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Corticosensitivity in inflammatory bowel disease: Role of glucocorticoid receptor polymorphisms
A102
Abstracts / Digestive and Liver Disease 38 (2006) A87–A120
use of antivirals might be useful for preventing undesirable interruption of biological therapy. doi:10.1016/j.dld.2006.07.052 PP 24 CORTICOSENSITIVITY IN INFLAMMATORY BOWEL DISEASE: ROLE OF GLUCOCORTICOID RECEPTOR POLYMORPHISMS S. De Iudicibus, S. Martelossi, G. Stocco, I. Drigo, P. Lionetti, A. Barabino, F. Bartoli, G. Decorti, A. Ventura I.R.C.C.S. Burlo Garofolo, Dipartimento di pediatria, Trieste, Italy Background. Glucocorticoids (GC) are used as first line antiinflammatory and immunosuppressive drugs in many inflammatory and autoimmune diseases and are effective in most patients with inflammatory bowel disease (IBD). However different clinical responses have been observed among patients suffering from such diseases: in particular, patients with Crohn’s disease (CD) have been classified as GC-dependents (when GCs are needed to keep the inflammatory disease quiescent) and GCnondependents (when a good response to the treatment is observed). Some polymorphisms, BclI, N363S and ER22/23EK in the glucocorticoid receptor gene (hGR) may be involved in GC sensitivity and could cause different clinical response to steroid treatment, and alteration of hypothalamouspituitary-adrenal (HPA) axis: the aim of this study was to evaluate the impact of hGR polymorphisms on GC sensitivity in IBD patients. Methods. The three hGR polymorphisms were studied by polymerase chain reaction-restriction fragment length polymorphism assay in 72 young patients, 43 CD and 29 ulcerative colitis (UC), and 100 healthy volunteers. Of the 72 patients, 34 were GC-dependents and 38 were GC-nondependents: the corticosteroid dependency was defined by successive relapses at dose tapering after GC treatment, while therapeutical success was identified with GC withdrawal without steroid requirement during at least 1 year. Results. The homozygous mutated genotype for BclI was significantly more frequent in CD patients (21.0%) than controls (8.00%; P = 0.04). No difference between controls and UC patients (6.90%; P = 1) was observed. This mutation was found to be associated with GC hypersensitivity, abdominal obesity, higher systolic blood pressure, fasting insulin levels and a higher insulin resistance index. The mutation could therefore lead to an increased sensitivity in peripheral and central glucocorticoid receptors, determining a raised susceptibility to feedback inhibition of GCs on the HPA axis. It is of interest that previous studies have demonstrated, in a subgroup of patients with CD, alterations of the HPA axis resulting in relative hypocortisolism. These results support the hypothesis that common polymorphisms in the hGR gene may have modulating effects on the relation between psychological factors and HPA axis regulation in patients with CD. When patients with IBD were divided in two groups according to GC response, a significant difference was evident for the BclI polymorphism (P = 0.007). Indeed the frequency of the mutated genotype was significantly higher in the GCnondependent group. Hence, patients with this polymorphism, associated with an increased sensitivity to GCs, respond well to the steroids and do less often need additional courses of this therapy, at least during the first year considered. No differences were observed for the other hGR gene polymorphisms. Conclusions. Three common polymorphisms of the hGR gene that may contribute to the large inter-individual variations in sensitivity to GCs and HPA axis activity were studied. The BclI mutated genotype is more frequent in CD patients, and this polymorphism may have modulating effects on cortisol responses to psychological stress, and in addition could have a role in the pathogenesis of
