Acne Vulgaris Treatment & Management

Treatment should be directed toward the known pathogenic factors involved in acne. These include follicular hyperproliferation, excess sebum, Cutibacterium acnes (formerly Propionibacterium acnes) infection, and inflammation. The grade and severity of the acne help in determining which of the following treatments, alone or in combination, is most appropriate.

Current consensus recommends a combination of topical retinoid and antimicrobial therapy as first-line therapy for almost all patients with acne. ^[2] The superior efficacy of this combination, compared with either monotherapy, results from complementary mechanisms of action targeting different pathogenic factors. Retinoids reduce abnormal desquamation, are comedolytic, and have some anti-inflammatory effects, whereas benzoyl peroxide is antimicrobial with some keratolytic effects and antibiotics have anti-inflammatory and antimicrobial effects. ^[2]

Note the images below.

Topical treatments

Retinoids

Topical retinoids are comedolytic and anti-inflammatory. They normalize follicular hyperproliferation and hyperkeratinization. Topical retinoids reduce the numbers of microcomedones, comedones, and inflammatory lesions. ^[35] Topical retinoids should be initiated as first-line therapy for both comedonal and inflammatory acne lesions and continued as maintenance therapy to inhibit further microcomedone formation. ^[35]

The most commonly prescribed topical retinoids for acne vulgaris include adapalene, tazarotene, and tretinoin. These retinoids should be applied once daily to clean, dry skin, but they may need to be applied less frequently if irritation occurs. Skin irritation with peeling and redness may be associated with the early use of topical retinoids and typically resolves within the first few weeks of use. ^[36] The use of mild, nonirritating cleansers and noncomedogenic moisturizers may help reduce this irritation. ^[35] Alternate-day dosing may be used if irritation persists.

Topical retinoids thin the stratum corneum, and they have been associated with sun sensitivity. ^[37] Instruct patients about sun protection. Also see Sunscreens and Photoprotection.

Topical antibiotics

Topical antibiotics are mainly used for their role against C acnes (formerly P acnes). They may also have anti-inflammatory properties. Topical antibiotics are not comedolytic, and bacterial resistance may develop to any of these agents. Commonly prescribed topical antibiotics for acne vulgaris include clindamycin, erythromycin, and, more recently, dapsone and minocycline.

Topical dapsone is a new sulfone antibiotic with anti-inflammatory properties that has been shown to be effective for mild-to-moderate acne, and it has a convenient once-daily application schedule. ^[38] It is available as 5% twice-daily and 7.5% once-daily formulations. ^[38] The current American Academy of Dermatology guidelines preceded the FDA approval of the 7.5% formulation. Although no research has compared the efficacy of the 5% formulation with the 7.5% formulation, both have been separately shown to be efficacious and safe. The 7.5% formulation has the additional compliance factor of once-daily application. ^{[33, 38]}

Minocycline topical foam 4% was evaluated in three 12-week phase 3 trials (n=2418) in patients aged 9 years or older. Each study demonstrated statistically significant disease improvement with minocycline topical compared with vehicle for the coprimary endpoint of absolute reduction of inflammatory lesions and investigator assessment. ^{[39, 40]}

Antibiotic resistance in C acnes (formerly P acnes) is common and is a significant threat to acne treatment. ^[33] Antimicrobials should be combined with a topical retinoids for greater clearing of lesions and to increase the potential for shortened antibiotic treatment. They should be used with benzoyl peroxide to reduce the likelihood of resistance. ^[2] Concurrent use of oral and topical antibiotics should be avoided and should not be used as monotherapy. If acne relapses, use the same antibiotic if it was previously effective. It may also be helpful to use benzoyl peroxide for 5-7 days between antibiotic courses to reduce resistance in organisms on the skin. ^[2]

Benzoyl peroxide products are also effective against C acnes (formerly P acnes), and bacterial resistance to benzoyl peroxide has not been reported. ^[41] Benzoyl peroxide products are available over the counter and by prescription in a variety of topical forms, including soaps, washes, lotions, creams, and gels. Benzoyl peroxide products may be used once or twice a day. These agents may occasionally cause a true allergic contact dermatitis. More often, an irritant contact dermatitis develops, especially if used with tretinoin or when accompanied by aggressive washing methods. ^[41] If intensive erythema and pruritus develop, a patch test with benzoyl peroxide is indicated to rule out allergic contact dermatitis.

