Ulcerative Colitis (UC) patients may experience a wide variety of symptoms, and there are well-documented gaps in individual patient care. This article reviews the mechanisms of action for newer investigational therapies that may offer the potential to optimize induction and maintenance of remission in patients with UC, as well as review the emergence of biomarkers that may help us personalize treatment in patients.
New Horizons in Ulcerative Colitis
New Horizons in Ulcerative Colitis
Achieving and maintaining clinical remission in ulcerative colitis (UC) remains a challenge for many patients. Novel therapies with new mechanisms of action are currently being investigated and offer the promise of overcoming factors that currently lead to primary and secondary nonresponse. New data are now available on the role that dual-action anti-integrins, newer Janus kinase inhibitors (JAK), interleukin-12 (IL-12)/interleukin-13 (IL-23) inhibitors, and sphingosine-1-phosphate (S1P) receptor modulators will play in achieving sustained remission in UC.
Primary Nonresponse in UC:
Primary nonresponse in UC is defined as the lack of improvement in endoscopic and clinical signs and symptoms following initial induction therapy. Some of the main factors leading to primary nonresponse include:
- Agent selection
- Disease severity
- Patient characteristics
The following are predictive factors for more aggressive therapy early in the course of treatment to prevent long-term sequelae in patients with moderate to severe UC1-4:
- Extensive colitis
- Deep colonic ulcers
- Age < 40 years
- Elevated C-reactive protein (CRP) and/or erythrocyte sedimentation rate (ESR)
- Requirement for glucocorticoids to maintain remission
- Comorbid infections such as Clostridioides difficile or cytomegalovirus (CMV)
The main goal of treatment for patients with UC is clinical and endoscopic remission.2 Primary response can be determined through symptom assessment, laboratory testing, and endoscopy with biopsies as needed. Selection of induction therapy should be individualized based on several factors such as patient preferences, patient characteristics, risk of adverse events (eg, infection), other medication use, and payer coverage.5
Anti-tumor necrosis factor (TNF) agents:
Studies have shown that the combination of an anti-TNF agents such as infliximab in combination with an immunomodulator such as azathioprine (or methotrexate in patients intolerant to azathioprine) is more effective than an anti-TNF agent alone.6 In addition to infliximab, other anti-TNF agents include adalimumab, certolizumab, and golimumab, although no direct head-to-head trials have been performed. Low serum albumin levels during the disease course have been shown to be associated with nonresponse or loss of response to anti-TNF therapy in patients with UC.7
The 2 agents currently available in the class of anti-integrin antibodies are vedolizumab and natalizumab. Due to its gut selectivity, vedolizumab is typically the preferred agent in patients at higher risk for infection or malignancy over other forms of induction therapy. Vedolizumab efficacy has been demonstrated in clinical trials,8 although its superiority over the anti-TNF adalimumab remains unclear as vedolizumab showed higher rates of clinical remission but lower rates of glucocorticoid-free clinical remission than adalimumab.9
IL-12 and IL-23 inhibitors:
Ustekinumab is an antibody that blocks the p-40 subunits of both IL-12 and IL-23; it can be used as initial therapy or in patients who have not responded to other therapies and has been shown to induce clinical and endoscopic remission in patients with moderate to severe UC.10
Secondary Nonresponse in UC:
Secondary nonresponse is when a patient initially responds to induction therapy but loses response during maintenance treatment. Factors that can influence secondary nonresponse include:
- Patient/disease changes over time
- Mechanistic escape
- Resistance to therapy
- Comorbid infections such as C. difficile or CMV
- Patient adherence
After ruling out infection as the source of symptoms, the decision to determine if current therapy is still effective should be based on both clinical symptoms as well as surrogate markers of inflammation, specifically CRP or fecal calprotectin levels.11 Once continued inflammation has been confirmed, clinicians should assess drug levels and determine if antibodies to the drug are present.
