Ulcerative Colitis: Rutgeerts P

Bisschops R, Rutgeerts P. · No affiliation provided · Endoscopy. · Pubmed #17163331 No free full text.

This publication has no abstract.

Rutgeerts P. · No affiliation provided · Am J Gastroenterol. · Pubmed #12385428 No free full text.

This publication has no abstract.

Breynaert C, Vermeire S, Rutgeerts P, Van Assche G. · Department of Internal Medicine, University Hospital Gasthuisberg, Leuven, Belgium. · Acta Gastroenterol Belg. · Pubmed #19317276 No free full text.

Abstract: Patients with inflammatory bowel disease (IBD) face an increased lifetime risk of developing colorectal cancer (CRC). Although CRC in IBD only accounts for 1-2% of all cases of CRC in the general population, it is responsible for approximately 15% of the mortality of patients with Crohn's disease (CD) and ulcerative colitis (UC). Independent factors associated with increased risk include long disease duration, extensive colonic involvement, young age at onset of IBD, severity of inflammation, primary sclerosing cholangitis, backwash ileitis and a family history of CRC. Many of these factors emphasise the role of inflammation as an underlying mechanism. Despite the differences between the molecular abnormalities found in colitis-associated dysplasia in comparison with sporadic CRC, IBD-associated cancer has a similar dysplasia-cancer sequence, similar frequencies of major chromosomal abnormalities, microsatellite instability and similar glycosylation changes. These similarities seem to outweigh the differences and make it reasonable to suggest that not only IBD-associated CRC but even sporadic colon cancer might be largely secondary to inflammation. Oxidative stress, apoptosis, COX-2 activity and a possible common inherited defective glycosylation are thought to play a key role in the pathogenesis of colitis-associated CRC. DNA alterations initiated in colonic crypts can expand to adjacent crypts through crypt fission. There seems little doubt that the increased risk of cancer in inflammatory bowel diseases is a result of the disease rather than an inherited phenomenon. An understanding of the definition and pathogenesis of CRC in IBD is crucial to optimise patient management. Further investigation is therefore necessary.

Vermeire S, Van Assche G, Rutgeerts P. · University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium. · Best Pract Res Clin Gastroenterol. · Pubmed #19258190 No free full text.

Abstract: The introduction of biological therapies has greatly advanced the therapeutic armamentarium of the inflammatory bowel diseases Crohn's disease and ulcerative colitis. At present, three anti-tumour necrosis factor (TNF) agents (infliximab, adalimumab and certolizumab pegol) and one anti-adhesion cytokine (natalizumab) have been approved and have shown efficacy in luminal and/or fistulizing Crohn's disease and/or in ulcerative colitis. Although the overall benefit/risk ratio for the anti-TNF agents is positive, of particular concern has been the problem of immunogenicity ascribed to the formation of antibodies to these molecules. Antibody formation is associated with allergic reactions and loss of response through decreased trough serum concentrations. Ways to reduce antibody formation include maintenance therapy, the use of concomitant immunomodulators and pre-treatment with corticosteroids. Other safety concerns include the occurrence of opportunistic infections, skin manifestations, and the rare but often lethal hepatosplenic T-cell lymphoma. The alpha-4 integrin natalizumab has been associated with three cases of progressive multifocal leucoencephalopathy and was the reason for which the drug was not approved in Europe, and is available only through a specialised programme in the US. We discuss the safety aspects of the biological agents in this chapter and, where available, give ways to prevent and/or treat them.

Rutgeerts P, Vermeire S, Van Assche G. · Division of Gastroenterology, University of Leuven Hospitals, Leuven, Belgium. · Gastroenterology. · Pubmed #19249397 No free full text.

