Cover of Maintenance treatments for acne vulgaris

Maintenance treatments for acne vulgaris

Acne vulgaris: management

Evidence review I

NICE Guideline, No. 198

London: National Institute for Health and Care Excellence (NICE); .
ISBN-13: 978-1-4731-4147-6
Copyright © NICE 2021.

Maintenance treatment for acne vulgaris

Review question

What is the effectiveness of topical or oral pharmacological and physical interventions as maintenance treatment for acne vulgaris?

Introduction

For some people acne is a relapsing condition that once treated may recur. This review sought to identify whether any treatment could be effectively used to maintain good outcomes once other treatments (including oral isotretinoin) had been discontinued.

Summary of the protocol

Please see Table 1 for a summary of the Population, Intervention, Comparison and Outcome (PICO) characteristics of this review.

Table 1. Summary of the protocol.

Table 1

Summary of the protocol.

For further details see the review protocol in appendix A.

Methods and process

This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual. Methods specific to this review question are described in the review protocol in appendix A and the methods document (supplementary document 1).

Declarations of interest were recorded according to NICE’s conflicts of interest policy.

Clinical evidence

Included studies

Overall 8 randomised controlled trials (RCTs) (Kawashima 2018; Leyden 2006; Poulin 2011; Thiboutot 2006; Thielitz 2007; Thielitz 2015; Truchuelo 2015; Vender 2012) and 1 open-label controlled study (Zhang 2004) were included in this review.

One RCT (Kawashima 2018) compared adapalene gel versus benzoyl peroxide gel in participants who had previously been treated with either benzoyl peroxide plus clindamycin, benzoyl peroxide plus adapalene, or adapalene plus clindamycin.

One RCT (Leyden 2006) compared tazarotene gel plus placebo versus tazarotene gel plus minocycline versus vehicle gel plus minocycline in participants who had previously been treated with tazarotene gel plus minocycline capsule.

One RCT (Truchuelo 2015) was a split-face study comparing retinoid combination versus vehicle in participants who had previously been treated with isotretinoin. One RCT (Vender 2012) compared tretinoin versus vehicle in participants who had also previously been treated with isotretinoin. One RCT (Thielitz 2015) compared azelaic acid versus observation; this study included a third treatment arm that was not included in the review because participants received adapalene gel for 9 months, which did not meet protocol eligibility criteria for treatment duration. Evidence from these 3 studies was analysed separately.

Two RCTs (Poulin 2011; Thielitz 2007) and 1 open-label study (Zhang 2004), although assessing adapalene, either reported certain outcomes that were not sufficiently similar to enable pooling (Poulin 2011; Zhang 2004) or compared adapalene regimens versus comparator regimens that were not sufficiently similar to other adapalene regimens to enable pooling (Thielitz 2007). Evidence from these 3 studies was therefore analysed separately. Poulin (2011) compared adapalene benzoyl peroxide (adapalene-BPO) versus vehicle to assess Investigator’s Global Assessment (IGA) success rate (percentage of participants rated worse from baseline), irritation (including erythema, scaling, dryness and stinging/burning) after 24 weeks of treatment. Zhang (2004) compared adapalene versus no treatment to assess the difference in mean percentage reduction in total lesions after 12 weeks of treatment. Thielitz (2007) compared adapalene gel/adapalene gel or vehicle versus vehicle/adapalene gel or vehicle.

However, it was possible to combine certain outcome data from 4 studies (3 RCTs and 1 open-label study) comparing adapalene regimens versus vehicle, no treatment or observation (Poulin 2011; Thiboutot 2006; Thielitz 2007; Zhang 2004). Treatment durations varied across the studies, ranging from 12 weeks to 24 weeks, and a subgroup analysis by treatment duration was therefore conducted.

The included studies are summarised in Table 2.

See the literature search strategy in appendix B and study selection flow chart in appendix C.

Excluded studies

Studies not included in this review are listed, and reasons for their exclusion are provided in appendix K.

Summary of clinical studies included in the evidence review

Summary of the studies included in this review are presented in Table 2.

Table 2. Summary of included studies.

Table 2

Summary of included studies.

See the full evidence table in appendix D and forest plots in appendix E.

Quality assessment of clinical studies included in the evidence review

See the evidence profiles in appendix F.

Economic evidence

Included studies

A single economic search was undertaken for all topics included in the scope of this guideline but no economic studies were identified which were applicable to this review question. See the literature search strategy in appendix B and economic study selection flow chart in appendix G.

Excluded studies

No economic studies were reviewed at full text and excluded from this review.

Economic model

No economic modelling was conducted for this review question, because the committee agreed that other topics were higher priorities for economic evaluation.

The committee’s discussion of the evidence

Interpreting the evidence
The outcomes that matter most

Clinician-rated and participant-reported improvement were prioritised by the guideline committee as critical outcomes because these indicate effectiveness of a specific intervention and also whether the person receiving the intervention perceives an improvement in acne vulgaris. Prevention of scarring was also chosen as a critical outcome because it may be associated with physical and psychological distress.

