Psoriasis: A Cutaneous or Systemic Disease

Transcription

1 Psoriasis: A Cutaneous or Systemic Disease Ian D.R. Landells, MD, FRCPC Clinical Chief Dermatology, Eastern Health Clinical Assistant Professor Disciplines of Medicine and Paediatrics Faculty of Medicine Memorial University of Newfoundland

2 Copyright 2017 by Sea Courses Inc. All rights reserved. No part of this document may be reproduced, copied, stored, or transmitted in any form or by any means graphic, electronic, or mechanical, including photocopying, recording, or information storage and retrieval systems without prior written permission of Sea Courses Inc. except where permitted by law. Sea Courses is not responsible for any speaker or participant s statements, materials, acts or omissions.

3 Disclosure of Potential Conflicts of Interest Ian D.R. Landells, MD, FRCPC Clinical Associate Professor Memorial University of Newfoundland Speaker Honoraria Abbvie, Janssen/J&J, Amgen/Pfizer, Merck, Valeant, Astellas, Pediapharm, Leo, Novartis, GSK Advisory Board Participant Abbvie, Janssen/J&J, Amgen/Pfizer, Celgene, Merck, Valeant, Roche, Galderma, Pediapharm, Leo, Graceway, Basilea, Astellas, GSK, Novartis, Allergan, Sanofi, Pfizer Clinical Trial Investigator Abbvie, Janssen/J&J, Amgen/Pfizer, Merck, Valeant, BMS, Celgene, Galderma, Allergan, Leo, Basilea, Novartis, Astellas, B&I, Sanofi 3

4 Overview and Epidemiology of Psoriasis Chronic, immune-mediated inflammatory disease of the skin 1 But really much more than the skin Affects 2-3% of people worldwide 2 An estimated 1 million Canadians have psoriasis 3 Nearly one quarter of psoriasis patients have moderate-tosevere disease 250, 000 in Canada ~150,000 people with psoriasis are being treated 60,000 of these patients have moderate-to-severe disease 1. Gudjonsson JE, Elder JT. Clin Dermatol 2007;25: NIAMS. NIH Publication No ; Guenther L, et al. J Cutan Med Surg 2004;8: National Psoriasis Foundation: Statistics 2003

5 Psoriasis is a Complex Disease Characteristics 80% 1,3 1% - 3% of Caucasian population affected Inflammatory skin disorder ~4% 4 Plaque ~2-6 1 % Inverse Psoriasis Lifelong, chronic relapsing disease Palmoplantar ~1-2%% Pustular 4 Various clinical features ~12% 4 ~2% 4 Nail psoriasis 3 Plaque-type psoriasis most common form Guttate Erythrodermic 1 Van der Kerkhof PCM, ed. Chapter 1. In: Textbook of psoriasis. 2nd ed. Blackwell Publishing; 2 Camisa C, ed. Chapter 1. In: Handbook of psoriasis. 1st ed. Blackwell Science; p Griffiths CE et al. Br J Dermatol. 2007;156(2): García-Diez A et al. Dermatology. 2008;216(2):137-51

6 Scalp Psoriasis

7 Inverse Psoriasis

8 Palmoplantar Pustular Psoriasis

9 Guttate Psoriasis

10 Erythrodermic Psoriasis

11 Don t Forget to Check

12 Mild Plaque Psoriasis - <3% BSA

13 Mod-Severe Plaque Psoriasis

14 Psoriasis Pathogenesis

15 Psoriasis Pathogenesis

16 Key Cytokines Involved in Psoriasis Key Cytokines TNF-α IL-12 IL-23 IL-17 IL-22 Functions: Drive differentiation or survival/expansion of Th cells 1 Cause keratinocytes to proliferate and produce inflammatory factors 1 Promote increased vascularity in the skin 2 1. Lowes MA, et al. Annu Rev Immunol. 2014;32: Heidenreich R, et al. Int J Exp Pathol. 2009;90:

