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Home , Dupilumab, Tildrakizumab

6/15/2021

Disclosure Serious Medications for Serious • Abbvie – speaker’s bureau, investigator Skin Disease: What you need to • UCB – Investigator know • Pfizer - Investigator Steve Daveluy MD [email protected]

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Objectives

At the conclusion of this talk, participants will be able to: My dermatologist thinks I need • Counsel patients on the safety and efficacy of isotretinoin to go on this medication. What • Perform laboratory monitoring for spironolactone in acne consistent with guidelines do you think? • Counsel patients on the safety of biologic and systemic dermatology treatments

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More than skin deep: Comorbidities Undertreatment of Psoriasis Atopic Hidradenitis Suppurativa Vitiligo Arthritis Depression Thyroid disease No treatment Cardiovascular Disease Anxiety disorder Diabetes Metabolic Syndrome ADHD Smoking Pernicious anemia • Mild: 36.6% - 49.2% Diabetes Anxiety Substance use disorder, Lupus Dyslipidemia Depression PCOS Rheumatoid arthritis • Moderate: 23.6% - 35.5% Non-alcoholic Fatty Liver Lymphoma Obesity Addison's disease IBD Dyslipidemia IBD • Severe: 9.4% - 29.7% Sjögren's syndrome Anxiety Diabetes mellitus Dermatomyositis Topicals alone: Depression Metabolic syndrome Cardiovascular disease, Scleroderma Alcohol Use IBD • Moderate: 29.5% Smoking Spondyloarthritis • Severe: 21.5% Sexual dysfunction 52.3% dissatisfied with treatment Int J Dermatol. 2018 Oct;57(10):1157-1164. J Am Acad Dermatol. 2021 Jan 23 Am J Clin Dermatol. 2018 Dec;19(6):821-838. J Eur Acad Dermatol Venereol. 2018 Dec;32(12):2058-2073. JAMA dermatology. 2013 Oct 1;149(10):1180-5. 5 6

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SkinSerious: Serious Medications Systemic Medications in Dermatology

Biologics Systemics Systemics Anti-TNF: Corticosteroids Corticosteroids , Etanercept, Methotrexate Methotrexate , Certolizumab Cyclosporine Cyclosporine Anti-IL 12/23: Hydroxychloroquine Typically Dermatology Hydroxychloroquine Dapsone Isotretinoin Dapsone Anti-IL 17: Isotretinoin Acitretin Isotretinoin , , Acitretin Apremilast Acitretin Azathioprine Azathioprine Anti-IL 23: Mycophenolate Mofetil Mycophenolate Mofetil , Apremilast Apremilast Anti-IL 4: Hydroxyurea Hydroxyurea

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Isotretinoin Isotretinoin Patient Perceptions

• 13-cis-retinoic acid 76.3% know about isotretinoin 69.7% know about side effects • Most effective therapy for mod-sev acne 8.7% know, but no idea SEs st 83.3% Dry Lips • 1 line for nodulocystic acne 18+ years old> under 18 50.6% Liver Damage • 120-150mg/kg cumulative (5-6mo course) Female>Male 26% Psychological SEs Treats all elements of pathogenesis: Sources: 80-90% 26% Acne Flare • 58.9% Friends Sebum production 17.3% Infertility Effective 20.7% Family • Keratinocyte proliferation 8.3% Teratogenicity 16.8% Internet • Cutibacterium acnes 8.1% Scarring • Inflammation 4.8% Physician

Dermatol Ther. 2019 May; 32(3):e12873 9 10

Isotretinoin History Isotretinoin Controversies

• 1982 introduced by Roche • 1984 black box warning teratogenicity Teratogenicity Depression Suicidality • 1989 Accutane Pregnancy Prevention Program mandate • 2000 Pregnancy test linked to prescription • 2002 Patent expires • 2005 iPledge program starts Inflammatory Hyperlipidemia Transaminitis Bowel Disease

Expert Rec Clin Pharmacol. 2016 Nov 1;9(11):1435-42. 11 12

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Isotretinoin Teratogenicity Isotretinoin Mental Health

• 50% of exposed: spontaneous abortion • Adolescence & Acne independent risk factors for depression • 25% of exposed: cardiovascular, skeletal birth • Depression correlates with acne severity defects • Suicidality: 2x girls, 3x boys with sig acne vs no/little • Start contraception 1 mo prior, continue 1 mo • 2 forms of birth control • 1998: FDA label: post • Monthly pregnancy tests “Accutane may cause depression, psychosis and, rarely, suicidal • iPledge ineffective at reducing pregnancy rate • Monthly counselling ideation, suicide attempts, and suicide.” • ~150 isotretinoin pregnancies annually in US • Preg Test 1 mo prior, post • 31% report sex with lapse in OCP or condom • 19% reporting abstinence had sex

