J.M. Azaña Defez, M.L. Martínez Martínez Doctors in Medicine and Surgery. Consultant Physicians at the Dermatology Service. Pediatric Dermatology Unit. University Hospital Complex of Albacete

Abstract Resumen Acne is a chronic inflammatory skin disease of El acné es una enfermedad cutánea inflamatoria the pilosebaceous unit of multifactorial etiology crónica del folículo pilosebáceo, de origen characterized by increased sebaceous secretion, multifactorial, caracterizada por: aumento de la comedone formation, inflammatory lesions and secreción sebácea, formación de comedones, lesiones risk of scarring sequelae. It is undoubtedly one inflamatorias y riesgo de secuelas cicatrizales. of the most frequent dermatological processes Es, sin duda, uno de los procesos dermatológicos in the daily clinical practice, especially in más frecuentes en la práctica clínica diaria, adolescence, although it can also appear in especialmente en la adolescencia, aunque también childhood and persist into adulthood. Adequate puede aparecer en niños y persistir en la edad management of this pathology is relevant, adulta. Es importante un manejo adecuado de esta as it can cause lower self-esteem and social patología, que puede producir una disminución de la dysfunction in patients, with the subsequent autoestima y disfunción social de los pacientes, con impact on quality of life. el consiguiente impacto en la calidad de vida.

Key words: Cutibacterium acnes; Grading and classification of acne; Acne management; Isotretinoin. Palabras clave: Acné; Cutibacterium acnes; Graduación y clasificación del acné; Manejo del acné; Isotretinoina.

Introduction Etiopathogenesis acne among the Spanish population Acne is a frequent inflammatory skin aged 12 to 18 years is 74%, without Acne is a multifactorial disease, produced disease of chronic course and polymor- significant differences regarding sex by: increased sebaceous secretion, follicu- phous in its clinical expression. and with a peak between 14 and 16 lar epidermal hyperproliferation, comedoge- years of age(2); therefore, it accounts nesis, bacterial colonization and induction for 25% of dermatological consul- of . cne is a chronic skin disease of tations. Acne is estimated to be of the pilosebaceous unit, of mul- moderate / severe intensity in about Acne is a disease of the piloseba- A tifactorial etiology, characteri- 20% of patients. ceous follicle, induced by androgens zed by its clinical polymorphism. It Its highest prevalence and intensity of adrenal and gonadal origin: its undoubtedly represents one of the occur around 14-15 years of age in onset correlates with the increase in dermatological processes of greatest females and somewhat later (16-18 sebaceous production triggered by interest in daily clinical practice. years) in males. Despite its prevalence this hormonal stimulus. The pilo- in adolescence, in 7-25% of patients it sebaceous unit is the target organ of Epidemiology will persist into adulthood. acne, explained by the distribution of In females, it can manifest a longer lesions in the areas with the highest Acne can appear in all stages of life, course; whilst in males, more serious concentration. although its prevalence is higher in ado- forms are identified(3). The factors involved in its deve- lescence and there seems to be a genetic There seems to be certain genetic lopment include: increased sebaceous predisposition. predisposition to develop acne: history secretion and follicular epidermal of acne is often found in parents, and hyperproliferation, which leads to Acne is one of the most frequent in addition, there is a high concor- the formation of: comedones (come- dermatological diseases, as it is dance in monozygotic twins(3,4). dogenesis), bacterial colonization by estimated that around 85% of the Seasonal variations in acne severity Cutibacterium acnes (formerly named population will present it throug- are observed, with a tendency to wor- Propionibacterium acnes) and induc- hout their lives(1). The prevalence of sen in winter(5). tion of inflammation(6).

