Acne

TREATMENT​

Treatment Approach

• In my view, it's reasonable to consider isotretinoin therapy for any patient requesting this.  Of course, if the patient has unrealistic expectations or demonstrably clear skin and is requesting isotretinoin in an attempt to attain an unreasonable cosmetic goal one should hesitate.  However, given the cost of topical medications and there general meager efficacy, the general exceptional safety of isotretinoin, and the drawbacks to prescribing multiple and prolonged courses of antibiotics, isotretinoin is, in my estimation, first line for acne in anyone seeking a safe, cost effective and reliably efficacious treatment.  

AAD Guidelines​ (38300170) - Figure

Methods of Assessing Efficacy

Investigators' Global Assessment (IGA)

• Researchers often use the investigators' global assessment (IGA) for acne, which has 5 grades, 0-4, with "0" being clear and "4" being severe. Typically, the end point is at least a 2-point drop in IGA score AND a rating of 0 or 1

DermSat-7

• DermSat-7 is a dermatology-specific 7-item questionnaire used to assess patient satisfaction with treatment.  It has been applied to patients treated with acne (37991774) and seemed to perform well with respect to assessing effectiveness, convenience, and overall satisfaction.  

Acne Fulminans​

• A proposed treatment algorithm published in the literature can be found here. 

Topical Treatments

Benzoyl Peroxide

• Typically poorly tolerated which may be secondary to percutaneous absorption as opposed to follicular penetration. Attempts to circumvent this include formulation into “microparticles” which are too large to penetrate the stratum corneum but are able to enter the follicle. 19588642

Comparing 2.5%, 5%, and 10% benzoyl peroxide on inflammatory acne vulgaris. Int J Dermatol. 1986. PMID: 2948929.

MY SUMMARY:  In this study, 2.5% benzoyl peroxide formulation was more effective than its vehicle and equivalent to the 5% and 10% and side effects of desquamation, erythema, and burning were less frequent with 2.5% compared to 10%.  In summary, lower concentration BP preparations provide similar efficacy with reduced side effects. We extrapolate these results to BP washes, but no confirmatory study exists.  As a result, in my practice I recommend BP in concentrations of 5% or less.   ​

Risk of Malignancy

• There have been some concerns about benzoyl peroxide and the generation of benzene products at body temperature. (39384016)

• Retrospective data shows to increased risk of leukemia, lymphoma, or internal malignancy with use of benzoyl peroxide. (39002561)​

  • There is no right answer presently as to whether the use of benzoyl peroxide is safe.  It has been pointed out that the amount of benzene produced by and exposed to by use of benzoyl peroxide may be similar to other exposures we are currently tolerant of, like a gas stove or oven.  It has also been pointed out that the production is highest and most significant at high temperatures so that maintaining cold chain storage may be a good practice to follow to ensure minimal exposure. (38909658)​

Retinoids

• Weakest to strongest: adapalene < tretinoin < tazarotene; we now have trifarotene, where does this fit?

• Tretinoin and tazarotene are Inactivated by BP (use BP am, retinoid pm).  Adapalene can be coadministered. I do not have an answer for trifarotene. 

• Retinoids are used at night because they are not photostable, not because they cause dramatic photosensitivity.  With proper precautions there should be no increased rates of photodamage as a result of using retinoids.

• Consensus opinion supported by multiple RCTs suggests topical retinoids significantly improve efficacy when added to antimicrobial therapy (topical or oral abx, or topical BP). 19376456​

Trifarotene (Aklief) - label

Randomized phase 3 evaluation of trifarotene 50 μg/g cream treatment of moderate facial and truncal acne. J Am Acad Dermatol. 2019. PMID: 30802558.

MY SUMMARY: This appears to be 2 of the clinical trials in the FDA label. For the face there was a 10-16% improvement over placebo in patients reaching clear or almost clear. For trunk an 11-13% improvement.

IMPORTANT RESULTS: For the 1214 patients treated with trifarotene and 1206 treated with vehicle, the week 12 facial success rates according to the IGA were 29.4% in PERFECT 1 and 42.3% in PERFECT 2 (vs 19.5% and 25.7% for vehicle [P < .001]); trifarotene had statistically significant superior success rates at week 4 (PERFECT 1) and week 8 (PERFECT 2). At week 12, the rates of success with trifarotene according to the truncal PGA were 35.7% in PERFECT 1 and 42.6% in PERFECT 2 (vs 25.0% and 29.9%, respectively for vehicle [each P < .001]). In both PERFECT 1 and 2, trifarotene was statistically significantly superior in achieving reductions in inflammatory and noninflammatory lesions on the trunk starting by week 4 in PERFECT 1 and by week 2 in PERFECT 2. Rates of success on the trunk were statistically significant for trifarotene versus for vehicle starting at week 8 in both studies.

