Updating the diagnosis and classification of rosacea Recommendations from the global ROSacea COnsensus (ROSCO) panel

Diagnosis and classification Introduction Methods About ROSCO Delphi process Results Diagnosis and classification Severity Psychosocial burden Treatment goals Ocular rosacea 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: 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.

Current diagnostic practice according to 2002 NRS recommendations Primary diagnostic criteria (≥1) Secondary features (occurring independently or with primary features) Transient erythema Persistent erythema Inflammatory papules/pustules Telangiectasia Phymatous changes Burning or stinging sensations Erythematous plaques Facial dryness and scaling Oedema Peripheral location Ocular signs/symptoms NRS, National Rosacea Society. Wilkin J, et al. J Am Acad Dermatol 2002; 46:584–7.

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 and confound severity assessment 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.

Measuring rosacea severity A variety of scales are used to measure rosacea severity1 Some are repurposed from other disease areas Larger-scale studies and validated scales are required for accurate and consistent severity measurement of individual features2 The greatest value is likely to be in objective, practical tools to: Set treatment targets Monitor treatment progress Existing severity scales for rosacea clinical features Phenotype Scale Flushing FAST; GFSS Persistent erythema IGA; CEA/PSA Telangiectasia None Papules/pustules Lesion counts, IGA Phymatous changes Ocular manifestations Pending CEA, Clinician’s Erythema Assessment; FAST, Flushing Asessment Tool; GFSS, Global Flushing Severity Score; IGA, Investigator’s Global Assessment; PSA, Patient’s Self-Assessment. 1. Hopkinson D, et al. J Am Acad Dermatol 2015; 73:138–43.e4. 2. Van Zuuren EJ, et al. Cochrane database Syst Rev 2015; 4:CD003262.

Psychosocial burden assessment The patient burden of rosacea can be significant1–4 Updated scales are still required to assess the psychosocial burden of rosacea Only 10% of Cochrane-review-eligible rosacea RCTs included quality-of-life assessments5 Less than half of the remaining studies reported participant-assessed changes in severity and satisfaction associated with these changes5 RosaQoL is the only rosacea-specific tool used to assess the psychosocial burden A 21-item scale6 Does not cover all clinical features (e.g. phyma)6 May have limited use in clinical practice RCT, randomised controlled trial. 1. Cresce ND, et al. J Drugs Dermatol 2014; 13:692–7; 2. Aksoy B, et al. Br J Dermatol 2010; 163:719–25; 3. Su D, Drummond PD. Clin Psychol Psychother 2012; 19:488–95; 4. Dirschka T, et al. Dermatol Ther (Heidelb) 2015; 5:117–27; 5. Van Zuuren EJ, et al. Cochrane database Syst Rev 2015; 4:CD003262; 6. Nicholson K, et al. J Am Acad Dermatol 2007; 57:213–21.

Diagnosis and classification Introduction Methods About ROSCO Delphi process Results Diagnosis and classification Severity Psychosocial burden Treatment goals Ocular rosacea 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, the Netherlands, 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 reach consensus on diagnosis and classification of rosacea To begin the development of a scale/grading system for physical and psychological features of rosacea To provide guidance on local/national adaptation

Diagnosis and classification Introduction Methods About ROSCO Delphi process Results Diagnosis and classification Severity Psychosocial burden Treatment goals Ocular rosacea 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 diagnosis, classification, severity and psychosocial burden 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

Diagnosis and classification Introduction Methods About ROSCO Delphi process Results Diagnosis and classification Severity Psychosocial burden Treatment goals Ocular rosacea Conclusions Adapting for local use

Results | Diagnosis and classification Diagnostic, major and secondary features of rosacea Diagnostic features (≥75% consensus) Major features (≥50% agreement) Secondary features (≥75% consensus) Persistent centrofacial erythema* Flushing/transient erythema Burning sensation Phymatous changes Inflammatory papules/pustules Stinging sensation Telangiectasia Oedema Ocular manifestations Dry sensation The central facial location of signs and symptoms is essential for the diagnosis of rosacea (17/18) The bilateral facial location of signs and symptoms is typical, but not essential, for the diagnosis of rosacea (15/17) *Associated with periodic intensification by potential trigger factors.

Discussion | Diagnosis and classification If flushing, inflammatory papules/pustules, telangiectasia or ocular manifestations are present, the addition of any other major feature could be diagnostic of rosacea Considerations, diagnostic requirements and exclusions for particular rosacea features Flushing/transient erythema Telangiectasia Inflammatory lesions Considerations Careful history required as may not be visibly apparent during assessment Age of onset Drug and immunosuppression history are important to determine whether due to rosacea Requirements for diagnosis Centrofacial location Centrofacial distribution (excluding the perinasal area) Should consist of inflammatory papules/pustules Exclusions Steroid use Sun damage Comedones* Eczema Drug reactions Seborrheic dermatitis Lupus *The presence of comedones may not exclude a diagnosis of rosacea since acne and rosacea may overlap in some patients.

