Acne, also known as acne vulgaris (AV), is a long-term skin disease that occurs when hair follicles are clogged with dead skin cells and oil from the skin. It is characterized by blackheads or whiteheads, pimples, oily skin and possible scarring. An intact stratum corneum and barrier, normal natural moisturizing factor and hyaluronic acid levels, normal Aquaporin-3 (AQP3) expression (localized at the basal lateral membranes of collecting duct cells in the kidney), and balanced sebum secretion are qualities of the skin that fall in the middle of the oily-dry spectrum. Patients rarely, if ever, complain about reduced sebum production, but elevated sebum production, yielding oily skin that can be a precursor to acne, is a common complaint. Several factors are known to influence sebum production. AV is mostly triggered by Propionibacterium acnes in adolescence, under the influence of normal circulating dehydroepiandrosterone (DHEA). It is a very common skin disorder which can present with inflammatory and non-inflammatory lesions chiefly on the face but can also occur on the upper arms, trunk, and back. Age, in particular, has a significant and well-known impact, as sebum levels are usually low in childhood, rise in the middle-to-late teen years and remain stable into the seventh and eighth decades until endogenous androgen synthesis dwindles. Sebum, the oily secretion of the sebaceous glands containing wax esters, sterol esters, cholesterol, di- and tri-glycerides and squalene, imparts an oily quality to the skin and is well known to play an important role in acne development. Acne can't be prevented or cured, but it can be treated effectively. The pimples and bumps heal slowly, and when one begins to go away, others seem to crop up. Depending on its severity, acne can cause emotional distress and scar the skin. Acne may cause scarring of the skin, but generally causes no long-term health problems. In self-body image, some parts of the body including face play an important role. Existence of even a minor lesion in this part may be unpleasant for the patient and seems large. This image can cause mental disorders including depression and anxiety, low self-esteem and decrease in social relationships. However, high levels of anxiety and depression in patients with facial acne are not related to oxidative stress, according to a study published online in the Journal of Cosmetic Dermatology.

 

Keywords: Acne, Skin care, Comedones, Pustules, Acne scars, Sebum, Propionibacterium acnes

 

Abbreviations: AV: Acne Vulgaris; AQP3: Aquaporin-3; DHEA: Dehydroepiandrosterone; CAM: Complementary and Alternative Medicine; IGF-1: Insulin-Like Growth Factor 1; HRQoL: Health-Related Quality of Life; SHBG: Sex Hormone-Binding Globulin; Cer: Ceramide; SM: Sphingomyelin; FSH: Follicle-Stimulating Hormone; 5α-DHT: 5α-dihydrotestosterone; PCOS: Polycystic Ovary Syndrome; SG: Sebaceous Gland; EPA: Eicosapentaenoic Acid; DHA: Docosahexaenoic Acid; AFA: Adult Female Acne; BP: Benzoyl peroxide; PIH: Post Inflammatory Hyperpigmentation; AAD: American Academy of Dermatology; MRSA: Methicillin-Resistant Staphylococcus aureus; COC: Combined Oral Contraceptive; RCTs: Randomized Controlled Trials; IGA: Investigator's Global Assessment; IPL: Intense Pulsed Light; NAFL: Non-Ablative Fractional Lasers

BACKGROUND

Historic Panorama of Acne Protection - The word ‘acne’ appears to evolve from Greek word ‘acme’ which means ‘point or spot’. Although acne is described in very ancient writings dating back to Eber’s Papyrus, its clear description is found after Fuch’s coined the term ‘Acne Vulgaris’ and Erasmus Wilson separated it from acne rosacea. The roots of acne have been traced all the way to three well known ancient civilizations viz., Egyptians, Greeks and Romans. Some Egyptian writings have mentioned that Pharaohs suffered from acne and had also made efforts to resolve it. In Ebers Papyrus the word ‘aku-t’ is cited that was later translated as ‘boils, blains, sores, pustules or any inflammatory swelling’ and is described to be treated with some animal origin preparations and honey. Ancient Egyptians around 3^rd century was of the opinion that acne is caused by telling lies. Tutankhamun, Egyptian Pharaoh of the 18^th dynasty had acne as evident from the anti-acne remedies in his tomb. From the historical records, both Hippocrates and Aristotle were aware of this ailment. Aristotle also explained this condition in detail.

INTRODUCTION

AV is a multifaceted skin disorder, affecting more than 85% of young individuals worldwide. It is the most common skin disease, and although it usually manifests during puberty and worsens throughout adolescence, epidemiological studies suggest that it can arise at any age. Apart from the classic belief that acne results from sebaceous gland hyperplasia, abnormal follicular differentiation with increased keratinization, microbial hyper-colonization of the follicular canal, and increased inflammation primarily through activation of the adaptive immune system may also be contributors. There are various types of acne, such as acne vulgaris, acne rosacea, acne cosmetica, acne fulminans and acne mechanica. In 2011, around 20% of the population in the US was affected with acne. According to the lesion type, acne can be classified into four main categories: non-inflammatory (purely comedone acne), mild papular, scarring papular and nodular; the latter three are inflammatory acne lesions. Acne treatment aims to lessen the inflammatory or non-inflammatory acne lesions, improve appearance, prevent or minimize potential adverse effects, and minimize any scarring. Pharmacological therapy is not always desirable because of the development of antibiotic resistance or the potential risk of adverse effects. Non-pharmacological therapies can be viable alternatives for conventional therapies. Acne severity is classified according to different scales. It is widely agreed, however, that the mild and moderate forms of acne display primary lesions only, while severe acne also includes nodules, cysts and eventually open lesions. It is noteworthy that acne severity and scarring have been related to P. acnes inflammatory factors, bacterial growth metabolites such as allergens, toxins, or porphyrins and enzymes. Acne is always accompanied by a variety of other signs and symptoms such as erythema, desquamation, burning, itching, dyschromia and pain. Furthermore, acne causes significant psychological morbidity in affected patients. Currently available systemic products include the retinoid isotretinoin, antibiotics or oral contraceptives, all of which are indicated for more severe acne, acne resistant to other therapies and nodulocystic, scarring acne. Although acne is widespread with numerous treatment options available, the condition is still not considered curable, prompting further investigation by the pharmaceutical industry. Commonly used treatments aim to reduce the number of inflammatory lesions, inhibit comedones, suppress the growth of Propionibacterium acne or reduce sebaceous gland size and secretory activity. People with acne often turn to complementary and alternative medicine (CAM), such as herbal medicine, acupuncture and dietary modifications, because of their concerns about the adverse effects of conventional medicines. Some researchers have concluded that genetic predisposition and hormonal influences play a more important role in acne than diet. Chinese herbal medicine, manual healing therapies (such as acupuncture and massage) and other traditional and folk remedies may follow similar mechanisms in the treatment of acne. Methodological and reporting quality limitations in the included studies weakened any evidence. All mainstream products can cause severe side effects including, paradoxically, the typical signs and symptoms of acne and there is therefore a demand for new innovative treatments.

ETIOLOGY

The pathogenesis is multifactorial with four primary pathogenic factors including: (a) abnormal hyperkeratinization of the pilosebaceous duct with comedo formation caused by increased androgens; (b) an increase in sebum production from the enlarged sebaceous gland caused by increased androgens; (c) colonization and proliferation of the duct with bacteria, most commonly P. acnes, although clear evidence of a causal relationship between P. acnes and AV is lacking; and (d) an inflammatory response caused by the immunological activity of P. acnes [1]. The adequate control of the four pathogenic mechanisms involved in the appearance of acne lesions is key to treatment success [2-8]. Several exacerbating factors have been suggested including diet, menstruation, sweating, personal stress, ultraviolet radiation, application of pomades and occupation [9]. Use of medications like lithium, steroids and anticonvulsants, exposure to excess sunlight, use of occlusive wear like shoulder pads, headbands backpacks and underwire brassieres, endocrine disorders like polycystic ovarian syndrome and even pregnancy have also reported [10]. The association between diet and acne can no longer be dismissed. Compelling evidence shows that high glycemic load diets may exacerbate acne (also, LGL diet that resulted in the improvement of acne lesions) [11-14]. Food with a high glycemic index is rapidly absorbed, increases serum glucose levels and stimulates increased glucose-dependent insulin signaling [15]. Elevated insulin levels stimulate the secretion of androgens and cause an increased production of sebum, growth of the sebaceous glands and hyperkeratinization, which plays a fundamental role in pathogenesis of AV [11,16-19]. High plasma levels of Insulin-Like Growth Factor 1 (IGF-1) which are caused by consumption of milk, stimulates proliferation of sebocytes, resulting in the development and progression of acne lesions. Skim milk contains less estrogen than whole milk. Estrogen is a hormone that may reduce acne [9,20-27]. There is a common medical and lay belief that women experience perimenstrual acne flares [28-31]. Summer aggravation of acne reported by 80% patient in a study due to sweating and increased humidity [32]. Acne has also been associated with impaired health-related quality of life (HRQoL), at times with negative impacts as great as that of severe and even life-threatening diseases [33]. However, Zari et al. [34] and Bagatin et al. [35] revealed positive association with menstruation, heat and humidity, sweating, use of makeup and cosmetic products, oily hair products, use of topical steroids, sleep disorders, excessive skin washing, possible resistance to P. acnes and squeezing pimples. Bondade et al. [36] found undesirable stressful life events and psychiatric comorbidity were more in acne patients than in controls. Stress and depression positively correlate with acne severity [34,37]. Acne can also develop in neonates but in most cases resolves spontaneously [38]. Acne neonatorum, which presents within the first four weeks of life, occurs in up to 20% of newborns. Additionally, childhood acne is strongly correlated with the development of persistent acne later in life (Exhibit 2).

