Growth hormone in inflammatory bowel disease

Crohn's disease and ulcerative colitis are inflammatory diseases of the gastrointestinal tract characterized by chronic relapsing inflammation and catabolism. Growth hormone/insulin-like growth factor-I axis is important in inflammatory bowel disease, because of the effects on epithelial cell kinetics, collagen deposition and immunomodulation. The potential of growth hormone as a therapeutic option in inflammatory bowel disease has been proven in various clinical settings. Acquired growth hormone resistance in inflammatory bowel disease seems to be mediated by a combination of undernutrition and active inflammation. In particular, proinflammatory cytokines, such as TNF-a and interleukin-6, have been implicated as potential mediators of growth hormone resistance. The introduction of anti-TNF-alpha monoclonal antibodies has proven very efficacious in patients with inflammatory bowel disease. By reducing cytokines levels in inflammatory cells of intestinal mucosa, infliximab could interfere with cytokine-induced growth hormone resistance. Recent in vivo data have shown that acquired growth hormone resistance in patients with inflammatory bowel disease may be reversed after the administration of anti-TNF-alpha therapy.     

Recent developments in the treatment of rheumatoid arthritis with targeted biological agents

Rheumatoid arthritis RA is a chronic systemic autoimmune inflammatory disease characterised by progressive joint damage. The pathophysiological processes involved in inflammatory reactions such as occur in RA and during infections have now been delineated, providing a scientific rationale for the use of biological and/or chemical entities targeted at specific sites of the inflammatory cascade in order to modulate inflammation. Currently available therapies for RA, such as myocrisin and sulfasalazine, were developed empirically without much regard for the basic physiological mechanisms of inflammation, and are not always effective at controlling the disease. The majority of the novel agents being developed for the treatment of RA are biological. However, their clinical effects have been transient, necessitating repeated treatments, many have to be administered parenterally, production costs are very high and some patients have developed antiglobulin responses. Consequently, chemical entities that can be taken orally have been developed. Clinical trials are awaited. Since the immune system is so complex, with pleiotropic cytokines and apparent redundancy in some of the regulatory networks, successful treatment of RA may require the administration of multiple agents targeted at different specific sites of the inflammatory cascade, or of different agents at different stages of the disease, in order to induce disease remission and maintain the response to therapy. However, since cytokines such as TNF-a and IL-1 play important physiological roles in the host's defence systems, chronic inhibition of these cytokines by targeted therapies may be associated with unwanted effects, e.g., infections. Long-term, carefully controlled studies are therefore necessary to assess the safety of selective targeting of processes involved in inflammation. In this chapter the current status and future prospects of these novel and advanced treatment modalities for RA are reviewed.     

Review article: biological activity markers in inflammatory bowel disease

BACKGROUND: Traditionally, inflammatory bowel disease activity is assessed by clinical activity indices that measure clinical symptoms and endoscopic indices that measure endoscopic inflammation. Biological markers are a non-invasive way of objectively measuring inflammation and can play an adjunctive or primary role in the assessment of disease activity. AIM: To review the data on biological markers for assessment of disease activity and prediction of relapse in inflammatory bowel disease. METHODS: To collect relevant articles, a PubMed search was performed from 1980 to 2006 using following search terms in combination: inflammatory bowel disease, biomarkers, inflammation, disease activity, relapse, acute phase reactants cytokines, interleukins, adhesion molecules, integrins, calprotectin and lactoferrin. RESULTS: Biological activity markers can be classified into serological, faecal and miscellaneous categories. Acute phase reactants levels correlate with disease activity and some can be used to help predict relapse. Cytokines and adhesion molecules are elevated in active disease inconsistently. Faecal markers are useful in assessment of disease activity and relapse. CONCLUSIONS: Acute phase reactants and faecal markers are useful to assess the disease activity in clinical practice. More data are required on cytokines and adhesion molecules. C-reactive protein, erythrocyte sedimentation rate, interleukins and faecal markers may be useful in predicting a relapse.     

