595776

research-article2015
CMSXXX10.1177/1203475415595776Journal of Cutaneous Medicine & SurgeryTan et al

Basic/Clinical Science

Journal of Cutaneous Medicine and Surgery

Evaluation of Evidence for Acne 1­–8

© The Author(s) 2015
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DOI: 10.1177/1203475415595776

Cumulative Dosing of 120-150 mg/kg jcms.sagepub.com

Jerry Tan1,2, Sanja Knezevic1, Sanwarjit Boyal2,

Brad Waterman1, and Toni Janik3

Abstract
Background: Oral isotretinoin (ISO) is the standard of care for severe inflammatory acne and a threshold dose of 120-150
mg/kg is widely regarded as increasing remission potential.
Objective: Our objective was to evaluate the evidence underlying ISO dosing of 120-150 mg/kg in acne remission.
Methods: A systematic literature search was performed using keywords “acne,” “isotretinoin,” “efficacy,” “dosing,”
“relapse,” and “remission.”
Results: Definitions for acne clearance, relapse/remission, and treatment endpoint vary widely across studies. Only 2 studies
explicitly evaluated the cumulative dose of 120-150 mg/kg for induction of acne remission—both low grade.
Conclusion: The threshold dose of 120-150 mg/kg for oral ISO is based on past parameters of treatment duration and
prior studies used vague or inconsistent definitions of clearance and remission. Optimal cumulative doses of ISO required to
induce remission appears to vary with severity.

Résumé
Contexte : L’isotrétinoïne (ISO) en administration orale est la norme de soin de l’acné inflammatoire sévère et on estime
généralement qu’une dose-seuil de 120-150 mg/kg augmente le potentiel de rémission.
Objectif : Nous voulions évaluer les preuves qui justifient l’administration d’une dose d’ISO de 120-150 mg/kg pour induire
la rémission de l’acné.
Méthodes : Nous avons effectué une recherche documentaire systématique à l’aide des mots-clés acne, isotretinoin, efficacy,
dosing, relapse et remission.
Résultats : La définition de ce qui constitue la disparition de l’acné, la rechute et la rémission, et de ce que sont les paramètres
d’évaluation du traitement, varie énormément d’une étude à l’autre. Seulement deux études évaluaient explicitement la dose
cumulative de 120-150 mg/kg pour induire la rémission de l’acné et toutes deux étaient de faible qualité.
Conclusion : La dose-seuil de 120-150 mg/kg d’ISO en administration orale est fondée sur d’anciens paramètres de durée
de traitement et les études antérieures avaient recours à des définitions incohérentes de la disparition et de la rémission. Les
doses cumulatives optimales d’ISO nécessaires pour induire la rémission de l’acné semblent varier en fonction de sa gravité.

Keywords
acne, isotretinoin, efficacy, clearance, dosing, remission, relapse

Oral isotretinoin (ISO) has been the standard of treatment for
acne vulgaris since its introduction over 3 decades ago due to
its efficacy in acute treatment and its potential for inducing
remission.1 The initial publication on ISO in treatment of
acne highlighted its capacity to induce clearance of nodules
and cysts and induce prolonged remission of such lesions.2
In the decade following its introduction, multiple publica-
tions including various acne guidelines advised cumulative
dosing of ISO 120-150 mg/kg over 4-6 months to reduce
acne recurrence.3-10 However, recent studies have observed
that higher cumulative doses of ISO are required.11,12 We
sought to evaluate the evidence for the 120-150 mg/kg ISO
dose recommendation in inducing acne remission.
1
Department of Medicine, University of Western Ontario, London, ON,
Canada
2
Windsor Clinical Research Inc, Windsor, ON, Canada
3
Windsor Regional Hospital, Windsor, ON, Canada
Corresponding Author:
Jerry Tan, MD, FRCPC, Windsor Clinical Research Inc, 2224 Walker Rd,
Ste 300, Windsor, ON N8W 5L7, Canada.
Email: jerrytan@bellnet.ca
2 Journal of Cutaneous Medicine and Surgery 

Figure 1.  PRISMA chart for systematic literature review on oral isotretinoin dosing.

