Research Article
Open Access
A Comprehensive Review of Acne Vulgaris
AK Mohiuddin1*
1Department of Pharmacy, World University of Bangladesh
AK Mohiuddin, Assistant Professor, Department of Pharmacy, World University of Bangladesh, 151/8, Green Road,
Dhanmondi, Dhaka – 1205, Bangladesh; E-mail:
@ ; Orcid Id: https://orcid.org/0000-0003-1596-9757.
Received: May 25, 2019; Accepted: June 6, 2019; Published: June 17, 2019
Citation: Mohiuddin AK (2019) A Comprehensive Review of Acne Vulgaris. Clin Res Dermatol Open Access 6(2): 1-34. DOI: http://dx.doi.org/10.15226/2378-1726/6/2/00186
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 noninflammatory
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 triglycerides, 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;
Keywords: Acne; skin care; comedones; pustules; acne scars; sebum; Propionibacterium acnes;
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 3rd century was of the opinion that acne is caused by telling lies. Tutankhamun, Egyptian Pharaoh of the 18th 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.
• 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 dermaroller 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.
• 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 3rd century was of the opinion that acne is caused by telling lies. Tutankhamun, Egyptian Pharaoh of the 18th 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.
• 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 dermaroller 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.Important terminology
Exhibit 1. Important terminology |
|
1. |
Whiteheads -closed plugged pores |
2. |
Blackheads -open plugged pores |
3. |
Papules-Small red, tender bumps |
4. |
Pimples-pustules, which are papules with pus at their tips |
5. |
Nodules-Large, solid, painful lumps beneath the surface of the skin |
6. |
Cystic lesions-Painful, pus-filled lumps beneath the surface of the skin |
7. |
Hirsutism- abnormal growth of hair on a woman's face and body. |
8. |
Alopecia-the partial or complete absence of hair from areas of the body where it normally grows; baldness. |
Acne Vulgaris (Av);
Aquaporin-3 (Aqp3);
Dehydroepiandrosterone (Dhea);
Complementary and Alternative Medicine (Cam);
Insulin-Like Growth Factor 1 (Igf-1);
Health-Related Quality Of Life (Hrqol);
Dehydroepiandrosterone (Dhea);
Sex Hormone-Binding Globulin (Shbg);
Ceramide (Cer);
Sphingomyelin (Sm);
Follicle-Stimulating Hormone (Fsh);
5α-Dihydrotestosterone (5α-Dht);
Polycystic Ovary Syndrome (Pcos);
Sebaceous Gland (Sg);
Eicosapentaenoic Acid (Epa);
Docosahexaenoic Acid (Dha);
Adult Female Acne (Afa);
Benzoyl Peroxide (Bp);
Post Inflammatory Hyperpigmentation (Pih);
American Academy Of Dermatology (Aad);
Methicillin-Resistant Staphylococcus Aureus (Mrsa);
Combined Oral Contraceptive (Coc);
Randomized Controlled Trials (Rcts);
Investigator’s Global Assessment (Iga);
Intense Pulsed Light (Ipl);
Non-Ablative Fractional Lasers (Nafl);
Aquaporin-3 (Aqp3);
Dehydroepiandrosterone (Dhea);
Complementary and Alternative Medicine (Cam);
Insulin-Like Growth Factor 1 (Igf-1);
Health-Related Quality Of Life (Hrqol);
Dehydroepiandrosterone (Dhea);
Sex Hormone-Binding Globulin (Shbg);
Ceramide (Cer);
Sphingomyelin (Sm);
Follicle-Stimulating Hormone (Fsh);
5α-Dihydrotestosterone (5α-Dht);
Polycystic Ovary Syndrome (Pcos);
Sebaceous Gland (Sg);
Eicosapentaenoic Acid (Epa);
Docosahexaenoic Acid (Dha);
Adult Female Acne (Afa);
Benzoyl Peroxide (Bp);
Post Inflammatory Hyperpigmentation (Pih);
American Academy Of Dermatology (Aad);
Methicillin-Resistant Staphylococcus Aureus (Mrsa);
Combined Oral Contraceptive (Coc);
Randomized Controlled Trials (Rcts);
Investigator’s Global Assessment (Iga);
Intense Pulsed Light (Ipl);
Non-Ablative Fractional Lasers (Nafl);
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 hypercolonization
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 secretary 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 [74].
The adequate control of the four pathogenic mechanisms involved in the appearance of acne lesions is key to treatment success [1-7]. Several exacerbating factors have been suggested including diet, menstruation, sweating, personal stress, ultraviolet radiation, application of pomades and occupation [8]. 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 [26]. 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) [9-12]. Food with a high glycemic index is rapidly absorbed, increases serum glucose levels and stimulates increased glucose-dependent insulin signaling [13]. 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 [9], [14-17]. 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], [18-25]. There is a common medical and lay belief that women experience perimenstrual acne flares [27-31]. 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, 2017 and Bagatin et. al, 2019 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 [34,35]. Bondade et.al, 2019 found undesirable stressful life events and psychiatric comorbidity were more in acne patients than in controls [36]. 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).
