Acne

Acne, or acne vulgaris, is a chronic inflammatory skin disease of the immune system-linked pilosebaceous unit, the hair follicle and its attached sebaceous gland. Its visible forms include comedones, papules, pustules, nodules and cysts, and it occurs most often on the face, back and chest. It is one of the most frequently encountered skin conditions worldwide, with high prevalence in adolescence and a substantial minority of cases persisting into adult life. Because it is common, long-lasting and visible, acne matters for public health and for individual quality of life. Its scars can be permanent, and the condition is closely associated with depression and anxiety.

Acne is best understood as a multifactorial disease. Four processes interact: excess sebum production, abnormal follicular hyperkeratinization, colonization by bacteria (notably Cutibacterium acnes), and a local inflammatory response. Androgens, genetic predisposition and environmental factors modify these processes. The article covers how these mechanisms were established, how the disease is classified and graded, and how it is diagnosed and treated. Treatments range from topical agents and systemic antibiotics to isotretinoin, hormonal therapy and procedures, and the choice among them is guided by severity, scarring risk and patient characteristics. The entry also addresses the growing concern over antibiotic resistance, the psychosocial burden of the disease, and current research directions.

Clinical features and lesion types

Primary lesions and how they relate

Acne lesions are organised around the pilosebaceous unit, the hair follicle together with its attached sebaceous gland. The lesions fall into two broad groups. Comedones are dilated hair follicles filled with sebum, desquamated keratinocytes, and bacteria. Open comedones (blackheads) have a follicle that stays dilated at the surface, so their plugs are readily extruded, whereas closed comedones (whiteheads) are sealed at the surface and their contents are harder to remove depending on whether the follicle is dilated or closed at the skin surface. Although comedones look non-inflammatory, they are the precursors of inflammatory lesions. When the follicle is colonised by bacteria such as Cutibacterium acnes, sebum is broken down into free fatty acids that irritate the follicular lining and attract inflammatory cells. The follicle may then rupture into the dermis, producing papules, and intense reactions produce purulent pustules eliciting an inflammatory response by neutrophils and then lymphocytes, which further disrupts the epithelium.

Deeper inflammatory lesions are nodules and cysts. Some deep comedones, sometimes called submarine comedones, are deep comedones with a diameter >5mm, often develop into nodular lesions. In the most severe disease, neighbouring nodules can connect beneath the skin and form large, deep sinuses. The lesion types are therefore best seen as a continuum rather than as separate diseases: several types of acne spots occur, often at the same time.

Mixed presentation

Most patients do not present with a single lesion type. Comedonal presentations, in which patients develop open and closed comedones with few inflammatory lesions, represent one end of a spectrum, while the great majority of patients have comedones alongside papules, pustules, and sometimes nodules. This mixture is why counts of non-inflammatory and inflammatory lesions are used together in clinical assessment and research, as discussed in the diagnosis and grading sections.

Distribution and sebaceous density

The face is the most frequently affected site, but it may spread to involve the neck, chest and back, and sometimes even more extensively over the body. The pattern follows sebaceous anatomy: acne vulgaris typically affects the areas of skin with the densest population of sebaceous follicles; these areas include the face, the upper part of the chest, and the back. Sebaceous glands are largest and most numerous in these regions, so they supply the greatest volume of sebum to the follicles, which is the substrate on which the early plugging process depends. Within the face, the pattern varies: in many patients, acne may predominate along the oily T-zone on the forehead, nose, and chin. In others, acne may predominate on the lower parts of the face, such as the cheeks and jaw, which is consistent with a hormonal distribution. Comedones can be difficult to recognise in darker skin, where skin-colored comedones may be difficult to appreciate and lead to incorrect or delayed diagnosis of acne.

Superficial and deep inflammatory lesions

Clinical descriptions usually separate lesions by depth. Superficial lesions include open and closed comedones (blackheads and whiteheads), papules (small, tender red bumps), and pustules (white or yellow "squeezable" spots). Deeper lesions include nodules (large painful red lumps) and pseudocysts (cyst-like fluctuant swellings). Deep lesions are typically more painful, persist longer, and carry a greater risk of scarring than superficial ones, which is why their presence is recorded separately.

Size thresholds

The boundary between papule and nodule, and between a pustule and a cyst, depends on the scheme used. Clinical trial protocols provide the most explicit definitions, and they do not agree. In one protocol, a papule is a small, solid elevation less than 5 mm in diameter. Most of the lesion is above the surface of the skin. and a nodule is an inflammatory lesion greater than or equal to 5 mm in diameter. Other protocols use a 10 mm cut-off, where a nodule is a firm (indurated) lesion greater than 10 mm in diameter and that is thicker or deeper than the average papule, or a 1 cm cut-off, where a nodule/cyst [is] generally more than 1.0 cm in diameter. Clinical texts commonly use the 5 mm threshold, under which nodulocystic acne is characterized by comedones, inflammatory lesions, and large nodules and cysts greater than 5 mm in diameter. Because these thresholds differ, comparisons between studies require care. Trial entry criteria also limit deep lesions; one protocol required that patients have two (2) or fewer cysts or nodules.

Classification, grading and variants

Common clinical categories

Clinical classification sorts acne by the lesion types that predominate and by how many are present, not by cause. Guideline authors describe a continuous range rather than separate diseases, with comedone-dominant cases at one end and deep, nodular, scarring disease at the other, as summarised in the German S3 guideline's account of a spectrum from mild comedonal acne to conglobate or fulminant disease with deep-seated inflammation. Two schemes are widely used. The Global Alliance system divides acne into 5 types according to severity (mild comedonal, mild papulopustular, moderate papulopustular, moderate nodular, and severe nodular), while the European four-level scale merges these into broader groups.

Severity grading has a longer history. A four-grade scale was established by Pillsbury, Shelley, and Kligman in 1956, based on overall lesion counts. Later count-based systems grade comedones and inflammatory lesions separately. One version counts lesions per half face: comedonal grade 1 is fewer than 10 comedones, grade 2 is 10 to 25, grade 3 is 25 to 50, and grade 4 is more than 50, while papulopustular grade 4 begins above 30 inflammatory lesions. The overall severity is graded from Grade 1 to Grade 4 depending on the number of lesions. Visual descriptors, such as whether lesions are hardly visible from 2.5 m away, are used alongside counts in other scales.

Size thresholds also vary. Superficial inflammatory lesions include papules and pustules (5 mm or less in diameter), and nodules are defined as firm, painful inflamed lesions larger than 10 mm. Other sources place the nodule threshold at 5 mm, so the cut-off depends on the document used.

Variants and special forms

Acne conglobata is a rare severe form. It is found most commonly in adult males, with few or no systemic symptoms, and it typically involves the trunk and upper limbs, with grouped comedones, sinus tracts and tissue destruction.

Acne fulminans is an abrupt, ulcerative, systemic variant. It is a rare and very severe form of acne conglobata associated with systemic symptoms, and it is most common in adolescent males between 13 and 22 years old. Its defining features include sudden onset, painful ulcerated chest and back lesions, fever and polyarthritis, and failure to respond to antibacterial therapy. Osteolytic bone lesions are described, and isotretinoin can precipitate the condition. Conglobate disease lacks this systemic pattern, and acne fulminans is distinguished from it partly by the absence of polyporous comedones.

Neonatal and infantile acne are defined by age of onset, and the sources differ on details. Neonatal acne usually appears within the first weeks of life. Sources disagree on whether it includes comedones: one describes superficial pustules on the face, neck and upper trunk of healthy newborns, with no comedones, while another describes open and closed comedones on the cheeks, chin and forehead. Infantile acne begins later in infancy. Reported onset ranges from roughly three to six months, to two months to one year, and it may include comedones, papules and pustules, and occasionally nodules and cysts. Its longer duration and greater inflammation carry a risk of scarring, and babies who experience infantile acne face an increased risk of developing severe acne in adolescence and later life.

Acne mechanica is caused by friction, pressure and occlusion, for example from helmets, chin straps, shoulder pads or tight collars. Papules and pustules appear in the areas that are repeatedly in contact with the equipment, and the lesions usually improve once the mechanical source is removed.

Early onset and mid-facial comedones

Longitudinal studies have linked early onset and comedones concentrated on the mid-face to a more persistent and severe course. The mechanism is not established. Possible explanations include a stronger genetic or androgenic load in these patients, but these are associations rather than proven causes, and follow-up studies are affected by attrition and recall bias.

Limits of classification

Categories overlap in practice. Comedones, papules and pustules often coexist, and grade boundaries are partly arbitrary. Scoring systems also disagree, as the thresholds for mild and moderate disease differ between scales. Clinicians usually handle this by using the most severe feature present as a guide, while allowing for isolated lesions. For example, one grade-3 description allows up to many non-inflammatory lesions and may have some inflammatory lesions, but no more than one small nodular lesion, so a single nodule does not automatically move a patient to a higher category.

Epidemiology and natural history

Prevalence and age pattern

Estimates vary with population and method, but acne is among the most common skin disorders. In the Global Burden of Disease (GBD) 2010 analysis it ranked eighth among skin diseases, with a global all-age prevalence of 9.38% The Global Burden of Disease Study 2010 found that acne vulgaris (henceforth acne) is the eight most common skin disease, with an estimated global prevalence (for all ages) of 9.38%. Among adolescents, reported figures range widely, from 35% to close to 100% of adolescents having acne at some point.

Onset follows puberty, when sebum output rises The onset of acne typically correlates with the onset of puberty, when sebum production increases. Prevalence peaks in the teenage years and then declines After reaching the late teenage years or young adulthood, acne prevalence rates follow a decreasing trend with increasing age. In the GBD 2021 analysis of people aged 10–24, adolescents aged 15–19 years had the highest age-specific prevalence rate, while adolescents aged 10–14 years experienced the largest increase from 1990 to 2021. Incidence peaks earlier: the age-specific global incidence rate of acne vulgaris peaked in individuals aged 10 to 14 years and decreased with age. Because prevalence reflects how long cases last as well as how many begin, the two curves peak at different ages.

Persistence into adulthood

Acne is no longer seen as confined to adolescence. Acne can persist into adulthood or set-up de novo in older persons. One summary of epidemiological data gives a prevalence of approximately 50% in women in their twenties and up to 26% in women in their forties. Persistence rates differ by population: a Taiwanese study found acne continuing into adult years in 38 percent of women and 46 percent of men.

