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 . In 2019, the third UK IBD Standards for adults and children were published following extensive patient and healthcare professional consultation . 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.
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 . However, anti-TNF failure is common . 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.
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 . 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 .
In current clinical practice, endoscopy remains the gold standard for assessing mucosal healing . 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 .
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 . 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 .
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 . 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.
Intestinal ultrasound (IUS) is an inexpensive, non-invasive, safe and repeatable, dynamic cross-sectional imaging technique for IBD. It has been demonstrated to be accurate and reliable both for initial diagnosis of IBD and for follow-up monitoring . Huge advantages of IUS are that it does not need any prior preparation of the patient and provides a real-time result. IUS can be performed in various hospital settings, which makes it the only point-of-care (POC) imaging technique available today .
The impact of POC IUS on daily decision making and the evolution in its use over the years were evaluated in this retrospective study, which included two consecutive cohorts of IBD patients in a real-world outpatient setting. The first cohort of patients, included between January 2016 and July 2018, was compared with a second cohort collected between October 2019 and December 2019.
Guselkumab plus golimumab combination therapy versus guselkumab or golimumab monotherapy in patients with ulcerative colitis (VEGA): A randomised, double-blind, controlled, phase 2, proof-of-concept trial
Despite a growing armamentarium of advanced therapies for Ulcerative Colitis (UC), fewer than 40% of patients maintain clinical remission at 12 months . Combination therapy utilising dual biologic or small molecule agents can be considered in highly selected, medically refractory cases; however, robust data to support dual therapy in routine clinical practice are still lacking . Inhibitors of TNF-α and IL-23 have demonstrated efficacy in the treatment of UC [3,4]. Data emerging from animal studies have suggested that their use in combination reduces colitis synergistically and may be more efficacious than treatment with either monotherapy .
This randomised double-blinded controlled phase 2 trial, named the VEGA trial, was conducted across 54 sites internationally and aimed to determine the efficacy and safety of combination therapy with guselkumab (GUS), an IL-23 p19 antagonist, plus golimumab (GOL), a TNF-α inhibitor, compared with either monotherapy in UC.
In recent years, there has been significant optimism in the field with the arrival of newer licensed therapies for patients living with IBD . Alongside the welcome arrival of new therapeutics, there has also been an appreciation that many (but not all) patients may have preferences for oral medications . In particular, targeting Janus kinases (JAKs) with oral small molecule treatments has proved to be a promising strategy. Indeed, tofacitinib, a pan-JAK inhibitor, was shown to have efficacy in patients with Ulcerative Colitis (UC), even in some instances where there had been loss of response or non-response to all prior licensed biologic options . With growing understanding of the pathways involved in UC, preferential inhibition of JAK1 has been investigated in the field of IBD, including with the JAK1 inhibitor, filgotinib. This is a medication already licensed for some rheumatological conditions and it was recently assessed in the context of UC in the phase 2b/3 SELECTION trial – with the results having previously been published, and demonstrating superiority of filgotinib over placebo in UC . In this current study, Dotan et al. assess efficacy of filgotinib based on prior treatment exposure and number of lines of therapy for instances of previous exposure to biologic therapy, based on a post-hoc analysis of data from the SELECTION trial. This study contributes to our understanding of how to sequence and position a new advanced therapy, in the context of a growing armamentarium of treatment options for patients living with UC.
The concept of treat to target (T2T) in Crohn’s Disease (CD) involves optimising therapy until a predetermined clinically relevant endpoint is met. In recent years, this endpoint has most commonly been a short-term biomarker response or endoscopic healing, but this has typically been juxtaposed with long-term patient reported outcomes (PROs) such as health-related quality of life (HRQoL) . The international STRIDE-2 guidelines emphasise the need for monitoring at frequent intervals to ensure that treatment targets agreed at the commencement of any therapy are actually being achieved. One of the big unknowns of such strategies, requiring frequent monitoring, has been their cost-efficiency. However, concerns about cost have been balanced by arguments that adequate monitoring may allow earlier and more appropriate initiation of advanced therapies, which may then result in better longer-term outcomes .
STARDUST (NCT03107793) was a phase 3b, open-label, randomised controlled trial that compared ustekinumab (UST) T2T with standard-of-care (SoC) treatment strategies in adult patients with moderate to severe CD. The primary results from this trial have previously been reported, and it is notable that endoscopic and biomarker endpoints were not statistically different between the two treatment strategies . However, it is also worth noting that while more patients in the T2T arm received q4w (4-weekly) dosing of UST (18.4% vs 0%), more patients in SoC received q8w (8-weekly) dosing (61.5% vs 38.8%). The original STARDUST trial included 440 patients, of whom 336 completed the first year of treatment and 323 (T2T, n=147; SoC, n=176) were subsequently enrolled to the long-term extension (LTE) period until week 104 (2-year mark). In this study, Panes et al. report on the HRQoL outcomes from patients in the LTE study from the STARDUST trial.
Proctocolectomy is a curative treatment for medically refractory Ulcerative Colitis (UC). However, a significant number of patients prefer to have continuity of their bowel and undergo a restorative ileal pouch–anal anastomosis (IPAA), after having had an initial subtotal colectomy. Unfortunately, pouchitis is a most common complication in patients with an IPAA: 81% of patients experience pouchitis in their lifetime, with 40% experiencing it in their first year of pouch formation . Multiple factors associated with pouchitis include mutations in NOD2/CARD15, genetic polymorphisms of interleukin-1 receptor antagonists [2–4], tumour necrosis factor allele 2 and toll-like receptor 1 .
The cause of pouchitis is multifactorial, including abnormal immune reaction to newly formed IPAA, change in the vascularity and anatomy of the bowel, faecal stasis and many other postulated factors. Single-cell analysis of CD45+ haematopoietic cells in the colon and pouch of UC patients has also highlighted genetic pathways that might contribute to the inflammation and disease severity seen in this condition . However, the aetiology of pouchitis remains poorly understood and this may explain why treatment of this condition has emerged as an important area of unmet research need in the field of IBD. The treatment currently ranges from probiotics, antibiotics, steroids and immunomodulators through to use of biologics. Unfortunately, 50% of patients develop recurrent pouchitis, and up to 20% develop chronic pouchitis. Typically, cases of medically refractory pouchitis have been treated with anti-tumour necrosis factor (anti-TNF), vedolizumab and ustekinumab, but the evidence base for this approach has been very limited, typically comprising only case series and retrospective studies. Until recently, there had been no double-blind, randomised placebo-controlled trial supporting use of any therapeutic in pouchitis. Therefore, there has been significant interest in the study by Travis et al., reporting the first placebo-controlled trial for treatment of pouchitis, with use of vedolizumab. The findings from this trial help to provide evidence supporting the use of gut-selective vedolizumab for patients living with an IPAA.
Despite an increasing number of therapeutic options for patients with Crohn's Disease (CD), one-third of individuals develop intolerance or lose response to current pharmacological treatments, and up to half of patients require surgery within ten years of diagnosis. One of the reasons often highlighted for such figures has been the increasing understanding that different sub-types of CD may require different treatment approaches. Indeed, multiple clinical and molecular studies in recent years have demonstrated the differences between ileal and colonic CD in terms of pathophysiological mechanisms , as well as clinical features such as disease progression and treatment efficacy. In fact, although there is a lack of reported data on the comparative efficacy of biologics in achieving segment-specific healing in CD , evidence from observational studies and post-hoc analyses of interventional trials has shown that deep ulcers in the ileum are more challenging to heal than those located in the colon , with rates of endoscopic healing after one year of therapy ranging from 19% to 38% .