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Consensus on the use of oral isotretinoin in dermatology - Brazilian Society of Dermatology How to cite this article: Bagatin E, Costa CS, Rocha MA, Picosse FR, Kamamoto CS, Pirmez R, et al. Consensus on the use of oral isotretinoin in dermatology - Brazilian Society of Dermatology. An Bras Dermatol. 2020;95(S1):19–38. ,☆☆ ☆☆ Study conducted at the Brazilian Society of Dermatology, Rio de Janeiro, RJ, Brazil.

Abstract

Background:

Isotretinoin is a synthetic retinoid, derived from vitamin A, with multiple mechanisms of action and highly effective in the treatment of acne, despite common adverse events, manageable and dose-dependent. Dose-independent teratogenicity is the most serious. Therefore, off-label prescriptions require strict criteria.

Objective:

To communicate the experience and recommendation of Brazilian dermatologists on oral use of the drug in dermatology.

Methods:

Eight experts from five universities were appointed by the Brazilian Society of Dermatology to develop a consensus on indications for this drug. Through the adapted DELPHI methodology, relevant elements were listed and an extensive analysis of the literature was carried out. The consensus was defined with the approval of at least 70% of the experts.

Results:

With 100% approval from the authors, there was no doubt about the efficacy of oral isotretinoin in the treatment of acne, including as an adjunct in the correction of scars. Common and manageable common adverse events are mucocutaneous in nature. Others, such as growth retardation, abnormal healing, depression, and inflammatory bowel disease have been thoroughly investigated, and there is no evidence of a causal association; they are rare, individual, and should not contraindicate the use of the drug. Regarding unapproved indications, it may represent an option in cases of refractory rosacea, severe seborrheic dermatitis, stabilization of field cancerization with advanced photoaging and, although incipient, frontal fibrosing alopecia. For keratinization disorders, acitretin performs better. In the opinion of the authors, indications for purely esthetic purposes or oil control are not recommended, particularly for women of childbearing age.

Conclusions:

Approved and non-approved indications, efficacy and adverse effects of oral isotretinoin in dermatology were presented and critically evaluated.

Keywords
Acne vulgaris; Dermatitis, seborrheic; Isotretinoin; Rosacea; Vitamin A

Introduction

Oral isotretinoin (13-cis-retinoic acid) is a retinoid, derived from vitamin A. It was synthesized in 1955, but it was only in 1973 that studies on its use in psoriasis, genetic disorders of keratinization, cystic acne, and basal cell carcinoma began. In the 1980s, it became the most effective option for treating nodular-cystic acne, and is currently indicated for moderate forms resistant to other treatments. It was approved for acne in the United States in 1982, in 1983 in Europe, and in 1990 in Brazil, revolutionizing the treatment of severe forms of acne.11 King K, Jones DH, Daltrey DC, Cunliffe WJ. A double-blind study of the effects of 13-cis-retinoic acid on acne, sebum excretion rate and microbial population. Br J Dermatol. 1982;107:583-90.55 Layton A. The use of isotretinoin in acne. Dermatoendocrinol. 2009;1:162-9.

Clinical (mucocutaneous) and laboratory (liver function and lipid profile) side effects are dose-dependent, predictable, manageable and reversible, except for teratogenicity. Acne is the only approved indication, although many off-label uses have been reported.66 Sladden MJ, Harman KE. What is the chance of a normal pregnancy in a woman whose fetus has been exposed to isotretinoin?. Arch Dermatol. 2007;143:1187-8.88 Bagatin E. Oral isotretinoin: the most promising dermatological off-label uses. Exp Rev Dermatol. 2010;5:617-26.

Isotretinoin acts as a prodrug, being converted into all-trans-retinoic acid (ATRA) in the cytoplasm of cells to be transported to the nucleus, where it binds to the nuclear retinoic acid receptor (RAR and RXR), isoforms a, b, and g.99 Balak DMW. Topical trifarotene: a new retinoid. Br J Dermatol. 2018;179:231-2. The known mechanisms of action are normalization of infundibular hyperkeratinization, inhibition of the production of cytokeratins 1, 10, and 14, filaggrin and matrix metalloproteinases (MMPs), and increase of cytokeratins 7, 13, and 19, laminin B1, and IL-1. Effects on proliferation, differentiation, apoptosis, and cell renewal, in addition to immunomodulation, are related to the regulation of gene expression, influencing nuclear transcription factors. There is activation of some genes (tumor suppressors or apoptotic, such as p53 and BAX and coding for collagen and fibronectin production) and inhibition of others (involved in lipid metabolism).1010 Plewig G, Dressel H, Pfleger M, Michelsen S, Kligman AM. Low dose isotretinoin combined with tretinoin is effective to correct abnormalities of acne. J Dtsch Dermatol Ges. 2004;2:31-45.1212 Karadag AS, Ertugrul DT, Bilgili SG, Takci Z, Akin KO, Calka O. Immunoregulatory effects of isotretinoin in patients with acne. Br J Dermatol. 2012;167:433-5. On apoptosis, ATRA increases the expression of the forkhead box O3 transcription factor (FOXO3), activates the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway and produces FOXO1 caspases, interrupting the cell cycle, by expressing the genes p21, 27 and 53.1313 Nelson A, Cong Z, Gilliland KL, Thiboutot D. TRAIL contributes to the apoptotic effect of 13-cis retinoic acid in human sebaceous gland cells. Br J Dermatol. 2011;165:526-33.1616 Melnik BC. Acne vulgaris: an inflammasomopathy of the sebaceous follicle induced by deviated FoxO1/mTORC1 signalling. Br J Dermatol. 2016;174:1186-8. Activation of FOXO1, a negative co-regulator of the androgen receptor, peroxisome proliferator-activated receptor-gamma (PPAR gamma), and liver X receptor-[alpha] sterol response element binding protein-1c (SREBP-1c), reduces lipogenesis. The attenuation of the mechanistic target of rapamycin complex 1 (mTORC1) stimulates the expression of PPAR gamma and SREBP-1c.1616 Melnik BC. Acne vulgaris: an inflammasomopathy of the sebaceous follicle induced by deviated FoxO1/mTORC1 signalling. Br J Dermatol. 2016;174:1186-8. Due to the negative regulation of genes related to insulin-like growth factor 1 (IGF1)/phosphatidylinositol 3-kinase (PI3K)/AKT (protein kinase B)/mTORC1 pathway and positive regulation of those responsible for FOXO1 and FOXO3/TRAIL/caspase pathways, there is suppression of sebogenesis and apoptosis of sebocytes.1616 Melnik BC. Acne vulgaris: an inflammasomopathy of the sebaceous follicle induced by deviated FoxO1/mTORC1 signalling. Br J Dermatol. 2016;174:1186-8.1818 Nelson AM, Gilliland KL, Cong Z, Thiboutot DM. 13-cis Retinoic acid induces apoptosis and cell cycle arrest in human SEB-1 sebocytes. J Invest Dermatol. 2006;126:2178-89. The activation of the p53 pathways represents the interconnection between the signaling pathways regulated positively or negatively by isotretinoin. The BAX protein induces apoptosis of keratinocytes with mutations induced by UV radiation; its expression is reduced by isotretinoin due to its anti-carcinogenic action.1414 Melnik BC. p53: key conductor of all anti-acne therapies. J Transl Med. 2017;15:195. It is the only drug that alone acts on the four etiopathogenic factors of acne: it reduces acroinfundibular hyperkeratinization and comedogenesis; suppresses sebogenesis, by reducing the size and activity of sebaceous glands by up to 90%; decreases the population of Cutibacterium acnes (C. acnes), formerly called Propionibacterium acnes (P. acnes) due to changes in the follicular microenvironment; and modulates inflammation by the negative regulation of toll-like 2 and 4 membrane receptors (TLR-2 and 4) in keratinocytes, sebocytes, monocytes, corneal cells, and immune cells.1818 Nelson AM, Gilliland KL, Cong Z, Thiboutot DM. 13-cis Retinoic acid induces apoptosis and cell cycle arrest in human SEB-1 sebocytes. J Invest Dermatol. 2006;126:2178-89.2222 Schroeder M, Zouboulis CC. All-trans-retinoic acid and 13-cis-retinoic acid: pharmacokinetics and biological activity in different cell culture models of human keratinocytes. Horm Metab Res. 2007;39:136-40. These receptors are activated by identification of the molecular patterns of C. acnes and, when inhibited, there is downregulation of the nuclear factor kappa B (NF-κB) pathways, which triggers the production of cytokines (IL-8, IL-1 β, IL-17, IFNγ) and activator protein 1 (AP-1) responsible for the synthesis of MMPs.1313 Nelson A, Cong Z, Gilliland KL, Thiboutot D. TRAIL contributes to the apoptotic effect of 13-cis retinoic acid in human sebaceous gland cells. Br J Dermatol. 2011;165:526-33.,2020 Dispenza MC, Wolpert EB, Gilliland KL, Dai JP, Cong Z, Nelson AM, et al. Systemic isotretinoin therapy normalizes exaggerated TLR-2-mediated innate immune responses in acne patients. J Invest Dermatol. 2012;132:2198-205. After 40 years, it is believed that not all mechanisms of action on the skin and other organs are elucidated. However, existing knowledge explains the efficacy in acne vulgaris and adverse events, justifying unapproved, off-label indications.2323 Nickle SB, Peterson N, Peterson M. Updated physician's guide to the off-label uses of oral isotretinoin. J Clin Aesthet Dermatol. 2014;7:22-34.2525 Forbat E, Ali FR, Al-Niaimi F. Dermatological indications for the use of isotretinoin beyond acne. J Dermatolog Treat. 2018;29:698-705.

The actions of isotretinoin in different cells, explaining its beneficial effects and adverse events, are summarized in Table 1.

Table 1
Mechanism of action of oral isotretinoin in different cell types

The purpose of this article is to present a consensus on the effects of oral isotretinoin on the skin and its indications for acne and others conditions not yet approved, despite the existence of relevant data in the consulted literature.

Methods

Eight dermatologists, experts in isotretinoin, were nominated to reach a consensus on the use of oral isotretinoin in dermatology, following the adapted DELPHI methodology. In the first phase, relevant topics were discussed and the text was structured, each author responsible for a different topic; in the second phase, a bibliographic review and drafting of the texts was carried out. The databases consulted were as follows: Cochrane Skin Group Specialized Register, Cochrane Library, MEDLINE, PubMed, Embase, and LILACS. The literature in Portuguese, English, and Spanish was searched using the following keywords isotretinoína, aliança terapêutica, dermatologia, acne vulgar, dermatite seborreica, rosácea, psoríase, ceratose actínica, envelhecimento da pele, dermatology, oral isotretinoin, off label use, off label prescribing, acne, skin diseases, rosacea, photoaging of skin, actinic keratosis, seborrheic dermatitis, psoriasis, alopecia. The first author and the mentor were responsible for compiling a single text and sending it for review by the others. In the third phase, both authors assessed the consensus on the texts; what reached 70% consensus remained in the final version.

Results/Discussion

Two topics on oral isotretinoin in dermatology were defined: acne vulgaris and relevant, off-label indications (inflammatory diseases of the skin and scalp, photoaging, and field cancerization). The results and discussion of each topic are presented below.

Acne vulgaris

Isotretinoin is the only drug that acts on all etiopathogenic factors of acne vulgaris, remaining the only monotherapy capable of providing prolonged remission or cure in up to 80% of patients, with one treatment cycle.