INTRODUCTION

AV is a multifaceted skin disorder, affecting more than 85% of young individuals worldwide. It is the most common skin disease, and although it usually manifests during puberty and worsens throughout adolescence, epidemiological studies suggest that it can arise at any age. Apart from the classic belief that acne results from sebaceous gland hyperplasia, abnormal follicular differentiation with increased keratinization, microbial hyper-colonization of the follicular canal, and increased inflammation primarily through activation of the adaptive immune system may also be contributors. There are various types of acne, such as acne vulgaris, acne rosacea, acne cosmetica, acne fulminans and acne mechanica. In 2011, around 20% of the population in the US was affected with acne. According to the lesion type, acne can be classified into four main categories: non-inflammatory (purely comedone acne), mild papular, scarring papular and nodular; the latter three are inflammatory acne lesions. Acne treatment aims to lessen the inflammatory or non-inflammatory acne lesions, improve appearance, prevent or minimize potential adverse effects, and minimize any scarring. Pharmacological therapy is not always desirable because of the development of antibiotic resistance or the potential risk of adverse effects. Non-pharmacological therapies can be viable alternatives for conventional therapies. Acne severity is classified according to different scales. It is widely agreed, however, that the mild and moderate forms of acne display primary lesions only, while severe acne also includes nodules, cysts and eventually open lesions. It is noteworthy that acne severity and scarring have been related to P. acnes inflammatory factors, bacterial growth metabolites such as allergens, toxins, or porphyrins and enzymes. Acne is always accompanied by a variety of other signs and symptoms such as erythema, desquamation, burning, itching, dyschromia and pain. Furthermore, acne causes significant psychological morbidity in affected patients. Currently available systemic products include the retinoid isotretinoin, antibiotics or oral contraceptives, all of which are indicated for more severe acne, acne resistant to other therapies and nodulocystic, scarring acne. Although acne is widespread with numerous treatment options available, the condition is still not considered curable, prompting further investigation by the pharmaceutical industry. Commonly used treatments aim to reduce the number of inflammatory lesions, inhibit comedones, suppress the growth of Propionibacterium acne or reduce sebaceous gland size and secretory activity. People with acne often turn to complementary and alternative medicine (CAM), such as herbal medicine, acupuncture and dietary modifications, because of their concerns about the adverse effects of conventional medicines. Some researchers have concluded that genetic predisposition and hormonal influences play a more important role in acne than diet. Chinese herbal medicine, manual healing therapies (such as acupuncture and massage) and other traditional and folk remedies may follow similar mechanisms in the treatment of acne. Methodological and reporting quality limitations in the included studies weakened any evidence. All mainstream products can cause severe side effects including, paradoxically, the typical signs and symptoms of acne and there is therefore a demand for new innovative treatments.

ETIOLOGY

The pathogenesis is multifactorial with four primary pathogenic factors including: (a) abnormal hyperkeratinization of the pilosebaceous duct with comedo formation caused by increased androgens; (b) an increase in sebum production from the enlarged sebaceous gland caused by increased androgens; (c) colonization and proliferation of the duct with bacteria, most commonly P. acnes, although clear evidence of a causal relationship between P. acnes and AV is lacking; and (d) an inflammatory response caused by the immunological activity of P. acnes [1]. The adequate control of the four pathogenic mechanisms involved in the appearance of acne lesions is key to treatment success [2-8]. Several exacerbating factors have been suggested including diet, menstruation, sweating, personal stress, ultraviolet radiation, application of pomades and occupation [9]. Use of medications like lithium, steroids and anticonvulsants, exposure to excess sunlight, use of occlusive wear like shoulder pads, headbands backpacks and underwire brassieres, endocrine disorders like polycystic ovarian syndrome and even pregnancy have also reported [10]. The association between diet and acne can no longer be dismissed. Compelling evidence shows that high glycemic load diets may exacerbate acne (also, LGL diet that resulted in the improvement of acne lesions) [11-14]. Food with a high glycemic index is rapidly absorbed, increases serum glucose levels and stimulates increased glucose-dependent insulin signaling [15]. Elevated insulin levels stimulate the secretion of androgens and cause an increased production of sebum, growth of the sebaceous glands and hyperkeratinization, which plays a fundamental role in pathogenesis of AV [11,16-19]. High plasma levels of Insulin-Like Growth Factor 1 (IGF-1) which are caused by consumption of milk, stimulates proliferation of sebocytes, resulting in the development and progression of acne lesions. Skim milk contains less estrogen than whole milk. Estrogen is a hormone that may reduce acne [9,20-27]. There is a common medical and lay belief that women experience perimenstrual acne flares [28-31]. Summer aggravation of acne reported by 80% patient in a study due to sweating and increased humidity [32]. Acne has also been associated with impaired health-related quality of life (HRQoL), at times with negative impacts as great as that of severe and even life-threatening diseases [33]. However, Zari et al. [34] and Bagatin et al. [35] revealed positive association with menstruation, heat and humidity, sweating, use of makeup and cosmetic products, oily hair products, use of topical steroids, sleep disorders, excessive skin washing, possible resistance to P. acnes and squeezing pimples. Bondade et al. [36] found undesirable stressful life events and psychiatric comorbidity were more in acne patients than in controls. Stress and depression positively correlate with acne severity [34,37]. Acne can also develop in neonates but in most cases resolves spontaneously [38]. Acne neonatorum, which presents within the first four weeks of life, occurs in up to 20% of newborns. Additionally, childhood acne is strongly correlated with the development of persistent acne later in life (Exhibit 2).

PATHOPHYSIOLOGY

Acne is proposed to be an IGF-1-mediated disease, modified by diets and smoking increasing insulin/IGF1-signalling [62]. The main hormones responsible for the development of AV include androgens, insulin and insulin-like growth factor-1. Other factors involved in this process are corticotropin-releasing hormone, α-melanocyte-stimulating hormone and substance P [63]. During puberty, alteration of the sebaceous lipid profile, called dysmenorrhea, stress, irritation, cosmetics and potential dietary factors lead to inflammation and formation of different types of acne lesions [64,65]. Distended follicles rupture and release proinflammatory chemicals into the dermis, stimulating inflammation. P. acnes, Staphylococcus epidermis and Malassezia furfur induce inflammation and induce follicular epidermal proliferation [65]. Androgens also affect the barrier function of the skin, and disturbances of barrier function may stimulate epidermal DNA synthesis. This leads to epidermal hyperplasia, which may also contribute to follicular hyperkeratosis in acne [66]. Foam cells are lipid-loaded macrophages and neutrophils that are generated from a massive uptake of oxidized lipid. Foam cells are a pathological hallmark of atherosclerosis, and have also been found in acne lesions [67]. Sphingolipids are a class of lipids composed of a backbone of spingoid bases that are modified to produce ceramide (Cer) and more complex compounds, such as sphingomyelin (SM) and glycosphingolipids [68], have both structural and biological functions in human epidermis. Ceramide is the central molecule in the sphingolipid pathway [69]. They are among the most important epidermal sphingolipids and compose about 50 % of intercellular stratum corneum lipids by mass and are involved in the prevention of transepidermal water loss [70]. Kaya et a. [71] reported AV patients had increased circulating levels of C16 SM, ceramide-1-phosphate (C1P) and lower circulating levels of C24 CER compared to healthy controls, which may provide prognostic value for the disease [71]. Sebum is particularly abundant at anatomic sites with high concentration of P. acnes and the sebum component oleic acid has been reported to promote growth of P. acnes in culture. Increased sebum production and follicular hyperkeratosis result in the development of microcomedones and changes in follicular milieu in intensive growth of P. acnes. With proliferation, P acnes secrete various several proinflammatory products. These include lipases, proteases, hyaluronidases and chemotactic factors. Immune response to P. acnes includes humoral and cell-mediated immunity as well as complement activation (Figure 1) [72,73].

ECONOMIC BURDEN OF AV

The economic burden of acne is substantial. This disorder is generally considered mild but represents a high economical and psychological burden for the society. Approximately 50 million individuals within the United States are affected by acne, making it one of the most common dermatological complaints in patients presenting to a general dermatology office [80-85]. Patients experience high levels of anxiety, depression and low self-esteem which leads to impaired quality of life. Therefore, treatment should focus on early intervention to decrease the physical and esthetic burden of the disease, and improvement of quality of life [81]. The cost is estimated to exceed $1 billion per year in USA for direct acne therapy, with $100 million spent on various acne products, as stated by Changqiang et al. [75]. According to Bhate et al. [79], it was over 3 billion dollars per year in terms of treatment and loss of productivity. With the rapid economic growth and concomitant changes of lifestyle in China, the demand for facial beauty has been surprisingly increased. In the general esthetic pursuit of fairer skin in East Asia, Chinese people increasingly pay attention to post-acne outcomes such as scars and PIH, in addition to the disease per se [76]. Zhang et al. [77] revealed that higher brand-name usage and a broader range of topical steroids prescribed by specialists than primary care, which were associated with increased costs. The most common drug class utilized was topical antibiotics, accounting for 63% of all prescriptions. Acne affects a large proportion of the Canadian population and has psychosocial and financial consequences. A 2016 study shows Oral isotretinoin 3 month costs ranged from $400to $500 (approx.) [78]. Many methods have been performed to achieve a satisfying outcome in acne scars but some of them were high cost and also were associated with low results and some complications [80].