Crohn’s disease. Our data also suggest that IBD patients with BclI mutated genotype respond well to GC treatment, and this mutation is significantly more frequent in GC-nondependent patients. We are now working to confirm these data in a larger group of patients. doi:10.1016/j.dld.2006.07.053 PP 25 THE ROLE OF RANKL/OPG SYSTEM IN BONE LOSS IN CHILDREN WITH INFLAMMATORY BOWEL DISEASE F. Civitelli, M. Paganelli, P.M. Strappini, C. Albanese, O. Borrelli, M. Danti, C. Bascietto, S. Cucchiara Unit`a di Gastroenterologia ed Epatologia Pediatrica, Universit`a La Sapienza, Rome, Italy Aim. The signalling pathway consisting of receptor activator of NF-kB (RANK), its ligand (RANKL), and osteoprotegerin (OPG) has been recently thought to be an important mediator between inflammation and bone loss. We aimed at evaluating the activation state of RANKL/OPG system and its relationship with low bone mineral density (BMD) in children with IBD. Methods. Lumbar spine BMD was measured by DEXA. Bone mineral apparent density (BMAD) was calculated. Plasma levels of total soluble RANKL (tsRANKL) and OPG were measured. They were then correlated with BMAD, body mass index (BMI), duration of disease, PCDAI, TNFand IL-6 plasma levels, cumulative dose and mean daily dose of steroids. Results. Thirty-seven subjects (25 CD, 12 UC) were studied (age 13.4 years, range 4.5–19.3). BMAD z-score was −1.2 ± 1.4, with no difference between CD and UC. Plasma levels of tsRANKL and OPG were 13.8 ± 12.0 ng/mL and 300 ± 104 pg/mL, respectively. No correlation was found between BMAD and OPG or tsRANKL. A direct relationship was found between the OPG/tsRANKL ratio and BMAD (r = 0.41), only in CD. In IBD, tsRANKL was inversely correlated to BMI z-score (r = −0.42). A significant correlation was found between BMI and both tsRANKL and OPG (r = 0.4) in CD but not in UC. OPG and tsRANKL did not correlate to inflammatory cytokines or to IBD therapy. Summary and conclusion. sRANKL, produced by both osteoblasts and activated T cells, is expected to be elevated only at the onset of bone loss. OPG has a protective role on bone loss and it has been found paradoxically elevated in adult IBD. Our patients had normal plasma levels of OPG as compared to vendor’s normal range. Furthermore we found a direct correlation between OPG/tsRANKL ratio and BMAD in CD, proving the protective role of OPG and the negative role of sRANKL on BMD. Interestingly, we found a significant relationship between both tsRANKL and OPG and nutritional status, which is implicated in the pathogenesis of low BMD in paediatric IBD. Running studies on RANKL/OPG system in healthy children will help us to better understand these findings. doi:10.1016/j.dld.2006.07.054
Abstracts / Digestive and Liver Disease 38 (2006) A87–A120
use of antivirals might be useful for preventing undesirable interruption of biological therapy. doi:10.1016/j.dld.2006.07.052 PP 24 CORTICOSENSITIVITY IN INFLAMMATORY BOWEL DISEASE: ROLE OF GLUCOCORTICOID RECEPTOR POLYMORPHISMS S. De Iudicibus, S. Martelossi, G. Stocco, I. Drigo, P. Lionetti, A. Barabino, F. Bartoli, G. Decorti, A. Ventura I.R.C.C.S. Burlo Garofolo, Dipartimento di pediatria, Trieste, Italy Background. Glucocorticoids (GC) are used as first line antiinflammatory and immunosuppressive drugs in many inflammatory and autoimmune diseases and are effective in most patients with inflammatory bowel disease (IBD). However different clinical responses have been observed among patients suffering from such diseases: in particular, patients with Crohn’s disease (CD) have been classified as GC-dependents (when GCs are needed to keep the inflammatory disease quiescent) and GCnondependents (when a good response to the treatment is observed). Some polymorphisms, BclI, N363S and ER22/23EK in the glucocorticoid receptor gene (hGR) may be involved in GC sensitivity and could cause different clinical response to steroid treatment, and alteration of hypothalamouspituitary-adrenal (HPA) axis: the aim of this study was to evaluate the impact of hGR polymorphisms on GC sensitivity in IBD patients. Methods. The three hGR polymorphisms were studied by polymerase chain reaction-restriction fragment length polymorphism assay in 72 young patients, 43 CD and 29 ulcerative colitis (UC), and 100 healthy volunteers. Of the 72 patients, 34 were GC-dependents and 38 were GC-nondependents: the corticosteroid dependency was defined by successive relapses at dose tapering after GC treatment, while therapeutical success was identified with GC withdrawal without steroid requirement during at least 1 year. Results. The homozygous mutated genotype for BclI was significantly more frequent in CD patients (21.0%) than controls (8.00%; P = 0.04). No difference between controls and UC patients (6.90%; P = 1) was observed. This mutation was