Abstract: Crohn's disease and ulcerative colitis are chronic disabling inflammatory bowel diseases (IBDs). Although the causes of IBD are unknown, defects in innate and adaptive immune pathways have been identified and biological therapies that target key molecules have been designed. Infliximab, a chimeric immunoglobulin (Ig)G1 monoclonal antibody to tumor necrosis factor, dramatically improved treatment of patients with Crohn's disease and ulcerative colitis. Infliximab has achieved treatment goals such as mucosal healing and decreasing the need for hospitalizations and surgeries. Although several anti-tumor necrosis factor therapies have been developed, there is a great need for drugs that target other pathways. Natalizumab, an antibody against the integrin alpha4 subunit, blocks leukocyte adhesion and has reached the clinic in the United States but has not been approved in the European Union; other anti-adhesion molecules currently are under development. Additional approaches under clinical development include therapeutics that target cytokines, such as interleukin-12/23, as well as those that block T-cell signaling. The use of recombinant human proteins, including immunoregulatory cytokines and growth factors, has not been successful so far. The efficacy of each therapy must be shown in carefully designed clinical programs. Biological therapies carry a definite safety risk, so their place in treatment algorithms must be defined carefully.

Van Assche G, Vermeire S, Rutgeerts P. · Division of Gastroenterology, University of Leuven Hospitals, Herestraat 49, Leuven, Belgium. · World J Gastroenterol. · Pubmed #18810767 links to  free full text

Abstract: Although systemic steroids are highly efficacious in ulcerative colitis (UC), failure to respond to steroids still poses an important challenge to the surgeon and physician alike. Even if the life time risk of a fulminant UC flare is only 20%, this condition is potentially life threatening and should be managed in hospital. If patients fail 3 to 5 d of intravenous corticosteroids and optimal supportive care, they should be considered for any of three options: intravenous cyclosporine (2 mg/kg for 7 d, and serum level controlled), infliximab (5 mg/kg IV, 0-2-6 wk) or total colectomy. The choice between these three options is a medical-surgical decision based on clinical signs, radiological and endoscopic findings and blood analysis (CRP, serum albumin). Between 65 and 85% of patients will initially respond to cyclosporine and avoid colectomy on the short term. Over 5 years only 50% of initial responders avoid colectomy and outcomes are better in patients naive to azathioprine (bridging strategy). The data on infliximab as a medical rescue in fulminant colitis are more limited although the efficacy of this anti tumor necrosis factor (TNF) monoclonal antibody has been demonstrated in a controlled trial. Controlled data on the comparative efficacy of cyclosporine and infliximab are not available at this moment. Both drugs are immunosuppressants and are used in combination with steroids and azathioprine, which infers a risk of serious, even fatal, opportunistic infections. Therefore, patients not responding to these agents within 5-7 d should be considered for colectomy and responders should be closely monitored for infections.

Panaccione R, Rutgeerts P, Sandborn WJ, Feagan B, Schreiber S, Ghosh S. · Department of Medicine, University of Calgary, Calgary, AB, Canada. · Aliment Pharmacol Ther. · Pubmed #18532990 No free full text.

Abstract: BACKGROUND: Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory diseases of the intestine, which frequently require surgery for complications or failure of medical therapy. AIM: To seek evidence and provide direction for clinicians on optimal strategies to enable steroid free remission in inflammatory bowel disease. METHODS: Scientific literature was reviewed using MEDLINIE with a specific focus on medical therapies for inducing and maintaining remission of CD and UC. The results were discussed at a roundtable meeting to reach a consensus on key issues. RESULTS: Several therapies have demonstrated efficacy for the treatment of active, moderate-to-severe CD and UC. These include agents, which induce remission [corticosteroids, infliximab and adalimumab (CD only)] or maintain remission and spare corticosteroids [azathioprine, mercaptopurine, methotrexate (CD only), infliximab and adalimumab (CD only)]. Wide variability exists in the use of these agents. CONCLUSION: Treatment strategy algorithms are developed for use of these therapies that maximize remission and minimize corticosteroid dependence in patients with moderate-to-severe CD and UC.

van Assche G, Vermeire S, Rutgeerts P. · Division of Gastroenterology, University of Leuven, Leuven, Belgium. · Minerva Gastroenterol Dietol. · Pubmed #17912187 No free full text.