Methods high, moderate, low and very low—with randomized con-

A systematic literature search for systematic reviews and pri-
mary research publications on this topic was conducted.
Search dates encompassed January 1, 1980, to December 31,
2013 and keywords were “acne,” “isotretinoin,” “efficacy,”
“dosing,” “relapse,” and “remission.” Inclusion criteria were
human studies, articles in English, patients with moderate to
severe acne, and prospective study design.13 Figure 1 pro-
vides further details on search outcomes and accountability.
Publications fulfilling search criteria were independently
evaluated by 2 raters (BW and SK) for study quality. This
was based on methodology relevant to determination of acne
relapse, not efficacy in acute treatment and used Grading of
Recommendations Assessment, Development and Evaluation
(GRADE) criteria.14 This method categorizes evidence as
trolled trials (RCTs) classified as high-quality and observa-
tional studies as low. These could then be downgraded based
on predefined criteria to evaluate for risk of bias. Very low
quality studies were excluded from consideration. Relapse is
considered the converse of remission, and these terms are
used throughout to relate to these concepts.
Results
Twenty studies fulfilled selection criteria (Tables 1 to 3) with
4 graded moderate quality, the remainder low. Literature was
divided into 3 phases corresponding to the predominating
feature of ISO use within these intervals: initial usage of ISO
with restrictions in daily dosing (1980-84; initial phase);
exploration of longer treatment durations (1985-1999;
Tan et al 3

Table 1.  Initial Phase of Oral Isotretinoin Use in Acne (1980-1984).

Treatment
Dosing (mg/kg/d Duration Relapse (%)
Trial Design and unless otherwise (weeks) or End Cumulative and Follow-Up Definition of
Study N GRADE specified) Criterion Dosing (mg/kg) Duration Relapse Comments

Peck et al 32 Observational 0.5-3.2 Course 1: 16 Unable to 15.6 Recurrence of acne Complete clearance
1982 16 cohort Mean daily: 0.9 Course 2: 16 calculate Follow-up 36 to nodules/cysts in 27/32
Low GRADE Course 3: up 41 months
to 24
Jones et al 76 RCT in 3 dose 0.1, 0.5, 1.0 16 weeks 11.2†, 56†, 112† 22, 10, 12.5 Not defined Recommended dose
1983 30 groups Follow-up 4 of 0.5 mg/kg/d for
Moderate months initial management
GRADE of acute acne
Strauss et al 141 RCT in 3 dose 0.1, 0.5, 1.0 20 weeks 14†, 70†, 140† 42, 20, 10 Unclear—values Recommend 0.5-1.0
1984 15 groups Follow-up 12 – given for mg/kg/d doses for
Moderate 18 months relapse are management of
GRADE those requiring nodulocystic acne
retreatment with
oral isotretinoin
Hennes et al 87 Observational 1.0-0, 1.0-0.2, Phase 1: 12 Unable to 21, 19, 53, 63 Requiring additional High initial dosage
1984 18 for efficacy and 0.5-0.2, 0.2-0.2, weeks calculate Follow-up at 12 therapy as judged of oral isotretinoin
relapse 4 groups were Phase 2: 12 months by the physician or is suggested for
Low GRADE treated in 2 weeks patient optimal long-term
phase Total 24 weeks therapeutic effects

Note. Values in the Dosing, Cumulative Dosing and Relapse columns are listed in a respective order.
†
Indicates calculated cumulative doses.

