Y-ECCO Literature Reviews
30September2020

Y-ECCO Literature Review: Radha Gadhok

Radha Gadhok

Laparoscopic ileocaecal resection versus infliximab for terminal ileitis in Crohn’s disease: retrospective long-term follow-up of the LIR!C trial  

Stevens TW, Haasnoot ML, D’Haens GR, Buskens CJ, De Groof EJ, Eshuis EJ, Gardenbroek TJ, Mol B, Stokkers PCF, Bemelman WA, Ponsioen CY on behalf of the LIR!C study group

Lancet Gastroenterol Hepatol 2020 Jun 30;S2468-1253(20)30117-5. doi: 10.1016/S2468-1253(20)30117-5. Online ahead of print.


Radha Gadhok
© Radha Gadhok

Introduction

The positioning of medical therapies in the management of Crohn’s Disease (CD) continues to be debated [1] whilst surgery is reserved for cases with disease complications or failure of medical therapy.  The LIR!C trial [2] provided evidence for  surgical resection as an alternative to infliximab (IFX) in the management of localised terminal ileitis, a common presentation of CD [3].

Briefly, the LIR!C trial reported quality of life scores (IBDQ) among 143 adult patients with terminal ileitis (<40 cm) who underwent randomisation to IFX induction/maintenance or ileocaecal resection. Patients were recruited from 29 secondary and tertiary Dutch and British centres. Exclusion criteria included non-inflammatory disease, prestenotic dilatation, abscess and previous surgery. Inclusion criteria included failing at least three months of conventional therapy [immunomodulator (IM) and/or corticosteroid (CS)] [2]

Posted in ECCO News, Committee News, Y-ECCO Literature Reviews, Volume 15, Issue 3, Y-ECCO

30September2020

Y-ECCO Literature Review: Rebecca Reynolds

Rebecca Reynolds

No benefit of continuing vs stopping 5-aminosalicylates in patients with ulcerative colitis escalated to anti-metabolite therapy

Singh S, Kim J, Zhu W, Dulai P, Sandborn WJ, Jairath V

Aliment Pharmacol Ther. 2020;52:481–91.


Rebecca Reynolds
© Rebecca Reynolds 

Introduction

First introduced by Svartz in 1942, 5-aminosalicylates (5-ASAs) are a well-established and effective first-line therapy for the induction and maintenance of remission in patients with mild-to-moderate Ulcerative Colitis (UC). They remain the most frequently prescribed medication for UC and are known to be effective and well tolerated [1]. Between 87% and 98% of UC patients receive 5-ASA treatment within the first year of diagnosis and 60%–87% continue on this treatment at ten years [2, 3].

Escalation to anti-metabolites (thiopurines or methotrexate) and/or biologic or small molecule therapy is often required for UC patients with a more aggressive disease course. Whilst it is now accepted that discontinuing 5-ASA therapy when escalating to a biologic is not associated with adverse outcomes, less is known about the therapeutic benefit of continuation of 5-ASAs with an antimetabolite [2, 4].

Singh et al conducted a retrospective cohort study to evaluate the pattern of 5-ASA use in patients with UC following escalation to an antimetabolite. The study evaluated patients escalated to antimetabolite therapy (stopping 5-ASA vs short-term 5-ASA use for <6 months vs persistent 5-ASA use for >6 months) and compared the risk of clinically important complications based on the pattern of 5-ASA use in these patients. They hypothesised that continuing 5-ASA therapy would not be more beneficial than stopping it.

Posted in ECCO News, Committee News, Y-ECCO Literature Reviews, Volume 15, Issue 3, Y-ECCO

30September2020

Y-ECCO Literature Review: Susanna Meade

Susanna Meade

Prominence of ileal mucosa-associated microbiota to predict postoperative endoscopic recurrence in Crohn’s disease

Sokol H, Brot L, Stefanescu C, et al.

Gut 2020;69:462–472.


Susanna Meade
© Susanna Meade

Introduction

The aetiopathogenesis of CD is multifactorial but includes the interaction between the microbiome and the host’s immune response. Up to 80% of patients with Crohn’s Disease (CD) require surgery during their lifetime and many factors are associated with postoperative recurrence (POR). Differential abundance of bacterial species is seen in patients with IBD compared with healthy individuals and several studies have suggested an association between microbiota composition and CD recurrence [1–3]. Altered mucosal gene expression and abundance of specific microbiota are associated with, and specific to, ileal CD [4].