CLINICAL DIAGNOSIS

The diagnosis of AV is primarily clinical. The common differential diagnosis of acne includes folliculitis, keratosis pilaris, perioral dermatitis, seborrheic dermatitis and rosacea. History and physical examination can help determine if there is an underlying cause of the acne, such as an exacerbating medication or endocrinologic abnormality causing hyperandrogenism (e.g. polycystic ovarian syndrome). Other dermatologic manifestations of androgen excess include seborrhea, hirsutism and androgenetic alopecia. Endocrinologic testing is not ordered routinely for women with regular menstrual cycles. Older women, especially those with new-onset acne and other signs of androgen excess (e.g. hirsutism, androgenic alopecia, menstrual irregularities, infertility), should be tested for androgen excess with measurements of total and free serum testosterone, dihydroepiandrosterone and luteinizing and follicle-stimulating hormone levels. Pelvic ultrasonography may show the presence of polycystic ovaries. In pre-pubertal children with acne, signs of hyperandrogenism include early-onset accelerated growth, pubic or axillary hair, body odor, genital maturation and advanced bone age (Exhibits 4-6) [82].

ACNE SCARS

Acne affects the face in a majority of cases, with many patients experiencing some degree of scarring, the severity of which correlates to acne grade. Acne scars result from an altered wound healing response to cutaneous inflammation, with inflammatory cell infiltrates found in nearly 80% of atrophic scars. Almost all scars (99%) originate from papules and pustules (inflammatory lesions) and post-inflammatory lesions [100-117]. Different P. acnes phylotypes differentially activate epidermal innate immunity, contributing to variations in acne severity. In patients not prone to scarring, early lesions have a large, non-specific immune response that subsides in resolving lesions. In contrast, in patients prone to scarring, early lesions are characterized by a smaller number of skin-homing CD4+ T-cells compared to non-scarring patients, a response that becomes more active in resolving lesions [118-130]. Studies report the incidence of acne scarring in the general population to be 1 to 11%. Having acne scars can be emotionally and psychologically distressing to patients. Rather than fading with time, the appearance of scars often worsens with normal aging or photodamage [131-137].

Ice pick scars are narrow, deep, and extend vertically to the deep dermis or subcutaneous tissue. Rolling scars occur from fibrous anchoring of the dermis to the subcutis, leading to superficial shadowing and an undulating appearance to the overlying skin. Boxcar scars are round-to-oval depressions with sharply demarcated vertical edges. Papular scars, unlike the depressed morphology of ice pick, rolling, and boxcar scars, are exophytic in nature and produce a cobblestone-like appearance (Exhibit 7).

PSYCHOLOGICAL IMPACT OF AV

Along with acne, having acne scars is a risk factor for suicide and also may be linked to poor self-esteem, depression, anxiety, altered social interactions, body image alterations, embarrassment, anger, lowered academic performance, and unemployment [137]. Studies have also shown that the psychological impact of acne appears to affect more females than males [35]. Facial appearance has an important role in self-perception, as well as in the interaction with others; face lesions cause a significant impact in women's quality of life [141-147]. The psychological impact of acne is generally significant and largely underestimated; stress during professional and private life, anxiety and sleep quality, in particular, have a reciprocal relationship with disease susceptibility and severity [145]. Suicidal ideation was found in 6-7% of acne patients. Psychological issues such as social dysfunction such as reduced/avoidance of social interactions with peers and opposite gender also reported. Acne can negatively influence the intension to participate in sports [142]. Psychiatric symptoms such as somatization, obsession, sensitivity, hostility, phobia, paranoid ideation, and psychoticism were associated with this skin disorder [143]. The degree of impairment in QOL significantly increased with increase of clinical severity of acne, with presence of post acne hyper pigmentation and scarring. In a study in Middle East, 23% of acne female students reported that they had difficulty in sports because of acne; while, a study among Scottish students found that 10% of acne sufferers avoided swimming and other sports because of embarrassment [144]. The management of adult female acne should encompass not just medical treatment of the symptoms, but also a comprehensive, holistic approach to the patient as a whole, her individual lifestyle factors and the impact of acne on her quality of life [145]. Compared with heterosexuals, sexual minorities report higher rates of depression, suicidal ideation and body image issues. Consequentially, sexual minorities with acne may be a group at high risk for development of mental health problems [146]. Sexual distress was particularly higher in female than in male patients with Acne Inversa. Surprisingly, severity of cutaneous alterations correlated neither with sexual dysfunctions nor with sexual distress [148]. The relationship between isotretinoin and depression is the most debated aspect of isotretinoin therapy [149]. It is prudent for the practitioner to continue to use isotretinoin to treat severe acne, while at the same time informing patients and their relatives that depressive symptoms should be actively assessed at each visit and, if necessary, referral to a psychiatrist and a discontinuation of isotretinoin should be considered [150].

ACNE MANAGEMENT

In recent years, due to better understanding of the pathogenesis of acne, new therapeutic modalities and various permutation and combinations have been designed. In topical agents; benzoyl peroxide, antibiotics, retinoids, etc., are the mainstay of treatment; can be given in combinations. While systemic therapy includes oral antibiotics, hormonal therapy and isotretinoin, depending upon the need of patients it has to be selected. Physical treatment in the form of lesion removal, photo-therapy is also helpful in few of them. Due to convenience, lower cost and difficulty getting an appointment with a dermatologist, the use of over-the-counter acne treatments is on the rise. Commonly referred to as “cosmeceuticals,” OTC acne treatments come in lotions, creams, washes, kits, scrubs, brushes and devices. Due to the sheer number of different OTC brands, plus newer products constantly being developed, it is hard for both physicians and patients to keep abreast of the numerous products. However, all treatments for AV are theoretically designed to target one or more of the pathogenic pathways involved in the development of AV lesions. In moderate acne, combination therapy has shown the most favorable results and typically consists of a regimen including benzoyl peroxide, topical antibiotics and a topical retinoid (tretinoin, adapalene or tazorotene). Tretinoin, adapalene and tazorotene demonstrate similar effectiveness in the reduction of inflammatory, non-inflammatory and total lesion counts after 12 weeks of treatment. Oral antibiotics may be tried for patients with a predominance of inflammatory lesions who have not responded favorably to the above topical treatments (Exhibit 8).

Acne prevention

The relationship between diet and acne is highly controversial. Several studies during the last decade have led dermatologists to reflect on a potential link between diet and acne. Selected dietary factors on the course of AV are milk and dairy products, chocolate, glycemic load of the diet, dietary fiber, fatty acids, antioxidants, zinc, vitamin A and iodine.

Milk and dairy products: High intakes (≥ 2 glasses/day) of full-fat dairy products were associated with moderate to severe acne. No significant associations were found between acne and intake of semi-skimmed or skimmed dairy products, and not with moderate intakes of any fat variety of dairy products [151]. Also, no significant association between yogurt/cheese and acne development was observed by Aghasi et al. [152]. However, a person can reduce or prevent acne breakouts by consuming fewer dairy products and fewer foods with a high glycemic index. Acne that occurs after ingestion of foods rich in iodine appears suddenly and is characterized by many papules. The association between acne and milk may also be a result of the iodine content of milk [9].

Chocolate restriction: Chocolate consumption primed human blood mononuclear cells to release more proinflammatory cytokines, interleukin-1β and TNFα, upon stimulation with Propionibacterium acnes. Because over-inflammation is an important contributor to acne pathogenesis and the anti-inflammatory dose effect of antibiotics has been demonstrated to be most effective in treating acne, it is plausible that altered cytokine profiles can contribute to worsening acne [153,154]. Dark chocolate contains more antioxidants than milk chocolate, which would lead to conclusion that it may have much smaller comedogenic effects [9]. Some say that avoiding things like meat, milk or chocolate improved their complexion.

Glycemic load: The improvement in acne and insulin sensitivity after a low-glycemic-load diet suggests that nutrition-related lifestyle factors may play a role in the pathogenesis of acne [155]. A high glycemic index (GI) and glycemic load (GL) diet may stimulate acne proliferative pathways by influencing biochemical factors associated with acne. A low GI and GL diet decreased IGF-1 concentrations, a well-established factor in acne pathogenesis [156]. Having fast food like fries/chips and soda can dramatically increase the calories, carbohydrate, fat, and GL of the nutritionally promoted fast-food meal [157]. Cordain et al. [158] suggested that a low-fat intake and low glycemic load diet may be the cause of acne absence in both populations. Processed foods, especially those with a high glycemic index, have been known to exacerbate acne. One study found that a control group consuming more fish and vegetables had a lower incidence rate of acne. Therefore, adopting a whole foods diet and reducing the intake of dairy products may help significantly reduce acne [159].

