The therapeutic landscape for inflammatory bowel disease (IBD) has expanded greatly in recent years. As a result, increasingly ambitious therapeutic goals are becoming realistic [1]. But is it worth steadily tightening them up and what are the potential risks involved? Prof. Raja Atreya explored these questions at the IBDnet Postgraduate Course.
The IBDnet Postgraduate Course took place for the 8th time from December 1 to 3, 2022 – this time again on site at the Wolfsberg Congress Center in Ermatingen. Participants were able to benefit from an interactive program around the latest developments and trends in the field of CED. With a focus on daily clinical practice, local CED experts as well as internationally renowned speakers shared their experiences and knowledge. This was also the case for Prof. Raja Atreya from the University Hospital Erlangen, who took a closer look at the risk-benefit ratio of targeted therapies in Crohn’s disease (MC) and ulcerative colitis (CU) in his presentation at the AbbVie Symposium.
Prevent complications with effective therapies
MC is considered a progressive disease and is associated with increasing complications, such as structural bowel damage – strictures, fistulas, and abscesses – as well as surgery. The cause of this can be found in uncontrolled inflammatory processes. Even in clinical remission, when affected individuals are virtually symptom-free, subclinical inflammatory activity often persists and the disease progresses [2].
Prof. Atreya emphasized: “The safety and efficacy of a therapy are more closely linked than initially assumed. The better we treat our patients, the more promising we can modify disease activity and thus prevent complications.”
And not only MC, CU can also present progressively and bring complications [3]. Thus, the severity and duration of inflammation are among the main risk factors for colitis-associated colorectal cancer [4] – another reason for treatment, according to Prof. Atreya. In fact, according to a survey (N = 460), the greatest fear of CU sufferers is developing colorectal cancer (37%) [5].
High disease activity – the greatest safety risk in IBD
In Prof. Atreya’s experience, patients often have safety concerns when targeted treatment is considered. However, the gastroenterologist impressively demonstrated with a series of study results that the greatest safety risk for those affected is uncontrolled disease activity in addition to steroid therapy:
- In a retrospective, population-based cohort study, MC was associated with increased mortality. The main causes of death were infections, parasitic diseases, and sepsis, which were also among the most common causes of death in CU patients [6].
- In the 5-year analysis of the TREAT registry study, MC patients who received infliximab (HR = 0.83) or immunomodulators (HR = 0.86) did not have increased mortality, but those who received steroids (HR = 2.14) did. In addition, moderate to very high disease activity was associated with both increased mortality (HR = 1.61) and incidence of serious infections (HR = 2.24) [7].
- The results of several meta-analyses and population-based cohort studies indicate that IBD is associated with an increased risk of venous thromboembolism (VTE), ischemic heart disease in the first year after diagnosis, and all acute arterial events, each of which may be associated with increased disease or inflammatory activity [8-10].
- In a large-scale Danish population-based cohort study of 20,795 people with IBD and 199,978 controls, the risk of myocardial infarction, stroke, and cardiovascular death was significantly increased during IBD relapses and periods of sustained disease activity compared with periods of remission [11].
Risk of infection under biological therapies [12, 13].
The risk of serious infections may decrease in the long term during treatment with TNF inhibitors, as shown by the recently published results of a Swedish retrospective cohort study of 980 IBD patients. For example, the incidence rate of serious infections was 2.19 per 100 patient-years in the year before starting treatment with a first TNF inhibitor and was still almost unchanged at 2.11 in the year after. More than a year after starting therapy, however, the incidence of serious infections had dropped significantly to an incidence rate of 0.56 [12] – likely due to decreasing disease activity as a result of therapy, according to the expert’s assessment. An association between biologic treatment and reduced risk of infection was also observed for vedolizumab: In an integrated safety analysis of more than 3,000 IBD patients, infections overall, upper respiratory tract infections, and lower respiratory tract and lung infections per 100 patient-years were significantly less frequent with the α4β7-integrin inhibitor than with placebo [13].
CED management: Maximum benefits with minimum risk
In therapeutic decision making, it is critical to find an optimal benefit-risk ratio. Prof. Atreya: “When starting a new treatment, I explain to my patients that the potential risks of therapy are offset by the manifest risks of uncontrolled disease activity (Figure 1).”
Figure 1: Potential benefits and risks that should be considered in therapeutic decision making. HEMI: Histo-Endoscopic Mucosal Improvement. Adapted from [14, 15].
More stringent treatment goals enable better outcomes [16, 17].
With the development of targeted therapies, the treatment goals in IBD have also evolved. Thus, according to the current STRIDE II recommendations, long-term endoscopic remission should be targeted [1]. According to Prof. Atreya, whether it is worthwhile to keep tightening the criteria for assessing treatment response depends on whether it can be shown in prospective studies that it can modify disease activity.
