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.

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.

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.

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.

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.

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.

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. 

Tight control for Crohn’s Disease with adalimumab-based treatment is cost-effective: An economic assessment of the CALM trial

Panaccione R, Colombel J-F, Travis SPL, Bossuyt P, Baert F, Vaňásek T, Danalıoğlu A, Novacek G, Armuzzi A, Reinisch W, Johnson S, Buessing M, Neimark E, Petersson J, Lee W-J, D’Haens GR GR

Gut 2019 Jul 8. doi: 10.1136/gut-jnl-2019-318256 [Epub ahead of print].

Introduction

Jennie Clough © Jennie Clough

It is widely accepted that a ‘treat-to-target’ (T2T) approach of continual assessment against established biomarkers and early treatment optimisation is important in preventing progression in Crohn’s Disease (CD) [1], and in 2015 the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) programme was initiated to define a T2T approach for CD [2].

CALM was an open-label, multicentre, randomised controlled phase 3 study comparing the outcome of a ‘tight control’ (TC) adalimumab-based treatment strategy against standard clinical symptom-based management (CM) for patients with early CD [3]. Treatment of patients in the TC arm was escalated in a stepwise manner in response to elevated C reactive protein (CRP) or faecal calprotectin, even in the absence of symptoms. A significantly higher proportion of patients in the TC group achieved the primary endpoint of mucosal healing (CDEIS<4) at 48 weeks compared to the CM group (46% vs 30%).

Perhaps unsurprisingly, a TC approach led to higher rates of adalimumab usage than a conventional approach [3]. Biologics constitute a significant cost in managing Inflammatory Bowel Disease, with other major cost drivers being hospital admission and surgical management [4]. As rates of surgery and hospitalisation have decreased with the advent of biologics [5, 6], costs have shifted to outpatient care, drug acquisition and infusion unit management [7].

This study sought to model the costs of a TC versus a conventional approach, to determine whether the increased biologic costs could be offset by a reduction in hospital attendance and need for surgery, and enhanced economic outputs associated with increased wellbeing.  

Infliximab induction regimens in steroid‐refractory acute severe colitis: A multicentre retrospective cohort study with propensity score analysis

Sebastian S, Myers S, Argyriou K, Martin G, Los L, Fiske J, Ranjan R, Cooper B, Goodoory V, Ching HL, Jayasooriya N, Brooks J, Dhar A, Shenoy AH, Limdi JK, Butterworth J, Allen PB, Samuel S, Moran GW, Shenderey R, Parkes G, Lobo A, Kennedy NA, Subramanian S, Raine T

Aliment Pharmacol Ther. 2019;50:675–683. doi: 10.1111/apt.15456..

Introduction

Joshua McGuire © Joshua McGuire

Acute Severe Ulcerative Colitis (ASUC) is a medical emergency which necessitates a colectomy in up to 30% of cases on index presentation [1]. The first-line treatment is with intravenous corticosteroids but up to 40% of patients will fail to respond [2]. Ciclosporin and infliximab are then well-recognised options for rescue therapy to avert the need for a colectomy and, whilst there appear to be no difference in response rates between these two choices [3], many experts favour infliximab owing to convenience and familiarity [4]. Up to 55% of patients do not respond to the standard dosing regimen of infliximab extrapolated from the outpatient setting [5]. The exaggerated clearance of infliximab in ASUC is increasingly better characterised [6]; this has led to the concept of accelerated dosing regimens although the efficacy of such regimens has yet to be evaluated by randomised controlled trials. A recent meta-analysis [7] of the available cohort studies showed no benefit of accelerated induction in reducing colectomy rates in steroid‐refractory disease; however, provider bias represents a significant barrier to answering this question. Propensity score matching seeks to address this provider bias.

No association between pseudopolyps and colorectal neoplasia in patients with inflammatory bowel diseases

Mahmoud R, Shah SC, Ten Hove JR, Torres J, Mooiweer E, Castaneda D, Glass J, Elman J, Kumar A, Axelrad J, Ullman T, Colombel JF, Oldenburg B, Itzkowitz SH; Dutch Initiative on Crohn and Colitis

Gastroenterology. 2019;156:1333–44.e3.

Introduction

Sailish Honap © Sailish Honap

Patients with Inflammatory Bowel Disease (IBD) are at an increased risk of developing high-grade dysplasia and colorectal carcinoma [1, 2]. The risk of carcinogenesis, driven by chronic inflammation, increases with several factors, including duration and anatomic extent of colitis, family history and the presence of primary sclerosing cholangitis (PSC). European clinical guidelines for colonoscopy surveillance in this high-risk cancer population also suggest a shorter surveillance interval for those with post-inflammatory polyps (PIPs), also known as pseudopolyps [3–5]. PIPs are a common finding, more so in Ulcerative Colitis (UC) than in Crohn’s Disease, and are formed after alternating cycles of inflammation and regeneration of the epithelial mucosa. However, data are conflicting and evidence is lacking in this field as previous case control studies have reported up to a 2.5-fold increased risk [6, 7] whereas a more recent cohort study showed no significant association between PIPs and colorectal neoplasia (CRN) [8]. The authors of this study aimed to use a large cohort study to further define the risk of CRN and PIPs in patients with Inflammatory Bowel Disease.