Abstract: Although the advent of infliximab has changed the treatment paradigm and goals in inflammatory bowel diseases (IBD), it does not provide a cure for IBD and recent evidence has demonstrated that the immunogenicity of this chimeric anti tumor necrosis factor (TNF) antibody is associated with secondary loss of response and intolerance. In ulcerative colitis the efficacy of infliximab was demonstrated in two large clinical trials, but long term maintenance efficacy data are lacking. Novel biological agents have entered clinical development and pioneering trials have been reported in the last two years. For Crohn's disease the fully human IgG1 anti TNF monoclonal adalimumab, the humanized pegylated Fab-fragment certolizumab-pegol and the humanized anti a4 integrin IgG4 antibody, natalizumab have yielded the most promising results in controlled trials, but also agents inhibiting the crucial IL12/interferon-g feedback loop suggest therapeutic potential. For severe ulcerative colitis infliximab has been shown to be an effective rescue treatment and the anti T-cell CD3 antibody has shown promising open label RESULTS: Crucial in the development of novel biological agents, however, is the benefit risk ratio. As illustrated by unexpected but devastating brain infections with antiadhesion molecules, clinicians should be aware that the powerful immunomodulatory capacity of biologicals necessitates a rigorous safety follow-up.

Rutgeerts P, Vermeire S, Van Assche G. · University Hospital Gasthuisberg, Department of Gastroenterology, Herestraat 49, Leuven 3052, Belgium. · Gut. · Pubmed #17369375 No free full text.

Abstract: The main goal of treatment for Crohn's disease and ulcerative colitis has always been the induction and maintenance of symptomatic improvement or at best remission. It has been shown by many studies that the long-term outcome of these diseases is not influenced by standard treatments and that the need for surgery is not decreasing in this population over the years. There is recent evidence that with immunosuppression and treatment with infliximab long-term healing of the bowel can be achieved and that this affects the outcome of both Crohn's disease and ulcerative colitis. We propose that future studies should focus on healing and disease course as primary outcome measures.

D'Haens G, Sandborn WJ, Feagan BG, Geboes K, Hanauer SB, Irvine EJ, Lémann M, Marteau P, Rutgeerts P, Schölmerich J, Sutherland LR. · University Hospital Gasthuisberg, Leuven, Belgium. · Gastroenterology. · Pubmed #17258735 No free full text.

This publication has no abstract.

Pierik M, Rutgeerts P, Vlietinck R, Vermeire S. · Department of Gastro-enterology, University of Hospital Gasthuisberg, Leuven, Belgium. · World J Gastroenterol. · Pubmed #16773681 links to  free full text

Abstract: Pharmacogenetics is the study of the association between variability in drug response and (or) drug toxicity and polymorphisms in genes. The goal of this field of science is to adapt drugs to a patient's specific genetic background and therefore make them more efficacious and safe. In this article we describe the variants in genes that influence either the efficacy or toxicity of common drugs used in the treatment of inflammatory bowel diseases (IBD), ulcerative colitis (UC), and Crohn's disease (CD) including sulfasalazine and mesalazine, azathioprine (AZA) and 6-mercaptopurine (6-MP), methotrexate (MTX), glucocorticosteroids (CSs) and infliximab. Furthermore, difficulties with pharmacogenetic studies in general and more specifically in IBD are described. Although pharmacogenetics is a promising field that already contributed to a better understanding of some of the underlying mechanisms of action of drugs used in IBD, the only discovery translated until now into daily practice is the relation between thiopurine S-methyltransferase (TPMT) gene polymorphisms and hematological toxicity of thiopurine treatment. In the future it is necessary to organize studies in well characterized patient cohorts who have been uniformly treated and systematically evaluated in order to quantitate drug response more objectively. An effort should be made to collect genomic DNA from all patients enrolled in clinical drug trials after appropriate informed consent for pharmacogenetic studies.

Van Assche G, Vermeire S, Rutgeerts P. · Division of Gastroenterology, University of Leuven Hospitals, Leuven, Belgium. · Curr Opin Gastroenterol. · Pubmed #16760752 No free full text.

