A Review of Selected Presentations From the 2021 AIBD Conference
December 9-11, 2021
The Past, Present, and Future of Inflammatory Bowel Disease
At the 2021 Advances in Inflammatory Bowel Diseases conference, Dr Stephen B Hanauer provided a keynote presentation about the past, present, and future of inflammatory bowel disease (IBD). Early treatments of IBD included aminosalicylates, corticosteroids, and thiopurines.1 The past 2 decades have seen the development of biologic therapies that specifically target key molecules involved in the pathology of IBD (Table 1). Infliximab, adalimumab, and golimumab are inhibitors of tumor necrosis factor (TNF) that have proven efficacy in treating both Crohn’s disease and ulcerative colitis. Although the antibodies that are used to treat IBD are immunogenic, immunogenicity can be controlled by means of high-dose induction therapy followed by a reduced dose during maintenance therapy, combined with immunomodulators. Combination therapy may be more effective than anti-TNF monotherapy, but may reduce safety and tolerability. Anti-TNF therapy is typically associated with an eventual loss of response, which may be attributed to immunogenicity, pharmacology, or loss of the mechanism of action. The initial response to biologic therapy can be improved by treating the patient earlier in the course of the disease and by using a treat-to-target strategy that can improve the odds of a complete response. Insights may be gained from pharmacokinetic/pharmacodynamic analyses and through therapeutic drug monitoring.
IBD is marked by the presence of lymphocytes and myeloid cells in the intestine. Antibodies against the integrins can reduce leukocyte migration to the intestine. Vedolizumab inhibits integrin α4β7 and was approved by the US Food and Drug Administration (FDA) for the treatment of patients with ulcerative colitis or Crohn’s disease in 2014. Etrolizumab, a monoclonal antibody directed at the β7 integrin, has shown mixed results in several IBD clinical trials.2 Ustekinumab is a monoclonal antibody directed against the interleukins (IL) 12 and 23, key mediators of mucosal inflammation. Ustekinumab received FDA approval for treating Crohn’s disease in 2016, followed by approval for ulcerative colitis in 2019. Monoclonal antibodies that target IL-12 and/or IL-23 that are in development include brazikumab, risankizumab, mirikizumab, and guselkumab. Small molecules directed to specific biologic targets are in development for IBD and may prove useful as monotherapy or in combination with antibody therapy.3 Small molecules may offer advantages over monoclonal antibodies in terms of ease of manufacture, shelf stability, and reduced immunogenicity. Tofacitinib, a small-molecule inhibitor of Janus kinase (JAK), received approval for the treatment of ulcerative colitis in 2018. The small-molecule JAK inhibitors in development for IBD include filgotinib and upadacitinib. JAK inhibitors are believed to reduce production of inflammatory cytokines associated with IBD. Although they have demonstrated efficacy, they are associated with an increased risk of thromboembolic events.4 Another class of small-molecule therapy is directed against the sphingosine-1-phosphate (S1P) receptor. Ozanimod received approval for the treatment of ulcerative colitis in 2020. Etrasimod is in development.
Given the limitations of currently available IBD therapies, combination regimens are of interest.5,6 To date, however, combinations have generally led to limited improvements in efficacy and increased safety concerns. In addition to the treat-to-target approach, another strategy to improve patient outcome is the use of new predictive tools, such as personalized medicine, proteomics, and serologic and fecal markers. These tools can also be applied to identify more narrow clinical phenotypes or subclasses of IBD, such as Crohn’s-like, colitis-like, early-onset, and postsurgical.
References
1. Hanauer SB. The past, present, and future of IBD. Paper presented at: the 2021 Advances in Inflammatory Bowel Diseases Conference; Orlando, Florida; December 9-11, 2021.
2. Coskun M, Vermeire S, Nielsen OH. Novel targeted therapies for inflammatory bowel disease. Trends Pharmacol Sci. 2017;38(2):127-142.
3. Sattler L, Hanauer SB, Malter L. Immunomodulatory agents for treatment of patients with inflammatory bowel disease (review safety of anti-TNF, anti-integrin, anti IL-12/23, JAK inhibition, sphingosine 1-phosphate receptor modulator, azathioprine/6-MP and methotrexate). Curr Gastroenterol Rep. 2021;23(12):30.
4. Dudek P, Fabisiak A, Zatorski H, Malecka-Wojciesko E, Talar-Wojnarowska R. Efficacy, safety and future perspectives of JAK inhibitors in the IBD treatment. J Clin Med. 2021;10(23):5660.
5. Hirten RP, Iacucci M, Shah S, Ghosh S, Colombel JF. Combining biologics in inflammatory bowel disease and other immune mediated inflammatory disorders. Clin Gastroenterol Hepatol. 2018;16(9):1374-1384.
6. Sands BE, Kozarek R, Spainhour J, et al. Safety and tolerability of concurrent natalizumab treatment for patients with Crohn’s disease not in remission while receiving infliximab. Inflamm Bowel Dis. 2007;13(1):2-11.
7. Mócsai A, Kovács L, Gergely P. What is the future of targeted therapy in rheumatology: biologics or small molecules? BMC Med. 2014;12:43.
8. Geigert J. The Challenge of CMC Regulatory Compliance for Biopharmaceuticals and Other Biologics. 2nd ed. New York, NY: Springer; 2013.
Personalized Medicine: Yesterday, Today, and Tomorrow
Dr Marla Dubinsky discussed personalized medicine.1 The current approach to selecting treatment for patients with IBD is imprecise. Relatively poor clinical outcomes are accompanied by patient dissatisfaction and concerns regarding expense. The available treatments are limited, and efficacy has plateaued. Personalized medicine identifies distinguishing disease characteristics for each patient, using analyses of genetics or other biomarkers, to tailor treatment based on the predicted response. Identification of disease characteristics that inform treatment offers the greatest chance of optimizing outcome.
Development of Models to Risk-Stratify Patients
Patients with IBD may initially be stratified according to risk based on characteristics such as age, extent and location of disease, biomarker levels, and other factors. In addition to disease characteristics, genetic and serologic markers can be examined. Rather than looking at a single gene, efforts are underway to develop genome-wide polygenic analyses that predict susceptibility to IBD. A genome-wide polygenic score was developed using 12,882 cases and 21,770 control subjects.2 The strategy identified patients who were at least 3 times more likely than the general population to develop IBD. A prospective inception cohort study of pediatric patients with newly diagnosed Crohn’s disease developed a model to predict the risk of stricturing.3 The model incorporated age, race, disease location, and antimicrobial serology. The risk of penetrating complications was reduced in patients who received early anti-TNFα therapy (hazard ratio [HR], 0.30; 95% CI, 0.10-0.89; P=.0296). However, the risk of stricturing complication was not affected (HR, 1.13). When added to the risk model, a signature of ileal genes that control extracellular matrix production was associated with an increased risk of stricturing (HR, 1.70; 95% CI, 1.12-2.57; P=.0120). In a study of 243 patients with Crohn’s disease, significant variables in a multivariate Cox model included specific disease locations, as well as serologic markers, such as antibodies to Saccharomyces cerevisiae (HR, 1.35; 95% CI, 1.16-1.58) and antineutrophil cytoplasmic antibodies (HR, 0.77; 95% CI, 0.62-0.95).4 Antibodies to CBir and OmpC have also been associated with a more aggressive course of Crohn’s disease.5
Personalized Medicine
Personalized medicine offers the possibility of matching the best treatment to patients based on specific disease characteristics. Oncostatin M (OSM) is a proinflammatory cytokine in the IL-6 family whose expression is increased in IBD patients. In a study of 162 patients with Crohn’s disease and 74 patients with ulcerative colitis, higher levels of OSM and the OSM receptor correlated with a reduced response to anti-TNF therapy.6 In addition to OSM, mRNA levels of IL-6, IL-1A, and IL-1B were elevated in intestinal mucosal biopsy samples compared with controls. Moreover, higher levels of OSM and OSM receptor expression correlated to increased disease severity. Based on unsupervised hierarchical clustering, increased expression of a group of cytokines associated with OSM levels in pretreatment intestinal biopsies was strongly associated with a lack of response to anti-TNF therapy. Similarly, expression of intestinal α4β7 predicted response to vedolizumab (Figure 1).7 Other biomarkers, such as triggering receptor expressed on myeloid cells 1 (TREM1), may also predict response to anti-TNF therapy (Figure 2).8
With many exciting developments providing new insights into this heterogeneous disease, it will be imperative to develop IBD disease assessment and treatment algorithms that improve the ability to match the right patient with the right treatment. These algorithms can incorporate genetic and serologic biomarkers, as well as patient and disease characteristics.