Clinicians often separate adolescent acne from adult-onset ("late-onset") disease. In one claims-based German analysis, the cut-off was age 25, and adolescent acne (younger than 25 years) was more frequent than adult acne (older than 25 years). Adult-onset and persistent disease share a relapsing course, and adult-onset disease is more often hormonal, with lesions on the lower face and jawline Adult-onset or persistent acne tends to follow a chronic, relapsing course and disproportionately affects women, who are more likely to present with hormonal and inflammatory subtypes involving the lower face and jawline. One systematic review suggests the prolonged adult course may weigh more heavily on quality of life than adolescent disease the often chronic and relapsing course of adult acne may be more detrimental to patient QoL.

Sex differences

Sex differences depend on age and on the study. In GBD 2010 estimates, the prevalence of acne was 8.96% in males, lower than the estimated prevalence of 9.81% in females. A systematic review of individual studies, however, found mixed results: only two papers revealing a higher odds of acne in females while another three demonstrated a higher odds of acne in males, and the pooled odds ratio for males versus females was close to 1 (a pooled odds ratio of 1.07 (95% CI 0.42–2.71) was obtained for sex (males with reference to females)). Earlier puberty in girls has been proposed to explain higher rates at younger ages Lynn et al. also noted higher acne prevalence in females at younger ages, possibly due to the earlier onset of puberty in females relative to males.

In young adults the pattern is clearer. Globally, the age-standardized prevalence rate of acne vulgaris in 2021 was approximately 25% higher in young women than in young men, although the gender gap in rates has narrowed slightly during the past 30 years. In one Asian comparison, adolescent acne was more common in males, but adult acne was more common in females in the same study.

Regional variation

Recorded prevalence is highest in high-development settings. GBD-based analyses report that the prevalence of acne was greatest in countries with a high sociodemographic index (SDI), particularly Western Europe, East Asia, and high-income areas of the Asia Pacific. The regions with the lowest prevalence rates were Central Europe, Tropical Latin America, and Central Asia. Within Asia, a Chinese survey found acne in 50.2 percent of primary and secondary school students and 44.5 percent of university undergraduates. Differences between countries may partly reflect how often people seek care, not only how often disease occurs.

Burden and study design

GBD analyses measure burden through prevalence, incidence and disability-adjusted life years (DALYs). Using the 2021 data, the number of prevalent cases of acne vulgaris in adolescents and young adults increased globally by 39.2%, from 132.4 million in 1990 to 184.3 million in 2021. Estimates depend heavily on methodology. A systematic review noted that the 35 articles reviewed differed in study design, acne definition and severity grading systems, variables studied and population characteristics. Measurement choices also change the result. A Korean-style claims analysis gives a lifetime prevalence of 73.3%, while point prevalence is a postulated global point prevalence of 9.4%. In a German cohort of teenagers, self-report gave a much higher figure than dermatologist assessment: acne was self-reported in 83.4 percent of subjects, whereas the objective prevalence was 63.6 percent, with 29.2 percent non-inflammatory and 34.4 percent inflammatory acne.

Pilosebaceous unit and sebum production

Anatomy of the pilosebaceous unit

The pilosebaceous unit is the structure formed by a hair follicle and the sebaceous gland attached to it. Each gland drains through a short sebaceous duct that opens into the upper part of the follicle, the infundibulum. Sebum therefore leaves the gland, rises along the follicular canal beside the hair shaft, and spreads over the skin surface. Sebaceous glands are largest and most numerous on the face, scalp, upper chest and back, which is why the lesions of acne cluster in these areas (see acne clinical features). The gland is holocrine. Sebocytes, the gland's specialised cells, are generated at the periphery, move toward the centre, accumulate lipid, and then die, releasing their entire contents as secretion. Sebum output therefore depends on continuous renewal of the sebocyte population, and the gland's activity is set by how fast that renewal and lipid loading proceed.

Androgen control and puberty

Androgens, mainly testosterone and its more potent derivative dihydrotestosterone (formed in the gland by 5α-reductase), act on androgen receptors in sebocytes. This signal enlarges the gland, increases the number of cells and raises lipid synthesis per cell. Before puberty, sebaceous glands are small and secrete little sebum. The rise in adrenal androgens (adrenarche) and the activation of gonadal steroid production (gonadarche) enlarge the glands and increase their output steeply during early adolescence, with the greatest activity usually reached in the mid to late teens. Sebocytes also respond to insulin and insulin-like growth factor signalling, which is discussed in the risk-factor section. Androgen sensitivity, rather than androgen concentration alone, appears to determine how strongly an individual gland responds.

Composition of sebum and de novo lipogenesis

Sebum is a complex lipid mixture with no protein component and little phospholipid. Measured compositions in human sebum report that triglycerides and free fatty acids together make up roughly 50–60%, wax esters 20–30%, squalene 10–16% and cholesterol esters 2–4%. Its fatty acids are mainly saturated and monounsaturated chains, a profile that differs from that of circulating lipids.

Sebocytes can obtain fatty acids either from blood lipoproteins or by synthesising them internally through de novo lipogenesis (DNL), in which acetyl-CoA is converted into fatty acids inside the cell. Stable-isotope studies in healthy volunteers showed that the principal source of sebum palmitate is DNL in the gland itself, with sebum palmitate turning over far faster than the palmitate carried in circulating very-low-density lipoprotein. A 2018 study by Esler and colleagues combined human skin samples with isotope tracing and reported that most human sebum is generated by DNL rather than recycled from circulating lipid, and that DNL was increased in acne and reduced by acetyl-CoA carboxylase inhibition. Estimates cited in later reviews place the DNL contribution to the principal sebum fatty acids, palmitate and sapienate, at around 80–85%. These estimates come from a limited number of human studies and are not uniform across individuals or body sites.

Metabolic and enzymatic pathways

DNL begins with acetyl-CoA carboxylase (ACC), which converts acetyl-CoA into malonyl-CoA; this is the committed and rate-limiting step. Fatty acid synthase then elongates the chain, mainly to palmitate (C16:0). Stearoyl-CoA desaturase introduces double bonds to produce monounsaturated fatty acids, and the desaturase FADS2 acts on palmitate to form sapienic acid (C16:1n-10), a characteristic sebaceous fatty acid with antibacterial activity. Wax esters are assembled from fatty acids and fatty alcohols, and squalene is produced through the mevalonate pathway. Transcription factors of the SREBP family coordinate these enzymes, and their activity is sensitive to nutritional and hormonal inputs.

Recent work describes sebocytes as metabolically active cells that draw nutrients from the blood and direct them toward sebum synthesis. Alongside DNL, glycogen turnover, glutamine-driven anaplerosis and the pentose phosphate pathway, which supplies the NADPH required for reductive synthesis, are proposed to fuel this process. The high metabolic demand of holocrine secretion may therefore be a mechanistic component of sebum production in its own right. The degree to which these pathways are altered in acne, and whether they are suitable targets for therapy, is addressed in the emerging-research section.

Follicular hyperkeratinization and comedogenesis

Failure of keratinocyte shedding and follicular plugging

The infundibulum, the upper part of the follicle, is lined by keratinocytes that normally separate and slough off so that sebum can reach the surface. In acne, these cells stay cohesive. Studies of the process describe the earliest change as an alteration of the infundibular wall at the junction with the sebaceous duct, where ductal keratinocytes proliferate and the spaces between their corneocytes shrink (The first step for comedogenesis is an epithelial wall alteration of the infundibulum, specially at the junction of the sebaceous gland duct with ductal keratinocytes hyperproliferation and reduced spaces of ductal corneocytes.). Ultrastructural observations add that follicular keratinocytes in comedones carry more desmosomes and tonofilaments, a feature linked to ductal hypercornification (follicular keratinocytes in comedones can be seen to possess increased numbers of desmosomes and tonofilaments, which result in ductal hypercornification.). The retained cells build up in the duct, and the obstruction typically lies in the infra-infundibulum, below the opening of the follicle (Obstruction of the pilosebaceous follicle canal takes place in the infrainfundibulum. This is due to anomalies in the proliferation, adhesion and differentiation of keratinocytes which do not detach from each other and block the lumen of the canal.).

From microcomedone to open and closed comedones

The earliest visible-precursor lesion is the microcomedone, which is usually too small to see clinically. Its interior is largely lipid containing clusters of bacteria, enclosed by a shell of corneocyte layers (The interior of microcomedones is mostly composed of lipids with clusters of bacteria, and their outer shell is made up of corneocyte layers). The expanding keratin mass is confined within a narrow space, and this pressure may reduce oxygen availability and favour the multiplication of C. acnes and further lipid accumulation (Due to increasing pressure from the expansion of the keratin layer in a confined space, hypoxia may facilitate the multiplication of C. acnes and lipid accumulation). The number and size of microcomedones correlate with acne severity, which is why they are treated as a measure of comedogenesis (There is a significant correlation between the severity of acne and the number and size of microcomedones (follicular casts), the presence of which is a measure of comedogenesis.). As the plug enlarges, the outcome depends on whether the follicular opening remains patent. A plug that reaches the surface through a open orifice forms an open comedone (blackhead), whose dark colour arises from oxidised lipid and melanin in the plug rather than from dirt. A plug sealed beneath a thin layer of epidermis forms a closed comedone (whitehead). Topical retinoids act at this stage, normalizing keratinization and inhibiting the formation of microcomedones (Products with retinoid activity, such as tretinoin, adapalene and tazarotene, normalize follicular keratinization, inhibit formation of microcomedones, decrease formation of inflammatory lesions, and speed resolution of comedones.).

Changes in follicular contents and lipids

Normal human sebum is a mixture in which triglycerides and fatty acids, taken together, account for the predominant proportion (about 57.5%), followed by wax esters (about 26%) and squalene (about 12%). Several alterations have been reported in acne. Linoleic acid is lower in acne sebum, and linoleic acid is a precursor of squalene and wax esters (Levels of linoleic acid, an essential fatty acid that is the precursor to squalene and wax esters, are lower in AV sebum). Squalene, in turn, is raised: in one pilot comparison it was upregulated in acne subjects by 2.2 fold on a quantitative basis. Oxidation of squalene produces squalene peroxide, which has been linked to comedogenesis and inflammation (squalene peroxide, a by-product of lipid peroxidation derived from sebum, has been recognized to play a crucial role in the development of inflammatory reactions as well as in cytotoxicity and comedogenesis.). Ceramide deficiency has been tied to barrier dysfunction and the hyperkeratinization that drives comedone formation (Ceramide deficiency contributes to skin barrier dysfunction, which has been directly tied to the follicular hyperkeratinization that drives comedone formation.). Comedo contents also differ markedly from surface lipid: in a small analysis of three patients, for the comedo, 90% of this sum was free fatty acids compared with only 25% for surface lipid. Some observations point the other way; for example, one study reported that the changes in sebum excretion rate and squalene were statistically significant only in women, but acne in men was associated with a significant decrease in the free fatty acid content or surface lipid. Such findings are based on small samples and have not been reconciled into a single model of which lipid change is decisive.

