New therapies for inflammatory bowel diseases

Currently, Inflammatory Bowel Disease (IBD) is considered an immune-mediated disease. The most widely accepted etiopathogenic hypothesis is that it is due to an inadequate interaction between the immune system and the microorganisms that form the normal intestinal flora. This abnormal interaction occurs in genetically predisposed subjects under the influence of various environmental factors (such as tobacco, diet, stress, or recurrent bacterial infections), which could act as triggers for alterations in the intestinal epithelial barrier. This would lead to an increase in the permeability of barrier, allowing the translocation of microbial products to the wall of the digestive tract, which would activate an acute cell-mediated immune response[1]. The failure of the anti-inflammatory regulatory mechanisms, together with an excess in the production of pro-inflammatory cytokines, would promote an aberrant immune response that would be self-perpetuating over time, thus giving rise to the chronic inflammation that characterizes IBD[2]. Since the first descriptions of Ulcerative Colitis (UC) and Crohn's Disease (CD), many treatments have been developed, with varying degrees of safety and efficacy. At the end of the 20th century, the first biological, called Infliximab, began to be used. A biological drug is one that has a biotechnological origin and arises from proteins derived from DNA and hybridization processes, which require living organisms as a fundamental part of the production process[3]. Undoubtedly, the appearance of biologics in the therapeutic arsenal of IBD was a very important advance in the treatment of these patients, a true revolution. Until that date, many of the patients who began to be treated with this biologic could only do with corticosteroids or by surgery. These drugs have been shown to be effective in reducing intestinal damage caused by chronic inflammation, the need for surgery and hospital admissions and, consequently, have improved the quality of life of many patients[4]. The demonstrated benefit of these drugs, especially when administered early, as well as their favorable safety profile, have led to their increasingly frequent use in the treatment of patients with IBD. They can be divided into - anti-TNF drugs (blocking the cytokine TNF-α), - Vedolizumab (blocking the integrin α4β7) and - Ustekinumab (blocking Interleukin 12 and 23). Recently, and only for use in UC, Tofacitinib (an inhibitor of the JAK-kinase pathway) has been approved and has demonstrated its efficacy in the treatment of moderate-severe active UC[5]. The management of all these drugs represents a challenge for the digestive specialist who must know their mechanisms of action and use them appropriately in patients with IBD. Anti-TNF drugs, being the oldest, are the ones with which we have the most experience and, therefore, they are usually used in the first line in those cases in which conventional drugs (corticosteroids and / or immunosuppressants) have failed. There are three currently marketed in Spain: Infliximab (for intravenous administration), Adalimumab (for subcutaneous administration) and Golimumab (for subcutaneous administration). Vedolizumab (administered intravenously), and Ustekinumab (administered subcutaneously, after a first intravenous administration) are characterized by having an excellent safety profile and a very low immunogenic potential compared to anti-TNF drugs. There are many lines of research currently underway to try to identify the clinical factors of the patient that would make one drug or another more useful in the first line. Other lines seek to identify genetic factors (it seems that mutations in the HLA DQA1 * 05 haplotype could increase immunogenicity to anti-TNF drugs[6]) and also molecular factors[7]. References: [1] Neurath MF. Cytokines in inflammatory bowel disease. Nat Rev Immunol. 2014; 14(5): 329-342. [2] Zhang YZ, Li YY. Inflammatory bowel disease: Pathogenesis. World J Gastroenterol. 2014; 20(1): 91-99. [3] Pithadia AB, Jain S. Treatment of inflammatory bowel disease (IBD). Pharmacol Rep. 2011; 63(3): 629-42. [4] Weisshof R, El Jurdi K, Zmeter N, Rubin DT. Emerging Therapies for Inflammatory Bowel Disease. Adv Ther. 2018; 35(11): 1746-1762. [5] 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(3): 627-644. [6] Sazonovs A, Kennedy NA, Moutsianas L, et al. 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. [7] Atreya R, Neurath MF. Mechanisms of molecular resistance and predictors of response to biological therapy in inflammatory bowel disease. Lancet Gastroenterol Hepatol. 2018; 3(11): 790-802.