Discontinuation of Infliximab in Patients With Ulcerative Colitis Is Associated With Increased Risk of Relapse: A Multinational Retrospective Cohort Study

Fiorino, Gionata; Navarro, Pablo; Ellul, Pierre; Felice, Carla; Karatzas, Pantelis; Silva, Marco; Lakatos, László; Bossa, Fabrizio; Ungar, Bella; Sebastian, Shaji; Furfaro, Federica; Karmiris, Konstantinos; Κατσάνος, Κωνσταντίνος; Muscat, Mark; Christodoulou, Dimitrios; Maconi, Giovanni; Kopylov, Uri; Magro, Fernando; Mantzaris, Gerassimos J.; Armuzzi, Alessandro; Boscá-Watts, Marta Maia; Ben‐Horin, Shomron; Bonovas, Stefanos; Danese, Silvio

doi:10.1016/j.cgh.2016.05.044

Cited by 39 publications

(39 citation statements)

References 17 publications

(14 reference statements)

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“…Drug discontinuation has been proposed but led to a high relapse rate. [4][5][6][7] Alternatively, treatment de-escalation by lowering the dose or increasing the interval between infusions allows decreasing drug exposure while maintaining efficacy. Recent data support the relevancy of de-escalation, as higher infliximab levels were reported to be linked to an increased risk of infections.…”

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confidence: 99%

Pharmacokinetic Parameters of Infliximab Influence the Rate of Relapse After De‐Escalation in Adults With Inflammatory Bowel Diseases

Petitcollin

Brochard

Siproudhis

et al. 2019

Clin Pharma and Therapeutics

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This study aimed at exploring the link among individual concentrations, pharmacokinetic parameters, and the probability of relapse after de‐escalation in a real‐world prospective cohort of patients with inflammatory bowel disease (IBD) who underwent infliximab treatment de‐escalation. Ninety‐one patients were included. A time‐varying compartment model was used to estimate individual pharmacokinetic parameters and trough concentrations. A Cox model was implemented to explore the parameters influencing the probability of relapse after de‐escalation. Volume, clearance, and trough before and after de‐escalation were linked to the relapse risk at the univariate step. Independent predictors of relapse were tobacco use and/or ulcerative colitis (P = 0.0093), a higher C‐reactive protein (CRP; P = 0.00064), and an infliximab trough < 2.4 μg/mL after de‐escalation (P = 0.0001). Patients with trough > 5.7 μg/mL are eligible to de‐escalation, but infliximab pharmacokinetics is highly variable in time. Therefore, drug monitoring is mandatory after de‐escalation to maintain trough > 2.4 μg/mL. Clearance monitoring seems an appealing approach for patient selection and relapse prediction.

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confidence: 99%

Pharmacokinetic Parameters of Infliximab Influence the Rate of Relapse After De‐Escalation in Adults With Inflammatory Bowel Diseases

Petitcollin

Brochard

Siproudhis

et al. 2019

Clin Pharma and Therapeutics

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“…Infliximab is a medication used to treat patients with autoimmune and chronic inflammatory diseases . Notably, besides improving joint pain, swelling and inflammation, infliximab also reduces the levels of serum insulin, fasting glucose and insulin resistance in patients with ankylosing spondylitis and rheumatoid arthritis .…”

Section: Discussionmentioning

confidence: 99%

“…Infliximab (Remicade ® ) is a chimeric monoclonal IgG1 antibody that specifically binds to TNF‐alpha and prevents the interaction of TNF‐alpha with TNF‐alpha receptor (TNFR) 1 and TNFR2 . For this reason, infliximab has been used to treat a variety of autoimmune and chronic inflammatory diseases such as rheumatoid arthritis, Crohn's disease, ulcerative colitis, psoriatic arthritis and ankylosing spondylitis . Interestingly, besides exerting anti‐inflammatory actions, infliximab has been also shown to improve insulin resistance.…”

Section: Introductionmentioning

confidence: 99%

“…17 For this reason, infliximab has been used to treat a variety of autoimmune and chronic inflammatory diseases such as rheumatoid arthritis, Crohn's disease, ulcerative colitis, psoriatic arthritis and ankylosing spondylitis. [18][19][20][21][22][23] Interestingly, besides exerting anti-inflammatory actions, infliximab has been also shown to improve insulin resistance. In this sense, rheumatoid arthritis patients receiving infliximab show decreased values of the homeostatic model assessment of insulin resistance (HOMA-IR) as well as increase in the quantitative insulin sensitivity check index (QUICKI).…”

