Hidradenitis Suppurativa: update on associated conditions, co-morbidities, and medical treatment DISCLOSURE OF RELATIONSHIPS WITH INDUSTRY Amit Garg, MD S013: Advice from Experts, Medical Dermatology Amit Garg, MD Professor and Founding Chair Department of Dermatology Hofstra Northwell School of Medicine Northwell Health DISCLOSURES AbbVie: Investigator Grant (grant support) AbbVie: Advisor (honorarium) Merck: Investigator (grant support) Pfizer: Advisor (honorarium) Janssen: Advisor (honorarium) Learning Objectives Co-morbidities HS lesions Nodules Abscess Tunnels Scarring Pathogenic factors for HS Hormones Microbiome Tobacco Obesity Stress Genetics Disease associations Describe new observational data on Associated Conditions and Co-Morbidities in HS Discuss updates on the medical management for HS Psychological Depression Anxiety Substance abuse Suicidality Sexual dysfunction CV Risk Tobacco Obesity Diabetes Dyslipidemia Atherosclerosis MACE Inflammatory Spondyloarthropathy SAPHO Pyoderma gangrenosum Crohn s disease Ulcerative colitis Endocrine PCOS Chromosomal Trisomy 21 Adapted from Hoffman et al. Sem Cut Med Surg. 2017;36:48 Peer Reviewed Publications in HS & Psoriasis Using Big Data to Fill Observational Gaps in HS IBM Watson Health Research Platform 50 million unique lives, representative of US population demographics Robust: combines claims and clinical data Power: able to study uncommon diseases and rare events within these diseases Validated cohort of >40,000 patients with HS in the Unites States Keyword search (title or abstract) 1
Disease Burden in the United States Burden of Disease in the US Prevalence Incidence Delay in diagnosis Receipt of Treatment Utilization of the Dermatology Visit Prevalence estimates vary significantly across the world (0.00033% to 4.1%) Differing geogrphic samples Selected and/or small cohorts Differing acquisition methods Claims analyses Chart reviews Patient administered questionnaires The true overall prevalence of HS is unknown HS Crude Prev. / 100,000 (95% CI) Stand. Prev / 100,000 (95% CI) Stand Prev (%) Overall 104 (103-105) 98 (97-99) 0.10 Female Male 141 (139-142) 60 (59-61) 137 (136-139) 58 (57-59) 0.14 0.06 0-17 18-29 30-39 40-49 50-59 60+ 14 (14-15) 155 (152-158) 182 (178-185) 156 (152-159) 122 (119-124) 50 (49-51) 15 (14-16) 150 (147-152) 172 (169-175) 150 (147-153) 119 (117-122) 49 (48-51) 0.02 0.15 0.17 0.15 0.12 0.05 Caucasian Af Am Biracial Other 98 (97-99) 331 (325-336) 227 (210-243) 38 (37-39) 95 (94-96) 296 (291-300) 218 (202-235) 36 (35-37) 0.10 0.30 0.22 0.04 Garg et al. JAMA Dermatol. 2017 May 10. doi: 10.1001 Garg et al. JAMA Dermatol. 2017 May 10. doi: 10.1001 HS Stand. Incid. / 100,000 (Ave Annual, 2006-2016) Stand. Incid. / 100,000 (One Year, 2015-2016) Overall 8.6 (8.6-8.7) 11.4 (11.1-11.8) Female Male 0-17 18-29 30-39 40-49 50-59 60+ 12.1 (12.0-12.2) 5.1 (5.0-5.2) 1.5 (1.4-1.6) 14.1 (13.8-14.4) 15.5 (15.2-15.7) 12.8 (12.6-13.1) 10.0 (9.8-10.2) 3.6 (3.5-3.7) 16.1 (15.5-16.6) 6.8 (6.5-7.2) 4.9 (4.4-5.4) 22.0 (21.0-23.2) 19.1 (18.1-20.2) 14.2 (13.3-15.2) 10.5 (9.8-11.3) 2.8 (2.6-3.1) Caucasian Af Am Biracial Other 8.5 (8.3-8.6) 25.3 (24.9-25.8) 19.3 (17.8-20.9) 3.1 (3.1-3.2) 11.7 (11.3-12.2) 30.6 (29.1-32.2) -- 4.5 (4.2-4.9) Garg et al. J Am Acad Dermatol 2017;77(1):118-122 Garg et al. J Am Acad Dermatol 2017;77(1):118-122 2