Dietary fiber: Patients with AV consumed daily 30 g of high fiber breakfast cereal (13 g fiber/serving), asignificant improvement in the skin condition was shown [159]. Fiber aids elimination of toxins and used hormones from the body. Fruits, vegetables, oats, other whole grains, beans and lentils are good sources. Some soluble dietary fiber components, such as oat bran, pectin and guar gum, stimulate fecal excretion of bile acids. High fiber intakes promote increased bacterial mass but do not alter the microflora composition [160]. Gastrointestinal dysfunction is an important risk factor for diseases of the sebaceous glands and is correlated with their occurrence and development [161], conversely proper digestion improves acne conditions. One study involving over 13,000 adolescents showed that those with acne were more likely to experience gastrointestinal symptoms such as constipation, halitosis, and gastric reflux. In particular, abdominal bloating was 37% more likely to be associated with acne and other seborrheic diseases [162].

Anti-oxidants: Al-Shobaili [39] revealed that plasma levels of malondialdehyde in acne patients were significantly higher as compared with that of the controls, whereas activities of the antioxidant enzymes superoxide dismutase and catalase were lower. Moreover, total antioxidant capacity was also low in acne patients as compared with that of the controls. Polyphenols are antioxidant molecules found in many foods including nuts, fruits, vegetables, chocolate, wine and tea. Polyphenols have antimicrobial, anti-inflammatory and antineoplastic properties. Recent studies suggest that tea polyphenols may be used for reducing sebum production in the skin and for treatment of AV. Again, green tea and green tea-lotus combination topicals could be used to treat skin diseases that are associated with increased sebum secretion, such as AV [163-165]. Apple polyphenols (APP) inhibited dexamethasone-induced lipid production and expression of sterol response element-binding protein-1 and its target enzymes, acetyl-CoA carboxylase and fatty acid synthase, in the sebocytes. Thus, APP may be useful to regulate sebum production and may alleviate sebum-involved skin disease [166]. Low vitamin A, E and zinc plasma levels have an important role in the pathogenesis of acne and in the aggravation of this condition. Supportive treatment with these vitamins and zinc in severe acne may lead to satisfactory results [114,167].

Frequent cleansing and sun protection: Washing and over-the-counter cleansers are common interventions in AV, but the clinical evidence for their benefit is poorly understood [168]. Cleansers reduced both inflammatory and non-inflammatory acne lesion counts, and might be helpful for acne treatment [169]. In addition to containing dyes and perfumes that can irritate and exacerbate acne, these cleansers often are too harsh and can result in excessive drying of the skin, which leads to overcompensation by the oil glands and ultimately to more oil on the surface of the skin [170]. However, cleansing the acne patient involves several considerations, including matching skin type to the right type of cleanser, optimal times and methods of cleansing, treating parts of the body other than the face and patient perceptions of the cause and treatment of acne. Soap-free cleansing products that have a similar pH to skin (5.5) are more suitable for people with acne. A reference pH range of 4.5 to 5.5 was considered normal for women and 4 to 5 was considered normal for men. Studies have shown that lowering the pH reduces the inflammatory TH2 response (CD4+ cells, orchestrate protective type 2 immune responses) and quickens barrier function recovery, thereby preventing epidermal hyperproliferation [171]. While sunscreens are often irritants, the best options for young, oily, acne-prone skin tend to have a water or light liquid base. Moisturizing sunscreens are appropriate for patients with dry, sun-damaged skin, as well as those who wear makeup, have other skin diseases or are easily irritated by products [44].

Avoid stress/tobacco: Stress is a well-attested contributor to AV pathogenesis. The basis for the association between emotional stress and the onset or exacerbation of acne is in several cutaneous neurogenic factors which interact with a pathogenic cascade in acne. Stress stimulates the release of pro-inflammatory cytokines and CRH, leading to increased levels of cortisol. Sleep deprivation associated with modern lifestyle and stress has an important impact on the hypothalamic-pituitary-adrenal axis and in increased secretion of stress-related hormones and may also be an aggravating factor for acne. Pythagorean Self-Awareness Intervention is a feasible and possibly effective stress management method for AV. Clinical evidence and experimental data showed a straight correlation between smoking habit and post-pubertal acne in which the clinically non-inflammatory (atypical) post-adolescent acne is the most frequent [131]. The comedonal form predominates in smokers and is characterized by the presence of micro and macro-comedones and few inflammatory lesions, which led the authors to describe this clinical form as “smoker’s face.” The sebaceous gland is sensitive to acetylcholine that is stimulated by nicotine. Acetylcholine leads to cellular modulation and differentiation, inducing hyper-keratinization and influencing sebum production and composition, as well as reducing antioxidant agents and increasing peroxidation of sebum components, such as squalene. Among patients with adolescent acne, the probability to be affected by current acne in smokers was between 2.6-6.3 times higher than in non-smokers [131]. However, it is worth bearing in mind that many successful quitters have found it motivational to watch their skin regain its tone and elasticity just weeks after smoking cessation [172-191].

Topical drugs

Topical treatment is the mainstay of acne therapy. The most commonly prescribed topical medications for acne include benzoyl peroxide, clindamycin and retinoids. Despite their effectiveness in treating mild to moderate acne vulgaris, these topical medications are found to be irritating and are historically associated with poor tolerability and diminished patient adherence. Thus, choosing the right formulation that will be effective and well tolerated is essential. Antibiotics targeting P. acnes have been the mainstay in acne treatment for the past four decades. Among them, macrolides, clindamycin and tetracyclines are the most widely prescribed. Novel formulations that optimize drug concentration and utilize improved delivery vehicles have helped to enhance the tolerability and efficacy and allow for less frequent application or co-application of drugs that were previously considered incompatible. In the near future, more effective treatments with fewer side effects are expected. The use of topical anti-androgens, coenzyme-A carboxylase inhibitors and insulin growth factor-1inhibitors to control sebum production seem promising. Selective RAR-agonists have the potential of becoming an alternative to the currently available retinoid therapy in the management of infundibular dyskeratosis with a better safety profile. Antibiotic use will probably decline as more effective options for controlling Cutine bacterium acnes colonization and the inflammation cascade emerge.

Benzoyl peroxide (Figure 3)

Benzoyl peroxide (BP) has been an important component of topical therapy for acne vulgaris for more than five decades due to its ability to markedly reduce Propionibacterium acnes and inflammatory acne lesions and its ability to moderately reduce non-inflammatory acne lesions [180]. It has mild sebostatic and keratolytic effects without a concern for the development of drug‐resistant bacteria. Studies suggested that AEs at the application site occurred more often in Japanese patients than western patients; most of the AEs were mild [172,177]. It is most effective when used in combination with other acne vulgaris therapies [35]. BP is a bactericidal agent. Combining BP with a topical antibiotic in a stable formulation has been proven in clinical trials to reduce total P acnes count by 99.7% after 1 week of therapy, eliminating both susceptible and resistant strains of P. acnes [179]. However, we have recently noticed BP's benefits as monotherapy in the treatment of acne. Topical BP also has mild sebostatic effects contributing to its keratolytic activity and efficacy in treating comedonal acne. BP is available as both over-the-counter and prescription formulations in concentrations of 2.5%, 5% and 10% [82]. Available preparations include lotions, creams, gels, foams, solutions, cleansing bars, cleansing lotions, cloths, pads, masks and shaving creams. Each application vehicle has specific instructions for the frequency of use. Combination products with BP and topical antibiotics or adapalene are more effective than either medication used alone [173]. Concentrations of BP above 5% are not recommended for use in adult women. It can also cause photosensitivity and bleaching of clothing [35]. It is used as 2.5%, 4% and 5% concentration in gel base [26]. BP in concentrations of 2.5%, 5% and 10% are equally effective at treating inflammatory acne. However, higher concentrations are associated with more adverse effects. It useful as monotherapy for mild acne or as an adjunct in the treatment of moderate to severe acne vulgaris [178]. Comedonal acne is more typical in young adolescents, but can occur in combination with inflammatory papules and pustules at any time. Topical retinoids have long been advocated for the treatment of comedonal acne. Adapalene 0.3%-BP 2.5% was found to be effective in patients with severe acne. Clindamycin-BP 1.2%/3.75% gel and clindamycin-BP 1.2%/2.5% gel was both found to be effective in severe acne with an apparent BP-dose response [181]. Clindamycin 1.2%-BP 3.75% gel may afford similar benefits to adapalene 0.3%-BP 2.5% gel in this sometimes difficult to treat patient population [174]. When acupuncture was combined with BP, serum excretion rate in women was reduced compared to BP alone [176]. In addition to use for facial acne vulgaris, cleanser formulations of BP are commonly used for truncal AV due to ease of use on a large body-surface area and to avoid bleaching of fabric. Short contact therapy utilizing a 2 min skin contact time with BP 9.8% emollient foam used once daily over a 2 week duration was highly effective in reducing the quantity of P acnes organisms on the back and provided comparable colony count reduction to “leave on” therapy using BP 5.3% emollient foam [182]. The FDA classifies benzoyl peroxide as pregnancy risk category C [186].

