Rosacea Update: Rosacea pathogenesis. Rosacea genetics. Disclosures. Rosacea: Etiology? Th1/Th17 is activated in rosacea skin

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1 Winter Clinical Big Island 20 min Rosacea Update: 2017 Diane M. Thiboutot, M.D. Professor of Dermatology The Pennsylvania State University College of Medicine Hershey, PA Disclosures Investigator or consultant for Allergan Celtaxsys Dermira Galderma Cassiopea Merz Mimetica Novan Novartis Photocure Sebacia Rosacea pathogenesis Rosacea: Etiology? Genetics Photodamage Helicobacter pylori Demodex folliculorum P. acnes Oxygen free radicals Bacterial antigens (Bacillus oleronius) Increased activity of kallikrein 5 Staphylococcus epidermidis IL 17 Th1/Th17 is activated in rosacea skin Rosacea genetics Buhl T et al. Journal of Investigative Dermatology advance online publication, 14 May

2 Rosacea: Genes v Environment; a cohort-based survey of 550 twins Rosacea and genetics? The Twins Days Festival is the largest annual gathering of twins and other multiples in the world. Study by dermatologists of 550 twins Authors found that approximately half of the contribution to the rosacea score could be accounted for by genetics and the other half by environment. Correlations between rosacea and UV radiation exposure, alcohol, smoking, skin cancer history, cardiac comorbidity, and age were identified. These findings may help improve current management and expectations of individuals affected by rosacea. Aldrich N et al. JAMA Dermatol. 2015;151(11): Genetic basis of rosacea: a Genomewide Association Study (GWAS) A genome-wide association study was conducted in 22,952 individuals whose genomes showed >97% European ancestry. Cases and controls were identified by an online questionnaire asking if a healthcare professional had ever diagnosed them with rosacea. Participants who answered yes were defined as cases (n=2,618), and those who answered no (n=20,334) were defined as controls. Rosacea is associated with alleles for HLA genes and a SNP on Chromosome 6 Rosacea alleles MHC class II genes HLA-DRB1*03:01 HLA-DQA1*05:01 HLA-DQB1*02:01 Rosacea SNPs SNP rs Chang A et al. Journal of Investigative Dermatology (2015) 135, ; Rosacea alleles have links to other immune and associated diseases Reported disease associations Allele Frequencies In Different Populations In order to make estimates of genetic ethnicity, we simply use what we know about the frequency of the alleles of those SNPs in the reference populations. Rosacea allele PD MS T1DM CD HLA-DRB1*03:01 X X X HLA-DQA1*05:01 X X HLA-DQB1*02:01 X X PD MS T1DM CD Parkinson's disease Multiple sclerosis Type 1 diabetes mellitus Celiac disease Chang A et al. Journal of Investigative Dermatology (2015) 135, ; www ancestry com/dna/resource/whitepaper/ancestrydna Ethnicity White Paper pdf 2

3 Rosacea and systemic disease: Recent explosion in epidemiologic studies What do they mean to me in my practice? Comorbidities with Reported Rosacea Positive associations* Comorbidity Level of Possible associations evidence Comorbidity Level of Crohn s disease 2A evidence Depression CVD +/- Migraine Ulcerative colitis +/- Rheumatoid arthritis +/- Anxiety Parkinson s disease Celiac disease Alzheimer s disease *Associations based on limited studies and does not Glioma account for variations in study design and possible Irritable bowel syndrome confounding Dementia Thyroid cancer Levels of evidence Basal cell carcinoma 2A Systematic review of cohort studies Type 1 diabetes mellitus Multiple sclerosis Cohort study Allergy (food) 4 3A Systematic review of case-controlled studies Allergy (airborne) 4 Case-controlled study Urogenital diseases 4 GERD 4 4 Small or underpowered cohort/case-controlled study Respiratory diseases 4 +/- Conflicting evidence Female hormone imbalance 4 Metabolic diseases 4 Oxford Levels of Evidence 1A 1B 2A 3A Type of Study Systematic review of randomized controlled trials (RCT) Randomized controlled trials Systematic review of cohort studies Cohort studies Systematic review of case-controlled studies Case-controlled studies 4 Case series 5 Expert opinion Types of Studies Experimental Randomized controlled trials (RCTs) Observational Cohort (Hazard ratio, risk, prevalence) any group of people who are linked in some way prospective retrospective Cross sectional (Odds ratio, Risk, prevalence) Analyzes data from a population at a specific point in time Case-controlled (Odds ratio) Identify people with an existing health problem ( cases ) and a similar group without the problem ( controls ) and then compare them with respect to exposure. Case series Outcome measures The Hazard Ratio can be interpreted as the chance of an event occurring in the treatment arm divided by the chance of the event occurring in the control arm. It represents point estimate at any given point of time, it is not cumulative estimate like relative risk and odds ratio Relative risk or risk ratio (R R) is the ratio of the probability of an event occurring in an exposed group to the probability of the event occurring in a comparison, non-exposed group The Odds Ratio (OR) is one of main ways to quantify how strongly the presence or absence of one property (eg disease) is associated with the presence or absence of another property (or disease) in a given population Rosacea Disease Associations: Cohort studies Danish health system: Egeberg A et al Parkinson s disease IRR 1.71 Depression IRR 1.89 Anxiety IRR 1.8 Glioma IRR 1.82 Dementia HR 1.42 Alzheimer s HR 1.92 Migraine HR 1.31 Cardiovascular dis. None Celiac HR 1.46 Crohn s HR 1.45 UC HR 1.19 IBS HR 1.34 Nurses Health Study II Risk of disease in rosacea pts: UC None CD HR 2.2 Spoendlin et al 2016 Risk of disease in rosacea pts: Thyroid cancer HR 1.59 BCC HR 1.5 Li W et al Brit J of Cancer (2015) 113,

