1.Pathophysiological factors for the occurrence of acne
The occurrence of acne is closely related to many factors such as excessive sebum secretion, hair follicle sebaceous duct obstruction, bacterial infection and inflammatory response. The pathophysiological basis for acne is the rapid development of sebaceous glands and excessive sebum secretion, which is directly governed by androgens. After puberty, the level of androgens, especially testosterone, increases rapidly. Testosterone is converted to dihydrotestosterone in the skin by the action of 5-alpha reductase, which binds to androgen receptors in sebaceous gland cells. Increased androgen levels promote the development of sebaceous glands and the production of large amounts of sebum. Some patients with acne have higher blood levels of testosterone than those without acne. In addition, progesterone and dehydroepiandrosterone in the adrenal cortex also have a pro-sebum effect. Sebum is mainly composed of squalene, wax esters, triacylglycerols and small amounts of sterols and cholesterol esters. Acne patients have higher levels of wax esters and lower levels of linoleic acid in their sebum, and the reduced content of linoleic acid reduces essential fatty acids around the hair follicle and promotes keratinization of the follicle epithelium.
Abnormal keratinization of the follicular sebaceous ducts is another important factor. Acne formation begins with the enlargement of the sebaceous follicles, and this enlargement is secondary to abnormal keratinization of the keratinocytes. In the lower part of the follicular funnel, the lamellar granules of keratin-forming cells are reduced and replaced by a large number of tension filaments, bridging granules, and lipid inclusion bodies.
The secretion and discharge of large amounts of sebum are prone to bacterial infections. Various microorganisms such as Propionibacterium acnes, Staphylococcus albicans and Malassezia are present in the hair follicles, with Propionibacterium acnes infection being the most important. Propionibacterium acnes is an anaerobic bacterium, and the obstruction of sebum discharge creates a good local anaerobic environment for it to proliferate. The esterase produced by Propionibacterium acnes can break down triacylglycerols in sebum and produce free fatty acids, which are the main factors leading to inflammatory damage in acne. In addition, P. acnes can also produce peptides that chemotactic neutrophils, activate complement and cause leukocytes to release various enzymes, inducing or aggravating inflammation.
In addition to the above factors, the occurrence of acne in some patients is also related to the immune function of the body, especially in some specific acne such as convergent acne and fulminant acne, where the immune response plays an important role.
2.Grading of acne
Acne classification is an important basis for acne treatment and efficacy evaluation. According to the nature and severity of acne lesions, acne can be classified into three degrees and four grades.
Grade 1 (mild): only acne;
Grade 2 (moderate): Inflammatory papules in addition to acne;
Grade 3 (moderate): pustules in addition to pimples and inflammatory papules;
Grade 4 (severe): nodules, cysts or scarring in addition to acne, inflammatory papules and pustules.
3.Local treatment of acne
3.1 Localized washing
Wash the face with water to remove the mixture of oil, dander and bacteria from the skin surface. However, excessive washing should not be done. Do not squeeze or scratch the acne. In addition, avoid using oily, greasy, powdered skin care cosmetics and ointments and creams containing glucocorticoids.
3.2 Topical medication
3.2.1 Retinoic acid drugs
①0.025%~0.1% retinoic acid (all-trans retinoic acid) cream or gel: This drug can regulate the differentiation of epidermal keratin-forming cells to dissolve and discharge acne. The skin is slightly irritated at the beginning of 5~12 d, such as local flushing, flaking, tightness or burning sensation, but it can gradually disappear. Therefore, it should be used from low concentration and applied once a night to avoid increasing drug irritation after light exposure, and topical application once a week after symptoms improve.
②13-cis-retinoic acid gel: regulate the differentiation of epidermal keratin-forming cells and reduce sebum secretion, once or twice a day.
③2nd 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.
3.2.2 Benzoyl peroxide
This drug is a peroxide, which slowly releases neo-oxygen and benzoic acid after topical application, and has the effects of killing Propionibacterium acnes, dissolving acne and astringency. It can be formulated into 2.5%, 5% and 10% lotions, emulsions or gels of different concentrations, and should be used from a low concentration. Gels containing 5% benzoyl peroxide and 3% erythromycin can improve the efficacy.
3.2.3 Antibiotics
Erythromycin, chloramphenicol or clindamycin (clindamycin) formulated with ethanol or propylene glycol at a concentration of 1% to 2% is more effective. 1% clindamycin phosphate solution without oil and ethanol in a water-soluble emulsion is suitable for acne patients with dry and sensitive skin. 1% clindamycin solution is equally effective.
3.2.4 Azelaic acid
This drug 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, and is effective for different types of acne. It can be formulated as a 15%-20% cream for external use, and its adverse effects are local erythema and stinging pain.
