Rosacea treatment update Recommendations from the global ROSacea COnsensus (ROSCO) panel

Introduction Methods Results Conclusions Adapting for local use About ROSCO Delphi process Results General skincare First-line treatment Combination therapy Maintenance therapy Ocular features Conclusions Adapting for local use

What is rosacea? A chronic inflammatory skin condition that predominantly affects the central area of the face No official or universally accepted definition,1 but comprises a combination of characteristic major features The prevalent rosacea classification and treatment system is by subtype, based on defined groups of primary features2–12 Characteristic major features of rosacea Transient erythema (flushing) Persistent erythema Telangiectasia Inflammatory papules/pustules Phymas Ocular abnormalities 1. van Zuuren EJ, et al. Cochrane database Syst Rev 2015; 4:CD003262; 2. Wilkin J, et al. J Am Acad Dermatol 2002; 46:584–7; 3. Dahl M V. Cutis 2004; 74:21–7,32–4; 4. Odom R. Cutis 2004; 74:5–8,32–4; 5. Mackley CL, Thiboutot DM. Cutis 2005; 75:25–9; 6. Powell FC. N Engl J Med 2005; 352:793–803; 7. Goldgar C, et al. Am Fam Physician 2009; 80; 8. Odom R, et al. Cutis 2009; 84:43–7; 9. Odom R, et al. Cutis 2009; 84:97–104; 10. Baldwin HE. J Drugs Dermatol 2012; 11:725–30; 11. Reinholz M, et al. J Dtsch Dermatol Ges 2013; 11:768–79; 12. Weinkle AP, et al. Clin Cosmet Investig Dermatol 2015; 8:159–77.

Potential overlap of rosacea features with subtype classification Patients with rosacea often present with a range of features that span multiple NRS subtypes, or progress between them1,2 ETR PPR Phymatous Ocular Facial erythema (transient and persistent) Telangiectasia Inflammatory papules/pustules Phymatous changes Ocular manifestations ETR, erythematotelangiectatic rosacea; PPR, papulopustular rosacea; NRS, National Rosacea Society. 1. Weinkle AP, et al. Clin Cosmet Investig Dermatol 2015; 8:159–77. 2. Tan J, et al. Br J Dermatol 2013; 169:555–62.

Transitioning from subtypes to phenotypes Rosacea presentation may be more accurately defined as “phenotype”, since features can span multiple subtypes or progress between them,1–3 Subtype classification may not fully cover the full range of clinical presentations A phenotype-based approach would address rosacea and its treatment in a manner more consistent with the patient’s individual experience phenotype /ˈfiːnə(ʊ)tʌɪp/ n. an individual’s observable characteristics that can be influenced by genetic or environmental factors.4 “As a provisional standard classification system, [the subtype classification] is likely to require modification in the future as the pathogenesis and subtypes of rosacea become clearer, and as its relevance and applicability are tested by investigators and clinicians.” – NRS, 20025 NRS, National Rosacea Society. 1. Powell FC. N Engl J Med 2005; 352:793–803. 2. Weinkle AP, et al. Clin Cosmet Investig Dermatol 2015; 8:159–77. 3. Tan J, et al. Br J Dermatol 2013; 169:555–62. 4. National Human Genome Research Institute. Available at: http://www.genome.gov/glossary/index.cfm?id=152. Accessed 21 March 2016; 5. Wilkin J, et al. J Am Acad Dermatol 2002; 46:584–7.

The need for a new approach Treatment outcomes Research and development Less common presentations (e.g. phymatous changes; ocular rosacea) receive less attention than the more common features such as inflammatory papules/pustules and erythema1 RCT evidence is still lacking for particular treatments or features,1 so physicians have limited guidance Subtype-based inclusion criteria/ outcome assessments in clinical trials may not address all presenting features1 Assessment methodologies in many clinical trials are variable and could be of higher quality1,2 RCT, randomised controlled trial. 1. van Zuuren EJ, et al. Cochrane database Syst Rev 2015; 4:CD003262; 2. Hopkinson D, et al. J Am Acad Dermatol 2015; 73:138–43.e4.

