Effect of therapeutic interventions on skeletal growth & development in paediatric inflammatory bowel disease

Malik, Umm ie Salma (2013) Effect of therapeutic interventions on skeletal growth & development in paediatric inflammatory bowel disease. PhD thesis, University of Glasgow.

Abstract

Crohn’s disease (CD) is a chronic inflammatory bowel disease. Once considered rare in the paediatric population, it is recognized with increasing frequency among children of all ages. Approximately 20-30% of all patients with CD present when they are younger than 20 years. With its increasing recognition, CD has become one of the most important chronic diseases that affect children and adolescents. In addition to the common gastrointestinal (GI) symptoms (diarrhoea, rectal bleeding, and abdominal pain) children often experience growth retardation, pubertal delay, and bone demineralization. In these children, maintenance of skeletal health is a complex process that is influenced by a number of different mechanisms including steroid therapy, the disease process, nutritional status, endocrine status and the response of the body to inflammatory mediators. The recent introduction of biologic therapy that targets specific mediators of the proinflammatory process is a promising adjunct in the therapeutic management of the child with chronic inflammation. These drugs may also exert beneficial effects on the adverse effects of inflammation on growth and skeletal development. It is unclear whether these beneficial effects are due to improvement in overall disease or due to a direct ‘anti-cytokine’ effect at the level of the target tissue involved in growth and skeletal development.
The hypothesis of this study was that the biologic therapy improves linear growth, puberty, bone health, body composition and muscle function in children with CD and this is associated with changes in the IGF-1 axis and markers of bone formation and bone resorption.

Chapter 1 is an extensive literature review about the effects of biologic therapy on growth and skeletal development in paediatric patients with chronic inflammatory conditions particularly inflammatory bowel disease (IBD). The main aim of this review was to summarize and evaluate effects of inflammation and biologic therapy on growth and skeletal development in children with chronic inflammatory conditions and to explore the areas of interest for further research.

Chapter 2 is the study about the growth in children receiving contemporary disease specific therapy in children with CD. The aim of this study was to assess the frequency of short stature and poor growth and their relationship to disease course and therapy in children with CD. Clinical records of all children with a confirmed diagnosis of CD, who were between 2yrs and 18yrs at the Royal Hospital for Sick Children, Glasgow were examined retrospectively. Data were collected at diagnosis, 1-yr, 2-yr and 3-yr after diagnosis and at maximum follow-up. The relationship of a number of factors including therapeutic modalities to two commonly used anthropometric markers of growth height velocity standard deviation scores (HVSDS) and change in height standard deviation scores (∆HtSDS) was examined. This study suggested that ∆HtSDS may be a more valid method of assessing and reporting longitudinal growth in children with chronic disease, particularly when there is a high prevalence of children of a peri-pubertal age. This study provides clear evidence that despite advances in therapy, short stature and slow growth continue to be encountered in a sub-group of children with CD.

Chapter 3 is about the effect of Infliximab therapy on growth, puberty and disease activity in children with CD. The aim of this study was to assess growth, puberty, markers of disease and concomitant therapy over the six months prior to starting Infliximab and for the 6 and 12 months following treatment. Clinical records of all children with IBD who were started on Infliximab therapy between 2003 and 2008 at the Royal Hospital for Sick Children were examined retrospectively. This study has shown an average improvement of approximately 50% in HV in the 6 months after the initiation of Infliximab therapy which was further sustained for a further 6 months. Improvement in growth was found to be better in those children who were responders as compared to non-responders suggests that growth improved as a result of disease control. Improvement in growth was also observed in children who remained pre-pubertal and those who had never been on glucocorticoids (GC) compared to those who had been on GC. This study suggests that increase in height may not be simply due to progress in pubertal status or reduction in glucocorticoid dose.

Chapter 4 is about the effect of Adalimumab therapy on growth in paediatric patients with CD. This is the one and only world wide multicentre study that adequately assess the effect of Adalimumab on linear growth in children with CD. The aim of this study was to assess the effect of Adalimumab therapy on growth, puberty and disease activity over the 6 months prior to and 6 months after starting Adalimumab treatment in children with CD. This study provides evidence that Adalimumab is associated with improvement in short term linear growth in children with CD who enter remission but not in those who do not. It is also more likely to happen in children who are on immunosuppression and those in early puberty but seems to be relatively independent of steroid use. These findings suggest that growth improves as a result of several interrelated factors, including improved disease control. It was also interesting to note that the growth response to Adalimumab varied dependent on the reason for discontinuing Infliximab; those who had an allergic reaction to Infliximab fared best.

