Therapeutic Strategies for Restoring Linear Growth in Children with Crohn’s Disease.
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Linear growth retardation affects up to 40% of children with Crohn’s disease (CD). It is caused by a combination of under\nutrition, and by a direct effect of cytokines on the axis linking human growth hormone (GH), insulin like growth factor\1 (IGF\1) and the growth plate of growing bones. In particular,the inflammation causes a functional insensitivity to GH, resulting in low circulating IGF\1. Current management is synonymous with the optimal management of childhood CD:to eliminate inflammation,and maintain remission. However, there is currently no consensus as to how to treat growth failure in patients whose inflammation remains intractable to treatment. This thesis examined the hypothesis that successful treatment of inflammation would improve linear growth in children with CD. We performed a series of retrospective studies examining a cohort of children aged ≤17 years with CD treated at Bart’s and The London Children Hospital. We determined the height standard deviation scores (SDS) of patients at diagnosis and investigated growth outcomes following treatments used to induce and maintain remission. These were:exclusive enteral nutrition (EEN), thiopurines and infliximab. Finally, as a potential new therapy, we considered the use of exogenously administered recombinant human IGF\1 (rhIGF\1) to restore plasma IGF\1 levels. We performed an open\labelled pharmacokinetic (PK) study of rhIGF\1 in 8 children with CD and growth failure. 9% of our patients had height SDS of \2 SDS at diagnosis; a four\fold increase compared to the normal age matched population. In addition, symptom duration negatively correlated with height SDS at diagnosis (r=\0.06; p=0.02). From 89 5 patients receiving EEN for primary induction of remission, 62.9% (56/89) of patients achieved complete remission. Over the course of 5 years, responders to EEN grew significantly better than non\responders (change in height SDS +0.18 [0.12] vs to \ 0.37 [0.13] respectively; p=0.005). This occurred despite no differences in duration of remission or treatment escalation between groups. 51% (26/51) patients treated with thiopurines were in remission at 12 months. These patients had improved growth (median change height SDS [IQR] 0.08 [\0.06 – 0.19] vs \0.24 [\0.61 \ \0.07] in non\responders; p=0.001). 39.2% (20/51) of these patients started anti\TNF therapy. However, over 12 months, we found that this conferred no improvement in growth (median [IQR] at 0 months\0.38 [\1.73 to \0.10] as compared to \0.61 [\ 1.72 to \0.09] at 12 months; p=0.43), irrespective of response to treatment. Subcutaneous treatment with 120 μg/kg twice daily rhIGF\1 restored plasma levels of IGF\1 in our patients, albeit it in some to high levels (median [range] concentration +2.09 [\1.27 to +5.21]). We were able to develop a PK mathematical model from these results to determine a more appropriate dosage. We found that in addition to patient’s age and weight, PCDAI also needs to be taken into consideration when determining dose. In summary, growth retardation is very common finding in paediatric CD. Response to EEN and thiopurines seems to result in beneficial effects upon growth. However, a number of children continued to have poor growth despite treatment. Our results show it is possible to increase circulating IGF\1 concentrations with exogenous injections, and develop a mathematical model to devise a dose to use in further trials.
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