Current Concepts in the Treatment of AcneCHAPTER 1

Acne vulgaris is a multifactorial, chronic, inflammatory disorder of the pilosebaceous unit characterized by polymorphic skin lesions in the form of open or closed comedones (blackheads and whiteheads) and inflammatory lesions, including papules, pustules, nodules, and cysts. The main pathogenic factors are follicular hyperkeratinization, sebum production, microbial colonization with Cutibacterium acnes (formerly Propionibacterium acnes), and innate and adaptive immune 2mechanisms. Also implicated are the neuroendocrine factors, genetics, and diet.¹ The implications of acne and acne scarring are often severe causing significant physical and psychological morbidity, poor self-image, anxiety, and depression.¹ Even though no single system for grading of acne has been universally recommended, the commonly used grading classifies acne into four grades:²

Benzoyl peroxide (BP) is antibacterial and comedolytic. Since no resistance has been reported, it is recommended to be used alone or in combination with topical antibiotics 4like clindamycin to prevent emergence of resistance. It can also be combined with adapalene for synergistic action. It is available as creams, washes, foams, and gels in strengths from 2.5 to 10%. Adverse effects include irritation which is concentration dependent, bleaching and staining of clothes, and contact allergy. Lesser concentrations and wash-off preparations are better suited for sensitive skin.

Systemic antibiotics have been the mainstay of acne therapy for moderate-to-severe inflammatory acne in combination with topicals.⁸ The main classes of drugs include macrolides like azithromycin and erythromycin, tetracyclines like doxycycline and minocycline, and beta-lactams like amoxicillin and cephalexin. The tetracycline class of antibiotics is recommended 6to be used as first line, acting by inhibiting the protein synthesis by binding to the 30S subunit of bacterial ribosome and having some anti-inflammatory effects like inhibiting chemotaxis and metalloproteinase activity. Minocycline along with tetracycline has been found to be useful in the treatment of acne with equal efficacy.⁹ Minocycline is available in the extended release form (at 1 mg/kg) and appears to be safe. Doxycycline is effective at 1.7–2.4 mg/kg and seems to be effective at even low doses of 20 mg twice daily or 40 mg daily.¹⁰ Tetracyclines are contraindicated in pregnancy, ≤8 years, and allergic cases when other classes of antibiotics should be used. Macrolides like azithromycin and erythromycin bind to 50S subunit of ribosome and also exhibit some anti-inflammatory properties. Azithromycin has primarily been used in acne in pulse dosing regimen from three times a week to four times a month given for 2–3 months or till the inflammatory lesions subside.¹¹ Trimethoprim/sulfamethoxazole by acting on folic acid pathway is bacteriostatic and has been used for treating acne traditionally, but is not routinely used now because of lack of efficacy and high degree of side effects including gastrointestinal disturbances, photosensitivity, blood dyscrasias, fulminant hepatic necrosis, respiratory hypersensitivity, and drug reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis. Similarly, penicillin class of antibiotics (like amoxicillin) and cephalosporins which act by inhibiting cell wall synthesis are sometime used particularly in pregnant patients or patients with allergies to other drugs. Adverse effects mainly include hypersensitivity reactions and gastrointestinal disturbances.¹² Adverse effects to systemic antibiotics though rare include vaginal candidiasis, drug eruptions, inflammatory bowel disease, pharyngitis, and Clostridium difficile infection.¹³ Specific side effects include photosensitivity secondary to tetracyclines particularly doxycycline and gastrointestinal disturbances. Minocycline has been associated with tinnitus, dizziness, and pigment 7deposition in skin, mucosae, and teeth more in patients taking higher doses for long durations.¹ Minocycline is associated with a higher risk of serious adverse effects than other tetracyclines including drug reaction with eosinophilia and systemic symptoms (DRESS), drug-induced lupus, pseudotumor cerebri, and other hypersensitivity reactions.^14,15 Macrolide antibiotics are associated with gastrointestinal disturbances (more with erythromycin), cardiac conduction abnormalities, hepatotoxicity, and cutaneous hypersensitivity reactions (more with azithromycin).¹ Antibiotic resistance remains a concern while prescribing systemic antibiotics and the current recommendations are to limit antibiotic use for the shortest possible duration, typically less than 3 months, which can be done by concomitant use of retinoids (topical or oral).¹⁶

