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A Brief Review on Acne Vulgaris: Pathogenesis, Diagnosis and Treatment

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Research & Reviews: Journal of Pharmacology
ISSN: 2230-9861 (online), ISSN: 2349-1299 (print)
Volume 4, Issue 3
www.stmjournals.com

A Brief Review on Acne Vulgaris: Pathogenesis,


Diagnosis and Treatment
Manoj A. Suva1*, Ankita M. Patel2, Neeraj Sharma1,
Chandrayee Bhattacharya1, Ravi K. Mangi1
1
Aksharpreet Institute of Pharmacy, Lakhabaval Road, Jamnagar, Gujarat, India
2
Shri Sarvajanik Pharmacy College, Mehsana, Gujarat, India

Abstract
Acne vulgaris is one of the most common dermatological disorders that afflict people in
their adolescence. Acne vulgaris or simply known as acne is a human skin disease
characterized by skin with scaly red skin (seborrhea), blackheads and whiteheads
(comedones), pinheads (papules), large papules (nodules), pimples and scarring. Acne
vulgaris is a disease of pilosebaceous unit characterized by the formation of open and
closed comedones, papules, pustules, nodules and cysts. Acne affects skin having dense
sebaceous follicles in areas including face, chest and back. Acne is not life threatening
but severe acne can affect psychological status and social activities. The present review
focuses on an epidemiology, etiology, pathogenesis, diagnosis, differential diagnosis and
management of acne with the pharmaceutical dosage forms of oral and topical
administrations. Various medicines for acne treatment includes benzoyl peroxide,
antibiotics, antiseborrheic medications, sulfur and sodium Sulphacetamide, anti-
androgen medications, salicylic acid, hormonal treatments, alpha hydroxy acid, retinoids,
azelaic acid, keratolytic soaps and nicotinamide. Currently laser and light devices and
minor subcision surgery have been also performed for acne treatment.

Keywords: Acne vulgaris, comedones, pilosebaceous unit, benzoyl peroxide,


antibiotics, laser treatment

*Author for Correspondence E-mail: manojsuva_0211@yahoo.co.in

INTRODUCTION nodulocystic [11]. The cystic acne occurs on


Acne vulgaris or simply known as acne is a buttocks, groin, armpit area, hair follicles and
human skin disease characterized by skin with perspiration ducts and affects deeper skin
scaly red skin (seborrhea), blackheads and tissue than common acne. Acne causes
whiteheads (comedones), pinheads (papules), scarring and psychological effects such as;
large papules (nodules), pimples and scarring reduced self-esteem and in rare cases
[1]. Acne affects skin having dense sebaceous depression or suicide [12, 13]. Reports showed
follicles in areas including face, chest and the incidence of suicidal tendency in patients
back [2]. Acne may be of inflammatory or with acne as about 7.1% [14]. Acne usually
non-inflammatory forms [3]. Due to changes occurs during adolescence [15]. The word
in pilosebaceous units lesions are caused by acne refers to the presence of papules, scars,
androgen stimulation. Acne occurs commonly comedones and pustules. The common form of
during adolescence, affecting about 80–90% acne is known as acne vulgaris. Many
of teenagers in the Western world and lower teenagers suffer from this type of acne. Acne
rate are reported in rural societies [4–7]. Acne vulgaris shows the presence of comedones.
is usually caused by increase in androgens
level like testosterone mainly during puberty Acne rosacea is synonym for rosacea and
in both male and female [8]. Acne reduces some persons not have acne comedones
over time and tends to disappear over the age associated with their rosacea, hence prefer the
[9, 10]. The large nodules called as cysts and term rosacea. Chloracne occurs due to
severe inflammatory acne called as exposure to polyhalogenated compounds.