Discussion | Diagnosis and classification There are difficulties with diagnosing rosacea in darker skin types: Erythema and telangiectasia may not be visible in skin phototypes V and VI This may be overcome with experience and appropriate history-taking (e.g. greater emphasis on hyperpigmentation and symptoms of irritation, such as burning and stinging) Other techniques, including skin biopsy can be considered

Diagnosis and classification Introduction Methods About ROSCO Delphi process Results Diagnosis and classification Severity Psychosocial burden Treatment goals Ocular rosacea Conclusions Adapting for local use

Results | Severity scales The severity of each sign or symptom should be rated independently rather than grouped into subtype (14/18), e.g.: Rosacea with mild persistent erythema and moderate inflammatory papules/pustules Rosacea with moderate flushing and severe phymatous changes Effective and validated scales are required in rosacea to help clinicians assess the severity of individual signs and symptoms in an objective manner (14/18) Cutaneous signs and symptoms of rosacea should be evaluated based on a categorical scale (17/18) Rosacea sign/symptom severity should be assessed using a 5-point categorical scale with the following categories (18/18): Clear/none Almost clear/minimal Mild Moderate Severe

Results | Severity scales Proposed severity scale dimensions Major feature Recommended dimension Flushing/transient erythema (18/18) Intensity; episode frequency; episode duration; area involved; associated symptoms Persistent erythema (18/18) Intensity; extent Inflammatory papules/pustules (18/18) Number of lesions; extent of facial involvement (Additional considerations: Lesional erythema intensity; non-facial area involvement) Telangiectasia (16/16) Vessel size; extent of involvement Phymatous changes (18/18)* Inflammation; cutaneous thickening; deformation; sites involved *A number of panellists also considered photographs essential to assess severity of phymatous changes, together with changes related to age.

Discussion | Severity scales Rosacea can vary in intensity through a natural cycle, which should be considered when a history is taken The timing of assessment should be reflective of a patient’s true severity levels (i.e. in the absence of trigger factors as far as is possible) There is potential for an overall rosacea grading score However, scales for each phenotype may not be relevant for every patient It is also important to consider patients with darker skin phototypes A patient-rated scale to capture the intensity of their symptoms should be considered for clinical practice Subsequent development of these scales are planned

Diagnosis and classification Introduction Methods About ROSCO Delphi process Results Diagnosis and classification Severity Psychosocial burden Treatment goals Ocular rosacea Conclusions Adapting for local use

Results | Psychosocial burden The psychosocial comorbidities of living with rosacea can adversely impact an individual’s well-being (17/18) The level of psychological burden of rosacea should influence treatment decisions (17/18) Physicians should routinely enquire about the psychosocial comorbidities of rosacea (16/16) The development of a practical tool to measure psychosocial comorbidities for patients who live with rosacea is needed (17/17) Research into psychosocial comorbidities for patients who live with rosacea warrants further investigation (15/15)

Discussion | Psychosocial burden More research is still needed into the major psychosocial comorbidities of rosacea A new rosacea-specific psychosocial tool should: Assess the psychosocial comorbidities for all major phenotypes (including rhinophyma, which is missing from the RosaQoL) Consider comorbid conditions, including poor self-esteem, social isolation, depression and anxiety Rosacea treatments are also associated with psychosocial comorbidities associated with rosacea treatments, e.g.: Disheartenment due to overly high treatment expectations The realisation that the requirement to reduce trigger factor exposure can lead to lifestyle limitations. When determining the psychosocial comorbidities of rosacea, it is necessary and important to assess treatment expectations and burden Patient-focused messages around psychosocial comorbidities can ensure successful management

Diagnosis and classification Introduction Methods About ROSCO Delphi process Results Diagnosis and classification Severity Psychosocial burden Treatment goals Ocular rosacea Conclusions Adapting for local use

Results | Treatment goal-setting Treatment goals in rosacea should be based on severity and psychosocial burden and should include: Achieving clear/almost clear skin (15/17) A reduction in severity of signs and symptoms (17/17) A reduction in frequency of sign and symptom flares (17/17) An improvement in patient-reported symptoms (visible and non-visible) (17/17) Achieving patient satisfaction with treatment (17/17) A reduction in the impact of rosacea on the patient (17/17) The majority of panellists agreed that they would treat an individual phenotype when it bothered the patient, regardless of severity

Diagnosis and classification Introduction Methods About ROSCO Delphi process Results Diagnosis and classification Severity Psychosocial burden Treatment goals Ocular rosacea Conclusions Adapting for local use

Results | Ocular features Minimum combination of features diagnostic of ocular rosacea: Either: lid margin telangiectasia and interpalpebral injection Or: Corneal findings/disease and scleral inflammation Grading of ophthalmological abnormalities in ocular rosacea, based on clinical opinion of the ROSCO panel ophthalmologists Severity Signs/symptoms Mild Mild blepharitis with lid margin telangiectasia Mild–moderate Blepharoconjunctivitis Moderate–severe Blepharo- keratoconjunctivitis Severe Sclerokeratitis, anterior uveitis Ocular features may present with or without skin disease 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 regarding ocular rosacea, where at least two out of three panellists agreed on a statement, since ocular rosacea is considered a multi-disciplinary challenge.1 1. Odom RB. Cutis 2004; 73:9–14.

Diagnosis and classification Introduction Methods About ROSCO Delphi process Results Diagnosis and classification Severity Psychosocial burden Treatment goals Ocular rosacea 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 Some think that the Delphi process is not necessarily ‘evidence-based’ and relies on clinical opinion1,7 However, the process is exploratory and well suited for issues which are difficult to define, expertise-specific and future-orientated, as in ROSCO8 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

Diagnosis and classification Introduction Methods About ROSCO Delphi process Results Diagnosis and classification Severity Psychosocial burden Treatment goals Ocular rosacea 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 Local practice and healthcare structure Access factors