Exabis Library

Educational objectives: 1. To understand the structural and functional features of the various anti-TNF agents, including originators and biosimilars 2. To review their use in Crohn's disease (CD), ulcerative colitis (UC) and in special indications 3. To have an overview of the optimal dosing of anti-TNFs, including therapeutic dose monitoring.

Anti-TNF were the first biological therapies available in IBD as well as in other immune-inflammatory disorders such as rheumatoid arthritis, spondyloarthritis and psoriasis. These agents can induce and maintain remission of CD and UC. They are also used in refractory pouchitis and microscopic colitis. Infliximab and adalimumab are approved in CD and UC, while certolizumab pegol is only approved for CD in some jurisdictions but not EU, and golimumab is approved for UC only. Biosimilars of infliximab and adalimumab are now available with all the indications of their originators. Data accumulate to support similar activity in both diseases, but some individual differences may be observed. Anti-TNF agents are increasingly used during pregnancy and for the treatment of extraintestinal manifestations of IBD.  Infliximab remains the best studied biological agent in IBD. The possibility of iv administration at high doses makes it the favored agent in fulminant colitis, fistulizing CD and in pyoderma gangrenosum. As all biological agents, anti-TNFS can induce anti-drug antibodies that represent the main cause of loss of response to these therapies. Continuous dosing beyond induction, combination therapy and premedication with hydrocortisone reduce this risk. Therapeutic dose monitoring and antibody detection are now available for all anti-TNF agents, the proactive use of which improves treatment outcome and preserves long-term response. Based on data with infliximab, anti-TNF may decrease immune response to SARS-CoV-2 infection and may decrease vaccine response. 

Educational objectives: 1. To understand the structural and functional features of the various anti-TNF agents, including originators and biosimilars 2. To review their use in Crohn's disease (CD), ulcerative colitis (UC) and in special indications 3. To have an overview of the optimal dosing of anti-TNFs, including therapeutic dose monitoring.

Anti-TNF were the first biological therapies available in IBD as well as in other immune-inflammatory disorders such as rheumatoid arthritis, spondyloarthritis and psoriasis. These agents can induce and maintain remission of CD and UC. They are also used in refractory pouchitis and microscopic colitis. Infliximab and adalimumab are approved in CD and UC, while certolizumab pegol is only approved for CD in some jurisdictions but not EU, and golimumab is approved for UC only. Biosimilars of infliximab and adalimumab are now available with all the indications of their originators. Data accumulate to support similar activity in both diseases, but some individual differences may be observed. Anti-TNF agents are increasingly used during pregnancy and for the treatment of extraintestinal manifestations of IBD.  Infliximab remains the best studied biological agent in IBD. The possibility of iv administration at high doses makes it the favored agent in fulminant colitis, fistulizing CD and in pyoderma gangrenosum. As all biological agents, anti-TNFS can induce anti-drug antibodies that represent the main cause of loss of response to these therapies. Continuous dosing beyond induction, combination therapy and premedication with hydrocortisone reduce this risk. Therapeutic dose monitoring and antibody detection are now available for all anti-TNF agents, the proactive use of which improves treatment outcome and preserves long-term response.

Discontinuation of anti-tumour necrosis factor alpha agents (anti-TNF) in patients with inflammatory bowel disease (IBD) in remission may reduce side effects and costs, but this has to be weighed against the risk of relapse. We developed a risk-stratified protocol for anti-TNF withdrawal, and aimed to assess the risk of relapse after risk-stratified anti-TNF withdrawal.

This was a single arm prospective observational cohort study. Patients were recruited between September 2018-2020 in 13 hospitals in the Netherlands. Inclusion criteria were a diagnosis of IBD, age >18 years, elective anti-TNF withdrawal in a patient with quiescent disease (according to the treating physician), no current or planned use of vedolizumab, ustekinumab or tofacitinib, no hospitalization, and no active or planned pregnancy. According to the protocol, patients were recommended to withdraw anti-TNF only when in endoscopic remission either without high-risk criteria (age at diagnosis <18 years, and for Crohn’s disease [CD]: smoking, stricturing/penetrating disease behaviour, small bowel resection >50cm), or when trough levels were undetectable. We constructed Kaplan-Meier curves with log-rank test to compare the risk of relapse in patients who discontinued anti-TNF in accordance with, versus against, the protocol. Cox regression analysis was performed to identify predictors of relapse.

