Efficacy and safety of topical treatments for seborrheic keratoses: a systematic review

Figures & data

Table 1. Efficacy of topical therapies for treatment of seborrheic keratoses.

Author	Intervention	Frequency	Study Design	n	Efficacy	Adverse events	Evidence Quality^A
Baumann et al. (3)	Arm 1: HP40 Arm 2: Vehicle solution (control)	Up to two applications, every three weeks	RCT^b	Arm 1: 467 Arm 2: 470	Complete clearance (PLA = 0) of all 4 SK: 6% HP40 vs. 0% vehicle control (p < .01). Complete clearance (PLA = 0) of ¾ SK: 18% HP40 vs. 0% vehicle control (p < .0001)	Pain, burning/stinging, pruritus, hyperpigmentation, hypopigmentation, erythema, scaling, crusting	1
DuBois et al. (12)	Arm 1: A-101 (32.5% HP) Arm 2: A-101 (40% HP) Arm 3: Vehicle solution (control)	Up to two applications, every three weeks	RCT	Arm 1: 39 Arm 2: 39 Arm 3: 41	Mean reduction in PLA grade: 1.7 A-101 40%, 1.4 A-101 32.5%, and 0.1 vehicle (p < .001, both concentrations vs. vehicle) PLA = 0 day 106: 59.5% A-101 40%, 46.2% A-101 32.5%, and 2.5% vehicle (p < .001, both concentrations vs. vehicle) PLA ≤ 1 day 106: 68% A-101 40%, 62% A-101 32.5%, 5% vehicle (p < .001 for both concentrations vs. vehicle)	Edema and erythema (during application), erythema, hyperpigmentation, scaling, bleeding	1
DuBois et al. (11,14,36)	Arm 1: HP40 Arm 2: HP45 Arm 3: Vehicle solution (control)	Not specified, 106 days	RCT^c	Arm 1: 103 Arm 2: 100 Arm 3: 50	Efficacy Mean per-patient percentage of all target SK clear at day 106: 49.5% HP40, 57.9% HP45, 3.7% vehicle (p < .0001). Target lesions clear on the face at day 106: 62.2% HP40, 67.2% HP45, 7.5% vehicle (p < .0001) Target lesions clear on the trunk at day 106: 43.4% HP40, 55.8% HP45, 1.42% vehicle (p < .0001) Only HP45 showed significance vs vehicle for lesions clear on extremities (40.5% vs 0%) The only significant difference observed between HP40 and HP45 was for target lesions clear on the trunk (p = .02). Onset of treatment effectiveness Statistically significant differences in the mean per-patient % of SK clear on the face, trunk, and extremities for HP40 and HP45 vs. vehicle observed as early as visit 4 (p < .0001) Statistically significant differences maintain through visits 6, 7, 8 (p < .0001) Statistically significant difference between HP40 and HP45 for trunk lesions clear at visits 6–8 (p ≤ .03)	Malaise, eyelid edema with HP40 Cellulitis with HP45 Mild erythema and scaling with HP40 and HP45	1
DuBois et al. (13)	HP40	Up to three applications, two weeks apart (if PLA ≥ 1)	OL	41	Mean PLA changes from baseline at days 85 and 113: -2.0 and -2.0 respectively. Day 113, 90.2% target lesions clear Both day 85 and 113: 85% reported being satisfied or very satisfied (SSA ≥ 4) with skin appearance. 80% and 83% reported being satisfied or very satisfied (SSA ≥ 4) with their treatment experience on day 85 and 113, respectively	Eyelid edema, administration-site irritation/discomfort	2
Callender et al. (35)	A-101 (40% hydrogen peroxide)	Up to four applications, every three weeks	OL	147	Efficacy not assessed	Pruritus, stinging, crusting, edema, erythema, scaling, hypopigmentation	2
Peredo et al. (37)	HP40	Patient 1: two treatments, three weeks apart Patient 2: two treatments, six weeks apart	CR	2	Patient 1: Complete resolution of all SKs Patient 2: SKs nearly clear without scarring	None reported	5
Schlesinger and Favre (38)	HP40	Single treatment	CR	2	Patient 1: majority of SK lesions had disappeared, and the remaining SK had reduced in size Patient 2: 2 lesions cleared, 2 lesions partially cleared, 2 lesions unaffected	Blistering, redness, and tenderness	5