References
1. Dubinsky M. Personalized medicine: yesterday, today and tomorrow. Paper presented at: the 2021 Advances in Inflammatory Bowel Diseases Conference; Orlando, Florida; December 9-11, 2021.
2. Khera AV, Chaffin M, Aragam KG, et al. Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations. Nat Genet. 2018;50(9):1219-1224.
3. Hyams JS, Thomas SD, Gotman N, et al. Clinical and biological predictors of response to standardised paediatric colitis therapy (PROTECT): a multicentre inception cohort study. Lancet. 2019;393(10182):1708-1720.
4. Siegel CA, Horton H, Siegel LS, et al. A validated web-based tool to display individualised Crohn’s disease predicted outcomes based on clinical, serologic and genetic variables. Aliment Pharmacol Ther. 2016;43(2):262-271.
5. Dubinsky M. What is the role of serological markers in the diagnosis of IBD? Inflamm Bowel Dis. 2008;(14 suppl 2):S185-S186.
6. West NR, Hegazy AN, Owens BMJ, et al; Oxford IBD Cohort Investigators. Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease. Nat Med. 2017;23(5):579-589.
7. Rath T, Billmeier U, Ferrazzi F, et al. Effects of anti-integrin treatment with vedolizumab on immune pathways and cytokines in inflammatory bowel diseases. Front Immunol. 2018;9:1700.
8. Verstockt B, Verstockt S, Dehairs J, et al. Low TREM1 expression in whole blood predicts anti-TNF response in inflammatory bowel disease. EBioMedicine. 2019;40:733-742.
Micronutrient Deficiencies in Inflammatory Bowel Disease
Dr Gary Lichtenstein discussed the micronutrient deficiencies that are seen in patients with IBD.1 These patients may have deficiencies in selenium, folic acid, vitamin A, and vitamin K, as well as vitamin B12, vitamin D, zinc, and iron.
Vitamin B12 Deficiency
In patients with Crohn’s disease, vitamin B12 deficiency can arise due to malabsorption (enteritis), absence of a terminal ileum, and, rarely, pernicious anemia.2 Risk factors in patients with Crohn’s disease include ileal resection or disease in more than 30 cm of the ileum, fistula, bacterial overgrowth in the small bowel, inadequate intake of vitamin B12, enteropathy resulting in protein loss, and hepatic dysfunction. Findings were equivocal in patients with ileal resection from 20 cm to 30 cm. Patients with ulcerative colitis are not predisposed to vitamin B12 deficiency. The clinical manifestations of vitamin B12 deficiency include megaloblastic anemia and neurologic dysfunction.
In patients with Crohn’s disease with ileal resection greater than 20 cm, vitamin B12 should be supplemented. Low-quality evidence suggests that oral and injected vitamin B12 may have similar efficacy.3 The best formulation of B12 for a certain patient is the one that he or she will take and tolerate. However, patients with very low serum vitamin B12 and symptoms benefit from the use of a parenteral formulation.
Vitamin D Deficiency
Vitamin D deficiency is present in up to 95% of patients with IBD.4 All patients should undergo evaluation for vitamin D deficiency.4 The clinical manifestations include secondary hyperparathyroidism, osteopenia, and osteoporosis. Vitamin D deficiency is diagnosed by measurement of the serum level of 25-hydroxy-vitamin D (25-OHD). A level of 25-OHD between 20 ng/mL and 50 ng/mL (50 nmol/L-125 nmol/L) is considered adequate for healthy individuals and is crucial for maintaining bone health and overall health.
Zinc Deficiency
Zinc deficiency occurs in up to 40% of patients with IBD and is underrecognized in this population.5,6 Among patients with Crohn’s disease in remission, as many as two-thirds may have zinc levels that are below normal. Risk factors and causes of zinc deficiency include various “ostomies,” fistulas, and profuse diarrhea. Clinical manifestations of zinc deficiency include dermatitis, diarrhea, dysgeusia, alopecia, and depressed immune function, which may result in frequent infections. Zinc levels can be measured in erythrocytes, neutrophils, lymphocytes, and hair. A zinc level below 60 μg/dL in plasma is considered deficient. Some patients, particularly those with severe diarrhea, should receive oral or parenteral zinc replacement with daily maintenance doses of 10 mg to 15 mg of elemental zinc. In an analysis of prospectively collected data from 773 patients with Crohn’s disease and 223 patients with ulcerative colitis, zinc deficiency was associated with an increased risk of subsequent hospitalization, surgery, and disease-related complications.7 Normalization of zinc levels was associated with improvement in the same outcomes in both Crohn’s disease and ulcerative colitis. It should be mentioned, however, that these studies may be limited by confounding according to indication.
Iron Deficiency
Iron deficiency anemia is present in up to 76% of patients with IBD.8 Iron deficiency correlates directly with disease activity and may arise owing to a lack of intake in the diet or malabsorption. Clinical manifestations include fatigue/weakness, microcytic anemia, and pica syndrome. Various iron formulations are available to tailor iron supplementation to the patient. High levels of hepcidin block the absorption of iron in the intestine as well as iron recycling, leading to anemia.9 In order to provide the best care for IBD patients, screening and treatment for deficiencies in iron and other micronutrients is imperative.
References
1. Lichtenstein GR. Deficiencies in IBD. Paper presented at: the 2021 Advances in Inflammatory Bowel Diseases Conference; Orlando, Florida; December 9-11, 2021.
2. Battat R, Kopylov U, Szilagyi A, et al. Vitamin B12 deficiency in inflammatory bowel disease: prevalence, risk factors, evaluation, and management. Inflamm Bowel Dis. 2014;20(6):1120-1128.
3. Wang H, Li L, Qin LL, Song Y, Vidal-Alaball J, Liu TH. Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency. Cochrane Database Syst Rev. 2018;3(3):CD004655.
4. Mouli VP, Ananthakrishnan AN. Review article: vitamin D and inflammatory bowel diseases. Aliment Pharmacol Ther. 2014;39(2):125-136.
5. Gîlcă-Blanariu GE, Diaconescu S, Ciocoiu M, Ștefănescu G. New insights into the role of trace elements in IBD. BioMed Res Int. 2018;2018:1813047.
6. Weisshof R, Chermesh I. Micronutrient deficiencies in inflammatory bowel disease. Curr Opin Clin Nutr Metab Care. 2015;18(6):576-581.
7. Siva S, Rubin DT, Gulotta G, Wroblewski K, Pekow J. Zinc deficiency is associated with poor clinical outcomes in patients with inflammatory bowel disease. Inflamm Bowel Dis. 2017;23(1):152-157.
8. Murawska N, Fabisiak A, Fichna J. Anemia of chronic disease and iron deficiency anemia in inflammatory bowel diseases: pathophysiology, diagnosis, and treatment. Inflamm Bowel Dis. 2016;22(5):1198-1208.