We enrolled 115 patients (CD: n=61, 53%), with a median follow-up time of 1.9 (IQR 1.8 – 2.1) years. Baseline endoscopic remission was confirmed in 103 (89.6%) patients, and 35 (30.4%) patients continued an immunomodulator. During follow-up, 57 (49.6%) patients relapsed (Figure 1). The relapse rate was similar in patients in endoscopic remission who withdrew anti-TNF in according with, versus against, the protocol (50.7% versus 44.4%, p=0.65), and in patients with versus without an immunomodulator (hazard rate [HR] 0.89, 95%CI 0.50 – 1.59), but was lower in patients with subtherapeutic anti-TNF trough levels (adjusted HR: 0.55, 95%CI: 0.31 – 0.99), and in patients with UC/IBD-unclassified (IBDU) who were treated with mesalamine maintenance therapy (HR: 0.35, 95%CI 0.13 – 0.94). Anti-TNF was reintroduced in 41 (71.9%) patients, with remission rates of 64.5% and 81.8% at 3 and 12 months, respectively. In 6 (15.0%) patients anti-TNF therapy was discontinued again due to primary non-response or loss of response.

The risk of relapse after anti-TNF withdrawal remains high in a strictly selected group of patients with uncomplicated IBD in endoscopic remission. Therapeutic drug monitoring prior to anti-TNF withdrawal, and mesalamine therapy for patients with UC or IBDU, may reduce the risk of relapse.

Older adults are the fastest growing subpopulation of patients with IBD, with approximately 15% diagnosed after 60 years-of-age. Moreover, environmental exposures are thought to play a significant role in the development of older-onset IBD, given the lower genetic risk. Antibiotics have been associated with development of IBD in earlier generations, but the impact on IBD risk in older adults is uncertain. In this population-based cohort study, we assessed the impact of cumulative antibiotic use, the timing of antibiotic use, and the association between specific antibiotic classes and the development of older-onset IBD.

Using Denmark nationwide registries, a cohort of residents ≥60 years-of-age was established between 2000-2018. Information on exposure to antibiotics was retrieved from the Danish National Prescription Register. The number of courses of antibiotics (overall and specific classes) was considered a time-varying variable. The outcome, IBD, was identified based on ICD-10 codes in the Danish National Patient Register. Incidence rate ratios (IRRs) for IBD according to antibiotic use 1 to 5 years prior to IBD diagnosis were calculated by log-linear Poisson regression, and adjusted for age, sex, and calendar period.

There were a total of 2,327,796 individuals aged 60 to 90 years included in the cohort, resulting in 22,670,484 person-years of follow-up. There were 10,773 new cases of ulcerative colitis (UC) and 3,825 new cases of Crohn’s disease (CD). Overall, any antibiotic use was associated with an IRR for the development of IBD (IRR 1.64, 95%CI 1.58-1.71), with a positive dose response observed (1 course of antibiotics IRR 1.27 95%CI 1.21-1.33; 2 courses IRR 1.54 95%CI 1.46-1.63; 3 courses IRR 1.66 95%CI 1.67-1.77; 4 courses IRR 1.96 95%CI 1.83-2.09; 5+ courses IRR 2.35, 95%CI 2.24-2.47). A higher IRR was noted between the timeframe of 1-2 years before diagnosis (IRR 1.87, 95%CI 1.79-1.94) as compared to 2-5 years before diagnosis (IRR 1.42, 95%CI 1.36-1.48). Additionally, all antibiotic classes were associated with the development of IBD, including those not used to treat gastrointestinal infections. Antibiotics with the highest IRR were fluoroquinolones (IRR 2.27, 95%CI 2.08-2.48), nitroimidazoles (IRR 2.21, 95%CI 1.95-2.50), and macrolides (IRR 1.74, 95%CI 1.64-1.84). All results remained statistically significant when stratifying by UC and CD, with effect estimates slightly higher for CD as compared to UC.

Use of antibiotics, regardless of class studied, was associated with an increased risk of older-onset IBD. This risk was highest one to two years prior to diagnosis, but persisted even prior to that, suggesting a link between overall antibiotic use and development of older-onset IBD.

Antibody responses following SARS-CoV-2 infection or a single-dose of SARS-CoV-2 vaccine are impaired in patients with inflammatory bowel disease treated with anti-TNF compared to those treated with vedolizumab, a gut-selective anti-integrin α4β7 monoclonal antibody.  

Here we sought to determine if patients treated with infliximab have attenuated serological and T cell responses and an increased risk of breakthrough COVID-19 infection following primary SARS-CoV-2 vaccination. 

Anti-spike (S) receptor binding domain (RBD) antibody concentration in 2306 infliximab-treated patients were compared to a cohort of 1045 vedolizumab-treated patients. Our primary outcome was anti-S RBD antibodies 2 to 10 weeks after a second dose of the BNT162b2 or ChAdOx1 nCoV-19 vaccines. Secondary outcomes were anti-spike T cell responses, durability of vaccine responses and risk of breakthrough infections following two doses of vaccine.

