INTRODUCTION
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
- Grade 1: Comedones, occasional papules
- Grade 2: Papules, comedones, and few pustules
- Grade 3: Predominant pustules, nodules, and abscesses
- Grade 4: Mainly cysts, abscesses, and widespread scarring.
The diagnosis of acne is mainly clinical. Microbiological testing though not routinely indicated may be required in suspicious cases of gram negative or staphylococcal folliculitis.1Investigations are required in females to rule out androgen excess and polycystic ovarian syndrome in patients that have concomitant hirsutism, female pattern alopecia, irregular menstrual history, or acanthosis nigricans or are relatively resistant to therapy or relapse quickly after treatment. These patients should be evaluated with total and free testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEAS), follicle-stimulating and luteinizing hormone, in addition to a lipid panel, thyroid panel, fasting and postprandial glucose and insulin levels, and vitamin D level. Obesity is also associated with acne, particularly inflammatory acne due to peripheral hyperandrogenism.3
Evaluation of acne to decide treatment includes severity of acne, skin type of the patient (dry, oily, or sensitive), products and medications used, presence of postinflammatory hyperpigmentation, acne scarring, and the psychological impact of acne. Management consists of topical therapy, which is the mainstay of treatment, with systemic therapy when indicated and procedural therapy in selected cases (Table 1).4,5 Topical therapies include benzoyl peroxide, topical antibiotics, retinoids, azelaic acid, salicylic acid, dapsone, and combinations.3
TOPICAL AGENTS
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.
Topical antibiotics act as antibacterial and anti-inflammatory agents by accumulating in the hair follicle. Topical clindamycin 1% and nadifloxacin 1% are used as topical agents, but they should not be used as monotherapy due to emergence of resistance. They are recommended in combination with benzoyl peroxide which enhances efficacy and prevents development of resistance.
Topical retinoids are the maintaining in anti-acne therapy. The three main topical agents include—(1) tretinoin (0.025–1% in cream, gel, or microsphere), (2) adapalene (0.1% gel), and (3) tazarotene (0.05%, 0.1% cream and gel). These are vitamin A derivatives which bind to retinoic acid receptors, tretinoin binding to alpha, beta, and gamma and adapalene and tazarotene selectively to beta and gamma with few differences in efficacy and side effects. They are the mainstay of therapy being comedolytic, inhibiting microcomedones and anti-inflammatory. They are recommended as monotherapy for comedonal acne or in combination with topical antibiotics like clindamycin or benzoyl peroxide or systemic antibiotics for severe forms. The most frequent side effects encountered include dryness, irritation, erythema, and burning (retinoid dermatitis) which can be reduced by decreasing the strength, using microsphere formulations, reducing contact time, frequency of application, and liberal use of emollients. Photosensitivity can be decreased by usage at night and coadministration of sunscreens. Tretinoin and benzoyl peroxide should not be used together as benzoyl peroxide may inactivate and oxidize tretinoin. Tretinoin and adapalene 5are pregnancy category C whereas tazarotene is category X. Retinoids are the Food and Drug Administration (FDA) approved for children ≥12 years. Fixed combination BP 2.5%/ adapalene 0.1% gel is approved for patients ≥9 years and tretinoin 0.05% micronized tretinoin gel for patients ≥10 years. Current data show that retinoids in younger patients are effective and are not associated with increased irritation or risk.
Azelaic acid 20% is a pregnancy category B drug that apart from being mildly comedolytic, antibacterial, and anti-inflammatory agent, also has hypopigmenting action, hence is useful to treat postinflammatory hyperpigmentation in pregnant patients, darker skin, Fitzpatrick skin type IV or greater, and in sensitive skin.
Dapsone 5% gel is a sulfone agent having moderate efficacy primarily in reduction of inflammatory lesions through its anti-inflammatory action.6 It has poor efficacy in comedonal acne and the benefit in women seems to exceed that in men and adolescents.7 Topical dapsone may be oxidized by coadministration of benzoyl peroxide producing an orange-brown coloration of skin which can be washed off.1 Topical dapsone is pregnancy category C and can be given to children above 12 years.