3.2.5 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. The method of use is to clean the skin, with a slightly diluted solution evenly coated with seborrhea obvious parts, about 20 minutes and then wash with water.
3.2.6 Sulfur lotion
5%~10% sulfur lotion has the effect of regulating the differentiation of keratin-forming cells and reducing free fatty acids in the skin, and also has a certain inhibitory effect on Propionibacterium acnes.
4.Antibiotic treatment of acne
Oral antibiotics are one of the effective methods for treating acne, especially moderate and severe acne. Among the many colonizing microorganisms (including Staphylococcus epidermidis, Propionibacterium acnes, Malassezia and other gram-negative bacilli), only live Propionibacterium acnes has a clear association with the aggravation of acne inflammation, so it is very important to choose antibiotics that are sensitive to Propionibacterium acnes. In addition to infection-induced inflammation, immune and nonspecific immune responses are also involved in the process of inflammatory damage in acne. Therefore, antibiotics that both inhibit Propionibacterium acnes multiplication 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, and others such as sulfamethoxazole-methoprene (cotrimoxazole) and metronidazole can also be used as appropriate, but β-lactam antibiotics should not be chosen. Among the tetracyclines, 1st generation tetracyclines such as tetracycline are poorly absorbed orally and have low sensitivity to Propionibacterium acnes; 2nd 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 important or commonly used antibiotics such as clarithromycin, roxithromycin, and levofloxacin are avoided.
Since antibiotics for acne mainly inhibit Propionibacterium acnes reproduction rather than non-specific anti-inflammatory effects, it is important to prevent or slow down the development of resistance in Propionibacterium acnes, which requires that the dose and course of medication should be standardized in the use of antibiotics for acne. 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. This includes.
① Avoid using them alone to treat acne, especially for long-term topical application;
②Treatment should be started in adequate doses and should not be reduced for maintenance once effective;
③Treatment should be discontinued or switched to other antibiotics in a timely manner when there is no efficacy 2-3 weeks after treatment, and attention should be paid to patient compliance and differentiation of Gram-negative bacterial folliculitis;
④Ensure an adequate course of treatment and avoid intermittent use;
⑤Propionibacterium acnes is a parasitic bacterium of normal skin, and treatment is aimed at effectively inhibiting its reproduction rather than achieving complete elimination;
(6) The drug resistance of Propionibacterium acnes can be monitored if conditions permit to guide the rational clinical use of drugs.
Adverse drug reactions should be noted during treatment, including the more common gastrointestinal reactions, drug rash, liver damage, photosensitivity reactions, vestibular involvement (e.g., dizziness, vertigo) and benign intracranial pressure elevation syndrome (e.g., headache). Rare adverse reactions include lupus-like syndrome, especially when applying minomycin, which should be used with caution or prohibited in patients with long-term alcohol consumption, hepatitis B, photosensitivity 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, and attention should be paid to drug interactions when combined with other systemic drug treatments.
5.Acne treatment with retinoic acid
Oral isotretinoin is the standard treatment for severe acne and is currently the most effective method for treating acne. Isotretinoin acts on all pathophysiological aspects of acne pathogenesis, and although the therapeutic effect is significant, it is not used as the first choice of treatment for mild acne as much as possible, considering its adverse effects.
Indications for the application of oral isotretinoin.
①Severe nodular cystic acne and its variant forms;
②Inflammatory acne with scar formation;
③Medium and severe acne that has failed to respond to the following treatments: 3 months of treatment with combination therapy, including systemic application of tetracyclines;
④Acne patients with severe psychological stress (disfigurement phobia);
⑤ Gram-negative bacillary folliculitis;
⑥Patients with frequent relapses requiring repeated and long course systemic antibiotics;
(7) A small number of patients who need rapid healing for some reason.
Dose: The commonly used dose is 0.25-0.5 mg/(kg.d), and the dose should not exceed 0.5 mg/(kg.d) in order to reduce adverse reactions. The duration 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 can be increased to 75 mg/kg if the cumulative dose reaches 60 mg/kg without satisfactory efficacy. However, even if grade 1 acne is completely cleared, 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 involves the use of isotretinoin 0.5 mg/(kg.d) for the first 7 d of each month. This approach has been shown to be more effective in patients who have relapsed after having completed a full course of treatment, in those with prolonged disease and in 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 isotretinoin 10-20 mg/d for 4-6 months can clear lesions more quickly, followed by topical retinoic acid to maintain efficacy. High-dose retinoic acid therapy is not advocated because the increase in efficacy is not significant and potentially serious toxic reactions may occur.
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 adverse effects, especially teratogenic effects. Patients should use strict contraception for 1 month prior to treatment and until 3 months after the end of treatment. If pregnancy occurs during the course of treatment, abortion must be managed. A small number of patients develop depressive symptoms with the use of retinoic acid. Patients with a history of depression or in the family should use the drug with caution and discontinue it immediately in the event of mood swings or any depressive symptoms.
