DOP049 Combination therapy of cyclosporine and vedolizumab is effective and safe for severe, steroid-resistant ulcerative colitis patients: A prospective study

Tarabar, Dino; Jurdi, Katia El; Yvellez, Olivia; Milenković, Zoran; Petrović, Stanko; Subotić, Bojana; Brocic, Tanja; Brcerevic, Irina; Latinovic, Olgica; Rubin, David T.

doi:10.1093/ecco-jcc/jjx180.086

Cited by 5 publications

(6 citation statements)

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“…Induction therapy with CNIs may show clinical effectiveness in patients with steroid-refractory acute severe UC, followed by vedolizumab as maintenance treatment. 48 CNIs might therefore be a potential alternative treatment to corticosteroids, if these would later appear to have more detrimental than beneficial effects in patients with active IBD and COVID-19.…”

Section: Discussionmentioning

confidence: 99%

Treatment of severe acute ulcerative colitis in SARS-CoV-2 infected patients: report of three cases and discussion of treatment options

Bourgonje

Linschoten

West

et al. 2021

Therap Adv Gastroenterol

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In the wake of the coronavirus disease 2019 (COVID-19) pandemic, it is unclear how asymptomatic severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-infected patients who present with acute severe ulcerative colitis (UC) can be treated effectively and safely. Standard treatment regimens consist of steroids, immunomodulatory drugs, and biological therapies, but therapeutic decision-making becomes challenging as there are uncertainties about how to deal with these drugs in patients with COVID-19 and active UC. Importantly, guidelines for this particular group of patients with UC are still lacking. To inform therapeutic decision-making, we describe three consecutive cases of patients with active UC and COVID-19 and discuss their treatments based on theoretical knowledge, currently available evidence and clinical observations. Three patients were identified through our national inflammatory bowel disease network [Initiative on Crohn’s and Colitis (ICC)] for whom diagnosis of SARS-CoV-2-infection was established by reverse transcription–polymerase chain reaction (RT-PCR) testing in nasopharynx, stools, and/or biopsies. Acute severe UC was diagnosed by clinical parameters, endoscopy, and histopathology. Clinical guidelines for SARS-CoV-2-negative patients advocate the use of steroids, calcineurin inhibitors, or tumor necrosis factor alpha (TNF-α)-antagonists as induction therapy, and experiences from the current three cases show that steroids and TNF-α-antagonists could also be used in patients with COVID-19. This could potentially be followed by TNF-α-antagonists, vedolizumab, or ustekinumab as maintenance therapy in these patients. Future research is warranted to investigate if, and which, immunomodulatory drugs should be used for COVID-19 patients that present with active UC. To answer this question, it is of utmost importance that future cases of patients with UC and COVID-19 are documented carefully in international registries, such as the SECURE-IBD registry.

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Section: Discussionmentioning

confidence: 99%

Treatment of severe acute ulcerative colitis in SARS-CoV-2 infected patients: report of three cases and discussion of treatment options

Bourgonje

Linschoten

West

et al. 2021

Therap Adv Gastroenterol

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“…Our results could explain the low and slow response rate of VDZ in patients with a large inflammatory burden whereby the efficacy of the drug could be completely or partially compromised by the increase in α 4 β 7 integrin expression in exosomes, which could bind and inactivate the drug. However, the initial combination of VDZ and steroids or calcineurin inhibitors could reduce exosome formation, decrease drug sequestration and increase VDZ efficacy [ 31 , 32 ].…”

Section: Discussionmentioning

confidence: 99%

“…compromised by the increase in α 4 β 7 integrin expression in exosomes, which could bind and inactivate the drug. However, the initial combination of VDZ and steroids or calcineurin inhibitors could reduce exosome formation, decrease drug sequestration and increase VDZ efficacy [31,32].…”

