FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses
Research recommendations for review question: For people with moderate to severe acne vulgaris what are the most effective treatment options?
Research question - reduced dose oral isotretinoin What is the efficacy of reduced dose oral isotretinoin in the management of acne vulgaris?
Why this is important Oral isotretinoin is prescribed by consultant dermatologist-led team for severe forms of acne resistant to adequate courses of standard therapy with systemic antibacterials and topical therapy. The daily dose typically ranges between 0.5mg to 1mg/kg, however dosage adjustments may be required for people with severe intolerances or whom are at higher risk of developing serious adverse effects. There is limited high-quality data on the efficacy and optimum treatment duration of reduced (less than 0.5mg/kg) daily dose isotretinoin in acne. Furthermore, there have been reports of the successful use of reduced daily dose isotretinoin, including weekly (mini) or bi-weekly (micro) dosage regime as maintenance therapy in people with recurrent relapse despite adequate response to multiple courses of isotretinoin. The evidence for reduced dose isotretinoin as maintenance therapy have been limited to case series and small cohort studies. Further research will help to establish if • reduced daily dose of oral isotretinoin is effective in the treatment of acne vulgaris • reduced dose isotretinoin regime is effective as maintenance therapy; and • the optimum duration of treatment.
Table 26: Research recommendation rationale Research question What is the efficacy of reduced dose oral isotretinoin in the management of acne vulgaris? Why is this needed Importance to ‘patients’ or the The daily dose of isotretinoin prescribed usually ranges between population 0.5mg – 1mg/kg. For some people, the dosage adjustment to the maximum tolerated dose may reduce the risk of adverse effects, as the risk of certain adverse effects is dose dependent. However, there is limited high-quality data on the effectiveness of reduced daily dose of isotretinoin for treating acne and the optimum duration of treatment.
In people with recurrent acne relapse despite adequate response to multiple courses of isotretinoin, reduced dose isotretinoin regime may be an attractive option. However, evidence for reduced dose isotretinoin in this population is limited to case series and small cohort studies. Relevance to NICE guidance There was limited evidence for the use of oral isotretinoin at a reduced daily dose in acne for the committee to make a strong recommendation. There was a lack of data on the use of low dose isotretinoin in acne maintenance therapy for any recommendations to be made. Therefore, research investigating the efficacy and safety of reduced dose oral isotretinoin is warranted.
394 Acne vulgaris: evidence reviews for management options for people with moderate to severe acne vulgaris (NMA) FINAL(June 2021)
FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses
Research question What is the efficacy of reduced dose oral isotretinoin in the management of acne vulgaris? Relevance to the NHS Acne vulgaris, which is the eighth most prevalent disease globally, affects the majority of teenagers and young adults and is common in the UK. Severe intolerance, significant adverse effects are dose dependent and therefore reduced dose oral isotretinoin may offer a safer and effective alternative to standard dose oral isotretinoin.
For people with recurrent relapsing acne, treatment options are currently limited and reduced daily dose including mini and micro dose regimes may be a suitable and effective option as maintenance treatment. National priorities • The Medicines and Healthcare Products Regulatory Agency (MHRA) in 2020 are in the process of conducting an in-depth review of psychiatric and sexual adverse effects of oral isotretinoin with the aim to reduce risk of these adverse effects. As many isotretinoin associated adverse effects are dose related, there is a clear benefit of investigating whether reduced dose oral isotretinoin is safe and effective. • Reducing antibiotic prescribing in order to prevent antimicrobial resistance is a national priority. It would be helpful to determine whether reduced dose oral isotretinoin would be an effective and safe alternative to repeated courses of oral and/or topical antibiotics in the treatment of acne and as maintenance therapy. Current evidence base Limited research has been conducted on this area and therefore additional, high-quality studies are required. Equality Not applicable Feasibility People receiving oral isotretinoin would need to be provided with adequate detailed information about the potential adverse effects of isotretinoin and participants in studies investigating reduced dose oral isotretinoin would need to be monitored for these adverse effects. Other comments Not applicable
Table 27: Research recommendation characteristics table Criterion Explanation Population People with: • severe forms of acne resistant to adequate courses of standard therapy with systemic antibacterials and topical therapy • refractory acne vulgaris despite previous treatment courses with standard daily dose oral isotretinoin • cleared acne who require maintenance treatment due to previous relapses. Intervention Reduced dose oral isotretinoin as: • reduced daily dose (less than 0.5mg/kg) • reduced dose regime (mini or micro) Comparator • Standard daily dose of isotretinoin • Treatment that includes an oral antibiotic
394 Acne vulgaris: evidence reviews for management options for people with moderate to severe acne vulgaris (NMA) FINAL(June 2021)
FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses
Criterion Explanation Outcomes • Clinician reported improvement, including change in acne lesion count • Patient reported improvement • Recurrence • Adverse events, in particular: - mucosal / cutaneous changes (for example new chelitis) - change in mood - new psychiatric diagnosis - suicidality Study design Randomised controlled trial Timeframe • 6 months (intervention) and 12 months (follow-up) for treatment study • 12 months (intervention) and 12 months (follow-up) for maintenance study Additional information Not applicable
Research question - physical modalities (excluding chemical peels) What is the effectiveness of physical modalities, (such as light devices) in the treatment of acne vulgaris orpersistent acne vulgaris-related scarring?