(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 [74].
The adequate control of the four pathogenic mechanisms involved in the appearance of acne lesions is key to treatment success [1-7]. Several exacerbating factors have been suggested including diet, menstruation, sweating, personal stress, ultraviolet radiation, application of pomades and occupation [8]. 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 [26]. 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) [9-12]. Food with a high glycemic index is rapidly absorbed, increases serum glucose levels and stimulates increased glucose-dependent insulin signaling [13]. 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 [9], [14-17]. 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], [18-25]. There is a common medical and lay belief that women experience perimenstrual acne flares [27-31]. 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, 2017 and Bagatin et. al, 2019 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 [34,35]. Bondade et.al, 2019 found undesirable stressful life events and psychiatric comorbidity were more in acne patients than in controls [36]. 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).
Exhibit 2.Sebaceous Gland and Acne [88], [101-115]
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Epidemiology
Acne is a very common skin disease with the prevalence
among adolescent is 80% or more [13, [29], [39-45]. Among
them 80% are teenagers [46-49]. Although this inquisitive
nature is considered a normal aspect of the maturation process,
approximately 80% to 90% of teenagers in the Western world
experience behavioral/emotional and physical/psychological
effects caused by acne [50]. About 60% of affected adolescents
have mild acne for which they use non-prescription preparations
without consulting a physician. The remaining 40% constitute
the population of acne patients seen in medical practice [4].
It is less common in African-Americans and Asians than in the
Caucasian population [9]. About 20% of the affected individuals
develop severe acne which results in scarring [26]. In youths,
overweight and obesity are inversely associated with acne
in a dose-dependent manner [51]. Overweight and obesity
are associated with acne in girls aged 18 and 19, but the same
association was not observed in boys [52]. However, Stewart et.al
2019 found no significant association between increased BMI
and AV [53]. Western nutrition is characterized by high calorie
uptake, high glycemic load, high fat and meat intake, as well as
increased consumption of insulin- and IGF-1-level elevating
dairy proteins. Intake of instant noodles, junk food, carbonated
drinks, snacks, processed cheeses, pork, chicken, nuts and
seaweed were significantly higher in acne patients than in the
controls. Moreover, positive associations between acne and the
consumption of other dairy products like instant breakfast drink,
sherbet, cream cheese and cottage cheese have been reported
[54]. Wang et al, 2019 reviewed that a nearly 50% of normal
women with acne did not have clinical or biochemical evidence
of hyperandrogenism [55]. More than 60% of women had an
increase in the number of inflammatory acne lesions in the late
luteal phase of the menstrual cycle [27-31]. Acne is common
during pregnancy. In fact, more than one out of every two
pregnant women can expect to develop acne [56]. Girls must be
made aware that cosmetic usage may be a potential aggravating
factor for their facial acne [57]. Because certain chemicals in
personal care products are suspected endocrine disrupters (e.g,
phthalates, parabens, triclosan) [58]. There are many causes
for acneiform eruptions including exposure to halogenated
aromatic hydrocarbons and use of antibiotics like macrolides and
penicillin. Other drugs that can also induce acneiform eruptions
include nystatin, isoniazid, corticotropin, naproxen, and
hydroxychloroquine. Many organisms can also induce acneiform
eruptions like infections by Proteus, Klebsiella, Escherichia coli,
and Enterobacter. Pityrosporum folliculitis caused by Malassezia
furfur may also present on the trunk and upper extremities with
pruritic eruptions [59]. Black individuals are more prone to post
inflammatory hyperpigmentation and specific subtypes such as
‘pomade acne’. The heritability of acne is almost 80% in firstdegree
relatives [60]. George et.al, 2018 revealed Food items and
cosmetics were attributed to exacerbation by 47.3% and 40%
of patients respectively. About 48% patients had first degree
relatives with present or past history of acne [61]. Daily soft
drink consumption significantly increases the risk of moderateto-
severe acne in adolescents, especially when the sugar intake
from any type of soft drink exceeds 100 g per day [84] (Exhibit-3).