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EPIDEMIOLOGY
In 2010, it was reported that acne affects
approximately 9.4% of the population [16]. It
affects about 90% of people during teenage
years and sometimes in adulthood [5]. About
20% people have moderate and severe cases.
Acne rates are low in rural areas and it may
not occur in the non-westernized people of
Paraguay and Papua New Guinea [7]. It is
more common in females 9.8% compared to
males 9.0% [16]. In over 40 years old subjects
about 1% of males and 5% of females have Fig. 2: Acne on the Back [20].
problems [5]. It affects all ethnic groups'
people and it is not clear if race affects rates of
disease [17, 18]. Acne affects 40 to 50 million
people which is about 16% in the United
States and approximately 3 to 5 million people
which is about 23% in Australia [19]. In the
United States, it is more severe in Caucasians
than African descent people [2].

Signs and Symptoms of Acne


It includes papules, nodules (large papules), Fig. 3: Acne on the Chest [20].
seborrhea (increased oil-sebum secretion),
comedones, pustules and scarring (Figures 1– Acne scars shows inflammation within the
3) [1]. The appearance of acne varies with skin dermis and it is created by the wound healing
color and it is also associated with resulting in collagen deposition at one spot
psychological and social problems [5]. [21]. In Table 1 type of scars are presented.

ETIOLOGY
Acne develops due to blockage of follicles,
hyperkeratinization and keratin plug formation
and sebum (microcomedo). With increased
androgen production, sebaceous glands are
enlarged and sebum production is increased.
The microcomedo may enlarge to form an
open comedo (blackhead) or closed comedo.
Comedones occur as a result of clogging of
sebaceous glands with sebum, naturally
occurring oil and dead skin cells [2].
Fig. 1: Acne on the Face.

Table 1: Types of Scars.


Scars Characteristics

Box car scars Angular scars occur on cheeks and can be either superficial or deep similar to chickenpox scars

Ice pick scars Deep pits are most common, sign of acne scarring

Rolling scars Wave like appearance in skin

Hypertrophic scars Thickened or keloid scars

Pigmented scars True scars, Change in the skin’s pigmentation, As a result of nodular or cystic acne, inflamed red mark

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Volume 4, Issue 3
ISSN: 2230-9861 (online), ISSN: 2349-1299 (print)

The naturally occurring commensal bacterium Psychological


Propionibacterium acnes can cause Studies shows that increased stress levels are
inflammation and inflammatory lesions like associated with increased acne severity [26].
infected pustules or nodules and papules in the The National Institutes of Health (USA) shows
dermis around the microcomedo or comedone that stress can cause acne flare [27]. In
resulting in redness, scarring or Singapore, study of adolescents observed
hyperpigmentation [2, 22]. positive correlation between stress levels and
acne severity [28].
Environmental Factors
It includes various factors like High-humidity, Infectious
Prolonged sweating, Increase in skin Propionibacterium acnes (P. acnes) are
hydration, Exposure to dirt or vaporized anaerobic bacterium species that mainly
cooking oil or certain chemicals like causes acne. Staphylococcus aureus has been
petroleum derivatives. discovered to play an important role since
normal pores colonized only by
Drug Use Propionibacterium acnes [29]. Specific clonal
Drugs like Phenytoin, Isoniazid, sub strains of P. acnes are also associated with
Phenobarbital, Lithium, Ethionamide, normal skin health and long term acne
Steroids, Azathioprine, Quinine and Rifampin problems. These strains have the capability of
causes acne [23]. changing, perpetuating or adapting to the
abnormal cycle of inflammation, oil
Hormonal production and inadequate sloughing activities
Menstrual cycles and puberty may also causes of acne pores. For at least 87 years, one
acne. During puberty, increase in androgens virulent strain of Propionibacterium acnes has
level causes the enlargement of follicular been circulating around Europe [30].
glands and sebum production is also increased Antibiotics resistance has been continuously
[2, 24]. Anabolic steroids produce similar increasing to P. acnes in vitro [31].
effect [25]. Several hormones are linked with
acne like the androgens testosterone, Diet
dihydrotestosterone, dehydroepiandrosterone The relationship between acne and diet
sulfate and insulin like growth factor 1 (IGF remains unclear although high glycemic diet is
-I). In later years development of acne vulgaris associated with worsening of acne [32–34].
is uncommon but rosacea incidence will There is a positive association between the
increase which is having similar symptoms in milk consumption and prevalence of acne
older age groups. Acne vulgaris in adult increases [33, 35, 36]. Reports showed that
women may be due to underlying condition consumption of chocolate and salt are not
such as; pregnancy, Cushing’s syndrome, associated with development of acne [33].
hirsutism or polycystic ovary syndrome. Acne Chocolate contains large amount of sugar that
climacterica refers to menopause associated can lead to high glycemic load. It might be
acne, occurs as production of the anti-acne possible that acne is linked with obesity and
ovarian hormones estradiol and progesterone insulin metabolism [37].
allowing the acnegenic hormone testosterone
to continuously exert its effects. Parasitic
Acne is linked with the parasitic mite
Genetic Demodex but it is not clear whether Demodex
The genetics of acne susceptibility is or Demodex associated bacteria causes the
polygenic as the disease does not follow effects [38–40].
classic Mendelian inheritance pattern.
PATHOGENESIS
There are multiple candidates for genes related Acne develops as a result of bacterial
to acne which includes polymorphisms in overgrowth and inflammation in the
Tumor necrosis factor-alpha, Interleukin-1 pilosebaceous units. The body’s hormone level
alpha, CYP1A1 [4]. alter pilosebaceous gland function and causes