Factors governing the rate of comedogenesis and its link to inflammation

The rate of plug formation depends on the level of androgen-driven sebum output, the composition of sebum, and local signalling that stimulates keratinocyte proliferation. The alteration of the follicle microenvironment is thought to prompt resident cells to release pro-inflammatory cytokines (The alteration of the follicle microenvironment stimulates skin-resident antigen presenting cells (APCs), sebocytes, and keratinocytes to produce proinflammatory cytokines, such as IL-1 b, IL-6, and TGF-b.). Interleukin-1α has received particular attention: high levels were reported in acne lesions, and exposure of isolated infundibula to IL-1α in vitro induced comedone formation (High levels of the pro-inflammatory cytokine IL-1α were reported in acne lesions in vivo, and previous work revealed that exposure of isolated infundibula and pilosebaceous units to IL-1α in vitro induced comedone formation). Toll-like receptor signalling in keratinocytes has been proposed as an upstream trigger for this release (TLR activation and secretion of IL-1α from keratinocytes may be initiating steps in comedogenesis and, therefore, critical to the pathophysiology of acne.). A reduction in linoleic acid is also thought to increase skin permeability, which allows inflammatory substances to enter and promotes comedogenesis (Decreased linoleic acid disrupts the skin barrier, allowing higher permeability for inflammatory substances and increased comedogenesis). The traditional view placed hyperkeratinization first, with inflammation following; the present interpretation treats the two as interacting processes, with inflammatory changes sometimes detectable before a microcomedone is visible.

Cutibacterium acnes and the microbial role

Ecology and colonization

Cutibacterium acnes (formerly Propionibacterium acnes) is a Gram-positive, non-spore-forming commensal that prefers anaerobic growth conditions. It is a normal member of the skin flora, but its numbers are low on the skin of young children: it is usually barely detectable on the skin of healthy preadolescents. Colonization rises at puberty, when sebum output increases. The bacterium concentrates in the pilosebaceous follicle, where it lives primarily on fatty acids in sebum. Studies comparing acne-affected skin with healthy skin have not consistently found a higher total load of the organism in acne. One analysis reported no difference in the load of C. acnes between the two groups, which led to the proposal that a shift in the microbial community, rather than an excess of this one species, may matter more.

Phylotypes and strain-level differences

The species is divided into six phylotypes: IA1, IA2, IB, IC, II, and III. Phylotype IA1 is the one most closely associated with acne. It predominates in isolates from moderate to severe acne, whereas IB, II, and III are more commonly isolated from soft tissues and medical implant infections. Acne-affected skin also differs in the variety of strains present. Loss of phylotype diversity, with enrichment of IA1 and reduction of II, correlates with severity, and the authors of one review summarize the principle as "quality over quantity," in which strain-specific pathogenicity is crucial. Phylotype II has been linked to healthy skin, which suggests a commensal role, possibly in competition with the pro-inflammatory phylotype IA1. Metagenomic work has found that the strain structure of C. acnes in acne patients differs from that of healthy individuals, despite their similar relative abundances. IA1 strains also produce more of several virulence-related traits, including enhanced biofilm formation, stronger adhesion to keratinocytes, and elevated secretion of pro-inflammatory factors. The role of IB and IC in acne is less clear.

Mechanisms of inflammation

The bacterium's products appear to drive inflammation in several ways. Its lipases act on sebum: free fatty acids produced when the bacterium breaks down sebum lipids accelerate the inflammatory reaction. Other secreted enzymes, including proteases and CAMP factors, can trigger inflammation and host tissue damage. Bacterial proliferation in the follicle also induces upregulation of proinflammatory cytokines by keratinocytes, sebocytes, or peripheral blood mononuclear cells. In vitro, IA1 has been shown to markedly elevate interleukin-6 in keratinocytes, and bacterial extracellular vesicles can induce an acne-like inflammatory response in skin models. Adaptive responses have also been reported: Th17 and Th17.1 cells were found in higher frequencies in the blood of acne patients than in healthy individuals. These findings come largely from cell culture, animal and small clinical studies, and their relevance to the in vivo lesion is still being tested.

The cause, consequence or modifier debate

The role of the bacterium is contested. One position holds that most published data point to a causal role for C. acnes phylotype IA1 in acne inflammation. Supporting this view is the fact that antimicrobial treatments reduce lesions, and some newer materials that selectively remove IA1 have reduced non-inflammatory lesions. A competing view places the origin of the lesion elsewhere. Comedones are regarded as the first lesion, and new genetics and molecular biology findings strongly suggest that abnormal differentiation of sebaceous progenitor cells causes comedones. On this account, the organism probably doesn't affect sebaceous differentiation. A related "comedo switch" hypothesis proposes that sebaceous gland atrophy leads to abnormal sebum composition, promoting the growth of pro-inflammatory C. acnes phylotype IA1, but critics note that it does not explain what triggers the aberrant signaling that causes the switch. Some authors therefore treat the bacterium as a modifier that amplifies an existing process, and suggest a feed-forward loop between the host and the bacterium that may well contribute to acne's chronic course. The question carries practical weight, since antibiotic use for acne noticeably contributes to microbial drug resistance.

Inflammation and immune response

Innate reaction: neutrophils and macrophages

Inflammatory acne begins when the follicle wall gives way. Once it does, the contents of the follicle spill into the surrounding dermis and set off a fast local reaction. Eventually, the rupture of the follicular walls causes extrusion of the content and a rapid inflammatory response. The cells that respond are largely recruited rather than resident. Neutrophils are not cells residing in the skin, but they accumulate in the skin in the course of inflammation. Time-course biopsies show their numbers climbing in lesions aged roughly 24 to 72 hours, the stage at which the lesion becomes clinically a pustule. Neutrophils emerge increasingly numerous in the 24 h and 72 h lesions, which are then clinically classified as pustules. Neutrophil-derived oxidants are proposed to weaken the follicular lining and push a papule toward suppuration, although this mechanism rests mainly on indirect evidence.

Macrophages play a dual part. They help clear <i>C. acnes</i> and regulate local lipids, but an excessive response can aggravate inflammation and contribute to scarring. Their vital functions include the regulation of lipid concentrations and facilitating the elimination of C. acnes. However, an immoderate immune reaction can provoke inflammation and subsequent acne scarring. Bacterial lipase oxidises lipids that accumulate in the pilosebaceous unit, and macrophages that take up these oxidised lipids become foam cells. Lipids that accumulate in the PSU are oxidized by C. acnes lipase, and macrophages can phagocytose oxidized lipids, consequently becoming foam cells. These foam cells express TREM2 and infiltrate in acne lesions. A TREM2-expressing macrophage subset appears to have limited antimicrobial capacity, which allows bacterial load to rise and promotes release of IL-18 and other chemokines.

Cytokines and signalling amplification

<i>C. acnes</i> acts on the innate immune system through several routes. At least four major pathways have been described by which Cutibacterium acnes interacts with the innate immune system to induce inflammation: through TLRs, activating inflammasomes, inducing the production of matrix metalloproteinases (MMPs), and stimulating antimicrobial peptide (AMP) activity. Through Toll-like receptor 2 in particular, the bacterium drives keratinocytes, sebocytes and monocytes to release a range of cytokines. Laboratory work has linked this output to NF-κB and MAPK signalling and to the NLRP3 inflammasome, and it has been observed in vivo in lesions. P. acnes is able to induce in vitro production of proinflammatory molecules (interleukins IL-1α/β, IL-8, IL-12, TNF-α, β-defensins) by the keratinocytes, sebocytes and monocytes but also in vivo in the acne lesions. This production is thereby via the TLR-2 receptor and the activation of the NF-κB and MAPK signaling pathways as well as via the NLRP3 inflammasome pathway.

Several cytokines have distinct roles. IL-1α appears to be an early actor: TLR activation and secretion of IL-1α from keratinocytes may be initiating steps in comedogenesis and, therefore, critical to the pathophysiology of acne. IL-8 and IL-12 have complementary effects. IL-8 contributes to the recruitment of neutrophils and further damage to the epithelium of sebaceous glands, whereas IL-12 promotes Th1-type response. A Th17 axis also appears to be engaged. IL-17A, a proinflammatory cytokine, increases CXC ligand (CXCL)8 production in epithelial cells and activates fibroblasts to recruit neutrophils. Type I interferon is another amplifier: C. acnes can also stimulate type I interferon (IFN-I) synthesis via the wiring of a TLR2-TRIF pathway in human macrophages. In addition, IFN-I stimulates and amplifies the secretion of chemokines and other immune mediators, contributing to inflammatory responses. Together these signals recruit more immune cells and sustain a feed-forward loop, and the bacterium's own enzymes add direct tissue injury. The bacterium produces lipase, hyaluronidase, and proteases and activate immune cells, thus causing inflammation.

Adaptive immunity and T cells

Lymphocytes contribute alongside the innate cells. Early lesions are dominated by CD4+ T-cells, the major leukocytes in the early (6–72 h) inflammatory infiltrates in acne lesions. Some authors propose that lymphocytes may play a more central role in early acne lesions than neutrophils, which are strongly attracted after the follicles have been disrupted. The Th17 pathway is one candidate for this role, since IL-17A positive T cells and the activation of Th17-related cytokines have been detected in lesions. CD8+ cells appear in later lesions. Humoral responses may also take part. Specific anti-<i>P. acnes</i> antibody could in principle activate complement and attack neutrophils due to C5A production, and a type IV cellular response has been postulated, although its contribution remains unproven.

Inflammatory changes in apparently uninvolved skin

Immune activity is not confined to visible lesions. Inflammatory cells have been reported in clinically normal skin of patients. Additionally, other inflammatory cells, especially CD4+ T cells and macrophages, are also observed in the perifollicular region and dermis in acne-uninvolved skin. Sampling of non-lesional skin also finds microcomedones, the earliest structural precursor of lesions. Analyses demonstrate the linear relationship between higher microcomedone index scores (i.e., the number and size of the microcomedones) and the appearance of inflammatory and non-inflammatory lesions. These observations suggest that immune changes may precede clinically apparent lesions and that the early disease process is not purely a surface event. The same skin, however, does not become inflamed merely because it carries the same microbes. Healthy skin does not exhibit inflammation or skin lesions, even in the continuous presence of the same microbes. What separates the two states, and whether the subclinical immune activity is cause or consequence, remains open.

