A Review of Selected Presentations From the 2020 Virtual AIBD Conference • December 9-12, 2020
Positioning Biologics and Small Molecules in the Management of Moderate to Severe IBD
Dr William J. Sandborn discussed how the roles of biologics and small molecules are evolving in the management of moderate to severe inflammatory bowel disease (IBD).1 First discussed was treatment sequencing. With regard to ulcerative colitis (UC), in a network meta-analysis, infliximab and vedolizumab achieved the highest rates of clinical remission and endoscopic improvement in patients receiving first-line therapy. For second-line therapy, the most effective agents were tofacitinib and ustekinumab. In this setting, tumor necrosis factor (TNF) blockers and vedolizumab have proved less effective at inducing clinical remission and endoscopic improvement.2 As for head-to-head trials, in the VARSITY trial, vedolizumab proved superior to adalimumab for the treatment of active UC over the course of a year.3
With regard to safety, TNF blockers are associated with granulomatous infections, serious infections, non-Hodgkin lymphoma, and demyelination (Table 1). Tofacitinib is linked to serious infections, pulmonary embolism, deep vein thrombosis, and hyperlipidemia. Importantly, vedolizumab and ustekinumab do not cause these complications.
Dr Sandborn proposed an algorithm for treating moderate to severely active UC. For mild to moderate disease, treatment with mesalamine, rectal therapies, and perhaps corticosteroids is the approach of choice. For moderate to severe disease, the algorithm includes first- and second-line therapies. With first-line therapies, the clinician should consider whether extraintestinal manifestations are present, in which case an anti-TNF agent may be appropriate. If the disease is primarily in the gut, then vedolizumab may be best because of its safety profile.
In the treatment of Crohn’s disease (CD), the absence of approved Janus kinase inhibitors means the choice is among infliximab, adalimumab (both anti-TNF agents), vedolizumab, and ustekinumab. In the first-line setting, outcomes have been strongest with the 2 TNF blockers. In the second-line setting, however, ustekinumab has demonstrated the greatest efficacy, with a narrow confidence interval. With regard to safety considerations, again vedolizumab and ustekinumab have proved safer than TNF blockers.
In a study presented at United European Gastroenterology Week Virtual 2020, clinical remission (Crohn’s Disease Activity Index score <150) was achieved with ustekinumab in patients who had not previously received a biologic drug and those who had previously failed biologic treatment. The anti-interleukin (IL) 23 drug guselkumab demonstrated a slight advantage over ustekinumab in attaining clinical remission.4 This comparison will proceed to a phase 3 investigation.
As with UC, the positioning of therapies for CD begins with a determination of whether the disease is mild to moderate or moderate to severe. In the former case, the appropriate treatment may be budesonide or corticosteroids. In the latter, efficacy must be weighed against side effects. Patients who are particularly risk-averse may prefer vedolizumab or ustekinumab, even in the first-line setting (Figure 1).5
Dr Sandborn also highlighted decision support tools for UC and CD. In the case of UC, research has shown that patients who have a longer duration of disease (>2 years), have never received an anti-TNF agent, had moderate as opposed to severe baseline endoscopy findings, and have normal albumin levels are most likely to respond to anti-integrin therapy with vedolizumab.6 In the case of CD, response and remission rates are better in patients without previous surgical resection, anti-TNF treatment, or fistulizing disease, with normal albumin levels, and with relatively low C-reactive protein levels.7
References
1. Sandborn WJ. Positioning biologics and small molecules in the management of moderate to severe IBD. Presented at: 2020 Virtual Advances in Inflammatory Bowel Diseases Conference; December 9-12, 2020.
2. Singh S, Murad MH, Fumery M, Dulai PS, Sandborn WJ. First- and second-line pharmacotherapies for patients with moderate to severely active ulcerative colitis: an updated network meta-analysis. Clin Gastroenterol Hepatol. 2020;18(10):2179-2191.e6.
3. Sands BE, Peyrin-Biroulet L, Loftus EV Jr, et al; VARSITY Study Group. Vedolizumab versus adalimumab for moderate-to-severe ulcerative colitis. N Engl J Med. 2019;381(13):1215-1226.
4. Sandborn W, Chan D, Johanns J, et al. The efficacy and safety of guselkumab induction therapy in patients with moderately to severely active Crohn’s disease: week 12 interim analyses from the phase 2 GALAXI 1 study. UEG Week abstract OP089. Presented at: UEG Week Virtual 2020; October 11-13, 2020.
5. Nguyen NH, Singh S, Sandborn WJ. Positioning therapies in the management of Crohn’s disease. Clin Gastroenterol Hepatol. 2020;18(6):1268-1279.
6. Dulai PS, Singh S, Casteele NV, et al. Development and validation of clinical scoring tool to predict outcomes of treatment with vedolizumab in patients with ulcerative colitis. Clin Gastroenterol Hepatol. 2020;18(13):2952-2961.e8.
7. Dulai PS, Boland BS, Singh S, et al. Development and validation of a scoring system to predict outcomes of vedolizumab treatment in patients with Crohn’s disease. Gastroenterology. 2018;155(3):687-695.e10.
Approach to Mild to Moderate IBD
Dr Sunanda Kane reviewed the treatment of mild to moderate IBD.1 In 2019, the American College of Gastroenterology issued new clinical guidelines for the treatment of adults with UC, in which urgency, measured as none, mild/occasional, or frequent, was added as a consideration.2 The fecal calprotectin level was also added.
