CALM Trial

Sasha Fehily  © ECCO

Introduction

There has been a recent shift in Crohn’s Disease (CD) management away from the conventional focus on short-term clinical outcomes and towards the maintenance of long-term remission.  In 2015 the International Organisation for the Study of Inflammatory Bowel Diseases released a consensus statement recommending a treat-to-target approach [1]. The STRIDE initiative recommended pursuing treatment escalation in order to achieve the treatment targets of clinical remission and mucosal healing, with adjunctive use of normal C-reactive protein (CRP) and faecal calprotectin (FC) levels. However, the authors noted that prospective studies would be needed to confirm that achievement of these targets would alter the natural history of disease and improve patients’ quality of life.

Serum Concentration of 7α-hydroxy-4-cholesten-3-one Are Associated With Bile Acid Diarrhea in Patients With Crohn's Disease

Battat R, Duijvestein M, Vande Casteele N, Singh S, Dulai PS, Valasek MA, Mimms L, McFarland L, Hester KD, Renshaw M, Jain A, Sandborn WJ, Boland BS

Clin Gastroenterol Hepatol. 2018 Nov 15. doi:10.1016/j.cgh.2018.11.012    

Ivan Lyutakov  © Ivan Lyutakov

Introduction

Inflammatory Bowel Disease (IBD) comprises a heterogeneous group of chronic inflammatory disorders with two main conditions, Crohn’s Disease (CD) and Ulcerative Colitis (UC) [1]. Bile acid malabsorption (BAM) and bile acid diarrhoea (BAD) have been recognised to be a common cause of chronic diarrhoea, and this recognition has led to the initiation of a search for new screening tests (biomarkers). BAM is one of the mechanisms leading to microscopic colitis, a key factor in the pathogenesis of irritable bowel syndrome-diarrhoea, and molecular mechanisms of BAM are found in IBD patients with or without involvement of the terminal ileum. BAM/BAD is more frequently found in CD than in UC, and the obvious aetiology for BAM in CD is either ileal resection or ileal disease [2]. The pathophysiology of diarrhoea in CD is multifactorial but there are two key factors, colonic water and electrolyte absorption, which can be impaired directly by colonic inflammation or indirectly by increased concentrations of bile acids having secretory effects, referred to as BAD [3].

Risankizumab in patients with moderate to severe Crohn's Disease: An open-label extension study

Feagan BG, Panés J, Ferrante M, Kaser A, D'Haens GR, Sandborn WJ, Louis E, Neurath MF, Franchimont D, Dewit O, Seidler U, Kim KJ, Selinger C, Padula SJ, Herichova I, Robinson AM, Wallace K, Zhao J, Minocha M, Othman AA, Soaita A, Visvanathan S, Hall DB, Böcher WO

Lancet Gastroenterol Hepatol. 2018;3:671–80. DOI: https://doi.org/10.1016/S2468-1253(18)30233-4   

James Gauci  © James Gauci

Introduction

Management of Crohn’s Disease involves the suppression of inflammation through administration of immunosuppressive drugs. While conventional therapies such as corticosteroids and thiopurines exert a broad effect on the immune system, the advent of biological agents has allowed for selective targeting of cytokines and integrins.

Unfortunately, a third of patients treated with tumour necrosis factor (TNF) antagonists demonstrate a primary non-response, with another third developing either secondary failure or intolerance. These patients will then have a lower chance of responding to treatment with other TNF antagonists or with the integrin antagonist vedolizumab.

