Nicholas Brownstone, MD

Acne is an extremely common skin disease and while particularly prevalent in adolescents, it can persist into adulthood as well. Most dermatology providers are very familiar with treating acne, as approximately 15% of the US population has suffered from acne and, by some estimates, nearly 9 out of 10 adolescents have also suffered from this condition. Julie Harper, MD, a board-certified dermatologist in private practice in Birmingham, Alabama, a founding director and past president of the American Acne and Rosacea Society, gave a presentation on acne treatment updates at the Maui Derm NP+PA Summer 2022 conference.

Before discussing treatments, Harper took time to highlight the goals of acne treatment and she shared her CLEAR acronym for effective treatment. The 3 most important goals of acne treatment are achieving meaningful improvements in lesion count, preventing sequalae, and improving quality of life. The CLEAR acronym can help accomplish this by reminding providers how to best counsel patients on effective treatment—C: communicate expectations, L: listen to customize treatment, E: treat early, A: treat aggressively, R; don’t resist isotretinoin. This was followed by a brief discussion on the role of topical therapy in acne treatment. Topical therapy is considered first-line treatment in most mild to moderate patients and it can be used as monotherapy or as combination therapy. However, topical antibiotics should rarely be used as monotherapy. There is also some utility for topical therapy in the treatment of acne sequelae.

Harper began her focused update on treatments with topical retinoids, which work by binding to the retinoic acid receptor, which modulates genes associated with acne etiology. Specifically, topical retinoids normalize follicular epithelial hyperkeratinization and are anti-inflammatory in nature. There have been 4 generations of FDA-approved topical retinoids, with the most recent approval for trifarotene 0.005% cream in 2019. This novel topical therapy is the first new retinoid molecule the FDA has approved in over 20 years and was studied on facial and truncal acne. In phase 3 clinical trials, trifarotene achieved a 42% IGA/PGA success rate at week 12 and a 65% absolute reduction in inflammatory lesions for both face and trunk.

 “Topical retinoids remain a cornerstone of acne treatment. I am grateful that we have seen innovation in this space. We have a whole new retinoid molecule, trifarotene, created to specifically and precisely target the retinoic acid receptors (RAR) receptor,” Harper said.

Harper followed her discussion of trifarotene with another retinoid, tazarotene lotion 0.045%. This medication was FDA approved in 2019 for daily use in patients 9 years and older with moderate-to-severe acne. In a phase 2 study, tazarotene lotion performed better than tazarotene 0.1% cream in percent change in mean inflammatory and non-inflammatory lesions at week 12.

 The novel vehicle, polymeric emulsion technology, allows for a lower percentage of active ingredients, which improves the tolerability of tazarotene, traditionally an irritating agent. Before moving on to oral agents, Harper mentioned 2 other important topical therapies. First was E-tretinoin 0.1%/E-BPO 3% cream, which can be stabilized together through microencapsulation technology. This technology also allows for improved tolerability of the medication. Next, clascoterone was highlighted and the unique mechanism of action was displayed. Clascoterone is a topical anti-androgen that binds to the androgen receptor and has limited systemic activity.

 In 1 clinical trial, IGA treatment success for clascoterone was 16.1% vs 7% for the vehicle. This medication is the first topical antiandrogen for acne and is appropriate for use in both male and female patients. “We all have a tendency to think of our oral antibiotics in the management of acne as being the heavy lifter once they are added to a treatment regimen, but in fact the topicals are the unsung heroes,” Harper said. “While there are no head-to-head studies, clinical trials consistently show more acne patients achieve clear or almost clear with topical agents than with oral antibiotics.”

Harper also discussed oral therapy, which she said is equally as important as topical therapy. Oral therapy is recommended for moderate-to-severe acne that does not respond to other treatments or for inflammatory acne that is nonresponsive to topical antibiotics. Sarecycline, the newest oral antibiotic therapy, offers a narrow spectrum of therapy because it has a minimal effect against gram-negative bacilli. The advantage of this narrow spectrum may be a reduced tendency to disrupt normal gut flora.

 Sarecycline is taken once a day with or without food, and adverse events, while uncommon, include nausea and vaginal yeast infections. Its activity against C acnes is equivalent to that of doxycycline and minocycline.

Harper highlighted spironolactone oral therapy, which is not FDA approved for acne treatment but remains a popular option. She reviewed some high-yield pearls when using spironolactone. There is no need to check potassium in healthy women (between aged 18 and 45 years).

