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Profile of ustekinumab and its potential in patients with moderate-to-severe Crohn's disease.

ABSTRACT: The advent of anti-tumor necrosis factor (TNF)-? therapy has been a major advance in the medical management of Crohn's disease (CD). However, a significant proportion of patients with CD do not respond adequately to treatment with these agents. Primary and secondary nonresponse to anti-TNF? therapy represents a common clinical challenge, and highlights the need for the development of additional medication options for CD. The proinflammatory cytokines interleukin (IL)-12 and IL-23 are thought to play a key role in the pathogenesis of CD, and serve as a potential target for additional biologic therapies. Monoclonal antibodies targeting IL-12/23 have shown efficacy in animal models of colitis, and are currently being studied in Phase III clinical trials of CD. This review focuses on ustekinumab, a fully human immunoglobulin G1 monoclonal antibody, which blocks activity of IL-12 and IL-23 through binding the p40 subunit, and describes the current efficacy and safety data for ustekinumab in patients with CD.

SUBMITTER: Tuskey A

PROVIDER: S-EPMC4041179 | biostudies-other | 2014

REPOSITORIES: biostudies-other

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Profile of ustekinumab and its potential in patients with moderate-to-severe Crohn's disease.

Tuskey Anne A Behm Brian W BW

Clinical and experimental gastroenterology 20140523

The advent of anti-tumor necrosis factor (TNF)-α therapy has been a major advance in the medical management of Crohn's disease (CD). However, a significant proportion of patients with CD do not respond adequately to treatment with these agents. Primary and secondary nonresponse to anti-TNFα therapy represents a common clinical challenge, and highlights the need for the development of additional medication options for CD. The proinflammatory cytokines interleukin (IL)-12 and IL-23 are thought to ...[more]

PMID: 24904220

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Project description:The fecal microbiota is a rich source of biomarkers that have previously been shown to be predictive of numerous disease states. Less well studied is the effect of immunomodulatory therapy on the microbiota and its role in response to therapy. This study explored associations between the fecal microbiota and therapeutic response of Crohn's disease (CD) patients treated with ustekinumab (UST; Stelara) in the phase 2 CERTIFI study. Using stool samples collected over the course of 22 weeks, the composition of these subjects' fecal bacterial communities was characterized by sequencing the 16S rRNA gene. Subjects in remission could be distinguished from those with active disease 6 weeks after treatment using random forest models trained on subjects' baseline microbiota and clinical data (area under the curve [AUC] of 0.844, specificity of 0.831, sensitivity of 0.774). The most predictive operational taxonomic units (OTUs) that were ubiquitous among subjects were affiliated with Faecalibacterium and Escherichia or Shigella The median baseline community diversity in subjects in remission 6 weeks after treatment was 1.7 times higher than that in treated subjects with active disease (P = 0.020). Their baseline community structures were also significantly different (P = 0.017). Two OTUs affiliated with Faecalibacterium (P = 0.003) and Bacteroides (P = 0.022) were significantly more abundant at baseline in subjects who were in remission 6 weeks after treatment than those with active CD. The microbiota diversity of UST-treated clinical responders increased over the 22 weeks of the study, in contrast to nonresponsive subjects (P = 0.012). The observed baseline differences in fecal microbiota and changes due to therapeutic response support the potential for the microbiota as a response biomarker.IMPORTANCE CD is a global health concern, with increasing incidence and prevalence, causing large economic and health care impacts. Finding prognostic biomarkers that give clinicians the ability to identify patients more likely to respond to CD treatment at diagnosis will reduce the time subjects receive drugs that are unlikely to be beneficial. OTUs associated with remission after treatment induction, especially Faecalibacterium, could be biomarkers for successful UST treatment of anti-tumor necrosis factor alpha (anti-TNF-?) refractory CD patients. More broadly, these results suggest that the fecal microbiota could be a useful noninvasive biomarker for directing or monitoring the treatment of gastrointestinal diseases.

Dataset Information

Profile of ustekinumab and its potential in patients with moderate-to-severe Crohn's disease.

Publications

Profile of ustekinumab and its potential in patients with moderate-to-severe Crohn's disease.

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