Salicylic acid (0.5–2%) is a comedolytic agent available as wash off or gel formulations used as adjunctive therapy.
Topical nicotinamide 2–4% gel is available in combination with clindamycin and has been useful in inflammatory acne.
SYSTEMIC ANTIBIOTICS
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 AGENTS
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.
Spironolactone is a potent antiandrogen acting by blocking the androgen receptors. It also inhibits 5-alpha-reductase and increases SHBG. Its use in acne is not FDA approved, but it has been used in doses of 50–200 mg daily and seen to reduce sebum production and acne severity. Side effects include diuresis, menstrual irregularities, breast enlargement, headache, and dizziness. It is a pregnancy category C drug and hence concomitant use of COCs is recommended to regulate pregnancy and for contraception. Hyperkalemia is rare in young healthy females and hence routine monitoring of potassium is not recommended before start of therapy, but should be done if patient is on angiotensin-converting enzyme inhibitors or receptor blockers and nonsteroidal anti-inflammatory drugs or digoxin, with monitoring required at baseline and after dose incrementation.20 Such patients should also be counseled by low dietary intake of potassium-rich food like coconut water. Spironolactone may safely be used with drospirenone-containing COCs. Spironolactone comes with a black box warning of carcinogenicity (thyroid, testicular, hepatic, and breast adenomas), though case reports of cancer have been rare and no real association has been found.219
Flutamide is a nonsteroidal antiandrogen used for prostate cancer and though not the FDA approved for acne, it has shown efficacy in doses 62.5 mg daily to 250 mg twice daily. Side effects include gastrointestinal distress, breast tenderness, hot flashes, headache, xerosis, decreased libido, and idiosyncratic fatal hepatotoxicity (dose and age related). Flutamide use for acne is discouraged, except when benefit outweighs risk.22
Low-dose prednisolone in doses ranging from 5 to 15 mg daily with or without COCs has been seen to be beneficial. They are currently indicated in acne fulminans in doses of 0.5–1 mg/kg/day and to prevent isotretinoin-induced acne fulminans-like reaction. They should never be given as monotherapy and should be slowly tapered as oral antibiotics/retinoids start to act.1
ISOTRETINOIN
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
MISCELLANEOUS THERAPIES
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
ROLE OF DIET IN ACNE
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
CONCLUSION
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.
REFERENCES
- Zaenglein AL, Pathy AL, Schlosser BJ, Alikhan A, Baldwin HE, Berson DS, et al. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol. 2016;74(5):945–73.e33.
- Adityan B, Kumari R, Thappa DM. Scoring systems in acne vulgaris. Indian J Dermatol Venereol Leprol. 2009;75:323–6.
- Tsai MC, Chen W, Cheng YW, Wang CY, Chen GY, Hsu TJ. Higher body mass index is a significant risk factor for acne formation in schoolchildren. Eur J Dermatol. 2006;16:251–3.
- Sacchidanand SA, Lahiri K, Godse K, Patwardhan NG, Ganjoo A, Kharkar R, et al. Synchronizing pharmacotherapy in acne with review of clinical care. Indian J Dermatol. 2017;62:341–57.
- Oon HH, Wong SN, Aw DCW, Cheong WK, Goh CL, Tan HH. Acne management guidelines by the dermatological society of Singapore. J Clin Aesthet Dermatol. 2019;12:34–50.
- Lucky AW, Maloney JM, Roberts J, Taylor S, Jones T, Ling M, et al. Dapsone gel 5% for the treatment of acne vulgaris: safety and efficacy of long-term (1 year) treatment. J Drugs Dermatol. 2007;6:981–7.
- Tanghetti E, Harper JC, Oefelein MG. The efficacy and tolerability of dapsone 5% gel in female vs male patients with facial acne vulgaris: gender as a clinically relevant outcome variable. J Drugs Dermatol. 2012;11:1417–21.