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The onset and persistence of the follicular channel and, later, by an due to a ductal hydration mechanism activity of the sebaceous glands is inflammatory reaction to a foreign that would favor the obstruction. This mainly due to the action of andro- body triggered by the rupture of the is the mechanism that explains the gens. After its activity in the postna- ductal wall. The cell wall of C. acnes exacerbation of acne lesions produced tal period, due to the maternal hor- contains a carbohydrate antigen that by the use of protective masks during monal influence, sebaceous glands stimulates the development of anti- the SARS-CoV-2 pandemic (“Mask remain minimized until puberty, bodies, which facilitate the inflam- acne”). when the size and number of lobes matory response. Various drugs, such as anabolic per gland increases, as a result of the There are multiple factors related steroids or contraceptives contai- androgenic stimulus (adrenarche). to acne exacerbation episodes. Various ning progestogens with androgenic The presence of this glandular acti- studies postulate that diet could be action, can exacerbate acne. In addi- vity is a necessary requirement for considered a stimulating factor for tion, there are numerous treatments the development of acne. There is acne, since foods that are high in such as: oral corticosteroids, isonia- a greater sebaceous secretion and, sugar and other carbohydrates, dairy zid, lithium or certain anti-cancer in addition, a qualitative alteration. products or proteins, would affect drugs, capable of inducing acneiform These events have been related to the serum insulin and insulin-like growth eruptions. development of hypercornification of factor (IGF-1), which would induce The use of high lipid-based cos- the sebaceous duct and changes in an increase in the production of avai- metic formulations, aggressive clea- surface microorganisms. The conse- lable androgens and the development ners or alkaline soaps can: alter the quence of hypercornification of the of acne(3). However, currently, there skin barrier, promote the formation sebaceous duct is microcomedone: is no scientific evidence with contro- of comedones and induce inflam- keratinocytes are grouped in dense lled studies to justify the restriction mation. clumps with monofilaments and of specific foods(10). The term exposome defines the lipid droplets, retaining the secreted The exacerbation of lesions in assorted environmental factors that sebum that distends the channel and stressful situations is a known fact, influence the development and seve- the gland. This microcomedone is the in relation to the neuroendocrine rity of a disease, in this case acne. primary acne lesion. regulation of sebocytes, the increase Identifying the negative exposome Acne is not an infectious process, in adrenal secretion and the manipu- factors can help reduce its impact and but there are microorganisms that lation of lesions. Conversely, acne has manage the disease(11). colonize and multiply in the folli- an undoubted psychosocial impact, cular duct, and that can play a role with consequent repercussions on Clinical manifestations in the pathogenesis. Cutibacterium quality of life. acnes (C. acnes), which predominates About 70% of patients report a Acne is an inflammatory skin disease with in areas rich in sebaceous glands, can premenstrual acne exacerbation. two main characteristics: lesional polymor- act as an opportunistic pathogen in This has been related to: increased phism and chronic course. acne. C. acnes is scantily present on hydration of the pilosebaceous duct, the skin surface, whereas it is the progressive decrease in estrogen levels In addition to seborrhea, open and/ dominant resident in the piloseba- with anti-inflammatory action and or closed comedones and inflamma- ceous unit; and the development of increased progesterone in this phase, tory lesions are observed such as: acne would be related, not with its with androgenic and pro-inflamma- papules, pustules and nodules, as well proliferation, but with the selection tory effects. as residual lesions (scars and pigmen- of certain types, especially the IA1 70% of patients show acne impro- tation alterations). phylotype, in a medium with increa- vement with sun exposure during the Regarding the distribution of the sed sebaceous secretion in addition summer months. This amelioration lesions, almost all the patients (99%) to balance alteration of the skin could be potentially explained by the present facial localization, accompa- microbiome(7,8). Also, the formation “camouflage” effect caused by tanning nied in more than half of the cases, of biofilm, an organized conglo- and an anti-inflammatory action of by involvement of the back (60%) and, merate of bacteria enhancing their the immune suppression induced by to a lesser extent, the pectoral area survival, could increase its pathoge- ultraviolet light(5). This is the theore- (15%). The majority of patients will nicity and resistance to antibiotics. tical foundation of phototherapy for refer to a gradual onset of the lesions These data open up new therapeutic acne. However, ultraviolet radiation around puberty, so that in cases in possibilities in the management of can also increase the comedogenic whom a sudden onset of these is acne (probiotics, anti-biofilm com- effect of sebaceous secretion and described, an underlying cause must pounds...)(9). cause significant exacerbations of acne be ruled out. In women with severe, The inflammation would not be (“acne Mallorca”, , tro- rapid-onset acne associated with hir- caused by the presence of bacteria in pical acne). sutism or menstrual irregularities, the the dermis, but by the action of bio- Activities in humid climates and existence of endocrinological patho- logically active mediators produced occlusion determine acne worsening logy (hyperandrogenism) must be by C. acnes, which diffuse from the in up to 15% of patients. It could be excluded.

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febrile ulcerative ”), is a rare variant in which a systemic immune reaction against C. acnes takes place(12). It is observed espe- cially in young men who, suddenly, develop inflammatory lesions pre- dominantly in the trunk, with sys- temic manifestations (fever, anore- xia, polyarthropathy, splenomegaly, aseptic osteolysis), together with marked leukocytosis. Blood cultu- res are sterile. Sometimes it can be induced by drugs (isotretinoin or androgens) and intercurrent infec- tions (Epstein-Barr virus). In terms of treatment, in addition to that indicated for acne, the use of oral Figure 1. Comedonian acne: open and closed comedones (“blackheads”). corticosteroids is required.

Special forms of acne of interest Types of lesions and dyschromias (post-inflammatory in Pediatrics hyperpigmented and hypopigmented Non-inflammatory lesions macules). Closed comedones are small firm Types of acne It has been associated with trans- papules with a whitish surface in placental stimulation of adrenal which, occasionally, the follicular Based on the clinical presen- androgen production, at least in cases opening is observed. Alternatively, tation and the predominance of of onset before the first year of life. open comedones present a blackish some of these lesions, classic cli- There are no other manifestations of central plug, due to the deposit of nical types of acne are distinguis- hyperandrogenism, because sebaceous melanin and the oxidation of sebum hed: comedonian, papule-pustular glands are the only ones capable of (Fig. 1). and nodular. Acne conglobata is a converting dehydroepiandrosterone severe and treatment-resistant form, to androstenedione and testosterone. Inflammatory lesions more frequently found in men and Occasionally, drugs such as pheny­ They derive from the previous ones with a more intense location on the toin, corticosteroids and halogens and include: trunk. It is characterized by deep have been implicated. • Superficial lesions: papules and papules and painful nodules, which It prevails in males, usually as a pustules (Fig. 2). can converge and form sinusoidal localized form, with especial invol- • Deep lesions: deep pustules and paths, and evolve to form depressed vement of the cheeks. In the neonatal nodules, when the inflammation and keloid scars. or period, the main differential diagno- affects the entire follicle. Nodules malignant acne, initially described sis must be established with benign are firm, painful lesions that can as a form of acne conglobata (“acute cephalic pustulosis, which is much be larger than 1 cm. They cons­ titute the characteristic lesion of what is known as acne conglobata. Although epidermoid can be seen in patients with acne, in most cases, the so-called “cysts” are not true , but rather deep nodules (nodular acne). Residual injuries Residual lesions are observed in up to 90% of patients, although they significant in only 22% of cases are. Figure 2. Inflammatory lesions can leave seque- Mild-moderate lae such as erythematous macules that inflammatory can persist for months, scars of various acne: comedones, characteristics (depressed, varioli- papules and form, ice pick, hypertrophic, keloid) pustules.

