Acne is a chronic inflammatory skin disease concerning the sebaceous glands with a prevalence of 70 to 87%, and has a psychological and social impact on adolescents that exceeds that of asthma and epilepsy. Treatment options for acne vary tremendously among dermatologists. Some treatments lack support in the literature, and some are even harmful to patients, society, and the patient’s economy. At the same time, it is essential to have a set of practical guidelines to regulate the treatment of physicians who work in dermatology clinics but have no formal training in dermatology specialties. Of course, guidelines are not set in stone and need to be updated periodically as new evidence-based medicine and new drugs become available.
Topical treatment of acne]
Topical washing: Care should be taken to wash the face with water to remove the oil and the mixture of dander and bacteria from the skin surface. However, excessive washing should not be done. Do not squeeze or scratch the acne with your hands. In addition, avoid using oily, fatty, powdered skin care cosmetics and ointments and creams containing hormonal ingredients.
Topical medication 1. Retinoic acid (1) 0.025%~0.1% retinoic acid (all-trans retinoic acid) cream or gel: This agent can regulate the differentiation of epidermal keratin-forming cells and dissolve and discharge acne. The skin is mildly irritated at the beginning of 5~12 days, such as local flushing, flaking and tightness or burning sensation, but it can gradually disappear. Therefore, it should be applied once a day at night starting from low concentration to avoid increasing drug irritation after light exposure, and topical application once a week after symptoms improve. (2) 13-cis-retinoic acid gel: regulates the differentiation of epidermal keratin-forming cells and reduces sebum secretion, once or twice daily. (3) Third-generation retinoids: 0.1% adapalene gel, once a night, has good efficacy in the treatment of mild to moderate acne. 0.1% tazarotene cream or gel, used once every other night to reduce local irritation. 2. Benzoyl peroxide: This drug is a peroxide, which slowly releases neo-oxygen and benzoic acid after topical application, which can kill Propionibacterium acnes, dissolve acne and have an astringent effect. It can be formulated into 2.5%, 5% and 10% lotions, emulsions or gels of different concentrations, and should be used from low concentrations. Antibiotics: Erythromycin, chloramphenicol or clindamycin, formulated with alcohol or propylene glycol at 1% to 2%, are more effective. 1% clindamycin phosphate solution is a water-soluble emulsion free of oil and alcohol, suitable for acne patients with dry and sensitive skin. 1% clindamycin hydrochloride solution is also effective. 4. azelaic acid. It can reduce the flora on the skin surface, in the hair follicles and sebaceous glands, especially has an inhibitory effect on Propionibacterium acnes and acne lysis effect, and is effective for different types of acne. Selenium disulfide: 2.5% selenium disulfide lotion has the effect of inhibiting fungi, parasites and bacteria, and can reduce the free fatty acid content of the skin. After cleansing the skin, dilute the solution slightly and apply it evenly on the seborrheic areas, and wash with water after about 20 min. 6. 5-10% sulfur lotion: It has the function of regulating the differentiation of keratin-forming cells and reducing the free fatty acid content of the skin, and also has a certain inhibitory effect on Propionibacterium acnes.
Antibiotic treatment for acne]
Oral antibiotics are one of the effective methods for treating acne, especially moderate to severe acne. Among the many colonizing microorganisms (including Staphylococcus epidermidis, Propionibacterium acnes, Malassezia furfur and other gram-negative bacilli), only live Propionibacterium acnes is clearly associated with an aggravated inflammatory response to acne. In addition to infection-induced inflammation, immune and nonspecific inflammatory responses are also involved in the formation of inflammatory damage in acne, so antibiotics that can both inhibit Propionibacterium acnes reproduction and take into account nonspecific anti-inflammatory effects should be given priority.
Combining the above factors with the pharmacokinetics of antibiotics, especially selective distribution at the seborrheic site, tetracyclines should be preferred, followed by macrolides, others such as cotrimoxazole and and metronidazole can also be used as appropriate, but β-lactam antibiotics should not be chosen. Among the tetracyclines, first-generation tetracyclines such as tetracycline are poorly absorbed orally and have low sensitivity to Propionibacterium acnes. Second-generation tetracyclines such as minocycline, doxycycline and lymetetracycline should be preferred, and the two should not be substituted for each other. For systemic infections currently the main or commonly used antibiotics such as clarithromycin, roxithromycin and levofloxacin are avoided. Since the important basis for effective antibiotic treatment of acne is the inhibition of Propionibacterium acnes reproduction, rather than the predominantly nonspecific anti-inflammatory effect, it is important to prevent or slow down the development of resistance in Propionibacterium acnes, which requires the standardization of drug dosage and regimen.
