrelations between nervous system, immunity and skin. Indeed, there are numerous cellular contacts between nerve fibers, cutaneous cells and immune cells; cutaneous cells can synthesize neuromediators and they express receptors to these molecules; neuromediators are able to modulate functions of cutaneous and/or immune cells. Using confocal or electron microscopy, connections between nerve fibers and cutaneous cells have been observed. In the skin, nerve fibers may secrete neuromediators: Substance P (SP), Vaso-Active Intestinal Peptide (VIP), somatostatin, Calcitonin- Gene Related Peptide (CGRP), Gastrin-Releasing Peptide (GRP), Neuropeptide Y, Peptide Histidine-Isoleucine (PHI), neurotensin, neurokinins A et B, bradykinin, acetylcholine, catecholamines, endorphins and enkephalins. Neurohormones such as prolactin, Melano-Stimulating Hormone (MSH) or Adreno-Corticotrophic Hormone (ACTH) are also expressed in the skin [24].

Skin conditions, such as AV, are sometimes thought of as insignificant in comparison with diseases of other organ systems. Physicians’s assumptions about the effects of a skin condition are often inaccurate. The psychological effect of AV is unique for each patient. Patients should be asked how much their acne bothers them, regardless of how severe it appears to physicians. Acne’s effect on psychosocial and emotional problems, however, is comparable to that of arthritis, back pain, diabetes, epilepsy, and disabling asthma [25]. Acne vulgaris often flares with stress and premenstrually. It has been reported that psychological stress perturbs epidermal permeability barrier homeostasis, and it may act as precipitant for inflammatory skin disorders [26]. This enables multidisciplinary approach with the cooperation of psychiatric and dermatologic for diagnostic procedures and treatment of patient with psychodermatologic disorders. In psychophysiologic disorders, psychiatric factors are significant instrumental in the etiology, course and management of skin disease. The skin disease is not caused by stress but appears to be precipitated or exacerbated by stress [27]. The proportion of patients reporting emotional triggers varies with the disease, ranging from approximately 50% in acne to greater that 90% in rosacea, alopecia areata, neurotic excoriations, and lichen simplex [28].

The habitual act of picking at acne lesions, apparently driven by compulsion and psychologic factors independent of acne severity, has been reported in the perpetuation of self-excoriation. Most patients with this disease are females with late onset acne. Psychiatric comorbidity of acne excoriee includes body image disorder, depression, anxiety, Obsessive-Compulsive Disorder (OCD), delusional disorders, personality disorders, and social phobias. Immature coping mechanisms and low self-esteem have also been associated with psychodermatology. Interesting gender differences have been observed in this disease. In men, self-excoriation is exacerbated by a coexisting depression or anxiety, while in women this behavior may be a manifestation of immature personality and serve as an appeal for help [29,30].

Stress signals induce release of hormones, including Corticotropin-Releasing Hormone (CRH) from the Paraventricular Nucleus (PVN) of the hypothalamus; then CRH will target the anterior pituitary to release ACTH [31]. In turn, ACTH regulates glucocorticoids (mainly cortisol in humans) secretion from the adrenal cortex [32]. Cortisol has several functions including negative feedback of the hypothalamus and anterior pituitary and induces epinephrine and norepinephrine secretion from the adrenal medulla [33]. Glucocorticoids, such as cortisol, may enhance cutaneous immune responses at low concentrations and suppress immune responses at high concentrations [34]. Stress signals also stimulate the Locus Coeruleus (LC) norepinephrine cells of the sympathetic nervous system. Neuropeptide products of the sympathetic response (SP, CRGP, and cutaneous Nerve Growth Factor (NGF)) have been shown to be proinflammatory and anti-inflammatory dependent on the immune cell type [31].

6.2.2.         Skin Peripheral Hypothalamic-Pituitary-Adrenal (HPA) Axis

The skin also developed a fully functional peripheral Hypothalamic-Pituitary- Adrenal (HPA) system where CRH, ACTH, and their receptors are produced in skin cells. Corticotropin-releasing hormone is produced by epidermal and hair follicle keratinocytes, melanocytes, sebocytes, and mast cells upon stress, Ultra Violet (UV) irradiation, and cutaneous pathology [35,36].

