Current Drug Targets - Volume 11, Issue 2, 2010

Crohn's disease is a chronic inflammatory bowel disease (IBD) that can affect the whole gastrointestinal tract, especially the ileo-colonic tract. The etiology of the disease still remains unknown [1]. Several mechanisms involved in the pathogenesis of the disease have been investigated, and Tumour Necrosis Factor (TNF)-α pathway seems to play a crucial role in the onset and maintenance of the chronic inflammatory process [2]. In the last fifteen years, the introduction of biological drugs acting as anti TNF-α agents caused a revolution in the treatment of IBD, especially for Crohn's disease. The introduction of the first anti TNF-α monoclonal antibody, infliximab, has changed the natural history of the disease, overall in terms of hospitalisation rate and need for surgery [3]. Up to now, three anti TNF-α have been demonstrated to be effective in the treatment of Crohn's disease: infliximab, adalimumab and certolizumab pegol. Infliximab is a chimeric monoclonal antibody that has been introduced in the treatment of Crohn's disease since 1995. During those years, efficacy of infliximab in inducing clinical remission [4], maintaining a longterm steroid-free remission, healing mucosal lesions, closing fistulas and reducing hospitalization rate and need for surgery [5] has been widely investigated and confirmed. Adalimumab is a more recent anti TNF-α fully human antibody. Although it has been introduced about ten years after infliximab, many studies have shown it to be as effective as infliximab in inducing and maintaining remission, healing mucosal lesions and closing fistulas, and decreaseing hospitalisation and need for surgery [6, 7]. Certolizumab is a pegylated anti TNF-α, given subcutaneously. Its efficacy in inducing and maintaining remission has been investigated in some randomised controlled trials, even though response and remission rates have been lower than the other two anti TNF-α agents [8]. It is currently used in clinical practice in Switzerland and Unites States, but not in Europe. Although the role of these drugs in the management of Crohn's disease is nowadays well established, several questions on different aspects of biological therapy remain unanswered. No direct comparison between infliximab, adalimumab and certolizumab has been ever done, so there is no clear evidence on what is the best agent to start with. Early introduction of biological agents in the treatment of Crohn's disease resulted to change the natural history of the disease in children [9], but no prospective studies have been conducted in adults. Long-term use of anti TNF-α agents in maintaining remission, that is more than 52 weeks, seems to be effective and safe [10], but no studies are able to tell the clinicians how long the therapy should be prolonged and what are risks and benefits of such long therapy. Risk of malignancies, infections and degenerating diseases has been also investigated. Anti TNF-α seem not to increase the risk for malignancies and degenerating diseases, and not significantly affect the risk to contract opportunistic infections, especially when used as monotherapy [11]. All studies mostly concern the use of infliximab, and they are limited in a relatively short time. Then, further studies on long-term safety, especially on the most recent anti TNF-α agents are needed as well as more prospective studies aim to evaluate the best strategies to prevent adverse events, especially for opportunistic infections. The use of anti TNF-α during pregnancy is still to be defined. A recent review of the Food and Drug Administration on the use of anti TNF-α for any indication during pregnancy has been published, showing that risk for congenital abnormalities increased. Other studies suggest no increase of the risk in IBD [12]. Biological agents have been largely studied in luminal and penetrating disease. Anyway, the role of anti TNF-a drugs in special situations, as a prevention of post-operative recurrence (POR) is still to be evaluated. Infliximab has been shown to be effective to prevent POR compared to placebo, even if on a small number of patients and on a short period of follow-up [13]. Confirmation of these preliminary results may open new therapeutic ways and, hopefully, change the natural history of the disease once more. At the moment, no evidence supports the use of anti TNF-α agents in preventing fibrosis. Anyway, some studies have been shown that the use of anti TNF-α can lead to significant regression of strictures in CD [14, 15]. This means that those agents may have positive effects by interfering and delaying the fibrogenesis at early stages. A clearer knowledge of the processes underlying fibrogenesis in CD, may help investigators to find a therapeutic role and timing for biological agents with this specific aim. “Menage a trois” among infliximab, adalimumab and certolizumab is a tremendous therapeutic choice for moderate-tosevere Crohn's disease. Several matters about the use of anti TNF-α agents remain unanswered and need further investigation.