extended dosing phase); lower daily and intermittent dosage
regimens and increasing cumulative doses (2000-2013; alter-
native dosing phase).
Evaluation of Acne Improvement
Seven of 20 studies used only acne lesion counts to quantify
acne improvement. Of these, 2 studies (both in the initial
phase) solely considered resolution of nodules and cysts,15,16
1 study considered just inflammatory lesions,17 and 4 consid-
ered all acne lesions (inflammatory and noninflammatory
lesions).18-21 Nine conducted pre- and posttreatment acne
severity assessments using acne-grading scales to measure
response to ISO treatment.4,21-29 Three used both methods,
and all 3 considered inflammatory and noninflammatory
lesions.30-32 One did not specify the method used to assess
improvement.11
Definition of End of Treatment
All studies from the initial phase used temporal endpoints
with durations ranging from 16 to 24 weeks,15,16,18,30 while
the 4 studies in extended duration phase used clinical
improvement as the endpoint. Specifically, clinical
improvement was evaluated by a Likert-type satisfaction
scale,22 absence of or clearance of either just inflammatory
lesions4,17 or all acne lesions.23 Five from the alternative
dosing phase used temporal endpoints.24,25,27,28,31 During
this phase, other definitions varied from clinical clearance
of all lesions,11,26 clearance of almost all lesions,19,32 or
cumulative dosing.20,29,32
Dosing Regimens
All 8 studies during the initial and extended duration phases
used only continuous daily dosing regimens.4,15-18,22,23,30
Three of 12 studies in the alternative dosing phase investi-
gated intermittent dosing schedules,24,28,31 and the remainder
used only continuous dosing.11,19-21,25-27,29,32 Two evaluated
very low-dose regimen of 20 mg/d27,28 and 1 evaluated high
cumulative dosing of 220 mg/kg and greater.11
Definitions of Acne Remission/Relapse
Nine studies referred to remission,4,16-18,23,26,27,30,32 but only 3
explicitly defined the term.17,26,32 The definitions varied from
those synonymous with clearance (“100% recovery of
lesions,”32 or “nil scores”26), to 1 indicating absence of
relapse (“mild recurrent lesions”17). In studies that made ref-
erence to remission but did not define it, 5 implied it as the
converse of relapse,4,16,18,23,30 and 1 used it to refer to clear-
ance.27 In the earliest of studies, relapse was defined as the
recurrence of acne nodules and cysts.16 One observational
study in the initial phase defined relapse as requiring addi-
tional therapy as judged by the physician or patient.18 Five
observational studies in the extended duration and alterna-
tive dosing phases defined relapse as acne severe enough to
require oral therapy.4,11,17,21,23 Seven studies used an increase
in acne grading scores as the definition for relapse, including
2 moderate grade RCTs from the alternative phase.24-27,29,31,32
One study used predefined lesion counts for comedones,
papules/pustules and nodulocystic lesions as a threshold for
determining relapse.20 Five studies had unclear definitions of
relapse or was not stated.15,19,22,28,30
4
Table 2.  Extended Duration Phase of Oral Isotretinoin Use in Acne (1985-1999).

Dosing (mg/kg/d Treatment Relapse (%)