The diagnosis of UC should include both an assessment of the extent of disease and a biopsy, which will determine histologic severity; a current goal in IBD care is to distinguish between activity and severity. An additional goal is to induce a clinical response or remission. Mucosal healing is crucial because it is associated with sustained, corticosteroid-free remission and prevents the need for hospitalization as well as surgery. Maintenance therapy should be established for each patient according to the response to induction therapy and the prognosis. Screening and treatment for anxiety and depressive disorders should also be part of management. The prevention of complications, such as cancer and infections, is another important goal.
Dr Kane also reviewed induction and maintenance therapy for mild to moderate UC (Table 2). Rectal administration of a 5-aminosalicylic acid (5-ASA) drug at a dose of 1 g/day is recommended for patients with mild proctitis, although many patients may be fine with a dose taken every other day, or even every third day, once remission has been attained. During maintenance, topical therapy can be discontinued for patients with mildly active left-sided or extensive UC, and just oral 5-ASA therapy can be used (≥2 g/day). Systemic corticosteroids should be restricted to induction treatment.
Successful treatment is defined as overall improvement at week 6 according to a clinical assessment of rectal bleeding and stool frequency and the results of sigmoidoscopy. In the ASCEND III trial, additional treatment did not necessarily lead to better outcomes.3 Clinicians must consider whether a patient’s disease activity is mild or moderate when a 5-ASA drug is prescribed. For patients with distal UC, research has shown that a combination of oral and rectal mesalamine therapy is better than either agent alone, even if given for only 1 to 2 weeks.4 If the combination can be continued for 6 weeks, then the chance of a successful outcome is even greater.
Budesonide MMX appears to be an effective agent for patients with UC who have failed 5-ASA treatment.5,6 Dr Kane presented a treatment algorithm for maximizing remission and minimizing corticosteroid dependence in UC, noting that budesonide MMX may be the best option for patients with mild to moderate disease, rather than prednisone.
Budesonide MMX is also important in the treatment of CD, in which it has proved almost as effective as prednisolone and superior to placebo and mesalamine for patients with active ileal and right-sided colonic disease. In addition, it may be effective for maintaining remission in mild to moderate CD. Sulfasalazine may also be effective when disease is limited to the colon. Patients must be advised to stop smoking and should be screened for depression and anxiety, both of which will impede improvement.
5-ASA drugs, budesonide, azathioprine, 6-mercaptopurine, and methotrexate are all potential options for treating mild to moderate CD. Lack of efficacy may be due to inadequate dosing, lack of adherence, or preferential metabolism via the thiopurine methyltransferase pathway.
References
1. Kane S. Approach to mild to moderate IBD. Presented at: 2020 Virtual Advances in Inflammatory Bowel Diseases Conference; December 9-12, 2020.
2. Rubin DT, Ananthakrishnan AN, Siegel CA, Sauer BG, Long MD. ACG Clinical Guideline: ulcerative colitis in adults. Am J Gastroenterol. 2019;114(3):384-413.
3. Sandborn WJ, Regula J, Feagan BG, et al. Delayed-release oral mesalamine 4.8 g/day (800-mg tablet) is effective for patients with moderately active ulcerative colitis. Gastroenterology. 2009;137(6):1934-1943.e1-3.
4. Safdi M, DeMicco M, Sninsky C, et al. A double-blind comparison of oral versus rectal mesalamine versus combination therapy in the treatment of distal ulcerative colitis. Am J Gastroenterol. 1997;92(10):1867-1871.
5. Sandborn WJ, Travis S, Moro L, et al. Once-daily budesonide MMX extended-release tablets induce remission in patients with mild to moderate ulcerative colitis: results from the CORE I study. Gastroenterology. 2012;143(5):1218-1226.e2.
6. Travis SP, Danese S, Kupcinskas L, et al. Once-daily budesonide MMX in active, mild-to-moderate ulcerative colitis: results from the randomised CORE II study. Gut. 2014;63(3):433-441.
Disease Activity Assessment: What Should We Do in Clinical Practice?
Dr Bruce E. Sands began his presentation by emphasizing how the goals of therapy have changed over time.1 Clinical response was once the target outcome, and then it was remission; today, clinicians are aiming for deep remission.
Dr Sands noted the importance of distinguishing between disease activity and disease severity. Disease activity reflects cross-sectional evaluation of biologic inflammatory impact on symptoms, signs, endoscopy, histology, and biomarkers. It asks how the patient is today. In contrast, disease severity is a measure of longitudinal and historical factors. An assessment of disease severity provides a more complete picture of a patient’s prognosis and overall burden of disease. This assessment asks about the course of disease since the diagnosis.2
To assess disease severity, physicians must consider the effect of the disease on the patient, the course of the disease, the presence of any complications, and the inflammatory burden. Because CD and UC are progressive disorders, both disease severity and disease activity must be factored into clinical decisions.
An assessment of disease severity in CD considers whether mucosal lesions, fistulae, abscesses, and strictures are present. An assessment of disease severity in UC considers the presence of mucosal lesions; number of hospitalizations; levels of C-reactive protein, albumin, and hemoglobin; extent of disease; daily symptoms; nocturnal bowel movements; and effect of the disease on daily activities.
Treating to target is a useful new concept in IBD, Dr Sands noted. Borrowed from other medical conditions, treating to target in the context of IBD means adjusting therapy to achieve certain targets and then further considering how to improve outcomes while avoiding long-term bowel damage and other complications.
