What further tx in ps a
-
Upload
kailen-tsai -
Category
Health & Medicine
-
view
98 -
download
0
description
Transcript of What further tx in ps a
What's MOA Got to Do With PsA/PsO?
More and more new bioagent of Rheuamtoid arthritis, what about Psoriasis ?
NEJM Volume 361:496-509
Then ?
induces proliferation of keratinocytes
NEJM 2009 Volume 361:496-509
T-Cell Differentiation Pathways
paTHOGENESIS
At least 10 psoriasis-susceptibility loci that involve functioning of the immune system are identified.1
Polymorphisms in the IL-12/IL-23 receptor, p40 subunit of IL-12 and IL-23, and p19 subunit of IL-23 strongly associate with psoriasis.1
Psoriasis and its comorbid conditions are thought to arise from chronically elevated levels of cytokines such as TNF-alpha, IL-1 beta, and IL-17.2
1 - Villaseñor-Park J et al. Cleve Clin J Med. 2012 Jun;79(6)413-232 - Kelley’s Textbook of Rheumatology. 9th ed
PsA : epidemiology
• Prevalence– Exact prevalence unknown: estimated 0.04%-1.2%– Among patients with PsO varies from 6%-42%
• Evidence suggests that 20-30% of PsO patients develop PsA
• Male: female ratio 1:1– Male predominance from axial form– Female predominance from peripheral form
• Onset: usually between 35 and 55 years, but important variability and within 10 years of onset psoriasis
PSA: peripheral joints
63% polyarticular 13% oligoarticular
Dactylitis 29-33.5% at first presentation 48% during follow-up
Enthesitis38%most common sites: Archilles and plantar fascia insertion
Frequency (%) of peripheral limb joint involvement in 129 patients with early psoriatic arthritis as assessed by joint tenderness and swelling
Kelley’s Textbook of Rheumatology, 9th ed
Peripheral Joint: Asymmetric Polyarticular Disease
A. Distal interphalangeal joint involvement and forearm lymphedema. B, Toe dactylitis with skin and nail changes. C, Predominat distal interphalangeal joint involvement. D, Arthritis mutilans
Image adapted from Kelley’s Textbook of Rheumatology. 9th ed
Psoriasis and enthesitis
• 1/3 of patients of psoriasis have subclincal enthesitis Int J Tissue React 2005, 27:159-162
• I/3 of the total no. of entehses in psoriatic patients have sign of enthesitisArthritis Rhum 2011, 40 :407-12
Nail and the enthesis: anatomic relationship
McGonagle D, et al. Dermatology. 2009;218(2):97-102
IL-23 and Resident T Cells Promote Enthesitis and Osteoproliferation
IL23 is a unifying factor in SpA (spondyloarthritis)
• IL23 sensitivity associated with PSO– IL 23R with SNPs (GA/Arg381Gln)
• IL23 over production is associated with SpA– IL23 production in PSO– HLA B27 misfoldingIL23 production– Inflammatory bowel disease IL 23 production– Subclinical ileitis in 70% SpA without overt IBD
• increase IL23 in terminal ileum in AS
– Success of IL23 neutralization in PSO
Nat Med 2011, 17(9)1055
IL-23 drives enthesitis in vivo
Nature Medicine 2012 : 1069-1077
Downr egulation of several inflammatory mediators, such as Il6 and Il1b, and genes involved in erosion of bone and tissue, such as Rankl, Ctsk and matrix metalloproteinases
Entheses contain an IL-23R+ resident cell
Nature Medicine 2012 : 1069-1077
CD45+ entheseal :CD3+CD4-
CD8-,
located at the entheseal interface between the tendon and bone
Entheses in culture respond to IL-23 by upregulating expression of Il17a, Il17f, Il22 and bonemorphogenic protein 7 (Bmp7)
IL-23 alone is sufficient to drive enthesitis in vivo
Nature Medicine 2012 : 1069-1077
IL-23R+CD4–CD8–T cells reside in the aortic root
Nature Medicine 2012 : 1069-1077
Nature Reviews Rheumatology 6, 477-485
Nature Reviews Rheumatology 6, 399-405 (July 2010)
Anti-TNFs in PsAOther Outcomes
Current RA Therapies: Can They Be Used in PsA?
• Only for arthritis have benefit , no use in skin lesion
Abatacept in PsAACR and PASI Responses at 169 Days
Emerging Therapies for PsA
Emerging Therapies for PsA (cont)
Ustekinumab Inhibits IL-12 and IL-23 by Targeting the p40 Subunit
PSUMMIT 1: Ustekinumab (IL-12/23i) in Psoriatic ArthritisACR20/50/70 Responders at Week 24
PSUMMIT2Efficacy of Ustekinumab in Psoriatic Arthritis at 24 Weeks
Change From Baseline in Modified Total vdH-S Score at 24 Weeks
• Randomised placebo-controlled , phase 3 trial to assess the safety and efficacy of ustekinumab in a patients with active psoriatic arthritis
• 104 sites, 14 countries (Nov 30, 2009-March 30, 2011)
• Inclusion criteria: active PsA for 6 M or longer despite 3Ms or more of treatment with DMARS or 4 weeks or more of treatment with NSAIDs, or both, or with intolerance to these treatment
• Active PsA: 5 or more swollen joints (of 66) , 5 or more tender joints ( of 68), CRP 3.0mg/L or more, active or documented Hx of plaque PsO
Lancet. 2013 Aug 31;382(9894):780-9
Median change from baseline at week 24 and 52 dactylitis
enthesitis
% of pts, PSAI75
Lancet. 2013 Aug 31;382(9894):780-9
Plaque Psoriasis with Nail Involvement was Improved
Absolute NAPSI scores ± standard deviation for Initial Responders improved from 4.2±1.84 at baseline and 1.1±1.47 at week 52 in the maintenance group
Rich P, et al. Br J Dermatol. 2013 Sep 30. doi:10.1111/bjd.12632. [Epub ahead of print]
GRAPPA Treatment Recommendations for Psoriatic Arthritis
ustekinumabustekinumab
ustekinumabustekinumab
Ustekinumab ?
TH17 CellsElevated in Patients With Psoriatic Arthritis
IL-17 Inhibitors in Development for PsA
Efficacy of IL-17 Inhibitors in Plaque Psoriasis
IL-6 Cell Types and Biologic Activities
Cytokine Signaling Pathways
ApremilastPDE4 inhibitor
PALACE 1Apremilast in PsA
Efficacy of Tofacitinib in Psoriasis
謝謝聆聽