Defining the Cellular Basis of Disease Persistence in Juvenile Idiopathic Arthritis

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children worldwide.

JIA is highly heterogenous, being associated with a diverse spectrum of long-term clinical outcomes ranging from sustained ‘drug free’ remission to rapidly progressive, severe arthritis that persists into adulthood.

Early, intensive treatment has been shown to significantly improve long-term clinical outcomes, increasing the probability of achieving inactive disease and/or clinical remission, and reduced joint damage.

As a result, treatment algorithms based on predictive biomarkers of specific disease trajectories are urgently needed for effective treatment stratification in early JIA.

We will test the hypothesis that severe disease in JIA can be predicted from early synovial tissue pathology defined at the cellular level, and that specific disease trajectories are associated with distinct effector cell pathways that form the cellular basis of severe arthritis.

Difficulties in sampling synovial tissue in children and the inability to systematically define the cellular landscape of the synovium at different stages of disease have combined to compound our understanding of the cellular basis of arthritis progression in JIA.

The development of ultrasound-guided, minimally invasive synovial biopsy procedures, that are used routinely for synovial tissue research in adult arthritis, combined with an increasingly sophisticated definition of the cellular heterogeneity of tissue at high resolution, using single cell profiling technologies, have revolutionised our ability to answer these important clinical and biological questions.

We will perform minimally-invasive synovial tissue biopsies during joint injection being performed during routine clinical care.

Using this approach, we will examine the synovial tissue of children with treatment-naïve oligoarticular onset JIA (oJIA, definition: <4 joints affected) biopsied at time of diagnosis.

Around a third of these children typically develop a more severe, extended form of arthritis (defined as >5 affected joints) after the first six months following diagnosis, while in others the arthritis remains limited to few joints.

The divergent clinical outcomes of this type of arthritis provide a unique opportunity to identify predictive biomarkers of severe disease.

Synovial tissue pathology will be defined at the single cell (sc) level using sc-RNA sequencing, multiplex imaging and high dimensional cytometry to build a spatiotemporal map of the cellular pathology.

Baseline synovial pathology will be mapped to specific disease trajectories based on the clinical outcome of arthritis at 1-year.

To define effector cells and pathways underlying the development of severe arthritis in oJIA, longitudinal tissue biopsies will be performed in children whose arthritis becomes severe (extended oJIA >4 joints affected) and compared with those in whom arthritis is already severe at the time of diagnosis (rheumatoid factor negative polyarticular JIA - RF- poly JIA).

We will use a combination of sc-RNAseq with Assay for Transposase-Accessible Chromatin (ATAC) sequencing to map inflammatory mediators to effector cell populations that underlie the development of severe arthritis. Our proposal is uniquely strengthened by combining expertise in adult and childhood arthritis immunobiology.

These studies are critical for future development of clinical trials informed by ‘precision pathology’ treatment stratification, based on therapeutic targeting of specific disease pathways underlying severe arthritis.