Welcome and Overview. Melodie Young, MSN, ANP-C Nurse Practitioner, Modern Dermatology Partner, Modern Research Associates Dallas, Texas

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2 Welcome and Overview Melodie Young, MSN, ANP-C Nurse Practitioner, Modern Dermatology Partner, Modern Research Associates Dallas, Texas

3 Advances in Biologic Therapies for Psoriasis April W. Armstrong, MD, MPH Associate Dean for Clinical Research, Associate Professor of Dermatology, Director of Clinical Research, Clinical and Translational Science Institute Director of Clinical Trials and Outcomes Research, Director of Psoriasis Program, Department of Dermatology Keck School of Medicine of USC Los Angeles, California

4 Disclosure: April W. Armstrong, MD, MPH Investigator and consultant for AbbVie, Celgene, Janssen, Lilly, Merck, Modernizing Medicine, Novartis, Pfizer, Regeneron, and Sanofi; speaker for AbbVie, Janssen, and Lilly

5 ROLE OF TH1 AND TH17 CELLS in Psoriasis Pathogenesis IL-12 TH1 IFN-γ TNF-α NAÏVE T CELL IL-23 TH17 IL-17A IL-17F IL-22 TNF-α Th1=type 1 helper. TH17=T helper 17. IFN-γ=interferon gamma (type II interferon). TNF-α=tumor necrosis factor-alpha. IL=interleukin. Alwan W, Nestle FO. Clin Exp Rheumatol. 2015;33(5 Suppl 93):S2-S6. Gaspari AA. J Am Acad Dermatol. 2006;54(3 Suppl 2):S67-S80. Mak RK, et al. Actas Dermosifiliogr. 2009;100(Suppl 2):2-13.

6 AAD Recommendations: PSORIASIS MANAGEMENT Psoriasis ± Psoriatic Arthritis (PsA) NO YES Limited Disease Extensive Disease Anti-TNF± MTX Topicals/Targeted Phototherapy UVB/PUVA Systemic Biologics Lack of Effect AAD=American Academy of Dermatology. TNF=tumor necrosis factor. MTX=methotrexate. UVB=ultraviolet B light. PUVA=psoralen plus ultraviolet light of A wavelength. Menter A, et al. J Am Acad Dermatol. 2008;58:

7 Treat To Target: The National Psoriasis Foundation Consensus When to assess? Treatment Target Target response at 12 weeks after treatment initiation BSA 1% Target response every 6 months during maintenance therapy BSA 1% BSA=body surface area. Armstrong AW et al. J Am Acad Dermatol. 2017;76(2):

8 FDA-Approved Biologics Drug Class Agent Indication TNF antagonists Etanercept Infliximab Adalimumab Psoriasis, PsA Psoriasis, PsA Psoriasis, PsA p40 IL-12/23 antagonist Ustekinumab Psoriasis, PsA IL-17 antagonists Secukinumab Ixekizumab Brodalumab Psoriasis, PsA Psoriasis Psoriasis FDA=US Food and Drug Administration.

9 IL-17 Inhibitors Secukinumab Fully human IgG1 monoclonal antibody Neutralizes IL-17A ligand Approved for psoriasis and PsA Ixekizumab Humanized IgG4 monoclonal antibody Neutralizes IL-17A ligand Approved for psoriasis Brodalumab Fully human anti IL-17A receptor monoclonal antibody Approved for psoriasis IgG=immunoglobulin G. Gaspari AA, et al. Dermatol Ther. 2015;28(4):

10 FDA-Approved Dosing of Biologic Agents for Moderate to Severe Plaque Psoriasis Secukinumab 300 mg (or 150 mg) every week for the first 5 weeks and then every 4 weeks thereafter Ixekizumab 160 mg (two 80 mg injections) at week 0, followed by 80 mg at weeks 2, 4, 6, 8, 10, and 12, then 80 mg every 4 weeks Brodalumab 210 mg at weeks 0, 1, 2, and every 2 weeks thereafter

11 Short-Term Head-to-Head Clinical Trials Among Biologics Approved for Psoriasis Greater Short-Term Efficacy Ustekinumab vs etanercept Secukinumab vs etanercept Secukinumab vs ustekinumab Ixekizumab vs etanercept Ixekizumab vs ustekinumab Brodalumab vs ustekinumab Ustekinumab Secukinumab Secukinumab Ixekizumab Ixekizumab Brodalumab *All doses used are FDA-approved doses. Etanercept dose is the high-dose 50 mg twice weekly for the first 3 months. Blauvelt A et al. J Am Acad Dermatol. 2017;76: Gordon KB et al. N Engl J Med. 2015; 373: Griffiths CE at el. N Engl J Med. 2010:362: Griffiths CEM et al. Lancet. 2015;386: Langley RG et al. N Engl J Med. 2014;371: Lebwohl M et al. N Engl J Med. 2015;373: New head-to-head data