Abstract: PURPOSE OF REVIEW: The purpose of this review is to summarize recent evidence describing specific complications associated with the use of biological therapy derived from controlled trials and from post-marketing surveillance. RECENT FINDINGS: Biological therapies, particularly anti-tumour necrosis factor antibodies, are increasingly used in patients with Crohn's disease and ulcerative colitis. Some adverse events, such as serious infections, are a consequence of the immunomodulatory effect of biological agents, while other complications, such as the induction of autoimmune phenomena, neurotoxicity and the development of an immune response to engineered proteins, are class or molecule-specific. Although the immunopathogenesis of these side effects is often a matter of debate, they have been observed not only in inflammatory bowel disease, but also in other immune disorders such as rheumatoid arthritis and psoriasis. SUMMARY: The benefits of biological agents clearly outweigh the risks. Nevertheless, they are associated with specific toxicity, and this requires the attention of the clinician.

Van Assche G, Vermeire S, Rutgeerts P. · Division of Gastroenterology, University of Leuven, Leuven, Belgium. · Dig Dis. · Pubmed #16699271 No free full text.

Abstract: Although the advent of infliximab has changed the treatment paradigm and goals in inflammatory bowel disease, it does not provide a cure for it and recent evidence has demonstrated that the immunogenicity of this chimeric anti-tumor necrosis factor antibody is associated with secondary loss of response and intolerance. In ulcerative colitis the efficacy of infliximab was demonstrated in two large clinical trials, but long-term maintenance efficacy data are lacking. Novel biological agents have entered clinical development and pioneering trials have been reported in the last 2 years. For Crohn's disease the fully human IgG1 anti-tumor necrosis factor monoclonal adalimumab, and the humanized anti-alpha4-integrin IgG4 antibody, natalizumab have yielded the most promising results in controlled trials, but also agents inhibiting the crucial interleukin-12/interferon-gamma feedback loop suggest therapeutic potential. For severe ulcerative colitis infliximab has been shown to be an effective rescue treatment and the anti-T-cell CD3 antibody has shown promising open-label results. Crucial in the development of novel biological agents, however, is the benefit:risk ratio. As illustrated by unexpected but devastating brain infections with anti-adhesion molecules, clinicians should be aware that the powerful immunomodulatory capacity of biologicals necessitates a rigorous safety follow-up.

Vermeire S, Van Assche G, Rutgeerts P. · Department of Internal Medicine, Division of Gastroenterology, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium. · Gut. · Pubmed #16474109 links to  free full text

Abstract: Laboratory markers have been investigated in inflammatory bowel disease (IBD) for diagnostic and differential diagnostic purposes, for assessment of disease activity and risk of complications, for prediction of relapse, and for monitoring the effect of therapy. The introduction of biological therapies in IBD has renewed interest in inflammatory markers (especially C reactive protein (CRP)), given their potential to select responders to these treatments. Of all the laboratory markers, CRP is the most studied and has been shown to have the best overall performance. CRP is an objective marker of inflammation and correlates well with disease activity in Crohn's disease (CD). Increased CRP levels are associated with better response rates and normal CRP levels predict high placebo response rates in clinical trials with biologicals. However, despite the advantages of CRP over other markers, it is still far from ideal. Furthermore, CRP correlates less well with disease activity in patients with ulcerative colitis (UC) as compared with CD. Other laboratory markers, including erythrocyte sedimentation rate (ESR), leucocyte and platelet count, albumin, and 1 acid glycoprotein (orosomucoid), have been studied either less extensively in IBD or have proven to be less useful than CRP. Faecal markers seem promising and may be more specific in detecting gut inflammation in patients with established IBD. Promising results have been reported with the use of faecal calprotectin in CD as well as in UC. Recent data however suggest that the performance of the faecal calprotectin test is superior for UC than for CD. Taken together, laboratory markers are useful and should be part of the global management of our IBD patients. They are however not magic and until more data become available, the use of CRP and other laboratory markers should be seen as an additive tool to clinical observation and physical examination rather than a replacement.

