Sargramostim for Active Crohn's Disease

Korzenik, Joshua R.; Dieckgraefe, Brian K.; Valentine, John F.; Hausman, Diana F.; Gilbert, Mark J.

doi:10.1056/nejmoa041109

Cited by 316 publications

(189 citation statements)

References 29 publications

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“…An alternative strategy is to block binding to lectins with bacterial components ( 68 ). Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been shown to be eff ective in a small controlled pilot study of Crohn ' s disease patients ( 69 ), but did not show benefi t in the primary end point of response defi ned by CDAI (Crohn ' s disease activity index) decrease ≥ 70 points in a larger multinational study ( 70 ). However, signifi cant secondary outcomes of more stringent response (CDAI decrease ≥ 100) and remission relative to placebo ( P < 0.01) in this phase 2 study , evidence of steroid sparing over 22 weeks ( 71 ), and detection of anti-GM-CSF antibodies in pediatric and adult patients with Crohn ' s disease, particularly those with ileal involvement ( 72 ) and increased permeability ( 73 ), lend credibility to this approach in selected patients.…”

Section: Microbial Complications Of Ibdmentioning

confidence: 99%

Intestinal Microbes in Inflammatory Bowel Diseases

Sartor¹,

Mazmanian²

2012

Am J Gastroenterol Suppl

177

152

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Section: Microbial Complications Of Ibdmentioning

confidence: 99%

Intestinal Microbes in Inflammatory Bowel Diseases

Sartor¹,

Mazmanian²

2012

Am J Gastroenterol Suppl

177

152

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“…Neutrophil recruitment and activation are key steps in the intestinal innate immune response observed in IBD (6)(7)(8), and studies with animal models of colitis highlight the relationship between neutrophil infiltration and disease severity (9)(10)(11). We recently reported results of a comprehensive analysis of histopathology, changes in gene expression, and nucleic acid damage occurring during progression of lower bowel disease in Rag2 −/− mice infected with Helicobacter hepaticus (Hh) (10).…”

mentioning

confidence: 99%

Chemical and cytokine features of innate immunity characterize serum and tissue profiles in inflammatory bowel disease

Knutson

Mangerich

Zeng

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

103

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Significance Our study investigates chemical damage associated with chronic inflammation and relates these macromolecular damage products to inflammatory bowel disease activity. Using mice as a model system, we show that chronic inflammatory responses that are common to mice and humans produce similar types and quantities of damage products in both species. Additional analysis of signaling molecules in the serum and tissue of diseased samples highlights the role of the innate immune response in the overall pathology of inflammatory bowel disease.

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“…In contrast, in experimental contact hypersensitivity, characterized by an increased GM-CSF expression (17), blockade of this cytokine had no effect on disease manifestation (18). Interestingly, in Crohn's disease, application of GM-CSF improved disease activity (19,20). Hence, GM-CSF has opposing effects in different inflammatory conditions.…”

mentioning

confidence: 99%

GM-CSF Modulates Autoantibody Production and Skin Blistering in Experimental Epidermolysis Bullosa Acquisita

Samavedam

Iwata

Müller

et al. 2014

The Journal of Immunology

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GM-CSF activates hematopoietic cells and recruits neutrophils and macrophages to sites of inflammation. Inhibition of GM-CSF attenuates disease activity in models of chronic inflammatory disease. Effects of GM-CSF blockade were linked to modulation of the effector phase, whereas effects on early pathogenic events, for example, Ab production, have not been identified. To evaluate yet uncharacterized effects of GM-CSF on early pathogenic events in chronic inflammation, we employed immunization-induced epidermolysis bullosa acquisita (EBA), an autoimmune bullous disease caused by autoantibodies to type VII collagen. Compared to wild-type mice, upon immunization, GM-CSF−/− mice produced lower serum autoantibody titers, which were associated with reduced neutrophil numbers in draining lymph nodes. The same effect was observed in neutrophil-depleted wild-type mice. Neutrophil depletion in GM-CSF−/− mice led to a stronger inhibition, indicating that GM-CSF and neutrophils have additive functions. To characterize the contribution of GM-CSF specifically in the effector phase of EBA, disease was induced by transfer of anti–type VII collagen IgG into mice. We observed an increased GM-CSF expression, and GM-CSF blockade reduced skin blistering. Additionally, GM-CSF enhanced reactive oxygen species release and neutrophil migration in vitro. In immunization-induced murine EBA, treatment with anti–GM-CSF had a beneficial effect on established disease. We demonstrate that GM-CSF modulates both autoantibody production and skin blistering in a prototypical organ-specific autoimmune disease.

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Sargramostim for Active Crohn's Disease

Abstract: This study was negative for the primary end point, but findings for the secondary end points suggest that sargramostim therapy decreased disease severity and improved the quality of life in patients with active Crohn's disease.

Cited by 316 publications

References 29 publications

Intestinal Microbes in Inflammatory Bowel Diseases

Intestinal Microbes in Inflammatory Bowel Diseases

Chemical and cytokine features of innate immunity characterize serum and tissue profiles in inflammatory bowel disease

GM-CSF Modulates Autoantibody Production and Skin Blistering in Experimental Epidermolysis Bullosa Acquisita

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