Emerging Therapies for Ulcerative Colitis–Induced Pain

US Pharm. 2024;49(3):5-12.

ABSTRACT: Ulcerative colitis (UC) is a chronic, inflammatory bowel disease with gut-brain axis dysfunction involvement in disease pathogenesis and abdominal and/or rectal pain serving as hallmark symptomatology. Corticosteroids and 5-aminosalicylates are mainstay anti-inflammatory medications for mild-to-moderate UC. Newer, more targeted therapies include tumor necrosis factor inhibitors, selective Janus kinase inhibitors, anti–interleukin-23 agents, sphingosine-1-phosphate receptor modulators, and integrin antagonists. Incorporating these drugs into treatment regimens is challenging due to the risk of cardiovascular and infectious adverse events. Supplemental pharmacologic therapies and nonpharmacologic interventions also have potential benefit.

Ulcerative colitis (UC) is a chronic, relapsing and remitting, immune-mediated, and potentially debilitating inflammatory bowel disease (IBD) of the gastrointestinal (GI) tract that primarily affects the large intestine (or colon) and rectum.¹ Approximately 1.25 million Americans have UC, with an incidence of 6.3 cases per 100,000 people.² While the precise etiology of UC remains unknown, 8% to 14% of patients have a family history of the disease, indicating a genetic component.¹ Other potential causes include autoimmune dysfunction, nonsteroidal anti-inflammatory drug (NSAID)–induced erosion of the mucosal barrier, and dysbiosis.¹ Despite no definitive cure for UC, nearly one-half of UC patients are in remission.³ The remaining 30%, 20%, and 1% to 2% of affected individuals experience mild, moderate, and severe disease activity, respectively.³

UC-associated inflammation involves disruption of the colonic epithelial barrier, whereby gut contents, including enteric microbiota, become exposed to gut-associated immune cells.^4,5 Namely, the increased intestinal permeability (or leaky gut) allows toxic bacterial lipopolysaccharides (LPS), which are normally sequestered to the gut, to enter the bloodstream and activate mechanisms that promote visceral hypersensitivity.⁶ Inflammation results from immune-system activation and leukocyte recruitment and infiltration into the gut mucosa.⁷ Leukocyte recruitment to the area is mediated by chemoattractants (e.g., CXCL8) and adhesion molecules located on the gastric mucosa (e.g., Mad-CAM1).¹ The subsequent T-cell response further damages the colonic epithelium.⁸ Inflammation also involves reduced colonic secretion of mucin that normally lubricates the epithelium and serves as a protective physical barrier to harmful microbes, which contributes to the dysregulated (i.e., heightened) gut mucosal immunity.^1,9  Specifically, mucin deficiency leads to an inflammatory cascade involving the immune mediators tumor necrosis factor (TNF)-alpha, interleukin (IL)-13, and natural killer cells.¹

Patients experience flares of disease activity that are characterized by adverse GI symptoms, such as abdominal pain; rectal urgency, tenesmus; blood, mucus, or pus in the stool; diarrhea; increased stool frequency (i.e., >3 stools/day); nocturnal bowel movements; fever; anemia; fatigue; loss of appetite; and weight loss.^1,10 These symptoms can lead to further complications, including bone loss, dehydration, inflammation of the skin and eyes, incontinence, toxic megacolon, colorectal cancer, and sexual dysfunction.^1,10 The most common extraintestinal manifestation of UC is arthritis, which is reported in approximately one-third of cases.¹¹ Environmental factors (e.g., stress, unhealthy diet, lack of exercise, poor sleep habits, air pollution) and certain foods can increase risk and trigger symptoms of UC.¹² Although commonly underdiagnosed, depression and anxiety are also associated with UC, which is partly attributable to dysregulation of the gut-brain axis (GBA) and dysbiosis.¹³ The GBA links intestinal functions to emotional and cognitive (i.e., affective) brain centers. These gut-brain interactions are heavily influenced by the profile of the enteric microbiota.^13,14 Given this psychological component, antidepressants and anxiolytics are commonly used in combination with UC medications.^15,16

Current American College of Gastroenterology (ACG) guidelines for managing UC in adults recommend that therapeutic management be directed by specific diagnosis, severity of inflammatory activity, and prognosis (e.g., steroid dependence, previous hospitalization, etc.).¹⁷ While UC medications generally induce and maintain remission, some may not provide adequate efficacy and/or may be poorly tolerated. This article will discuss emerging UC treatments, focusing on how they restore optimal intestinal health by reducing inflammation. Nonpharmacologic treatment approaches, including psychological therapies and lifestyle modifications, are also covered. Alarmingly, a recent survey reported that pharmacists lack confidence about managing IBD.¹⁸ As medication experts and frontline healthcare professionals, pharmacists should be knowledgeable about the challenges that UC patients face and comfortable with helping them manage their pain. 