Rutgeerts P, Van Assche G, Vermeire S. · Department of Medicine, Division of Gastroenterology, University of Leuven, Leuven, Belgium. · Aliment Pharmacol Ther. · Pubmed #16441465 No free full text.

Abstract: Infliximab, the chimeric monoclonal IgG1 antibody to tumour necrosis factor, is indicated for refractory luminal and fistulizing Crohn's disease and extra-intestinal manifestations of inflammatory bowel disease. Recently, the active ulcerative colitis trials (ACT) studies have shown that infliximab is also efficacious to treat ulcerative colitis resistant to standard therapy. Induction with 5 mg/kg infliximab at weeks 0, 2 and 6 is advocated. The response to infliximab is improved when concomitant immunosuppressive therapy is given. As the majority of patients will relapse if not retreated, a long-term strategy is necessary. Although episodic therapy can be used, the optimal strategy is systematic maintenance treatment with 5 mg/kg intravenous (i.v.) every 8 weeks. Long-term maintenance therapy with infliximab results in a reduction of the rate of complications, hospitalizations and surgeries associated with Crohn's disease. Safety problems with the monoclonal antibody infliximab treatment mainly concern the formation of antibodies to infliximab, which may lead to infusion reactions, loss of response and serum sickness-like delayed infusion reactions. Latent tuberculosis needs to be screened for. The rate of other opportunistic infections is slightly increased mainly in patients treated concomitantly with immunosuppression. There is no evidence that malignancy rates in patients treated with antitumour necrosis factor strategies are increased.

Vermeire S, Van Assche G, Rutgeerts P. · Department of Medicine, Division of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium. · Nat Clin Pract Gastroenterol Hepatol. · Pubmed #16327837 No free full text.

Abstract: C-reactive protein (CRP) is an acute-phase protein that is produced in large amounts by hepatocytes, upon stimulation by the cytokines interleukin-6, tumor-necrosis-factor-alpha and interleukin-1beta, during an acute-phase response. CRP is an objective marker of inflammation and, in gastrointestinal diseases such as Crohn's disease and acute pancreatitis, its levels correlate well with clinical disease activity. In contrast to its use as a marker in Crohn's disease, however, CRP is a less reliable marker of inflammation and disease activity in patients with ulcerative colitis, except perhaps for severe, extensive colitis. The increased production of CRP after an acute-phase stimulus, such as active gut inflammation, might explain why strong anti-inflammatory agents, such as anti-tumor-necrosis-factor-alpha antibodies and other biologic agents, work particularly well in patients with increased levels of CRP. CRP is also useful as a laboratory marker to predict prognosis and relapse in patients with Crohn's disease and acute pancreatitis. Elevated CRP levels have been associated with an increased risk of colorectal cancer and are a marker of poor prognosis, indicating more advanced disease and, possibly, reduced survival. An important question that remains is how often CRP levels should be measured. Until there are more data, the use of CRP and of other biomarkers should be seen as an additional tool that aids clinical observation and physical examination, but that cannot replace it.

Rutgeerts P. · Department of Medicine, University of Leuven, Leuven, Belgium. · Eur J Surg Suppl. · Pubmed #16144202 No free full text.

Abstract: Considerable advances have been made in the treatment of inflammatory bowel disease (IBD) mainly in that of Crohn's disease, but many questions still remain. We need to develop treatments that modify the disease. The use of immunomodulation using cytokines and anti-cytokines is an important step to achieve this goal. The standard is now the chimeric monoclonal antibody against tumour necrosis factor (TNF) in Crohn's disease. These treatments, however, are associated with problems of immunogenicity and autoimmunity. Moreover a proportion of patients do not respond to treatment and we do not have measurements that predict response. The optimal use and the combined treatment with immunosuppression are under investigation. The safety of this treatment in the long-term is also not established. These costly drugs are not suitable for the management of mild to moderate Crohn's disease and ulcerative colitis (UC). If it turns out that the antigenic drive of the inappropriate immune reaction is in the lumen of the gut changing the gut flora by using probiotics may be the way to go.

