Data from Stephen Smith - Curated by EPG Health - Last updated 25 October 2018
Management strategies in IBD
The introduction of biologic therapies in the last 20 years has revolutionised the management of IBD. However, questions remain over the best approach to its management, such as when to introduce, switch and de-escalate biologics. Several posters and presentations addressed these topics at UEG Week 2018; here is a selection of some of the highlights.
Establishing current clinical practice
Inducing and maintaining steroid-free disease remission is the standard treatment goal for patients with ulcerative colitis, but how are physicians currently managing their patients to achieve this? A presentation by Dr Alessandro Armuzzi from the Complesso Integrato Columbus, Catholic University of Rome, Italy, provided insights into the treatments used for the management of moderate-to-severe ulcerative colitis from doctors in the EU5 (France, Germany, Italy, Spain, United Kingdom).
Among the 1,060 recorded patients with a complete treatment history, 47.1% received aminosalicylate (5-ASA) and/or steroids as their first-line therapy. The remaining 52.9% received either an immunomodulator or biologic, which unsurprisingly, increased as patients progressed into the second- and third-lines of therapy (Figure 1).
Figure 1: First-, second- and third-line immunomodulator/biologic treatment choices for patients with moderate-to-severe ulcerative colitis. ADA, adalimumab; GOL, golimumab; IFX, infliximab; IM, immunomodulator; VDZ, vedolizumab.
As patients’ disease progressed, and they received further lines of treatment, the percentage who were receiving biologics with concomitant immunomodulators increased. However, among patients receiving biologic therapy, a substantial number received dose escalations/increased dosing frequency above that indicated for the treatments as part of their maintenance therapy. This was observed in 39.1%, 36.1%, 30.9% and 20.8% of patients receiving infliximab, adalimumab, vedolizumab and golimumab, respectively suggesting these patients experienced suboptimal disease control at standard doses.
A similar question was addressed by Dr Philip Jenkinson and colleagues from NHS Lothian in Edinburgh, Scotland who used a retrospective review of health records in Edinburgh to identify 841 patients who had received a biologic for the management of their IBD. Among 665 patients with Crohn’s disease, 73.1% received infliximab, 25.4% received adalimumab and 1.6% received vedolizumab as first-line therapy. Of these patients, 238 required second-line therapy with 79.4%, 10.9%, 7.6% and 2.5% receiving adalimumab, infliximab, vedolizumab and ustekinumab, respectively. The choice of therapy continued to change as 74.5% of patients requiring third-line therapy were prescribed vedolizumab with the remainder receiving ustekinumab. As additional and novel treatments continue to become available for the management of IBD, the sequencing of those treatments is becoming of increasing importance. As Dr Jenkinson said, mapping treatment sequencing to patient outcomes must be a priority for IBD research.
Should we switch to another anti-TNF?
With one-third of IBD patients not responding to anti-TNF therapies and a significant number of initial responders subsequently losing response or developing intolerance, should patients be treated with an alternative anti-TNF? While fairly common practice, as can be seen in Dr Jenkinson’s data, the evidence supporting its efficacy and safety remains scarce. Dr María Casanova from the Hospital Universitario de La Princesa in Madrid, Spain, presented her results from the ENEIDA registry looking at patients with IBD who switched to a second or third anti-TNF therapy after failure or intolerance to a previous anti-TNF drug.
Of the 1,022 patients (50% male; 73% Crohn’s disease) who were switched to a second anti-TNF therapy, 21% needed to switch as they failed to respond to the first anti-TNF while 51% had a loss of response and 28% developed an intolerance. In response to a second anti-TNF therapy, 45% of patients achieved remission although a loss of response was observed at a rate of 19% per patient-year of follow-up. Factors shown to be predictive of not achieving remission with a second anti-TNF treatment were combination therapy with an immunosuppressant (OR = 1.9; 95% CI, 1.5–2.5; p<0.0001), previous non-response (vs. intolerance; OR = 1.6; 95% CI, 1.1–2.3; p=0.007) and previous loss of response (vs. intolerance; OR = 1.5; 95% CI, 1.2–2.0; p=0.003). Meanwhile, factors associated with a higher risk of loss of response to the second anti-TNF were ulcerative colitis (vs. Crohn’s disease; HR = 1.6; 95% CI, 1.1–2.1; p=0.005) and combination therapy with an immunosuppressant (HR = 2.4; 95% CI, 1.8–3.0; p<0.0001).
The success of a second anti-TNF therapy appears to be associated with the reason for withdrawing from the first anti-TNF drug. While a significant number achieved remission, approximately 50% of them subsequently experienced a loss of response. However, treatment with a third anti-TNF option was able to induce remission in 55% of patients, although again a loss of response was observed in a significant number of patients (22% per patient-year of follow-up). While efficacy was observed for several patients with the use of additional anti-TNFs, it is also important to note a good tolerability profile with adverse events observed in only 15% and 7% of patients after introduction of the second and third anti-TNF treatments, respectively.