Expert Rec Clin Pharmacol. 2016 Nov 1;9(11):1435-42. Expert Rec Clin Pharmacol. 2016 Nov 1;9(11):1435-42. 13 14

Isotretinoin Mental Health Isotretinoin Mental Health Evidence

• 2000 B.J. Stupak suicide- 17 yo son of MI congressman Bart Stupak • 5756 pts with hx of prior suicide attempt: no increase risk on • Lawsuit: ruled in favor of Roche- lack of evidence of association isotretinoin • 2002: Charles Bishop crashed plane. Note sympathizing with Osama • 346 pts: Isotretinoin: 84.4% satisfaction; sig improvements in QoL, Bin Laden. anxiety, depression • Family filed $70mil wrongful death. Dropped in 2007 • 7195 pts: no association with depression, psychosis, suicidality • 2012 BBC3 documentary “Dying for Clear Skin” • Meta-analysis: no evidence of association with depression, suicide • Jesse Jones: 24yo. 3 mo course. Suicide 2 years later. • Anecdotal reports: discuss mood change with patients • Note: “Roaccutane seems to have changed the way my mind and body works..”

Expert Rec Clin Pharmacol. 2016 Nov 1;9(11):1435-42. Expert Rec Clin Pharmacol. 2016 Nov 1;9(11):1435-42. 15 16

Isotretinoin IBD Isotretinoin IBD Evidence

• 2003: UC $25mil lawsuit Reversed • 1 case-control: minimally increased risk of UC (OR 4.36), not Crohns • 2008: UC $10.5mil lawsuit Overturned • Not corroborated in larger case-control & cohort studies • 2012: 4 cases in consolidated trial- 2 pts awarded $9mil each • Mayo clinic study: isotretinoin decreased risk of IBD (OR 0.33) • FDA AE Reporting System: 2,214 cases • Meta-analysis: no increased risk of IBD with isotretinoin exposure 87.8% reported by attorneys, 6% physicians, 5.1% consumers

Expert Rec Clin Pharmacol. 2016 Nov 1;9(11):1435-42. Expert Rec Clin Pharmacol. 2016 Nov 1;9(11):1435-42. 17 18

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Isotretinoin and Labs Isotretinoin Summary

Triglycerides • Teratogenic- requires contraception • 1.5% elevation exceeding 400, none required discontinuation • iPledge doesn’t work, but required Liver Enzymes • No causal association with mental illness • 11% increased AST/ALT • No causal association with IBD • Transient, reversible, none required discontinuation • Associated with rare, transient, reversible increase in triglyceride, AST, ALT • Check baseline and after 1 month at full dose • 80-90% Effective • >80% patient satisfaction

Expert Rec Clin Pharmacol. 2016 Nov 1;9(11):1435-42. Expert Rec Clin Pharmacol. 2016 Nov 1;9(11):1435-42. 19 20

Acitretin Acitretin Safety

• 2nd generation retinoid Common Rare • Psoriasis: modulates keratinocyte proliferation & downstream • Dry lips/skin (>75%) • Hyperostosis- mixed evidence (<1%) inflammatory pathways • Hair loss (10-25%) • Hepatitis – transient AST/ALT • Half-life 2-4 days • Sticky skin (<25%) elevation in ~1/3 patients • Alcohol: re-esterification to Etretinate (lipophilic) • Elevated triglycerides (66%), total • Idiosyncratic hepatitis rare • Avoid contraception for 3 years post therapy cholesterol (33%) • Very rare pancreatitis (triglycerides) • Pseudotumor cerebri case report

Dermatol Ther. 2020; 10(4):589-613. J Am Acad Dermatol. 1999;41(3 Pt 2):S7-S12. J Eur Acad Dermatol Venereol. 2009;23(Suppl 2):1–70. 21 22

Apremilast Spironolactone • Antiandrogen, competes with 5⍺-Reductase • Phosphodiesterase-4 (PDE4) inhibitor Condition Efficacy Dose Range • PASI75: 33% week 16, 61% week 32 (typical dose) • 49.4% experienced side effect, average of 1/patient Acne 66-86% 25-200mg (100mg) • 23.4% withdrew due to AEs (headache) • Diarrhea (15.6%) Female Pattern 35-75% 100-200mg Alopecia (200mg) • Headache (11.7%) Hidradenitis 35-84% 75-150mg (100mg) • Nausea/Loose stool (6.5%) Suppurativa • URI (6-7%) Hirsutism 38-51% 50-200mg (200mg)