Dr Sands also discussed mucosal healing. Data suggest that partial healing may be sufficient.3 The Ulcerative Colitis Endoscopic Index of Severity may seem complex, but it can be applied in practice fairly simply, Dr Sands noted. However, endoscopic scoring in UC does not necessarily reflect what is happening microscopically. Furthermore, histologic activity can persist even when mucosal healing suggests remission.4
The many evolving grading scales for histology are not all equivalent. Dr Sands suggested avoiding complications by applying the following criteria for histologic quiescence in UC: no more than 5% of crypts with neutrophils, no erosions, and no ulcers. If these are fulfilled, then the disease is histologically quiescent.
The corresponding situation in CD is more complicated. Dr Sands pointed out that endoscopic software enables clinicians to score various criteria automatically as part of the colonoscopy report. Cross-sectional imaging is also important for evaluating CD activity. Clinicians should look at thickening, hyperenhancement, and the severity of edema and ulcers. Patients with transmural healing on cross-sectional imaging are likely to have better outcomes and a reduced need for surgery and hospitalization.5
Finally, Dr Sands discussed the role of biomarkers in monitoring disease activity. The fecal calprotectin level is widely used in CD; the higher the score, the greater the endoscopic activity. In the CALM study, the outcomes of patients managed with the treat-to-target approach, which included biomarker monitoring, were greatly superior to the outcomes of those who received clinical management.6
Patients with UC can be categorized as low risk or high risk and monitored accordingly. Low-risk patients can be seen every 6 to 12 months, for example. High-risk patients should be seen every 3 to 4 months, with the calprotectin level checked every 2 to 3 months. An endoscopic examination should be performed if a patient is experiencing symptoms or has abnormal biomarker findings (Figure 2).7
References
1. Sands BE. Disease activity assessment: what should we do in clinical practice? Presented at: 2020 Virtual Advances in Inflammatory Bowel Diseases Conference; December 9-12, 2020.
2. Peyrin-Biroulet L, Panés J, Sandborn WJ, et al. Defining disease severity in inflammatory bowel diseases: current and future directions. Clin Gastroenterol Hepatol. 2016;14(3):348-354.e17.
3. Peyrin-Biroulet L, Sandborn W, Sands BE, et al. Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE): determining therapeutic goals for treat-to-target. Am J Gastroenterol. 2015;110(9):1324-1338.
4. Christensen B, Hanauer SB, Erlich J, et al. Histologic normalization occurs in ulcerative colitis and is associated with improved clinical outcomes. Clin Gastroenterol Hepatol. 2017;15(10):1557-1564.e1.
5. Fernandes SR, Rodrigues RV, Bernardo S, et al. Transmural healing is associated with improved long-term outcomes of patients with Crohn’s disease. Inflamm Bowel Dis. 2017;23(8):1403-1409.
6. Colombel JF, Panaccione R, Bossuyt P, et al. Effect of tight control management on Crohn’s disease (CALM): a multicentre, randomised, controlled phase 3 trial. Lancet. 2018;390(10114):2779-2789.
7. Panes J, Jairath V, Levesque BG. Advances in use of endoscopy, radiology, and biomarkers to monitor inflammatory bowel diseases. Gastroenterology. 2017;152(2):362-373.e3.
Precision Medicine in IBD
Dr Maria T. Abreu explored several reasons for pursuing precision medicine in IBD.1 Because no single cause exists, no single cure exists. The range of treatments is expanding, with many different targets. The emergence of biomarkers is increasing the feasibility of tailoring treatment, and data are accruing on combination therapies. Each patient requires a unique approach that can be adapted as needed as care proceeds.
With regard to genetics, children who have mutations in IL-10 and the IL-10 receptor pathway overproduce IL-1 and can often be treated effectively with anti–IL-1 strategies, as well as hematopoietic bone marrow transplant. However, although more than 240 confirmed loci are associated with IBD, and more than 50 genes are associated with very early–onset IBD, genetic features have so far not been tightly tied to responses to specific treatment approaches in adults. Dr Abreu noted that in the management of IBD, clinicians often move from one treatment approach to another without allowing sufficient time for a response, and without stratifying patients according to phenotype, genotype, or meta-type.
Biomarkers are emerging as an important feature that can be applied in precision medicine in IBD. Data from a pediatric study showed that the biological signature correlating perforation and fibrotic complications is present in pediatric patients with IBD before treatment.2 In addition, investigators have found distinct changes in DNA methylation and transcription patterns in the colon epithelium of patients with CD and patients with UC, compared with controls.3
The HLA-DQ polymorphism is likely to become important for patient stratification. Over 30% of patients with IBD have this polymorphism, and data show that anti-TNF agents are most effective in this population when combined with immunomodulators. Antidrug antibodies almost always develop in patients with the HLA-DQ polymorphism who are taking anti-TNF agents alone (Figure 3).4
In her presentation, Dr Abreu also discussed the microbiome, which is altered in patients with IBD, as a component of precision medicine. A study found higher rates of butyrate and short-chain fatty acid synthesis in the patients who were more likely to go into remission with anti-TNF therapy.5 Adherent-invasive Escherichia coli bacteria are found in approximately 40% of patients with ileal CD.6 In one ongoing study, a comparison of antibiotic treatment vs no treatment is being conducted in patients with these bacteria to see if outcomes differ. Several studies of fecal microbiota transplant are ongoing that may further inform the
relevance of the microbiome in tailoring IBD care.
The microbiome may be significant in determining which patients can stop treatment once they are in deep remission. The STORI trial found that a decreased abundance of Firmicutes and Bacteroidetes bacteria and an increased abundance of Proteobacteria organisms were associated with earlier relapse after 6 months of corticosteroid-free remission following treatment with infliximab.7 Protein, metabolomic, and fecal metagenomic biomarkers may also inform decisions about halting treatment.