Clindamycin (Figure 4)

Due to the significant increase of P. acnes strains resistant to clindamycin and erythromycin, the use of these substances alone is contra-indicated [185]. Cutibacterium acnes (C. acnes) can become an exacerbating factor in acne vulgaris, where clindamycin was found to be resistant, as reported by Aoki et al. [187]. Clindamycin can be administered into the body by multiple routes. It is available topically as a foam, gel, lotion or solution for treatment of acne vulgaris. The most common side effects experienced with topical use include pruritis, xeroderma, erythema, burning, exfoliation or oily skin [183]. Treatment with clindamycin phosphate 1.2% and tretinoin 0.025% resulted in continuous improvement of facial acne over the course of 12 weeks, along with improved QOL and a tolerable safety profile, supporting the use of this combination in clinical practice [184]. Tolerability profile of ClinP/Tret gel is beneficial when combining different topical therapies and formulations in a given patient, as cutaneous irritation is an adverse factor that can reduce adherence and prevent a successful therapeutic outcome [189]. It is also easy for patients to handle and apply and has the advantage of not containing BP which can bleach hair and fabrics [190]. ClinP/Tret gel has a favorable safety profile following UV/visible irradiation and a low potential for phototoxicity and photo-allergy, currently available for the once-daily topical treatment of acne [191]. Patients with Fitzpatrick Skin Type V and VI treated with clindamycin phosphate 1.2%/ BP 3.75% gel experienced significant reductions in facial acne severity, lesion counts and PIH severity/distribution. Tolerability was excellent [188]. A triple-combination regimen incorporating oral minocycline (dosed by patient weight), BP foaming cloths 6% QD and clindamycin phosphate 1.2%/ tretinoin 0.025% gel QD can substantially improve moderate to severe acne vulgaris [192]. Zeichner et al. [193] reported similar cutaneous S/Es with a fixed-dose tretinoin 0.025%/clindamycin phosphate 1.2% gel in combination with a benzoyl peroxide 6% foaming cloth compared with ClinP/Tret gel alone for facial acne. Clindamycin often discussed along with the macrolides but are not chemically related, it belongs to a group of medicines known as lincosamide or lincomycin antibiotics. Clindamycin is pregnancy category B.

Retinoids (Figure 5)

Topical retinoids are creams, lotions and gels containing medicine derived from Vitamin A. These compounds result in proliferation and reduced keratinization of skin cells independent of their functions as a vitamin and devoid of bacterial resistance. American Academy of Dermatology (AAD) states “retinoids are the core of topical therapy for acne because they are comedolytic, resolve the precursor microcomedone lesion and are anti-inflammatory;” further, they “allow for maintenance of clearance” [194]. Local adverse effects, including erythema, dryness, itching, and stinging, occur frequently during the early treatment phase. Their impact varies with the vehicle formation, skin type, frequency and mode of application, use of moisturizers and environmental factors such as sun exposure or temperature [195]. Retinoids act to normalize desquamation by reducing keratinocyte proliferation and promoting differentiation. Isotretinoin, tretinoin and tazarotene also suppress Toll-like receptor expression. Blocking these pathways reduces the release of inflammatory cytokines and nitric oxide and inhibits cellular inflammation [194]. Topical retinoids are safe and efficacious for the treatment of AV. They should be used in combination with benzoyl peroxide to optimize results in patients. Adapalene has a superior tolerability profile amongst topical retinoids [196-199]. Developed in response to concerns about the instability of tretinoin, the naphthoic acid derivative adapalene was found in vitro to be photostable and not degraded in the presence of BP. Again, adapalene/BP was rated as more successful with a significantly greater reduction in all lesions counts compared to any other therapy at the conclusion of the trial [200-204]. Higher concentrations of retinoids such as adapalene 0.3%/BP 2.5% have shown increased efficacy, particularly among patients with moderately severe and severe acne – a population at high risk for scarring [196]. Adapalene supplied as a 0.1% cream, gel, and lotion and 0.3% gel are prescription only products. It is less irritating compared to other topical retinoids, applied once daily, either in the morning or at bedtime to a clean face. The patient should be advised to wash the face with a gentle cleanser and allow the face to dry thoroughly [197]. Tretinoin 0.05% gel exhibits a greater anti-acne efficacy than adapalene 0.1% gel, but has higher skin irritation potential [198]. Chandrashekhar et.al, 2015 stated tretinoin 0.025% nanogel formulation is more efficacious and better tolerated than its conventional 0.05% gel formulation [200]. Harper et al. [201] detailed a similar polymeric formulation of tretinoin 0.05% lotion with an incidence of erythema, dryness and skin burning. Combination of tretinoin 0.05% cream and Aloe vera topical gel (50%) with was well tolerated and significantly more effective than tretinoin 0.05% cream alone for the treatment of mild to moderate acne vulgaris [202]. Deshmukh et al. [203] found that topical combination of 1% Nadifloxacin and 0.025% Tretinoin was caused greater reduction in facial acne lesions than 1% Clindamycin and 0.025% Tretinoin in patients of mild to moderate AV. This could be due to the fact that Nadifloxacin is reported to have potent action against P. acnes, Staphylococcus epidermidis and methicillin-resistant Staphylococcus aureus (MRSA), with no cross-resistance (Exhibit 9) [203].

Azelaic acid (Figure 6)

Azelaic acid is a naturally occurring saturated C9-dicarboxylic acid which has been shown to be effective in the treatment of comedonal acne and inflammatory acne, as well as hyperpigmentary skin disorders [205-210]. It is an anti-acne drug by inhibiting thioredoxin reductase enzyme of Propionibacterium acnes that affects the inhibition of bacterial DNA synthesis which occurs in the cytoplasm. Azelaic acid (20% cream or 15% gel) is recommended as the first line of treatment in monotherapy for non-inflammatory and inflammatory acne, applied twice a day [35]. Azelaic acid 15% foam is effective and safe in the treatment of facial acne vulgaris [205]. Treatment with azelaic acid 20 % cream significantly improves acne severity and disease-related QoL in adult women [209]. Azelaic acid must penetrate through the stratum corneum to the sebaceous tissue and into cytoplasm by passing through thick peptidoglycan of P. acnes. Thus, it is necessary to increase the penetration of azelaic acid that formulated based ethosome. Azelaic acid ethosome-based cream showed better activity to against P. acnes than marketed azelaic acid preparation (Zelface^® cream) [206]. Combined azelaic acid 20% and salicylic acid 20% are recommended at early stage of treatment if patients have more inflammatory lesions, while trichloroacetic acid 25% chemical peel is recommended if patients have more non-inflammatory lesions. Chemical peeling is effective in controlling mild-moderate acne in SPT III-IV (Fitzpatrick skin type) [207]. Again, a hormonal blockade conducted by ethinylestradiol plus a new generation of progesterone derived of spironolactone with anti-androgenic activity was compared to topical treatment with azelaic acid, it showed better statistical improvement in women with mild to moderate acne [208].

Dapsone (Figure 7)

Topical dapsone is used for both comedonal and papular acne, though there are some concerns with G6PD deficient individuals [26]. Treatment of AV with dapsone gel, 5% requires twice-daily dosing and some patients may not adhere to this regimen. Dapsone gel, 7.5% applied topically once daily is an effective, safe and well-tolerated treatment for acne over 12 weeks and offers similar local tolerability compared with vehicle and had a safety and tolerability profile similar to that of twice-daily dapsone gel, 5% in patients aged ≥ 12 years [211-224]. However, Monotherapy with dapsone gel, 5% administered twice daily was safe and effective for treatment of facial acne in women with and well tolerated in patients with all skin phototypes who were treated for moderate acne [220,222]. Dapsone 7.5% gel is a viable option to add to the armamentarium for treatment of truncal AV [216]. Draelos et al. [225] found that treatment response with dapsone gel, 7.5% in racial subgroups was similar. Tanghetti et al. [226] revealed that once-daily dapsone gel, 7.5% was efficacious for acne regardless of baseline total lesion count, with superior efficacy in females and similar tolerability in males and females. It has been shown to be useful when combined with doxycycline and then alone as maintenance for long periods, with the advantage of having no risk for bacterial resistance in patients with AV [35]. The combination oral doxycycline hyclate 100 mg with topical dapsone 5% gel twice daily is an effective and well-tolerated regimen to treat moderate to severe acne vulgaris. After discontinuation of doxycycline, topical dapsone 5% gel is effective at maintaining a therapeutic response. Topical dapsone 5% gel can be used effectively for long-term acne maintenance treatment without the risk of developing antibiotic resistance [217]. Incorporation of dapsone in methylprednisolone aceponate 0.1% ointment broadens the therapeutic options for topical treatment, in particular for patients with chronic inflammatory dermatoses associated with a neutrophilic pathogenesis [212]. Drugs which inhibit cytochrome P-450 should be used with caution in patients receiving dapsone [213]. Careful patient selection and close monitoring during treatment are mandatory to provide safe and effective use of dapsone [215]. Bilosomes as novel vesicular carrier for the cutaneous delivery of the sulfone compound, Dapsone, for topical treatment of acne represented about 1.5-fold higher drug retained in the bilosomes treated skin, compared to dapsone alcoholic solution [214].