Trial Design unless otherwise Duration or End Cumulative Dosing and Follow-Up
Study N and GRADE specified) Criterion (mg/kg) Time Definition of Relapse Comments
Harms et al 89 Observational 0.5, 0.75, 1.0 Until clearing of Mean: 95 (range: 14.6 More than 3 new Patients under 20 years old were
1986 17 cohort IL. Cure was 30-293) Follow-up inflammatory more likely to relapse. No
Low GRADE 3 or fewer IL mean 14 nodulocystic lesions on relationships between relapse
on the face or months face or trunk warranting and total dose or duration.
trunk. (range: 3.5- retreatment with oral
47) isotretinoin
Chivot et al 172 Observational Mean daily: 0.57 ± Until complete Mean: 97.72 ± 22 21 Lesions not controlled Young patients (15-20) relapsed
1990 23 cohort 0.2 mg/kg (range: clearing of IL (range: 36-240) Follow-up by local treatment and more often, and a higher initial
Low GRADE 0.29-1) and NIL (score mean 19 ± warranting renewed severity score was related to
of 0 using their 5 months treatment with increased relapse
own scale) (range: 12- isotretinoin and > 20% of
41) initial severity score
Lehucher- 188 Observational 0.5-1.0 2 months after Mean: 102 38 Greater than grade 2, Dose-related response up to 150
Ceyrac et cohort clinical cure Follow-up requiring retreatment mg/kg. Patients with microcystic
al 1993 4 Low GRADE (the absence of every 6 with oral isotretinoin acne and females with gynaeco-
new IL) months, or endocrinological problems at
earlier if increased risk of relapse.
progression
of acne
Hermes et al 94 Observational Week 1: 10 mg/d 1 month after no Mean: 112.3 ±76.0 33 Not stated Treatment until full resolution
1998 22 cohort Week 2: 20 mg/d new lesions and (range: 24-375) Follow-up of acne is recommended over
Low GRADE Week 3: 30 mg/d up development of approx. 31 fixed treatment durations.
to 50 mg/d no new lesion months Majority of relapses occur
Mean daily: 31.4 mg/d within 12 months of treatment
± 7.2 cessation.
 Table 3.  Alternative Dosing Phase of Oral Isotretinoin Use in Acne (2000-2013).

Dosing (mg/kg/d
Trial Design unless otherwise Treatment Duration Cumulative Relapse (%) and
Study N and GRADE specified) or End Criterion Dosing (mg/kg) Follow-Up Time Definition of Relapse Comments
Mandekou- 64 Observational 0.15-0.4, 0.5-1.0 Not stated Mean: 78.9 9.4, 3.1 Acne severe enough A total dose ≥ 120 mg/kg was
Lefaki et al comparative (range: 36- Follow-up over 7 to require oral recommended for preventing
2003 21 Low GRADE 147) Mean: years treatment again relapses
175 (range:
45-440)
Al-Mutairi et al 117 Observational 0.5-1.0 Up to 150 mg/kg (2-8 Up to 150 42 Papular, pustular, and The relapse rate became
2005 29 cohort months) Follow-up 2-12 nodular acne of progressively lower with
Low GRADE months mod/severe grade 8 increasing cumulative dose
weeks after stopping
treatment
Ghalamkarpour 83 Observational 0.5 6 months 91.5† 19 Increase in the severity Clearance to grade 0 was 65%
et al 2006 25 cohort Follow-up mean 8.7 ± of acne grade during after 6 months of treatment.
Low GRADE 2.3 months follow-up, compared 4% of patients had to undergo
to levels at end of retreatment with isotretinoin.
treatment
Ghaffarpour et 109 Observational 0.71 ± 0.20 (range: Healing of almost Mean total: 18.4 Not stated Higher initial dosing and
al 2006 19 cohort 0.2-1.43) all IL with no 111.5 ± 33.9 Follow-up mean 4.4 ± individualizing treatment
Low GRADE Mean daily: 0.56 new lesions (if (range: 35.2- 0.8 years duration based on clinical
intolerance-reduced 200) response may lead to good
to 20 mg/d for 1 response rate. Mean time to
additional month) relapse was 1.28 years.
Amichai et al 638 Observational 20 mg/d 6 months Age 12-20: 4.3 Emergence of 20 mg/d was found to be
2006 27 cohort 70.2 Age 21- Follow-up up to 4 pretreatment effective in the treatment
Low GRADE 35: 66.8 years severity (moderate) of moderate acne. Relapses
more common in females
with PCOS.
Quéreux et al 52 Observational 0.3-1.0 Until no acne (only Mean: 137 52 Reincrease in acne Risk of relapse higher in
2006 26 cohort Mean daily: 0.73 achieved in 46%) (range: 108- Follow-up average 24 score those in partial remission,
Low GRADE (range: 0.36-1) 180) months young age, high number of
comedones, truncal acne.
Majority of relapses in 1 year.
Akman et al 66 RCT 3 arms: 10 months, 7 months, Mean: 14, 0, 0 Emergence of Intermittent dosing
2007 24 Moderate 0.5 × first 10 d/ 6 months 24.95 ± 14.7, Follow-up 12 months pretreatment acne recommended in patients that
GRADE month × 6 48.84 ± 10.6, scores cannot tolerate conventional
months, 0.5 × 1 101.37 ± 19.2 dosing. Patients receiving
month, then first conventional dosing had fewer
10 d for months relapses than those receiving
2-6, 0.5 × 6 low intermittent dosing.
months
(continued)