9. Pagani A, Nai A, Silvestri L, Camaschella C. Hepcidin and anemia: a tight relationship. Front Physiol. 2019;10:1294.
Preparing for Inflammatory Bowel Disease Care in the Next Pandemic: Lessons Learned From COVID-19
Dr David T. Rubin discussed COVID-19 and future pandemics.1 The COVID-19 pandemic presented specific problems for the IBD population, such as lack of access to care and confusion regarding the risks. Several areas of success were reported. There was rapid coordination and collaboration among practitioners, regular updates and reassurances, effective use of social media, support from colleagues, and numerous recommendations from expert panels. IBD societies provided guidance based on input from national and international experts.
The inevitable advance of climate change, population growth, and the human push to inhabit environments that are occupied by animals are among the factors that set the stage for another pandemic.2 Dr Rubin outlined steps to take to prepare for the next pandemic.
Eight Steps to Prepare for the Next Pandemic
Develop a National Network of
IBD Providers and Patients for Crisis Management
The development of a network for rapid evaluation and assessment of emerging diseases would enable real-time guidance and recommendations for patients with IBD and their health care providers. The group could identify priorities for investment and strategic planning for future epidemics.
Prioritize Health Care Workers’ Mental Health
The mental well-being of health care workers should be addressed according to specific occupations.3 A national IBD network would provide early and organized communication regarding situation dynamics, such as who is affected, how dangerous the situation is, and the tools that are available to address the situation. Worker safety must be a priority.
Manage the Education and
Improvement of Patients and
Medical Professionals
COVID-19 outcomes are worse among patients who are taking corticosteroids, underscoring the need to achieve sustained, functional remission without corticosteroids wherever possible. Proactive disease monitoring should be emphasized.4
Develop a Pandemic Preparedness Plan
Offices should stockpile personal protective equipment. It is important to develop policies for every independent practice related to telehealth and working from home. Safety net plans need to be in place for employees, along with the means to rapidly communicate with patients en masse.
Identify and Fund Research
Priorities for IBD
Research priorities for IBD should include uptake and response to COVID-19 vaccination, as well as long COVID-19. Clinicians need a detailed understanding of viral entry through the angiotensin-converting enzyme 2 (ACE2) receptor. Other areas of research should include infectious complications of therapies in patients with active IBD, the efficacy of antiviral therapies in patients receiving treatment for IBD, pandemic effects on the mental health of patients with IBD and their health care providers, and social determinants of health in IBD and the impact of social factors on access to care.
Address Access Issues for the
Underserved
Patients with IBD who lack adequate access to health care clearly have worse outcomes. Similarly, access to vaccination is disproportionately lacking among economically disadvantaged patients. A higher level of disease activity and the use of corticosteroids were associated with worse outcomes from COVID-19.5,6
Build Trust: End Discrimination and Bias in Clinical Trial Recruitment
Enrollment of patients in clinical trials should reflect the true population of IBD patients. Trial investigators should follow good participatory practice, and thus include a spectrum of patients across racial and ethnic minorities.7 By expanding the pool of patients who are recruited into clinical trials, the medical community can build trust with patients.
Promote Legislative Priorities
for the IBD Population in the United States
Numerous legislative goals must be pursued at the federal, local, and institutional levels. Politicians must be held accountable to science and public health. There should be increased federal funding of pandemic preparedness for vulnerable populations, as well as for health care workers and patients. Benefits for the health care workforce at academic institutions and hospital-based practices should be protected.
References
1. Rubin DT. Preparing for IBD care in the next pandemic: lessons learned from COVID-19. Paper presented at: the 2021 Advances in Inflammatory Bowel Diseases Conference; Orlando, Florida; December 9-11, 2021.
2. Yong E. We’re already barrelling toward the next andemic. ttps://www.theatlantic.com/health/archive/2021/09/america-prepared-next-pandemic/620238/. Updated September 29, 2021. Accessed December 27, 2021.
3. Prasad K, McLoughlin C, Stillman M, et al. Prevalence and correlates of stress and burnout among U.S. healthcare workers during the COVID-19 pandemic: a national cross-sectional survey study. EClinicalMedicine. 2021;35:100879.
4. Cornerstones Health. Cornerstones IBD Checklists and Tools. https://www.cornerstoneshealth.org/ibd-checklists/. Accessed December 27, 2021.
5. Bezzio C, Saibeni S, Variola A, et al. Outcomes of COVID-19 in 79 patients with IBD in Italy: an IG-IBD study. Gut. 2020;69(7):1213-1217.
6. Brenner EJ, Pigneur B, Focht G, et al. Benign evolution of SARS-Cov2 infections in children with inflammatory bowel disease: results from two international databases. Clin Gastroenterol Hepatol. 2021;19(2):394-396.e5.
7. Cohen NA, Silfen A, Rubin DT. Inclusion of under-represented racial and ethnic minorities in randomized clinical trials for inflammatory bowel disease. Gastroenterology. 2022;162(1):17-21.
Positioning Medications: Yesterday, Today, and Tomorrow
Dr Edward V. Loftus discussed how to position medications in IBD.1 With several biologics and small molecules currently available and in the pipeline for the treatment of IBD, choosing the optimal first- and second-line therapies for each patient has become more complex.1 The difficulty is compounded by disease heterogeneity, patient factors, and a lack of trials that directly compare outcomes from different drugs.
The multicenter, blinded, active-controlled, randomized phase 3b SEAVUE study compared ustekinumab vs adalimumab as induction and maintenance treatment in 386 patients with moderately to severely active Crohn’s disease, without prior exposure to a biologic therapy.2 The primary endpoint was clinical remission at 52 weeks, based on a Crohn’s Disease Activity Index (CDAI) score of less than 150. At week 52, the rates of clinical remission were 61.0% with adalimumab vs 64.9% with ustekinumab, a difference that did not reach statistical significance (95% CI, –5.5% to 13.5%; P=.417). Rates of clinical remission through week 52 are shown in Figure 3. A major secondary endpoint was corticosteroid-free clinical remission at week 52. These rates were 60.7% for adalimumab vs 57.4% for ustekinumab (P=.485). An adverse event (AE) required discontinuation of treatment in 11.3% of the adalimumab arm vs 6.3% of the ustekinumab arm. Serious AEs were reported in 16.4% vs 13.1%, respectively.
A retrospective study evaluated safety outcomes in patients with IBD who had received treatment with vedolizumab or a TNF antagonist.3 Rates of serious infection did not differ for the entire population of patients with IBD (HR, 0.92) or for the subset of patients with Crohn’s disease (HR, 1.1). There was a reduced rate of serious infections in patients treated with vedolizumab vs a TNF antagonist (HR, 0.68; P<.05).
Treatment decisions can be guided by distinguishing patients with IBD who have severe disease that requires intervention from those with less severe disease or who are more risk-averse.4 For patients with severe disease, infliximab and adalimumab are appropriate as first-line treatments. For the risk-averse patient or one with comorbidities, ustekinumab and vedolizumab are reasonable choices. Results from the phase 3b VARSITY trial showed that, in patients with ulcerative colitis, vedolizumab was superior to adalimumab in terms of clinical remission at week 52 (31.3% vs 22.5%; P=.0061).5 Vedolizumab was superior to the TNF antagonist in the subpopulation of anti-TNF–naive patients (34.2% vs 24.3%; P=.0070), but not in patients with prior exposure to a TNF antagonist (20.3% vs 16.0%; P=.4948). Vedolizumab also was slightly better in terms of mucosal healing at week 52, specifically in patients without prior exposure to TNF-directed therapy (43.1% vs 29.5%; P=.0005). An analysis of histologic remission also supported the superiority of vedolizumab vs adalimumab in the VARSITY study.6
A meta-analysis in patients with moderately to severely active ulcerative colitis without prior exposure to biologic therapy found that infliximab led to the highest rates of endoscopic remission among patients receiving induction therapy.7 The surface under the cumulative ranking (SUCRA) was 0.95 for infliximab, followed by 0.76 for vedolizumab.7 In patients with prior anti-TNF exposure, tofacitinib was best (SUCRA, 0.91), followed by ustekinumab (SUCRA, 0.83).