Why this is important Physical treatments for acne are popular with people because they have the benefit of treating a local area without systemic effects. They can be used in people with co-morbidities or side effects where other treatments are unsuitable. They are currently available in the private sector but there is no standardisation of treatment modalities or duration. Many different physical therapies have been described for acne including: • Comedone extraction • Phototherapy – including UVB, intense pulsed light, blue and red light • Photochemical therapy (e.g. photodynamic therapy) • Laser • Photopneumatic therapy (e.g. intense pulsed light + vacuum) • Photothermal therapy (eg gold nanoparticles +light or laser) Physical treatments are also used for acne scarring. These include: • Punch excision • CO2 laser • Dermabrasion • Radiofrequency (e.g. fractional microneedling, bipolar) Further research is required to determine the most effective physical treatments for acne and acne scarring. This could open the way to wider availability in the NHS.
Table 28: Research recommendation rationale Research question What is the effectiveness of physical modalities (such as light devices) in the treatment of acne vulgaris or persistent acne vulgaris-related scarring? Why is this needed
394 Acne vulgaris: evidence reviews for management options for people with moderate to severe acne vulgaris (NMA) FINAL(June 2021)
FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses
Research question What is the effectiveness of physical modalities (such as light devices) in the treatment of acne vulgaris or persistent acne vulgaris-related scarring? Importance to ‘patients’ or the Physical treatments for acne are popular with people because population they have the benefit of treating a local area without systemic effects. They can be used in people with co-morbidities or side effects where other treatments are unsuitable. There is evidence from small studies that physical therapies including various light sources with or without addition of chemical or physical photosensitiser may be effective in all grades of acne. There is also some evidence to support CO2 laser treatment for acne scarring. However, the studies are too small or of insufficient quality to allow recommendations to be made. Relevance to NICE guidance Currently physical treatments for acne vulgaris cannot be recommended. Weak recommendation can be made for CO2 laser for acne scarring, but stronger evidence is required to allow a stronger recommendation. which would lead to wider availability on NHS. Relevance to the NHS Acne vulgaris is the most common skin condition affecting the majority of teenagers and young adults. Acne scarring leads to lifelong psychological distress for some people. Physical treatments for acne could provide an alternative for people unwilling or unable to use other treatment modalities. With more evidence of effectiveness and cost effectiveness these treatments may become available on the NHS. Physical treatments for acne scarring may benefit the NHS by reducing psychological morbidity. National priorities There are 2 national priorities, one is to improve young people’s mental health and another is to reduce antibiotic prescribing to prevent resistance. • Improving the mental health of young people is a national priority. Improving acne can have a positive impact on mental health. Rates of depression and suicide are increasing in the under 25-year-old age group, especially amongst men 20-25 years old. (suicides in the UK 2019 ons.gov.uk). In 2018 the government produced a paper ‘Transforming children’s and young people’s mental health provision’, including improving services for those 16-25 years old. This aligns with a need to understand support required for young people with acne vulgaris https://www.gov.uk/government/consultations/transforming- children-and-young-peoples-mental-health-provision-a-green- paper/quick-read-transforming-children-and-young-peoples- mental-health-provision • Acne has traditionally been treated with long courses of antibiotics. If any particular type of physical treatment could be identified as having a positive impact on acne vulgaris then it may lead to a decreased need for antibiotics. Antibiotic resistance is rising in the UK and the government wants to optimise antibiotic prescribing to prevent the development of superbugs. Keeping people well informed would therefore help to address this priority (Tackling antimicrobial resistance 2019–2024 The UK’s five-year national action plan Published 24 January 2019. HM Government) https://assets.publishing.service.gov.uk/government/uploads/s ystem/uploads/attachment_data/file/784894/UK_AMR_5_year _national_action_plan.pdf
394 Acne vulgaris: evidence reviews for management options for people with moderate to severe acne vulgaris (NMA) FINAL(June 2021)
FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses
Research question What is the effectiveness of physical modalities (such as light devices) in the treatment of acne vulgaris or persistent acne vulgaris-related scarring? Current evidence base It is hard to draw conclusions from the current evidence. There are a lack of existing randomised controlled trials in physical treatments for acne and acne scarring, and those which have been done have been variable quality on small numbers of participants. Equality Access to any recommended physical treatments for acne or acne scarring currently differs across the country and according to socioeconomic group. They are mainly available in the private sector. Feasibility Physical treatments need to be supervised, even if they are delivered at home. There would be significant NHS costs associated with setting up provision for physical treatments, but this may be offset by benefits. A time commitment from participants would be required. Other comments Not applicable
Table 29: Research recommendation characteristics table - (a) relates to acne management and (b) persistent acne vulgaris-related scarring management Criterion Explanation Population a) Adults with acne vulgaris.
b) Adults with persistent acne vulgaris-related scarring Intervention a) any physical intervention (excluding chemical peels) for acne, for example: • A range of light therapies
b) any physical intervention for acne scarring, for example • CO2 laser single or multiple treatments Comparison a) no treatment or another active treatment.
b) no treatment for acne scarring Outcome a) Participant reported improvement, clinician reported improvement in lesion count b) Participant reported improvement, clinician reported improvement in scar appearance a) Recurrence a&b) Side effects: participant and clinician reported, including pigmentary changes and scarring Study design Randomised controlled trial Timeframe a) • 3-6 months (intervention) • 6 month (follow-up) b) • Intervention period • 6 and 12 month follow up Additional information Ideally longer term follow-up data collection would also be useful.
394 Acne vulgaris: evidence reviews for management options for people with moderate to severe acne vulgaris (NMA) FINAL(June 2021)
FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses
Research question - chemical peels What is the effectiveness of chemical peels in the treatment of acne vulgaris or persistent acne vulgaris-related scarringacne?
Why this is important Chemical peels are used to remove the surface of the skin. Peels may be ‘superficial’ for treatment of acne vulgaris, removing the dead layer of skin, or ‘deeper’ for atrophic scar management. They are usually applied repeatedly as a course of treatment. Chemical peels are currently not used as standard treatment in the NHS but are available to buy by the public and can be provided by private aesthetic practitioners. The use of chemical peels has potential to change acne and acne scarring management, as an alternative to those who cannot use, tolerate, or are resistant, to other treatments. Therefore, further research is needed to establish its effectiveness.
Table 30: Research recommendation rationale Research question What is the effectiveness of chemical peels in the treatment of acne vulgaris or persistent acne vulgaris-related scarringacne? Why is this needed Importance to ‘patients’ or Chemical peels have the potential to be used as an alternative for the population people who cannot use, tolerate, or are resistant, to other treatments but they are not currently available in the NHS. Relevance to NICE guidance Chemical peels are currently not routinely offered as a treatment of acne vulgaris or acne associated scarring in the NHS and there is insufficient evidence to make a strong recommendation. Relevance to the NHS Acne vulgaris is the most common skin condition affecting the majority of teenagers and young adults. Acne scarring leads to lifelong psychological distress for some people. Chemical peels for acne could provide an alternative for people unwilling or unable to use other treatment modalities. With more evidence of effectiveness and cost effectiveness these treatments may become available on the NHS. Chemical peels for acne scarring may benefit the NHS by reducing psychological morbidity. National priorities • Acne has traditionally been treated with long courses of antibiotics. If chemical peels are shown to be effective in the management of acne vulgaris then it may lead to a decreased need for antibiotics. Antibiotic resistance is rising in the UK and the government wants to optimise antibiotic prescribing to prevent the development of superbugs. Keeping people well informed would therefore help to address this priority (Tackling antimicrobial resistance 2019–2024 The UK’s five-year national action plan Published 24 January 2019. HM Government) https://assets.publishing.service.gov.uk/government/uploads/sy stem/uploads/attachment_data/file/784894/UK_AMR_5_year_n ational_action_plan.pdf • There are safety concerns about the use of oral retinoids (https://www.gov.uk/government/publications/isotretinoin-for- severe-acne-uses-and-effects) so provision of alternative therapy would be welcome if safe and effective.