5
6
Table 3. (continued)

Dosing (mg/kg/d
Trial Design unless otherwise Treatment Duration Cumulative Relapse (%) and
Study N and GRADE specified) or End Criterion Dosing (mg/kg) Follow-Up Time Definition of Relapse Comments
Lee et al 49 RCT 3 arms: 24 weeks Mean: 90.0 ± 12.5, 17.6, 56.3 Deterioration to Low-dose similar to
2011 31 Moderate 0.5-0.7, 0.25-0.4, 16.7 Follow-up 12 months moderate or more conventional regimen in
GRADE 0.5-0.7 × 1 week 60.8 ± 11.7 severe acne based on maintaining remission, and
per month 22.3 ± 4.0 GAGS score both were significantly better
than intermittent dosing.
Boyraz and 60 Observational 20 mg/d, 0.5-0.7 × Treatment for 6-8 Unable to 0, 10 Unclear Continuous low dose regimen
Mustak 2013 comparative 1 week per each months calculate Follow-up 6 months appears to be slightly superior
28
Low GRADE month to intermittent dosing in
preventing relapse
Morales- 142 Observational 0.5-1.0 Until minimum 120-150 26 > 15 comedones or Male gender was predictive
Cardona and cohort cumulative dose of Follow-up 24 months > 15 papules and/ factor for relapse.
Sánchez- Low GRADE 120 mg/kg achieved or pustules or >1 Maintenance therapy
Vanegas 2013 nodulocystic significantly reduced relapse.
20

Blasiak et al 180 Observational 2 post hoc No new acne for Overall mean: Overall: 32.7 Follow- Requiring treatment Higher cumulative doses
2013 11 cohort groups based on 1 month during 264.3 up 12 months with a prescription significantly decreased relapse
Low GRADE cumulative dose: therapy Mean high High dose group: 27 topical or oral rates without increasing
<220 mg/kg dose group: Lower dose group: 47 acne medication adverse effects
>220 mg/kg 309.8 after a course of
Mean low dose isotretinoin
group: 170.8
Cakir et al 2013 96 Observational 0.5-1.0 From 120 to 150 120-150 Early (<1 yr): 8.3 Late ECLA papulopustular PCOS and patient age were
32
cohort depending on (<2 yrs): 16.6 lesion score >2, associated with late relapse.
Low GRADE response Follow-up mean 10 ± comedonal lesion Number of nodules at start
3 and 21 ± 3 months score >3, or the of treatment were associated
for early and late presence of ≥1 with both early and late
relapse, respectively nodules relapse.

