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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.
·
The ancient Greeks knew acne as
‘tovoot’- ‘the first growth of the beard’ hence it was associated with puberty.
Ancient Romans has guided initial treatment of acne.
·
In ancient Rome, acne was treated with
baths as people there believed that the pores of the skin may be lifted and
cleaned with a mixture of sulfur in the mineral baths. Cassius in 3 AD
interpreted that since this disorder is related to puberty, it is known by the
name of ‘akmas’. In the 4th century AD, the court physician of Theodosius
advised acne victims to wipe their “pimples” with a cloth while watching a
falling star and the pimples would then ‘fall from the body.
·
Ibn Sina (980-1037) in his legendary
text ‘Al Qanoon Fil Tib’ (The Cannon of Medicine) has depicted the
etiopathogenesis and clinical presentation of Busoore labaniya (acne).
·
In the Elizabethan era (1558-1603), the
appearance of women was given primordial importance. Acne at that time was also
contributed to witchcraft. For the management of these pimples, different type
of mercury makeup was also in use. The caustic mercury erodes the flesh. Hence
forth, people restored to the sulfur treatments of antique times.
·
Riolanus and Jonston associated acne
with disorders of menstruation in 1638 and 1648, respectively. Jonston (1648)
also linked acne with heterosexual behavior pattern in a manner very close to
present day psychosomatic ideas on the subject.
·
In 1920, Jack Breitbart of the Revlon
Corporation invented benzoyl peroxide for the treatment of acne which was more
effective and smelled better than the sulfur treatments of the past.
·
Around 1930, laxatives were in common
use for treatment of acne.
·
In 1950s Tetracycline was for the first
time prescribed for acne as it was noticed that acne was caused by bacteria.
·
In 1960s, the topical treatment Retin-A
was developed to alleviate acne. Retin-A has produced great results and is
still in use.
·
In 1980s, a novel medication Accutane
(Isotretinoin) for acne appeared in the markets of America. It was found
extremely effective but severe side effects were also noted viz., stroke,
seizure, heart attack and hair loss.
·
In 1990, laser therapy made its
evolvement in treating acne and is now widely used remedy as it clears the
recent as well as old scars left by acne besides active lesions.
·
In 2000, the blue/red therapy was
developed along with laser therapy for easy treatment of acne. Microneedling
with derma roller emerged as a novel treatment modality for the treatment of
acne scars.
·
Fernandes, in 2006, developed
percutaneous collagen induction therapy with the derma-roller.
·
Vaccine against inflammatory acne has
been tested successfully in mice in 2007 and many such studies and trials are
detailed in several journals till then (Exhibit
1).
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
The individual contributions of authors: N/A
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