Mitsuhashi et al. (15)	Arm 1: Tacalcitol 2 µg/g Arm 2: Calcipotriol 50 µg/g Arm 3: Maxacalcitol 25 µg/g Arm 4: Salicylic acid (control)	One or two times daily for 3–12 months (average 7.3 months)	RCT	Arm 1: 45 Arm 2: 34 Arm 3: 37 Arm 4: 30	30% excellent clinical response (>80% decrease) 17.8% Tacalcitol 35.3% Calcipotriol 40.5% Maxacalcitol 47% good clinical response (40% ≤ x ≤80% decrease) 42.4% Tacalcitol 50.0% Calcipotriol 48.6% Maxacalcitol Tacalcitol < calcipotriol  = maxacalcitol	None reported	1
Yousefi et al. (16)	50 µg/g calcipotriol ointment	Twice daily for twelve weeks	OL	30	Mean baseline size: 9.3 ± 2.95 mm; Mean 12-week size: 2.02 ± 1.94 mm (p < .05). Mean percent improvement 80.46 ± 17.66%; 6 patients demonstrated 100% improvement. An intermediate negative correlation existed between the tumor size and the improvement.	Mild erythema and pruritus	2
Herron et al. (17)	Arm 1: Calcipotriene 0.005% ointment Arm 2: Tazarotene 0.1% cream Arm 3: Imiquimod 5% cream Arm 4: Cryosurgery (positive control) Arm 5: Vanicream (negative control)	Arm 1: Once daily application for four months Arm 2: Twice daily for four months	SCT^a	Arm 1: 15 Arm 2: 15 Arm 3: 15 Arm 4: 15 Arm 5: 15	BID tazarotene 0.1% application caused clinical and histological improvement in 7/15 patients; indistinguishable from normal skin and showed no SK histologically Once daily application of calcipotriene 0.005% ointment, tazarotene 0.1% cream, imiquimod 5%, and Vanicream did not result in clinical improvement. One treatment with cryosurgery led to clinical and histological improvement of all lesions treated with no scarring nor recurrence.	None reported with calcipotriene Burning, pruritus, erythema with tazarotene Erythema, burning, ulceration with imiquimod	1
Sutedja et al. (18)	Arm 1: Topical 5-FU Arm 2: Calcipotriol Arm 3: Cryosurgery (control)	Twice daily for three months	SCT^a	Arm 1: 18 Arm 2: 18 Arm 3: 18	Week 12 mean percentage of decrease in lesion size: 24.06% 5-FU, 6.18% Calcipotriol, 100% cryosurgery Improvement with more than 80% decrease in lesion size: 3/18 SK 5-FU, 0/18 SK Calcipotriol, 18/18 SK cryosurgery.	Not documented	1
Wijayanti et al. (19)	Tretinoin 0.05% cream	Four weeks	CR	1	Remission was not obtained	Not documented	5
Tsuji and Morita (21)	5-FU cream and topical polyethylene glycol containing 0.1% gentamycin	5-FU cream daily for 21 days, then topical polyethylene glycol for 6 months (to prevent secondary infection and induce epithelization of the eroded lesion)	CR	1	After 6 months of treatment, the area of the lesion showed normal-looking skin with long hairs covering the treated area No signs of recurrence for approximately 7 years following treatment	Intralesional erythema, edema, and erosion (onset 5–7 days after treatment)	5
Burkhart and Burkhart (23)	Topical 50% urea-in a vehicle containing vitamin E, lactic acid, and zinc (+superficial scraping)	Daily until ointment sample used; superficial scraping with fingernail once or twice per week	OL	20	Reasonable agreement that some reduction of thickness could be achieved Preference to continue using the product after completion of 6 weeks of therapy: 8.3/10 points	None reported	2
Campione et al. (22)	Solution 42% urea, 6% lactic acid, 5% mandelic acid, 2% salicylic acid, 0.2% thuja, beta-glucan, allantoin, hyaluronic acid, marine collagen, and alpha-bisabolol	Twice daily for thirty days	OL	20	Significant reduction in SK thickness and number, confirmed by epiluminescence microscopy Global Daily Life Quality Index improved by 99.95% 95% excellent tolerability, 5% good tolerability, 0% fair tolerability	Administration-site erythema	2