Acne vulgaris, a chronic, immune-mediated, multifactorial inflammatory disease that affects the pilosebaceous unit is among the three most prevalent dermatoses worldwide.2626 Hay RJ, Johns NE, Williams HC, Bolliger IW, Dellavalle RP, Margolis DJ, et al. The global burden of skin disease in 2010: an analysis of the prevalence and impact of skin conditions. J Invest Dermatol. 2014;134:1527-34. It can generate physical (scarring) and psychological sequelae, second only to eczema.2727 Karimkhani C, Dellavalle RP, Coffeng LE, Hay RJ, Langan SM, Nsoesie EO, et al. Global skin disease morbidity and mortality: an update from the global burden of disease study 2013. J Am Acad Dermatol. 2015;3:383-91. It affects 80% to 90% of the world population at some stage in life, with a peak prevalence between 16–20 years.2828 Ghodsi ZS, Orawa H, Zouboulis CC. Prevalence, severity, and severity risk factors of acne in high school pupils: a community-based study. J Eur Acad Dermatol Venereol. 2009;129:2136-41.3232 Shen Y, Wang T, Zhou C, Wang X, Tian S, Liu Y, et al. Prevalence of acne vulgaris in Chinese adolescents and adults: a community-based study of 17,345 subjects in six cities. Acta Derm Venereol. 2012;92:40-4. According to a survey among members of the Brazilian Society of Dermatology and other epidemiological studies, acne vulgaris is the leading cause of dermatology consultations.3333 Sociedade Brasileira de Dermatologia, Miot HA, Penna GO, Ramos AM, Penna AM, Schmidt SM, et al. Profile of dermatological consultations in Brazil (2018). An Bras Dermatol. 2018;93:916-28.3535 Wilmer EN, Gustafson CJ, Ahn CS, Davis AS, Feldman SR, Huang WW, et al. Most common dermatologic conditions encountered by dermatologists and nondermatologists. Cutis. 2014;94:285-92.

The clinical effectiveness of oral isotretinoin is superior to other acne treatments, promoting healing or prolonged remission,3636 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;74:945-73. improving quality of life, and reducing psychosocial damage; however, adverse effects are observed in up to 90% of patients.3636 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;74:945-73.3939 Chernyshov PV, Tomas-Aragones L, Manolache L, Svensson A, Marron SE, Evers SA, et al. Which acne treatment has the best influence on health-related quality of life? Literature review by the European Academy of Dermatology and Venereology Task Force on Quality of Life and Patient Oriented Outcomes. J Eur Acad Dermatol Venereol. 2018;32:1410-9. Figs. 1 and 2 illustrate patients treated with oral isotretinoin, with healing of acne and absence of recurrence after two years of follow-up. Some controversies about rare and serious events, particularly depression, suicide, and inflammatory bowel disease (IBD), have not been proven to be causally associated.4040 Costa CS, Bagatin E, Martimbianco AL, Silva EM, LúcioMM, Magin P, et al. Oral isotretinoin for acne. Cochrane Database Syst Rev. 2018;11:CD009435. It was approved for severe acne (conglobata and nodular-cystic), but evidence demonstrated in controlled randomized clinical trials (CRCTs) since 1980, in systematic reviews (SRs), consensuses, and recommendations of dermatology societies allowed to expand the indication for nodular-cystic and moderate papulopustular forms resistant to other treatments, with tendency to scarring, and emotional and social functional impairment.11 King K, Jones DH, Daltrey DC, Cunliffe WJ. A double-blind study of the effects of 13-cis-retinoic acid on acne, sebum excretion rate and microbial population. Br J Dermatol. 1982;107:583-90.,22 Peck GL, Olsen TG, Butkus D, Pandya M, Gross EG, et al. Isotretinoin versus placebo in the treatment of cystic acne. A randomized double-blind study. J Am Acad Dermatol. 1982;6 Pt 2 Suppl:735-45.,3636 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;74:945-73.,3838 Rademaker M, Wishart JM, Birchall NM. Isotretinoin 5mg daily for low-grade adult acne vulgaris – a placebo-controlled, randomized double-blind study. J Eur Acad Dermatol Venereol. 2014;28:747-54.,4040 Costa CS, Bagatin E, Martimbianco AL, Silva EM, LúcioMM, Magin P, et al. Oral isotretinoin for acne. Cochrane Database Syst Rev. 2018;11:CD009435.7474 The Australasian College of Dermatologists. The Australasian College of Dermatologists. Position Statement Isotretinoin for treatmentof acne. Available from: https://www.dermcoll.edu.au/wp-content/uploads/ACD-Position-Statement-isotretinoin-June-2018.pdf [accessed 20.10.19].
https://www.dermcoll.edu.au/wp-content/u...
A single course of the drug leads to cure in two-thirds of patients. Recurrences may take place, but they are milder and manageable with topical treatments.6666 Webster GF, Leyden JJ, Gross JA. Results of a phase III, double-blind, randomized, parallel-group, non-inferiority study evaluating the safety and efficacy of isotretinoin-Lidose in patients with severe recalcitrant nodular acne. J Drugs Dermatol. 2014;13:665-70. Some characteristics of the disease favor recurrence and retreatment.6666 Webster GF, Leyden JJ, Gross JA. Results of a phase III, double-blind, randomized, parallel-group, non-inferiority study evaluating the safety and efficacy of isotretinoin-Lidose in patients with severe recalcitrant nodular acne. J Drugs Dermatol. 2014;13:665-70.,7575 Lehucher-Ceyrac D, de La SP, Chastang C, Morel P. Predictive factors for failure of isotretinoin treatment in acne patients: results from a cohort of 237 patients. Dermatology. 1999;198:278-83.7878 Del Rosso JQ. Face to face with oral isotretinoin: a closer look at the spectrum of therapeutic outcomes and why some patients need repeated courses. J Clin Aesth Dermatol. 2012;5:17-24.

Figure 1
18-year-old teenager, with moderate inflammatory acne on the face and trunk for four years, presenting scars, with a relevant negative impact on quality of life. The patient had been submitted to four cycles of oral cyclin, associated with topical combination of benzoyl peroxide and adapalene, with improvement and recurrence after two to three months. During the last cycle, the clinical picture worsened. The patient was treated with oral isotretinoin, 40 mg/kg/day (0.6 mg/kg/day), with total lesion regression after four months and maintenance for another month (total dose = 100 mg/kg/day) – regimen based on recent publications.7777 Rademaker M. Isotretinoin: dose, duration and relapse. What does 30 years of usage tell us?. Australas J Dermatol. 2013;54.,8080 Leyden JJ, Del Rosso JQ, Baum EW. The use of isotretinoin in the treatment of acne vulgaris: clinical considerations and future directions. J Clin Aesth Dermatol. 2014;7 Suppl:S3-21.8282 Tan J, Boyal S, Desai K, Knezevic S. Oral Isotretinoin: new developments relevant to clinical practice. Dermatol Clin. 2016;34:175-84. Photos before and after treatment with oral isotretinoin. Maintenance treatment with adapalene 0.1% gel, for 12 months. There was no recurrence.

Figure 2
A 22-year-old patient with acne conglobata on the face alone for 15 months. Previously treated with oral antibiotics and topical products (whose names the patient was unable to report), without improvement. Treatment with isotretinoin 20 mg/day (0.3 mg/kg/day) and prednisone 40, 30, 20, and 10 mg/day every seven days was initiated. The duration of treatment, always with the same daily dose, was 18 months (160 mg/kg), until complete resolution of the lesions. A maintenance treatment with benzoyl peroxide 5% was maintained for 12 months. There was no recurrence.

Table 2 presents indications, contraindications, and warnings for use, in addition to the acne characteristics related to the need for retreatment. Despite 31 CRCTs, two SRs concluded that studies with better methodology and less heterogeneous as to the efficacy outcomes are needed, particularly comparative studies between the use of oral isotretinoin and the use of oral antibiotics associated to topical agents (combinations of retinoid and benzoyl peroxide). In addition, studies should include a greater number of participants, mainly females, prepubescents, and patients with trunk involvement; the long-term efficacy outcomes must be assessed, especially the superiority of this drug in terms of cure or prolonged remission of acne.4040 Costa CS, Bagatin E, Martimbianco AL, Silva EM, LúcioMM, Magin P, et al. Oral isotretinoin for acne. Cochrane Database Syst Rev. 2018;11:CD009435.,7070 Vallerand IA, Lewinson RT, Farris MS, Sibley CD, Ramien ML, Bulloch AG, et al. Efficacy and adverse events of oral isotretinoin for acne: a systematic review. Br J Dermatol. 2018;178:76-85.

Table 2
Indications, contraindications, warnings, and characteristics of isotretinoin in the treatment of acne, and conditions related to the need for retreatment

The approved dose in the package insert is 0.5 to 1 mg/kg/day, taken after meals, due to the lipophilic character of the molecule, except for the isotretinoin-lidose variant, not available in Brazil, which can be administered while fasting.6666 Webster GF, Leyden JJ, Gross JA. Results of a phase III, double-blind, randomized, parallel-group, non-inferiority study evaluating the safety and efficacy of isotretinoin-Lidose in patients with severe recalcitrant nodular acne. J Drugs Dermatol. 2014;13:665-70.,7979 Williams HC, Dellavalle RP, Garner S. Acne vulgaris. Lancet. 2012;379:361-72. A CRCT compared the daily dose at two meals vs. single dose; no difference was observed in efficacy, but adverse effects were more frequent with the use of a single dose.6767 Ahmad HM. Analysis of clinical efficacy, side effects, and laboratory changes among patients with acne vulgaris receiving single versus twice daily dose of oral isotretinoin. Dermatol Ther. 2015;28:151-157. However, there is a preference for a single dose, due to greater treatment adherence.7979 Williams HC, Dellavalle RP, Garner S. Acne vulgaris. Lancet. 2012;379:361-72. An SR analyzed CRCT with different daily doses and therapeutic regimens.4040 Costa CS, Bagatin E, Martimbianco AL, Silva EM, LúcioMM, Magin P, et al. Oral isotretinoin for acne. Cochrane Database Syst Rev. 2018;11:CD009435. The effectiveness was greater among groups that received a conventional or low dose (<0.5 mg/kg/day) daily when compared with intermittent use, in monthly pulses or alternate days.5656 Akman A, Durusoy C, Senturk M, Koc CK, Soyturk D, Alpsoy E. Treatment of acne with intermittent and conventional isotretinoin: a randomized, controlled multicenter study. Arch Dermatol Res. 2007;299:467-73.,6262 Lee JW, Yoo KH, Park KY, Han TY, Li K, Sei 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.,6868 Dhaked RD, Meena RS, Maheshwari A, Agarwal US, Purohit S. A randomized comparative trial of two low-dose oral isotretinoin regimens in moderate to severe acne vulgaris. Indian Dermatol Online J. 2016;7:378-85. Mild adverse effects were more frequently observed with daily and continuous use, under low or conventional doses.5555 Kapadia NF, Khalid G, Burhany T, Nakhoda T. Comparative efficacy and safety and efficacy of systemic 13-cis retinoic acid 20mg/day vs. 40mg/day in acne vulgaris. J Pak Assoc Dermatol. 2005;15:238-41.,5656 Akman A, Durusoy C, Senturk M, Koc CK, Soyturk D, Alpsoy E. Treatment of acne with intermittent and conventional isotretinoin: a randomized, controlled multicenter study. Arch Dermatol Res. 2007;299:467-73.,6060 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.,6262 Lee JW, Yoo KH, Park KY, Han TY, Li K, Sei 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.,6868 Dhaked RD, Meena RS, Maheshwari A, Agarwal US, Purohit S. A randomized comparative trial of two low-dose oral isotretinoin regimens in moderate to severe acne vulgaris. Indian Dermatol Online J. 2016;7:378-85. Intermittent use was less effective and is not recommended.3636 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;74:945-73. Recently, studies have shown a tendency toward lower daily doses (0.1–0.5 mg/kg, up to 5 mg) for moderate acne, with a longer duration, up to 18 months, presenting less adverse events, better tolerability, and recurrence rates similar to those observed with conventional dose, maintaining treatment for two to four months after total lesion resolution.3838 Rademaker M, Wishart JM, Birchall NM. Isotretinoin 5mg daily for low-grade adult acne vulgaris – a placebo-controlled, randomized double-blind study. J Eur Acad Dermatol Venereol. 2014;28:747-54.,7171 Nast A, Dréno B, Bettoli V, Mokos ZB, Degitz K, Dressler C, et al. European evidence-based (S3) guideline for the treatment of acne – update 2016 – short version. J EurAcad Dermatol Venereol. 2016;30:1261-8.,8080 Leyden JJ, Del Rosso JQ, Baum EW. The use of isotretinoin in the treatment of acne vulgaris: clinical considerations and future directions. J Clin Aesth Dermatol. 2014;7 Suppl:S3-21.8282 Tan J, Boyal S, Desai K, Knezevic S. Oral Isotretinoin: new developments relevant to clinical practice. Dermatol Clin. 2016;34:175-84. Prolonged duration is necessary in severe cases and in extra-facial involvement.7777 Rademaker M. Isotretinoin: dose, duration and relapse. What does 30 years of usage tell us?. Australas J Dermatol. 2013;54. The approved total dose (120 to 150 mg/kg) is maintained in clinical studies, consensuses, and dermatological practice; however, there has never been a CRCT-based rationale.8181 Borghi A, Mantovani L, Minghetti S, Giari S, Virgili A, Bettoli V, et al. Low-cumulative dose isotretinoin treatment in mild-to-moderate acne: efficacy in achieving stable remission. J EurAcad Dermatol Venereol. 2011;25:1094-8.8484 Tan J, Knezevic S, Boyal S, Waterman B, Janik T. Evaluation of evidence for acne remission with oral isotretinoin cumulative dosing of 120–150mg/kg. J Cutan Med Surg. 2016;20:13-20. Studies with a better methodology have shown that a fixed total dose is not the best reference for the duration of treatment, which must consider individual conditions, regression of the disease, and maintenance for two to four months after total resolution of the lesions.4040 Costa CS, Bagatin E, Martimbianco AL, Silva EM, LúcioMM, Magin P, et al. Oral isotretinoin for acne. Cochrane Database Syst Rev. 2018;11:CD009435.,7171 Nast A, Dréno B, Bettoli V, Mokos ZB, Degitz K, Dressler C, et al. European evidence-based (S3) guideline for the treatment of acne – update 2016 – short version. J EurAcad Dermatol Venereol. 2016;30:1261-8.,7777 Rademaker M. Isotretinoin: dose, duration and relapse. What does 30 years of usage tell us?. Australas J Dermatol. 2013;54.,8181 Borghi A, Mantovani L, Minghetti S, Giari S, Virgili A, Bettoli V, et al. Low-cumulative dose isotretinoin treatment in mild-to-moderate acne: efficacy in achieving stable remission. J EurAcad Dermatol Venereol. 2011;25:1094-8.,8282 Tan J, Boyal S, Desai K, Knezevic S. Oral Isotretinoin: new developments relevant to clinical practice. Dermatol Clin. 2016;34:175-84.,8484 Tan J, Knezevic S, Boyal S, Waterman B, Janik T. Evaluation of evidence for acne remission with oral isotretinoin cumulative dosing of 120–150mg/kg. J Cutan Med Surg. 2016;20:13-20.,8585 Rademaker M. Making sense of the effects of the cumulative dose of isotretinoin in acne vulgaris. Int J Dermatol. 2016;55:518-23.

