Management options for refractory acne
Evidence review H
NICE Guideline, No. 198
Authors
National Guideline Alliance (UK).Management options for refractory acne
Review question
What is the effectiveness of topical or oral pharmacological and physical interventions in treatment resistant acne vulgaris?
Introduction
Acne vulgaris improves or clears with appropriate treatment in many cases. However, in some individuals, the acne vulgaris may not respond adequately to treatment. This may include a lack of adequate response during the treatment or a deterioration in the acne vulgaris after the course of treatment has been completed. Treatment options for refractory acne vulgaris will depend on the extent and severity of the disease as well as the previous treatment(s) that the affected individual has used. Those with treatment resistant acne may therefore require adjustment to the treatment duration, additional or alternative options tailored to their individual needs. Finding the most effective treatment for refractory acne is therefore the aim of this evidence review.
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.
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
A systematic review of the clinical literature was conducted but no studies were identified which were applicable to this review question.
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
No studies were identified which were applicable to this review question (and so there are no evidence tables in Appendix D). No meta-analysis was undertaken for this review (and so there are no forest plots in Appendix E).
Quality assessment of included studies in the evidence review
No studies were identified which were applicable to this review question.
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 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.
Acceptability, tolerability and relapse were important outcomes as they indicate effectiveness and acceptability of the intervention. Side effects were also chosen as an important outcome as they indicate the safety of an intervention.
The quality of the evidence
No studies were identified which were applicable to this review question.
Benefits and harms
The recommendations are largely based on the committee’s knowledge and clinical experience as there was no evidence identified on refractory acne. However, when recommending what further treatment to offer, the committee also considered evidence about relative effectiveness of treatments for mild to moderate and moderate to severe acne summarised in other evidence reviews (see evidence reports E1 and F1). This evidence was taken into account because the treatment that would follow a failure to improve, or a relapse would depend on the severity of acne after the first treatment. The committee noted that the level of severity could have changed after the first treatment; potentially becoming worse if the acne was unresponsive, or less severe if it had responded adequately but later relapsed.
The committee discussed 2 situations. What to do when treatment has failed (once or several times) and what to do when the first treatment showed adequate improvement but there is a relapse. Even though the population of the review was people with acne vulgaris which has not responded to previous treatment, in the committee’s experience the person with acne would view a relapse also as a failure of treatment and they therefore made recommendations for both of these situations.
In the discussion of further treatments after treatment failure or relapse, they referred back to the recommendations they had made for the following treatment options (which were recommended as first-line treatment options based on the results from the network meta-analyses and pairwise comparisons of treatments described in evidence reports E1, E2, F1 and F2):
- a fixed combination of topical benzoyl peroxide and topical adapalene for any acne severity
- a fixed combination of a topical retinoid with topical clindamycin for any acne severity
- a fixed combination of topical benzoyl peroxide with topical clindamycin for mild to moderate acne
- fixed combination of topical adapalene and topical benzoyl peroxide, with either oral lymecycline or oral doxycycline for moderate to severe acne
- topical azelaic acid with either oral lymecycline or oral doxycycline for moderate to severe acne.
Failure to respond to treatment
The committee discussed several scenarios for further treatment after treatment failure. They agreed that failure to respond adequately (as jointly decided by the healtlhcare professional and the person with acne) would usually be established when the person’s acne would be reviewed. In the first instance the committee made recommendations related to failure after 1 treatment taking into account acne severity. In cases where mild to moderate acne vulgaris failed to respond to a 12-week course of appropriate first-line treatment, the committee agreed that the affected person could benefit from another choice of the appropriate options according to level of severity. The committee discussed that in their experience mild to moderate acne is likely to respond to a different topical treatment option if the first one has not worked because of the different treatments’ mechanisms of action. In cases where moderate to severe acne vulgaris failed to respond to a 12-week course of a first-line treatment that did not contain an oral antibiotic, the committee discussed that the next option would usually be one that contained an oral antibiotic so they made a weak recommendation for this. They decided to make this a weak recommendation because this treatment choice would depend on preferences as well as likely future treatment (for instance if a need for treatment with oral isotretinoin in anticipated). For moderate to severe acne that failed to respond to a first treatment that includes an oral antibiotic, the committee agreed that the affected person could be referred to a consultant dermatologist-led team for consideration of oral isotretinoin. The committee agreed that oral isotretinoin was often effective in this situation and their recommendation is consistent with the MHRA safety advice on isotretinoin for severe acne: uses and effects as well as the 2020 drug safety update that isotretinoin should be prescribed for people with severe forms of acne that is resistant to adequate courses of standard therapy with systemic antimicrobials.
