595776 research-article2015
CMSXXX10.1177/1203475415595776Journal of Cutaneous Medicine & SurgeryTan et al
Basic/Clinical Science
Evaluation of Evidence for Acne Remission With Oral Isotretinoin Cumulative Dosing of 120-150 mg/kg
Journal of Cutaneous Medicine and Surgery 1–8 © The Author(s) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1203475415595776 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 publications 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: [email protected]
2
Journal of Cutaneous Medicine and Surgery
Figure 1. PRISMA chart for systematic literature review on oral isotretinoin dosing.
Methods A systematic literature search for systematic reviews and primary 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 provides 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
high, moderate, low and very low—with randomized controlled trials (RCTs) classified as high-quality and observational 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;
3
Tan et al Table 1. Initial Phase of Oral Isotretinoin Use in Acne (1980-1984). Treatment Relapse (%) Duration Dosing (mg/kg/d and Follow-Up Cumulative Trial Design and unless otherwise (weeks) or End Duration Criterion Dosing (mg/kg) specified) GRADE
Study
N
Peck et al 1982 16
32
Observational cohort Low GRADE
0.5-3.2 Mean daily: 0.9
Jones et al 1983 30
76
RCT in 3 dose groups Moderate GRADE RCT in 3 dose groups Moderate GRADE
Strauss et al 1984 15
141
Hennes et al 1984 18
87
Unable to calculate
0.1, 0.5, 1.0
Course 1: 16 Course 2: 16 Course 3: up to 24 16 weeks
0.1, 0.5, 1.0
20 weeks
14†, 70†, 140†
Comments
Recurrence of acne Complete clearance 15.6 nodules/cysts in 27/32 Follow-up 36 to 41 months
11.2†, 56†, 112† 22, 10, 12.5 Follow-up 4 months
Unable to Phase 1: 12 1.0-0, 1.0-0.2, Observational calculate for efficacy and 0.5-0.2, 0.2-0.2, weeks 4 groups were Phase 2: 12 relapse weeks treated in 2 Low GRADE Total 24 weeks phase
Definition of Relapse
Not defined
Recommended dose of 0.5 mg/kg/d for initial management of acute acne Recommend 0.5-1.0 mg/kg/d doses for management of nodulocystic acne
Unclear—values given for relapse are those requiring retreatment with oral isotretinoin Requiring additional High initial dosage 21, 19, 53, 63 of oral isotretinoin therapy as judged Follow-up at 12 by the physician or is suggested for months optimal long-term patient therapeutic effects 42, 20, 10 Follow-up 12 – 18 months
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; alternative 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 considered 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 investigated 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 reference 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 clearance.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 additional therapy as judged by the physician or patient.18 Five observational studies in the extended duration and alternative 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 Until complete Mean: 97.72 ± 22 clearing of IL (range: 36-240) and NIL (score of 0 using their own scale) 2 months after Mean: 102 clinical cure (the absence of new IL)
172 Observational Mean daily: 0.57 ± cohort 0.2 mg/kg (range: Low GRADE 0.29-1)
188 Observational 0.5-1.0 cohort Low GRADE
94 Observational Week 1: 10 mg/d 1 month after no Mean: 112.3 ±76.0 cohort Week 2: 20 mg/d new lesions and (range: 24-375) Low GRADE Week 3: 30 mg/d up development of to 50 mg/d no new lesion Mean daily: 31.4 mg/d ± 7.2
Chivot et al 1990 23
LehucherCeyrac et al 1993 4
Hermes et al 1998 22
Mean: 95 (range: 30-293)
Until clearing of IL. Cure was 3 or fewer IL on the face or trunk.
89 Observational 0.5, 0.75, 1.0 cohort Low GRADE 14.6 Follow-up mean 14 months (range: 3.547) 21 Follow-up mean 19 ± 5 months (range: 1241) 38 Follow-up every 6 months, or earlier if progression of acne 33 Follow-up approx. 31 months
Relapse (%) Cumulative Dosing and Follow-Up (mg/kg) Time
Harms et al 1986 17
Treatment Duration or End Criterion
N
Dosing (mg/kg/d unless otherwise specified)
Study
Trial Design and GRADE
Table 2. Extended Duration Phase of Oral Isotretinoin Use in Acne (1985-1999).
Comments
Not stated
Treatment until full resolution of acne is recommended over fixed treatment durations. Majority of relapses occur within 12 months of treatment cessation.