Dr Loftus offered several recommendations. He noted that head-to-head data are limited. Infliximab is still a leading first-line treatment for many patients. For patients with ulcerative colitis, vedolizumab is a strong choice as first-line treatment and a reasonable option for the second line. Tofacitinib is an excellent biologic therapy for the second-line treatment of ulcerative colitis. Adalimumab is a reasonable choice for patients who do not respond to infliximab, especially in the setting of Crohn’s disease. Ustekinumab is an excellent biologic therapy for the second-line treatment of Crohn’s disease and possibly ulcerative colitis.
References
1. Loftus EV. Positioning medications: yesterday, today and tomorrow. Paper presented at: the 2021 Advances in Inflammatory Bowel Diseases Conference; Orlando, Florida; December 9-11, 2021.
2. Sands BE, Irving PM, Hoops T, et al. Ustekinumab versus adalimumab for induction and maintenance therapy in moderate-to-severe Crohn’s disease: the SEAVUE study [DDW abstract 775d]. Gastroenterology. 2021;161(suppl 2).
3. Kirchgesner J, Desai RJ, Beaugerie L, Schneeweis S, Kim SC. Risk of serious infections associated with vedolizumab versus tumor necrosis factor antagonists in patients with inflammatory bowel disease: a multinational, population-based cohort study [UEGW abstract OP011]. UEG Journal. 2020;8(8 suppl):14-15.
4. Nguyen NH, Singh S, Sandborn WJ. Positioning therapies in the management of Crohn’s disease. Clin Gastroenterol Hepatol. 2020;18(6):1268-1279.
5. Sands BE, Peyrin-Biroulet L, Loftus EV Jr, et al. Vedolizumab versus adalimumab for moderate-to-severe ulcerative colitis. N Engl J Med. 2019;381(13):1215-1226.
6. Peyrin-Biroulet L, Loftus EV Jr, Colombel JF, et al. Histologic outcomes with vedolizumab versus adalimumab in ulcerative colitis: results from an efficacy and safety study of vedolizumab intravenous compared to adalimumab subcutaneous in participants with ulcerative colitis (VARSITY). Gastroenterology. 2021;161(4):1156-1167.e3.
7. 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.
Highlights From the 2021 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 2021 AIBD conference featured exciting presentations pertaining to the many different agents and strategies available for the management of patients with IBD.
Dr Stephen Hanauer gave a keynote lecture focusing on the past, present, and future of IBD.1 Dr Hanauer reviewed earlier treatments, such as the aminosalicylate sulfasalazine. Aminosalicylates are rapidly absorbed in the proximal GI tract, but they act primarily in a topical manner.2 They are very well tolerated. In contrast, corticosteroids can be associated with notable adverse events.3 Dr Hanauer also reviewed the role of delayed-release budesonide MMX in the treatment of patients with active ulcerative colitis. Corticosteroids are not suitable for maintenance therapy, but they are effective for inductive treatment in patients with moderate disease.4 Thiopurines can be corticosteroid-sparing in ulcerative colitis and Crohn’s disease. They can be used in combination with biologic agents to reduce immunogenicity. However, thiopurines are associated with neoplasia, including nonmelanoma skin cancer and lymphoma, as well as infectious complications (primarily viral pathogens).5 In addition, genetic polymorphisms are associated with adverse events such as bone marrow suppression, transaminitis, and pancreatitis.
Biologic therapy is effective for Crohn’s disease and ulcerative colitis.6 All monoclonal antibodies are immunogenic, but the extent varies. In general, combination therapy is more effective than monotherapy. Combination therapy is especially beneficial for anti-TNF agents.7 Data do not suggest that the use of antimetabolite therapy in combination with ustekinumab or vedolizumab is superior to biologic monotherapy.8 However, these are no prospective, randomized, controlled trials evaluating monotherapy vs combination therapy with these agents. This statement is based upon retrospective post-hoc analyses of primary controlled trials. There are several ways to improve the initial response. Treatment early in the course of the disease is associated with an improved response to therapy with the treat-to-target approach. Clinicians can evaluate pharmacokinetics and pharmacodynamics, and perform prospective therapeutic drug monitoring. The role of prospective monitoring has not yet been well established by clinical trials. However, the practice is logical and therefore used by many clinicians.
There are many exciting new and novel molecules, with different mechanisms of action. Ozanimod, a sphingosine-1-phosphate (S1P) receptor 1 and 5 modulator, was recently added to the therapeutic armamentarium.9 Other S1P agents are in development. The JAK inhibitor tofacitinib is currently approved for the treatment of moderate-to-severe ulcerative colitis. Two other JAK inhibitors are currently in development: filgotinib and upadacitinib. Filgotinib is approved in the European Union. Upadacitinib is undergoing clinical trials.10 Other agents approved by the FDA include the anti-adhesion molecules natalizumab and vedolizumab, the anti–interleukin (IL) 12/23 antagonist agent ustekinumab, and the anti-TNF agents infliximab, adalimumab, golimumab, and certolizumab pegol. Other specific IL-23 antagonists are in development.
Dr Hanauer discussed the concept of combining biologics.1 Although combination therapy has been widely used in other specialties, such as oncology, potential roadblocks to this approach include the possible safety issues associated with a high level of immune suppression and the cost of therapy. This strategy has become a standard approach for the treatment of various malignancies. Currently, there is limited experience with the use of biologic combinations in patients with IBD.11 It appears that biologic combinations would be reasonable in certain patient populations.
Dr Hanauer noted that future advances in therapy will require new predictive tools, such as omics, serologic markers, and serum and fecal biomarkers to continue to define clinical phenotypes. An important treatment tenet will be to use pharmacology to optimize efficacy and safety. Clinicians use the treat-to-target strategy to maintain tight control. Definitions of pathogenesis and susceptibility will be important components of the therapeutic armamentarium.
Dr Marla Dubinsky discussed personalized medicine, which uses genetics or other biomarkers to guide treatment decisions for different groups of patients.12 Dr Dubinsky noted that personalized medicine shifts the emphasis from reaction to prevention, thus overcoming limitations of traditional medicine. With personalized medicine, clinicians can identify patients with high-risk disease, and initiate appropriately aggressive treatment while reducing the risk of adverse events.
Many arenas today follow an empirical strategy; treatment reflects a one-size-fits-all approach.13 A treatment is administered, and the clinician evaluates efficacy. The biologic approach attempts to identify which patients will respond best to a particular agent and to predict the response. The trial-and-error approach has not demonstrated the best outcomes. It is more costly because many more patients receive treatment, and it is less efficient. Patients may be dissatisfied if they do not respond, and the probability of response is not high. This approach was driven by limited biologic options. There are now more available treatments. It is possible to begin to use the biologic approach in clinical practice. For example, no more than a third of patients will achieve remission. The response rate is approximately 50% to 60% in clinical trials of novel or existing biologics.14,15 To increase this rate, it may be necessary to administer combination therapy and/or to select specific patient populations for treatment.
In the future, the biologic approach will likely become more common. A biologic approach to IBD would consider the patient’s prognostic markers. Patients who have a poor prognosis might be candidates for a rapid step-up approach. Patients with a better prognosis might benefit from a slower approach, with less aggressive therapy associated with fewer potential adverse events. Clinicians should strive for the endpoint of disease modification. The AGA has provided guidance with suggestions to use specific parameters to stratify disease according to risk.16 In ulcerative colitis, risk factors for colectomy include age younger than 40 years, extensive colitis, corticosteroid-requiring disease, deep ulcers, history of hospitalization, high levels of C-reactive protein or a high erythrocyte sedimentation rate, infection with Clostridioides difficile, and cytomegalovirus. In Crohn’s disease, risk factors for rapid disease progression include age younger than 30 years at diagnosis, extensive anatomic involvement, perianal disease, severe rectal disease, deep ulcers, prior surgical resection, stricturing behavior, and penetrating behavior. This management protocol is one of the first attempts in the IBD arena to risk-stratify patients, thereby allowing treatment with appropriate interventions based upon the expected prognosis.
