IBD: Current Treatments
The ultimate goal of treatment for IBD is to induce remission for either UC or CD, based initially on whether the patient is diagnosed with mild, moderate, or severe disease.
Ulcerative Colitis:
UC treatment depends on disease extent and the presence of extraintestinal manifestations. For those with mild to moderate disease limited to the rectum, aminosalicylates are the mainstays. For those patients with moderate disease, oral glucocorticoids or immunomodulators such as tumor necrosis factor (TNF)-alpha inhibitors may be used. Other agents such as Janus kinase (JAK) inhibitors, integrin receptor antagonists, and interlukin (IL) 12/23 inhibitors may also be considered.1
Crohn’s Disease:
CD treatment depends on how much of the GI tract is involved, as well as extraintestinal complications and the degree of fistulizing or structuring disease. Treatment for mild disease usually starts with mesalamine, then budesonide. For more extensive disease, systemic prednisone is often necessary with the goal of weaning within 6 weeks. In those who cannot wean, an immunomodulating agent such as 6 mercaptopurine, azathioprine, or low-dose methotrexate can be used. In those with moderate to severe disease, anti-TNF therapy should be initiated. Patients may then cycle through integrin receptor antagonists, IL-12/23 inhibitors, or others.1
With regard to biologics and small molecules, early research identified a role of specific inflammatory markers in the pathogenesis of IBD. For example, TNF-alpha levels were found to be significantly higher in patents with IBD versus controls, and associated with elevations in IL-6 levels and CRP.2,3 Recognition of these relationships led to the development of anti-TNF antibodies that are efficacious in the management of IBD, though limited by the potential for loss of efficacy, a parenteral mode of administration, and potential hypersensitivity reactions that might also lead to the development of neutralizing antibodies.4,5
Beyond the first-generation biologics, a recognition of the importance of IL-23 stimulation resulting in downstream activation of pathways related to JAK/STAT phosphorylation has led to novel therapeutics. Agents such as ustekinumab (IL-12/23 blocker) and risankizumab (IL-23 blocker) limit immune cell activation and subsequent cytokine production and inflammation.5.6 Vedolizumab and natalizumab are integrin receptor antagonists that block this cascade as well.5
New and emerging small-molecule JAK inhibitors are also a novel way of achieving endoscopic healing and clinical remission in patients with UC and CD.7 Tofacitinib is an oral JAK inhibitor that mainly inhibits JAK1 and JAK3, thereby blocking the downstream effects of a large subset of proinflammatory cytokines, including IL-2, IL-3, IL-4, IL-5, IL-6, IL-12, IL-15, IL-21, and interferon-γ.8-10 Upadacitinib acts similarly; it is an orally administered selective JAK1 inhibitor for use in adults with moderate-to-severe active UC who have had an inadequate response or intolerance to 1 or more TNF blockers.11,12
References
- McDowell C, Farooq U, Haseeb M. StatPearls [Internet]. Inflammatory bowel disease. May 1, 2022. https://www.ncbi.nlm.nih.gov/books/NBK470312/.
- Mahmud N, O’Connell MA, Stinson J, et al. Tumour necrosis factor-alpha and microalbuminuria in patients with inflammatory bowel disease. Eur J Gastroenterol Hepatol. 1995;7(3):215-219.
- Worledge KL, Godiska R, Barrett TA, et al. Oral administration of avian tumor necrosis factor antibodies effectively treats experimental colitis in rats. Dig Dis Sci. 2000;45(12):2298-2305.
- Pache I, Rogler G, Felley C. TNF-alpha blockers in inflammatory bowel diseases: practical consensus recommendations and a user’s guide. Swiss Med Wkly. 2009;139(19-20):278-287.
- Harris C, Cummings JRF. JAK1 inhibition and inflammatory bowel disease. Rheumatol (Oxford). 2021;60(suppl 2):ii45-ii51.
- Benson JM, Peritt D, Scallon BJ, et al. Discovery and mechanism of ustekinumab: a human monoclonal antibody targeting interleukin-12 and interleukin-23 for treatment of immune-mediated disorders. MAbs. 2011; 3(6):535-545.
- Oo C, Kalbag S. Leveraging the attributes of biologics and small molecules, and releasing the bottlenecks: a new wave of revolution in drug development. Expert Rev Clin Pharmacol. 2016;9(6):747-749.
- Coskun M, Salem M, Pedersen J, et al. Involvement of JAK/STAT signaling in the pathogenesis of inflammatory bowel disease. Pharmacol Res. 2013;76:1-8.
- Danese S, Grisham M, Hodge J, et al. JAK inhibition using tofacitinib for inflammatory bowel disease treatment: a hub for multiple inflammatory cytokines. Am J Physiol Gastrointest Liver Physiol. 2016;310:G155-G162.
- 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.
- Sandborn WJ, Ghosh S, Panes J, et al. Efficacy of upadacitinib in a randomized trial of patients with active ulcerative colitis. Gastroenterol. 2020;158:2139-2149.
- Vermeire S, Danese S, Zhou W, et al. OP23 Efficacy and safety of upadacitinib as induction therapy in patients with moderately to severely active ulcerative colitis: results from phase 3 U-ACCOMPLISH study. J Crohns Collitis. 2021;15(suppl 1):S021-S022.
