Volume 64 - 2001 - Fasc.2 - Symposium
Preface Biological therapies for Inflammatory Bowel Diseases: Are we finally going to modify the disease course ?
It is clear that the introduction of immunomodulation therapy, especially with the chimeric monoclonal antiTNF antibody, in the past five years is thoroughly changing our approach to the treatment of inflammatory bowel disease (IBD). This novel therapy emerges at a time that immunosuppression with azathioprine finally gained wide acceptance for the treatment of Crohn's disease and ulcerative colitis.3
The changing epidemiology of inflammatory bowel diseases
Epidemiological studies of inflammatory bowel disease are important in order to find possible clues to the still unknown etiology, as well as for the planning of the health service. In supplement to short-term studies, reporting the actual state of the disease, long-term studies are requisited to follow up the development of inflammatory bowel disease. Inflammatory bowel disease has become more frequent during the past decades, with an approximate prevalence of 0.5% in the northern part of the world. A changed disease panorama can be noted with increasing median age at diagnosis, a growing entity of patients with colorectal Crohn's disease and a shift towards more distal ulcerative colitis. The increased age at diagnosis is attributed to a postponement of the age-specific incidence peak. While the difference between gender has levelled off, difference still exists in young adults in Crohn's disease and in elderly in ulcerative colitis. Colorectal cancer has become a matter also in Crohn's disease.
Genetics of inflammatory bowel disease - an update
The pathogenesis of ulcerative colitis (UC) and Crohn's disease (CD) is still unknown, but epidemiological studies show clear evidence of genetic susceptibility3
Biologicals : principles, techniques and mechanisms of action
Biological agents for the treatment of IBD are the result of both the explosion of knowledge precipitated by the techniques of molecular biology, and by the ability to use these same techniques to produce agents. Thus, there has been a greatly facilitated translation of basic knowledge into clinical therapy. An astounding number of biologic agents are currently in development for the treatment of IBD and other immune-mediated conditions. These include native microbiologic preparations isolated for beneficial properties, recombinant cytokines and anticytokines, monoclonal antibodies, antisense oligonucleotides, and in the future, somatic gene therapy. This work seeks to describe the principles and techniques of biologic agent development, as well as prime sites of action targeted by these agents. Recent advances in the techniques of molecular biology have made possible unprecedented progress in the treatment of many conditions. The techniques of molecular biology have provided new methods of drug discovery and at the same time have elucidated new therapeutic targets. Most notable has been the progress made in the treatment of chronic inflammatory and immune mediated conditions, including inflammatory bowel disease. This paper is intended to highlight the methodological principles behind biologic agents, methods of discovery and production, and to highlight potential therapeutic targets for these new agents. [Product Details...]
Inflammatory Bowel Disease Clinic, Division of Gastroenterology and Hepatology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, U.S.A.
Tissue effects of anti-TNF therapies
TNF-? is a pro-inflammatory cytokine produced by monocytes, macrophages and T cells that can affect proliferation, differentiation and function of virtually every cell type. The biologic effects of TNF-?? include stimulation of the acute phase response, cytotoxicity, cachexia, and potentially lethal shock. Furthermore, TNF-? stimulates IL- I and IL-6 production, expression of adhesion molecules, procoagulant 3
Biological therapies of inflammatory bowel disease
The cause of chronic inflammation in inflammatory bowel disease is unknown, and damage to the intestinal mucosa leads to a rather restricted repertoire of lesions. As a result, unambiguous phenotyping of inflammatory bowel diseases has been difficult. Because until recently no useful animal models for inflammatory bowel disease were available, following the introduction of corticesteroids in the 50-ies, research concerning the pathogenesis and treatment of inflammatory bowel disease did not yield important new breakthroughs for many years. In the last decade, new techniques became 3
Standard immunosuppression in IBD : current practice
The use of immunosuppressive drug therapy in the treatment of IBD has a long history. Although preliminary experience with agents such as, azathioprine (AZA) and 6-mercaptopurine (6-MP) began in the 1960s, only in the past decade has the use of these drugs to treat patients with refractory Crohn's disease become a standard of care. Enthusiasm for the use of immunosuppression in ulcerative colitis has also increased but remains limited. This article reviews the current use of immunosuppressive therapy for both Crohn's disease and ulcerative colitis.
Crohn's disease therapy : step up or top down therapy
In most Crohn's disease scenarios a step-up approach has been used to initiate therapy according to disease severity. However, this approach has ignored the concept of inductive therapy followed by maintenance treatment to prevent relapse. It is apparent from clinical trials that the success of maintenance approaches will depend upon the inductive therapy. Furthermore, the step-up approach often results in steroid-dependent or refractory disease. The potential of aggressive initial therapy followed by step-down maintenance therapy affords the potential to modify the disease course, a possibility that has not been accomplished by current therapeutic algorithims.
Biologics in peri-operative management of Crohn's disease
The role of biologics for peri-operative Crohn's disease will remain speculative until the accumulation of clinical trial data. The potential positioning of peri-operative biologic therapies includes the prevention of surgery, minimizing surgical morbidity or prevention or delaying post-operative disease recurrence. To date, there is limited, indirect data regarding the potential for infliximab to prevent surgery via the effective treatment of refractory disease and the improvement in ristulizing disease. Although there is no controlled data regarding the impact of biologics on surgical morbidity, patients with stricturing disease have undergone resection without added morbidity. Post-operative trials are certainly needed to ascertain the impact on the inevitability of disease recurrence.
Can we influence fibrosis in Crohn's disease ?
Despite recent advances in the therapy of active Crohn's disease (CD) fibrostenosis remains a challenging complication of the disease. 'ftansmural inflammation of CD is associated with phenotypic switch of the mesenchymal cells resulting in proliferation and coliagen deposition. Both resident myofibroblasts and smooth muscle are candidate progenitor cells of the ribrogenic cells in CD stenoses. The principal growth factors involved in intestinal fibrosis have not been identified although TGF-pl and 2, PDGF and IL1 may be involved. Research aimed at elucidating the basic mechanisms underlying fibrosis in the gut has been hindered by the lack of an adequate animal model. Recently, however, new rodent models of chronic inflammation with distinct fibrosis have been described. Cell culture research has provided more information about possible pathways that may limit uncontrolled mesenchymal proliferation in the inflamed intestinal wall. The modulator role of neurotransmitters such as VIP, nitric oxide and prostaglandines is an important target for therapeutic intervention. Interfering with the phenotypic switch of mesenchymal cells may offer new therapeutic perspectives in the prevention of fibrostenosis. Further in vitro and animal studies as well as restenosis prevention studies are needed to develop pharmacological tools in the prevention of Crohn's disease fibrostenosis. (Acta -astroenterol. belg., 2001, 64, 193-196).
Crohn's disease, ulcerative colitis or indeterminate colitis - how important is it to differentiate ?
In most patients coming to the general practitioner or specialist with a history of bloody diarrhoea, bacteria or drugs are the most likely causative agents and it will be possible to make a diagnosis fairly easily. Because of differences in treatment, ulcerative colitis (UC) and Crohn's disease (CD) must however seriously be considered especially in younger patients, with severe symptoms and whenever the history is prolonged. A variety of cotitides may indeed be clinically confused with UC and CD. Pathological nlimics that should not be missed include infectious diseases such as Campylobacter colitis, yersiniosis, amoebiasis and others ; druginduced diseases (due to nonsteroidal antiinflammatory drugs ... ) ; diverticular disease-associated colitis ; intestinal endometriosis ; intestinal vasculitis and Beh@et's disease and iatrogenic conditions such as graft-versus-host-disease and radiation colitis. In most situations a precise diagnosis of these conditions should be possible when all data are available. The term "indeterminate colitis" is used, when a diagnosis of chronic idiopathic inflammatory bowel disease (IBD) is suggested, but the differential diagnosis between U C and CD can not be solved. This occurs in approximately 5 % of all patients with IBD. Diagnostic problems can occur in acute fulminant colitis, acute prolonged colitis, chronic relapsing disease and pouchitis. Indeterminate colitis is essentially a temporary diagnosis. Surgical and medical treatment of these patients can be difficult. When surgical treatment is indicated, the type of surgery must be seriously considered. The clinical course of patients with indeterminate colitis is usually more severe when compared with classical UC and these patients require often more severe medical treatment. Diagnostic problems can also arise in longstanding IBD, either UC and CD. Relapse of symptoms can be due to intercurrent infection (CMV is one of the candidates). Medical treatment can influence the microscopic features and induce a discontinuous inflammation in UC, reminiscent of CD. In cases of doubt, the original biopsies should be reviewed to ascertain the diagnosis, and orient treatment.
