Interventions for Rosacea: Updated Systematic Review Based on Phenotype Approach

1. Interventions for rosacea based on the phenotype approach: An updated systematic review including GRADE assessments Esther J van Zuuren1, Zbys Fedorowicz2, Jerry Tan3, Mireille MD van der Linden4, Bernd WM Arents5, Ben Carter6, Lyn Charland7 1Dermatology Department, Leiden University Medical Centre, Leiden, 2333 ZA, the Netherlands 2DynaMed Plus, EBSCO Health, 10 Estes Street, Ipswich, MA 01938, United States 3Department of Medicine, University of Western Ontario, London, Canada 4Department ofDermatology, Amsterdam University Medical Centres, Amsterdam, Netherlands 5Skin Patients Netherlands (Huidpatiënten Nederland), Nieuwegein, the Netherlands 6Biostatistics and Health Informatics, King's College London; Institute of Psychiatry, Psychology & Neuroscience, London, UK 7Independent researcher and consumer referee, Quebec, Canada British Journal of Dermatology. DOI: 10.1111/bjd.17590

2. Dr Esther van Zuuren

3. Introduction What’s already known? • Rosacea is a chronic facial inflammatory dermatosis • The diagnosis and classification of rosacea have evolved from a subtype to a phenotype approach • Effective and safe interventions include brimonidine in temporarily reducing persistent erythema; laser and light based therapies for mainly telangiectasia; topical azelaic acid, metronidazole and ivermectin, along with oral doxycycline and isotretinoin for papules/pustules; and topical ciclosporin ophthalmic emulsion for ocular rosacea

4. Objective • Updating our systematic review on interventions for rosacea • to examine the different management options and to determine the most effective strategies in the treatment of rosacea • to align evidence-based treatment options with the new phenotype approach

5. Methods • We searched: CENTRAL in The Cochrane Library, MEDLINE, EMBASE, LILACS, Science Citation Index, and five ongoing trials registers (up to March 2018) for randomised controlled trials in people with rosacea • We did not apply language restrictions and several articles were translated • Two authors independently assessed the titles and abstracts from the searches and the obtained full-text papers of all potentially eligible included studies

6. Methods • Our primary outcomes were: • quality of life • participant-assessed rosacea severity • proportion of participants reporting an adverse event • Secondary outcome measures were: • physician-assessed rosacea severity • assessment of erythema and telangiectasia • lesion counts • time to improvement • duration of remission

7. Methods • Data extraction independently by two authors • Risk of bias assessment with Cochrane Collaboration's domain-based assessment tool independently by two authors • RR for dichotomous outcomes and MD for continuous outcomes (and 95% confidence intervals). Pooling using random effects model • All analyses were undertaken using RevMan 5.3 (The Nordic Cochrane Centre, Copenhagen, Denmark) • GRADE approach to rate the certainty of evidence for prespecified outcomes of main comparisons

8. Results • 152 RCTs included, 20.944 patients with mean age of 48.6 years • 16 studies at low risk, 84 at unclear risk, 52 at high risk of bias • No RCTs of treatments for transient erythema and flushing • For persistent erythema: • high certainty evidence that topical brimonidine 3 mg/g gel reduced erythema according to patients and physicians (peak 3-6 hours) • moderate certainty evidence that topical oxymetazoline 1% cream reduced erythema according to patients and physicians (peak 3-6 hours)

9. Results • For erythema and telangiectasia • low to moderate certainty evidence that (long) PDL, Nd:YAG laser and intense pulsed light therapy are effective • For papules/pustules – topical treatments • high certainty evidence that azelaic acid (15%/20%) and ivermectin 1% reduce lesion counts • moderate certainty evidence that metronidazole (0.75%/1%) and minocycline foam reduce lesion counts • moderate certainty evidence that ivermectin 1% appeared slightly more effective than metronidazole 0.75% for reducing lesion counts

10. Results • For papules/pustules – systemic treatments for reducing lesion counts • moderate certainty evidence for effectiveness doxycycline 40 mg • moderate certainty evidence that minocycline 100 mg is as effective as doxycycline 40 mg • low certainty evidence for effectiveness tetracycline and minocycline 45 mg • low certainty evidence that doxycycline 40 mg is as effective as doxycycline 100 mg but with fewer adverse events with 40 mg • very low certainty evidence that azithromycin is as effective as doxycycline 100 mg • high certainty evidence for effectiveness isotretinoin 0.25 mg/kg • moderate certainty evidence that isotretinoin 0.3 mg/kg is slightly more effective than doxycycline 100 mg

11. Results • For ocular rosacea • low certainty evidence for ciclosporin 0.05% ophthalmic emulsion • low certainty evidence ciclosporin 0.05% ophthalmic emulsion was more effective than doxycycline 100–200 mg • moderate certainty evidence for oral omega 3 fatty acids • Combination treatments • brimonidine in morning and ivermectin in evening are effective for treating erythema and papules/pustules • Maintenance treatments • topical ivermectin 1%, metronidazole 0.75% and azelaic acid 15% are effective for maintenance regarding papules/pustules

12. Discussion • This updated review focuses on studies and comparisons that were likely to provide evidence-based and reliable treatment options, within a phenotype approach • Limitations were: • no RCTs of treatments for phymas, transient erythema and flushing • lack of response of principal investigators of included studies for missing details • our prespecified outcomes ‘Time until improvement’ and ‘Duration of remission’ were minimally to not addressed • lack of standardised and validated scales • Future research should place a greater emphasis on the management and treatment of rosacea based the phenotype approach

13. Discussion • For most treatments, or combinations thereof, there is no clear evidence favouring any with regard to fewer adverse events • More participants experienced an adverse event with topical azelaic acid, topical minocycline and oral isotretinoin, when compared with vehicle or placebo • isotretinoin is teratogenic and should therefore not be prescribed to pregnant women or women that are trying to become pregnant • rare adverse events with minocycline like autoimmune hepatitis, lupus erythematosus and hyperpigmentation of the skin and tissues

14. Discussion • Supplementary file 1 is the complete and latest updated version of the systematic review “Interventions for rosacea” • It includes all 93 comparisons, including 25 Summary of findings tables with certainty of evidence for predefined outcomes • This review can therefore be the basis for developing or updating evidence-based guidelines and for guidance in clinical decision making

15. ConclusionsWhat does this study add? • Phenotype-based approach with GRADE certainty of evidence assessments • Topical oxymetazoline reduces temporarily persistent erythema (moderate certainty evidence) • There is moderate certainty of evidence that topical minocycline is effective in treating papules/pustules, and oral minocycline 100mg is as effective as doxycycline 40 mg • Low dose isotretinoin 0.25 mg/kg greatly reduces papules/pustules compared to placebo (high certainty evidence) • Omega-3 fatty acids improve symptoms of dry eyes and tear gland function (moderate certainty evidence)

16. The research team Esther Zbys Jerry Mireille Bernd Ben Lyn van Zuuren Fedorowicz Tan v/d Linden Arents Carter Charland

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