17 Proposed Model for Immunopathology of Psoriasis Chronic Inflammatory Loop Keratino cyte Dendritic Cell (DC) IF N-γ TNF -α Macroph Plasmacyt age Innate oid Immune DC System Cells Natural Killer T Cell IL-12 Activated DC IL-23 Th1 Th17 Th22 IFN-γ TNFα IL- 22 Keratinocyte Proliferation TNFα TNFα IL- 17A/ F Proinflamm atory Cytokine Production Increased Inflammation Formation of Psoriatic Plaques Other Cytokines 17

18 Proposed Model for Immunopathology of Psoriasis Chronic Inflammatory Loop Keratino cyte Dendritic Cell (DC) Macroph age TNF -α Plasmac ytoid DC Natural Killer T Cell IL-12 Th1 Activated DC TNF-α IL-23 Th22 Th17 IFN-γ TNFα IFNγ IL- 22 TN F-α Keratinocyte Proliferation IL- 17A/F Proinflamm atory Cytokine Production Increased Inflammatio n Formation of Psoriatic Plaques Other cytokines 18

19 Psoriasis - The Tie that Binds Chronic state of systemic inflammation Co-morbidities now recognized Multi-system disease Multi-discipline approach

20 1 Kimball et al. Am J Clin Dermatol 2005;6: Naldi et al. Br J Dermatol 1992;127: Mrowietz U et al. Arch Dermatol Res Dec;298(7): ; photo from Psycho-social Morbidity and Psoriasis Psychosocial burden, 1,2,3 Reactive Depression Higher suicidal ideation Alcoholism

21 Psycho-social Morbidity and Psoriasis The National Psoriasis Foundation survey reported that psoriasis patients in the youngest group (18 to 34 years of age) contemplated suicide (10%) experienced depression (54%)

22 Mrowietz U et al. Arch Dermatol Res Dec;298(7): Psoriatic Arthritis Psoriatic Arthritis 7-30% Spondyloarthropathies

23 Psoriatic Arthritis 7-30% OF PsO PTS - Usually sero-negative Men and women affected equally 1 Disease onset between age Psoriasis precedes PsA in 2/3 Usually by ~10yrs More than one-half of the patients with PsA may have evidence of erosions on x-rays 4,5 Up to 40% of the patients develop severe, erosive arthropathy 4,5E Spondylitis & Enthesitis also seen 1 Jiaravuthisan et al. J Am Acad Dermatol. 2007;57: De jong et al. Dermatology. 1996;193(4): Van Laborde S, Scher RK. Dermatol Clin. 2000;18:37-46

24 Enthesitis Hochberg, M., et al. Rheumatology 3 rd edition McGonagle D, et al. Arthritis Rheum 2003;48:

25 Nail Psoriasis Nail psoriasis 40-50% Griffiths CE et al. Br J Dermatol. 2007;156(2):

26 Incidence of Nail Psoriasis in Patients With Psoriasis 15% 50% of psoriasis patients have nail involvement 1 Fingernails > Toenails Only 1% 5% in patients have nail involvement without other cutaneous findings 3 Up to 85% of patients with PsA have nail involvement 1 Jiaravuthisan et al. J Am Acad Dermatol. 2007;57: De jong et al. Dermatology. 1996;193(4): Van Laborde S, Scher RK. Dermatol Clin. 2000;18:37-46

27 Nail Psoriasis Linked to Positively associated with longer duration and greater extent of skin disease 1 Higher incidence in PsA patients compared with psoriasis alone 2-4 Severe disease is correlated to enthesitis, polyarticular disease and unremitting and progressive arthritis 4 Nail pathology may provide a mechanistic link between skin disease and joint disease in PsA 3,4 1 de Jong EM, et al. Dermatology. 1996;193(4): ; 2 Jiaravuthisan MM, et al. J Am Acad Dermatol. 2007; 57:1-27; 3 Williamson L, et al. Rheumatology. 2004;43: ; 4 Lawry M. Dermatol Ther. 2007:20;60-67.