References
1. Abreu MT. Precision medicine in inflammatory bowel diseases. Presented at: 2020 Virtual Advances in Inflammatory Bowel Diseases Conference; December 9-12, 2020.
2. Kugathasan S, Denson LA, Walters TD, et al. Prediction of complicated disease course for children newly diagnosed with Crohn’s disease: a multicentre inception cohort study. Lancet. 2017;389(10080):1710-1718.
3. Howell KJ, Kraiczy J, Nayak KM, et al. DNA methylation and transcription patterns in intestinal epithelial cells from pediatric patients with inflammatory bowel diseases differentiate disease subtypes and associate with outcome. Gastroenterology. 2018;154(3):585-598.
4. Sazonovs A, Kennedy NA, Moutsianas L, et al. HLA-DQA1*05 carriage associated with development of anti-drug antibodies to infliximab and adalimumab in patients with Crohn’s disease. Gastroenterology. 2020;158(1):189-199.
5. Aden K, Rehman A, Waschina S, et al. Metabolic functions of gut microbes associate with efficacy of tumor necrosis factor antagonists in patients with inflammatory bowel diseases. Gastroenterology. 2019;157(5):1279-1292.e11.
6. Glasser AL, Boudeau J, Barnich N, Perruchot MH, Colombel JF, Darfeuille-Michaud A. Adherent invasive Escherichia coli strains from patients with Crohn’s disease survive and replicate within macrophages without inducing host cell death. Infect Immun. 2001;69(9):5529-5537.
7. Rajca S, Grondin V, Louis E, et al. Alterations in the intestinal microbiome (dysbiosis) as a predictor of relapse after infliximab withdrawal in Crohn’s disease. Inflamm Bowel Dis. 2014;20(6):978-986.
Applying IBD Guidelines in the Real World
Dr Corey A. Siegel began his presentation by noting that in most cases, the management of a patient with IBD does not fit perfectly into any specific set of guidelines.1 Recent IBD guidelines consist of over 150 recommendations and include some conflicting information.2-7 Insurance companies are not always willing to comply with the current standard of care, adding further complexity to the application of IBD guidelines in the real world (Figure 4).8
Dr Siegel focused on several guidelines. Patients with UC should be treated to achieve mucosal healing and the resolution of inflammatory changes, specified as a Mayo Endoscopic Score of 0 or 1. In this context, a score of 0 indicates normal colonoscopy findings; a score of 1 indicates mild erythema, blunting of the vascular pattern, and possibly some mild friability. Attempting to achieve a score of 0 or 1 is more practical than trying to achieve a score of 0 in all patients. Fixation on a score of 0 as the goal may lead clinicians to cycle through drugs too rapidly, and a score of 1 may be attained more easily.
Dr Siegel also discussed combination therapy with infliximab. When used as induction therapy for patients with moderate to severely active UC, infliximab should be combined with a thiopurine, according to data from the UC SUCCESS trial and other studies.2,9
Many clinicians are being told by insurance companies that adalimumab should be used for first-line treatment of adult outpatients with moderate to severe UC. Data from the VARSITY trial, in which vedolizumab was more effective than adalimumab, invalidate that instruction.10 Presenting these data to payors may lead to coverage changes on a patient-by-patient basis.
In addition, Dr Siegel noted that he disagreed with the suggestion by the American Gastroenterological Association to combine an anti-TNF agent, vedolizumab, or ustekinumab with a thiopurine or methotrexate rather than use biologic monotherapy.4 The rates of biologic immunogenicity vary.11 Combination therapy decreases biologic immunogenicity, but adding a second drug decreases the safety benefit of vedolizumab and ustekinumab.
Until about 2016, the vast majority of patients received either corticosteroids or 5-ASA drugs as first-line treatment; very few patients received immunomodulators or biologics at the start of care. A study found that more than 60% of patients were started on a corticosteroid and never received any other drug during the course of their treatment, an approach that is not in line with current guidelines or data.12
For patients with CD at low risk for progression, the use of symptomatic treatment alone is an effective approach. Patients with mild disease do not require 5-ASA drugs, for example. Budesonide may be useful as needed, but this group of patients can be treated for symptoms alone as long as the patients are monitored and tested.
In the postoperative setting, patients should undergo colonoscopy after 6 to 12 months. Anti-TNF agents are safe to begin within 4 weeks of surgery. Anti-TNF agents are the drug category of choice because the relative risks are much lower than those associated with other medications.
References
1. Siegel CA. Applying IBD guidelines in the real world. Presented at: 2020 Virtual Advances in Inflammatory Bowel Diseases Conference; December 9-12, 2020.
2. Rubin DT, Ananthakrishnan AN, Siegel CA, Sauer BG, Long MD. ACG Clinical Guideline: ulcerative colitis in adults. Am J Gastroenterol. 2019;114(3):384-413.
3. Lichtenstein GR, Loftus EV, Isaacs KL, Regueiro MD, Gerson LB, Sands BE. ACG Clinical Guideline: management of Crohn’s disease in adults. Am J Gastroenterol. 2018;113(4):481-517.
4. Feuerstein JD, Isaacs KL, Schneider Y, Siddique SM, Falck-Ytter Y, Singh S; AGA Institute Clinical Guidelines Committee. AGA Clinical Practice Guidelines on the management of moderate to severe ulcerative colitis. Gastroenterology. 2020;158(5):1450-1461.