Note. Values in the Dosing, Cumulative Dosing and Relapse columns are listed in a respective order.
†
Indicates calculated cumulative doses.
Tan et al 7
Cumulative Doses and Acne Relapse Rates
Two studies evaluated cumulative dosing of 120-150 mg/kg;
both from the alternative dosing phase and evaluated as low
grade.20,32 Reported relapse rates were 17% and 26% after a
24-month follow-up.
Of the 4 moderate grade studies, none evaluated the
cumulative dose of 120-150 mg/kg explicitly for induction
of acne remission. Two from the initial phase used 3 different
daily dosing regimens with calculated cumulative doses
ranging from 11.2-112 mg/kg and 14-140 mg/kg. Reported
relapse rates were 10-22% at 4-month follow-up,30 and
10-42% at 12- to 18-month follow-up, respectively.15 The 2
studies from the alternative dosing phase used cumulative
doses of 24.95-101.37 mg/kg, and 22.3-90.0 mg/kg, and
reported relapse rates of 0-14% and 12.5-56.2%, respec-
tively, with follow-up periods of 12 months.24,31
Cumulative Doses and Acne Severity
Five studies evaluated patients with severe acne,11,15-18 7 mod-
erate to severe acne,20-22,24,26,29,30 3 moderate acne,27,28,31 and
the remainder evaluated patients with varying severities. Of
the 5 in severe acne, 2 did not report cumulative doses or it
could not be calculated.16,18 Of the 3 studies evaluating
patients with only moderate acne, 1 did not report cumulative
dose. In the remaining studies, lack of comparability of study
designs (specifically treatment endpoint) excluded determi-
nation of optimal dosing for different acne severities.
Discussion
Despite more than 3 decades of widespread clinical use, the
ideal dosing regimen to achieve long-term remission of acne
with oral ISO is still unclear. The paucity of high-quality evi-
dence is due to observational study designs and inconsistent
definitions of critical operational terms, specifically acne
improvement, endpoint for treatment completion, and remis-
sion/relapse.
The concept of disease remission is intrinsically depen-
dent on attainment of disease clearance. Given the variance
in use of the terms “acne remission” and “relapse,” consis-
tent contemporary definitions are imperative. Furthermore,
prior use of the term “acne clearance” is also ambiguous and
inconsistent. For example, the abstract of the first publica-
tion on ISO in acne reported that 13 of 14 (93%) patients
experienced “complete clearing of their disease.”2 However,
the only acne lesions that were evaluated in that publication
were nodules and cysts. As the study did not account for
comedones, papules, and pustules—the presence of such
lesions would not exclude declaration of “clear.” More recent
studies considered all acne lesions in assessment of acne
improvement.18-20,23-26,30-32
While earlier studies were conducted in severe nodulo-
cystic acne, recent studies have addressed mild and moderate
acne. Cumulative doses required to achieve acne clearance
(treated for 1 additional month beyond complete clearance)
were 81 mg/kg in 1 study of mild and moderate acne,33 up to
90 mg/kg in a study for moderate acne (treated for 24
weeks),31 and 66.8-70.2 mg/kg in another study for moderate
acne (treated for 6 months).
While numerous studies consider attainment of a predeter-
mined acne grade as a threshold for improvement,4,23,25,26,29,32
there is no standardization regarding magnitude of improve-
ment nor most appropriate grading system. Furthermore,
most of these studies focused on facial acne. As truncal acne
has been found to respond more slowly to treatment,15,16 ISO
doses used to achieve facial clearance likely underestimate
the total dosage required for overall clearance.
Variability in treatment end-point criteria renders compa-
rability between studies difficult. For example, 1 study used
an end-point of “no new lesions for one month.” However, it
is uncertain how new lesions were differentiated from those
preexisting or resolving and if any number of comedones
