The UEG Week 2020 scientific programme took place under a new virtual congress platform on 10th–13th October 2020. The Opening Session marked the start of the meeting and began with current and past presidents alike delivering a powerful message about the efforts and desire to ensure the continuation of UEG Week while maintaining a comprehensive and immersive experience. Axel Dignass, UEG President, passed on his sincere thanks to all delegates who registered for UEG Week Virtual 2020, welcoming both the European and global community, and describing UEG Week as a truly worldwide event for the gastroenterology community.
“UEG is proud to deliver a virtual congress with the continued goal of improving the quality of care of gastrointestinal patients throughout Europe and the world.”
Axel Dignass, UEG President
An overview of UEGW 2020 sessions and attendees
Herbert Tilg, Chair of the Scientific Committee, welcomed the global gastrointestinal community to this year’s UEG Week, highlighting it as the most important forum for new research and insights within the field of gastrointestinal health with a world-class and renowned faculty gathered for the comprehensive three-day meeting.
“This year’s UEGW scientific programme enables today’s science to be tomorrow’s medicine.”
Herbert Tilg, Chair of the Scientific Committee
INFLAMMATORY BOWEL DISEASE (IBD)
Severine Vermeire, University Hospitals, Leuven, Belgium, provided an overview of novel treatment options and strategies for IBD. Dr Vermiere highlighted that the management of IBD has witnessed a true revolution over the two previous decades, although unmet treatment needs continue to remain even today, given that 60–80% of patients globally do not achieve remission. In addition, the ongoing symptoms of IBD truly impact upon patient quality of life. However, Dr Vermeire noted that there is a promising treatment pipeline for IBD over the next decade through advanced treatments such as signalling inhibitors. The key factor in driving treatment development and subsequent effectiveness is the understanding of underlying pathways that lead to IBD in individual patients, as only then will subgroups of patients be identified that are defined by specific disease pathways.
Key endpoints in patients with IBD
Laurent Peyrin-Biroulet, Nancy University Hospital, Vandoeuvre-lès-Nancy, France, provided a brief overview of combination therapies for IBD in 2020. Combination of ‘traditional’ therapies have a long history in IBD, and combining biologics with different mechanisms of action may help to improve efficacy, but both benefits and risks have been reported using this approach (e.g. patients with Crohn’s disease [CD] treated with anti-tumour necrosis factors [anti-TNFs] plus thiopurines were more likely to have a corticosteroid-free clinical remission than those receiving azathioprine monotherapy, but also had an increased risk of infection). Of note, combination therapy with azathioprine appears to improve efficacy by increasing pharmacokinetic features of infliximab. New oral molecules will provide the opportunity for these agents to be combined with other biologics, although the main obstacles to this therapeutic approach will be uncertainty about safety and associated cost. Of note, there are limited published data regarding the efficacy and safety of combination targeted therapy in IBD specifically, highlighting the need for further trials. The ongoing Phase IV EXPLORER study is currently investigating the efficacy and immunogenicity of triple combination therapy with vedolizumab, adalimumab and methotrexate followed by maintenance vedolizumab in biologic-naïve patients with CD (NCT02764762). An additional therapeutic approach to the treatment of IBD is bispecific antibodies, which combine two distinct binding specificities within a single biologic to allow the simultaneous targeting of multiple disease-causing cytokines or pathways. Although primarily used in oncology thus far, the unique combinatorial mechanism of action of bispecific antibodies may provide new therapeutic options for a broad range of clinical applications, including IBD.
Silvio Danese, Istituto Clinico Humanitas, Milan, Italy, explored the development of small molecules for the treatment of IBD. Historically, the medical management of IBD has been based on the use of several small-molecule drugs, including corticosteroids, immunomodulators (e.g. thiopurines and methotrexate), and aminosalicylates. Over the last 20 years, the approval of monoclonal antibodies has provided a revolution in the management of IBD with the availability of anti-TNFs (e.g. infliximab and adalimumab), anti-integrins (e.g. natalizumab and vedolizumab), and anti-interleukin (IL)-23. However, monoclonal antibodies have limitations in terms of efficacy, safety and cost. In addition, some patients may develop a loss of response to anti-TNFs over time. Problems with the current IBD treatment paradigm with biological therapies could be tackled by the intrinsic characteristics of small-molecule drugs such as the Janus kinase (JAK) inhibitors and sphingosine 1-phosphate (S1P) modulators.