Dr Dubinsky also discussed genetic markers. The presence of the NOD2 gene in patients with Crohn’s disease is associated with complicated disease, which is defined as development of strictures and the need for surgery.17 This discovery suggested that we could predict the phenotype, as well as the disease itself. More than 200 genes are associated with IBD; not all are as predictive as the NOD2 gene. The need for aggressive intervention increases with the number of serologic markers, such as CBir, outer membrane protein C (OmpC), and anti-saccharomyces cerevisiae antibodies (ASCA).18 Penetrating behavior, stricturing behavior, and surgical disease correspond to the number of positive markers. These characteristics indicate that the patient has a poor prognosis and will require aggressive treatment to minimize the risk of disease complications. Researchers have evaluated other extracellular and matrix gene expressions in a similar fashion.19
It will be key to make this information readily available for patients’ care. In 2016, Dr Corey Siegel published a clinical decision support tool that used a patient’s prognosis to guide selection of treatment and predict response.20 Different disease states are associate with different signature cytokine profiles. Patients with ankylosing spondylitis, psoriatic arthritis, and rheumatoid arthritis respond differently to different therapeutic agents. There is a suggestion that the presence of specific gene signatures may be able to predict response,21 but this concept is less advanced in IBD. A recent study suggested that oncostatin M might be able to help predict response to anti-TNF therapy in patients with IBD.22 A prospective trial is currently underway evaluating the influence of this biomarker on response to therapy.23 Data suggest that levels of TREM-1 may predict response to anti-TNF therapy.24 Intestinal expression of the integrin alpha 4/beta 7 predicts response to vedolizumab.25 Levels of IL-22 predict response to treatments that target the p19 subunits of IL-23.26
This area has evolved since thiopurine methyltransferase metabolism (TPMT) was evaluated to predict the metabolism of azathioprine in 1989.27 Different milestones have improved our understanding of drug metabolism, and provided insight into how this information can be used in dosing based upon an agent’s pharmacogenetics. Studies recently evaluated the association between thiopurine methyltransferase and NUDT15, a genetic marker that can predict response to azathioprine or 6-mercaptopurine and is commonly used in clinical practice.28,29 Levels of thiopurine methyltransferase and NUDT15 are measured prior to initiation of therapy with azathioprine or 6-mercaptopurine. Use of thiopurines to treat IBD is associated with pancreatitis in up to 17% of patients.30 This rate varies according to the presence of specific HLA genes. The risk of pancreatitis is 9% in heterozygotes and 17% in homozygotes of different HLA genes, such as HLA-DRB1*07:01 and HLA-DQA1*02:01.
The presence of the genetic marker HLA DQA105 is associated with a higher rate of immunogenicity against anti-TNF therapy.31 Theoretically, it might be helpful to test patients for this maker. Patients who are positive should receive dual therapy (anti-TNF biologic therapy and immunomodulator therapy). This strategy has not been evaluated in a prospective randomized trial, but it is enticing. Anti-TNF therapy can be associated with paradoxical psoriasis, but only in patients with 2 certain SNPs, according to a small study.32 Skin taping can be used to evaluate for atopic dermatitis and psoriasis, in order to identify distinct profiles.33 Skin taping is in the initial stages of assessment.
An algorithm is needed to help guide management to decrease the risks of nonresponse and immunogenicity, as well as to profile patients to determine when their disease course will require aggressive therapy, such as biologic agents. Many ongoing studies are addressing these questions. The era of precision medicine has arrived.
At the AIBD meeting, I discussed recognition and management of micronutrient deficiencies in patients with IBD.34 Many micronutrient deficiencies arise in patients with IBD. My presentation focused on iron, vitamin B12, zinc, and vitamin D. These nutrient deficiencies are often overlooked, and the downstream effects can be substantial. The many different etiologies for vitamin B12 deficiency include gastric issues such as autoimmune gastritis; pernicious anemia; post-gastrectomy surgery, such as a Billroth II surgery; and intestinal resection.35 Typically, 20 cm to 30 cm of active ileal disease or the lack of 20 cm to 30 cm of the ileum in patients with Crohn’s disease can prevent adequate absorption of vitamin B12. Pancreatic disease can be associated with aberrant vitamin B12 absorption. Exocrine pancreatic insufficiency is a condition characterized by deficiency of the exocrine pancreatic enzymes, resulting in the inability to digest food properly, or maldigestion. The exocrine pancreas produces 3 specific types of enzymes: amylase, lipase, and protease. These pancreatic enzymes are normally present and function to cleave the R proteins (also known as haptocorrin and transcobalamin 1), which are produced in the salivary glands. When vitamin B12 couples with the R proteins, this serves to protect the vitamin B12 from degradation in the acidic environment of the stomach. The next step that occurs is that another binding protein for B12—intrinsic factor (a protein synthesized by gastric parietal cells that is secreted in response to histamine, gastrin, and pentagastrin, as well as the presence of food)—comes into play. Several proteases are made in the pancreas and get secreted into the lumen of the duodenum. The 2 major pancreatic proteases are trypsin and chymotrypsin. In the duodenum, proteases digest the R-proteins and release their bound vitamin B12 to become unbound vitamin B12. The unbound vitamin B12 then couples and binds with intrinsic factor to form an intrinsic factor/vitamin B12 complex that can be effectively absorbed in the terminal ileum. The intrinsic factor protects the vitamin B12 from catabolism by intestinal bacteria to facilitate its uptake.
It is important to recognize that R proteins have a higher affinity to vitamin B12, so they compete with intrinsic factor to bind the vitamin B12. When exocrine pancreatic insufficiency is present, the R proteins are not cleaved (since there is a lack of trypsin and chymotrypsin production) and the vitamin B12-R protein complex is not taken up in the terminal ileum, leading to serum vitamin B12 deficiency. In addition, patients may be vegetarian or vegan, and lack B12 in their diet. Medications associated with B12 deficiency include proton pump inhibitors, metformin, colchicine, cholestyramine, and nitrous oxide.36 Some rare congenital deficiencies of the intrinsic tract receptor or transcobalamin deficiency can also cause B12 deficiency. Thus, it is clear that IBD is not the only reason that patients may become deficient in vitamin B12.
In Crohn’s disease, malabsorption with inflammation in the ileum is the classic cause of vitamin B12 deficiency.37 The deficiency can develop over time, as resection of the ileum may lead to inadequate surface area for absorption of nutrients. Pernicious anemia can create an antibody against intrinsic factor, which the ileum needs to absorb B12. Patients with Crohn’s disease may have undergone a resection that removed more than 30 cm of the ileum. Fistulas can bypass the ileum. Small intestinal bacterial overgrowth can occur, and the bacteria themselves metabolize vitamin B12 and decrease the amount of vitamin B12 available for absorption. There may be reduced intake or increased physiologic requirements, protein-losing enteropathy, or liver dysfunction. Clinically, this may manifest as megaloblastic anemia or neurologic dysfunction, such as neuropathy or dementia.
Vitamin B12 deficiency can be seen in up to 25% of patients with J pouches, which could be due to a decrease in absorption of vitamin B12 overall.38 There may be fecal stasis, small intestinal bacterial overgrowth with bacterial utilization of vitamin B12, and villous atrophy. Vitamin B12 deficiency is often overlooked in patients with J pouches. Based on clinical experience, I recommend that these patients undergo annual testing of their serum vitamin B12 levels.