5. Ko CW, Singh S, Feuerstein JD, Falck-Ytter C, Falck-Ytter Y, Cross RK; American Gastroenterological Association Institute Clinical Guidelines Committee. AGA Clinical Practice Guidelines on the management of mild-to-moderate ulcerative colitis. Gastroenterology. 2019;156(3):748-764.
6. Nguyen GC, Loftus EV Jr, Hirano I, Falck-Ytter Y, Singh S, Sultan S; AGA Institute Clinical Guidelines Committee. American Gastroenterological Association Institute Guideline on the management of Crohn’s disease after surgical resection. Gastroenterology. 2017;152(1):271-275.
7. Feuerstein JD, Nguyen GC, Kupfer SS, Falck-Ytter Y, Singh S; American Gastroenterological Association Institute Clinical Guidelines Committee. American Gastroenterological Association Institute Guideline on therapeutic drug monitoring in inflammatory bowel disease. Gastroenterology. 2017;153(3):827-834.
8. Yadav A, Foromera J, Feuerstein I, Falchuk KR, Feuerstein JD. Variations in health insurance policies regarding biologic therapy use in inflammatory bowel disease. Inflamm Bowel Dis. 2017;23(6):853-857.
9. Panaccione R, Ghosh S, Middleton S, et al. Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis. Gastroenterology. 2014;146(2):392-400.e3.
10. Sands BE, Peyrin-Biroulet L, Loftus EV Jr, et al; VARSITY Study Group. Vedolizumab versus adalimumab for moderate-to-severe ulcerative colitis. N Engl J Med. 2019;381(13):1215-1226.
11. Vermeire S, Gils A, Accossato P, Lula S, Marren A. Immunogenicity of biologics in inflammatory bowel disease. Therap Adv Gastroenterol. 2018;11:1756283X17750355.
12. Siegel CA, Yang F, Eslava S, Cai Z. Treatment pathways leading to biologic therapies for ulcerative colitis and Crohn’s disease in the United States. Clin Transl Gastroenterol. 2020;11(2):e00128.
Highlights From the 2020 Virtual Advances in Inflammatory Bowel Diseases Conference: Commentary
Gary R. Lichtenstein, MD
Professor of Medicine
Director, Center for Inflammatory Bowel Disease
University of Pennsylvania Health System
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania
The annual Advances in Inflammatory Bowel Diseases (AIBD) Conference reviews important issues and developments in the field of inflammatory bowel disease (IBD) management each year. In 2020, the conference was presented via a virtual format for the first time. Highlights of the 2020 Virtual AIBD Conference included oral presentations on the application of guidelines in the real world, the use of biologic agents and small molecules for moderate to severe IBD, and the role of precision medicine.
Real-World Application of Guidelines
Dr Corey A. Siegel discussed the application of IBD guidelines in the real world.1 There have been numerous recent advances in IBD, many of which have been reflected in recent guidelines. Since 2017, there have been a total of 6 different IBD guidelines that have been published by the American College of Gastroenterology and the American Gastroenterological Association.2-7 Within these guidelines, there are more than 150 recommendations, and many of them overlap and some even conflict. In addition, several of these guidelines are not presented in a user-friendly and easy-to-remember format, particularly for individuals who are not well versed in IBD. As a consequence, individual scenarios may have to be looked up, and clinicians may not always recall every nuance of a guideline, thus requiring that they go back to reread it. It would be a major advance if guidelines could be incorporated into electronic medical records. For example, if a practitioner prescribed corticosteroids, an alert or reminder could be made that referred to any related guidelines, such as whether tests are needed if the patient is on corticosteroids for a prespecified number of days.
It is difficult for practitioners to follow guidelines completely; in fact, many practitioners do not follow them very well. This was highlighted in a retrospective, observational study that Dr Siegel and colleagues recently published using administrative claims data from the Truven Health MarketScan Commercial and Medicare Database.8 They found that 63% of Crohn’s disease patients (n=16,260) who were started on a corticosteroid received only that treatment, and some patients received up to 10 cycles of corticosteroid therapy. Biologic agents were used in only 3% of patients initially and in combination with immunomodulators in 1% of patients overall. These numbers are substantially lower than expected and are concerning because they highlight that the majority of these patients were not treated according to the current standard of practice.
In his presentation, Dr Siegel highlighted that many insurance companies also do not follow guidelines when it comes to the current standard of care. A study from 2017 reviewed the top 125 insurance companies (according to market share in 2014) and examined the first 50 with online policies on vedolizumab and anti–tumor necrosis factor (TNF) use. This evaluation showed that early intensive intervention or top-down therapy was allowed by only 2% of ulcerative colitis policies and 10% of Crohn’s disease policies. In addition, at that time, 34% of policies required that patients had to fail to respond to 2 drugs before they could receive a biologic agent, and the vast majority of policies (90%) required stepwise drug therapy.9 These findings go against current clinical practice as well as current guidelines.
In addition, Dr Siegel related that patients in clinical practice may not necessarily be representative of what is assessed directly in clinical trials. A study by Dr Christina Ha and colleagues found that only approximately 31% of patients seen in an office practice would be able to enroll in clinical trials.10 If approximately two-thirds of patients in an office-based practice would not necessarily have met the eligibility criteria for enrolling in clinical trials and current clinical IBD guidelines are not adhered to, a large burden is being placed on the practitioner, and patient management becomes more challenging.
In particular, these impediments make management of patients with IBD more difficult for practitioners who treat not just IBD but a multitude of other gastrointestinal conditions, such as gastroesophageal reflux disease, liver disease, and colon cancer.