394 Acne vulgaris: evidence reviews for management options for people with moderate to severe acne vulgaris (NMA) FINAL(June 2021)
FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses
Research question What is the effectiveness of chemical peels in the treatment of acne vulgaris or persistent acne vulgaris-related scarringacne? • Improving the mental health of young people is a national priority. If chemical peels are safe and effective to improve acne it may help improve self-esteem and confidence. Rates of depression and suicide are increasing in the under 25-year-old age group, especially amongst men 20-25 years old. (suicides in the UK 2019 ons.gov.uk). In 2018 the government produced a paper ‘Transforming children’s and young people’s mental health provision’, including improving services for those 16-25 years old. More effective acne treatment can have a positive impact on mental wellbeing and therefore addresses this priority. https://www.gov.uk/government/consultations/transforming- children-and-young-peoples-mental-health-provision-a-green- paper/quick-read-transforming-children-and-young-peoples- mental-health-provision Current evidence base There was no evidence for the use of chemical peels, either alone or combined, in moderate to severe acne treatment. There was some evidence that chemical peels may be effective in the treatment of mild to moderate acne. However, there was a low number of studies with small sample size. None of the studies compared effectiveness of chemical peels against placebo. The evidence base for chemical peels in treatment of acne associated scarring was low to very low quality with small sample size and limited follow-up time. Equality None specified Feasibility This research is feasible Other comments Not applicable
Table 31: Research recommendation characteristics table – (a) relates to acne management and (b) persistent acne vulgaris-related scarring management Criterion Explanation Population a) Adults with acne vulgaris.
b) Adults with persistent acne vulgaris-related scarring Intervention a) Chemical peels for the treatment acne b) Chemical peels for the treatment of acne associated scarring Comparison Any other peel Any other treatment Placebo Outcome a) Patient reported improvement, clinician reported improvement in lesion count b) Patient reported improvement, clinician reported improvement in scar appearance a) Recurrence a&b) Side effects: patient and clinician reported, including pigmentary changes and scarring Study design Randomised control trial or split-face trial Timeframe Likely treatment over 3 months with follow up to 3 years Additional information Not applicable
394 Acne vulgaris: evidence reviews for management options for people with moderate to severe acne vulgaris (NMA) FINAL(June 2021)
FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses
Research question – hormone-modifying agents in the treatment of acne
What is the effectiveness of hormone modifying agents in the treatment of acne vulgaris?
Why this is important Hormone modifying agents are used in the management of acne based on clinical expertise and experience. These treatments may be beneficial for people requiring long-term maintenance or those who do not wish to take oral antibiotics or isotretinoin. There is currently limited evidence of efficacy and long-term safety. Hormone modifying agents may include: • Oral spironolactone • Oral cyproterone acetate (alone or combined with ethinyl oestradiol) • Oral combined oral contraceptive preparations containing drospirenone or other anti- androgenic progesterones • Oral metformin (indirect antiandrogenic effect) • Topical clascoterone Further research is required to determine the efficacy of hormone modifying agents in the treatment of acne vulgaris.
