Impaired Bone Health in Inflammatory Bowel Disease: A Case-Control Study in 80 Pediatric Patients

Peer reviewe

T cell lymphoproliferative disorders associated with anti-tumor necrosis factor alpha antibody therapy for ulcerative colitis: literature summary

The enhanced risk of development of lymphoproliferative disorders in patients with inflammatory bowel disease has been attributed to immunosuppressive/immunomodulatory therapies. Infliximab is a chimeric monoclonal immunoglobulin G1 antibody directed against tumor necrosis factor alpha (TNF-α) that was approved by the Food and Drug Administration (FDA) in 1998 as an effective therapeutic agent against inflammatory bowel disease. Malignant lymphomas of both B and T cell lineage have been described in patients undergoing therapy involving TNF-α blockade. To date, eight cases of Epstein–Barr virus (EBV)-negative hepatosplenic T cell lymphoma associated with infliximab have been reported to the FDA’s Adverse Event Reporting System, as well as several other T cell lymphoproliferative disorders with aggressive clinical outcomes. We present the histologic, immunophenotypic, and molecular features of a T cell lymphoproliferative disorder involving the axillary lymph node of a 33-year-old male following infliximab treatment for ulcerative colitis. These EBV-negative lymphomas suggest that lymphoproliferative disorders following infliximab treatment for inflammatory bowel disease may involve EBV-independent immune dysregulation. The spectrum of lymphoproliferative disorders associated with infliximab and the potential mechanisms by which they occur are discussed

Infliximab in paediatric inflammatory bowel disease

AbstractInfliximab has been widely used in paediatric Crohn's disease, mainly in luminal and fistulous disease refractory to standard treatment and for extraintestinal manifestations. Moreover, there is growing experience with its use in refractory ulcerative colitis. Infliximab has shown similar efficacy and safety in children as in adult population. It is postulated that its early use in paediatric inflammatory bowel disease, as a bridging treatment until the onset of action of other immunomodulators, could reduce the use of steroids and change the natural history of the disease as well. The effect of infliximab on mucosal healing could also contribute to the normal growth and sexual maturation in these patients

Infliximab Induces Clonal Expansion of γδ-T Cells in Crohn's Disease: A Predictor of Lymphoma Risk?

BACKGROUND: Concominant with the widespread use of combined immunotherapy in the management of Crohn's disease (CD), the incidence of hepato-splenic gamma-delta (γδ)-T cell lymphoma has increased sharply in CD patients. Malignant transformation of lymphocytes is believed to be a multistep process resulting in the selection of malignant γδ-T cell clones. We hypothesised that repeated infusion of anti-TNF-α agents may induce clonal selection and that concurrent treatment with immunomodulators further predisposes patients to γδ-T cell expansion. METHODOLOGY/PRINCIPAL FINDINGS: We investigated dynamic changes in the γδ-T cells of patient with CD following treatment with infliximab (Remicade®; n=20) or adalimumab (Humira®; n=26) using flow cytometry. In patients with a high γδ-T cell level, the γδ-T cells were assessed for clonality. Of these 46 CD patients, 35 had a γδ-T cells level (mean 1.6%) comparable to healthy individuals (mean 2.2%), and 11 CD patients (24%) exhibited an increased level of γδ-T cells (5-15%). In the 18 patients also receiving thiopurines or methotrexate, the average baseline γδ-T cell level was 4.4%. In three male CD patients with a high baseline value, the γδ-T cell population increased dramatically following infliximab therapy. A fourth male patient also on infliximab monotherapy presented with 20% γδ-T cells, which increased to 25% shortly after treatment and was 36% between infusions. Clonality studies revealed an oligoclonal γδ-T cell pattern with dominant γδ-T cell clones. In support of our clinical findings, in vitro experiments showed a dose-dependent proliferative effect of anti-TNF-α agents on γδ-T cells. CONCLUSION/SIGNIFICANCE: CD patients treated with immunomodulators had constitutively high levels of γδ-T cells. Infliximab exacerbated clonal γδ-T cell expansion in vivo and induced γδ-T cell proliferation in vitro. Overall, young, male CD patients with high baseline γδ-T cell levels may be at an increased risk of developing malignant γδ-T cell lymphomas following treatment with anti-TNF-α agents