 There is no evidence of an increased risk of breast cancer, despite its FDA black box warning stating that “spironolactone has been shown to be a tumorigen in chronic toxicity study in rats.”

 Spironolactone takes 2 to 3 months to achieve optimal efficacy. An ideal way to use this medication is in combination with other acne treatments (topical therapies or oral antibiotics) and it even can be used in combination with oral contraceptives.

 Practically, dosage should be between 25 and 200 mg, but Harper prefers a maximum dose of 100 mg. A higher dose of spironolactone will lead to a high rate of side effects.

Harper ended her talk with isotretinoin, one of the most commonly used medications for the treatment of acne. She noted that the goal of isotretinoin therapy is complete clearance with 1 course of treatment while minimizing adverse effects and risks. An appropriate end point often varies by provider but a study by Tan et al found that the traditional end point dose of 120 to 150 mg/kg appears to vary with severity.

 Optimal end point dosing of isotretinoin has the goal of preventing relapse. Relapse can be defined in different ways, such as deterioration in acne requiring systemic therapy and those who require retreatment with oral isotretinoin.

 Relapses still occur in 20% to 30% of cases and less than 120 mg/kg is considered a cumulative dose that is too low. Patient characteristics that make relapse more common include younger age, male gender, severe presentation, females with polycystic ovary syndrome, and patients who present with a large number of comedones.

Harper reviewed laboratory monitoring with isotretinoin therapy. A study by Zane et al found that the greatest perturbation in laboratory abnormalities on isotretinoin were in triglycerides and total cholesterol.

 As such, the FDA package insert states that “blood lipid determination should be performed before isotretinoin is given and then at intervals until lipid response is established, which is usually about 4 weeks.” A meta-analysis on laboratory evaluation of isotretinoin found that while lab values demonstrated a change from baseline, none of them were considered high risk changes.

 The authors recommended performing lipid and hepatic panels at baseline and 2 months after therapy, with repeat labs dictated by medical history.

Harper wrapped up her presentation with a discussion on the risk of depression and suicide in patients on isotretinoin therapy, a traditionally contentious topic. A systematic review on the topic conducted by Huang et al in 

The Journal of The American Academy of Dermatology

 analyzed 31 studies and found that only 1 had evidence to show that isotretinoin significantly increased the risk of depression.

 The authors concluded that although individual susceptibility to depression cannot be ruled out, isotretinoin can be safely used without increasing the risk of depression. Another medical expenditure panel survey study, which utilized questionnaires like the Kessler 6-Item Psychological Distress Scale, found that patients on isotretinoin had fewer depressive symptoms than those on oral antibiotics and had less psychological distress.

It is exciting to see new innovation in the treatment of acne and review the critical data on traditional therapies. Given the frequency with which this condition is seen in the dermatologist’s office, the management of acne is always an important topic to stay updated on.

This article originally appeared on Dermatology Times.

1. Tan J, Thiboutot D, Popp G, et al. Randomized phase 3 evaluation of trifarotene 50 μg/g cream treatment of moderate facial and truncal acne. 

. 2019;80(6):1691-1699. doi:10.1016/j.jaad.2019.02.044

2. Tanghetti EA, Kircik LH, Green LJ, et al. A phase 2, multicenter, double-blind, randomized, vehicle-controlled clinical study to compare the safety and efficacy of a novel tazarotene 0.045% lotion and tazarotene 0.1% cream in the treatment of moderate-to-severe acne vulgaris. J Drugs Dermatol. 2019;18(6):542.

3. Hebert A, Thiboutot D, Stein Gold L, et al. Efficacy and Safety of Topical Clascoterone Cream, 1%, for Treatment in Patients With Facial Acne: Two Phase 3 Randomized Clinical Trials. 

 2020;156(6):621- 630. doi:10.10 01/jamadermatol.2020.0465

4. Zhanel G, Critchley I, Lin LY, Alvandi N. Micro-biological profile of sarecycline, a novel targeted spectrum tetracycline for the treatment of acne vulgaris. 

. 2019;63(1):e01297-18. doi:10.1128/A AC.01297-18

5. Plovanich M, Weng QY, Mostaghimi A. Low usefulness of potassium monitoring among healthy young women taking spironolactone for acne. 