Table 32: Research recommendation rationale Research question What is the effectiveness of hormone modifying agents in the treatment of acne vulgaris? Why is this needed Importance to ‘patients’ or the Hormone modifying agents may be an alternative option for population people with acne who do not wish to take or have contraindications to oral antibiotics or isotretinoin. It can be used long-term with minimal monitoring and can form part of the maintenance treatment in acne. There is insufficient evidence from the review to make recommendations though it is used in clinical practice for selective patients. Relevance to NICE guidance Hormone modifying agents are currently not included in the recommendations for acne management. More research and high-quality evidence may lead to widening the recommendation on acne management and help individuals access these treatments as part of their care. Relevance to the NHS Acne vulgaris is the most common skin condition affecting the majority of teenagers and young adults. In some people, acne may persist or develop in adulthood. Hormone modifying agents could provide an alternative option in the treatment of acne, which requires minimal monitoring and may be offered in primary care and for maintenance treatment.
National priorities There are 2 national priorities, one is to improve young people’s mental health, and another is to reduce antibiotic prescribing to prevent resistance. There is also an MHRA review underway regarding isotretinoin prescribing due to concerns about safety. • Improving the mental health of young people is a national priority. Improving acne can have a positive impact on mental health. Rates of depression and suicide are increasing in the under 25-year-old age group, especially amongst men 20-25 years old. (suicides in the UK 2019 ons.gov.uk). In 2018 the
394 Acne vulgaris: evidence reviews for management options for people with moderate to severe acne vulgaris (NMA) FINAL(June 2021)
FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses
Research question What is the effectiveness of hormone modifying agents in the treatment of acne vulgaris? government produced a paper ‘Transforming children’s and young people’s mental health provision’, including improving services for those 16-25 years old. This aligns with a need support young people with acne vulgaris, highlighting the importance of timely treatment and its impact on the person’s mental wellbeing. https://www.gov.uk/government/consultations/transforming- children-and-young-peoples-mental-health-provision-a-green- paper/quick-read-transforming-children-and-young-peoples- mental-health-provision • Antibiotic resistance is rising in the UK and the government wants to optimise antibiotic prescribing to prevent the development of multi-drug resistant pathogens. If hormone modifying agents have been shown to be an effective treatment in acne, this will lead to reduction in antibiotic prescribing. (Tackling antimicrobial resistance 2019–2024 The UK’s five-year national action plan Published 24 January 2019. HM Government) https://assets.publishing.service.gov.uk/government/uploads/s ystem/uploads/attachment_data/file/784894/UK_AMR_5_year _national_action_plan.pdf • Hormone modifying agents may be an alternative treatment option for individuals who do not wish to or have contraindications to isotretinoin. This is important as there is currently an ongoing review by the MHRA on the safety of isotretinoin. Current evidence base There is limited evidence available for the use of hormone modifying agents in the treatment of acne. The trials were small, with differing primary outcomes and were of varying quality. It is hard to draw conclusions from the current evidence. Equality The use of hormone modifying agents in the treatment of acne currently differs across the country and may be more readily available in the private sector. Oral hormone modifying agents which are anti-androgenic are used in females. Topical hormone modifying agents have been shown to be safe in males and children aged 9 and above. Feasibility Hormone modifying agents are low cost, and available in primary care. Minimal monitoring is required for long-term use. Other comments Not applicable
Table 33: Research recommendation characteristics table - (a) relates to acne management in adult females and (b) acne management in adult or adolescent Criterion Explanation Population a) Adult females with acne vulgaris b) Adults or adolescents with acne vulgaris
Intervention a) Any oral or topical anti-androgen, for example: • Spironolactone • Oral cyproterone acetate • Topical clascoterone
b) Any topical anti-androgen, for example
394 Acne vulgaris: evidence reviews for management options for people with moderate to severe acne vulgaris (NMA) FINAL(June 2021)
FINAL Management options for people with moderate to severe acne vulgaris - network meta-analyses
Criterion Explanation • Topical clascoterone
Comparison No treatment or another active treatment.
Outcome • Participant reported improvement, clinician reported improvement in lesion count • Recurrence • Side effects: participant and clinician reported, including pigmentary changes and scarring Study design Randomised controlled trial Timeframe Intervention period • 6 months (intervention) • 6 month (follow-up) Additional information Ideally longer term follow-up data collection would also be useful.
394 Acne vulgaris: evidence reviews for management options for people with moderate to severe acne vulgaris (NMA) FINAL(June 2021)