Diagnosis

Diagnosing UC entails assessing GI symptoms, noninvasively measuring biomarkers, performing a colonoscopy, and conducting pathology tests.¹⁰ Factors supporting a UC diagnosis include a history of diarrhea and rectal bleeding; abnormal blood levels of C-reactive protein (CRP), hemoglobin, ferritin, and liver enzymes; detection of the bacterial toxin Clostridioides difficile in the stool; presence of calprotectin, a marker of intestinal inflammation, in the stool; detection of inflammation and ulcers with colonoscopy and tissue biopsy; and pathological complications, including chronic architectural and inflammatory changes.¹⁰ Patients can also be screened for vitamin D and iron levels, which are typically low in UC.^19-21 While the exact etiology of UC-associated pain remains unknown, potential culprits include chronic intestinal inflammation or related complications such as abscesses, strictures, or ulceration.²² The stimulation of colonic sensory neurons by inflammatory-mediated vasodilation may also play a key role in eliciting pain.²³ UC pain is assessed using multiple tools, including the short IBD questionnaire (SIBDQ), McGill Pain questionnaire, and clinical activity index (CAI).^24,25 Pain serves as a primary marker of UC disease flares and progression as well as a sign that more aggressive therapy may be indicated.²² With surgical colectomy reserved as a last resort, mainstay pharmacologic treatments for UC are immunosuppressant drugs and biologics, which reduce the number and severity of disease flares. To reduce the risk of adverse side effects, emerging therapies are geared toward providing pain relief in a targeted, site-specific manner. 

Gut-Brain Axis Dysfunction in UC

The GBA mediates bidirectional communication between the enteric nervous system (ENS) and CNS.¹⁴ The gut and brain directly impact each other through multiple mechanisms along this axis, including those mediated by the autonomic nervous system (ANS) and hypothalamic-pituitary-adrenal (HPA) axis.¹⁴ The gut microbiota influence neural pathways along the GBA through conversion of dietary foodstuffs into short-chain fatty acids (SCFAs), such as butyrate.²⁶ Butyrate reduces visceral sensitivity in part by attenuating pain transduction to the CNS and pain perception.²⁶ Butyrate also exhibits anti-inflammatory properties by reducing proinflammatory cytokines and GI mucosal permeability, thereby preventing LPS-mediated inflammation.²⁷ Some preclinical data indicate that orally administered butyrate attenuates inflammation and improves mucosal lesion profile in a mouse model of acute UC.²⁸ The brain, in turn, plays a key role in maintaining optimal GI function, primarily by managing gut microbiota composition via regulation of immune and enterochromaffin cells.²⁹ The CNS also influences gut microbiota via ANS control of GI motility and permeability.¹⁴ UC patients often experience psychological stress in the forms of depression and anxiety, which promotes a proinflammatory state and increases relapse risk.^13,30 The gut microbiota regulates serotonergic and dopaminergic signaling along the GBA to maintain neurotransmitter balance, which reinforces the notion that pain not only results from the physical progression of the disease but also from worsening inflammation related to emotional stress.^31,32

Emerging Pharmacologic Treatments

Pharmacotherapy selection and delivery methods are governed by disease flares and progression.  Two mainstay drug classes, corticosteroids and 5-aminosalicylates (5-ASAs), have been used for decades to reduce flares and promote remission.²² However, corticosteroids are not indicated for long-term management due to their adverse effects, and more severe cases of UC are often unresponsive to 5-ASA.²² The development of TNF-alpha inhibitors (TNFi) was a tremendous breakthrough for managing UC, as these agents are tailored to target specific inflammatory pathways involved in disease flares and exhibit a fairly acceptable side-effect profile.²² However, unresponsiveness occurs in ~30% of TNFi-treated patients, with up to 10% of responders gradually losing therapeutic benefit every year.²² Recently, other immunomodulators, such as Janus kinase inhibitors (JAKi) and integrin antagonists, have been incorporated into treatment regimens. Supplemental therapies such as vitamin D, iron, and probiotics may also be beneficial. In general, current ACG guidelines prioritize induction and maintenance of remission while minimizing adverse effects.