. 2015;151(9):941-944. doi:10.1001/jamadermatol.2015.34

6. Wei C, Bovonratwet P, Gu A, Moawad G, Silver-berg JI, Friedman AJ. Spironolactone use does not increase the risk of female breast cancer recurrence: a retrospective analysis. 

. 2020;83(4):1021-1027. doi:10.1016/ j.jaad.2020.05.081

7. Garg V, Choi JK, James WD, Barbieri JS. Long-term use of spironolactone for acne in women: a case series of 403 patients. 

. 2021;84(5):1348-1355. doi:10.1016/j.jaad.2020.12.071

8. Tan J, Knezevic S, Boyal S, Waterman B, Janik T. Evaluation of evidence for acne remission with oral isotretinoin cumulative dosing of 120-150 mg/kg. 

. 2016;20(1):13-20. doi:10.1177/1203475415595776

9. Strauss JS, Rapini RP, Shalita AR, et al. Isotretinoin therapy for acne: results of a multicenter dose-response study. 

 1984;10(3):490 -496. doi:10.1016/s0190-9622(84)80100-0

10. Layton AM, Knaggs H, Taylor J, Cunliffe WJ. Isotretinoin for acne vulgaris--10 years later: a safe and successful treatment. 

. 1993;129(3):292-296. doi :10.1111/j.1365-2133.1993.tb11849. x

11. Zane LT, Leyden WA, Marqueling AL, Manos MM. A population-based analysis of laboratory abnormalities during isotretinoin therapy for acne vulgaris. 

. 20 06;142(8):1016 -1022. doi:10.10 01/archderm.142.8.1016

12. Huang YC, Cheng YC. Isotretinoin treatment for acne and risk of depression: a systematic review and meta-analysis. 

. 2017;76(6):1068 -1076.e9. doi:10.1016/ j.jaad.2016.12.028

13. Hekmatjah J, Chat VS, Sierro TJ, Read C, Kassardjian AA, Armstrong AW. Differences in depression and distress between acne patients on isotretinoin vs oral antibiotics. 

. 2021;20(2):172-177. doi:10.36849/JDD.5559

14. J. Harper, H. Baldwin, D. Eichenfield. Acne and Rosacea Update 2022. Presented at Maui Derm NP+PA Summer 2022; June 23-25, 2022; Colorado Springs, Colorado.

Articles

Julie Harper, MD, a board-certified dermatologist in private practice in Birmingham, Alabama, a founding director and past president of the American Acne and Rosacea Society, offers the latest in acne treatment.

Latest Acne Treatment Pearls

Roger I. Ceilley, MD, FAAD, FACMS, clinical professor of dermatology at the University of Iowa in Des Moines, detailed what people need to know about this crucial topic in his presentation on photoprotection at the 2022 Fall Clinical Dermatology Conference for PAs & NPs.

He set the stage for his indepth analysis by noting that sunlight is the major environmental risk factor for melanoma. Ceilley cited a study that showed between 89% and 95% of annual melanoma cases are caused by solar UV radiation exposure.

 “The authors concluded that avoidance of UV radiation will reduce the incidence of malignant melanoma,” he said.

However, he noted that while UV radiation exposure without protection may be responsible for “the vast majority” of melanoma cases, it is not the only driver for this potentially deadly skin disease. As a 2021 study reported, “indoor tanning beds, immunosuppression, family history and rare congenital diseases, moles, and obesity [also] contribute to the disease”.

Next, Ceilley presented evidence for the fact that sunscreen reduces melanoma risk. He specifically mentioned a study from Australia which followed 1,621 patients and found that melanoma risk was significantly lowered by regular sunscreen use.

 Another study was reviewed which concluded that sunscreen use likely reduced skin cancer incidence by 10-15% and that sunscreen should be a component of a comprehensive sun protection strategy.

 “Sunscreens are an important part of sun protection that includes avoiding the midday sun and wearing sun-protective clothing”, said Ceilley.

When it comes to SPF, the number on the package may not match up with the amount of sun protection provided in average patient populations due to inadequate or improper use. People often don’t apply the recommended amount of sunscreen, so Ceilley offered tips how to apply it effectively. Given that patients apply sunscreens at densities far less than that utilized to determine the SPF value listed on the product label, a real-world/actual usage study concluded that SPF 100+ sunscreen was significantly more effective than SPF 50+ sunscreen.