Posted in ECCO News, Committee News, Y-ECCO Literature Reviews, Volume 15, Issue 3, Y-ECCO

30June2020

Y-ECCO Literature Review: Samantha Baillie

Samantha Baillie

HLADQA1*05 genotype predicts anti-drug antibody formation and loss of response during infliximab therapy for Inflammatory Bowel Disease

Wilson A, Peel C, Wang Q, Pananos A, Kim R

Alimentary Pharmacology and Therapeutics 2020;51:356–63. doi: 10.1111/apt.15563.


Samantha Baillie
© Samantha Baillie

Introduction

The anti-TNF monoclonal antibody infliximab offers an effective treatment for patients with Inflammatory Bowel Disease (IBD) refractory to conventional immunomodulator therapies. Successful biologic therapy can lead to clinical and endoscopic remission as well as reduced hospitalisation and requirement for surgery [1].

Unfortunately, as a large protein and chimeric antibody, infliximab is immunogenic and this frequently leads to formation of anti-drug antibodies (ADA), with subsequent secondary loss of response (LOR), drug discontinuation and adverse reactions [2]. Identifying patients at increased risk of developing antibodies prior to treatment may establish which individuals require closer drug level monitoring, concomitant immunomodulator therapy and observation for adverse events.

Previous work by Sazonovs et al. identified the first genetic locus to be robustly associated with immunogenicity to anti-TNF therapies [3]. The HLADQA1*05 allele variant rs2097432, carried by approximately 40% of Europeans, significantly increased the rate of formation of infliximab ADA. In the study reviewed here, Wilson et al. aimed to independently identify whether presence of the variant allele was associated with increased risk of ADA formation, LOR, drug discontinuation and adverse events.

Posted in ECCO News, Committee News, Y-ECCO Literature Reviews, Volume 15, Issue 2, Y-ECCO

30June2020

Y-ECCO Literature Review: Michael De Gregorio

Michael De Gregorio

Higher anti-tumour necrosis factor levels are associated with perianal fistula healing and fistula closure in Crohn’s Disease

Plevris N, Jenkinson PW, Arnott ID, Jones GR, Lees CW

Eur J Gastroenterol Hepatol 2020;32(1):32–37. DOI: 10.1097/MEG.0000000000001561


Michael De Gregorio
© Michael De Gregorio

Introduction

Perianal fistulising Crohn’s Disease is a challenging phenotype affecting more than 20% of patients diagnosed with Crohn’s Disease. It is associated with debilitating symptoms and significant morbidity, with subsequent reduced quality of life and increased disease-related work disability.

Currently treatment remains challenging, incorporating surgical and medical management; the latter is driven largely by biologic agents, specifically anti-tumour necrosis factor (TNF) agents such as adalimumab (ADA) and infliximab (IFX). Whilst ADA and IFX have proven efficacy in inducing and maintaining fistula healing and closure, a significant proportion of patients fail to respond or lose response over time. Increasing evidence suggests that this is in part due to sub-therapeutic drug levels, with or without the presence of antibodies to anti-TNF agents (ATA), with higher target drug levels required for fistula healing compared to mucosal healing in Crohn’s Disease. However, data evaluating the correlation between anti-TNF levels and perianal fistula outcomes, particularly with ADA, remain limited.

The aim of this study was to assess the association between anti-TNF levels and perianal fistula healing and closure with maintenance ADA and IFX therapy.

Posted in ECCO News, Committee News, Y-ECCO Literature Reviews, Volume 15, Issue 2, Y-ECCO

30June2020

Y-ECCO Literature Review: Raphael Luber

Raphael Luber

Pre-treatment frailty is independently associated with increased risk of infections after immunosuppression in patients with Inflammatory Bowel Diseases

Kochar B, Cai W, Cagan A, Ananthakrishnan AN

Gastroenterology 2020 Feb 25;S0016-5085(20)30243-2. doi: 10.1053/j.gastro.2020.02.032. Online ahead of print.


Raphael Luber
© Raphael Luber

Introduction

The growing arsenal of therapies available for Inflammatory Bowel Disease (IBD) is improving IBD physicians’ ability to target remission. However, risk of infectious complications associated with immunosuppression is a reality that weighs in the minds of physicians and patients alike, affecting the acceptability of these treatments [1]. Both treatment- and patient-related risk factors for infection have been identified in observational studies. Systemic steroids and combination anti-tumour necrosis factor (anti-TNF) and immunomodulator therapy are particularly associated with increased risk of infection, while non-modifiable patient factors include older age and non-IBD comorbidities [2–4]. Accordingly, this perceived risk results in reduced use of effective therapies in older people, despite risk of disease progression and a need for surgery similar to that in young people [5,6].