Dose-dependent mucocutaneous clinical adverse events are common, such as cheilitis, which affects 90–100% of patients, and cutaneous, ocular, and nasal mucosa xerosis. They are manageable with the use of lip lubricants, and ocular and nasal emollients, and they regress with dose reduction or treatment suspension.3636 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;74:945-73. Other rare events include alopecia, pyogenic granuloma, photosensitivity, arthralgia, myalgia, headache, anorexia, insomnia, and irritability.7070 Vallerand IA, Lewinson RT, Farris MS, Sibley CD, Ramien ML, Bulloch AG, et al. Efficacy and adverse events of oral isotretinoin for acne: a systematic review. Br J Dermatol. 2018;178:76-85. The most serious risk is teratogenicity, which is dose-independent.44 Sampaio SAP, Bagatin E. A 65-year experience treating acne, including 26 years with oral isotretinoin. An Bras Dermatol. 2008;83:361-7.,4040 Costa CS, Bagatin E, Martimbianco AL, Silva EM, LúcioMM, Magin P, et al. Oral isotretinoin for acne. Cochrane Database Syst Rev. 2018;11:CD009435. Pregnancy can have a normal course in 65–85% of cases, but there is a risk of miscarriage (10.9–20%) and embryopathies (18–28%), with craniofacial, central nervous system, thymus, and cardiovascular anomalies.44 Sampaio SAP, Bagatin E. A 65-year experience treating acne, including 26 years with oral isotretinoin. An Bras Dermatol. 2008;83:361-7.77 Tkachenko E, Singer S, Sharma P, Barbieri J, Mostaghimi A. US Food and Drug Administration reports of pregnancy and pregnancy-related adverse events associated with isotretinoin. JAMA Dermatol. 2019;155:1175-9. The possibility of pregnancy must be ruled out (by testing and waiting for menstruation); prescription of oral contraceptives or intrauterine devices associated with condoms is mandatory for women of childbearing age, unless hysterectomized.44 Sampaio SAP, Bagatin E. A 65-year experience treating acne, including 26 years with oral isotretinoin. An Bras Dermatol. 2008;83:361-7.,8383 Roche. Roacutan (isotretinoína) Produtos Roche Químicos e Farmacêuticos S.A. Available from: http://www.anvisa.gov.br/datavisa/fila_bula/frmVisualizarBula.asp?pNuTransacao=14365632016&pIdAnexo=3212245 [accessed 20.10.19].
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The measurement of blood chorionic beta-gonadotropin should be requested beforehand and monthly, during treatment. There are no risks for future pregnancies, which are authorized one month after the end of treatment.8383 Roche. Roacutan (isotretinoína) Produtos Roche Químicos e Farmacêuticos S.A. Available from: http://www.anvisa.gov.br/datavisa/fila_bula/frmVisualizarBula.asp?pNuTransacao=14365632016&pIdAnexo=3212245 [accessed 20.10.19].
http://www.anvisa.gov.br/datavisa/fila_b...
,8686 Wiegand UW, Chou RC. Pharmacokinetics of oral isotretinoin. J Am Acad Dermatol. 1998;39 Pt 3:S8-12.

The hypothesis of triggering psychiatric disorders and IBD has caused numerous lawsuits in the United States. However, no CRCT has demonstrated these associations.4040 Costa CS, Bagatin E, Martimbianco AL, Silva EM, LúcioMM, Magin P, et al. Oral isotretinoin for acne. Cochrane Database Syst Rev. 2018;11:CD009435.,7070 Vallerand IA, Lewinson RT, Farris MS, Sibley CD, Ramien ML, Bulloch AG, et al. Efficacy and adverse events of oral isotretinoin for acne: a systematic review. Br J Dermatol. 2018;178:76-85. Qualitative analysis of 14 non-randomized studies on serious adverse events, nine on psychiatric adverse events, and seven on IBD did not demonstrate an increased risk.4040 Costa CS, Bagatin E, Martimbianco AL, Silva EM, LúcioMM, Magin P, et al. Oral isotretinoin for acne. Cochrane Database Syst Rev. 2018;11:CD009435.,8787 Jick SS, Kremers HM, Vasilakis-Scaramozza C. Isotretinoin use and risk of depression, psychotic symptoms, suicide, and attempted suicide. Arch Dermatol. 2000;136:1231-6.9595 Lee SY, Jamal MM, Nguyen ET, Bechtold ML, Nguyen DL. Does exposure to isotretinoin increase the risk for the development of inflammatory bowel disease? A meta-analysis. Eur J Gastroenterol Hepatol. 2016;28:210-6. Two other SR with meta-analysis assessed depression and IBD, and did not detect an increased risk due to exposure to isotretinoin. In contrast, reduced levels of depression have been demonstrated in comparison with topical therapy.9696 Kaymak Y, Taner E, Taner Y. Comparison of depression, anxiety and life quality in acne vulgaris patients who were treated with either isotretinoin or topical agents. Int J Dermatol. 2009;48:41-6.

Acne is related to psychosocial damage, increased risk of depression, and suicide, conditions already present in adolescence.8181 Borghi A, Mantovani L, Minghetti S, Giari S, Virgili A, Bettoli V, et al. Low-cumulative dose isotretinoin treatment in mild-to-moderate acne: efficacy in achieving stable remission. J EurAcad Dermatol Venereol. 2011;25:1094-8.,9797 Halvorsen JA, Stern RS, Dalgard F, Thoresen M, Bjertness E, Lien L. Suicidal ideation, mental health problems, and social impairment are increased in adolescents with acne: a population-based study. J Invest Dermatol. 2011;131:363-70. Some subgroups may be more susceptible to depression and psychosis induced by isotretinoin in an idiosyncratic manner.4040 Costa CS, Bagatin E, Martimbianco AL, Silva EM, LúcioMM, Magin P, et al. Oral isotretinoin for acne. Cochrane Database Syst Rev. 2018;11:CD009435.,9898 Suarez B, Serrano A, Cova Y, Baptista T. Isotretinoin was not associated with depression or anxiety: a twelve-week study. World J Psychiatry. 2016;6:136-42. Personal and/or family history of depression are not contraindications to the use of the drug in low daily doses and monitoring of mood and behavior in the daily routine, with the help of a psychiatrist.8181 Borghi A, Mantovani L, Minghetti S, Giari S, Virgili A, Bettoli V, et al. Low-cumulative dose isotretinoin treatment in mild-to-moderate acne: efficacy in achieving stable remission. J EurAcad Dermatol Venereol. 2011;25:1094-8.

Increased risk of IBD has already been associated with previous use of antibiotics and acne itself.7272 American Academy of Dermatology. Position statement on isotretinoin (Approved by the Board of Directors December 9, 2000; amended by the Board of Directors March 25, 2003, March 11, 2004, November 13, 2010 and February 19, 2018). Available from: https://server.aad.org/Forms/Policies/Uploads/PS/PS-Isotretinoin.pdf [accessed 20.10.19].
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,9191 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.,9999 Margolis DJ, Fanelli M, Hoffstad O, Lewis JD. Potential association between the oral tetracycline class of antimicrobials used to treat acne and inflammatory bowel disease. Am J Gastroenterol. 2010;105:2610-6. Thus, a history of IBD is not a contraindication for isotretinoin.

Acne flares in the first eight weeks of treatment are related to sebocyte apoptosis, antigen release, and intense inflammatory response, being observed in 15–18% of patients, with spontaneous resolution.100100 Borghi A, Mantovani L, Minghetti S, Virgili A, Bettoli V. Acute acne flare following isotretinoin administration: potential protective role of low starting dose. Dermatology. 2009;218:178-80. However, they can mimic fulminant acne, without systemic symptoms, and with intense inflammation, ulceration, scabs, and scars.101101 Greywal T, Zaenglein AL, Baldwin HE, Bhatia N, Chernoff KA, Del Rosso JQ, et al. Evidence-based recommendations for the management of acne fulminans and its variants. J Am Acad Dermatol. 2017;77:109-17. The drug should be kept at a low dose and associated with prednisone, 0.5–1 mg/kg/day for two to four weeks or until resolution. Severe and extensive acne (face, chest, and back), macrocomedones, and family history indicate initiation of treatment with low daily dose (0.1–0.2 mg/kg), associated with prednisone in the first two to four weeks; low dose is maintained for eight weeks and may or may not be increased gradually, along with fractional corticosteroid withdrawal.3636 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;74:945-73.,4242 Thiboutot DM, Dréno B, Abanmi A, Alexis AF, Araviiskais E, Cabal MI, et al. Practical management of acne for clinicians: an international consensus from the Global Alliance to Improve Outcomes in Acne. J Am Acad Dermatol. 2018;78 Suppl 1:S1-23.,100100 Borghi A, Mantovani L, Minghetti S, Virgili A, Bettoli V. Acute acne flare following isotretinoin administration: potential protective role of low starting dose. Dermatology. 2009;218:178-80.102102 Lee YH, Scharnitz TP, Muscat J, Chen A, Grupta-Elera G, Kirby JS. Laboratory monitoring during isotretinoin therapy for acne: a systematic review and meta-analysis. JAMA Dermatol. 2016;152:35-44.