Androgen receptor antagonists

Clascoterone 1% topical cream is a first-in-class topical androgen receptor inhibitor approved by the FDA for acne vulgaris in patients aged 12 years and older. The exact mechanism is unknown. In vitro studies suggest clascoterone competes with androgens, specifically dihydrotestosterone, for binding to the androgen receptors within the sebaceous gland and hair follicles. 

Approval of clascoterone topical was supported by two phase 3 randomized trials including 1440 patients. At week 12, treatment success rates showed statistically significant improvement for patients receiving clascoterone (18.4% and 20.3%) compared with the vehicle alone (9% and 6.5%) (0.001%). ^[42]  

Systemic treatments

Oral antibiotics

Systemic antibiotics are a mainstay in the treatment of moderate-to-severe inflammatory acne vulgaris. ^[33] These agents have anti-inflammatory properties, and they are effective against C acnes (formerly P acnes). The tetracycline group of antibiotics is commonly prescribed for acne. The more lipophilic antibiotics, such as doxycycline and minocycline, are generally more effective than tetracycline. ^[33]

Sarecycline is a new first-in-class tetracycline-derived antibiotic indicated for adults and children aged 9 years and older with non-nodular moderate-to-severe acne vulgaris. Compared with currently available tetracyclines, it has a narrow spectrum of activity, including less activity against enteric gram-negative bacteria, and it also elicits anti-inflammatory effects. Clinical trials showed efficacy compared with placebo to be statistically significant. Onset of efficacy, observed by improvement of inflammatory lesions, was evident at the first follow-up visit (ie, 3 weeks). ^[43]

Greater efficacy may also be due to less C acnes (formerly P acnes) resistance to minocycline. However, C acnes (formerly P acnes) resistance is becoming more common with all classes of antibiotics currently used to treat acne vulgaris. ^[44] C acnes (formerly P acnes) resistance to erythromycin has greatly reduced its usefulness in the treatment of acne. ^[33]

Subantimicrobial therapy or concurrent treatment with topical benzoyl peroxide may reduce the emergence of resistant strains. ^[45] Comparing subantimicrobial 40-mg doxycycline, 100-mg doxycycline, and placebo, Moore et al found a comparable percentage of patients clear of acne between at the 40-mg and 100-mg doses, both significantly higher than placebo. ^[46] Additionally, less drug-related adverse events were found with the 40-mg subantimicrobial dosing. Enteric-coated, delayed-release formulations of doxycycline can further reduce gastrointestinal adverse effects. ^[47]

Oral antibiotic use can lead to vaginal candidiasis; doxycycline can be associated with photosensitivity; and minocycline has been linked to pigment deposition of the skin, mucous membranes, and teeth. ^[33]

The emergence of antibiotic-resistant bacteria, other than C acnes (formerly P acnes), is a contentious debate. An early study by Miller et al found increased skin carriage of coagulase-negative staphylococci in not only acne patients with prolonged use of antibiotics, but also in their close contacts. ^[48] On the contrary, a study by Fanelli et al found that Staphylococcus aureus remained sensitive to tetracycline even after prolonged use of that antibiotic for acne. ^[49] This has significant ramifications when considering efforts to control the spread of methicillin-resistant S aureus (MRSA), because tetracycline group antibiotics are currently one of the primary options for outpatient treatment of MRSA infection.

Other antibiotics, including trimethoprim alone or in combination with sulfamethoxazole, and azithromycin, reportedly are helpful. ^{[50, 51]}

Hormonal therapies

Some hormonal therapies may be effective in the treatment of acne vulgaris. Estrogen can be used to decrease sebum production. Additionally, it reduces ovarian production of androgens by suppressing gonadotrophin release. ^[35] Oral contraceptives also increase hepatic synthesis of sex hormone–binding globulin, resulting in an overall decrease in circulating free testosterone. Combination birth control pills have shown efficacy in the treatment of acne vulgaris. ^[52]