IBD treatment paradigm issues with biological therapies could be tackled by intrinsic characteristics of small-molecule drugs
JAK inhibition has emerged as a novel strategy to modulate downstream cytokine signalling during immune-mediated diseases. These drugs target various cytokine signalling pathways that participate in the pathogenesis of IBD. Tofacitinib, a JAK inhibitor targeting predominantly JAK1 and JAK3, has been approved for the treatment of UC, and there are other specific JAK inhibitors (filgotinib, upadacitinib and peficitinib) under development that may be effective in UC and/or CD. Similarly, lymphocyte trafficking can now be targeted by S1P receptor (S1PR) agonism, a novel strategy that acts, in part, by interfering with lymphocyte recirculation through blockade of lymphocyte egress from lymph nodes. S1PR agonists (fingolimod, ozanimod and etrasimod) are being studied in IBD and other immune-mediated disorders.
What are the limitations of biologics for the treatment of IBD?
Arthur Kaser, University of Cambridge, Cambridge, United Kingdom, explored treatments for IBD which are expected to become available over the next five years. Two pharmacological principles have been successfully used for IBD treatment: inhibition of cellular signalling and interference with leukocyte trafficking. Besides TNF, interleukin (IL)-23 is a promising drug target, and antibodies for the combined inhibition of IL-23 and IL-12 (ustekinumab and briakinumab) or selective IL-23 inhibition (brazikumab, risankizumab and mirikizumab) seem to be effective in CD, with emerging evidence also for UC. Of interest, IL-23 blockade may be a more effective approach compared with IL-12/IL-23 inhibition based on available data from patients with moderate-to-severe plaque psoriasis. Anti-integrin therapy is a new frontline strategy in the treatment of IBD. The anti-β7 integrin antibody etrolizumab is currently being investigated for safety and efficacy in CD and UC in several Phase III studies. Etrolizumab, an anti-β7 monoclonal antibody, inhibits both trafficking of immune cells into the gut and their inflammatory effects on the gut lining. Ongoing clinical studies are investigating a number of therapeutic combinations, for example, combining anti-TNFs and IL-23 inhibitors in IBD, although comparing therapeutic options or strategies remains a key challenge due to the increase in the number of novel drugs for IBD. New targets for IBD treatment include natural killer group 2 member D (NKG2D), an activating immune receptor expressed by T cells and innate lymphoid cells, and may be linked to mucosal damage in CD. Anti-NKG2D (NNC0142-0002) is an antagonising human immunoglobulin G4 monoclonal antibody that binds to NKG2D receptors and is currently under investigation.
Orally available IBD therapeutics include JAK inhibitors, S1P modulators, phosphodiesterase 4 inhibitors and integrin antagonists
Focus on acute severe ulcerative colitis (ASUC)
Raja Atreya, University of Erlangen-Nürnberg, Germany, provided an overview of the medical management of acute severe ulcerative colitis (ASUC). ASUC is a potentially life-threatening condition, characterised by clinical and laboratory assessment using the modified Truelove and Witts criteria, with adult patients needing to be admitted to hospital for assessment and intensive management.
Modified Truelove and Witts criteria
CRP, C-reactive protein
All patients admitted with ASUC should have the following, with close monitoring after admission:
- Standard blood sampling
- Stool culture and Clostridium difficile (C. difficile) assay
- Radiological imaging
- Flexible sigmoidoscopy, with close monitoring after admission
Patients with ASUC should be treated with high-dose intravenous (IV) corticosteroids, such as methylprednisolone 60 mg daily or hydrocortisone 100 mg every 6 hours, and should receive prophylactic low-molecular weight heparin. Of note, nearly half of all patients are likely to fail with IV corticosteroids. Patients who do not respond to corticosteroid therapy after 3 days should be considered for second-line ‘rescue’ therapy or surgery in the form of IV infliximab or cyclosporin for those patients who had not previously failed thiopurine therapy. Of note, head-to-head comparisons between cyclosporin and infliximab have demonstrated equivalent efficacy, with long-term colectomy-free survival after initial rescue therapy appearing to be similar with both. Indices predictive of failure to IV corticosteroids in ASUC include:
Indices predictive of failure to IV corticosteroids in patients with ASUC
Responders to cyclosporin require maintenance treatment, typically being converted to an oral dose twice that of the IV dose and administered in divided doses twice daily (target trough cyclosporin concentration of 150–250 ng/mL). While oral cyclosporin should be continued for several months as bridging therapy, Dr Atreya explained that long-term outcomes are much better if thiopurine maintenance therapy is given. Vedolizumab and ustekinumab have also demonstrated efficacy as a maintenance treatment. Dose optimisation of infliximab in the acute phase may be needed due to various factors, such as the high TNF burden in ASUC, proteolytic degradation of the anti-TNF leading to increased drug clearance, and faecal losses of infliximab from increased gut permeability due to severe inflammation. Tofacitinib can be used in the induction and maintenance of UC remission in patients where anti-TNFs have failed.