Section: Introductionmentioning

confidence: 99%

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Infliximab ameliorates tumor necrosis factor‐alpha‐induced insulin resistance by attenuating PTP1B activation in 3T3L1 adipocytes in vitro

et al. 2018

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Insulin resistance is the inability to respond to insulin and is considered a key pathophysiological factor in the development of type 2 diabetes. Tumor necrosis factor-alpha (TNF-alpha) can directly contribute to insulin resistance by disrupting the insulin signalling pathway via protein-tyrosine phosphatase 1B (PTP1B) activation, especially in adipocytes. Infliximab (Remicade ) is a TNF-alpha-neutralizing antibody that has not been fully studied in insulin resistance. We investigated the effect of infliximab on TNF-alpha-induced insulin resistance in 3T3L1 adipocytes in vitro, and examined the possible molecular mechanisms involved. Once differentiated, adipocytes were cultured with 5 mmol L 2-deoxy-D-glucose- H and stimulated twice with 2 μmol L insulin, in the presence or absence of 5 ng/mL TNF-alpha and/or 10 ng/mL infliximab. Glucose uptake was measured every 20 minutes for 2 hour, and phosphorylated forms of insulin receptor (IR), insulin receptor substrate-2 (IRS-2), protein kinase B (AKT) and PTP1B were determined by Western blotting. TNF-alpha-treated adipocytes showed a significant 64% decrease in insulin-stimulated glucose uptake as compared with control cells, whereas infliximab reversed TNF-alpha actions by significantly improving glucose incorporation. Although IR phosphorylation remained unaltered, TNF-alpha was able to increase PTP1B activation and decrease phosphorylation of IRS-2 and AKT. Notably, infliximab restored phosphorylation of IRS-2 and AKT by attenuating PTP1B activation. This work demonstrates for the first time that infliximab ameliorates TNF-alpha-induced insulin resistance in 3T3L1 adipocytes in vitro by restoring the insulin signalling pathway via PTP1B inhibition. Further clinical research is needed to determine the potential benefit of using infliximab for treating insulin resistance in patients.

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“…The results from a recent retrospective study [39] indicated that 48 % of patients who maintained clinical remission for at least 12 months and then discontinued IFX had clinical relapses. The rate of relapse was significantly higher in patients who discontinued IFX (23.3 per 100 person-years) compared to patients who did not discontinue IFX (7.2 per 100 personyears).…”

Section: Anti-tnfa Treatmentmentioning

confidence: 99%

Recent trends and future directions for the medical treatment of ulcerative colitis

Mizuno

Nanki

Sugimoto

et al. 2016

Clin J Gastroenterol

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Recently, several medical treatments for ulcerative colitis (UC) have been developed, including 5-aminosalicylic acids (5-ASAs), corticosteroids, thiopurine, calcineurin inhibitors, and anti-tumor necrosis factor (TNF) a treatments. Treatment options including calcineurin inhibitors and anti-TNF treatment for refractory UC are discussed in this article. Furthermore, upcoming treatments are introduced, such as golimumab, vedolizumab, AJM300, tofacitinib. Budesonide foamwill be used as one treatment option in patients with distal colitis. Herbal medicine, such as Qing-Dai is also effective for active UC and may be useful for patients who are refractory to antiTNFa treatments. In the near future, physicians will able to use many different treatments for UC patients. However, we should not forget 5-ASA and corticosteroids as the fundamental treatments for UC patients.

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Discontinuation of Infliximab in Patients With Ulcerative Colitis Is Associated With Increased Risk of Relapse: A Multinational Retrospective Cohort Study

Abstract: In a multinational retrospective cohort study of patients with UC in sustained clinical remission, we associated discontinuation of infliximab with an increased risk of relapse. Treatment re-initiation is effective and safe.

Cited by 39 publications

References 17 publications

Pharmacokinetic Parameters of Infliximab Influence the Rate of Relapse After De‐Escalation in Adults With Inflammatory Bowel Diseases

Pharmacokinetic Parameters of Infliximab Influence the Rate of Relapse After De‐Escalation in Adults With Inflammatory Bowel Diseases

Infliximab ameliorates tumor necrosis factor‐alpha‐induced insulin resistance by attenuating PTP1B activation in 3T3L1 adipocytes in vitro

Recent trends and future directions for the medical treatment of ulcerative colitis

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