Exhibit 3.Acne Myths/Misconception Vs Study Result
Myth/Misconception |
Study Result |
In particular, no effect has been established between chocolate, dairy products, shellfish, or fatty foods [116]. |
Dark chocolate consumption appears to affect the facial skin of young men by enhancing corneocyte desquamation and promoting bacterial colonization of the residual skin surface components [117]. |
Any dairy, such as milk, yogurt, and cheese, was associated with an increased OR for acne in individuals aged 7–30 years [20]. |
|
Four ounces of shrimp provides about 325 -375 milligrams of omega-3 fatty acids [118]. After 10 weeks of omega-3 fatty acid supplementation, inflammatory and non-inflammatory acne lesions decreased significantly [105]. |
|
Isotretinoin, Retinol (Vitamin A), carotenoids (provitamin A) and retinoids (Vitamin A metabolites) are absorbed better with parallel intake of vegetable oils [11]. |
|
Weight loss and the use of metformin are both associated with lower plasma insulin levels and decreased androgen levels and therefore for acne patients, a weight loss diet may be indicated [119,120]. |
Low glycemic loads, with or without metformin, has been associated with greater reduction in acne lesion counts compared with high loads [53]. |
There were no significant correlations between IGF-1and acne severity [120]. |
Plasma IGF-1 levels positively correlate with severity of acne [18]. |
Too much sex or masturbation may worsen acne. when females begin having a regular sex life their acne will be improved [116], [121]. Masturbation results in general debility, unnatural pale eyes and forehead acne [122]. |
Despite popular myth, diet, lack of exercise, lack of hygiene, greasy hair hanging over the face, and masturbation do not have any effect [123]. After adjustment for sex and age, the presence of acne remained highly associated with less sexual activity [124]. |
open comedones or blackheads are full of dirt [125]. |
The dark color of blackheads has nothing to do with dirt: They look dark because this kind of blackhead is “open” and the skin pigment melanin reacts with oxygen in the air [83]. |
One should pop pimples at first sight. |
Although squeezing pimples may make skin look better in the short term, it might force the pus even deeper into skin, which can make it become even more inflamed and the chance that the area will become dark as it tries to heal [83]. |
Sitting in the Sun to Clear Pimples |
AV is aggravated by sunlight. Acne solaris a form of acne that appears and relapses after sun exposure. However, clinicians should not be didactic in their recommendations regarding diet, hygiene and face-washing, and sunlight to patients with acne. Advice should be individualized [126-128]. |
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.al, 2019 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 secretes various several proinflammatory products. These
include lipases, proteases, hyaluronidases, and chemotactic
factors. Immune response to P. acnes includes humoral and cellmediated
immunity as well as complement activation (Figure 1)
[72,73].
Figure 1:Molecular mechanisms by which P. acnes may contribute to the pathogenesis of AV [74].
(1) P. acnes is involved in the formation of microcomedones.
(2) P. acnes colonization leads to an increase in the cohesiveness of corneocytes during the formation of comedones;
(3) in vitro studies have suggested that P. acnes produces lipases, proteases, hyaluronidases, and phosphatases that may cause tissue injury;
(4) P. acnes induces the expression of the proinflammatory cytokines IL-8, IL-12, IL-1α, IL-1β, and tumor necrosis factor alpha by innate cells, such as keratinocytes and monocytes, through the TLR2-dependent pathway;
(5) host cells have developed a protective antimicrobial response to P. acnes such as antimicrobial lipids, AMPs (human beta-defensin 2, psoriasin and cathelicidin, exhibiting synergistic activities and inducing proinflammatory cytokines/ chemokines via TLR4- and CD14-dependent mechanisms;
(6) the peptidoglycan-polysaccharide complexes and lipoteichoic acids of P. acnes stimulate proinflammatory cytokines released from monocytes, demonstrating their high antigenicity in severe acne patients. Increased expression of TLR2 and TLR4 in vivo was found in the epidermal layers of acne lesions for the sensing of peptidoglycans and lipopolysaccharides (LPSs), respectively;
(7) P. acnes induces the growth of keratinocytes in vitro and upregulates the production of proinflammatory cytokines via a heat-shock GroEL protein;
(8) MMPs, produced by different types of cells, including keratinocytes and sebocytes, play important roles in acne inflammation, dermal matrix destruction and hyperproliferative skin disorders. MMPs also cause rupture of the pilosebaceous follicle to exacerbate inflammation. For example, P. acnes induces the expression of MMP-9 in keratinocytes for the inflammatory process;
(9) P. acnes lysates can directly modulate the differentiation of keratinocytes by inducing the expression of b1, a3, a6s, and aVb6 integrins and filaggrin during the formation of comedones;
(10) P. acnes produces additional neutrophil chemotactic factors and is ingested by neutrophils within the sebaceous follicle, resulting in the release of hydrolases from neutrophils to disrupt the follicular wall; and (11) P. acnes results in the formation of C5a in inflammatory acne lesions by activating both the classical and alternative complement pathways.
(1) P. acnes is involved in the formation of microcomedones.