Usually, the daily dose of minocycline and doxycycline is 100-200 mg, which can be taken orally once or in 2 doses; tetracycline is 1.0 g daily, taken orally in 2 doses on an empty stomach; erythromycin is 1.0 g, taken orally in 2 doses. The course of treatment should be no less than 6 weeks, but should not exceed 12 weeks. Antibiotics for acne mainly inhibit the reproduction of Propionibacterium acnes, rather than non-specific anti-inflammatory effects, so it is important to prevent or slow down the development of drug resistance in Propionibacterium acnes. Usually, the dose of minomycin and doxorubicin is 100-200mg/d, which can be taken orally once or in 2 doses, tetracycline 1.0g/d, taken orally in 2 doses on an empty stomach, and erythromycin 1.0g/d, taken orally in 2 doses. The treatment course is 6-12 weeks. Antibiotic treatment of acne should pay attention to how to avoid or reduce the development of drug resistance. These include: ① Avoid using them alone to treat acne, especially for long-term topical application; ② Treatment should be started in adequate doses and should not be reduced for maintenance once effective; ③ Discontinue or switch to other antibiotics promptly when there is no efficacy 2-3 weeks after treatment, and pay attention to patient compliance and differentiate between gram-negative bacterial folliculitis; ④ Ensure an adequate course of treatment and avoid intermittent use; ⑤ Propionibacterium acnes is a parasitic bacteria of normal skin. Treatment is aimed at effectively inhibiting its reproduction rather than achieving complete elimination. Therefore, the dose should not be unprincipledly increased or the course of treatment extended, let alone as a maintenance treatment or even as a measure to prevent relapse; 6. The treatment should pay attention to the adverse drug reactions, including the more common gastrointestinal reactions, drug rash, liver damage, photosensitivity reactions, vestibular involvement (such as dizziness, vertigo) and benign intracranial pressure elevation syndrome (such as headache), etc. Rare adverse reactions include lupus-like syndrome, especially the application of minomycin. It should be used with caution or prohibited for patients with long-term alcohol consumption, hepatitis B, photosensitive dermatitis, etc. Tetracyclines should not be used in pregnant women and children under 16 years of age. Dividing the daily dose of minomycin into oral doses or using the extended-release dosage form once a night may partially reduce adverse reactions. Discontinue the drug promptly in case of serious adverse reactions or if the patient cannot tolerate it and treat the symptoms. Both macrolides and tetracyclines are prone to drug interactions, so care should be taken when combining with other systemic medications.
Treatment of acne with retinoic acid]
Oral isotretinoin is the standard treatment for severe acne and is currently the most effective treatment for acne. Isotretinoin acts on all pathophysiological aspects of acne pathogenesis, and although the therapeutic effect is remarkable, it is not used as the first choice of treatment for mild acne as much as possible, considering its side effects.
Indications for the use of oral isotretinoin: (1) severe nodular cystic acne and its variant forms; (2) inflammatory acne with scar formation; (3) moderate to severe acne that has not responded to the following treatments: 3 months of treatment with combination therapy, including systemic application of tetracyclines; (4) acne patients with severe psychological stress (disfigurement phobia); (5) gram-negative bacillary folliculitis; (6) the need for frequent relapses Repeated and long course systemic application of antibiotics; ⑦ Few patients who need rapid healing for some reason. Dosage: The common dose is 0.25-0.5 mg/kg/d. In order to reduce side effects, the dose should not exceed 0.5 mg/kg/d. The course of treatment is determined by the patient’s body weight and the daily dose used. The minimum cumulative dose is targeted at 60 mg/kg, but if the cumulative dose reaches 60 mg/kg without satisfactory efficacy, it can be increased to 75 mg/kg. However, even if the acne is completely cleared at one point, the probability of permanent cure is significantly reduced if isotretinoin is discontinued before the 60 mg/kg domain value is reached. There is also so-called shock therapy, which is the use of isotretinoin 0.5 mg/kg per day for the first 7 days of the month, which has been shown to be more effective in patients who have relapsed after a full course of treatment, those with prolonged disease and those with treatment-resistant acne.