28 Nail Anchored by Entheses Extensor tendon Superficial & deep laminae Nail Flexor tendon Deep lamina

29 Other Inflammatory Disorders Crohn s Disease 2 Ulcerative Colitis 1 Durrani Am J Ophthalmol. 2005;139(1): Bernstein CN et al. Gastroenterology 2005;129:

30 Inflammatory Bowel Disease The Prevalence Ratios (95% CIs) of Having IBD if a Person Has a Diagnosis of Psoriasis Crohn s disease = 1.52 ( ) UC = 1.56 ( ) Bernstein Gastroenterology 2005;129: Psoriasis occurs in 7-11% of the IBD population compared to 2-3% of the general population Tavarela et al. Aliment Pharmacol Ther. 2004;20 s4:50-3

31 Iritis Ocular inflammation is a common feature of PsA occuring in almost 30% PsA patients Conjunctivitis (20%)I Iritis occurring in 7% of the pts Van de Kerkhof Textbook of Psoriasis 2 nd ed p.34

32 Metabolic Syndrome 1 Pearce DJ et al. J Dermatolog Treat. 2005;16(5-6): Kimball et al. Am J Clin Dermatol 2005;6: Mrowietz U et al. Arch Dermatol Res Dec;298(7): Mallbris L et al. Curr Rheumatol Rep. 2006;8(5):355-63; photo from

33 Metabolic Syndrome Respective prevalence rates of risk factors in those with severe psoriasis, mild psoriasis, and in controls follows: Diabetes (7.1%, 4.4%, 3.3%) Hypertension (20%, 14.7%, 11.9%) Hyperlipidemia (6%, 4.7%, 3.3%) Obesity (20.7%, 15.8%, 13.2%) Smoking (30.1%, 28%, 21.3%) Neimann A et al. J Am Acad Dermatol 2006;55:829-35

34 Comorbidities in Psoriasis Patients Ocular inflammation 3 (Iritis/Uveitis/ Episcleritis) Psychosocial burden, 2,4,5 Reactive Depression Higher suicidal ideation Alcoholism Crohn s Disease 6 Ulcerative Colitis Psoriatic Arthritis % Spondyloarthropathies Metabolic Syndrome: 1,2,5, 8 Arterial Hypertension Dyslipidaemia Insulin resistent Diabetes Obesity higher CVD risk Plaque Psoriasis and other forms Nail psoriasis % 1 Pearce DJ et al. J Dermatolog Treat. 2005;16(5-6): Kimball et al. Am J Clin Dermatol 2005;6: Durrani Am J Ophthalmol. 2005;139(1): Naldi et al. Br J Dermatol 1992;127: Mrowietz U et al. Arch Dermatol Res Dec;298(7): Bernstein CN et al. Gastroenterology 2005;129: Griffiths CE et al. Br J Dermatol. 2007;156(2): Mallbris L et al. Curr Rheumatol Rep. 2006;8(5):355-63

35 Co-Morbidities & Paediatric PsO Database of 1.3 million Germans 2.6% (~34,000) with psoriasis 0.7% <20 yrs of age Crohn s x prevalance in PsO pts <20 yrs Hyperlipidemia 2.2 x Diabetes 2.0 x Hypertension 2.0 x Obesity 1.7 x M.Augustin et al. Epidemiology and comorbidity of psoriasis in children. BJD; :

36 Psoriasis is a marker of underlying systemic disease Psoriasis patients have increased prevalence of conditions that are: Metabolic Inflammatory Psychosocial Severe Psoriasis may be associated with: Psoriatic Arthritis Other Inflammatory Conditions Nail Disease CV disease Increased risk

37 Also Severe PsO associated with increased risk of death Patient with Severe PsO Patient with Mild PsO 50% increased risk of death compared to patients with no PsO Not associated with increased risk of death Gelfand et al, Arch Dermatol 2007;143(12):1493-9

38 Psoriasis: Chronic life long disease Immune Dysregulation inflammation Genes Environment Obesity Hypertension Diabetes Dyslipidemia Others Cytokines Platelet hyperreactivity Endothelial dysfunction Prothrombotic activity Time Psoriatic plaques Pustular disorders Psoriatic arthritis Crohn s disease Cardiovascular disease Christophers E. Clin Dermatol 2007;25:529

