Withdrawal of infliximab or concomitant immunosuppressant therapy in patients with Crohn’s disease on combination therapy (SPARE): a multicentre, open-label, randomised controlled trial
Louis E, Resche-Rigon M, Laharie D, et al; GETAID and the SPARE-Biocycle research group
Therapeutic strategies for Crohn’s Disease have evolved over the past decade, with mounting evidence that achieving deep remission (defined as clinical, biochemical and endoscopic remission) is associated with better long-term outcomes [1, 2]. Combination therapy with infliximab and azathioprine has been shown to be superior to either infliximab or azathioprine monotherapy in achieving clinical remission and endoscopic healing in azathioprine-naive patients, thus supporting the paradigm of early disease management and the use of treatment combinations to increase treatment success [3]. Concerns regarding the implications of long-term combination therapy, such as infections and lymphoproliferative disorders, have provided the rationale for a formal clinical trial of treatment de-escalation.
The aim of this trial was to compare the relapse rate and the time spent in remission over 2 years between patients continuing combination therapy and those stopping infliximab or immunosuppressant therapy.
Crohn’s Disease (CD) is a chronic condition resulting in continuous or episodic inflammation that manifests endoscopically with mucosal ulcerations, strictures, bleeding and/or fistulae. Clinical response and clinical remission have been identified as immediate and medium-term treatment targets, respectively. Endoscopic remission (ER) has been recognised as a long-term treatment target, one specifically associated with improved disease outcomes and reduced bowel damage and colectomy rates [1]. Recommendations from the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative of the International Organization for the Study of IBD (IOIBD) were recently updated. In this update, it was suggested that changes in therapy should be considered in patients who do not achieve ER [2].
In current clinical practice, endoscopy remains the gold standard for assessing mucosal healing [3]. Serial endoscopic examinations are therefore typically performed in cases of IBD, beginning at diagnosis and thereafter following changes in treatment, to document disease activity and extent and assess therapeutic response.
To measure and quantify mucosal inflammation objectively, different endoscopic indices have been implemented in clinical practice and clinical trials. Among these, the Simple Endoscopic Score for Crohn’s Disease (SES-CD) and the Crohn’s Disease Endoscopic Index of Severity (CDEIS) have been the most used metrics in clinical trials [1].
Compared to the CDEIS and other indices, the SES-CD offers the advantages of both simplicity and ease of use. Furthermore, the SES-CD has proven responsive to changes in disease activity, with good intra- and inter-observer agreement [4]. The SES-CD contains four parameters, each of which receives a uniform score between 0 and 3 in all disease locations. The SES-CD therefore assumes no differential weighting of each individual parameter according to its importance in predicting ER while on active therapy. In essence, the SES-CD score lacks prognostic potential.
In a prior study, it was observed that each of the SES-CD parameters has its own prognostic value in predicting treatment response and ER; further, this value is non-linear among disease locations [5].
Implications for sequencing of biologic therapy and choice of second anti-TNF in patients with inflammatory bowel disease: results from the Immunogenicity to Second Anti-TNF therapy (IMSAT) therapeutic drug monitoring study
Anti-TNF monoclonal antibodies play an important role in the management of immune-mediated inflammatory diseases, including Inflammatory Bowel Disease [1]. However, anti-TNF failure is common [2]. Loss of response is usually associated with the development of anti-drug antibodies and low anti-TNF drug levels.
The aim of this study was to evaluate the relationship between immunogenicity to a patient’s first anti-TNF therapy and immunogenicity and drug persistence to the second anti-TNF therapy, irrespective of drug sequence.
In the United Kingdom (UK), approximately 500,000 people live with IBD, and in the coming decade it is anticipated that the prevalence of IBD will surpass 1% of the population [1]. In 2019, the third UK IBD Standards for adults and children were published following extensive patient and healthcare professional consultation [2]. The IBD Standards cover seven domains: service design and delivery; pre-diagnosis referral pathways; management of the newly diagnosed patient; flare management, including self-management and timely access to specialist advice; surgery including pre- and postoperative care; inpatient medical care; and ongoing long-term treatment and monitoring in both secondary and primary care.
Inflammatory Bowel Disease (IBD) is a long-term condition of the gut which is known to impact the quality of life and social functioning of those affected due to the chronic nature of symptoms. These factors, along with communication across the gut–brain axis, cause many patients to suffer from mental health disorders such as anxiety and depression [1]. Previously, the magnitude of these comorbidities had not been established, but recent studies [1, 2] have found the prevalence to be high: a third of all patients and a half of those with an active IBD flare have been found to suffer from anxiety, while depression has been found to affect a quarter of patients and a third of those with active symptoms.
Furthermore, compared with controls, patients with IBD and mental health disorders show increased use of healthcare resources (both primary care visits and emergency secondary care visits) and increased use of antidepressant and anxiolytic medications [2]. While antidepressant medications are commonly used to treat anxiety and depression in IBD [3], understanding of how effectively these treatments are prescribed remains limited, and this is particularly true regarding the adequacy of duration of treatment in this cohort.
This population-based study was performed in the United Kingdom and used data from the primary care setting that was routinely collected electronically in general practices as part of the Clinical Practice Research Datalink (CPRD). The authors looked to review the antidepressant prescribing in primary care for those diagnosed with IBD. They focused on the rate of antidepressant treatment initiation following IBD diagnosis, the duration of antidepressant treatment according to international guidelines, potential risks of inadequate antidepressant treatment duration and general trends in antidepressant prescribing.
