Acne is an inflammatory disease of the sebaceous follicle that occurs commonly in developed countries during puberty and increasingly persists into adulthood. Environmental factors, especially a Western diet with high intake of hyperglycemic carbohydrates and milk/dairy products as well as a genetic disposition play a causal role (Dréno et al. 2018). Quantitative and qualitative changes of sebum disturb acroinfundibular cornification with formation of comedones (follicular retention hyperkeratosis), disturb the follicular barrier function, promote follicular inflammation, and modify the sebofollicular microbiome with biofilm formation of Propionibacterium acnes (P. acnes). The activation of innate and cell-mediated adaptive immunity induces inflammation of the sebaceous follicles in predisposed skin areas rich in sebaceous glands such as the face, chest, and back. Acne can leave scars of varying forms and degrees, leading to psychological stress and reduced quality of life.

Acne is the most common dermatological disease worldwide, especially in developed countries with Western dietary habits (Melnik 2018). A prevalence of up to 85% with a peak at 15-18 years of age is observed in adolescents (Moradi Tuchayi et al. 2015). On the other hand, populations with a predominantly Paleolithic diet (no milk, no cereals, little sugar), such as the Kitava islanders in Papua New Guinea, do not suffer from acne even during the climax of puberty (Cordain et al. 2002). In past decades, acne usually showed a spontaneous regression after puberty. More frequently now acne persists into adulthood. A de novo occurrence in adult women without a noticeable history in puberty is increasingly observed. The earlier acne begins, the more severe is its course, and the more likely it is to have a genetic predisposition. Both sexes are affected with approximately the same frequency, with higher degrees of severity being found in males. About 15-30% of all adolescent acne patients need medical treatment.

In the foreground of acne pathogenesis is the increased proliferation and hypertrophy of the sebaceous glands with increased and altered synthesis of sebum lipids (Fig. 1 ). Acne sebum contains increased concentrations of free monounsaturated fatty acids (MUFAs), which exert pro-inflammatory and comedogenic effects. Increased pituitary secretion of growth hormone (GH) enhances hepatic synthesis and release of insulin-like growth factor-1 (IGF-1), the principal effector hormone of puberty, which promotes gonadal and adrenal androgen synthesis and drives sebaceous lipogenesis. Individuals with congenital IGF-1 deficiency (Laron’s syndrome with a non-functional GH receptor mutation) and individuals with non-functional androgen receptors (ARs) do not experience acne (Ben-Amitai et al. 2011).

IGF-1 activates the kinase AKT, which increases the activity of the growth factor-and amino acid-sensitive kinase mechanistic target of rapamycin complex 1 (mTORC1) (Cong et al. 2019). mTORC1 is the central regulatory hub of metabolism and promotes the expression of the lipogenic transcription factors sterol regulatory-element binding factor 1 (SREBP1) and peroxisome proliferator-activated receptor-γ (PPARγ), which are both critically involved in sebaceous lipogenesis. In addition, AKT activates the E3 ubiquitin-protein ligase mouse double minute 2 (MDM2), the key negative regulator of the transcription factor p53, a potent suppressor of AR expression and mTORC1 activity. Furthermore, AKT inhibits the activity of the metabolic transcription factor FoxO1 (Agamia et al. 2016), which functions as a nuclear co-suppressor of AR and SREBP1. Overexpressed TOR (Agamia et al. 2016;Monfrecola et al. 2016) and SREBP1 in sebaceous glands of acne patients stimulate sebaceous lipogenesis (Zhou et al. 2018) and sebum fatty acid desaturation leading to increased synthesis of MUFAs. Bacterial lipase, which releases proinflammatory MUFAs, is already increased in microcomedones (Josse et al. 2020).

Androgens also activate AKT and subsequently mTORC1 via activation of mechanistic target of rapamycin complex 2 (mTORC2). Androgens via binding to ARs enhance androgen signaling (Chen and Zouboulis 2009;Ju et al. 2017), which in conjunction with overexpressed IGF-1 maximizes sebaceous lipogenesis. Acne sebum contains increased amounts of total sebaceous lipids and MUFAs, especially oleic and sapienic acid. MUFAs are pro-inflammatory, increase biofilm formation of P. acnes, and impair infundibular barrier function. P. acnes biofilm expresses higher amounts of the virulence factor bacterial lipase, which further increases the concentration of sebum free fatty acids. The displacement of linoleic acid by MUFAs in epidermal acylceramides of the sebaceous follicular epithelium impairs the follicular barrier function and promotes inflammation. Skin surface lipids from acne patients exhibit a reduction in the chain length of ceramides and increased levels of MUFAs, which compromise epidermal barrier function.

Sequencing of the genome of P. acnes identified bacterial strains (phylotypes) with increased lipase synthesis as well as higher expression of immunogenic P. acnes membrane epitopes. Activated mTORC1 increases the expression of hypoxia-inducible factor 1α (HIF-1α), the key transcription factor driving Th17 cell polarization. P. acnes and free palmitic acid stimulate toll-like receptor 2 (TLR2) and activate the NLRP3 inflammasome, resulting in pro-inflammatory Th17 immune responses with increased synthesis of interleukin 17 and interleukin 1β with subsequent neutrophil attraction.

Free palmitic acid and oleic acid are comedogenic and induce follicular keratinization (retention hyperkeratosis) with formation of comedones in the acroinfundibulum of the sebaceous follicle. The excessive activation of matrix metalloproteinases leads to the destruction of perifollicular tissue with scars.

The high prevalence of adolescent acne (>85%) in developed countries clearly excludes the predominance of genetic factors for the majority of acne patients. However, family studies and twin studies show a genetic predisposition for the occurrence of acne. Genetic polymorphisms of AR with lower CAG repeats (<20) have been associated with acne. Transcriptional activity of AR is controlled by p53, FoxO1, DDB2 and AR gene polymorphisms. Gene polymorphisms of IGF1 that increase IGF-1 expression and genetic polymorphisms that attenuate transforming growth factor-β (TGF-β) signaling increase the disposition to acne.

Acne lesions can be divided into primary (noninflammatory), secondary (inflammatory), and postinflammatory (hypo-or hyperpigmentations, scars) lesions. Enhanced IGF-1/insulin signal transduction with increased AKT-mTORC1 activity and decreased nuclear FoxO1 has been demonstrated in sebaceous glands of patients with acne. AKT activates mouse double minute 2 (MDM2), the critical inhibitor of the transcription factor p53. The resulting overstimulation of mTORC1 promotes the expression of the key lipogenic transcription factor SREBP1, which in concert with the androgen receptor (AR) induces sebaceous lipogenesis and generates pro-inflammatory and comedogenic monounsaturated fatty acids (MUFAs). mTORC1 also induces hypoxia-inducible factor 1 α (HIF-1α),a key driver of Th17 cell differentiation. IL-17 attracts leucocytes and promotes inflammation. Acne-specific metabolic deviations not only exist during puberty, but also in acne-associated syndromes with insulin resistance and mTORC1-driven Western diseases such as obesity and type 2 diabetes mellitus (acne: the metabolic syndrome of the sebaceous follicle). The Western diet with increased consumption of hyperglycemic carbohydrates and milk/dairy products over-stimulates insulin/IGF-1-mTORC1 signal transduction, which explains the dominant role of nutrition in the pathogenesis of epidemic acne vulgaris. Excessive consumption of whey protein and casein concentrates, rich sources of the branched-chain amino acids (BCAAs), are activators of mTORC1 and are used to build muscle mass with an increased risk of bodybuilding acne (Table 1 ). Abbreviations: AR: androgen receptor; GH: growth hormone; IGF-1: insulin-like growth factor-1; AKT: kinase AKT; MDM2: mouse double minute 2; mTORC1: mechanistic target of rapamycin complex 1; SREBP1: sterol regulatory-element binding protein 1; FoxO1: forkhead box O1; MUFA: monounsaturated fatty acid; HIF-1α; hypoxia-inducible factor 1α; IL-17: interleukin 17 Primary Non-Inflammatory Acne Signs include follicular filaments, micro-comedones, and closed and open comedones.

Follicular filaments: The large infundibular channels are filled with paste-like contents. When pressure is applied to the follicular openings, whitish spikes can be expressed. These filaments are normal components of a sebaceous follicle. A comedo may develop from a follicle filament consisting of a cocoon-like scaffold of about 20-40 corneocytes layered on top of each other and enclosing a vellus hair, bacteria, and sebum in the center.

Microcomedones: The first sign of acne, only microscopically visible, is a follicular cornification with conversion of a follicular filament into a compact comedo. The infundibulum is balloon-like, with about 40-80 horny cell layers enclosing two to three vellus hairs, numerous bacteria, and sebum.

Closed comedones: The continuous addition of corneocytes results in a compact horny cell mass. The infundibular epithelium becomes a comedone epithelium. The acroinfundibulum is tied up like a tobacco bag. Closed comedones become visible when the overlying skin is stretched: Whitish nodules (whitehead) with a tiny central pore appear.

Open comedones: Through continuous growth, closed comedones change into open comedones. The black plug (blackhead) consists of a scaffold of many hundreds of firmly adherent concentrically layered corneocytes, sebum, numerous Propionibacteria, and apical Pityrosporum fungi. Sebum flows through labyrinthine channels (lacunae) undisturbed to the skin surface. The vellus hair follicle continuously forms a vellus hair. The extruded telogen hair gets caught in the plug of comedones. In later inflammatory changes, these hairs encroach into the corium and cause chronic foreign body reactions. The blackish discolored apical part of open comedones contains melanin (blackhead), which is derived from the melanocytes of the acroinfundibula. Very dark-skinned people have especially black comedones, people with albinism in contrast have light comedones.

Any primary acne can lead to inflammation. Open comedones are relatively inert and rarely undergo inflammatory transformation. Some patients, especially those with acne conglobata or acne fulminans, react so early with inflammation in the microcomedone stage that closed or open comedones barely develop. Interleukin-1β and interleukin-17 are of particular importance in the formation of the inflammatory infiltrate, which consists mainly of neutrophil granulocytes.

Papules and pustules: Inflammatory changes in the comedone epithelium with immigration of lymphocytes and granulocytes with epithelial rupture cause papules and pustules. Parts of the comedones are extruded into the connective tissue, which promotes severe inflammation.

Nodules: These are persistent changes over weeks and months with foreign body granulomas as a result of the comedone components dispersed in the dermis.

Hemorrhagic nodules: If several papules coalesce, 5-15 mm in size, fluctuating and abscessing nodules filled with hemorrhagic or purulent secretion are formed. They are typical of acne conglobata, causing pain and healing with scars. They are actually not epithelial-lined cysts in histology.

Draining sinus: They are typical for severe acne progression, especially in acne conglobata and acne fulminans. Common sites are nasolabial folds, nasal root, corner of the Increased insulin/IGF-1 signal transduction Increased puberty-associated adrenal (DHEAS) and gonadal (androstendione, testosterone) androgen formation Puberty-induced upregulation of the somatotropic axis (GH-IGF-1) with physiological insulin resistance of puberty; IGF1 gene polymorphisms with increased IGF-1 expression; GH over-secreting pituitary adenomas Pathologically increased adrenal androgen formation in adrenal hyperplasia, adrenogenital syndrome, adrenal tumor, Cushing’s syndrome Increased intake of carbohydrates with high glycemic index, milk and other dairy products, which increase endogenous insulin and IGF-1 synthesis Polycystic ovary syndrome with hyperandrogenemia Polycystic ovary syndrome with insulin resistance, reactive hyperinsulinemia and increased IGF-1 serum levels and over-activated mTORC1 Systemic androgen supply (iatrogenic, androgen abuse, gestagens with androgenic residual activity) HAIR-AN syndrome (hyperandrogenism, insulin resistance, acanthosis nigricans) Gonadal hyperandrogenemia: androgen-forming testicular or ovarian tumors causing hyperandrogenism; androgen receptor gene polymorphisms with short CAG repeats with increased androgen receptor transactivation Insulin resistance in acne-associated syndromes such as PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, acne conglobata) and SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, osteitis) with increased formation of interleukin-1β Gene polymorphisms of damage-specific DNA binding protein 2 (DDB2), which regulates androgen receptor catabolism Insulin resistance and reactive hyperinsulinemia through smoking Increased intake of androgens for body building Abuse of BCAA-rich whey and casein concentrates, which enhance insulin/IGF-1 synthesis and mTORC1 activity eye, cheeks, and lower jaw margin. They are bulbous, up to 10 cm long, fluctuating, subcutaneous strands with numerous fistula openings to the skin surface. The labyrinthine duct system is partially lined with epithelium. Under pressure, a hemorrhagic and purulent, foul-smelling secretion is released, which emerges in several places. Abscessing fistulas heal extremely poorly; exacerbations can occur at any time.