39 Psoriasis Treatment

40 The Rule of Tens: Defining Current Severe Psoriasis Patients who fulfill any one of the three criteria below Should be considered to have severe psoriasis Require (most likely) active intervention BSA involved > 10% PASI score > 10 DLQI* >10 OR *Patient-reported outcome assessing limitations due to impact of skin disease on: symptoms and feelings, daily activities, leisure, work/school, personal relationships, inconvenience of treatment Finlay AY. Br J Dermatol. 2005;152 (5):861-7 Dubertret L et al. Br J Dermatol. 2006;155 (4)

41 PASI: Assessing Extent and Severity of Psoriasis Clinical response is measured by % reduction in PASI PASI PASI PASI 31 2 Moderate Severe 1 Heydendael V et al, N Engl J Med. 2003;14;349(7): Courtesy of Dr. Dalakir, Denmark

42 Treatment Goals in Psoriasis: Significant and Rapid Improvement of the Disease 75% improvement in PASI (PASI 75) PASI 20.0 PASI 0.7 > PASI 75 Week 0 Week 10 Skin Clearance: Ultimate Goal Sustained response Long-term safety Improved QoL

43 Treatment of Psoriasis was very difficult not that long ago

44 Treatment of Psoriasis was very difficult not that long ago

45 Therapeutic Options in Psoriasis Topical treatments Coal tar, etc. Vitamin D analogues Topical retinoids Topical corticosteroids Phototherapy UVB PUVA Traditional systemic treatment Acitretin Methotrexate Cyclosporine Biologics Callen JP, et al. J Am Acad Dermatol 2003;49:897 Menter A, et al. J Am Acad Dermatol 2008;58:826 Lebwohl M, et al. J Am Acad Dermatol 2001;45:487 Lebwohl M, et al. J Am Acad Dermatol 2001;45:649

46 Systemic Treatment Options to Patient: Oral Agents: Acitretin» Hard on liver and can elevate lipids.» Works well in about 20-40% of patients Methotrexate» Hard on liver and can drop blood cells. Can affect lungs.» Works well in about 30-50% of patients. Cyclosporine» Hard on kidneys and causes increase blood pressure and lipids. Increased risk of mailgnancy» Works well in 60-80% of patients. Phototherapy: (Need to be close to light unit) Either twice per week (PUVA) for 15+ weeks. Three times per week (nb & bbuvb) for 10+ weeks. Works well in 60-80% of patients. Biological Agents: Injectables from twice weekly to every 3 months.

47 % Patients Achieving PASI 75 Non-biologic Systemic Therapies for Moderate to Severe Psoriasis Response by PASI 75 at primary endpoints (8-16 wks) 1,2 Cyclosporin100 5 : MTX 5 : Retinoids 5 : PUVA 6 : No head Toxicity to head trials Nephrotoxicity, Arterial Hypertension, Malignancy Hepatotoxicity, Bone marrow toxicity Teratogenicity, Hyperlipidaemia, Hepatotoxicity 60 Cutaneous 52 malignancies 25 0 Acitretin mg/d MTX 4 15 mg/wk CSA 4,8 3-5 mg/kg/d Phototherapy times QW 1 Stern R. JAMA 2003;290: Miller & Feldman. Exp Op Pharmacother 2006,7: Geiger JM. Skin Therapy Lett ;8(4):1 4 Heydendael V et al. NEJM. 2003;14;349(7): EMEA Prod. Specific SPCs 6 Katz KA et al. J Invest Dermatol. 2002;118(6): Mrowietz & Asadullah. Trends Mol Med. 2005;11(1):43. 8 Flytstrom I et al, Br J Dermatol Dec 7;158(1):

48 Apremilast (Otezla) PDE4 Inhibitor 30 mg PO BID 29% achieved PASI 75 at 16 wks Approved for PsO and PsA No lab monitoring Diarrhea & Depression reported