Biologics: Several biologics are FDA-approved for use in UC. These agents include TNFi, JAKi, IL inhibitors, and integrin receptor antagonists. Current American Gastroenterological Association guidelines recommend them as first-line therapy for moderate-to-severe UC, specifically the TNFi infliximab and adalimumab.³³ They can be used as monotherapy or in combination with other nonbiological agents.³³ They are generally safe and highly efficacious in inducing and maintaining remission and promoting long-term mucosal healing, especially when combined with other immunomodulators, such as methotrexate, azathioprine, and cyclosporine.³³ Biosimilars are biologics that are highly similar to already FDA-approved reference biologics. Clinically, biosimilars are equally safe and effective, yet less expensive. Although biologics and biosimilars are extremely effective in UC treatment, they are costly, and there are concerns regarding hypersensitivity reactions and the development of antibody tolerance.³³

TNFi: Increased TNF levels are well implicated in the etiology and pathogenesis of intestinal inflammation and pain.³⁴ TNFi, including etanercept (Enbrel) and infliximab, restore intestinal eubiosis and dampen disease severity in ankylosing spondylitis, a chronic, inflammatory, autoimmune disease characterized by a reduction in SCFA-producing bacteria, as well as in IBD-related spondyloarthritis.^35-38 IBD patients treated with TNFi also display improved mental health, as assessed by a quality-of-life questionnaire, supporting the notion that poor intestinal health adversely affects mental health.³⁹ AVX-470 is an up-and-coming TNFi with promising clinical trial results as an orally administered polyclonal immunoglobin with potentially fewer side effects and decreased immunogenicity.⁴⁰ This agent is relatively stable against intestinal degradation, allowing for oral administration and, thus, offering a more patient-friendly alternative to SC and IV routes.⁴⁰ Furthermore, AVX-470’s larger molecular structure decreases its systemic absorption, which theoretically lowers the risk of systemic immunosuppression and related complications.⁴⁰ Despite AVX-470 being a bovine-derived biologic, studies have shown that patients do not develop antibovine antibodies, decreasing the risk of hypersensitivity reactions.⁴¹ Furthermore, AVX-470 exhibits similar efficacy to infliximab in vitro.⁴¹ 

JAKi: Activation of the JAK/STAT signaling pathway increases the production of inflammatory cytokines and chemokines that drive leukocyte migration and inflammatory processes within the gut.^42,43 There are currently four known JAKs: JAK1, JAK2, JAK3, and tyrosine kinase 2, with each playing a role in immune function.⁴⁴ JAKi block these signaling pathways, thereby suppressing immune system activation and reducing inflammation.⁴⁴ FDA-approved tofacitinib (Xeljanz) mainly inhibits JAK3 and JAK1 and, to a lesser extent, JAK2.^45,46 Its use is reserved for adults with moderate-to-severe UC who are refractory or intolerant to TNFi.^47,48 Upadacitinib (Rinvoq) is a JAKi that selectively targets JAK1; it is also slightly selective to JAK2.⁴⁴ In a study comparing the effectiveness of upadacitinib treatment to placebo in reducing UC-associated abdominal pain over 8 weeks of therapy, the percentage of patients who experienced no abdominal pain increased from 10% to 50.2% versus 10% to 23.8% with placebo.⁴⁹ 

Anti-IL-23 Agents: The cytokine IL-23 plays a key role in inflammation.⁵⁰ In particular, increased expression of the p19 subunit of IL-23 directly induces chronic intestinal inflammation.⁵¹ Mirikizumab (Omvoh) is the most recently approved anti-IL-23 agent.⁵² Whereas other anti-IL-23 agents, such as ustekinumab (Stelara), target the p40 subunit present in multiple cytokines, mirikizumab along with risankizumab (Skyrizi) selectively target the p19 subunit, which is IL-23–specific.^52-54 Mirikizumab is a viable option for inducing and maintaining remission with a decreased need for steroid use.⁵² The LUCENT program determined that 97.8% of patients taking mirikizumab during the maintenance or remission trial were not taking glucocorticoids.⁵² This specificity may benefit patients who experience treatment failures with immunosuppressive agents that cause more global immunosuppression (i.e., corticosteroids, JAKi).⁵²

Sphingosine-1 Phosphate (S1P) Receptor (S1PR) Modulators: S1PR signaling is implicated in IBD.⁵⁵ Specifically, S1PR engagement contributes to inflammation partly by facilitating lymphocyte trafficking.⁵⁶ S1PR modulators bind to five S1P receptor subtypes located on immune cells to prevent their release into the blood, which aids in reducing the levels of inflammation and pain experienced by UC patients.^57,58 When bound to receptor subtypes 1 and 5 (S1P1 and S1P5, respectively), S1PR modulators attenuate cell proliferation, lymphocyte migration, and cytokine production, all of which mediate intestinal inflammation.⁵⁹ These agents also induce receptor internalization, which further aids in reducing inflammation.⁶⁰ Ozanimod (Zeposia) is the first approved S1PR modulator for the treatment of moderately to severely active UC.⁵⁸ Ozanimod has shown promising long-term safety and efficacy, as rates of clinical and histological remission are higher at Week 32 versus Week 8.⁵⁸ Moreover, remission is maintained for long periods without a decline in responsiveness or increased risk of significant infections.⁵⁸ Etrasimod (Velsipity), the most recently approved S1PR modulator to treat moderate-to-severe UC, has high affinity to S1P1,4,5 and minimal activity at S1P3.⁶¹