Genetic, hormonal and environmental risk factors

Heritability and genetic loci

The strongest evidence for a genetic component comes from twin and family studies. Heritability has been consistently estimated at around 80% in twin studies. In an Australian cohort of 4,491 twins and siblings aged 10 to 24, the polychoric correlation was 0.86 for monozygotic pairs and 0.42 for dizygotic pairs, and the best-fitting model gave a heritability of 0.85 for acne severity (r MZ = 0.86, 95% CI [0.81, 0.90]) than for dizygotic twins (r DZ = 0.42, 95% CI [0.35, 0.47]). Earlier twin work reported concordance of 98% in monozygotic pairs against 46% in dizygotic pairs in a study of 95 pairs of twins with acne. Family history also tracks with clinical course: a family history of acne is associated with earlier onset, more retentional lesions, and a higher risk of relapse after oral isotretinoin.

Genome-wide association studies (GWAS) have identified a growing set of risk loci. A 2022 meta-analysis of 20,165 cases from nine European-ancestry cohorts identified 29 novel genome-wide significant loci and replicated 14 of the 17 previously identified risk loci, bringing the total number of reported acne risk loci to 46. A 2023 meta-analysis reported two novel loci, 11q12.2 and 17q25.3, that contain genes encoding key enzymes involved in lipid biosynthesis pathways, and pointed to Wnt and MAPK signalling as candidate pathways. Studies of disease severity have been far fewer and less consistent. The Australian twin GWAS did not reach genome-wide significance for severity, although suggestive signals were found near PIK3R1, a gene that has a potential regulatory effect on sebocyte differentiation. Replication across cohorts is also uneven; a UK cohort did not detect association at 8q24 or any of the loci reported for the earlier study group.

Hormonal and insulin–IGF-1 signalling

Acne is closely tied to puberty. It becomes manifest relatively late in puberty, at or shortly after peak height velocity in boys and menarche in girls. Insulin-like growth factor 1 (IGF-1) is a central candidate mediator: IGF-1 is overexpressed in the epidermis and pilosebaceous units of acne patients compared to controls, and increased serum IGF-1 levels correlate with acne lesion counts in females and with increased sebum secretion rates in male acne patients. Insulin and IGF-1 both act through the insulin receptor and IGF-1 receptor, eliciting common downstream signalling through the PI3K–AKT–mTORC1 pathway. Within this model, hyperinsulinemia suppresses insulin-like growth factor-binding protein 3, raising free IGF-1 activity and sebum production, and mTORC1 activation promotes sebaceous gland growth, lipid synthesis and keratinocyte proliferation. Supporting observations include the reported absence of acne in individuals with Laron syndrome, a GH receptor defect with low IGF-1 levels who never develop acne. Acne is also associated with insulin-resistant states, especially polycystic ovary syndrome (PCOS), which results in hyperinsulinemia. Pharmacological evidence is limited: in a 12-week randomised open-label study, metformin was evaluated as an adjunct for moderate to severe facial acne, and the proposed rationale is that its mTORC1 inhibition may improve acne.

Diet: glycaemic load and dairy

Dietary associations are the most debated environmental factor. A 2022 systematic review concluded that high glycemic index and increased daily glycemic load intake were positively associated with acne genesis and acne severity, an observation supported by randomized controlled trials, although the effect was judged modest. Dairy evidence is less consistent; the literature on whether dairy product intake is associated with acne is mixed and may depend on sex, ethnicity, and cultural dietary habits. A 2025 meta-analysis of five studies (716 participants) found no significant pooled associations between dietary glycemic load, dairy intake, or fatty acids and acne risk, and the authors graded certainty as moderate for glycemic and dairy outcomes and low for fatty acids. Such discrepancies likely reflect small samples, heterogeneous exposure measurement, self-reported intake and differing control groups, not only true differences between populations.

Obesity, smoking, stress and medications

Obesity, smoking, psychological stress and certain drugs have all been examined as contributors, but the evidence is mostly from cross-sectional and case-based studies. Associations between higher body mass index and acne have been reported in adolescent and adult samples, and insulin resistance is the most plausible link, though the direction of causation is difficult to establish. Smoking has been linked to acne in some population surveys, particularly in adult women, yet cohort data remain limited. Stress is commonly reported by patients as an aggravating factor; the evidence rests largely on self-reported questionnaires, which are vulnerable to recall bias. Medications linked to acne-like eruptions, including corticosteroids, lithium, anabolic androgenic steroids and some antiepileptic and targeted cancer drugs, are typically documented through case reports and pharmacovigilance rather than controlled trials. Across these exposures, epidemiological studies face recurring problems: cross-sectional designs cannot establish temporal order, confounding by age, sex and puberty stage is common, and control groups are sometimes unrepresentative.

Scarring and post-inflammatory changes

Atrophic, hypertrophic and keloidal scars

Acne scars are usually grouped into atrophic scars, which result from tissue loss, and hypertrophic or keloidal scars, which result from tissue overgrowth. Eighty to ninety percent of people with acne scars have scars associated with a loss of collagen, so atrophic forms dominate, and the atrophic group includes ice pick, rolling and boxcar subtypes, while hypertrophic and keloid scars are the less common trophic forms.

Each atrophic subtype has a characteristic shape. Ice-pick lesions are narrow, funnel-like pits with steep walls and a fibrous floor (irregular borders, jagged edges and sharp margins). Macular atrophic scars are shallow and soft, and their base can be easily creased (). Hypertrophic scars are pink raised lesions that persist within the borders of the original site of injury, whereas keloids are reddish-purple and frequently extend beyond the borders of the original site of injury. Papular scars, which are skin-coloured papules most often seen on the chin and back, have been described as a neglected category ().

Frequency estimates depend on how the categories are defined. In one retrospective series of 416 patients, dermatologists found atrophic scars in 98.56%, keloid scars in 12.74% and papular scars in 11.06% (). These percentages sum to more than 100 because individual patients often carry more than one scar type, so the figures describe prevalence within the cohort rather than a mutually exclusive split.

Mechanisms of scar formation

Normal repair proceeds through inflammation, tissue formation, and tissue remodeling, and these phases overlap. New collagen synthesis by fibroblasts typically starts about three to five days after injury, and early tissue is rich in type III collagen before a shift toward type I collagen as scars mature (). Macrophages contribute growth factors that drive fibroblast migration and proliferation ().

The direction of the error determines the scar type. An inadequate response yields a depressed scar with reduced collagen deposition, while an exuberant response produces a raised fibrotic nodule (). In acne, the process starts with damage to the follicle: the pore wall can break down, and when lesion contents spill into the surrounding tissue, deeper scars tend to follow (). Inflammation damages dermal collagen and elastic fibres, which may then be lost or abnormally proliferate (). Matrix-degrading metalloproteinases, including MMP-1, MMP-3 and MMP-9, have been reported to rise in inflammatory lesions (). Hypertrophic and keloidal scars are associated with excess collagen deposition and reduced collagenase activity (). One proposed model treats keloids and hypertrophic scars as points on a spectrum of reticular dermal inflammation, with keloids reflecting stronger inflammation (). Keloids recur at high rates after treatment ().

Post-inflammatory hyperpigmentation and hypopigmentation

Post-inflammatory hyperpigmentation (PIH) is not a scar. After an inflammatory lesion, , and the excess melanin is deposited in the epidermis, producing flat, darker patches. When inflammation reaches deeper, pigment can fall into the dermis, where it may be retained by immune cells (). Because PIH involves colour rather than structure, it is mostly a color issue, whereas a true acne scar is a texture and structure issue. PIH generally fades, though the timescale is long; most patients notice a significant improvement in three to 24 months. Its frequency is higher in darker skin, since darker skin naturally contains more melanocytes and these cells tend to be more reactive to inflammatory triggers. Lighter skin more often develops transient red or pink marks, termed post-inflammatory erythema ().

Post-inflammatory hypopigmentation, in which the affected area becomes paler than surrounding skin, is less extensively characterised in the sources reviewed here, and its course and mechanisms are less well defined than those of PIH.

Role of early treatment

Scarring is closely tied to the intensity and duration of the lesion. Small blemishes tend to produce shallow scars that heal quickly (), whereas intense or prolonged inflammation breaks down collagen, and imperfect healing may fail to rebuild it. Since scarring depends on how long and how strongly inflammation persists, prompt control of inflammatory lesions is generally considered the most direct way to limit permanent damage. Established atrophic and hypertrophic scars are harder to correct, and procedural options such as laser treatment are discussed in a separate section.

Psychosocial impact and quality of life

Quality-of-life burden

Dermatology studies usually measure the burden of acne with the Dermatology Life Quality Index (DLQI), a short self-completed questionnaire, sometimes supplemented by acne-specific scales such as the Acne Quality of Life Scale (AQOL). In an outpatient sample from Saudi Arabia, the mean DLQI was about 6, a level the authors described as a moderate effect on daily life. DLQI scores (6.04 ± 6.05) indicate that acne had a moderate effect on patients' quality of life. A Lithuanian survey reported higher burdens, with about 96.5% of the responders having a reduced quality of life due to acne.

Scores do not track clinical grading closely. In one study of acne patients, no significant correlation was found between acne severity and scores from AQOL and DLQI. Instead, the same study found that anxiety and depression levels were positively correlated with these quality of life measures. This pattern suggests that the subjective experience of acne depends heavily on psychological state, not only on the number or grade of lesions. Not all studies agree: one Turkish cohort found no significant differences between the acne and control groups in the HAD anxiety and depression subscale scores.

Depression, anxiety, self-esteem and social avoidance

A meta-analysis of 42 studies reported a significant association of acne vulgaris with depression (r = 0.22) and anxiety (r = 0.25), which are modest correlations. A later systematic review of 23 studies concluded that patients with acne vulgaris have a significantly higher level of anxiety, depression, and stress. The same review found that results for self-esteem, loneliness and general symptom checklists were inconsistent, and attributed much of this heterogeneity to country, study design, and assessment tools.

Within individual cohorts, the risk appears concentrated in certain groups. In a Pakistani-style hospital cohort of 150 patients, female AV patients reported significantly higher depression, anxiety, and stress levels compared to males. The same study found that patients with facial acne had higher levels of depression, anxiety, and stress. In a Lithuanian sample, the prevalence of suicidal thoughts was high: 38.4% had anxiety symptoms, 23.1% had depression symptoms and 12.9% had suicidal thoughts due to acne. A UK review of psychiatric adverse reactions noted that suicidal ideation was more than twice that of those with no or little acne and in boys it was 3 times higher.

