Biologic Therapy in Crohn’s Disease–What We Have Learnt So Far

Author(s): Kinga Majchrzak, Jakub Fichna*

Journal Name: Current Drug Targets

Volume 21 , Issue 8 , 2020

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Graphical Abstract:


Crohn’s disease (CD) is an autoimmune disorder from the group of inflammatory bowel diseases. The etiology of CD is not clear; currently, the interaction between the genetic, immunological and environmental factors is assumed as the cause of the disease. Partial knowledge of those factors has led to the development of drugs, which control the clinical symptoms and improve the overall condition of the infected; the main objective of the modern therapeutic strategies is the induction and maintenance of remission. Among the wide range of available treatments, older generation molecules: mesalazine, corticosteroids and thiopurine derivatives as well as biological drugs and biosimilars can be distinguished. Moreover, some novel biologics and small molecule drugs have shown potential in CD clinical trials, providing safe and effective results. This article provides an overview of the achievements in the field of biologic therapy, its efficacy and safety with an indication of future directions in CD treatment.

Keywords: Crohn's disease, nonsteroidal anti-inflammatory drugs, biological therapy, monoclonal antibodies, biosimilars.

Petkowicz B, Berger M, Szeszko U, Piotrkowicz J. Nieswoiste zapalenia jelit - Diagnostyka, etiologia oraz objawy z uwzglȩdnieniem zmian w jamie ustnej. Gastroenterol Pol 2011; 18(1): 35-40.
Schwartzberg DM, Brandstetter S, Grucela AL. Crohn’s Disease of the Esophagus, Duodenum, and Stomach. Clin Colon Rectal Surg 2019; 32(4): 231-42. []. [PMID: 31275069].
Baumgart DC, Carding SR. Inflammatory bowel disease: cause and immunobiology. Lancet 2007; 369(9573): 1627-40. []. [PMID: 17499605].
Margulies SL, Kurian D, Elliott MS, Han Z. Vitamin D deficiency in patients with intestinal malabsorption syndromes--think in and outside the gut. J Dig Dis 2015; 16(11): 617-33. []. [PMID: 26316334].
Khor B, Gardet A, Xavier RJ. Genetics and pathogenesis of inflammatory bowel disease. Nature 2011; 474(7351): 307-17. []. [PMID: 21677747].
Polińska B, Matowicka-karna J, Kemona H. Cytokiny w nieswoistych zapalnych chorobach jelit The cytokines in infl ammatory bowel disease. Postep Hig Med Dosw 2009; pp. 389-94.
Atkins D, Furuta GT. Mucosal immunology, eosinophilic esophagitis, and other intestinal inflammatory diseases. J Allergy Clin Immunol 2010; 125(2)(Suppl. 2): S255-61. []. [PMID: 20176262].
Rosenstiel P, Sina C, Franke A, Schreiber S. Towards a molecular risk map--recent advances on the etiology of inflammatory bowel disease. Semin Immunol 2009; 21(6): 334-45. []. [PMID: 19926490].
Schweitzer N, Manns MP. Extraintestinal manifestations of inflammatory bowel disease: Autoimmune hepatitis Crohn’s Dis Ulcerative Colitis From Epidemiol Immunobiol to a Ration Diagnostic Ther Approach 2012; 565--78..
Philpott DJ, Viala J. Towards an understanding of the role of NOD2/CARD15 in the pathogenesis of Crohn’s disease. Best Pract Res Clin Gastroenterol 2004; 18(3): 555-68. []. [PMID: 15157827].
Vavricka SR, Rogler G. New insights into the pathogenesis of Crohn’s disease: are they relevant for therapeutic options? Swiss Med Wkly 2009; 139(37-38): 527-34. [PMID: 19838869].
Strober W, Fuss I, Mannon P. The fundamental basis of inflammatory bowel disease. J Clin Invest 2007; 117(3): 514-21. []. [PMID: 17332878].