49 Biologic Therapies TNF-A inhibitors Chronic Inflammatory Loop Dendritic Cell (DC) IL-12 Th1 IFN-γ TNFα Proinflamm atory Cytokine Production Increased Inflammation IF N-γ TNF-α Activated DC TNF-α Keratinocyte Proliferation IL-22 Formation of Psoriatic Plaques Keratino cyte Macroph age Innate Immune System Cells Plasmacyt oid DC Natural Killer T Cell IL-23 Th17 Th22 TNF-α IL- 17A/ F Other Cytokines 49

50 Biologic Therapies Anti IL12/23 Chronic Inflammatory Loop Dendritic Cell (DC) IL-12 Th1 IFN-γ TNFα Proinflamm atory Cytokine Production Increased Inflammation IF N-γ TNF -α Activated DC TNF-α Keratinocyte Proliferation IL-22 Formation of Psoriatic Plaques Keratino cyte Macroph age Innate Immune System Cells Plasmacyt oid DC Natural Killer T Cell IL-23 Th17 Th22 TNF-α IL- 17A/ F Other Cytokines 50

51 Biologic Therapies Anti-IL17 Chronic Inflammatory Loop Dendritic Cell (DC) IL-12 Th1 IFN-γ TNFα Proinflamm atory Cytokine Production Increased Inflammation IF N-γ TNF -α Activated DC TNF-α Keratinocyte Proliferation IL-22 Formation of Psoriatic Plaques Keratino cyte Macroph age Innate Immune System Cells Plasmacyt oid DC Natural Killer T Cell IL-23 Th17 Th22 TNF-α IL- 17A/ F Other Cytokines 51

52 Biologic Therapies Anti IL23 Chronic Inflammatory Loop Dendritic Cell (DC) IL-12 Th1 IFN-γ TNFα Proinflamm atory Cytokine Production Increased Inflammation IF N-γ TNF -α Activated DC TNF-α Keratinocyte Proliferation IL-22 Formation of Psoriatic Plaques Keratino cyte Macroph age Innate Immune System Cells Plasmacyt oid DC Natural Killer T Cell IL-23 Th17 Th22 TNF-α IL- 17A/ F Other Cytokines 52

53 % Patients Achieving PASI 75 Biologic Agents for Moderate to Severe Plaque Psoriasis (no head to head trials!) Short Term Efficacy of Biologics at primary endpoint by PASI 75 Week 12 TNFa inhibition 3,4 Week 16 5 Week ETA 25mg BIW ETA 50mg BIW 0 Ada 40 mg EOW 1x 80mg induction 0 IFX 5 mg/kg Wk 0,2 6 1 Lebwohl M et al. N Engl J Med. 2003;349(21): Gordon KB et al. JAMA. 2003;17;290(23): Papp KA et al. Br J Dermatol. 2005;152(6): Leonardi C et al. N Engl J Med. 2003;20;349(21): Menter A et al. J Am Acad Dermatol. 2008:58: Reich K et al. Lancet 2005; 366; 1367.

54 Biologic Agents for Moderate to Severe Plaque Psoriasis (no head to head trials!) Short Term Efficacy of Systemic Agents at primary endpoint by PASI 75

55 Efficacy of IL-17 Inhibition Agent/Dose Brodalumab 210mg Ixekizumab 150 mg Secukinumab 300 mg PASI 75 PASI 90 PASI 100 Endpoint ACR 20/Wk/Dose Wk Wk 52 (140 mg) 56 Wk 52 (280 mg) Wk Wk 12 Wk Wk 24 (300mg) 51 Wk24 (150 mg)

56 Efficacy of IL-23 Inhibition

57 Psoriasis Conclusions Chronic, immune-mediated inflammatory disease of the skin 1 Associated with numerous co-morbidities Initiate treatment that effectively clears the patient s skin and observe for co-morbidities & Choose treatment effective against psoriasis and co-morbidities Evaluate and monitor skin & co-morbidities in concert with medical colleagues

58 Thank You!!