Disease Burden: delays in diagnosis Disease Burden: closing the gaps Global cohort of 517 HS patients Mean time between onset of sxs and 1 st visit with any physician 2.3 years Time between onset of sxs to HS diagnosis 7.2 years Misdiagnoses, inappropriate treatments, and fragmented care disease progression and related morbidity Br J Dermatol 2015;173(6):1546 HS patients have higher disease specific costs for acute care facilities than Psoriasis patients. ED visits HS patients 7.41% vs 2.6% for Pso patients) vs 4.2% for severe Pso patients Hospitalizations HS patients 5.1% vs 1.6% for Psoriasis patients vs 2.5% for severe Pso patients J Amer Acad Dermatol. 2015;73(4):609 Disease Burden: closing the gaps Dermatologists are uniquely positioned to close quality and cost of care gaps for patient with HS Garg et al. JAMA Dermatol.2016;152(5):553 Garg et al. JAMA Dermatol.2016;152(5):553 3
Low Utilization of the Dermatology Ambulatory Encounter Among HS Patients Associated Diseases Unpublished data Alzheimer s disease Trisomy 21 Inflammatory Bowel Disease Acne PCOS Pyoderma gangrenosum Spondyloarthropathy Thyroid disease Lymphomas Sleep Apnea Garg et al. unpublished data Gamma Secretase One third of HS patients report a positive Fam Hx Gamma-secretase LOF mutation in a subset of familial HS Multiscaffold protein complex responsible for intra-membrane protein cleavage of many substrates. Nicastrin subunit most commonly mutated Science 2010;330:1065 Candidate substrate: Notch and PI3K/AKT signaling, which regulate KC proliferation and differentiation J Invest Dermatol. 2013;133(3):601 Lancet Neurol. 2010;9(2):215 Dev Cell. 2004;7(5):731 Br J Dermatol. 2013;168(4):876 Science. 2010;19;330(6007):1065 Br J Dermatol.2016;174(3):522 Br J Dermatol 2013;168:871 Gamma Secretase γ-secretase knockouts (mouse) HS-like epidermal and follicular histologic abnormalities Infundibular plugging, cyst formation, and disappearance of sebaceous glands However, no inflammation, abscess,fistulae, or scarring Notch knockouts (mouse) similar to gamma-secretase knockouts, but without infundibular plugging Mice do not have apocrine glands Not all HS patients have γ-secretase mutation There may be substrates other than Notch Br J Dermatol 2013;168:871 Dermatology. 2012;225(1):9 Dev Cell. 2004;7(5):731 4
HS and Incident Alzheimer s Disease In the brain, γ-secretase cleaves amyloid precursor protein development of β-amyloid plaques Trisomy 21 and HS Absolute risk Crude OR Adjusted OR Azh Dis 0.2% (65/27,755) 0.34 (95% CI 0.26-0.43) 1.23 (95% CI 0.96-1.56) Garg et al. J Am Acad Dermatol 2017;77(1):176 Br J Dermatol 2014;170(6):1375 Trisomy 21 and Incident HS Trisomy 21 and Incident HS HS Prevalence T21 Not T21 P Value 2.1% (256/11,936) 0.3% (46,860/16,813,290) <0.001 HS Odds Crude OR 7.84 (95% CI 6.93-8.88) Adjusted OR* 5.24 (95% CI 4.62-5.94) *Adjusted for age, gender, obesity Garg et al. Br J Dermatol. 2017 Jun 29. doi: 10.1111/bjd.15770 Trisomy 21 and Incident HS HS & Inflammatory Bowel Disease Cross sectional study in 1,076 HS patients Europe IBD Crohn s UC Prevalence 3.3% (95% CI 2.3-4.4) 2.5% (95% CI 1.6-3.4) 0.8% (95% CI 0.3-1.4) Prevalence of IBD in HS was 4-8 times higher than general European population No difference in phenotype between HS and HS-IBD Garg et al. Br J Dermatol. 2017 Jun 29. doi: 10.1111/bjd.15770 J Am Acad Dermatol 2017;76:49 5
HS & Inflammatory Bowel Disease Cross sectional study in 7,732 HS patients Danish national registry Crohn s UC Prev in HS 0.8% 1.3% Prev in Popl 0.3% 0.7% Odds Ratio Hazard Ratio 2.04 (1.59-2.62) 2.19 (1.44-3.34) 1.75 (1.44-2.13) 1.63 (1.18-2.27) Cardiovascular Co-morbidity Tobacco smoking Obesity Dylipidemia Diabetes / MetS Major Adverse Cardiac Event J Am Acad Dermatol 2017;76:49 Tobacco/Nicotine and HS Nicotine receptors strongly expressed on follicular epithelium. Up-regulation of nicotinic ACh receptors in HS infundibula Modulates PMN chemotaxis, cytokine production, and macrophage function Down regulation of antimicrobial peptides (beta-defensin) Polyaromatic hydrocarbons and dioxins in cigarette smoke bind to immunomodulatory aryl hydrocarbon receptors Infundibular hyperkeratosis / hyperplasia Tobacco Smoking and