12 Considerations in Treatment With IL-17 Inhibitors in Psoriasis: ORAL CANDIDIASIS

13 Oral Candidiasis in Psoriasis Patients Treated With IL-17 Inhibitors Image: Am J Clin Dermatol, A clinician's guide to the diagnosis and treatment of candidiasis in patients with psoriasis, volume 17, 2016, page 332, Armstrong AW, Bukhalo M, Blauvelt A. (Fig 1a Oral candidiasis in a patient with psoriasis). With permission of Springer.

14 Oral Candidiasis in Psoriasis Patients Treated With IL-17 Inhibitors (cont.) Oral candidiasis occurs in <1% of patients treated with IL-17 inhibitors If diagnosis is unclear, scrape the lesion with a tongue blade for microscopic examination Typically not a reason for discontinuing IL-17 inhibitor Mild oral candidiasis: topical antifungal (clotrimazole troches or nystatin suspension 4 times daily for 7-14 days) Moderate oral candidiasis: oral fluconazole 200 mg daily for 7 days Armstrong AW, et al. Am J Clin Dermatol. 2016;17: Image: Am J Clin Dermatol, A clinician's guide to the diagnosis and treatment of candidiasis in patients with psoriasis, volume 17, 2016, page 332, Armstrong AW, Bukhalo M, Blauvelt A. (Fig 1a Oral candidiasis in a patient with psoriasis). With permission of Springer.

15 Considerations in Treatment With IL-17 Inhibitors in Psoriasis: INFLAMMATORY BOWEL DISEASES (IBD)

16 SECUKINUMAB AND IBD: Exposure-Adjusted IR of IBD (CD and UC) Across Treatments for 52 Weeks Any Secukinumab 300 mg* (n=1410) Any Secukinumab 150 mg* (n=1395) Secukinumab 300 mg, 150 mg, or Other Doses (n=3430) Exposure-Adjusted Incidence Overall, n (IR) (95% CI) Etanercept (n=323) IBD 3 (0.26) (0.05, 0.75) 4 (0.35) (0.10, 0.90) 9 (0.33) (0.15, 0.63) 1 (0.34) (0.01, 1.90) CD 0 (0, 0.31) 2 (0.18) (0.02, 0.63) 3 (0.11) (0.02, 0.32) 0 (0, 1.26) UC 2 (0.17) (0.02, 0.61) 2 (0.18) (0.02, 0.63) 4 (0.15) (0.04, 0.38) 1 (0.34) (0.01, 1.90) IR=incidence rate per 100 subject-years. CD=Crohn s disease. UC=ulcerative colitis. CI=confidence interval. *Includes subjects from phase 3 studies only who were randomized to the specified secukinumab dose at the study start and subjects on placebo who were rerandomized to secukinumab at Week 12. Includes subjects from phase 2 and 3 studies who were randomized to any dose of secukinumab at the study start and subjects on placebo who were re-randomized to secukinumab at Week 12. Etanercept data are from 1 pivotal phase 3 trial, FIXTURE. Anal fistula and sclerosing cholangitis, although not true IBDs, were also retrieved because of the broad search criteria applied. 2 of the 3 cases of CD had a prior history of CD, and the third case was in a subject who had gastrointestinal symptoms at baseline suggestive of undiagnosed active CD the event resolved with therapy and did not cause study treatment discontinuation; 2 of the 4 UC cases had a prior history of UC. van de Kerkhof PC et al. J Am Acad Dermatol. 2016;75(1):83-98.

17 Ixekizumab and CD IR (Patients With Event/100 PYs) IR±95% CI Weeks (Phase 3 RCT) Weeks (Phase 3 RCT) Integrated Safety Population (7 Trials) 0 n (%) N Placebo Etanercept Ixekizumab Q4W 0 (0.0) (0.0) (0.1) 1161 Ixekizumab Q4W 1 (0.2) 416 All Patients on Ixekizumab 9 (0.2) 4209 Incidence of reported CD was low and rates remained stable over time PY=patient-year. RCT=randomized controlled trial. Q4W=every 4 weeks Strober B, et al. Fall Clinical Dermatology Conference; Las Vegas, Nevada; October 20-23, 2016.