Sewell GW, Marks DJB, Segal AW. Europe PMC Funders Group The immunopathogenesis of Crohn ’ s disease : a three-stage model 2015; 21(5:): 506--13..
Marks DJB, Rahman FZ, Sewell GW, Segal AW. Crohn’s disease: an immune deficiency state. Clin Rev Allergy Immunol 2010; 38(1): 20-31. []. [PMID: 19437144].
Barrett M, Chandra SB. A review of major Crohn’s disease susceptibility genes and their role in disease pathogenesis. Genes Genomics 2011; 33(4): 317-25. [].
Zhou L, Braat H, Faber KN, Dijkstra G, Peppelenbosch MP. Monocytes and their pathophysiological role in Crohn’s disease. Cell Mol Life Sci 2009; 66(2): 192-202. []. [PMID: 18791847].
Radwan P, Radwan-Kwiatek K, Tabarkiewicz J, Skrzydło-Radomańska B, Roliński J. Rola komórek dendrytycznych w nieswoistych zapaleniach jelit. Gastroenterol Pol 2007; 14(2): 123-6.
Radwan P, Radwan-Kwiatek K, Skrzydło-Radomańska B. The role of enteric microflora in inflammatory bowel disease. Prz Gastroenterol 2009; 4(1): 1-6.
Strober W, Fuss IJ. Proinflammatory cytokines in the pathogenesis of inflammatory bowel diseases. Gastroenterology 2011; 140(6): 1756-67. [Internet]. []. [PMID: 21530742].
Gutkowski K, Gutkowska D. Rola mechanizmów immunologicznych w patogenezie nieswoistych zapaleñ jelit The role of immunological mechanisms in the pathogenesis of inflammatory bowel diseases 2006; 13((3):): 197--20..
Armuzzi A, Pascalis B. De , et al. Infliximab in Crohn ’ s disease :early and long-term treatment 2008;; 271--9..
Mazmanian SK, Round JL, Kasper DL. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 2008; 453(7195): 620-5. []. [PMID: 18509436].
Rescigno M. The intestinal epithelial barrier in the control of homeostasis and immunity. Trends Immunol 2011; 32(6): 256-64. []. [PMID: 21565554].
Chow J, Tang H, Mazmanian SK. Pathobionts of the gastrointestinal microbiota and inflammatory disease. Curr Opin Immunol 2011; 23(4): 473-80. []. [PMID: 21856139].
Takaishi H, Matsuki T, Nakazawa A, et al. Imbalance in intestinal microflora constitution could be involved in the pathogenesis of inflammatory bowel disease. Int J Med Microbiol 2008; 298(5-6): 463-72. []. [PMID: 17897884].
Sobieszczańska B. Prace poglądowe Rola bakterii w chorobie Leśniowskiego-Crohna 2010; 10:: 38- -40..
K. N. Treatment for the maintenance of remission in inflammatory bowel disease. Gastroenterol Pol 2010; 17(2): 129-32. [Internet].
Dobrowolska-Zachwieja A, Jakubowska-Burek L. Korzyści leczenia biologicznego u osób z nieswoistymi chorobami zapalnymi jelit. Prz Gastroenterol 2010; 5(2): 68-76.
Van Assche G, Dignass A, Panes J, et al. European Crohn’s and Colitis Organisation (ECCO). The second European evidence-based Consensus on the diagnosis and management of Crohn’s disease: Definitions and diagnosis. J Crohn’s Colitis 2010; 4(1): 7-27. []. [PMID: 21122488].
Lichtenstein GR, Bengtsson B, Hapten-White L, Rutgeerts P. Oral budesonide for maintenance of remission of Crohn’s disease: a pooled safety analysis. Aliment Pharmacol Ther 2009; 29(6): 643-53. []. [PMID: 19035972].
Rutgeerts P, Feagan BG, Lichtenstein GR, et al. Comparison of scheduled and episodic treatment strategies of infliximab in Crohn’s disease. Gastroenterology 2004; 126(2): 402-13. []. [PMID: 14762776].