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acne. Follicular epithelial cells abnormally the comedones development [42] (Figure 4).
differentiated and forms tighter intracellular Changes in the skin’s natural flora are linked
adhesions and shed less. That leads to the with androgen related sebum production.
development of microcomedones or Diseases like congenital adrenal hyperplasia,
hyperkeratotic plugs which enlarge to form polycystic ovarian syndrome and endocrine
noninflammatory open or closed comedones tumors result in a high level of androgens in
[41]. Androgens are causative factors for acne body and associated with the development of
which induces sebum production leading to acne vulgaris [43].

Fig. 4: Basic Mechanisms Involved in the Acne Pathogenesis.

The acne spreading depends on pilosebaceous inflammatory response. In lesion initiation,


gland density and morphology and it is abnormal proliferation and differentiation
common in the face, chest, neck and back. leads to the occurrence of microcomedone in
Non-inflammatory acne is characterized by the the initial lesion [46–48].
formation of closed or open comedones. Open
comedones also known as blackheads shows This is followed by (i) the accumulation of
dark colored hyperkeratotic plugs within the sebum in the follicle lumen, causing a plug,
follicular opening which is related to the either open or closed (ii) inflammatory
melanin oxidation but not dirt, as it is a components leaking from a follicle to the
common disbelief. Closed comedones also dermis. An acne lesion thus forms. A patient’s
known as whiteheads are white to flesh toned immune sensitivity toward acne associated
in color and not have a central open pore [41]. antigens and skin integrity can affect the
initiation of acne lesions. According to the
Propionibacterium acnes a normal component genomic data of Propionibacterium acnes
of the cutaneous flora, invade the publicly released in 2004, acne virulence
pilosebaceous unit using lipid rich sebum as a factors encoded in the genome can degrade
nutrient source and grow in the presence of host tissue and trigger inflammation [49, 50].
increased sebum production leading to
inflammation via complement activation and There are several molecular cues that cause the
the release of metabolic byproducts, proteases progression of acne virulence. One is the
and neutrophil-attracting chemotactic factors presence of Christie, Atkins, Munch-Peterson
[41, 44]. When comedones ruptures, the (CAMP) factor of Propionibacterium acnes
contents of the pilosebaceous unit spread into and a secretory protein with its co-hemolytic
the adjacent dermis and it leads to activity of the host acid sphingomyelinase
development of inflammatory acne vulgaris (ASMase). CAMP and ASMase can be
lesions such as; cysts, nodules, papules and utilized for the development of drugs to inhibit
pustules [41, 45]. or to suppress bacterial overgrowth to prevent
the acne progression.
Sometime cysts may adhere to form channels
or draining sinuses. The acne vulgaris occurs The synergistic lysis of erythrocytes via the
due to increased sebum secretion, ductal CAMP reaction has been found in
keratinocyte hyperproliferation, excess growth Propionibacterium acnes [51,52]. The CAMP
of acne-associated bacteria and host reaction was described as sheep erythrocytes

