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Meta-Analysis
. 2018 Nov 24;11(11):CD009435.
doi: 10.1002/14651858.CD009435.pub2.

Oral isotretinoin for acne

Caroline S Costa  1 , Ediléia Bagatin, Ana Luiza C Martimbianco, Edina Mk da Silva, Marília M Lúcio, Parker Magin, Rachel Riera
Affiliations
Meta-Analysis

Oral isotretinoin for acne

Caroline S Costa et al. Cochrane Database Syst Rev. .

Abstract

Background: Acne vulgaris, a chronic inflammatory disease of the pilosebaceous unit associated with socialisation and mental health problems, may affect more than 80% of teenagers. Isotretinoin is the only drug that targets all primary causal factors of acne; however, it may cause adverse effects.

Objectives: To assess efficacy and safety of oral isotretinoin for acne vulgaris.

Search methods: We searched the following databases up to July 2017: the Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO and LILACS. We updated this search in March 2018, but these results have not yet been incorporated in the review. We also searched five trial registries, checked the reference lists of retrieved studies for further references to relevant trials, and handsearched dermatology conference proceedings. A separate search for adverse effects of oral isotretinoin was undertaken in MEDLINE and Embase up to September 2013.

Selection criteria: Randomised clinical trials (RCTs) of oral isotretinoin in participants with clinically diagnosed acne compared against placebo, any other systemic or topical active therapy, and itself in different formulation, doses, regimens, or course duration.

Data collection and analysis: We used standard methodological procedures expected by Cochrane.

Main results: We included 31 RCTs, involving 3836 participants (12 to 55 years) with mild to severe acne. There were twice as many male participants as females.Most studies were undertaken in Asia, Europe, and North America. Outcomes were generally measured between eight to 32 weeks (mean 19.7 weeks) of therapy.Assessed comparisons included oral isotretinoin versus placebo or other treatments such as antibiotics. In addition, different doses, regimens, or formulations of oral isotretinoin were assessed, as well as oral isotretinoin with the addition of topical agents.Pharmaceutical companies funded 12 included trials. All, except three studies, had high risk of bias in at least one domain.Oral isotretinoin compared with oral antibiotics plus topical agentsThese studies included participants with moderate or severe acne and assessed outcomes immediately after 20 to 24 weeks of treatment (short-term). Three studies (400 participants) showed isotretinoin makes no difference in terms of decreasing trial investigator-assessed inflammatory lesion count (RR 1.01 95% CI 0.96 to 1.06), with only one serious adverse effect found, which was Stevens-Johnson syndrome in the isotretinoin group (RR 3.00, 95% CI 0.12 to 72.98). However, we are uncertain about these results as they were based on very low-quality evidence.Isotretinoin may slightly improve (by 15%) acne severity, assessed by physician's global evaluation (RR 1.15, 95% CI 1.00 to 1.32; 351 participants; 2 studies), but resulted in more less serious adverse effects (67% higher risk) (RR 1.67, 95% CI 1.42 to 1.98; 351 participants; 2 studies), such as dry lips/skin, cheilitis, vomiting, nausea (both outcomes, low-quality evidence).Different doses/therapeutic regimens of oral isotretinoinFor our primary efficacy outcome, we found three RCTs, but heterogeneity precluded meta-analysis. One study (154 participants) reported 79%, 80% and 84% decrease in total inflammatory lesion count after 20 weeks of 0.05, 0.1, or 0.2 mg/kg/d of oral isotretinoin for severe acne (low-quality evidence). Another trial (150 participants, severe acne) compared 0.1, 0.5, and 1 mg/kg/d oral isotretinoin for 20 weeks and, respectively, 58%, 80% and 90% of participants achieved 95% decrease in total inflammatory lesion count. One RCT, of participants with moderate acne, compared isotretinoin for 24 weeks at (a) continuous low dose (0.25 to 0.4 mg/kg/day), (b) continuous conventional dose (0.5 to 0.7 mg/kg/day), and (c) intermittent regimen (0.5 to 0.7 mg/kg/day, for one week in a month). Continuous low dose (MD 3.72 lesions; 95% CI 2.13 to 5.31; 40 participants; one study) and conventional dose (MD 3.87 lesions; 95% CI 2.31 to 5.43; 40 participants; one study) had a greater decrease in inflammatory lesion counts compared to intermittent treatment (all outcomes, low-quality evidence).Fourteen RCTs (906 participants, severe and moderate acne) reported that no serious adverse events were observed when comparing different doses/therapeutic regimens of oral isotretinoin during treatment (from 12 to 32 weeks) or follow-up after end of treatment (up to 48 weeks). Thirteen RCTs (858 participants) analysed frequency of less serious adverse effects, which included skin dryness, hair loss, and itching, but heterogeneity regarding the assessment of the outcome precluded data pooling; hence, there is uncertainty about the results (low- to very-low quality evidence, where assessed).Improvement in acne severity, assessed by physician's global evaluation, was not measured for this comparison.None of the included RCTs reported birth defects.