Emerging biotherapies for inflammatory bowel disease

The immunological and genetic pathogeneses of inflammatory bowel disease (IBD) have been well studied, but not well elucidated in recent years. Accordingly, the pharmacological treatment of IBD is focusing upon the individual pathologic step (targeting therapy). It has recently become apparent that new drugs such as biological immunomodulating agents and anti-inflammatory cytokines have better short-term effects in some respects than conventional drugs, and they could change the treatment strategy of IBDs in the near future. Many options are now available to treat IBD. The choice depends on the type of IBD, the location of inflammation and the severity of symptoms. Many key processes in the inflammatory cascade have been targeted by cytokine and anticytokine therapies ranging from antigen presentation, T cell activation, overproduction of pro-inflammatory cytokines and migration of inflammatory cells to blockade of effector signals. TNF-alpha plays an important role in the induction of other cytokines as well as in the upregulation of adhesion molecules in chronic IBDs, Crohn's disease (CD) and ulcerative colitis. In fact, the most successful approaches so far in the treatment of IBD have been anti-TNF strategies. In contrast, the use of antiadhesion molecules strategies has been demonstrated to be ineffective in IBD.     

Emerging biotherapies for inflammatory bowel disease

The immunological and genetic pathogeneses of inflammatory bowel disease (IBD) have been well studied, but not well elucidated in recent years. Accordingly, the pharmacological treatment of IBD is focusing upon the individual pathologic step (targeting therapy). It has recently become apparent that new drugs such as biological immunomodulating agents and anti-inflammatory cytokines have better short-term effects in some respects than conventional drugs, and they could change the treatment strategy of IBDs in the near future. Many options are now available to treat IBD. The choice depends on the type of IBD, the location of inflammation and the severity of symptoms. Many key processes in the inflammatory cascade have been targeted by cytokine and anticytokine therapies ranging from antigen presentation, T cell activation, overproduction of pro-inflammatory cytokines and migration of inflammatory cells to blockade of effector signals. TNF-α plays an important role in the induction of other cytokines as well as in the upregulation of adhesion molecules in chronic IBDs, Crohn’s disease (CD) and ulcerative colitis. In fact, the most successful approaches so far in the treatment of IBD have been anti-TNF strategies. In contrast, the use of antiadhesion molecules strategies has been demonstrated to be ineffective in IBD.     

Section Review Pulmonary-Allergy,Dermatological, Gastrointestinal & Arthritis: The current status and future prospects for biological targeted therapies for rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic systemic autoimmune inflammatory disease which leads to progressive joint damage. Currently available therapies, such as myocrisine and sulphasalazine, were developed empirically without much regard for the basic physiological mechanisms of inflammation and are not always effective at controlling the disease. The pathophysiological processes involved in the inflammatory reactions that occur, for example, in RA and during infection, have now been delineated, thus, providing a scientific rationale for the use of biological and/or chemical entities targeted at specific sites of the inflammatory cascade in order to modulate inflammation. The majority of these agents are biological and clinical trials in RA are in progress. Although the results obtained in some of the studies using single agents have been encouraging, the clinical effects have been transient, necessitating repeated dosing. This, along with the requirement for intravenous administration for many of these agents, the high production costs and the occurrence of antiglobulin responses in a number of patients, has fueled the development of chemical entities that can be administered orally and that are directed at specific cellular targets; clinical trials are awaited. Since the immune system is very complex with pleiotropic cytokines and apparent redundancy in some of the regulatory networks, in order to induce disease remission and maintain the response to therapy, it may be necessary to use multiple agents targeted at different specific sites of the inflammatory cascade or different agents at different stages of the disease. Cytokines such as TNF-α and IL-1 play important physiological roles in the host's defence systems. Hence, chronic inhibition of these cytokines by targeted therapies may be associated with unwanted effects such as infection. Long-term, carefully controlled studies are necessary to assess the safety of selective targeting of processes involved in inflammation. Finally, attempts at controlling chronic inflammation have been made by inducing immune tolerance using orally ingested biological preparations, such as bacterial extracts and collagen. This paper reviews the current status and future prospects of these novel modalities for modulating rheumatoid inflammation.     