Vermeire S, Rutgeerts P. · University Hospital Gasthuisberg Leuven, Division of Gastroenterology-Herestraat, Leuven 49-3000, Belgium. · Genes Immun. · Pubmed #16107869 No free full text.

Abstract: The research on genetic susceptibility of inflammatory bowel diseases (IBD) has been tremendous and over 10 chromosomal regions have been identified by genome-wide scanning. Further fine mapping as well as candidate gene studies have already led to the identification of a number of susceptibility genes including CARD15, DLG5, OCTN1 and 2, NOD1, HLA, and TLR4. The CARD15 gene is undoubtedly replicated most widely and most understood at present. CARD15 is involved in the recognition of bacterial peptidoglycan-derived muramyl dipeptide (MDP) and will stimulate secretion of antimicrobial peptides including alpha-defensins (also called cryptdins) to protect the host from invasion. Genetic research in IBD has advanced our understanding of the clinical heterogeneity of the disease and has started to tackle the complex interactions between genetic risk factors and environmental risk factors in IBD. Genes also interfere with the metabolization of drugs and may influence the clinical response and the drug-related toxicity. Interesting pharmacogenetic data with respect to steroids, azathioprine, and infliximab have been generated in IBD. Overall, it is anticipated that genetic markers in the future will be implemented in an integrated molecular diagnostic and prognostic approach of our patients.

Van Assche G, Vermeire S, Rutgeerts P. · Division of Gastroenterology, University of Leuven, Leuven, Belgium. · Curr Opin Gastroenterol. · Pubmed #15930985 No free full text.

Abstract: PURPOSE OF REVIEW: Despite the advent of the anti-TNF agent, infliximab, an important unmet medical need characterizes the medical treatment of inflammatory bowel diseases. This review aims to summarize recent progress in the field. RECENT FINDINGS: For Crohn's disease, the fully human IgG1 anti-TNF monoclonal antibody, adalimumab and the humanized anti-alpha4 integrin IgG4 antibody, natalizumab have yielded the most promising results in controlled trials, but agents inhibiting the crucial IL12/interferon-gamma feedback loop also suggest therapeutic potential. Maintenance treatment with azathioprine, although efficacious, is not tolerated by up to 25% of individuals, but 6-thioguanine, an active metabolite, is associated with liver toxicity and is no longer recommended.For severe ulcerative colitis, low intravenous cyclosporine doses have been demonstrated to be efficacious, and may serve to limit the toxicity with this agent. Biologic treatment is being developed to target severe ulcerative colitis. Efficacy of infliximab to stop fistula draining as a maintenance agent for fistulizing Crohn's disease has been demonstrated in a large controlled trial, but MRI imaging indicates that the improvement of inflammation in fistula tracks is delayed. SUMMARY: In conclusion, medical therapy of inflammatory bowel diseases is a constantly moving field and recent evolutions will undoubtedly change clinical practice in the years to come.

Van Assche G, Rutgeerts P. · Division of Gastroenterology, Univ. Hospital Leuven, 49 Herestraat, B-3000 Leuven, Belgium. · Am J Physiol Gastrointest Liver Physiol. · Pubmed #15647604 links to  free full text

Abstract: Adhesion molecules regulate the influx of leukocytes in normal and inflamed gut. They are also involved in local lymphocyte stimulation and antigen presentation within the intestinal mucosa. In intestinal inflammation, many adhesion molecules are upregulated, but alpha4-integrins most likely hold a key position in directing leukocytes into the inflamed bowel wall. Therapeutic compounds directed against trafficking of leukocytes have been designed and are being developed as a novel class of drugs in the treatment of Crohn's disease and ulcerative colitis. This review deals with the immunological aspects of leukocyte trafficking focused on gut homing of T cells. Second, the changes in adhesion molecules and T cell trafficking during intestinal inflammation are discussed. Finally, we review the clinical data that have been gathered with respect to the therapeutic potential and the safety of antiadhesion molecule treatment. Antegren, or natalizumab, a humanized anti-alpha4 integrin IgG4 antibody, has been most extensively evaluated and may be close to registration. A more specific humanized alpha4beta7-integrin MLN-02 has shown preliminary clinical efficacy in ulcerative colitis, and both antergren and MLN-02 appear to be very safe. Trials with the anti-ICAM-1 antisense oligonucleotide ISIS-2302 in steroid refractory Crohn's disease have provided conflicting efficacy data. In the near future, some of these novel biological agents may prove valuable therapeutic tools in the management of refractory inflammatory bowel disease, although it is too early to define the patient population that will benefit most from these agents.

