The Addition of an Immunosuppressant After Loss of Response to Anti-TNFα Monotherapy in Inflammatory Bowel Disease: A 2-Year Study

Macaluso, Fabio Salvatore; Sapienza, C.; Ventimiglia, Marco; Renna, Sara; Rizzuto, G.; Orlando, R.; Pisa, Marta Di; Affronti, M.; Orlando, Elisabetta; Cottone, Mario; Orlando, Ambrogio

doi:10.1093/ibd/izx010

Cited by 19 publications

(15 citation statements)

References 29 publications

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“…Furthermore, as a different concept from SONIC, SUCCESS, and DIAMOND study, some study has been made of whether the additional administration of thiopurine restores therapeutic responsiveness when LOR occurs with anti-TNF-α antibody monotherapy. Macaluso et al reported an analysis of 46 IBD patients treated with anti-TNF-α antibody and additionally treated with thiopurines, methotrexate, and mycophenolate mofetil (Macaluso et al, 2018). Results of this study show that additional combination therapy was effective in 42.4 of CD and 53.8% of UC.…”

Section: Relationship Of Thiopurines With Biological Agents and Small-molecule Drugsmentioning

confidence: 59%

Thiopurines: Recent Topics and Their Role in the Treatment of Inflammatory Bowel Diseases

et al. 2021

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Ulcerative colitis (UC) and Crohn's disease (CD) are chronic inflammatory bowel diseases (IBD) of unknown etiology, characterized by repeated relapse and remission. The efficacy of thiopurine in IBD was first reported in the late 1960s. Thiopurines are used to alleviate the symptoms of IBD, especially UC. These drugs have a steroid-sparing potential and are widely used for the purpose of maintaining long-term remission in steroid-dependent cases. Therefore, thiopurines tend to be used long-term, but adverse events that accompany long-term use, such as lymphoproliferative disorders, must be monitored with care. In contrast, thiopurine plays a critical role in controlling the immunogenicity of biologics. Furthermore, although thiopurine is an old drug, new findings, including the prediction of serious adverse events such as severe alopecia and acute advanced leukopenia, by nudix hydrolase 15 gene polymorphism analysis, as well as the possibility of appropriate drug monitoring by detailed analysis of 6-thioguanine nucleotides have been clarified. However, the consequences of thiopurine withdrawal have not been determined and further studies, including randomized controlled trials, are necessary to answer the clinical question regarding the scenarios in which thiopurine withdrawal is possible.

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Section: Relationship Of Thiopurines With Biological Agents and Small-molecule Drugsmentioning

confidence: 59%

Thiopurines: Recent Topics and Their Role in the Treatment of Inflammatory Bowel Diseases

et al. 2021

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“…With global prevalence of IBD on the rise, a prognostic for anti-TNFα therapy response is crucial to addressing the challenges associated with clinical use of potent immunomodulators [2]. To date, no studies have identified a set of biomarkers that have translated to clinical practice [10][11][12][13][14][49][50][51].…”

Section: Discussionmentioning

confidence: 99%

“…To date, there is no clear predictive factor of response or loss of response to anti-TNFα therapies [10]. Although several studies have identified single biomarker predictors of response, none has translated well for clinical practice [11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

A Multi-mRNA Prognostic Signature for Anti-TNFα Therapy Response in Patients with Inflammatory Bowel Disease