Other adverse effects of isotretinoin are mainly dryness of the skin mucosa. There is a temporary exacerbation of acne in the initial phase. 5% of patients experience photosensitivity, joint and muscle pain, severe night blindness during night driving, severe hair loss, and blood triacylglycerols may be elevated. Liver function and lipid tests are performed prior to the start of treatment and are reviewed after 1 month of treatment. If both are normal, no further blood tests are required.
Long-term high dose application may cause epiphyseal deformities such as osteomalacia, calcification of spinal ligaments, and osteoporosis. It should be noted that isotretinoin should not be applied simultaneously with tetracyclines or systemically with glucocorticoids, because isotretinoin and glucocorticoids may synergistically induce an increase in intracranial pressure. Vivamate can also replace isotretinoin, but it is slightly poorly absorbed orally, with a slow onset of action and relatively mild adverse effects.
6. Hormonal treatment of acne
6.1 Application of estrogens and anti-androgenic drugs
6.1.1 Estrogens
Estrogens include two major categories: estrogen and progestin. It is believed that androgens play a role in the development of acne. Female patients with moderate to severe acne should be treated with estrogen and progestin if they have high androgen levels, high androgen activity such as seborrhea, acne, hirsutism, androgenic alopecia (SAHA) or polycystic ovary syndrome (PCOS). Combination contraceptives may also be considered for women with late-onset acne and those with significant premenstrual acne. The U.S. Food and Drug Administration (FDA) has approved birth control pills for the treatment of acne in women >15 years of age.
Mechanism of action of oral estrogen and progestin for 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 (SHBG) in the liver, the concentration of active estrogens in the serum is reduced, thus playing an anti-sebum secretion role.
②Estrogen can increase the amount of SHBG synthesis 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) Progesterone.
① is a 5-alpha reductase inhibitor, 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: Oral contraceptives are a combination of estrogen and progestin, and their type selection is also very important. Some birth control pills contain sex hormone 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.
At present, the drugs often chosen to treat acne are compounded cyclopentone acetate tablets (Daine-35, Diane35, each tablet contains 2mg of cyclopentone acetate + 35ug of ethinyl estradiol), starting with one tablet on the first day of the menstrual cycle for 21d, stopping for 7d, and repeating the medication for 21d after another period, effective after 2-3 months, for a course of 3-4 months. For patients with particularly high seborrhea, the effect of conventional treatment with contraceptive pills is often not good. The efficacy can be significantly improved by taking 50-100 mg of cyproterone acetate on top of oral Daine-35 at 5-14 d of the menstrual cycle. Adverse effects include small amount of uterine bleeding, breast distension, upper abdominal discomfort and facial skin redness, weight gain, deep vein thrombosis, and appearance of chloasma.
6.1.2 Other anti-hormone therapy
Amphiregulin: Amphiregulin, also known as spironolactone, is an aldosterone compound. Mechanism of action.
①Competitive inhibition of dihydrotestosterone binding to the receptors of skin target organs, thus affecting its action and inhibiting the growth of sebaceous glands and sebum secretion.
②Inhibit 5-alpha reductase and reduce the conversion of testosterone to dihydrotestosterone. The recommended dose is 1-2mg/(kg.d) for 3-6 months. Adverse effects are menstrual irregularities (the probability of occurrence 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.
Mecamidine (cimetidine) has a weak anti-androgenic effect, competitively blocking the binding of dihydrotestosterone to its receptors without affecting serum androgen levels, thereby inhibiting sebum production. The recommended dose is 200 mg 3 times daily for 4-6 weeks.
6.2 Application of glucocorticoids
Glucocorticoids have the function of inhibiting androgen secretion caused by hyperadrenocorticism, anti-inflammatory and immunosuppressive effects.
Oral glucocorticoids are mainly used for fulminant acne or coalescent acne, because these types of acne are often associated with excessive immune response and inflammation, and the brief use of glucocorticoids can play an immunosuppressive and anti-inflammatory role. However, care should be taken that glucocorticoids themselves are anti-inflammatory and trigger acne. Oral administration is only available in patients with more severe inflammation and in small, short-term doses.
Recommended dosage.
①Fulminant acne: Prednisone 20-30 mg/d for 4-6 weeks, followed by a gradual reduction over 2 weeks and the addition of oral retinoic acid.
②For acne conglobata or acne fulminans with exacerbation during oral treatment with retinoic acid, give 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, is an anti-inflammatory to inhibit the high secretion of pro-adrenal hormones early in the morning and inhibit the production of androgens by the adrenal glands and ovaries, and is gradually reduced after improvement. Fisher et al. believe that high doses of glucocorticoids have an anti-inflammatory effect, while low doses have an anti-androgenic effect.