In vivo evaluation with reflectance confocal microscopy (RCM) and optical coherence tomography (OCT) demonstrated that acne lesions are preceded by an increase of large bright follicles in the area corresponding to infundibular keratinization, followed by an increment of inflammation such as small bright cells upon RCM and enhancement of a vascular network upon OCT, which return to normal after the resolution of inflammation (Manfredini et al. 2019).

Post-inflammatory scars, pigmentary disorders, fistulated comedones, and cysts can develop.

Scars and pigmentary changes: They are an expression of severe inflammatory acne or abnormal healing.

Fistulated comedones: Here two or more comedones are connected by epithelialized duct systems. They are found almost exclusively on the back and neck.

Secondary comedones and acne cysts: Cysts are 1-5 cm in size, hemispherical skin-colored, bulging skin-elastic nodules above skin level. A pore is recognizable centrally. Spontaneously or under pressure, a cheesy white foul-smelling material is emptied. Cysts can rupture again and again; they do not heal spontaneously. In order to avoid abscesses due to ruptures, they should be removed surgically.

Scars: They are feared and often remain a lifelong stigma of this disease. Their morphology is extremely diverse, often with multiple scar types in the same patient. On the face there are funnel-shaped scars (ice-pick scars), others are wave-like (rolling scars) or varioliform (boxcar scars). Ice-pick scars must be differentiated from atrophodermia vermiculata, a rare genodermatosis (see ▶ Chap. 57, “Genodermatoses II”). On the chest and back there are either thin atrophic scars (atrophic macular scars) or small follicular white scars that look like closed comedones (perifollicular papular scars). Particularly feared are hypertrophic scars or genuine keloids, which occur preferentially on the shoulders, lateral upper arm parts, sternum, or upper back.

Acne may be present at birth, at puberty, or persist into adulthood. It shows a broad clinical spectrum from only a few comedones to numerous papules and pustules or conglobating nodes in acne conglobata. Acne fulminans is characterized by the most severe manifestations, often accompanied by extensive systemic symptoms. The three most common acne forms are acne comedonica, acne papulopustulosa, and acne conglobata, which are discussed first, including their therapy. Acne vulgaris is usually understood to represent the clinical spectrum from acne comedonica to acne papulopustulosa (Fig. 2 ).

At the beginning of puberty, small comedones develop centrofacially, which extend to the whole face and upper parts of the trunk at different speeds and extents. Few blackheads indicate a mild course, while numerous comedones, especially closed comedones, indicate a severe course requiring intensive therapy.

Inflammatory comedones with papules and pustules are prominent. The face, neck, chest, and back may be affected. If the inflammation expands into the deeper part of the dermis through repeated rupture of comedones and papules, painful persistent nodules occur. There is a risk of scarring. The process is unpredictable and can take years.

This is a severe disease that occurs primarily in men. Prominently displayed are countless papules, pustules, and abscessing nodules as well as fistulas and various types of scars. Acne conglobata is always accompanied by severe seborrhea. Large areas of the skin on the trunk suffer deep damage. Typical is the V-shaped involvement of the chest and back. Skin areas not otherwise affected by acne may be affected: the neck, scalp, auricles, upper arms, forearms, buttocks, and thighs. The course is protracted. Patients experience intense suffering from this serious disease. An increased C-reactive protein (CRP) indicates systemic inflammation. Untreated acne conglobata rarely resolves.

The severity of acne is classified according to the type and number of skin lesions, of which acne conglobata is a particularly severe entity. In addition, psychosocial effects on the patient, difficulties in working life, protracted course, and resistance to therapy are further criteria for assessing the severity of acne. Psychosomatic co-morbidity is found in about 30% of acne patients. Acne patients are often prone to depression and social phobia. Anxiety disorders are much more common in acne than in other chronic diseases. Selfesteem in acne patients is often affected. The level of suffering does not always correlate with the objective severity of the disease. Young men with acne conglobata have the highest suicide rates among patients with skin disorders. To determine the morphological severity of acne and to objectify therapy control, the type and number of acne lesions on one half of the face can be counted (Table 2 ).

Compact horny cell masses (comedones) are found in the infundibula of sebaceous follicles with prominent bacterial layers, perifollicular fibrosis with lymphocytic and granulocytic infiltrates in papules and pustules. Accumulation of T-lymphocytes and neutrophils surrounding the follicle epithelium are the earliest changes. Foreign body giant cells phagocytize corneocytes, hair, and bacteria. The sebaceous follicles are destroyed. There are retracted or elevated scars. In acne conglobata some follicles are extensively damaged. Frequently adjacent perifollicular inflammatory infiltrates become confluent. Hemorrhagic necrosis may be present.

Laboratory tests are not necessary for the diagnosis of typical acne vulgaris during puberty. Endocrinological examinations are important in cases of prepubertal, unusual, therapyresistant, or persistent acne. In particular, endocrinological diseases with hyperandrogenemia (increased gonadal or adrenal androgens) and insulin resistance (increased HOMA-IR) ) such as polycystic ovary syndrome (testosterone, free androgen index, dehydroepiandroserone sulphate, DHEAS) and adrenogenital syndrome (increased 17-hydroxyprogesterone especially after ACTH stimulation, increased DHEAS) should not be overlooked (Fig. 3 ).

Treatment adapted to the stage and severity of the disease shortens the course, alleviates the severity of the disease, and prevents scars (Table 3 ). Guidelines support an effective therapeutic approach, but should be individually adapted (Zaenglein et al. 2016). Treatment is topical, systemic, or combined, depending on the degree of severity, and is aimed at targeting as many pathogenetic factors as possible (Table 3 ) (Plewig et al. 2019). This usually requires a combination of several substances with additive or synergistic mechanisms of action. A major synergistic mode of action of all acne therapies is to attenuate mTORC1-and androgen signaling and to enhance the expression of p53 and FoxO1. A prerequisite for successful therapy is the patient’s motivation to actively participate. False concepts and unrealistic expectations are often present. They should be addressed directly and replaced with rational objectives.

Retinoids, benzoyl peroxide, antibiotics, azelaic acid, in different types of combinations, and occasionally with shortterm glucocorticoids for severe inflammation, are used for topical treatment.

Retinoids: Retinoids are substances that have a chemical structure or biological activity that derives from vitamin A (retinol). Retinoids have a pivotal place in acne therapy: • Tretinoin (vitamin A acid or all-trans-retinoic acid), 0.05% cream or solution, or 0.025% combined with topical clindamycin or erythromycin. The first retinoid used in acne therapy, therefore the reference substance of topical retinoids • Isotretinoin (13-cis-retinoic acid), 0.05% or 0.1% cream or gel, alone or combined with erythromycin • Adapalene (third-generation polyaromatic retinoid), 0.1% or 0.3% gel or cream, alone or combined with benzoyl peroxide • Tazarotene, a retinoid approved primarily for the treatment of psoriasis, in some countries also for acne therapy, 0.1% or 0.5% gel

• Motretinide (second-generation monoaromatic retinoid), approved for acne therapy in Switzerland 0.1% cream or solution.

Retinoids act comedolytically by inhibiting maturation and reducing the number of comedones as well as by promoting comedone elimination. In keratinocytes, retinoic acid induces the expression of the transcription factor p53, which suppresses keratinocyte proliferation. Retinoids are essential for maintenance therapy to prevent the development of new microcomedones (anti-comedogenic effect). They also reduce papules and pustules through their anti-inflammatory effect. Fixed-combination preparations of retinoids with In the morning topical therapy with benzoyl peroxide, in the evening topical retinoids like adapalene, isotretinoin, or tretinoin Acne papulopustulosa Topical retinoids alternating with benzoyl peroxide or antibiotic. Benzoyl peroxide or antibiotic in the morning, the retinoid in the evening. Topical antibiotics as monotherapy can no longer be recommended due to increasing antibiotic resistance Azelaic acid as an alternative for mild forms or as supplementation to dark-skinned patients to prevent or treat postinflammatory hyperpigmentation With significant inflammation, systemic therapy with antibiotics, e.g., minocycline 50-100 mg/day or doxycycline 50-100 mg/day, for about 4-6 weeks. Never combine oral and systemic antibiotics. Combine oral antibiotics with topical benzoyl peroxide or retinoids. Oral contraceptives can be prescribed for women with persistent acne Acne conglobata Isotretinoin 0.3-0.5 mg/kg body weight/day, for women in combination with oral contraceptives of the antiandrogen type. For severe inflammation, additionally glucocorticoids (for 1-3 weeks prednisolone 0.3-0.5 mg/kg/day in decreasing dosage), 1-2 weeks prior to isotretinoin, or overlapping Abscessing nodules Glucocorticoids intralesional (not in the periorbital areas because of the danger of Hoigné syndrome), repetition is possible Atrophic scars Dermabrasion, laser, excision, chemical peeling Hypertrophic and keloid scars Glucocorticoids under occlusion three times/week for 8 h, glucocorticoids intralesionally, cryotherapy antibiotics (erythromycin or clindamycin) or with benzoyl peroxide are available. The skin-irritating effect of retinoids depends on the type of retinoid, its concentration, and the vehicle. Adapalene and isotretinoin irritate less than tretinoin. Retinoids may irritate the skin, and lead to erythema (“sunburn from the tube”), a burning skin sensation, exfoliation, and temporary exacerbation until habituation sets in. Preparations in nanoparticles or microspheres reduce irritation and enhance penetration. They are usually used once a day, preferably in the evening. They should not be used during pregnancy or lactation to avoid the risk of retinoid embryotoxicity through extensive topical use.

Benzoyl peroxide: Use of this product leads to a marked reduction of P. acnes and S. epidermidis. It works more rapidly and more effectively than any antibiotic, with up to 90% reduction of P. acnes and 40% reduction of free fatty acids within a few days. The mechanism of action includes the generation of oxidative stress, which enhances p53 expression. Released free oxygen radicals (ROS) attack bacterial cell membranes and thus compromise biofilm formation of P. acnes. Bacterial resistance does not develop. The combination with local or oral antibiotic therapy reduces the development of antibiotic resistance. Benzoyl peroxide is considered the standard of local acne therapy. Compared to retinoids, the comedolytic activity is less pronounced. Benzoyl peroxide is available as 2.5-10% gel, cream, or wash solution. Fixed-combination preparations contain benzoyl peroxide and adapalene, clindamycin, or erythromycin. Local irritations such as itching, scaling, or tightness are dose dependent and can be reduced by a short contact therapy (washing solution). Benzoyl peroxide is not photocarcinogenic, mutagenic, or co-carcinogenic. Contact sensitization rarely occurs. The bleaching of hair and textiles should always be discussed. Benzoyl peroxide can be used in pregnancy and during lactation.

Antibiotics: The antibiotics used for inflammatory acne are bacteriostatic against Gram-positive organisms, antiinflammatory, and reduce the concentrations of free fatty acids in the follicle. Three substances are available: erythromycin, clindamycin, and nadifloxacin. They are used in different vehicles, i.e., solution, gel, emulsion, cream, or ointment, in concentrations between 1% and 4%. The steadily increasing resistance of Propionibacteria worldwide is a cause for concern. Generous use of the fluoroquinolone nadifloxacin in acne therapy should be critically evaluated since this substance belongs to the reserve antibiotics and resistance also occurs with topical application. Topical dapsone is used in some countries to treat mild to moderate acne. Topical antibiotic therapy should be as short as possible and should not be combined with oral antibiotics or other classes of antibiotics (risk of multidrug resistance). A combination of local antibiotics with benzoyl peroxide is highly recommended and decreases the risk of antibiotic resistance. This can be done in a fixed combination, alternately or at intervals. Retinoid combinations also make sense through additive and synergistic effects. Systemic absorption of clindamycin can rarely cause pseudomembranous colitis, mainly in children or adolescents.

Azelaic acid: This can be used as 15% gel or 20% cream in acne therapy. It is a naturally occurring C9 dicarboxylic acid with an effect on follicle keratinization and on P. acnes. Azelaic acid disturbs mitochondrial integrity and function and suppresses keratinocyte proliferation. The absence of bacterial resistance development and the low irritation potential compared to topical retinoids are advantageous, which is why azelaic acid can be used in atopic skin diathesis. Transient burning or a stinging sensation has been reported by many patients on treatment initiation. Since the substance inhibits melanin formation, it contributes to the reduction of post-inflammatory hyperpigmentation, which occurs more commonly in dark-skinned people. Application during pregnancy and lactation is possible.

