The skin weighs an average of 4 kg (8.8 lb), covers an area of about 2 m 2  (22 sq ft), and is made of three distinct layers: the  epidermis ,  dermis , and  subcutaneous tissue . [ 1 ]  The two main types of human skin are  glabrous skin , the nonhairy skin on the palms and soles (also referred to as the "palmoplantar" surfaces), and hair-bearing skin. [ 16 ]  Within the latter type, hairs in structures called  pilosebaceous units  have a  hair follicle ,  sebaceous gland , and associated  arrector pili  muscle. [ 17 ]   In the embryo , the epidermis, hair, and glands are from the  ectoderm , which is chemically influenced by the underlying  mesoderm  that forms the dermis and subcutaneous tissues. [ 18 ] [ 19 ] [ 20 ]


The epidermis is the most superficial layer of skin, a  squamous epithelium  with several  strata : the  stratum corneum ,  stratum lucidum ,  stratum granulosum ,  stratum spinosum , and  stratum basale . [ 21 ]  Nourishment is provided to these layers via  diffusion  from the dermis, since the epidermis is without direct blood supply. [ 22 ]  The epidermis contains four cell types:  keratinocytes ,  melanocytes ,  Langerhans cells , and  Merkel cells . Of these, keratinocytes are the major component, constituting roughly 95% of the epidermis. [ 16 ]  This stratified squamous epithelium is maintained by cell division within the stratum basale, in which differentiating cells slowly displace outwards through the stratum spinosum to the stratum corneum, where cells are continually shed from the surface. [ 16 ]  In normal skin, the rate of production equals the rate of loss; about two weeks are needed for a cell to migrate from the basal cell layer to the top of the granular cell layer, and an additional two weeks to cross the stratum corneum. [ 23 ]


The dermis is the layer of skin between the epidermis and subcutaneous tissue, and comprises two sections, the  papillary dermis  and the  reticular dermis . [ 24 ]  The superficial papillary dermis  interdigitates  with the overlying  rete ridges  of the epidermis, between which the two layers interact through the basement membrane zone. [ 24 ]  Structural components of the dermis are  collagen ,  elastic fibers , and  ground substance  also called extra fibrillar matrix. [ 24 ]  Within these components are the pilosebaceous units, arrector pili muscles, and the  eccrine  and  apocrine glands . [ 21 ]  The dermis contains two vascular networks that run parallel to the skin surface—one superficial and one deep plexus—which are connected by vertical communicating vessels. [ 21 ] [ 25 ]  The function of blood vessels within the dermis is fourfold: to supply nutrition, to regulate temperature, to modulate inflammation, and to participate in wound healing. [ 26 ] [ 27 ]


The subcutaneous tissue is a layer of fat between the dermis and underlying  fascia . [ 5 ]  This tissue may be further divided into two components, the actual fatty layer, or  panniculus adiposus , and a deeper vestigial layer of muscle, the  panniculus carnosus . [ 16 ]  The main cellular component of this tissue is the  adipocyte , or fat cell. [ 5 ]  The structure of this tissue is composed of septal (i.e. linear strands) and  lobular  compartments, which differ in microscopic appearance. [ 21 ]  Functionally, the subcutaneous fat insulates the body, absorbs trauma, and serves as a reserve energy source. [ 5 ]


Diseases of the skin include  skin infections  and  skin neoplasms  (including  skin cancer ). [ 28 ]


In 1572,  Geronimo Mercuriali  of  Forlì ,  Italy , completed  De morbis cutaneis  ('On the diseases of the skin'). It is considered the first scientific work dedicated to  dermatology .


The physical examination of the skin and its appendages, as well as the mucous membranes, forms the cornerstone of an accurate diagnosis of cutaneous conditions. [ 29 ]  Most of these conditions present with cutaneous surface changes termed "lesions," which have more or less distinct characteristics. [ 30 ]  Often proper examination will lead the physician to obtain appropriate historical information and/or laboratory tests that are able to confirm the diagnosis. [ 29 ]  Upon examination, the important clinical observations are the (1) morphology, (2) configuration, and (3) distribution of the lesion(s). [ 29 ]  With regard to morphology, the initial lesion that characterizes a condition is known as the "primary lesion", and identification of such a lesions is the most important aspect of the cutaneous examination. [ 30 ]  Over time, these primary lesions may continue to develop or be modified by regression or trauma, producing "secondary lesions". [ 1 ]  However, with that being stated, the lack of standardization of basic dermatologic terminology has been one of the principal barriers to successful communication among physicians in describing cutaneous findings. [ 21 ]  Nevertheless, there are some commonly accepted terms used to describe the macroscopic morphology, configuration, and distribution of skin lesions, which are listed below. [ 30 ]


"Configuration" refers to how lesions are locally grouped ("organized"), which contrasts with how they are distributed (see next section).


"Distribution" refers to how lesions are localized. They may be confined to a single area (a patch) or may be in several places. Some distributions correlate with the means by which a given area becomes affected. For example, contact dermatitis correlates with locations where allergen has elicited an allergic immune response.  Varicella zoster virus  is known to recur (after its initial presentation as  chicken pox ) as  herpes zoster  ("shingles"). Chicken pox appears nearly everywhere on the body, but herpes zoster tends to follow one or two dermatomes; for example, the eruptions may appear along the bra line, on either or both sides of the patient. [ citation needed ]


Acne  ( /ˈækni/   ACK-nee ), also known as  acne vulgaris , is a long-term  skin condition  that occurs when  dead skin cells  and  oil from the skin  clog  hair follicles . [ 10 ]  Typical features of the condition include  blackheads or whiteheads ,  pimples , oily skin, and possible  scarring . [ 1 ] [ 2 ] [ 11 ]  It primarily affects skin with a relatively high number of  oil glands , including the face, upper part of the chest, and back. [ 12 ]  The resulting appearance can lead to lack of confidence,  anxiety , reduced  self-esteem , and, in extreme cases,  depression  or  thoughts of suicide . [ 3 ] [ 4 ]


Susceptibility to acne is primarily genetic in 80% of cases. [ 2 ]  The roles of diet and  cigarette smoking  in the condition are unclear, and neither  cleanliness  nor exposure to sunlight are associated with acne. [ 2 ] [ 13 ] [ 14 ]  In both  sexes ,  hormones  called  androgens  appear to be part of the underlying mechanism, by causing increased production of  sebum . [ 5 ]  Another common factor is the excessive growth of the bacterium  Cutibacterium acnes , which is present on the skin. [ 15 ]


Treatments for acne are available, including lifestyle changes, medications, and medical procedures. Eating fewer  simple carbohydrates  such as  sugar  may minimize the condition. [ 7 ]   Treatments applied directly to the affected skin , such as  azelaic acid ,  benzoyl peroxide , and  salicylic acid , are commonly used. [ 8 ]   Antibiotics  and  retinoids  are available in  formulations  that are applied to the skin and  taken by mouth  for the treatment of acne. [ 8 ]  However,  resistance to antibiotics  may develop as a result of antibiotic therapy. [ 16 ]  Several types of  birth control pills  help prevent acne in women. [ 8 ]  Medical professionals typically reserve  isotretinoin  pills for severe acne, due to greater potential side effects. [ 8 ] [ 17 ]  Early and aggressive treatment of acne is advocated by some in the medical community to decrease the overall long-term impact on individuals. [ 4 ]


In 2015, acne affected approximately 633   million people globally, making it the eighth-most common disease worldwide. [ 9 ] [ 18 ]  Acne commonly occurs in  adolescence  and affects an estimated 80–90% of teenagers in the  Western world . [ 19 ] [ 20 ] [ 21 ]  Some rural societies report lower rates of acne than industrialized ones. [ 21 ] [ 22 ]  Children and adults may also be affected before and after puberty. [ 23 ]  Although acne becomes less common in adulthood, it persists in nearly half of affected people into their twenties and thirties, and a smaller group continues to have difficulties in their forties. [ 2 ]


The severity of acne vulgaris (Gr. ἀκμή, "point" + L.  vulgaris , "common") [ 24 ]  can be classified as mild, moderate, or severe to determine an appropriate treatment regimen. [ 20 ]  There is no universally accepted scale for grading acne severity. [ 15 ]  The presence of clogged skin follicles (known as  comedones ) limited to the face with occasional inflammatory lesions defines mild acne. [ 20 ]  Moderate severity acne is said to occur when a higher number of inflammatory  papules  and  pustules  occur on the face, compared to mild cases of acne, and appear on the trunk of the body. [ 20 ]  Severe acne is said to occur when  nodules  (the painful 'bumps' lying under the skin) are the characteristic facial lesions, and involvement of the trunk is extensive. [ 20 ] [ 25 ]


The lesions are usually, polymorphic, meaning they can take many forms, including open or closed comedones (commonly known as blackheads and whiteheads), papules, pustules, and even nodules or cysts so that these lesions often leave behind sequelae, or abnormal conditions resulting from a previous disease, such as scarring or hyperpigmentation. [ 26 ]


Large nodules were previously called  cysts . The term  nodulocystic  has been used in the medical literature to describe severe cases of inflammatory acne. [ 25 ]  True cysts are rare in those with acne, and the term  severe nodular acne  is now the preferred terminology. [ 25 ]


Acne inversa  (L.  invertō, "upside-down") and  acne rosacea  (rosa, "rose-colored" + -āceus, "forming") are not forms of acne and are alternate names that respectively refer to the skin conditions  hidradenitis suppurativa  (HS) and  rosacea . [ 27 ] [ 28 ] [ 29 ]  Although HS shares certain overlapping features with acne vulgaris, such as a tendency to clog skin follicles with skin cell debris, the condition otherwise lacks the hallmark features of acne and is therefore considered a distinct skin disorder. [ 27 ]


Typical features of acne include  increased secretion  of oily  sebum  by the skin, microcomedones, comedones, papules, nodules (large papules), pustules, and often results in scarring. [ 30 ] [ 31 ]  The appearance of acne varies with skin color. It may result in psychological and social problems. [ 20 ]


Acne  scars  are caused by  inflammation  within the  dermis  and are estimated to affect 95% of people with acne vulgaris. [ 32 ]  Abnormal healing and dermal inflammation create the scar. [ 33 ]  Scarring is most likely to take place with severe acne but may occur with any form of acne vulgaris. [ 32 ]  Acne scars are classified based on whether the abnormal healing response following dermal inflammation leads to excess  collagen  deposition or loss at the site of the acne lesion. [ 34 ]


Atrophic acne scars have lost collagen from the healing response and are the most common type of acne scar (accounting for approximately 75% of all acne scars). [ 33 ] [ 34 ]  Ice-pick scars, boxcar scars, and rolling scars are subtypes of atrophic acne scars. [ 32 ]  Boxcar scars are round or ovoid indented scars with sharp borders and vary in size from 1.5–4 mm across. [ 33 ]  Ice-pick scars are narrow (less than 2  mm  across), deep scars that extend into the dermis. [ 33 ]  Rolling scars are broader than ice-pick and boxcar scars (4–5 mm across) and have a wave-like pattern of depth in the skin. [ 33 ]


Hypertrophic scars  are uncommon and are characterized by increased collagen content after the abnormal healing response. [ 33 ]  They are described as firm and raised from the skin. [ 33 ] [ 35 ]  Hypertrophic scars remain within the original margins of the wound, whereas  keloid scars  can form scar tissue outside of these borders. [ 33 ]  Keloid scars from acne occur more often in men and people with darker skin, and usually occur on the trunk of the body. [ 33 ]


