Acne is a chronic inflammatory skin disease of the sebaceous glands with a prevalence of 70% to 87% and a psychological and social impact on adolescents that exceeds that of asthma and epilepsy. Treatment options for acne vary widely among dermatologists, with some treatments having uncertain efficacy and lacking a basis in the literature of clinical trials; some are even harmful to patients, creating a bad social impact and causing financial damage to patients.
Therefore, for clinicians who are currently practicing clinical dermatology without formal dermatology specialty training, it is essential to have a set of proven guidelines for the treatment of acne to regulate their treatment. Of course, guidelines are not set in stone, and as new evidence-based medical evidence and new drugs are developed, acne treatment needs to be kept up to date and updated regularly.
1. Acne Occurrence
Pathophysiological factors of acne occurrence The occurrence of acne is closely related to many factors such as excessive sebum secretion, follicular 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 to produce free fatty acids, which is the main factor 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 glucocorticoid ingredients.
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 that slowly releases neo-oxygen and benzoic acid after topical application, which 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 (clojibromycin) formulated with ethanol or propylene glycol at a concentration of 1% to 2% are more effective. 1% clindamycin phosphate solution is a water-soluble lotion free of oil and ethanol 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. The 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 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.
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, so antibiotics that 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, 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 treatment for 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 osteophytes, 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: estrogens and progestins. 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 of contraceptives may also be considered for women with late-onset acne and those whose acne worsens significantly before menstruation. 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 the choice of their type 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 50-100mg of cyproterone acetate on top of oral Daine-35 at 5-14d of the menstrual cycle. Adverse reactions include small amounts of uterine bleeding, breast distension, upper abdominal discomfort and facial skin redness, weight gain, deep vein thrombosis, and the appearance of chloasma.