More than 3 new Patients under 20 years old were inflammatory more likely to relapse. No nodulocystic lesions on relationships between relapse face or trunk warranting and total dose or duration. retreatment with oral isotretinoin Lesions not controlled Young patients (15-20) relapsed by local treatment and more often, and a higher initial warranting renewed severity score was related to treatment with increased relapse isotretinoin and > 20% of initial severity score Greater than grade 2, Dose-related response up to 150 requiring retreatment mg/kg. Patients with microcystic with oral isotretinoin acne and females with gynaecoendocrinological problems at increased risk of relapse.
Definition of Relapse
5
64
MandekouLefaki et al 2003 21
Observational cohort Low GRADE
Observational cohort Low GRADE
Observational cohort Low GRADE
RCT Moderate GRADE
Ghaffarpour et 109 al 2006 19
638
52
66
Amichai et al 2006 27
Quéreux et al 2006 26
Akman et al 2007 24
Mean: 78.9 (range: 36147) Mean: 175 (range: 45-440) Up to 150 mg/kg (2-8 Up to 150 months)
Not stated
Treatment Duration Cumulative or End Criterion Dosing (mg/kg)
42 Follow-up 2-12 months
9.4, 3.1 Follow-up over 7 years
Relapse (%) and Follow-Up Time Acne severe enough to require oral treatment again
Definition of Relapse
A total dose ≥ 120 mg/kg was recommended for preventing relapses
Comments
(continued)
Papular, pustular, and The relapse rate became nodular acne of progressively lower with mod/severe grade 8 increasing cumulative dose weeks after stopping treatment 19 0.5 6 months 91.5† Increase in the severity Clearance to grade 0 was 65% Follow-up mean 8.7 ± of acne grade during after 6 months of treatment. 2.3 months follow-up, compared 4% of patients had to undergo to levels at end of retreatment with isotretinoin. treatment 0.71 ± 0.20 (range: Healing of almost Mean total: 18.4 Not stated Higher initial dosing and 0.2-1.43) all IL with no 111.5 ± 33.9 Follow-up mean 4.4 ± individualizing treatment Mean daily: 0.56 new lesions (if (range: 35.20.8 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. 20 mg/d 6 months Age 12-20: 4.3 Emergence of 20 mg/d was found to be 70.2 Age 21- Follow-up up to 4 pretreatment effective in the treatment 35: 66.8 years severity (moderate) of moderate acne. Relapses more common in females with PCOS. 0.3-1.0 Until no acne (only Mean: 137 52 Reincrease in acne Risk of relapse higher in Mean daily: 0.73 achieved in 46%) (range: 108- Follow-up average 24 score those in partial remission, (range: 0.36-1) 180) months young age, high number of comedones, truncal acne. Majority of relapses in 1 year. 3 arms: 10 months, 7 months, Mean: 14, 0, 0 Emergence of Intermittent dosing 0.5 × first 10 d/ 6 months 24.95 ± 14.7, Follow-up 12 months pretreatment acne recommended in patients that 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
Observational 0.5-1.0 cohort Low GRADE
Observational cohort Low GRADE
Ghalamkarpour et al 2006 25
Dosing (mg/kg/d unless otherwise specified)
Observational 0.15-0.4, 0.5-1.0 comparative Low GRADE
83
Al-Mutairi et al 117 2005 29
N
Study
Trial Design and GRADE
Table 3. Alternative Dosing Phase of Oral Isotretinoin Use in Acne (2000-2013).
6
180
Observational 0.5-1.0 cohort Low GRADE From 120 to 150 depending on response
Overall mean: 264.3 Mean high dose group: 309.8 Mean low dose group: 170.8 120-150
Until minimum 120-150 cumulative dose of 120 mg/kg achieved
Observational 2 post hoc No new acne for cohort groups based on 1 month during Low GRADE cumulative dose: therapy 220 mg/kg
Observational 0.5-1.0 cohort Low GRADE
Unable to calculate
Mean: 90.0 ± 16.7 60.8 ± 11.7 22.3 ± 4.0
Note. Values in the Dosing, Cumulative Dosing and Relapse columns are listed in a respective order. † Indicates calculated cumulative doses.
32
Cakir et al 2013 96
Blasiak et al 2013 11
20
142 MoralesCardona and SánchezVanegas 2013
28
Observational 20 mg/d, 0.5-0.7 × Treatment for 6-8 comparative 1 week per each months Low GRADE month
60
24 weeks
Boyraz and Mustak 2013
3 arms: 0.5-0.7, 0.25-0.4, 0.5-0.7 × 1 week per month
RCT Moderate GRADE
49
Treatment Duration Cumulative or End Criterion Dosing (mg/kg)
Lee et al 2011 31
Dosing (mg/kg/d unless otherwise specified)
N
Trial Design and GRADE
Study
Table 3. (continued)
Definition of Relapse
Comments
Early (3, or the for early and late presence of ≥1 relapse, respectively nodules
Overall: 32.7 Follow- Requiring treatment up 12 months with a prescription High dose group: 27 topical or oral Lower dose group: 47 acne medication after a course of isotretinoin
PCOS and patient age were associated with late relapse. Number of nodules at start of treatment were associated with both early and late relapse.
