By Dr. Eileen Murray MD FRCPC (biography and disclosures) Disclosures: Served as a consultant for the pharmaceutical industry and participated in clinical research evaluating new therapies for psoriasis and atopic dermatitis. Mitigating potential bias: Treatments or recommendations are unrelated to products/services/treatments involved in disclosure statements.
What I did before
Acne vulgaris is a distressing disease beginning at puberty, involving the pilosebaceous follicles of the skin on the face, chest, and back.
The incidence of acne in teenagers is nearly 100%. Treating teenagers with acne was an exceptionally important part of my practice.
When I began, treatment choices included two lotions, one combining methylprednisolone, neomycin sulfate, aluminum chlorhydroxide, and sulfur; the second combining sulfacetamide sodium with sulfur. We also prescribed benzoyl peroxide (BPO) gel 5 or 10% and oral antibiotics, usually tetracycline or erythromycin.
Enthusiastic and motivated to help, I carefully explained to each teenager, the changes happening in their skin, gave advice on daily skincare, and advised what they needed to avoid using. I also explained how the medications worked and gave advice on controlling the side effects. The most effective treatment at the time was the combination of benzoyl peroxide 5 or 10% gel applied once or twice daily with oral tetracycline 500mg twice daily.
To my surprise, many patients returned dissatisfied showing little improvement. I carefully reassessed and prescribed a different combination of oral or topical therapy. Despite this, improvement was slow and erratic.
What changed my practice
When I was referred several disabled, institutionalized young adults with acne, I prescribed the same treatments and to my surprise, they all had marked improvement or complete clearing at their follow-up visits.
This made me stop and think. What was the difference?
In this case, the nursing staff were applying and giving the medication and the treatment worked. Obviously, my other patients were not adhering to my advice. Why not? What could I do?
What I do now
Firstly, I greatly shortened my discussion of pathophysiology, giving them only a concise, clear explanation. I spent more time trying to involve them in the process, reassuring them that if they used the treatment this way, it would work.
The first follow-up visit was much sooner in order to be able to reassure and encourage them to continue the treatment. There was an improvement that I could see that they likely could not. Decreased numbers of closed comedones (small cream coloured papules) is an early sign. I also discovered that patients would stop the treatment when the skin cleared, thinking their acne was gone. I made sure they knew that the treatment was not a cure but rather it would prevent new lesions from occurring and would, if they continued treating it keep their skin clear. My success rate improved immensely.
Pathogenesis of acne
We knew that increased androgen production at puberty stimulated sebaceous glands and increased ductal proliferation of epithelial cells blocking the follicles. Increase in sebum production allowed for proliferation of the anaerobic bacterium, Propionibacterium acnes (P.acnes). The bacteria release lipases and proteases, that degrade and disrupt the follicular wall and cytokines that cause inflammation.
It has now been determined that at puberty as well as an increase in androgens, there is an increase insulin-like growth factor1 (IGF-1).
IGF-1 stimulates the synthesis of adrenal and gonadal androgen. It also increases 5-alpha reductase and augments mitogenic signally pathways of insulin receptors. Factors that increase IGF-1 include insulin, hyperglycemic foods, milk, dairy proteins, and smoking. (1)(2)
Treatment recommendations for acne now (3)
Our recommendations to all patients now include ways to reduce insulin resistance: including decreasing intake of milk and dairy proteins, eating a low glycemic index diet, and not smoking.
Mild Acne:
Patients with mild acne have few or localized comedones and superficial inflammatory lesions with no scarring.
Treat with a topical antibiotic or BPO once a day, along with a topical retinoid once a day. BPO slowly releases oxygen killing P. acnes and reduces the amount of free fatty acids that increase comedo formation.
Topical retinoids reduce both proliferation of the follicular ductal cells and inflammation. Topical retinoids include tretinoin 0.01, 0.05 or 0.1% cream, adapalene 0.1% cream or 0.1%, 0.3% gel, tazarotene 0.05 or 0.1%. cream or gel, and trifarotene 0.005% cream.
Adapalene is the mildest and least irritating, while tazarotene is the most potent. The main side effect is skin irritation, redness, and peeling. Treat patients with sensitive skin with lower concentrations and creams rather than gels.
To mitigate irritation, reduce frequency of application to every second or third night and mandate use of moisturizers and gentle cleansers.
Other medications include azelaic acid 15% gel and topical antibiotics including dapsone 5% gel, erythromycin gel 1% combined with 3% BPO and clindamycin 1% lotion, or 1% with BPO 3 or 5%. Topical retinoids are also available in combination with antibiotics or BPO. Combinations are efficacious and help improve compliance. However, they are more expensive.