Chun et al. (24)	65% focal TCA peel weight/volume, unbuffered	One application every 1–2 months (mean 1.5 courses of treatment)	OL	23	Effect of TCA peels: 57% excellent, 26% good, 13% fair, 4% poor 78% satisfaction rate over 70%; 13% satisfaction rate 50–70%; 9% satisfaction rate less than 50%	Moderate stinging (during application)	2
Komalasari et al. (25)	80% TCA solution	Single application	CR	1	Significant improvement, leaving minimal hyperpigmentation macules without alopecia	None reported	5
Lacarrubba et al. (26)	Nitric-zinc oxide solution, organic acids (acetic, lactic, oxalic acid), copper salt, water	Up to four applications, every other week	OL	15	74% complete clinical and dermoscopic clearance, average of three applications (range two-four) at eight weeks 26% partial response with minimal persistent residual spots at eight weeks 0% relapse of cleared lesions at 6-month follow-up, although some cases of minimal hypopigmentation	Transient post-treatment erythema, minimal residual hypopigmentation	2
Tribó et al. (27)	Nitrizinc Complex topical solution	Up to two applications, one application per month	OL	32	At month 6: 71.9% patients (80% lesions) showed complete elimination; 93.3% lesions showed at least 50% reduction Subjective treatment and cosmetic satisfaction: 8.66/10 and 8.07/10, respectively At month 3, 89.3% of the patients had good (no scarring, slight dyschromia) or excellent (no residual scar or pigmentation) outcomes; this ratio reached 100% at month 6	Erythema, hypopigmentation, mild pain/burning/pruritus	2
Feuerman et al. (28)	Solcoderm	Every two weeks until completely healed (mean 1.3 treatments)	OL	36	62.3% total healing of lesion without any remnant; 13.0% total healing of lesion with erythema; 24.6% partial healing of lesion, persistence of crust Erythema no longer seen at the site 15 weeks after treatment	Burning (during application)	2
Klaus et al. (29)	Arm 1: Lac-Hydrin (12% ammonium lactate lotion) Arm 2: Vehicle solution (control)	Twice daily for sixteen weeks	SCT^a	Arm 1: 58 Arm 2: 58	Lac-Hydrin lotion significantly reduced the height (elevation) of SK No significant difference in width of lesions or number of lesions Initially keratotic lesions: 1/45 became flat, 14/45 became smooth, 30/45 remained keratotic Initially smooth lesions: 1/11 became flat, 10/11 remained smooth Initially light brown lesions: 8/40 became skin-colored, 32/40 remained light brown Initially dark brown lesions: 1/5 became light brown, 4/5 remained dark brown	Not documented	1
Cuevas et al. (32)	5% potassium dobesilate cream	Single daily application for six months	CR	1	Complete clearance of the lesions observed at the end of treatment Results maintained at 1 year follow-up visit	None reported	5
Rosen et al. (33)	Ingenol Mebutate 0.05% gel	Once daily for three days	OL	24	15% CCR in SK lesions	Erythema, flaking/scaling, swelling, vesiculation/pustulation	2
Afify and Hana (34)	Arm 1: 1% Diclofenac sodium Arm 2: 10% Ibuprofen, 85% aqueous gel, 5% isopropyl myristate (control)	Twice daily for eight weeks	SCT^a	Arm 1: 30 Arm 2: 30	Arm 1: Statistically significant difference in lesion surface area (p = .001) Mean percent change in lesion surface area: 61.7% ± 17.06% Mean size before treatment: 1.88 ± 1.35 cm2; mean size after treatment: 0.72 ± 0.61 cm^2 after treatment Arm 2: No statistically significant difference in lesion surface area (p = .057).	None reported	1