Adrenocorticotropic hormone stimulates IL-18 production in skin keratinocytes, as IL-18 is a pro-inflammatory cytokine that enhances T-cell activity and promotes T helper type 2 (Th2) cytokines production [37]. Since CRH down- regulates IL-18 in keratinocytes, IL-18 may participate in the negative feedback loop to regulate HPA axis activity.38 In sebocytes, ACTH can work through the melanocortin-5 receptor (MC5R) and induce sebocytes differentiation [39].

6.2.3.         The Development in Acne Vulgaris Pathophysiology

Acne vulgaris pathophysiology is characterized by increased colonization ofP. Acnes anaerobic bacteria, increased sebum production from the sebaceous glands, inflammation, and hyper-keratinization. The role of stress has long been suspected to induce AV flares by clinical experiences and anecdotal observations [40,41]. During its development, the role of skin peripheral HPA axis has been studied in the pathophysiology of AV. Corticotropin-releasing hormone and its receptors have been detected on sebocytes. It was shown that CRH promotes lipogenesis in sebocytes through up-regulation of a key enzyme [42]. In addition, CRH stimulates keratinocytes production of IL-6 and IL-11, and CRH also may have important activity on keratinocyte function [43]. Adrenocorticotropic hormone and α-MSH also contribute to sebum production and possibly worsen the acne phenotype [44].

The role of neuropeptide, specifically substance P in acne has been studied extensively. Facial skin from AV patients show marked increase of substance P- positive nerve fibers around the sebaceous glands and around acne lesions [45]. Substance P induces gene expression of Peroxisome Proliferator-Activated Receptor (PPAR)-γ, which plays a unique role in stimulating sebocyte lipogenesis. It also stimulates various pro-inflammatory cytokines release from sebocytes, including IL-1, IL-6, and TNF-α[38].

7.      Conclusion

The concept of NICS means narrow interrelations between nervous system, immunity and skin. Indeed, there are numerous cellular contacts between nerve fibers, cutaneous cells and immune cells; cutaneous cells can synthesize neuromediators and they express receptors to these molecules; neuromediators are able to modulate functions of cutaneous and/or immune cells.

Psychodermatology describes an interaction between psychiatric or a psychological problems to skin disorders. Therefore, it is suggest that for many skin disorders including AV requires comprehensive management in accordance by understand the development of AV pathophysiology.

Figure 1:A schematic representation of the hypothalamus, anterior pituitary, adrenal cortex and sympathetic nervous interaction with the cutaneous immune system [31].

3Figure 2:A schematic representation of HPA axis.

1.       Rademaker M, Garioch J, Simpson N (1989) Acne in schoolchildren: no longer a concern for dermatologists. Br Med J 298:1217-1220.

2.       Gupta MA, Gupta AK (2003) Psychiatric and Psychological Co-Morbidity in Patients with Dermatologic Disorders: epidemiology and management. Am J ClinDermatol 4:833-842.

3.       Pang M-LT, Eichenfield LF (2008) Acne. Dalam: Neinstein LS, Gordon CM, Katzman DK, Rosen DS, Woods ER, editor. Adolescent Health Care A Practical Guide. Edisi ke-5. Philadelphia: Lippincott Williams &Wilkins;. h. 299-308.

4.       Schäfer T, Nienhaus A, Vieluf D, Berger J, Ring J (2001) Epidemiology of acne in the general population: the risk of smoking. Br J Dermatol 145:100-104.

5.       James WD (2005) Clinical practice. Acne. N Engl J Med 352:1463-1472.

6.       Green J, Sinclair RD (2001) Perceptions of acne vulgaris in final year medical student written examination answers. AustralasJ Dermatol 42:98-101.

7.       Chiu A, Chon SY, Kimball AB (2003) The response of skin disease to stress: changes in the severity of acne vulgaris as affected by examination stress. Arch Dermatol 139:897-900.

8.       Kilkenny M, Stathakis V, Hibbert M, Patton G, Caust J, et al. (1997) Acne in Victorian adolescents: Associations with age, gender, puberty and psychiatric symptoms. J Paediatr Child Health 33:430-433.