Integrin Antagonists: Expressed on immune cells, integrins interact with cell-adhesion molecules to regulate leukocyte trafficking, which is well implicated in the etiopathogenesis of UC.^62-64 Integrin α4β7 is gut-tropic, and anti-integrin α4β7 autoantibodies serve as a novel UC biomarker.^65,66 The anti–integrin agent vedolizumab (Entyvio), which blocks α4β7 subunits, was recently FDA-approved as both an induction and maintenance therapy in adult patients with moderate-to-severe UC. The efficacy of etrolizumab as an IBD induction and maintenance therapy is being evaluated in phase III clinical trials. Etrolizumab blocks leukocyte trafficking via α4β7 as well as cell adhesion via α4β7 integrins.⁶⁴

Supplemental Therapies for UC

Antidepressants: Antidepressants are often prescribed for IBD patients for pain and GI upset related to psychological stress.⁶⁷ Although there is limited evidence of the effectiveness of antidepressants in maintaining remission in UC patients, these agents may mitigate depression and anxiety, thus increasing self-esteem and sociability.⁶⁷ Selective serotonin reuptake inhibitors and tricyclic antidepressants can increase quality of life by decreasing inflammation, as they reduce the production of several proinflammatory cytokines that mediate IBD.⁶⁷ Ultimately, doubts remain about whether antidepressants truly help to maintain remission.⁶⁷

Vitamin and Mineral Supplementation: In addition to standard pharmacotherapy, many UC patients require supplementation with vitamins and/or minerals. Although data are limited, it appears that low serum vitamin D levels correlate with worse patient outcomes.⁶⁸ Considering that vitamin D has beneficial effects on bone health and immune function, supplementation in vitamin D–deficient patients is recommended.⁶⁸ Iron deficiency anemia occurs in ~50% of IBD patients and can be cost-effectively treated with iron supplementation.^20,21 However, orally administered iron exerts adverse side effects, such as nausea, vomiting, altered bowel habits, and abdominal pain, which can hinder adherence.²⁰ It can also adversely affect the microbiome and exacerbate UC activity.²⁰ Although newer oral iron formulations elicit fewer side effects, IV formulations that bypass absorption in the GI tract are currently most preferable.^20,21

Omega-3 Fatty Acids: Omega-3 fatty acids are recommended in the treatment of some autoimmune diseases, such as rheumatoid arthritis.⁶⁸ They could also benefit UC patients, in whom there is increased oxidative stress and reduced antioxidant capacity.⁶⁸ Omega-3 fatty acids reduce the production of the inflammatory mediators IL-1, IL-6, and TNF-alpha.⁶⁸ Despite these potential anti-inflammatory effects, their use as supplementation in UC remains uncertain.⁶⁸

Probiotics: Probiotic use decreases the occurrence of acute complications and pain associated with UC.⁶⁸ Specifically, they may increase the time between flares and reduce symptom severity.⁶⁹ Randomized, controlled trials report an increase in the number of clinical remissions compared with placebo.⁷⁰ Beneficial bacterial strains include Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus paracasei, Lactobacillus bulgaricus, and Streptococcus thermophilus.⁷¹ In some cases, probiotic use performed comparably to the 5-ASA agent mesalamine.^68-79 Interestingly, oral butyrate add-on therapy to mesalamine lowers fecal calprotectin levels and improves UC symptoms, thus promoting remission.⁷² Probiotics are less costly than standard UC medications. are not linked to serious adverse effects in most populations, and could protect against other bowel disorders.⁷³ The quality of evidence in many trials is generally rated low, however, and they may be contraindicated in individuals with a compromised immune system, such as those taking long-term or high-dose corticosteroids.^68,74

Nonpharmacologic Management of UC

Psychological Therapies: Psychological interventions may mitigate the side effects that are prevalent with traditional UC regimens, such as headache, nausea, abdominal pain, and diarrhea. Thus, they have been assessed as alternatives to medication and/or as add-on therapies.⁷⁵ These interventions include stress management, cognitive behavioral therapy, hypnotherapy, and mindfulness therapy, all of which focus on alleviating psychological stress to develop a stronger tolerance to the condition.⁷⁶ Psychological therapies also serve as potentially beneficial adjunctive treatments for depression and anxiety, as they may help patients develop stress-coping strategies that attenuate UC symptoms and reduce relapse risk.⁷⁶ Gut-directed hypnotherapy (GDH) targets the GBA by increasing patients’ awareness of the connection between their psychological and intestinal health.⁷⁶ GDH not only improves overall symptoms related to IBD, but it also helps UC patients remain in remission significantly longer compared with individuals who have not undergone GDH.⁷⁶ Six weeks of relaxation training reduced pain intensity, frequency, and duration in UC patients.⁷⁷ Also, patients used fewer words to describe their pain and experienced reduced physiological distress.⁷⁷ Since pain is subjective, however, the extent to which stress management therapy effectively relieves pain may vary based on individual perspectives.