Qualitative work adds detail on the mechanisms of distress. Participants described poor self-esteem and feelings of unattractiveness, which led to avoiding being photographed and other consequences of a broken image of self. Social withdrawal and avoidance of visible situations are therefore recurring themes in the literature, although they are harder to quantify than scores on standard instruments.

Persistence after lesions resolve

Psychological effects do not necessarily end when active inflammation settles. One review argued that many of these psychiatric comorbidities are characterized by high likelihoods of recurrence, suggesting that the resolution of active acne does not represent the cessation of concurrently acquired psychopathological symptoms. Early distress can also become entrenched: associated maladaptive thought processes, mental illnesses, and avoidant social behaviors are not so easily reversed once established.

Scarring is the main reason for this persistence. Atrophic scars are permanent, and in a small retrospective study of 86 patients with scars, 62% of patients exhibited depressive symptoms according to the PHQ-9, and 84% reported a diminished quality of life according to the DLQI. Scar-related distress also appears to be less favourable than distress from active acne: those with acne tended to exhibit hope for improvement, while those with acne scars were more likely to report hopelessness and an unwillingness to accept their condition. Early treatment is therefore relevant to psychological outcomes as well as to physical ones, because it is important to intervene early in active acne cases, both to prevent scarring and to mitigate psychosocial stressors associated with it.

Integration into treatment and screening

Current guidance treats psychological assessment as part of acne care rather than a separate concern. The AAD guideline summary notes that clinicians should monitor all acne patients—especially those on isotretinoin—for depression, anxiety, and suicidal ideation, and it lists significant psychosocial burden as one reason to consider isotretinoin. The patient health questionnaire-2 and the patient health questionnaire-9 are validated instruments that enable dermatologists to efficiently screen for depression before and after isotretinoin is initiated. Because no predictive test exists, no specific predictive test or questionnaire has been identified to establish which patients may be at increased risk of psychiatric disorders, so screening serves mainly as a monitoring tool.

Evidence on isotretinoin and mood is mixed. A large claims-based cohort found that compared to the general population, acne patients prescribed isotretinoin were less likely to engage in suicidal behavior. Another analysis found comparable risk for major depressive disorder and suicide attempts, but a significantly elevated risk for suicidal ideation when isotretinoin was compared with oral antibiotics. A prospective study of 143 patients found that isotretinoin treatment for moderate-to-severe acne was not associated with an increase in symptoms of depression or anxiety. Quality-of-life outcomes are also measured as part of treatment assessment: in one study of isotretinoin-treated patients, DLQI scores decreased from 13.2 to 4.2 (p < 0.001).

Diagnosis and assessment

Acne is diagnosed clinically. The clinician looks at the types of lesion present, where they sit on the body, and the patient's history, including age at onset, menstrual pattern, medication use and previous treatment. No single laboratory test confirms the condition. Comedones are the feature that most helps separate acne from its mimics, because many conditions that resemble acne lack them. Lesion type matters as much as lesion count, so a diagnosis usually names the dominant lesion type (comedonal, papulopustular or nodulocystic) and the distribution (face, chest, back, or a combination).

Grading and severity assessment

Severity is assessed in three broad ways: global severity grading, lesion counting and multimodal digital imaging. Global grading compares a patient with written descriptions or standard photographs and is quick, so it suits routine practice. Lesion counting tallies each lesion type in defined facial regions and is more time-consuming but more reproducible; it is therefore the usual choice in clinical trials. Some reviews report excellent reliability for lesion counts when the same trained rater repeats the count, but agreement between different raters is lower.

Several scales are in use. The Global Acne Grading System (GAGS) scores six areas (forehead, each cheek, nose, chin, and chest and upper back), weights each area by size, and grades the most severe lesion in that area from 0 (none) to 4 (nodule). Its total ranges from 0 to 44, and commonly cited cut-offs call scores of 1–18 mild, 19–30 moderate, 31–38 severe and 39 or more very severe. The Investigator's Global Assessment, derived from a text-based scale, became the template for many trial endpoints. The Hayashi scale counts inflammatory lesions, and the Global Evaluation of Acne (GEA) scale is a six-point photo-numeric system. Michaelson's early lesion-count method weighted comedones at 0.5, papules at 1, pustules at 2, infiltrates at 3 and cysts at 4. Because no scale is universally accepted, studies using different instruments are difficult to compare directly. Agreement between raters also varies by tool: in one small study, Investigator's Global Assessment showed the highest concordance, while the LEEDS technique showed only fair agreement.

Differential diagnosis

Several conditions can mimic acne. Rosacea is the most important in adults, especially late-onset cases. It typically causes persistent central facial erythema, telangiectasia, papules and pustules, but lacks comedones, and it tends to affect an older group without nodules or scarring. Demodex mites are thought to drive rosacea, whereas Cutibacterium acnes is considered the more important organism in acne. Perioral dermatitis presents with grouped papules and pustules around the mouth and nostrils, sparing the vermilion border; the perioral distribution is the best clue, and facial Demodex infestation can resemble it. Pyogenic folliculitis usually yields Staphylococcus aureus on culture, while Demodex and pityrosporum folliculitis are caused by mites and yeast-like organisms respectively. Drug eruptions, including acneiform reactions to anti-tuberculous and anti-epileptic drugs, must also be considered, and topical or inhaled corticosteroids can produce an acneiform or rosacea-like eruption. Steroid-associated lesions are typically perioral, lack comedones, occur in older patients than typical acne, and resolve when the steroid is stopped; a history of recent steroid use is therefore essential.

Laboratory investigation

Most patients with acne need no laboratory tests. Investigations are reserved for specific reasons: to look for infection, to explore an underlying cause, or to monitor treatment. In women, hormone testing is considered when there is a possibility of pregnancy (which affects treatment choice), signs of hyperandrogenism such as those suggesting polycystic ovary syndrome or congenital adrenal hyperplasia, signs of excess prolactin, or signs of Cushing syndrome. Where hormone levels are measured, timing matters: morning samples taken early in the menstrual cycle are the usual recommendation. A consensus report from an androgen excess and PCOS committee recommends measuring total testosterone, free testosterone and DHEAS in women with adult acne, a stance that goes further than routine practice in many settings. Its supporting investigations for suspected adrenal or cortisol-related causes, such as 17-hydroxyprogesterone or cortisol testing, are reserved for patients with additional clinical features. Commercial "hormone profiles" marketed directly to consumers are not part of standard assessment.

Topical treatments

Main classes and mechanisms

Vitamin A derivatives act on the follicular epidermis mainly through retinoic acid receptors. Topical retinoids are derivatives of vitamin A and are effective in treating both comedonal and inflammatory acne by binding to retinoic acid receptors (RARs), reducing keratinocyte proliferation and exhibiting anti-inflammatory effects. Their main action is on the comedone: they normalize follicular keratinization and so prevent new microcomedones from forming, but they have little direct antibacterial effect.

Benzoyl peroxide, introduced for acne in 1934, is an oxidant with a different target. Benzoyl peroxide (BPO) was introduced in the treatment of acne in 1934. Despite the fact that only few randomized trials have been published, BPO is considered the standard in topical acne treatment. Its lipophilic nature helps it penetrate into the pilosebaceous duct, where it generates oxidative free radicals by converting them into benzoic acid and hydrogen peroxide, thereby causing the death of the causative bacteria. Because the killing mechanism is oxidative rather than based on a single molecular target, it is not associated with the problems of antimicrobial resistance.

Azelaic acid, a naturally occurring dicarboxylic acid, combines several actions. It has anti-inflammatory, comedolytic, and antimicrobial properties and is used as a topical treatment for acne, and bacterial resistance associated with azelaic acid has not been detected yet. Topical antibiotics such as clindamycin, erythromycin and doxycycline are the fourth class. Their benefit rests largely on dampening inflammation: along with eliminating Propionibacterium acnes, the main mechanism of topical antibiotics is their antiinflammatory effect.

Evidence for newer sebum-targeting agents

Clascoterone 1% cream is the principal newer topical agent aimed at sebum. It is a topical androgen receptor inhibitor: clascoterone is thought to inhibit androgen receptor signaling in sebocytes by competing with DHT for receptor binding, leading to reduced sebum production, decreased inflammatory signaling, and improvement of acne lesions. Two phase 3 randomized trials compared it with vehicle in patients aged 9 years and older with moderate to severe facial acne, and the authors concluded that it appears to demonstrate favorable efficacy and safety with low adverse event rates.

Direct evidence on sebum output is more recent and smaller. In a single-site, exploratory 12-week study of 40 patients with mild-to-moderate acne, significant percentage reductions from baseline were observed in sebum measurements (27%), ILC (54%), and NILC (34%; all p < 0.001). A later report from a 52-week follow-up of the same group described continued cumulative sebum reduction. Such studies are not controlled trials of sebum as an outcome, and researchers did not measure the effect of clascoterone on sebum production in participants during the pivotal phase 3 trials. Network meta-analysis data suggest that TC appears to reduce both inflammatory and non-inflammatory lesion count and may lead to treatment success.

Evidence for the wider topical field is weaker than the number of products suggests. A Cochrane-derived systematic review found that the strongest evidence was available for azelaic acid, which performed worse than benzoyl peroxide and comparably to tretinoin, and it described the overall evidence base as low-quality.

Local adverse effects and adherence

Irritation and dryness are the most common local effects of topical acne therapy. Both can cause dryness or irritation but generally have manageable side effects. Benzoyl peroxide irritation is dose-related: the effect is dose-dependent, but the irritation increases with higher concentrations. Its oxidative action also has practical consequences, since patients should be advised that BPO may bleach colored and dark clothing, bedding and even hair.

In combination products, the commonest effect is dry skin during the first weeks. In the adapalene–benzoyl peroxide trial, adverse events were more frequent with the combination therapy (mainly due to an increase in mild-to-moderate dry skin), occurred early in the study, and were transient. Tolerability differs within the retinoid class: among topical retinoids, adapalene exhibits a better tolerance profile. Local irritation is a recognized cause of nonadherence; a review of clinical practice notes that intolerance to drugs and poor adherence to treatment are the challenges faced at the dermatology clinic.

Rationale for combination regimens

Acne has several interacting drivers, so topical combinations target more than one at once. Retinoids help normalize keratinization and reduce inflammation, while benzoyl peroxide exhibits potent antimicrobial activity against C. acnes. Each class also covers the others' gaps: retinoids increase penetration and reduce comedones, while topical antibiotics primarily address inflammation.

The fixed-dose gel combining adapalene 0.1% with benzoyl peroxide 2.5% is the best-studied example. In a randomized trial of 1,670 patients, adapalene–BPO was significantly more effective than corresponding monotherapies, with significant differences in percentage lesion count change observed as early as 1 week. A systematic review of eight trials covering 4,596 individuals reached a similar conclusion about its efficacy and safety. Because benzoyl peroxide does not select for resistance, the combination is generally presented as one that is safe and effective and does not contribute to antibiotic resistance, which is an advantage over combinations that include topical antibiotics.