Acetyl coenzyme A carboxylase inhibitor (Figure 8)

The increasing emergence of microbial resistance associated with antibiotics, teratogenicity, particularly associated with systemic isotretinoin and the need for an adverse drug profile, which can be tolerated by the patient, make the need of new pathogenesis relevant anti-acne agents an emerging issue. The compounds under investigation include olumacostat glasaretil, cortexolone 17α-propionate, stearoyl-CoA desaturase 1 inhibitors, agents affecting the melanocortin system, omiganan and minocycline [227-229]. Olumacostat glasaretil (OG) is a small molecule inhibitor of acetyl coenzyme A (CoA) carboxylase (ACC), the enzyme that controls the first rate-limiting step in fatty acid biosynthesis. Inhibition of ACC activity in the sebaceous glands is designed to substantially affect sebum production, because over 80% of human sebum components contain fatty acids. OG inhibits de novo lipid synthesis in primary and transformed human sebocytes, including the synthesis of triglycerides, diglycerides, cholesteryl esters, wax esters and phospholipids [226]. OG was well tolerated and showed evidence of efficacy [227]. It reduces both saturated and monounsaturated fatty acyl chains in sebaceous lipids. Topical OG application decreases hamster ear sebaceous gland size and shows efficacy in treating patients with acne vulgaris [228]. Triglycerides and fatty acids together make up the largest portion of sebum content; therefore, OG has the potential to decrease sebum output. Further, when evaluated in animal models, topical OG consistently reduced sebaceous gland size. Dermira, a biopharmaceutical company, released data from a Phase 2b trial conducted for a topical sebum production inhibitor, OG (formerly DRM01) (Figure 9) [229].

Topical anti-androgens (Figure 10)

Topical spironolactone may be effective for the treatment of acne patients with increased sebum secretion. The 5% spironolactone topical gel resulted in a decrease in the total acne lesions (TLC) in acne vulgaris, while it had no significant efficacy in the acne severity index [230]. RCTs have shown mixed results in the improvement of acne, which indicates that topical spironolactone gel is not an effective alternative for systemic spironolactone [231]. Cortexolone 17α-propionate 1% cream was very well tolerated, and was significantly better than placebo regarding TLC [232]. Cortexolone 17α-propionate competitively inhibits endogenous androgen binding at the human androgen receptor level without inhibiting the skin 5α-reductase. Cortexolone 17α-propionate 1% cream was also clinically more effective than tretinoin 0.05% cream but this difference was not statistically significant [98]. Stearoyl-CoA desaturase-1 (SCD-1) catalyzes the formation of delta9-monounsaturated fatty acids from saturated precursors. Upon topical application to the skin of mice as a 1% solution, XEN103 induces pronounced sebaceous gland atrophy with a rapid onset after a few days of dosing, both sebaceous gland numbers and size being reduced by 50 to 75% and without any signs of skin irritation [233]. Omiganan pentahydrochloride is a synthetic, cationic, antimicrobial peptide that is being developed for the prevention of catheter-related infections and the treatment of acne and rosacea. It has been demonstrated to be rapidly bactericidal and fungicidal, with significant dose-dependent activity against a broad spectrum of infectious organisms. These results further confirm that the drug has the potential as a topical antimicrobial agent [234].

Minocycline (Figure 11)

Oral tetracyclines-especially doxycycline and minocycline-are frequently prescribed for the treatment of moderate-to-severe acne, given their anti-inflammatory properties and their effect on P. acnes reduction. Minocycline is an effective treatment for moderate to moderately-severe inflammatory acne vulgaris. It is an oral antibiotic; use has lessened due to safety concerns (including potentially irreversible pigmentation), a relatively high cost, and no evidence of any greater benefit than other acne treatments [235]. FMX101 4% is a topical minocycline foam is a new class of topical minocycline products has been developed for the treatment of acne and rosacea that decreases the risk for antibiotic resistance while maintaining safety and efficacy, hydrophilic gel studies reported greater treatment efficacy than the lipophilic foam studies. Reduced both inflammatory and non-inflammatory lesions and improved Investigator's Global Assessment scores in patients with moderate-to-severe acne [236,237]. Once-daily topical application of minocycline foam 4% did not lead to significant systemic exposure to minocycline. It appears to be a well-tolerated treatment option for individuals with moderate-to-severe acne [238]. BPX-01 was developed to directly deliver minocycline through the epidermis and into the pilosebaceous unit to achieve localized treatment with lower doses of drug [239]. However, because BPX-01 (another topical minocycline in trial) is topical and exhibits negligible systemic exposure, the likelihood of adverse events associated with oral minocycline use is much lower. BPX-01 2% formulation is a promising treatment for moderate-to-severe non-nodular, inflammatory acne vulgaris in both reductions of inflammatory lesions and also overall improvement in facial acne according to IGA [240].

ORAL DRUGS FOR ACNE MANAGEMENT

Not all acne clears up with topical medications. Oral medications, also called systemic medications, work internally to improve the skin. Persistent or severe cases of acne are difficult to control and in the majority of cases require oral medications. A hot, humid climate with an increased risk of sweating can also make it worse. Severe acne (sometimes called cystic acne or nodular acne) creates large, deep, inflamed breakouts. Topical medications can't get deep enough to effectively treat these types of blemishes. All oral acne medications are prescription only. There are no over-the-counter alternatives. People who shave should use safety razors with a sharp blade or an electric shaver. Most patients on oral antibiotics should notice improvements after about 6 weeks. A course may last from 4 to 6 months. Pregnant or breastfeeding mothers should take an erythromycin instead of tetracycline. Long-term oral antibiotic use in acne may be associated with a variety of adverse effects including antibiotic resistance, pharyngitis, inflammatory bowel disease and breast and colon cancer.

Isotretinoin (Figure 12)

Isotretinoin is a retinoic acid derivative mostly used in the treatment of cystic acne vulgaris [241-254]. Oral isotretinoin is FDA-approved for the treatment of severe recalcitrant AV but can also be used to treat patients with moderate acne that is either treatment-resistant or relapses quickly after discontinuation of oral antibiotic therapy. Several studies have shown that isotretinoin effectively decreases sebum production, the number of acne lesions and acne scarring [98]. The treatment for the average patient is carried out during two to ten months [248]. Isotretinoin is the most effective treatment available, but serious adverse effects, including a possible association with depression and suicide, limit its use, further studies are needed to identify those patients who would benefit from an early referral to a mental health professional when Isotretinoin is initiated [241]. However, Huang et al. [242] revealed that isotretinoin treatment for acne does not appear to be associated with an increased risk for depression. Moreover, the treatment of acne appears to ameliorate depressive symptoms. Botsali et al. [243] further ensured an improvement for neurocognitive functions in isotretinoin patients and none of them was evaluated as depressive by the psychiatric examination. iPLEDGE is the mandatory regulatory program for isotretinoin in the United States, aimed to prevent isotretinoin-related teratogenicity [244]. Isotretinoin is still the best treatment for severe nodulocystic acne. However, it must be taken into consideration its teratogenic effect on pregnant women and its association with inflammatory bowel disease, depression and suicidal ideas [245]. Soyuduru et al. [246] found that five months of isotretinoin therapy in AV patients causes insulin resistance and the increase in insulin resistance is not dependent on age, BMI, BFM and lipid levels of these patients. Isotretinoin can induce hyperhomocysteinemia and decreased serum folic acid level, which may be a risk for cardiovascular disease and thrombosis, as well as psychoses. Van et al. [247] revealed a study in Vietnam where a low dose isotretinoin treatment had effectiveness in decrease the severity of disease without significant changes in the plasma homocysteine level as well as the serum folic acid level. Fouladgar et al. [249] stated that corneal sensitivity decreases after three months of treatment with isotretinoin. This decrease is more pronounced at higher ages and in women. Approximately 80% of pregnant women are exposed to isotretinoin within the recommended 30 days of contraception or during pregnancy. North America and the European Union implemented the pregnancy prevention program [250]. Tasli et al. [251] stated complaint of nasal obstruction. Conventional and low dose isotretinoin regimens are associated with increased dermcidin (an antimicrobial peptide secreted by sweat glands that attacks any bacteria on our skin) expression [252]. Reduced dermcidin concentration in sweat in patients with inflammatory acne may permit proliferation of P. acnes in pilosebaceous units, resulting in progression of inflammatory acne [253]. Isotretinoin was the main component found in milk 10 to 12 h after a dose while the metabolite was the primary component in milk 22 to 24 h after the previous dose [255]. A review of adverse reaction reports on retinoids causing a breast reaction submitted to a French pharmacovigilance center found 22 cases of gynecomastia was associated with isotretinoin use. 14 of the cases were gynecomastia, 6 were galactorrhea and 2 were of both gynecomastia and galactorrhea. Gynecomastia and/or galactorrhea were unilateral for almost half of the reported retinoid cases [256]. Exposing to isotretinoin among pregnant women has still occurred due to detrimental adherence to risk reduction programs which resulted in live-born infants with different kinds of abnormalities. Despite the known serious adverse effect of isotretinoin, the use of drug was not based on the guidelines in some cases, which needs more attentions to prevent the severe drug related problems [257].

