Mechanism of action study of Ustekinumab treatment in psoriatic arthritis:
Impact on cellular and molecular pathways of synovial inflammation and tissue remodeling

Psoriatic arthritis is an inflammatory arthritis and can presents with
arthritis, axial disease, psoriatic skin and nail lesions, dactylitis and
enthesitis. The prevalence of active psoriatic lesions in PsA patients is
reported between 6-48%. Current treatment consists primarily of
disease-modifying anti-rheumatic drugs, despite lack of large evidence for
clinical benefit and as a second line treatment TNF-inhibitors with a well
proven efficacy in psoriatic arthritis. TNF blockade has a major impact on
signs and symptoms of PsA but:
1. only 50% of the patients respond well and tolerate the treatment
2. TNF blockade does not induce long-lasting remission as almost all patients
relapse within a few week after interruption of the treatment
3. TNF blockade does not halt the structural damage
There is thus a high unmet medical need for alternatives for TNF blockade in
this disease.



Based on the role of IL-17/IL23 in various inflammatory and autoimmune models
various biological drug against IL17 and IL23 are currently in clinical
development. Ustekinumab, a monoclonal antibody against p40, has proven
efficacy and safety in plaque psoriasis and is approved and reimbursed for this
indication. An early phase II study by Gottlieb et al (lancet 2009) indicated
clinical benefit of this drug in PsA. More recently, the large phase III
Psummit I and Psummit II trials confirmed the efficacy and safety of
ustekinumab in PsA (McInnes et al, Lancet 2013). Ustekinumab significantly
improved psoriatic arthritis symptoms including skin lesions and ACR20 response
(50 v.s. 12 in placebo) and was well tolerated. 1 year results show that the
treated patients maintained a better clinical improvement compared with placebo
and the treatment had a good safety profile. Based on these data, ustekinumab
is the first non-TNFi biological to be approved for treatment of PsA and is
expected to be soon reimbursed in many European countries, including the
Netherlands.

Besides the obvious clinical issues which need to be further addressed in phase
III and/or phase IV trials, these observations raise the question which
down-stream cellular and molecular pathways involved in PsA pathogenesis are
affected by p40 blockade. This includes the inflammatory pathways and,
specifically, the quantitative and qualitative impact of the treatment on the
IL-17 producing cells and the overall cytokine milieu. An additional point of
interest, however, is the stromal remodelling and osteoproliferation leading to
new bone formation, as this process does not seem to be significantly modulated
by other treatments (in particular TNF blockers) and thus represents an
important unmet medical need in SpA/PsA management. Recent studies have yielded
new insights on the potential mechanisms of structural remodelling in SpA,
focusing mainly on BMP and Wnt signalling. Additionally, we have recently
identified a unique stromal cell signature in SpA synovitis and have related
this to the presence of a specific remodelling cell population in the target
tissues (Yeremenko et al, Arthritis Rheum 2012). Whether this cell population
is directly involved in ankylosis or is a surrogate marker for this process is
currently under investigation. Of relevance for the present proposal, the
stromal cell signature is not significantly modulated by TNF blockade.

This MoA study aims to provide insights in the depth and width of the
immunomodulation by IL-23/12 p40 blockade by assessing the impact on molecular
pathways of disease, including but not restricted to cytokine production, in
the primary target tissue. These data are relevant to support clinical efficacy
as well as safety data. Moreover, it will teach us whether IL-23/12 p40
blockade has any impact on important pathways of structural remodeling in PsA.
If the case, this may point to a unique feature of IL-23/12 p40 blockade over
established treatments which warrants further long-term imaging studies on new
bone formation. Finally, an unbiased gene expression analysis will allow us to
determine the specific molecular profiles of IL-23/12 p40 blockade versus TNF
blockade and may thereby help to identify novel biomarkers for tailored
therapy.

Objective
Please describe:
• the specific goal to be reached by the study
• the hypothesis to be answered by the study

The overall aim of the study is to determine which downstream cellular and
molecular pathways involved in PsA pathogenesis are modulated by IL23/12 P40
blockade. As we have ample evidence that relevant disease-specific pathways are
found in the primary target tissues, in particular in synovial tissue obtained
from peripheral joints, but not in peripheral blood, we will strongly focus on
this compartment by obtaining paired biopsies before and after treatment.

The primary objective is to assess the effect of IL23/12 P40 blockade on:
- the global synovial histology and inflammatory infiltration
- the number and type of IL-17 producing cells in PsA synovitis
- the synovial stromal cell signature
- the pan-genomic synovial gene expression profile

The secondary objective is to compare which molecular disease pathways are
affected by IL23/12 P40 blockade and not by TNF blockade and thereby identify
molecular biomarkers which may help to determine which patients may benefit
from this treatment in comparison with anti-TNF treatment.

Non-interventional, open-label, phase IV study in which patients receiving
ustekinumab treatment from their own treating physician will be monitored for
24 weeks, including synovial biopsies and paired peripheral blood withdrawal at
week 0,12 and 24. Effectiveness/mechanism of action will be measured by
determination of different parameters as described in section *efficacy and
effectiveness assessments*. Safety will be monitored by adverse events
reporting and routine hematology and chemistry variables at visits including
bloodwithdrawal.

The study will primarily be conducted in the Academic Medical Center/University
of Amsterdam (Prof. Baeten).

low risk