A serum level of less than 200 pg/mL is considered abnormal.39 Elevation of homocysteine and methylmalonic acid is a confirmatory biomarker. Data from 2 randomized controlled trials suggest that efficacy may be similar between oral and intramuscular injections of vitamin B12.40,41 These studies had small numbers of patients. However, it is comforting to realize that some patients may not need injections to treat their vitamin B12 deficiency. In addition, there are many ways to administer supplements of vitamin B12: intramuscular, oral, sublingual, intranasal, and subcutaneous. The intramuscular formulation provides the best bioavailability for a patient who needs rapid vitamin B12 supplementation. The level of evidence is higher for the intramuscular route than for the other routes of administration. However, patients should receive the formulation that works best for them.
Heightened inflammatory states, such as active IBD, are associated with vitamin D deficiency. Approximately 16% to 95% of patients with IBD will have a vitamin D deficiency.42 Causes include ileal disease or resection that impairs bile acid resorption, which leads to fat malabsorption.43 Vitamin D is a fat soluble vitamin. Clinically, a vitamin D deficiency may result in osteopenia, osteoporosis, and secondary hyperparathyroidism. The diagnosis can be made by measuring the blood level of vitamin D. In the serum, vitamin D has a half-life of 15 days.
Vitamin D should be measured in patients with IBD. There is no evidence to support routine supplementation with fat-soluble vitamins in patients with IBD. Supplementation should be reserved for patients with risk factors for low levels or malabsorption. The National Institutes of Health recently published a consensus document categorizing levels of vitamin D.44 A level of 12 ng/mL to less than 20 ng/mL is inadequate. A level of 20 ng/mL to 50 ng/mL is an appropriate goal to minimize the risk of osteopenia, osteoporosis, and other bone-related conditions. (This categorization reflects a recent update; the previous lower level was 30 ng/mL.) Levels above 50 ng/mL can be associated with toxicity. There is a perception that cardiovascular calcification of the coronaries can occur in patients with higher vitamin D levels and may be associated with the presence of a higher rate of coronary artery disease.
Supplementation with vitamin D may prevent disease relapse in patients with IBD. In a 2018 meta-analysis, the rate of IBD disease activity relapse was significantly lower among patients treated with vitamin D vs those in the control group.45 There were no significant differences between the low dose and the high dose of vitamin D. Supplementation with vitamin D is therefore advantageous for abnormal bone mineral density, and may also decrease the chance of relapse in patients with IBD.
Maximum accumulation of calcium occurs in the mid-teenage years, and it may not be made up later in life. Decrease in bone mineral density can occur with poor calcium intake or vitamin D deficiency, as seen in approximately one-third of patients, as well as in individuals who have an increased level of systemic inflammation or decreased physical activity. Corticosteroids can also severely impact bone density.46 A dose of 7.5 mg for 3 months is enough to lead a patient to develop an abnormal bone mineral density. Patients treated with this dose or higher should undergo bone density assessment with a DEXA scan. According to guidelines from the ACG, bone mineral density should be measured in patients treated with corticosteroids for longer than 3 months, malnourished or very thin patients with inactive disease, amenorrheic patients, and postmenopausal women regardless of disease status.47 These guidelines are currently being updated.
In Crohn’s disease, approximately two-thirds of patients have low levels of zinc.48 A deficiency is defined as less than 60 μg/dL in the plasma. Levels can be measured in erythrocytes, neutrophils, lymphocytes, and hair.49,50 Risk factors for low serum zinc levels include the presence of ostomies, fistulas, and profuse diarrhea.51 Zinc deficiency can lead to depressed immunity, frequent infections, diarrhea, dysgeusia, and alopecia. Zinc is an essential mineral and coenzyme for cellular reactions. Serum zinc levels vary with serum albumin and fluctuate with intake, inflammation, pregnancy, and diurnal rhythm. Zinc deficiency is underrecognized. Low alkaline phosphatase can suggest a zinc deficiency because alkaline phosphatase is a zinc metalloenzyme. Oral and fractional zinc can be administered, with maintenance doses of 10 mg/day to 15 mg/day.
The presence of anemia is another common finding among patients with IBD.52 Anemia is defined by hemoglobin levels at or below 12 g/dL for women, 13 g/dL for men, 12 g/dL for children ages 12 to 13 years, 11.5 g/dL for children ages 5 to 11 years, and 11 g/dL for children ages 6 months to 5 years. Iron deficiency has several causes, such as poor dietary intake, gastrointestinal bleeding, and malabsorption of inflamed mucosa in the duodenum.53 Active inflammation traps the iron within enterocytes. Iron deficiency can manifest in many ways, such as fatigue, weakness, microcytic anemia, restless legs syndrome, dyspnea on exertion, and pica. Some patients eat ice. Serum hepcidin levels rise in the presence of active inflammation. The presence of elevated serum hepcidin levels block ferroportin (the iron transport protein located in the enterocyte in the duodenum and proximal jejunum) from absorbing iron.
For mild anemia, clinicians often initiate treatment with an oral formulation of iron. Parenteral iron is used in patients with severe anemia or in those patients with a history of blood transfusion. Hepcidin antagonists are under investigation for patients with chronic disease, such as rheumatoid arthritis, IBD, pneumonia, or other disorders of inflammation. Hepcidin blocks the uptake of iron. Iron deficiency is often present, but underrecognized and untreated in patients with IBD. Failure to test for iron deficiency is common.
Dr David Rubin discussed treatment of patients with IBD during the COVID-19 pandemic and preparations for future pandemics.54 COVID-19 has accounted for substantial morbidity and mortality throughout the world. There were many problems with the approach to COVID-19, including inadequate national preparedness, lack of available testing, misinformation, and politicization of public health issues. In the field of IBD, there was success. There were regular updates and reassurances, and effective use of social media. The Surveillance Epidemiology of Coronavirus Under Research Exclusion registry was assimilated to help study the effect of COVID-19 on IBD and associated treatments.55 The AGA, the ASGE, the ACG, the Crohn’s & Colitis Foundation, and the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) were among many societies that came forth to help physicians, patients, and caregivers better understand what was transpiring. International meetings were held virtually to share knowledge and allow for collaboration.
In April 2021, the IOIBD published guidelines regarding vaccination in patients with IBD.56 The guidelines recommended that all patients with IBD receive the COVID-19 vaccination, once they were eligible. Patients should receive whichever vaccine was available to them. The best time to administer the vaccine was the earliest opportunity to do so. There was no need for a patient to discontinue IBD therapy for vaccination. The vaccination should not be deferred in a patient receiving immune-modifying therapy. Patients should try to decrease exposure to corticosteroids.
Dr Rubin and I published an ACG clinical practice update for patients with IBD who develop COVID-19.57 The article reviews management strategies for various phases of the disease. A study that assessed patient portal messaging (“MyChart messages”) demonstrated an increase of 100% from before the pandemic to September 2021.54,58 Many patients did not want to visit their health care deliverer’s office for medical care. This increase placed strains not only on the patients, but also on advanced practice practitioners and physicians.
The pandemic impacted the mental health of health care workers. Surveys noted difficulties in coping, stress, sleeping problems, worry, sadness, physical pain, and anger.59 The disease and associated management strategies led to challenging levels of stress for many health care workers.
Discontinuation of IBD therapy was not recommended, as it could lead to relapses. Currently, most people who are hospitalized with or dying from COVID-19 are not vaccinated.60,61 The United States was instrumental to the rapid development of vaccines and testing. The FDA approved the vaccines in world-record times. However, the United States ranks 38th in vaccination rates worldwide (as of September 2021).62 We are not keeping up with the rates we hoped to achieve.