Systemic antibiotics and antibiotic resistance

Oral antibiotics in clinical use

Oral tetracycline-class drugs are the systemic antibiotics most often used for moderate-to-severe inflammatory acne. The American Academy of Dermatology's 2024 guideline gives a strong recommendation to oral doxycycline, alongside topical benzoyl peroxide, retinoids and antibiotics Strong recommendations are made for benzoyl peroxide, topical retinoids, topical antibiotics, and oral doxycycline. Sarecycline, a narrower-spectrum tetracycline, received FDA approval in 2018 for patients aged 9 and older and was designed to target Cutibacterium acnes, the pathogenic bacterium in acne vulgaris, which may reduce the risk of resistance. Tetracyclines also carry drug-related costs, including gut dysbiosis, gastrointestinal upset, photosensitivity, dizziness, and vertigo. An expert consensus panel concluded that oral antibiotics are appropriate for moderate-to-severe disease when they are paired with topical therapy and their duration is individualised oral antibiotics should be combined with topical treatments, and duration of use should be determined based on individualized patient care.

How exposure selects for resistant bacteria

Tetracycline resistance in Bacteria may develop resistance to the tetracycline-class antibiotics primarily by one of two main mechanisms: (a) Efflux pump and (b) ribosomal protection. Resistance in C. acnes was absent in early surveys: a 1976 study found no resistant isolates among more than 1000 patients. Subsequent estimates suggested roughly 20–25% resistance in the 1970s and 1980s, 50–60% in the 1990s and 2000s, and about 75% in the 2000s and 2010s, before a fall to 30–40% between 2010 and 2020. The same review attributed the later decline to better awareness of resistance and less superfluous prescribing This fall in resistance levels could be attributed to improved understanding of the dangers of antibiotic resistance, and changes in prescribing habits resulting in a decrease in their superfluous usage by clinicians. The estimates come from a single narrative review, so their precision is limited.

Longer courses are linked to more resistance. Prospective data indicate higher resistance rates among patients treated beyond guideline-recommended durations Prolonged exposure has been associated with an increased prevalence of tetracycline-resistant Cutibacterium acnes, with prospective data indicating higher resistance rates among patients treated beyond guideline-recommended durations (9). In a single-centre retrospective cohort, courses longer than 16 weeks carried a 2.3-fold higher hazard of recurrence at 12 months than 6–12-week courses, without better short-term response. The authors described this finding as hypothesis-generating. Resistance also rises with prior antibiotic treatment and with treatment duration in published series It has also been demonstrated that there is a higher level of resistance in patients who were treated with antibiotics for acne before.

The public-health dimension extends beyond the individual patient. Acne is a common reason for antibiotic prescribing, and the use of antibiotics has been associated with changes in skin and gut microbiomes. In a UK general-practice cohort, the mean duration of therapy was 175.1 days. Of antibiotic courses, 62% were not associated with a topical retinoid; 29% exceeded 6 months in duration. The authors estimated that aligning all regions with the shortest-duration region would avoid approximately 3.3 million antibiotic days per year in the United Kingdom. A modelling study estimated that capping tetracycline courses at 16 weeks could reduce tetracycline use in dermatology by about 15%.

Guideline recommendations on duration and combination therapy

Guidelines converge on limiting systemic antibiotics and avoiding monotherapy, but they differ on exact duration. The 2024 AAD guideline states that systemic antibiotics should be used for the shortest duration possible, typically no more than 3-4 months. A European recommendation is reported more strictly, the European recommendation to administer for no longer than 3 months, whereas a 2014 European expert statement is described elsewhere as allowing 3 to 4 months. The Global Alliance to Improve Outcomes in Acne advised reassessing antibiotic therapy at 6 to 8 weeks and transitioning to maintenance with a topical retinoid plus benzoyl peroxide or azelaic acid. Benzoyl peroxide is central to the combination approach because it is recommended that benzoyl peroxide should always be added when long-term oral antibiotic use is deemed necessary. Current guidance also notes that there is no guideline addressing retreatment with oral antibiotics for acne flares subsequent to the initial course of antibiotics.

Resistance patterns and regional monitoring

A 2024 systematic review and meta-analysis covering 27 countries over four decades pooled resistance data across the included studies. Pooled resistance was 31.0% for clindamycin and 36.6% for erythromycin, whereas pooled rates for tetracyclines were lower, for example 7.9% for doxycycline and 6.2% for tetracycline. Variation between countries was marked: clindamycin resistance rates ranged from 1.7% in Turkey to 90.3% in the UK. Between continents, Clindamycin resistance varied from 11.2% in the Americas to 58.9% in Africa. Over time, the same review reported that The resistance rate has increased from 25.5% (1983–2014) to 35.4% (2015–2023), and it highlighted rising macrolide resistance. Regional studies show similar heterogeneity. A Bulgarian study found tetracycline resistance of 36.4% in acne-associated strains versus 22.2% in non-acneic strains, while a Colombian study reported The resistance found of C. acnes to cyclines was lower than that reported in other studies. Measured resistance also depends on the testing standard: the same meta-analysis found that erythromycin resistance was 37.8% by EUCAST criteria and 35.8% by CLSI criteria. The authors called for continuous surveillance for effective acne management.

Systemic isotretinoin

Isotretinoin (13-cis-retinoic acid) is an oral vitamin A derivative that has been used for acne since the early 1980s. Its exact mechanism is still incompletely understood, but its effects on the pilosebaceous unit are well documented. In one biopsy study of upper-back skin, sebaceous glands were about 76% smaller after eight weeks of treatment, and their multilobular structure was largely lost. Sebum output falls alongside gland size; some reviews report suppression of up to about 90%. The proposed explanations include reduced proliferation of basal sebocytes, inhibition of terminal sebocyte differentiation, and suppression of sebaceous lipid synthesis, together with lower inflammatory signalling in sebum. The drug binds nuclear retinoid receptors only weakly, which makes its strong sebostatic effect unexpected. Part of its activity may come from conversion to other retinoids, but that conversion does not explain all of its pharmacological effects.

Isotretinoin was approved by the US Food and Drug Administration on 7 May 1982 under the brand name Accutane, for severe, recalcitrant nodular acne that had not responded to conventional therapy, including systemic antibiotics. Later guidance has kept its use for severe nodulocystic acne, acne with scarring, and disease that fails other treatments. The labelled regimen is typically 0.5–1.0 mg/kg/day for 15–20 weeks. Early series reported clearance or near-clearance in most treated patients after a single course, and many patients remain in remission afterwards. However, long-term remission is not assured, and the published figures depend heavily on how relapse is defined. Reported relapse rates range from about 9% to 65%. A 2025 cohort of 19,907 patients found that 22.5% needed further systemic acne treatment and 8.2% received a repeat course. In that cohort, female sex was linked to a higher relapse rate, and a greater cumulative dose (in mg/kg) was linked to a lower rate, whereas higher daily doses beyond the conventional range added little benefit. Relapse most often occurs within the first year or so after treatment ends. Small studies suggest that topical retinoid maintenance may reduce relapse, but the evidence base is limited.

Teratogenicity is the central safety concern. Within a year of marketing, the US Centers for Disease Control and Prevention documented adverse pregnancy outcomes among women who had taken the drug in the first trimester, and in 1983 doctors in New Jersey reported the first human case of isotretinoin-associated birth defects. A review cited prenatal exposure as carrying a 20–35% risk of major congenital malformations, including craniofacial, cardiovascular and neurological defects. The drug also causes mucocutaneous dryness, raised blood lipids and liver enzymes, and musculoskeletal symptoms. Concerns about depression, suicidality and inflammatory bowel disease have been studied extensively, and the evidence for a causal link remains contested. Treatment therefore requires pregnancy testing and contraception counselling, as well as periodic checks of fasting lipids and liver function, as set out in the labelling.

The regulatory response developed in stages. The label carried pregnancy warnings from the outset and was later strengthened, and the US adopted progressively more demanding programmes to prevent fetal exposure. The most recent of these is iPLEDGE, a risk evaluation and mitigation strategy made mandatory in March 2006. It requires registration of prescribers, pharmacies and patients, and it links dispensing to pregnancy testing. Ethicists have argued that such a programme restricts patient autonomy and creates a burden on prescribers and patients, and the debate over whether it reduces pregnancies has continued.

Hormonal therapies

Combined oral contraceptives

Combined oral contraceptives suppress luteinising hormone (LH)-driven androgen production and increase sex hormone binding globulin. The estrogen component, usually ethinyl estradiol, also works directly to decrease both the size of the sebaceous gland and sebum production. Raised SHBG binds avidly to dihydrotestosterone and testosterone, reducing the unbound fractions available for binding to androgen receptors. Progestin choice matters. With many COC regimens, the beneficial effect of estrogen is counteracted by androgenic progestins, which negate estrogen-induced hepatic SHBG synthesis. Newer progestins such as cyproterone acetate and drospirenone possess anti-androgenic activity.

Clinical support comes from early open studies and later randomized trials, which reported significant regression of mild to moderate acne, with low-dose pills causing no more side effects than placebo. Current US guidance treats COCs as a conditional recommendation, alongside spironolactone and some oral antibiotics. Conditional recommendations are made for topical clascoterone, salicylic acid, and azelaic acid, as well as for oral minocycline, sarecycline, combined oral contraceptive pills, and spironolactone. Brands show generally similar efficacy in treating acne, so the choice rests on patient preference, contraceptive needs, comorbidities, access and cost. Dermatologists should discuss contraceptive options and provide individualized shared decision-making with patients.

Spironolactone and other antiandrogens

Spironolactone is an aldosterone antagonist with antiandrogenic activity, making it useful in the treatment of acne. It has been used off-label for acne since the 1980s, and it has not been officially approved by the Food and Drug Administration for this indication, although medical professionals widely accept it. Dose matters. The earliest randomized trial established that doses of 150 to 200 mg daily conferred the greatest benefit compared to doses less than 150 mg daily, whereas the largest trial showed spironolactone is effective at a dose of 100 mg/day. Usual practice is to start at 50 mg daily and increase to 100 mg daily within 2 to 4 weeks if tolerated. Evidence quality remains a limitation: a systematic review found evidence of limited quality to underpin the expert endorsement of spironolactone at the doses typically used in everyday practice.