The committee then discussed the issue of failing 2 treatments. This scenario is clear for people with moderate to severe acne because once they had a treatment that includes an oral antibiotic they would be considered for referral to a consultant dermatologist-led team regardless of whether it was a first or second treatment. They therefore focused on the situation where mild to moderate acne has failed to respond to 2 different 12-week courses of treatment. There were concerns by the committee that people with mild to moderate acne would remain on ineffective treatments for too long and that other options should be explored with specialists on a case by case basis. They therefore recommended that in these cases referral to a consultant dermatologist-led team should be considered.
Relapse after treatment
In cases where acne vulgaris, regardless of severity, relapses after an adequate improvement when treated with a course of appropriate first-line treatment, the committee recommended considering another course of the same or alternative treatment option. The committee agreed that another course of the effective treatment may well be appropriate since it previously improved the acne (as long as it was tolerated). However, they acknowledged that another option may well be preferred, for example if the first one involved antibiotics a change to a different treatment would avoid development of antibiotic resistance.
In cases where acne vulgaris relapsed after a successful treatment with oral isotretinoin and was mild to moderate in terms of severity, the committee agreed that an appropriate treatment option for mild to moderate acne severity should be offered. The committee agreed that when acne relapses after isotretinoin it may be in a milder form and in these cases treatments for mild to moderate acne are more appropriate, avoiding for example the side effects of oral antibiotics or another course of oral isotretinoin.
In cases where acne vulgaris relapsed after a successful treatment with oral isotretinoin and was moderate to severe in terms of severity, the committee recommended 2 treatment options as most likely to be effective: a 12-week course of an appropriate treatment option or a referral to a consultant dermatologist-led team to explore further options which may or may not be a further course of isotretinoin depending on preference and length of previous treatment success.
The committee agreed that recommending a referral to a consultant-led team after acne vulgaris relapsed after a treatment with 2 separate courses of oral isotretinoin, may lead to a change in the current clinical practice. However, they agreed that it is important for safety reasons to have a specialist review to explore reasons why acne continues to relapse even after two successful isotretinoin treatments.
The committee noted that there is variation in current practice in the use of a low dose of oral isotretinoin prescribed long-term to prevent relapse. Their experience suggests that this may have some success to control acne but there was no published evidence to recommend this approach. This particular gap in the evidence was identified in the network meta-analysis related to treatment for moderate to severe acne and therefore the effectiveness of a reduced dose of isotretinoin was prioritised for a research recommendation (see appendix L in evidence review F1).
Cost effectiveness and resource use
No economic evidence on the cost effectiveness of management options for refractory acne was identified. Due to lack of evidence specific to refractory acne, the committee decided to consider the economic evidence available for first line treatments (see evidence reports E1 and F1), which was the only evidence available on the cost-effectiveness of treatments for acne, and also use their knowledge and clinical experience in order to make recommendations for acne not responding to treatment or for acne that has relapsed. The committee acknowledged that the relative cost-effectiveness of treatments used as first line may differ from their relative cost-effectiveness if they are used as further-line treatments in acne that has not responded to treatment, because the relative effectiveness of treatments may be different (and overall the treatment effectiveness is likely to be lower in refractory acne). However, they expressed the opinion that this evidence was still appropriate to consider alongside their expert clinical opinion as this was the only evidence, of good quality, available (so it was better than using their expert clinical opinion alone) and because, based on their clinical experience, they did not anticipate major differences in the relative cost-effectiveness of treatments being used as first- versus further-line. The committee noted that the available evidence for first-line treatment of acne refers to a new ‘episode’ of acne and includes people with a first and people with subsequent acne episodes; therefore, this evidence is directly applicable to new episodes of acne after relapse.