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Mechanical acne It refers to the appearance of acne lesions in areas subjected to prolonged friction. Continuous irritation of the superficial area of ​​the pilosebaceous duct and excessive hydration of the area due to occlusion, would be the factors involved in its appearance. The distribution of lesions and the mecha- nical history facilitates the diagnosis. A current example would be acne exacerbated or triggered by the use of protective face masks(16), which was interestingly already referred to in Asian literature in a previous coro- Figure 3. navirus epidemic(17). Monomorphic drug acne (oral suppurativa corticosteroids). It is an inflammatory process with a chronic and recurrent course, which more frequent (20% of neonates), with Endocrine acne predominantly affects: armpits, groin onset within the first weeks of life, The term is used in those women and anogenital area, sometimes asso- consisting of papulopustular lesions who besides acne associate other ciated with severe inflammatory acne on the cheeks, but without comedones manifestations of hyperandroge- with which, as mentioned previously, it shares physiopathogenic mecha- and associated with colonization by nism, and where polycystic ovary (18) Malassezia (M. sympodialis and M. syndrome is the most frequent con- nisms . It usually begins during furfur). dition. SAHA syndrome (Seborrhea, puberty, although there are childhood The treatment of infantile acne is Acne, and Alopecia) is an cases and its etiopathogenesis involves similar to that of acne vulgaris (see acronym for the main manifestations familial, endocrine factors (obesity, hyperandrogenism) and local irrita- below), but excluding oral tetracycli- of this dermatological androgeniza- (18) nes. Only exceptionally has oral iso- tion entity(15). Hormonal investiga- tion . It is characterized by: come- tretinoin been used in this form(13). tions are necessary for its diagnosis donal lesions, papules, pustules, and and management. painful nodules that converge into Excoriated acne large abscesses with sinus discharge Although it is more frequent in Acne induced by topical substances and a tendency to cicatrize in the young women, it can also be diag- It includes different clinical forms, areas previously described. nosed in adolescence in patients who notably cosmetic acne, which predo- Diagnosis manipulate the lesions, causing ero- minates in women and is related to the sions or ulcerations with the risk of use of comedogenic cosmetics. Also, The diagnosis is based on clinical exami- superinfection and scarring. The most excessive washing as an attempt to nation. The use of scales to determine the severe cases can hide relevant psycho- improve acne can aggravate it (deter- predominant type of lesion and its severity logical disorders that will require spe- gent acne). will guide the treatment. cialized evaluation(14). Drug-induced acne It is not a true acne as it is a mono- morphic process without - Figure 4. nes, which is why it is referred to as Orange follicular drug-induced acneiform eruptions. fluorescence: Its onset is chronologically related to relationship the start of the treatment involved. with porphyrins Many drugs can be involved in its produced by C acnes. This appearance, the most common being indicates that corticosteroids (Fig. 3), but also: the patient does antiepileptic drugs, antituberculosis not undergo drugs, lithium, vitamin B, halogena- treatment ted compounds (iodides or bromides) or that the and epidermal growth factor receptor microorganism inhibitors, among others. is resistant.

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Table I. Qualitative staging of acne Basic concepts

Non- Grade 0 Preacne: seborrhea, isolated midface comedones inflammatory The treatment of acne should Grade 1 Comedonian begin by knowing the clinical his- tory and response to other drugs that Inflammatory Grade 2 Superficial inflammatory or papulopustular have been administered to the patient, Grade 3 Deep or nodular inflammatory in order to design an individualized plan for maximum effectiveness. Low Grade 4 Nodule-cystic (“furunculoid”, conglobata) adherence to treatment sometimes conditions results not turning out as expected, hence it is essential to The diagnosis of acne is a clinical are of limited use in daily practice. indicate and explain some of the most one, based on the presence of come- The simplest is a qualitative clas- relevant aspects of this, specifically, dones and/or inflammatory lesions. sification, taking into account the on the progress of the process, which Examination with Wood’s light will type of dominant lesion(1) (Table may require treatment during months allow to observe the presence of C. I), which can be completed accor- or years. acnes in the comedones, as it emits ding to the severity (mild, moderate, Compliance improvement is a red-orange fluorescence due to the severe). increased by using topical products production of porphyrins (Fig. 4). with fixed combinations, rather Only in case of suspected endocrine Treatment than multiple products separately. acne, will complementary examina- Combination products have two tions be carried out to rule out hype- The treatment of choice will be combined advantages: on the one hand, they randrogenism. topical products containing antibiotics, act against several pathogenic factors In addition to the predominant retinoids, or benzoyl peroxide; while, in of acne simultaneously and, on the type of lesion and its location, there case of non-response or moderate-severe other, they simplify the therapeutic acne, oral treatment with antibiotics or are multiple systems for assessing the regimen. Patients should be informed isotretinoin will be prescribed. severity of acne(19,20), although they that clinical improvement will not be

Table II. Acne. Therapeutic algorithm

Mild Moderate Severe Type of acne Comedonian Papulopustular Papulopustular Nodule-cystic Conglobata/Fulminant

1st choice Topical BP + topical ATB Oral ATB + Oral ATB + Oral isotretinoin +/– oral retinoid topical retinoid topical retinoid corticosteroid +/– BP +/– BP Topical retinoid + topical ATB / BP Topical retinoid + BP +/– topical ATB

2nd choice Azelaic acid Azelaic acid Change oral ATB Oral isotretinoin Salicylic acid Salicylic acid + change topical High doses of oral ATB Topical dapsone retinoid +/– BP / Change oral ATB + azelaic acid + change topical topical retinoid retinoid +/– BP / + azelaic acid BP

Alternative Contraceptive/ Contraceptive/ Contraceptive/ for females oral antiandrogen oral antiandrogen oral antiandrogen

Maintenance Topical Topical retinoid Topical retinoid Topical retinoid Topical retinoid retinoid +/– +/– +/– BP BP BP

Refractory Exclude Gram Exclude Gram to treatment negative negative folliculitis

ATB: antibiotic; BP: benzoyl peroxide (Zaenglein AL, Thiboutot DM. Acne vulgaris. Dermatology, 4th Edition. Bolognia JL, Schaffer JV, Cerroni L. 2019. ISBN: 9788491133650. eBook ISBN: 9788491134633).

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Retinoids achieved immediately, but rather after or hair. Tolerance increases if applied 6-8 weeks of treatment. Topical retinoids prevent the forma- not immediately after the skin wash, In order to minimize irritation tion of comedones and inflammatory but minutes later. It can be used from topical treatments, it should be lesions, normalize the desquamation of during pregnancy and lactation. indicated that the initial application keratinocytes, and have an anti-inflam- can be gradual to improve tolerance matory effect. They include: retinoic Topical antibiotics during the first few weeks. We must acid, isotretinoin, adapalene, tazaro- instruct the patient in the use of non- tene (in Spain this is indicated for the They have antibacterial action, comedogenic moisturizers, along treatment of psoriasis) and, recently, inhibiting the growth and activity of with the avoidance of products that tripharo­tene. The latter has been C. acnes and a direct and indirect anti- contribute to the development of approved as a 0.005% cream, being a inflammatory effect. They are used acne. The use of a mild daily wash fourth-generation retinoid for the treat- as part of combination treatments for soap is advisable, while excessive ment of acne vulgaris on the face and mild-moderate papulopustular acne. hygiene can alter the skin barrier and trunk, from 12 years of age onwards. The most frequently used are clin- increase the irritation potential of the Tripharotene selectively targets gamma damycin and erythromycin, in con- treatment. retinoic acid (RAR-γ) receptors, the centrations of 1-4%. Nadifloxacin 1% In the follow-up clinics, the the- most common ones in the skin(21). is a topical quinolone that also appears rapeutic plan should be reinforced Topical retinoids also enhance the to have certain antiandrogenic action and inquire the presence of possi- penetration of associated topical anti- in vitro, in addition to inhibiting the ble triggers or aggravating factors. microbials, thereby increasing their activation of T cells and keratino- In patients refractory to treatment, efficacy. They are used as monothera­ cytes. folliculitis due to gram-negative orga- ­py for comedonal acne and as part of a Monotherapy use is not recom- nisms should be excluded, especially combination therapy for mild-mode­ mended, due to the possible develop- in patients receiving continuous anti- rate papule-pustular acne(22). They ment of resistance to antibiotics and biotic treatment. Regarding diet, as achieve a 40-70% reduction in come­ the slower onset of action. In the case mentioned above, it is not necessary dones and inflammatory lesions(23). of macrolides, resistances greater than to make dietary restrictions, except in They are also recommended as a 50% of strains of C. acnes have been case the patient relates acne appea- maintenance treatment to prevent reported in some countries(24). For rance to certain foods or in case of recurrences. Different concentra- this reason, they should be disconti- deterioration with the consumption tions are used, depending on sever- nued once improvement is appreciated of abundant skimmed milk, or foods ity and clinical tolerance, in aqueous and, in case of ineffectiveness after 6 with a high sugar load. creams or gels. The recommendation to 8 weeks, when another treatment The main objective of acne is to start with low concentrations or should be considered. The combina- treatment is to avoid the appearance short application times, and gradually tion of topical antibiotic with topical of scars, so the treatment must be increase according to tolerance. retinoid or benzoyl peroxide reduces as early as possible, with treatment The most frequent side effects are: the possibility of resistance(22). modality appropriate to the severity irritant dermatitis and photosensi- Side effects are less frequent com- and extension. Table II shows a the- tivity. In 20% of patients, a transient pared to those of oral antibiotics and rapeutic algorithm(1) to be followed increase in inflammatory lesions may generally mild and local (pruritus, in patients with acne. In general, the occur. It is contraindicated in preg- xerosis). Pseudomembranous colitis use of an oral or topical antibiotic in nancy due to its proven teratogenic is a rare complication associated with monotherapy should be avoided, in properties with oral administration. topical clindamycin. Nadifloxacin order to reduce the risk of bacterial Benzoyl peroxide should not be used in children under resistance. 14 years of age, as it is a fluoroqui- It is an antimicrobial agent with nolone. Topical treatment anti-inflammatory and comedolytic Azelaic acid activity, its main action being the Topical treatment will be pres- neutralization of C. acnes in the hair Azelaic acid is a dicarboxylic acid cribed in all patients with acne, in follicles, thus achieving a bacterios- that exhibits antimicrobial and anti- monotherapy in mild acne and, com- tatic and possibly bactericidal effect, comedogenic activity(25). It is used for bined with systemic treatment, in similar to topical antibiotics and comedonal and inflammatory acne. It cases of moderate or severe acne. In without being associated with anti- is available as 20% cream and 15% addition, after systemic treatment, microbial resistance. It is marketed in gel, and its main side effect is mild maintenance topical retinoids should different concentrations (from 2.5% to irritation. It can be used in pregnancy be applied. The patient should be 10%) and galenic forms (creams, gels, and lactation. insisted on applying it not only to the cleansers), alone or in combination Other topical treatments lesions, but also to the areas suscepti- with other active ingredients. ble of presenting them, so as to avoid Its main side effects are irritation, Salicylic acid is used as a comedo- their appearance. in addition to discoloring dark clothes lytic and antibacterial. It is used in

