Current approaches for optimizing the benefit of biologic therapy in ulcerative colitis

Sofia, M. Anthony; Rubin, David T.

doi:10.1177/1756283x16643242

Cited by 14 publications

(8 citation statements)

References 55 publications

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“…In the sera and colonic tissues of UC patients, the levels of IL-1β, IL-6 and TNF-α were significantly higher than those of normal subjects, while down-regulation of them could prevent UC ( Galli et al, 2011 ; Roberts-Thomson et al, 2011 ; Groeger et al, 2013 ). Clinically, tocilizumab, the IL-6 receptor (IL-6R) antibody, has been used to treat UC ( Nishimoto et al, 2008 ; Wu et al, 2015 ); TNF-α antibody is also effective for UC management, especially for severe disease, and its bio-similars are confirmed with well safety and efficacy ( Sofia and Rubin, 2016 ; Komaki et al, 2017 ). Therefore, repairment of mucosal barrier and inhibition of inflammation are effective strategies for UC treatment.…”

Section: Introductionmentioning

confidence: 99%

Bergenin, Acting as an Agonist of PPARγ, Ameliorates Experimental Colitis in Mice through Improving Expression of SIRT1, and Therefore Inhibiting NF-κB-Mediated Macrophage Activation

Wang

et al. 2018

Front. Pharmacol.

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Bergenin, isolated from the herb of Saxifraga stolonifera Curt. (Hu-Er-Cao), has anti-inflammatory, antitussive and wound healing activities. The aim of the present study was to identify the effect of bergenin on experimental colitis, and explored the related mechanisms. Our results showed that oral administration of bergenin remarkably alleviated disease symptoms of mice with dextran sulfate sodium (DSS)-induced colitis, evidenced by reduced DAI scores, shortening of colon length, MPO activity and pathologic abnormalities in colons. Bergenin obviously inhibited the mRNA and protein expressions of IL-6 and TNF-α in colon tissues, but not that of mucosal barrier-associated proteins occludin, E-cadherin and MUC-2. In vitro, bergenin significantly inhibited the expressions of IL-6 and TNF-α as well as nuclear translocation and DNA binding activity of NF-κB-p65 in lipopolysaccharide (LPS)-stimulated peritoneal macrophages and RAW264.7 cells, which was almost reversed by addition of PPARγ antagonist GW9662 and siPPARγ. Subsequently, bergenin was identified as a PPARγ agonist. It could enter into macrophages, bind with PPARγ, promote nuclear translocation and transcriptional activity of PPARγ, and increase mRNA expressions of CD36, LPL and ap2. In addition, bergenin significantly up-regulated expression of SIRT1, inhibited acetylation of NF-κB-p65 and increased association NF-κB-p65 and IκBα. Finally, the correlation between activation of PPARγ and attenuation of colitis, inhibition of IL-6 and TNF-α expressions, NF-κB-p65 acetylation and nuclear translocation, and up-regulation of SIRT1 expression by bergenin was validated in mice with DSS-induced colitis and/or LPS-stimulated macrophages. In summary, bergenin could ameliorate colitis in mice through inhibiting the activation of macrophages via regulating PPARγ/SIRT1/NF-κB-p65 pathway. The findings can provide evidence for the further development of bergenin as an anti-UC drug, and offer a paradigm for the recognization of anti-UC mechanisms of compound with similar structure occurring in traditional Chinese medicines.

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Section: Introductionmentioning

confidence: 99%

Bergenin, Acting as an Agonist of PPARγ, Ameliorates Experimental Colitis in Mice through Improving Expression of SIRT1, and Therefore Inhibiting NF-κB-Mediated Macrophage Activation

Wang

et al. 2018

Front. Pharmacol.