Several TNF antagonists, mainly monoclonal antibodies, have shown to be efficacious in the therapy of Crohn's disease. Despite the fact that they have been used for over a decade, their precise mechanism of action is still a matter of investigation. The effects of anti-TNF agents are mediated by multiple mechanisms including direct neutralization of soluble TNF and interaction with membrane-bound TNF. Anti-TNF agents may act by reduction of proinflammatory cytokine levels, elimination or clearance of active inflammatory cells from inflamed tissue which can conceptually be achieved by a number of mechanisms including apoptosis induction, antibody and complement mediated cytotoxicity and inhibition of cell migration into the intestinal tissue. Regulatory events both in the cellular and intracellular levels probably play a role as well. Finally, effects of anti-TNF agents may vary according to their physical contact with TNF leading to different binding avidities, conformational changes and variable downstream effects. These effects may also be influenced by structural differences in the non-TNF binding domain which affects the ability of each drug to interact with the immune system. Our understanding of these mechanisms of action is limited by the fact that much of the data was obtained using artificial in vitro systems of which their relevance to the in vivo situation is uncertain.

The natural course of Crohn's disease is characterized by the progression from primarily inflammatory disease to a complicated stricturing or penetrating disease. These irreversible complications lead to repeated surgery and considerable disability. Therefore it may be argued that a window of opportunity for intensive treatment exists early in the disease course. Healing of the mucosa has been shown to be a strong predictor of improved outcome of Crohn's disease on the long-term, in terms of disease control, hospitalizations, and surgery. Anti-tumor necrosis factor (TNF)-α therapy has shown to be a strong inducer of mucosal healing and it may be argued that early treatment with anti-TNF's and/or immunomodulators may be the preferable approach in selected patients. The main concern with such strategies is safety, especially the risk of lymphoma's and infections. This paper aims to review the existing data regarding the benefits and disadvantages of inverting the classic step up therapeutic paradigm.

When to stop anti-TNF therapy in Crohn's disease (CD)? This is a very important question both for patients and physicians. There is no published evidence to clearly and definitely answer this question. However data on natural history of CD, long term safety of biologics, outcome after immunosuppressors (IS) cessation and some preliminary studies on biologics cessation may help us to discuss this topic. One could argue that there is currently no good reason to stop anti-TNF therapy in a patient who is in stable remission and can tolerate this drug very well. The decision to stop an anti-TNF treatment is thus currently based on a compromise between the benefits/risks and cost of such long term treatment. While it appears now clearly that prolonged anti-TNF therapy is associated with favourable outcome with sustained remission, reduced surgeries and hospitalisation as well as absence of significant increase in mortality or cancers, the cost-effectiveness which is probably favourable for short and mid-term treatment (up to one year), may be less optimal for very long term treatment. In this perspective however, prospective studies should be performed to adequately assess long term evolution, disease outcome, safety and global cost of strategies based on treatment reduction with IS maintenance alone or even full treatment cessation.

Despite the fact that anti-TNF alpha antibodies are well-tolerated and highly effective in Crohn's disease 25% to 40% of patients who initially benefited from the treatment are developing intolerable adverse events or are losing their response during maintenance therapy. The molecular mechanisms of loss of response are not fully understood, but clinicians face this clinical problem. The Aim of this paper is to review the clinical strategies to face loss of response to anti- TNF alpha antibodies in Crohn's disease.

The introduction in the mid-1990s of tumor necrosis factor (TNF) antagonists changed the treatment of inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis (UC), refractory to conventional medications (corticosteroids, immunomodulators). This review summarizes current data on the long-term efficacy and safety of anti- TNF therapy in IBD beyond 1 year. We searched Medline, the Cochrane Library, Embase, and Ovid Medliner for relevant studies. Infliximab, adalimumab and certolizumab are effective in maintaining clinical remission in luminal Crohn's disease. Infliximab and adalimumab are also effective in maintaining long-term fistula closure in Crohn's disease. Only infliximab has been evaluated in UC in the long term, with similar data on its effectiveness than in CD. In addition to the maintenance of clinical remission, TNF antagonists have the ability to maintain long-term mucosal healing, resulting in a reduced risk of surgery. With 2010 on the horizon, we have no good reasons to stop anti-TNF therapy in IBD patients because of its efficacy in maintaining remission and a risk-benefit ratio that remains in its favor. It is now clear that patients in deep remission, comprising clinical, biological, and endoscopic remission, are at lower risk of relapse after withdrawal of anti-TNF therapy.

Today up to 40% of Crohn's disease patients receive a concomitant therapy of TNF blockers in combination with thiopurines or methotrexate. Although data of prospective controlled trails are rare, some recently published studies indicate a more rapid onset of remission and increased mucosal healing following concomitant therapy in short term. However, data confirming the need or benefit of concomitant immunosuppressive therapy once remission has been reached remains unknown. Concomitant therapy lowers TNF-alpha induced immunogenicity, but the question of whether ATI formation also lowers the efficiency of TNF-alpha antagonists has not yet been answered to a level that would justify the use of concomitant immunosuppression. Knowing that immunosuppression increases the risk for opportunistic infections and lymphomas the potential risks and of concomitant therapy must be well balanced against the benefit. This article aims to interpret the available data on the efficiency, immunogenicity, and safety of concomitant therapy in patients under anti-TNF therapy.