(2) P. acnes colonization leads to an increase in the cohesiveness of corneocytes during the formation of comedones;
(3) in vitro studies have suggested that P. acnes produces lipases, proteases, hyaluronidases, and phosphatases that may cause tissue injury;
(4) P. acnes induces the expression of the proinflammatory cytokines IL-8, IL-12, IL-1α, IL-1β, and tumor necrosis factor alpha by innate cells, such as keratinocytes and monocytes, through the TLR2-dependent pathway;
(5) host cells have developed a protective antimicrobial response to P. acnes such as antimicrobial lipids, AMPs (human beta-defensin 2, psoriasin and cathelicidin, exhibiting synergistic activities and inducing proinflammatory cytokines/ chemokines via TLR4- and CD14-dependent mechanisms;
(6) the peptidoglycan-polysaccharide complexes and lipoteichoic acids of P. acnes stimulate proinflammatory cytokines released from monocytes, demonstrating their high antigenicity in severe acne patients. Increased expression of TLR2 and TLR4 in vivo was found in the epidermal layers of acne lesions for the sensing of peptidoglycans and lipopolysaccharides (LPSs), respectively;
(7) P. acnes induces the growth of keratinocytes in vitro and upregulates the production of proinflammatory cytokines via a heat-shock GroEL protein;
(8) MMPs, produced by different types of cells, including keratinocytes and sebocytes, play important roles in acne inflammation, dermal matrix destruction and hyperproliferative skin disorders. MMPs also cause rupture of the pilosebaceous follicle to exacerbate inflammation. For example, P. acnes induces the expression of MMP-9 in keratinocytes for the inflammatory process;
(9) P. acnes lysates can directly modulate the differentiation of keratinocytes by inducing the expression of b1, a3, a6s, and aVb6 integrins and filaggrin during the formation of comedones;
(10) P. acnes produces additional neutrophil chemotactic factors and is ingested by neutrophils within the sebaceous follicle, resulting in the release of hydrolases from neutrophils to disrupt the follicular wall; and (11) P. acnes results in the formation of C5a in inflammatory acne lesions by activating both the classical and alternative complement pathways.
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 [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, 2019 [75]. According
to Bhate et. al, 2013, it was over 3 billion dollars per year in
terms of treatment and loss of productivity [79]. 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, 2017 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 [77]. 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].
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 prepubertal children with acne, signs of
hyperandrogenism include early-onset accelerated growth, pubic
or axillary hair, body odor, genital maturation and advanced bone
age [82] (Exhibit-4, 5 and Exhibit-6).
Exhibit 4. Grading severity of acne [26], [82,83]
Grade |
Severity |
Clinical findings |
I |
Mild |
Open and closed comedones (blackheads or whiteheads) with few inflammatory papules and pustules. Open comedones are due to plugging of the pilosebaceous orifice by sebum on the skin surface. Closed comedones are due to keratin and sebum plugging the pilosebaceous orifice below the skin surface. The more oil builds up, the more likely it is that bacteria will multiply and lead to inflammatory acne. Acne is also considered to be “mild acne” if someone only has a few pimples, or only has small ones. |
II |
Moderate |
Inflammatory lesions present as a small papule with erythema. Inflamed pimples are called “papules” (small bumps) or “pustules” (filled with yellow pus), mainly on face. |
III |
Moderately severe |
Numerous papules and pustules, and occasional inflamed nodules, also on chest and back |
IV |
Severe |
People who have severe forms of acne have a lot of papules and pustules, as well as nodules on their skin. These nodules are often reddish and painful. The acne may lead to scarring. |
Exhibit 5. Clinical Diagnosis of Acne [86], [89-100]
Diagnosis |
Differentiating characteristics |
Bacterial folliculitis |
Abrupt eruption; spreads with scratching or shaving; variable distribution. Because both AV and folliculitis can present as inflammatory erythematous papules, pustules or nodules, they are often hard to distinguish. |
Acne keloidalis nuchae |
Often seen in black patients; lesions localized to the posterior neck; initially papules and pustules that may progress to confluent keloids |
Acneiform eruptions |
Secondary to systemic medications, topical corticosteroid medications, contrast dye, and cosmetic products; may be abrupt in onset and correlation with exposure; improvement with cessation of exposure. |
Chloracne |
Comedones, pustules, and cysts that localize to the post-auricular area, axillae, and groin; history of exposure to halogenated aromatic hydrocarbons; patient may have other systemic manifestations |
Favre-Racouchot |
Open and closed comedones on periorbital and malar areas; no inflammatory lesions; patients are usually older with a history of significant sun exposure |