Tazarotene 0.045% lotion (Arazlo) - label

Novel Polymeric Lotion Formulation of Once-Daily Tazarotene (0.045%) for Moderate-to-Severe Acne: Pooled Phase 3 Analysis. J Drugs Dermatol. 2020. PMID: 32549090.

MY SUMMARY: Phase 3 clinical trial from FDA label, ~12% more patients achieved clear or almost clear when using drug vs placebo. RESULTS: Treatment success at week 12 was greater with tazarotene 0.045% lotion versus vehicle (30.4% vs 17.9%; P<0.001). The most frequent treatment-emergent AEs related to tazarotene treatment were application site pain (5.3%), dryness (3.6%), and exfoliation (2.1%).

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. PMID: 31251546.

MY SUMMARY: Tazarotene 0.045% lotion may be equally as efficacious as tazarotene 0.1% cream but better tolerated.

RESULTS: At less than half the concentration, tazarotene 0.045% lotion was numerically more effective than tazarotene 0.1% cream. Mean percent reductions in inflammatory and noninflammatory lesions were 63.8% and 56.9%, compared with 60.0% and 54.1% with tazarotene 0.1% cream at week 12. Treatment success assessed by the investigator or patients’ self-assessment was also numerically greater with tazarotene 0.045% lotion. There were no significant differences in patient satisfaction or QoL between the two active treatments. Both were well-tolerated, however, there were more treatment-related adverse events with tazarotene 0.1% cream (5.6% versus 2.9%); most common being application site pain.

Bakuchiol

• A "natural retinol alternative" derived from the Psoralea Corylifolia plant. 0.5% concentration was shown to be equivalent to similar retinol concentration with fewer side effects.

Prospective, randomized, double-blind assessment of topical bakuchiol and retinol for facial photoageing. Br J Dermatol. 2019. PMID: 29947134.

METHODS: This was a randomized, double-blind, 12-week study in which 44 patients were asked to apply either bakuchiol 0·5% cream twice daily or retinol 0·5% cream daily. A facial photograph and analytical system was used to obtain and analyse high-resolution photographs of patients at 0, 4, 8 and 12 weeks. Patients also completed tolerability assessment questions to review side-effects. During study visits, a board-certified dermatologist, blinded to study group assignments, graded pigmentation and redness.

RESULTS: Bakuchiol and retinol both significantly decreased wrinkle surface area and hyperpigmentation, with no statistical difference between the compounds. The retinol users reported more facial skin scaling and stinging.​

Topical Antibiotics

Minocycline, topical (Amzeeq) - Label

Efficacy and Safety of a Novel Topical Minocycline Foam for the Treatment of Moderate to Severe Acne Vulgaris: A Phase 3 Study; JAAD 2020, PMID: 31163231.

MY SUMMARY: Overall, attributable effect size was relatively small, with 11% more patients reaching clear or almost clear with topical minocycline compared to placebo.
IMPORTANT RESULTS: FMX101 4% (topical minocycline) was significantly superior to vehicle for the second coprimary end point of IGA treatment success (percentage of participants achieving an IGA score of clear or almost clear with a ≥2-grade improvement) at week 12 (30.8% vs 19.6%, respectively; risk ratio, 1.58; 95% CI, 1.32-1.88; P<.0001)​

Other Topical Therapies

Clindamycin phosphate 1.2%/adapalene 0.15%/benzoyl peroxide 3.1% gel

• An RCT showed a 25-30% success rate (>/= 2 grade change from EGSS, which is basically identical to the IGA) and a 20-25% reduction in lesion count compared to vehicle, in line with other topical therapies. 37656094​

DMT310 (Spongilla lacustris powdered mixture)

• DMT310 is powdered mixture of spongilla lacustris, a sponge species, and is billed as a "natural, topical product" for acne that is novel particularly in its once-weekly application.  It showed efficacy similar to other topicals, with a 26% of patients experiencing a 2 grade drop or more of IGA score and a score of 0 or 1, over placebo. 37295506​