Moderate Acne:
Patients have many comedones, papules, and pustules and a few nodules, not only on the face but also on the chest and back. There is often violaceous or red discoloration of the skin and some ice-pick or atrophic scars.
As well as a topical retinoid or a topical combination, most require oral treatment with either erythromycin, or tetracycline, 250 to 500mg BID.
Metformin, as an adjunctive treatment, has shown benefit for patients with moderate to severe acne responding poorly to treatment. (1)(2)
Women with persistent acne benefit from treatment with antiandrogens, including spironolactone and oral contraceptives. (4)
Severe Acne:
Patients have widespread inflammatory papules, pustules, and possibly nodules, with scarring. All, regardless of age, need treatment with isotretinoin.
Treat patients with 0.04 to 0.20 mg/kg/day, until completely clear plus one more month. (2,3) With lower doses, the success rate is the same but with increased tolerability and fewer long-term sequelae. A total cumulative dose is no longer recommended. (5)(6)
Indications for using oral isotretinoin include patients without significant improvement after three months of treatment, patients with scarring as well as those with severe inflammatory acne.
Patients on isotretinoin require monitoring!
Enroll women of childbearing age in the Pregnancy Prevention Program with routine pregnancy testing.
Studies have shown that monthly monitoring is unnecessary. Lee YH et al (7) suggest a lipid and hepatic panel at baseline and again after two months of treatment and more frequent monitoring dictated by baseline abnormalities or medical history. The recommendations by Willoughby and Rosenthal are similar, but at that time recommended daily dosing was higher. (8)
Recommended Isotretinoin Monitoring in Acne (8):
- Pre-Isotretinoin
- Pregnancy test
- Fasting Cholesterol
- Fasting TG
- ALT
- CBC and Differential
- Repeat once at 4 weeks
- Repeat abnormal tests
- Repeat with dose increases
- Monthly pregnancy tests
- Normal cholesterol and CBC are not repeated
References:
- Azadi A, Forouzani-Haghighi B, Dorvash MR. Metformin: a promising outlook in treatment of acne vulgaris. Int J Pharm Clin Res. 2016;8(9):1274-1277. Accessed October 14, 2020. http://impactfactor.org/PDF/IJPCR/8/IJPCR,Vol8,Issue9,Article2.pdf (View)
- Lee JK, Smith AD. Metformin as an adjunct therapy for the treatment of moderate to severe acne vulgaris. Dermatol Online J. 2017;23(11). Accessed October 14, 2020. https://escholarship.org/uc/item/53m2q13s (View)
- Yuka A, Baibergenova A, Dutil M, et al. Management of acne: Canadian clinical practice guideline. CMAJ. 2016;188(2):118-126. doi:
- Mohamed LE. Hormonal treatment of acne vulgaris: an update. Clin Cosmet Investig Dermatol. 2016;9:241-248. doi:10.2147/CCID.S114830 (View)
- Rao PK, Bhat RM, Nandakishore B, Dandakeri, S, Martis J, Hamath GH. Safety and efficacy of low-dose isotretinoin in the treatment of moderate to severe acne vulgaris. Indian J Dermatol. 2014;59(3):316. doi:10.4103/0019-5154.131455 (View)
- Borghi A, Mantovani L, Minghetti S, Giari S, Virgili A, Bettoli V. Low-cumulative dose isotretinoin treatment in mild-to-moderate acne: efficacy in achieving stable remission. J Eur Acad Dermatol Venereol. 2011;25(9):1094-1098. doi:10.1111/j.1468-3083.2010.03933.x (Request with CPSBC or view with UBC)
- Lee YH, Scharnitz TP, Muscat J, Chen A, Gupta-Elera G, Kirby JS. Laboratory monitoring during isotretinoin therapy for acne: a systematic review and meta-analysis. JAMA Dermatol. 2016;152(1):35-44. doi:10.1001/jamadermatol.2015.3091 (Request with CPSBC or view with UBC)
- Willoughby JS, Rosenthal D. Monitoring isotretinoin therapy in acne: rational use of laboratory tests. J Cutan Med Surg. 1997;1(2):72-77. doi:10.1177/120347549700200203 (Request with CPSBC or view with UBC)
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Thanks for this interesting article. With regard to moderate acne, I’m curious about the rationale behind recommending long courses of antibiotics rather than proceeding straight to low dose isotretinoin, especially in those without any pregnancy concerns. If less onerous blood monitoring is now the standard of care, wouldn’t it make more sense to avoid the consequences of long term antibiotic use and just use low dose retinoids?
Does treatment for Adults with acne change? And why?