Review article: steroid resistance in inflammatory bowel disease - mechanisms and therapeutic strategies

BACKGROUND: Steroid resistance in inflammatory bowel disease presents a difficult clinical challenge. The advent of biological therapies coupled with an increasing understanding of the pathogenesis of inflammatory bowel disease has provided new therapeutic options. METHODS: We review the available literature of the mechanisms behind steroid resistance. In addition, we outline some of the options available for treating those patients who fail to respond adequately to glucocorticoids. RESULTS: Approximately 30% of patients prescribed glucocorticoids will not achieve clinical remission. Many such patients are offered immunosuppressive or, recently, biological agents. However, these agents are ineffective in a large proportion of patients. Immunosuppressive agents only bring 40-60% of patients into remission, and biological agents typically induce remission in just 40% of patients. In this review, the possible explanations for glucocorticoid resistance are discussed. Recent evidence suggests that in many patients it is mediated by interleukin-2. Basiliximab, a biological agent that interrupts interleukin-2 signalling, has shown significant benefit in early clinical studies. CONCLUSIONS: Patients who fail to respond to steroid therapy should have alternative agents introduced in a timely fashion. Steroid refractory inflammatory bowel disease remains a difficult condition to treat, but new therapies and managements are emerging.     

Pyrazolones as therapeutics for kinase-mediated inflammatory disorders

Many of the current approaches toward therapies for inflammatory diseases target the inhibition of various kinases. Overexpression or inappropriate activation of these kinases is known to trigger various inflammatory diseases via aberrant phosphorylation of protein targets, including inflammatory diseases such as rheumatoid arthritis (RA), osteoarthritis (OA) and inflammatory bowel disease (IBD). A series of pyrazolone-based kinase inhibitors are presented with some biological data for a few of the representative compounds. These publications demonstrate the versatility of the pyrazolone heterocycle as an ATP mimetic.     

Interleukin-18 bioactivity: a novel target for immunopharmacological anti-inflammatory intervention

Interleukin-18 is a member of the interleukin-1 family of cytokines with pro-inflammatory and tumor-suppressive properties. Its ability to potently enhance the production of interferon-γ indicates in particular the crucial function of interleukin-18 as an immunomodulatory molecule. In fact, high levels of interleukin-18 are detected in human diseases associated with immunoactivation including viral or bacterial infections and chronic inflammation. Animal models suggest suppression of interleukin-18 bioactivity as a novel therapeutic concept specifically for the treatment of chronic inflammatory diseases such as rheumatoid arthritis, Crohn's disease, and psoriasis. Here we introduce into the biology of interleukin-18 and review immunopharmacological strategies that aim at reducing interleukin-18 bioactivity in human disease.     

Biologic therapy for inflammatory bowel disease

Despite all of the advances in our understanding of the pathophysiology of inflammatory bowel disease (IBD), we still do not know its cause. Some of the most recently available data are discussed in this review; however, this field is changing rapidly and it is increasingly becoming accepted that immunogenetics play an important role in the predisposition, modulation and perpetuation of IBD. The role of intestinal milieu, and enteric flora in particular, appears to be of greater significance than previously thought. This complex interplay of genetic, microbial and environmental factors culminates in a sustained activation of the mucosal immune and non-immune response, probably facilitated by defects in the intestinal epithelial barrier and mucosal immune system, resulting in active inflammation and tissue destruction. Under normal situations, the intestinal mucosa is in a state of 'controlled' inflammation regulated by a delicate balance of proinflammatory (tumour necrosis factor [TNF]-alpha, interferon [IFN]-gamma, interleukin [IL]-1, IL-6, IL-12) and anti-inflammatory cytokines (IL-4, IL-10, IL-11). The mucosal immune system is the central effector of intestinal inflammation and injury, with cytokines playing a central role in modulating inflammation. Cytokines may, therefore, be a logical target for IBD therapy using specific cytokine inhibitors. Biotechnology agents targeted against TNF, leukocyte adhesion, T-helper cell (T(h))-1 polarisation, T-cell activation or nuclear factor (NF)-kappaB, and other miscellaneous therapies are being evaluated as potential therapies for IBD. In this context, infliximab is currently the only biologic agent approved for the treatment of inflammatory and fistulising Crohn's disease. Other anti-TNF biologic agents have emerged, including CDP 571, certolizumab pegol (CDP 870), etanercept, onercept and adalimumab. However, ongoing research continues to generate new biologic agents targeted at specific pathogenic mechanisms involved in the inflammatory process. Lymphocyte-endothelial interactions mediated by adhesion molecules are important in leukocyte migration and recruitment to sites of inflammation, and selective blockade of these adhesion molecules is a novel and promising strategy to treat Crohn's disease. Therapeutic agents that inhibit leukocyte trafficking include natalizumab, MLN-02 and alicaforsen (ISIS 2302). Other agents being investigated for the treatment of Crohn's disease include inhibitors of T-cell activation, peroxisome proliferator-activated receptors, proinflammatory cytokine receptors and T(h)1 polarisation, and growth hormone and growth factors. Agents being investigated for treatment of ulcerative colitis include many of those mentioned for Crohn's disease. More controlled clinical trials are currently being conducted, exploring the safety and efficacy of old and new biologic agents, and the search certainly will open new and exciting perspectives on the development of therapies for IBD.     