Potential benefits of a phenotype approach Treatment outcomes Research and development May better address the spectrum of presenting features Target the aspects that most trouble the patient Broaden the patient spectrum across clinical trial recruitment and assessment measures A consolidated body of clinical evidence may support treatment decisions in the absence of RCT evidence

Introduction Methods Results Conclusions Adapting for local use About ROSCO Delphi process Results General skincare First-line treatment Combination therapy Maintenance therapy Ocular features Conclusions Adapting for local use

About ROSCO: An international consensus project Expert panel Objectives 17 dermatologists from Argentina, Brazil, Canada, China, France, Germany, India, Ireland, Singapore, South Africa, the UK and the USA 3 ophthalmologists from Germany (n=1) and the USA (n=2) Process overseen by two chairpersons, who were involved in panel selection and Delphi design To gain expert opinion and formulate a treatment algorithm for rosacea based on best evidence and clinical practice To provide guidance on local/national adaptation

Introduction Methods Results Conclusions Adapting for local use About ROSCO Delphi process Results General skincare First-line treatment Combination therapy Maintenance therapy Ocular features Conclusions Adapting for local use

Methods | Modified Delphi process All dermatologists completed the surveys and contributed at the meeting Not all panellists answered all questions All ophthalmologists completed the ocular surveys In addition, one participated at the meeting Dr Mark Mannis only ROSCO panel 17 dermatologists 3 ophthalmologists Dermatology e-survey 1 Ophthalmology e-survey 1 Dermatology e-survey 2 Ophthalmology e-survey 2 Dermatology e-survey 3 Face-to-face meeting

Methods | Modified Delphi process (continued) Questionnaire development and administration Consensus statements assessed level of agreement as ‘strongly disagree’, ‘disagree’, ‘agree’ or ‘strongly agree’ Consensus: ≥75% ‘agree’ or ‘strongly agree’ Some questions were open-ended to allow for the development of consensus statements in a subsequent round of voting Meeting process Points without consensus at survey stage were discussed at the meeting Panellists received an overview of each topic followed by workshop exercises on rosacea treatment Discussions incorporated GRADE quality of evidence from the Cochrane review on ‘interventions for rosacea’,1 to combine available evidence with clinical experience After each workshop, consensus statements were constructed and voted on Voting was conducted by keypads and panellists were blinded to individual votes If consensus was not reached, panellists discussed, refined the statement, and re-voted GRADE, Grading of Recommendations Assessment, Development and Evaluation. 1. van Zuuren EJ, et al. Interventions for rosacea. Cochrane database Syst Rev 2015; 4:CD003262.

Introduction Methods Results Conclusions Adapting for local use About ROSCO Delphi process Results General skincare First-line treatment Combination therapy Maintenance therapy Ocular features Conclusions Adapting for local use

Results | General skin care The education and instruction of proper general skin care is essential for all patients with rosacea, to ensure the best possible treatment outcomes (15/18) Essential skin care advice elements are: Use of sunscreen SPF 30+ (17/18) Frequent use of moisturisers (15/18) Use of gentle over-the-counter cleansers (16/18) Known trigger avoidance (18/18) General skin care was agreed to be the main management strategy for the secondary features of dry appearance, dry sensation and stinging sensation (12/15) *Associated with periodic intensification by potential trigger factors.

Introduction Methods Results Conclusions Adapting for local use About ROSCO Delphi process Results General skincare First-line treatment Combination therapy Maintenance therapy Ocular features Conclusions Adapting for local use

Results | First-line treatment *There is no high-quality evidence for flushing treatments; consensus on this statement is based on case reports and clinical evidence. †Persistent centrofacial erythema associated with periodic intensification by potential trigger factors. ‡Doxycycline 40 mg modified release superior to placebo; doxycycline 40 mg modified release non-inferior to doxycycline 100 mg. No inference possible from indirect comparison.

Introduction Methods Results Conclusions Adapting for local use About ROSCO Delphi process Results General skincare First-line treatment Combination therapy Maintenance therapy Ocular features Conclusions Adapting for local use

Results | Combination therapy Multiple cutaneous features of rosacea can be treated with more than one agent simultaneously (15/15) If first-line treatment fails, physicians should either consider an alternative first-line option, or add an additional first-line agent (16/17) Considerations Moderate and severe presentations of major features require a combination of treatments, which could include: General skin care Physical modalities Pharmaceutical agents The exception was telangiectasia, where opinion was divided over the use of mono- or combination therapy at any severity level Opinion was also divided on whether mild presentations of primary features should be treated with mono- or combination therapy

Introduction Methods Results Conclusions Adapting for local use About ROSCO Delphi process Results General skincare First-line treatment Combination therapy Maintenance therapy Ocular features Conclusions Adapting for local use

Results | Maintenance therapy The approach to rosacea maintenance therapy depends on treatment modality and patient desire for ongoing therapy (17/17) The minimum treatment to maintain control should be used (17/17) It is important to allow treatments sufficient duration to take effect before switching to an alternative. The definition of ‘sufficient time’ is specific to the treatment (17/17)

Introduction Methods Results Conclusions Adapting for local use About ROSCO Delphi process Results General skincare First-line treatment Combination therapy Maintenance therapy Ocular features Conclusions Adapting for local use