SCT: self-controlled trial; HP40: 40% hydrogen peroxide solution; RCT: randomized controlled trial; HP45: 45% hydrogen peroxide solution; PLA: Physician Lesion Assessment; SK: seborrheic keratosis; OL: open label; TCA: trichloroacetic acid; CR: case report; HP: hydrogen peroxide; SSA: subject satisfaction assessment; BID: twice daily; CCR: clinical clearance rate; 5-FU: 5% fluorouracil.

^ASee Table 2 for Quality Rating Scheme for Studies and Other Evidence.

^aSelf-controlled study (different lesion on the same patient used for control group).

^bResults combined from two identical studies.

^cContains results from three papers.

Table 2. Quality rating scheme for studies and other evidence.

1 Properly powered and conducted randomized clinical trial; systematic review with meta-analysis

2 Well-designed controlled trial without randomization; prospective comparative cohort trial

3 Case-control studies; retrospective cohort study

4 Case series with or without intervention; cross-sectional study

5 Opinion of respected authorities; case reports

Figure 1. PRISMA flow-diagram of the search process utilized in this review (7). The search strategy conducted with four databases yielded 395 records; 200 duplicate records were excluded before screening. Of the remaining 195 records, title and abstract screening excluded an additional 156 records. 41 full-text reports were sought for retrieval and assessed for eligibility, of which 15 were excluded for various reasons. 26 reports met the inclusion criteria; six randomized controlled trials, four non-randomized controlled trials, ten non-randomized open-label studies, and six case reports were included in the systematic review.

Baumann LS, Blauvelt A, Draelos ZD, et al. Safety and efficacy of hydrogen peroxide topical solution, 40% (w/w), in patients with seborrheic keratoses: Results from 2 identical, randomized, double-blind, placebo-controlled, phase 3 studies (A-101-SEBK-301/302). J Am Acad Dermatol. 2018;79(5):869–877. Article

 PubMed Web of Science ®Google Scholar

DuBois JC, Jarratt M, Beger BB, et al. A-101, a proprietary topical formulation of High-Concentration hydrogen peroxide solution: a randomized, Double-Blind, Vehicle-Controlled, parallel group study of the Dose-Response profile in subjects with seborrheic keratosis of the face. Dermatol Surg. 2018;44(3):330–340.

 PubMed Web of Science ®Google Scholar

DuBois J, Grande K, Bradshaw M, et al. Effectiveness of hydrogen peroxide topical solution 40% and 45% (w/w) in patients with seborrheic keratoses on the trunk, extremities, and face: Results of a phase 2, randomized, double-blind, vehicle-controlled, parallel group study. J Am Acad Dermatol. 2019;81(4):AB197.

 Web of Science ®Google Scholar

DuBois J, Grande K, Bradshaw M, et al. Safety of hydrogen peroxide topical solution 40% and 45% (w/w) in patients with seborrheic keratoses on the trunk, extremities, and face: Results of a phase 2, randomized, double-blind, vehicle-controlled, parallel-group study. J Am Acad Dermatol. 2019;81(4):AB271.

 Web of Science ®Google Scholar

DuBois J, Grande K, Schnyder J, et al. Assessing patient satisfaction with hydrogen peroxide topical solution, 40% (w/w) treatment of seborrheic keratoses on the face, neck, and décolletage: Objectives and design of the phase IV, openlabel SK-FAN study. J Clin Aesthetic Dermatol. 2019;12(5):S32.

 Google Scholar

DuBois J, Grande K, Rhodes T, et al. Assessing patients’ satisfaction with hydrogen peroxide topical solution, 40% for treatment of raised seborrheic keratoses. J Drugs Dermatol. 2020;19(12):1184–1191.

 PubMed Web of Science ®Google Scholar

Callender VD, Frankel EH, Weiss JS, et al. An open-label study of the safety of A-101, a 40% hydrogen peroxide topical solution, in patients with seborrheic keratoses. J Am Acad Dermatol. 2018;79(3):AB39.

 Web of Science ®Google Scholar

Peredo M, Murphy E, Karibayeva D. Clinical experience with 40% hydrogen peroxide topical solution for the treatment of seborrheic keratosis. J Drugs Dermatol. 2019;18(7):s173–s177.

 PubMed Web of Science ®Google Scholar

Schlesinger TE, Favre C. Enhancing outcomes in seborrheic keratosis: using a novel treatment solution. J Drugs Dermatol. 2019;18(7):s178–s182.

 PubMed Web of Science ®Google Scholar

Mitsuhashi Y, Kawaguchi M, Hozumi Y, et al. Topical vitamin D3 is effective in treating senile warts possibly by inducing apoptosis. J Dermatol. 2005;32(6):420–423.