After an inflamed nodular acne lesion resolves, it is common for  the skin to darken  in that area, which is known as  postinflammatory hyperpigmentation  (PIH). The inflammation stimulates specialized pigment-producing skin cells (known as  melanocytes ) to produce more  melanin  pigment, which leads to the skin's darkened appearance. [ 36 ]  PIH occurs more frequently in people with  darker skin color . [ 37 ]  Pigmented scar is a common term used for PIH, but is misleading as it suggests the color change is permanent. Often, PIH can be prevented by avoiding any aggravation of the nodule and can fade with time. However, untreated PIH can last for months, years, or even be permanent if deeper layers of skin are affected. [ 38 ]  Even minimal skin exposure to the sun's  ultraviolet rays  can sustain hyperpigmentation. [ 36 ]  Daily use of  SPF  15 or higher  sunscreen  can minimize such a risk. [ 38 ]  Whitening agents like  azelaic acid ,  arbutin  or else may be used to improve hyperpigmentation. [ 39 ]


Risk factors for the development of acne, other than genetics, have not been conclusively identified. Possible secondary contributors include hormones, infections, diet, and stress. Studies investigating the impact of smoking on the incidence and severity of acne have been inconclusive. [ 2 ] [ 40 ] [ 41 ]  Cleanliness ( hygiene ) and sunlight are not associated with acne. [ 14 ]


Acne appears to be highly  heritable ;  genetics  explain 81% of the variation in the population. [ 15 ]  Studies performed in affected  twins  and  first-degree relatives  further demonstrate the strongly inherited nature of acne. [ 2 ] [ 15 ]  Acne susceptibility is likely due to the influence of multiple genes, as the disease does not follow a classic  (Mendelian)  inheritance pattern. These gene candidates include  certain variations  in  tumor necrosis factor-alpha (TNF-alpha) ,  IL-1 alpha , and  CYP1A1  genes, among others. [ 19 ]  The 308 G/A  single nucleotide polymorphism  variation in the gene for  TNF  is associated with an increased risk for acne. [ 42 ]  Acne can be a feature of rare genetic disorders such as  Apert's syndrome . [ 15 ]  Severe acne may be associated with  XYY syndrome . [ 43 ]


Hormonal activity, such as occurs during  menstrual cycles  and  puberty , may contribute to the formation of acne. During puberty, an increase in sex hormones called  androgens  causes the skin follicle glands to grow larger and make more oily sebum. [ 12 ]  The androgen hormones  testosterone ,  dihydrotestosterone  (DHT), and  dehydroepiandrosterone  (DHEA) are all linked to acne. High levels of  growth hormone  (GH) and  insulin-like growth factor 1  (IGF-1) are also associated with worsened acne. [ 44 ]  Both androgens and IGF-1 seem to be essential for acne to occur, as acne does not develop in individuals with  complete androgen insensitivity syndrome  (CAIS) or  Laron syndrome  (insensitivity to GH, resulting in very low IGF-1 levels). [ 45 ] [ 46 ]


Medical conditions that commonly cause a high-androgen state, such as  polycystic ovary syndrome ,  congenital adrenal hyperplasia , and  androgen-secreting tumors , can cause acne in affected individuals. [ 47 ] [ 48 ]  Conversely, people who  lack androgenic hormones  or are  insensitive to the effects of androgens  rarely have acne. [ 47 ]  Pregnancy can increase androgen levels, and consequently, oily sebum synthesis. [ 48 ] [ 49 ]  Acne can be a side effect of  testosterone replacement therapy  or  anabolic steroid  use. [ 1 ] [ 50 ]  Over-the-counter  bodybuilding  and  dietary supplements  often contain illegally added anabolic steroids. [ 1 ] [ 51 ]


The  anaerobic bacterial  species  Cutibacterium acnes  (formerly  Propionibacterium acnes ) contributes to the development of acne, but its exact role is not well understood. [ 2 ]  There are specific sub-strains of  C. acnes  associated with normal skin and others with moderate or severe inflammatory acne. [ 52 ]  It is unclear whether these undesirable strains evolve on-site or are acquired, or possibly both depending on the person. These strains have the capability of changing, perpetuating, or adapting to the abnormal cycle of inflammation, oil production, and inadequate sloughing of dead skin cells from acne pores. Infection with the parasitic mite  Demodex  is associated with the development of acne. [ 31 ] [ 53 ]  It is unclear whether eradication of the mite improves acne. [ 53 ]


High- glycemic-load  diets have been found to have different degrees of effect on acne severity. [ 7 ] [ 54 ] [ 55 ]  Multiple  randomized controlled trials  and nonrandomized studies have found a lower-glycemic-load diet to be effective in reducing acne. [ 54 ]  There is weak observational evidence suggesting that dairy milk consumption is positively associated with a higher frequency and severity of acne. [ 53 ] [ 54 ] [ 56 ] [ 57 ] [ 58 ]  Milk contains  whey protein  and hormones such as bovine IGF-1 and precursors of dihydrotestosterone. [ 54 ]  Studies suggest these components promote the effects of insulin and IGF-1 and thereby increase the production of androgen hormones, sebum, and promote the formation of comedones. [ 54 ]  Available evidence does not support a link between eating chocolate or salt and acne severity. [ 56 ] [ 57 ]  Few studies have examined the relationship between  obesity  and acne. [ 2 ]   Vitamin B 12  may trigger skin outbreaks similar to acne (acneiform eruptions), or worsen existing acne when taken in doses exceeding the  recommended daily intake . [ 59 ]


There are few high-quality studies to demonstrate that stress causes or worsens acne. [ 60 ]  Despite being controversial, some research indicates that increased acne severity is associated with high stress levels in certain contexts, such as hormonal changes seen in  premenstrual syndrome . [ 61 ] [ 62 ]


Some individuals experience severe intensification of their acne when they are exposed to hot humid climates; this is due to bacteria and fungus thriving in warm, moist environments. This climate-induced acne exacerbation has been termed  tropical acne .
Mechanical obstruction of  skin follicles  with helmets or chinstraps can worsen pre-existing acne. [ 63 ]  However, acne caused by mechanical obstruction is technically not acne vulgaris, but another  acneiform eruption  known as  acne mechanica .


Several medications can also worsen pre-existing acne; this condition is the  acne medicamentosa  form of acne. Examples of such medications include  lithium ,  hydantoin ,  isoniazid ,  glucocorticoids ,  iodides ,  bromides , and  testosterone . [ 43 ]  When acne medicamentosa is specifically caused by  anabolic–androgenic steroids  it can simply be referred to as  steroid acne .


Genetically susceptible individuals can get acne breakouts as a result of  polymorphous light eruption ; a condition triggered by sunlight and artificial UV light exposure. This form of acne is called  Acne aestivalis  and is specifically caused by intense  UVA light  exposure. Affected individuals usually experience seasonal acne breakouts on their upper arms, shoulder girdle, back, and chest. The breakouts typically occur one-to-three days after exposure to intese UVA radiation. Unlike other forms of acne, the condition spares the face; this could possibly be a result of the pathogenesis of polymorphous light eruption, in which areas of the skin that are  newly  exposed to intense ultraviolet radiation are affected. Since faces are typically left uncovered at all stages of life, there is little-to-no likelihood for an eruption to appear there.  Studies show  that both polymorphous light eruption outbreaks and the acne aestivalis breakout response can be prevented by topical antioxidants combined with the application of a broad spectrum sunscreen. [ 64 ]


Acne vulgaris is a chronic skin disease of the  pilosebaceous unit  and develops due to blockages in the skin's  hair follicles . [ 52 ]


Traditionally seen as a disease of adolescence, acne vulgaris is also observed in adults, including post-menopausal women. Acne vulgaris manifested in adult female is called  adult female acne  (AFA), defined as a chronic inflammatory disease of the pilosebaceous unit. [ 26 ]  Particularly in AFA, during the menopausal transition, a relative increase in androgen levels occurs as estrogen levels begin to decline, so that this hormonal shift can manifest as acne; while most women with AFA exhibit few acne lesions and have normal androgen levels, baseline investigations, including an androgen testing panel, can help rule out associated comorbidities such as  polycystic ovarian syndrome ,  congenital adrenal hyperplasia , or tumors. [ 26 ]


The blockages in the skin's  hair follicles  that cause acne vulgaris manifestations occur as a result of the following four abnormal processes: increased oily  sebum  production (influenced by  androgens ),  excessive deposition of the protein keratin  leading to comedo formation, colonization of the follicle by  Cutibacterium acnes  ( C. acnes ) bacteria, and the local release of pro-inflammatory chemicals in the skin. [ 52 ]


The earliest pathologic change is the formation of a plug (a  microcomedone ), which is driven primarily by excessive growth, reproduction, and accumulation of  skin cells  in the hair follicle. [ 1 ]  In healthy skin, the skin cells that have died come up to the surface and exit the pore of the hair follicle. [ 10 ]  In people with acne, the increased production of oily sebum causes the dead skin cells to stick together. [ 10 ]  The accumulation of dead skin cell debris and oily sebum blocks the pore of the hair follicle, thus forming the microcomedone. [ 10 ]  The  C. acnes   biofilm  within the hair follicle worsens this process. [ 47 ]  If the microcomedone is superficial within the hair follicle, the skin pigment  melanin  is exposed to air, resulting in its  oxidation  and dark appearance (known as a blackhead or open comedo). [ 1 ] [ 10 ] [ 20 ]  In contrast, if the microcomedone occurs deep within the hair follicle, this causes the formation of a whitehead (known as a closed comedo). [ 1 ] [ 10 ]


The main hormonal driver of oily sebum production in the skin is  dihydrotestosterone . [ 1 ]  Another androgenic hormone responsible for increased sebaceous gland activity is  DHEA-S . The  adrenal glands  secrete higher amounts of DHEA-S during  adrenarche  (a stage of  puberty ), and this leads to an increase in sebum production. In a sebum-rich skin environment, the naturally occurring and largely  commensal  skin bacterium  C. acnes  readily grows and can cause  inflammation  within and around the follicle due to activation of the  innate immune system . [ 10 ]   C. acnes  triggers skin inflammation in acne by increasing the production of several pro-inflammatory  chemical signals  (such as  IL-1α ,  IL-8 ,  TNF-α , and LTB4); IL-1α is essential to comedo formation. [ 47 ]


C. acnes'  ability to bind and activate a class of  immune system  receptors known as  toll-like receptors  (TLRs), especially  TLR2  and  TLR4 , is a core mechanism of acne-related skin inflammation. [ 47 ] [ 65 ] [ 66 ]  Activation of TLR2 and TLR4 by  C. acnes  leads to increased secretion of IL-1α, IL-8, and TNF-α. [ 47 ]  The release of these inflammatory signals attracts various immune cells to the hair follicle, including  neutrophils ,  macrophages , and  Th1 cells . [ 47 ]  IL-1α stimulates increased skin cell activity and reproduction, which, in turn, fuels comedo development. [ 47 ]  Furthermore, sebaceous gland cells produce more  antimicrobial peptides , such as  HBD1  and  HBD2 , in response to the binding of TLR2 and TLR4. [ 47 ]


C. acnes  also provokes skin inflammation by altering the fatty composition of oily sebum. [ 47 ]  Oxidation of the  lipid   squalene  by  C. acnes  is of particular importance. Squalene oxidation activates  NF-κB  (a protein complex) and consequently increases IL-1α levels. [ 47 ]  Additionally, squalene oxidation increases  5-lipoxygenase  enzyme activity, which catalyzes the conversion of  arachidonic acid  to  leukotriene B4  (LTB4). [ 47 ]  LTB4 promotes skin inflammation by acting on the  peroxisome proliferator-activated receptor alpha  (PPARα) protein. [ 47 ]  PPARα increases the activity of  activator protein 1  (AP-1) and NF-κB, thereby leading to the recruitment of inflammatory  T cells . [ 47 ]   C. acnes'  ability to convert sebum  triglycerides  to pro-inflammatory  free fatty acids  via secretion of the enzyme  lipase  further explains its inflammatory properties. [ 47 ]  These free fatty acids spur increased production of  cathelicidin , HBD1, and HBD2, thus leading to further inflammation. [ 47 ]