Diet: Maintaining a healthy diet is generally associated with improved GI function.⁷⁸ Healthy eating habits include consuming a balanced diet and following a healthy eating pattern (e.g., eating smaller, more frequent meals).⁷⁸ In UC patients, these healthy eating habits play a role in minimizing inflammation, resulting in a profound alleviation of pain.⁷⁸ Though specific dietary options may be individualized, general dietary changes should include a reduction of alcohol, sodium, saturated fat, commercially prepared foods, and lactose consumption, all of which are representative of a low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) diet.⁷⁸ Adhering to a low-FODMAP diet has been directly associated with significant improvements in UC-induced pain and overall quality of life.⁷⁸

Exercise: Regular exercise is beneficial for overall health by improving cardiovascular function and reducing inflammation and stress levels. Reducing inflammation and stress may reduce pain in UC patients, although there is no established link between the two.⁷⁹ In preclinical, forced treadmill exercise studies in mice, UC symptoms were potentiated rather than attenuated despite a reduction in proinflammatory cytokines.⁸⁰ Interestingly, mice allowed to voluntarily exercise displayed reduced UC symptomatology, suggesting that forced exercise induces a stress response that aggravates UC symptoms and pain.⁸⁰ Whereas some UC patients report experiencing reduced stress and pain alleviation with exercise, others report flares of pain when engaging in exercises that stress the abdomen, such as jogging, sitting up, and bending over.⁸¹ The extent to which exercise is beneficial in managing UC may, therefore, depend on the type of exercise as well as an individual’s attitude towards exercise, specific needs, and/or state of condition.⁸¹

Role of the Pharmacist

Individuals with UC face complex therapeutic regimens in addition to significant disease burdens that can negatively affect overall quality of life. As the most accessible healthcare professionals, pharmacists have the opportunity to help patients manage therapeutic challenges, especially pain. By remaining knowledgeable about upcoming treatment options, pharmacists will not only be able to help providers determine the best course of action but also confidently educate and counsel patients about the origins of UC-induced pain and how medications and lifestyle changes may help alleviate it. Inflammation in UC patients can contribute to inflammation-induced comorbidities (e.g., cancer, renal disease, cardiovascular disease, arthritis), resulting in the need for medication therapy management to monitor for polypharmacy. Empathetically discussing these topics with patients will improve their understanding of their condition and treatments and may aid in medication adherence, which is essential for achieving remission. By maintaining an open dialogue with UC patients about their pain and individual needs, pharmacists can offer encouragement and personalize treatment recommendations.