 Ceilley stressed that these results demonstrate that there is a need for sunscreen labelled with SPFs greater than 50+ to provide consumers with better choices for sunscreen products. In summary, he remarked, “higher SPF sunscreens have multiple clinical benefits to users.” He highlighted a specific study which demonstrated that an SPF 80 formulation proved more effective than an SPF 50 formulation in a single application model during a high UV test environment.

 When it comes to sunscreen protection beyond UV, “tinted sunscreens and those with antioxidants appear to be helpful in protecting against visible and infrared light damage to the skin,” Ceilley said.

Ceilley then touched upon absorption concerns with topical sunscreens. In the safety studies that were conducted, serum levels for risk were selected arbitrarily without scientific evidence and he reported that the theoretical risk of absorption has not been seen clinically, despite the fact that the tens of millions of people using sunscreen each summer weekend effectively constitute a large-scale experiment, in Ceilley’s view. Ceilley touched upon the most recent controversy specifically regarding oxybenzone in sunscreen as a cancer causing agent. He cited a 2018 study which reviewed oxybenzone and sunscreen and offered tips on counseling patients in a clinical setting on this controversial issue.

 Ceilley suggested that in discussion with patients, it is important to begin by emphasizing the data supports the fact that sunscreen use lowers skin cancer risk. He also advised informing patients that while laboratory evidence suggests oxybenzone may have negative environmental effects, the conditions in those experiments were not reflective of real-world conditions and thus are inconclusive. Patients may use inorganic sunscreens if they prefer, but should be informed about their disadvantages. For patients concerned about benzene toxicity, Ceilley cited research that shows that sunscreen users had lower levels of blood benzene than never-users, suggesting other factors may be a stronger influence than sunscreen.

 Ceilley also reminded healthcare practitioners that the best sunscreen choice is one patients will use consistently and that cost and cosmetic acceptability are also factors.

Ceilley ended his talk by reinforcing that photoprotection is an important topic for both providers and patients alike and that there are data to show that it lowers skin cancer risk. Unfortunately, there still represents a knowledge gap in the public perception of the benefits of sunscreen and its proper usage. The public needs better education on the benefits of high SPF levels, the safety of sunscreens and better understanding appropriate use of systemic photoprotection and skin supplements.

Ceilley serves as a consultant for Biofrontera, Sun Pharma and Ferndale.

1. Ceilley RI. What You Really Need to Know About Photoprotection. Presented at the 2022 Fall Clinical Conference for PAs & NPs, held June 3-5, 2022; Scottsdale, AZ.

2. Juzeniene A, Grigalavicius M, Baturaite Z, Moan J. Minimal and maximal incidence rates of skin cancer in Caucasians estimated by use of sigmoidal UV dose–incidence curves. 

International Journal of Hygiene and Environmental Health

. 2014;217(8):839-844. doi:10.1016/j.ijheh.2014.06.002

3. Saginala K, Barsouk A, Aluru JS, Rawla P, Barsouk A. Epidemiology of Melanoma. Med Sci (Basel). 2021 Oct 20;9(4):63. doi: 10.3390/medsci9040063. PMID: 34698235; PMCID: PMC8544364.

4. Green AC, Williams GM, Logan V, Strutton GM. Reduced melanoma after regular sunscreen use: randomized trial follow-up. J Clin Oncol. 2011;29(3):257-263. doi:10.1200/JCO.2010.28.7078

5.Olsen CM, Wilson LF, Green AC, et al. Cancers in Australia attributable to exposure to solar ultraviolet radiation and prevented by regular sunscreen use. 

. 2015;39(5):471-476. doi:10.1111/1753-6405.12470

6.Williams JD, Maitra P, Atillasoy E, Wu MM, Farberg AS, Rigel DS. SPF 100+ sunscreen is more protective against sunburn than SPF 50+ in actual use: Results of a randomized, double-blind, split-face, natural sunlight exposure clinical trial. 

Journal of the American Academy of Dermatology

. 2018;78(5):902-910.e2. doi:10.1016/j.jaad.2017.12.062

7. Mirsky RS, Prado G, Svoboda RM, Rigel DS. Oxybenzone and Sunscreens: A Critical Review of the Evidence and a Plan for Discussion with Patients. 

8. Olsen CM, Wilson LF, Green AC, et al. Cancers in Australia attributable to exposure to solar ultraviolet radiation and prevented by regular sunscreen use. 

Recent research puts the role of sunscreens in a whole new light, including need-to-know information on SPF, how to improve adherence and address patient concerns about sunscreen safety, and more.