Report of the CCFA Pediatric Bone, Growth and Muscle Health Workshop, New York City, November 11-12, 2011, With Updates

Growth retardation, delayed puberty, decreased bone mass, altered bone architecture, hypovitaminosis D and skeletal muscle mass deficits are common in children with inflammatory bowel diseases. The Crohn's and Colitis Foundation of America sponsored a multidisciplinary workshop on the subject of Bone and Skeletal Growth in Pediatric IBD, held in New York City in November 2011. The topic of the workshop was a key recommendation of the Foundation's Pediatric Challenges meeting in 2005. The Litwin Foundation provided a generous grant to support this crucial research and workshop through the CCFA. The workshop featured 15 presentations by researchers from the United States, Canada, Switzerland, Germany, and the United Kingdom and a number of posters elucidating diverse aspects of the problem of growth retardation and compromised bone health in pediatric Crohn's disease and ulcerative colitis. The workshop comprised original, basic, and clinical research and relevant reviews of underlying genetics, molecular biology, endocrinology, immunology, and bone physiology research. Investigators funded by CCFA and the Litwin Family Foundation are marked by an asterisk after their name in the text. Workshop presentations fell under 3 broad categories: Mechanisms of Suppression and Growth of Bone Cell Function by Inflammation, Impact of IBD on Growth and Bone Health, and Approaches to Address Growth Failure and Low Bone Mass in Children with IBD, summarized herein. We have cited the publications that resulted from this granting mechanism in the appropriate section and references for pertinent updates on each topic

The impact of inflammation on bone mass in children

Bone is a dynamic tissue. Skeletal bone integrity is maintained through bone modeling and remodeling. The mechanisms underlying this bone mass regulation are complex and interrelated. An imbalance in the regulation of bone remodeling through bone resorption and bone formation results in bone loss. Chronic inflammation influences bone mass regulation. Inflammation-related bone disorders share many common mechanisms of bone loss. These mechanisms are ultimately mediated through the uncoupling of bone remodeling. Cachexia, physical inactivity, pro-inflammatory cytokines, as well as iatrogenic factors related to effects of immunosuppression are some of the common mechanisms. Recently, cytokine signaling through the central nervous system has been investigated for its potential role in bone mass dysregulation in inflammatory conditions. Growing research on the molecular mechanisms involved in inflammation-induced bone loss may lead to more selective therapeutic targeting of these pathological signaling pathways

China as a Means to an End: Analysing China's Infrastructure Investment in Africa: A Case Study of Kenya

Undergraduate thesis Submitted to the Business Administration Department Ashesi University In partial Fulfillment of the Bachelor of Science Degree in Business Administration.The reality of China’s global economic power and influence is that the Asian nation’s actions often have resulting effects on other nations around the world. Expansive initiatives such as the “Belt and Road Initiative” (BRI) and the “21st Maritime Silk Road” valued at trillions of dollars embody the superpower’s ambition and equal capacity to boost its economic growth. With trade as a channel of priority in achieving that economic expansion, the implications of China’s global expansion initiatives are applicable not only to African nations but to future dealings involving Africa-China collaboration. Evidence from study findings details complementary and competitive impacts with direct or indirect effects. As such, Africa has every incentive to gain an understanding of the effects China’s infrastructure investment can have on Africa’s development, and the livelihoods of the citizens of partner nations to the BRI. This study explores the impacts of China’s infrastructure on countries in Sub-Saharan Africa. Considering 42 Sub-Saharan African nations have assented to collaboration between them and China, understanding the implications of this cooperation can enable African nations to navigate the growing Africa-China relationship. By making an in-depth country-level analysis of the impacts China’s infrastructure investment has, measured through a case study of Kenya’s Standard Gauge Railway, this case realized a holistic picture of how beneficial Africa’s cooperation with China truly is, given the nature of these impacts on livelihood and development. Polarised views on the topic of China’s SSA influence provide further significance for the study’s findings. The findings hold relevance in relation to the creation of Africa-centered policy for future international interactions.Ashesi Universit