Many clinicians have anecdotally observed patients opting out of colonoscopies due to unpleasantness related to the procedure, and within Inflammatory Bowel Disease (IBD) populations a number of factors have been implicated in non-adherence, including logistics, health perceptions, stress and procedure problems (including discomfort) [1].
Prior studies have demonstrated patient preferences for propofol sedation over midazolam and fentanyl sedation for outpatient colonoscopy in general [2]. Furthermore, propofol has been shown to be safe, without severe adverse events or accidents [3], and nurse-administered propofol has specifically proven to be an efficient means of sedation for endoscopy in low-risk patients [4]. Nevertheless, this area has yet to be explored in the specific cohort of IBD patients.
Modern management of IBD requires the employment of ileocolonoscopy for diagnosis, as well as for the surveillance and guidance of future management. The investigators here looked to fill the aforementioned knowledge gap through design of a trial investigating the effectiveness of deep nurse-administered propofol sedation (NAPS), versus moderate midazolam and fentanyl sedation, as a means of improving patient satisfaction and future attitude towards colonoscopies.
Traditionally, treatment of Crohn’s Disease (CD) has focused on symptomatic, clinical and corticosteroid-free remission. However, more recent studies have shown that endoscopic remission is associated with more favourable patient long-term outcomes [1, 2]. It has been hypothesised that more intense treatment regimens may increase the likelihood of endoscopic remission in CD patients. Previous studies (such as that performed by the DIAMOND study group) have indicated that adalimumab trough levels are higher in CD patients who achieve an endoscopic response and mucosal healing at weeks 26 and 52 [3]. Further to that, the personalised anti-TNF therapy in Crohn's Disease study (PANTS) demonstrated that low drug levels were predictive of anti-tumour necrosis factor (anti-TNF) treatment failure [4].
Various methods of dose optimisation have been postulated, such as higher induction doses, therapeutic drug monitoring (TDM) to guide dose optimisation during the maintenance phase or a clinically adjusted (CA) dose optimisation strategy.
Vedolizumab (VDZ) was the first biologic to be approved for Ulcerative Colitis (UC) and Crohn’s Disease (CD) after the age of anti-tumour necrosis factor antagonists (anti-TNF). The role of thiopurines in combination with anti-TNFs in the management of IBD is well recognised. However, the role for combination of VDZ with thiopurines is uncertain [1, 2]. This study aimed to investigate the comparative effectiveness of VDZ in combination with a thiopurine versus VDZ monotherapy in the management of both UC and CD.
The influence of proton pump inhibitor therapy on the outcome of infliximab therapy in inflammatory bowel disease: a patient-level meta-analysis of randomized controlled studies
The management of Inflammatory Bowel Disease (IBD) has evolved significantly over the last two decades [1, 2], as the development of biologic therapy has increased dramatically the rates of induction and prolonged maintenance of remission in patients with IBD. Infliximab (an anti-tumour necrosis factor) was the first biologic therapy to be approved for the treatment of IBD [3] and remains the biologic therapy with which clinicians have the most clinical experience [4].
Due to comorbidities, patients are frequently on other medications in addition to infliximab. How these other concomitant medications influence the response to infliximab therapy is largely unexplored.
Proton pump inhibitors (PPIs) are the first-line treatment for many digestive disorders such as gastro-oesophageal reflux disease (GORD), peptic ulcers, eosinophilic oesophagitis and dyspepsia [5]. PPIs are one of the most used family of medications in the United States, with more than 50 million prescriptions filled every year [6].
A few retrospective trials have attempted to investigate the impact of concomitant PPI therapy on response to infliximab in patients with IBD; however, these studies have suffered from the presence of many confounders, such as the lack of data on smoking status or the increased risk for gastroenteritis and C. difficile infection amongst patients treated with PPIs.
To increase the power to detect differential effects of PPI treatment on patients treated with infliximab in randomised trials and to allow adjustment for confounding factors, the investigators performed a patient-level meta-analysis of IBD randomised controlled clinical trials from the Yale Open Data Access (YODA) Framework.
Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) is often the preferred surgical intervention for patients with medically refractory Ulcerative Colitis [1]. A significant proportion of patients with IPAA develop pouch-related symptoms characterised by increased pouch emptying, urgency, bloody exudates and cramps. Such symptoms can occur secondary to inflammatory disorders, including idiopathic pouchitis, which affects up to 50% of patients, or other conditions such as pre-pouch ileitis [2]. Symptoms can also be due to non-inflammatory disorders, with irritable-pouch dysfunction accounting for more than a third of symptomatic patients.
The most commonly accepted disease activity index is the Pouchitis Disease Activity Index (PDAI), which combines symptoms, endoscopy findings and histology. A total PDAI 7 is considered diagnostic for pouchitis but is not specific [3].
The gold standard investigation is pouchoscopy, which allows endoscopic and histological assessment of the pouch, pre-pouch ileum and cuff [4]. However, it is an invasive and often uncomfortable procedure for patients. In some cases the alternative strategy of empirical antibiotic therapy for every symptomatic episode is adopted, but this comes with the risks associated with unnecessary antibiotic use.
In this cross-sectional study, Ardalan et al. sought to assess the role of non-invasive gastrointestinal ultrasound (GIUS) and faecal calprotectin (FCP) testing in the investigation of pouchitis.