7.Chinese medicine treatment of acne
Chinese medicine treatment should be divided into types of treatment and added or subtracted according to the symptoms. For acne with red papules, it is recommended to clear the lungs and stomach; for acne with pustules, it is recommended to detoxify and disperse the knots; for acne before menstruation, it is recommended to regulate the flushing method; for acne with aggregation, pigmentation or scarring after healing, it is recommended to activate blood 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 10min each time.
Diet therapy: patients should eat less high sugar, high fat, wine, spicy and other stimulating food, eat more vegetables (bean sprouts, bok choy, pungent high vegetables, winter melon, loofah, bitter melon, water chestnut) 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.
8.Physiotherapy for acne
For acne patients who cannot tolerate medication or do not want to receive medication, physical therapy is the best choice. Currently, physiotherapy is commonly used to effectively treat acne, including photodynamic therapy, laser therapy and fruit acid therapy.
8.1 Photodynamic therapy
The use of specific wavelengths of light activates the porphyrins metabolized by Propionibacterium acnes to treat acne 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-Aminoketovaleric acid (5-AALA) are mainly used to treat various types of common acne in clinical practice.
Treatment protocol: 1-2 times per week, blue light energy is 48 J/cm2, red light is 126 J/cm2, 4-8 times for 1 treatment course. There was slight itching during the treatment, and some patients showed slight flaking after the treatment, and no significant adverse effects were found. The experiment proved that photodynamic therapy can inhibit sebaceous gland secretion, reduce the number of acne and inflammatory lesions, and promote tissue repair to different degrees.
8.2 Fructic acid therapy
Fruit acids are widely found in fruits, sugar cane and yogurt in nature. They have simple molecular structure, small molecular mass, non-toxic and odorless, strong permeability, safe action and do 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.
8.3 Laser therapy
1 450 nm laser, intense pulsed light (IPL), pulsed dye laser and fractional laser are among the effective methods for treating acne and acne scarring, and can also be combined with medication. 1450 nm laser is a laser approved by the U.S. Food and Drug Administration (FDA) 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.
8.4 Other treatments
①Pimple picking This is one of the current effective methods of acne treatment, but it is necessary to use medication at the same time to radically inhibit the production and development of acne.
②Glucocorticoid injection in nodules and/or cysts Helps to rapidly eliminate inflammation and is a very effective treatment for larger nodules and cysts.
③Cyst excision and drainage For large cysts, excision and drainage is an effective way to avoid later lesion mechanization and scar formation.
9.Grading 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 Method, which is based on the number of lesions, or according to the Acne Classification Method, which emphasizes the nature of 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 combined application of physical therapy such as blue light, photodynamic therapy, and fruit acid therapy.
Grade 3: These patients often require a combination therapy approach, in which the systematic use of antibiotics is one of their basic treatments, and an adequate course of treatment should be ensured. The most frequently used combination therapy is oral antibiotics combined with topical retinoic acid preparations, and also topical peroxymethylphenidate can be used at the same time. Hormonal therapy has also been used with good results in female patients requiring contraception or with other gynecologic indications. Other combination therapies described in this guideline can also be used, such as red and blue light and photodynamic therapy, but attention should be paid to the interactions and contraindications between tetracyclines and isotretinoin drugs, as well as the development of photosensitivity. Those with poor results can be treated with oral isotretinoin alone or with concomitant topical peroxynivalenol. For those who need more than 3 months of systemic antibiotic application, it is necessary to combine such antibacterial agents that do not cause bacterial resistance as peroxymethylphenidate 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 patients with more inflammatory papules and pustules, a combination of systemic antibiotics combined with peroxynivalenol can also be applied first, and then switched to oral isotretinoin for lesions such as cysts and nodules after the lesions have improved significantly. The methods used for Grade 3 acne described above and the combination treatments described in this guideline may also be tried.
Regardless of the grade of acne, it is important to maintain treatment after symptoms have improved.
10. Combination therapy for acne
The combination of oral antibiotics and topical retinoic acid can have a synergistic effect through their different pathways of action. The combination of these two methods can clear inflammatory damage and acne faster than antibiotics alone. Also topical retinoic acid can shorten the duration of antibiotic treatment, increase antibiotic penetration and increase follicular cell turnover, thus allowing more antibiotics to reach the sebaceous units and reducing the incidence of drug resistance.
Combination therapy is now the standard of care for mild to moderate acne. The advantages of combination therapy are.
(i) The clinical efficacy of antibiotics and topical retinoic acid is significantly better than that of antibiotics alone;
(ii) Faster onset of action on inflammatory damage and acne;
(3) Combination of peroxymethylphenidate or topical retinoic acid with oral antibiotics can reduce the incidence of drug resistance;
④Topical benzoyl peroxide should be used in combination with antibiotics when prolonged antibiotic use is required;
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.