Section: Plos Onementioning

confidence: 99%

Circulating exosomes express α4β7 integrin and compete with CD4+ T cells for the binding to Vedolizumab

et al. 2020

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Vedolizumab (VDZ) is a therapeutic monoclonal antibody approved for the treatment of inflammatory bowel diseases (IBD). VDZ selectively binds to the α4β7 integrin and blocks trafficking of a specific subset of gastrointestinal-homing T-lymphocytes to inflamed tissue. Although VDZ has shown promising results in numerous clinical studies a subgroup of patients do not respond adequately. Mechanistic insights and prognostic biomarkers able to predict which patients might benefit from VDZ therapy are currently lacking. Circulating exosomes were isolated from serum of blood donors and VDZ-treated patients by polymer-based precipitation. The surface expression of α4β7 integrin was evaluated by flow cytometry and the levels of exosome-bound VDZ were investigated by Promonitor-VDZ ELISA kit. The capacity of exosomes to interfere with the adhesion of VDZ-treated CD4+ T cells was assessed by adhesion assay. In this study, we showed that serum exosomes isolated from both blood donor and ulcerative colitis patients express on their surface the VDZ target α4β7 integrin. We observed an increased exosomal sequestration of VDZ in anti-TNF exposed patients compared to anti- TNFα naïve patients, according to a greater expression of α4β7 integrin on vesicles surface. Circulating exosomes could compete for VDZ binding with CD4+ T cells since we found that the amount of VDZ bound to T cells was impaired in the presence of exosomes. In addition, we demonstrated that exosomes bind VDZ, which consequently becomes unable to block MadCAM-1-mediated adhesion of lymphocytes. Circulating exosomes might contribute to drug sequestration, possibly affecting the therapeutic efficacy of VDZ in IBD patients. Our data suggest that previous biologic therapy may have altered the sequestration capacity of circulating exosomes, thus reducing the efficacy of VDZ in patients who failed anti-TNF agents.

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“…While vedolizumab is approved as an induction and maintenance agent, it's relatively slow onset of action (compared to anti-TNF agents) means that it is primarily employed due to its maintenance properties and precludes it’s use over infliximab in severe disease (and especially hospitalized acute severe UC), except in the context of bridging co-induction therapy with either steroids or cyclosporine. 83,84 Furthermore, though vedolizumab is approved for use in CD, the trial data are not as impressive as for UC, and as such it is less frequently considered a first-line therapy in this condition, especially small bowel CD. Also, while the gut specificity is promoted with respect to the safety of vedolizumab, this property theoretically limits its efficacy in the treatment of patients with significant extra-intestinal manifestations, 11 though a recent multicenter cohort study suggested vedolizumab may have some benefit with resolution of inflammatory arthritis in close to half of patients.…”

Section: Positioning Of Currently Available Biologic Therapies In CLImentioning

confidence: 99%

The current state of the art for biological therapies and new small molecules in inflammatory bowel disease

et al. 2018

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The emergence of biologic therapies is arguably the greatest therapeutic advance in the care of inflammatory bowel disease (IBD) to date, allowing directed treatments targeted at highly specific molecules shown to play critical roles in disease pathogenesis, with advantages in potency and selectivity. Furthermore, a large number of new biologic and small-molecule therapies in IBD targeting a variety of pathways are at various stages of development that should soon lead to a dramatic expansion in our therapeutic armamentarium. Additionally, since the initial introduction of biologics, there have been substantial advances in our understanding as to how biologics work, the practical realities of their administration, and how to enhance their efficacy and safety in the clinical setting. In this review, we will summarize the current state of the art for biological therapies in IBD, both in terms of agents available and their optimal use, as well as preview future advances in biologics and highly targeted small molecules in the IBD field.

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DOP049 Combination therapy of cyclosporine and vedolizumab is effective and safe for severe, steroid-resistant ulcerative colitis patients: A prospective study

Cited by 5 publications

References 0 publications

Treatment of severe acute ulcerative colitis in SARS-CoV-2 infected patients: report of three cases and discussion of treatment options

Treatment of severe acute ulcerative colitis in SARS-CoV-2 infected patients: report of three cases and discussion of treatment options

Circulating exosomes express α4β7 integrin and compete with CD4+ T cells for the binding to Vedolizumab

The current state of the art for biological therapies and new small molecules in inflammatory bowel disease

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