- If there are low drug levels and no antibodies to the drug, the clinician should adjust the dose of the current drug
- If there are low drug levels and high levels of antibodies, the clinicians should switch to another drug in the class
- If there are high drug levels and no antibodies, the clinician should switch to a drug with a different mechanism of action
Novel Mechanisms of Action of Biologics and Small Molecules in UC:
Unlike other anti-integrins, etrolizumab is a novel, gut-selective, anti-integrin antibody that has a dual mechanism of action specifically targeting the β7 subunit of both the α4β7 and αEβ7 integrins (see Figure 1). Similar to vedolizumab, etrolizumab binding to β7 prevents the interaction between α4β7 and its endothelial ligand, mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1), thus blocking T-cells from entering the gut lamina propia.12 Unlike either vedolizumab or natalizumab, etrolizumab also blocks the interaction between TGF-β-induced αEβ7+ T cells on their ligand E-cadherin located on the intestinal epithelium, thus disengaging the T-cell from the endothelial cell to prevent further epithelial damage due to inflammation.12,13 Etrolizumab is currently being studied in multiple ongoing clinical trials (see Figure 2). Phase 2 data have shown improvements in clinical and endoscopic response, as well as in patient-reported outcomes (see Figure 3).
Figure 1: Mechanism of Action of Etrolizumab – A Dual-Action Anti-Integrin
Figure 2: Ongoing Clinical Trials for Etrolizumab
Figure 3: Improvements With Etrolizumab: Phase 2 Study Results
Heterodimeric pro-inflammatory cytokines IL-12 and IL-23 induce T-helper (TH) lymphocytes such as TH1 and TH17, respectively, thus activating the JAK/signal transducers and activators of transcription (STAT) pathway.14 While agents such as ustekinumab inhibit both IL-12 and IL-23, novel therapies look to target IL-23 in patients with UC as the IL-12 pathway is also involved in immune response and anti-tumor activity. Novel interleukin antibodies such as risankizumab,15,16 brazikumab,17 mirikizumab,18 and guselkumab19 that target IL-23 by specifically inhibiting the p19 protein are currently being investigated.
JAK inhibitors are tyrosine kinases that play a significant role in signaling transduction for cytokines and growth factors; they are comprised of JAK1, JAK2, JAK3, and TYK2. The activation of specific cell membrane receptors by circulating cytokines results in the phosphorylation of STATs leading to cell proliferation, growth, differentiation, and migration. Blocking the JAK/STAT pathway inhibits the role of pro-inflammatory cytokines.20 Because of the role that the JAK enzymes play across many biological processes, selectivity is important when attempting to minimize the risk of adverse events.21
Tofacitinib is a nonspecific small molecule JAK inhibitor, with preferential inhibition of JAK1 and JAK3, whose efficacy in ulcerative colitis was demonstrated in the OCTAVE trials, although with higher risks of infection.22 To reduce serious side effects, selectivity for JAK1 is now being investigated with filgotinib,23 upadacitinib,24,25 and peficitinib.26
S1P Receptor Modulators:
An important factor in immune surveillance is the role of naïve T lymphocytes, whose activation occurs in secondary lymphoid organs such as lymph nodes or Peyer’s patches guided by S1P.27 S1P receptor subtypes are being investigated as a target for treatment in UC. Ozanimod and etrasimod are S1P agonists that prevent the release of lymphocytes from the lymph node (see Figure 4). Ozanimod is an S1P1 and S1P5 agonist currently being investigated in phase 3 trials after showing efficacy in a phase 2 clinical trial.28 Etrasimod is an S1P1, S1P4, and S1P5 modulator that was also shown to be efficacious in achieving clinical remission in a phase 2 trial, and phase 3 studies are underway.29
Figure 4 – Mechanism of Action of S1P Receptor Modulators
With the advent of newer mechanisms of action in drugs that may potentially be used to treat UC, there are promising therapies in the near-term clinical pipeline. To treat patients effectively with either current or newer agents will require monitoring patients closely for signs of nonresponse; dosing therapy according to the severity of the disease; and, when facing nonresponse, selecting the appropriate approach of either adjusting the dosage or switching therapy based on mechanism of action.
- Dias CC, Rodrigues PP, da Costa-Pereira A, Magro F. Clinical predictors of colectomy in patients with ulcerative colitis: systematic review and meta-analysis of cohort studies. J Crohns Colitis. 2015;9:156.