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lysis by Staphylococcus aureus several extracellular hydrolases, such as;


sphingomyelinase C and CAMP factor sialidase, endoglycoceramidases and
produced by some streptococcal species. hyaluronate lyase. Propionibacterium acnes
lipase is responsible for bacterial colonization
The sphingomyelin and phospholipids are in sebaceous follicles [52]. Other
hydrolyzed by the enzyme followed by cell inflammatory reactions localized in the acne
lysis [53]. Propionibacterium acnes CAMP lesion include chemo attractant molecules that
factor can be utilized by Staphylococcus recruit polymorphonuclear leukocytes and
aureus to enhance hemolysis in acne lesion lymphocytes, the production of the
[54]. A mutagenesis method has been inflammatory cytokines, and the complement
developed to knock out the genes encoding activation [58]. The pathogenesis of acne can
CAMP factors in P. acnes [55]. be triggered by toll like receptor 2 which
regulates many immune response genes.
The sialidase bacterial cell wall anchoring Propionibacterium acnes activate the
factor produced by Propionibacterium acnes pilosebaceous unit and induce the production
can catalyze the hydrolysis of sialic acid from of IL-12 and IL-8 of monocytes via the TLR2
the surface of mammalian cells and lead to cell pathway. TLR2 and TLR4 expression is
death. The immunization of sebocytes with increased in the acne lesions of the epidermis.
recombinant sialidase has been found to This inflammation can lead to
neutralize Propionibacterium acnes induced hyperproliferation of the ductal epidermis. IL-
toxicity in sebocytes and sialidase vaccinated 8 recruits neutrophils to the pilosebaceous unit
ICR mice showed reduced erythema on the in which degradative enzymes ruptured the
ears [56,57]. This innovative medicine could follicular epithelium [59]. The role of
be developed for acne treatment. The Propionibacterium acnes in the pathogenesis
Propionibacterium acnes genome encodes of acne is shown in Figure 5.

Fig. 5: Propionibacterium Acne Role in Acne Pathogenesis [60].

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DIAGNOSIS whiter than acne whiteheads and most


Scales used for grading the severity of acne commonly seen around the eyes.
vulgaris are as follows: d) Perioral dermatitis.
a) Pillsbury scale: It give classification of the e) Pityrosporum folliculitis: It predominates
acne based on severity ranging from 1 on the trunk [63].
(least severe) to 4 (most severe).
b) Cook's acne grading scale: It utilizes MANAGEMENT
images to grade severity ranging from 0 Various medicines for acne treatment includes
(least severe) to 8 (most severe). benzoyl peroxide, antibiotics, antiseborrheic
c) Leeds acne grading technique: It counts medications, sulfur and sodium
and categorizes inflammatory and non- Sulphacetamide, anti-androgen medications,
inflammatory lesions grade ranging from 0 salicylic acid, hormonal treatments, alpha
to 10 [61]. hydroxy acid, retinoids, azelaic acid,
keratolytic soaps and nicotinamide [64]. Laser
and light devices and minor subcision surgery
is also performed. Benzoyl peroxide is first
line treatment for mild and moderate acne due
to its effectiveness and mild side effects like
irritant dermatitis, dryness of the skin, redness
and peeling. It helps to prevent formation of
comedones caused by P. acnes bacterium and
has anti-inflammatory properties [2]. Topical
application increases sensitivity to the sun and
sunscreen is combined to prevent sunburn.
Benzoyl peroxide is often combined with
antibiotics. Benzoyl peroxide is found to be
equally effective as antibiotics at all
concentrations, although it does not produce
bacterial resistance [65].