Spironolactone may also be used in the treatment of acne vulgaris. ^[53] Spironolactone binds the androgen receptor and reduces androgen production. Adverse effects include dizziness, breast tenderness, and dysmenorrhea. ^[35] Dysmenorrhea may be lessened by coadministration with an oral contraceptive. In two 2017 retrospective studies, spironolactone has been shown to be effective in reducing inflammatory lesions in multiple areas of the body with minimal adverse effects. ^{[54, 55]} Currently, more high-powered randomized controlled trials are needed to assess the efficacy of spironolactone monotherapy in treating acne, but spironolactone should be considered in recalcitrant acne, in women who do not tolerate or have contraindications to oral contraceptives, and to prevent antibiotic resistance. ^[35] A 2015 large retrospective study of healthy women aged 18-45 years confirms potassium monitoring is unnecessary for these patients while taking spironolactone. ^[56] Pregnancy must be avoided while taking spironolactone because of the risk of feminization of the male fetus, and spironolactone is not recommended for males because of the potential for gynecomastia. ^{[35, 54]} While a black box warning regarding possible cancer risk was placed on spironolactone many years ago after rats fed high doses of the medication developed both benign and malignant tumors, several large retrospective and longitudinal studies have found no association with cancer. ^[57]

Isotretinoin

Isotretinoin is a systemic retinoid that is highly effective in the treatment of severe, recalcitrant acne vulgaris. ^[33] Isotretinoin causes normalization of epidermal differentiation, depresses sebum excretion by 70%, is anti-inflammatory, and even reduces the presence of C acnes (formerly P acnes). ^[58]

Isotretinoin therapy should be initiated at a dose of 0.5 mg/kg/d for 4 weeks and increased as tolerated until a cumulative dose of 120-150 mg/kg is achieved. ^[33] Coadministration with steroids at the onset of therapy may be useful in severe cases to prevent initial worsening. ^[33] Some patients may respond to doses lower than the standard recommendation dosages. A lower dose (0.25-0.4 mg/kg/d) may be as effective in clearing acne as the higher dose given for the same period and with greater patient satisfaction. However, the benefit of prolonged remission is not as great with such therapy as with standard doses. ^[59] Lower intermittent dosing schedules (1 wk/mo) are not as effective. ^[59]

Some patients only require one course of oral isotretinoin for complete acne remission, while others require additional courses of isotretinoin therapy. A study found 38% of the patients had no acne during 3-year follow up, and, among the remaining patients, 17% were controlled with further topical therapy, 25% with topical and oral antibiotics, and 20% with second course of isotretinoin. ^[60] Relapse is more likely in younger or female patients. ^[60]

Isotretinoin is a teratogen, so pregnancy must be avoided. Contraception counseling is mandatory, and two negative pregnancy test results are required prior to the initiation of therapy in women of childbearing potential. The baseline laboratory examination should also include cholesterol and triglyceride assessment, hepatic transaminase levels, and a CBC count. Pregnancy tests and a lipid panel and liver enzyme examination should be repeated monthly during treatment while dosing is changing. Once a level dose is used and the lipids, liver enzymes, and CBC count are normal, these tests may be discontinued. ^[35] Other adverse effects include dry skin, lips, and eyes; muscle aches; and headaches. Patients experiencing severe headaches, decreased night vision, or adverse psychiatric events should stop taking isotretinoin immediately. ^[35]

Acne-associated mood changes and depression have also been reported during treatment, but a 2017 meta-analysis involving 1411 cases found no increased risk of depression with isotretinoin use. ^[61] Some of the studies that reported a positive causal relationship between isotretinoin and depression included a dose-response relationship with depression of up to 3 mg/kg/day of isotretinoin; however, this high of a dose is not usually prescribed for acne. ^[62] Other studies have described new-onset depression in both isotretinoin and antibiotic groups, suggesting depression is associated with acne, regardless of treatment. ^[63] Therefore, it is important to consider the risk of depression among all patients with acne.

Inflammatory bowel diseases (IBDs) have also been controversially linked to isotretinoin use. A number of case reports have linked isotretinoin with the onset of IBD, with a wide variety of severity of acne, dose of isotretinoin, and duration of treatment prior to the development of IBD. ^[64] Subsequent case-control and cohort studies had conflicting results, with some suggesting no association between isotretinoin and IBD and others suggesting an association between isotretinoin and ulcerative colitis but not Crohn disease ^{[65, 66, 67, 68]} Finally, a 2016 large meta-analysis, indexing more than 9 million cases to reduce effects of selection bias and confounding factors, showed isotretinoin is not associated with an increased risk of Crohn disease or ulcerative colitis. ^[69] A US Food and Drug Administration(FDA)–mandated registry is now in place for all individuals prescribing, dispensing, or taking isotretinoin. For more information on this registry, see iPLEDGE. This registry aims to further decrease the risk of pregnancy and other unwanted and potentially dangerous adverse effects during a course of isotretinoin therapy.