Biologics and Small Molecules for Moderate to Severe IBD
Dr William J. Sandborn discussed the use of biologic agents and small molecules in patients with moderate to severe IBD and highlighted treatment sequencing, new therapies, and individualizing treatment.11 In addition, he reviewed first- and second-line treatment options, which have been evolving over time. Different biologic agents are now available, but there are very little comparative effectiveness data that have been derived from randomized, controlled, blinded research. Thus, if a patient has clinical, endoscopic, and laboratory features that suggest that the patient merits use of a biologic agent to treat his or her IBD, the question is which biologic agent should be initiated.
At present, the only prospective, randomized, controlled data published in full manuscript form focusing on comparative effectiveness in patients with IBD come from the VARSITY trial, which compared vedolizumab with adalimumab for the treatment of active ulcerative colitis (Table). This trial showed superiority for vedoliz-umab over adalimumab in endoscopic improvement and clinical remission. For corticosteroid-free clinical remission, there was no significant difference between the 2 treatment groups.12
Because such comparisons have been performed directly only for 2 other agents (although they have not yet been published as full manuscripts), assessment often relies upon the use of network meta-analyses. This research can help estimate the positioning of biologic agents but is not as reliable as head-to-head trials, which are the gold standard. Thus, there is a need for additional comparative effectiveness trials. Two were completed in 2020 and presented in abstract form only, and several other trials are currently ongoing.
When deciding among different biologic agents, practitioners should consider whether the agents have any associated risks (eg, serious infections, lymphoma risk, demyelination, deep vein thrombosis, pulmonary embolism). For example, we know that anti-TNF therapy is not appropriate in a patient who has had optic neuritis or multiple sclerosis because such treatment can worsen outcomes.13 Vedoliz-umab and ustekinumab are often considered to be among the safest biologic agents currently in use.
Several agents have been approved for patients with moderate to severe ulcerative colitis, including tofacitinib, infliximab, adalimumab, golimumab, vedolizumab, and ustekinumab. When deciding which agent to use, it is important to assess whether patients have extraintestinal manifestations and whether they have comorbidities that would make it inadvisable to receive certain treatment. For example, if a patient has preexisting deep vein thrombosis, tofacitinib might not be the first choice for treatment. On the other hand, if a patient has pyoderma gangrenosum, anti-TNF therapy might be considered for treatment. Practitioners should assess the patients’ clinical scenario to determine which therapy is most appropriate as a first-line agent.
Appropriate medical therapy is also important for high-risk Crohn’s disease. Dr Sandborn presented recommendations based upon data extracted from a recent network meta-analysis; however, this approach to determine which agent is most appropriate is not embraced by all clinical practitioners.
In his presentation, Dr Sandborn also reviewed new agents, including filgotinib, which is undergoing phase 3 clinical evaluation, and ozanimod, which prevents lymphocyte egress from lymph nodes and hence lessens bowel-related inflammation. Ozanimod, an oral sphingosine-1-phosphate receptor modulator, has been shown to selectively inhibit sphingosine-1-phosphate subtypes 1 and 5, whereas filgotinib has been shown to selectively inhibit subtype 1. Dr Sandborn discussed induction data14 from a 10-week trial on ozanimod in patients with moderate to severe ulcerative colitis that were presented at United European Gastroenterology (UEG) Week Virtual 2020. Ozanimod demonstrated superiority over placebo in terms of clinical remission and response, endoscopic improvement, and mucosal healing. Also at UEG Week Virtual 2020, maintenance data on ozanimod were highlighted that demonstrated persistence of clinical remission and response, endoscopic improvement, maintenance of remission, corticosteroid-free remission, mucosal healing, and durable remission. All of the prespecified trial endpoints were met.15 At the same meeting, filgotinib showed superiority over placebo for induction of patients with moderate to severe ulcerative colitis,16 and it was able to maintain remission at week 58 more than placebo.17 Given the initial success of ozanimod, there are likely to be other similar compounds within the class of sphingosine-1-phosphate receptor modulators investigated for use in patients with IBD in the future.
Finally, Dr Sandborn reviewed data on clinical decision support tools and companion diagnostic testing for the future. He and his colleagues recently created a prognostic decision tool that stratified treatment outcomes for patients with ulcerative colitis in the VICTORY consortium. The researchers investigated different factors, such as disease duration greater than or equal to 2 years, no prior anti-TNF use, moderate disease at baseline endoscopy, and baseline serum albumin concentration, and assigned a certain number of points for each factor to determine the probability of response to vedolizumab. Fewer than 13 points indicated a low probability of response, 13 to 19 points an intermediate probability, and more than 19 points a high probability.18 Other similar tools are also in development.
Precision Medicine
Dr Maria T. Abreu discussed precision medicine and addressed several areas of interest, including whether we can predict if individual patients will develop more severe disease, and additionally who should receive early aggressive treatment; whether we can better match treatment to patients; and whether we can predict who is able to stop medical therapy and maintain remission.19 She also discussed how to incorporate biomarkers into clinical trials, and specifically what they do and how they help us.