Glucocorticoids: They can be used for a few days in highly inflammatory acne like acne conglobata, also to reduce granuloma pyogenicum-like lesions with systemic isotretinoin therapy.

Systemically, antibiotics, isotretinoin, and antiandrogens are used for acne.

Antibiotics: Systemic antibiotics are indicated for acne papulopustulosa. They possess anti-inflammatory effects, inhibit P. acnes, S. epidermidis, and bacterial lipases, and thereby decrease sebum free fatty acids. In vitro tetracyclines and macrolides suppress intracellular degradation of retinoic acid by inhibition of p450 and may thus functionally synergize with retinoic acid. Increasing bacterial resistance and rare severe side effects of minocycline should be noted. Tetracyclines and macrolides are the classes recommended for acne.

• Doxycycline is the tetracycline of first choice, at a dosage of 50 mg twice daily as introductory therapy and 50 mg/ day as maintenance therapy. The tolerance is good, but phototoxicity and the risk of esophageal ulcers (no evening intake) must be discussed. • Minocycline is used in the same dosage as doxycycline with the same effectiveness. The substance may cause dizziness or headache. Blue or black pigment chelate deposits in numerous tissues such as skin, mucous membranes, sclera, nail bed, thyroid gland, and bones are rare side effects. The phototoxicity is lower. Very rare but fulminant are drug-induced lupus erythematosus syndrome, autoimmune hepatitis, and pANCA-positive polyarthritis nodosa cutanea. Immediate termination of treatment is required in these cases. • Lymecycline is a second-generation tetracycline that offers the advantage of better tolerability and lower phototoxic potential. In comparative studies it was shown to be as effective as minocycline 50 mg/day. The dosage is 300 mg/day. • Sarecycline, a once-daily, narrow-spectrum tetracycline antibiotic, is approved by the US Food and Drug Administration (FDA) to treat moderate to severe acne at 1.5 mg/kg body weight/day. Its long-term benefit over doxycycline or minocycline remains to be confirmed. • Macrolides: Erythromycin was commonly used for acne therapy but is no longer recommended due to the widespread resistance of P. acnes. Newer, better tolerated, more expensive macrolides such as roxithromycin, clarithromycin, and azithromycin can be prescribed under certain circumstances, depending on the preparation, in a dosage between 150 and 250 mg twice daily for a few weeks. Macrolides can be used in childhood, and in women during pregnancy. • Other antibiotics: Clindamycin can only be used short term as an alternative due to possible severe side effects (diarrhea, pseudomembranous colitis). Cotrimoxazole (sulfamethoxazole and trimethoprim) is used in some countries with potential side effects like allergic reactions, erythema multiforme, Lyell syndrome.

General guidelines for systemic antibiotic therapy: Laboratory testing before initiation of therapy (blood count, transaminases, bilirubin, creatinine) is recommended for patients with pre-existing illnesses. In the case of inconspicuous baseline values, laboratory controls during therapy are generally not necessary. The adverse effects of systemic antibiotic therapy include changes in physiological microflora (diarrhea, candidiasis) and resistance induction. To avoid the development of resistance, topical and systemic antibiotics should not be combined. The combination with benzoyl peroxide or topical retinoids is recommended. However, combination of isotretinoin with tetracyclines or macrolides should be avoided because of the risk of increased intracranial pressure (pseudotumor cerebri). Isotretinoin (13-cis retinoic acid), the precursor drug of all-trans retinoic acid, and p450-inhibiting antibiotics may have synergistic effects in raising intracranial retinoic acid levels (Hellmann- Regen et al. 2014;Regen et al. 2015). Low-dose isotretinoin can be combined with macrolides, but the necessity for and benefit of this regimen have not been confirmed. Recent studies have not provided any evidence of a loss of efficacy of hormonal contraceptives through oral tetracycline administration. Tetracyclines are contraindicated for children up to 10 years of age, in pregnancy, and in lactation. The treatment should not exceed 3 months. Repeat treatments are possible. Clinical response should be expected not earlier than 6-8 weeks of use.

Isotretinoin: Isotretinoin (13-cis-retinoic acid), the stereoisomer of the all-trans-retinoic acid, is the only oral retinoid for acne therapy. It is usually used as monotherapy. Isotretinoin inhibits all major pathogenetic factors of acne: the increased synthesis of sebaceous lipids (>90%), hypercolonization of P. acnes including antibiotic-resistant strains (Ryan-Kewley et al. 2017), comedo formation, and inflammation. Isotretinoin is the most effective acne therapy and is often necessary for severe, therapy-resistant acne, especially acne conglobata and acne fulminans. The prescription of systemic isotretinoin is indicated only for severe acne that has been shown to be resistant to adequate standard therapies with systemic antibiotics and topical therapy. Decisions should be made individually based on the needs and wishes of the patients and long-term outcomes.

Isotretinoin has a dose-dependent sebosuppressive, exfoliative or comedolytic, anticomedogenic, and antiinflammatory effect. The primary mode of action is apoptosis of sebocytes (Melnik 2016a). Isotretinoin is used as a prodrug in the cell to all-trans retinoic acid, which translocates into the cell nucleus after binding to cellular retinoic acid binding protein 2 (CRABP-2) and induces pro-apoptotic transcriptional changes of gene expression including p53 (Melnik 2017;Shi et al. 2018), which is inactivated in immortalized sebocytes (Melnik et al. 2019), TRAIL, and FoxO1 after activation of retinoic acid receptors. The reduction of sebum impairs growth and biofilm formation and activity of P. acnes. Isotretinoin also reduces serum levels of IGF-1.

Adverse effects: All dose-dependent undesirable effects of isotretinoin can also be explained by apoptosis: mucocutaneous cheilitis, dry vestibulitis nasi, nosebleeds, sebostasis, and dry genital mucous membranes. In particular, myopathy can be aggravated at increased physical stress with an increase in creatine kinase. Apoptosis of liver cells explains the increase in transaminases. Isotretinoin induces an increased synthesis of very low-density lipoproteins (secondary hypertriglyceridemia) (see ▶ Chap. 117, “Systemic Therapy”). Because of the tendency to an increase in intracranial pressure (pseudotumor cerebri), isotretinoin should not be combined with tetracyclines. In rare cases depression can develop with treatment with isotretinoin, even very rarely suicide risk, in which an increased apoptosis of hypothalamic neurons induced by isotretinoin is suspected. It is advisable to inform patients with a predisposition to depression about the possible, rare occurrence of depressive moods and to monitor these patients cloesely (Singer et al. 2019). Activating polymorphisms of the retinoic acid receptor-α (RARA) provide an explanation for the increased disposition to the manifestation of depression under isotretinoin therapy. In isolated cases, oral isotretinoin therapy was observed to reduce night vision, which is important for drivers and pilots.

Diabetes mellitus, organ transplantation, and various other accompanying medications are not contraindications to isotretinoin therapy. An increased occurrence of irritable bowel syndrome has been inconsistently reported with isotretinoin therapy. In irritable bowel syndrome there is an increased rate of apoptosis of intestinal epithelial cells. Appropriate caution is therefore warranted.

Teratogenicity: Isotretinoin has teratogenic effects, which are induced by increased apoptosis of neural crest cells (Melnik 2018). Therefore, isotretinoin should not be used in women of childbearing age without contraception. If pregnancy occurs while on treatment with isotretinoin, there is a high risk of organ malformations. Comprehensive written consent with written documentation is required. In the case of minors, the parents must be involved in the planning of the therapy. The doctor must be sure that patients and parents understand the risks of isotretinoin therapy. No prescription must be given without safe contraception. Pregnancy must be ruled out before the start of treatment. This is done by a qualitative analysis of the morning urine on β-hCG. Patients should be advised by a gynecologist who will provide safe contraception. This should be initiated 1 month before the start of isotretinoin therapy; the safest approach is to have a second pregnancy test when the next menstruation begins before the start of treatment. The prescription, which is valid for only 7 days, will only be handed out after these conditions have been fulfilled, whereby only 30 capsules can be prescribed at a time. Monthly pregnancy tests are recommended. Contraception for medical reasons must be continued for 1 month after the end of the therapy.

Laboratory:

The following laboratory values should be determined before isotretinoin therapy: Blood count, creatinine, bilirubin, SGOT, SGPT, γ-GT, cholesterol, and triglycerides. Under therapy, liver and fat values are monitored at 6-week intervals in the first 3 months, afterwards every 3 months.

Dosage: A dosage of 0.2-0.5 mg/kg body weight/day is preferred. The drug is usually given as a single dose with a high-fat meal (better absorption), but higher doses can be divided into two single doses. Dosages of 1.0 mg/kg body weight/day are rarely required. Higher doses cause stronger undesirable effects. The duration of therapy is generally 3-6 months at least, but always until the acne has been cleared. Repeat treatments are possible. A cumulative dose above 100 mg/kg body weight/day has been proposed to lead to long-term remission, but the regimens and results are diverse. Simultaneous use of deep peelings, wax epilation, and ablative laser therapy should be avoided for 6 months after the end of isotretinoin administration.

Antiandrogens: Acne-associated seborrhea can be reduced by systemic antiandrogens in the form of hormonal contraceptives. Compared to isotretinoin, sebum suppression is significantly lower. The number of comedones is also influenced. The mechanism of action is based on inhibition of the androgen receptor and/or suppression of ovarian androgen synthesis. Antiandrogen therapy is indicated if women of childbearing age show obvious premenstrual exacerbation of acne, other virilizing disorders (androgenetic alopecia, hirsutism, polycystic ovary syndrome), do not respond sufficiently to conventional therapy, if there is a desire for oral hormonal contraception, or if safe contraception becomes necessary as part of systemic isotretinoin therapy. The combination of ethinyl estradiol with the antiandrogens cyproterone acetate and chlormadinone acetate and the progestins dienogest, desogestrel, or drospirenone is recommended. An increased risk of thrombophilia and breast cancer should be considered and explained to the patient. To initiate antiandrogen therapy cooperation with a gynecologist is recommended. Spironolactone at 50-100 mg daily is used in some countries as an antiandrogen, but well-controlled studies are lacking. Antiandrogenic therapy is not suitable as a primary monotherapy for uncomplicated acne and is always used in combination with other anti-acne drugs. An antiandrogenic treatment of at least 12 months is recommended.

Other systemic therapies: Glucocorticoids are not used as a standard therapy for acne. In individual cases, such as the exacerbation of acne under systemic isotretinoin therapy or in acne fulminans, the initial use of prednisolone (0.5-1.0 mg body weight/day) for several weeks is highly effective. Dapsone can be used as an alternative to oral isotretinoin in severe acne, but is very much inferior in effectiveness. Recent evidence in moderate to severe acne supports the therapeutic efficacy of metformin as an adjuvant, which activates p53 expression and attenuates mTORC1 signaling (Melnik 2017;Robinson et al. 2019).

Dietary intervention: A Western diet with increased intake of carbohydrates with a high glycemic index increases levels of insulin and free IGF-1, whereas a low glycemic load diet decreases serum insulin and IGF-1 levels (Smith et al. 2007;Burris et al. 2018). Milk has a high insulinemic index >100. The insulinotropic effect of milk is mediated by whey proteins, which are a rich source of mTORC1-activating branched-chain amino acids BCAAs (Melnik 2015). The casein fraction of milk increases hepatic IGF-1 synthesis (Hoppe et al. 2004(Hoppe et al. , 2005. High milk consumption increases postprandial insulin levels and enhances basal levels of circulatory IGF-1. Epidemiological studies support the acne-inducing and acne-aggravating effect of milk, especially skim milk and other dairy products (Juhl et al. 2018). A dietary restriction of hyperglycemic carbohydrates in combination with metformin improves acne in preliminary studies. Dietary intervention in acne essentially corresponds to a Paleolithic diet in which cereals, sugar, milk (especially low-fat milk), and milk products are avoided (Melnik and Zouboulis 2013). The effectiveness of dietary intervention can only be assessed after 3 months. A dose-response relationship regarding aggravation or improvement of acne as well as individual differences in the nutritional intervention remain unclear and require large-scale studies.