The committee agreed that choosing among alternative cost-effective first-line treatment options for people with acne who fail to respond to first-line treatment, according to their level of symptom severity, is likely to comprise efficient use of resources, as there is good economic evidence (based on the guideline economic analysis) supporting the cost-effectiveness of recommended first-line options and the committee expressed the opinion that this evidence is unlikely to be very different for the same treatments when used as further line treatment options. For people with mild to moderate acne who fail to respond adequately to 2 consecutive 12-week treatments, the committee agreed that referral to specialist care incurs extra costs but ensures further assessment and appropriate care, which in turn are expected to lead to benefits for people with acne that are likely to outweigh associated specialist care costs. For people with moderate to severe acne who fail to respond adequately to a 12-week treatment that includes oral antibiotics, the committee agreed that referral to specialist care for consideration of treatment with oral isotretinoin ensures efficient use of resources, as the guideline economic analysis demonstrated the cost-effectiveness of treatment with oral isotretinoin in specialist care. The recommendations of treatments following relapse include either already recommended first-line treatment options and are thus supported by the guideline economic evidence (which, as explained earlier, is directly applicable to acne that has relapsed); or referral to a specialist dermatology care, the benefits of which are expected by the committee to outweigh associated costs as they ensure further assessment and appropriate care of persistent acne. In all cases, timely referral to specialist dermatology services is likely to result in savings further down the care pathway, as it is expected to lead to health improvements before clinical symptoms of refractory acne (acne that has not responded to treatment and acne after a relapse) become more severe and require more resource intensive, and thus costlier, management.
Recommendations supported by this evidence review
This evidence review supports recommendations 1.5.15 and 1.5.16 as well as 1.6.1 to 1.6.4 in the guideline. Other evidence supporting these recommendations can be found in the evidence reviews on management of mild to moderate acne and management of moderate to sever acne (evidence report E1/E2 and F1/F2).
References
No studies were identified for this review.
Appendices
Appendix A. Review protocol
Appendix B. Literature search strategies
Appendix C. Clinical evidence study selection
Appendix D. Evidence tables
Evidence tables for review question: What is the effectiveness of topical or oral pharmacological and physical interventions in treatment resistant acne vulgaris?
No evidence was identified which was applicable to this review question.
Appendix E. Forest plots
Forest plots for review question: What is the effectiveness of topical or oral pharmacological and physical interventions in treatment resistant acne vulgaris?
No evidence was identified which was applicable to this review question.
Appendix F. GRADE tables
GRADE tables for review question: What is the effectiveness of topical or oral pharmacological and physical interventions in treatment resistant acne vulgaris?
No evidence was identified which was applicable to this review question.
Appendix G. Economic evidence study selection
Appendix H. Economic evidence tables
Economic evidence tables for review question: What is the effectiveness of topical or oral pharmacological and physical interventions in treatment resistant 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 in treatment resistant 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 in treatment resistant 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 in treatment resistant acne vulgaris?
Clinical studies
Download PDF (1.4M)
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 in treatment resistant acne vulgaris?
No research recommendations were made for this review question.
Final
Evidence reviews underpinning recommendations 1.5.15 and 1.5.16 as well as 1.6.1 to 1.6.4 in the NICE guideline
These evidence reviews were developed by the National Guideline Alliance which is a part of the Royal College of Obstetricians and Gynaecologists
Disclaimer: The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian.
Local commissioners and/or providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.
NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn.