10. M. P. MARTINEZ MONTIEL 23/5/06 08:40 Página 265 1130-0108/2006/98/4/265-291 REVISTA ESPAÑOLA DE ENFERMEDADES DIGESTIVAS REV ESP ENFERM DIG (Madrid) Copyright © 2006 ARÁN EDICIONES, S. L. Vol. 98. N.° 4, pp. 265-291, 2006 POINT OF VIEW Biologic therapies for chronic inflammatory bowel disease M. P. Martínez-Montiel and M. T. Muñoz-Yagüe Service of Digestive Diseases. Hospital Universitario 12 de Octubre. Madrid, Spain ABSTRACT Martínez-Montiel MP, Muñoz-Yagüe MT. Biologic therapies for chronic inflammatory bowel disease. Rev Esp Enferm Dig Crohn's disease (CD) and ulcerative colitis (UC) make up the 2006; 98: 265-291. so-called chronic inflammatory bowel disease (IBD). Advances in the understanding of IBD pathophysiologic mechanisms in the last few years have allowed the development of novel therapies such as biologic therapies, which at least theoretically represent a more INTRODUCTION specific management of this disease with fewer side effects. Cur- rently, the only effective and widely accepted biologic therapy for the treatment of intraluminal, fistulizing CD, both for remission in- Crohn’s disease (CD) and ulcerative colitis (UC) make duction and maintenance, is infliximab. The role of other mono- up the so-called inflammatory bowel disease (IBD). Ad- clonal antibodies such as adalimumab is not clearly established. It vances in the knowledge of this condition’s etiopathogene- could be deemed an alternative for patients with allergic reactions sis have been correlated to the development of novel thera- to infliximab, and for those with lost response because of anti-in- peutic agents. Medical treatment is currently the fliximab antibody development. However, relevant issues such as dosage and administration regimen remain to be established. Anti- cornerstone for managing these conditions, and surgery is integrin α4 therapies, despite encouraging results in phase-3 stud- reserved for complications or treatment refractoriness (1). ies, are still unavailable, as their marketing authorization was held The available therapeutic armamentarium includes anti-in- back in view of a number of reports regarding progressive multifo- flammatory drugs (aminosalicylates and steroids), antibi- cal leukoencephalopathy cases. Immunostimulating therapy may otics, and immune modulators (azathioprine, 6-mercaptop- be highly relevant in the near future, as it represents a novel strat- egy against disease with the inclusion of granulocyte-monocyte urin, cyclosporin and methotrexate). All these drugs result colony-stimulating factors. in a nonspecific suppression of inflammatory processes, Regarding ulcerative colitis, results from the ACT-1 and ACT-2 and their use during the past few years has determined a studies showed that infliximab is also useful for the management relevant advance in BDI control. However, their efficacy is of serious UC flare-ups not responding to standard treatment, which will lead to a revision of therapeutic algorithms, where this limited and they are not exempt from side effects. Biologic drug should be given preference before intravenous cyclosporine. therapies, at least theoretically, would be more therapeuti- In the next few years, the role of anti-CD3 drugs (vilisilizumab), cally effective with fewer side effects, and thus would rep- T-cell inhibiting therapies, and epithelial repair and healing stimu- resent more specific means for the management of the dis- lating factors will be established. ease. The efficacy and safety of infliximab in intraluminal, fistulizing Crohn’s disease (2-5), both for response induc- Key words: Inflammatory bowel disease. Crohn’s disease. Ulcer- tion and response maintenance, has resulted in research on ative colitis. Therapy. new biologic therapies directed against specific mecha- nisms within the inflammatory process. BIOLOGIC THERAPIES Recibido: 22-11-05. Aceptado: 22-11-05. Biologic therapies are made up of five agent classes (6): 1. Natural or modified preparations of biologic origin. Correspondencia: M. P. Martínez-Montiel. Servicio de Medicina del Apara- to Digestivo. Hospital Universitario 12 de Octubre. Madrid. Ctra. de Andalu- These include blood products, hormones, and vaccines cía, km 5,400; 28041 Madrid. e-mail: pilarmarmon1,2,3@telefónica.net (with living, attenuated or dead organisms). 10. M. P. MARTINEZ MONTIEL 23/5/06 08:40 Página 266 266 M. P. MARTÍNEZ-MONTIEL AND M. T. MUÑOZ-YAGÜE REV ESP ENFERM DIG (Madrid) 2. Recombinant peptides or proteins. Under normal conditions, the mucosa contains a num- 3. Antibody-based therapies. ber of epithelial cells devoted to antigen presentation. 4. Nucleic acid-based therapies. These include M cells, which transport intraluminal anti- 5. Gene and cellular therapies. gens to lymphoid follicles or Peyer plates, and dendritic Biologic preparations used in clinical practice or cur- cells, which through M cells or the sending out of prolon- rently under assessment for the management of IBD gations among enterocytes can capture and present intra- mainly include recombinant proteins, antibodies and nu- luminal antigens to naive T cells in lymphoid follicles or cleic acids. Peyer plates (8). Activated lymphocytes then secrete in- terferon gamma (IFNγ) and IL-2, and non-differentiated T cells maturate into effector T cells (Th1 or Th2) or reg- FUNDAMENTALS OF BIOLOGIC THERAPIES ulator T cells (Th3 or Tr1) in response to stimuli received from antigen-presenting cells (8,10). Excessive effector T IBD is presently considered the product of an abnor- cell numbers leads to an excessive production of proin- mal immune response to harmless intraluminal antigens flammatory cytokines with the aim of eliminating the occurring in a genetically predisposed host and resulting pathogenic agent. Once their goal is achieved, anti-in- in a chronic inflammation of the gastrointestinal tract in flammatory cytokines, including IL-10, Th3 cells, and association with tissue damage (7). trophic factors, arrest the inflammatory response. Defects Under normal conditions, the immune system can rec- in this slowing mechanism lead to severe inflammatory ognize harmless intraluminal antigens, versus which it aggression to tissues, and the development of disease will exert immune tolerance. In the presence of various clinical manifestations. In contrast, regulator T cell abun- pathogens, the immune system may initiate a number of dance determines immune tolerance and anergy (13). downregulated responses, thereby preventing tissue le- Classically, Crohn’s disease has a Th1-type cytokine sions and allowing the elimination of causal agents. The profile resulting from immature T-cell exposure to IL-12, fact that both CD and UC clinically manifest in a hetero- IL-18 or IL-23. Th1 cells produce IL-2 and IFN-γ. IFN-γ geneous manner (site, severity, response to treatment) is increases the expression of adhesion molecules in en- believed to result from a number of changes in im- dothelial cells, which facilitates inflammatory cell re- munoregulatory pathways, which in turn would reflect cruitment and activates macrophages. The latter in turn the genetic variability of environmental influence (8). generate free radicals and large numbers of proinflamma- Thus, IBD would be a consequence of a complex interre- tory cytokines (TNF-α, IL-1, IL-6, IL-8, IL-12, IL-18). lation between genetic, environmental, and microbial In patients with CD, intestinal mucosa T cells have been factors, which would induce a sustained inflammation of shown to be apoptosis-resistant, which leads to T-cell ac- the bowel mucosa supported by mucosal barrier changes cumulation and a perpetuation of inflammatory response and immune system defects (9). (9). This phenomenon seems to depend on IL-6, which The first defense line in the gastrointestinal tract is the may activate anti-apoptotic genes in intestinal T lympho- bowel epithelium, made up of a single cylindrical, epithe- cytes (14). Ulcerative colitis has a Th2-type cytokine pro- lial cell layer with tight intercellular junctions to create a file characterized by IL-4, IL-5, and IL-10 production. virtually impenetrable barrier for macromolecules (ex- Th2 response implicates natural killer T-cell (NKT) acti- cept for nutrients and invasive germs). Furthermore, all vation, and these cells may be responsible for inflamma- this is lined with mucus, which blocks the passage of tion through IL-13 production (15). It is currently accept- pathogens and intraluminal antigens into the lamina pro- ed that ulcerative colitis entails a mixed, Th1 and Th2 pria (8). In addition, secretory IgA agglutinates bacteria immune response, which would account for the response and viruses into large complexes that are then included in elicited using anti-TNF therapy. It is also currently ac- the mucus and cleared with the feces with no contact with cepted that CD is characterized by high IFN-γ and low the epithelium (10,11). The mucosal barrier has been IL-13 production, whereas UC is characterized by high seen to be disturbed in IBD, with the presence of abnor- IL-13 production in intestinal lamina propria cells (15). mal intercellular junctions and decreased mucus produc- Inflammation as induced in the intestinal mucosa is am- tion, which allows antigens to freely enter the lamina pro- plified by the recruitment of circulating “naïve” T cells, pria (8). During inflammation, tissue damage can be activated T cells, and polymorphonuclear cells into in- repaired using cytoprotective factors such as the trans- flamed areas through an interaction between adhesion forming growth