This inflammatory cascade typically leads to the formation of inflammatory acne lesions, including  papules , infected  pustules , or  nodules . [ 1 ]  If the inflammatory reaction is severe, the follicle can break into the deeper layers of the dermis and  subcutaneous tissue  and cause the formation of deep nodules. [ 1 ] [ 67 ] [ 68 ]  The involvement of AP-1 in the aforementioned inflammatory cascade activates  matrix metalloproteinases , which contribute to local tissue destruction and scar formation. [ 47 ]


Along with the bacteria  C. acnes , the bacterial species  Staphylococcus epidermidis  ( S. epidermidis ) also takes a part in the physiopathology of acne vulgaris. The proliferation of  S. epidermidis  with  C. acnes  causes the formation of  biofilms , which blocks the hair follicles and pores, creating an  anaerobic  environment under the skin. This enables for increased growth of both  C. acnes  and  S. epidermidis  under the skin. The proliferation of  C. acnes  causes the formation of  biofilms  and a  biofilm matrix , making it even harder to treat the acne. [ 69 ]


Acne vulgaris is diagnosed based on a medical professional's clinical judgment. [ 15 ]  The evaluation of a person with suspected acne should include taking a detailed medical history about a family history of acne, a review of medications taken, signs or symptoms of excessive production of androgen hormones, cortisol, and growth hormone. [ 15 ]  Comedones (blackheads and whiteheads) must be present to diagnose acne. In their absence, an appearance similar to that of acne would suggest a different skin disorder. [ 29 ]  Microcomedones (the precursor to blackheads and whiteheads) are not visible to the naked eye when inspecting the skin and require a  microscope to be seen . [ 29 ]  Many features may indicate that a person's acne vulgaris is sensitive to hormonal influences. Historical and physical clues that may suggest hormone-sensitive acne include onset between ages 20 and 30; worsening the week before a woman's period; acne lesions predominantly over the jawline and chin; and inflammatory/nodular acne lesions. [ 1 ]


Several scales exist to grade the severity of acne vulgaris, but disagreement persists about the ideal one for diagnostic use. [ 70 ] [ 71 ]  Cook's acne grading scale uses photographs to grade severity from 0 to 8, with higher numbers representing more severe acne. This scale was the first to use a standardized photographic protocol to assess acne severity; since its creation in 1979, the scale has undergone several revisions. [ 71 ]  The Leeds acne grading technique counts acne lesions on the face, back, and chest and categorizes them as inflammatory or non-inflammatory. Leeds scores range from 0 (least severe) to 10 (most severe) though modified scales have a maximum score of 12. [ 71 ] [ 72 ]  The Pillsbury acne grading scale classifies the severity of the acne from grade 1 (least severe) to grade 4 (most severe). [ 70 ] [ 73 ]


Many skin conditions can mimic acne vulgaris, and these are collectively known as  acneiform eruptions . [ 29 ]  Such conditions include  angiofibromas ,  epidermal cysts ,  flat warts ,  folliculitis ,  keratosis pilaris ,  milia ,  perioral dermatitis , and  rosacea , among others. [ 20 ] [ 74 ]  Age is one factor that may help distinguish between these disorders. Skin disorders such as perioral dermatitis and keratosis pilaris can appear similar to acne but tend to occur more frequently in childhood. Rosacea tends to occur more frequently in older adults. [ 20 ]  Facial redness triggered by heat or the consumption of alcohol or spicy food is also more suggestive of rosacea. [ 75 ]  The presence of comedones helps health professionals differentiate acne from skin disorders that are similar in appearance. [ 8 ]   Chloracne  and  occupational acne  due to exposure to certain chemicals & industrial compounds, may look very similar to acne vulgaris. [ 76 ]


Many different treatments exist for acne. These include  alpha hydroxy acid , anti-androgen medications, antibiotics, antiseborrheic medications,  azelaic acid ,  benzoyl peroxide ,  hormonal  treatments,  keratolytic  soaps,  nicotinamide  (niacinamide),  retinoids , and  salicylic acid . [ 77 ] [ 78 ]  Acne treatments work in at least four different ways, including the following: reducing inflammation, hormonal manipulation, killing  C. acnes , and normalizing skin cell shedding and sebum production in the pore to prevent blockage. [ 15 ]  Typical treatments include topical therapies such as antibiotics, benzoyl peroxide, and retinoids, and systemic therapies, including antibiotics, hormonal agents, and oral retinoids. [ 20 ] [ 79 ]


Recommended therapies for first-line use in acne vulgaris treatment include topical retinoids, benzoyl peroxide, and topical or oral antibiotics. [ 80 ]  Procedures such as light therapy and laser therapy are not first-line treatments and typically have only an  add on  role due to their high cost and limited evidence. [ 79 ]  Blue light therapy is of unclear benefit. [ 81 ]  Medications for acne target the early stages of  comedo  formation and are generally ineffective for visible skin lesions; acne generally improves between eight and twelve weeks after starting therapy. [ 15 ]


People often view acne as a short-term condition, some expecting it to disappear after puberty. This misconception can lead to depending on self-management or problems with long-term adherence to treatment. Communicating the long-term nature of the condition and better access to reliable information about acne can help people know what to expect from treatments. [ 82 ] [ 83 ]


In general, it is recommended that people with acne do not wash affected skin more than twice daily. [ 15 ]  The application of a fragrance-free  moisturizer  to sensitive and acne-prone skin may reduce irritation. Skin irritation from acne medications typically peaks at two weeks after onset of use and tends to improve with continued use. [ 15 ]  Dermatologists recommend using cosmetic products that specifically say non-comedogenic, oil-free, and will not clog pores. [ 15 ]


Acne vulgaris patients, even those with oily skin, [ 84 ]  should moisturize in order to support the skin's moisture barrier since skin barrier dysfunction may contribute to acne. [ 84 ]  Moisturizers, especially  ceramide -containing moisturizers, as an adjunct therapy are particularly helpful for the dry skin and irritation that commonly results from topical acne treatment. Studies show that ceramide-containing moisturizers are important for optimal skin care; they enhance acne therapy adherence and complement existing acne therapies. [ 84 ]  In a study where acne patients used 1.2% clindamycin phosphate / 2.5% benzoyl peroxide gel in the morning and applied a micronized 0.05% tretinoin gel in the evening the overwhelming majority of patients experienced no cutaneous adverse events throughout the study. It was concluded that using ceramide cleanser and ceramide moisturizing cream caused the favorable tolerability, did not interfere with the treatment efficacy, and improved adherence to the regimen. [ 85 ]  The importance of preserving the acidic mantle and its barrier functions is widely accepted in the scientific community. Thus, maintaining a pH in the range 4.5 – 5.5 is essential in order to keep the skin surface in its optimal, healthy conditions. [ 86 ] [ 87 ] [ 88 ] [ 89 ] [ 90 ]


Causal  relationship is rarely observed with diet/nutrition and dermatologic conditions. Rather, associations – some of them compelling – have been found between diet and outcomes including disease severity and the number of conditions experienced by a patient. Evidence is emerging in support of medical nutrition therapy as a way of reducing the severity and incidence of dermatologic diseases, including acne.  Researchers observed a link between high glycemic index diets and acne. [ 91 ]  Dermatologists also recommend a  diet low in simple sugars  as a method of improving acne. [ 54 ]  As of 2014, the available evidence is insufficient to use milk restriction for this purpose. [ 54 ]


Benzoyl peroxide  (BPO) is a first-line treatment for mild and moderate acne due to its effectiveness and mild side-effects (mainly  skin irritation ). In the skin follicle, benzoyl peroxide kills  C. acnes  by oxidizing its proteins through the formation of oxygen  free radicals  and  benzoic acid . These free radicals likely interfere with the bacterium's metabolism and ability to make proteins. [ 92 ] [ 93 ]  Additionally, benzoyl peroxide is mildly effective at breaking down comedones and inhibiting inflammation. [ 80 ] [ 93 ]  Combination products use benzoyl peroxide with a topical antibiotic or retinoid, such as  benzoyl peroxide/clindamycin  and  benzoyl peroxide/adapalene , respectively. [ 37 ]  Topical benzoyl peroxide is effective at treating acne. [ 94 ]


Side effects include increased  skin photosensitivity , dryness, redness, and occasional peeling. [ 95 ]  Sunscreen use is often advised during treatment, to prevent  sunburn . Lower concentrations of benzoyl peroxide are just as effective as higher concentrations in treating acne but are associated with fewer side effects. [ 93 ] [ 96 ]  Unlike antibiotics, benzoyl peroxide does not appear to generate  bacterial antibiotic resistance . [ 95 ]


Retinoids  are medications that reduce inflammation, normalize the follicle  cell life cycle , and reduce sebum production. [ 47 ] [ 97 ]  They are structurally related to  vitamin A . [ 97 ]  Studies show dermatologists and primary care doctors underprescribe them for acne. [ 15 ]  The retinoids appear to influence the cell life cycle in the follicle lining. This helps prevent the  accumulation of skin cells  within the hair follicle that can create a blockage. They are a first-line acne treatment, [ 1 ]  especially for people with dark-colored skin. Retinoids are known to lead to faster improvement of postinflammatory hyperpigmentation. [ 37 ]


Topical retinoids include  adapalene ,  retinol ,  retinaldehyde ,  isotretinoin ,  tazarotene ,  trifarotene , and  tretinoin . [ 49 ] [ 98 ] [ 99 ]  They often cause an initial flare-up of acne and facial  flushing  and can cause significant skin irritation. Generally speaking, retinoids increase the skin's  sensitivity to sunlight  and are therefore recommended for use at night. [ 1 ]  Tretinoin is the least expensive of the topical retinoids and is the most irritating to the skin, whereas adapalene is the least irritating but costs significantly more. [ 1 ] [ 100 ]  Most formulations of tretinoin are incompatible for use with benzoyl peroxide. [ 15 ]  Tazarotene is the most effective and expensive topical retinoid but is usually not as well tolerated. [ 1 ] [ 100 ]  In 2019 a tazarotene lotion formulation, marketed to be a less irritating option, was approved by the FDA. [ 101 ]  Retinol is a form of vitamin A that has similar but milder effects and is present in many over-the-counter moisturizers and other topical products.