In some conditions, such as adolescents with severe acne, continuous low doses of isotretinoin can be used. In these patients, acne dissolution is poor in the initial stages, but a 4-6 month course of 10-20 mg/d of isotretinoin can clear the rash more quickly, followed by topical retinoic acid to maintain efficacy. High-dose retinoic acid therapy is not advocated because there is no significant improvement in efficacy, but the potential toxicity may be severe. Counseling and interpretation of the patient prior to the systematic use of retinoic acid is very important. It should be explained to the patient that retinoic acid can cause many side effects, especially teratogenic effects. Patients should use strict contraception for 1 month prior to treatment until a negative pregnancy test is obtained within 3 months of the end of treatment. If pregnancy occurs during treatment, an abortion must be performed. A small number of patients develop depressive symptoms with the use of retinoic acid. Patients with a history or family history of depression should use the drug with caution and discontinue it as soon as mood swings occur or any depressive symptoms appear. Other side effects of isotretinoin are mainly dryness of the skin mucosa. There is a temporary exacerbation of acne in the beginning phase. 5% of cases have photosensitivity, joint and muscle pain, severe night blindness during night driving, severe hair loss, and blood triglycerides may be elevated. Liver function and lipid tests are performed before treatment is started and reviewed after 1 month of treatment. If both are normal, no further hematologic testing is required. Long-term high dose application may cause epiphyseal deformities such as osteomalacia, calcification of spinal ligaments, and osteoporosis. Isotretinoin should not be applied concurrently with tetracyclines, nor should glucocorticoids be applied systemically at the same time, as both have the potential to synergistically induce an increase in intracranial pressure. Vivamate can also replace isotretinoin, but it is slightly poorly absorbed orally, has a slow onset of action, and has relatively mild side effects.
Hormone therapy for acne]
Application of estrogens and anti-androgenic drugs 1. Estrogens Estrogens include two major groups: estrogens and progestins. It is currently believed that androgens play a role in the development of acne. Female patients with moderate or severe acne should be treated with estrogen and progestin early if they are accompanied by high androgen levels, signs of high androgen activity (seborrhea, acne, hirsutism, androgenic alopecia: abbreviated as (SAHA) or the presence of polycystic ovary syndrome (PCO). Combined use of birth control pills may also be considered in female patients with late-onset acne and those whose acne worsens significantly before menstruation. The FDA has approved birth control pills for the treatment of acne in women over the age of 15. The mechanism of action of oral estrogen and progestin in the treatment of acne (1) Estrogen: (1) By reducing the excessive secretion of androgens caused by ovarian and adrenocortical hyperfunction, and by stimulating the synthesis of sex hormone-binding globulin (SAHA) in the liver, the concentration of active estrogen in the serum is reduced, which plays an anti-sebum secretion role. ②Estrogen can increase the amount of SHBG and decrease the amount of free testosterone. (3) Estrogen has the effect of reducing the volume of sebaceous glands and inhibiting lipid synthesis in sebaceous gland cells. (2) Progestins: ① are 5α reductase inhibitors, which can reduce the amount of testosterone and dehydrotestosterone in plasma through negative feedback inhibition. (ii) It can inhibit the ability of sebaceous gland cells and keratin-forming cells to convert testosterone. (3) Cyproterone acetate can also block the binding of sex hormones to their receptors. (3) Estrogen and progesterone can also act directly on hair follicle sebaceous glands to reduce sebum secretion and inhibit acne formation.