were considered acceptable.11
The bioavailability of oral ISO is 60% lower during the
fasted compared to the fed state for conventional ISO.34 This
cohort of studies made little reference to dosing instructions
for study participants—the absence of which may contribute
to variability in dosing effectiveness. Nevertheless, higher
cumulative doses consistently resulted in lesser relapse rates
compared to lower within the same study.11,15,21,30,31 To
achieve consistent bioavailability, intake of ISO with stan-
dardized fat content during formal studies is warranted. A
formulation of ISO that reduces variability in bioavailability
between fed and fasted states may also be of value.35
Finally, several risk factors have been identified in these
studies which may impact acne remission/relapse including
young age, male gender, and initial severity of acne. These
were found to be significant predictors of relapse, regardless
of cumulative dose administered.29,35 In addition, specific clin-
ical presentations have also been associated with a higher risk
of relapse: females with PCOS, acne localized to the torso, as
well as a large number of comedones.29,32 These features pro-
vide guidance for clinicians in predicting need for retreatment
and for researchers planning future investigations.
Conclusions
The current evidence underpinning the 120-150 mg/kg
cumulative threshold-dosing regimen is equivocal and is
based on 2 low grade studies. Cumulative ISO doses
required for clearance appear lower for acne of mild to
moderate severity and higher for more severe acne. Multiple
elements contribute to the variability in achieving remis-
sion, and risks for recurrence may be due to factors identi-
fied in prior studies, as well as some not yet determined.
Future investigations should use clinically relevant end-
points as end of treatment criteria and define treatment suc-
cess in acne accurately.
8 Journal of Cutaneous Medicine and Surgery 
Declaration of Conflicting Interests
The author(s) declared the following potential conflicts of interest
with respect to the research, authorship, and/or publication of this
article: J. Tan has been an advisor, investigator, and/or speaker for
Allergan, Cipher, Dermira, Galderma, Roche, and Valeant. The
other authors have no conflicts of interest to declare.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
References
1. Rademaker M. Isotretinoin: dose, duration and relapse.
What does 30 years of usage tell us? Australas J Dermatol.
2013;54(3):157-162.
2. Peck GL, Olsen TG, Yoder FW, et al. Prolonged remissions of
cystic and conglobate acne with 13-cis-retinoic acid. N Engl J
Med. 1979;300(7):329-333.
3. Layton AM, Knaggs H, Taylor J, Cunliffe WJ. Isotretinoin for
acne vulgaris—10 years later: a safe and successful treatment.
Br J Dermatol. 1993;129(3):292-296.
4. Lehucher-Ceyrac D, Weber-Buisset MJ. Isotretinoin and acne
in practice: a prospective analysis of 188 cases over 9 years.
Dermatology. 1993;186(2):123-128.
5. Cunliffe WJ, Layton AM. Oral isotretinoin: patient selection
and management. J Dermatol Treat. 1993;4:S10-S15.
6. Layton AM, Cunliffe WJ. Guidelines for optional use of
isotretinoin in acne. J Am Acad Dermatol. 1992;27:S2-S7.
7. Layton AM, Stainforth JM, Cunliffe WJ. Ten years’ experi-
ence of oral isotretinoin for the treatment of acne vulgaris. J
Dermatol Treat. 1993;4:S2-S5.
8. Strauss JS, Krowchuk DP, Leyden JJ, et al. Guidelines of
care for acne vulgaris management. J Am Acad Dermatol.
2007;56(4):651-663.
9. Nast A, Dréno B, Bettoli V, et al. European evidence-based
(S3) guidelines for the treatment of acne. J Eur Acad Dermatol
Venereol. 2012;26(suppl 1):1-29.
10. Gollnick H, Cunliffe W, Berson D, et al. Management of acne:
a report from a Global Alliance to Improve Outcomes in Acne.
J Am Acad Dermatol. 2003;49(suppl 1):S1-S37.
11. Blasiak RC, Stamey CR, Burkhart CN, Lugo-Somolinos A,
Morrell DS. High-dose isotretinoin treatment and the rate of