- Rubin DT, Ananthakrishnan AN, Siegel CA, et al. ACG clinical guideline: ulcerative colitis in adults. Am J Gastroenterol. 2019;114:384-413.
- Fumery M, Singh S, Dulai PS, et al. Natural history of adult ulcerative colitis in population-based cohorts: a systematic review. Clin Gastroenterol Hepatol. 2018;16:343.
- Khan NH, Almukhtar RM, Cole EB, Abbas AM. Early corticosteroids requirement after the diagnosis of ulcerative colitis diagnosis can predict a more severe long-term course of the disease - a nationwide study of 1035 patients. Aliment Pharmacol Ther. 2014;40:374.
- Bhat S, Zahorian T, Robert R, Farraye FA. Advocating for patients with inflammatory bowel disease: how to navigate the prior authorization process. Inflamm Bowel Dis. 2019;25:1621.
- 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;146:392.
- Morita Y, Bamba S, Takahashi K, et al. Prediction of clinical and endoscopic responses to anti-tumor necrosis factor-alpha antibodies in ulcerative colitis. Scand J Gastroenterol. 2016;51:934-941.
- Feagan BG, Rutgeerts P, Sands BE, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2013;369:699-710.
- Sands BE, Peyrin-Biroulet L, Loftus EV Jr, et al. Vedolizumab versus adalimumab for moderate-to-severe ulcerative colitis. N Engl J Med. 2019;381:1215-1226.
- Sands BE, Sandborn WJ, Panaccione R, et al. Ustekinumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2019;381:1201-1214.
- Mosli MH, Zou G, Garg SK, et al. C-reactive protein, fecal calprotectin, and stool lactoferrin for detection of endoscopic activity in symptomatic inflammatory bowel disease patients: a systematic review and meta-analysis. Am J Gastroenterol. 2015;110:802-819.
- Tang MT, Keir ME, Stefanich EG, et al. nonclinical and clinical pharmacology, pharmacokinetics and pharmacodynamics of etrolizumab, an anti‐β7 integrin therapy for inflammatory bowel disease. Aliment Pharmacol Ther. 2018;47:1440-1452.
- Vermeire S, O’Byrne S, Keir M, et al. Etrolizumab as induction therapy for ulcerative colitis: a randomized, controlled, phase 2 trial. Lancet. 2014;384:309-318.
- Moschen AR, Tilg H, Raine T. IL-12, IL-23 and IL-17 in IBD: immunobiology and therapeutic targeting. Nat Rev Gastroenterol Hepatol. 2018;16:185-196.
- Feagan BG, Sandborn WJ, D’Haens G, et al. Induction therapy with the selective interleukin-23 inhibitor risankizumab in patients with moderate-to-severe Crohn’s disease: a randomized, double-blind, placebo-controlled phase 2 study. Lancet. 2017;389:1699-1709.
- Feagan BG, Panes J, Ferrante M, et al. Risankizumab in patients with moderate to severe Crohn’s disease: an open-label extension study. Lancet Gastroenterol Hepatol. 2018;3:671-680.
- 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;153:77-86.e76.
- A SPECIAL MEETING REVIEW EDITION: Highlights in Inflammatory Bowel Disease From the 14th Congress of ECCO. A Review of Selected Presentations From the 14th Congress of the European Crohn’s and Colitis Organization (ECCO). March 6-9, 2019. Copenhagen, Denmark. Maintenance Treatment With Mirikizumab, a P19-Directed IL-23 Antibody: 52-Week Results in Patients With Moderately to Severely Active Ulcerative Colitis. Gastroenterol Hepatol. 2019;15(suppl 2):1-24.
- A study of guselkumab in participants with moderately to severely active ulcerative colitis (QUASAR). https://clinicaltrials.gov/ct2/show/NCT04033445. Accessed March 27, 2020.
- Boland BS, Vermeire S. Janus Kinase antagonists and other novel small molecules for the treatment of Crohn’s disease. Gastroenterol Clin North Am. 2017;46:627-644.
- Villarino AV, Kanno Y, Ferdinand JR, et al. Mechanisms of JAK/STAT signaling in immunity and disease. J Immunol. 2015;194:21-27.