Śliwiński Z. Zjawiska oporności i zależności kortykosteroidowej u osób z choroba̧ Leśniowskiego-Crohna. Prz Gastroenterol 2009.
Beaulieu DB, Ananthakrishnan AN, Issa M, et al. Budesonide induction and maintenance therapy for Crohn’s disease during pregnancy. Inflamm Bowel Dis 2009; 15(1): 25-8. []. [PMID: 18680195].
Panaccione R, Rutgeerts P, Sandborn WJ, Feagan B, Schreiber S, Ghosh S. Review article: treatment algorithms to maximize remission and minimize corticosteroid dependence in patients with inflammatory bowel disease. Aliment Pharmacol Ther 2008; 28(6): 674-88. []. [PMID: 18532990].
Gadowska-Cicha A, Latos W, Niepsuj KJ, Sieroń A, Leśniowskiego-crohna LC, Odcinku WG, et al. RE:view 2005; 1(7): 5-6.
Eder P, Łykowska-Szuber L, Stawczyk-Eder K, Krela-Kaźmierczak I, Linke K. Mechanizmy działania inhibitorów czynnika martwicy nowotworów α. Prz Gastroenterol 2011.
Chan AC, Carter PJ. Therapeutic antibodies for autoimmunity and inflammation. Nat Rev Immunol 2010; 10(5): 301-16. [Internet]. []. [PMID: 20414204].
Powroźnik B, Kubowicz P, Pȩkala E. Przeciwciała monoklonalne w terapii celowanej. Postepy Hig Med Dosw 2012; 66: 663-73.
Brennan FM, Chantry D, Jackson A, Maini R, Feldmann M. Inhibitory effect of TNF alpha antibodies on synovial cell interleukin-1 production in rheumatoid arthritis. Lancet 1989; 2(8657): 244-7. []. [PMID: 2569055].
Elliott MJ, Maini RN, Feldmann M, et al. Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor α. Arthritis Rheum 1993; 36(12): 1681-90. []. [PMID: 8250987].
Horiuchi T, Mitoma H, Harashima S, Tsukamoto H, Shimoda T. Transmembrane TNF-α: structure, function and interaction with anti-TNF agents. Rheumatology (Oxford) 2010; 49(7): 1215-28. []. [PMID: 20194223].
Ksiądzyna D, Rybak M. Działania niepożądane antagonistów TNF-α w leczeniu nieswoistych zapaleń jelit Adverse effects of TNF-α antagonists in the treatment of inflammatory bowel diseases 2009; 16( (5):): 403--8..
Bosani M, Ardizzone S, Porro GB. Biologic targeting in the treatment of inflammatory bowel diseases. Biologics 2009; 3: 77-97. [PMID: 19707398].
Targan SR, Hanauer SB, van Deventer SJ, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn’s disease. Crohn’s Disease cA2 Study Group. N Engl J Med 1997; 337(15): 1029-35. []. [PMID: 9321530].
D’Haens G. Risks and benefits of biologic therapy for inflammatory bowel diseases. Gut 2007; 56(5): 725-32. []. [PMID: 17440187].
Hoentjen F, Bodegraven AA. , Van. Safety of anti-tumor necrosi factor therapy in inflammatory bowel disease. 2009;; 15:: 2067--73..
Siegel CA, Marden SM, Persing SM, Larson RJ, Bruce E. NIH Public Access 2010;; 7( (8) 874-81)
Kolarz B, Targońska-Stepniak B, Darmochwał-Kolarz D, Majdan M. Autoimmunizacja w trakcie terapii biologicznej z zastosowaniem antagonistów TNF. Postepy Hig Med Dosw 2007; 61: 478-84.
Sprakes MB, Hamlin PJ, Warren L, Greer D, Ford AC. Adalimumab as second line anti-tumour necrosis factor alpha therapy for Crohn’s disease: A single centre experience. J Crohn’s Colitis 2011; 5(4): 324-31. [Internet]. []. [PMID: 21683302].
