B-cell-depletion therapy with rituximab is efficacious against steroid-dependent nephrotic syndrome (NS) in children and adults. Safety data are limited. Results of small studies have suggested that rituximab is usually well tolerated but that adverse events (such as severe mucocutaneous reactions, fatal infusion reactions, progressive multifocal leukoencephalopathy, and bowel perforation) can occur. We report here the first case (to our knowledge) of a pediatric patient with refractory minimal-change NS who developed severe immune-mediated ulcerative gastrointestinal disease 42 days after rituximab therapy. The disease was characterized by deep ulcers throughout the intestines and predominantly affected the colon. The child presented with severe abdominal pain, bloody diarrhea, weight loss, and fever. Her inflammatory markers were significantly elevated. Extensive evaluation revealed no evidence of infections and no characteristics of defined inflammatory bowel disease or Behçet disease. Colonoscopy revealed severe intestinal inflammation with deep ulcers. Histology of the colonic biopsy specimens revealed extensive infiltrates predominantly composed of CD8(+) T lymphocytes and evidence of high forkhead box P3 (FOXP3) expression. During this significant gastrointestinal disease, the NS remained quiescent. Corticosteroid therapy successfully controlled the severe immune-mediated intestinal inflammation after rituximab therapy. NS relapsed subsequently when CD19(+) and CD20(+) B-cell populations recovered.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplastic disorder, characterized by recurrent nosebleeds (epistaxis), multiple telangiectases and arteriovenous malformations (AVMs) in major organs. Mutations in Endoglin (ENG or CD105) and Activin receptor-like kinase 1 (ACVRL1 or ALK1) genes of the TGF-β superfamily receptors are responsible for HHT1 and HHT2 respectively and account for the majority of HHT cases. Haploinsufficiency in ENG and ALK1 is recognized at the underlying cause of HHT. However, the mechanisms responsible for the predisposition to and generation of AVMs, the hallmark of this disease, are poorly understood. Recent data suggest that dysregulated angiogenesis contributes to the pathogenesis of HHT and that the vascular endothelial growth factor, VEGF, may be implicated in this disease, by modulating the angiogenic–angiostatic balance in the affected tissues. Hence, anti-angiogenic therapies that target the abnormal vessels and restore the angiogenic–angiostatic balance are candidates for treatment of HHT. Here we review the experimental evidence for dysregulated angiogenesis in HHT, the anti-angiogenic therapeutic strategies used in animal models and some patients with HHT and the potential benefit of the anti-angiogenic treatment for ameliorating this severe, progressive vascular disease.

Background Pathological angiogenesis is an intrinsic component of chronic intestinal inflammation, which results in remodeling and expansion of the gut microvascular bed. Endoglin is essential for endothelial cell function and physiological angiogenesis. In this study, we investigated its potential role in the regulation of inflammation by testing the response of Endoglin heterozygous (Eng+/-) mice to experimental colitis. Methods C57BL/6 Eng+/- and littermate control mice drank water supplemented with 3% dextran sulfate sodium (DSS) for 5 days and were monitored for up to 26 days for clinical signs of colitis. Inflammation, crypt damage and angiogenic index were scored on histological sections of distal colon. Levels of the vascular endothelial growth factor (VEGF) and angiopoietins were measured by real time polymerase chain reaction, ELISA and/or Western blots. Vascular permeability was assessed using Evans Blue. Results Eng+/- and control mice developed acute colitis, which peaked at day 9. While control mice recovered by days 19-26, Eng+/- mice progressed to chronic colitis and showed numerous vascular protrusions penetrating into the serosa of the inflamed distal colon. Prior to DSS induction, VEGF levels and vascular permeability were higher in the distal colon of Eng+/- mice, while angiopoietin 1 and 2 levels were unchanged. In the chronic phase of colitis, VEGF levels were increased in both groups of mice and remained significantly higher in the Eng+/- mice. Conclusions Higher VEGF levels and increased vascular permeability in the distal colon may predispose Eng+/- mice to progress to chronic and persistent bowel inflammation, associated with pathological angiogenesis.

Endoglin is a coreceptor of the TGF-β superfamily predominantly expressed on the vascular endothelium and selective subsets of immune cells. We previously demonstrated that Endoglin heterozygous (Eng +/−) mice subjected to dextran sulfate sodium (DSS) developed persistent gut inflammation and pathological angiogenesis. We now report that colitic Eng +/− mice have low colonic levels of active TGF-β1, which was associated with reduced expression of thrombospondin-1, an angiostatic factor known to activate TGF-β1. We also demonstrate dysregulated expression of BMPER and follistatin, which are extracellular regulators of the TGF-β superfamily that modulate angiogenesis and inflammation. Heightened colonic levels of the neutrophil chemoattractant and proangiogenic factor, CXCL1, were also observed in DSS-treated Eng +/− mice. Interestingly, despite increased macrophage and neutrophil infiltration, a gut-specific reduction in expression of the key phagocytic respiratory burst enzymes, NADPH oxidase 2 (Nox-2) and myeloperoxidase, was seen in Eng +/− mice undergoing persistent inflammation. Taken together, these findings suggest that endoglin is required for TGF-β superfamily mediated resolution of inflammation and fully functional myeloid cells.