Targeting inflammation, protecting the brain
A systematic review conducted independently at UWE Bristol has highlighted the potential impact of immunomodulatory therapies—particularly methotrexate (MTX)—on the developing brain. This work is especially relevant for children receiving treatment for inflammatory conditions, including those with rare disorders such as Camptodactyly‑Arthropathy‑Coxa Vara‑Pericarditis (CACP).
Presented at MLSFF 2026, this research combines literature synthesis, MRI evidence, and a custom 3D‑printed brain model to illustrate how MTX‑associated white‑matter changes may influence long‑term neurodevelopment. The findings emphasise the need to re‑evaluate MTX as a routine first‑line therapy in paediatrics.
Real‑world problem
Children with inflammatory conditions often require early and sustained immunomodulatory treatment. However, the developing brain is uniquely vulnerable, and the neurological effects of drugs such as MTX remain under‑recognised. Rare conditions like CACP are particularly affected by gaps in research, and diagnostic uncertainty can influence treatment decisions.
As a result, children may be exposed to therapies that carry risks not yet fully understood. This work aims to address these concerns by examining the evidence for drug‑related brain changes and highlighting the importance of safeguarding neurodevelopment during treatment.
A systematic literature search was performed across PubMed, MEDLINE, and the Cochrane Library. Using defined inclusion and exclusion criteria, studies published between 1996 and 2025 were selected if they examined paediatric brain outcomes or provided mechanistic insight into cytokine‑mediated neurotoxicity. Research focusing solely on adults or non‑neurological outcomes was excluded.
The review identified several key findings. MRI studies reported white‑matter lesions and Dawson‑finger‑like patterns in children exposed to MTX. Mechanistic evidence linked MTX‑induced adenosine accumulation to neurotoxic pathways, while TNF‑α inhibition was associated with an increased incidence of inflammatory brain disease. Structural changes were noted in regions responsible for cognition and emotional regulation, underscoring the potential long‑term impact of early immunomodulatory exposure.
Digital brain model
To support communication of these findings, a digital paediatric brain model was created in Nomad Sculpt and subsequently 3D‑printed in clear coloured resin. The left hemisphere, printed in blue, represented healthy development, while the right hemisphere, printed in red, illustrated MTX‑associated white‑matter injury, including pitting and cellular damage patterns. The transparent resin allowed light to pass through the model, enabling viewers to visualise and physically interact with the structural differences—bridging the gap between abstract data and tangible understanding.
Taken together, these findings suggest that MTX and certain cytokine‑targeting therapies may influence brain development more significantly than previously recognised. They also highlight the importance of considering rare conditions such as CACP within broader paediatric research, as insights from these disorders may inform safer treatment strategies across multiple diseases.
The extent to which early immunomodulatory exposure can influence brain plasticity was particularly striking. It was unexpected to see how a drug widely regarded as a paediatric “gold standard” could be associated with structural brain changes, especially given its known contraindications in pregnancy. Additionally, the subtle role of diagnostic uncertainty in shaping treatment pathways underscored the need for greater precision in managing rare conditions.
Implications for the real world
These discoveries have important clinical implications. They highlight the need for more cautious prescribing of MTX in children, alongside routine neurological monitoring for those receiving immunomodulatory therapies. The findings also emphasise the value of earlier and more rigorous genetic testing to support accurate diagnosis and avoid unnecessary exposure to potentially harmful treatments. This study highlighted how misdiagnosis of CACP syndrome as JIA can result in children receiving JIA‑related drugs that offer no benefit for CACP symptoms.
More broadly, this work reinforces the importance of investing in research on rare conditions, which may reveal shared mechanisms and inform safer therapeutic approaches across paediatric inflammatory diseases. For example, the PRG4 gene—which encodes lubricin—plays a key role in joint homeostasis and inflammatory regulation. Insights from PRG4 biology may offer a springboard for developing novel treatments that modulate inflammation more precisely, potentially benefiting both rare conditions like CACP and more common paediatric inflammatory disorders.
Future directions
Further research is essential to evaluate the long‑term neurodevelopmental outcomes of MTX use in children. Expanded clinical studies will be crucial to validate MRI‑based findings and clarify the mechanisms underlying drug‑related brain changes. Improved diagnostic pathways, including genetic testing, will help ensure that children receive the most appropriate treatment. Finally, greater attention to rare conditions such as CACP—and deeper investigation into genes such as PRG4—may uncover new insights that benefit a wider patient population.
This research project was conceived, led, and completed independently by Abrar Kholwadia.