Periorificial dermatitis |
Papules and pustules in the periorificial distribution; often exacerbated by topical corticosteroid use |
Pyoderma faciale |
Rapid onset of erythema, abscesses, cysts, and possible sinus tracts, no comedones |
Syringoma |
Noninflammatory papules that typically localize to the eyelids and malar cheeks; skin biopsy test results show dilated cysts with tadpole appearance |
Drug-induced acne |
There are many causes for acneiform eruptions including exposure to halogenated aromatic hydrocarbons and use of antibiotics like macrolides and penicillin. Other drugs that can also induce acneiform eruptions include nystatin, isoniazid, corticotropin, naproxen, hydroxychloroquine, cyclosporin A, antimycotics, gold salts, isotretinoin, clofazimine, epidermal growth factor receptor inhibitors (cetuximab, gefitinib, and erlotinib), and interferon-beta. |
Hidradenitis suppurativa (HS), also called acne inversus. |
Double comedo; starts as a painful boil; sinus tracts. A nearly 40% of individuals with HS report an affected first-degree relative, suggesting a hereditary component with an autosomal dominant transmission pattern. It is a chronic inflammatory skin condition with lesions including deep-seated nodules and abscesses, draining tracts, and fibrotic scars. These lesions most commonly occur in intertriginous areas and areas rich in apocrine glands. Among the most common are axillary, groin, perianal, perineal, and inframammary locations. |
Miliaria |
“Heat rash” in response to exertion or heat exposure; non-follicular papules, pustules, and vesicles. Miliaria is a clinical diagnosis. Laboratory tests are often inconclusive and not helpful. Dermoscopy has been found to be a useful tool, particularly in people with darker skin, revealing large white globules with surrounding darker halos (white bullseye). When in doubt, a skin punch biopsy would be useful to help with diagnosis. |
Perioral dermatitis |
Papules and pustules confined to the chin and nasolabial folds; clear zone around the vermilion border. |
Adenoma sebaceum |
Small waxy papules over the medial cheeks, nose, and forehead; multiple lesions associated with tuberous sclerosis; skin biopsy test results show dermal fibrosis and vascular proliferation and dilatation (angiofibromas). Facial angiofibromas are also a feature of multiple endocrine neoplasia type I and, rarely, Birt-Hogg-Dubé syndrome. |
Pseudofolliculitis barbae |
Affects curly-haired persons who regularly shave closely, with a high prevalence in men of subequatorial African ancestry and, to a much lesser extent, Indo‐Europeans. But it can affect both men and women of all ethnicities. Invariably reported as being associated with shaving, also evidence suggests a strong genetic component in patients with persistent PFB. |
Rosacea |
Erythema and telangiectasias; no comedones. Rosacea can also involve the eyes and even a bulbous nose. Acne is seen most commonly in teens, while rosacea occurs most often much later. Also, unlike in patients with rosacea, blackheads are generally present, and bumps and pimples on the trunk and arms are common. |
Seborrheic dermatitis |
Greasy scales and yellow-red coalescing macules or papules. Seborrheic dermatitis presents as ill-defined erythematous patches with greasy scale distributed on the eyebrows, glabella, paranasal skin, nasolabial folds, beard, scalp, and chest. Azelaic acid may be especially valuable in this application because of its efficacy in treating concomitant rosacea and acne. |
Exhibit 6. Laboratory tests in patients with suspected hormonal acne [29]
Testosterone |
Minimal to modest elevations of <200 ng/dL are suggestive of a benign cause of ovarian or adrenal cause while above this level; neoplasia of ovarian or adrenal origin should be suspected. |
Androstenedione |
Secreted equally by ovaries and adrenals and follows a circadian rhythm making early morning samples, the best to analyze. |
DHEA |
High levels of DHEA >8,000 ng/dL and dehydroepiandrosterone sulfate (DHEAS) should raise concern of adrenal tumors, while levels of DHEAS (4,000–8,000 ng/dL) indicate benign adrenal hyperplasia. |
SHBG |
Decreased levels of SHBG lead to free unbound testosterone in excess, resulting in more manifested signs. |
Prolactin |
Elevated prolactin could point out to hypothalamic or pituitary causes for further assessment and investigation. |
17-Hydroxy progesterone |
Elevated (>200 ng/dl) in congenital adrenal hyperplasia or non-classic congenital adrenal hyperplasia due to deficiency or absence of 21α-hydroxylase. |
Luteinizing hormone |
Follicle-stimulating hormone (FSH) ratio: a ratio of >2 is indicative of possible PCOS. |
Fasting and postprandial insulin |
Overweight and obese patients should be checked for insulin levels. |
Serum cortisol |
High levels are an indication of adrenal neoplasia. |
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 [175]. 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, nonspecific 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 [141].
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 photo damage [137], (figure-2) (Exhibit-7).