While using isotretinoin, the patient is considered at high risk for abnormal healing and the development of excessive granulation tissue following procedures. ^[70] Many dermatologists delay elective procedures, such as dermabrasion or laser resurfacing (eg, with carbon dioxide laser or erbium:YAG laser), for up to 1 year after completion of therapy.

Intralesional steroid injections have been found to be beneficial for large inflammatory lesions. Comedone removal does not affect the course of the disease, but it does improve the patient’s appearance. ^[33] Additionally, some patients may benefit from superficial peels that use glycolic or salicylic acid, although more research needs to be conducted to establish best practice for these modalities.

Of all forms of laser and light therapy, the most evidence is with photodynamic therapy (PDT) in treating acne. ^[33] PDT involves a photosensitizer applied to the skin, time allowed for it to be absorbed by the pilosebaceous units, and then application of a light source to activate the photosensitizer, generating reactive oxygen species to damage the glands and reduce Cutibacterium acnes (formerly Propionibacterium acnes). A 2016 Cochrane review was unable to draw firm conclusions regarding the benefit of light therapy in acne, owing to the variation in wavelength, dose, photosensitizer, comparator interventions, and treatment frequency that were studied. ^[71] However, despite the interstudy variation, many individual trials show PDT to be effective in reducing lesions in mild-to-severe acne, with 5-aminolevulinic acid and methyl aminolevulinate photosensitizers and red light source as promising treatment components. ^{[72, 73]}

There is also a growing body of evidence for laser treatment of acne, standalone or in the context of PDT. However, similar to light therapy, the power and quality of research is limited by small patient numbers, lack of a control population, and comparison to standard therapies. Nonetheless, preliminary studies have shown improvement in acne, and even potential long-lasting effects with the 1550-nm erbium-glass laser, 1064-nm Nd:YAG laser, and PDT with laser. ^[74]

In December 2014, the FDA approved Bellafill, the first dermal filler indicated for acne scarring. Bellafill is a bovine collagen dermal filler.

If the patient is feeling depressed while taking isotretinoin, refer him or her to a specialist for help.

Diet therapy has been suggested. Fulton et al performed a study on chocolate, having teenage patients with acne consume 1 bar of chocolate each day. Some of the patients improved and some worsened, but the vast majority were unchanged. ^[75] This study helped decrease the emphasis on diet as a causal factor in acne vulgaris. However, investigators always returned to the diet question. Data suggest that the westernization of certain Native American populations and the related consumption of unhealthy "junk" foods (eg, potato chips, soft drinks) has had a negative impact on general and skin health, resulting in acne flares. Skim milk, compared with full-fat milk, has been found to have a positive association with acne, especially in teenagers and young adults. ^{[76, 77]} Causation was not able to be drawn from the case control studies, but the mechanism involving hormonal constituents of the skim milk has been postulated. ^[76] . Whey protein is a commonly used supplement that has been suggested to worsen acne and should be discontinued if flaring of the condition is associated with its use.

Investigators have also focused on a low-glycemic diet to avoid stress from high-carbohydrate diets and to reduce insulin levels. A study found that 12 weeks of a high-protein, low–glycemic load diet decreased the total amount of acne lesions, and this may lead to dermatologists recommending the South Beach Diet to patients with acne. ^[23] However, guideline groups have not found benefit in acne treatment or control with dietary restrictions. ^[33]

Hyperkalemia is a potential dangerous adverse effect from spironolactone; however, a 2015 large retrospective study of healthy women aged 18-45 years confirms potassium monitoring is unnecessary for these patients while taking spironolactone. ^[56] Plovanich et al found the rate of hyperkalemia in patients taking spironolactone is equivalent to the minimal baseline rate of hyperkalemia in this population, and, of the hyperkalemia cases, none was clinically significant.