Rheumatology 2010 Birmingham 21 April 2010 Phenotypes and Classification of Psoriasis Christopher E.M. Griffiths
Abbott Centocor Incyte Galderma Janssen-Cilag Leo Pharma Lynxx Novartis Pfizer Schering-Plough Declaration of Interests
1808 Robert Willan
Translational Medicine
Psoriasis Phenotypes Clinical Severity Genetics Early-onset / late-onset Biologics Classification
Psoriasis Common, 2-3% population UK 75% onset < 40 yrs Peaks of onset 16-22 yrs and 55-60 yrs Male = female Gene/environment interaction Triggers: Streptococcal infection Stress Drugs
Chronic Plaque Psoriasis Red, scaling symmetrical plaques Elbows, knees, scalp & sacrum Plaque (90% of cases) Guttate Sebo-psoriasis Flexural Acrodermatitis Continua of Hallopeau Generalised Pustular Erythrodermic Nails 50%; arthritis approx 20%
Flexural Psoriasis
Sebo-Psoriasis
Annular
What is the natural history of psoriasis?
What is the natural history of psoriasis? 40% patients with guttate develop chronic plaque psoriasis
Koebner Phenomenon Marker of disease activity
Acrodermatitis Continua of Hallopeau
Genetics of Psoriasis Chromosomal Linkage Psors 1 Psors 2 Psors 3 Psors 4 Psors 5 Psors 6 Psors 7 (LOD score > 3) Significant 6p 17q 4q 1q 3q 19p 1p Probable 2q 6q 8q 16q 20p
Genetics of Psoriasis Chromosomal Linkage Significant Probable Psors 1 Psors 2 6p 17q 2q 6q HLA Cw6 55% Early Onset Psors 3 4q 8q Psors 4 1q 16q Psors 5 3q 20p Psors 6 19p Psors 7 1p (LOD score > 3)
Genome-Wide Association Study Nair et al Nat Genetics 2009;41
Genome-Wide Association Study Nair et al Nat Genetics 2009;41
Genome-Wide Association Study Nair et al Nat Genetics 2009;41
Palmo-Plantar Pustulosis Not Psoriasis No Association with HLA Cw6 25% have chronic plaque psoriasis Onset 40+ y 9 Female : 1 Male > 90% current or ex-smokers
HLA-Cw6-Positive and HLA-Cw6-Negative Patients have Differing Phenotypes Gudjonsson et al J Invest Dermatol 2002; 118:362-5 HLA Cw6 Negative associated with: Arthritis Nail dystrophy Later age of onset
Late-onset Psoriasis is NOT Associated with PSORS1 Patients with onset > 50 yrs of age Unlike early onset psoriasis there is no link to HLA- Cw6, Corneodesmosin or HCR Allen et al J Invest Dermatol 2005; 124:103
Late-onset Psoriasis is NOT Associated with PSORS1 Patients with onset > 50 yrs of age Unlike early onset psoriasis there is no link to HLA- Cw6, Corneodesmosin or HCR Are Early and Late-Onset Psoriasis Separate Diseases? Allen et al J Invest Dermatol 2005; 124:103
Human Epidermal Langerhans Cells
Human Epidermal Langerhans Cells TNF and IL-1β induce LC migration from epidermis
NORMAL LCs in Early Onset Psoriasis : No Response to Cytokine Stimuli LC/mm 2 (x10-2 ) 16 14 12 10 8 6 4 2 DPC 16 14 12 10 8 6 4 (27.5) 2 ac DPC TNF-α sal TNF-α 16 14 12 10 8 6 4 (23.2) 2 IL-1β (21.8) sal IL-1β PSORIASIS LC/mm 2 (x10-2 ) 16 14 12 10 8 6 4 2 DPC TNF-α 16 16 14 14 12 12 10 10 8 8 6 6 4 4 (5.2) 2 (1.5) 2 ac DPC sal TNF-α IL-1β (0.4) sal IL-1β Cumberbatch, Singh, Dearman, Young, Kimber, Griffiths J Exp Med 2006; 203:953-6
Late-onset psoriasis: LC migration to IL-1β is normal NORMAL LATE ONSET EARLY ONSET 16 16 16 14 14 14 12 12 12 LC/mm 2 (x10-2 ) 10 8 6 LC/mm 2 (x10-2 ) 10 8 6 LC/mm 2 (x10-2 ) 10 8 6 4 4 4 2 2 2 sal IL-1β Mean decrease 25.4% (+/-7.6) sal IL-1β Mean decrease 28.7% (+/-4.2) sal IL-1β 1.6% decrease Shaw et al J Invest Dermatol 2010
Drug therapies are replacing a lot of medicines as we used to know it George W. Bush
What do biologics tell us about psoriasis?