Advances in the therapy of rheumatoid arthritis with biological agents

Rheumatoid arthritis (RA) is the most common chronic systemic autoimmune inflammatory disease. The physiology of inflammation has been systemically studied and this has provided specific therapeutic targets for its modulation. The classical treatments of the disease, such as myocrisin and sulphasalazine, are not always effective at controlling the disease. This has necessitated the development of novel agents for treating RA, most of which are biological in nature and are targeted at specific sites of the inflammatory cascades. Advances in molecular biology have heralded the advent of bio-drugs (recombinant proteins) and gene therapy in which specific genes are introduced to locally enhance in vivo gene expression or suppress gene(s) of interest with a view to downregulating inflammation. Some bio-drugs, such as antitumour necrosis factor-α (TNF-α) antibodies and interleukin-1 receptor antagonists (IL-1Ra) have been tested, shown to be effective, and are licensed for clinical use. The clinical effects that have been observed are transient, necessitating repeated treatments and increasing the risk of vaccination effects. Anti-inflammatory cytokines, such as IL-4, IL-10, transforming growth factor-β (TGF-β) and interferon-β (IFN-β) are undergoing clinical trials. Many of these agents have to be administered parenterally and production costs are very high. Consequently, chemical entities which can be taken orally need to be developed. Since the immune system is very complex with pleiotropic cytokines and redundancy in some of the regulatory networks, it may be necessary to use multiple agents targeting different specific sites of the inflammatory cascade or different agents that could be given at different stages of the disease, in order to induce disease remission and maintain the response to it. Cytokines and other mediators play important physiological roles in the host’s defence systems against infections and malignancy. The chronic inhibition, exogenous administration or constitutive overexpression of some cytokines may therefore lead to the development of side effects. Thus, carefully controlled long-term studies will be required to assess the safety of selective targeting of processes involved in the physiology of inflammation. This review summarises the important developments in the biotherapy of RA.     

Cytokine and anti-cytokine therapies for inflammatory bowel disease

Although the pathogenesis of inflammatory bowel disease (IBD) remains elusive, it appears that there is chronic activation of the immune and inflammatory cascade in genetically susceptible individuals. Current disease management guidelines have therefore focused on the use of anti-inflammatory agents, aminosalicylates and corticosteroids. These conventional therapies continue to be a first choice in the management of IBD. Immunomodulators, such as azathioprine, 6-mercaptopurine, methotrexate or cyclosporin, are demonstrating increasing importance against steroid-resistant and steroid-dependent patients. However, some patients are still refractory to these therapies. Recent advances in the understanding of the pathophysiological conditions of IBD have provided new immune system modulators as therapeutic tools. Other immunosuppressive agents including FK506 and thalidomide have expanded the choice of medical therapies available for certain subgroups of patients. Furthermore, biological therapies have begun to assume a prominent role. Studies with chimeric monoclonal anti-TNF-alpha antibody treatment have been reported with dramatic successes. However, observations in larger numbers of treated patients are needed to explicate fully the safety of or risks posed by this agent such as developing lymphoma, or other malignancies. Another anti-inflammatory cytokine-therapy includes anti anti-IL-6R, anti-IL-12 or toxin-conjugated anti IL-7R, recombinant cytokines (IL-10 or IL-11). Given the diversity of proinflammatory products under its control, NF-kappaB may be viewed as a master switch in lymphocytes and macrophages, regulating inflammation and immunity. Although some of them still need more confirmatory studies, those immune therapies will provide new insights into cell-based and gene-based treatment against IBD in near future.     