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various galenic presentations at 0.5- concentrations. Contraceptives widely used one, with doses ranging 2%, in non-inflammatory forms, improve: seborrhea, androgenic alope- between 50-100 mg per day, the most being less effective than topical ret- cia, SAHA syndrome and late-onset frequent side effect being photosensi- inoids. Its main side effects are: ery- acne, in addition to regulating men- tivity. They are generally well tolera- thema and scaling. strual disturbances. Its main objective ted, and serious side effects are rare. The α-hydroxy acids are used in is to offset the effect of androgens on Tetracyclines should not be used in the comedonian forms at various the sebaceous glands. children under 8 years of age, due to concentrations and, in general, with Its main indications in patients their effects on the developing skele- good tolerance. The most used one is with acne are: failure of antibiotic ton and dentition. glycolic acid, which can be found in treatment, when oral isotretinoin is Treatments are usually maintai- presentations combined with tretinoin contraindicated or inappropriate, and ned for at least a month and a half, and topical clindamycin. if, in addition to acne, it is necessary because as with other treatments, its Niacinamide is the active form of to control the menstrual cycle or as a clinical effect takes weeks to be appre- vitamin B3, with anti-inflammatory contraceptive method. Better results ciated, reducing the dose or suspen- properties. It has been used as 4% seem to be obtained, even with nor- ding treatment once the appearance hydroalcoholic gel in the treatment mal serum androgen levels, in women of inflammatory lesions diminishes, of mild acne. with predominantly inflammatory usually after 3 months. Combined treatment lesions on the lower half of the face They should be avoided as and neck who frequently present with monotherapy, associating topical reti- Combinations with retinoids premenstrual exacerbations of their noids or benzoyl peroxide, if neces- are recommended as a first line of acne. sary: ​​repeat treatment, use the same treatment for mild-moderate and Thrombosis is one of the most seri- antibiotic if it was effective, and avoid papulopustular acne. Combinations ous side effects of oral contraceptives the simultaneous use of topical and of various therapeutic agents allow which depends, over all, on the estro- oral antibiotics, so as not to favor the to target multiple pathogenic fac- gens used and their dose. In order to appearance of resistance. tors of acne. On the other hand, the reduce this side effect, the oral con- Oral isotretinoin combination of antibiotics with ben- traceptive of choice should be one zoyl peroxide reduces the possibility that combines 30 mg or less of ethinyl 13-cis-retinoic acid of vitamin A of bacterial resistance. Marketed estradiol (estrogen) with gestagen. If or isotretinoin is indicated in severe fixed-dose combinations include the our aim is to treat signs of androg- nodule-cystic acne, refractory to following: enization, the oral contraceptives of other treatments or that can lead to • 0.1% adapalene plus 5% benzoyl choice would be those with progesto- scarring. It constitutes the therapeutic peroxide, applied daily as a gel. gens with an antiandrogenic effect: pillar of severe acne, but also for acne • Clindamycin 1% plus benzoyl cyproterone acetate, chlormadinone that has an important impact on the peroxide 5% gel, which is more acetate, drospirenone, dienogest, and quality of life of the patient: inflam- effective than both products used nomegestrol acetate(26). According to matory acne resistant to conventional separately. a meta-analysis, cyproterone acetate treatment and chronic forms of recu- • 0.025% tretinoin plus 1% clinda- and drospirenone were found to be the rrent tendency, in addition to gram- mycin gel. most effective progestogens in treat- negative folliculitis, facial pyoderma • 0.02% tretinoin plus 4% glycolic ing acne(27). The response is observed and severe forms of . acid, plus 0.8% clindamycin gel. from the third month of treatment, It acts on all the factors involved in and it should be maintained for a the pathophysiology of acne. Systemic treatment year, in the absence of side effects, It is usually administered at doses with risk of recurrence upon discon- of 0.5-0.6 mg/kg per day (from 0.1 Indicated in patients with mode- tinuation, thus its association to other to 2 mg/kg/day), maintaining the rate-severe acne or in the absence of treatments. treatment until reaching a total dose response to topical treatment in mild Oral antibiotics of 120 to 150 mg/kg, so as to reduce or mild-moderate acne. Also indicated the possibility of relapses. Doses in cases of extensive skin involvement. They are used in moderate-severe can be modified based on clinical Hormonal treatment inflammatory acne. They produce an response and side effects. It should anti-inflammatory action through be taken with meals to enhance its Most combined contraceptives the inhibition of the growth of C. absorption. Low-dose isotretinoin (estrogen + progestogen) have the acnes, in addition to reducing the regimens (0.25-0.4 mg/kg/day) are ability to improve acne and hirsutism amount of free fatty acids and, thus, effective, with fewer side effects, but to a greater or lesser extent, which is their irritating effect. The most used higher recurrence rates(28). why they are useful in the patient with ones are: oral tetracyclines (doxy- The clinical response is excellent hyperandrogenism, but it is also an cycline, minocycline) and macroli- (Fig. 5), most of the cases responding effective treatment in women with des (erythromycin, azithromycin and to a single 6-month course, although, acne, regardless of androgen serum josamycin). Doxycycline is the most in general, the results are not evident