Higher cumulative doses significantly decreased relapse rates without increasing adverse effects
12.5, 17.6, 56.3 Deterioration to Low-dose similar to Follow-up 12 months moderate or more conventional regimen in severe acne based on maintaining remission, and GAGS score both were significantly better than intermittent dosing. 0, 10 Unclear Continuous low dose regimen Follow-up 6 months appears to be slightly superior to intermittent dosing in preventing relapse 26 > 15 comedones or Male gender was predictive Follow-up 24 months > 15 papules and/ factor for relapse. or pustules or >1 Maintenance therapy nodulocystic significantly reduced relapse.
Relapse (%) and Follow-Up Time
7
Tan et al
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%, respectively, 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 moderate 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 determination 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 evidence is due to observational study designs and inconsistent definitions of critical operational terms, specifically acne improvement, endpoint for treatment completion, and remission/relapse. The concept of disease remission is intrinsically dependent on attainment of disease clearance. Given the variance in use of the terms “acne remission” and “relapse,” consistent contemporary definitions are imperative. Furthermore, prior use of the term “acne clearance” is also ambiguous and inconsistent. For example, the abstract of the first publication 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 nodulocystic 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 predetermined acne grade as a threshold for improvement,4,23,25,26,29,32 there is no standardization regarding magnitude of improvement 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 comparability 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 standardized 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 clinical 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 provide 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 remission, and risks for recurrence may be due to factors identified in prior studies, as well as some not yet determined. Future investigations should use clinically relevant endpoints as end of treatment criteria and define treatment success in acne accurately.
8 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, authorship, and/or publication of this article.
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Journal of Cutaneous Medicine and Surgery 17. Harms M, Masouyé I, Radeff B. The relapses of cystic acne after isotretinoin treatment are age-related: a long-term followup 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 isotretinoin. 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 vulgaris. 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 conventional, low-dose and intermittent oral isotretinoin in the treatment 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 syndrome: 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 costeffectiveness 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.
CMSXXX10.1177/1203475415595776Journal of Cutaneous Medicine & SurgeryTan et al
Basic/Clinical Science
Evaluation of Evidence for Acne Remission With Oral Isotretinoin Cumulative Dosing of 120-150 mg/kg
Journal of Cutaneous Medicine and Surgery 1–8 © The Author(s) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1203475415595776 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 publications 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: [email protected]
2
Journal of Cutaneous Medicine and Surgery
Figure 1. PRISMA chart for systematic literature review on oral isotretinoin dosing.
Methods A systematic literature search for systematic reviews and primary 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 provides 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
high, moderate, low and very low—with randomized controlled trials (RCTs) classified as high-quality and observational 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;
3
Tan et al Table 1. Initial Phase of Oral Isotretinoin Use in Acne (1980-1984). Treatment Relapse (%) Duration Dosing (mg/kg/d and Follow-Up Cumulative Trial Design and unless otherwise (weeks) or End Duration Criterion Dosing (mg/kg) specified) GRADE
Study
N
Peck et al 1982 16
32
Observational cohort Low GRADE
0.5-3.2 Mean daily: 0.9
Jones et al 1983 30
76
RCT in 3 dose groups Moderate GRADE RCT in 3 dose groups Moderate GRADE
Strauss et al 1984 15
141
Hennes et al 1984 18
87
Unable to calculate
0.1, 0.5, 1.0
Course 1: 16 Course 2: 16 Course 3: up to 24 16 weeks
0.1, 0.5, 1.0
20 weeks
14†, 70†, 140†
Comments
Recurrence of acne Complete clearance 15.6 nodules/cysts in 27/32 Follow-up 36 to 41 months
11.2†, 56†, 112† 22, 10, 12.5 Follow-up 4 months
Unable to Phase 1: 12 1.0-0, 1.0-0.2, Observational calculate for efficacy and 0.5-0.2, 0.2-0.2, weeks 4 groups were Phase 2: 12 relapse weeks treated in 2 Low GRADE Total 24 weeks phase
Definition of Relapse
Not defined
Recommended dose of 0.5 mg/kg/d for initial management of acute acne Recommend 0.5-1.0 mg/kg/d doses for management of nodulocystic acne