Potential new drugs for therapy of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease is a major health problem with cigarette smoking as its major risk factor. Current therapies are directed against the symptoms (e.g., breathlessness and mucus production) or the chronic airway inflammation. However, the excessive annual decline in lung function and the airway inflammation have not yet been shown to be improved by these strategies. New potential drug therapies are directed against specific components of the inflammation. Novel drugs have been developed for treatment of inflammatory diseases including chronic obstructive pulmonary disease in order to antagonise cytokines and chemokines such as TNF-alpha, CXC chemokine ligand 8 (IL-8) or CC chemokine ligand 2 (monocyte chemoattractant protein 1) that orchestrate the inflammatory process. Some of these drugs are shown to be effective in patients with other chronic inflammatory diseases but still have to prove their efficacy in the treatment of chronic obstructive pulmonary disease.     

A review of standard and novel therapies in Crohn’s disease

Crohn’s disease (CD) is one of the inflammatory bowel diseases characterised by transmural inflammation of various segments of the gut. The pathogenesis of the disease remains obscure and medical and surgical therapy is limited. This review highlights the basic clinical features of the disease as well as some recent insights into the aetiology of the disease. Standard medical therapy is discussed and more recent biologic therapies including the use of anti-TNF-α antibodies are described. The changing focus of therapy, from non-specific anti-inflammatory medications to targeted biologic therapies, is reviewed. A number of novel therapeutic targets and patented therapies are reviewed and future directions for research and clinical testing are discussed.     

Novel targets for antiinflammatory and antiarthritic agents

Inflammation is a complex pathological condition associated with exaggerated human immune system involving various activated immune cells and bio-molecules. Treatment of inflammatory diseases particularly chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease etc. has been a big challenge for scientists as there are no safe drugs available for cure. Current therapeutic approaches to the treatment of inflammatory diseases are centered on cycloxygenase (both COX-1 and 2) proinflammatory enzymes but present available drugs of this category are associated with undesirable gastrointestinal and cardiovascular side effects. Recent scientific advents draw out the secrets of inflammation cache and understanding the involvement of several factors acting as stimulators or inhibitors thus opening new avenues for drug discoveries. Several bio-molecules such as proinflammatory cytokines, components of signal transduction and matrix degrading enzymes resolve inflammatory responses, might be new targets for treatment of chronic inflammatory diseases. This review gathers recent advances in drug research focusing interleukin-1, TNF-alpha, p38 kinase, c-Jun N-terminal kinase MAP kinase, NFkappaB, and matrix metalloproteinases. The biological roles of these inflammatory mediators are clearly understood thus offering new targets for design of novel inhibitors for incurable inflammatory diseases. This also provides an overview of the current nonsteroidal antiinflammatory agents.     

Potential new drugs for therapy of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease is a major health problem with cigarette smoking as its major risk factor. Current therapies are directed against the symptoms (e.g., breathlessness and mucus production) or the chronic airway inflammation. However, the excessive annual decline in lung function and the airway inflammation have not yet been shown to be improved by these strategies. New potential drug therapies are directed against specific components of the inflammation. Novel drugs have been developed for treatment of inflammatory diseases including chronic obstructive pulmonary disease in order to antagonise cytokines and chemokines such as TNF-α, CXC chemokine ligand 8 (IL-8) or CC chemokine ligand 2 (monocyte chemoattractant protein 1) that orchestrate the inflammatory process. Some of these drugs are shown to be effective in patients with other chronic inflammatory diseases but still have to prove their efficacy in the treatment of chronic obstructive pulmonary disease.     

