for further bioagent tx of PsA/PsO, more focus in MOA

1. What's MOA Got to Do With
PsA/PsO?
More and more new bioagent of Rheuamtoid arthritis,
what about Psoriasis ?

3. NEJM Volume 361:496-509
Then ?

4. induces proliferation
of keratinocytes
NEJM 2009 Volume 361:496-509

7. 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)413-23
2 - Kelley’s Textbook of Rheumatology. 9th ed

8. 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

9. PSA: peripheral joints
63% polyarticular
13% oligoarticular
Dactylitis
29-33.5% at first presentation
48% during follow-up
Enthesitis
38%
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

10. 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

11. 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 enthesitis
Arthritis Rhum 2011, 40 :407-12

12. Nail and the enthesis:
anatomic relationship
McGonagle D, et al. Dermatology. 2009;218(2):97-102

14. 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 misfoldingIL23 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

15. IL-23 drives enthesitis in vivo
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
Nature Medicine 2012 : 1069-1077

16. 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 bone
morphogenic protein 7 (Bmp7)

17. IL-23 alone is sufficient to drive
enthesitis in vivo
Nature Medicine 2012 : 1069-1077

18. IL-23R+CD4–CD8–T cells reside in
the aortic root
Nature Medicine 2012 : 1069-1077

19. Nature Reviews Rheumatology 6, 477-485

20. Nature Reviews Rheumatology 6, 399-405 (July
2010)

23. • Only for arthritis have benefit , no use in skin lesion

33. • 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

34. Median change from
baseline at week 24 and
52
dactylitis
enthesitis
% of pts,
PSAI75
Lancet. 2013 Aug 31;382(9894):780-9

35. 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]

36. ustekinumab ustekinumab
ustekinumab ustekinumab
Ustekinumab ?

46. 謝謝聆聽