REFERENCES

1. Lynch WD, Hsu R. Ulcerative colitis. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2023.
2. Lewis JD, Parlett LE, Jonsson Funk ML, et al. Incidence, prevalence, and racial and ethnic distribution of inflammatory bowel disease in the United States. Gastroenterology. 2023;165(5):1197-1205.e2.
3. Crohn’s and Colitis Foundation of America. The facts about inflammatory bowel diseases. 2014. www.crohnscolitisfoundation.org/sites/default/files/2019-02/Updated%20IBD%20Factbook.pdf. Accessed January 8, 2024.
4. Belkaid Y, Hand TW. Role of the microbiota in immunity and inflammation. Cell. 2014;157(1):121-141.
5. Zou J, Liu C, Jiang S, et al. Cross talk between gut microbiota and intestinal mucosal immunity in the development of ulcerative colitis. Infect Immun. 2021;89(9):e0001421.
6. Yu S, Sun Y, Shao X, et al. Leaky gut in IBD: intestinal barrier-gut microbiota interaction. J Microbiol Biotechnol. 2022;32(7):825-834.
7. Veny M, Fernandez-Clotet A, Panes J. Controlling leukocyte trafficking in IBD. Pharmacol Res. 2020;159:105050.
8. Casalegno Garduno R, Dabritz J. New insights on CD8(+) T cells in inflammatory bowel disease and therapeutic approaches. Front Immunol. 2021;12:738762.
9. Grondin JA, Kwon YH, Far PM, et al. Mucins in intestinal mucosal defense and inflammation: learning from clinical and experimental studies. Front Immunol. 2020;11:2054.
10. Gros B, Kaplan GG. Ulcerative colitis in adults: a review. JAMA. 2023;330(10):951-965.
11. Levine JS, Burakoff R. Extraintestinal manifestations of inflammatory bowel disease. Gastroenterol Hepatol (NY). 2011;7(4):235-241.
12. Vedamurthy A, Ananthakrishnan AN. Influence of environmental factors in the development and outcomes of inflammatory bowel disease. Gastroenterol Hepatol (NY). 2019;15(2):72-82.
13. Peppas S, Pansieri C, Piovani D, et al. The brain-gut axis: psychological functioning and inflammatory bowel diseases. J Clin Med. 2021;10(3):377.
14. Carabotti M, Scirocco A, Maselli MA, Severi C. The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems. Ann Gastroenterol. 2015;28(2):203-209.
15. Yuan X, Chen B, Duan Z, et al. Depression and anxiety in patients with active ulcerative colitis: crosstalk of gut microbiota, metabolomics and proteomics. Gut Microbes. 2021;13(1):1987779.
16. Mikocka-Walus A, Prady SL, Pollok J, et al. Adjuvant therapy with antidepressants for the management of inflammatory bowel disease. Cochrane Database Syst Rev. 2019;4(4):CD012680.
17. Rubin DT, Ananthakrishnan AN, Siegel CA, et al. ACG clinical guideline: ulcerative colitis in adults. Am J Gastroenterol. 2019;114(3):384-413.
18. Prasad SS, Keely S, Talley NJ, et al. Pharmacists’ confidence in managing patients with inflammatory bowel disease. Pharmacy (Basel). 2020;8(2):68.
19. Ananthakrishnan AN. Vitamin D and inflammatory bowel disease. Gastroenterol Hepatol (NY). 2016;12(8):513-515.
20. Kumar A, Brookes MJ. Iron therapy in inflammatory bowel disease. Nutrients. 2020;12(11):3478.
21. Stein J, Dignass AU. Management of iron deficiency anemia in inflammatory bowel disease–a practical approach. Ann Gastroenterol. 2013;26(2):104-113.
22. Hazel K, O’Connor A. Emerging treatments for inflammatory bowel disease. Ther Adv Chronic Dis. 2020;11:2040622319899297.
23. Bielefeldt K, Davis B, Binion DG. Pain and inflammatory bowel disease. Inflamm Bowel Dis. 2009;15(5):778-788.
24. Limsui D, Pardi DS. Quality of life in ulcerative colitis. www.medscape.org/viewarticle/572039. Accessed November 30, 2023.
25. Coates MD, Lahoti M, Binion DG, et al. Abdominal pain in ulcerative colitis. Inflamm Bowel Dis. 2013;19(10):2207-2214.
26. Vanhoutvin SALW, Troost FJ, Kilkens TOC, et al. The effects of butyrate enemas on visceral perception in healthy volunteers. Neurogastroenterol Motil. 2009;21(9):952-e76.
27. Canani RB, Di Costanzo M, Leone L, et al. Potential beneficial effects of butyrate in intestinal and extraintestinal diseases. World J Gastroenterol. 2011;17(12):1519-1528.
28. Vieira ELM, Leonel AJ, Sad AP, et al. Oral administration of sodium butyrate attenuates inflammation and mucosal lesion in experimental acute ulcerative colitis. J Nutr Biochem. 2012;23(5):430-436.
29. Martin CR, Osadchiy V, Kalani A, Mayer EA. The brain-gut-microbiome axis. Cell Mol Gastroenterol Hepatol. 2018;6(2):133-148.
30. Ge L, Liu S, Li S, et al. Psychological stress in inflammatory bowel disease: psychoneuroimmunological insights into bidirectional gut-brain communications. Front Immunol. 2022;13:1016578.
31. Barandouzi ZA, Lee J, Del Carmen Rosas M, et al. Associations of neurotransmitters and the gut microbiome with emotional distress in mixed type of irritable bowel syndrome. Sci Rep. 2022;12(1):1648.