Isotretinoin is an oral retinoid that is very effective for severe nodular acne, and moderate acne that is stubborn to other treatments. [ 1 ] [ 20 ]  One to two months of use is typically adequate to see improvement. Acne often resolves completely or is much milder after a 4–6 month course of oral isotretinoin. [ 1 ]  After a single round of treatment, about 80% of people report an improvement, with more than 50% reporting complete remission. [ 20 ]  About 20% of people require a second course, but 80% of those report improvement, resulting in a cumulative 96% efficacy rate. [ 20 ]


There are concerns that isotretinoin is linked to adverse effects, like  depression ,  suicidality , and  anemia . There is no clear evidence to support some of these claims. [ 1 ] [ 20 ]  Isotretinoin has been found in some studies to be superior to antibiotics or placebo in reducing acne lesions. [ 17 ]  However, a 2018 review comparing inflammatory lesions after treatment with antibiotics or isotretinoin found no difference. [ 102 ]  The frequency of adverse events was about twice as high with isotretinoin use, although these were mostly dryness-related events. [ 17 ]  No increased risk of suicide or depression was conclusively found. [ 17 ]


Medical authorities strictly regulate isotretinoin use in women of childbearing age due to its known  harmful effects in pregnancy . [ 20 ]  For such a woman to be considered a candidate for isotretinoin, she must have a confirmed negative  pregnancy test  and use an effective form of  birth control . [ 20 ]  In 2008, the United States started the  iPLEDGE  program to prevent isotretinoin use during pregnancy. [ 103 ]  iPledge requires the woman to have two negative pregnancy tests and to use two types of birth control for at least one month before isotretinoin therapy begins and one month afterward. [ 103 ]  The effectiveness of the iPledge program is controversial due to continued instances of contraception nonadherence. [ 103 ] [ 104 ]


People may apply antibiotics to the skin or take them orally to treat acne. They work by killing  C. acnes  and reducing inflammation. [ 20 ] [ 95 ] [ 105 ]  Although multiple guidelines call for healthcare providers to reduce the rates of prescribed oral antibiotics, many providers do not follow this guidance. [ 106 ]  Oral antibiotics remain the most commonly prescribed systemic therapy for acne. [ 106 ]  Widespread  broad-spectrum antibiotic  overuse for acne has led to higher rates of antibiotic-resistant  C. acnes  strains worldwide, especially to the commonly used  tetracycline  (e.g.,  doxycycline ) and macrolide antibiotics (e.g., topical  erythromycin ). [ 16 ] [ 95 ] [ 105 ] [ 106 ]  Therefore, dermatologists prefer antibiotics as part of combination therapy and not for use alone. [ 15 ]


Commonly used antibiotics, either applied to the skin or taken orally, include  clindamycin , erythromycin,  metronidazole ,  sulfacetamide , and tetracyclines (e.g., doxycycline or  minocycline ). [ 49 ]  Doxycycline 40 milligrams daily (low-dose) appears to have similar efficacy to 100 milligrams daily and has fewer gastrointestinal side effects. [ 15 ]  However, low-dose doxycycline is not FDA-approved for the treatment of acne. [ 107 ]  Antibiotics applied to the skin are typically used for mild to moderately severe acne. [ 20 ]  Oral antibiotics are generally more effective than topical antibiotics and produce faster resolution of inflammatory acne lesions than topical applications. [ 1 ]  The  Global Alliance to Improve Outcomes in Acne  recommends that topical and oral antibiotics are not used together. [ 105 ]


Oral antibiotics are recommended for no longer than three months as antibiotic courses exceeding this duration are associated with the development of antibiotic resistance and show no clear benefit over shorter durations. [ 105 ]  If long-term oral antibiotics beyond three months are used, then it is recommended that benzoyl peroxide or a retinoid be used at the same time to limit the risk of  C. acnes  developing antibiotic resistance. [ 105 ]


The antibiotic  dapsone  is effective against inflammatory acne when applied to the skin. It is generally not a first-line choice due to its higher cost and a lack of clear superiority over other antibiotics. [ 1 ] [ 15 ]  Topical dapsone is sometimes a preferred therapy in women or for people with sensitive or darker-toned skin. [ 15 ]  It is not recommended for use with benzoyl peroxide due to the risk of causing yellow-orange skin discoloration with this combination. [ 10 ]  Minocycline is an effective acne treatment, but it is not a first-line antibiotic due to a lack of evidence that it is better than other treatments, and concerns about its safety compared to other tetracyclines. [ 108 ]


Sarecycline  is the most recent oral antibiotic developed specifically for the treatment of acne, and is FDA-approved for the treatment of moderate to severe inflammatory acne in patients nine years of age and older. [ 109 ] [ 110 ] [ 111 ]  It is a  narrow-spectrum  tetracycline antibiotic that exhibits the necessary antibacterial activity against pathogens related to acne vulgaris and a low propensity for inducing antibiotic resistance. [ 112 ] [ 113 ]  In clinical trials, sarecycline demonstrated clinical efficacy in reducing inflammatory acne lesions as early as three weeks and reduced truncal (back and chest) acne. [ 111 ] [ 114 ]


In women, the use of  combined birth control pills  can improve acne. [ 115 ]  These medications contain an  estrogen  and a  progestin . [ 116 ]  They work by decreasing the production of androgen hormones by the ovaries and by decreasing the free and hence biologically active fractions of androgens, resulting in lowered skin production of sebum and consequently reduce acne severity. [ 10 ] [ 117 ]  First-generation progestins such as  norethindrone  and  norgestrel  have androgenic properties and may worsen acne. [ 15 ]  Although oral estrogens decrease IGF-1 levels in some situations, which could theoretically improve acne symptoms, [ 118 ] [ 119 ]  combined birth control pills do not appear to affect IGF-1 levels in fertile women. [ 116 ] [ 120 ]   Cyproterone acetate -containing birth control pills seem to decrease total and free IGF-1 levels. [ 121 ]  Combinations containing third- or fourth-generation  progestins , including  desogestrel ,  dienogest ,  drospirenone , or  norgestimate , as well as birth control pills containing cyproterone acetate or  chlormadinone acetate , are preferred for women with acne due to their stronger antiandrogenic effects. [ 122 ] [ 123 ] [ 124 ]  Studies have shown a 40 to 70% reduction in acne lesions with combined birth control pills. [ 117 ]  A 2014  review  found that oral antibiotics appear to be somewhat more effective than birth control pills at reducing the number of inflammatory acne lesions at three months. [ 125 ]  However, the two therapies are approximately equal in efficacy at six months for decreasing the number of inflammatory, non-inflammatory, and total acne lesions. [ 125 ]  The authors of the analysis suggested that birth control pills may be a preferred first-line acne treatment, over oral antibiotics, in certain women due to similar efficacy at six months and a lack of associated antibiotic resistance. [ 125 ]  In contrast to combined birth control pills,  progestogen-only birth control  forms that contain androgenic progestins have been associated with worsened acne. [ 106 ]


Antiandrogens  such as cyproterone acetate and  spironolactone  can successfully treat acne, especially in women with signs of excessive androgen production, such as increased  hairiness  or skin production of sebum, or  scalp hair loss . [ 10 ] [ 49 ]  Spironolactone is an effective treatment for acne in adult women. [ 126 ] [ 127 ]  Unlike combined birth control pills, it is not approved by the United States  Food and Drug Administration  for this purpose. [ 1 ] [ 37 ] [ 126 ]  Spironolactone is an  aldosterone antagonist  and is a useful acne treatment due to its ability to additionally block the  androgen receptor  at higher doses. [ 37 ] [ 106 ]  Alone or in combination with a birth control pill, spironolactone has shown a 33 to 85% reduction in acne lesions in women. [ 117 ]  The effectiveness of spironolactone for acne appears to be dose-dependent. [ 117 ]  High-dose cyproterone acetate alone reportedly decreases acne symptoms in women by 75 to 90% within three months. [ 128 ]  It is usually combined with an estrogen to avoid  menstrual irregularities  and  estrogen deficiency . [ 129 ]  The medication appears to be effective in the treatment of acne in males, with one study finding that a high dosage reduced inflammatory acne lesions by 73%. [ 130 ] [ 131 ]  However, spironolactone and cyproterone acetate's side effects in males, such as  gynecomastia ,  sexual dysfunction , and decreased  bone mineral density , generally make their use for male acne impractical. [ 130 ] [ 131 ] [ 132 ]


Pregnant and lactating women should not receive antiandrogens for their acne due to a possibility of  birth disorders  such as  hypospadias  and  feminization  of male babies. [ 49 ]  Women who are sexually active and who can or may become pregnant should use an effective method of contraception to prevent pregnancy while taking an antiandrogen. [ 133 ]  Antiandrogens are often combined with birth control pills for this reason, which can result in additive efficacy. [ 37 ] [ 134 ]  The FDA added a  black-box warning  to spironolactone about possible  tumor  risks based on  preclinical research  with very high doses (>100-fold clinical doses) and cautioned that unnecessary use of the medication should be avoided. [ 80 ] [ 106 ] [ 135 ]  However, several large  epidemiological studies  subsequently found no greater risk of tumors in association with spironolactone in humans. [ 106 ] [ 136 ] [ 137 ] [ 138 ]  Conversely, strong associations of cyproterone acetate with certain  brain tumors  have been discovered and its use has been restricted. [ 139 ] [ 140 ] [ 141 ]  The brain tumor risk with cyproterone acetate is due to its strong  progestogenic  actions and is not related to antiandrogenic activity nor shared by other antiandrogens. [ 139 ] [ 142 ] [ 141 ]


Flutamide , a pure  antagonist  of the androgen receptor, is effective in treating acne in women. [ 128 ] [ 143 ]  It appears to reduce acne symptoms by 80 to 90% even at low doses, with several studies showing complete acne clearance. [ 128 ] [ 144 ] [ 145 ]  In one study, flutamide decreased acne scores by 80% within three months, whereas spironolactone decreased symptoms by only 40% in the same period. [ 145 ] [ 146 ] [ 147 ]  In a large long-term study, 97% of women reported satisfaction with the control of their acne with flutamide. [ 148 ]  Although effective, flutamide has a risk of serious  liver toxicity , and cases of death in women taking even low doses of the medication to treat androgen-dependent skin and hair conditions have occurred. [ 149 ]  As such, the use of flutamide for acne has become increasingly limited, [ 148 ] [ 150 ] [ 151 ]  and it has been argued that continued use of flutamide for such purposes is unethical. [ 149 ]   Bicalutamide , a pure androgen receptor antagonist with the same mechanism as flutamide and with comparable or superior antiandrogenic  efficacy  but with a far lower risk of liver toxicity, is an alternative option to flutamide in the treatment of androgen-dependent skin and hair conditions in women. [ 133 ] [ 152 ] [ 153 ] [ 154 ]


Clascoterone  is a  topical  antiandrogen that has demonstrated effectiveness in the treatment of acne in both males and females and was approved for clinical use for this indication in August 2020. [ 155 ] [ 156 ] [ 157 ] [ 158 ] [ 159 ]  It has shown no systemic absorption or associated antiandrogenic side effects. [ 158 ] [ 159 ] [ 160 ]  In a small direct head-to-head comparison, clascoterone showed greater effectiveness than topical isotretinoin. [ 158 ] [ 159 ] [ 160 ]   5α-Reductase inhibitors  such as  finasteride  and  dutasteride  may be useful for the treatment of acne in both males and females but have not been adequately evaluated for this purpose. [ 1 ] [ 161 ] [ 162 ] [ 163 ]  Moreover, 5α-reductase inhibitors have a strong potential for producing birth defects in male babies and this limits their use in women. [ 1 ] [ 162 ]  However, 5α-reductase inhibitors are frequently used to treat  excessive facial/body hair  in women and can be combined with birth control pills to prevent pregnancy. [ 161 ]  There is no evidence as of 2010 to support the use of  cimetidine  or  ketoconazole  in the treatment of acne. [ 164 ]


Hormonal treatments for acne such as combined birth control pills and antiandrogens may be considered first-line therapy for acne under many circumstances, including desired contraception, known or suspected hyperandrogenism, acne during adulthood, acne that flares premenstrually, and when symptoms of significant sebum production (seborrhea) are co-present. [ 164 ]  Hormone therapy is effective for acne both in women with hyperandrogenism and in women with normal androgen levels. [ 164 ]