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informed consent document should be completed. The patient should be informed of the therapeutic effects of isotretinoin and taught to control or prevent side effects (adequate hydration, artificial tears to control dry eyes and nose, avoid irritants, elude alcoholic beve- rages, photoprotection, avert blood donation during the treatment...). Recurrence of acne is not uncom- mon, in most patients with a good response to conventional therapy, but in some cases, a new cycle of treatment with isotretinoin must be Figure 5. Deep inflammatory acne: before and after treatment with isotretinoin. indicated. It usually happens in the first year after treatment, and is rare after 3 years. Factors associated with until 1-2 months after starting the beyond 700-800 mg/dl is a criterion risk of recurrence include: a low daily treatment, a period in which even a for stopping treatment. Full blood dose of isotretinoin (0.1-0.5 mg/kg) certain exacerbation can be observed. count can show: anemia, leukopenia, or not reaching a certain total dose Side effects depend on the admi- thrombocytosis or thrombopenia, and (120-150 mg/kg), severe or prolonged nistered dose and, in general, are elevated ESR. acne, women of more than 25 years similar to those of hypervitaminosis Psychiatric side effects such as: at the onset of treatment, endocrine A. Almost all patients present with increased risk of depression, sui- abnormalities, patients under 16 years cheilitis and, more than 50%, cuta- cide, psychosis, and aggressive and of age and acne located on the trunk. neous and mucosal xerosis. Xero- violent behaviors have been descri- Maintenance treatment with topical phthalmia, alteration of night vision, bed, although the causal relations- retinoids can reduce recurrence risk conjunctivitis, keratitis, headache hip or mechanism of action remains by avoiding the formation of micro- and epistaxis can also be observed. unclear. A prevalence of depression of comedones. Myalgias can affect 15% of patients, 1-11% has been described in patients The investigations to be carried being the most frequent musculos- receiving isotretinoin, a similar per- out prior to prescribing the treatment keletal manifestations. Rarely, long- centage to that observed in patients include: full blood count, liver term hyperostosis or osteoporosis has receiving oral antibiotic treatment, so function tests, triglyceride concentra- been described, hence radiological it cannot be established as a cause(31). tions and a urine pregnancy test in studies are not indicated in standard Despite this, the majority of patients the case of females. The next check- treatments. Exceptionally, an associa- experience improvement in the up, including liver function and lipid tion with inflammatory bowel disease psychosocial repercussions related profile, should take place after a has been described, without finding, to acne, once treatment has begun. month; if everything remains within to date, an increased risk in patients In any case, it is important that the normality, it is not necessary to repeat treated with isotretinoin(29). The rela- patient and his family are aware of them, as long as we are dealing with tionship with diabetes has been stu- these data, in addition to identi- a patient on usual doses and without died, identifying that treatment with fying patients at risk and the possible other underlying pathology(32-33). isotretinoin significantly increases the appearance of any related symptoms. In conclusion, it is fair to say that level of serum adiponectin, but does In case of severe headache, abnormal isotretinoin is an effective medica- not alter the state of insulin resistance night vision or psychiatric manifes- tion, which can achieve the definitive in patients with acne(30). Its concomi- tations, isotretinoin treatment must “cure” in a high percentage of cases, tant administration with tetracyclines be stopped. with a comfortable administration is contraindicated, due to the increa- Isotretinoin is teratogenic, pro- and known dosage, and with contro- sed risk of benign intracranial hyper- ducing its maximum effect in the llable side effects which, in general, tension. third week of gestation, so women are well tolerated. Digestive symptoms are rare. More of childbearing age should not start frequent is the elevation of transami- treatment until they have a negative Other treatments nases that can appear in 15% of the pregnancy test, which should be cases. In addition, triglycerides can repeated monthly. It is essential to Phototherapy increase in up to 25% of patients, recommend contraceptive methods especially in the first month, and from 1 month before to 1 month after Phototherapy targets C. acnes, a they tend to decrease when the dose the end of treatment. Patients must producer of porphyrins, especially decreases. Triglyceride concentrations be adequately informed and a specific coproporphyrin III. These porphyrins

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can be activated by light, at specific Adjuvant treatment • Although rare, differential diagno- wavelengths (blue light at 415 nm and Comedone removal sis with other processes. mixed blue-red light at 415 and 660 • Finally, whenever treatment with nm), producing a photodynamic effect This technique achieves immediate isotretinoin is considered, as it is a capable of destroying these bacteria. improvement, which must be maintai- drug that requires prescription by It has been used in mild or moderate ned with topical retinoids that prevent a specialist and a medical inspector forms of inflammatory acne, with the formation of new microcomedo- visa. In these cases, the follow-up variable response. nes. Macrocomedones are a cause of will be coordinated with the spe- Photodynamic therapy therapeutic failure and do not usually cialist. respond to treatment with topical or The combination of topical ami- oral retinoids; hence the need to eli- Bibliography nolevulinic acid or methylamino- minate them. levulinate, metabolized to proto- The asterisks show the interest of the article in Chemical exfoliation (“chemical the opinion of the authors. porphyrin IX in the pilosebaceous peels”) 1.*** Zaenglein AL, Pathy AL, Schlosser BJ, unit, a powerful photosensitizer, and Alikhan A, Baldwin HE, Berson DS, et al. the subsequent activation by a light It is indicated once acne is con- Guidelines of care for the management of source with a specific wavelength, trolled, for the treatment of superficial acne vulgaris. J Am Acad Dermatol. 2016; would lead to: reduction of sebaceous scars or residual hyperpigmentation. 74: 945-73. α secretion, destruction of C. acnes and The following are used: -hydroxy 2. Guerra A. Estudio epidemiológico descrip- also decreased ductal hyperkeratini- acids (especially glycolic acid), trichlo- tivo transversal sobre la prevalencia del acné zation. roacetic acid or salicylic acid. en la población adolescente española. Act Dermatol. 2001; 11: 1-6. Intense pulsed light and laser Cryotherapy 3. Heng AHS, Chew FT. Systematic review of the epidemiology of acne vulgaris. Sci The pulsed dye laser at 585 nm, Cryotherapy of liquid nitrogen and Rep. 2020; 10: 5754. the neodymium: YAG at 1320 nm spray applicators has been used, espe- 4. Lichtenberger R, Simpson MA, Smith C, and the 1450 nm diode laser have cially in scar lesions. Barker J, Navarini AA. Genetic architec- been used in inflammatory acne, but Surgery ture of acne vulgaris. J Eur Acad Dermatol with transient improvement, which Venereol. 2017; 31: 1978-90. together with the discomfort that it Surgery can be performed in case 5. González-Cantero A, Arias-Santiago S, generates, makes it of limited perfor- of scar lesions. It would include: Buendía-Eisman A, Molina-Leyva A, mance. removal of depressed scars (“lift tech- Gilaberte Y, Fernández-Crehuet P, et al. ¿Existe variación en los diagnósticos der- Zinc nique”), classic dermabrasion, the use matológicos entre la temporada de frío vs of filling material in deep scars with calor? Un subanálisis del estudio DIA- It does not improve comedones, a non-fibrotic base or laser therapy. DERM (España 2016). Actas Dermosifi- but it does show some efficacy in liogr. 2019; 110: 734-43. treating inflammatory acne. Its action Role of the Primary Care 6. Zaenglein AL. Acne vulgaris. N Engl J is due to: inhibition of neutrophil che- pediatrician Med. 2018; 379: 1343-52. motaxis, inhibition of 5α-reductase 7. Scholz CF, Kilian M. The natural history and tumor necrosis factor. Oral route Acne in the majority of patients of cutaneous propionibacteria, and reclassi- fication of selected species within the genus (200 mg/day, administered outside of can be managed in the Primary Care Propionibacterium to the proposed novel meals) has been indicated. Its main setting. A correct treatment includes: genera Acidipropionibacterium gen.nov., side effects are gastrointestinal (nau- early onset and appropriate therapy Cutibacterium gen.nov. and Propionibac- sea, vomiting, epigastric pain). to the type of acne, use of combined terium gen.nov. Int J Syst Evol Microbiol. 2016; 66: 4422-32. Corticosteroids treatments, never use antibiotics in monotherapy nor associate topical 8.*** Dréno B, Pécastaings S, Corvec S, Veraldi S, Its use is associated with the and oral antibiotics and, in the follow- Kharmari A, Roques C. Cutibacterium acnes (Propionibacterium acnes) and acne vulgaris: appearance of acne lesions (corticoid up, reinforce the therapeutic plan and a brief look at the latest updates. J Eur Acad drug acne); however, they may be assess the response and tolerance to Dermato Venereol. 2018; 32: 5-14. indicated in certain cases. Thus, in the treatment. Referral to the derma- 9. Pécastaings S, Roques C, Nocera Th, severe inflammatory forms, liable tologist would be considered in the Peraud C, Mengeaud V, Khamari A, et al. to exacerbation at the beginning of following cases: Characterisation of Cutibacterium acnes treatment with isotretinoin, a short • Severe forms of acne. phylotypes in acne and in vivo explorato- ry evaluation of Myrtacine. J Eur Acad course of oral corticosteroids rapidly • Moderate forms without response Dermatol Venereol. 2018; 32: 15-23. reduces the number of lesions and the to prescribed topical and/or oral 10. Claudel JP, Auffret N, Leccia MT, Poli F, risk of exacerbating them with reti- treatments. Dréno B. Acne and nutrition: hypothesis, noid. Similarly, intralesional injec- • Patients with important psychoso- myths and facts. J Eur Acad Dermatol. tion of corticosteroids may be useful cial repercussions of the disease. 2018: 32: 1631-7. in large, recent-onset inflammatory • Suspicion of an associated under- 11. Dréno B, Bettoli V, Araviiskaia E, Sánchez lesions. lying endocrine disorder. Viera M, Bouloc A. The influence of expo-