One of the questions that is commonly discussed is which patients are likely to develop more severe disease and who needs earlier treatment. In 2017, data on ileal gene stratification were published showing that ileal gene signatures were able to help clinicians risk-stratify patients.20 In addition, epigenetic research of colonic epithelium of patients with Crohn’s disease and patients with ulcerative colitis has shown that distinct DNA methylation and transcription patterns might be present that differ from controls.21
In an effort to see if we can better
match patient responses to specific therapies and predict patient prognosis, genes have been evaluated. There are more than 200 genes associated with IBD at the present time, as well as 30 Crohn’s disease–specific loci and 23 ulcerative colitis–specific loci. There are also 110 IBD loci that are common to both pathways and that can be seen in Mycobacterium, leprosy, and other immune disorders.22-24 More than 50 genes have been associated with very early–onset IBD.25
In her discussion, Dr Abreu highlighted that the classic step-up treatment approach initiates therapy with 5-aminosalicylic acid, corticosteroids, azathioprine, and subsequently a biologic agent. In contrast, top-down treatment starts with a biologic agent such as an anti-TNF agent plus an immunomodulator, and then the immunomodulator is classically stopped after a period of time while maintaining the anti-TNF agent or biologic agent. She mentioned that it may eventually be possible to stratify patients to treatment based on phenotype, genotype, and metatype.
She also noted that, interestingly, HLA-DQA1*05 has been associated with the development of antibodies to anti-TNF therapy.26 There is clearly a difference between patients with and without HLA-DQA1*05, but whether it becomes a useful tool for the clinician in clinical practice is an important issue.
In addition, Dr Abreu noted that the microbiome may be an important tool that enables the clinician to take advantage of precision medicine. The metabolome state might predict response to biologic agents, especially anti-TNF therapy.27 A prospective study of stool metagenomes of IBD patients who were initiating biologic treatment found that butyrate–producing bacteria was more abundant at baseline in Crohn’s disease patients who responded to treatment. Baseline enrichment occurred in 13 microbial pathways in Crohn’s disease patients who responded to therapy. In responders, microbial changes noted at week 14 remained up to a year.28 This is exciting work because it allows for better prediction. There are also many other ongoing studies trying to improve prediction of patient outcomes.
Fecal microbiota transplantation (FMT) was discussed as well. FMT was initially pioneered in patients with Clostridioides difficile infection, and then its utility was assessed in the treatment of patients with ulcerative colitis. However, there have been only a few small randomized, controlled clinical trials assessing the efficacy of FMT in the treatment of patients with IBD.29 Interestingly, SER-287, a live biotherapeutic formulated for oral dosing, is composed of Firmicute spores. These bacterial spores are resistant to gastric acid, allowing formulation into capsules for effective colonic delivery. This product, which has been nicknamed “FMT in a pill,” has undergone phase 1b research30 and is now entering larger trials. This compound appears reasonably effective, but phase 3 research is needed to determine whether it truly is effective at treating patients. There are several selective microbiome modulators in various phases of development for the treatment of different diseases.
Finally, Dr Abreu discussed which patients can stop medications and whether there is a microbiome signature that predicts response or relapse in patients. These particular hypotheses have not been adequately evaluated and represent areas of current research.
Disclosures
Dr Lichtenstein has consulted for AbbVie, American Regent, Celgene, Eli Lilly, Endo Pharmaceuticals, Ferring, Gilead, Janssen Orthobiotech, Merck, Morphic Therapeutics, Pfizer Pharmaceuticals, Prometheus Laboratories, Romark, Salix Pharmaceuticals/Valeant, Shire Pharmaceuticals, Takeda, and UCB; conducted research for Celgene, Janssen Orthobiotech, and UCB; served on the DSMB for Eli Lilly; received honoraria (CME program) from American Regent, Merck, and Romark; and received funding to the University of Pennsylvania (IBD fellow education) from Janssen Orthobiotech, Pfizer Pharmaceuticals, and Takeda.
References
1. Siegel CA. Applying IBD guidelines in the real world. Presented at: 2020 Virtual Advances in Inflammatory Bowel Diseases Conference; December 9-12, 2020.
2. Rubin DT, Ananthakrishnan AN, Siegel CA, Sauer BG, Long MD. ACG Clinical Guideline: ulcerative colitis in adults. Am J Gastroenterol. 2019;114(3):384-413.
3. Lichtenstein GR, Loftus EV, Isaacs KL, Regueiro MD, Gerson LB, Sands BE. ACG Clinical Guideline: management of Crohn’s disease in adults. Am J Gastroenterol. 2018;113(4):481-517.
4. Feuerstein JD, Isaacs KL, Schneider Y, Siddique SM, Falck-Ytter Y, Singh S; AGA Institute Clinical Guidelines Committee. AGA Clinical Practice Guidelines on the management of moderate to severe ulcerative colitis. Gastroenterology. 2020;158(5):1450-1461.
5. Ko CW, Singh S, Feuerstein JD, Falck-Ytter C, Falck-Ytter Y, Cross RK; American Gastroenterological Association Institute Clinical Guidelines Committee. AGA Clinical Practice Guidelines on the management of mild-to-moderate ulcerative colitis. Gastroenterology. 2019;156(3):748-764.
6. Nguyen GC, Loftus EV Jr, Hirano I, Falck-Ytter Y, Singh S, Sultan S; AGA Institute Clinical Guidelines Committee. American Gastroenterological Association Institute Guideline on the management of Crohn’s disease after surgical resection. Gastroenterology. 2017;152(1):271-275.
7. Feuerstein JD, Nguyen GC, Kupfer SS, Falck-Ytter Y, Singh S; American Gastroenterological Association Institute Clinical Guidelines Committee. American Gastroenterological Association Institute Guideline on therapeutic drug monitoring in inflammatory bowel disease. Gastroenterology. 2017;153(3):827-834.