Azelaic acid  is effective for mild to moderate acne when applied topically at a 15–20% concentration. [ 67 ] [ 165 ] [ 166 ] [ 167 ]  Treatment twice daily for six months is necessary, and is as effective as topical benzoyl peroxide 5%, isotretinoin 0.05%, and erythromycin 2%. [ 168 ]  Azelaic acid is an effective acne treatment due to its ability to reduce skin cell accumulation in the follicle and its  antibacterial  and  anti-inflammatory  properties. [ 67 ]  It has a slight skin-lightening effect due to its ability to inhibit melanin synthesis. Therefore, it is useful in treating individuals with acne who are also affected by post-inflammatory hyperpigmentation. [ 1 ]  Azelaic acid may cause skin irritation. [ 169 ]  It is less effective and more expensive than retinoids. [ 1 ]  Azelaic acid also led to worse treatment response when compared to benzoyl peroxide. When compared to tretinoin, azelaic acid makes little or no treatment response. [ 170 ]


Salicylic acid  is a topically applied  beta-hydroxy acid  that  stops bacteria from reproducing  and has keratolytic properties. [ 171 ] [ 172 ]  It is less effective than retinoid therapy. [ 20 ]  Salicylic acid opens obstructed skin pores and promotes the shedding of epithelial skin cells. [ 171 ]   Dry skin  is the most commonly seen side effect with topical application, though  darkening  of the skin can occur in individuals with darker skin types. [ 1 ]


Topical and oral preparations of  nicotinamide  (the  amide  form of  vitamin B 3 ) are alternative medical treatments. [ 173 ]  Nicotinamide reportedly improves acne due to its anti-inflammatory properties [ 173 ]  (influencing neutrophil  chemotaxis , inhibiting the release of histamine, suppressing the lymphocyte transformation test, and reducing nitric oxide synthase production induced by cytokines), [ 78 ]  its ability to suppress sebum production, and its wound healing properties. [ 173 ]  Topical and oral preparations of zinc are suggested treatments for acne; evidence to support their use for this purpose is limited. [ 174 ]  Zinc's capacities to reduce inflammation and sebum production as well as inhibit  C. acnes  growth are its proposed mechanisms for improving acne. [ 174 ]   Antihistamines  may improve symptoms among those already taking isotretinoin due to their anti-inflammatory properties and their ability to suppress sebum production. [ 175 ]


Hydroquinone  lightens the skin when applied topically by inhibiting  tyrosinase , the enzyme responsible for converting the amino acid  tyrosine  to the skin pigment  melanin , and is used to treat acne-associated post-inflammatory hyperpigmentation. [ 36 ]  By interfering with the production of melanin in the  epidermis , hydroquinone leads to less hyperpigmentation as darkened skin cells are naturally shed over time. [ 36 ]  Improvement in skin  hyperpigmentation  is typically seen within six months when used twice daily. Hydroquinone is ineffective for hyperpigmentation affecting deeper layers of skin such as the  dermis . [ 36 ]  The use of a  sunscreen  with  SPF  15 or higher in the morning with reapplication every two hours is recommended when using hydroquinone. [ 36 ]  Its application only to affected areas lowers the risk of lightening the color of normal skin but can lead to a temporary ring of lightened skin around the hyperpigmented area. [ 36 ]  Hydroquinone is generally well-tolerated; side effects are typically mild (e.g., skin irritation) and occur with the use of a higher than the recommended 4% concentration. [ 36 ]  Most preparations contain the preservative  sodium metabisulfite , which has been linked to rare cases of  allergic reactions , including  anaphylaxis  and severe  asthma  exacerbations in susceptible people. [ 36 ]  In extremely rare cases, the frequent and improper application of high-dose hydroquinone has been associated with a systemic condition known as  exogenous ochronosis  (skin discoloration and  connective tissue  damage from the accumulation of  homogentisic acid ). [ 36 ]


Combination therapy—using medications of different classes together, each with a different mechanism of action—has been demonstrated to be a more effective approach to acne treatment than monotherapy. [ 10 ] [ 49 ]  The use of topical benzoyl peroxide and  antibiotics  together is more effective than antibiotics alone. [ 10 ]  Similarly, using a topical retinoid with an antibiotic clears acne lesions faster than the use of antibiotics alone. [ 10 ]  Frequently used combinations include the following: antibiotic and benzoyl peroxide, antibiotic and topical retinoid, or topical retinoid and benzoyl peroxide. [ 49 ]  Dermatologists generally prefer combining benzoyl peroxide with a retinoid over the combination of a topical antibiotic with a retinoid. Both regimens are effective, but benzoyl peroxide does not lead to antibiotic resistance. [ 10 ]


Although sebaceous gland activity in the skin increases during the late stages of pregnancy, pregnancy has not been reliably associated with worsened acne severity. [ 176 ]  In general, topically applied medications are considered the first-line approach to acne treatment during pregnancy, as they have little systemic absorption and are therefore unlikely to harm a developing  fetus . [ 176 ]  Highly recommended therapies include topically applied  benzoyl peroxide  ( pregnancy category  C) and azelaic acid (category B). [ 176 ]  Salicylic acid carries a category C safety rating due to higher systemic absorption (9–25%), and an association between the use of anti-inflammatory medications in the third trimester and adverse effects to the developing fetus including  too little amniotic fluid in the uterus  and early closure of the babies'  ductus arteriosus  blood vessel. [ 49 ] [ 176 ]  Prolonged use of salicylic acid over significant areas of the skin or under  occlusive (sealed) dressings  is not recommended as these methods increase systemic absorption and the potential for fetal harm. [ 176 ]  Tretinoin (category C) and adapalene (category C) are very poorly absorbed, but certain studies have suggested  teratogenic  effects in the first trimester. [ 176 ]  The data examining the association between maternal topical retinoid exposure in the first trimester of pregnancy and adverse pregnancy outcomes is limited. [ 177 ]  A systematic review of observational studies concluded that such exposure does not appear to increase the risk of major  birth defects ,  miscarriages ,  stillbirths ,  premature births , or  low birth weight . [ 177 ]  Similarly, in studies examining the effects of topical retinoids during pregnancy, fetal harm has not been seen in the second and third trimesters. [ 176 ]  Nevertheless, since rare harms from topical retinoids are not ruled out, they are not recommended for use during pregnancy due to persistent safety concerns. [ 177 ] [ 178 ]  Retinoids contraindicated for use during pregnancy include the topical retinoid tazarotene, and oral retinoids isotretinoin and  acitretin  (all category X). [ 176 ]  Spironolactone is relatively contraindicated for use during pregnancy due to its antiandrogen effects. [ 1 ]  Finasteride is not recommended as it is highly teratogenic. [ 1 ]


Topical antibiotics deemed safe during pregnancy include clindamycin, erythromycin, and metronidazole (all category B), due to negligible systemic absorption. [ 49 ] [ 176 ]   Nadifloxacin  and dapsone (category C) are other topical antibiotics that may be used to treat acne in pregnant women but have received less study. [ 49 ] [ 176 ]  No adverse fetal events have been reported from the topical use of dapsone. [ 176 ]  If retinoids are used there is a high risk of abnormalities occurring in the developing fetus; women of childbearing age are therefore required to use effective  birth control  if retinoids are used to treat acne. [ 20 ]  Oral antibiotics deemed safe for pregnancy (all category B) include  azithromycin ,  cephalosporins , and  penicillins . [ 176 ]  Tetracyclines (category D) are contraindicated during pregnancy as they are known to deposit in developing fetal teeth, resulting in yellow discoloration and  thinned tooth enamel . [ 1 ] [ 176 ]  Their use during pregnancy has been associated with the development of  acute fatty liver of pregnancy  and is further avoided for this reason. [ 176 ]


Limited evidence supports  comedo extraction , but it is an option for comedones that do not improve with standard treatment. [ 8 ] [ 80 ]  Another procedure for immediate relief is the injection of a corticosteroid into an inflamed acne comedo. [ 80 ]   Electrocautery  and  electrofulguration  are effective alternative treatments for comedones. [ 179 ]


Light therapy  is a treatment method that involves delivering certain specific wavelengths of light to an area of skin affected by acne. Both regular and  laser light  have been used. The evidence for  light therapy  as a treatment for acne is weak and inconclusive. [ 8 ] [ 180 ]  Various light therapies appear to provide a short-term benefit, but data for long-term outcomes, and outcomes in those with severe acne, are sparse; [ 181 ]  it may have a role for individuals whose acne has been resistant to topical medications. [ 10 ]  A 2016 meta-analysis was unable to conclude whether light therapies were more beneficial than placebo or no treatment, nor the duration of benefit. [ 182 ]


When regular light is used immediately following the application of a  sensitizing substance  to the skin such as  aminolevulinic acid  or  methyl aminolevulinate , the treatment is referred to as  photodynamic therapy  (PDT). [ 106 ] [ 165 ]  PDT has the most supporting evidence of all light therapy modalities. [ 80 ]  PDT treats acne by using various forms of light (e.g., blue light or red light) that preferentially target the pilosebaceous unit. [ 106 ]  Once the light activates the sensitizing substance, this generates  free radicals  and  reactive oxygen species  in the skin, which purposefully damage the sebaceous glands and kill  C. acnes  bacteria. [ 106 ]  Many different types of nonablative lasers (i.e., lasers that do not vaporize the top layer of the skin but rather induce a physiologic response in the skin from the light) have been used to treat acne, including those that use infrared wavelengths of light. Ablative lasers (such as  CO 2  and fractional types) have also been used to treat active acne and its scars. When ablative lasers are used, the treatment is often referred to as  laser resurfacing  because, as mentioned previously, the entire upper layers of the skin are vaporized. [ 183 ]  Ablative lasers are associated with higher rates of adverse effects compared with non-ablative lasers, with examples being post-inflammatory hyperpigmentation, persistent facial redness, and persistent pain. [ 8 ] [ 184 ] [ 185 ]  Physiologically, certain wavelengths of light, used with or without accompanying topical chemicals, are thought to kill bacteria and decrease the size and activity of the glands that produce sebum. [ 165 ]  Disadvantages of light therapy can include its cost, the need for multiple visits, the time required to complete the procedure(s), and pain associated with some of the treatment modalities. [ 10 ]  Typical side effects include  skin peeling , temporary reddening of the skin, swelling, and post-inflammatory hyperpigmentation. [ 10 ]


Dermabrasion  is an effective therapeutic procedure for reducing the appearance of superficial atrophic scars of the boxcar and rolling varieties. [ 33 ]  Ice-pick scars do not respond well to treatment with dermabrasion due to their depth. [ 33 ]  The procedure is painful and has many potential side effects such as skin sensitivity to sunlight,  redness , and  decreased pigmentation of the skin . [ 33 ]  Dermabrasion has fallen out of favor with the introduction of laser resurfacing. [ 33 ]  Unlike dermabrasion, there is no evidence that  microdermabrasion  is an effective treatment for acne. [ 8 ]


Dermal or subcutaneous  fillers  are substances injected into the skin to improve the appearance of acne scars. Fillers are used to increase natural  collagen  production in the skin and to increase skin volume and decrease the depth of acne scars. [ 186 ]  Examples of fillers used for this purpose include  hyaluronic acid ;  poly(methyl methacrylate)   microspheres  with collagen; human and bovine collagen derivatives, and fat harvested from the person's own body (autologous fat transfer). [ 186 ]


Microneedling  is a procedure in which an instrument with multiple rows of tiny needles is rolled over the skin to elicit a wound healing response and stimulate collagen production to reduce the appearance of atrophic acne scars in people with darker skin color. [ 183 ]  Notable adverse effects of microneedling include post-inflammatory hyperpigmentation and tram track scarring (described as discrete slightly raised scars in a linear distribution similar to a tram track). The latter is thought to be primarily attributable to improper technique by the practitioner, including the use of excessive pressure or inappropriately large needles. [ 183 ] [ 187 ]