Christoph Högenauer, Medical University of Graz, Austria, explored the management of infective complications in ASUC. Many different types of infection can occur in patients with ASUC under rescue therapy, including sepsis, pneumonia, urinary tract infections and skin infections. Of note, a number of these infections, such as sepsis and pneumonia, can lead to patient death.
Risk factors for developing pneumocystis jiroveci pneumonia (PJP) in ASUC
- Age >55–65 years
- High-dose corticosteroid therapy (15 mg prednisone or equivalent)
- Lymphopenia (total lymphocyte count <600 cells/mm3)
- Multiple immunosuppressive agents
- Comorbidities, particularly pulmonary diseases
While PJP is rarely reported for single immunosuppression, antibiotic prophylaxis in IBD is recommended for patients on triple immunosuppression and should also be considered in double immunosuppression (especially if one is a calcineurin inhibitor). All patients with acute severe colitis in ASUC should undergo stool testing for C. difficile and flexible sigmoidoscopy along with biopsies for diagnosis of cytomegalovirus (CMV) colitis. Dr Högenauer highlighted that it can be difficult to differentiate between a UC flare, latent CMV infection and true CMV colitis. There is ongoing consensus for the use of antiviral therapy (e.g. ganciclovir) in CMV colitis in steroid-refractory patients with UC in order to reduce the risk for colectomy. Improved surveillance and reporting of opportunistic infections are needed to further elucidate risk factors for acquisition of infection in IBD.
What are the risk factors for infective complications in ASUC?
Willem A. Bemelman, Amsterdam University Medical Centers, Netherlands, provided a brief overview of the surgical management of ASUC. There has been a significant decline in emergent UC colectomy rates in the USA; however, the overall need for surgery appears unchanged given stable ileal pouch anal anastomosis rates. This suggests a limited impact on overall surgery rates with a shift from emergent to elective colectomy. Postoperative intra-abdominal septic complications (IASCs) are the most feared risks of surgery and there is some evidence to suggest that steroid use, previous surgical history, a preoperative abscess, and low albumin levels may be associated with higher rates of IASCs in CD. Knowledge about those risk factors may influence treatment and procedure-related decisions. Laparoscopic colectomy and ileostomy remain the standard approaches to the surgical management of ASUC.
What are the emergency and subacute scenarios for the surgical management of ASUC?
IBD in pregnancy
Irit Avni-Biron, Rabin Medical Center, Petach Tikva, Israel, provided an overview of the monitoring and management of IBD in pregnancy. Non-invasive biomarkers of inflammation for monitoring IBD are important in pregnancy. While clinical and laboratory markers are often affected by the physiological adaption that occurs during pregnancy, faecal calprotectin (FC) is a useful biomarker and effective tool for assessing disease activity in pregnancy. In addition, FC is correlated with physician global assessment (PGA). FC in pregnant women with moderate-severe IBD was significantly higher in individuals with clinical disease activity compared with those without. FC correlated with higher levels of clinical disease activity across all gestational periods.
Why is FC an effective tool for assessing disease activity in patients with IBD during pregnancy?
Dr Avni-Biron highlighted that intestinal ultrasound during pregnancy was feasible in patients with IBD and correlates well with high clinical disease activity, with a similar diagnostic accuracy for disease activity as compared with magnetic resonance imaging and computerised tomography. For endoscopy use during pregnancy, ECCO guidelines note that gastroscopy, sigmoidoscopy/colonoscopy, and endoscopic retrograde cholangiopancreatography are generally considered to be safe in pregnancy; however, these procedures should only be performed where there is a strong need and in the second trimester, if possible. Active disease is the strongest predictor of adverse pregnancy outcomes with a two-fold increased risk of preterm delivery, two/three-fold increased risk of low birth weight, and four/five-fold increased risk of a still birth (based on data for patients with CD). These findings highlight the need for effective therapy with a rapid onset of action, ability to be used as a maintenance treatment, and suitable safety profile. Short-acting formulations of corticosteroids instead of long-acting formulations should be used in pregnant women with IBD, although prolonged use (>15 mg/day) has been associated with increased risk of preterm delivery and intrauterine infection. The use of anti-TNF therapy during pregnancy is not associated with an increased risk of adverse outcomes or congenital abnormalities, with treatment continued into the third trimester reducing relapses rates and demand for corticosteroids.
Patient risk factors and comorbidities in IBD
Laurent Beaugerie, Sorbonne University, Paris, France, explored treatment decision-making based on IBD patient risk factors and comorbidities. Factors with a potential impact on expected efficacy and safety of IBD drugs include:
What factors have a potential impact on the expected efficacy and safety of IBD drugs?