Oral contraceptives are a combination of estrogen and progestin, and the choice of their type is also very important. Some birth control pills contain androgenic components, and certain synthetic progestins have cross-reactivity with androgen receptors, which can reduce SHBG and increase the amount of free testosterone, thus aggravating or causing acne. Currently, the drug of choice is Diane35 (each tablet contains 2mg of cyclopentone acetate + 35ug of ethinyl estradiol), which should be taken daily for 21 days starting on the first day of the menstrual cycle, then stopped for 7 days and repeated for 21 days after another period, for 2-3 months. For patients with particularly high seborrhea, the effect of conventional contraceptive treatment is often not good. The efficacy can be significantly improved by taking 50-100mg of cyproterone acetate on the 5th-14th days of the menstrual cycle in addition to the oral dose of Daing-35. Adverse reactions include small amount of uterine bleeding, breast distension, upper abdominal discomfort and facial skin redness, weight gain, deep vein thrombosis, appearance of chloasma, etc. 2. Other anti-hormone therapy Andrographolide: also known as spironolactone, is an aldosterone compound. Mechanism of action: ① competitively inhibit the binding of dihydrotestosterone to the receptors of skin target organs, thus affecting its action and inhibiting the growth of sebaceous glands and sebum secretion. ②Inhibit 5α reductase and reduce the conversion of testosterone to dihydrotestosterone. The recommended dose is 1-2 mg/kg/d for 3-6 months. Side effects are menstrual irregularities (the incidence is positively correlated with the dose), nausea, drowsiness, fatigue, dizziness or headache and hypercalcemia. Contraindicated in pregnant women. Not recommended for male patients, who may experience breast development and breast tenderness after use. Metacycline (cimetidine): It has weak anti-androgenic effect and can competitively block the binding of dihydrotestosterone to its receptors, but does not affect serum androgen levels, thus inhibiting sebum secretion. The recommended dose is 200 mg/dose, 3 times daily for 4-6 weeks. Application of glucocorticoids Glucocorticoids have the function of inhibiting androgen secretion caused by hyperadrenocorticism, anti-inflammatory and immunosuppressive effects.
Oral glucocorticosteroids are mainly used for fulminant acne or coalescent acne because these types of acne are often related to excessive immune and inflammatory reactions, and brief use of glucocorticosteroids can play an immunosuppressive and anti-inflammatory role. It should be noted, however, that glucocorticoids themselves can induce acne. Oral use should only be used in patients with more severe inflammation, and in small, short-term doses.
Recommended dosage: ①Fulminant acne: Prednisone 20-30 mg/day for 4-6 weeks, followed by a gradual reduction over 2 weeks, after which oral retinoic acid is started. (ii) Aggregate acne or fulminant acne with exacerbation during oral retinoic acid treatment, prednisone 20-30 mg/d for 2-3 weeks, followed by gradual reduction over 6 weeks; also discontinue oral retinoic acid or reduce the dose to 0.25 mg/kg/d, and then increase or decrease the dose according to the condition. ③ Prednisone 5 mg/d or dexamethasone 0.375-0.75 mg/d, taken every night, can inhibit the high secretion of pro-adrenal hormones in the early morning and inhibit the production of androgens by the adrenal glands and ovaries, and gradually reduce the dose after improvement. For patients with acne that worsens before menstruation, prednisone 5 mg/day can be started 10 days before menstruation until the onset of menstruation. Fisher et al. suggested that high doses of glucocorticoids have anti-inflammatory effects, while low doses have anti-androgenic effects.
Chinese medicine treatment for acne]
Chinese medicine treatment should be differentiated into types of treatment and added or subtracted according to the symptoms. The treatment of red papular acne is recommended to clear the lungs and stomach; the treatment of pustular acne is recommended to detoxify and disperse the knots; the treatment of premenstrual acne is recommended to regulate the flushing method; and the treatment of aggregated acne, post-pigmentation or scarring is recommended to activate blood circulation and disperse stasis. Acupuncture therapy: The acupuncture points of Dazhi, Spleen Yu, Foot San Li, Hegu, and Sanyinjiao are often selected, and the method of flat tonic and flat diarrhea is used. Ear acupuncture therapy: the patient’s bilateral ear lung points as the main points, with the Shen Men, sympathetic, endocrine, subcortical points buried Wang Bu Liuxing seeds, external fixed with adhesive tape, massage the upper points 3 times a day, about 10 minutes each time. Diet therapy: patients are advised to eat less sweets, fat, wine, spicy and other stimulating foods, more vegetables (bean sprouts, bok choy, pungent high vegetables, winter melon, loofah, bitter melon, water chestnuts) and fruits. Drink mung bean soup regularly to clear lung heat and remove dampness and toxicity. Eating more food containing long fiber and keeping the bowels open is effective in preventing acne. In addition, avoid using oily and powdered skin care cosmetics and ointments and creams containing hormones. Wash your face twice a day with warm water, do not use strong alkaline soap, wipe away facial fat and dirt when washing, and prohibit your fingers from squeezing facial papules, pimples and pustules to prevent scarring.