Hormonal therapy includes combined oral contraceptive (COC) pills, spironolactone, and flutamide. COCs contain both an estrogen and progesterone. There are currently four COCs approved by the FDA namely—(1) ethinylestradiol (EE)/norgestimate, (2) EE/norethindrone acetate/ferrous fumarate, (3) EE/drospirenone, and (4) EE/drospirenone/levomefolate. In addition EE (35 mg) with cyproterone acetate (2 mg), a progestin with antiandrogenic properties is available in Europe, India and other countries. They act via their antiandrogenic effects by decreasing androgen production by ovaries, increasing sex hormone-binding globulin (SHBG) which binds to free testosterone and renders it unavailable for binding to androgen receptors and decreasing 5-alpha-reductase activity.¹⁷ COCs should only be used when the benefit outweighs the risk and are particularly helpful in treating acne in women who also desire contraception or have signs of androgen excess. The adverse effect profile includes cardiovascular risk, venous thromboembolic events, risk of 8myocardial infarction, and breast and cervical cancer.^18,19 It has been recommended that COC should be avoided for acne in girls within first 2 years of menarche and in <14 years unless it is clinically warranted. Drospirenone-containing COCs are FDA approved for 14 years and norgestimate- and norethindrone-containing COCs for 15 years or over.¹ Women with signs of hyperandrogenism such as hirsutism, premenstrual flares of acne, acne along jawline, and female pattern hair loss should be investigated for underlying cause and will benefit with COCs. For acne, they can be used alone or in combination with other treatment like oral antibiotics or spironolactone. Acne reduction with COC use takes time usually up to three cycles, hence it may be recommended to add another medication for the initial few months.

It is FDA approved for severe recalcitrant acne in >30 years and acts by decreasing sebum production, acne lesions, and scarring. It has also been used in moderate acne which is either treatment resistant or relapsing quickly on oral and topical antibiotic therapy.^23,24 It is indicated in severe nodulocystic acne, in moderate acne which is causing severe scarring, is treatment recalcitrant, or causing psychosocial distress. It is given initially at 0.5 mg/kg/day and increased to 1 mg/kg/day after the first month as tolerated with a cumulative dose of 120–150 mg/kg/day with some studies supporting higher doses for lesser relapse.²⁵ In moderate acne which is treatment resistant or quick relapsing cases, lower doses of 0.25–0.4 mg/kg/day and low cumulative dose are effective and comparable to higher doses preventing the adverse effects and leading to improved tolerability.²⁶ Isotretinoin is highly lipophilic and is best absorbed with food. Common adverse effects include mucocutaneous, musculoskeletal, and ophthalmic and rarer effects including inflammatory bowel disease, depression, cardiovascular risk factors, bone mineralization, 10risk of scarring, and Staphylococcus aureus (S. aureus) colonization. Several conflicting studies exist on association between inflammatory bowel disease and isotretinoin intake, but current evidence is insufficient to prove an association/causality between the two.²⁷ Similarly, even though depression, anxiety, mood disturbances, and suicidal ideation have been reported in patients taking isotretinoin, no causality has been established in population-based studies with some indicating improvement in mood, memory, and executive function in those on treatment. Short-term increase in serum cholesterol, triglycerides, and transaminases is known with isotretinoin therapy and lipid profile and liver function tests should be assessed before and during therapy.¹ Delayed wound healing and hypertrophic scarring and keloid formation have been previously shown to occur in those on therapy, even though recent studies show safety with chemical peels, dermabrasion, and lasers. Hence, it has been recommended that superficial procedures can be safely performed, but more aggressive procedures such as dermabrasion should be delayed for 6–12 months when possible, but careful consideration may be given on a case-by-case basis.^1,28–30 Higher rates of colonization by S. aureus causing minor skin infections like folliculitis, cheilitis, and abscesses while on therapy have been shown. The teratogenic effects in the form of retinoid embryopathy are well known due to which it is imperative for all men and women on isotretinoin to enroll and adhere to iPLEDGE risk management program which requires to abstain from sex or to use two contraceptive methods to prevent pregnancy while on therapy. Patient independent forms of birth control like long-acting reversible contraceptives should be considered whenever appropriate.¹

Chemical peels like salicylic acid and glycolic acid may help noninflammatory comedonal acne when multiple treatments 11are given, but the results are not long lasting.^31,32 Among laser and light devices, photodynamic therapy (PDT) has the most evidence. In PDT, a photosensitizer such as aminolevulinic acid which is absorbed by sebocytes is applied to skin for 15 minutes to 3 hours followed by laser or light device used to activate it, producing singlet oxygen species damaging the sebaceous glands. This has shown to be beneficial, but studies are needed to develop guidelines for the same.³³ Intralesional triamcinolone acetonide for large nodulocystic lesions has been seen to cause rapid improvement. Side effects include local atrophy and adrenal suppression because of systemic absorption which can be managed by lesser concentration and dosing.³⁴ Alternative therapies having poor clinical evidence include tea tree oil, oral barberry extract, and gluconolactone solution. Even though they are a part of over-the-counter cosmetic products, there are no guidelines for their use in the management of acne.^35,36

Given the current data, no specific dietary changes are recommended in the management of acne, but high glycemic index diet may be associated with higher risk and low glycemic index diet may be associated with therapeutic response.³⁷ Some association has also been postulated with consumption of dairy products like skimmed milk and ice cream, which may increase acne particularly in women who consumed ≥two glasses of skimmed milk per day.^38,39 No association with consumption of yoghurt and cheese has been found. Similarly, even though some benefit has been seen with antioxidants (including oral zinc), fish oil, and probiotics, there are no current recommendations for the same.^40,41

Acne is a multifactorial chronic inflammatory disease, hence multiple treatment modalities are required for appropriate and 12adequate treatment. The goal of therapy is resolution of lesions, without scarring. Hence selection of appropriate treatment is essential.