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“…Currently, two biological classes are available for the treatment of UC: TNF antagonists (infliximab, adalimumab, and golimumab) and anti-integrin therapy (vedolizumab) [ 76 ]. The development of biologic therapies for the treatment of UC has added an important treatment option, particularly for moderate to severe disease that does not respond to other therapies [ 2 , 76 , 77 ]. Studies of patient preferences have also reported that patients with UC strongly prefer medical therapy to surgical intervention [ 78 , 79 ].…”

Section: Current Misunderstandingsmentioning

confidence: 99%

Ulcerative Colitis: Shifting Sands

et al. 2019

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Ulcerative colitis (UC) is a chronic inflammatory bowel disease associated with considerable disease burden. We review some current misconceptions about UC in adults with the aim of optimizing care for patients. Although UC and Crohn’s disease (CD) are considered discrete diseases, distinctions between them are not always clear-cut and phenotypes may change over time. Patient management should take into account disease manifestations, disease severity and extent, and response to prior treatments. Although disease extent often defines severity, distal UC is not always less disabling than extensive disease as patients can progress to more extensive disease. In addition, severe proctitis can give rise to severe and debilitating symptoms, with a substantial impact on health-related quality of life. UC carries an increased risk of colorectal cancer (CRC) compared with CD; however, more recent data indicate a similar risk of CRC in CD with colonic involvement as with UC. Corticosteroids are widely used to induce remission in UC, and prolonged use of steroids in patients with UC is common, but corticosteroid-free maintenance of remission is an important therapeutic goal. Although biologic therapies provide a valuable treatment option in UC, they are not clinically effective in all patients and are also associated with secondary loss of response.

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“…To prevent LOR during maintenance treatment with mAb drugs, clinical research has led to new institutional recommendations for dosing in IBD treatment. These efforts are well-documented in publications (45)(46)(47), and encompass approved mAb drugs with diverse mechanisms of action.…”

Section: Development Of Anti-drug Antibodiesmentioning

confidence: 99%

Individualized Dosing of Therapeutic Monoclonal Antibodies—a Changing Treatment Paradigm?

Strik

Wang

Ruff

et al. 2018

AAPS J

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The introduction of monoclonal antibodies (mAbs) to the treatment of inflammatory bowel disease (IBD) was an important medical milestone. MAbs have been demonstrated as safe and efficacious treatments of IBD. However, a large percentage of patients either fail to respond initially or lose response to therapy after a period of treatment. Although there are factors associated with poor treatment outcomes in IBD, one cause for treatment failure may be low mAb exposure. Consequently, gastroenterologists have begun using therapeutic drug monitoring (TDM) to guide dose adjustment. However, while beneficial, TDM does not provide sufficient information to effectively adjust doses. The pharmacokinetics (PK) and pharmacodynamics (PD) of mAbs are complex, with numerous factors impacting on mAb PK and PD. The concept of dashboard-guided dosing based on Bayesian PK models allows physicians to combine TDM with factors influencing mAb PK to individualize therapy more effectively. One issue with TDM has been the slow turnaround of assay results, either necessitating an additional clinic visit for a sample or reacting to TDM results at a subsequent, rather than the current, dose. New point-of-care (POC) assays for mAbs are being developed that would potentially allow physicians to determine drug concentration quickly. However, work remains to understand how to determine what target exposure is needed for an individual patient, and whether the combination of POC assays and dashboards presents a safe approach with substantial outcome benefit over the current standard of care.

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Current approaches for optimizing the benefit of biologic therapy in ulcerative colitis

Cited by 14 publications

References 55 publications

Bergenin, Acting as an Agonist of PPARγ, Ameliorates Experimental Colitis in Mice through Improving Expression of SIRT1, and Therefore Inhibiting NF-κB-Mediated Macrophage Activation

Bergenin, Acting as an Agonist of PPARγ, Ameliorates Experimental Colitis in Mice through Improving Expression of SIRT1, and Therefore Inhibiting NF-κB-Mediated Macrophage Activation

Ulcerative Colitis: Shifting Sands

Individualized Dosing of Therapeutic Monoclonal Antibodies—a Changing Treatment Paradigm?

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