It is important to prepare for the next pandemic. Dr Rubin offered several recommendations based on lessons learned from the COVID-19 pandemic.54 The recommendations focus on investments in public health, congressional and legal responses, and social networking. There are high stakes to not taking these steps. It would be advantageous to develop a national network of IBD providers and patients for crisis management. The network could also include societies such as the ACG, the AGA, the Crohn’s and Colitis Foundation, and the Centers for Disease Control, as well as representatives from industry.
Occupational stress is another major area that has been influenced by COVID-19. The stress of treating patients has taken a high toll on health care workers.63 Education of patients and colleagues is of paramount importance. Different organizations have provided several approaches. The key is education. It is necessary to stress that vaccination, mask-wearing, and social isolation when appropriate can decrease rates of infection. A pandemic preparedness plan is important. Practices should stockpile personal protective equipment, establish protocols related to telehealth and working from home, develop a safety net plan for coworkers and employees, and communicate the plan to patients en masse. The plan should be reviewed twice annually.
There are several research priorities for IBD. Access issues for the underserved is an important concern that is critical for the appropriate treatment of patients. COVID-19 outcomes were worse among patients with higher disease activity and who were receiving corticosteroids. Disadvantaged patients were more likely to have difficulties in accessing vaccines. Vaccination is one of the most important ways to decrease the risk and severity of COVID-19.
It is also necessary to build trust and end discrimination and bias in recruitment of clinical trials. Trials lack representation of many different individuals of different backgrounds, making it more difficult to generalize data to all patients.64 There are also legislative steps for policy makers at the federal, local, and institutional levels.
As Dr Rubin summarized, the goals are to prioritize a national network of IBD providers and patients for crisis management, prioritize health care workers’ mental health, improve management and education of patients and colleagues, develop a pandemic preparedness plan, identify and fund research priorities for IBD, address access issues to the underserved, build trust, end discrimination bias in clinical trial recruitment, and establish legislative priorities for the IBD population in the United States.54 With these steps, we can be better prepared for future pandemics.
Disclosure
Dr Lichtenstein has consulted for AbbVie, American Regent, Bristol Myers Squibb, Celgene, Eli Lilly, Endo Pharmaceuticals, Ferring, Gilead, MedEd Consultants, Morphic Therapeutics, Prometheus Laboratories, Romark, Salix Pharmaceuticals/Valeant, Sandoz, Shire Pharmaceuticals, and UCB; conducted research for Bristol Myers Squibb, Celgene, and UCB; served on the Data Safety Monitoring Board for Eli Lilly; and received honoraria (CME program) from American Regent and Romark. He is a consultant and performed research for Janssen Ortho Biotech and Takeda, with funding directed to the University of Pennsylvania (IBD fellow education). He is a consultant for Pfizer Pharmaceuticals, with funding directed to the University of Pennsylvania (IBD fellow education). He has performed CME activities for Allergan, the American Gastroenterological Association, CHEMED, Imedex, Ironwood, the University of Kentucky, and Vindico. He is a consultant and received an honorarium (CME program) from Merck. He is a consultant (stock options) for Virgo.
References
1. Hanauer SB. The past, present, and future of IBD. Paper presented at: the 2021 Advances in Inflammatory Bowel Diseases Conference; Orlando, Florida; December 9-11, 2021.
2. Nielsen OH, Munck LK. Drug insight: aminosalicylates for the treatment of IBD. Nat Clin Pract Gastroenterol Hepatol. 2007;4(3):160-170.
3. Waljee AK, Wiitala WL, Govani S, et al. Corticosteroid use and complications in a US inflammatory bowel disease cohort. PLoS One. 2016;11(6):e0158017.
4. Abdalla MI, Herfarth H. Budesonide for the treatment of ulcerative colitis. Expert Opin Pharmacother. 2016;17(11):1549-1559.
5. Hanauer SB, Sandborn WJ, Lichtenstein GR. Evolving considerations for thiopurine therapy for inflammatory bowel diseases-a clinical practice update [commentary]. Gastroenterology. 2019;156(1):36-42.
6. Velayos FS, Sandborn WJ. Positioning biologic therapy for Crohn’s disease and ulcerative colitis. Curr Gastroenterol Rep. 2007;9(6):521-527.
7. Nguyen DL, Flores S, Sassi K, Bechtold ML, Nguyen ET, Parekh N. Optimizing the use of anti-tumor necrosis factor in the management of patients with Crohn’s disease. Ther Adv Chronic Dis. 2015;6(3):147-154.
8. Yzet C, Diouf M, Singh S, et al. No benefit of concomitant immunomodulator therapy on efficacy of biologics that are not tumor necrosis factor antagonists in patients with inflammatory bowel diseases: a meta-analysis. Clin Gastroenterol Hepatol. 2021;19(4):668-679.e8.
9. Sandborn WJ, Feagan BG, D’Haens G, et al. Ozanimod as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2021;385(14):1280-1291.
10. Sandborn WJ, Ghosh S, Panes J, et al. Efficacy of upadacitinib in a randomized trial of patients with active ulcerative colitis. Gastroenterology. 2020;158(8):2139-2149.e14.
11. Ahmed W, Galati J, Kumar A, et al. Dual biologic or small molecule therapy for treatment of inflammatory bowel disease: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2021;S1542-3565(21)00344-X.
12. Dubinsky M. Personalized medicine: yesterday, today and tomorrow. Paper presented at: the 2021 Advances in Inflammatory Bowel Diseases Conference; Orlando, Florida; December 9-11, 2021.
13. Noor NM, Verstockt B, Parkes M, Lee JC. Personalised medicine in Crohn’s disease. Lancet Gastroenterol Hepatol. 2020;5(1):80-92.
14. 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.
15. Singh S, Murad MH, Fumery M, et al. Comparative efficacy and safety of biologic therapies for moderate-to-severe Crohn’s disease: a systematic review and network meta-analysis. Lancet Gastroenterol Hepatol. 2021;6(12):1002-1014.
16. Sandborn WJ. Crohn’s disease evaluation and treatment: clinical decision tool. Gastroenterology. 2014;147(3):702-705.
17. Yamamoto S, Ma X. Role of Nod2 in the development of Crohn’s disease. Microbes Infect. 2009;11(12):912-918.
18. Dubinsky MC, Kugathasan S, Mei L, et al. Increased immune reactivity predicts aggressive complicating Crohn’s disease in children. Clin Gastroenterol Hepatol. 2008;6(10):1105-1111.
19. 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.
20. Siegel CA, Horton H, Siegel LS, et al. A validated web-based tool to display individualised Crohn’s disease predicted outcomes based on clinical, serologic and genetic variables. Aliment Pharmacol Ther. 2016;43(2):262-271.
21. Salvador-Martín S, Raposo-Gutiérrez I, Navas-López VM, et al. Gene signatures of early response to anti-TNF drugs in pediatric inflammatory bowel disease. Int J Mol Sci. 2020;21(9):3364.
22. West NR, Hegazy AN, Owens BMJ, et al; Oxford IBD Cohort Investigators. Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease. Nat Med. 2017;23(5):579-589.
23. ClinicalTrials.gov. Study to evaluate safety, tolerability and efficacy of GSK2330811 in Crohn’s disease (COSMIS). https://clinicaltrials.gov/ct2/show/NCT04151225. Identifier: NCT04151225. Accessed December 27, 2021.
24. Verstockt B, Verstockt S, Dehairs J, et al. Low TREM1 expression in whole blood predicts anti-TNF response in inflammatory bowel disease. EBioMedicine. 2019;40:733-742.
25. Rath T, Billmeier U, Ferrazzi F, et al. Effects of anti-integrin treatment with vedolizumab on immune pathways and cytokines in inflammatory bowel diseases. Front Immunol. 2018;9:1700.
26. Sands BE, Chen J, Feagan BG, et al. Efficacy and safety of MEDI2070, an antibody against interleukin 23, in patients with moderate to severe Crohn’s disease: a phase 2a study. Gastroenterology. 2017;153(1):77-86.e6.