32. Hamamah S, Aghazarian A, Nazaryan A, et al. Role of microbiota-gut-brain axis in regulating dopaminergic signaling. Biomedicines. 2022;10(2):436.
33. Feuerstein JD, Isaacs KL, Schneider Y, et al. AGA clinical practice guidelines on the management of moderate to severe ulcerative colitis. Gastroenterology. 2020;158(5):1450-1461.
34. Scharl M. Pathophysiological role of TNF in inflammatory bowel disease: TNF and its effect on innate immune defense. In: Rogler G, Hibi T, Herfarth H, Nielsen OH, eds. Anti-Tumor Necrosis Factor Therapy in Inflammatory Bowel Disease. Basel, Switzerland: Karger; 2015:34.
35. Dai Q, Xia X, He C, et al. Association of anti-TNF-α treatment with gut microbiota of patients with ankylosing spondylitis. Pharmacogenet Genomics. 2022;32(7):247-256.
36. Onuora S. Anti-TNF therapy reverses gut dysbiosis in AS. Nat Rev Rheumatol. 2020;16(1):2.
37. Ditto MC, Parisi S, Landolfi G, et al. Intestinal microbiota changes induced by TNF-inhibitors in IBD-related spondyloarthritis. RMD Open. 2021;7(3):e001755.
38. Yin J, Sternes PR, Wang M, et al. Shotgun metagenomics reveals an enrichment of potentially cross-reactive bacterial epitopes in ankylosing spondylitis patients, as well as the effects of TNFi therapy upon microbiome composition. Ann Rheum Dis. 2020;79(1):132-140.
39. Horst S, Chao A, Rosen M, et al. Treatment with immunosuppressive therapy may improve depressive symptoms in patients with inflammatory bowel disease. Dig Dis Sci. 2015;60(2):465-470.
40. Harris MS, Hartman D, Lemos BR, et al. AVX-470, an orally delivered anti-tumour necrosis factor antibody for treatment of active ulcerative colitis: results of a first-in-human trial. J Crohns Colitis. 2016;10(6):631-640.
41. Hartman DS, Tracey DE, Lemos BR, et al. Effects of AVX-470, an oral, locally acting anti-tumour necrosis factor antibody, on tissue biomarkers in patients with active ulcerative colitis. J Crohns Colitis. 2016;10(6):641-649.
42. Heneghan AF, Pierre JF, Kudsk KA. JAK-STAT and intestinal mucosal immunology. JAKSTAT. 2013;2(4):e25530.
43. Coskun M, Salem M, Pedersen J, Nielsen OH. Involvement of JAK/STAT signaling in the pathogenesis of inflammatory bowel disease. Pharmacol Res. 2013;76:1-8.
44. Nakase H. Understanding the efficacy of individual Janus kinase inhibitors in the treatment of ulcerative colitis for future positioning in inflammatory bowel disease treatment. Immunol Med. 2023;46(3):121-130.
45. Liu E, Aslam N, Nigam G, Limdi JK. Tofacitinib and newer JAK inhibitors in inflammatory bowel disease-where we are and where we are going. Drugs Context. 2022;11:2021-11-4.
46. Flanagan ME, Blumenkopf TA, Brissette WH, et al. Discovery of CP-690,550: a potent and selective Janus kinase (JAK) inhibitor for the treatment of autoimmune diseases and organ transplant rejection. J Med Chem. 2010;53(24):8468-8484.
47. Cutolo M. The kinase inhibitor tofacitinib in patients with rheumatoid arthritis: latest findings and clinical potential. Ther Adv Musculoskelet Dis. 2013;5(1):3-11.
48. Riese RJ, Krishnaswami S, Kremer J. Inhibition of JAK kinases in patients with rheumatoid arthritis: scientific rationale and clinical outcomes. Best Pract Res Clin Rheumatol. 2010;24(4):513-526.
49. Danese S, Tran J, D’Haens G, et al. Upadacitinib induction and maintenance therapy improves abdominal pain, bowel urgency, and fatigue in patients with ulcerative colitis: a post hoc analysis of phase 3 data. Inflamm Bowel Dis. 2023;29(11):1723-1729.
50. Duvallet E, Semerano L, Assier E, et al. Interleukin-23: a key cytokine in inflammatory diseases. Ann Med. 2011;43(7):503-511.
51. Sewell GW, Kaser A. Interleukin-23 in the pathogenesis of inflammatory bowel disease and implications for therapeutic intervention. J Crohns Colitis. 2022;16(suppl 2):ii3-ii19.
52. D’Haens G, Dubinsky M, Kobayashi T, et al. Mirikizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2023;388(26):2444-2455.
53. Parigi TL, Iacucci M, Ghosh S. Blockade of IL-23: what is in the pipeline? J Crohns Colitis. 2022;16(suppl 2):ii64-ii72.
54. Vuyyuru SK, Shackelton LM, Hanzel J. Targeting IL-23 for IBD: rationale and progress to date. Drugs. 2023;83(10):873-891.
55. Zou F, Wang S, Xu M, et al. The role of sphingosine-1-phosphate in the gut mucosal microenvironment and inflammatory bowel diseases. Front Physiol. 2023;14:1235656.
56. Obinata H, Hla T. Sphingosine 1-phosphate and inflammation. Int Immunol. 2019;31(9):617-625.
57. Choi D, Stewart AP, Bhat S. Ozanimod: a first-in-class sphingosine 1-phosphate receptor modulator for the treatment of ulcerative colitis. Ann Pharmacother. 2022;56(5):592-599.