Figure 2:Acne Scar Types [139]. 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. Acne Effects [83], [136-140]
Atrophic scars |
Atrophic acne scarring is an unfortunate, permanent complication of AV, which may be associated with significant psychological distress. It is most likely related to inflammatory mediators and enzymatic degradation of collagen fibers and subcutaneous fat. The most basic, practical, system divides atrophic acne scars into the following three main types: a) icepick, b) rolling, and c) boxcar scars |
(a) Icepack |
Icepick scars are narrow (<2 mm), deep, sharply margined epithelial tracts that extend vertically to the deep dermis or subcutaneous tissue. |
(b) Rolling |
Rolling scars occur from dermal tethering of otherwise relatively normal-appearing skin and are usually wider than 4 to 5 mm. Abnormal fibrous anchoring of the dermis to the subcutis leads to superficial shadowing and a rolling or undulating appearance to the overlying skin. |
(c) Boxcar |
Boxcar scars are round to oval depressions with sharply demarcated vertical edges, similar to varicella scars. They are clinically wider at the surface than icepick scars and do not taper to a point at the base. |
Hypertrophic scars |
These raised scars can form on chest, back or shoulders, particularly in people who have severe acne. They develop if too much connective tissue is produced while the wound is healing. This type of acne scar is less common. |
Papular Scars |
Papular scars can clinically mimic closed comedones, acne, and granulomas, leading to an unnecessary delay in appropriate treatment. Active acneiform lesions causing any type of scars should be treated aggressively with systemic therapy to prevent further progression of scarring. Papular scars are 3 to 4mm skin-colored cobblestone-like papules distributed anywhere on the body but, in our clinical experience, most commonly on the chin, nose, and back. Also known as white papular acne scars, these flesh-colored papules are often incorrectly diagnosed as acne and do not respond to traditional acne treatments. |
Keloid Scars |
Keloids result from abnormal wound healing in response to skin trauma or inflammation. Keloid development rests on genetic and environmental factors. Higher incidences are seen in darker skinned individuals of African, Asian, and Hispanic descent. Keloid scars also form when too much connective tissue is made. Unlike hypertrophic scars, though, they are bigger than the original inflamed area. This is a very rare type of acne scarring. In keloids, the fibroblastic phase continues, unchecked, resulting in the clinical and histopathological findings. |
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 [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].
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-thecounter
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, noninflammatory, 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).
Exhibit 8. Different treatment options for acne [305]
Treatment Methods |
Examples |
Topical |
Retinoids: adapalene, isotretinoin, motretinide, retinoyl-β-glucuronide, tazarotene, tretinoin |
Antibiotics: clindamycin, erythromycin |
|
Diverse: azelaic acid, benzoyl peroxide, chemical peels, corticosteroids, dapsone, hydrogen peroxide, niacinamide, salicylic acid, sodium sulfacetamide, sulfur, triclosan |
|
Systemic |
Retinoids: isotretinoin |
Antibiotics: azithromycin, clindamycin, co-trimoxazole, doxycycline, erythromycin, levofloxacin, lymecycline, minocycline, roxithromycin |
|
Hormonal: contraceptives |
|
Diverse: clofazimine, corticosteroids, ibuprofen, zinc sulfate |
|
Complementary and Alternative Medicines (CAM) |
Achillea millefolium, amaranth, antimicrobial peptides, arnica, asparagus, basil oil, bay, benzoin, birch, bittersweet nightshade, black cumin, black walnut, borage, Brewer’s yeast, burdock root, calendula, celandine, chamomile, chaste tree, Commiphora mukul, copaiba oil, coriander, cucumber, duckweed, Du Zhong extract, English walnut, Eucalyptus dives, fresh lemon, garlic, geranium, grapefruit seeds, green tea, jojoba oil, juniper twig, labrador tea, lemon grass, lemon, minerals, neem, oak bark, onion, orange peel, orange, Oregon grape root, patchouli, pea, petitgrain, pine, pomegranate rind extract, poplar, probiotics, pumpkin, resveratrol, rose myrtle, rhubarb, Rosa damascena, rosemary, rue, safflower oil, sandalwood, seaweed, soapwort, Sophora flavescens, specific antibodies, stinging nettle, sunflower oil, Taraxacum officinale, taurine bromamine, tea tree oil, thyme, turmeric, vinegar, vitex, witch hazel, Withania somnifera and yerba mate extract |
Physical Treatment |
Comedone extraction, cryoslush therapy, cryotherapy, electrocauterization, intralesional corticosteroids and optical treatments |
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.
A. Milk and dairy products: High intakes (≥2 glasses per 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, 2018 [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].
B. 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 antiinflammatory 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 [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.
C. 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, 2002 suggested that a low-fat intake and low glycemic load diet may be the cause of acne absence in both populations [158]. 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].
D. Dietary Fiber: Patients with AV consumed daily 30 g of high fiber breakfast cereal (13 g fiber/serving), a significant 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].
E. Anti-oxidants: Al-Shobaili, 2014 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 [39]. 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 [167], [114].
F. Frequent Cleansing and Sun Protection: Washing and overthe- 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 5.5 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].
G. 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 have 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 [258-260]. 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 macrocomedones 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 [261]. 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 nonsmokers [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 [262].
A. Milk and dairy products: High intakes (≥2 glasses per 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, 2018 [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].
B. 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 antiinflammatory 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 [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.
C. 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, 2002 suggested that a low-fat intake and low glycemic load diet may be the cause of acne absence in both populations [158]. 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].