- Sandborn WJ, Su C, Sands BE, et al. Tofacitinib as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2017;376:1723-1736.
- Vermeire S, Schreiber S, Petryka R, et al. Clinical remission in patients with moderate-to-severe Crohn’s disease treated with filgotinib (the FITZROY study): results from a phase 2, double-blind, randomized, placebo-controlled trial. Lancet. 2017;389:266-275.
- Sandborn WJ, Feagan BG, Panes J, et al. Safety and efficacy of ABT-494 (Upadacitinib), an oral JAK1 inhibitor, as induction therapy in patients with Crohn’s disease: results from CELEST. Gastroenterology. 2017;152:S1308-S1309.
- Panes J, Sandborn WJ, Loftus EV, et al. Efficacy and safety of upadacitinib maintenance treatment for moderate to severe Crohn’s disease: results from the CELEST study. J Crohns Colitis. 2018;12:S238-S239.
- Sands BE, Sandborn WJ, Feagan BG, et al. Peficitinib, an oral Janus kinase inhibitor, in moderate-to-severe ulcerative colitis: results from a randomized, phase 2 study. J Crohns Colitis. 2018;12:1158-1169.
- Mendoza A, Fang V, Chen C, et al. Lymphatic endothelial S1P promotes mitochondrial function and survival in naive T cells. Nature. 2017;546:158-161.
- Sandborn WJ, Feagan BG, Wolf DC, et al. Ozanimod induction and maintenance treatment for ulcerative colitis. N Engl J Med. 2016;374:1754-1762.
- Sandborn WJ, Peyrin-Biroulet L, Zhang J, et al. Efficacy and Safety of Etrasimod in a Phase 2 Randomized Trial of Patients With Ulcerative Colitis. Gastroenterology. 2020;158:550-561.
In accordance with the ACCME Standards for Commercial Support, Global Learning Collaborative (GLC) requires that individuals in a position to control the content of an educational activity disclose all relevant financial relationships with any commercial interest. GLC resolves all conflicts of interest to ensure independence, objectivity, balance, and scientific rigor in all its educational programs.
Christina Ha, MD, FACG, AGAF
Associate Professor of Medicine
Cedars-Sinai IBD Center
Los Angeles, CA
Speakers Bureau: AbbVie, Genentech, IBD Remedy, Janssen, Medical Speakers Network, Pfizer, Salix, Takeda
David T. Rubin, MD
Professor of Medicine
University of Chicago Medicine
Consulting Fees: AbbVie, Abgenomics, Allergan, Inc., Biomica, Boehringer Ingelheim, Ltd., Bristol-Myers Squibb, Celgene Corp./Syneos, Check-cap, Dizal Pharmaceuticals, GalenPharma/Atlantica, Genentech/Roche, Gilead Sciences, Glenmark Pharmaceuticals, GlaxoSmithKline, Janssen Pharmaceuticals, Lilly, Mahana Therapeutics, Medtronic, Narrow River Mgmt, Pfizer, Prometheus Laboratories, Reistone, Seres Therapeutics, Shire, Takeda, Target PharmaSolutions, Inc.
Grant Support: AbbVie, Genentech/Roche, Janssen Pharmaceuticals, Prometheus Laboratories, Shire, Takeda
Other: GoDuRn, LLC. (Co-Founder)
- Stephen Chavez has nothing to disclose.
- Ann Early has nothing to disclose.
- Amanda Hilferty has nothing to disclose.
- Brian McDonough, MD, FAAFP has nothing to disclose.
- William A. Mencia, MD has nothing to disclose.
- Tricia O’ Leary has nothing to disclose.
After participating in this educational activity, participants should be better able to:
- Compare the mechanisms of action for novel anti-integrin antibodies that may offer the potential to optimize induction and maintenance of remission patients with ulcerative colitis
- Devise real-world strategies to overcome barriers to optimal care of patients with ulcerative colitis, such as the limited effectiveness of traditional biologic therapy and ongoing challenges in defining treatment targets
This activity is designed to meet the educational needs of Gastroenterologist, and Primary Care physicians, Pediatricians and NP/PA who treat patients with ulcerative colitis.
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