Sakaram¹,

Hasin-Brumshtein²,

Khatri

et al. 2021

Diagnostics

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Background: Anti-TNF-alpha (anti-TNFα) therapies have transformed the care and management of inflammatory bowel disease (IBD). However, they are expensive and ineffective in greater than 50% of patients, and they increase the risk of infections, liver issues, arthritis, and lymphoma. With 1.6 million Americans suffering from IBD and global prevalence on the rise, there is a critical unmet need in the use of anti-TNFα therapies: a test for the likelihood of therapy response. Here, as a proof-of-concept, we present a multi-mRNA signature for predicting response to anti-TNFα treatment to improve the efficacy and cost-to-benefit ratio of these biologics. Methods: We surveyed public data repositories and curated four transcriptomic datasets (n = 136) from colonic and ileal mucosal biopsies of IBD patients (pretreatment) who were subjected to anti-TNFα therapy and subsequently adjudicated for response. We applied a multicohort analysis with a leave-one-study-out (LOSO) approach, MetaIntegrator, to identify significant differentially expressed (DE) genes between responders and non-responders and then used a greedy forward search to identify a parsimonious gene signature. We then calculated an anti-TNFα response (ATR) score based on this parsimonious gene signature to predict responder status and assessed discriminatory performance via an area-under-receiver operating-characteristic curve (AUROC). Results: We identified 324 significant DE genes between responders and non-responders. The greedy forward search yielded seven genes that robustly distinguish anti-TNFα responders from non-responders, with an AUROC of 0.88 (95% CI: 0.70–1). The Youden index yielded a mean sensitivity of 91%, mean specificity of 76%, and mean accuracy of 86%. Conclusions: Our findings suggest that there is a robust transcriptomic signature for predicting anti-TNFα response in mucosal biopsies from IBD patients prior to treatment initiation. This seven-gene signature should be further investigated for its potential to be translated into a predictive test for clinical use.

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“…However, data from large, blinded trials are still lacking, and the optimal scheduling of proactive TDM remains to be fully elucidated. In addition, it should be noted that when TDM is not available, the addition of an immunosuppressant after loss of response to anti-TNF monotherapy may result in treatment success [18] .…”

Section: Therapeutic Drug Monitoringmentioning

confidence: 99%

Enhancing treatment success in inflammatory bowel disease: Optimising the use of anti-TNF agents and utilising their biosimilars in clinical practice

Armuzzi

Bouhnik

Cummings

et al. 2020

Digestive and Liver Disease

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Anti-tumour necrosis factor (TNF) agents such as infliximab and adalimumab have greatly altered the treatment landscape in inflammatory bowel disease (IBD). However, there are remaining unmet needs and opportunities to optimise their use. Recent data suggest that proactive therapeutic drug monitoring may lead to more efficient usage of these agents, with potential for higher rates of corticosteroid-free clinical remission than with reactive monitoring. Expanded application of faecal calprotectin measurements may also be valuable, given the ease of use of the assay and its proven effectiveness as a diagnostic tool and predictor of relapse risk. From a practical viewpoint, improved multidisciplinary working may be essential to optimise patient care, with IBD nurse specialists playing an increasingly central role within this model. Finally, the availability of biosimilars of the anti-TNF agents allow drug costs to be reduced without compromising safety or efficacy-thereby providing opportunities to improve accessibility. Alongside extensive data on originator to biosimilar infliximab switch, new studies are beginning to demonstrate the safety of biosimilar to biosimilar switch, as well as adalimumab biosimilar transitions. The risk of a nocebo effect when switching to a biosimilar can be reduced through improved patient education and preparation.

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The Addition of an Immunosuppressant After Loss of Response to Anti-TNFα Monotherapy in Inflammatory Bowel Disease: A 2-Year Study

Abstract: In the largest cohort on this argument reported to date, the addition of an IM was an effective and safe optimization strategy after loss of response to anti-TNFα monotherapy. Low doses of IM were sufficient to achieve a clinical response.

Cited by 19 publications

References 29 publications

Thiopurines: Recent Topics and Their Role in the Treatment of Inflammatory Bowel Diseases

Thiopurines: Recent Topics and Their Role in the Treatment of Inflammatory Bowel Diseases

A Multi-mRNA Prognostic Signature for Anti-TNFα Therapy Response in Patients with Inflammatory Bowel Disease

Enhancing treatment success in inflammatory bowel disease: Optimising the use of anti-TNF agents and utilising their biosimilars in clinical practice

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