Results | Ocular features Expectations for recognition and referral Expectations for treatment and management No referral from a dermatologist for very mild ocular rosacea features that do not bother the patient Referral should be considered for ocular features of greater severity, which cannot be controlled with lid hygiene A dermatologist should recognise the following as ocular rosacea features: Blepharitis Blurred vision Foreign body sensation Interpalpebral bulbar hyperaemia Photophobia Redness Tearing Telangiectasia No treatment prior to referral Exception: prescription of artificial tear substitutes for mild ocular burning/ stinging UV-coated sunglasses and lid hygiene are important general eye care factors for managing ocular rosacea Proper instruction/teaching of general eye care can ensure the best possible treatment outcomes Optimal lid hygiene consists of: Warm compresses Meibomian gland expression Dilute baby shampoo scrubs Lubricating drops. Note: Since only three ophthalmologists were involved in the ROSCO project, the ocular rosacea outcomes may be less generalisable to all ophthalmologists than those relating to cutaneous features. The purpose of this section is to indicate current thinking amongst ophthalmologists expert in ocular rosacea, where at least two out of three panellists agreed on a statement, since ocular rosacea is considered a multi-disciplinary challenge. 1. Odom RB. Cutis 2004; 73:9–14.

Results | Ocular features Treatment options for ocular rosacea by severity level Mild (mild blepharitis with lid margin telangiectasia) Moderate (blepharoconjunctivitis/ blepharokerato- conjunctivitis) Severe (sclerokeratitis) Topical Lid hygiene Lid hygiene + cyclosporine Lid hygiene + topical corticosteroids Systemic Dietary supplementation Doxycycline 40 mg MR Doxycycline ≥50 mg Multiple treatments may be used simultaneously, e.g. a topical and a systemic agent Ocular signs/symptoms may present with or without skin disease *May not be necessary for some mild cases. Note: Since only three ophthalmologists were involved in the ROSCO project, the ocular rosacea outcomes may be less generalisable to all ophthalmologists than those relating to cutaneous features. The purpose of this section is to indicate current thinking amongst ophthalmologists expert in ocular rosacea, where at least two out of three panellists agreed on a statement, since ocular rosacea is considered a multi-disciplinary challenge. MR, modified release. 1. Odom RB. Cutis 2004; 73:9–14.

Introduction Methods Results Conclusions Adapting for local use About ROSCO Delphi process Results General skincare First-line treatment Combination therapy Maintenance therapy Ocular features Conclusions Adapting for local use

Strengths and limitations of the project The Delphi process is increasingly used to develop treatment guidelines and recommendations, due to its systematic, democratic approach and scope for qualitative evidence assessment1–7 The majority of voting relied on clinical opinion and there may have been good evidence contradicting a particular statement It is a concern of some researchers that the Delphi process is not necessarily ‘evidence-based’ and relies on clinical opinion1,7 However, the process is exploratory in nature and well suited for issues such as those addressed by ROSCO which are difficult to define, expertise-specific and future-orientated8 Blinded voting and consideration of published evidence was used to overcome these concerns as far as possible 1. Armon K, et al. Arch Dis Child 2001; 85:132–42; 2. Behrens A, et al. Cornea 2006; 25:900–7; 3. Jefferson A, et al. PLoS One 2016; 11:e0146824; 4. Maxwell GP, et al. Plast Reconstr surgery Glob open 2015; 3:e557; 5. Westby MD, et al. Arthritis Care Res (Hoboken) 2014; 66:411–23; 6. van de Velde CJH, et al. Eur J Cancer 2014; 50:1.e1–1.e34; 7. Jones J, Hunter D. BMJ 1995; 311:376–80; 8. Fletcher AJ, Marchildon GP. Int J Qual Methods 2014; 13:1–18.

Conclusions Recommendations Implications A phenotype approach to rosacea diagnosis, severity grading and management Patient-focused goal-setting Development of a novel psychosocial tool to evaluate the burden of rosacea ROSCO provides a global perspective on rosacea diagnosis and classification with representation from Africa, Asia, Europe, North/South America, which can be adapted for local guidelines The recommended updated approach is likely to improve management in all patients with rosacea by individualising therapy

Introduction Methods Results Conclusions Adapting for local use About ROSCO Delphi process Results General skincare First-line treatment Combination therapy Maintenance therapy Ocular features Conclusions Adapting for local use

Adapting for local use ROSCO is a global project and provides a basis for adaptation and development of local clinical practice guidelines When adapting for local use, you may wish to consider: Patient values/preferences Treatment availability Cost