Spironolactone

Spironolactone, a synthetic 17-lactone steroid, acts as a non-selective mineralocorticoid receptor antagonist with moderate affinity for both progesterone and androgen receptors [258-266]. It is an effective second-line treatment option for post-adolescent acne, with a low risk of short-term adverse effects such as hyperkalemia [267,268]. A reduction in sebum may be achieved by blocking dihydrotestosterone binding to the androgen receptor within sebocytes and inhibiting androgen-induced sebocyte proliferation. The systemic effects of spironolactone on adrenal synthesis of androgen precursors may also contribute to clinical efficacy, although at therapeutic doses this may be unlikely. The diuretic effect of spironolactone may benefit women who experience a premenstrual acne flare associated with fluid retention [267]. The safety of long-term spironolactone use is well established given that it has been approved by the U.S. FDA since 1960. Because androgens mediate increased sebum production, they have been implicated in the pathophysiology of acne which led to the current acceptance of spironolactone as a non-antibiotic alternative to traditional systemic treatments for women with acne [231]. Spironolactone regulates sebaceous gland activity by blocking androgen receptor. It is a valuable alternative in women with acne in whom oral isotretinoin has failed. Combined oral contraceptives and spironolactone are good options [265]. First and second-generation oral contraceptives decrease the efficacy of spironolactone, confirming the interest of using two third or fourth-generation oral contraceptives [263]. In monotherapy, 80% of the patients present menstrual irregularity. The combined use of spironolactone with topical retinoid seems to provide a superior response to the retinoid treatment isolated in adult female acne. It can be used to promote androgen blockade in patients using levonorgestrel intrauterine devices or to increase androgen blockade in those who opt for combined oral contraceptive pills. A retrospective study of spironolactone found that there is no need for periodic control of potassium levels in young women, who do not have nephropathies, and are not users of other medications that may increase potassium levels [35]. Spironolactone (25 mg/day) can also be used in males. It decreases the production of androgens and blocks the actions of testosterone. If given to females, then pregnancy should be avoided because the drug can cause feminization of the fetus [26]. For this, spironolactone is classified as a Pregnancy Category C. Without the need for regular blood testing or the risk of severe teratogenicity, spironolactone is an attractive alternative to treatment with isotretinoin [231]. Spironolactone may have similar clinical effectiveness to that of oral tetracycline-class antibiotics [264]. A study shows the effectiveness of spironolactone to treat acne in Asian women, with a 47% good response using an initial dose of 200 mg/day, then reducing the dose every 4 weeks. Spironolactone’s side effects are dose-dependent and the most frequent are increase of diuresis, headache, dizziness, menstrual irregularity, breast pain, fatigue and hyperpotassemia [265].

Oral antibiotics (Figure 13)

Oral antibiotic medications are commonly prescribed as second-line therapy for patients with mild-to-moderate acne that is not adequately controlled with topical agents alone and oral antibiotics have been a mainstay in the treatment of acne for decades and function by exerting an antibacterial effect by reducing the follicular colonization of Propionibacterium acnes. Systemic antibiotics also have anti-inflammatory and immunomodulatory properties. Tetracyclines, including sub-antimicrobial dose doxycycline, macrolides (notably azithromycin), trimethoprim-sulfamethoxazole, cephalosporins, and fluoroquinolones as treatment options for acne vulgaris. Antibiotic use for acne not only promotes resistance in Propionibacterium acnes, but also affects other host bacteria with pathogenic potential [269,270]. Limiting systemic antibiotic use may also reduce the risk of inflammatory bowel disease (for tetracyclines), pharyngitis (for tetracyclines), C. difficile infection and Candida vulvovaginitis; however, studies have shown that these associations are limited. Penicillin, erythromycin and cephalosporin are thought to have the best safety profile during pregnancy. There are three categories of antibiotic agents that range from those that are likely to reduce the effectiveness of OCPs (rifampin), those that are associated with OCP failure in three or more reported cases (ampicillin, amoxicillin, metronidazole and tetracycline) and those that were associated with OCP failure in at least one case report (cephalexin, clindamycin, dapsone, erythromycin, griseofulvin, isoniazid, phenoxymethylpenicillin, talampicillin and trimethoprim) [98].

Tetracycline treatments, which include minocycline, doxycycline and tetracycline, are considered first-line therapy in patients with moderate-to-severe inflammatory acne except in certain circumstances including pregnancy, age <8 years or known allergy [271]. Tetracycline medications including minocycline and doxycycline are classified as FDA pregnancy category D. Tetracycline agents should not be used during pregnancy because use during the second and third trimester is known to cause discoloration of the teeth and bones [272,273]. GI side effects, including “pill esophagitis,” are perhaps the most common concerning side effect associated with the use of oral doxycycline [274]. Oral azithromycin pulse therapy may be a good alternative to doxycycline in the management of acne for those unable to tolerate doxycycline (Exhibit 10) [275].

Azithromycin, 500 mg thrice weekly for 12 weeks, is a safe and effective treatment of acne vulgaris with excellent patient compliance with few S/Es [276,277]. Oral desloratadine had antiacne properties and when combined with azithromycin plus isotretinoin protocol, it significantly improves severe acne lesions and minimizes the ADEs [278]. Nakase et al. [279] reported low-level fluoroquinolone-resistant mutants with the Ser101Leu or Asp105Gly substitution in GyrA could be obtained from selection with ciprofloxacin and levofloxacin during in vitro mutation experiments [279]. Other antibiotics such as amoxicillin, erythromycin and bactrim are sometimes used, and if bacterial overgrowth or infection is masquerading as acne, other antibiotics such as ciprofloxacin may be used in pseudomonas related 'acne' [26]. Metronidazole gel (2%) is an effective, safe and well-tolerated topical medication for moderate AV. Its mechanism of action is thought to be associated with its anti-inflammatory, immunosuppressive, and/or antimicrobial properties [280]. Metronidazole has an excellent record of safety during pregnancy and is frequently used as the treatment of choice for several common non-dermatologic infections during pregnancy (Figures 14 and 15) [281].

Intracrine secretion involves the synthesis of active androgens in peripheral organs, such as the skin, where the androgens exert their action in the same cells where synthesis takes place without release into the general circulation. A large portion of androgens are also synthesized in the skin from inactive adrenal precursors including, dehydroepiandrosterone (DHEA), DHEA-sulfate (DHEA-S) and androstenedione. Besides sebaceous glands, other androgen-sensitive components of skin are hair follicles, sweat glands, epidermis and dermis, containing enzymes responsible for converting DHEA, DHEA-S and androstendione into the potent androgens dihydrotestosterone (DHT) and testosterone. DHT and testosterone are the major androgens that interact with the androgen receptors on sebaceous glands with DHT being 5 to 10 times more potent than testosterone. This conversion of inactive adrenal precursors to potent androgen occurs in sebaceous glands in the presence of several key steroidogenic enzymes: 3-Beta-hydroxysteroid dehydrogenase (3B-HSD), 17-Beta-hydroxysteroid dehydrogenase (17B-HSD) and 5α-reductase. Estrogen is known to suppress sebum production when given in sufficient amounts. Other mechanisms for estrogen’s effect include direct opposition effect on testosterone and inhibition of testosterone secretion. In addition, through the metabolization of estrogen in the liver, estrogen increases sex hormone-binding globulin (SHBG). SHBG has a high affinity for testosterone and will bind to it preferentially over estrogen. Since testosterone and its conversion to DHT are the primary androgens in acne, increased SHBG leads to improvement in acne.

ORAL CONTRACEPTIVE PILLS (OCPs)

Currently, there are three types of oral contraceptive pills: combined estrogen-progesterone, progesterone only and the continuous or extended use pill. Use of combined pills for acne has been formally approved by the FDA for specific brands. The majority of women take OCP’s to prevent pregnancy, but 14% used them for non-contraceptive reasons [282]. The beneficial effect of OCPs is related to a decrease in ovarian and adrenal androgen precursors; to an increase in SHBG, which limits free testosterone; and to a decrease in 3a-androstenediol glucuronide conjugate, the catabolite of DHT formed in peripheral tissues (Figure 15). There are now four different combined oral contraceptive pills that are FDA approved for the treatment of acne since its first introduction in 1960. Hormonal therapies are effective and well tolerated options for the treatment of acne vulgaris in adolescents with and without endocrine disorders. They can be used as monotherapy or in conjunction with benzoyl peroxide, topical retinoic acid or antibiotics [282-291]. In the case of hormonal disturbances, the use of hormonal contraception not only improves the cosmetic situation of the patient but is also necessary to decrease the risks related to hyperandrogenemia [286]. According to WHO recommendations, the contraindications to oral contraception are as follows: pregnancy, breast feeding, history of deep venous thrombosis and thromboembolic event, active liver disease, smoking after the age of 35 years, migraine, breast cancer, hypertension, diabetes mellitus with vascular changes and long-term immobilization [287]. There was a significant reduction in the expression of TLR-2 (Toll-like receptor expression) in the skin of adult females with facial acne who used azelaic acid 15% gel or combined oral contraceptive (drospirenone + ethinylestradiol). Rocha et al. [283] suggested a possible anti-inflammatory effect of oral contraceptive and azelaic acid in AFA via modulation of this receptor. Contraceptive pills can have side effects such as headaches, breast tenderness and nausea. The pills that reduced acne had ethinyl estradiol in them, combined with one of the following drugs: levonorgestrel, norethindrone, norgestimate, drospirenone, cyproterone acetate, chlormadinone acetate, dienogest or desogestrel. Cyproterone acetate has not been approved for contraceptive use in Germany, but it can be prescribed for the treatment of acne [284]. Cyproterone acetate (2 mg of cyproterone acetate and 0.35 of ethinyl estradiol) after 3 months of treatment caused visible improvement in acne in 40%. More than 85% of patient finished the study, which suggests very good compliance and tolerability [285]. Animal studies showed that cyproterone acetate in high doses only is associated with congenital malformations. There is a possibility of abnormal sexual differentiation of the fetus or other teratogenic effects [288]. Chlormadinone acetate was more effective in the treatment of acne than levonorgestrel and was more anti-androgenic than dienogest [289]. Ethinyl estradiol/chlormadinone acetate 30 mcg/2 mg once daily is more effective for the treatment of acne and dysmenorrhea in women with mild to moderate AV and dysmenorrhea than ethinyl estradiol/drospirenone 30 mcg/3 mg [289] (Figure 16).