Physiotherapy for Acne]
For acne patients who cannot tolerate medication or do not want to receive medication, physical therapy is the best option. Currently, the physical therapies commonly used to effectively treat acne are photodynamic therapy, laser therapy and fruit acid therapy. Photodynamic therapy (PDT): Through the use of specific wavelengths of light to activate the porphyrins metabolized by Propionibacterium acnes, acne is treated through phototoxic reactions, induction of cell death and stimulation of macrophages to release cytokines and promote self-healing of lesions. At present, blue light alone (415nm), blue light combined with red light (630nm) and red light + 5-ALA therapy are mainly used to treat various types of acne vulgaris. Treatment protocol: 1-2 times a week, blue light energy is 48 J/cm2, red light is 126 J/cm2, 4-8 times a course of treatment. There was slight itching during the treatment, and some patients showed slight flaking after the treatment, and no significant side effects were found. Experiments have shown that photodynamic therapy can inhibit sebaceous gland secretion, reduce the number of acne and inflammatory lesions, and promote tissue repair to varying degrees. Fruit acid therapy: Fruit acid is widely found in fruits, sugar cane and yogurt in nature, with simple molecular structure, small molecular weight, non-toxic and odorless, strong permeability, safe action, and does not damage the epidermal barrier function. The mechanism of action of fruit acids is to reduce the adhesion of keratin-forming cells by interfering with the binding force on the cell surface, accelerate the shedding and renewal of epidermal cells, and at the same time stimulate dermal collagen synthesis and enhance the moisturizing function. The higher the concentration of fruit acid, the longer the action time, the better its effect, but the relative adverse effects are also greater. Treatment protocol: Apply fruit acids (hydroxyacetic acid) at concentrations of 20%, 35%, 50%, and 70% once every 2-4 weeks for acne treatment, with 4 times being a course of treatment. Inflammatory lesions and non-inflammatory lesions had varying degrees of remission, with remission rates of 30%-61%. Increasing the number of treatments can improve the efficacy. Laser therapy: 1450nm laser, intense pulsed light (IPL), pulsed dye laser and fractional laser are among the effective treatments for acne and acne scarring, and can also be combined with medications. 1450nm laser is an FDA-approved laser for the treatment of acne. Intense pulsed light can help fade the red marks in the later stages of inflammatory acne. Fractional laser has some improvement for acne scarring. Other treatments: ①Acne picking: This is one of the most effective methods of acne treatment available, but it is necessary to use medication at the same time to inhibit the production and development of acne at the root. ②Glucocorticoid injection in nodules/cysts: It helps to eliminate inflammation quickly and is a very effective treatment for larger nodules and cysts. ③Cyst excision and drainage: For very large cysts, excision and drainage is an effective way to avoid later lesion mechanization and formation of scarring.
Graded treatment of acne]
The grading of acne reflects the severity of acne and the nature of the lesions, so the treatment of acne should be based on the grading of acne and the selection of appropriate treatment drugs and methods. Whether acne is graded according to the International Modified Classification, which is based on the number of lesions, or the Acne Classification, which emphasizes the nature of the lesions, the treatment options are basically the same. Of course, the treatment plan for acne is not set in stone and should be flexible according to the actual situation of the patient, fully reflecting the principle of individualized treatment.
Grade 1: Topical treatment is generally used. If only acne is present, topical vitamin A acid preparations are the best choice. Some medical skin care products that have the effects of exfoliating, dissolving acne, inhibiting sebum secretion, and antibacterial can also be used as an adjunctive treatment.