Cyclosporine in ulcerative colitis : state of the art
Forty percent of patients with severe ulcerative colitis will fail to respond to intravenous corticosteroids. Cyclosporine and other calcineurin inhibitors offer an alternative to colectomy for these patients. Intravenous cyclosporine will induce remission within 14 days in 50-80% of patients who fail intravenous corticosteroids. The long-term response rates for responding patients are 40-60 %. Subsequent maintenance therapy with azathioprine or 6-mercaptopurine is recommended at the present time, although the uncontrolled studies underlying this observation have yielded variable results. Toxicity occurs frequently in patients treated with high dose cyclosporine, and there is a small risk of opportunistic infection and death. Pilot studies have suggested that the microemulsion cyclosporine formulation Neoral and tacrolimus may also be of benefit in this patient population. Additional studies to determine the dose response of intravenous cyclospoirine, to determine the role of azathioprine for maintenance, and to determine the efficacy of Neoral and tacrolimus are needed.
Biological therapies for ulcerative colitis
Biological therapies are being increasingly investigated for the treatment of inflammatory bowel disease. However, a great deal more study has been devoted to studies of Crohn's disease rather than ulcerative colitis. Ulcerative colitis, like Crohn's disease, represents an area of high clinical need, particularly for those patients who have disease inadequately responsive to corticosteroids and 5aminosalicylates. The distinct anatomic distribution of inflammation in ulcerative colitis represents an important model for study, with the entire involved mucosa entirely accessible to endoscopy. In addition, there is an opportunity for local delivery of biologic agents in left-sided disease. Distinct pathogenetic factors in ulcerative colitis raise the possibility of therapies quite different from those used in Crohn's disease. This work describes the current state of knowledge regarding biological therapy in ulcerative colitis. The role of probiotic therapy, and studies of cytokine-directed therapies, therapies targeting adhesion and recruitment, and restitution and repair are described.
Safety of biologics : current issues and future concerns
Advances in biotechnology have yielded new options for the management of chronic inflammatory diseases. During the past five years numerous monoclonal antibodies, several cytokines and systemic antisense have all been evaluated in patients with active Crohn's disease. One of these products, infliximab, is now approved for clinical use (1,2). The fundamental potential of the biologics, enhanced efficacy as a result of selective targeting of key inflammatory mediators, seems on the verge of fulfillment. However our knowledge of the human immune system remains rudimentary. Therefore it is important that the safety of these agents is carefully evaluated. This review describes the overall process of evaluating the potential
Restorative resections for ulcerative colitis
Restorative coloproctectomy with ileo-anal anastomosis and ileal reservoir, first described by Parks and Nicholls in 1978 (1), evolved as a valid alternative to a permanent ileostomy in the surgical treatment of Ulcerative Colitis. Although the pouch operation seems to be an unique opportunity to preserve anal function and at the same time cure the disease, the pouch is not a return to normal. All potential candidates should be 3
Refractory pouchitis
The introduction of reconstructive surgery following proctocolectomy for ulcerative colitis has made a substantial improvement in the quality of life for the majority of patients. Although a temporary stoma is usually required, the fashioning of an ileal-anal pouch avoids a perirnanent 3
Advancement flap plasty for the closure of anal and recto-vaginal fistulas in Crohn's disease
The management of anal fistulas in patients with IBD continues to be extremely challenging and, indeed, somewhat frustrating. Despite a global closure rate of about 75%, all patients should be informed about the risk of infection, early failure, eventual temporary defunctioning stoma and the possibility of late recurrence (about 15%). Closure of a RVF in Crohn's disease should not be considered an easy undertaking, especially in patients with several Crohn localisations. The technique can be adapted to the local situation. Construction of a temporary stoma is not mandatory. However, stoma construction seems to be beneficial when extensive perianal or recto-vaginal dissection including eventual tissue interposition is required. Advancement flaps are an attractive surgical alternative for the management of all anal transsphincteric fistulas, also in Crohn's disease, because sphincter architecture and function are well preserved. Improved medical treatment and the changed approach from conservative to reparative surgery may well have resulted in a decreased need or at least in a delay of the need for a proctectomy. Although the surgical principles of advancement flap techniques are sound, these techniques have not been used for many decades. Skills needed, problematic approach, suboptimal quality of local tissues have contributed to its selective use and to the absence of prospective randomised studies.