Unclear—values given for relapse are those requiring retreatment with oral isotretinoin Requiring additional High initial dosage 21, 19, 53, 63 of oral isotretinoin therapy as judged Follow-up at 12 by the physician or is suggested for months optimal long-term patient therapeutic effects 42, 20, 10 Follow-up 12 – 18 months
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; alternative 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 considered 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 investigated 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 reference 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 clearance.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 additional therapy as judged by the physician or patient.18 Five observational studies in the extended duration and alternative 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 Until complete Mean: 97.72 ± 22 clearing of IL (range: 36-240) and NIL (score of 0 using their own scale) 2 months after Mean: 102 clinical cure (the absence of new IL)
172 Observational Mean daily: 0.57 ± cohort 0.2 mg/kg (range: Low GRADE 0.29-1)
188 Observational 0.5-1.0 cohort Low GRADE
94 Observational Week 1: 10 mg/d 1 month after no Mean: 112.3 ±76.0 cohort Week 2: 20 mg/d new lesions and (range: 24-375) Low GRADE Week 3: 30 mg/d up development of to 50 mg/d no new lesion Mean daily: 31.4 mg/d ± 7.2
Chivot et al 1990 23
LehucherCeyrac et al 1993 4
Hermes et al 1998 22
Mean: 95 (range: 30-293)
Until clearing of IL. Cure was 3 or fewer IL on the face or trunk.
89 Observational 0.5, 0.75, 1.0 cohort Low GRADE 14.6 Follow-up mean 14 months (range: 3.547) 21 Follow-up mean 19 ± 5 months (range: 1241) 38 Follow-up every 6 months, or earlier if progression of acne 33 Follow-up approx. 31 months
Relapse (%) Cumulative Dosing and Follow-Up (mg/kg) Time
Harms et al 1986 17
Treatment Duration or End Criterion
N
Dosing (mg/kg/d unless otherwise specified)
Study
Trial Design and GRADE
Table 2. Extended Duration Phase of Oral Isotretinoin Use in Acne (1985-1999).
Comments
Not stated
Treatment until full resolution of acne is recommended over fixed treatment durations. Majority of relapses occur within 12 months of treatment cessation.
More than 3 new Patients under 20 years old were inflammatory more likely to relapse. No nodulocystic lesions on relationships between relapse face or trunk warranting and total dose or duration. retreatment with oral isotretinoin Lesions not controlled Young patients (15-20) relapsed by local treatment and more often, and a higher initial warranting renewed severity score was related to treatment with increased relapse isotretinoin and > 20% of initial severity score Greater than grade 2, Dose-related response up to 150 requiring retreatment mg/kg. Patients with microcystic with oral isotretinoin acne and females with gynaecoendocrinological problems at increased risk of relapse.
Definition of Relapse
5
64
MandekouLefaki et al 2003 21
Observational cohort Low GRADE
Observational cohort Low GRADE
Observational cohort Low GRADE
RCT Moderate GRADE
Ghaffarpour et 109 al 2006 19
638
52
66
Amichai et al 2006 27
Quéreux et al 2006 26
Akman et al 2007 24
Mean: 78.9 (range: 36147) Mean: 175 (range: 45-440) Up to 150 mg/kg (2-8 Up to 150 months)
Not stated
Treatment Duration Cumulative or End Criterion Dosing (mg/kg)
42 Follow-up 2-12 months
9.4, 3.1 Follow-up over 7 years
Relapse (%) and Follow-Up Time Acne severe enough to require oral treatment again
Definition of Relapse
A total dose ≥ 120 mg/kg was recommended for preventing relapses
Comments
(continued)
Papular, pustular, and The relapse rate became nodular acne of progressively lower with mod/severe grade 8 increasing cumulative dose weeks after stopping treatment 19 0.5 6 months 91.5† Increase in the severity Clearance to grade 0 was 65% Follow-up mean 8.7 ± of acne grade during after 6 months of treatment. 2.3 months follow-up, compared 4% of patients had to undergo to levels at end of retreatment with isotretinoin. treatment 0.71 ± 0.20 (range: Healing of almost Mean total: 18.4 Not stated Higher initial dosing and 0.2-1.43) all IL with no 111.5 ± 33.9 Follow-up mean 4.4 ± individualizing treatment Mean daily: 0.56 new lesions (if (range: 35.20.8 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. 20 mg/d 6 months Age 12-20: 4.3 Emergence of 20 mg/d was found to be 70.2 Age 21- Follow-up up to 4 pretreatment effective in the treatment 35: 66.8 years severity (moderate) of moderate acne. Relapses more common in females with PCOS. 0.3-1.0 Until no acne (only Mean: 137 52 Reincrease in acne Risk of relapse higher in Mean daily: 0.73 achieved in 46%) (range: 108- Follow-up average 24 score those in partial remission, (range: 0.36-1) 180) months young age, high number of comedones, truncal acne. Majority of relapses in 1 year. 3 arms: 10 months, 7 months, Mean: 14, 0, 0 Emergence of Intermittent dosing 0.5 × first 10 d/ 6 months 24.95 ± 14.7, Follow-up 12 months pretreatment acne recommended in patients that 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
Observational 0.5-1.0 cohort Low GRADE
Observational cohort Low GRADE
Ghalamkarpour et al 2006 25
Dosing (mg/kg/d unless otherwise specified)
Observational 0.15-0.4, 0.5-1.0 comparative Low GRADE
83
Al-Mutairi et al 117 2005 29
N
Study
Trial Design and GRADE
Table 3. Alternative Dosing Phase of Oral Isotretinoin Use in Acne (2000-2013).