D. Dietary Fiber: Patients with AV consumed daily 30 g of high fiber breakfast cereal (13 g fiber/serving), a significant 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].
E. Anti-oxidants: Al-Shobaili, 2014 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 [39]. 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 [167], [114].
F. Frequent Cleansing and Sun Protection: Washing and overthe- 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 5.5 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].
G. 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 have 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 [258-260]. 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 macrocomedones 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 [261]. 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 nonsmokers [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 [262].
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 less 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 Cutinebacterium acnes
colonization and the inflammation cascade emerge.
A. Benzoyl Peroxide
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
noninflammatory acne lesions [180]. It has mild sebostatic and
keratolytic effects without a concern for the development of drugresistant
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-minute 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],
(Figure-3).
Figure 3:Benzoyl peroxide
B. Clindamycin
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,
2019 [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 photoallergy,
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 triplecombination
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,
2013 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 [193]. 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 (Figure-4)
Figure 4:Clindamycin Hydrochloride
C. Retinoids
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
[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 [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, 2019 detailed a similar polymeric formulation
of tretinoin 0.05% lotion with an incidence of erythema, dryness,
and skin burning [201]. 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, 2019 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 [203], (Figure-5) (Exhibit-9).
Figure 5:Retinoids
Exhibit 9. News of celebrities who got rid of their acne
News |
Comment |
Natalie Portman says going vegan changed everything [129]. |
The frequency of vegetables and fish intake was significantly higher in the control group than in the acne group [54]. |
Victoria Beckham eats a lot of salmon [129]. |
Salmon is rich omega-3 fatty acids. There is some evidence that fish oil supplementation is associated with an improvement in overall acne severity, especially for individuals with moderate to severe acne [130]. |
Rihanna cuts back on booze. I cut out all alcohol and overdo the water," she said [129]. |
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. |
Scarlett Johansson always washes her face and makeup brushes [129] |
Antibacterial face washes can have a positive effect in mild acne, but might also irritate more sensitive skin. There is no clear evidence that acne vulgaris is related to poor hygiene or that frequent face washing lessens acne [82]. Acne is unavoidable but can be controlled by regular washing of the face by a pH balancing wash which is available as benzoyl peroxide and salicylic acid face wash [26]. |
Cameron Diaz wrote that fast food was plaguing her skin. In "The Body Book," Diaz wrote "My acne wasn't totally gone, but it was significantly better." [129] |
Plenty of fast-food items are high on the glycemic index, elicit a rapid shift in blood glucose and insulin levels. Insulin also stimulates the synthesis of androgens leading to high sebum production, a recognized correlate of acne severity [10]. On the contrary, low-glycemic-index foods increased SHBG and reduced androgen levels; this is important since higher SHBG levels were associated with lower acne severity [11]. |
"Whenever it's been really bad, I've gone to the dermatologist to get those cortisone shots. Those are amazing.….” Emma Stone [132]. |
Low doses of corticosteroids, such as prednisone (2.5 or 5mg), can suppress adrenal androgen production and are recommended in late congenital adrenal hyperplasia, acute inflammatory lesions in AFA, and short-term treatment of very severe acne [35]. While short-term use of corticosteroids is associated with mild side effects, long-term use can result in hypertension, peptic ulcer disease, ocular damage, neuropsychiatric effects, hematologic and musculoskeletal effects. Patients need close monitoring and follow up and should also be advised not to exceed the prescribed treatment and to only discontinue use under medical supervision [133,134]. |
After years of struggling with breakouts, Bella Thorne turned to the powerful anti-acne drug Accutane [132]. |
Isotretinoin is a vitamin A-derivative 13-cis-retinoic acid, which is the most effective therapy for acne to date. It targets all four processes during acne development, including normalization of follicular desquamation, reduction of sebaceous gland activity, inhibition of the proliferation of Propionibacterium acnes and anti-inflammatory effects. It cured around 85% of patients after an average treatment course of 4 months. However, risk of depression associated with the use of isotretinoin has been a major concern for a long time [75]. |
"I never used to understand the importance of washing my brushes, but it's so important" Miley Cyrus [132] |
With each use, your makeup brushes become coated with more than just residue. They pick up sebum, dead skin and airborne dust and dirt. They need to be cleaned regularly AND properly. If not, all of this debris will build up and negatively affect future makeup applications and decrease the life expectancy of brushes. The most dangerous consequence of dirty brushes – they become a playground for bacteria that can cause skin problems and possible infection [135]. |
D. Azelaic Acid
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
hiperpigmentary skin disorders [210]. It is an antiacne 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 diseaserelated
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], (Figure-6).
Figure 6:Azelaic Acid
E. Dapsone
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 twicedaily
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 [218,219], [221], [223,224].