27. Lennard L, Van Loon JA, Weinshilboum RM. Pharmacogenetics of acute azathioprine toxicity: relationship to thiopurine methyltransferase genetic polymorphism. Clin Pharmacol Ther. 1989;46(2):149-154.
28. Walker GJ, Harrison JW, Heap GA, et al. Association of genetic variants in NUDT15 with thiopurine-induced myelosuppression in patients with inflammatory bowel disease. JAMA. 2019;321(8):773-785.
29. Grover N, Bhatia P, Kumar A, et al. TPMT and NUDT15 polymorphisms in thiopurine induced leucopenia in inflammatory bowel disease: a prospective study from India. BMC Gastroenterol. 2021;21(1):327.
30. Heap GA, Weedon MN, Bewshea CM, et al. HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants. Nat Genet. 2014;46(10):1131-1134.
31. Sazonovs A, Kennedy NA, Moutsianas L, et al; PANTS Consortium. 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.
32. Bucalo A, Rega F, Zangrilli A, et al. Paradoxical psoriasis induced by anti-TNFα treatment: evaluation of disease-specific clinical and genetic markers. Int J Mol Sci. 2020;21(21):7873.
33. Proper SP, Azouz NP, Mersha TB. Achieving precision medicine in allergic disease: progress and challenges. Front Immunol. 2021;12:720746.
34. Lichtenstein GR. Deficiencies in IBD. Paper presented at: the 2021 Advances in Inflammatory Bowel Diseases Conference; Orlando, Florida; December 9-11, 2021.
35. Wentworth BJ, Copland AP. Revisiting vitamin B12 deficiency: a clinician’s guide for the 21st century. https://www.practicalgastro-digital.com/practicalgastro/december_2018/MobilePagedArticle.action?articleId=1458298#articleId1458298. Posted December 2018. Accessed December 27, 2021.
36. Lachner C, Steinle NI, Regenold WT. The neuropsychiatry of vitamin B12 deficiency in elderly patients. J Neuropsychiatry Clin Neurosci. 2012;24(1):5-15
37. Kuisma J, Nuutinen H, Luukkonen P, Järvinen H, Kahri A, Färkkilä M. Long term metabolic consequences of ileal pouch-anal anastomosis for ulcerative colitis. Am J Gastroenterol. 2001;96(11):3110-3116.
38. Coull DB, Tait RC, Anderson JH, McKee RF, Finlay IG. Vitamin B12 deficiency following restorative proctocolectomy. Colorectal Dis. 2007;9(6):562-566.
39. Lindenbaum J, Rosenberg IH, Wilson PW, Stabler SP, Allen RH. Prevalence of cobalamin deficiency in the Framingham elderly population. Am J Clin Nutr. 1994;60(1):2-11.
40. Bolaman Z, Kadikoylu G, Yukselen V, Yavasoglu I, Barutca S, Senturk Tl. Oral versus intramuscular cobalamin treatment in megaloblastic anemia: a single-center, prospective, randomized, open-label study. Clin Ther. 2003;25(12):3124-3134.
41. Kuzminski AM, Del Giacco EJ, Allen RH, Stabler SP, Lindenbaum J. Effective treatment of cobalamin deficiency with oral cobalamin. Blood. 1998;92(4):1191-1198.
42. Mouli VP, Ananthakrishnan AN. Review article: vitamin D and inflammatory bowel diseases. Aliment Pharmacol Ther. 2014;39(2):125-136.
43. Schmidt DR, Holmstrom SR, Fon Tacer K, Bookout AL, Kliewer SA. Regulation of bile acid synthesis by fat-soluble vitamins A and D. J Biol Chem. 2010;285(19):14486-14494.
44. Vitamin D: Fact Sheet for Health Professionals. https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/. Updated August 17, 2021. Accessed December 28, 2021.
45. Li J, Chen N, Wang D, Zhang J, Gong X. Efficacy of vitamin D in treatment of inflammatory bowel disease: a meta-analysis. Medicine (Baltimore). 2018;97(46):e12662
46. Picado C, Luengo M. Corticosteroid-induced bone loss. Prevention and management. Drug Saf. 1996;15(5):347-359.
47. Farraye FA, Melmed GY, Lichtenstein GR, Kane SV. ACG clinical guideline: preventive care in inflammatory bowel disease. Am J Gastroenterol. 2017;112(2):241-258.
48. Weisshof R, Chermesh I. Micronutrient deficiencies in inflammatory bowel disease. Curr Opin Clin Nutr Metab Care. 2015;18(6):576-581.
49. Prasad AS. Laboratory diagnosis of zinc deficiency. J Am Coll Nutr. 1985;4(6):591-598.
50. Lowe NM, Fekete K, Decsi T. Methods of assessment of zinc status in humans: a systematic review. Am J Clin Nutr. 2009;89(6):2040S-2051S.
51. Naber TH, van den Hamer CJ, Baadenhuysen H, Jansen JB. The value of methods to determine zinc deficiency in patients with Crohn’s disease. Scand J Gastroenterol. 1998;33(5):514-523.
52. Murawska N, Fabisiak A, Fichna J. Anemia of chronic disease and iron deficiency anemia in inflammatory bowel diseases: pathophysiology, diagnosis, and treatment. Inflamm Bowel Dis. 2016;22(5):1198-1208.
53. Oldenburg B, Koningsberger JC, Van Berge Henegouwen GP, Van Asbeck BS, Marx JJ. Iron and inflammatory bowel disease. Aliment Pharmacol Ther. 2001;15(4):429-438.
54. Rubin DT. Preparing for IBD care in the next pandemic: lessons learned from COVID-19. Paper presented at: the 2021 Advances in Inflammatory Bowel Diseases Conference; Orlando, Florida; December 9-11, 2021.
55. SECURE-IBD Database: Surveillance Epidemiology of Coronavirus (COVID-19) Under Research Exclusion. https://covidibd.org. Accessed December 28, 2021.
56. Siegel CA, Melmed GY, McGovern DP, et al. SARS-CoV-2 vaccination for patients with inflammatory bowel diseases: recommendations from an international consensus meeting. Gut. 2021;70(4):635-640
57. Lichtenstein GR, Rubin DT. Coronavirus and patients with inflammatory bowel disease: management strategies for the practicing clinician. Am J Gastroenterol. 2020;115(10):1566-1569.
58. Shah S. Average MyChart messages per month at the University of Chicago. Internal data from the University of Chicago Medicine.
59. Forrest CB, Xu H, Thomas LE, et al; HERO Registry Research Group. Impact of the early phase of the COVID-19 pandemic on US healthcare workers: results from the HERO registry. J Gen Intern Med. 2021;36(5):1319-1326.
60. CDC COVID Data Tracker. Rates of COVID-19 cases and deaths by vaccination status. https://covid.cdc.gov/covid-data-tracker/#rates-by-vaccine-status. Accessed December 29, 2021.
61. CDC COVID Data Tracker. Rates of laboratory-confirmed COVID-19 hospitalizations by vaccination status. https://covid.cdc.gov/covid-data-tracker/#covidnet-hospitalizations-vaccination. Accessed December 29, 2021.
62. Yong E. We’re already barrelling toward the next pandemic. https://www.theatlantic.com/health/archive/
2021/09/america-prepared-next-pandemic/620238. Updated September 29, 2021.
63. Prasad K, McLoughlin C, Stillman M, et al. Prevalence and correlates of stress and burnout among U.S. healthcare workers during the COVID-19 pandemic: a national cross-sectional survey study. EClinicalMedicine. 2021;35:100879.
64. Cohen NA, Silfen A, Rubin DT. Inclusion of under-represented racial and ethnic minorities in randomized clinical trials for inflammatory bowel disease. Gastroenterology. 2022;162(1):17-21.