Subcision  is useful for the treatment of superficial atrophic acne scars and involves the use of a small needle to loosen the fibrotic adhesions that result in the depressed appearance of the scar. [ 188 ] [ 189 ] [ 190 ]


Chemical peels  can be used to reduce the appearance of acne scars. [ 33 ]  Mild peels include those using  glycolic acid ,  lactic acid ,  salicylic acid ,  Jessner's solution , or a lower concentration (20%) of  trichloroacetic acid . These peels only affect the  epidermal layer of the skin  and can be useful in the treatment of superficial acne scars as well as skin pigmentation changes from inflammatory acne. [ 33 ]  Higher concentrations of trichloroacetic acid (30–40%) are considered to be medium-strength peels and affect the skin as deep as the  papillary dermis . [ 33 ]  Formulations of trichloroacetic acid concentrated to 50% or more are considered to be deep chemical peels. [ 33 ]  Medium-strength and deep-strength chemical peels are more effective for deeper atrophic scars but are more likely to cause side effects such as skin pigmentation changes, infection, and  small white superficial cysts known as milia . [ 33 ]


Researchers are investigating complementary therapies as treatment for people with acne. [ 191 ]   Low-quality evidence  suggests topical application of  tea tree oil  or  bee venom  may reduce the total number of skin lesions in those with acne. [ 191 ]  Tea tree oil appears to be approximately as effective as  benzoyl peroxide  or salicylic acid but is associated with  allergic contact dermatitis . [ 1 ]  Proposed mechanisms for tea tree oil's anti-acne effects include antibacterial action against  C. acnes  and anti-inflammatory properties. [ 66 ]  Numerous other plant-derived therapies have demonstrated positive effects against acne (e.g.,  basil oil ;  oligosaccharides  from  seaweed ; however, few well-done studies have examined their use for this purpose. [ 192 ]  There is a lack of high-quality evidence for the use of  acupuncture ,  herbal medicine , or  cupping therapy  for acne. [ 191 ]


Many over-the-counter treatments in many forms are available, which are often known as  cosmeceuticals . [ 193 ]  Certain types of  makeup  may be useful to mask acne. [ 194 ]  In those with oily skin, a water-based product is often preferred. [ 194 ] [ 195 ]


Acne usually improves around the age of 20 but may persist into adulthood. [ 77 ]  Permanent physical scarring may occur. [ 20 ]  Rare complications from acne or its treatment include the formation of  pyogenic granulomas ,  osteoma cutis , and  acne with facial edema . [ 196 ]  Early and aggressive treatment of acne is advocated by some in the medical community to reduce the chances of these poor outcomes. [ 4 ]


There is good evidence to support the idea that acne and associated scarring negatively affect a person's psychological state, worsen mood, lower self-esteem, and are associated with a higher risk of  anxiety disorders ,  depression , and  suicidal thoughts . [ 3 ] [ 32 ] [ 53 ] [ 82 ]


Misperceptions about acne's causative and aggravating factors are common, and people with acne often blame themselves, and others often blame those with acne for their condition. [ 197 ] [ 82 ]  Such blame can worsen the affected person's sense of self-esteem. [ 197 ]  Until the 20th century, even among dermatologists, the list of causes was believed to include excessive sexual thoughts and  masturbation . [ 198 ]  Dermatology's association with  sexually transmitted infections , especially  syphilis , contributed to the stigma. [ 198 ]


Another  psychological  complication of acne vulgaris is  acne excoriée , which occurs when a person persistently picks and scratches pimples, irrespective of the severity of their acne. [ 61 ] [ 199 ]  This can lead to significant scarring, changes in the affected person's skin pigmentation, and a cyclic worsening of the affected person's anxiety about their appearance. [ 61 ]


Globally, acne affects approximately 650 million people, or about 9.4% of the population, as of 2010. [ 200 ]  It affects nearly 90% of people in Western societies during their teenage years, but can occur before adolescence and may persist into adulthood. [ 19 ] [ 20 ] [ 23 ]  While acne that first develops between the ages of 21 and 25 is uncommon, it affects 54% of women and 40% of men older than 25 years of age [ 49 ] [ 201 ]  and has a lifetime prevalence of 85%. [ 49 ]  About 20% of those affected have moderate or severe cases. [ 2 ]  It is slightly more common in females than males (9.8% versus 9.0%). [ 200 ]  In those over 40 years old, 1% of males and 5% of females still have problems. [ 20 ]


Rates appear to be lower in rural societies. [ 22 ]  While some research has found it affects people of all ethnic groups, [ 202 ]  acne may not occur in the non-Westernized peoples of  Papua New Guinea  and  Paraguay . [ 203 ]


Acne affects 40–50 million people in the United States (16%) and approximately 3–5 million in Australia (23%). [ 125 ] [ 204 ]  Severe acne tends to be more common in people of Caucasian or Amerindian descent than in people of African descent. [ 21 ]


Historical records indicate that  pharaohs  had acne, which may be the earliest known reference to the disease.  Sulfur 's usefulness as a topical remedy for acne dates back to at least the reign of  Cleopatra  (69–30 BCE). [ 205 ]  The sixth-century  Greek  physician  Aëtius of Amida  reportedly coined the term " ionthos " ( ίονθωξ ,) or " acnae ", which seems to be a reference to facial skin lesions that occur during "the ' acme ' of life" ( puberty ). [ 206 ]


In the 16th century, the French physician and botanist  François Boissier de Sauvages de Lacroix  provided one of the earlier descriptions of acne. He used the term "psydracia achne" to describe small, red, and hard  tubercles  that altered a person's facial appearance during adolescence and were neither itchy nor painful. [ 206 ]


The recognition and characterization of acne progressed in 1776 when  Josef Plenck  (an  Austrian  physician) published a book that proposed the novel concept of classifying skin diseases by their elementary (initial) lesions. [ 206 ]  In 1808 the  English   dermatologist   Robert Willan  refined Plenck's work by providing the first detailed descriptions of several skin disorders using morphologic terminology that remains in use today. [ 206 ]   Thomas Bateman  continued and expanded on Robert Willan's work as his student and provided the first descriptions and illustrations of acne accepted as accurate by modern dermatologists. [ 206 ]   Erasmus Wilson , in 1842, was the first to make the distinction between acne vulgaris and rosacea. [ 207 ]  The first professional medical  monograph  dedicated entirely to acne was written by  Lucius Duncan Bulkley  and published in New York in 1885. [ 198 ] [ 208 ]


Scientists initially hypothesized that acne represented a disease of the skin's hair follicle, and occurred due to blockage of the pore by sebum. During the 1880s, they observed bacteria by microscopy in skin samples from people with acne. Investigators believed the bacteria caused comedones, sebum production, and ultimately acne. [ 206 ]  During the mid-twentieth century, dermatologists realized that no single hypothesized factor (sebum, bacteria, or excess keratin) fully accounted for the disease in its entirety. [ 206 ]  This led to the current understanding that acne could be explained by a sequence of related events, beginning with blockage of the skin follicle by excessive dead skin cells, followed by bacterial invasion of the hair follicle pore, changes in sebum production, and inflammation. [ 206 ]


The approach to acne treatment underwent significant changes during the twentieth century. Retinoids became a medical treatment for acne in 1943. [ 97 ]  Benzoyl peroxide was first proposed as a treatment in 1958 and remains a staple of acne treatment. [ 209 ]  The introduction of oral tetracycline antibiotics (such as minocycline) modified acne treatment in the 1950s. These reinforced the idea amongst dermatologists that bacterial growth on the skin plays an important role in causing acne. [ 206 ]  Subsequently, in the 1970s,  tretinoin  (original trade name Retin A) was found to be an effective treatment. [ 210 ]  The development of oral  isotretinoin  (sold as Accutane and Roaccutane) followed in 1980. [ 211 ]  After its introduction in the United States, scientists identified isotretinoin as a medication highly likely to cause birth defects if taken during pregnancy. In the United States, more than 2,000 women became pregnant while taking isotretinoin between 1982 and 2003, with most pregnancies ending in  abortion  or  miscarriage . Approximately 160 babies were born with birth defects due to maternal use of isotretinoin during pregnancy. [ 212 ] [ 213 ]


Treatment of acne with topical crushed dry ice, known as cryoslush, was first described in 1907 but is no longer performed commonly. [ 214 ]  Before 1960, the use of X-rays was also a common treatment. [ 215 ] [ 216 ]


The costs and social impact of acne are substantial. In the United States, acne vulgaris is responsible for more than 5 million  doctor  visits and costs over  US$ 2.5 billion each year in  direct costs . [ 13 ]  Similarly, acne vulgaris is responsible for 3.5 million doctor visits each year in the  United Kingdom . [ 20 ]  Sales for the top ten leading acne treatment brands in the US in 2015 amounted to $352   million. [ 217 ]


Acne vulgaris and its resultant scars are associated with significant social and academic difficulties that can last into adulthood. [ 32 ] [ 218 ]  During the  Great Depression , dermatologists discovered that young men with acne had difficulty obtaining jobs. [ 198 ]  Until the 1930s, many people viewed acne as a trivial problem among middle-class girls because, unlike  smallpox  and  tuberculosis , no one died from it, and a feminine problem, because boys were much less likely to seek medical assistance for it. [ 198 ]  During  World War II , some soldiers in tropical climates developed such severe and widespread  tropical acne  on their bodies that they were declared medically  unfit for duty . [ 198 ]


Efforts to better understand the mechanisms of sebum production are underway. This research aims to develop medications that target and interfere with the hormones that are known to increase sebum production (e.g.,  IGF-1  and  alpha-melanocyte-stimulating hormone ). [ 10 ]  Other sebum-lowering medications such as topical antiandrogens,  peroxisome proliferator-activated receptor  modulators, and inhibitors of the  stearoyl-CoA desaturase-1   enzyme  are also a focus of research efforts. [ 10 ] [ 106 ]  Particles that release  nitric oxide  into the skin to decrease skin inflammation caused by  C. acnes  and the  immune system  have shown promise for improving acne in early clinical trials. [ 106 ]  Another avenue of early-stage research has focused on how to best use laser and light therapy to selectively destroy sebum-producing glands in the skin's hair follicles to reduce sebum production and improve acne appearance. [ 10 ]


The use of  antimicrobial peptides  against  C. acnes  is under investigation as a treatment for acne to overcoming antibiotic resistance. [ 10 ]  In 2007, scientists reported the first  genome   sequencing  of a  C. acnes   bacteriophage  (PA6). The authors proposed applying this research toward the development of  bacteriophage therapy  as an acne treatment to overcome the problems associated with long-term antibiotic use, such as bacterial resistance. [ 219 ]  Oral and topical  probiotics  are under evaluation as treatments for acne. [ 220 ]  Probiotics may have therapeutic effects for those affected by acne due to their ability to decrease skin inflammation and improve skin moisture by increasing the skin's  ceramide  content. [ 220 ]  As of 2014, knowledge of the effects of probiotics on acne in humans was limited. [ 220 ]


Decreased levels of  retinoic acid  in the skin may contribute to comedo formation. Researchers are investigating methods to increase the skin's production of retinoic acid to address this deficiency. [ 10 ]  A  vaccine  against inflammatory acne has shown promising results in mice and humans. [ 52 ] [ 221 ]  Some have voiced concerns about creating a vaccine designed to neutralize a stable community of normal skin bacteria that is known to protect the skin from colonization by more harmful microorganisms. [ 222 ]


Acne can  occur on cats , [ 223 ]  dogs, [ 224 ]  and horses. [ 225 ] [ 226 ]


Angiofibroma  ( AGF ) is a descriptive term for a wide range of benign skin or  mucous membrane  (i.e. the outer membrane lining body cavities such as the mouth and nose)  lesions  in which individuals have:


AGF lesions share common  macroscopic (i.e. gross)  and microscopic appearances. Grossly, AGF lesions consist of multiple papules, one or more skin-colored to erythematous, dome-shaped nodules, or usually just a single tumor. Microscopically, they consist of spindle-shaped and stellate-shaped cells centered around dilated and thin-walled blood vessels in a background of coarse bundles of  collagen  (i.e. the main fibrous component of  connective tissue ). [ 2 ]  Angiofibromas have been divided into different types but commonly a specific type was given multiple and very different names in different studies. [ 2 ]


These papule, nodule, and/or tumor lesions occur on the:  1)  face and are typically termed fibrous papules;  2)  penis and are typically termed pearly penile papules; and  3)  underneath a fingernail or toenail and are typically termed periungual angiofibromas. Some of these cutaneous AGF lesions occur in individuals with one or more of 3 different  genetic diseases :  tuberous sclerosis ,  multiple endocrine neoplasia type 1 , and  Birt-Hogg-Dube syndrome . [ 3 ]  The following are examples of these cutaneous angiofibromas and their alternate names.