Chapter 5 is Longitudinal observational prospective study of changes in physical growth, IGF-1 axis, bone health, body composition, muscle function and disease activity at baseline (BL), 2 weeks (2wk), 6 weeks (6wk), 6 and 12 months (6M & 12M) following biologic therapy in paediatric patients with CD. The aim of this longitudinal observational prospective study was to assess changes in physical growth, puberty, IGF-1 axis, bone health; body composition and muscle function following biologic therapy in paediatric patients with CD. Patients either newly diagnosed or patients with long-lasting disease in clinical relapse, who started treatment with biologic therapy as part of their standard clinical management, were recruited. A non significant improvement was observed in both ∆HtSDS and HVcms/yr at 12M as compared to BL. Individually, the majority of the children experienced improvement in clinical activity and improvement of the systemic inflammatory markers. A significant increase in biomarker of bone formation bone specific alkaline phosphatase (BALP) and a non-significant increase in a biomarker of bone resorption cross-linked c-terminal telopeptides (CTX-1) was observed from BL to 12M. This observation suggests the beneficial effect of biologic therapy on bone formation.
This study showed a significant change in fat mass (FM (kg) in paediatric patients with CD following biologic therapy an effect that has not been reported extensively in previously published studies. A significant change in both fat free mass (FFM (kg) and fat free mass index (FFMI(kg/m²) shows that the treatment with anti-TNF-α therapy also had a significant impact on fat mass accrual. This is the first study that charts the effect of biologic therapy on changes in lower limb muscle function using jumping mechanography in paediatric patients with CD. A non significant change was observed in jump height (m), V-max (m/s), EFI (%), efficiency % from BL to 12M following biologic therapy and a significant increase in both F-max (kN), and P-max (kW) at 12M. Despite the fact that the increase in efficiency % of the movement was not significant but however, the change was likely to be through improvements in jump height and velocity thereby indicating higher muscular flexibility. These data are suggestive of an effect of biologic therapy on lower limb muscle function through improvements in the mechanical efficiency of the muscle. Thus, it is possible that the better muscle function is mediated through the effect of biologic therapy on muscle mass.
Peripheral quantitative computed tomography (PQCT) for tibia and radius both indicated significant increase in fat and muscle cross sectional area (Fat-CSA (mm²) and Mus-CSA (mm²). Moreover, tibia pQCT also indicated significant change in stress strain index (SSI (mm³) a surrogate marker of bone strength, at 12M of therapy. No significant changes were observed in total body, lumbar spine (L2-L4), proximal femur and femoral neck bone mineral density (BMD (g/cm²), insulin like growth factor-1 (IGF-1(ng/ml), insulin like growth factor binding proteins (IGFBP-3 (ng/ml), IGFBP-2 (ng/ml) and acid labile subunits (ALS (ng/ml) following biologic therapy.
In conclusion, these prospective studies of growth, bone health, body composition and muscle function have suggested that biologic therapy in children with CD has a beneficial effect on muscle mass and muscle function and which can be observed over the first year of therapy for conclusive explanation of these changes these data needs to be adjusted for body size. These positive changes are also associated with an increase in bone turnover where the change in bone formation is much greater than bone resorption. These favourable effects on bone health were not accompanied by marked changes in BMD as assessed by DXA but did show some beneficial effects on pQCT assessed SSI, a surrogate marker of bone strength. It is possible that controlling disease activity with biologic therapy may positively outweigh the effects of CD on growth, body composition, muscle function and bone health. The results of this preliminary study need to be confirmed in a larger group of children. An improved understanding of the effect of biologic therapy may improve future therapy directed at promoting growth and skeletal development in a diverse group of children. Further studies are required to understand the duration of the window of opportunity during which linear growth, bone and muscle mass in children with CD can be optimised.

Chapter 6 focuses on the main findings of this thesis and discusses potential limitations of this methodology, and outlines some important and interesting extensions for future research in paediatric patients with CD following biologic therapy.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Crohn,s disease, Infliximab, Adalimumab, growth, bone health, inflammatory bowel disease, skeletal development
• Subjects: R Medicine > RJ Pediatrics > RJ101 Child Health. Child health services
• Colleges/Schools: College of Medical Veterinary and Life Sciences
• Supervisor's Name: Ahmed , Professor Syed Faisal and Russell, Dr. Richard Kay
• Date of Award: 2013
• Depositing User: Miss Umm ie salma Malik
• Unique ID: glathesis:2013-4421
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 02 Jul 2013 10:54
• Last Modified: 02 Jul 2013 10:56
• URI: https://theses.gla.ac.uk/id/eprint/4421