Antibiotics
Antibiotics are used in more severe cases due
to their antimicrobial activity against P. acnes
along with anti-inflammatory properties. They
are becoming less effective with increasing
resistance of P. acnes worldwide [2, 65].
Antibiotics including clindamycin,
erythromycin and tetracyclines such as;
doxycycline, oxytetracycline, lymecycline and
Fig. 6: Acne Grades and Severity [62].
minocycline are topically applied or orally
administered for treatment of acne (Table 2).
(i) Acne, grade I; multiple open comedones
(ii) Acne, grade II; closed comedones (iii)
Antiseborrheic Drugs
Acne, grade III; papulopustules (iv) Acne,
Sulfur is used in concentrations varying from 1
grade IV; multiple open comedones,
to 10% and act as an antiseborrheic and mild
closed comedones, and papulopustules,
keratolytic but it produces bad odor and the
plus cysts (Figure 6).
staining of clothes. Alcohol-ether in equal
parts and zinc sulfate also act as sebum
Differential Diagnosis
reducing agents [66].
a) Acne rosacea: It is commonly observed in
middle age or later in life.
Topical Sulfur and Sodium Sulphacetamide
b) Folliculitis and boils: It may present with
Sulfur is used as a drying agent and
pustular lesions similar to acne.
antibacterial agent. It is present in washes,
c) Milia: It is small keratin cysts that may be
lotions, creams, foam formulations,
confused with whiteheads. They may be

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prescription and nonprescription masks. It can been shown to be effective for older women
be useful for treatment of rosacea and [73].
seborrhoeic dermatitis. Sodium
Sulphacetamide is often combined with sulfur Topical Retinoids
and has anti-inflammatory properties. Sodium Topical retinoids possess anti-inflammatory
Sulphacetamide can treat acne and used for the properties and act by normalizing the follicle
sensitive skin acne patient [67]. cell life cycle and prevent hyperkeratinization
of these cells that can create a blockage. It
Salicylic Acid includes tretinoin, adapalene and tazarotene.
Salicylic acid has bactericidal and keratolytic They are related to vitamin A and similar to
properties and hence lessens acne. Salicylic isotretinoin and have much milder side effects
acid open obstructed skin pores and promotes like skin irritation and flushing [2]. Retinol a
shedding of epithelial skin cells but it causes form of vitamin A has mild effects and is used
hyperpigmentation of the skin in individuals in many over the counter moisturizers and
with darker skin types [2]. other topical products.

Anti-androgen Treatment Oral Retinoids


In females acne can be treated with the use of Isotretinoin is effective for treatment of
combined oral contraceptives [45]. Third or moderate and severe acne and after one to two
fourth generation progestins such as months of use improvement is seen. In about
norgestimate, desogestrel or drospirenone 80% of people, a single course reports
combination product may be more beneficial complete remission in more than 50% patients
[68]. Oestrogenic oral contraceptive is an and 20% of patients require a second course.
effective for acne [69]. Due to androgenic Adverse effects includes dry skin, nose bleeds,
properties of oral contraceptive norethisterone muscle pains, increased liver enzymes and
is contradicted in acne [70]. Anti-androgen increased lipid levels in the blood. There is a
cyproterone combined with 50 µg of high risk of fetal abnormalities during
ethinylestradiol is available as Dianette® pregnancy. There is no evidence that oral
which is most effective hormonal intervention retinoids increase the risk of adverse effects
[71]. A combination of ethinylestradiol with like depression and suicide [5]. Chemical
drospirenone available as Yasmin® has been peeling of the skin is used for the treatment of
found to be effective [72]. Spironolactone has acne and peeling is superficial.