Laboratory alterations correspond to 2% of the detected adverse events.7070 Vallerand IA, Lewinson RT, Farris MS, Sibley CD, Ramien ML, Bulloch AG, et al. Efficacy and adverse events of oral isotretinoin for acne: a systematic review. Br J Dermatol. 2018;178:76-85. The serum dosages most frequently altered, according to SRs and meta-analyses, are as follows: triglycerides (44%), total cholesterol, LDL-cholesterol (33%), and liver enzymes (11%).7070 Vallerand IA, Lewinson RT, Farris MS, Sibley CD, Ramien ML, Bulloch AG, et al. Efficacy and adverse events of oral isotretinoin for acne: a systematic review. Br J Dermatol. 2018;178:76-85.,103103 Barbieri JS, Shin DB, Wang S, Margolis DJ, Takeshita J. The clinical utility of laboratory monitoring during isotretinoin therapy for acne and changes to monitoring practices over time. J Am Acad Dermatol. 2020;82:72-9. There is no evidence that these elevations increase cardiovascular risk.3636 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;74:945-73.,4040 Costa CS, Bagatin E, Martimbianco AL, Silva EM, LúcioMM, Magin P, et al. Oral isotretinoin for acne. Cochrane Database Syst Rev. 2018;11:CD009435. Previous liver and lipid profiles are recommended, repeated after one month and every three months.8383 Roche. Roacutan (isotretinoína) Produtos Roche Químicos e Farmacêuticos S.A. Available from: http://www.anvisa.gov.br/datavisa/fila_bula/frmVisualizarBula.asp?pNuTransacao=14365632016&pIdAnexo=3212245 [accessed 20.10.19].
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Analysis of laboratory monitoring concluded that tests requested less frequently are safe and economical, since changes are rare or discreet and reversible. Thus, a lipid and hepatic profile is recommended at baseline and after two months; subsequently, only the altered exams should be repeated, according to the patient's medical history.102102 Lee YH, Scharnitz TP, Muscat J, Chen A, Grupta-Elera G, Kirby JS. Laboratory monitoring during isotretinoin therapy for acne: a systematic review and meta-analysis. JAMA Dermatol. 2016;152:35-44. Thus, a lipid and hepatic profile is recommended at baseline and after two months; subsequently, only the altered exams should be repeated, according to the patient's medical history.102102 Lee YH, Scharnitz TP, Muscat J, Chen A, Grupta-Elera G, Kirby JS. Laboratory monitoring during isotretinoin therapy for acne: a systematic review and meta-analysis. JAMA Dermatol. 2016;152:35-44. However, some authors and even the Brazilian Unified Health System (Sistema Único de Saúde [SUS]) still recommend frequent monitoring. A very recent study also concluded that the quality of care for patients with acne can be improved by reducing the frequency of assessment of lipids and hepatic function and eliminating the blood count assessment.103103 Barbieri JS, Shin DB, Wang S, Margolis DJ, Takeshita J. The clinical utility of laboratory monitoring during isotretinoin therapy for acne and changes to monitoring practices over time. J Am Acad Dermatol. 2020;82:72-9. The possibility of interference with strength, fatigue, and muscle endurance was investigated and no difference was observed in a study that compared patients with individuals who did not use isotretinoin.104104 Yildizgoren MT, Rifaioglu EN, Demirkapi M, Ekiz T, Mixoogyllari A, Turhanoglu A. Isotretinoin treatment in patients with acne vulgaris: does it impact muscle strength, fatigue, and endurance?. Cutis. 2015;96:33-66. Thus, CPK measurements are only indicated if the patient has severe muscle pain.105105 Kaymak Y. Creatine phosphokinase values during isotretinoin treatment for acne. Int J Dermatol. 2008;47:398-401.

The risk of abnormal scarring with the use of isotretinoin was assessed; five recently published guidelines concluded that there was no evidence to delay superficial cosmetic procedures, biopsies, and dermatological surgeries without involvement of muscle planes (Table 3). A retrospective observational study demonstrated no tendency to hypertrophic scarring and keloid among acne patients who used oral isotretinoin.106106 Guadanhim LR, Gonçalves RG, Bagatin E. Observational retrospective study evaluating the effects of oral isotretinoin in keloids and hypertrophic scars. Int J Dermatol. 2016;55:1255-8. On the contrary, some recent publications have emphasized that the use of lasers is safe, even producing better results in the case of scars, if started in the last month of treatment with isotretinoin.107107 Spring LK, Krakowski AC, Alam M, Bhatia A, Brauer J, Cohen J, et al. Isotretinoin and timing of procedural interventions: a systematic review with consensus recommendations. JAMA Dermatol. 2017;153:802-9.111111 Waldman A, Bolotin D, Arndt KA, Dover JS, Geronemus RG, Chapas A, et al. ASDS Guidelines Task Force: consensus recommendations regarding the safety of lasers, dermabrasion, chemical peels, energy devices, and skin surgery during and after isotretinoin use. Dermatol Surg. 2017;43:1249-62.

Table 3
Dermatological procedures for patients currently using or recently having used oral isotretinoin

Off-label prescriptions

Inflammatory diseases

Rosacea

It is believed that isotretinoin may act on rosacea by modulating innate immunity and reducing the inflammatory response through the negative regulation of TLR-2 expression in keratinocytes. Off-label use is indicated for moderate to severe papule-pustular rosacea, at a low daily dose (0.25–0.3 mg/kg), for four months, with a slow and progressive reduction. Maintenance treatment is mandatory, with topic medication (metronidazole, azelaic acid, or ivermectin), or isotretinoin in microdoses (20 mg/week), with laboratory control and assessment of pregnancy risk.112112 Nikolowski J, Plewig G. Oral treatment of rosacea with 13-cis-retinoic acid. Hautarzt. 1981;32:575-84.126126 Andrade FM, Picosse FR, da Cunha LP, Valente CM, Bezerra FM, Miot HA, et al. Ocular surface changes in the treatment of rosacea: comparison between low-dose oral isotretinoin and doxycycline. Arq Bras Oftalmol. 2020;83:109-12.

The use of oral isotretinoin for severe rosacea was first reported in 1981 in a German study that demonstrated efficacy and longer periods of remission when compared with usual treatments. Daily doses of 0.05 mg/kg, 0.5 mg/kg, or 1 mg/kg were used for 12–28 weeks. There was a 50% regression of inflammatory lesions in two weeks and 95% in eight weeks. Only telangiectasias and chronic conjunctivitis showed little improvement. Remissions were observed for more than 12 months. Side effects were mild cheilitis and a slight increase in triglycerides and cholesterol.112112 Nikolowski J, Plewig G. Oral treatment of rosacea with 13-cis-retinoic acid. Hautarzt. 1981;32:575-84. A multicenter study, including 92 patients, lasting 20 weeks and using the same doses, concluded that isotretinoin is effective in rosacea refractory to previous recommended treatments.113113 Hoting E, Paul E, Plewig G. Treatment of rosacea with isotretinoin. Int J Dermatol. 1986;25:660-3. A CRCT compared isotretinoin, at a dose of 10 mg/day, with 0.025% tretinoin cream or both, for 16 weeks and another 16 weeks of maintenance with tretinoin or placebo cream in severe rosacea, with no differences and no advantage of the association. Adverse events were minimal and well tolerated.114114 Ertl GA, Levine N, Kligman AM. A comparison of the efficacy of topical tretinoin and low-dose oral isotretinoin in rosacea. Arch Dermatol. 1994;130:319-24.

The use of oral isotretinoin in the treatment of rosacea has been reported since the 1980s, in most cases by European and American authors. It is worth mentioning the first publication in Latin America in 1994, by a Chilean author who observed, in a series of six cases treated for three to six months with a dose of 0.5 mg/kg/day, rapid remission of papules and pustules, improvement in ocular manifestations, few side effects, and maintenance of results for approximately 15 months.115115 Gajardo J. Severe rosacea treated with oral isotretinoin. Rev Med Chil. 1994;122:177-9.

A multicenter, double-blinded, randomized study included 573 patients with papule-pustular and phymatous rosacea comparing different doses (0.3; 0.5; 1 mg/kg/day) vs. doxycycline 100 mg/day, 14 days and then 50 mg/day vs. placebo. After 12 weeks, the dose of 0.3 mg/kg/day was more effective than placebo, with efficacy equal to or greater than doxycycline (reduction of 90% vs. 83% of lesions) and fewer side effects.116116 Gollnick H, Blume-Peytavi U, Szabó EL, Meyer KG, Hauptmann P, Popp G, et al. Systemic isotretinoin in the treatment of rosacea – doxycycline- and placebo-controlled, randomized clinical study. J Dtsch Dermatol Ges. 2010;8:505-15.

Another multicenter, randomized study, including 156 patients, compared the dose of 0.25 mg/kg/day (n = 108) vs. placebo (n = 48), for four months. The primary outcome (90% reduction in the number of lesions) was observed in 57% vs. 10% of the patients. Four-month recurrence was observed in 58% of patients. Studies have been suggested to investigate the minimum dose to maintain remission.117117 Sbidian E, Vicaut É, Chidiack H, Anselin E, Cribier B, Dréno B, et al. A randomized-controlled trial of oral low-dose isotretinoin for difficult-to-treat papulopustular rosacea. J Invest Dermatol. 2016;136:1124-9.

To control recurrences, continuous microdoses have been proposed. Twelve patients with recurrent rosacea were treated with 10–20 mg/day for four to six months and subsequently received a maintenance dose of 0.03–0.17 mg/kg/day (mean: 0.07 mg/kg/day) for up to 33 months. There was an improvement in quality of life, suggesting that microdosing would be a better option than multiple cycles of antibiotic therapy.118118 Hofer T. Continuous “microdose” isotretinoin in adult recalcitrante rosacea. Clin Exp Dermatol. 2004;29:204-5. In another study, 25 patients were treated with a dose of 20 mg/day for four months, with rapid reduction of erythema and inflammatory lesions; subsequently, a slow dose reduction was performed for six months, up to 20 mg/week. At 11 months, 45% of cases presented recurrence.119119 Uslu M, Savk E, Karaman G, Sendur N. Rosacea treatment with intermediate-dose isotretinoin: follow-up with erythema and sebum measurements. Acta Derm Venereol. 2012;92:73-7.

Fulminant rosacea is a unique, rare, highly inflammatory form in the center of the face, with an abrupt onset and the presence of papules, pustules, nodules, and sinus tracts draining sero-purulent, coalescent secretion. The treatment of choice is isotretinoin associated with prednisone, 40–60 mg/day. The initial daily dose of 0.2–0.5 mg/kg is recommended, increasing to 0.5–1 mg/kg for three to four months.120120 Walsh RK, Endicott AA, Shinkai K. Diagnosis and treatment of rosacea fulminans: a comprehensive review. Am J Clin Dermatol. 2018;19:79-86.

