25 July 2018

CHARMS: 10 years on

Prof Wedderburn who leads a study on childhood arthritis

Professor Lucy Wedderburn leads an impressive study into childhood arthritis that has brought together teams and findings from across the UK, and around the world.

This is the Childhood Arthritis Response to Medication Study (CHARMS), which has been supported by Sparks and Great Ormond Street Hospital (GOSH) Children’s Charity. Together, those involved hope to gain a better understanding of the causes of arthritis in children, and how best to treat those affected.

What is juvenile idiopathic arthritis?

CHARMS is looking into a condition called juvenile idiopathic arthritis (JIA). This is the name for a range of conditions that all have one symptom in common – an inflammation in one or more joints before a child turns 16. The condition is caused when a child’s immune system goes into overdrive and attacks their own tissues.

Around one in 1,000 children in the UK have JIA, and due to the variable nature of the condition, some families find the definition hard to process. Sparks-funded researcher Lucy Wedderburn, Professor in Paediatric Rheumatology at UCL Great Ormond Street Institute of Child Health and a Consultant at Great Ormond Street Hospital (GOSH) explains:

“For children at one end of the spectrum, it can be a very severe disease. Back when I was training, there were children who still died of the condition. It’s a very severe disease that affects many parts of the body and has many complications. But at the other end of the spectrum, a child might have arthritis in just one joint. In that case, we could give them an injection, they could get better and it may never come back.”

What is CHARMS?

CHARMS is now 10 years old and has evolved a lot over the past decade. In short, it’s a study that aims to help predict which children will respond well to certain JIA medications, and which won’t. This would help to predetermine which children will benefit from standard treatments, and which need to be fast-tracked onto more powerful treatments. Professor Wedderburn explains: “CHARMS has done the first ever comprehensive genetic study to understand whether differences in a child’s DNA can affect the way they respond to drugs. The study observes the cells we think are causing the arthritis, how they are affected by the drug methotrexate, and looks at whether we could devise a blood test that would predict if the drug is going to work or not.

Research into childhood arthritis

Thanks to this research, the CHARMS team has also now successfully introduced the first ever test to determine how a child will react to different drugs. This simple blood test gives parents of children with JIA an indication of their child’s chance of getting better on the medication methotrexate. Having this knowledge helps doctors and families to make a more informed decision.

A nationwide project

Reaching this point wouldn’t have been possible without collaboration. For the past 10 years, the team at GOSH has been working with a team in Manchester, who lead on the genetics work. CHARMS now involves seven hospitals across the UK, and Professor Wedderburn highlights the importance of having a diverse set of patient data to work with: “We’re very aware that GOSH patients may be at the severe end of the spectrum, and we need to include children with all forms and all levels of severity of JIA.”

“It’s important that people do things collaboratively – it’s better for the children if everyone does that”

Data Manager and Study Coordinator, Cherelle Allen, manages the study across all seven centres, collecting data and samples, and conducting follow-ups with the families involved. “In total, CHARMS recruited over 1,000 children and young people,” says Cherelle. “Then three and a half years ago, we went to the Medical Research Council to ask for funding to put CHARMS together with other ongoing studies for the disease. And together, we had the involvement of 5,000 families.”

A worldwide project

JIA affects children all over the world and there are many projects researching the causes and potential treatments. Professor Wedderburn explains how the study brought together teams from across the world: “It’s a small field, so we already knew that colleagues in other countries, such as the Netherlands, were doing similar things to us. We reached out to them and they shared some of their information and samples, so we could look at genetic information from a larger number of patients. This type of study needs lots of cases, and in the end, 800 children worldwide took part in the genetic study for CHARMS. “We still need to gather more data, but we did identify a set of genes that seemed to influence the failure or success of a drug, which is exciting. We’re now at the stage where we could start to validate those findings.”

Collaborating with other countries has connected the team at GOSH with a larger European network of patients who represent many countries. Professor Wedderburn says: “We wouldn’t have gathered enough patient data to make these findings without the Dutch and Czechs. It was vital that they partnered with us. It’s important that people do things collaboratively – it’s better for the children if everyone does that.”

The power of psychology

Another poignant observation to come from this study has been the substantial influence that psychology can have on a child’s healing process. Professor Wedderburn says: “We think the way that parents cope with their child’s diagnosis can affect their child’s outcome.” The team recognised that having well-informed parents with a positive attitude could help to support children through their treatment.

“You realise how useful sharing their experience is for those families”

From this discovery, the team decided to empower parents and guardians with better and more readily available information. Together with some of the parents involved in the study, they designed a website, full of useful information parents can access to find out more. Professor Wedderburn says: “Just being together in the website focus group was empowering for some parents. You realise how useful sharing their experience is for those families.”
The team are currently testing to see whether having the support of a professional website for six to twelve months helps families to cope with diagnosis and treatment. If the website works well, the plan is to make it publicly available.

Progression to CLUSTER

Following the success of CHARMS, Professor Wedderburn and colleagues have recently been awarded £5 million by the Medical Research Council for a new project called CLUSTER. The Medical Research Council put out a call for researchers to identify disease areas where tailoring treatments to each child – known as personalised or stratified medicine – would be a huge benefit and could become a reality. They received applications covering 50 disease areas, and only four were given funding – CLUSTER is one of them.

CLUSTER is a UK-wide consortium of researchers who will look at personalised treatments for JIA and uveitis, an eye condition associated with JIA. Uveitis is a serious condition that can cause children to become blind, so diagnosing children early is crucial.

The project brings together scientists from Manchester, Liverpool, Cambridge, Bristol and London. It will build on the work conducted as part of CHARMS and will develop the research by gathering more patient data and exploring the causes and treatment of uveitis. Over five years, those involved in the project aim to identify which children are at risk from uveitis, predict long-term outcomes for these children, help doctors identify the best treatment, and identify new therapies and drugs with fewer side effects.

Hopes for the future

The ultimate aim for those involved in CHARMS and CLUSTER is to prevent long-term health problems associated with JIA. Professor Wedderburn says: “We know that a key way to prevent serious problems in adult life is if the child gets into remission quickly. If you get the right drug early and you don’t stop the medication until it’s safe to do so, then you will cut down on joint damage, disability and weakness. For CLUSTER, just being able to detect uveitis early and knowing who is at risk of losing their sight would be a huge leap forward.“

The impact

Joe was diagnosed with juvenile arthritis when he was six years old which left him unable to walk at times. Thanks to being involved in Prof Wedderburn’s research, he’s now a fit 17-year-old who stars for his local football team.

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