Understanding why treatments for juvenile idiopathic arthritis affect children differently has never been well understood – until now. Dr Chrissy Bolton and Professor Lucy Wedderburn speak to Helen Quinn about groundbreaking new research uncovering the unique architecture of cells and signals inside the joint, which could lead to quicker drug approvals and more accurate personalised care for children with this condition.

The diagnosis, treatment and management of arthritis in childhood, known as juvenile idiopathic arthritis (JIA), have until now relied on surrogate data, such as blood samples, inferences from trials in adults with rheumatoid arthritis (RA) and more recently paediatric trials. In efforts to control the disease, clinicians often try multiple drugs in children on a trial-and-error basis, resulting in unintended side effects and disruption to children’s lives.

But now, in a world first study led by Professors Lucy Wedderburn and Adam Croft from Great Ormond Street Hospital (GOSH) and University College London, and the University of Birmingham and Birmingham Children’s Hospital, respectively, researchers Dr Chrissy Bolton and Chris Mahony, have directly analysed tissue samples from children with JIA.

Published in the journal Science Translational Medicine, the study aimed to determine the underlying disease processes in synovial tissue and uncover the disease mechanisms that are unique to children.

Mapping arthritis in the joints of children

JIA affects more than 10,000 children in the UK and causes swelling, stiffness and pain in the joints, which over time can lead to joint damage and long-term disability. Using advanced imaging and gene-profiling technologies, Dr Bolton, a Medical Research Council clinical research training fellow, is uncovering the unique architecture of cells and signals inside the joints of children.

Working alongside Professors Wedderburn and Croft, her work highlights the critical role of paediatric-specific studies in understanding childhood arthritis.

To date, researchers working in the field of JIA have only had access to samples from fluid in the children’s joint cavities. However, as Dr Bolton explains, the arthritis is not located there.

‘The disease is occurring in that lining of the joint and so we’re always getting an extrapolation of the disease,’ she says. This means that key cell types are not all captured and are therefore missing from the interpretation, including the connective tissue fibroblasts and endothelial cells.

‘Increasingly, we know from adults that these cells are absolutely fundamental to the inflammatory response – to what’s perpetuating and driving inflammation in the disease. If we’re not capturing those cell states, we’re only ever getting part of the picture,’ she adds.

By examining the actual tissue and linings of the joints in different patients, the research team can create detailed maps of the joints to reveal variations between children of different ages and cell changes in those with more severe disease.

Collecting tissue samples from JIA patients

Since biopsies are safe, feasible and tolerable in adults, Professors Wedderburn and Croft and their team were confident that they could perform them in children. Working with families who were keen to be involved, they collected small tissue samples from the joint lining when children were undergoing injections of medicine into the joint.

Using advanced imaging and gene-profiling technologies to analyse joint tissue, including repeated biopsies from some patients, the team were able to determine the cell architecture and start to see which proteins and genes were being expressed. Ultimately, they hope to identify children whose disease goes into remission and discover traits that may predict this outcome.

‘This is one of the huge advances that’s been made possible in the last five or so years. With tiny fragments of tissue, you can get a huge amount of information about what’s happening in that tissue site because of the advances in technologies,’ Dr Bolton says.

The analysis initially included 20 children, and with such a small sample size the team did not expect to find ‘anything super meaningful’. However, the results surprised them.

Unique cellular fingerprints uncovered in JIA patients

A clear age-related difference in the types of cells present in the joints was observed, with teenagers and younger children showing distinct cellular profiles. This suggests that the disease may act differently across different age groups.

In younger children, the inflamed joints have more plasma cells, whilst in older children, more myeloid cells are present. The dominant presence of these different types of immune cells suggests that the underlying immune mechanisms driving JIA may change with age.

‘Even in just 10 children, there were such striking differences in the teenagers versus the youngest children,’ Dr Bolton explains. And that’s something, she says, that warrants further investigation across the spectrum of childhood development. ‘We don’t analyse them [children] differently at the moment and we don’t treat them differently,’ she adds.

The mapping also revealed that the joints of children with arthritis differ markedly from those of adults. As people age, the joint lining becomes increasingly irregular, making it difficult to discern the joint’s architecture. In children, the joint structure is clearer, helping researchers to identify the processes that drive JIA.

Children’s cell populations are also more uniform, making it easier to detect disease-related differences. This contrasts starkly with adults, whose joints exhibit a diverse mix of cells influenced by lifestyle and environmental factors.

‘We now have a wealth of data to actually start to ask those questions that we weren’t powered to ask before,’ says Dr Bolton.

Making sense of enormous new ‘atlas’ data sets

Analysing the biopsy findings and mapping out cells required the expertise of an experienced and diverse team. This included a skilled histopathologist who collected and analysed slices of the samples, a ‘bioinformatics wizard’ who processed the vast quantities of data acquired, clinicians and research nurses in the hospital, interventional radiologists for the biopsies and a laboratory team to process the samples.

‘Trying to understand what’s actually significant in the course of this disease, and trying to align the therapeutic and translational relevance to these ginormous atlas data sets, is actually part of the difficulty,’ Dr Bolton says. ‘There’s a huge army of healthcare professionals and researchers who’ve contributed to the work, as well as the parents and families who make it possible.’

Progressing research and drug approvals in JIA

As the lead of the UK-based CLUSTER consortium exploring stratified medicine in JIA, consultant of paediatric rheumatology Professor Wedderburn is excited that this study has inspired many in the JIA research community. Many colleagues have asked to join the research and use the data, and the team has over 100 more families signed up to be involved.

‘It’s a bit of a snowball effect now because more and more people can see this is now possible,’ says Professor Wedderburn. ‘We feel really optimistic – this opens many new doors, more than we’ve had for 20 years.’

Future work is likely to include further analysis, following the team’s discovery that genes linked to severe JIA are actively expressed in joint-lining cells that form a protective barrier. Damage to this barrier is associated with worse disease outcomes and difficulty achieving remission. Ongoing research aims to develop treatments that could restore the barrier and promote long-term remission in children.

The research also highlights the potential to accelerate drug approvals for children. By comparing biological data from JIA with that from adult arthritis, researchers can demonstrate to regulators that certain drugs may work similarly in both groups, reducing the need for large paediatric trials and shortening the decade-long delay that often separates adult and paediatric access to the same treatments.

‘We’ve broken down some of the silos between adult arthritis research and paediatric arthritis,’ Professor Wedderburn says. ‘Our patients grow up to be young adults, and so it’s actually a huge bonus for the field that we’re working together scientifically.’

Future hopes for personalised medicine

This research also strengthens the development of personalised medicines for children with JIA, leading to novel, biologically based methods for classifying and grouping children with arthritis. Through the use of molecular data and computer-based models, disease progression could be better predicted, as well as drug response, leading to optimal treatment choices for each child.

Ultimately, this understanding of the complexities of the tissues in JIA could revolutionise its treatment. The hope is that the snowball of success seen in JIA could continue and inform other conditions. As Professor Wedderburn concludes: ‘It’s a big ask, but all specialities want this now. We understand that you can’t do that without understanding the tissue, and we’ve sort of grasped that nettle. We’re looking forward to the future, there’s much more to do.’