There are no controlled and randomized studies on the use of oral isotretinoin in phymatous rosacea. A Singapore author reported, in a letter, a reduction in rhinophyma in one patient, after six months of treatment with isotretinoin, 20 mg/day, with a tendency to recurrence after eight months. That author remarked that it is an option to reduce the lesion for later surgical or laser procedures.121121 Wee JS, Tan KB. Phymatous rosacea presenting with leonine facies and clinical response to isotretinoin. Australas J Dermatol. 2017;58:72-3. In the last published SR, it was not possible to include studies on phyma.122122 van Zuuren EJ, Fedorowicz Z, Tan J, van der Linden MMD, Arents BWM, Carter B, et al. Interventions for rosacea based on the phenotype approach: an updated systematic review including GRADE assessments. Br J Dermatol. 2019;181:65-79. By suppressing the sebaceous gland and decreasing sebogenesis, isotretinoin could delay the progression of the phyma when used in the pre-fibrotic phase, with better results in young patients, but recurrence is observed after drug discontinuation.122122 van Zuuren EJ, Fedorowicz Z, Tan J, van der Linden MMD, Arents BWM, Carter B, et al. Interventions for rosacea based on the phenotype approach: an updated systematic review including GRADE assessments. Br J Dermatol. 2019;181:65-79.,123123 Korting HC, Schöllmann C. Current topical and systemic approaches to treatment of rosacea. J Eur Acad Dermatol Venereol. 2009;23:876-82. The global consensus panel, ROSaceaCOnsensus (ROSCO), indicates isotretinoin as a therapeutic option in the severe inflammatory (papulopustular) form and in inflamed phyma, in an early stage, with a high degree of recommendation.124124 Schaller M, Almeida LMC, Bewley A, Cribier B, Dlova NC, Kautz G, et al. Rosacea treatment update: recommendations from the global ROSaceaCOnsensus (ROSCO) panel. Br J Dermatol. 2017;176:465-71.

Regarding ocular rosacea, a review article indicated the benefit and safety of isotretinoin.125125 Webster G, Schaller M. Ocular rosacea: a dermatologic perspective. J Am Acad Dermatol. 2013;69 Suppl 1:S42-3. A recent comparative study with doxycycline, published by Brazilian ophthalmologists and dermatologists, showed that although doxycycline was more effective, isotretinoin, at a dose of 10 mg/day, also improved blepharitis and conjunctivitis, without adverse events.126126 Andrade FM, Picosse FR, da Cunha LP, Valente CM, Bezerra FM, Miot HA, et al. Ocular surface changes in the treatment of rosacea: comparison between low-dose oral isotretinoin and doxycycline. Arq Bras Oftalmol. 2020;83:109-12.

An SR, using the Cochrane methodology, concluded that isotretinoin has a high degree of recommendation for moderate to severe papular-pustular rosacea, relapsing cases or those unresponsive to antibiotic therapy, and for inflamed phymas. The dose of 0.25 mg/kg/day for 12–16 weeks is greater than that of doxycycline, 50–100 mg/day. Topical maintenance is always recommended.122122 van Zuuren EJ, Fedorowicz Z, Tan J, van der Linden MMD, Arents BWM, Carter B, et al. Interventions for rosacea based on the phenotype approach: an updated systematic review including GRADE assessments. Br J Dermatol. 2019;181:65-79.

The Ibero-Latin American Rosacea Studies Group has published a treatment algorithm including low daily dose isotretinoin for the papule-pustular and hyperplastic/phymatous gland subtypes.127127 Grupo Ibero-Latinoamericano de Estudio de la Rosácea (GILER) - CILAD, Kaminsky A, Flórez White M, Piquero MartínJ, Herane MI, Medina JCD, et al. Informe de Consenso Ibero-Latinoamericano 2016 sobre la clasificación clínica y terapéutica de la rosácea: report of the 2016 Ibero-Latin-American Consensus about clinical and therapeutic classification of rosacea. Med CutanIber Lat Am. 2016;44:6-10. A Canadian guideline presented the same recommendation.128128 Asai Y, Tan J, Baibergenova A, Barankin B, Cochrane CL, Humphrey S, et al. Canadian clinical practice guidelines for rosacea. J Cutan Med Surg. 2016;20:432-45. A review article highlights the excellent results of this drug for rosacea and recommends that dermatologists consider this option, since its safety has been determined after more than 30 years of use, reducing the use of oral antibiotics for chronic disease.129129 Watson KD, Miest RY, Tollefson MM. Isotretinoin for acne and rosacea. Semin Cutan Med Surg. 2016;35:79-86.,130130 Del Rosso JQ, Tanghetti E, Webster G, Gold LS, Thiboutot D, Gallo RL, et al. Update on the management of rosacea from the American Acne & Rosacea Society (AARS). J Clin Aesthet Dermatol. 2019;12:17-24. The American Society of Acne and Rosacea, in its consensus, suggests isotretinoin for diffuse mid-facial erythema with papules and pustules, granulomatous rosacea, and early phyma.131131 Brzezinski P, Borowska K, Chiriac A, Smigielski J. Systemic isotretinoin treatment and pregnancy: a comparative study of two groups of women: a retrospective analysis of 569 women. Our Dermatol Online. 2017;9(4e):e2. A low dose is effective, with fewer side effects and good adherence. There is a need for clinical and laboratory control and attention to teratogenicity.132132 Aksoy B, Altaykan-Hapa A, Egemen D, Karagoz F, Atakan N, et al. The impact of rosacea on quality of life: effects of demographic and clinical characteristics and various treatment modalities. Br J Dermatol. 2010;163:719-25. As it affects the face, rosacea has a negative impact on quality of life and its control provides benefits in patients’ emotional, social, and professional lives.133133 Sanders MGH, Pardo LM, Franco OH, Ginger RS, Njisten T, et al. Prevalence and determinants of seborrhoeic dermatitis in a middle-aged and elderly population: the Rotterdam Study. Br J Dermatol. 2018;178:148-53.

Seborrheic dermatitis (SD)

SD is a chronic, recurrent inflammatory dermatosis, located in areas of high concentration of sebaceous glands: face (88%), retroauricular region, scalp (70%), anterior chest (27%), lower limbs (2%), upper limbs (1%), and flexures (5%).133133 Sanders MGH, Pardo LM, Franco OH, Ginger RS, Njisten T, et al. Prevalence and determinants of seborrhoeic dermatitis in a middle-aged and elderly population: the Rotterdam Study. Br J Dermatol. 2018;178:148-53.

Despite little knowledge about its etiopathogenesis, it is admitted that the efficacy of isotretinoin in SD is explained by the sebo-suppressive action and modulation of innate immunity and inflammatory response, i.e., downregulation of TLR-2 and the NF-κB pathway, with reduction in cytokine production. In SD, TLR-2 is activated by lipophilic fungi of the genus Malassezia, in adults and Candida spp. in infants, present in the normal skin microbiota,134134 Ionescu MA, Baroni A, Brambilla L, Cannavò SP, Cristaudo A, Vedove CD, et al. Double blind clinical trial in a series of 115 patients with seborrheic dermatitis: prevention of relapses using a topical modulator of Toll like receptor 2. G Ital Dermatol Venereol. 2011;146:185-9.,135135 Tanaka A, Cho O, Saito C, Saito M, Tsuboi R, Sugita T. Comprehensive pyrosequencing analysis of the bacterial microbiota of the skin of patients with seborrheic dermatitis. Microbiol Immunol. 2016;60:521-6. explaining the option of topical treatment of SD with antifungals.136136 Alizadeh N, Monadi Nori H, Golchi J, Eshkevari SS, Kazemnejad E, Darjani A. Comparison the efficacy of fluconazole and terbinafine in patients with moderate to severe seborrheic dermatitis. Dermatol Res Pract. 2014;2014:705402. Topical immunomodulators and corticosteroids are also used137137 Gupta AK, Versteeg SG. Topical treatment of facial seborrheic dermatitis: a systematic review. Am J Clin Dermatol. 2017;18:193-213.; in extensive conditions resistant to topical treatment, systemic treatment with corticosteroids or isotretinoin may be necessary. This drug is a second-line treatment, used in clinical practice, but there is no definition of dose and duration of treatment. The need for laboratory control and pregnancy prevention is emphasized.138138 Borda LJ, Perper M, Keri JE. Treatment of seborrheic dermatitis: a comprehensive review. J Dermatolog Treat. 2019;30:158-69.

The first report of successful use of isotretinoin in SD, in a low daily dose, was published in Germany in 2003.139139 Geissler SE, Michelsen S, Plewig G. Very low dose isotretinoin is effective in controlling seborrhea. J Dtsch Dermatol Ges. 2003;1:952-8. Subsequently, a 14-year-old adolescent with pityriasis versicolor (PV) on the back and severe acne was treated with 40 mg of isotretinoin, twice daily (1 mg/kg/day) for five months. Clinical and mycological cure of PV was observed, suggesting a role against Malassezia directly or by reducing the skin's lipid content due to the xerosis caused by the drug, interfering with the microbiota's conditions, since this fungus is lipophilic.140140 Bartell H, Ransdell BL, Ali A. Tinea versicolor clearance with oral isotretinoin therapy. J Drugs Dermatol. 2006;5:74-5.

A patient with severe facial SD for 22 years was treated with isotretinoin, 0.3 mg/kg/day, with improvement after 30 days; the dose was reduced to 0.15 mg/kg, every other day for two months, with complete remission.141141 Gualtieri B, Panduri S, Chiricozzi A, Romanelli M. Improvement of severe facial seborrheic dermatitis following low-dose isotretinoin therapy. G Ital Dermatol Venereol. 2018 [Online ahead of print]. In 2017, a review of 46 cases, 40 associated with acne, 57% women, mean age 26 years, with non-responsive SD, treated with doses of 0.05–0.51 mg/kg/day (mean: 33 weeks), associated with topical ketoconazole and hydrocortisone, showed total regression or excellent response in 89% of the cases; one patient presented no improvement.142142 Rademaker M. Low-dose isotretinoin for seborrhoeic dermatitis. J Cutan Med Surg. 2017;21:170-1. A study that compared 10 mg/day, on alternate days, with salicylic acid and piroctone olamine topical treatment (shampoo and soap) for six months, in parallel groups, observed a reduction in the clinical score in both groups; however, this reduction was greater in the isotretinoin group, with reduction in the rate of sebaceous secretion and no effect on the quantity and species of Malassezia.143143 Kamamoto CSL, Sanudo A, Hassun KM, Bagatin E. Low-dose oral isotretinoin for moderate to severe seborrhea and seborrheic dermatitis: a randomized comparative trial. Int J Dermatol. 2017;56:80-5.,144144 Kamamoto CSL, Nishikaku AS, Gompertz OF, Melo AS, Hassun KM, Bagatin E. Cutaneous fungal microbiome: Malassezia yeasts in seborrheic dermatitis scalp in a randomized, comparative and therapeutic trial. Dermatoendocrinol. 2017;9:e1361573. The role of Malassezia in the pathogenesis of SD remains controversial.

Psoriasis

Isotretinoin, as well as etretinate and acitretin, act in the control of psoriasis by converting keratinocytes in the cytoplasm into all-trans retinoic acid, which penetrates the nucleus, binds to nuclear receptors, and activates specific regions of DNA, involved in regulating growth and cell differentiation and apoptosis. Thus, it reduces the hyperproliferation of keratinocytes, which is one of the events involved in the pathogenesis of psoriasis.2424 Khalil S, Bardawil T, Stephan C, Darwiche N, Abbas O, Ghani A, et al. Retinoids: a journey from the molecular structures and mechanisms of action to clinical uses in dermatology and adverse effects. J Dermatolog Treat. 2017;28:684-96.