Fibrous papules are also termed facial angiofibromas and were formerly and incorrectly termed adenoma sebaceum (fibrous papules are unrelated to sebaceous glands [ 4 ] ). They develop in up to 8% of the general adult population and occur as 1 to 3 [ 5 ]  pink to red, [ 4 ]  dome-shaped papules in the central areas of the face, nose, and/or lips. [ 6 ]  About 75% of individuals with tuberous sclerosis present with fibrous papules in their infancy or early childhood; when associated with this rare disease, the lesions often occur as multiple papules [ 5 ]  in symmetrical, butterfly-shaped patterns over both cheeks and the nose. [ 7 ]  Fibrous papules also occur in individuals with multiple endocrine neoplasia type 1 (a study done in Japan found that 43% of individuals with this genetic disease bore facial angiofibromas) [ 8 ]  and, uncommonly, in individuals with Birt-Hogg-Dube syndrome. [ 9 ]


Pearly penile papules are also termed  papillae coronae glandis  and  hirsutoid papillomas . The condition of having such papules or papillae is called  hirsuties papillaris coronae glandis  or  papillomatosis coronae glandis  or  papillomatosis coronae penis . [ 10 ]  These lesions develop in up to 30% of males during their puberty or, less commonly, early adulthood. They typically occur as numerous white-colored to skin-colored papules located circumferentially around the  corona of the penis  or, less commonly, the ventromedial aspect of the corona near the  penis's frenulum . [ 11 ]  ( Vestibular papillomatosis , also named hirsutoid vulvar papillomas, vulvar squamous papillomatosis, micropapillomatosis labialis, and squamous vestibular micropapilloma, is the female equivalent of pearly penile papules in men. [ 12 ]  It has not been formally termed an angiofibroma.)


Periungual angiofibromas are also termed Koenen's tumors, periungual fibromas, and subungual fibromas. [ 13 ]  In addition, these tumors were formerly regarded as a type of acral angiofibroma (see below description). [ 14 ]  These lesions present as multiple nodules or tumors under multiple finger and/or toe nails of individuals with tuberous sclerosis [ 4 ]  or in one case the Birt-Hogg-Dube syndrome. [ 15 ]  Periungual angiofibromas have also been reported to occur in individuals that do not have these genetic diseases. [ 16 ]  Periungual angiofibromas tumors can be highly mutilating finger/toe-nail lesions. [ 4 ]


Oral fibromas are also termed irritation fibromas, focal fibrous hyperplasia, and traumatic fibromas. [ 17 ]  These lesions are nodules that occur on the buccal mucosa (i.e. mucous membranes lining the cheeks and back of the lips) or lateral tongue. [ 18 ]  They may be irritating or asymptomatic and are the most common tumor-like lesions in the oral cavity. Oral fibromas are not  neoplasms ; they are hyperplastic (i.e. overgrowth) reactions of fibrous tissue to local trauma or chronic irritation. [ 19 ]


Nasopharyngeal angiofibromas, also termed juvenile nasopharyngeal angiofibromas, fibromatous hamartomas, or angiofibromatous hamartoma of the nasal cavity, are large benign tumors (average size 5.9 cm in one study) that develop almost exclusively in males aged 9 to 36 years old. They commonly arise in the  nasopharynx  (i.e. upper part of the throat that lies behind the nose) and typically have attachments to the  sphenopalatine foramen ,  clivus , and/or root of the  pterygoid processes of the sphenoid  bone. These tumors may expand into various other nearby structures including the  cranial cavity . [ 20 ]  Nasopharyngeal angiofibromas are highly vascularized tumors consisting of  fibroblasts  (i.e.  connective tissue  cells) in a dense collagen  matrix  (i.e. tissue background). Studies have suggested that these tumors are due to the expression of male sex hormones (i.e.  androgens  and  progesterones ), genetic factors, molecular alterations (i.e. changes in the normal characteristics of cells that lead to abnormal cell growth), and/or  human papillomavirus infection . [ 21 ]


Angiofibroma of soft tissue is also named angiofibroma, not otherwise specified, by the World Health Organization, 2020. The Organization also classified these lesions as in the category of benign  fibroblastic and myofibroblastic tumors . [ 22 ]  These tumors more often afflict females, [ 23 ]  typically occur in adults (median age 49 years), have a median size of ~3.5 cm, and develop in a leg near to, and may invade, a large joint. Less uncommonly, they occur in the back, abdominal wall,  pelvic cavity , or breast. Angiofibroma of soft tissue tumors consist of uniform, bland, spindle-shaped cells and a prominent vascular network consisting of small thin-walled branching blood vessels in a variably collagenous tissue background. Its tumor cells contain an  AHRR - NCOA2  fusion gene in 60% to 80% of cases and a  GTF2I - NCOA2  or  GAB1 - ABL1  fusion gene in rare cases. [ 24 ]


Cellular angiofibroma is usually a small, slow-growing tumor arising in the  vulva - vaginal  areas of adult woman and the  inguinal - scrotal  areas of adult men although some of these tumors, especially in men, can grow up to 25 cm. Affected men are usually older (7th decade) than women (5th decade). [ 25 ]  Less commonly. cellular angiofibromas have occurred in various other superficial soft tissue areas throughout the body. [ 26 ]  These tumors are edematous (i.e. abnormally swollen with fluid), highly vascular, spindle-shaped cell lesions with a variable amount of fibrous stroma. [ 25 ]  In 2020, the World Health Organization classified cellular angiofibroma tumors in the category of benign  fibroblastic/myofibroblastic tumors . [ 22 ]  The tumor cells in these lesions contain chromosome and gene abnormalities including a loss of one of the two  RB1  genes. It has been suggested that the loss of this gene contributes to the development of cellular angiofibroma tumors. [ 27 ]


Acral angiofibromas are also termed superficial acral fibromyxomas, digital fibromyxomas, acquired digital fibrokeratomas, acquired periungual fibrokeratomas, garlic clove fibromas, [ 28 ]  digital fibromas, and cellular digital fibromas. [ 14 ]  At one time, periungual angiofibromas were regarded as a type of acral angiofibroma (see above description). [ 14 ]  Acral refers to distal sites of the ears, nose, hands, fingers, feet, and toes. Acral angifibromeae occur primarily in areas close to the nails of fingers and toes (~80% of cases) [ 28 ]  or, less commonly, palms of the hands or soles of the feet. [ 14 ]  The tissues of this tumor consists of bland spindle-shaped and star-shaped cells within a  collagen fiber -rich stroma containing prominent blood vessels and  mast cells . [ 28 ]


Angiofibroma of soft tissue  ( AFST ), also termed angiofibroma, not otherwise specified, is a recently recognized and rare disorder that was classified in the category of benign  fibroblastic and myofibroblastic tumors  by the World Health Organization in 2020. [ 1 ]  An AFST tumor is a neoplasm (i.e. growth of tissue that is not coordinated with the normal surrounding tissue and persists in growing even if the original trigger for growth is removed) that was first described by A. Mariño-Enríquez and C.D. Fletcher in 2012. [ 2 ]


AFST tumors typically occur in a leg but can occur in other locations; they develop in older children and adults including elderly individuals. AFSTs are slow-growing, often painless tumors composed primarily of spindle-shaped cells and a prominent vascular network. The spindle-shaped cells are  benign tumor  cells that in almost all cases have  chromosome abnormalities  that are thought to contribute to their abnormal development and/or growth. [ 3 ]


AFST tumors are commonly treated by surgical excision although in uncommon cases they recur at the site of their removal and require further surgical treatment. [ 2 ]  They do not metastasize to distant tissues and overall have a good prognosis. [ 4 ]


AFST tumors commonly present as slowly growing, painless, deep-seated lumps in individuals aged 6 to 86 years old (median age 47-50 years in different studies). [ 4 ]  The tumors are most common in the lower extremities but uncommonly occur in the back, chest wall,  iliac crest ,  groin  and nearby lower lateral abdominal region, [ 4 ]   abdominal cavity ,  pelvic cavity , [ 5 ]  breast, [ 3 ]   cheek ,  temporal region of the head  and, in a report on 24 AFST cases done in Shanghai, the upper limb in 3 cases and, in 1 case each, the  retroperitoneum   and liver. [ 6 ]  The tumors' longest diameters have ranged from 1.2 to 10 cm (mean: 5.1 cm) [ 4 ]  and 0.8 to 14 cm (mean: 4.6 cm) [ 6 ]  in two different studies.


Grossly , AFST tumors, when visible on skin, are located in the skin's  subcutaneous tissue  or the  fascia  layer below the subcutaneous tissue. [ 3 ]  They may be infiltrating deeper into these tissues [ 4 ]  and/or into nearby large joints. [ 3 ]  Regardless of location, however, most of these tumors are well-circumscribed. [ 5 ]


Histopathological  microscopic analyses of  hematoxylin and eosin-stained  AFST tissues generally reveal bland appearing spindle-shaped cells and a prominent small, thin-walled blood vessels network in a background of alternating myxoid  connective tissue  areas and more highly cellular collagen fiber-rich connective tissue areas. (Myxoid indicates areas that appear more blue or purple than normal due to their high uptake of the hematoxylin stain.) Typically, these tumors appear well-circumscribed but some cases show them infiltrating into adjacent normal adipose tissues, connective tissues, skeletal muscles, and/or joints. [ 4 ]   Immunohistochemistry  analyses (i.e. identifying specific proteins in cells using antibodies that bind to these proteins) of AFST tissues detect cells bearing  estrogen receptor ,  CD163   and  NCOA2  proteins in 100% of cases;  MUC1  (also termed EMA) protein in 46% of cases;  desmin  protein in 22% of cases;  ACTA2  (also termed α-SMA),  CD34 , and  STAT6  proteins in 10% or fewer cases, and  S100  and  cytokeratin  proteins in no cases.