retrial, relapse, and adverse effects in patients with acne vul-
garis. JAMA Dermatol. 2013;149(12):1392-1398.
12. Cyrulnik AA, Viola KV, Gewirtzman AJ, Cohen SR. High-dose
isotretinoin in acne vulgaris: improved treatment outcomes and
quality of life. Int J Dermatol. 2012;51(9):1123-1130.
13. Nast A, Rosumeck S, Sammain A, Sporbeck B, Rzany B.
Methods report on the development of the European S3 guide-
lines for the treatment of acne. J Eur Acad Dermatol Venereol.
2012;26(suppl 1):e1-e41.
14. Schunemann H, Santesso N. The GRADE approach and sum-
mary of findings table. 2010. Available at: http://cebgrade.
mcmaster.ca/Intro/index.html
15. Strauss JS, Rapini RP, Shalita AR, et al. Isotretinoin therapy
for acne: results of a multicenter dose-response study. J Am
Acad Dermatol. 1984;10(3):490-496.
16. Peck GL, Olsen TG, Butkus D, et al. Isotretinoin versus placebo
in the treatment of cystic acne. A randomized double-blind
study. J Am Acad Dermatol. 1982;6(suppl 4 pt 2):735-745.
17. Harms M, Masouyé I, Radeff B. The relapses of cystic acne
after isotretinoin treatment are age-related: a long-term follow-
up study. Dermatologica. 1986;172(3):148-153.
18. Hennes R, Mack A, Schell H, Vogt HJ. 13-cis-retinoic acid in
conglobate acne. A follow-up study of 14 trial centers. Arch
Dermatol Res. 1984;276(4):209-215.
19. Ghaffarpour G, Mazloomi S, Soltani-Arabshahi R, Seyed KS.
Oral isotretinoin for acne, adjusting treatment according to
patient’s response. J Drugs Dermatol. 2006;5(9):878-882.
20. Morales-Cardona CA, Sánchez-Vanegas G. Acne relapse rate
and predictors of relapse following treatment with oral isotreti-
noin. Actas Dermosifiliogr. 2013;104(1):61-66.
21. Mandekou-Lefaki I, Delli F, Teknetzis A, Euthimiadou R,
Karakatsanis G. Low-dose schema of isotretinoin in acne vul-
garis. Int J Clin Pharmacol Res. 2003;23(2-3):41.
22. Hermes B, Praetel C, Henz BM. Medium dose isotretinoin
for the treatment of acne. J Eur Acad Dermatol Venereol.
1998;11(2):117-121.
23. Chivot M, Midoun H. Isotretinoin and acne—a study of
relapses. Dermatologica. 1990;180(4):240-243.
24. 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(10):467-473.
25. Ghalamkarpour F, Nasiri S. Isotretinoin in treatment of acne:
its efficacy, side effects, and recurrence rate of disease. Arch
Iran Med. 2006;9(3):228-230.
26. Quéreux G, Volteau C, N’Guyen JM, Dréno B. Prospective
study of risk factors of relapse after treatment of acne with oral
isotretinoin. Dermatology. 2006;212(2):168-176.
27. Amichai B, Shemer A, Grunwald MH. Low-dose isotreti-
noin in the treatment of acne vulgaris. J Am Acad Dermatol.
2006;54(4):644-646.
28. Boyraz N, Mustak PK. Comparison of the efficacies of intermittent
and continuous low-dose isotretinoin regimens in the treatment of
moderate acne vulgaris. Int J Dermatol. 2013;52(10):1265-1267.
29. Al-Mutairi N, Manchanda Y, Nour-Eldin O, Sultan A.
Isotretinoin in acne vulgaris: a prospective analysis of 160
cases from Kuwait. J Drugs Dermatol. 2004;4(3):369-373.
30. Jones DH, King K, Miller AJ, Cunliffe WJ. A dose-response
study of 13-cis-retinoic acid in acne vulgaris. Br J Dermatol.
1983;108(3):333-343.
31. Lee JW, Yoo KH, Park KY, et al. Effectiveness of conven-
tional, low-dose and intermittent oral isotretinoin in the treat-
ment of acne: a randomized, controlled comparative study. Br
J Dermatol. 2011;164(6):1369-1375.
32. Cakir GA, Erdogan FG, Gurler A. Isotretinoin treatment in
nodulocystic acne with and without polycystic ovary syn-
drome: efficacy and determinants of relapse. Int J Dermatol.
2013;52(3):371-376.
33. Borghi A, Mantovani L, Minghetti S. Low-cumulative dose
isotretinoin treatment in mild-to-moderate acne: efficacy in
achieving stable remission. J Eur Acad Dermatol Venereol.
2011;25(9):1094-1098.
34. Simpson NB. Social and economic aspects of acne and the cost-
effectiveness of isotretinoin. J Dermatol Treat. 1993;4(suppl
2):S6-S9.
35. 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(6):665-670.