The report of four cases of extensive psoriasis in women treated with 0.6 mg/kg/day of isotretinoin associated with phototherapy, with oral 8-methoxypsoralen and exposure to UVA (PUVA), showed reduction in the number of PUVA sessions.145145 Anstey A, Hawk JL. Isotretinoin-PUVA in women with psoriasis. Br J Dermatol. 1997;136:798-9. Two randomized clinical studies described the benefit of this drug, at a dose of 0.5 mg/kg/day, associated with narrowband ultraviolet B (NB-UVB) or PUVA, for disseminated plaque psoriasis, reducing the number of phototherapy sessions. The option for isotretinoin is due to the shorter period of contraception, due to its shorter half-life in relation to etretinate or acitretin.146146 Mortazavi H, Khezri S, Hosseini H, Khezri F, Vasigh M. A single blind randomized clinical study: the efficacy of isotretinoin plus narrow band ultraviolet B in the treatment of psoriasis vulgaris. Photodermatol Photoimmunol Photomed. 2011;27:159-61.,147147 Gahalaut P, Soodan PS, Mishra N, Rastogi MK, Soodan HS, Chauhan S. Clinical efficacy of psoralen+sunlight vs. combination of isotretinoin and psoralen+sunlight for the treatment of chronic plaque-type psoriasis vulgaris: a randomized hospital-based study. Photodermatol Photoimmunol Photomed. 2014;30:294-301. For the same reason, isotretinoin was used, with excellent results, in a female teenager with generalized pustular psoriasis at a dose of 1.0 mg/kg/day and in two other adult patients at doses of 1.5–2.0 mg/kg/day, for four months.148148 Al-Shobaili H, Al-Khenaizan S. Childhood generalized pustular psoriasis: successful treatment with isotretinoin. Pediatr Dermatol. 2007;24:563-4.,149149 Wilken R, Sharma A, Patel F, Maverakis E. Successful treatment of palmoplantar pustulosis with isotretinoin. Dermatol Online J. 2015;21, 13030/qt4b4776gb. In a recent SR on the treatment of palmoplantar pustulosis, it was not possible to demonstrate evidence for any treatment, except for potent or systemic topical corticosteroids.150150 Obeid G, Kirby L, Hughes C, Sbidian E, Le Cleah L. Interventions for chronic palmoplantar pustulosis. Cochrane Database Syst Rev. 2020;1:CD011628.

Other systemic treatment options for psoriasis are available, such as methotrexate, cyclosporine, and a large number of immunobiologicals. Retinoid monotherapy has limited efficacy, but can be useful when combined with corticosteroids in pustular psoriasis and phototherapy in HIV-positive individuals, as it has no immunosuppressive effect.151151 Arnone M, Takahashi MDF, Carvalho AVE, Bernardo WM, Bressan AL, Ramos AMC, et al. Plaque psoriasis diagnostic and treatment guidelines. An Bras Dermatol. 2019;94:S76-107.

Hidradenitis suppurativa (HS)

Isotretinoin in HS is not the treatment of choice; effectiveness is variable and can be explained by anti-inflammatory actions (TLR-2 modulation), and reduced expression of genes related to keratinocyte hyperproliferation.2424 Khalil S, Bardawil T, Stephan C, Darwiche N, Abbas O, Ghani A, et al. Retinoids: a journey from the molecular structures and mechanisms of action to clinical uses in dermatology and adverse effects. J Dermatolog Treat. 2017;28:684-96.

HS is a chronic inflammatory disease, difficult to treat, with a negative impact on quality of life, with nodules, fistulas, abscesses, and scars. Deep excision of the lesions is the curative treatment. The use of isotretinoin, alone or in association with other treatments, has been mentioned in the literature, with variable results, in the most severe forms, as an option to reduce lesions and facilitate surgery later.152152 Jørgensen AR, Thomsen SF, Ring HC. Isotretinoin and hidradenitis suppurativa. Clin Exp Dermatol. 2019;44:e155-6. In a retrospective study including 209 patients, 39 treated with isotretinoin, at a dose of 0.5–1.2 mg/kg/day, for four to 12 months, 14 (36%) patients presented improvement, with benefit for performing surgery.153153 McPhie ML, Bridgman AC, Kirchhof MG. Combination therapies for hidradenitis suppurativa: a retrospective chart review of 31 patients. J Cutan Med Surg. 2019;23:270-6. Another recent study assessed drug combinations for HS in 31 patients and demonstrated the benefit of isotretinoin associated with spironolactone, in milder, initial cases, an ideal time to introduce treatment and prevent disease progression.154154 Patel N, McKenzie SA, Harview CL, Truong AK, Shi VY, Chen L, et al. Isotretinoin in the treatment of hidradenitis suppurativa: a retrospective study. J Dermatolog Treat. 2019;:1-3.

Photoaging

Oral isotretinoin can improve the clinical, histological, and molecular characteristics of photodamage in the skin, possibly due to its conversion to all-trans retinoic acid or tretinoin.2424 Khalil S, Bardawil T, Stephan C, Darwiche N, Abbas O, Ghani A, et al. Retinoids: a journey from the molecular structures and mechanisms of action to clinical uses in dermatology and adverse effects. J Dermatolog Treat. 2017;28:684-96. Topical use of tretinoin is the treatment of choice, with the highest level of evidence for moderate to severe photoaging.155155 Kircik LH. Histologic improvement in photodamage after 12 months of treatment with tretinoin emollient cream (0,02%). J Drugs Dermatol. 2012;11:1036-40.157157 Bouloc A, Vergnanini AL, Issa MCJ. A double-blind randomized study comparing the association of retinol and LR2412 with tretinoin 0.025% in photoaged skin. Cosmet Dermatol. 2015;14:40-6. Its mechanisms of action are as follows: reversal of mutations in the p53 gene, reduced MMPs, increased tissue inhibition of metalloproteinase (TIMPs), and reduced loss and accelerated recovery of nuclear retinoid receptors after exposure to UV radiation.2424 Khalil S, Bardawil T, Stephan C, Darwiche N, Abbas O, Ghani A, et al. Retinoids: a journey from the molecular structures and mechanisms of action to clinical uses in dermatology and adverse effects. J Dermatolog Treat. 2017;28:684-96.,158158 Gericke J, Ittensohn J, Mihály J, Alvarez S, Alvarez R, Töröcsik D, et al. Regulation of retinoid-mediated signaling involved in skin homeostasis by RAR and RXR agonists/antagonists in mouse skin. PLoS One. 2013;8:e62643.

Regarding its use in photoaging, an author from El Salvador reported, for the first time, his experience on the use of isotretinoin as an adjunct to cosmetic procedures. Despite being randomized, the study was open and uncontrolled, including 120 patients. The dose was 10 or 20 mg/day, without reference to the criterion used, three times a week, for only two months, in a group of patients undergoing varied procedures (chemical peels, botulinum toxin, collagen filling, blepharoplasty, liposuction, fat graft, facelift), without explaining whether the use was previous or concomitant. The clinical outcomes, which are difficult to assess, were as follows: pore size, pigmentation, wrinkles, thickness, elasticity, and skin color. The results were compared to those of the group that did not receive the drug and were considered better with the association.159159 Hernandez-Perez E, Khawaja HA, Alvarez TY. Oral isotretinoin as part of the treatment of cutaneous aging. Dermatol Surg. 2000;26:649-52. Another five studies were published by Brazilian authors (details in Table 4).160160 Kalil CL, Fachinello FZ, Lamb FM, Comunello LN. Use of oral isotretinoin inphotoaging therapy. Skinmed. 2008;7:10-4.164164 Bravo BS, Azulay DR, Luiz RR, Mandarim-de-Lacerda, Cuzzi T, Azulay MM. Oral isotretinoin in photoaging: objective histological evidence of efficacy and durability. An Bras Dermatol. 2015;90:479-86. One of them, which included 188 patients, only compared the clinical and histological effects of doses of 10 or 20 mg, on alternate days for two to six months, and found no differences.161161 Rabello-Fonseca RM, Azulay DR, Luiz RR, Mandarim-de-Lacerda CA, Cuzzi T, Manela-Azulay M. Oral isotretinoin in photoaging: clinical and histopathological evidence of efficacy of an off-label indication. J Eur Acad Dermatol Venereol. 2009;23:115-23. The two randomized studies used isotretinoin, at a dose of 20 mg, on alternate days, for three and six months, and were compared to the use of only photoprotector and moisturizer or topical tretinoin, respectively. In both cases, there was no superiority of isotretinoin in terms of clinical, histological, and immunohistochemical outcomes, except for the expression of the epidermal p53 protein, which had a significant reduction with the use of the evaluated oral drug. As for safety, no adverse clinical or laboratory events were observed, except for mild cheilitis and xerosis.162162 Bagatin E, Parada MO, Miot HA, Hassun KM, Michalany B, Talarico S. A randomized controlled trial about the use of oral isotretinoin for photoaging. Int J Dermatol. 2010;49:207-14.,163163 Bagatin E, Guadanhim LR, Enokihara MM, Sanudo A, Talarico S, Miot HA, et al. Low-dose oral isotretinoin versus topical retinoic acid for photoaging: a randomized, comparative study. Int J Dermatol. 2014;53:114-22.

Table 4
Details of the six studies on oral isotretinoin for skin aging

Field cancerization – multiple actinic keratoses

The concept of field cancerization is old, and was based on histopathological studies of multifocal neoplasms of the oral mucosa that can coalesce, relapse, and develop new lesions. It was later extended to the skin, where UV radiation causes mutations in the p53 gene, resulting in multiple actinic keratoses and non-melanoma skin cancer.164164 Bravo BS, Azulay DR, Luiz RR, Mandarim-de-Lacerda, Cuzzi T, Azulay MM. Oral isotretinoin in photoaging: objective histological evidence of efficacy and durability. An Bras Dermatol. 2015;90:479-86.167167 Philipp-Dormston WG. Field cancerization: from molecular basis to selective field-directed management of actinic keratosis. Curr Probl Dermatol. 2015;46:115-21.

Oral isotretinoin improves the clinical, histological, and immunohistochemical parameters of field cancerization, notably reducing the epidermal p53 protein.162162 Bagatin E, Parada MO, Miot HA, Hassun KM, Michalany B, Talarico S. A randomized controlled trial about the use of oral isotretinoin for photoaging. Int J Dermatol. 2010;49:207-14.,163163 Bagatin E, Guadanhim LR, Enokihara MM, Sanudo A, Talarico S, Miot HA, et al. Low-dose oral isotretinoin versus topical retinoic acid for photoaging: a randomized, comparative study. Int J Dermatol. 2014;53:114-22.

The mechanism of action of retinoids in the prevention and treatment of non-melanoma skin cancer is not fully understood. They are known to have antiproliferative and anti-apoptotic actions, regulate keratinocyte differentiation and apoptosis, interfere with tumor initiation, reduce regulation of proto-oncogenes, and alter the expression of p53 and pro-apoptotic caspases.168168 Wright TI, Spencer JM, Flowers FP. Chemoprevention of non-melanoma skin cancer. J Am Acad Dermatol. 2006;54:933-46.170170 Cheepala SB, Yin W, Syed Z, Gill JN, McMillian A, Kleiner HE, et al. Identification of the B-Raf/Mek/Erk MAP kinase pathway as a target for all-trans retinoic acid during skin cancer promotion. Mol Cancer. 2009;8:27. They work by preventing the proliferation of human papillomavirus (HPV), a known co-carcinogen.171171 Troyanova-Slavkova S, Eickenscheidt L, Pönnighaus JM, Kowalzick L. Low-dose prophylactic oral isotretinoin treatment for 18 years in a patient with epidermodysplasia verruciformis and numerous squamous cell carcinomas. Hautarzt. 2018;69:1033-8.

Studies involving oral retinoids have focused on the prevention and treatment of non-melanoma skin tumors that are only part of the cancerization process. Details of the studies that used it for treatment are presented in Table 5.172172 Feldman RJ, Maize JC. Multiple keratoacanthomas in a young woman: report of a case emphasizing medical management and a review of the spectrum of multiple keratoacanthomas. Int J Dermatol. 2007;46:77-9.175175 Lippman SM, Meyskens FL. Treatment of advanced squamous cell carcinoma of the skin with isotretinoin. Ann Intern Med. 1987;107:499-502.