Restriction of hyperinsulinotropic foods:

• Milk, low-fat milk, dairy products such as yoghurt, milk ice cream, whey, cream cheese, and whey protein concentrates (insulinemic index >100) • Sweets, milk chocolate, potato chips, cornflakes, white bread, French fries, wheat noodles, fast food (high glycemic index) • Saturated fats and fats with high content of n-6 fatty acids, especially arachidonic acid, in lard, pork liver, liver sausage, egg yolk (pro-inflammatory), trans fat • Smoking (induces insulin resistance) • Frequent snacks (snacking) • Soft drinks containing high amounts of sugar (cola, lemonades).

Preference of less insulinotropic food:

• Foods rich in dietary fibers, salads, low-sugar fruits, vegetables, and berries • Whole grain bread and muesli with vegan milk replacements, preferably own cooking with • Fresh vegetables (no fast food) • Consumption of sea fish (tuna, salmon, herring, mackerel) or other foods high in n-3 fatty acids (anti-inflammatory and mTORC1 inhibiting) • Complete meal breaks lasting several hours • Mineral water, unsweetened teas.

Adjuvant phototherapy, dermatocosmetics/acne toilet and treatment of scars are important from the patient’s compliance, but have less evidence of efficacy.

Phototherapy: UV therapy of acne is obsolete. Blue light treatment (415 nm) has a slight antimicrobial and antiinflammatory effect. Photodynamic therapy of acne is not recommended by us but is a common adjuvant treatment in Asian countries.

Dermatocosmetics: These adjuvant measures include medical cleansing and mechanical (abrasives) and chemical peeling (α-hydroxy acids such as glycolic acid, trichloroacetic acid, or salicylic acid). Hydrophilic bases such as hydrogels or oil-in-water emulsions are particularly suitable for skin care. The treated acne skin with damaged epidermal barrier function often requires moisturizing, hydrophilic and non-greasy cleansing, and care products. Camouflaging cosmetics can be used for acne-prone skin as well as in any stage of acne therapy. Cosmetics should not contain comedogenic ingredients.

Manual comedone extraction (acne toilet): This is preferably used for acne comedonica. Open comedones can be expressed with a comedone extractor. Closed comedones are first scratched with a lancet or cannula. Manual comedone extraction contributes to the visible improvement of findings and compliance.

Scar treatment: Acne scars can be improved by a range of conservative and surgical treatments, but the patient should not expect complete restitution. Fistulated comedones can be split and hypertrophic scars can be treated by cryosurgery. When selecting therapy measures, it must be taken into account that the skin appearance can improve spontaneously over years. The evidence for the effectiveness of available scar treatments is generally very low.

Acne often shows a persistent course and tends to recur. For this reason, maintenance therapy should always be initiated after primary therapy in order to avoid or delay recurrences. Systemic isotretinoin therapy, which often leads to the healing of acne, must sometimes be repeated in individual cases. Topical retinoids such as adapalene are well suited for maintenance therapy as they prevent new microcomedones. Patients should control their dietary lifestyle.

Various syndromes associated with hyperandrogenemia, insulin resistance, or autoinflammation are often associated with persistent or severe acne (Chen et al. 2011).

Of particular clinical importance is the frequent polycystic ovary syndrome (PCO syndrome), which occurs in 5-20% of all women. It is characterized by hyperandrogenemia, hyperandrogenism, insulin resistance, oligo-and anovulation, and polycystic ovaries. Overactivation of mTORC1 is a recently recognized feature of PCO syndrome (Liu et al. 2016). Often acne (up to 30%), syndrome-specific hirsutism, and less commonly androgenetic alopecia are present. Diagnosis is made clinically, supported by sonographic detection of ovarian cysts (the absence of ovarian cysts does not exclude PCO syndrome), increased laboratory parameters of anti-Muellerian hormone, non-pulsatile luteinizing hormone (LH), free testosterone, total testosterone, free androgen index, HOMA index, insulin, C-peptide and IGF-1, and often pathological oral glucose tolerance test. Increased serum levels of BCAA have been linked to insulin resistance in PCO syndrome. In women with therapy-refractory acne or adult acne, the PCO syndrome should be taken into account first and foremost for differential diagnosis.

Therapy requires cooperation with gynecologists. The focus is on weight normalization, reduction of insulin resistance, antiandrogenic treatment with hormonal contraceptives (e.g., 35 μg ethinyl estradiol and 2 mg cyproterone acetate) and, if applicable, off-label use of metformin (up to twice 1,000 mg/ day depending on body weight) to improve insulin sensitivity and further reduction of androgen levels (Teede et al. 2019).

Otherwise, acne papulopustulosa or acne conglobata is treated as usual.

The Hyperandrogenism-Acne-Insulin Resistance-Acanthosis Nigricans syndrome is perceived by some authors as a special variant of PCO syndrome, while by others as an “umbrella” term. Patients show clear characteristics of hyperandrogenism such as seborrhea, hirsutism, acne, androgenetic alopecia, menstrual disorders, deep voice, clitoral enlargement, and changes in muscle mass, insulin resistance, diabetes mellitus type 2 as well as acanthosis nigricans (see ▶ Chap. 101, “Benign Epithelial Tumors”). These patients have high levels of insulin, testosterone, and androstenedione, but normal levels of LH and prolactin. Increased ovarian androgen synthesis is usually observed. The syndrome is thought to be caused by severe insulin resistance due to mutations of the insulin receptor with compensatory hyperinsulinemia and hyperandrogenism (Rager and Omar 2006). It is unclear whether obesity is a primary or confounding factor in the pathogenesis.

Antiandrogens such as cyproterone acetate, spironolactone, and flutamide can be used in combination with oral contraceptives added to metformin and further acne therapy.

The adrenogenital syndrome (congenital adrenal hyperplasia ¼ CAH) can be the only symptom that causes late onset and therapy-resistant or unusually easily recurrent acne. A severe classical form, which already manifests itself in early childhood, is distinguished from the more frequent nonclassical form (NCAH) (see ▶ Chap. 99, “Endocrine Diseases”). Mutations in the CYP21A2 gene leading to reduced cortisol formation due to 21-hydroxylase deficiency result in increased ACTH stimulation of the adrenal gland with increased formation of DHEAS. The evidence is provided by the determination of elevated basal levels of 17α-hydroxyprogesterone (>2 ng/ml) and is confirmed by the ACTH stimulation test, in which the 17α-hydroxyprogesterone levels often exceed 10 ng/ml. If the ACTH stimulation test is positive, prednisolone (2.5-5.0 mg/day) or dexamethasone (0.25-0.75 mg/day) is administered to correct the adrenal pituitary axis. In 10-30% of women with PCO syndrome, NCAH with hyperinsulinemia and decreased insulin sensitivity (increased HOMA-IR) is found (see ▶ Chap. 99, “Endocrine Diseases”). (Chamot et al. 1986) The rare SAPHO syndrome (Synovitis, Acne, Pustulosis, Hyperostosis, Osteitis) is mainly observed in children and adolescents. Three diagnostic criteria proposed by rheumatologists include:

• Occurrence of chronic recurrent multifocal osteomyelitis with and without skin manifestations, • Acute or chronic sterile arthritis, usually associated with palmoplantar pustulosis or severe acne, or • Sterile osteitis in the presence of a skin symptom.

The SAPHO syndrome is characterized by a rheumatoid factor negative osteoarthropathy, which can be associated with various dermatological diseases. These include above all acne, but also acne inversa, folliculitis et perifolliculitis capitis abscedens et suffodiens, psoriasis, pustular psoriasis, palmoplantar pustulosis, Sweet syndrome, Sneddon-Wilkinson disease, and pyoderma gangrenosum. This is from a rheumatologist’s point of view. Dermatologically, they are various independent diseases, therefore the extension of the definition is questionable. The sternocostoclavicular hyperostosis associated with palmoplantar pustulosis, first described in Japan, represents the essential feature of this syndrome complex. Acne is typically in a severe form like acne conglobata or acne fulminans, while mild acne vulgaris is a common manifestation but may be unrelated. Inflammatory bone involvement is usually found in the anterior thoracic segment, especially sternoclavicular or manubriocostal, sacroiliac, and at the extremity joints, and is detected by magnetic resonance imaging and bone scintigraphy. Increased leukocytic synthesis of interleukin-8 and tumor necrosis factor-α (TNFα) has been observed. A TNFα-induced insulin resistance could be of pathogenetic importance in the occurrence of severe acne in some of the patients with SAPHO syndrome.

Acne and pustulosis usually respond well to oral isotretinoin. The efficacy of biphosphonates (oral or intravenous pamidronate 60 mg over 3 days) on sterile arthritis has been well confirmed. TNFα blockers such as infliximab may be used to treat resistant cases, but seem less effective for acne, while the database is too small to judge the efficacy of biologics targeting IL-1 and IL-17/IL-23. Cooperation with other disciplines is advisable. (Plewig and Kligman 1975) Acne fulminans is an acute febrile ulcerating acne conglobata with polyarthralgias and reactive leukocytosis. It is increasingly, but also controversially, regarded as a special form of the SAPHO syndrome. There is an overlap of symptoms, but there are also significant differences such as the rare occurrence of osteomyelitis in acne fulminans and female predominance in SAPHO syndrome.

This rare, acute-onset severe disease occurs almost exclusively in boys aged 13-16 years. Severe general symptoms develop within a few days to weeks. Strongly inflammatory skin changes like acne conglobata with hemorrhagic necrosis on the chest, back, shoulders, and upper arms erupt and lead to painful, extensive bleeding skin necrosis and granuloma pyogenicum-like vascular proliferations (exuberant granulation tissue) (Fig. 4 ). Typical symptoms are painful sacroiliac, hip, knee, and elbow problems, which cause the patient to bend over and make it difficult to stand up or sit down. Radiologically, aseptic bone necrosis can be detected, especially in the sternoclavicular joint. General symptoms include fever, elevated erythrocyte sedimentation rate, severe leukocytosis, proteinuria, erythema nodosum, hepatosplenomegaly, and leukocytoclastic vasculitis. Acne fulminans induced by oral isotretinoin has been described and is also called pseudo-acne fulminans due to the absence of systemic symptoms.

Systemic prednisolone (1.0 mg/kg body weight/day) is initially given for a few weeks or until the symptoms improve significantly. One to two weeks later, isotretinoin should be used in low doses (0.2-0.5 mg/kg body weight/day) for several months, possibly with continuation of low-dose glucocorticoids. The administration of topical glucocorticoids to the acute ulcerating skin lesions is useful. In individual cases, successful treatment of acne fulminans in the context of SAPHO syndrome with the TNFα inhibitor infliximab has been observed.

1.2.6 PAPA Syndrome (Lindor et al. 1997) OMIM 604416 AD 15q24-q25.1 PSTPIP1

Adapter protein with pyrin binding

The clinical triad of pyogenic sterile arthritis, pyoderma gangrenosum, and acne conglobata has been described under the acronym PAPA syndrome and is an autoinflammatory disease. Aseptic, seronegative non-axial arthritis, which usually affects knee, elbow, or ankle joints, occurs early in childhood. Severe acne or acne conglobata only occurs during puberty, while pyoderma gangrenosum usually occurs during childhood or adolescence but also in adulthood. The syndrome is associated with mutations of the proline serine threonine phosphatase-interacting protein 1 (PSTPIP1/CD2BP1) gene. Mutated PSTPIP1 proteins have an increased binding capacity to pyrin (Shoham et al. 2003), an inhibitor of inflammation. Mutation-induced changes in the cellular localization of PSTPIP1 result in an increase in the activity of inflammasomes accompanied by increased secretion of interleukin-1β (IL-1β) and TNFα. Association with Crohn’s disease, ulcerative colitis, or autoimmune hepatic disease has been described, indicating some common pathogenic pathways (Marzano et al. 2016).

Since pyrin is expressed by neutrophil granulocytes but not by T or B cells, neutrophil infiltrates result in association with sterile arthritis, acne, pyoderma gangrenosum, and other neutrophilic dermatoses. The acne of PAPA syndrome manifests only in puberty under the influence of upregulated androgens and IGF-1.

Although pyoderma gangrenosum in PAPA syndrome responds to systemic glucocorticoids, the TNFα inhibitor infliximab and IL-1 receptor antagonist anakinra are much more effective, but the acne response appears to be inconsistent (Brenner et al. 2009).

The PASH syndrome represents the combined occurrence of pyoderma gangrenosum, acne, and hidradenitis suppurativa (acne inversa/dissecting terminal hair folliculitis) and belongs to the autoinflammatory syndromes. The underlying genetic defect has not yet been characterized. Few patients show severe acne, while a mild acne is common and may not be associated with the syndrome. In contrast to PAPA syndrome, pyogenic arthritis is absent. A therapy trial with a TNFα inhibitor or IL-1 receptor blockade may be considered.