6
180
Observational 0.5-1.0 cohort Low GRADE From 120 to 150 depending on response
Overall mean: 264.3 Mean high dose group: 309.8 Mean low dose group: 170.8 120-150
Until minimum 120-150 cumulative dose of 120 mg/kg achieved
Observational 2 post hoc No new acne for cohort groups based on 1 month during Low GRADE cumulative dose: therapy 220 mg/kg
Observational 0.5-1.0 cohort Low GRADE
Unable to calculate
Mean: 90.0 ± 16.7 60.8 ± 11.7 22.3 ± 4.0
Note. Values in the Dosing, Cumulative Dosing and Relapse columns are listed in a respective order. † Indicates calculated cumulative doses.
32
Cakir et al 2013 96
Blasiak et al 2013 11
20
142 MoralesCardona and SánchezVanegas 2013
28
Observational 20 mg/d, 0.5-0.7 × Treatment for 6-8 comparative 1 week per each months Low GRADE month
60
24 weeks
Boyraz and Mustak 2013
3 arms: 0.5-0.7, 0.25-0.4, 0.5-0.7 × 1 week per month
RCT Moderate GRADE
49
Treatment Duration Cumulative or End Criterion Dosing (mg/kg)
Lee et al 2011 31
Dosing (mg/kg/d unless otherwise specified)
N
Trial Design and GRADE
Study
Table 3. (continued)
Definition of Relapse
Comments
Early (3, or the for early and late presence of ≥1 relapse, respectively nodules
Overall: 32.7 Follow- Requiring treatment up 12 months with a prescription High dose group: 27 topical or oral Lower dose group: 47 acne medication after a course of isotretinoin
PCOS and patient age were associated with late relapse. Number of nodules at start of treatment were associated with both early and late relapse.
Higher cumulative doses significantly decreased relapse rates without increasing adverse effects
12.5, 17.6, 56.3 Deterioration to Low-dose similar to Follow-up 12 months moderate or more conventional regimen in severe acne based on maintaining remission, and GAGS score both were significantly better than intermittent dosing. 0, 10 Unclear Continuous low dose regimen Follow-up 6 months appears to be slightly superior to intermittent dosing in preventing relapse 26 > 15 comedones or Male gender was predictive Follow-up 24 months > 15 papules and/ factor for relapse. or pustules or >1 Maintenance therapy nodulocystic significantly reduced relapse.
Relapse (%) and Follow-Up Time
7
Tan et al
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%, respectively, 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 moderate 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 determination 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 evidence is due to observational study designs and inconsistent definitions of critical operational terms, specifically acne improvement, endpoint for treatment completion, and remission/relapse. The concept of disease remission is intrinsically dependent on attainment of disease clearance. Given the variance in use of the terms “acne remission” and “relapse,” consistent contemporary definitions are imperative. Furthermore, prior use of the term “acne clearance” is also ambiguous and inconsistent. For example, the abstract of the first publication 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 nodulocystic 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 predetermined acne grade as a threshold for improvement,4,23,25,26,29,32 there is no standardization regarding magnitude of improvement 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 comparability 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 standardized 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 clinical 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 provide 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 remission, and risks for recurrence may be due to factors identified in prior studies, as well as some not yet determined. Future investigations should use clinically relevant endpoints as end of treatment criteria and define treatment success in acne accurately.
8 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, authorship, and/or publication of this article.
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