Table 5
Studies involving oral isotretinoin, non-melanoma skin cancer, actinic keratoses, and field cancerization

The reported indications for prevention include: multiple non-melanoma skin cancers (> 5 per year); multiple actinic keratoses (AKs); eruptive keratoacanthomas or occurring in transplanted and/or immunosuppressed patients, xeroderma pigmentosum, exposure to chronic phototherapy, and verruciform epidermodysplasia.171171 Troyanova-Slavkova S, Eickenscheidt L, Pönnighaus JM, Kowalzick L. Low-dose prophylactic oral isotretinoin treatment for 18 years in a patient with epidermodysplasia verruciformis and numerous squamous cell carcinomas. Hautarzt. 2018;69:1033-8.,176176 DiGiovanna JJ. Retinoid chemoprevention in the high-risk patient. J Am Acad Dermatol. 1998;39 Pt 3:S82-5.183183 Moshell AN. Prevention of skin cancer in xeroderma pigmentosum with oral isotretinoin. Cutis. 1989;43:485-90.

Little is known about the use of retinoids in multiple AKs and field cancerization in immunocompetent or immunodepressed patients, at risk of developing non-melanoma skin cancer. The delimitation of field cancerization and the methodology to evaluate the effectiveness of therapies for its control is challenging. The most used method is treatment in a restricted, well-defined area, and counting of AKs with primary resolution. The recommended doses range from 0.25 to 6 mg/kg/day, lasting from months to years.184184 Figueras NI, Cerio R, Dirschka T, Dréno B, Lear JT, Pellacani G, et al. Defining the actinic keratosis field: a literature review and discussion. J Eur Acad Dermatol Venereol. 2018;32:544-63.,185185 Ianhez M. Skin field cancerization – an in vivo model to prevent nonmelanoma skin cancer: expanding the alternatives for treatment Commentary. Br J Dermatol. 2018;179:1026-7.

Considering that AKs are early signs of field cancerization and studies on oral retinoids are scarce,186186 Ianhez M, Fleury LF Jr, Miot HA, Bagatin E. Retinoids for prevention and treatment of actinic keratosis. An Bras Dermatol. 2013;88:585-93.188188 Stockfleth E. The importance of treating the field in actinic keratosis. J Eur Acad Dermatol Venereol. 2017;31:8-11. the present authors highlight the most recent study with oral isotretinoin, 10 mg/day vs. 0.05% cream tretinoin, on alternate nights. The results were similar, with a 28% decrease in the number of new AKs, after destruction of all visible AKs with cryotherapy. An improvement was observed in the immunohistochemical parameters with reduced expression of epidermal p53 and BAX proteins. The genes that encode these proteins undergo mutations induced by UV radiation, and start to act as tumor inducers instead of inducing apoptosis of keratinocytes, which were also mutated as a protective mechanism against carcinogenesis.189189 Ianhez M, Pinto SA, Miot HA, Bagatin E. A randomized, open, controlled trial of tretinoin 0.05% cream vs. low-dose oral isotretinoin for the treatment of field cancerization. Int J Dermatol. 2019;58:365-73.

Acitretin is mostly used in immunocompromised individuals, while isotretinoin is preferred for immunocompetent patients and women with the potential to become pregnant, due to its shorter half-life. Low doses are less effective to justify its use in the treatment of non-melanoma skin cancer. However, for prevention in high-risk patients, high doses and long-term treatment should be discouraged, due to the risk of adverse events; low doses are justified to stabilize field cancerization.190190 Levine N, Moon TE, Cartmel B, Bangert JL, Rodney S, Dong Q, et al. Trial of retinol and isotretinoin in skin cancer prevention: a randomized, double-blind, controlled trial. Southwest Skin Cancer Prevention Study Group. Cancer Epidemiol Biomarkers Prev. 1997;6:957-61.192192 Otley CC, Stasko T, Tope WD, Lebwohl M. Chemoprevention of nonmelanoma skin cancer with systemic retinoids: practical dosing and management of adverse effects. Dermatol Surg. 2006;32:562-8.

Hair and scalp diseases

Frontal fibrosing alopecia (FFA)

FFA is characterized by the retreat of the line of hair implantation and loss of eyebrows and, at times, body hair, and also by facial papules, red glabellar spots, depression of the frontal veins, and association with lichen planus pigmentosus.193193 Miteva M, Camacho I, Romanelli P. TostiA. Acute hair loss on the limbs in frontal fibrosing alopecia: a clinicopathological study of two cases. Br J Dermatol. 2010;163:426-8.196196 Vañó-Galván S, Rodrigues-Barata AR, Urech M, Jiménez-Gómez N, Saceda-Corralo D, Poli J, et al. Depression of the frontal veins: a new clinical sign of frontal fibrosing alopecia. J Am Acad Dermatol. 2015;72:1087-8. It is an epidemic, since in two decades it is no more a “recently described” disease and has become the most common scarring alopecia, according to a multicenter study.197197 Pirmez R, Duque-Estrada B, Donati A, Campos-do-Carmo G, Valente NS, Romiti R, et al. Clinical and dermoscopic features of lichen planus pigmentosus in 37 patients with frontal fibrosing alopecia. Br J Dermatol. 2016;175:1387-90.

A retrospective study compared isotretinoin 20 mg/day (n = 29), acitretin 20 mg/day (n = 11), and finasteride 5 mg/day (n = 14), for an average of 13.5 months. The objectives of not increasing the distance between the glabella and the hair line after 12 months and maintaining the results after one year of treatment were achieved in 76% and 73% vs. 72% and 73% of patients treated with isotretinoin and acitretin, respectively, and in 43% of those treated with finasteride.198198 Vañó-Galván S, Saceda-Corralo D, Blume-Peytavi U, Cucchía J, Dlova NC, Dias MF, et al. Frequency of the types of alopecia at twenty-two specialist hair clinics: a multicenter study. Skin Appendage Disord. 2019;5:309-15. Another retrospective study included 291 patients with lichen planus pilar, of whom 26 had FFA. Of these, seven were treated with isotretinoin, 20 mg/day and four with isotretinoin associated with finasteride or dutasteride. Six had a complete response with isotretinoin, as well as the four who received the combined treatment. All patients used topical tacrolimus and clobetasol concomitantly. The response was assessed by clinical photos, perifollicular scaling, and papules, without any objective method.199199 Rakowska A, Gradzińska A, Olszewska M, Rudnicka L. Efficacy of isotretinoin and acitretin in treatment of frontal fibrosing alopecia: retrospective analysis of 54 cases. J Drugs Dermatol. 2017;16:988-92. In three patients treated with isotretinoin 20 mg/day in the first month and 0.5 mg/kg/day in the second and third months, the facial papules improved and regressed after 15 days. However, signs of disease activity, erythema, and perifollicular scaling remained.200200 Babahosseini H, Tavakolpour S, Mahmoudi HA, Baligh K, Teimourpour A, Seyede-Zahra G, et al. Lichen planopilaris: retrospective study on the characteristics and treatment of 291 patients. J Dermatolog Treat. 2019;30:598-604. A later study reported reduction of facial papules after two to four months with isotretinoin, 10 mg every other day, in ten patients.201201 Pirmez R, Duque-Estrada B, Barreto T, Quintella DC, Cuzzi T. Successful treatment of facial papules in frontal fibrosing alopecia with oral isotretinoin. Skin Appendage Disord. 2017;3:111-3. Recently, two cases treated with isotretinoin, 10 mg/day, presented improvement in the papules after 30–45 days of treatment.202202 Pedrosa AF, Duarte AF, Haneke E, Correia O. Yellow facial papules associated with frontal fibrosing alopecia: a distinct histologic pattern and response to isotretinoin. J Am Acad Dermatol. 2017;77:764-6. In the last three studies, the progression of FFA was not evaluated. To date, data in the literature do not allow an absolute conclusion about the efficacy of this drug in FFA. Further studies are needed.

Dissecting cellulitis (DC)

DC is a neutrophilic primary scarring alopecia with follicular pustules, nodules, intercommunicating abscesses, and irreversible follicular destruction. It can constitute the tetrad of follicular occlusion when associated with pilonidal cyst, hidradenitis, and acne conglobata.203203 Flores-Terry MÁ, García-Arpa M, Franco-Muñóz M, González-Ruiz L. Facial papules in frontal fibrosing alopecia: good response to isotretinoin. Actas Dermosifiliogr. 2018;109:831-3.,204204 Ramos-e-Silva M, Pirmez R. Red face revisited: disorders of hair growth and the pilosebaceous unit. Clin Dermatol. 2014;32:784-99.

The first report of therapeutic success with isotretinoin, at a dose of 0.5 mg/kg/day for three months, showed relapse and the need for two more cycles of 1 mg/kg/day until remission.205205 Segurado-Miravalles G, Camacho-Martínez FM, Arias-Santiago S, Serrano-Falcón C, Serrano-Ortega S, et al. Epidemiology, clinical presentation and therapeutic approach in a multicentre series of dissecting cellulitis of the scalp. J Eur Acad Dermatol Venereol. 2017;31:e199-200. Three patients with DC received 1 mg/kg/day, then 0.75 mg/kg/day, for maintenance, for nine to 11 months, without recurrence after ten months (one patient) and after two years and six months (two patients). The authors suggested high doses and prolonged treatment to reduce relapses.206206 Taylor AE. Dissecting cellulitis of the scalp: response to isotretinoin. Lancet. 1987;2:225. A retrospective study, including seven patients treated with a dose of 0.75 mg/kg/day for nine to 12 months, found no recurrence at 16–42 months.207207 Scerri L, Williams HC, Allen BR. Dissecting cellulitis of the scalp: response to isotretinoin. Br J Dermatol. 1996;134:1105-8. A retrospective study of 51 patients treated with 0.5–0.8 mg/kg/day observed complete remission in 92% of the patients after three months and frequent relapses.208208 Koudoukpo C, Abdennader S, Cavelier-Balloy B, Gasnier C, Yédomon H. Dissecting cellulitis of the scalp: a retrospective study of 7 cases confirming the efficacy of oral isotretinoin. Ann Dermatol Venereol. 2014;141:500-6. In another report of 28 patients treated with a mean dose of 30 mg/day, seven had reduced inflammatory activity; relapse and need for retreatment were not specified.208208 Koudoukpo C, Abdennader S, Cavelier-Balloy B, Gasnier C, Yédomon H. Dissecting cellulitis of the scalp: a retrospective study of 7 cases confirming the efficacy of oral isotretinoin. Ann Dermatol Venereol. 2014;141:500-6.

Doses of 10 mg/day to 1 mg/kg/day, duration, maintenance doses, and varying associations have been reported in the literature. Despite the small number of reports, frequent relapses, and few studies with long follow-up, a SR concluded that, even without evidence, oral isotretinoin is considered the treatment of choice for DC.204204 Ramos-e-Silva M, Pirmez R. Red face revisited: disorders of hair growth and the pilosebaceous unit. Clin Dermatol. 2014;32:784-99.

Quinquaud folliculitis decalvans (QFD)

Quinquaud folliculitis decalvans is a rare, chronic, and recurrent neutrophilic scarring alopecia that affects young adults of both sexes. It is characterized by fibrotic plaques of alopecia with tufts of hair on the periphery, erythema, follicular pustules, flaking, and crusts. Its etiology is unclear, and no therapy is capable of inducing prolonged remission. Isotretinoin can act by inhibiting the migration of neutrophils and modulating innate immunity against Gram-positive bacteria, through negative regulation of TLR-2. Isotretinoin is widely cited, with differences regarding efficacy, safety, time to remission, and relapses.209209 Badaoui A, Reygagne P, Cavelier-Balloy B, Pinquier L, Deschamps L, Crickx B, et al. Dissecting cellulitis of the scalp: a retrospective study of 51 patients and review of literature. Br J Dermatol. 2016;174:421-3.

