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

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