4 Rosacea disease associations: Case-controlled studies UK General Practice Migraine adj OR 1.22 (women) History of UC in both groups yielded a 1.65 OR of rosacea (rosacea cases and controls) History of CD 1.49 OR of rosacea Danish Celiac disease Type 1 diabetes OR 2.03 (F) OR 2.59 (F) Rheumatoid arthritis OR 2.14 (M&F) Multiple sclerosis OR 1.65 (F) Tetracyclines protective against rosacea comorbidities? Spoendlin et al JAAD 2013;69: Spoendlin et al Inflamm Bowel Dis Mar;22(3):680-7 Egeberg A et al. J Am Acad Dermatol 2016;74: Are tetracyclines protective against vascular disease in rosacea patients? Electronic medical records from the Veterans Integrated Service network-8 (Florida, Georgia and Puerto Rico) were used to perform a retrospective observational cohort study Identified patients with the ICD-9 diagnosis of acne or rosacea from Patients had follow-up for at least 18 months Are tetracyclines protective against vascular disease in rosacea patients? Overall, rosacea patients who were prescribed a tetracycline had an odds ratio of 0.69 (CI , P<0.05) for the development of vascular disease when compared with those not prescribed a tetracycline For reasons of availability within the VA, most patients were prescribed between mg daily Dosal J et al. J Invest Dermatol 2014; 134: Dosal J et al. J Invest Dermatol 2014; 134: Cochrane review: April 2015 Rosacea Therapy High quality evidence to support the effectiveness of topical azelaic acid topical ivermectin Brimonidine Doxycycline Isotretinoin Moderate quality evidence was available for topical metronidazole and oral tetracycline. Low quality evidence for low dose minocycline, laser and intense pulsed light therapy cyclosporin ophthalmic emulsion for ocular rosacea. van Zuuren et al. The Cochrane Library 2015 Issue 4 4

5 Low-dose isotretinoin for rosacea Patients with at least 8 inflammatory lesions were randomized (2:1) to receive 0.25mg/kg/day isotretinoin or placebo for 4 months Rosacea and biomarkers improve with modified-release doxycycline Skin protein N=170 KLK MMP Serine protease Cathelicidin 57% of isotretinoin patients had at least 90% reduction in lesions at 4 months vs. 10.4% placebo 58% of isotretinoin patients relapsed with 4 months after treatment ended The definition of relapse was not provided Sbidian et al. Journal of Investigative Dermatology (2016) 136, Baseline 170 subjects: 84 doxy 86 placebo Tape strip Week 12 of Modifiedrelease doxycycline DiNardo A et al. J Am Acad Dermatol 2016;74: Skin gene expression (PCR) N=73 KLK5 MMP9 CAMP DelRosso J et al Cutis 2014 Mar;93(3): What do patients want to know about rosacea? N=309 advice posts from an online rosacea forum Advice about treatments Triggers Diet Skin care 53 Special presentations of rosacea Two A et al J Am Acad Dermatol 2015;72: Alina H et al. J Dermatolog Treat, 2016; 27(2):