In a retrospective study involving 82 patients, 16 (20%) used isotretinoin; eight (50%) improved, but the duration of the response was only three months.210210 Litaiem N, Toumi A, Zeglaoui F. Comment on “Folliculitis decalvans: effectiveness of therapies and prognostic factors in a multicenter series of 60 patients with long-term follow-up”. J Am Acad Dermatol. 2019;80:e83. A multicenter, prospective study included 60 patients with QFD and different treatments; 15 (25%) were treated with isotretinoin for three months, with no difference in efficacy compared with the combination of rifampicin and clindamycin in the five-year follow-up. The authors developed a therapeutic protocol for QFD, suggesting isotretinoin only for severe cases, when a response is not maintained with other treatments.211211 Vaño-Galván S, Molina Ruiz AM, Fernandez Crehuet P, Rodrigues-Barata AR, Arias-Santiago S, Serrano-Falcón C, et al. Folliculitis decalvans: a multicentre review of 82 patients. J Eur Acad Dermatol Venereol. 2015;29:1750-7. Another study assessed 39 patients treated with isotretinoin 0.1–1.02 mg/kg/day for a mean of 2.5 months; 82% presented a partial or complete response. Doses above 0.4 mg/kg/day and lasting more than three months have been associated with the best response.212212 Miguel-Gómez L, Rodrigues-Barata AR, Molina-Ruiz A, Martorell-Calayud A, Fernández-Crehuet P, Grimat R, et al. Folliculitis decalvans: effectiveness of therapies and prognostic factors in a multicenter series of 60 patients with long-term follow-up. J Am Acad Dermatol. 2018;79:878-83.

Recent SRs have shown controversial results. One concluded that isotretinoin is the treatment with the largest number of publications, despite the limited response213213 Aksoy B, Hapa A, Mutlu E. Isotretinoin treatment for folliculitis decalvans: a retrospective case-series study. Int J Dermatol. 2018;57:250-3.; the other concluded that the ideal option is the combination of clindamycin and rifampicin, with level of evidence 3.214214 Rambhia PH, Conic RZ, Murad A, Atanaskova-Mesinkovska N, Piliang M, Berfeld W, et al. Updates in therapeutics for folliculitis decalvans: a systematic review with evidence-based analysis. J Am Acad Dermatol. 2019;80:794-801.

Other diseases with keratinization and inflammation disorders

The modulation of the inflammatory response and keratinocyte hyperproliferation and differentiation justifies the indication of isotretinoin for keratinization disorders with inflammation and difficult treatment. There are case reports and citations in reviews, with no conclusions about dose and duration. Genodermatoses need continuous treatment and there are no data on long-term risks.

Results of studies justifying recommendation

Pityriasis rubra pilaris

A chronic, papular-desquamative disease, of unknown familial or acquired etiology. Its treatment is difficult, and includes UVB associated with coal tar, topical corticosteroids, calcipotriene, keratolytics, oral retinoids, methotrexate, azathioprine, and cyclosporine. The use of isotretinoin has been reported since the 1980s, with good results.215215 Thomas J, Aguh C. Approach to treatment of refractory dissecting cellulitis of the scalp: a systematic review. J Dermatolog Treat. 2019:1-6.,216216 Goldsmith LA, Weinrich AE, Shupack J. Pityriasis rubra pilaris response to 13-cis-retinoic acid (isotretinoin). J Am Acad Dermatol. 1982;6 Pt 2 Suppl:710-5. A recent SR included 182 studies and 475 patients. Among those treated with retinoids, isotretinoin led to a good response in 61%; etretinate in 47%; and acitretin in 24%. The authors suggested that the first-line treatment is isotretinoin, followed by methotrexate and immunobiologicals. Cutaneous xerosis is aggravated by the drug and requires the use of emollients.217217 Dicken CH. Isotretinoin treatment of pityriasis rubra pilaris. J Am Acad Dermatol. 1987;16 Pt 1:297-301.

Cutaneous lupus erythematosus (LE)

Isotretinoin 0.2–1 mg/kg/day was indicated as an option for refractory cases of subacute LE, chronic LE, and hyperkeratotic forms, with efficacy similar to hydroxychloroquine. However, adverse events and faster relapse are more frequent; in practice, it is little used. Contraindicated in the association of LE and Sjogren's syndrome.218218 Kromer C, Sabat R, Celis D, Mössner R. Systemic therapies of pityriasis rubra pilaris: a systematic review. J Dtsch Dermatol Ges. 2019;17:243-59.

Generalized granuloma annular

A non-infectious granulomatous disease, with papules and plaques, of unknown cause. There is no effective treatment. There are reports in the literature of the use of isotretinoin 0.5 mg/kg/day for two to six months, in the case of generalized forms, with good response but with recurrence; maintenance at a low daily dose is suggested.219219 D’Erme AM, Milanesi N, Difonzo EM, Lotti T, Gola M. Treatment of refractory subacute cutaneous lupus erythematosus with oral isotretinoin: a valid therapeutic option. Dermatol Ther. 2012;25:281-2.

Human papilloma virus (HPV)/condyloma acuminatum

Oral isotretinoin 0.5–1 mg/kg/day was effective for condyloma of the cervix and mucocutaneous warts, especially when flat and recalcitrant.220220 Pasmatzi E, Georgiou S, Monastirli A, Tsambaos D. Temporary remission of disseminated granuloma annulare under oral isotretinoin therapy. Int J Dermatol. 2005;44:169-71.,221221 Georgala S, Katoulis AC, Georgala C, Bozi E, Mortakis A. Oral isotretinoin in the treatment of recalcitrant condylomata acuminata of the cervix: a randomised placebo-controlled trial. Sex Transm Infect. 2004;80:216-8. There may be no response, even at a dose of 1 mg/kg/day; however, it contributes to the reduction of the volume or multiplicity of lesions, favoring supporting treatments.

Darier's disease

A genetic dermatosis, with extensive areas of hyperkeratotic papules and plaques. Case reports and a review article reported improvement with isotretinoin at daily doses of 0.2–0.7 mg/kg. As a chronic disease, there is a need for continuous use with surveillance of hepatotoxicity, hypertriglyceridemia, and teratogenicity.222222 Yang TH, Lee TH, Huang YC. Oral isotretinoin for treating mucocutaneous human papillomavirus infections: a systematic review and meta-analysis. Indian J Dermatol Venereol Leprol. 2019;85:569-77.224224 Eimer L, Lagodin C, Bonavia P, Stringa M, Rébora I, Anaya J. Darier-White disease treated with oral isotretinoin. Arch Argent Pediatr. 2011;109:e63-6.

Others

Varied and off-label indications, with no possibility of conclusions on efficacy and safety as they are single reports, include: aquagenic keratoderma, oral mucosa ulcer perioral dermatitis, Galli-Galli disease, acne-like rash secondary to vemurafenib, dermatophytosis, lichen planopilaris and lichen planus pigmentosus, Cushing's disease, sebaceous hyperplasia, Fordyce granules, multiple steatocystoma, reticulated confluent papillomatosis (Gougerot-Carteaud), and erosive pustular dermatosis of the scalp.225225 Sehgal VN, Srivastava G, Sardana K. Isotretinoin – unapproved indications/uses and dosage: a physician's reference. Int J Dermatol. 2006;45:772-7.239239 Erkek E, Ayva S, Atasoy P, Emeksiz MC. Confluent and reticulated papillomatosis: favourable response to low-dose isotretinoin. J Eur Acad Dermatol Venereol. 2009;23:1342-3.

Table 6 presents a summary of approved and off-label indications for oral isotretinoin in dermatology, regarding doses and treatment times, reported in clinical studies, guidelines for conduct, and consensuses.

Table 6
Summary of doses and treatment time for approved and unapproved indications for oral isotretinoin, according to clinical studies, case series, case reports, and consensuses

Perspectives

For the cure of acne, the present authors consider it relevant to expand the prescription of isotretinoin for adolescents and adults, as well as the prescription of anti-androgens (contraceptives and spironolactone) for adult women, thus reducing the prescription of oral antibiotics, considering the growing alert about bacterial resistance. The still very high use of these drugs is worrisome, lasting from over six months up to one year or more (mean: 331 days), according to a 2016 study that highlights the lack of knowledge of or disregard of the recommendations on the rational use of antibiotics.240240 Petersen BO, Bygum A. Erosive pustular dermatosis of the scalp: a case treated successfully with isotretinoin. Acta Derm Venereol. 2008;88:300-1. It is known that there is no minimum age to prescribe isotretinoin, since acitretin is indicated for children of any age to treat severe keratinization disorders. However, it is necessary to guide the patient and family that use in pre-adolescents may imply the need for new treatment cycles; a new cycle can begin after three months.241241 Nagler AR, Milam EC, Orlow SJ. The use of oral antibiotics before isotretinoin therapy in patients with acne. J Am Acad Dermatol. 2016;74:273-9. Until now, and considering that the patent of isotretinoin has expired, there appears to be no interest from the pharmaceutical industry in conducting multicenter, randomized and controlled studies aimed at future approvals for other dermatoses. Only studies with appropriately-sized samples and high quality methodology will allow approval by regulatory agencies and the possibility of establishing levels of evidence in accordance with international standards.242242 Tuchayi SM, Makrantonaki E, Ganceviciene R, Dessinioti C, Feldman SR, Zouboulis CC. Acne vulgaris. Nat Rev Dis Primers. 2015;1:15029.245245 CEBM. The Oxford Centre for Evidence Based Medicine 2009 Levels of Evidence guidelines were originally used. [cited 17.04.20] Available from: https://www.cebm.net/2009/06/oxfordcentre-evidence-based-medicine-levelsevidence-march-2009.
https://www.cebm.net/2009/06/oxfordcentr...
Perhaps the development of a new oral retinoid that can meet other indications, in addition to acne and psoriasis, could expand the use of these drugs in dermatology.

Conclusions

This consensus aims to guide dermatologists on the use of oral isotretinoin for the benefit of patients. There is only level I evidence (SR and meta-analysis) with respect to efficacy and safety, ensured by adverse event monitoring, in the treatment of acne vulgaris. For rosacea, its use in low daily doses is mentioned in one SR, without mentioning the level of evidence. For the other indications, the literature is scarce, generally based on case reports, some even anecdotal, and rare randomized clinical studies with small samples (seborrheic dermatitis, photoaging), with no possibility of determining the level of evidence. However, some dermatological conditions that are difficult to control and for which oral isotretinoin was attempted due to its multiple mechanisms of action are worth mentioning. There was a 100% consensus among the authors of this manuscript that off-label indications are expanding and should be included. In turn, in the opinion of the authors, indications for purely esthetic purposes or oil control are not recommended, particularly for women of childbearing age. Finally, common sense is needed to prescribe a teratogenic drug, particularly for off-label prescriptions, in which the responsibility lies entirely with the physician.

  • How to cite this article: Bagatin E, Costa CS, Rocha MA, Picosse FR, Kamamoto CS, Pirmez R, et al. Consensus on the use of oral isotretinoin in dermatology - Brazilian Society of Dermatology. An Bras Dermatol. 2020;95(S1):19–38.
  • ☆☆
    Study conducted at the Brazilian Society of Dermatology, Rio de Janeiro, RJ, Brazil.
  • Financial support
    Brazilian Society of Dermatology – SBD.

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Publication Dates

  • Publication in this collection
    24 Mar 2021
  • Date of issue
    Nov-Dec 2020

History

  • Received
    19 Dec 2019
  • Accepted
    11 May 2020
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