Tumour necrosis factor alpha (TNF-alpha) inhibitors ensure valuable treatment advantages for patients with inflammatory bowel diseases (IBD) by offering a more targeted anti-inflammatory therapy. In contrast, there is concern that it might increase the risk of long-term complications including infections and the risk for malignancies and non- Hodgkin's lymphoma (NHL). Although the results from hospital- and population-based studies are conflictive, the results of a meta-analysis suggest that patients receiving purine analogues for the treatment of IBD have a lymphoma risk 4-fold higher than expected. Analyses of lymphoma risk in patients receiving biologic agents directed against tumour necrosis factor-alpha are confounded by concomitant use of immunosuppressive agents in most of these patients. Nevertheless, in a recent meta-analysis, a 3-fold increased risk of NHL was found in patients with previous immunomodulator exposure, while scattered case reports point to the potentially increased risk of a rare form of NHL (Hepatosplenic T-cell lymphoma) with the use of azathioprine-anti-TNF combination. The absolute rate of these events remains, however low and should be weighed against the substantial benefits associated with treatment. In contrast, data obtained from observational studies and registries did not show an increased risk for solid tumours or lymphoma in patients with anti- TNF exposure. The aim of this review is to summarize the available evidence on the association between malignancy and anti-TNF treatment in IBD.

Perianal fistulas are a major problem of patients with Crohn's disease (CD), and occur in up to 40 % of patients. The treatment of fistulising perianal CD has recently largely evolved as a result of improvements of pharmacological and surgical approaches and the introduction of anti-TNF treatment. Especially the use of anti-TNF agents in complex or refractory perianal fistulas has been proven as the most effective medical treatment of this difficult to treat disease. Infliximab and adalimumab are the two currently available anti-TNF agents that both have shown significant efficacy in the treatment and sustained remission of perianal fistulising CD with comparable fistula closure rates. However, despite this treatment a large number of patients have continuous disease activity and high relapsing rates, whereas only a small percentage of them have a complete fistula healing. Therefore, the optimal outcome is still dependent on a multidisciplinary approach with a close interaction between gastroenterologists and surgeons. The individualised treatment based on anti-TNF agents with the rational combination of antibiotic use, surgery and immunosuppressive therapy is, currently, the suggested treatment in order to achieve remission of a persistent perianal fistula. Large randomised studies are required for the long-term evaluation of the efficacy in modifying the disease course of this combined approach.

The advent of biological therapy has had a significant impact on the management of patients with inflammatory bowel disease. Nevertheless, anti-TNF-alpha agents are still used with caution, driven by concerns about the risk of infection. Stringent post-marketing surveillance programmes and registries have allowed early recognition of problems, highlighting an increased risk of infectious complications. Although the focus is on biological drugs, other immunomodulators have been less well scrutinised and similarly carry considerable risks of infection. It remains unclear whether the risk of infection from anti-TNF therapy is any different from conventional immunomodulators such as azathioprine or methotrexate, although it appears to be less than that ascribed to corticosteroids. The majority of patients on anti-TNF agents are on concomitant immunosuppressive medication, which makes ascribing risk to a specific drug more difficult. The risk of life-threatening opportunistic infections associated with anti-TNF therapy has obliged us to re-consider methods of prevention of infection and to develop guidelines for risk-stratification of patients with a diagnosis of inflammatory bowel disease. This encompasses vaccination and chemoprevention, appropriate treatment of underlying infection, patient education, travel advice and careful monitoring whilst on anti-TNF therapy. Contingency planning is essential. Implementing these preventative strategies will have an appreciable impact on the organisation of care and on current clinical practice.

Recurrence of Crohn's disease (CD) is extremely frequent after surgery and its prevention remains a fundamental problem in the medical management of these patients. As of today, none of the medications traditionally used to treat the spontaneous disease (i.e. mesalamine, steroids, immunosuppressives and antibiotics) has shown a clear benefit. Recent data, coming from our center and from a small RCT do indicate that infliximab is extremely effective in preventing this complication in the large majority of patients. While additional, larger studies may be desirable, the strength and consistency of the available data suggest that future trials may merely confirm these observations. A number of issues however remain to be solved and include the long term strategy in patients treated for years with infliximab, whether treating early endoscopic lesions may be as effective as preventing them and whether immuno-soppressives should be used together with infliximab. A thorough understanding of the mechanisms by which infliximab appears so effective in the postoperative setting may provide us with essential information regarding patients’ management and, ultimately, highlight the molecular mechanisms at the very basis of Crohn's disease.