- Gold LS, Cruz A, Eichenfield L, Tan J, Jorizzo J, Kerrouche N, et al. Effective and safe combination therapy for severe acne vulgaris: a randomized, vehicle-controlled, double-blind study of adapalene 0.1%-benzoyl peroxide 2.5% fixed-dose combination gel with doxycycline hyclate 100 mg. Cutis. 2010;85:94–104.
- Garner SE, Eady A, Bennett C, Newton JN, Thomas K, Popescu CM. Minocycline for acne vulgaris: efficacy and safety. Cochrane Database Syst Rev. 2012;(8):CD002086.
- Leyden JJ, Bruce S, Lee CS, Ling M, Sheth PB, Stewart DM, et al. A randomized, phase 2, dose-ranging study in the treatment of moderate to severe inflammatory facial acne vulgaris with doxycycline calcium. J Drugs Dermatol. 2013;12:658–63.
- Antonio JR, Pegas JR, Cestari TF, Do Nascimento LV. Azithromycin pulses in the treatment of inflammatory and pustular acne: efficacy, tolerability and safety. J Dermatolog Treat. 2008;19:210–5.
- Fenner JA, Wiss K, Levin NA. Oral cephalexin for acne vulgaris: clinical experience with 93 patients. Pediatr Dermatol. 2008;25:179–83.
- Margolis DJ, Fanelli M, Kupperman E, Papadopoulos M, Metlay JP, Xie SX, et al. Association of pharyngitis with oral antibiotic use for the treatment of acne: A cross-sectional and prospective cohort study. Arch Dermatol. 2012;148:326–32.
- Shaughnessy KK, Bouchard SM, Mohr MR, Herre JM, Salkey KS. Minocycline-induced drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome with persistent myocarditis. J Am Acad Dermatol. 2010;62:315–8.
- Tripathi SV, Gustafson CJ, Huang KE, Feldman SR. Side effects of common acne treatments. Exp Opin Drug Saf. 2013;12:39–51.
- Tan J, Gold LS, Schlessinger J, Brodell R, Jones T, Cruz A, et al. Short-term combination therapy and long-term relapse prevention in the treatment of severe acne vulgaris. J Drugs Dermatol. 2012;11:174–80.
- Arowojolu AO, Gallo MF, Lopez LM, Grimes DA. Combined oral contraceptive pills for treatment of acne. Cochrane Database Syst Rev. 2012;(6):CD004425.
- Katsambas AD, Dessinioti C. Hormonal therapy for acne: why not as first line therapy? facts and controversies. Clin Dermatol. 2010;28:17–23.
- Gierisch JM, Coeytaux RR, Urrutia RP, Havrilesky LJ, Moorman PG, Lowery WJ, et al. Oral contraceptive use and risk of breast, cervical, colorectal, and endometrial cancers: a systematic review. Cancer Epidemiol Biomarkers Prev. 2013;22:1931–43.
- Plovanich M, Weng QY, Mostaghimi A. Low usefulness of potassium monitoring among healthy young women taking spironolactone for acne. JAMA Dermatol. 2015;151:941–4.
- Biggar RJ, Andersen EW, Wohlfahrt J, Melbye M. Spironolactone use and the risk of breast and gynecologic cancers. Cancer Epidemiol. 2013;37:870–5.
- George R, Clarke S, Thiboutot D. Hormonal therapy for acne. Semin Cutan Med Surg. 2008;27:188–96.
- Agarwal US, Besarwal RK, Bhola K. Oral isotretinoin in different dose regimens for acne vulgaris: a randomized comparative trial. Indian J Dermatol Venereol Leprol. 2011;77:688–94.
- Lee JW, Yoo KH, Park KY, Han TY, Li K, Seo SJ, et al. Effectiveness of conventional, low-dose and intermittent oral isotretinoin in the treatment of acne: a randomized, controlled comparative study. Br J Dermatol. 2011;164:1369–75.