Optimised infliximab monotherapy is as effective as optimised combination therapy, but is associated with higher drug consumption in Inflammatory Bowel Disease

Drobne D, Kurent T, Golob S, Švegl P, Rajar P, Hanžel J, Koželj M, Novak G, Smrekar N, Ferkolj I, Štabuc B

Aliment Pharmacol Ther. 2019;49:880–9

Aravind Gokul Tamilarasan  © Aravind Gokul Tamilarasan

Introduction

Since the publication of the landmark SONIC trial in 2010 [1], the use of combination biologic–immunomodulator therapy has been considered best standard practice for patients with Inflammatory Bowel Disease (IBD) who have failed topical therapies or immunomodulators (thiopurines or methotrexate). More recently, real-world data from the PANTS (Personalised anti-TNF therapy in Crohn’s Disease) study demonstrated the benefit of combination therapy (particularly for infliximab) in the form of higher week 54 remission rates and prevention of immunogenicity [2]. Notably, the week 54 remission rates were independent of infliximab trough levels or immunogenicity status, suggesting additional benefits apart from improving the pharmacokinetics of infliximab. This study aimed to provide further real-world data on the effect of combination therapy on clinical and pharmacokinetic outcomes.

Early combined immunosuppression may be effective and safe in older patients with Crohn’s disease: post hoc analysis of REACT

Singh S, Stitt LW, Zou G, et al.

Aliment Pharmacol Ther. 2019;49:1188–94.

Introduction

Georgina Cunningham  © Georgina Cunningham

Due to the ageing population and the chronicity of the disease, increasing numbers of patients with Inflammatory Bowel Disease (IBD) are now over the age of 60 [1]. The management of IBD in this group poses some challenges, mainly centered on the balance between risk of immunosuppression and the burden of active disease [2]. Although older IBD patients usually display a more indolent disease course, they are more likely to be hospitalised and have higher in-hospital mortality than their younger counterparts [3]. There is no doubt that there is room for improvement in our management of IBD in elderly patients, and guidance is needed to help physicians decide whether more aggressive treatment strategies, widely accepted in certain younger IBD patients [4], are also warranted in this cohort, and especially those at high risk of disease complications.

Predictors of anti-TNF treatment failure in anti-TNF-naive patients with active luminal Crohn’s disease: A prospective, multicentre, cohort study

Kennedy NA, Heap GA, Green HD, Hamilton B, Bewshea C, Walker GJ, Thomas A, Nice R, Perry MH, Bouri S, Chanchlani N, Heerasing NM, Hendy P, Lin S, Gaya DR, Cummings JRF, Selinger CP, Lees CW, Hart AL, Parkes M, Sebastian S, Mansfield JC, Irving PM, Lindsay J, Russell RK, McDonald TJ, McGovern D, Goodhand JR, Ahmad T, UK Inflammatory Bowel Disease Pharmacogenetics Study Group*

Lancet Gastroenterol Hepatol. 2019;4:341–53

Introduction

Misha Kabir  © Misha Kabir

The anti-TNF monoclonal antibodies infliximab and adalimumab have been integral to the management of Crohn’s Disease over the past two decades. However, primary non-response and secondary loss of response in the first year of treatment remain common, at 10%–40% [1–3] and 23%–46% [4] respectively. Immunogenicity has been implicated as an important predictive factor for anti-TNF therapy failure. However, target-to-treat drug and anti-drug antibody concentrations have not yet been validated in an adequately powered prospective study. The Personalised Anti-TNF Therapy in Crohn’s Disease Study (PANTS) aimed to investigate the factors that predict primary non-response, non-remission and adverse events with anti-TNF therapy in luminal Crohn’s Disease.

Rates and characteristics of postcolonoscopy colorectal cancer in the Swedish IBD population: What are the differences from a non-IBD population?

Stjärngrim J, Ekbom A, Hammar U, Hultcrantz R, Forsberg AM

Gut 2018 Dec 15; doi: 10.1136/gutjnl-2018-316651

Introduction

Rohit Rao  © Rohit Rao

Individuals with IBD have an increased risk of colorectal cancer (CRC) [1, 2]. In an effort to address this, societal guidelines recommend surveillance colonoscopy 8–10 years after diagnosis and at varying intervals thereafter, depending on risk [3, 4]. A 2017 Cochrane systematic review [5] demonstrated a benefit in this strategy, noting reductions in the development of both CRC and the rate of CRC‐associated death. Despite this, dysplasia detection is challenging and CRC still accounts for 10%–15% of all IBD deaths [6, 7]. Of further concern is the reported increased rate of post-colonoscopy colorectal cancer (PCCRC) in IBD. 

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.

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.

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.