Baert F, Vermeire S, Noman M, Van Assche G, D'Haens G, Rutgeerts P. · Department of Gastroenterology, at the University Hospital Gasthuisberg, Leuven, Belgium. · Acta Clin Belg. · Pubmed #15641402 No free full text.

Abstract: The conventional medical treatment of IBD consists of aminosalicylates, corticosteroids, immunosuppressive drugs (azathioprine, 6-mercaptopurin, methotrexate, cyclosporin) and antibiotics. The only drugs able to modify the disease course are azathioprine, its metabolite 6-mercaptopurin and methotrexate. However, these drugs have a slow onset of action and are associated with important side-effects in some patients, necessitating the discontinuation of the drug. Moreover, up to 60% of patients do not respond to these drugs long-term. Fortunately, the management of IBD has entered a new era in the beginning of the 1990s with the development of new biological therapies, selectively blocking the inflammatory cascade. The novel molecules have arisen from the increasing knowledge about the disease pathogenesis and their production has been precipitated by the techniques of molecular biology. Infliximab, the first available biological for Crohn's disease has certainly revolutionised standard treatment. Because of its profound clinical, endoscopic and histological effects, the standard step up approach in the treatment of IBD has been challenged. A large array of new rationally designed biologicals, with a better safety profile and equally selectively acting is underway, and is likely to change our current practise even more dramatically in the next decade.

Vermeire S, Van Assche G, Rutgeerts P. · Department of Medicine, Division of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium. · Inflamm Bowel Dis. · Pubmed #15472532 No free full text.

Abstract: The production of CRP occurs almost exclusively in the liver by the hepatocytes as part of the acute phase response upon stimulation by IL-6, TNF-alphaand IL-1-betaoriginating at the site of inflammation. Its short half-life makes CRP a valuable marker to detect and follow up disease activity in Crohn's disease (CD). In contrast, ulcerative colitis has only a modest to absent CRP response despite active inflammation, and the reason for this is unknown. In CD, serum levels of CRP correlate well with disease activity and with other markers of inflammation as the CDAI, serum amyloid, IL-6 and faecal calprotectin. CRP is a valuable marker for predicting the outcome of certain diseases as coronary heart disease and haematological malignancies. An increased CRP (>45 mg/L) in patients with IBD predicts with a high certainty the need for colectomy and this by reflecting severe ongoing and uncontrollable inflammation in the gut. Finally, trials with anti-TNF and anti-adhesion molecules have shown that a high CRP predicts better response to these drugs. However, whether we need to include CRP as an inclusion criterion for future trials with biologicals is still a matter of debate.

Rutgeerts P, Van Assche G, Vermeire S. · Department of Medicine, Division of Gastroenterology, University of Leuven, Belgium. · Gastroenterology. · Pubmed #15168370 No free full text.