Severity Patient with severe disease and where standard therapy cannot be used or continued
Severity Patient with severe disease and where standard therapy cannot be used or continued PASI >10 Dermatology Life Quality Index (DLQI > 10
IL-23 is associated with psoriasis and drives epidermal hyperplasia in mice Chan et al J Exp Med 2006;203:2577-87
Ustekinumab Anti-IL12/IL23 Responses at 12 Weeks are Superior to Etanercept 100 PASI 75 PASI 90 Patients (%) 80 60 40 57 68* 74** 23 36*** 45*** 20 0 Etanercept (n=347) Ustekinumab 45 mg (n=209) Ustekinumab 90 mg (n=347) Etanercept (n=347) Ustekinumab 45 mg (n=209) Ustekinumab 90 mg (n=347) Number of injections: 24 2 2 24 2 2 *p=0.012 for superiority vs. etanercept; **p<0.001 for superiority vs. etanercept; ***p<0.001 vs. etanercept Griffiths CEM, et al. New Engl J Med 2010
New-Onset Psoriasis in Patients with RA Receiving Anti-TNF Harrison et al Ann Rheum Dis 2008 9826 anti-tnf; 2880 DMARDs BSR Registry Manchester 25 incident cases of new psoriasis; and 9 flares of psoriasis in anti-tnf group; none in DMARDs IR 1.04 anti-tnf; 0 DMARDs Adalimumab sig high rate compared to Etanercept (4.6) and Infliximab (3.5)
New-Onset Psoriasis in Patients with RA Receiving Anti-TNF Harrison et al Ann Rheum Dis 2008 9826 anti-tnf; 2880 DMARDs BSR Registry Manchester 25 incident cases of new psoriasis; and 9 flares of psoriasis in anti-tnf group; none in DMARDs IR 1.04 anti-tnf; 0 DMARDs Adalimumab sig high rate compared to Etanercept (4.6) and Infliximab (3.5) TNF down-regulates IFNα
T-cell targeted therapies Alefacept and Efalizumab 25% response Is this due to polymorphisms in LFA or are these identifying different forms of psoriasis?
Genetics of Psoriasis Chromosomal Linkage Psors 1 Psors 2 Psors 3 Psors 4 Psors 5 Psors 6 Psors 7 (LOD score > 3) Significant 6p 17q 4q 1q 3q 19p 1p Probable 2q 6q 8q 16q 20p Different Diseases??
Phenotype
Phenotypes 17 Species
Phenotypes
Large Plaque Small Plaque
Phenotypes of Plaque Psoriasis Br J Dermatol 2007;156:258
Phenotypes of Plaque Psoriasis In future may classify according to molecular phenotyping Br J Dermatol 2007;156:258
Mean Weight 93 Kgs
Comorbidities in Psoriasis Patients Ocular inflammation (Iritis/Uveitis/ Episcleritis) Psychosocial burden Reactive Depression Higher suicidal ideation Alcoholism Crohn s Disease Ulcerative Colitis Psoriatic Arthritis 7-30% Spondyloarthropathies Metabolic Syndrome: Arterial Hypertension Dyslipidaemia Insulin resistent Diabetes Obesity higher CVD risk Plaque Psoriasis and other forms Nail psoriasis 40-50%
Summary Different forms of psoriasis: clinical observational research Genotypes Biologics provide insights Severity incorporates physical & psychosocial measures Need to ascertain determinants of CVD risk Biomarkers?