Anti-S RBD antibody concentrations were lower in patients treated with infliximab than in those treated with vedolizumab, following a second dose of BNT162b2 (567.3 U/mL [6.1] vs 4601.1 U/mL [5.3], p <0.0001) and ChAdOx1 nCoV-19 (183.9 U/mL [5.0] vs 789.4 U/mL [3.5], p <0.0001) vaccines (Fig. 1).  

Vaccination with the BNT162b2 vaccine compared to the ChAdOx1 nCoV-19 was independently associated with a 3.7-fold [95% CI 3.30 – 4.13] higher anti-S RBD antibody concentration (p < 0.0001) (Fig. 2). 

There were no significant differences in the magnitude of anti-spike T cell responses observed in infliximab- compared with vedolizumab-treated patients after one or two doses of either vaccine.  

Antibody half-life was shorter in infliximab- than vedolizumab-treated patients following two-doses of BNT162b2 (4.0 weeks [95% CI 3.8 – 4.1] vs 7.2 weeks [95% CI 6.8 – 7.6]) and ChAdOx1 nCoV-19 (5.3 weeks [95% CI 5.1 – 5.5] vs 9.3 weeks [95% CI 8.5 – 10.2], p value < 0.0001).  

Breakthrough SARS-CoV-2 infections were more frequent (5.8% (202/3467) vs 3.9% (66/1691), p = 0.0032) and the time to breakthrough shorter in patients treated with infliximab than vedolizumab (p = 0.0023) (Fig. 3).  

Higher anti-S RBD antibody concentrations following a second dose of SARS-CoV-2 vaccine protected against breakthrough SARS-CoV-2 infection: overall, for every 10-fold rise in anti-S RBD antibody level we observed a 0.8-fold reduction in odds of breakthrough infection ([95% CI 0.70 – 0.99], p = 0.035).  

Infliximab was associated with attenuated, less durable vaccine induced anti-S RBD antibody responses and a 50% increase in breakthrough SARS-CoV-2 infection. Further follow-up is required to assess whether third primary doses can mitigate the effects of infliximab on anti-S RBD antibody responses.

Many papers in the past underpinned the possible role of appendicectomy. Appendectomy as a therapy for Ulcerative Colitis might work in mild ulcerative colitis. In the ACCURE, patients are randomized to medical therapy only or with appendectomy after induction of remission. Incidence of exacerbations is taken as primary endpoint. The first results will be available in one year time.

In the PASSION, patients with moderate to severe ulcerative colitis refractory to anti-TNF that were referred for colectomy were offered appendectomy. At 8 years follow up 1 out of three were colectomies, 1 out of three were having minor medication being biological free, and 1 out of five was on Tofacitinib. Endoscopic response was observed in at least in 1 out of 4. The Costa study is a patient preference model were patients are randomized or can choose either appendectomy of Tofacitinib when completely refractory to anti-TNF and Vedoluzimab. At this point 75% of the required patients are included.

There is accumulating evidence that appendectomy mitigates the disease course of ulcerative colitis

Sponsored by ECCO

A discussion between a guidelines methodologist and a clinician regarding (potential) limitations of GRADE methodology and whether OCEBM still has a place in clinical guidelines.

Educational objectives:
1) A recap of strengths and challenges of using GRADE methodology
2) Discussion of the role of Oxford levels of evidence in clinical guidelines
3) Critical thought regarding how evidence based guidelines are developed

This is a tandem talk between Joana Torres and Stefanos Bonovas on clinical practice guidelines' potential benefits and harms.

Educational objectives

Understand how to assess safety of a drug in real life practice

Understand the differences between small molecules and biologics

Understand how IBD drugs can be classified according to their safety profile

Understand how to improve IBD drug safety

Summary

Biologics differ from small molecules by many aspects, among which the chemistry, their degradation and their mechanism of action. These aspects may directly influence safety. Safety of a drug is itself difficult to quantify and qualify. The safety profile depends on the available data, strongly depending also on the time of apparition of the drug on the market and its widespread use. Most of the comparative data on safety generated through network meta-analyses or head to head trials correspond to relatively short duration of use of the drug and relatively small population compared to what would be needed to really assess safety. Therefore no or only minor differences are disclosed by these studies. If we adopt a pragmatic classification of side effects, we could classify them into mild-moderate intolerance, cumulative toxicity, major side effects that can be prevented or treated, major side effects that can hardly be prevented or treated, serious adverse events potentially lethal. When analysing the safety profiles of currently available drugs according to such classification, we find both small molecules and biologics with all these kinds of side effects. Therefore, if we can currently consider that some drugs are associated with lower or higher safety concerns, there is no difference between biologics and small molecules, the mechanism of action being sometimes closer between one small molecule and one biologic than between two biologics. Instead of safer drug or beside safer drug, we should maybe mainly aim at a safer use of these drugs.