 PubMed Web of Science ®Google Scholar

Yousefi M, Nabaei L, Ghasemnia H, et al. Eficacy of calcipotriol in the treatment of seborrheic keratosis: a pilot study. Iran J Dermatol. 2013;16(66):132–136.

 Google Scholar

Herron MD, Bowen AR, Krueger GG. Seborrheic keratoses: a study comparing the standard cryosurgery with topical calcipotriene, topical tazarotene, and topical imiquimod. Int J Dermatol. 2004;43(4):300–302.

 PubMed Web of Science ®Google Scholar

Sutedja EVA, Suwarsa OKI, Febrina DIA. Comparison of the effectiveness of topical 5-fluorouracil, topical calcipotriol, and cryosurgery in seborrheic keratosis. J Dermatol Nurses’ Assoc. 2020;12(2):85–88.

 Google Scholar

Wijayanti W, Nurdin AR, Widita W, et al. A case of atypical seborrheic keratoses mimicking porokeratosis. Forum Nordic Dermato Venerol. 2020;25(3):1–3.

 Google Scholar

Tsuji T, Morita A. Giant seborrheic keratosis on the frontal scalp treated with topical fluorouracil. J Dermatol. 1995;22(1):74–75.

 PubMedGoogle Scholar

Campione E, Cosio T, Di Prete M, et al. Effectiveness of a cosmetic device containing a combination of alpha- and beta-hydroxy acids, urea, and thuja for the treatment of seborrheic keratoses. J Cosmetic Dermatol. 2022;21(5):2113–2119.

 PubMed Web of Science ®Google Scholar

Burkhart CG, Burkhart CN. Use of a keratolytic agent with occlusion for topical treatment of hyperkeratotic seborrheic keratoses. Skinmed. 2008;7(1):15–18.

 PubMedGoogle Scholar

Chun EY, Lee JB, Lee KH, et al. Focal trichloroacetic acid peel method for benign pigmented lesions in Dark-Skinned patients. Dermatol Surg. 2004;30(4 Pt 1):512–516; discussion 516.

 PubMed Web of Science ®Google Scholar

Komalasari DN, Djawad K, Nurdin AR, et al. Unusual clinical manifestation of seborrheic keratosis on the scalp successfully treated with topical trichloroacetic acid: an atypical case report. Pan Afr Med J. 2020;37:1–6.

 Web of Science ®Google Scholar

Lacarrubba F, Rita Nasca M, Elisa Verzì A, et al. A novel topical agent in the treatment of seborrheic keratoses: an open-label pilot study with clinical and dermoscopic evaluation. J Am Acad Dermatol. 2017;76(6):AB19.

 Web of Science ®Google Scholar

Tribó MJ, Aladren S, Garre A, et al. A novel nitrizinc complex® solution for topical treatment of seborrhoeic keratosis: an interventional clinical study. Eur J Dermatol. 2019;29(2):203–208.

 PubMed Web of Science ®Google Scholar

Feuerman EJ, Katzenelson V, Halevy S. Solcoderm in the treatment of solar and seborrheic keratoses. Dermatologica. 1984;168(SUPPL. 1):33–35.

 PubMedGoogle Scholar

Klaus MV, Wehr RF, Rogers Iii RS, et al. Evaluation of ammonium lactate in the treatment of seborrheic keratoses. J Am Acad Dermatol. 1990;22(2 Pt 1):199–203.

 PubMed Web of Science ®Google Scholar

Cuevas P, Angulo J, Salgüero I, et al. Clearance of seborrhoeic keratoses with topical dobesilate. BMJ Case Reports. 2012;2012(jun21 1):bcr0120125628.

 PubMedGoogle Scholar

Rosen R, Freeman M, Zibert JR, et al. Ingenol mebutate 0 05% gel reduces cancer cells in squamous cell carcinoma in situ and shows marginal effect in seborrhoeic keratosis. Br J Dermatol. 2014;171:50.

 Google Scholar

Afify AA, Hana MR. Comparative evaluation of topical diclofenac sodium versus topical ibuprofen in the treatment of seborrheic keratosis. Dermatol Ther. 2020;33(6):e14370.

 PubMed Web of Science ®Google Scholar

Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Syst Rev. 2021;10(1):89.

 PubMed Web of Science ®Google Scholar