Are there benefits to early intervention with biologics?
Biologics have changed the face of IBD management, but when should they be prescribed to patients? While some physicians advocate for the early use of biologics, this is clearly not always the case in clinical practice. In Dr Jenkinson’s cohort of patients, the median duration from IBD diagnosis to biologic introduction was 4.9 years although the interquartile range spread from 1.3 to 11 years, highlighting significant heterogeneity. To assess the benefits of early intervention with anti-TNF treatments in Crohn’s disease, Dr Seitz from the Helios Klinikum in Munich, Germany, performed a retrospective analysis of 242 patients. The cohort of patients was divided into early intervention (defined as an anti-TNF therapy introduced <24 months from diagnosis) and late intervention (≥24 months from diagnosis) with the patients in the early intervention group typically being younger, having more upper GI manifestations and having received less corticosteroids, azathioprine, 5-ASA, and methotrexate. Other factors such as extraintestinal manifestations, bowel strictures and disease activity were comparable at the time of anti-TNF introduction. Outcomes of the two-year observation period are shown in Figure 2.
Figure 2: Patient outcomes following early- or late-intervention with an anti-TNF over a two-year observation period. n.s., not significant.
Early intervention with anti-TNF treatment in patients with Crohn’s disease resulted in improved rates of mucosal healing and lower rates of strictures compared to late intervention. While the reduced need for surgery did not reach statistical significance, this could have been a consequence of the small sample size. Therefore, early intervention with anti-TNF therapies in patients with Crohn’s disease seems to alter the course of the disease, reducing bowel damage and potentially the need for surgery.
The role of biologic treatments in both reducing the need for surgery, but also preventing complications associated with surgery is a topic of interest. Of the patients with Crohn’s disease that undergo surgery, 80% experience endoscopic postoperative recurrence (POR) within one year. Adrienn Erős presented her findings from an analysis of published studies assessing whether anti-TNF therapies were more effective at preventing POR than conventional therapies (mesalamine, thiopurines, placebo). In 10 studies, 709 patients with Crohn’s disease were assessed and it was observed that anti-TNF treatments were significantly more effective at preventing clinical and endoscopic POR than conventional therapies (OR = 0.501; 95% CI, 0.319–0.786; p=0.003 and OR = 0.157; 95% CI, 0.069–0.359; p<0.001, respectively). While no differences were observed between the outcomes with infliximab or adalimumab, it was determined that patients receiving biologics before surgery should continue to receive them post-surgery to help maintain remission.
Similar results were seen in a study assessing the rate of postoperative complications in patients receiving anti-TNF therapy preoperatively. Dr Braun from the IBD Center Munich, Germany, shared results showing that the use of anti-TNF treatments before surgery did not increase the risk of postoperative complications, repeat operations or longer hospital stays compared to those who did not receive anti-TNF treatment. Furthermore, the data suggested that anti-TNF therapy may have a protective effect with fewer late complications observed in the anti-TNF treated patients compared to those who did not receive an anti-TNF drug.
Managing relapse following anti-TNF de-escalation?
De-escalation of anti-TNF therapy comes with an increased risk of relapse. How many patients relapse though, and is it possible to predict who is more likely to relapse? A poster presentation from Dr Camille Lucidarme of the CHU Pontchaillou, Rennes, France assessed the outcomes of 96 patients who underwent infliximab de-escalation (dose reduction or infusion interval increase) following achievement of clinical and biological remission.
The cumulative probabilities of relapse following infliximab de-escalation was 16% at year one, but this increased to 47% by year two. Factors associated with an increased risk of relapse were smoking (HR = 2.2, 95% CI, 1.07–4.58; p=0.03), diagnosis of ulcerative colitis (HR = 2.9; 95% CI, 1.45–5.98; p=0.0028), and an absence of combination therapy at infliximab initiation (HR = 2.65; 95% CI, 1.34–5.1). So, is it possible to prevent relapse in patients undergoing de-escalation? Dr Lucidarme’s data suggest that therapeutic drug monitoring offer useful insights. A reduced risk of relapse was seen (HR = 0.48; 95% CI, 0.24–0.96; p=0.03) when infliximab trough levels were >3 mg/L following de-escalation suggesting it may be possible to predict those patients at risk of relapse and modify their treatment accordingly.
With increasing clarity over the optimisation of treatment strategies for different populations of patients with IBD, questions still remain over the sequencing of therapeutic options. Join us again tomorrow when we will share some of the latest real-world data for currently available treatments.