JEADV. 2018 Oct; 32(10):e393 Curr Rheumatol Rep 21, 36 (2019). Clin Exp Dermatol. 2020 Dec;45(8):986-993. 23 24

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Spironolactone Safety Spironolactone Safety

• Well tolerated • 2016 Guidelines: no need to monitor K in young (<45) healthy females • 15% stop due to AEs • Blackbox warning: “Tumorigenic: Shown to be a tumorigen in chronic • Common: hypotension, diuresis, menstrual irregularities, nausea, toxicity animal studies.” diarrhea, breast tenderness • 2.3 Million women: no increased risk of breast, ovarian, uterine, • Rare: hepatitis, facial pigmentation cervical cancers • Teratogenic- fetal feminization • International Agency for Research on Cancer: lack of evidence to support carcinogenicity • Safe for alopecia in breast cancer survivors

J Am Acad Dermatol. 2016;74(5):945-973.

Clin Exp Dermatol. 2020 Dec;45(8):986-993. Cancer Epidemiol. 2013; 37(6): 870-875 J Am Acad Dermatol. 2020;83(4):1021-1027. 25 26

Biologics Biologics in Psoriasis

TNF⍺ IL-17 Infliximab IL-23 IL-12/23 Secukinumab Etarnercept Risankizumab Ustekinumab Ixekizumab Adalimumab Tildrakizumab Brodalumab Certolizumab

Side Effects

J Invest Dermatol. 2009;129(6):1339-1350 27 28

TNF⍺ Inhibitors Anti-TNF⍺ Rare Adverse Events

• Psoriasis, Hidradenitis Suppurativa • Opportunistic Infections - not significant • Infusion Reaction (Infliximab) 3-22% • Reactivation of Latent TB • Injection site reaction (3-20%) • Hep B reactivation • Infections: URI, nasopharyngitis, UTI (3-25%) = Placebo • CHF Exacerbation?? • Demyelinating disease (MS) – reversible • Lupus-like reaction - reversible • Paradoxical reactions: Psoriasis, HS Ann Rheum Dis. 2009;68(5):702-709. Curr Rheumatol Rep. 2019 Jun 6;21(7):36. J Dermatol. 2018 Mar;45(3):279-286. J Dermatol. 2018 Mar;45(3):279-286. Curr Rheumatol Rep. 2019 Jun 6;21(7):36. 29 30

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TNF⍺ CHF & Malignancy IL-12/23 Ustekinumab

CHF onset/exacerbation • Injection site reaction • Infliximab- more hospitalizations/death than placebo in CHF trial • URIs • RA: CHF sig less common with TNFi • Hep B reactivation • EF<50%, NYHA III/IV- no TNF; new CHF- stop TNF • MACE: Meta-analysis: nonsignificant increase Malignancy • Increased lymphoma risk in RA and IBD • No increase: psoriasis, hidradenitis suppurativa • Increased risk NMSC

Am J Med. 2004 Mar 1;116(5):305-11. Br J Dermatol2015; 173: 1183–1190. JAMA.2011;306(8):864-71. Chung ES et al. Circulation.2003;107:3133-40 Arthritis Rheum.2004;50:1040-50 31 32

IL-17 Secukinumab, Ixekizumab, Brodalumab IL-23 Risankizumab, Tildrakizumab

• Injection site reaction • Injection site reaction • URI • URIs • Mucocutaneous Candida 1-4% (none serious) • Tinea infection • Exacerbation of IBD • No serious AEs, including no serious infections • ?Depression/Suicidality: Brodalumab REMS program. 3 attempts, 1 • FDA Label: “May increase risk of infection.” completed. Improved depression/anxiety scores: no association. • Rare: neutropenia (mild, spontaneous resolution)

J Cutan Med Surg 2016; 20: 293–303. Curr Rheumatol Rep 21, 36 (2019). J Eur Acad Dermatol Venereol. 2019 Sep;33(9):1676-1684. 33 34

IL-4 Dupilumab Summary

• • Isotretinoin is a highly-effective and safe medication • Blocks IL-4 receptor->inhibits IL-4 & IL-13 activity for acne • Overall adverse effect rate similar to placebo • Spironolactone: potassium monitoring is not necessary for healthy women <45 • Common: nasopharyngitis, URI, injection site reaction • Most patients on biologics have no side effects • Decreased risk skin infection • Severe skin disease warrants appropriate therapy • Conjunctivitis 1-5% - not seen in asthma, Nasal polyposis

Steve Daveluy MD

J Am Acad Dermatol. 2018 Mar;78(3 Suppl 1):S28-S36. [email protected]

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