9.       Smithard A, Glazebrook C, Williams H (2001) Acne prevalence, knowledge about acne and psychological morbidity in mid‐adolescence: a community‐based study. Br J Dermatol 145:274-279.

10.    Collier CN, Harper JC, Cantrell WC, Wang W, Foster KW, et al. (2008) The prevalence of acne in adults 20 years and older. J Am AcadDermatol 58:56-59.

11.    Goulden V, Clark S, Cunliffe W (1997) Post‐adolescent acne: a review of clinical features. Br J Dermatol 136:66-70.

12.    Zeichner JA, Baldwin HE, Cook-Bolden FE, Eichenfield LF, Fallon-Friedlander S, et al. (2017) Emerging Issues in Adult Female Acne. J ClinAesthetDermatol 10:37-46.

13.    Thiboutot D, Gollnick H, Bettoli V, Dréno B, Kang S, et al. (2009) New insights into the management of acne: An update from the Global Alliance to Improve Outcomes in Acne group. J Am AcadDermatol 60:S1-S50.

14.    Lee C, Lim H (2003) Cutaneous diseases in Asians. DermatolClin. 21:669-677.

15.    Taylor SC, Cook-Bolden F, Rahman Z, Strachan D (2002) Acne vulgaris in skin of color. J Am AcadDermatol 46:S98-S106.

16.    Kurokawa I, Danby FW, Ju Q, Wang X, Xiang LF, et al. (2009) New developments in our understanding of acne pathogenesis and treatment. ExpDermatol 18:821-832.

17.    Zanglein AL, Thiboutot (2012) Acne Vulgaris. Dalam: Bolognia JL, Jorizzo JL, Schaffer JV, Callen JP, Cerroni L, Heymann WR, dkk., editor. Dermatology. Edisi ke-3. New York: Elsevier Saunders. 545-558.

18.    Cappel M, Mauger D, Thiboutot D (2005) Correlation Between Serum Levels of Insulin-like Growth Factor 1, Dehydroepiandrosterone Sulfate, and Dihydrotestosterone and Acne Lesion Counts in Adult Women. Arch Dermatol. 141:333-338.

19.    Goulden V, McGeown C, Cunliffe W. (1999) The familial risk of adult acne: a comparison between first-degree relatives of affected and unaffected individuals. Br J Dermatol 141:297-300.

20.    Xu S, Wang H, Fan X, Sun L, Yang S, et al. (2007) The familial risk of acne vulgaris in Chinese Hans–a case‐control study. J EurAcadDermatolVenereol 21:602-605.

21.    He L, Yang Z, Yu H, Cheng B, Tang W, et al. (2006) The Relationship Between CYP17–34T/C Polymorphism and Acne in Chinese Subjects Revealed by Sequencing. Dermatol 212:338-342.

22.    Rosso JQD (2016) Improved Understanding of Inflammation in Acne Pathophysiology: Leading to New Developments in Treatment. PractDermatol.45-51.

23.    Yadav S, Narang T, Kumaran MS (2013) Psychodermatology: A comprehensive review. Indian J DermatolVenereolLeprol. 79:176-192.

24.    Misery L (1996) Neuro-immuno-cutaneous system (NICS). Pathol-Biol 44:867-874.

25.    Mallon E, Newton J, Klassen A, Stewart-Brown S, Ryan T, et al. (1999) The quality of life in acne: a comparison with general medical conditions using generic questionnaires. Br J Dermatol 140:672-676.

26.    Garg A, Chren M-M, Sands LP, Matsui MS, Marenus KD, et al. (2001) Psychological Stress Perturbs Epidermal Permeability Barrier Homeostasis: Implications for the Pathogenesis of Stress-Associated Skin Disorders. Arch Dermatol. 137:53-59.

27.    Koo JYM, Lee CS (2003) General Approach to Evaluating Psychodermatological Disorders. Dalam: Koo JYM, Lee CS, editor. Psychocutaneous Medicine. Edisi ke-1. New York: Marcel Dekker 1-12.