Other antiandrogen strategies have a narrower evidence base. Older work noted that cyproterone acetate-containing combinations are particularly effective in treating acne, since this progestin also has a direct peripheral anti-androgenic action in blocking the androgen receptor.

Patient selection and hormonal assessment

Acne is rarely linked to high circulating androgens, but female acne patients have definite increases in ovarian and adrenal androgen levels when compared to appropriate controls. Hormonal therapy is therefore most relevant for women with acne and other features of hyperandrogenism. Pills are used to treat signs of hyperandrogenism in women, including acne vulgaris and comedonal acne, hirsutism, seborrhoea and female pattern hair loss. Spironolactone should be especially considered in women who have failed to respond to a 3-month course of oral antibiotic therapy, those who have relapsed following a successful course of oral antibiotic therapy, and where topical therapy is either insufficient or impractical. While patients with underlying polycystic ovarian syndrome may benefit from the additional effects of spironolactone on hirsutism, spironolactone can be used irrespective of the presence of an underlying endocrinological disorder. Male patients are generally excluded, because its anti-androgenic activity can cause undesirable side effects, such as breast enlargement in men.

Adverse effects and contraindications

For COCs, the principal concern is thrombotic risk. The oral contraceptive pill is associated with a small but significantly increased risk of venous thromboembolic events. Before starting therapy, individual clinical examinations, screening, and individual risk assessments particularly for venous thromboembolism risk must be conducted. Data on breast cancer risk are conflicting, while use of these medications does confer measurable protection from endometrial and ovarian cancer.

For spironolactone, menstrual changes (21%) and polyuria (13%) were common, while breast symptoms, dizziness, headache, fatigue and gastrointestinal effects were less common, and hyperkalemia (3%) occurred in a minority. Potassium monitoring has low usefulness in young healthy women. Contraindications include hyperkalemia (high potassium levels), Addison disease, also called primary adrenal insufficiency, and concurrent eplerenone use. Kidney disease is also a recognised contraindication, as is pregnancy: spironolactone is not suitable for pregnant women because it could affect the fetus. Menstrual irregularity is significantly more common with the 200 mg dose, and its frequency could be significantly reduced by concomitant use of a COC. Combining the two drugs has been studied: a cohort study found the combination with a drospirone-containing oral contraceptive pill to be well tolerated and not associated with a higher risk of hyperkalemia.

Procedural and physical therapies

Light- and laser-based treatments

Light-based options include intense pulsed light (IPL), vascular lasers such as pulsed dye and Nd:YAG lasers, and photodynamic therapy (PDT), in which a topical photosensitizer is activated by light. A 2025 systematic review of vascular lasers covered 32 studies involving 1,520 patients, with 18 studies on Intense Pulsed Light (IPL), 9 on Pulsed Dye Laser (PDL), and 10 on Neodymium-Doped Yttrium Aluminum Garnet (Nd:YAG) lasers. For PDT, the most common photosensitizers were 5-aminolevulinic acid, methyl aminolevulinate, and indocyanine green, and the light sources included red light, blue light and IPL (the light sources showed similar efficacy). A 2024 systematic review of PDT, covering 4340 patients, reported a partial clinical response, with lesion counts as the most frequent outcome.

Earlier syntheses were more cautious. A 2008 evidence-based review of controlled trials found 16 randomized controlled trials (RCT) and 3 controlled trials (CT) ... involving a total of 587 patients, and concluded that optical treatments could improve inflammatory acne in the short term, with the most consistent results for PDT. The same review noted that IPL-assisted PDT seems to be superior to IPL alone, but that only two trials compare optical vs. conventional treatments. One head-to-head trial reported a lesion-count reduction of 42.40% ± 23.87% for IPL and 57.76% ± 20.37% for benzoyl peroxide after the third session. Adverse effects are a recurring feature: PDT has been associated with burning sensations, pain, itching, blisters, pruritus, hyperpigmentation, and erythema.

Chemical peels

Peels for acne have mostly been tested in small, split-face designs. In a placebo-controlled trial of 26 patients with moderate acne, one side of the face received a 40% glycolic acid peel and the other a placebo; the glycolic acid side had better responses for noninflammatory lesions than for inflammatory lesions. A randomized comparison of 30% salicylic acid and 50% glycolic acid in 50 participants with mild to moderate acne found that the SA group showed a more rapid reduction in inflammatory lesions. Peels have also been evaluated for scarring: a split-face trial of 100 patients in Pakistan compared 20% salicylic acid with 35% glycolic acid, and the salicylic side was effective in 67% patients while glycolic acid was found to be effective in 61% patients. A payer-commissioned review of the evidence noted that RCTs comparing chemical peels to topical or oral medications for moderate-to-severe acne were not identified.

Surgical and mechanical procedures for scars

Post-acne scarring is the most common permanent consequence of acne vulgaris. Subcision is the main mechanical technique: a needle or blunt cannula is passed beneath the scar to cut fibrotic strands and form new connective tissue, thereby elevating the atrophic scars. Punch techniques are used for different scar types; one review notes that punch excision may be an effective treatment for ice-pick scars, while punch grafting and excision are also described as options for acne scars. Dermal grafting and filler-based augmentation are used in the same setting, although the highest-quality evidence for them is limited.

Combined approaches are common. In a split-face trial of 40 patients, subcision followed by cross-linked hyaluronic acid filler and subcision followed by fractional CO2 laser each improved scars more than subcision alone, with no significant difference between the two combinations. In another split-face study, combining PRP with subcision resulted in a better improvement (32.08%) than subcision alone (8.33%). Fractional resurfacing has its own limits: it is not clear if the carbon dioxide laser or the erbium laser alone provides a long-term significant improvement, and fractional resurfacing has been reported to help only subsets of acne scars. Retrospective series of single-session combinations, such as subcision with a fractional CO2 laser in 42 patients, have reported large improvements on the ECCA grading scale and none of the patients had severe adverse effects after the procedure.

Quality of evidence

The evidence base for procedures is uneven. A Cochrane review of light therapies included 71 RCTs (4211 participants, median sample size 31), and its reviewers judged that most studies reported adverse effects, but inadequately, with the quality of evidence rated as very low for several outcomes. Scar-treatment reviews make a similar point: one notes limited randomized controlled trials that aimed to determine which treatment options should be considered the gold standard, and suggests that combining interventions would likely produce more benefit compared to the implementation of a single method. Because combined regimens are usually tested in small, single-centre or retrospective studies, the additive benefit of each component remains uncertain.

Special populations

Pregnancy and breastfeeding

Treatment choices in pregnancy turn mainly on fetal exposure, so topical agents with little systemic absorption are generally preferred. Azelaic acid and benzoyl peroxide are considered safe and effective options for mild to moderate acne, working locally with minimal systemic absorption. Topical clindamycin or erythromycin are used as alternatives to oral antibiotics, since oral tetracycline may affect the developing teeth and bones of the baby. Systemic corticosteroids are usually avoided in the first trimester because of an association with cleft lip and palate, and isotretinoin is teratogenic and contraindicated during pregnancy. Topical retinoids are also regarded as unsuitable: some products, such as retinoids, aren't safe to use during pregnancy or while nursing.

During breastfeeding, the concern is transfer into breast milk. Benzoyl peroxide products or salicylic acid medication are commonly suggested to clear up acne. Isotretinoin and topical dapsone are generally avoided because of unclear risks to the breastfed infant. Clinicians also advise keeping products off the chest, since the infant should not come into contact with these products. Pregnancy-associated acne is often transient: post-pregnancy acne is usually temporary and tends to improve as hormone levels return to normal.

Neonatal and infantile acne

Neonatal acne is a self-limiting condition in which baby acne affects approximately 20% of newborns under 6 to 8 weeks of age. Sources disagree on its morphology. One dermatology reference describes superficial pustules on the face, neck and upper trunk, with no comedones (whiteheads or blackheads) present. Another describes open and closed comedones on the cheeks, chin and forehead. The cause is thought to involve maternal androgens transferred across the placenta and androgens from the fetal adrenal gland and neonatal testes, which stimulate sebaceous glands. Management is usually minimal: neonatal acne usually resolves without treatment. Parents are advised not to squeeze lesions, as this may cause secondary infection and/or scarring.

Infantile acne is a distinct and less common entity, affecting approximately 2% of infants. It begins after the first weeks of life and is characterised by comedones with papules and pustules, and occasionally nodules and cysts, in children from a few months of age, lasting until about 2 years of age. Because it can lead to long-term scarring, persistent cases warrant treatment. Topical agents such as benzoyl peroxide, adapalene or erythromycin gel can help. Oral erythromycin is used for severe disease, and very occasionally isotretinoin is needed to prevent scarring. The majority of children require only topical treatment, and it usually subsides by the age of 2 years. Because acne that appears after this point often signals the development of infantile acne and can indicate an underlying health condition. referral for evaluation is advised. The cause of infantile acne is not established, though increased sebaceous gland secretion from androgens and genetic factors are proposed.

Adolescents, adult women and adult men

Guideline-level recommendations differ by age and sex, but the evidence base is uneven. Most trial data on hormonal treatment come from women, and the strongest evidence for hormonal therapy relates to women with PCOS. In adolescents, the approach has shifted. In 2015 the American Association of Clinical Endocrinology changed first-line therapy in adolescents from symptom management with oral contraceptives to metformin. A later systematic review of randomized trials found that metformin caused significantly greater BMI reduction with improvement in dysglycemia, while oral contraceptives resulted in only modest improvement in cycle frequency and acne scores. The choice between first-line agents remains varied among pediatric endocrinologists.

For adult women, combined oral contraceptives are first-line treatment for acne in women with PCOS. For adult men, the recommended framework relies on topical agents, antibiotics and isotretinoin for severe disease, with hormonal agents used far less commonly.

Comorbidities: PCOS and diabetes

Polycystic ovary syndrome is closely tied to acne because it combines hyperandrogenism with insulin resistance. In one retrospective study of 305 women with PCOS, 56.4% had acne, and elevated insulin resistance markers and DHEAS levels were highly correlated with the presence and severity of the condition. Treatment is therefore built around the endocrine picture. First-line therapy includes combined oral contraceptive pills with antiandrogenic progestins, and spironolactone is an effective adjunct. Where indicated, metformin addresses insulin resistance and may improve acne and ovulatory function. Oral contraceptives do not address insulin-related disease, since starting them early does not target hyperinsulinemia, an important contributing mechanism. Oral isotretinoin is reserved for refractory disease with careful risk management. Terminology is also changing: polyendocrine metabolic ovarian syndrome (PMOS) is the new name for the condition formerly known as polycystic ovary syndrome.