Grade 2: Treatment for grade 1 acne is usually used, but oral antibiotics may be used for those with more inflammatory papules and pustules and where topical treatment is not effective. This type of acne can also be treated with combination therapy, such as oral antibiotics combined with topical retinoic acid preparations, or coupled with physical therapy such as blue light, photodynamic therapy, or fruit acid therapy.
Grade 3: This type of patient often requires a combination therapy approach in which the systematic use of antibiotics is one of its basic treatments, and an adequate course of treatment should be ensured. The most commonly used combination therapy is oral antibiotics plus topical retinoic acid preparations and also topical benzoyl peroxide. Hormonal therapy has also been used with good results in female patients who require contraception or have other gynecologic indications. Other combination therapies described in the guidelines may be used (e.g., red and blue light, photodynamic therapy, etc.), but attention should be paid to the interactions and contraindications between tetracyclines and isotretinoin agents and the development of photosensitivity. Those with poor results can be treated with oral isotretinoin alone or with concomitant topical peroxynivalenol. For those who require more than 3 months of systemic antibiotic application, the addition of an antibacterial agent such as peroxymethylphenidate that does not cause bacterial resistance is necessary to prevent and reduce the development of drug resistance.
Grade 4: Oral isotretinoin is the most effective treatment for this group of patients and can be used as first-line therapy. For those with more inflammatory papules and pustules, a combination of systemic antibiotics and topical peroxynivalenol can also be used first, and then switch to oral isotretinoin for the remaining lesions such as cysts and nodules after these lesions have significantly improved. The methods used for Grade 3 acne above and the combination treatments described in this guideline may also be tried.
Regardless of the grade of acne, maintenance therapy after symptomatic improvement is very important. Maintenance treatment is usually topical retinoic acid preparations alone.
Combination therapy for acne]
Oral antibiotics and topical retinoic acid can have synergistic effects through different independent pathways of action, and the combination of these two approaches can clear lesions faster than antibiotics alone for inflammatory damage and acne. Concomitant use of topical retinoic acid can shorten the duration of antibiotic treatment, increase antibiotic penetration and increase follicular cell turnover, thereby allowing more antibiotics to reach the sebaceous units and reducing the incidence of drug resistance.
Combination therapy is currently the standard of care for mild to moderate acne. Advantages of combination therapy: (1) the clinical efficacy of antibiotics combined with topical retinoic acid is significantly better than that of antibiotics alone; (2) faster onset of action on inflammatory damage and acne; (3) the combination can target different pathophysiological factors; (4) topical retinoic acid can increase antibiotic penetration and accelerate antibiotic use. Principles of combination therapy: ① oral antibiotics should be combined with topical topical retinoic acid, which can act on 3 pathogenic factors; ② oral antibiotics should not be combined with topical antibiotics (increase bacterial resistance without increasing the efficacy); ③ peroxymethylphenidate or topical retinoic acid combined with oral antibiotics can reduce the incidence of drug resistance; ④ topical peroxymethylphenidate should be combined when prolonged antibiotics are needed; ⑤ The combination of topical retinoic acid and benzoyl peroxide can be used daily with one or both drugs alternately in the morning and evening.
Maintenance treatment for acne]
The importance of maintenance therapy: After a course of systemic application of isotretinoin and systemic application of antibiotics, and if the symptoms of acne in the acute phase have improved (improvement rate >90%), maintenance therapy should be considered to prevent recurrence whenever possible; because all current treatments for acne only inhibit its pathogenesis, not cure it. Therefore, it is necessary to follow all treatments with maintenance therapy. After the initial systemic treatment is completed, topical retinoic acid is the main method of maintenance therapy, and in the presence of inflammatory damage, a combination of peroxynivalenol may be considered.
The necessity of maintenance therapy: ① Microcomedones are the early pathological process of all acne damage; ② The process of microcomedone formation remains permanent and persistent after acne clearance; ③ Avoidance of microcomedone formation has an acne preventive effect; ④ The main mechanism of action of retinoic acid is to interfere with the pathological process of microcomedones. Maintenance regimen: ① Topical topical retinoic acid: the main choice of maintenance treatment; ② Duration of maintenance treatment: 6-12 months; ③ Benzoyl peroxide: combined with topical retinoic acid can reduce resistance after antibiotic treatment; ④ Choice of second-line treatment drugs: azelaic acid and salicylic acid.