LASER THERAPY

Laser therapies are increasingly becoming part of or an adjunct to the medical treatment of active acne and are a useful treatment modality. Studies of lasers in the treatment of acne, including erbium glass, Nd:YAG, pulse dye laser (PDL), potassium titanyl phosphate (KTP) laser, and laser-based photodynamic therapy, have been published [292-294]. Lasers including infrared wavelengths and pulsed dye lasers; light devices including blue light, red light and broadband light; and photodynamic therapy with aminolevulinic acid and methylaminolevulinic acid have been shown to be effective in the treatment of acne vulgaris. The optimal outcomes are achieved with photodynamic therapy combined with medical therapy. Acne scarring has been best treated with lasers, including non-ablative infrared lasers, fractional non-ablative and ablative laser resurfacing, and most recently needle-based radiofrequency devices. Unique combination of lasers appears to be safe in patients with Fitzpatrick Skin Type IV and might be useful in treating moderate-to-severe acne vulgaris. Kang et al. [295] stated that approximately 80% of the patients reported overall satisfaction. Laser therapy is advantageous because it is an in-office treatment, which ensures patient adherence to therapy. In addition, it offers no systemic side effects that might complicate treatment when using oral acne medications. Although many different lasers have been studied for the treatment of acne, only a few studies to date have evaluated a combination of lasers, which include PDL with either a 1,064-nm Nd:YAG or a 1,450 nm diode laser. Lasers studied include the 1,540 nm erbium:glass laser, 1,550 nm fractionated erbium:glass laser, pulsed-dye laser (PDL), q-switched 1,064 nm neodymium-doped yttrium aluminium garnet (Nd:YAG) laser, fractional 1,320 nm Nd:YAG laser, 1,450 nm diode laser and 532 nm potassium titanyl phosphate laser. In addition, the 1,450 nm diode laser has been shown to reduce sebum production [295]. The novel IPL filter at wavelength of 400-600 nm and 800-1,200 nm provides an effective option to treatment of inflammatory acne lesions, especially for Pillsbury I-II acne patients, with minimal reversible side effects, such as transient post-inflammatory pigmentation. Intense pulsed light (IPL) has become a well-recognized method in the treatment of acne vulgaris [296]. Various types of lasers have been utilized in the treatment of scars since the 1980s, beginning with continuous wave argon, CO₂ and Nd:YAG 1064 lasers, followed by the application of PDL and Er:YAG lasers for scar revision [297]. Most recently, fractional photothermolysis with ablative and non-ablative fractionated lasers have found use as effective treatments for scars. For hypertrophic scars and keloids, the most common non-ablative laser has been the pulsed dye laser (PDL: 585 to 595 nm). For atrophic facial scars, the most commonly used non-ablative lasers are Nd:YAG and 1450 nm diode laser. One study reported an improvement of 40 to 45% with 1320 nm Nd:YAG or 1450 nm diode laser treatment after an average of three consecutive monthly treatment sessions, as assessed by patient satisfaction surveys, histologic evaluations and skin texture measurements. Non-ablative lasers have minimal downtime and produce gradual results, with the most significant improvement noted between 3 and 6 months following the final laser treatment [298]. PDL is effective in improving the vascularity, pliability, color, and height of hypertrophic scars and keloids. Previous studies have reported a 57% to 83% improvement in clinical appearance and texture of hypertrophic scars after one to two PDL treatments [299,300]. Non-ablative fractional lasers (NAFL) have been shown to significantly improve the pigmentation and thickness of surgical scars, atrophic scars, hypertrophic scars and hypopigmented scars. A study by Tierney et al. [301] comparing 1550-nm NAFL to 595-nm PDL for the treatment of surgical scars showed that NAFL outperformed PDL and 83% of patients preferred the half of the scar treated with a non-ablative fractional laser. A study by Niwa et al. [297] examined NAFL in the treatment of hypertrophic scars and found 26% to 75% clinical improvement after two to three treatment sessions done at 4 week intervals. Ablative laser resurfacing, with CO₂ or Er:YAG lasers, has been shown to be effective for traumatic and surgical scars, especially when resurfaced within 6 to 10 weeks after trauma or surgery or even immediately after surgery. CO₂ and Er:YAG lasers are also effective for atrophic scars due to their ability to smooth scar texture and stimulate collagen production within facial atrophic scars, although patients must consider the potential for significant downtime as re-epithelialization typically takes 4 to 7 days with Er:YAG and 7 to 10 days with the CO₂ laser. While requiring more downtime, ablative lasers usually produce a higher degree of clinical improvement. For acne scars, previous head-to-head studies have suggested that CO₂ laser produces superior results while Er:YAG is better tolerated with less downtime. Raised scars and shallow boxcar scars improve the most with laser resurfacing, while icepick scars are more challenging to treat and may necessitate secondary resurfacing. Non-ablative lasers are also useful for acne scars [294].

EPILOGUE

A better understanding of the pathophysiological mechanisms driving acne has allowed for the development of more effective topical and systemic therapies. These can be prescribed in logical combinations to target each relevant pathological factor and thus ensure optimal acne management. Each patient should receive education regarding acne and the available treatment options. A realistic explanation of the benefits, risks and expected outcomes of each therapy must be provided to promote autonomy. Patients also need to understand that, although most cases of acne can be cleared with available treatments, therapy requires time, and in the early weeks of treatment their acne may worsen. However, with frequent reassurance and follow-up, many patients will comply with treatment and achieve an acceptable outcome. Maintenance therapy is an important consideration as acne represents a chronic disease and frequently recurs without an ongoing treatment regimen. Among all pathogenetic factors of acne, inflammation seems to be rediscovered and anti-inflammatory concepts seem to become the new trend of systemic and topical acne treatment. Acne scars may have a damaging effect on a person's physical, mental and social well‐being. Although a wide range of treatments are used, there is a lack of high‐quality evidence on which is the most effective for acne scars. Despite the interest on the development of topical treatments for acne in the last decades, systemic treatment is still a milestone, especially in the treatment of moderate-to-severe scarring types of the disease. The establishment of new systemic drugs for acne is based on the consideration of successes and pitfalls of the past and the emerging knowledge of the future.

CHAPTER SUMMARY

Acne is estimated to affect approximately 10% of the global population, making it the eighth most prevalent disease worldwide. Several studies have confirmed that acne can affect a person's quality of life, self-esteem and mood in an adverse manner. Acne treatments take a considerable share of dermatology OTC product market. Also, increasingly various prescription acne treatments are becoming qualified as OTC products due to their history of long-term safety and efficacy. The issue of antibiotic resistance also impacts the prescribing patterns and treatment algorithms. The standard of care for the treatment of mild-to-moderate acne still lies with topical therapies. Poor adherence is one of the critical and negatively impacting factors affecting acne treatment outcomes. Moreover, limited patient education and awareness about acne treatment is also a roadblock to successful treatment. The acne therapy market is moving from mono therapy towards combination therapy options. The most likely reason is higher efficacy of combinations that consider the multifactorial pathogenesis of acne, reduced resistance levels and the ease of single product use versus two separate mono therapies. Laser and light modalities, although not sufficiently studied for first-line use, show promise for the future.

ACKNOWLEDGEMENT

It’s a great honor and gratitude to be pharmacists in research and education process. All pharmacists, officials, journalists, magazine analysts and associates that I met in this purpose, were very kind and helpful. I’m thankful to Isabel Cristina Valente Duarte de Sousa, M.D. Dermatology; Hospital ABC Santa Fe, Mexico City Area, Mexico for her precious inputs. I’m also grateful to seminar library of Faculty of Pharmacy, University of Dhaka and BANSDOC Library, Bangladesh for providing me books, journal and newsletters. The greatest help was from students and colleagues who continually supported me in collection and data extraction from books, journals, newsletters and precious time in discussion followed by providing information on different types of cosmetics in use. A portion of this article is long been lectured as course material. So, it is very much helpful for me to deliver better than before as many more things are studied.

COMPLIANCE WITH THE ETHICAL ISSUES

Ethics approval and consent to participate

Animal and Human experiment: N/A

Human Data Submission Approval: N/A

Consent for publication

Consent to publish Individual Person’s data: N/A

Availability of data and materials

Data sharing: Please contact author for data requests.

Competing interests

The author declares that he has no competing interests.

Funding

Funding from individual/Organization: N/A

Authors’ contributions

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