In 60-80% of cases, the cells in AFST tumors express the  AHRR - NCOA2   fusion gene . A fusion gene is a hybrid gene formed from two previously independent genes as a result of a  translocation ,  interstitial deletion , or  chromosomal inversion . [ 5 ]  The  AHRR  gene (i.e. gene for the aryl hydrocarbon receptor repressor protein) is located at  band  15.33 on the  short (or "p") arm  of  chromosome 5  (cite designation: 5p15.33); [ 7 ]  The  NCOA2  gene (i.e. gene for the nuclear receptor coactivator 2 protein) is located at band 13.3 on the long (or "q") arm of  chromosome 8  (cite designation: 8q13.3). [ 8 ]  A translocation between these two chromosomes creates the  AHRR-NCOA2  fusion gene (fusion gene designation: t(5;8)(q15;q13)). [ 9 ]   AHRR  is a  tumor suppressor gene  that when fused to other genes is found in the cells of , and thought to promote, various  leukemias  and neoplasms. It is thought to similarly promote the development and/or progression of AFST tumors. [ 4 ]  While most commonly associated with the  AHRR-NCOA2  fusion gene, rare AFST tumor cases have also been shown to be associated with  GAB1 - ABL1 ,  GTF2I -NCOA2, NCOA2- ETV4 , ETV4-AHRR , [ 4 ]  and    NAB2 - STAT6 [ 4 ]  fusion genes.


The diagnosis of AFST depends on its presentation (particularly its location), histopathology (particularly the expression of certain proteins by its tumor cells), and the presence of specific fusion genes (e.g.  AGRR-NCOA2 ) in its tumor cells. Among benign tumors,  cellular angiofibroma  and  solitary fibrous tumor  may be confused with AFST. Cellular angiofibroma differs from AFST in its typical location (i.e.  inguinal ,  scrotal , and  vulva  areas), its distinct histology of rounded, non-branching vessels, high cellularity, and cells with small nuclei, and its tumor cells' loss of the  RB1  gene. Solitary fibrous tumors differ from AFST tumors in their common location in the lungs'  pleurae , their characteristic branching dilated, staghorn-shaped blood vessels, and their tumor cells' expression of CD34 and STAT6 proteins in the majority of the cases. AFTS tumors may also be confused with three malignant tumors,  low-grade fibromyxoid sarcoma ,  myxofibrosarcoma , and  myxoid liposarcoma . Low-grade fibromyxoid sarcomas tend to be less cellular and have less prominent blood vessel than AFST; they also differ from AFST in that their tumor cells commonly express the  MUC4  protein and  FUS-CREB3L1 ,  FUS-CREBL2 , or,  EWSR1-CREB3L1  fusion genes. Myxofibrosarcoma tumors commonly show overt malignant features such as highly infiltrating margins, tumor cells with eosinophilic  cytoplasm , atypical  nuclei , and rapid proliferation rates as evidenced by their high  mitotic indexes . Myxoid liposarcoma tumors consist of round or slightly fusiform cells in a myxoid matrix, vacuolated  lipoblasts  (i.e. cells that are precursors to  fat cells ), and arborizing networks of thin-walled capillaries. [ 3 ]  In all of these cases, the presence of one of the AFST-associated fusion genes cited in the previous section lends support for the diagnosis of AFST. [ 3 ] [ 9 ]


AFST tumors are typically treated by total surgical resection in order to remove all tumor tissue. [ 4 ]  Uncommonly, these tumors have recurred at the site of their removal, particularly in cases where a portion of the original tumor was not removed. [ 5 ]  Recurrences have occurred 4-120 months after the original resections [ 4 ]  and have been treated by a second surgical resection. [ 2 ]  Overall, AFST tumors have a good prognosis. [ 4 ]


Atrophia Maculosa Varioliformis Cutis  (AMVC) is an idiopathic noninflammatory macular  atrophy  subtype that affects young people. Clinically, it is distinguished by a variety of shaped, shallow, sharply demaracated depressions. [ 1 ]


The clinical feature of AMVC is the spontaneous onset of atrophic lesions that are usually on the face of adolescents. These lesions can be round, oval, linear, curvilinear, or rectangular with a regular margin and clearly defined edges. The sites most commonly affected are the bilateral malar regions. However the  mandibular  region and forehead may also be impacted. The absence of prior inflammatory or traumatic events at the lesion site is characteristic of this condition. [ 2 ]  There have been reports of extrafacial involvement, such as lesions on the forearm, posterior aspect of the pinna, and periumbilical area. [ 3 ] [ 4 ]  The lesion may range in size from 0.2-2 cm in length and 0.2-0.5 cm in width; neither exfoliation nor pigmentary changes may be present. They are cicatricial and depressed in comparison to the surrounding skin. [ 2 ]


Although the exact cause of AMVC is unknown, a familial occurrence that has been documented in the past raises the possibility that the condition is inherited rather than the result of an environmental insult. [ 5 ] [ 3 ]  There have been reports of cases linked to  pachydermodactyly  and extrahepatic  biliary atresia , although these links might be accidental. [ 6 ] [ 7 ]


Patients with facial atrophic lesions with well-defined edges and no  erythema , induration, pigmentary changes, or honeycombed pattern are typically diagnosed with AMVC primarily based on clinical findings. With a comparatively normal dermis, a small reduction in or fragmentation of the  elastic fibers , no  fibrosis , and little to no inflammation beneath the shallow depression of the  epidermis , the histological features are nonspecific. [ 8 ]


Autoimmune skin diseases  occur when the  immune system  of an infected animal attacks its own skin. [ 1 ]  In  dogs , autoimmune skin diseases are usually not detected until visible symptoms appear, which differs from detection in humans who are able to verbally express their concerns. [ 2 ]   Genetics , nutrition, and external environmental factors all collectively contribute to increasing the probability an autoimmune skin disease occurring. [ 3 ]  The severity of symptoms varies based on the specific disease present and how far it has progressed. Diagnosis often requires the onset of visible symptoms and for a  biopsy  to be performed. For many diseases, the condition itself cannot be cured, but a veterinarian can prescribe medications and other forms of treatment to help manage the symptoms of the dog. [ 4 ]


The immune system has the ability to differentiate between the  cells  of the body and foreign cells. However, in dogs affected by an  autoimmune disease , the immune system loses the ability to make this distinction, causing the immune system to attack the body. [ 5 ]  Autoimmune diseases in the base layer of the  epidermis  are characterized by damage to the connective tissue and vesicle formation located below the  epidermis  layer and the  dermis  layer below it. [ 6 ] [ 7 ]  There are many autoimmune diseases, and they all vary in impact to the dog and progress at their own rates. [ 8 ]


Dogs suffering from autoimmune diseases of the  skin  may experience a variety of symptoms, including persistent  itching  and scratching, lesions, wounds, blisters, and other skin damage, as well as loss of skin  pigment . [ 5 ]  Two cases of autoimmune diseases that are often found include  Discoid lupus erythematosus  (DLE) and  Pemphigus . DLE can develop into  Systemic Lupus Erythematosus  (SLE). [ 9 ]  The initial stage of DLE is marked by a loss of skin  pigment . The skin becomes red and  sores  appear on the  nose . The  palate  can undergo  erosion , ulceration, and injury to the nasal palate, as well as damage to the nostrils and the tissue around the eyes and ears. In  chronic  and severe cases, visual scar tissue often occurs. [ 9 ]


Most symptoms occur after the outer epidermis and inner dermis of the skin are affected by the disease. When this happens, the layers of the skin begin to separate, leading to painful lesions and pustules. [ 2 ]  The compromised integrity of the skin barrier not only exacerbates the discomfort experienced by the dog, but also heightens the risk of secondary  bacterial  infections. The weakening of the skin's protective layers forms an environment susceptible to  microbial  infiltration, which could lead to severe complications. Intervening within an earlier time frame and targeted management strategies are essential to minimize further adverse effects. [ 10 ]


Another autoimmune skin disease which can occur in dogs is  vitiligo . In addition to humans, vitiligo can be found in a variety of animals, including  cats ,  horses , and  dogs . Vitiligo is a type of autoimmune disease that damages  melanocytes  in the skin, lips, and  oral cavity . Melanocytes are cells that contain pigments such as  melanin . These pigments give rise to an organism's  phenotype , which determines skin and hair color. [ 11 ]  Melanocytes are also found in other parts of the body, such as the oral  mucosa , eye,  cochlea , and the  meninges . In addition to vitiligo, there are other autoimmune diseases that target melanocytes, such as  Vogt-Koyanagi-Harada  (VKH) syndrome, and  Uveodermatological  (UDS) syndrome. [ 12 ]  Vogt-Koyanagi-Harada syndrome is an autoimmune disease that affects the eyes. In addition to depigmentation of the skin, the disease is characterized by a combination of conditions, including uveitis, acute iridocyclitis, choroiditis, and retinal detachment. [ 13 ]


When  pemphigus  occurs in humans, the skin will begin to blister due to  antibodies  attacking the adhesive proteins in epidermal cells, which causes them to separate. Different types of pemphigus can be identified based on the depth of separation present in the skin. Many forms of pemphigus can be identified in dogs using methods similar to those employed for humans. [ 14 ]


Pemphigus vulgaris  is rare in humans and animals, but is often fatal if left untreated. In dogs, the disease presents itself so similarly to the way it occurs in humans that dogs can be used as models for the disease in humans. [ 4 ]  When the disease first begins to manifest itself, lesions are usually evident in the oral cavity of the dog. [ 9 ]  Aside from these blisters, the dog may be mostly  asymptomatic  before the disease progresses further. [ 4 ]  The blisters are easily ruptured and become painful upon doing so, [ 4 ]  which can cause the dog to have difficulty eating. [ 15 ]  As the disease progresses, the infected dog can become severely infirm, and may succumb to further  infection . [ 4 ]  Sometimes symptoms are characterized by  lymphadenopathy , which involves loss of appetite, weakness,  fever , and in rare cases,  sepsis . [ 9 ]


Pemphigus foliaceus  is the most common autoimmune skin disease in dogs, making up around one-third of all canine autoimmune disorders. [ 16 ]  This disease usually affects areas of the ears and face. [ 9 ]  Early symptoms are characterized by  depigmentation  of the nasal  palate , dorsal cleft in the  mouth , the  ear , and the periocular area around the eye. Itching, pain, and weakness of the body have been observed in some cases. Other symptoms of  Pemphigus foliaceus  include hair loss, formation of pustules, and erosions with ulcers. These symptoms can appear on the dog's feet, groin area, and trunk if left untreated. [ 16 ]


The immune system functions in many ways to eliminate foreign substances and particles introduced to the body. This revolves around  T-cell  differentiation, where mature T-cells with receptors for non-self cells target foreign  antigens  and act with other cells to dispose of them. [ 17 ]  There are two mechanisms of tolerance found in the immune system. [ 6 ]  The first mechanism is positive selection by the  thymus , where only  T-cells  are selected. T-cells recognize  peptides  in the  Histocompatibility Complex  (MHC). [ 6 ]  The second mechanism is negative selection, where T-cells that recognize self-antigens with too high an affinity are removed through the process of  apoptosis  and are not allowed to enter the body's circulation.


Incidences of autoimmune skin diseases can vary based on several factors. Some of these factors include the  breed , age, and sex of the dog, along with individual genetics and environmental factors. [ 3 ]


In terms of vitiligo, certain breeds of dogs have a higher chance of developing the disease based on their genetics. These breeds include  Rottweilers ,  German Shepherds ,  Old English Sheepdogs ,  Doberman Pinchers ,  Dachshunds , and  German Shorthaired Pointers . [ citation needed ]  However, the exact prevalence of this disease in dogs is currently unknown, as it is likely under-reported. [ 2 ]  Certain dog breeds that have been documented with Vogt-Koyanagi-Harada (VKH) syndrome include Akitas, Samoyeds, Irish Setters, Golden Retrievers, Saint Bernards, Australian Sheepdogs, and Shetland Sheepdogs. [ 13 ]