TNF and IL23 Blocking Agents Gene Expression Ratios in the Psoriatic Arthritis Synovium

1. STUDY SYNOPSIS 1.1 Rationale Psoriatic arthritis (PsA) is a chronic inflammatory disease, leading to impaired function, reduced quality of life, comorbidities and increased mortality. Fortunately, improved knowledge about disease mechanisms catalyzed rapid development of effective targeted therapies for this disease. PsA is a clinically heterogenous disease. Connections between clinical manifestations, disease activity, disease severity and entheseal/synovial molecular patterns are still not understood. In addition, although many treatments targeting different molecules or cytokines are now available, clinicians are still facing difficulties in the treatment choice, owing to the lack of reliable markers improving patients stratification. In the present project, we want to take advantage of our expertise in the field to compare global molecular profiles up- or down-regulated in synovitis of patients with PsA resistant to conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs), before and after administration of targeted therapies, in order to identify molecular markers associated with response to therapy. This may allow us to move further towards precision medicine.

1.2 Aim of the study We intend to evaluate global transcriptomic effects of ustekinumab (IL-12/IL-23/p40 blocker) and guselkumab (IL-23/p19 blocker) in synovial biopsies from csDMARD-resistant, biologic-naive patients with PsA, obtained prior to and 24 weeks after initiation of therapy. In parallel, synovial biopsies will be obtained before and after initiation of adalimumab (a widely used TNFα blocker) to evaluate the different molecular pathways affected by the different drugs. In order to deliver, this project will be based on the use of an Affymetrix platform (GeneChip HGU133 Plus2.0 chips). We and others amply demonstrated the power of this analytical approach in identifying synovial pathways associated with disease activity and response to therapy in the past (resulting in the development of a diagnostic and theranostic commercial kit). However, the material collected throughout the study will be a unique opportunity to carry out a more exploratory single cell RNASeq procedure on our samples, thereby potentially unravelling molecular effects of therapies in specific cell populations. Identification of the synovial effects of those treatments in psoriatic arthritis will be a step forward in understanding not only the mode of action of the drug at the site of inflammation, but also in the identification of molecular patterns associated with good response to therapy. The main advantage of our approach compared to other biomarker studies, is that we use synovial material as such, and not peripheral blood, which is a more remote location in terms of cellular targets of the drug. This project takes advantage of our strong experience in the field of molecular profiling of synovial biopsies, and evaluation of responses to biological agents. Key to the success of our translational approach is the association of reliable molecular techniques with a well-validated clinical evaluation of disease activity and response to therapy, using a panel of clinical, biological and imaging techniques.

1.3 Study design Dual centre, 24-week open-label randomised study in subjects with clinically active peripheral PsA receiving treatment with the relevant drugs. Synovial biopsies will be obtained from patients before and after 24 weeks of treatment with the different drugs.

1.4 Study population DMARD-resistant, biological naive patients with a diagnosis of psoriatic arthritis according to the CASPAR criteria with at least one swollen joint (either small or big joint) who are planning to receive treatment with one of the targeted drugs. In total, 36 patients will be included. Patients will be randomized 1:1:1 between: Group 1 (n=12): ustekinumab 45 mg (or 90 mg for patients > 100 kg) subcutaneously at baseline (W0), 4 weeks later (W4), and every 12 weeks until week 24 (i.e. W0, W4, and W16). Group 2 (n=12): guselkumab 100 mg subcutaneously (regardless of the weight of the patient) at weeks 0 and 4, followed by a maintenance dose every 8 weeks through week 24 (i.e. W0, W4, W12 and W20). Group 3 (n=12): adalimumab 40 mg (regardless of the weight of the patient), subcutaneously every other week, starting from the baseline until week 24 (i.e.W0, W2, W4, W6, W8, W10, W12, W14, W16, W18, W20 and W22).

1.5 Synovial biopsy procedure Synovial biopsies will be harvested either by ultrasound guided biopsy (USGB) for small joints (wrist, MCP, PIP), or large joints (elbow, knee, ankle) or by needle-arthroscopy procedure (NAP) for large joints such as the knee.