found to be associated with GC hypersensitivity, abdominal obesity, higher systolic blood pressure, fasting insulin levels and a higher insulin resistance index. The mutation could therefore lead to an increased sensitivity in peripheral and central glucocorticoid receptors, determining a raised susceptibility to feedback inhibition of GCs on the HPA axis. It is of interest that previous studies have demonstrated, in a subgroup of patients with CD, alterations of the HPA axis resulting in relative hypocortisolism. These results support the hypothesis that common polymorphisms in the hGR gene may have modulating effects on the relation between psychological factors and HPA axis regulation in patients with CD. When patients with IBD were divided in two groups according to GC response, a significant difference was evident for the BclI polymorphism (P = 0.007). Indeed the frequency of the mutated genotype was significantly higher in the GCnondependent group. Hence, patients with this polymorphism, associated with an increased sensitivity to GCs, respond well to the steroids and do less often need additional courses of this therapy, at least during the first year considered. No differences were observed for the other hGR gene polymorphisms. Conclusions. Three common polymorphisms of the hGR gene that may contribute to the large inter-individual variations in sensitivity to GCs and HPA axis activity were studied. The BclI mutated genotype is more frequent in CD patients, and this polymorphism may have modulating effects on cortisol responses to psychological stress, and in addition could have a role in the pathogenesis of
Crohn’s disease. Our data also suggest that IBD patients with BclI mutated genotype respond well to GC treatment, and this mutation is significantly more frequent in GC-nondependent patients. We are now working to confirm these data in a larger group of patients. doi:10.1016/j.dld.2006.07.053 PP 25 THE ROLE OF RANKL/OPG SYSTEM IN BONE LOSS IN CHILDREN WITH INFLAMMATORY BOWEL DISEASE F. Civitelli, M. Paganelli, P.M. Strappini, C. Albanese, O. Borrelli, M. Danti, C. Bascietto, S. Cucchiara Unit`a di Gastroenterologia ed Epatologia Pediatrica, Universit`a La Sapienza, Rome, Italy Aim. The signalling pathway consisting of receptor activator of NF-kB (RANK), its ligand (RANKL), and osteoprotegerin (OPG) has been recently thought to be an important mediator between inflammation and bone loss. We aimed at evaluating the activation state of RANKL/OPG system and its relationship with low bone mineral density (BMD) in children with IBD. Methods. Lumbar spine BMD was measured by DEXA. Bone mineral apparent density (BMAD) was calculated. Plasma levels of total soluble RANKL (tsRANKL) and OPG were measured. They were then correlated with BMAD, body mass index (BMI), duration of disease, PCDAI, TNFand IL-6 plasma levels, cumulative dose and mean daily dose of steroids. Results. Thirty-seven subjects (25 CD, 12 UC) were studied (age 13.4 years, range 4.5–19.3). BMAD z-score was −1.2 ± 1.4, with no difference between CD and UC. Plasma levels of tsRANKL and OPG were 13.8 ± 12.0 ng/mL and 300 ± 104 pg/mL, respectively. No correlation was found between BMAD and OPG or tsRANKL. A direct relationship was found between the OPG/tsRANKL ratio and BMAD (r = 0.41), only in CD. In IBD, tsRANKL was inversely correlated to BMI z-score (r = −0.42). A significant correlation was found between BMI and both tsRANKL and OPG (r = 0.4) in CD but not in UC. OPG and tsRANKL did not correlate to inflammatory cytokines or to IBD therapy. Summary and conclusion. sRANKL, produced by both osteoblasts and activated T cells, is expected to be elevated only at the onset of bone loss. OPG has a protective role on bone loss and it has been found paradoxically elevated in adult IBD. Our patients had normal plasma levels of OPG as compared to vendor’s normal range. Furthermore we found a direct correlation between OPG/tsRANKL ratio and BMAD in CD, proving the protective role of OPG and the negative role of sRANKL on BMD. Interestingly, we found a significant relationship between both tsRANKL and OPG and nutritional status, which is implicated in the pathogenesis of low BMD in paediatric IBD. Running studies on RANKL/OPG system in healthy children will help us to better understand these findings. doi:10.1016/j.dld.2006.07.054