Oral Antibiotics

Resistance

• The impact of antibiotic treatment for acne on microbial resistance, both systemic and as it relates to acne pathogenesis, is an on going topic of research. There is evidence that topical and oral antibiotics are associated with the formation of resistant P. acnes, which can be a cause of severe infections and has been found on contacts of patients with acne treated with antibiotics. (28636689)  However, evidence for the impact of P. acnes resistance on treatment response and acne relapse is not substantial. Yet, many recommend limiting treatment with antibiotics to 3 months (in practice they are used much longer) and using concurrent benzoyl peroxide or topical retinoid therapy to limit resistance. (19376456)

• Although topical antibiotics have been shown to increase rates of resistant S. aureus, the use of oral tetracyclines is associated with lower S. aureus carriage rates without increased resistance. (28636689) 

Sarecycline (Seysara) - Label

Once-Daily Oral Sarecycline 1.5 mg/kg/day Is Effective for Moderate to Severe Acne Vulgaris: Results From Two Identically Designed, Phase 3, Randomized, Double-Blind Clinical Trials; JDD 2018, PMID: 30235387.

MY SUMMARY: Clinical trials for FDA drug approval. Overall, attributable effect size was relatively small, with only ~8-11% more patients reaching clear or almost clear compared to placebo.
RESULTS: In SC1401 (sarecycline n=483, placebo n=485) and SC1402 (sarecycline n=519, placebo n=515), at week 12, IGA success (≥ 2-grade improvement and score 0 [clear] or 1 [almost clear]) rates were 21.9% and 22.6% (sarecycline), respectively, versus 10.5% and 15.3% (placebo; P less than 0.0001 and P equals 0.0038). Onset of efficacy in inflammatory lesions occurred by the first visit (week 3), with mean percentage reduction in inflammatory lesions at week 12 in SC1401 and SC1402 of -51.8% and -49.9% (sarecycline), respectively, versus -35.1% and -35.4% (placebo; P<0.0001). Onset of efficacy for absolute reduction of noninflammatory lesion count occurred at week 6 in SC1401 (P<0.05) and week 9 in SC1402 (P<0.01). In SC1401, the most common TEAEs (in ≥ 2% of either sarecycline or placebo group) were nausea (4.6% sarecycline]; 2.5% [placebo]), nasopharyngitis (3.1%; 1.7%), headache (2.7%; 2.7%), and vomiting (2.1%; 1.4%) and, in SC1402, nasopharyngitis (2.5%; 2.9%) and headache (2.9%; 4.9%). Most were not considered treatment-related. Vestibular (dizziness, tinnitus, vertigo) and phototoxic (sunburn, photosensitivity) TEAEs both occurred in ≤1% of sarecycline patients. Gastrointestinal TEAE rates for sarecycline were low. Among females, vulvovaginal candidiasis (SC1401: 1.1% [sarecycline] and 0 [placebo]; SC1402: 0.3% and 0) and mycotic infection (0.7% and 0; 1.0% and 0) rates were low.

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Hormonal therapies

Oral Contraceptive Pills

Meta-analysis Comparing Efficacy of Antibiotics Versus Oral Contraceptives in Acne Vulgaris; JAAD 2014, PMID: 24880665.

MY SUMMARY: Meta-analaysis of RCTs.  OCPs inferior efficacy to antibiotics at 3 mo, but equivalent at 6 mo: 37% vs. 48% and 55% vs. 53% lesion reduction at 3 and 6 mo, resp. Both better than placebo: 25%, 29% lesion reduction at 3, 6 mo, resp. Meta-analaysis of RCTs.
CONCLUSIONS: Although antibiotics may be superior at 3 months, OCPs are equivalent to antibiotics at 6 months in reducing acne lesions and, thus, may be a better first-line alternative to systemic antibiotics for long-term acne management in women.

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Isotretinoin 

Risk of Inflammatory Bowel Disease/Irritable Bowel Syndrome

Kridin K, Ludwig RJ. Isotretinoin and the risk of inflammatory bowel disease and irritable bowel syndrome: A large-scale global study. J Am Acad Dermatol. 2023. PMID: 36529376.

SUMMARY: Compared lifetime risk of Crohn's, UC, and irritable bowel syndrome (IBS) between patients receiving isotretinoin vs oral antibiotics.  HR for isotretinoin use was 1.05 (0.89-1.24), 1.13 (0.95-1.34), and 0.82 (0.76-0.89) for the 3, respectively.  There was an elevated risk of UC during the first 6mo after initiation of therapy, HR 1.93 (1.29-2.88), with an absolutely increased risk of 5 cases per 10,000 patients.