Other less defined autoinflammatory syndromes associated with acne have been proposed, such as PAPASH (pyoderma gangrenosum, acne, psoriasis, arthritis, suppurative Fig. 4 Acne fulminans with conglobating nodules and hemorrhagic crusts hidradenitis) (Garzorz et al. 2016), PASS (pyoderma gangrenosum, acne, and spondyloarthritis), and PAC (pyoderma gangrenosum, acne, colitis ulcerosa) syndromes, with pyoderma gangrenosum as the primary essential feature.

1.2.8 Apert Syndrome (Apert 1906;Solomon et al. 1970) OMIM 101200 AD 10q.26 FGFR2 Activated FGFR2 signal transduction

The autosomal dominant Apert syndrome (synonym: acrocephalosyndactyly syndrome) is characterized by synostosis of the distal extremities, vertebrae, and cranial bones. Early ossification of the cranial sutures causes craniofacial deformities such as turribrachycephaly, hypertelorism, proptosis of the eyes, dental anomalies, cleft palate, and syndactyly of the fingers and toes. The dermatological characteristic is a severe acne occurring early at the beginning of puberty, which also spreads to the extensor sides of the forearms. Two heterozygous gain-of-function mutations of fibroblast growth factor receptor-2 (FGFR2) increase cellular signal transduction with activation of the phosphoinositol-3 kinase/AKT cascade (Melnik 2009a). Apert syndrome responds to systemic isotretinoin.

1.2.9 Acneiform Nevus (Munro and Wilkie 1998) While the germline mutation of FGFR2 (Ser252Trp) induces acne in Apert syndrome, the same mutation causes acneiform nevus in the form of a genetic mosaic of the skin (Melnik et al. 2008) (see ▶ Chap. 58, “Mosaicism and Epidermal Nevi”). Here, an inflammatory acne with comedones, papules, and pustules is usually found unilaterally on the trunk along the Blaschko lines; it intensifies during puberty and responds well to low-dose oral isotretinoin (10 mg/day or every second day).

Acne in Infancy and Childhood 1.3.1 Acne Neonatorum (Kraus 1913) Affected newborns already show closed comedones, papules, and pustules on seborrheic shiny facial skin immediately after birth. The frequency is about 20% of newborns, if the occurrence of individual comedones is included. Boys are affected preferentially. Prior to birth, the placenta produces more CRH (corticotropin-releasing hormone), which increases the fetal adrenal synthesis of dehydroepiandrosterone sulfate (DHEAS), which promotes sebum production for the formation of vernix caseosa. The newborn acne is short lasting and heals without scars. It should be differentiated from comedone-free neonatal cephalic pustulosis associated with the fungus Malassezia furfur in some cases (Fig. 5 ).

This occurs in the third to sixth months of life mainly in boys and persists for many months, and is less frequent but more severe than acne neonatorum (Jansen et al. 2006). The face shows numerous inflammatory lesions, occasionally also conglobating nodules (acne conglobata infantum) with a tendency to scarring. Topical or systemic treatment is often required as for acne vulgaris. Oral macrolides are mostly preferred. In severe cases, systemic isotretinoin therapy is indicated.

” Occasionally acne infantum requires endocrinological clarification, whereby an adrenogenital syndrome should be excluded.

1.4.1 Adult Acne/Postadolescent Acne/Acne Tarda Adult acne usually occurs in adult women after the age of 25 years. In these patients, the acne has either not regressed (persistent type) or, in the majority, has just started after the age of 25 years (late-onset type) (Capitanio et al. 2010). The causes are multifactorial, including stress, hormonal changes, smoking, obesity, and nutrition. In particular, the PCO syndrome should be considered in severe cases. In many women, acne displays premenstrual exacerbation, accompanied by increased follicular inflammation and the appearance of papular or nodular acne in the lower half of the face. Mixed images with rosacea or perioral dermatitis may exist. In adult acne with menstrual disturbances, endocrinological diagnostics should be performed to exclude hyperandrogenemia and insulin resistance.

Even without hormonal abnormalities in the peripheral blood, patients usually respond well to long-term oral antiandrogen therapy. Low-dose isotretinoin orally (off-label use) quickly shows beneficial effects. Possible side effects and teratogenicity should be noted.

Special Forms of Acne

Bodybuilding acne. Androgen abuse stimulates sebaceous gland hypertrophy, causes seborrhea, and often induces mild to fulminant acne (Fig. 6 ). Illegally obtained androgens are often used for doping to build muscle mass. Suppliers offer a large number of preparations through the internet. The abuse of anabolic steroids has reached epidemic dimensions in teenagers and young men (Melnik et al. 2007). Iatrogenic administration of androgens can also trigger acne. Androgen abuse can trigger an acne surge for the first time or exacerbate a pre-existing acne. Acne papulopustulosa, acne conglobate, and acne fulminans may result. For bodybuilding and fitness training, androgen and whey protein abuse are frequently combined, whereby the effects of the androgens and whey proteins potentiate the activation of androgen, insulin, and IGF-1 signaling (Melnik 2009b).

Information about the considerable risks regarding endocrinological, cardiovascular, neurological, psychiatric, and oncological diseases is important. The immediate discontinuation of anabolic steroids and protein concentrates is indicated, as well as an acne therapy appropriate to the stage. (Sulzberger et al. 1946) Staying in a humid-hot tropical environment or working in similarly conditioned workplaces (blast furnaces, smelters) can lead to worsening of pre-existing acne with acne conglobata-like symptoms.

Minimal acne becomes such a psychological burden for some patients, mostly girls or young women, that minimal acne lesions can be treated by expression, squeezing, or scratching. Instruments such as needles and tweezers are often used. In the foreground are polymorphic lesions: hemorrhagic encrusted excoriations, flat ulcerations, which heal only slowly because they are always reworked and end with hyper-and hypopigmentation as well as scars. Common sites are forehead-hair line, cheeks, chin, chest section, and easily accessible upper shoulder areas (Fig. 7 ). Although the original acne has mostly healed, the excoriations continue. In most cases, compulsive neurotic behavior is present.

Mild acne therapeutics together with psychotherapeutic intervention occasionally help; in severe cases professional psychotherapeutic support should always be sought.

If acne and acne-like symptoms occur in atypical places or outside the typical age of acne, a contact acne or acne venenata (venenum, Latin ¼ poison) should be considered.

A variety of comedogenic substances can trigger contact acne. Mainly affected are people with seborrhea and active or pre-existing acne. The following disease patterns are typical.

This is a typical female disease mostly beyond the actual age of acne. Cosmetics containing comedogenic substances lead to dense, predominantly closed comedones and isolated papulopustules at the most frequent application sites after prolonged intensive use: forehead, cheeks, perioral region.

1.6.2 Pomade Acne (Plewig et al. 1970) A very similar clinical picture arises when comedogenic pomades are used by different ethnic groups to care for curly hair and these are transferred to the face. Common sites are the forehead and cheeks. Therapeutically the triggering products are discontinued, and locally retinoids or azelaic acid can accelerate the healing process.

Epidemiology This was the most common form of work-related acne in the 1970s, but is now less common. The triggers are lubricating, drilling, and crude oils as well as tar used in the metalworking industry, in road construction, the automobile industry, and in the manufacture and handling of wood-impregnating agents and roofing felt.

This results from contact with technical oils (oil acne) or tar products (tar acne). In contrast to acne vulgaris, vellus hair follicles are also affected. Papulopustules, followed by comedones at the contact (face, back of the hand, forearms) or chafing areas of the oil-or tar-soaked clothing, characterize the clinical picture. In contact areas with substances containing tar, phototoxic reactions and hyperpigmentation may be associated.

Topical retinoids or azelaic acid. It is essential to avoid acneinducing workplace substances by use of protective measures at the place of occupation.

Smoker Acne (Capitanio et al. 2009) An increased prevalence of micro-and macrocomedones as well as small cysts on the cheeks without inflammatory phenomena is preferentially found in adult smokers. This atypical acne is perceived by some authors as a distinctive form of acne. Nicotine, aromatic hydrocarbons, and smoke-induced interleukin-1α as well as insulin resistance from smoking have been discussed as triggers. The correlation with the duration and intensity of smoking is unclear. Abstinence from smoking and topical retinoids are recommended for treatment.

Physical Acne 1.8.1 Acne Mechanica (Mills and Kligman 1975) Chronic mechanical stress at common acne sites can trigger characteristic acne. It occurs, for example, at pressure and abrasion points or when wearing headbands. Also “fiddler’s neck” belongs to this group.

It is important to remove the mechanical component. Topically, retinoids or azelaic acid are used.

Solid Facial Edema in Acne (Connelly and Winkelmann 1985) The rare persistent facial edema, initially described in association with acne, is more frequently observed in association with rosacea and is therefore addressed there (Sect. 4.8).

1.10 Acne-Like Diseases 1.10.1 Medication-Induced Acne-Like Eruptions Numerous drugs may cause acne-like or acneiform eruptions. These mostly acutely occurring acneiform exanthemas have a monomorphous appearance and do not show any comedones at first (Figs. 8 and 9 ). In acneiform lesions, a follicular inflammation is primarily visible, and secondary comedones can appear later. It is noticeable that numerous drugs known as P450 cytochrome inducers can trigger acnelike eruptions. These include rifampicin, phenobarbital, glucocorticosteroids (steroid acne), phenytoin, psoralens, ciclosporin A, and tetracyclines (see ▶ Chap. 35, “Cutaneous Adverse Drug Reactions”). Acneiform skin changes occur in oncological patients treated with epidermal growth factor receptor (EGFR) inhibitors such as cetuximab, EGFR kinase inhibitors such as gefitinib, or mTOR inhibitors such as sirolimus. They disrupt follicular epidermal barrier function resulting in P. acnes-induced production of interleukin 36y, which drives acneiform skin toxicity (Satoh et al. 2020).

Other acneiform diseases, mostly pathogen-related folliculitis, can be distinguished: Pityrosporum folliculitis, bacterial folliculitis, especially Gram-negative folliculitis, demodex folliculitis, folliculitis in HIV infection, eosinophilic folliculitis.

The causative agent should be removed. Topical retinoids work well against steroid acne. Treatment of eruptions induced by the administration of EGFR antagonists, which are not true acne, is described in ▶ Chap. 35, “Cutaneous Adverse Drug Reactions.”

Despite its name, it is an acutely occurring acne-like eruption. Halogens can also exacerbate existing acne, especially on the face and back. Sources are cough syrups, sedatives, sleeping pills, antidepressants, diet preparations, especially from sea algae (kelp acne), health teas, and some multivitamin tablets. Bromoderm and iododerm are discussed in the chapter on drug reactions (see ▶ Chap. 35, “Cutaneous Adverse Drug Reactions”). Treatment Sunlight exposure should be avoided. Application of sun protection agents effective in the UV-A and UV-B range as well as appropriate protective clothing is recommended. Retinoids or azelaic acid accelerate the healing process.

1.10.4 Gram-Negative Folliculitis (Fulton et al. 1968) This clinical picture simulating an acne papulopustulosa can develop after several months of antibiotic therapy of acne or rosacea and be the cause of an alleged resistance to therapy

The most common causes are accidental exposure to halogenated aromatic hydrocarbons in the course of industrial accidents, chronic exposure during production processes, food contamination, and poisoning.

In the strict sense, chloracne is not acne, but an involution of sebaceous glands accompanied by comedones. Contamination may occur via the skin, gastrointestinal tract, or respiratory tract. Chloracne develops insidiously or peracutely, depending on the toxin and dose. Severe neurological, gastrointestinal, nephrological, and cardiac symptoms may be associated with severe sequelae including a fatal outcome. Chloracne usually occurs several weeks after exposure to halogenated aromatic hydrocarbons (Ju et al. 2009;Schlessinger and Schlessinger 2018). Possible sources of contamination are electrical conductors, insecticides, fungicides, herbicides, wood preservatives, industrial fats, and food contaminations. The following chemical compounds trigger chloracne: polychlorinated and polybrominated naphthalenes and biphenyls, polychlorinated dibenzofurans, polychlorinated dibenzodioxins, tetrachloroazobenzenes and tetrachloroazooxybenzenes. 2,3,7,8tetrachloro-dibenzo-p-dioxin (TCDD) is a strong inducer of arylhydrocarbon hydroxylase (CYP1A1) (Panteleyev and Bickers 2006).