In diabetes, the interaction runs in both directions. One narrative review describes insulin therapy in females with type 1 diabetes as an overlooked iatrogenic cause of PCOS in adolescents. Evidence specifically addressing acne treatment choices in people with diabetes is limited, so decisions usually rest on the underlying endocrine and metabolic profile rather than on the acne alone.

History of understanding and treatment

Early descriptions and the sebaceous link

Acne is one of the oldest recorded skin conditions. Acne has plagued mankind since antiquity. For most of that time, clinicians described comedones and inflamed lesions in terms of their appearance, and the link to the sebaceous apparatus rested on clinical observation rather than on any measured mechanism. The epidemiological framing of acne as a near-universal feature of adolescence took shape in the early twentieth century. In 1931 Bruno Bloch examined roughly 4,000 children in Zurich and found comedones so common in young people that he regarded them as a physiological concomitant of puberty rather than a disease confined to a minority.

Microbiology: from the "acne bacillus" to Cutibacterium

The bacterial story began in the 1890s. The organism known in the medical literature as the "acne bacillus" was first observed by Paul Gerson Unna in 1896, in microscopic sections of acne comedones. Thomas Caspar Gilchrist's 1900 study of more than 300 vesicular and pustular lesions, which also examined the etiology of acne vulgaris, gave the organism its first formal name, Bacillus acnes. Its taxonomic position then shifted several times. In 1909 Orla-Jensen placed it in the genus Propionibacterium, based on its ability to produce propionic acid during fermentation. In 1923 Bergey moved it to Corynebacterium on the basis of similarity to other organisms in that group. The name Propionibacterium acnes was later retained, and in 2016, P. acnes was taxonomically reclassified as a result of biochemical and genomic studies, becoming Cutibacterium acnes.

The causal role of the organism has been debated throughout this period. Early experiments showed that injecting bacteria into sterile keratinous cysts could rupture them, which supported the idea that the organism was inflammatory in its own right. The use of antibiotics from the 1960s onward produced clinical improvement together with falls in bacterial counts, and that combination renewed the debate. Later, the emergence of antibiotic-resistant strains during therapy again reopened the question of whether the bacterium drives disease, reflects it, or simply tracks it.

Introduction of major treatments in the twentieth century

Systemic antibiotics, principally tetracyclines, became the standard for inflammatory acne in the 1960s and remained the dominant systemic option for decades. Isotretinoin had a different origin. Isotretinoin, a retinoid synthesized by Hoffmann-LaRoche in the 1960s and patented in 1969, was initially intended to be a preventive agent for skin cancer. Its dermatological potential emerged from the work of Gary Peck at the US National Institutes of Health, who in the 1970s found that the drug was effective against treatment-resistant severe acne. The drug was first approved in the United States on May 7, 1982, for severe, recalcitrant, nodular acne in patients who had not responded to conventional therapy, including systemic antibiotics. Shortly after its introduction, teratogenicity was recognized as a major hazard, and the regulatory response developed in stages. The US FDA introduced the iPLEDGE program in 2006, which required monthly pregnancy tests, documentation of contraceptive use, and repeated information about side effects.

Topical benzoyl peroxide and retinoids, together with antibiotic-based lotions, became the core of mild-to-moderate treatment during the same period, and their combination with systemic therapy shaped the later consensus on multimodal care.

Evolution of guidelines

Professional guidance has moved from single-drug algorithms toward combination and stewardship-oriented recommendations. In the United States, the American Academy of Dermatology issued acne guidelines in 2016. The American Academy of Dermatology's 2016 guidelines for the management of acne vulgaris were updated with a systematic review, which resulted in 18 evidence-based recommendations and 5 good practice statements. The updated version, published on January 30 in the Journal of the American Academy of Dermatology in 2024, covered grading, laboratory testing, topical and systemic antibiotic therapy, hormonal agents, oral isotretinoin, physical modalities, and dietary and environmental factors. It also concluded that the evidence was insufficient for recommendations on chemical peels, lasers and light devices, microneedling, and dietary change. Among the strongest messages was the advice to combine agents: a greater proportion of patients treated with combined benzoyl peroxide and a topical retinoid achieved success on the Investigator Global Assessment scale at 12 weeks than those given vehicle, and patients taking antibiotics were advised to use benzoyl peroxide as well.

In Europe, the EuroGuiDerm group produced the S3 guideline in 2016, and a further update has since been issued. The update revised recommendations on benzoyl peroxide safety, selection of systemic antibiotics, pregnancy, isotretinoin dosing, and hormonal treatments including spironolactone. Its central statements were that isotretinoin should be used where possible for severe papulopustular and moderate nodular disease, and that systemic antibiotic use should generally be limited to 3 months, unless specific clinical circumstances justify a longer course. Across both regions, the direction of change has been toward limiting antibiotic exposure while expanding the range of topical and hormonal options.

Emerging research and open questions

Sebum-directed drugs

Because excess sebum is one of the core pathogenic processes, several groups are developing drugs that act on sebaceous lipid synthesis directly. The most advanced example is denifanstat, an oral inhibitor of fatty acid synthase (FASN), the enzyme that supports de novo lipogenesis in sebocytes. Work in cultured human sebocytes and in clinical trial participants reported that FASN inhibition lowered sebum lipids FASN inhibition reduced sebum lipids in human sebocytes in vitro and in participants of clinical trials in vivo. In a Phase 2 study, the 50 mg dose produced a median 61.3% reduction in total lesion counts at week 12, compared with 34.2% for placebo At Week 12, the 50 mg dose of denifanstat produced a median 61.3% reduction in total lesion counts versus 34.2% for placebo.

The Phase 3 trial, run in China, enrolled 480 patients with moderate to severe acne. Patients were randomized 1:1 to denifanstat 50 mg orally or placebo for 12 weeks. Success on the Investigator's Global Assessment was reached by about 34% of the treatment group and about 17% of the placebo group IGA success, which was defined as a score of 0 (clear) or 1 (almost clear) with at least a 2-grade improvement from baseline, was achieved by approximately 34% of patients receiving denifanstat, compared with roughly 17% in the placebo arm. The developer also describes an anti-inflammatory component, with reduced cytokine secretion and suppressed Th17 differentiation alongside the lipid effect (see T cell and cytokine pathways in the immune section). The only adverse events above 5% were dry skin and dry eye Adverse events occurring at a rate greater than 5% were limited to dry skin and dry eye.

The open-label extension reported longer-term data. The sponsor reported 57% IGA success and a 72% reduction in total lesions at 52 weeks including 57% IGA success, 72% reduction in total lesions, and 77% reduction in inflammatory lesions. Because this phase was open-label and sponsor-reported, these figures are not directly comparable with placebo-controlled results. Regulatory progress is also under way: The agency issued a "Study May Proceed" letter for a Phase 3 trial of the fatty acid synthase (FASN) inhibitor in moderate to severe acne.

Skin microbiome and targeted antimicrobial approaches

Research has moved away from simply suppressing C. acnes load. Reviews note that some studies link the bacterium to severity while others find it on healthy skin, which suggests that strain-level differences and overall community balance matter While certain studies associate C. acnes with acne severity, others show this bacterium's presence in healthy skin, suggesting that strain-specific differences and overall microbial balance play crucial roles. Two approaches are being tested: probiotics and bacteriophages, which are intended to restore microbial balance or to target pathogenic strains without disturbing the wider community Emerging therapeutic approaches, such as probiotics and bacteriophage therapy, aim to restore microbial equilibrium or selectively target pathogenic strains without disturbing the broader microbiome.

Phage work has so far been largely preclinical. Investigators have isolated phages from patient samples, with one study obtaining 15 phages from 64 clinical samples we attempted to isolate 15 phages specific to C. acnes from 64 clinical samples obtained from patients with acne vulgaris. A phase 1 cosmetic trial aimed to identify phages against C. acnes in people with mild to moderate acne, and reported broad-spectrum candidates, including phages active against antibiotic-resistant strains In a phase 1 cosmetic randomized clinical trial, Golembo and the team aimed to identify and characterize phages targeting C. acnes in subjects with mild to moderate acne. They found broad-spectrum phages, including those targeting antibiotic-resistant strains, with safe and specific genomes. Earlier reviews stated that there was no human efficacy evidence for phage therapy in acne there is no evidence on bacteriophage therapy in the treatment of acne in humans. Probiotic-type interventions have shown similarly small signals; one small facial study applied a cream containing heat-killed Lactobacillus plantarum to one side of the face in 15 women and reported a reduction in C. acnes and in redness applied a base cream including heat-killed L. plantarum-GMNL6 on one side of the face in 15 females. The treatment significantly reduced the amount of C. acnes and reduced, inclusively, the red areas and the porphyrin. The field's main constraints are the lack of standardized methods and the scarcity of longitudinal studies the lack of standardized methodologies, limited longitudinal studies, and the narrow focus on bacterial communities are major limitations in current research.

Anti-inflammatory targets

Phosphodiesterase-4 (PDE4) inhibitors are a major class under investigation. They raise intracellular cyclic AMP and reduce the synthesis of inflammatory cytokines Apremilast is an oral phosphodiesterase-4 enzyme inhibitor that modulates the immune system by increasing intracellular cyclic adenosine monophosphate levels and inhibiting inflammatory cytokines synthesis. The best-characterized compounds, such as apremilast, have been studied mainly in psoriasis and psoriatic arthritis, and newer oral PDE4 inhibitors such as orismilast are in development New oral PDE4 inhibitors are being developed, such as orismilast (LEO-32731), mufemilast (Hemay005), difamilast (OPA-15406) or lotamilast (E6005/RVT-501), among others. Their effect on innate inflammasome signalling, including IL-1β release, has not been established the effect of apremilast on innate immunity, notably inflammasome activation and regulation of IL-1β release, remains unknown.

Biologic agents that block cytokines used in other immune-mediated skin diseases remain largely hypothetical for acne. The most specific preclinical signal comes from a study of C. acnes CAMP factors in mice, which reported that anti-IL-8 treatment had therapeutic potential demonstrating the therapeutic potential of anti-IL-8 treatment.

Unresolved questions

Acne is commonly described as the product of four interacting processes: sebum overproduction, follicular hyperkeratinization, colonization by C. acnes, and inflammation It is a multifactorial disease that involves increased sebum production, hyperkeratinization of the pilosebaceous unit, Propionibacterium acnes (Cutibacterium acnes) colonization, and inflammation. Their causal order is still disputed. It is unclear whether sebum excess initiates plugging, whether bacterial growth drives inflammation or responds to it, and whether inflammation alone can produce the lesion pattern. The reasons some people with acne continue to have active disease into adulthood are also not settled, and the existing model does not fully explain that persistence.

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