Nelson AL, Dhimolea E, Reichert JM. Development trends for human monoclonal antibody therapeutics. Nat Rev Drug Discov 2010; 9(10): 767-74. [Internet]. []. [PMID: 20811384].
Karmiris K, Paintaud G, Noman M, et al. Influence of trough serum levels and immunogenicity on long-term outcome of adalimumab therapy in Crohn’s disease. Gastroenterology 2009; 137(5): 1628-40. [Internet]. []. [PMID: 19664627].
Colombel JF, Sandborn WJ, Rutgeerts P, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial. Gastroenterology 2007; 132(1): 52-65. []. [PMID: 17241859].
Hanauer SB, Sandborn WJ, Rutgeerts P, et al. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn’s disease: the CLASSIC-I trial. Gastroenterology 2006; 130(2): 323-33. []. [PMID: 16472588].
Sandborn WJ, Hanauer SB, Rutgeerts P, et al. Adalimumab for maintenance treatment of Crohn’s disease: results of the CLASSIC II trial. Gut 2007; 56(9): 1232-9. []. [PMID: 17299059].
Nesbitt A, Fossati G, Bergin M, et al. Mechanism of action of certolizumab pegol (CDP870): in vitro comparison with other anti-tumor necrosis factor α agents. Inflamm Bowel Dis 2007; 13(11): 1323-32. []. [PMID: 17636564].
Goel N, Stephens S. Certolizumab pegol 2009; 137--47..
Sandborn WJ, Feagan BG, Fedorak RN. etal Ustekinumab Crohn’s Disease Study Group. A randomized trial of Ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn’s disease. Gastroenterology 2008; 135(4): 1130-41. []. [PMID: 18706417].
Luo J, Wu SJ, Lacy ER, et al. Structural basis for the dual recognition of IL-12 and IL-23 by ustekinumab. J Mol Biol 2010; 402(5): 797-812. [Internet]. []. [PMID: 20691190].
Feagan BG, Sandborn WJ, Gasink C. etal UNITI–IM-UNITI Study Group. Ustekinumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med 2016; 375(20): 1946-60. []. [PMID: 27959607].
Battat R, Kopylov U, Bessissow T, et al. Association between ustekinumab trough concentrations and clinical, biomarker, and endoscopic outcomes in patients with crohn’s disease. Clin Gastroenterol Hepatol 2017; 15(9): 1427-1434.e2. []. [PMID: 28365485].
Nelson SML, Nguyen TM, McDonald JWD, MacDonald JK. Natalizumab for induction of remission in Crohn’s disease. Cochrane Database Syst Rev 2018;; 8CD006097
[] [PMID: 30068022]
Warnke C, Menge T, Hartung HP, et al. Natalizumab and progressive multifocal leukoencephalopathy: what are the causal factors and can it be avoided? Arch Neurol 2010; 67(8): 923-30. []. [PMID: 20697042].
Williet N, Boschetti G, Fovet M, et al. Association between low trough levels of vedolizumab during induction therapy for inflammatory bowel diseases and need for additional doses within 6 months. Clin Gastroenterol Hepatol 2017; 15(11): 1750-1757.e3. []. [PMID: 27890854].
Yacoub W, Williet N, Pouillon L, et al. Early vedolizumab trough levels predict mucosal healing in inflammatory bowel disease: a multicentre prospective observational study. Aliment Pharmacol Ther 2018; 47(7): 906-12. []. [PMID: 29384209].
Vermeire S, Loftus EV Jr, Colombel JF, et al. Long-term efficacy of vedolizumab for Crohn’s disease. J Crohn’s Colitis 2017; 11(4): 412-24. [PMID: 27683798].
Sandborn WJ, Feagan BG, Rutgeerts P, et al. GEMINI 2 Study Group. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med 2013; 369(8): 711-21. []. [PMID: 23964933].
Langrish CL, McKenzie BS, Wilson NJ, de Waal Malefyt R, Kastelein RA, Cua DJ. IL-12 and IL-23: master regulators of innate and adaptive immunity. Immunol Rev 2004; 202: 96-105. []. [PMID: 15546388].