Why Do We Need New Treatments for Rheumatoid Arthritis?*

Rheumatoid arthritis is a chronic systemic autoimmune inflammatory disease characterized by progressive joint damage. The classical treatments of the disease such as myocrisin and sulphasalazine, are not always effective at controlling the disease. This has necessitated the development of novel agents for treating rheumatoid arthritis. Most of these drugs are biological in nature and are targeted at specific sites of the inflammatory cascade of reactions. A number of clinical trials have been conducted. The clinical effects that have been observed are transient, necessitating repeated treatments and the risk of vaccination effects. Many of these agents have to be administered parenterally, production costs are very high. Consequently, chemical entities which can be taken orally need to be developed. Since the immune system is very complex with pleiotropic cytokines and redundancy in some of the regulatory networks, it may therefore be necessary to use multiple agents targeted at different specific sites of the inflammatory cascade or that different agents could be given at different stages of the disease, to induce disease remission and maintain the response to therapy. Cytokines such as tumour necrosis factor (TNF) and interleukin 1 (IL-1) play important physiological roles in the host's defence systems against infections and malignancy. The chronic inhibition of these cytokines by targeted therapies may therefore lead to the development of side effects. Thus, carefully controlled long-term studies will be required to assess the safety of selective targeting of processes involved in inflammation. A more recent novel approach is to target hypoxic tissues with bioreductive agents. Thus, some of the established rheumatoid arthritis treatments could be linked to bioreductive agents and released in hypoxic tissues where inflammation is occurring. This review summarizes the important developments in the therapy of rheumatoid arthritis. There is no doubt that despite these developments we need to develop new and advanced treatment modalities for rheumatoid arthritis.     

A critical approach to new forms of treatment of Crohn's disease and ulcerative colitis

Most patients with inflammatory bowel disease can be managed with conventional immunosuppressive therapy. The choice of agents to prevent relapses of inflammatory bowel disease must be based on efficacy, toxicity and cost. Studies in animal models of inflammatory bowel disease indicate that chronic intestinal inflammation results from enhanced immune responses to bacteria that are present normally in the lumen. Loss of tolerance, an abnormal function or defective healing of the mucosal barrier may all give raise to chronic intestinal inflammation. This hypothesis is the basis of new therapies aimed at either decreasing the levels of luminal bacterial antigens and/or selectively blocking detrimental mucosal immune responses. Anti-TNF is an example of this novel approach that is very effective in Crohn's disease. The use of biological therapy is costly, however, and the long-term complications are not yet known. The recent increase of tuberculosis in patients treated with anti-TNF indicates that careful monitoring is necessary. It is clear that the new forms of treatment may play an important role in tailoring the appropriate drug to a specific group of patients. However, for the time being, fine-tuning in the use of conventional immunosuppression is necessary. New knowledge in the pharmacogenetics of these compounds allows improvements to be made in their use. It is to be hoped that a critical approach in the use of current and future drugs, taking into account the advances in the aetiopathogenesis of inflammatory bowel disease, will contribute to the quality of life of patients with inflammatory bowel disease.     

Glucocorticoids and IL-10, but not 6-MP, 5-ASA or sulfasalazine block endothelial expression of MAdCAM-1: implications for inflammatory bowel disease therapy

BACKGROUND: Enhanced MAdCAM-1 (mucosal addressin cell adhesion molecule-1) expression is associated with the aetiology of inflammatory bowel disease, but little is known about MAdCAM-1: regulation, or how inflammatory bowel disease therapies modulate MAdCAM-1. AIM: To examine how agents currently used to treat inflammatory bowel disease affect MAdCAM-1: induced by tnf-alpha in an in vitro model of inflammatory bowel disease. METHODS: Endothelial monolayers were pretreated with dexamethasone (DEX): 5-aminosalicylic acid (5-ASA), 6-mercaptopurine (6-MP), sulfasalazine or interleukin-10: (IL-10: prior to TNF-alpha (20 ng/mL), and MAdCAM-1: measured by Western blotting, RT-PCR, EMSA and lymphocyte adhesion assays. RESULTS: MAdCAM-1: was induced dose- and time-dependently by TNF-alpha on endothelial cells. Either dexamethasone or IL-10: reduced TNF-alpha-induced MAdCAM-1: protein, mRNA and lymphocyte adhesion. However, neither 5-ASA, sulfasalazine nor 6-MP blocked MAdCAM-1 induction. CONCLUSIONS: Our data indicate that dexamethasone or IL-10 can exert therapeutic activity in inflammatory bowel disease through MAdCAM-1 inhibition. 5-ASA, sulfasalazine and 6-MP, while beneficial in inflammatory bowel disease, do not directly control MAdCAM-1, and are beneficial through inhibition of other inflammatory processes.