18 Ixekizumab and UC IR (Patients With Event/100 PYs) IR±95% CI Weeks (Phase 3 RCT) Weeks (Phase 3 RCT) Integrated Safety Population (7 Trials) 0 n (%) N 0.0 Placebo 0 (0.0) Etanercept 0 (0.0) Ixekizumab Q4W 0 (0.-) 1161 Ixekizumab Q4W 1 (0.2) 416 All Patients on Ixekizumab 10 (0.2) 4209 Incidence of UC was low and rates remained stable over time Strober B, et al. Fall Clinical Dermatology Conference; Las Vegas, Nevada; October 20-23, 2016.

19 Summary Advances in biologic therapies have enabled achievement of rigorous clinical endpoints in patients with psoriasis Treating-to-target, comparative effectiveness, and assessment of benefitrisk ratio are important research directions IL-17 class of medications offer robust efficacy and tolerable safety profile

20 Psoriatic Arthritis for Dermatology Providers Rebecca Muntean, MD, ND, FACR Clinical Rheumatologist, Providence Health & Services Faculty, University of Washington WWAMI Regional Medical Education Faculty, Providence Spokane Internal Medicine Investigator, Premier Clinical Research Spokane, Washington

21 Disclosure: Rebecca Muntean, MD, ND, FACR Speaker for Janssen

22 MEET JAMES This photo is not the actual patient.

23 James James is a 26-year-old teacher who scheduled an appointment with me last summer. His main question was, Can you fix my fingers and toes? Images courtesy of Dr. Muntean. This photo is not the actual patient.

24 James (cont.) L This photo is not the actual patient. Image courtesy of Dr. Muntean.

25 James (cont.) R Image courtesy of Dr. Muntean. This photo is not the actual patient.

26 James (cont.) L Image courtesy of Dr. Muntean. This photo is not the actual patient.

27 James (cont.) R Image courtesy of Dr. Muntean. This photo is not the actual patient.

28 James (cont.) Image courtesy of Dr. Muntean. This photo is not the actual patient.

29 James (cont.) Image courtesy of Dr. Muntean. This photo is not the actual patient.

30 Psoriatic Arthritis (PsA) PsA mutilans is an extreme form of PsA. It is quite rare, with estimated prevalence ~5% In general, PsA is clinically a heterogeneous disorder, with 5 types described as follows: Distal predominant pattern Oligoarticular asymmetrical Polyarticular rheumatoid arthritis-like Spondylitis Arthritis mutilans

31 Pathogenesis of PsA MCH-TCR Dendritic cell Naïve T cell IL-17 IL-12/23 IL-21 IL-22 IL-23 IL-1 TNF IL-6 IFN-γ IFN-α Coates LC, et al. Semin Arthritis Rheum. 2016;46: IL-1 TGF-β1 IL-1 TNF IL-17 signaling cascade camp/pka signaling cascade JAK signaling cascade MAPK signaling cascade NF Κ B signaling cascade Macrophage Basophil Mast cell Eosinophil Neutrophil Keratinocyte Synoviocyte Osteoclast Osteoblast CD8 T cell Pruritus swelling Skin inflammation? Erosion New bone formation Hyperkeratosis Hyperkeratosis Dermal, epidermal, and synovial inflammation Bone resorption New bone formation Enthesitis

32 PsA Can Present With Axial disease Enthesitis Dactylitis Nail disease Uveitis

33 Recognition of Early PsA Subclinical disease in patients with psoriasis Improving detection of PsA among patients with psoriasis: Screening tools in dermatology practices Risk factors to develop PsA

34 Easy Screening Tools for Dermatology Providers There are 4 screening tools available. EARP Early ARthritis for Psoriatic patients (most sensitive) ToPAS II Toronto Psoriatic Arthritis Screen II (most specific) PASE Psoriatic Arthritis Screening and Evaluation PEST Psoriasis Epidemiology Screening Tool Mishra S, et al. Br J Dermatol. 2017;176(3):

35 Example Tinazzi I ET AL. Rheumatology (Oxford). 2012;51:

36 Screening and Comorbidities Screening for PsA Comorbidities in PsA Screening tools with high sensitivity and specificity CV, DM (metabolic syndrome) Also increase mortality CV=cardiovascular. DM=diabetes mellitus.