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some on acne. J Eur Acad Dermatol. 2018; update from the Global Alliance to Im- 33. Barbieri JS, Shin DB, Wang S, Margo­ 32: 812-9. prove Outcomes in Acne group. J Am Acad lis DJ, Takeshita J. The clinical utility of 12. Bocquet-Trémoureux S, Corvec S, Kham- Dermatol. 2009; 60: S1-50. laboratory monitoring during isotretinoin mari A, Daqniele MA, Boisrobert A, Dre- 23. Haider A, Shaw JC. Treatment of acne therapy for acne and changes to monitoring nó B. Acne Fulminans and Cutibacterium vulgaris. JAMA. 2004; 292: 726-35. practices over time. J Am Acad Dermatol. 2020; 82: 72-9. acnes phylotypes. J Eur Acad Dermatol. 24. Walsh TR, Efthimiou J, Dréno B. System- 2020; 34: 827-33. atic review of antibiotic resistance in acne: 34. de Lucas Laguna R. Acné. Pediatr Integral. 13. Miller IM Echeverria B, Torrelo A, Jemec an increasing topical and oral threat. Lancet 2016; XX(4): 227-33. GB. Infantile acne treated with oral isotre- Infect Dis. 2016; 16: e23-33. Recommended bibliography tinoin. Pediatr Dermatol. 2013; 30: 513-18. 25. Williams HC, Dellavalle RP, Garner S. 14. Anzengruber F, Ruhwinkel K, Ghosh A, Acne vulgaris. Lancet. 2012; 379: 361-72. - Zaenglein AL, Pathy AL, Schlosser BJ, Klaghofer R, Lang UE, Navarini AA. 26. Requena C, Llombart B. Oral Contracepti- Alikhan A, Baldwin HE, Berson DS, et al. Wide range of age of onset and low refer- ves in Dermatology. Actas Dermosifiliogr. Guidelines of care for the management of ral rates to psychiatry in a large cohort of 2020; 111: 351-6. acne excoriée at a Swiss tertiary hospital. J acne vulgaris. J Am Acad Dermatol. 2016; Dermatol Treat. 2018; 29: 277-80. 27. Arowojolu AO, Gallo MF, López LM, 74: 945-73. Grimes DA. Combined oral contraceptive 15. Orfanos CE, Adler YD, Zouboulis CC. Interesting article describing the current recom- pills for treatment of acne. Cochrane Da- mendations in the management of acne. They The SAHA syndrome. Horm Res. 2000; tabase Syst Rev. 2012; 7: CD004425. 54: 251-8. highlight the importance of topical retinoid in 28. Lee JW, Yoo KH, Park KY, Han TY, Li K, all patients with mild-moderate acne, combined 16. Han C, Shi J, Chen Y, Zhang Z. Increased Seo SJ, et al. Effectiveness of conventional, either with benzoyl peroxide or topical antibiotic, flare of acne caused by long-time mask low-dose and intermittent oral isotretinoin always avoiding the latter in monotherapy, in or- wearing during COVID-19 pandemic in the treatment of acne: a randomized, der to reduce the risk of bacterial resistance. For among general population. Dermatol Ther. controlled comparative study. Br J Der- moderate-severe acne, oral antibiotic treatment 2020; 29: e13704. matol. 2011; 164: 1369-75. should be added, or in case of lack of response 17. Tan KT, Greaves MW. N95 acne. Int J 29. Lee SY, Jamal MM, Nguyen ET, Bechtold to it, oral isotretinoin in monotherapy should be Dermatol. 2004; 43: 522-3. ML, Nguyen DL. Does exposure to isotre- started. 18. Bandera A, de Lucas R. Aspectos epide- tinoin increase the risk for the development - Dréno B, Pécastaings S, Corvec S, Veraldi miológicos, clínicos y terapéuticos en situa- of inflammatory bowel disease? A meta- S, Kharmari A, Roques C. Cutibacterium ciones especiales: hidradenitis supurativa analysis. Eur J Gastroenterol Hepatol. acnes (Propionibacterium acnes) and acne infantil. Actas Dermosifiliogr. 2016; 107: 2016; 28: 210-6. 51-60. vulgaris: a brief look at the latest updates. 30. Sai TY, Liu HW, Chao YC, Huang YC. J Eur Acad Dermato Venereol. 2018; 32: 19. Puig L, Guerra-Tapia A, Conejo-Mir J, To- Effects of isotretinoin on glucose metab- 5-14. ribio J, Berasategui C, Zsolt I. Validation olism in patients with acne: A systematic The bacteria Cutibacterium acnes (formerly of the Spanish Acne Severity Scale (Escala review and meta-analysis. J Dtsch Derma- known as Propionibacterium acnes) is part of a de Gravedad del Acne Espanola - EGAE). tol Ges. 2020; 18: 539-45. Eur J Dermatol. 2013; 23: 233-40. healthy skin, however, it can also act as an op- 31. Huang YC, Cheng YC. Isotretinoin treat- portunistic pathogen in the appearance of acne 20. 0’Brien SC, Lewis JB, Cunlife WJ. The ment for acne and risk of depression: A vulgaris. The novelties identified in the etiopatho- Leeds revised acne grading system. J Der- systematic review and meta-analysis. J Am genesis of acne place C. acnes in a different posi- matol Treat. 1998; 9: 215-20. Acad Dermatol. 2017; 76: 1068-76.e9. tion than previously considered. The proliferation 21. Scott LJ. Trifarotene: First Approval. 32. Lee YH, Scharnitz TP, Muscat J, Chen of C. acnes would not act as a trigger, since acne Drugs. 2019; 79: 1905-9 A, Gupta-Elera G, Kirby JS. Laboratory patients do not harbor more C. acnes in their fo- 22. Thiboutot D, Gollnick H, Bettoli V, Dréno Monitoring during Isotretinoin Therapy llicles than normal individuals. Instead, the loss B, Kang S, Leyden JJ, et al. Global Alli- for Acne: A Systematic Review and Me- of microbial diversity in the skin, coupled with ance to Improve Outcomes in Acne. New ta-analysis. JAMA Dermatol. 2016; 152: the activation of innate immunity, could lead to insights into the management of acne: an 3544. this chronic inflammatory condition.