As explained by Kochar et al., however, chronological age does not capture the physiological heterogeneity in older populations, possibly leading to treatment being unnecessarily conservative in some. Furthermore, reliance on chronological age may lead to underappreciation of risk in younger people. Accordingly, more accurate tools for risk stratification of patients in the setting of immunosuppressive therapies are required.

Posted in ECCO News, Committee News, Y-ECCO Literature Reviews, Volume 15, Issue 2, Y-ECCO

12March2020

Y-ECCO Literature Review: Gregory Sebepos-Rogers

Gregory Sebepos-Rogers

Addition of azathioprine to the switch of anti-TNF in patients with IBD in clinical relapse with undetectable anti-TNF trough levels and antidrug antibodies: a prospective randomised trial

Roblin X, Williet N, Boschetti G, Phelip JM, Del Tedesco E, Berger AE, Vedrines P, Duru G, Peyrin-Biroulet L, Nancey S, Flourie B, Paul S.

Gut. 2020 Jan 24. doi: 10.1136/gutjnl-2019-319758. [Epub ahead of print]


Gregory Sebepos-Rogers
© Gregory Sebepos-Rogers

Introduction

Anti-tumour necrosis factor-α (anti-TNF) has historically been the mainstay of biologic therapy in Inflammatory Bowel Disease (IBD). However, of those who initially respond to anti-TNF, almost 50% will suffer secondary loss of response (SLR) over subsequent years [1,2]. This SLR is primarily predicated on suboptimal anti-TNF trough levels, with or without detectable anti-drug antibodies (ADAs) [3]. Furthermore the prospective, observational study by Kennedy et al. demonstrated that suboptimal anti-TNF trough levels at week 14 predicted ADAs, low trough levels and worse clinical outcomes [4]. This risk was mitigated for both infliximab and adalimumab by the use of immunomodulators such as azathioprine. This corroborates the retrospective data from other cohorts showing how the addition of an immunomodulator can restore clinical response and favourable pharmacokinetics [5–7]. Remission rates when switching to a second anti-TNF have been shown to be lower when the reason to withdraw the first anti-TNF is SLR as compared to intolerance (45% vs 61%) [8]. In the event that SLR to anti-TNF is due to immunogenicity, a switch to another anti-TNF is associated with a risk of ADA to this new therapy [9,10]. A number of patients will also be on anti-TNF monotherapy at the time of switching having de-escalated from previous combination therapy. We know that open-ended prescription of anti-TNF with azathioprine is not without additional risk, notably infection and lymphoma [11]. Furthermore, de-escalation to anti-TNF monotherapy after a period of combination therapy has been shown in most studies not to impact on relapse rates (49% monotherapy versus 48% combination therapy) [12]. It is in precisely this important group of patients that Roblin et al. sought to compare the use of azathioprine in combination with a second anti-TNF versus this second anti-TNF as monotherapy. Over a follow-up period of 2 years, the rates of clinical and immunogenic failure, and of adverse events, were compared.

Posted in ECCO News, Committee News, Y-ECCO Literature Reviews, Volume 15, Issue 1, Y-ECCO

12March2020

Y-ECCO Literature Review: Neil Chanchlani

Neil Chanchlani

Proactive monitoring of adalimumab trough concentration associated with increased clinical remission in children with Crohn's Disease compared with reactive monitoring

Assa A, Matar M, Turner D, Broide E, Weiss B, Ledder O, Guz-Mark A, Rinawi F, Cohen S, Topf-Olivestone C, Shaoul R, Yerushalmi B, Shamir R