37 GRAPPA Treatment Schema for Active PsA Which Domains Are Involved? Assess Activity, Impact, and Prognostic Factors Peripheral Arthritis Axial Disease Enthesitis Dactylitis Skin Nails NSAIDs and IA corticosteroids as indicated DMARDs (MTX, SSZ, LEF), TNFi or PDE4i Biologics (TNFi, IL12/23i, IL17i) or PDE4i Switch biologics (TNFi, IL12/23i, or IL17i) Physiotherapy and NSAIDs NSAIDs only TNFi, IL17i or IL12/23i* Switch biologics TNFi, IL17i or IL12/23i*) No direct evidence for therapies in axial PsA*, recommendations based on axial SpA literature Physiotherapy NSAIDs Biologics (TNFi, IL12/23i, IL17i) or PDE4i Switch biologics (TNFi, IL12/23i, IL17i) or PDE4i CS injections: consider on an individual basis due to potential for serious side effects; no clear evidence for efficacy Corticosteroid Injections as indicated NSAIDs DMARDs (MTX, SSZ, LEF) or PDE4i Biologics (TNFi, IL12/23i) Switch biologics (TNFi, IL12/23i, IL17i) or PDE4i Topicals as indicated Topicals (keratolytics, steroids, vitamin D analogs, emollients, calcineurin i) Phototherapy or DMARDs (MTX, CSA, acitretin, fumaric acid esters) or PDE4i Biologics (TNFi, IL12/23i, IL17i) or PDE4i Switch biologics (TNFi, IL12/23i, IL17i) or PDE4i Topical or procedural or DMARDs (CSA, LEF, MTX, acitretin) Biologics (TNFi, IL12/23i, IL17i) or PDE4i Switch biologics (TNFi, IL12/23i, IL17i) or PDE4i Consider previous therapy, patient choice, other disease involvement and comorbidities. Choice of therapy should address as many domains as possible. Standard therapeutic route Expedited therapeutic route Coates LC, Kavanaugh A, Mease PJ, et el. Group for Research and Assessment of Psoriasis and Psoriatic Arthritis 2015 treatment recommendations for psoriatic arthritis. Arthritis Rheumatol. 2016;68(5): Treat, periodically re-evaluate, and modify therapy as required. Green text identifies conditional recommendations for drugs that do not currently have regulatory approvals or for which recommendations are based on abstract data only. GRAPPA=Group for Research and Assessment of Psoriasis and Psoriatic Arthritis. NSAIDs=nonsteroidal antiinflammatory drugs. IA=intraarticular. DMARDs=disease-modifying antirheumatic drugs. MTX=methotrexate. SSZ=sulfasalazine. LEF=leflunomide. TNFi=tumor necrosis factor inhibitor. PDE-4i=phosphodiesterase 4 inhibitor (apremilast). IL=interleukin. SpA=spondyloarthritis. CS=corticosteroid. CSA=cyclosporin A.

38 Treatment for James, Patient With PsA Mutilans and Axial Involvement (SI Joints) Per GRAPPA recommendations Axial involvement (SI joints) NSAIDs, PT Biological DMARDs (approved in PsA: 5 TNFi, 1 IL12/23, 1 IL-17i) ± for step up therapy conventional DMARDs SI=sacroiliitis. PT=physical therapy.

39 References Alamanos Y, Voulgari PV, Drosos AA. Incidence and prevalence of psoriatic arthritis: a systematic review. J Rheumatol. 2008; 35(7): Coates LC, Kavanaugh A, Mease PJ, et el. Group for Research and Assessment of Psoriasis and Psoriatic Arthritis 2015 Treatment Recommendations for Psoriatic Arthritis. Arthritis Rheumatol. 2016;68(5): Husni ME, Mease PJ. Managing comorbid disease in patients with psoriatic arthritis. Curr Rheumatol Rep. 2010;12(4): Mishra S, Kancharla H, Dogra S, Sharma A. Comparison of four validated psoriatic arthritis screening tools in diagnosing psoriatic arthritis in patients with psoriasis (COMPAQ Study). Br J Dermatol. 2017;176(3): Tinazzi I, Adami S, Zanolin EM, et al. The early psoriatic arthritis screening questionnaire: a simple and fast method for the identification of arthritis in patients with psoriasis. Rheumatology (Oxford). 2012;51(11): Veale D, Rogers S, Fitzgerald O. Classification of clinical subsets in psoriatic arthritis. Br J Rheumatol. 1994;33:

40 Lisa s Patient Journey and Faculty Panel Discussion Facilitated by Melodie Young, MSN, ANP-C Nurse Practitioner, Modern Dermatology Partner, Modern Research Associates Dallas, Texas Featuring Lisa Lambert A patient with psoriasis and psoriatic arthritis

41 Disclosures: Melodie Young, MSN, ANP-C and Lisa Lambert Melodie Young, MSN, ANP-C Advisor for AbbVie, Janssen, Lilly, and Novartis, speaker for AbbVie, Janssen, Lilly, and Novartis, and consultant for AbbVie Lisa Lambert No relevant financial relationship to disclose

42 Lisa s Patient Journey and Faculty Panel Discussion Facilitated by Melodie Young, MSN, ANP-C Nurse Practitioner, Modern Dermatology Partner, Modern Research Associates Dallas, Texas Featuring Lisa Lambert A patient with psoriasis and psoriatic arthritis

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