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, 2017 found that Treatment
response with dapsone gel, 7.5% in racial subgroups was similar
[225]. Tanghetti et.al, 2018 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 [226]. 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 broaden
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], (Figure-7).
Figure 7:Dapsone
F. Acetyl Coenzyme A Carboxylase Inhibitor
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 [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) [229], (Figure-8 and Figure-9).
Figure 8:Olumacostat glasaretil
Figure 9: Olumacostat glasaretil (OG) blocks acetyl coenzyme-A carboxylase in sebocytes to inhibit the production of free fatty acids (FFA) [229]
G. Topical Anti-androgens
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],(
Figure-10).
Figure 10: Topical Anti-androgens
H. Minocycline
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
noninflammatory 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 nonnodular,
inflammatory acne vulgaris in both reduction of inflammatory
lesions and also overall improvement in facial acne according to
IGA [240], ( Figure-11).
Figure 11:Minocycline
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 requires 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.
A. Isotretinoin
Isotretinoin is a retinoic acid derivative mostly used in the
treatment of cystic acne vulgaris [254]. Oral isotretinoin is FDAapproved
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, 2017 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 [242]. Botsali et.al, 2019
further ensured an improvement for neurocognitive functions
in isotretinoin patients and none of them was evaluated as
depressive by the psychiatric examination [243]. 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., 2019 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 [246]. 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, 2019 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 [247]. Fouladgar et.al, 2018 stated that corneal sensitivity
decreases after three months of treatment with isotretinoin.
This decrease is more pronounced at higher ages and in women
[249]. 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, 2018 stated complaint of nasal obstruction [251].
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 hours after a dose while the metabolite was the primary
component in milk 22 to 24 hours 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.
Fourteen of the cases were gynecomastia, 6 were galactorrhea
and 2 were of both gynecomastia and galactorrhea. Gynecomastia
and/or galactorrhea was 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], (Figure-12).
Figure 12:Isotretinoin
B. Spironolactone
Spironolactone, a synthetic 17-lactone steroid, acts as a nonselective
mineralocorticoid receptor antagonist with moderate
affinity for both progesterone and androgen receptors [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 [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
per 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 per
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].
C. Oral Antibiotics
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), trimethoprimsulfamethoxazole,
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],( Figure-13).
Figure 13:(a) Tetracycline and (b) Doxycycline
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 [275] (Exhibit-10).
Exhibit 10. Factors Differentiate Doxycycline and Minocycline for The Treatment of Acne Vulgaris [274]
Point of Comparison |
Study Results |
Phototoxicity |
Minocycline exhibits negligible photosensitivity while doxycycline exhibits dose-related phototoxicity. |
Vestibular side effects |
Vestibular side effects, such as vertigo and dizziness, are not characteristic side effects associated with doxycycline use. Minocycline-associated vertigo usually becomes evident after the first dose or within the first few doses, which allows discontinuation of therapy should this side effect occur. |
Efficacy comparisons |
Although both minocycline and doxycycline have a long overall track record of widespread use with well-recognized efficacy, and safety when used to treat AV, prescription tracking data as depicted above has more recently shown that doxycycline is most commonly prescribed by dermatologists, followed by immediate-release minocycline formulations and extended-release minocycline tablets. |
Other adverse reactions |
potentially serious adverse effects that have been reported with minocycline and are very unlikely or nonexistent with doxycycline. These include drug-associated lupus-like syndrome, autoimmune hepatitis, and drug hypersensitivity syndrome with associated systemic manifestations (i.e., hepatitis, pneumonitis), in addition to other minocycline-specific side effects, such as vertigo/dizziness and patterns of cutaneous and/or mucosal hyperpigmentation. |
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, 2016
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 [281], (Figure-14 and Figure-15).
D. 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) [306]. 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 [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, 2017 suggested a possible anti-inflammatory effect of oral contraceptive and azelaic acid in AFA via modulation of this receptor [283]. 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).
They can be used as monotherapy or in conjunction with benzoyl peroxide, topical retinoic acid, or antibiotics [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, 2017 suggested a possible anti-inflammatory effect of oral contraceptive and azelaic acid in AFA via modulation of this receptor [283]. 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).
Figure 14:(a) Azithromycin and (b) Ciprofloxacin
Figure 15:Hormonal regulation of skin pathogenesis [211]. 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.
Figure 16:Hormonal contraceptives
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 [292,293]. 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 nonablative infrared
lasers, fractional nonablative 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, 2019 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 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 nonablative
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 nonablative
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. 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 [301,302]. A study by Niwa et al. 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 [297]. 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 [303,304]. 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 ice pick scars are more
challenging to treat and may necessitate secondary resurfacing.
Non-ablative lasers are also useful for acne scars [294,303].
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 wellbeing.
Although a wide range of treatments are used, there is a
lack of high‐quality evidence on which are 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.
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-tomoderate
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 firstline
use, show promise for the future.
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.
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.
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