Evaluation of Evidence for Acne Remission With Oral Isotretinoin Cumulative Dosing of mg/kg

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1 595776CMSXXX / Journal of Cutaneous Medicine & SurgeryTan et al research-article2015 Review Article Evaluation of Evidence for Acne Remission With Oral Isotretinoin Cumulative Dosing of mg/kg Journal of Cutaneous Medicine and Surgery 2016, Vol. 20(1) The Author(s) 2015 Reprints and permissions: sagepub.com/journalspermissions.nav DOI: / jcms.sagepub.com Jerry Tan 1,2, Sanja Knezevic 1, Sanwarjit Boyal 2, Brad Waterman 1, and Toni Janik 3 Abstract Background: Oral isotretinoin (ISO) is the standard of care for severe inflammatory acne and a threshold dose of mg/kg is widely regarded as increasing remission potential. Objective: Our objective was to evaluate the evidence underlying ISO dosing of 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 mg/kg for induction of acne remission both low grade. Conclusion: The threshold dose of 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. 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 mg/kg over 4-6 to reduce acne recurrence However, recent studies have observed that higher cumulative doses of ISO are required. 11,12 We sought to evaluate the evidence for the mg/kg ISO dose recommendation in inducing acne remission. 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 () 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. 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. 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. jerrytan@bellnet.ca

2 14 Journal of Cutaneous Medicine and Surgery 20(1) Figure 1. PRISMA chart for systematic literature review on oral isotretinoin dosing. 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 ( ; initial phase); exploration of longer treatment durations ( ; extended dosing phase); lower daily and intermittent dosage regimens and increasing cumulative doses ( ; 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) 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 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

3 Tan et al 15 Table 1. Initial Phase of Oral Isotretinoin Use in Acne ( ). Study N Trial Design and Dosing (mg/kg/d unless otherwise specified) Treatment Duration (weeks) or End Criterion Cumulative Dosing (mg/kg) Relapse (%) and Follow-Up Duration Definition of Relapse Comments Peck et al 32 Observational cohort Jones et al RCT in 3 dose groups Moderate Strauss et al 141 RCT in 3 dose groups Moderate Hennes et al Observational for efficacy and relapse Mean daily: 0.9 Course 1: 16 Course 2: 16 Course 3: up to 24 Unable to calculate 15.6 Follow-up 36 to , 0.5, weeks 11.2, 56, , 10, 12.5 Follow-up 4 0.1, 0.5, weeks 14, 70, , 20, 10 Follow-up , , , , 4 groups were treated in 2 phase Phase 1: 12 weeks Phase 2: 12 weeks Total 24 weeks Unable to calculate 21, 19, 53, 63 Follow-up at 12 Recurrence of acne nodules/cysts Not defined Unclear values given for relapse are those requiring retreatment with oral isotretinoin Requiring additional therapy as judged by the physician or patient Complete clearance in 27/32 Recommended dose of 0.5 mg/kg/d for initial management of acute acne Recommend mg/kg/d doses for management of nodulocystic acne High initial dosage of oral isotretinoin is suggested for optimal long-term therapeutic effects Note. Values in the Dosing, Cumulative Dosing and Relapse columns are listed in a respective order. Indicates calculated cumulative doses. improvement as the endpoint. Specifically, clinical improvement was evaluated by a Likert-type satisfaction scale, 22 absence of or clearance of either just inflammatory lesions 4,17 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/d 27,28 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 ,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 Cumulative Doses and Acne Relapse Rates Two studies evaluated cumulative dosing of 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 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 mg/kg and 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 mg/kg, and mg/kg, and reported relapse rates of 0-14% and %, respectively, with follow-up periods of ,31

4 Table 2. Extended Duration Phase of Oral Isotretinoin Use in Acne ( ). Study N Trial Design and Dosing (mg/kg/d unless otherwise specified) Treatment Duration or End Criterion Cumulative Dosing (mg/kg) Relapse (%) and Follow-Up Time Definition of Relapse Comments Harms et al 89 Observational cohort Chivot et al 172 Observational cohort Lehucher- Ceyrac et al Observational cohort Hermes et al 94 Observational cohort 0.5, 0.75, 1.0 Until clearing of IL. Cure was 3 or fewer IL on the face or trunk. Mean daily: 0.57 ± 0.2 mg/kg (range: ) Until complete clearing of IL and NIL (score of 0 using their own scale) after clinical cure (the absence of new IL) Week 1: 10 mg/d Week 2: 20 mg/d Week 3: 30 mg/d up to 50 mg/d Mean daily: 31.4 mg/d ± month after no new lesions and development of no new lesion Mean: 95 (range: ) Mean: ± 22 (range: ) 14.6 Follow-up mean 14 (range: ) 21 Follow-up mean 19 ± 5 (range: 12-41) Mean: Follow-up every 6, or earlier if progression of acne Mean: ±76.0 (range: ) 33 Follow-up approx. 31 More than 3 new inflammatory nodulocystic lesions on face or trunk warranting retreatment with oral isotretinoin Lesions not controlled by local treatment and warranting renewed treatment with isotretinoin and > 20% of initial severity score Greater than grade 2, requiring retreatment with oral isotretinoin Patients under 20 years old were more likely to relapse. No relationships between relapse and total dose or duration. Young patients (15-20) relapsed more often, and a higher initial severity score was related to increased relapse Dose-related response up to 150 mg/kg. Patients with microcystic acne and females with gynaecoendocrinological problems at increased risk of relapse. Not stated Treatment until full resolution of acne is recommended over fixed treatment durations. Majority of relapses occur within 12 of treatment cessation. 16