Taylor MT, Margolis DJ, Kwatra SG, Barbieri JS. A propensity score matched cohort study identifying an association of acne, but not oral antibiotic or isotretinoin use, with risk of incident inflammatory bowel disease. J Am Acad Dermatol. 2023. PMID: 36682724.

SUMMARY: Compared risk of IBD within year of being diagnosed with acne in those not receiving oral medications, starting isotretinoin, or starting tetracycline class antibiotics compared to patients without an acne diagnosis.  There was no increased risk of IBD with either tetracyclines or isotretinoin, and there approached a statistically significant protective effect of tetracyclines and UC (OR 0.78, 0.61-1.00).  There was an increased odds of both Crohn's and UC in patients diagnosed with acne but never having received systemic medications for acne, and patients without an acne diagnosis: for Crohn's, OR 1.56 (1.30-1.87), for UC, OR 1.62 (1.33-1.97).​

Wright S, Strunk A, Garg A. Risk of new-onset inflammatory bowel disease among patients with acne vulgaris exposed to isotretinoin. J Am Acad Dermatol. 2021. PMID: 32682881.

RESULTS: The crude 6-month IBD incidence was 0.08% (21/27,230) among isotretinoin-exposed patients with AV compared to 0.04% (254/631,089) among those unexposed. The crude 1-year IBD incidence was 0.10% (28/27,230) among isotretinoin exposed patients with AV and 0.08% (477/631,089) among those unexposed. The odds of developing IBD within 6 months were 87% higher among isotretinoin-exposed patients with AV compared to those unexposed (adjusted odds ratio, 1.87; 95% confidence interval [CI], 1.20-2.93), although the absolute difference was small (risk difference, 2.6 more cases per 10,000 patients; 95% CI, 0.7-4.5). There was no significant difference in the odds of developing IBD at 1 year between isotretinoin-exposed and unexposed patients with AV (adjusted odds ratio, 1.40; 95% CI, 0.95-2.05).​

Risk of Depression and Suicide​

Studies against the link

Risk of Suicide and Psychiatric Disorders Among Isotretinoin Users: A Meta-Analysis [published correction appears in JAMA Dermatol. 2024. PMID: 38019562.

• Meta-analysis of over 1.6 million patients. 

• Overall, showed no increased risk of suicide and actually showed decreased risk in isotretinoin users at 2, 3, and 4 years following treatment. 

• No association with any psychiatric disorders.

• Studies with a higher percentage of male participants showed higher 1-year absolute risk of completed suicide (compared to studie with a lower percentage of participants who were male, not compared to placebo).​

Studies supporting the link

Bremner JD. Isotretinoin and neuropsychiatric side effects: Continued vigilance is needed. J Affect Disord Rep. 2021. PMID: 37168254.

• Best review I have come across analyzing concerns for isotretinoin and psychiatric illness/suicide.  ​

Risk of Sexual Side Effects in Men

• Although this publication was not available in our library, a synopsis from the AAD indicated that "A study published in the International Journal of Dermatology evaluated whether isotretinoin exposure is associated with sexual dysfunction in male patients with acne. In this cohort study that assessed data from 13,600 patients with acne treated with isotretinoin versus a matched group comprising 13,600 patients with acne treated with tetracycline-class antibiotics, there were no significant differences in the risk of sexual health outcomes, including erectile dysfunction, sexual dysfunction, decreased libido, or PDE5 inhibitor use between the two groups.  Similar results were observed when comparing patients treated with isotretinoin with those with acne treated without systemic medications. The authors conclude that isotretinoin exposure does not appear to affect male sexual health in patients with acne." (37839021)​​​

Lab Monitoring

• Baseline screening tests: Triglycerides and cholesterol (non-fasting ok), ALT; this assumes normal dosing (up to 1mg/kg daily) and otherwise healthy.

• Labs to monitor:

  • With standard dosing (up to 1mg/kg/day), recheck labs at 2 months after peak dosing and if normal, no more monitoring. Overall, mean duration to abnormalities occurs at ~50-60 days, hence the 2 month check.