Authors' conclusions: Evidence was low-quality for most assessed outcomes.We are unsure if isotretinoin improves acne severity compared with standard oral antibiotic and topical treatment when assessed by a decrease in total inflammatory lesion count, but it may slightly improve physician-assessed acne severity. Only one serious adverse event was reported in the isotretinoin group, which means we are uncertain of the risk of serious adverse effects; however, isotretinoin may result in more minor adverse effects.Heterogeneity in the studies comparing different regimens, doses, or formulations of oral isotretinoin meant we were unable to undertake meta-analysis. Daily treatment may be more effective than treatment for one week each month. None of the studies in this comparison reported serious adverse effects, or measured improvement in acne severity assessed by physician's global evaluation. We are uncertain if there is a difference in number of minor adverse effects, such as skin dryness, between doses/regimens.Evidence quality was lessened due to imprecision and attrition bias. Further studies should ensure clearly reported long- and short-term standardised assessment of improvement in total inflammatory lesion counts, participant-reported outcomes, and full safety accounts. Oral isotretinoin for acne that has not responded to oral antibiotics plus topical agents needs further assessment, as well as different dose/regimens of oral isotretinoin in acne of all severities.

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Conflict of interest statement

Caroline S Costa: I received a grant from Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (Capes), fundacao do Ministerio da Educacao (MEC), a Brazilian government granting agency. Ediléia Bagatin: I received money from Bayer for: board membership for studies and research on adult female acne; for expert testimony on work for guidelines of treatment for adult female acne; for lectures in the Continuing Medical Education Program on adult female acne; and support for participation in the International Congress of Dermatology to present work on adult female acne. Ana Luiza C Martimbianco: none known Edina MK da Silva: none known Marília M Lúcio: none known Parker Magin: none known Rachel Riera: none known

Figures

1
1
Study flow diagram.
2
2
Study (nonRCT, cohort and case‐control) flow diagram.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
4
4
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
5
5
Forest plot of comparison: 1 Oral isotretinoin versus any oral antibiotic plus any topical agent, outcome: 1.1 Improvement in acne severity assessed by a decrease in total inflammatory lesion count, measured in participants who were treated for a minimum period of 16 weeks.
6
6
Forest plot of comparison: 1 Oral isotretinoin versus any oral antibiotic plus any topical agent, outcome: 1.2 Frequency of serious adverse effects.
See this image and copyright information in PMC

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Herane 2009 {published data only}
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References to ongoing studies

IRCT201104094310N6 {published data only}
    1. IRCT201104094310N6. Comparison of therapeutic effects of oral erythromycin along with low dose oral isotretinoin and oral erythromycin and low dose flutamide versus doxycyclin in female severe acne vulgaris. apps.who.int/trialsearch/Trial2.aspx?TrialID=IRCT201104094310N6 (first received 19 April 2014).
IRCT2013110315246N1 {published data only}
    1. IRCT2013110315246N1. Acne cure rate in patients hyperandrogenism with two drugs of decuttane and cyproterone compound [Comparison of therapiotic effects of oral flutamide and cyproteron compound on female moderate acne]. apps.who.int/trialsearch/Trial2.aspx?TrialID=IRCT2013110315246N1 (first received 14 December 2013).

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