HS Frequencies of tobacco smokers within HS cohorts ranges from approximately 30% to as high as 98%. Most analyses based on small sample sizes with little heterogeneity limited generalizability Surgeon 2005;3:23 Exp Dermatol 2006;15:480 Life Sci 2007;80:2214 Int J Dermatol 2005;44:535 Dermatol Clin 2016; 34:51 Exp Dermatol 2012; 21:735 Tobacco Smoking & HS Tobacco Smoking & HS Severity Study König et al Dermatology 1999 Country Cohort size Match / Control Race / Ethn OR Germany 63 Age, Sex -- 9.4 Study Sartorius et al BJD 2009 Country Sweden Denmark Cohort size 115 Severity Measure Modified HS Score (HSS) Score Smokers 41 Former Smokers 27 Non Smokers 22 Revuz et al JAAD 2008 Schmitt et al An Bras Dermatol 2012 Schrader et al JAAD 2014 France 302 Age, Sex -- 12.5 Brazil 15 Age, Sex -- 3.2 Netherland 846 Age, Sex -- -- Schrader et al JAAD 2014 Canoui-Poitrine et al JAAD 2009 Vazquez et al JID 2013 Matusiak et al JAAD 2009 Netherlands 846 Hurley No association (adjusted analysis) France 302 Sartorius No association US (Olmstead) 268 Hurley No association (adjusted analysis) Poland 54 Hurley No association 6
Tobacco Smoking & HS Unpublished data HS and MACE Retrospective analysis Danish national registry 5964 HS patients and matched controls MACE: MI, Stroke, CV-associated death All-cause mortality Garg et al. Unpublished data JAMA Dermatol. 2016;152(4):429 HS and MACE HS and MACE JAMA Dermatol. 2016;152(4):429 JAMA Dermatol. 2016;152(4):429 HS and MACE Psychiatric Co-morbidity Depression Anxiety Substance Abuse Sexual health Suicidality JAMA Dermatol. 2016;152(4):429 7
HS and Substance Abuse Medical Management Unpublished data Topical /Oral Abx IL / Systemic Steroids Oral Retinoids Anti-Androgens Oral-Hypoglucemics Zinc TNFa inhibition IL 12/23 inhibition IL 17 inhibition Garg et al. Unpublished data Clinical Trials in HS Medical Therapies: active, not yet recruiting, recruiting, enrolling Drug Molecule Efficacy studies Adalimumab mab TNFa 2 Apremilast PDE4 inhib 2 IFX-1 Intralesional Triamcinolone Complement inhibitor Glucocorticoid 1 Secukinumab mab IL 17a 1 1 Two Phase III trials (PIONEER I and PIONEER II): safety and efficacy of ADA vs Placebo compare continuation of a weekly dose vs a dose reduction assess maintenance of response after discontinuation Primary endpoint (HiSCR) 50% reduction from baseline in total abscess and inflammatory nodule count, with no increase in the abscess or draining-fistula count ClinicalTrials.gov, July 2017 N= 633 total across 101 sites in 14 countries Mod to Severe HS, inadequate response to oral Antibiotics Randomized Double Blind Placebo Controlled Period 1 (12wks) Period 2 (24 wks) 8
IL 12/23 in Lesional Dermis J Am Acad Dermatol. 2011;65(4):790 IL 12/23 Inhibition: Ustekinumab IL 17 in Lesional Dermis Open-label study, n=17 Ustekinumab 45 or 90 mg (Pso dosing) at wks 0, 4, 16 and 28, then monitored for another 12 wks Outcome : msartorius or HiSCR 50 40 wks 6/17 (35%) marked improvement in mss 3/17 (18%) moderate improvement in mss 8/17 (47%) achieved HiSCR 50 Br J Dermatol 2016;174:839 J Am Acad Dermatol. 2011;65(4):790 9
IL 17 Inhibition Challenges to Address Scattered case reports of efficacy Trials are on the way! How well do our existing instruments measure HS? Have we (experts and patients) defined what needs to be measured in HS? And can we agree? What do existing instruments capture well? Not so well? How reliable are HS measurement instruments? Hurley, Modified Sartorius, HS Severity Index, HS-PGA, HiSCR, AISI, HS4 How well do our instruments measure change in disease status? HIdradenitis SuppuraTiva core outcomes set International Collaboration Thank you Amit Garg, MD Professor and Founding Chair Department of Dermatology Hofstra School of Medicine Northwell Health 10