  • Triglycerides and cholesterol are most important (abnormalities ~20%) (27189824); Grade 3 or higher triglyceride abnormalities in 1%, no grade 3 or higher cholesterol abnormalities (31228528)

  • ALT is also usually checked although abnormalities are rare (~2% 27189824, 0.5% for grade 3 or higher 31228528) and occur only slightly higher than at baseline frequency. 

• Leukopenia and thrombocytopenia occurs in 1% and is clinically insignificant = no need to check. (27189824) No grade 3 or higher CBC abnormalities reported (31228528) although anecdotally I have had 1 patient with a grade 4 leukopenia that completely recovered after medication cessation.

• Grading of abnormal values are in the chart below:​​​​

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Procedural Treatments

• These include lasers and non-laser light treatments. They are alternative treatment options in selected patients that do not respond or are unable to tolerate conventional therapies. Their efficacy is derived from the ability to target P. acnes (UVA/UVB, blue light, blue and red light combination), sebaceous gland activity (ALA + PDT, infrared lasers, radiofrequency), or both (PDL, KTP, IPL). (23619435)

Lasers

Treatment of Moderate to Severe Acne and Scars With a 650-Microsecond 1064-nm Laser and Isotretinoin; JDD 2020, PMID: 32574021.

CONCLUSIONS: The 650-microsecond, 1064-nm laser in combination with low-dose isotretinoin is safe and effective in patients with acne complicated by atrophic scars and genetically prone to post-acne scarring.​

1726nm Lasers

• There are two big categories for device "authorization" by the FDA: 510(k) clearance and the more stringent PMA (premarket approval). In 2022, two 1726nm lasers received 510(k) clearance by the FDA for the treatment of acne, first AviClear and then Accure.  As pointed out by this article, the two devices use the same wavelength but are distinctly different lasers, with Accure being the device targeted towards medical professionals with the potential for delivery of overall higher energy, and AviClear a device geared more towards medispas.  

Novel 1726 nm laser demonstrates durable therapeutic outcomes and tolerability for moderate-to-severe acne across skin types. J Am Acad Dermatol. 2023, PMID: 37328000.

SUMMARY: This was the study cited used to support the FDA 510(k) clearance of AviClear.  Treatment consists of 3 sessions lasting 30-40 minutes, administered every 3 weeks (ranging from 2-5 weeks), requires no anesthetic, and was well-tolerated (no AEs).  At least 50% reduction in inflammatory acne lesions was seen in ~33% of patients at 4 weeks after the final treatment, and this increased to ~80% at 12 weeks and ~87% at the final 26-week post treatment eval.  Percentage of subjects clear or almost clear at baseline was 0%, increasing to 9%, 36% and ~42% at 4, 12, and 26 weeks post treatment.  Notably, there was no control or placebo group. ​

Laser-like devices

• TheraClearX (37361383) is another light device mixed with a vacuum ("photopneumatic") with FDA clearance for the treatment of acne.  It is not a laser in that it does not emit a single wavelength (monochromatic) of light that are all in phase (coherence) and parallel (collimated).  It admits a broad spectrum of light from 500-1200nm with peaks in the ~825nm and ~890nm range, among other smaller peaks (37361383).​

Photodynamic Therapy

• Chlorophyll-a PDT is better than PDT alone: SB-RCT, split face, in 24 patients of dark-skin asian descent. (24930587)​

Future Directions

TNF-alpha inhibitors

• A systemic review showed mixed results but that TNFis may be effective in treating refractory acne. (36930143)​​

Acne Scarring (35792196, 35469981)​​

• Scar types and treatment chart, here.

• Color

  • Erythematous scars​ - IPL, 595nm PDL for skin types I-IV; PDL for skin type V

  • Hyperpigmented - Q-switched 755nm Alexandrite with or without IPL for Skin types I-IV; 1064 ND-YAG for skin types V or VI

  • Hypopgimented - bimatoprost 0.03% gel BID and tretinoin 0.025% cream nightly

• Timing​

  • After acne is in remission, or controlled with topical therapy alone.  ​

  • After isotretinoin, 6mo wait before treatment is still recommended, although this may only be necessary for full-face dermabrasion or ablative laser.

• Topical therapies​

  • adapalene 0.3%, tazarotene, adapalene plus BP, retinoic acid 0.025% and glycolic acid 12% combination have been shown effective​

• Microneedling, chemical peels​, fillers, and a multitude of lasers can all be effective.

• Surgical modalities including subcision, punch excision, punch elevation, and dermabrasion are sometimes implemented.

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