The skin shows innumerable closed and open comedones, later large inflammatory epidermal and fistulating cysts, acne conglobata, and acne inversa-like lesions in a wide distribution where sebaceous follicles and terminal hair follicles can be found (Fig. 10 ). Histologic findings show infundibular hyperkeratinization of the sebaceous follicles with an involution of sebaceous glands and sweat glands, which lose their secretory capacity and are replaced by keratinizing cells.

Dioxin-induced modifications of stem cell differentiation are probably responsible for the morphological changes. Halogenated aromatic hydrocarbons interrupt endocrine signal axes and increase carcinogenesis. The ligand-bound arylhydrocarbon receptor is an important regulatory transcription factor that suppresses the activity of the androgen receptor. The involution of the sebaceous glands in chloracne is most likely explained by toxic effects on stem cells.

In the case of acute intoxications, the rapid and thorough removal of sources, especially contaminated clothing, is a priority. The fecal excretion of fat-soluble halogenated aromatic hydrocarbons can be accelerated by oral administration of a synthetic fat (olestra). Chloracne is extremely resistant to therapy. Topical retinoids or oral isotretinoin may be tried to remove comedones. If chloracne is suspected, the workplace, household, and contact persons should be examined immediately, involving environmental toxicology laboratories.

Acne Inversa (Plewig and Steger 1989) Dissecting Terminal Hair Folliculitis (Chen and Plewig 2017)

Hidradenitis suppurativa, dissecting terminal hair folliculitis (DTHF), likely variants are cutis-verticis-gyrata-like acne inversa, folliculitis et perifolliculitis capitis abscedens et

The disease is rare, but probably underestimated or underdiagnosed. In the classic non-syndromic form of Caucasian descent, the ratio of women to men is 3:1. Gender predominance varies in different ethnic groups. Occurrence before puberty is extremely rare. Patients are always older than those otherwise affected by acne conglobata and are often obese and heavy smokers. Certain subtypes are more common in young men of dark skin.

The focus is on the destruction of the infundibula of terminal hair follicles in intertriginous skin areas. A Th17-mediated immune response with a reduced proportion of regulatory T-cells (Treg) has been observed (Frew et al. 2018). Obesity with mTORC1 activation and smoking act as important provocation factors that promote Th17 cell differentiation and impair Treg differentiation. Perifollicular Tregs maintain hair follicle stem cell homeostasis in a Notch-dependent manner. Recently, perturbation of the hair follicle stem cell compartment with a lack of certain quiescent bulge stem cell population and increased proliferating progenitor cells have been reported (Orvain et al. 2020). Characteristic is the inverse (intertriginous) inflammatory infiltration of terminal hair follicles as an anatomical initiating point, where the fragile infundibula rupture, with activation of the IL-1β pathway (Witte-Händel et al. 2019). The apocrine sweat glands that bind to the terminal hair follicles are only affected secondarily. Nicotine abuse, irritation and occlusion (deodorants, shaving, tight clothing), and bacterial superinfection are considered as trigger factors. In sporadic cases, no genetic defect has been detected so far. In familial acne inversa/ dissecting terminal hair folliculitis (especially in Chinese families) mutations of the γ-secretase complex (Wang et al. 2010;Pink et al. 2011;Liu et al. 2011;Li et al. 2020) lead to an impairment of the Notch receptor signaling pathway with impairment of the integrity of the infundibular epithelium Xiao et al. 2016). The syndromic form, which is associated with pyoderma gangrenosum, acne conglobata, and inflammatory bowel disease, is discussed as part of the autoinflammatory syndromes.

Clinical manifestations are heterogeneous and overlapping, while suggestions of certain phenotypes are not validated.

The folliculitis lesions follow an inverse pattern, predominantly in the intertriginous areas like the armpits, neck, scalp, submammary region, groin, perineum, anal fold, and external genitals. There are additional changes at the buttocks, thighs, and lower legs. Other typical areas affected by acne are rarely or hardly involved. Linear, fluctuating, furunculous nodules develop, which perforate, secrete purulent secretions, and slowly expand into bead-like ducts (Figs. 11 and 12) . The healing takes place in a typical way with fistulated comedones. According to Hurley, the disease severity can be divided into three clinical stages, which, however, is very general and does not represent the diversity of clinical manifestations.

Many other systems such as Sartorius scores, Hidradenitis Suppurativa Clinical Response, Hidradenitis Suppurativa Severity Score System, and Severity Assessment of Hidradenitis Suppurativa to include patient-reported sufferers, have been proposed to assess the clinical severity and follow up the treatment (Hessam et al. 2018). DTHF can occur alone, in association with a second disease, or even in a syndromic way. Metabolic syndromes including diabetes mellitus, inflammatory bowel diseases especially Crohn’s disease, and psoriasis are among the most commonly associated diseases (De Vita et al. 2018), which indicate a common pathogenetic pathway. Associated psychiatric disorders such as depression, suicide attempts, and substance abuse as well as cardiovascular risks like major adverse cardiac events highlight the serious consequences of the Fig. 11 Acne inversa/dissecting terminal hair folliculitis, armpit disease (Egeberg et al. 2016a). The impact on quality of life and co-morbidity burden are even higher than psoriasis. The diagnosis is rarely made at an early stage. The patients are treated for years under the diagnoses “chronic recurrent furuncles or sweat gland abscesses,” “coccyx fistula,” or “rectum fistula.” The severe intertriginous inflammation, which lasts for decades, should lead to the correct diagnosis. The disease results in a severe impairment in quality of life. Social exclusion with a high tendency to alcohol or nicotine abuse, problems at work and in the family, is often disease related. Secondary amyloid A amyloidosis and even squamous cell carcinomas may occur. This is not merely the postinflammatory Marjolin ulcer, but in many cases a squamous cell carcinoma in the anogenital region closely associated with oncogenic human papillomaviruses (HPV) (Scheinfeld 2014) (Marjolin ulcer, see ▶ Chap. 103, “Malignant Epithelial Tumors”). Cancer recurrence and metastasis can be a serious concern (Chapman et al. 2018).

The earliest change is a hyperplasia and segmental spongiosis of the epithelium in the acroinfundibulum of the terminal hair follicles with microcomedones in the ampulae of the apocrine sweat gland ducts. Furthermore, tunnel-like epithelial strands and fistulas form a bizarre labyrinth from the epidermis deep into the subcutaneous fat tissue with abscesses, fibrosis, and inflammation. Secondarily, apocrine and eccrine sweat glands are destroyed by the expansion of abscesses.

Highly elevated CRP and leukocytosis are typical. Increased serum levels of interleukin 17 (IL-17) are reported.

Genuine acne and acne inversa/DTHF may overlap. In chronic recurrent axillary or inguinal furunculosis or abscesses, acne inversa/dissecting terminal hair folliculitis should be considered. Extraintestinal Crohn’s disease, inguinal lymphogranuloma, vegetative pyoderma, actinomycosis, and tuberculosis should be distinguished.

Drug treatment is usually insufficient at an advanced stage.

Long-term results and treatment guidelines are pending. Biologics such as infliximab and adalimumab can be helpful in severe cases (Zouboulis et al. 2019), but are expensive and off-label in many countries, while usually palliative and transient, with common recurrences after weaning. On trial are antagonists targeting IL-17 or IL-12/23. Oral metformin treatment (three times 500 mg/day; off-label use) has been observed to improve the clinical picture in a small series of patients.

Metformin inhibits mTORC1 and mTORC1-hypoxia-inducible factor 1α-driven Th17 polarization. Acitretin 25 mg/day (neotigasone) seems more effective than isotretinoin. The only promising long-term measure for severe cases is the early and generous surgical removal of the affected intertriginous inflammatory skin areas (Bieniek et al. 2010). The recurrence rates decrease with increasing radicalness of the interventions. The operations are often extensive and require special plastic surgery measures. Incisions of the abscessing changes alone are inadequate and should only be made in the acute stage of severe pain. The success of the surgical intervention depends both on the localization and the type of subsequent wound closure. Radical excision with subsequent secondary wound healing or skin transplantation leads to the best results. Larger operations are usually performed in inpatient conditions under tumescent local or general anesthesia. The exact demonstration of the fistula can be done preoperatively by ultrasonography or MRT and intraoperatively by marking with methylene blue or patent blue. There are evidence-based recommendations for stageappropriate therapy (Table 4 ).

Pilonidal cyst, sacrococcygeal dermoid, coccyx fistula.

The incidence is estimated at 26 per 100,000 inhabitants. The disease usually manifests in the second to third decades of life, predominantly in men (2:1).

The pilonidal sinus was traditionally considered to be a preformed skin invagination, whereby a primary cause often remains unexplained. Broken terminal hairs penetrate with their ends close to the roots into the subcutaneous fat tissue and cause a foreign body granuloma (trichogranuloma). A similarity to acne inversa/DTHF in the early stage of histology has been emphasized. Bacterial superinfection can lead to abscessing and fistulating inflammation. Friction, pressure, obesity, overt hairiness, sacral hyperhidrosis, and lack of hygiene favor the development. Familial clustering occurs. The pilonidal sinus may also be associated with acne inversa/DTHF; the combination was formerly called acne tetrade.

The most common localization is in the sacrococcyx in or above the anal fold. Pilonidal sinus is also described in umbilical, genital, and retroauricular areas, and in interdigital spaces in hairdressers. Often there is a symptom-free opening on the surface of the skin, which only becomes symptomatic through an infection of the duct. Then abscessing, tender, bright red, inflammatory, subcutaneous nodules develop that break open and empty purulent secretions. In chronic cases, the abscessing inflammation leads to an acne-inversa-like picture with spread of the fistulated ducts into the adjacent skin and secondary formation of further fistulas. The pilonidal sinus persists for life and can become inflammatory at any time. A squamous cell carcinoma can rarely develop over 20 years.

This is the same as for acne inversa/DTHF.

Follicular hyperplasia/hyperkeratosis of the terminal hair follicles with interfollicular epidermal hyperplasia surrounded by an early infundibular lymphocytic infiltrate. Depending on the course of the disease, there may be an epithelium-lined duct with hair parts reaching to the skin surface or a granulomatous inflammatory reaction of the connective tissue with formation of subcutaneous nodules and fistulae.

Conservative measures have not proved curative. Incision and drainage under antibiotic cover are only recommended in acute inflammatory cases with bacterial superinfection. The therapy of choice is the generous, complete excision of the fistulae, if possible in a symptom-free stage. Open wound healing usually shows lower recurrence rates (McCallum et al. 2008). Laser epilation of anogenital hairs is proposed to prevent relapse, but is not well evidencebased. Clindamycin (2-3 times 300 mg/day) (possibly clindamycin 2-3 times 300 mg/day i.v. in the first 5 days) (or minocyclin 100 mg/day orally) in combination with rifampicin 2 times 300 mg/day orally over 1-3 months Stage 2

As stage 1, limited excision of locally recurrent lesions Stage 3

As stage 1, infliximab (5.0 mg/kg body weight i.v.) or adalimumab (40 mg s.c.) once or twice Radical excision of the affected area with 1-2 cm safety margin General information Abstinence from smoking, weight reduction Local disinfectant measures In women with signs of hyperandrogenism/hyperandrogenemia endocrinological clarification and use of antiandrogens (in particular antiandrogenic contraceptives with cyproterone acetate) 4 Rosacea

This chronic inflammatory facial dermatosis is characterized by progressive flushing, and over time papules and pustules, occasionally nodes, on diffuse erythema with telangiectasias, often accompanied by diffuse connective tissue and sebaceous gland hyperplasia and individual eye involvement. Extrafacial rosacea involves the hairless scalp and the anterior chest.

The disease is relatively common, especially in light-skinned individuals (skin phototype I-II) of Celtic origin from early adulthood, with an age peak between 40 and 50 years. The prevalence in dark-skinned people (skin phototype III-V) is probably underestimated. The first symptoms of rosacea, such as increased flush tendency and persistent livid red facial erythema, can occur before the age of 20 years when acne is still present. Early manifestations in childhood can occur.

Reported co-morbidities of rosacea may include migraine, metabolic syndrome (hypertension, diabetes mellitus, and dyslipidemia), coronary artery disease (Egeberg et al. 2016b), gastrointestinal disorders like Helicobacter pylori infection, ulcerative colitis, celiac disease, dementia, Parkinson’s disease, rheumatic disease like rheumatoid arthritis, psychiatric disorders especially depression, and malignancies such as non-melanoma skin cancers (Holmes et al. 2018). These reflect the multifaceted genetic and environmental aspects of rosacea (Aldrich et al. 2015). The diagnosis bias in retrospective database studies should be kept in mind, while the causality and strength of association and the gender difference need critical evaluation.