Relapse, acceptability, tolerability and side effects were important outcomes as they indicate effectiveness of the intervention and how likely people are to adhere to a treatment regime.

The quality of the evidence

The quality of the evidence ranged from very low to moderate quality, with most of the evidence being of low or very low quality. This was predominately due to risk of bias of studies and imprecision in the effect estimates. The committee noted that a number of studies did not report allocation concealment or blinding and there were high attrition rates in a couple of studies, all of which lowered their confidence in the findings. There were also some small studies which made the effect size uncertain due to large confidence intervals.

Benefits and harms

The committee agreed that there was little evidence to inform decision making on the most effective maintenance treatment because it only investigated a small number of all possible maintenance options. So they used their expertise and experience, as well as the evidence, to make recommendations.

Based on their knowledge and experience, the committee decided to recommend good, continued skin care for all people with acne. The committee agreed that it is important to encourage good skin care regimens because this would help maintain the improvements achieved by the acne treatment.

The committee discussed that maintenance treatment is not always necessary for everyone who has achieved acne clearance following completion of treatment, as in many cases acne is unlikely to return after successful treatment. Also, in some people the acne may be mild after treatment which may no longer be a problem for the person and they might prefer not to have maintenance treatment. Therefore, the committee decided that it was good clinical practice to explain to the person with acne following completion of treatment that maintenance treatment may not always be required for everyone.

Based on evidence from 2 studies where acne had improved rather than cleared and treatment was effectively maintaining this improvement, the committee decided that it could be appropriate for people where acne frequently relapses after treatment because a maintenance treatment could also reduce the likelihood of acne recurring.

There was some limited evidence of very low quality reporting clinician rated improvement using topical retinoid (adapalene) combined with benzoyl peroxide versus a sham treatment. Since this combination was also found to be effective as a first-line treatment (see evidence reports E1, E2, F1 and F2) the committee decided to made a weak recommendation for this topical combination to be considered as a maintenance treatment.

Even though the committee agreed that the combination treatment of adapalene and benzoyl peroxide demonstrated the best clinical effect, they discussed that other options should be available for those unable to tolerate this treatment. There was some evidence of moderate to low quality suggesting that topical retinoids (adapalene, tretinoin) or topical azelaic acid had some benefit for small numbers of people versus sham treatment or placebo. Although there was no evidence of discontinuation or discontinuation due to side effects for people using topical retinoids for up to 24 weeks, from their knowledge and experience, the committee agreed that retinoids can cause skin dryness and irritation, and are light sensitising so there is potential for side effects. Furthermore, the committee discussed that retinoids should not be used in pregnancy and that there are possible resource implications associated with retinoid use (for example in relation to the pregnancy prevention programmes for people with child bearing potential). Very low quality evidence from one study comparing benzoyl peroxide to a topical retinoid (adapalene) showed no difference between the two interventions on relapse or the side effects of erythema and dryness. The committee discussed that benzoyl peroxide is commonly prescribed in clinical practice and provides more options as it is available in different strengths. Therefore, the committee agreed to make a weak recommendation for the use of a topical monotherapy of adapalene, azelaic acid, or benzoyl peroxide maintenance treatments if a fixed combination of topical benzoyl peroxide and topical adapalene or either of the component parts is not tolerated.

The committee noted that the majority of the evidence reviewed participants at 12 weeks and discussed that 6 to 8 weeks is the minimum time required to see a response to a treatment. Therefore, the committee agreed that a review should take place at 12 weeks.

Cost effectiveness and resource use

No economic evidence was identified for this review question. The recommendations made by the committee on discussing the value of continued appropriate skin care to all people with acne and the value of maintenance treatment, in particular to specific subgroups of people with acne, have minimal healthcare resource implications relating to the health professionals’ time to provide advice. The committee expressed the view that offering maintenance treatment to people with a history of frequent relapse after treatment is likely to lead to health benefits for these populations at a relative low cost (as drug acquisition costs of the recommended topical treatments are low), and potential future cost-savings, as these populations, without maintenance treatment, may need to contact health services for refractory or relapsing acne and require more costly treatment in the future. The committee agreed that reviewing maintenance treatment after 12 weeks in order to decide whether to continue or not ensured efficient use of resources by avoiding prolonged use of treatment that is not effective or not needed anymore.

Other factors the committee took into account

The committee discussed their experience with low dose isotretinoin as a maintenance treatment. There is variation in clinical practice with some healthcare providers prescribing this whereas other do not. Given a lack of evidence the committee decided not to make a recommendation, but recommended further research to investigate the effectiveness of a reduced dose of oral isotretinoin which could potentially also be used as maintenance treatment (see appendix L in evidence review F1 related to more severe forms of acne where isotretinoin can be prescribed).

Recommendations supported by this evidence review

This evidence review supports recommendations 1.7.1 to 1.7.5 in the guideline.