Gastroenterology. 2019;157:985–96.e2. doi: 10.1053/j.gastro.2019.06.003


Neil Chanchlani
© Neil Chanchlani

Introduction

Therapeutic drug monitoring (TDM) of the anti-TNF monoclonal antibodies, infliximab and adalimumab, in patients with Inflammatory Bowel Disease is gradually being adopted into routine clinical practice in the United Kingdom [1] and United States [2]. The aim of TDM, measuring an individual’s drug and anti-drug antibody levels, is to assess compliance, drug metabolism and immunogenicity with a view to guiding adjustments or changes in management in order to improve clinical outcomes1. TDM can be proactive, with routine measurement of drug level and anti-drug antibody regardless of clinical outcome, or reactive, with measurement of drug level and anti-drug antibody in the setting of loss of response [3]. Compared to empirical dosing alone, TDM used reactively, at the time of loss of response to an anti-TNF treatment, improves durability of response and safety and leads to significant cost savings [4,5]. The evidence base supporting proactive over reactive TDM is, however, less clear. Two randomised controlled trials done in adults (TAXIT [6] and TAILORIX [7]) did not demonstrate any differences in biological, endoscopic or corticosteroid-free remission between groups, though these trials were limited by methodological limitations and isolating the effect of proactive TDM on defined outcomes was difficult. In contrast, multiple observational studies have concluded that there is less risk of treatment failure and relapse, higher rates of drug persistence and better clinical outcomes in patients who undergo proactive TDM compared to reactive TDM [8–11]. The authors aimed to add to this debate by carrying out a pragmatic, randomised controlled trial assessing whether proactive TDM is superior to reactive testing in children with Crohn’s Disease.

Posted in ECCO News, Committee News, Y-ECCO Literature Reviews, Volume 15, Issue 1, Y-ECCO

12March2020

Y-ECCO Literature Review: Jonathan Blackwell

Jonathan Blackwell

Vedolizumab versus adalimumab for moderate-to-severe Ulcerative Colitis

Sands BE, Peyrin‑Biroulet L, Loftus E, Danese S, Colombel JF, Toruner M, Jonaitis L, Abhyankar B, Chen J, Rogers R, Lirio RA, Bornstein JD, Schreiber S, for the VARSITY Study Group

N Engl J Med 2019;381:1215–26. doi: 10.1056/NEJMoa1905725


Jonathan Blackwell
© Jonathan Blackwell

Introduction

The management of Ulcerative Colitis (UC) increasingly involves the use of a biologic agent. Placebo-controlled trials have demonstrated the efficacy of both adalimumab, a tumour necrosis factor (TNF) inhibitor, and vedolizumab, an integrin inhibitor. However, variation in study design makes comparison between such trials difficult. This is particularly evident when comparing rates of clinical remission in the placebo groups of different trials. For example, in the ULTRA 2 trial, which established the superiority of adalimumab over placebo in moderate to severe UC, the 52-week clinical remission rate in the placebo group was just 8.5% compared to 15.9% in GEMINI 1, the placebo-controlled trial of vedolizumab [1,2]. In the absence of head-to-head trials between biologics there is a lack of data to inform clinicians of the best choice of agent. VARSITY is the first head-to-head trial to compare the efficacy and safety of vedolizumab and adalimumab in moderate to severely active UC.

Posted in ECCO News, Committee News, Y-ECCO Literature Reviews, Volume 15, Issue 1, Y-ECCO

17December2019

Y-ECCO Literature Review: Hajir Ibraheim

Hajir Ibraheim

Efficacy and safety of mirikizumab in a randomized phase 2 study of patients with Ulcerative Colitis

Sandborn WJ, Ferrante M, Bhandari BR, Berliba E, Feagan BG, Hibi T, Tuttle JL, Klekotka P, Friedrich S, Durante M, Morgan-Cox M, Laskowski J, Schmitz J, D'Haens GR

Gastroenterology. 2019;doi: https://doi.org/10.1053/j.gastro.2019.08.043. [Epub ahead of print]

Introduction


Hajir Ibraheim
© Hajir Ibraheim

Interleukin-23 (IL23) contributes to the pathogenesis of chronic inflammatory diseases, including Ulcerative Colitis (UC), by maintaining and amplifying T helper 17 cells and stimulating many innate immune cells. IL-23 is a heterodimeric cytokine composed of a p40 subunit (shared by IL12) and a p19 subunit (IL-23p19). Ustekinumab, a monoclonal antibody targeting the shared p40 subunit, is effective for treatment of Crohn’s Disease (CD) and psoriasis [1–3]. However, studies in patients with psoriasis have suggested that selective targeting of the IL23 pathway by blocking IL-23p19 is more effective than ustekinumab [4, 5]. Whilst promising phase 2 results have been observed in CD patients following treatment targeting IL-23p19 [6, 7], the role of this therapeutic strategy in UC is unknown. Mirikizumab (LY3074828) is a humanised immunoglobulin G4 (IgG4)-variant monoclonal antibody that binds to the IL-23p19 subunit. The current study evaluated the efficacy and safety of mirikizumab for the treatment of patients with moderate-to-severely active UC. 

Posted in ECCO News, Committee News, Y-ECCO Literature Reviews, Volume 14, Issue 4, Y-ECCO

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