A hereditary disposition (rosacea diathesis) is usually present. Cathelicidin and its proinflammatory and antimicrobial cleavage product LL-37 are elevated in rosacea skin (Yamasaki et al. 2007;Park et al. 2018). In rosacea, excessive endoplasmic reticulum stress (ER stress) is discussed as the cause of an increased inflammatory tendency, activated innate immunity with increased toll-like receptor 2 (TLR2) expression, and vascular dysregulation (Melnik 2014(Melnik , 2016bPark et al. 2019). Rosacea patients initially tend to flush and later present with persistent erythema with vascular telangiectasias, stasis of small and large veins and lymphatic vessels. In addition, perivascular edema, extravasation of lymphocytes, and later accumulation of neutrophil granulocytes perivascular and diffuse in the upper and middle corium may occur. Papules, pustules, and granulomatous reactions develop and in the further course diffuse connective tissue and sebaceous gland hyperplasia, which develops into phymas. Chronic UV exposure leads to increased ER stress and release of proinflammatory cytokines. All clinical trigger factors of rosacea such as UV light, heat, cold, skin irritants, hot spices (capsaicin), red wine (resveratrol), and emotional stress can be interpreted as ER stressors. Neurogenic factors are also considered, whereas neurogenic rosacea is still a controversial clinical subtype (Scharschmidt et al. 2011). In older rosacea patients with enlarged sebaceous follicle ducts, numbers of Demodex folliculorum mites increase, which, however, do not play a causal role at the beginning of etiopathogenesis (Chen et al. 2015).

The dietary influence on rosacea is much less clear than that on acne. The available studies are mainly observational, descriptive, and non-quantitative. Worsening of facial flushing induced by hot spices, coffee, and alcohol beverages can be disease nonspecific, while general avoidance is not evidencebased. Associations between rosacea and the gastrointestinal microbiome remain to be clarified (Nam et al. 2018).

This is a clinical diagnosis. Common sites are the nose, cheeks, forehead, and chin (Fig. 13 ). Rarer localizations are retroauricular zones, the hairless scalp, and V-shaped chest and back region. The course is chronic, recurrent, or progressive over years or decades.

A number of general (Short Form 36/SF-36), the dermatology life quality index (DLQI), and the willingness-to-pay (WTP)) or disease-specific (rosacea-specific quality-of-life instrument (RosQol)) questionnaire studies are used to evaluate and compare health-related quality-of-life impact associated with rosacea. An earlier German study showed an overall lower burden of rosacea as compared to psoriasis, atopic dermatitis, and vitiligo. This may change due to different sociocultural backgrounds, public awareness, and therapeutic advances. The essential drawbacks in questionnaire studies should be considered.

Rosacea can be divided into three stages and special forms.

The first signs are mostly flushing, then longer lasting and finally persistent erythema in the face, neck, and V-chest. They are triggered by non-specific stimuli. Rosacea patients react faster, more frequently, and longer to such stimuli than those with healthy skin. The congestive involvement often lasts for days and becomes a strong psychological burden for many patients.

As the vascular changes progress, persistent erythema develops (erythema congestivum). Telangiectasias and extensive livid red vascular dilations are added in the upper and deeper venous facial plexus. This is the reason for the historical comparison with the bright red color of copper (copper fin, couperose).

Papules and pustules initially occur discretely, then more and more obviously, individually or in groups. The pustules have a normal bacterial follicular flora or are sterile. There are also multiple Demodex mites. A diffuse edema is added. The healing of inflammatory lesions is initially scarless. Relapses continue and the lesions spread to the forehead hairline and the lateral parts of the face. The scalp and lateral neck areas can also be affected. Other extrafacial localizations are rare. These include rosacea of the scalp in androgenetic alopecia or the presternal area.

In the later course, rosacea can also be accompanied by diffuse connective tissue and sebaceous gland hyperplasia (phymas) (Figs. 14 and 15 ). The patients show a very large-pored, inflammatory thickened, edematous skin (peau d’orange) (Gallo et al. 2018).

It is stage-dependent with dilated venous and lymphatic vessels in the upper corium in actinically damaged skin, and perivascular lymphocytic infiltrates. Papules and pustules of rosacea show spongiotic changes in sebaceous gland infundibula with lymphocytic and granulocytic infiltrates. Variable findings are collagen proliferation, diffuse sebaceous gland enlargement, circumscribed sebaceous gland hyperplasia, epithelial cell granulomas, foreign body giant cells, as well as Demodex mites scattered within follicles and in the surrounding corium.

Mild forms are treated topically, severe cases with additional systemic treatment (Table 5 ). General information: All irritating local applications should be avoided, such as irritating soaps, alcoholic solutions and shaving lotions. The regular use of sunscreens as a covering cosmetic or make-up is part of every rosacea therapy. Topically available drugs for the treatment of rosacea inhibit the excessive ER stress cathelicidin-LL37 signaling cascade at various levels.

Brimonidine and oxymetazoline: Brimonidine is the first approved topical therapy (brimonidine 3.3% or brimonidine tartrate 5% gel) that can positively influence the persistent facial flushing of rosacea through selective activation of the α2-adrenergic receptors, specifically α 2A , and thus the inhibition of vasodilatation. A rapid onset of the effect within a few hours can be expected. The long-term benefit/risk ratio is unclear and an increased rebound erythema is observed in up to 15% of treated patients. Oxymetazoline hydrochloride 1.0% cream, an α 1A -adrenoceptor agonist, has been approved by the FDA to treat persistent facial redness. The general response rates to these agents vary at 40-70% in short-term (after 1 week) to long-term (after 52 weeks) observations based on different evaluation scores. Intradermal botulinum toxin has been demonstrated to improve refractory erythema. Their long-term effects remain unclear.

Metronidazole: Metronidazole is most commonly used for topical treatment of rosacea as 0.75%, 1%, or 2% gel, cream, or lotion once or twice a day. Anti-inflammatory effects are responsible for the therapeutic success, which is more pronounced in papulopustular rosacea than in persistent erythema. Metronidazole reduces reactive oxygen species, inhibits T-cell-mediated immune responses, and presumably proteolysis of cathelicidin to LL37.

Azelaic acid: Azelaic acid is used once or twice a day in rosacea as a 15% gel. The 20% cream can be beneficial for very sensitive or dry skin. Azelaic acid has anti-inflammatory properties a similar to metronidazole. It inhibits kallikrein 5 and the expression of TLR2. Individual differences in response to azelaic acid and metronidazole are observed.

Ivermectin: Ivermectin 1% cream is available for topical treatment of rosacea papulopustulosa. The cream is applied once a day. Clinical studies have shown a therapeutic superiority over topical 0.75% metronidazole and 15% azelaic acid. Ivermectin inhibits the ER-stress-activated kinase p38 and is also antiparasitic to Demodex mites, which are usually increased in rosacea (Taieb et al. 2016).

Antibiotics: The preparations commonly used in acne therapy can be considered for their anti-inflammatory effect, especially erythromycin and clindamycin.

The systemic therapy of rosacea (partly off-label) includes tetracyclines, macrolides, metronidazole, and isotretinoin.

Tetracycline: They are standard in all inflammatory forms of rosacea. Doxycycline or minocycline are the treatments of choice. Usually once to twice 50 mg/day given for a few weeks until most inflammatory changes have regressed, often followed by low-dose maintenance therapy. Doxycycline is also available in sub-antimicrobial doses (40 mg/day) with slow drug release, but is more expensive than conventional tetracyclines. Tetracyclines inhibit TLR2 expression and cathelicidin proteolysis to LL37 mediated by kallikrein.

Macrolides: Erythromycin, roxithromycin, azithromycin, or clarithromycin are available as alternatives, especially in cases of intolerance to tetracyclines, resistance to therapy, or contraindications such as pregnancy. They are not approved for rosacea treatment.

Metronidazole: This is effective in selected patients, such as papulopustular rosacea with simultaneous demodicosis. The dosage is three times 250-300 mg/day for 10-14 days. The drug is not approved for this indication. Side effects such as diarrhea, nausea, metallic taste, peripheral neuropathy, or alcohol intolerance (disulfiram/Antabus-like side effects) limit the applicability. Isotretinoin: Severe and fulminant rosacea respond very well to off-label use of isotretinoin treatment with 0.1-0.3 and rarely up to 0.5 mg/kg body weight/day for 1-3 months (van Zuuren and Fedorowicz 2016). A dosage of 0.3 mg/kg body weight/day for 3 months is as effective as 100 mg/day doxycycline and probably leads to prolonged improvement. Contraindications and precautions (teratogenicity) must be monitored as in acne therapy. Isotretinoin inhibits the expression of TLR2 and sebaceous gland-derived cathelicidin expression.

Clonidine, a mainly α 2A -adrenergic receptor agonist, has been used systemically to treat facial flushing and redness, with ill-defined effective doses and controversial results. The efficacy of β-blockers like propranolol is anecdotal, while recent studies showed the benefit of carvedilol with an unclear mechanism of action.

Disturbing telangiectasias can be improved with laser or IPL (intense pulsed light) technology.

Many patients want camouflage (cover-up) cosmetics to hide the erythema and inflammatory lesions. A number of such products are available, some with additional light protection filters. Small additions of a green pigment conceal the erythema.

Special Forms of Rosacea 4.7.1 Lupoid Rosacea

Lupus miliaris disseminatus faciei (Fox 1877;Lewandowsky 1917), granulomatous rosacea.

Disseminated brownish-red papules and nodules with lupoid infiltrate in diascopy are found. Commonly affected areas are the upper and lower eyelids, cheekbone region, and perioral zone. Extrafacial manifestations can occur. In addition, signs of rosacea can usually be found, albeit discretely. The course is chronic, often over years. There are different views as to whether granulomatous rosacea and lupus miliaris disseminatus faciei are the same or independent disease entities.

Perioral dermatitis, steroid-induced rosacea, cutaneous tuberculosis, or small nodular sarcoidosis are to be distinguished. Bacteriological and molecular (polymerase chain reaction (PCR)) studies are negative. It is neither a skin tuberculosis nor a tuberculid reaction.

Centrally caseating epitheloid granulomas.

Treatment is administered systemically with tetracyclines (minocycline or doxycycline, 2 times 50 mg/day), shortterm glucocorticoids (about 20-40 mg prednisolone per day or equivalent dose for 7-14 days) or, preferably, low-dose isotretinoin (10-20 mg/day).

4.7.2 Steroid-Induced Rosacea (Leyden et al. 1974) If rosacea is treated with glucocorticoid-containing topical agents for a longer period of time, rosacea first improves and then exacerbates with steroid atrophy, increasing telangiectasia, dark red erythema, and follicular papulopustules. Local immunosuppression by the glucocorticoid promotes the proliferation of Demodex folliculorum mites. After tapering off the glucocorticoids, there are often violent outbreaks with burning and a tight feeling in the face. After a slow regression of the glucocorticoid side effects, the actual clinical picture, rosacea, reappears. Another clinical picture is steroid-induced rosacea-like dermatitis without pre-existing rosacea and with an unclear long-term course of the disease.

The treatment is carried out systemically with antibiotics after exclusion of Gram-negative bacteria or with low-dose isotretinoin. Topical calcineurin inhibitors (pimecrolimus, tacrolimus) are used successfully (off-label use) to accelerate glucocorticoid withdrawal, but should not be used for too long.

Rarely, similar to acne conglobata, large, fluctuating, hemorrhagic coalescing nodules, indurated sections, and plaques develop, but only on the face. The course is highly chronic.

Oral isotretinoin therapy (0.3-0.5 mg/kg body weight/day) for 6 months (off-label use) or longer, often accompanied by low-dose systemic steroids initially.

Unknown. This very rare facial disease occurs acutely to peracutely almost exclusively in young women (forehead, cheeks, nose, chin) and represents the maximal variant of rosacea conglobata.

Sudden onset, frequently during pregnancy or during initiation of oral contraception. Elevated carbuncles appear with fluctuating nodules and numerous pustules (Fig. 16 ). The general condition is not affected, except for a reactive psychological stress. There is an absence of comedones or other signs of acne. The original assumption that it is a pyoderma gave the disease its original name. Rosacea fulminans can be triggered by high intake of halogens (iodine, bromine) as drugs or X-ray contrast agents.

In the upper and lower corium there are signs of rosacea with vascular dilatation and lymphocytic infiltrate. It is an extensive epithelial cell inflammation extending into the connective tissue septa of the subcutaneous connective tissue with fusing abscesses and erythrocyte extravasations.