Clinical case

17-year-old female patient, with no relevant personal history. She presents facial injuries since a few years, which have experienced aggravation in recent months. She had been diagnosed of acne, and received treatment with doxycycline in monotherapy and various topical treatments later, with poor response. She had her menar- che at age 11; and associates menstrual irregularities. On examination she presents: open and closed come- dones, papules, pustules and nodules on the cheeks and, to a lesser extent on the forehead; seborrhea and hirsutism in the examined areas (scored 10 points on the Ferriman / Gallwey scale).

PEDIATRÍA INTEGRAL - en 175 Subsequently, the following accreditation quiz of Pediatría Integral collects questions on this topic, which must be answered online through the website: www.sepeap.org. In order to obtain certification by the Spanish “formación continuada” national health system for health professionals, 85% of the questions must be answered correctly. The accreditation quizzes of the different numbers of the journal may be submitted during the period indicated in the “on-line” quiz.

Acne b. To not drink alcohol. b. Mild inflammatory acne. c. Use contraceptive methods c. Superficial inflammatory acne. 1. Please state which of the following during the entire treatment and d. Rosacea. is NOT involved in the pathogene- one month after finishing it. e. Deep or nodular inflammatory sis of acne: d. Frequent application of skin acne. a. Excess of sebaceous secretion. moisturizer on a daily basis. b. Follicular epidermal hyperpro- e. To not wear contact lenses. 7. Complementary test to REQUEST liferation. would be: c. Pathogenic infection by Strep- 4. State which of the following a. None, as this is only a clinical tococcus Epidermidis. treatments can be prescribed, both diagnosis. d. Bacterial colonization. in summer and winter WITHOUT b. Bacterial culture of pustules. precautions, regarding sun exposu- e. Induction of inflammatory res- c. Blood analysis including hor- ponse. re: monal determinations to study a. Topical tretinoin. hyperandrogenism. 2. An 18-year-old young man b. Acid azelaic. d. Skin biopsy. suddenly presents: fever, joint pain, c. Oral doxicillin. e. Cytokine profile study for auto- papules, pustules and nodules that d. Oral isotretinoin. inflammatory disease. evolve into ulcers and scabs, mainly e. Topical adapalene. on the trunk. Leukocytosis is iden- 8. Regarding the TREATMENT, af- tified. Indicate the most likely ter analytical results and if there is DIAGNOSIS: 5. Please indicate which of the fo- llowing treatments is the BASIS no contraindication, the following a. Chickenpox. of topical acne treatment: should be prescribed: b. Drug rash. a. Prolonged course of oral doxy- a. Clindamycin. c. Acute folliculitis. cycline in monotherapy. b. Erythromycin. d. Acne fulminans. b. Combined topical treatment of c. Tretinoin e. Acne conglobata. clindamycin + retinoids. d. Dapsone plus erythromycin. c. Oral doxycycline associated with 3. Indicate which of the following e. Clindamycin plus glycolic acid. topical clindamycin. recommendations regarding d. Oral isotretinoin associated with treatment with Isotretinoin would Clinical cases oral doxycycline. NOT be appropriate for a 17-year- e. Oral isotretinoin associated with old male patient: 6. The patient in our CASE has: an oral hormonal contraceptive a. Avoid sun exposure. a. Non-inflammatory acne. without androgenic action.

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