Abstract: Infliximab, the chimeric monoclonal immunoglobulin (Ig)G1 antibody to tumor necrosis factor (TNF) has changed our therapy of Crohn's disease. Infliximab is indicated in refractory luminal and fistulizing Crohn's disease. In patients with luminal disease, a single intravenous (i.v.) dose of 5 mg/kg is efficacious; in fistulizing disease, an i.v. loading therapy of 5 mg/kg at weeks 0, 2, and 6 is advocated. Because the majority of patients will relapse if not re-treated, a long-term strategy is necessary. The optimal long-term approach is systematic re-treatment with 5 mg/kg every 8 weeks. Episodic therapy on relapse also is possible but is less efficacious and frequently is associated with problems resulting from the formation of antibodies to infliximab (ATI). If treatment is episodic, maintenance therapy with immunosuppression (azathioprine [AZA]/6-mercaptopurine [6-MP] or methotrexate) is mandatory. Trial data suggest that systematic maintenance with 8 weekly doses of infliximab decreases the rate of complications, hospitalizations, and surgeries. These effects probably are achieved thanks to thorough healing of the bowel. Infliximab also is indicated in treating corticosteroid-dependent Crohn's disease and extraintestinal manifestations of Crohn's disease. There are no data yet that support its use as first-line therapy. The data in ulcerative colitis (UC) are conflicting and we should await the results of 2 large controlled trials (ACT1 and ACT2) to position infliximab in the treatment of UC. Other anti-TNF strategies have been less effective than infliximab in the treatment of IBD until now. The results with thalidomide are promising but much more research into small molecules inhibiting TNF and other proinflammatory cytokines is necessary. Safety problems with antibody treatment mainly concern immunogenicity leading to infusion reactions, loss of response, and serum sickness-like delayed infusion reactions. The rate of opportunistic infections is increased mainly in patients treated concomitantly with immunosuppression. Other adverse events associated with anti-TNF strategies are demyelinating disease and worsening of congestive heart failure. Malignancy rates in patients treated with anti-TNF strategies do not seem to be increased.

Rutgeerts P. · Dept. of Medicine, University Hospital Leuven, Belgium. · Scand J Gastroenterol Suppl. · Pubmed #12797678 No free full text.

Abstract: Modern therapy for inflammatory bowel disease implies that therapy should be disease modifying rather than merely symptomatic. To achieve this goal, induction and maintenance of bowel healing are mandatory. Long-term bowel healing results in fewer hospitalizations and less surgery. Only immunosuppression therapy and biological approaches, or a combination of both, result in long-term healing of the bowel mucosa. Unsolved issues are when these drugs should be initiated and whether we should aim at eradicating the bowel inflammation from the onset of therapeutic intervention immediately following diagnosis. Identification of genetic and serologic parameters which allow prediction of the course of the disease would be useful for identifying patients who need aggressive treatment early in the disease. Once total control of the disease is achieved, long-term maintenance of a healed bowel is important. We hypothesize that changing the gut flora, e.g. using probiotics, may allow maintenance of bowel healing after induction with biologicals and immunosuppression.

van Assche G, Rutgeerts P. · Division of Gastroenterology, University Hospital Leuven, Belgium. · Inflamm Bowel Dis. · Pubmed #12131614 No free full text.

Abstract: Adhesion molecules regulate the influx of leukocytes in normal and inflamed gut. Some of these molecules such as MadCAM-1 are specific for the gastrointestinal endothelium, but in inflammatory bowel diseases most of the adhesion factors are up-regulated. Adhesion molecules also are involved in local lymphocyte stimulation and antigen presentation within the intestinal mucosa. Recently, therapeutic compounds directed against trafficking of lymphocytes toward the gut mucosa have been designed, and are being developed as a novel class of drugs in the treatment of Crohn's disease (CD) and ulcerative colitis. This review deals with the immunological aspects of leukocyte trafficking focused on gut homing of T cells. Secondly, the changes in adhesion molecules and T-cell trafficking during intestinal inflammation are discussed. Finally, we review the clinical data that have been gathered in trials of biological therapies directed against adhesion molecules. Both antiintercellular adhesion molecule-1 (ICAM-1) and anti-alpha4 integrin strategies are being developed. Trials with the anti-ICAM-1 antisense oligonucleotide, ISIS-2302, in steroid-refractory CD have provided conflicting efficacy data. The anti-alpha4 integrin antibodies natalizumab (Antegren) and LDP-02 are in phase III and phase II trials, respectively. In the near future, these novel biological agents may prove valuable therapeutic tools in the management of refractory IBD.