Thank you for this great review.
Few Questions:
1) I usually require 2 negative pregnancy tests prior to starting isotretinoin (1 serum and 1 urine PT day of prescribing). Do you require this of your patients?
2) I also time the serum pregnancy test within 7 days of their menstruation and start the isotretinoin during their menstruation with a same day negative urine PT, as a triple check not pregnant before starting. Too restrictive?
3) I understood that cumulative dose not necessary for moderate acne but for severe acne, the recurrence rate is higher if not targeted to weight. Can you please clarify if one should still target to weight in severe acne?
4) Some patients need maintenance isotretinoin twice a week. How do you practically monitor pregnancy tests and prescribe in these cases since it can be an indefinite duration? Do you still only release monthly prescriptions after confirmed negative pregnancy test?
5) Do you discuss risk of premature epiphyseal plate closure with adolescents? Any role of checking xray/bone age pre-treatment?
Many thanks
Thank you for your review. Your recommended dose per kg per day of Isotretinoin is much lower than what was previously recommended (and seems to be the standard in drug references). 0.5mg/kg/d x4 weeks, split BID, and then 1mg/kg/d x 120d. Can you explain your rationale here?
What do you do if the cholesterol is abnormal while on isotretinoin? I would imagine that this is a transient short-term effect while on the med that should resolve when they come off, but is there a threshold where you stop therapy prematurely due to elevated cholesterol?
Hi,
Thanks for the beautifully written article.
Please a few questions about the topicals:
1) can I use the combo (bpo / abx) at the same time as the topical retinoids eg both in the evenings
2) when will moisturizer be used
Many thanks once again
1. Re: Question from Ed Weiss
This is a very pertinent question. I agree that isotretinoin is much preferred to long term antibiotic use. The new treatment recommendations are that if there is poor or no improvement within 3months even with moderate acne, to start treatment with isotretinoin. Also, we now have evidence that metformin is helpful. it is also safer than long term antibiotics. With more studies it could become recommended instead of antibiotics.
2. Re: Question from Tracy
Yes, I would say that the new recommendations apply to treatment of adults with acne. The recommended treatments now help resolve the underlying physiological abnormalities of acne and are safer with fewer side effects. Adult women with persistent acne often do well with anti-androgen hormonal therapy.
3. Re: Question from Cindy Huang
I obtain a negative test before treatment and ask the patient not to start treatment until the third day of their period. I also recommend that they use two forms of contraception and to continue to use this for one moth after treatment. I also obtain a monthly pregnancy test while they are on treatment.
Isotretinoin blood levels return to normal within two weeks of discontinuing the drug.
I also warn them to not fall madly in love while on treatment.
I commend your cautiousness. The pharmaceutical suppliers of the drug have pregnancy prevention protocols for the patients. I would recommend reviewing them.
The new recommendations no longer target the isotretinoin dose to weight in either moderate or severe acne. Instead the recommendation is to continue treatment until clear plus one month. The lower dose is more tolerable with fewer side effects with equivalent efficacy.
Patients requiring maintenance treatment are rare. The risk would depend on the dose. Treatment with a dose of 10mg twice weekly would be very low risk. However, I would suggest using hormonal therapy e.g. oral contraceptives for treating the acne in those of childbearing age and the low dose isotretinoin regime in those who are not.
I do not discuss this risk. The evidence for premature closure with the doses used to treat acne is extremely weak. The studies reporting this were patients on very high doses of the drug. If your patient wants to be a professional basketball player, then you might wish to proceed as you suggest.
4. Re: Question from Anon
The recommendation for using the lower doses over a longer period is quite recent. Lower doses seem to be as effective with fewer side effects and better tolerability.
5. Re: Question from Marlies Houwing
I’m glad you asked this question. You are quite right. There is really no evidence to show that increased cholesterol levels while on treatment are at all dangerous and once off, levels quickly return to normal.
However, 25% of patients will have increased fasting triglyceride levels. In most it is double or triple their normal level and not worrisome. A few though will have much higher levels. There have been reported cases of pancreatitis and even some deaths. If the fasting TG goes up to 8, I decrease the dose of isotretinoin, test monthly and recommend a low fat diet and no alcohol for the remainder of course of treatment.
6. Re: Question from Regina Agbulu
Benzoyl peroxide is a potent oxidizing agent and could interfere with efficacy so I would recommend that the topical retinoid be applied at bedtime and the BPO combination in the morning.
Good question. Most of the topical treatments dry the skin. I recommend applying moisturizer after the medication has been absorbed into the skin. Wait about 15 to 20 minutes before applying. Moisturizes are also more effective if you dampen the skin before applying.