In contrast to other forms of rosacea, healing can occasionally occur with atrophic scars. The absence of relapse after successful therapy remains inexplicable. The other signs of rosacea persist.

This is initiated with glucocorticoids, 0.5-1.0 mg/kg body weight prednisolone (or equivalent dose) for 1-3 weeks, then tapered over 1-2 weeks. In conjunction with glucocorticoid treatment or after regression of the inflammatory changes, further oral treatment with isotretinoin can be instituted. Macrolide antibiotics are indicated during pregnancy.

These diffuse or tuberous connective tissue and sebaceous gland hyperplasias are associated with rosacea II and III. They are almost exclusively observed in men. In some

A distinction is made between skin infiltrates of lymphocytic leukemia, cutaneous B-or T-cell lymphoma, pseudolymphoma, sarcoidosis (Lupus pernio), eosinophilic granuloma, or connective tissue hyperplasia in patients undergoing cyclosporin therapy.

In early stages, isotretinoin therapy alone, 0.3-0.5 mg/kg body weight/day, for 6 months or longer is sufficient. Otherwise surgical procedures such as dermabrasion, laser ablation, or scalpel or razor blade removal are indicated.

Up to 30% of rosacea patients have eye involvement. The association between rosacea of the skin and inflammation of the eye is often underestimated, especially if the eye complaints are prominent and the skin involvement is only discrete. Ophthalmic rosacea includes blepharitis, conjunctivitis sicca, iritis, iridocyclitis, hypopyon iritis, and keratitis with ulceration (Fig. 17 ). The skin and eye manifestations can run separately for years. Rosacea keratitis has an unfavorable prognosis as it can lead to clouding of the cornea, perforation, and blindness. Isolated and occasionally one-side eye involvement can occur. The diagnosis is made on the basis of history and clinical findings; an ophthalmological examination and co-treatment are required. Potential co-existence of rosacea with atopic eczema, both in the face and the eyes, can pose a challenge for diagnosis and treatment.

Other forms of chronic conjunctivitis in IgE-mediated allergies, chronic UV exposure, Demodex blepharitis, or allergic contact dermatitis, often involving eye preparations, have to be distinguished.

Doxycycline is the drug of choice (Quaterman et al. 1997) . Minocycline is also recommended but is less effective. After significant improvement, the lowest effective maintenance dose should be found. Often a surprisingly low dosage of 50 mg every second day is sufficient to suppress the eye inflammation. In contrast to other forms of rosacea, oral isotretinoin therapy in ophthalmic rosacea does not achieve the desired improvement, and occasionally even a deterioration due to the increasing dryness of the conjunctiva is observed. One therapy option is the use of 1.5% azithromycin eye drops. The long-term therapeutic effect of topical cyclosporin remains to be determined.

Solid Facial Edema in Rosacea (Connelly and Winkelmann 1985) 4.8.1 Synonyms Rosaceous lymphedema, persistent swelling of the face in rosacea, Morbihan disease, according to the Breton district of Morbihan (Degos et al. 1973).

The etiopathogenesis is unknown. Characteristic are, numerous mast cells and their effect on the development of fibrosis is discussed.

Women and men are both affected. There are padded swellings on the forehead, nasal bridge, upper and lower eyelids, nasolabial folds, and cheeks. The swellings are coarse, solid, and not compressible (Fig. 18 ). At the same time rosacea can exist. The disease does not correlate with the severity of rosacea, which is often only slightly pronounced. An analogous clinical picture is seen at younger age in association with acne. It remains unclear whether rosacea and acne are causes or incidental findings with the same facial localization. The course is chronic, persistent, and slowly progressive. Patients develop an increasingly swollen face with a transition to induration. Concurrence of severe solid facial

Melkersson-Rosenthal syndrome is a possible differential diagnosis. In acute cases, systemic lupus erythematosus, dermatomyositis, or cutaneous mucinosis should be excluded.

Deep biopsy shows the extent of fibrosis with dilated blood vessels, lymphatic vessels, and a striking number of mast cells.

Treatment is very challenging. Low-dose isotretinoin (0.1-0.3 mg/kg body weight/day) combined with the mast cell stabilizer ketotifen (2 times 1 mg/day) may be tried for 3-6 months, usually longer to achieve satisfactory results. A good response to systemic of doxycycline (200 mg/day) or minocycline (100 mg/day) for 3 to 6 months with shortcourse systemic steroids has been reported. Single case reports on improvement with omalizumab deserve attention.

Manual lymphatic drainage can be considered as an adjuvant measure.

4.9 Rosacea-Like Diseases 4.9.1 Demodicosis They colonize the hair follicles with their heads down. Demodex folliculorum lives in the follicle duct, Demodex brevis in the depths of the sebaceous gland. The human is the exclusive host of these ectoparasites; the clinical picture is well known in veterinary medicine and particularly involves some dog breeds. There is a smooth transition from a typical but asymptomatic early adult colonization with about three to five mites in individual follicles to the clinical appearance of folliculitis. The females colonize the follicle and produce eggs and excrements. This results in inflammation of the infundibula populated by entire mite families with ruptures of the follicle wall, granulocyte migration, and foreign body granulomas to the mite bodies displaced into the corium.

Mostly in older adults grouped papules are found, often only unilaterally accentuated on the cheeks, nasolabial folds, nose or forehead, periorbitally or periauricularly, covered by pityriasiform scaling (Fig. 19 ). In rare cases, abscessing nodes may appear. Occasionally there is severe itching. Mite involvement of the sebaceous glands at the edge of the eyelid (Demodex blepharitis) causes encrustation, eczema, photophobia, and foreign body sensation. The disease is categorized into a primary or secondary form based on local or systemic immunosuppression and is morphologically classified as demodicosis spinulosa, papulopustulosa, granulomatosa, nodulocystica, or fulminans. Secondary demodicosis in childhood is observed especially in acute lymphocytic leukemia.

Mites can be detected by a drop of a cyanoacrylate rapid adhesive placed on a glass slide and pressed directly onto the cheek skin. The spreading adhesive drop polymerizes within 1 min. Careful rolling of the slide removes the horny layer and follicle filaments from the sebaceous follicles, including the Demodex mites. After covering with an immersion oil, living mites can be seen with a microscope. The ophthalmologist can visualize them with an ophthalmoscope, especially after expressing the sebaceous Meibomian gland infundibula at the edge of the eyelid or at the base of plucked cilia. Studies using confocal laser microscopy often show numerous mites.

Spongiotic folliculitis and epithelioid granulomas are typical of demodicosis. Mites are also detectable in histopathological sections at different levels of the follicular canal.

The disease is chronic and does not respond to conventional rosacea therapy.

An antiparasitic medication, acaricide or arachnicide, for use against scabies mites or lice can be tried. Topical treatment with permethrine, malathione, or ivermectin cream (off-label use) is an alternative.

Metronidazole, 3 times 250-300 mg/day for 10-14 days, can be used in severe Demodex diseases. Ivermectin (200 μg/kg body weight as single dose) may also be considered (off-label use), in particular for therapy-refractory Demodex blepharitis.

4.9.2 Perioral Dermatitis (Mihan and Ayres 1964)

Perioral dermatitis is not a special form of rosacea. It is presented here because of the similarity to some forms of rosacea. Excessive use of cosmetics, including sunscreen and skin-care products, triggers irritative folliculitis of the vellus hair follicles in predisposed individuals (mostly atopic) after varying periods of use. Individual components are suspected, but precise identification has not yet been established. Regression after abstinence and relapse after reuse support this concept. The connection between the topical application of glucocorticoids and perioral dermatitis is particularly important. Often there are minor facial changes that are treated topically with glucocorticoids. After a temporary improvement, perioral dermatitis appears. Potent glucocorticoids trigger the clinical picture more quickly and intensely. Sunlight and artificial UV radiation can aggravate perioral dermatitis, but are not primary causes.

Women aged 25-40 years are most frequently affected, with inflammatory reddened, succulent, 1-2 mm in size, hemispherical to pointed conical follicular papules on erythematous ground next to larger infiltrated areas, especially on the lateral eyelids. The skin changes are mostly monomorphic and comedones are missing (Fig. 20 ). A further development to papulovesicular, papulopustular, or papulosquamous eruptions is possible. Common sites are nasolabial folds and the perioral region with the typical narrow, apparently free zone around the lips, chin, glabella, and the lateral parts of the lower eyelids, and sometimes also with extensive involvement of the upper eyelids, cheeks, and forehead. Sometimes the disease only occurs around the eyes (periorbital type). As A special form is the lupoid or granulomatous perioral dermatitis. There is a dense aggregation of larger succulent reddish-brown papules and papulosquamous lesions, which show a lupoid infiltrate on pressing with a glass spatula. Histological granulomatous perioral dermatitis is usually the result of local glucocorticoid pretreatment. The disease is more common in children of color and is also referred to as Afrocaribbean facial eruption of childhood (Facial Afro-Caribbean Childhood Eruption, FACE) (Williams et al. 1990).

Rosacea, demodicosis, and glucocorticoid side effects in underlying diseases such as rosacea, acne, and atopic or seborrheic eczema should be distinguished.

Typical are spongiosis of the epidermis and vellus hair follicles, edema, slight lymphocytic perivascular infiltrates, and parakeratosis, especially around the follicle ostia. Epitheloid granulomas are found in lupoid perioral dermatitis.

Characteristics of rosacea such as actinic elastosis, telangiectasias, and Demodex mites are missing.

The disease is chronic and lasts for months, with varying severity from day to day. Deteriorations may result from further applications of cosmetics and skin-care products or UV radiation. In case of improper glucocorticoid treatment, the most severe forms of the disease may occur after temporary improvement, with all the signs of corticoderma (see ▶ Chap. 33, “Other Types of Dermatitis”). After removing the external triggers, especially glucocorticoids, exacerbations may occur initially.

Topical A prerequisite for successful therapy is the discontinuation of all local treatment measures, in particular glucocorticoids (Jansen et al. 2010). Potent topical glucocorticoids such as triamcinolone acetonide should be replaced with mild glucocorticoids during a short transition period of several days to counteract an acute exacerbation of perioral dermatitis to avoid loss of compliance. The calcineurin inhibitor pimecrolimus in cream form can be considered. Hydrophilic care products can be applied thinly if there is a marked feeling of tightness. Metronidazole or azelaic acid can be considered as local therapeutics, but initial intolerance is not uncommon. Granulomatous skin reactions can rarely occur with topical calcineurin inhibitors.

The treatment of choice is doxycycline or minocycline, 50 mg twice daily, and depending on the response, with dose reduction after approximately 2 weeks on 50 mg/day for further 2-4 weeks. Macrolides can also be used. They are recommended for the reason of fertility and pregnancy. Isotretinoin (off-label use) is very effective, especially in severe, recalcitrant, relapsing and lupoid forms. Often a very low-dose monotherapy with 0.1 mg/kg body weight/day for 2-3 months can be effective. For women of childbearing age, the requirements described for treatment of acne remain because of teratogenicity. 4.9.3 Haber Syndrome (Sanderson and Wilson 1965)

This very rare, probably autosomal-dominant genodermatosis exhibits several skin changes: Rosacea-like dermatosis with flush reactions, telangiectasias, pustules, and atrophic scars (in contrast to rosacea), multiple seborrheic keratoses on the trunk, palmoplantar keratoderma and flexural reticular hyperpigmentation similar to Dowling-Degos disease/reticular acropigmentation of Kitamura.

The seborrheic keratoses partly show intraepidermal clonal proliferation (Borst-Jadassohn phenomenon).

The facial changes respond to conventional rosacea therapy. Light protection is recommended.

Neutrophilic Sebaceous Adenitis (Renfro et al. 1993) This rare disease predominantly manifests in men as anular plaques on the face similar to a pseudolymphoma, lupus erythematosus, granuloma faciale or classic eosinophilic pustular folliculitis (Ofuji). The diagnosis is made histologically. Neutrophilic granulocytes are found in and around sebaceous glands. Medicines or sun irradiation can trigger the disease. Spontaneous regression is common. Vulvar sebaceous adenitis probably involves ectopic sebaceous glands.

Patients often have two or more acne-or rosacea-like diseases of sebaceous follicles or vellus hair follicles or terminal hair follicles at the same time or successively, which represents a challenge of differential diagnosis. More frequently encountered clinical overlapping presentations are shown in the overview.

Overlapping of Acne and Other Sebaceous Gland Diseases and Acne-Like Eruptions