28.    Cotterill J (1990) Psychophysiological aspects of eczema. SeminDermatol 9:216-219.

29.    Gupta MA, Gupta AK, Schork NJ (1994) Psychosomatic Study of Self-Excoriative Behavior Among Male Acne Patients: Preliminary Observations. Int J Dermatol 33: 846-848.

30.    Jafferany M (2007) Psychodermatology: A Guide to Understanding Common Psychocutaneous Disorders. Prim Care Companion J Clin Psychiatry 9:203-213.

31.    Hall JM, Podawiltz A, Mummert DI, Jones H, Mummert ME (2012) Psychological Stress and the Cutaneous Immune Response: Roles of the HPA Axis and the Sympathetic Nervous System in Atopic Dermatitis and Psoriasis. Dermatol Res Pract. 2012: 1-11.

32.    Tsigos C, Chrousos GP (2002) Hypothalamic–pituitary–adrenal axis, neuroendocrine factors and stress. J Psychosom Res 53:865-871.

33.    Miyazaki Y, Yokozeki H, Awad S, Igawa K, Minatohara K, ET AL. (2000) Glucocorticoids Augment the Chemically Induced Production and Gene Expression of Interleukin-1α through NF-κB and AP-1 Activation in Murine Epidermal Cells. J Invest Dermatol. 115:746-752.

34.    Sephton SE, Dhabhar FS, Keuroghlian AS, Giese-Davis J, McEwen BS, et al. (2009) Depression, cortisol, and suppressed cell-mediated immunity in metastatic breast cancer. Brain BehavImmun 23:1148-1155.

35.    Kono M, Nagata H, Umemura S, Kawana S, Osamura RY (2001) In situ expression of corticotropin-releasing hormone (CRH) and proopiomelanocortin (POMC) genes in human skin. FASEB J 15:2297-2299.

36.    Slominski A, Wortsman J, Pisarchik A, Zbytek B, Linton EA, et al. (2001) Cutaneous expression of corticotropin-releasing hormone (CRH), urocortin, and CRH receptors. FASEB J 15:1678-1693.

37.    Park HJ, Kim HJ, Lee JY, Cho BK, Gallo RL, et al. (2007) Adrenocorticotropin Hormone Stimulates Interleukin-18 Expression in Human HaCaT Keratinocytes. J Invest Dermatol 127:1210-1216.

38.    Chen Y, Lyga J (2014) Brain-Skin Connection: Stress, Inflammation and Skin Aging. Inflamm Allergy Drug Targets 13:177-1790.

39.    Zhang L, Li W-H, Anthonavage M, Eisinger M (2006) Melanocortin-5 receptor: A marker of human sebocyte differentiation. Peptides 27:413-420.

40.    Georgin-Lavialle S, Moura DS, Bruneau J, Chauvet-Gélinier J-C, Damaj G, et al. (2014) Leukocyte telomere length in mastocytosis: Correlations with depression and perceived stress. Brain BehavImmun35:51-57.

41.    Perry JC, Guindalini C, Bittencourt L, Garbuio S, Mazzotti DR, et al. (2013) Whole blood hypoxia-related gene expression reveals novel pathways to obstructive sleep apnea in humans. RespirPhysiolNeurobiol 189:649-654.

42.    Zouboulis CC, Seltmann H, Hiroi N, Chen W, Young M(2002) Corticotropin- releasing hormone: An autocrine hormone that promotes lipogenesis in human sebocytes. Proc Natl Acad Sci USA 99:7148-7153.

43.    Zbytek B, Mysliwski A, Slominski A, Wortsman J, Wei ET, et al. (2002) Corticotropin- releasing hormone affects cytokine production in human HaCaT keratinocytes. Life Sci 70:1013-1021.

44.    Zhang X, Lin S, Funk WE, Hou L (2013) Environmental and occupational exposure to chemicals and telomere length in human studies. Occup Environ Med 70:743-749.

45.    Tyrka A, Price L, Kao H, Porton B, Marsella S, et al. (2010) Childhood Maltreatment and Telomere Shortening: Preliminary Support for an Effect of Early Stress on Cellular Aging. Biol Psychiatry 67:531-534.