5 Table 3. Alternative Dosing Phase of Oral Isotretinoin Use in Acne ( ). Study N Trial Design and Dosing (mg/kg/d unless otherwise specified) Treatment Duration or End Criterion Cumulative Dosing (mg/kg) Relapse (%) and Follow-Up Time Definition of Relapse Comments Mandekou- Lefaki et al Observational comparative Al-Mutairi et al 117 Observational cohort Ghalamkarpour 83 Observational et al cohort Ghaffarpour et 109 Observational al cohort Amichai et al 638 Observational cohort Quéreux et al 52 Observational cohort Akman et al 66 RCT Moderate , Not stated Mean: 78.9 (range: ) Mean: 175 (range: ) Up to 150 mg/kg (2-8 ) 9.4, 3.1 Follow-up over 7 years Up to Follow-up Follow-up mean 8.7 ± ± 0.20 (range: ) Mean daily: 0.56 Healing of almost all IL with no new lesions (if intolerance-reduced to 20 mg/d for 1 additional month) Mean total: ± 33.9 (range: ) 20 mg/d 6 Age 12-20: 70.2 Age 21-35: Mean daily: 0.73 (range: ) 3 arms: 0.5 first 10 d/ month 6, month, then first 10 d for 2-6, Until no acne (only achieved in 46%) 10, 7, 6 Mean: 137 (range: ) Mean: ± 14.7, ± 10.6, ± Follow-up mean 4.4 ± 0.8 years 4.3 Follow-up up to 4 years 52 Follow-up average 24 14, 0, 0 Follow-up 12 Acne severe enough to require oral treatment again Papular, pustular, and nodular acne of mod/severe grade 8 weeks after stopping treatment Increase in the severity of acne grade during follow-up, compared to levels at end of treatment A total dose 120 mg/kg was recommended for preventing relapses The relapse rate became progressively lower with increasing cumulative dose Clearance to grade 0 was 65% after 6 of treatment. 4% of patients had to undergo retreatment with isotretinoin. Not stated Higher initial dosing and individualizing treatment duration based on clinical response may lead to good response rate. Mean time to relapse was 1.28 years. Emergence of pretreatment severity (moderate) Reincrease in acne score Emergence of pretreatment acne scores 20 mg/d was found to be effective in the treatment of moderate acne. Relapses more common in females with PCOS. Risk of relapse higher in those in partial remission, young age, high number of comedones, truncal acne. Majority of relapses in 1 year. Intermittent dosing recommended in patients that cannot tolerate conventional dosing. Patients receiving conventional dosing had fewer relapses than those receiving low intermittent dosing. (continued) 17

6 Table 3. (continued) Study N Trial Design and Dosing (mg/kg/d unless otherwise specified) Treatment Duration or End Criterion Cumulative Dosing (mg/kg) Relapse (%) and Follow-Up Time Definition of Relapse Comments Lee et al 49 RCT Moderate Boyraz and Mustak Morales- Cardona and Sánchez- Vanegas Observational comparative 142 Observational cohort 3 arms: , , week per month 20 mg/d, week per each month 24 weeks Mean: 90.0 ± ± ± 4.0 Treatment for Until minimum cumulative dose of 120 mg/kg achieved Unable to calculate 12.5, 17.6, 56.3 Follow-up 12 0, 10 Follow-up Follow-up 24 Deterioration to moderate or more severe acne based on GAGS score Low-dose similar to conventional regimen in maintaining remission, and both were significantly better than intermittent dosing. Unclear Continuous low dose regimen > 15 comedones or > 15 papules and/ or pustules or >1 nodulocystic appears to be slightly superior to intermittent dosing in preventing relapse Male gender was predictive factor for relapse. Maintenance therapy significantly reduced relapse. Blasiak et al 180 Observational cohort Cakir et al Observational cohort 2 post hoc groups based on cumulative dose: <220 mg/kg >220 mg/kg No new acne for 1 month during therapy From 120 to 150 depending on response Overall mean: Mean high dose group: Mean low dose group: Overall: 32.7 Followup 12 High dose group: 27 Lower dose group: Early (<1 yr): 8.3 Late (<2 yrs): 16.6 Follow-up mean 10 ± 3 and 21 ± 3 for early and late relapse, respectively Requiring treatment with a prescription topical or oral acne medication after a course of isotretinoin ECLA papulopustular lesion score >2, comedonal lesion score >3, or the presence of 1 nodules Higher cumulative doses significantly decreased relapse rates without increasing adverse effects PCOS and patient age were associated with late relapse. Number of nodules at start of treatment were associated with both early and late relapse. Note. Values in the Dosing, Cumulative Dosing and Relapse columns are listed in a respective order. Indicates calculated cumulative doses. 18

7 Tan et al 19 Cumulative Doses and Acne Severity Five studies evaluated patients with severe acne, 11, 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 ,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 mg/kg in another study for moderate acne (treated for 6 ). 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 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. 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. References 1. Rademaker M. Isotretinoin: dose, duration and relapse. What does 30 years of usage tell us? Australas J Dermatol. 2013;54(3):

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