8. Siegel CA, Yang F, Eslava S, Cai Z. Treatment pathways leading to biologic therapies for ulcerative colitis and Crohn’s disease in the United States. Clin Transl Gastroenterol. 2020;11(2):e00128.
9. Yadav A, Foromera J, Feuerstein I, Falchuk KR, Feuerstein JD. Variations in health insurance policies regarding biologic therapy use in inflammatory bowel disease. Inflamm Bowel Dis. 2017;23(6):853-857.
10. Ha C, Ullman TA, Siegel CA, Kornbluth A. Patients enrolled in randomized controlled trials do not represent the inflammatory bowel disease patient population. Clin Gastroenterol Hepatol. 2012;10(9):1002-1007.
11. Sandborn WJ. Positioning biologics and small molecules in the management of moderate to severe IBD. Presented at: 2020 Virtual Advances in Inflammatory Bowel Diseases Conference; December 9-12, 2020.
12. Sands BE, Peyrin-Biroulet L, Loftus EV Jr, et al; VARSITY Study Group. Vedolizumab versus adalimumab for moderate-to-severe ulcerative colitis. N Engl J Med. 2019;381(13):1215-1226.
13. Simsek I, Erdem H, Pay S, Sobaci G, Dinc A. Optic neuritis occurring with anti-tumour necrosis factor alpha therapy. Ann Rheum Dis. 2007;66(9):1255-1258.
14. Sandborn W, D’Haens GR, Wolf DC, et al. Ozanimod as induction therapy in moderate-to-severe ulcerative colitis: results from the phase 3, randomized, double-blind, placebo-controlled True North study. UEG Week abstract LB02. Presented at: UEG Week Virtual 2020; October 11-13, 2020.
15. Danese S, Feagan B, Wolf DC, et al. Ozanimod as maintenance therapy in patients with moderate-to-severe ulcerative colitis: results from the phase 3, randomized, double-blind, placebo-controlled True North study. UEG Week abstract LB10. Presented at: UEG Week Virtual 2020; October 11-13, 2020.
16. Feagan BG, Loftus EV Jr, Danese S, et al. Efficacy and safety of filgotinib as induction therapy for patients with moderately to severely active ulcerative colitis: results from the phase 2b/3 selection study. UEG Week abstract LB19. Presented at: UEG Week Virtual 2020; October 11-13, 2020.
17. Peyrin-Biroulet L, Loftus EV Jr, Danese S, et al. Efficacy and safety of filgotinib as maintenance therapy for patients with moderately to severely active ulcerative colitis: results from the phase 2b/3 selection study. UEG Week abstract LB20. Presented at: UEG Week Virtual 2020; October 11-13, 2020.
18. Dulai PS, Singh S, Casteele NV, et al. Development and validation of clinical scoring tool to predict outcomes of treatment with vedolizumab in patients with ulcerative colitis. Clin Gastroenterol Hepatol. 2020;18(13):2952-2961.e8.
19. Abreu MT. Precision medicine in inflammatory bowel diseases. Presented at: 2020 Virtual Advances in Inflammatory Bowel Diseases Conference; December 9-12, 2020.
20. Kugathasan S, Denson LA, Walters TD, et al. Prediction of complicated disease course for children newly diagnosed with Crohn’s disease: a multicentre inception cohort study. Lancet. 2017;389(10080):1710-1718.
21. Howell KJ, Kraiczy J, Nayak KM, et al. DNA methylation and transcription patterns in intestinal epithelial cells from pediatric patients with inflammatory bowel diseases differentiate disease subtypes and associate with outcome. Gastroenterology. 2018;154(3):585-598.
22. Cleynen I, Boucher G, Jostins L, et al. Inherited determinants of Crohn’s disease and ulcerative colitis phenotypes: a genetic association study. Lancet. 2016;387(10014):156-167.
23. Liu JZ, van Sommeren S, Huang H, et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat Genet. 2015;47(9):979-986.
24. Jostins L, Ripke S, Weersma RK, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012;491(7422):119-124.
25. Uhlig HH, Schwerd T, Koletzko S, et al. The diagnostic approach to monogenic very early onset inflammatory bowel disease. Gastroenterology. 2014;147(5):990-1007.e3.
26. Sazonovs A, Kennedy NA, Moutsianas L, et al. HLA-DQA1*05 carriage associated with development of anti-drug antibodies to infliximab and adalimumab in patients with Crohn’s disease. Gastroenterology. 2020;158(1):189-199.
27. Aden K, Rehman A, Waschina S, et al. Metabolic functions of gut microbes associate with efficacy of tumor necrosis factor antagonists in patients with inflammatory bowel diseases. Gastroenterology. 2019;157(5):1279-1292.e11.
28. Ananthakrishnan AN, Luo C, Yajnik V, et al. Gut microbiome function predicts response to anti-integrin biologic therapy in inflammatory bowel diseases. Cell Host Microbe. 2017;21(5):603-610.e3.
29. Narula N, Kassam Z, Yuan Y, et al. Systematic review and meta-analysis: fecal microbiota transplantation for treatment of active ulcerative colitis. Inflamm Bowel Dis. 2017;23(10):1702-1709.
30. Henn MR, O’Brien EJ, Diao L, et al. A phase 1b safety study of SER-287, a spore-based microbiome therapeutic, for active mild to moderate ulcerative colitis. Gastroenterology. 2021;160(1):115-127.e30.
31. Lichtenstein GR. Highlights from the 2019 Advances in Inflammatory Bowel Diseases Conference: commentary. Gastroenterol Hepatol (N Y). 2019;15(12)(suppl 6):12-19.