- Blasiak RC, Stamey CR, Burkhart CN, Lugo-Somolinos A, Morrell DS. High-dose isotretinoin treatment and the rate of retrial, relapse, and adverse effects in patients with acne vulgaris. JAMA Dermatol. 2013;149:1392–8.
- Amichai B, Shemer A, Grunwald MH. Low-dose isotretinoin in the treatment of acne vulgaris. J Am Acad Dermatol. 2006;54:644–6.
- Etminan M, Bird ST, Delaney JA, Bressler B, Brophy JM. Isotretinoin and risk for inflammatory bowel disease: a nested case-control study and meta-analysis of published and unpublished data. JAMA Dermatol. 2013;149:216–20.
- Chandrashekar BS, Varsha DV, Vasanth V, Jagadish P, Madura C, Rajashekar ML. Safety of performing invasive acne scar treatment and laser hair removal in patients on oral isotretinoin: a retrospective study of 110 patients. Int J Dermatol. 2014;53:1281–5.
- Kim HW, Chang SE, Kim JE, Ko JY, Ro YS. The safe delivery of fractional ablative carbon dioxide laser treatment for acne scars in Asian patients receiving oral isotretinoin. Dermatol Surg. 2014;40:1361–6.
- Yoon JH, Park EJ, Kwon IH, Kim CW, Lee GS, Hann SK, et al. Concomitant use of an infrared fractional laser with low-dose isotretinoin for the treatment of acne and acne scars. J Dermatolog Treat. 2014;25:142–6.
- Dréno B, Fischer TC, Perosino E, Poli F, Viera MS, Rendon MI, et al. Expert opinion: efficacy of superficial chemical peels in active acne management—what can we learn from the literature today? Evidence-based recommendations. J Eur Acad Dermatol Venereol. 2011;25:695–704.
- Ilknur T, Demirtasoglu M, Bicak MU, Ozkan S. Glycolic acid peels versus amino fruit acid peels for acne. J Cosmet Laser Ther. 2010;12:242–5.
- Wang XL, Wang HW, Zhang LL, Guo MX, Huang Z. Topical ALA PDT for the treatment of severe acne vulgaris. Photodiagnosis Photodyn Ther. 2010;7:33–8.
- Lee SJ, Hyun MY, Park KY, Kim BJ. A tip for performing intralesional triamcinolone acetonide injections in acne patients. J Am Acad Dermatol. 2014;71:e127–8.
- Enshaieh S, Jooya A, Siadat AH, Iraji F. The efficacy of 5% topical tea tree oil gel in mild to moderate acne vulgaris: a randomized, double-blind placebo-controlled study. Indian J Dermatol Venereol Leprol. 2007;73:22–5.
- Fouladi RF. Aqueous extract of dried fruit of Berberis vulgaris L. in acne vulgaris, a clinical trial. J Diet Suppl. 2012;9:253–61.
- Smith RN, Mann NJ, Braue A, Makelainen H, Varigos GA. The effect of a high-protein, low glycemic-load diet versus a conventional, high glycemic-load diet on biochemical parameters associated with acne vulgaris: a randomized, investigator-masked, controlled trial. J Am Acad Dermatol. 2007;57:247–56.
- Kwon HH, Yoon JY, Hong JS, Jung JY, Park MS, Suh DH. Clinical and histological effect of a low glycaemic load diet in treatment of acne vulgaris in Korean patients: a randomized, controlled trial. Acta Derm Venereol. 2012;92:241–6.
- Sardana K, Garg VK. An observational study of methionine-bound zinc with antioxidants for mild to moderate acne vulgaris. Dermatol Ther. 2010;23:411–8.
- Jung GW, Tse JE, Guiha I, Rao J. Prospective, randomized, open-label trial comparing the safety, efficacy, and tolerability of an acne treatment regimen with and without a probiotic supplement and minocycline in subjects with mild to moderate acne. J Cutan Med Surg. 2013;17:114–22.
- Khayef G, Young J, Burns-Whitmore B, Spalding T. Effects of fish oil supplementation on inflammatory acne. Lipids Health Dis. 2012;11:165.