References

  • Kawashima 2018

    Kawashima M., Miyachi Y., Efficacy of BPO 2.5% Gel in the Acute and Maintenance Periods for Moderate or Severe Facial Acne Vulgaris, J Dermatol Dis, 5, 273, 2018

  • Leyden 2006

    Leyden, J., Thiboutot, D. M., Shalita, A. R., Webster, G., Washenik, K., Strober, B. E., Shupack, J., Comparison of tazarotene and minocycline maintenance therapies in acne vulgaris: a multicenter, double-blind, randomized, parallel-group study, Arch Dermatol, 142, 605–12, 2006 [PubMed: 16702498]

  • Poulin 2011

    Poulin, Y., Sanchez, N. P., Bucko, A., Fowler, J., Jarratt, M., Kempers, S., Kerrouche, N., Dhuin, J. C., Kunynetz, R., A 6-month maintenance therapy with adapalene-benzoyl peroxide gel prevents relapse and continuously improves efficacy among patients with severe acne vulgaris: results of a randomized controlled trial, Br J Dermatol, 164, 1376–82, 2011 [PubMed: 21457209]

  • Thiboutot 2006

    Thiboutot, D. M., Shalita, A. R., Yamauchi, P. S., Dawson, C., Kerrouche, N., Arsonnaud, S., Kang, S., Adapalene gel, 0.1%, as maintenance therapy for acne vulgaris: a randomized, controlled, investigator-blind follow-up of a recent combination study, Arch Dermatol, 142, 597–602, 2006 [PubMed: 16702497]

  • Thielitz 2007

    Thielitz, A., Sidou, F., Gollnick, H., Control of microcomedone formation throughout a maintenance treatment with adapalene gel, 0.1%, J Eur Acad Dermatol Venereol, 21, 747–53, 2007 [PubMed: 17567301]

  • Thielitz 2015

    Thielitz, A., Lux, A., Wiede, A., Kropf, S., Papakonstantinou, E., Gollnick, H., A randomized investigator-blind parallel-group study to assess efficacy and safety of azelaic acid 15% gel vs. adapalene 0.1% gel in the treatment and maintenance treatment of female adult acne, J Eur Acad Dermatol Venereol, 29, 789–96, 2015 [PubMed: 25399481]

  • Truchuelo 2015

    Truchuelo, M. T., Jimenez, N., Mavura, D., Jaen, P., Assessment of the efficacy and safety of a combination of 2 topical retinoids (RetinSphere) in maintaining post-treatment response of acne to oral isotretinoin, Actas Dermo-Sifiliograficas, 106, 126–32, 2015 [PubMed: 25306870]

  • Vender 2012

    Vender, R., Double-blinded, vehicle-controlled proof of concept study to investigate the recurrence of inflammatory and noninflammatory acne lesions using tretinoin gel (Microsphere) 0.04% in male patients after oral isotretinoin use, Dermatology Research and Practice (no pagination), 2012 [PMC free article: PMC3345215] [PubMed: 22577372]

  • Zhang 2004

    Zhang, J., Li, L. F., Tu, Y. T., Zheng, J., A successful maintenance approach in inflammatory acne with adapalene gel 0.1% after an initial treatment in combination with clindamycin topical solution 1% or after monotherapy with clindamycin topical solution 1%, Journal of Dermatological Treatment, 15, 372–378, 2004 [PubMed: 15764049]

Appendices

Appendix B. Literature search strategies

Literature search strategies for review question: What is the effectiveness of topical or oral pharmacological and physical interventions as maintenance treatment for acne vulgaris?

Clinical search

Download PDF (263K)

Economic search

Download PDF (131K)

Appendix H. Economic evidence tables

Economic evidence tables for review question: What is the effectiveness of topical or oral pharmacological and physical interventions as maintenance treatment for acne vulgaris?

No economic evidence was identified which was applicable to this review question.

Appendix I. Economic evidence profiles

Economic evidence profiles for review question: What is the effectiveness of topical or oral pharmacological and physical interventions as maintenance treatment for acne vulgaris?

No economic evidence was identified which was applicable to this review question.

Appendix J. Economic analysis

Economic analysis for review question: What is the effectiveness of topical or oral pharmacological and physical interventions as maintenance treatment for acne vulgaris?

No economic analysis was conducted for this review question.

Appendix K. Excluded studies

Excluded clinical and economic studies for review question: What is the effectiveness of topical or oral pharmacological and physical interventions as maintenance treatment for acne vulgaris?

Clinical studies

The excluded studies list below relates to all evidence reviews that used the same search output and these are studies that are excluded from all of them: mild-to-moderate NMA, moderate-to-severe NMA, mild-to-moderate pairwise and moderate-to-severe pairwise reports, as well as from refractory acne, maintenance of acne and polycystic ovary syndrome.

Table 18. Excluded studies and reasons for their exclusion.

Table 18

Excluded studies and reasons for their exclusion.

Economic studies

No economic evidence was identified for this review.

Appendix L. Research recommendations

Research recommendations for review question: What is the effectiveness of topical or oral pharmacological and physical interventions as maintenance treatment for acne vulgaris?

No research recommendations were made for this review question.