Table 2: Current Medical Treatments of Acne Vulgaris [61].


Administration Drug or dosage form Treatment features
Tetracycline, Doxycycline, Minocycline, Drugs should be taken daily, High patient compliance,
Oral
Isotretinoin (13-cis-retinoic acid) Adverse effects limit the use of the drugs
Benzoyl peroxide, Clindamycin,
Local administration of drugs, Ease of termination of
Topical Erythromycin, Tetracycline, Tretinoin,
drug action, Adverse effects limit the use of the drugs
Tazarotene, Green tea extracts
Liposomes, Solid lipid nanoparticles, Sustained release of drugs, More effective than topical
Particle-based Drug
Nanostructured lipid carriers, Micro gel, Higher flux of drug across the skin, Effective for
delivery system
emulsions follicular targeting
Fewer adverse effects than systemic/topical
Light based Endogenous porphyrins (coproporphyrin administration and Drug delivery system, Light therapy
therapy** III), 5-aminolevulinic acid alone or along with liposomal drugs reported, Not a
first line therapy for acne vulgaris
* For particle-based Drug delivery system, **this therapy use either topical drugs or particle based drug delivery system
along with light irradiation.

Procedures [2]. There is no report that microdermabrasion


Comedo extraction may help patient with is effective. As of 2012, report for light
comedones that are not treated with standard therapy and lasers is insufficient for regular
treatment [74]. Corticosteroids are injected use [74]. Light therapy is an expensive
into the acne comedone for immediate relief treatment and provides short term benefit and

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Acne Vulgaris Review Suva et al.

there is a lack of long term outcome data in term antibiotic therapy and bacterial resistance
patients with severe acne [2, 75]. Laser [88].
surgery can be used to reduce the scars left
behind by acne [76]. Boils can be removed by CONCLUSION
surgical lancing in patients with cystic acne Acne vulgaris is most common skin disorders
[12]. In a double blind, randomized study, a that affect people in their adolescence. Acne
comparison was done between alpha-hydroxy vulgaris is characterized by skin with
(30% glycolic acid) versus beta-hydroxy (30% seborrhea, blackheads and comedones,
salicylic acid) peels and it was found that both papules, papules, pimples and scarring.
peels were equally effective for acne treatment Various scales used for grading the severity of
[77]. Subcision is occasionally used to treat acne vulgaris are Pillsbury scale, cook's acne
acne scars. Subcision involves insertion of a grading scale and Leeds acne grading
tri-beveled hypodermic needle through skin technique. Various medicines for acne
surface puncture and maneuvering its edges to treatment includes benzoyl peroxide,
break down subcuticular fibrotic strands to antibiotics like erythromycin, clindamycin,
release the skin from the underlying tetracyclines, antiseborrheic medications like
connective tissue [78]. It appears to be equally sulfur and sodium sulphacetamide, anti-
effective as collagen filler [79]. androgen medications like norgestimate,
desogestrel or drospirenone, Dianette®,
Laser and Light Devices Yasmin®, salicylic acid, hormonal treatments,
The reports showed that photodynamic alpha hydroxy acid, retinoids, azelaic acid,
therapy, light emitting diode therapy and keratolytic soaps and nicotinamide. Currently
combination of pneumatic energy and light has laser and light devices and minor subcision
been successfully used with traditional surgery have been also performed for acne
therapies for treatment of acne [80]. For the treatment. Recently genome sequencing of P.
treatment of acne combination product acnes bacteriophage (PA6) identified which
Isolaz™ (Aesthera, Pleasanton, CA, USA) could enhance the development of a potential
uses a vacuum with broad band light source bacteriophage therapy to treat acne.
has been shown to be effective in 11 patients
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