58. Sandborn WJ, Feagan BG, Hanauer S, et al. Long-term efficacy and safety of ozanimod in moderately to severely active ulcerative colitis: results from the open-label extension of the randomized, phase 2 TOUCHSTONE study. J Crohns Colitis. 2021;15(7):1120-1129.
59. Dal Buono A, Gabbiadini R, Alfarone L, et al. Sphingosine 1-phosphate modulation in inflammatory bowel diseases: keeping lymphocytes out of the intestine. Biomedicines. 2022;10(7):1735.
60. Choden T, Cohen NA, Rubin DT. Sphingosine-1 phosphate receptor modulators: the next wave of oral therapies in inflammatory bowel disease. Gastroenterol Hepatol (NY). 2022;18(5):265-271.
61. Choi D, Becker M, Ivanov M, Bhat S. Etrasimod: a sphingosine-1-phosphate receptor modulator for the treatment of ulcerative colitis. Ann Pharmacother. 2024:10600280231225770.
62. Garlatti V, Lovisa S, Danese S, Vetrano S. The multiple faces of integrin-ECM interactions in inflammatory bowel disease. Int J Mol Sci. 2021;22(19):10439.
63. Dotan I, Allez M, Danese S, et al. The role of integrins in the pathogenesis of inflammatory bowel disease: approved and investigational anti-integrin therapies. Med Res Rev. 2020;40(1):245-262.
64. Gubatan J, Keyashian K, Rubin SJS, et al. Anti-integrins for the treatment of inflammatory bowel disease: current evidence and perspectives. Clin Exp Gastroenterol. 2021;14:333-342.
65. Kuwada T, Shiokawa M, Kodama Y, et al. Identification of an anti-integrin αvβ6 autoantibody in patients with ulcerative colitis. Gastroenterology. 2021;160(7):2383-2394.e21.
66. Livanos AE, Dunn A, Fischer J, et al. Anti-integrin αvβ6 autoantibodies are a novel biomarker that antedate ulcerative colitis. Gastroenterology. 2023;164(4):619-629.
67. Wang L, Liang C, Chen P, et al. Effect of antidepressants on psychological comorbidities, disease activity, and quality of life in inflammatory bowel disease: a systematic review and meta-analysis. Therap Adv Gastroenterol. 2023;16:17562848231155022.
68. Radziszewska M, Smarkusz-Zarzecka J, Ostrowska L, Pogodziński D. Nutrition and supplementation in ulcerative colitis. Nutrients. 2022;14(12):2469.
69. Kruis W, Fric P, Pokrotnieks J, et al. Maintaining remission of ulcerative colitis with the probiotic Escherichia coli Nissle 1917 is as effective as with standard mesalazine. Gut. 2004;53(11):1617-1623.
70. Fujiya M, Ueno N, Kohgo Y. Probiotic treatments for induction and maintenance of remission in inflammatory bowel diseases: a meta-analysis of randomized controlled trials. Clin J Gastroenterol. 2014;7(1):1-13.
71. Fedorak RN. Probiotics in the management of ulcerative colitis. Gastroenterol Hepatol (NY). 2010;6(11):688-690.
72. Vernero M, De Blasio F, Ribaldone DG, et al. The usefulness of microencapsulated sodium butyrate add-on therapy in maintaining remission in patients with ulcerative colitis: a prospective observational study. J Clin Med. 2020;9(12):3941.
73. Verna EC, Lucak S. Use of probiotics in gastrointestinal disorders: what to recommend? Therap Adv Gastroenterol. 2010;3(5):307-319.
74. Doron S, Snydman DR. Risk and safety of probiotics. Clin Infect Dis. 2015;60(suppl 2):S129-S134.
75. Hilsden RJ, Verhoef MJ, Rasmussen H, et al. Use of complementary and alternative medicine by patients with inflammatory bowel disease. Inflamm Bowel Dis. 2011;17(2):655-662.
76. Keefer L, Taft TH, Kiebles JL, et al. Gut-directed hypnotherapy significantly augments clinical remission in quiescent ulcerative colitis. Alimentary Pharmacol Ther. 2013;38(7):761-771.
77. Shaw L, Ehrlich A. Relaxation training as a treatment for chronic pain caused by ulcerative colitis. Pain. 1987;29(3):287-293.
78. Tamizifar B, Arab A. Effects of comprehensive dietary advice on the physical and mental health of patients with ulcerative colitis during the remission phase: a parallel randomized controlled clinical trial. Int J Food Prop. 2020;23(1):1834-1844.
79. De Sousa JFM, Paghdar S, Khan TM, et al. Stress and inflammatory bowel disease: clear mind, happy colon. Cureus. 2022;14(5):e25006.
80. Cook MD, Martin SA, Williams C, et al. Forced treadmill exercise training exacerbates inflammation and causes mortality while voluntary wheel training is protective in a mouse model of colitis. Brain Behav Immun. 2013;33:46-56.
81. Lamers CR, de Roos NM, Koppelman LJM, et al. Patient experiences with the role of physical activity in inflammatory bowel disease: results from a survey and interviews. BMC Gastroenterol. 2021;21(1):172.

To comment on this article, contact rdavidson@uspharmacist.com.