Age is one of the strongest risk factors for infections, with global incidence rates of serious infections that are two/three-fold greater and higher mortality rates (10%) in patients aged ≥65 years compared with younger patients. The risk of thiopurine-induced lymphomas can be lowered by limiting the use of thiopurines in patients who are seronegative for Epstein-Barr virus (particularly young male patients) and in older men. The risk of lymphoma related to monotherapy with anti-TNF agents is still unclear. While there are no robust data on carcinogenic effects of recently developed IBD drugs, physicians should try to implement a pause in the use of immunosuppressive therapy (except in patients with severe disease and no therapeutic alternative) and prioritise the use of IBD drugs with lowest carcinogenic effects for patients with previous cancer at substantial risk of recurrence. The combination of corticosteroids/thiopurines and anti-TNF agents exposes patients to higher risks of serious and opportunistic infections than anti-TNF monotherapy, and anti-TNF agents are associated with opportunistic bacterial and fungal infections, particularly in older patients. Generally though, serious infections related to uncontrolled IBD activity are more frequent than serious infections that may be purely attributed to IBD drugs. Venous thromboembolism (VTE) is increasingly prevalent among hospitalised patients with IBD and has substantial mortality and economic impact. These findings drive the need for widespread prophylaxis against and early detection of VTE among patients with IBD. Corticosteroids are increasingly being considered as an independent risk of VTE (two/three-fold increase) after best adjustment for associated inflammation.
What are the risk factors for VTE in IBD?
Decision-making process for patients with uncontrolled IBD at high risk of VTE
- The potential use of systematic heparin prophylaxis in patients hospitalised for IBD flare could be considered if suitable
- Advice from specialists in haemostasis in complex cases may be helpful to better estimate the patient’s risk level of VTE and choose the best anticoagulant regimen when prophylaxis is indicated
- Anti-TNFs/ustekinumab/vedolizumab could be used instead of corticosteroids and tofacitinib if suitable
Laurent Peyrin-Biroulet, Nancy University Hospital, Vandoeuvre-lès-Nancy, France, explored therapeutic endpoints for CD and UC. Current treat-to-target (T2T) recommendations in CD include the composite endpoint of clinical/patient-reported outcome remission (defined as resolution of abdominal pain and normalisation of bowel habit) and endoscopic remission (defined as resolution of ulceration). CRP and FC are deemed to be adjunctive measures of inflammation, not targets, for monitoring CD. In addition, histologic remission is also not considered as a target. When questioning a possible move to complete endoscopic remission as a therapeutic target, Dr Peyrin-Biroulet commented that this was too ambitious given that available clinical data suggest that this secondary endpoint does not typically produce significant results compared with other parameters such as endoscopic response and endoscopic remission. While mucosal healing (active magnetic resonance enterography [MRE] with inactive colonoscopy) is currently accepted as one of the best treatment targets in CD, residual bowel wall inflammation can still be detected by cross-sectional imaging, even in patients with sustained mucosal healing. A future target may be transmural healing (inactive MRE and colonoscopy) given that it has been associated with improved long-term outcomes in CD.
Patients with transmural healing present different characteristics to those with mucosal healing or no healing
Current T2T recommendations in UC include the composite endpoint of clinical/patient-reported outcome remission (defined as resolution of rectal bleeding and normalisation of bowel habits) and endoscopic remission (defined as resolution of friability and ulceration at flexible sigmoidoscopy or colonoscopy [Mayo 0–1]). As with CD, CRP and FC are deemed to be adjunctive measures of inflammation, not targets, for monitoring CD. In addition, while histopathology is a sensitive measure of inflammation, it is currently not used as a target due to the lack of evidence of clinical utility.
Histological healing is the ultimate therapeutic goal in UC. Histologic healing requires complete recovery of the colonic mucosa, with absence of inflammation or structural changes. Histologic improvements have been linked with improved clinical outcomes, such as a reduced risk of relapse and need for surgery/hospitalisation and a reduced risk of developing cancer. Hence, there is a current rationale to aiming for histologic remission in UC. The first validated histological index for UC is now available – the Nancy index – which is easy to use and reproducible.
The Nancy index
Dr Laurent Peyrin-Biroulet suggested that the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) recommendations should be updated to incorporate FC as treatment target for both CD and UC. In addition, when considering disease modification as a therapeutic goal, early disease control and monitoring in a T2T approach with tight monitoring may be the best way to modify the disease course and positively impact on patients’ lives.
In summary, UEGW Virtual 2020 was a successful meeting with attendees able to remotely access new data and insights, crash courses, clinical experiences, patient perspectives, and best practices that will hopefully stimulate new ways of thinking and ultimately translate into optimal patient care within the gastroenterology field.
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