In a follow-up of the CALM study of 122 MC patients, those who experienced endoscopic or deep remission (defined as Crohn’s Disease Activity Index [CDAI] < 150, Crohn’s Disease Endoscopic Index of Severity [CDEIS] < 4 without deep ulceration and no steroids for ≥ 8 weeks) were significantly less likely to have disease progression over a median period of three years than those who had not achieved these treatment goals after one year. Among these, deep remission was associated with an even greater risk reduction for progression than endoscopic remission (HR 0.23 [95% CI: 0.09-0.32] vs. 0.46 [95% CI: 0.31-0.60]) [16]. Moreover, mucosal healing in MC was associated with long-term clinical remission in a meta-analysis [18].
And even in CU, stricter treatment goals can improve outcome in the long term: According to another meta-analysis, the 12-month risk of clinical recurrence was 52% lower in sufferers with endoscopic remission than in those with only clinical remission. If histological remission was also present, this risk decreased by an additional 63% [17].
Conclusion
So how can we guarantee patient safety?
“Ultimately, we need to make treatment decisions based on the individual’s risk profiles. There is no such thing as the MC patient or the CU patient,” Prof. Atreya emphasized at the end of his talk, summing up, “Effective therapies are safe therapies because they modify disease activity, reduce inflammation, and thus not only improve patients’ quality of life but also reduce the risk of disease-associated complications .”
Source: AbbVie Lunch Symposium: “Benefit risk assessment in IBD: Are my therapy goals worth it?” at the 8th IBDnet Postgraduate Course on December 2, 2022 in Wolfsberg/Ermatingen.
Literature
1 Turner D et al. STRIDE-II: An Update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative of the International Organization for the Study of IBD (IOIBD): Determining Therapeutic Goals for Treat-to-Target strategies in IBD. Gastroenterology, 2021. 160(5): p. 1570-1583.
2 Pariente B et al. Development of the Crohn’s disease digestive damage score, the Lémann score. Inflamm Bowel Dis, 2011. 17(6): p. 1415-22.
3 Torres J et al. Ulcerative colitis as a progressive disease: the forgotten evidence. Inflamm Bowel Dis, 2012. 18(7): p. 1356-63.
4. de Campos Silva EF et al. Risk factors for ulcerative colitis-associated colorectal cancer: A retrospective cohort study. Medicine (Baltimore), 2020. 99(32): p. e21686.
5 Thompson KD et al. Patients with Ulcerative Colitis Are More Concerned About Complications of Their Disease than Side Effects of Medications. Inflamm Bowel Dis, 2016. 22(4): p. 940-7.
6 Hutfless SM et al. Mortality by medication use among patients with inflammatory bowel disease, 1996-2003. Gastroenterology, 2007. 133(6): p. 1779-86.
7. Lichtenstein GR et al. Serious infection and mortality in patients with Crohn’s disease: more than 5 years of follow-up in the TREAT™ registry. Am J Gastroenterol, 2012. 107(9): p. 1409-22.
8 Kirchgesner J et al. Increased risk of acute arterial events in young patients and severely active IBD: a nationwide French cohort study. Gut, 2018. 67(7): p. 1261-1268.
9 Rungoe C et al. Risk of ischaemic heart disease in patients with inflammatory bowel disease: a nationwide Danish cohort study. Gut, 2013. 62(5): p. 689-94.
10 Yuhara H et al. Meta-analysis: the risk of venous thromboembolism in patients with inflammatory bowel disease. Aliment Pharmacol Ther, 2013. 37(10): p. 953-62.
11 Kristensen SL et al. Disease activity in inflammatory bowel disease is associated with increased risk of myocardial infarction, stroke and cardiovascular death–a Danish nationwide cohort study. PLoS One, 2013. 8(2): p. e56944.
12 Holmgren J et al. The Risk of Serious Infections Before and After Anti-TNF Therapy in Inflammatory Bowel Disease: A Retrospective Cohort Study. Inflamm Bowel Dis, 2022.
13 Colombel JF et al. The safety of vedolizumab for ulcerative colitis and Crohn’s disease. Gut, 2017. 66(5): p. 839-851.
14 Raine T et al. ECCO Guidelines on Therapeutics in Ulcerative Colitis: Medical Treatment. J Crohns Colitis, 2022. 16(1): p. 2-17.
15 Rubin DT et al. ACG Clinical Guideline: Ulcerative Colitis in Adults. Am J Gastroenterol, 2019. 114(3): p. 384-413.
16 Ungaro RC et al. Deep Remission at 1 Year Prevents Progression of Early Crohn’s Disease. Gastroenterology, 2020. 159(1): p. 139-147.
17. Yoon H et al. Incremental Benefit of Achieving Endoscopic and Histologic Remission in Patients With Ulcerative Colitis: A Systematic Review and Meta-Analysis. Gastroenterology, 2020. 159(4): p. 1262-1275.e7.
18 Shah SC et al. Systematic review with meta-analysis: mucosal healing is associated with improved long-term outcomes in Crohn’s disease. Aliment Pharmacol Ther, 2016. 43(3): p. 317-33.
The references can be requested by professionals at medinfo.ch@abbvie.com.
With the financial support of AbbVie AG, Alte Steinhauserstrasse 14, 6330 Cham.
CH-HUMG-230002_01/2023
Contribution online since 06.02.2023