Mucosal healing has been incorporated in the assessment of treatment efficacy in ulcerative colitis, but in Crohn's disease this concept has only emerged after biological therapies have been evaluated in clinical trials. Systemic steroids don't induce mucosal healing in Crohn's disease, but purine analoges and anti TNF agents have a potential to heal mucosal ulcerations. Evidence for mucosal healing has now been provided for the anti TNF agents infliximab, adalimumab and certolizumab. For infliximab mucosal healing is associated with a reduction in hospitalizations and surgeries. On the contrary, the benefit of treating patients with IBD more intensively until they achieve mucosal healing has not been proven. In clinical practice assessing mucosal healing should be considered in patients with persistent symptoms despite adequate therapy and when treatment discontinuation is being considered.

The incidence of inflammatory bowel disease (IBD; Crohn’s disease, ulcerative colitis) is highest during the peak reproductive years, hence the increased concern with the safety of IBD drugs during pregnancy. Over the past 11 years, anti-TNF-α antibody therapy has emerged as a treatment approach for refractory IBD patients who have failed to achieve or maintain remission with corticosteroids and immunomodulator agents. The TNF-α inhibitors (anti-TNFs; infliximab, adalimumab, certolizumab pegol) have proven successful in inducing and maintaining remission of moderateto- severe IBD, but recommendations for the use of these compounds during pregnancy have lacked consensus. Balanced against the potential risk of these drugs on the fetus is the well-established fact that high disease activity has been found to poorly affect pregnancy outcomes in IBD, and the potential use of anti-TNF agents may control disease flare and severity during pregnancy. Concerns regarding the effect of anti-TNFs on the pregnancy and fetus have been assuaged by registry data which has demonstrated an overall positive safety record. Both the U.S. Food and Drug Administration and the European Crohn's and Colitis Organization categorize anti-TNF agents as safe during pregnancy. New knowledge regarding the physiologic timing of placental transfer of therapeutic antibody subclasses and pegylated antibody fragments from the mother into the fetus has also helped to allay concerns. This review will examine the present state of knowledge regarding the use of anti-TNFs in pregnant women with IBD.

Crohn's disease (CD) is a chronic panenteric disease of unknown aethiology which tends to progress in spite of medical or surgical treatment. Intestinal fibrosis is among the most common complications of CD, resulting in stricture formation in the small intestine and colon. About 75% of CD patients will undergo surgery at least once over the course of their disease and fibrotic strictures represent the main indication for surgery and the first cause of hospitalization and costs for CD patients. Clinical management of intestinal strictures depends on the type of stricture: inflammatory strictures are treated medically and are usually responsive to treatment, while fibrotic strictures require surgery. Clinical decisions regarding the right treatment choice for such conditions require proper knowledge on what to expect from the emerging drug strategies and surgical techniques. To achieve optimal results in patient management an approach combining the expertise of both gastroenterologist and colorectal surgeon is essential. This review aims at providing clinicians with an overview on fibrotic strictures in CD patients. Particular focus will be placed on the principal imaging modalities, and the medical, endoscopic and surgical treatment options with relative indications, according to the most recent evidence available.

Inflammatory bowel diseases (IBD) are idiopathic chronic inflammations: the etiology of Crohn's disease (CD) and ulcerative colitis (UC) is still largely unknown. Environmental and genetic factors in combination with the microbial flora or specific microorganisms trigger an event, leading to the activation of an intestinal immune response. Immune and non-immune cells create a cross talk via the secretion of soluble mediators and expression of cell adhesion molecules, resulting in further cell activation. Mediators such as cytokines and chemokines play a role in cell recruitment and polarization, intercellular signal amplification or activation and differentiation. Considering these aspects, medical management of inflammatory bowel disease has changed considerably over the past decade. Advances in biotechnology has allowed for the introduction of many biologic therapies, other than anti-TNF therapies. Many of these drugs showed clinical benefit for induction and maintenance therapy, both in UC and CD. Although numerous, at present only monoclonal anti-TNF antibodies are currently available worldwide. Other biological agents have been tested or are under evaluation. This paper systematically reviews the mechanism-of-action, efficacy, short-term and, where available, long-term safety of biological agents that have been approved for the treatment of IBD or are under evaluation which target different molecules other than tumor necrosis factor α (TNF-α).