Hofmann SR, Ettinger R, Zhou YJ, et al. Cytokines and their role in lymphoid development, differentiation and homeostasis. Curr Opin Allergy Clin Immunol 2002; 2(6): 495-506. []. [PMID: 14752332].
Heller F, Florian P, Bojarski C, et al. Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution. Gastroenterology 2005; 129(2): 550-64. []. [PMID: 16083712].
Kolls JK, Lindén A. Interleukin-17 family members and inflammation. Immunity 2004; 21(4): 467-76. []. [PMID: 15485625].
Changelian PS, Moshinsky D, Kuhn CF, et al. The specificity of JAK3 kinase inhibitors. Blood 2008; 111(4): 2155-7. []. [PMID: 18094329].
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): 8468-84. []. [PMID: 21105711].
Dowty ME, Lin J, Ryder TF, et al. The pharmacokinetics, metabolism, and clearance mechanisms of tofacitinib, a janus kinase inhibitor, in humans. Drug Metab Dispos 2014; 42(4): 759-73. []. [PMID: 24464803].
Meyer DM, Jesson MI, Li X, et al. Anti-inflammatory activity and neutrophil reductions mediated by the JAK1/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthritis. J Inflamm (Lond) 2010; 7: 41. []. [PMID: 20701804].
Sandborn WJ, Ghosh S, Panes J, Vranic I, Wang W, Niezychowski W. Study A3921043 Investigators. A phase 2 study of tofacitinib, an oral Janus kinase inhibitor, in patients with Crohn’s disease. Clin Gastroenterol Hepatol 2014; 12(9): 1485-93.e2. []. [PMID: 24480677].
Sandborn WJ, Panés J, Zhang H, Yu D, Niezychowski W, Su C. Correlation Between Concentrations of Fecal Calprotectin and Outcomes of Patients With Ulcerative Colitis in a Phase 2 Trial. Gastroenterology 2016; 150(1): 96-102. []. [PMID: 26376350].
Boland BS, Sandborn WJ, Chang JT. Update on janus kinase antagonists in inflammatory bowel disease. Gastroenterol Clin North Am 2014; 43(3): 603-17.
Sandborn WJ, Feagan BG, Panes J, D’Haens GR, Colombel JF, Zhou Q, 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(5): S1308-9. [Internet]. [].
Cleynen I, Vermeire S. The genetic architecture of inflammatory bowel disease: past, present and future. Curr Opin Gastroenterol 2015; 31(6): 456-63. []. [PMID: 26444824].
Weiser M, Simon JM, Kochar B, et al. Molecular classification of Crohn’s disease reveals two clinically relevant subtypes. Gut 2018; 67(1): 36-42. []. [PMID: 27742763].
Lee JC, Lyons PA, McKinney EF, et al. Gene expression profiling of CD8+ T cells predicts prognosis in patients with Crohn disease and ulcerative colitis. J Clin Invest 2011; 121(10): 4170-9. []. [PMID: 21946256].
Ben-Horin S, Lahat A, Amitai MM, Klang E, Yablecovitch D, Neuman S, et al. P392 Comprehensive video capsule endoscopy-based monitoring predicts short and long-term risk of disease flares in small bowel Crohn’s disease: A prospective cohort study. J Crohn’s Colitis 2018. [].
Ananthakrishnan AN, Luo C, Yajnik V, et al. Gut Microbiome function predicts response to anti-integrin biologic therapy in inflammatory bowel diseases. Cell Host Microbe 2017; 21(5): 603-610.e3. []. [PMID: 28494241].
Zhou Y, Xu ZZ, He Y, et al. Gut microbiota offers universal biomarkers across ethnicity in inflammatory bowel disease diagnosis and infliximab response prediction. mSystems 2018; 3(1): e00188-17. []. [PMID: 29404425].

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Year: 2020
Published on: 20 June, 2020
Page: [792 - 806]
Pages: 15
DOI: 10.2174/1389450121666191218123203
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