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.     

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.     

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.     

Novel therapies for rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease that causes significant morbidity and mortality. The pathogenesis outlined to date in RA consists of a cascade of pro-inflammatory cytokines and chemokines leading to the recruitment of inflammatory cells and the self perpetuation of inflammation, ultimately leading to cartilage and bone destruction. The dramatic progress in understanding the molecular immunology in RA has led to a transition from conventional treatment with aggressive immune suppression to targeted biological-based therapies that control the inflammatory pathways associated with RA. This article reviews the current biological and small-molecule therapies approved for the treatment of RA and those in development, including antibodies, tolerising agents and vaccines.     

Novel therapies for rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease that causes significant morbidity and mortality. The pathogenesis outlined to date in RA consists of a cascade of pro-inflammatory cytokines and chemokines leading to the recruitment of inflammatory cells and the self perpetuation of inflammation, ultimately leading to cartilage and bone destruction. The dramatic progress in understanding the molecular immunology in RA has led to a transition from conventional treatment with aggressive immune suppression to targeted biological-based therapies that control the inflammatory pathways associated with RA. This article reviews the current biological and small-molecule therapies approved for the treatment of RA and those in development, including antibodies, tolerising agents and vaccines.     

Gene therapy targets for rheumatoid arthritis

Rheumatoid arthritis (RA) is the most common chronic systemic autoimmune inflammatory disease whose pathogenesis is not fully understood. The physiology of inflammation has been systematically studied and has provided specific targeted strategies for the modulation of inflammation. A number of biological agents targeted at reducing the inflammatory cascade of pathophysiological reactions have been developed. Some, such as interleukin-1 receptor antagonist (IL-1Ra), antitumour necrosis factor (TNF) α antibodies and TNF soluble receptors, have been tested and are now in use clinically. The clinical effects that have been observed are transient, necessitating repeated treatments. Advances in molecular biology have opened ways for the development of gene therapy in which specific genes are introduced, using either viral or non-viral ex vivo and in vivo gene transfer techniques, to locally enhance in vivo gene expression or suppress gene(s) of interest with a view to downregulating inflammatory responses. The proof of concept has been provided in a number of animal models of inflammatory arthritis. Strategies for production of cytokine inhibitors, such as soluble TNF receptors, or anti-inflammatory cytokines, such as IL-4, IL-10, transforming growth factor β (TGF-β) and interferon β (IFN-β), have been developed. Other approaches involve the regulation of cartilage and bone erosion using IL-1Ra and tissue inhibitors of metalloproteinases, modulating apoptotic pathways in the rheumatoid synovium and the use of decoy oligonucleotides to nuclear factor κB (NF-κB), whose local application has been shown to be effective in downregulating joint inflammation in rat models of arthritis. Cytokines and other mediators play important physiological roles in the host’s defence system against infections and malignancy. Their chronic inhibition or their constitutive expression by gene therapy may lead to the development of side effects. Thus, carefully regulated gene expression during long-term studies will be required to assess the safety of selective targeting of processes involved in inflammation. This review summarises the important developments in gene therapy for RA.     

Review article: the expanding role of biological agents in the treatment of inflammatory bowel disease - focus on selective adhesion molecule inhibition

Inflammatory bowel disease presents in various forms. Its increasing incidence indicates that modern lifestyle triggers disease in genetically susceptible individuals. We present a model for inflammatory bowel disease pathophysiology and review the new biological therapies available. These biological agents have been developed to antagonise the processes of pathogenic inflammation, such as the reduction in T-lymphocyte apoptosis, increase in T-lymphocyte proliferation and increase in T-lymphocyte trafficking into the intestinal mucosa. Inhibitors of various inflammatory cytokines, including some antagonists to tumour necrosis factor, are effective therapies for inflammatory bowel disease. However, this class is associated with the risk of rare, but serious, side-effects, such as opportunistic infections and demyelinating diseases. The administration of anti-inflammatory cytokines, including interleukin-10 and interleukin-11, may theoretically be effective in reducing inflammation, although the clinical development of some of these therapies has been terminated. The selective inhibition of the adhesion molecules involved in T-lymphocyte trafficking can be effective in reducing gut inflammation. Of the selective adhesion molecule inhibitors under investigation, natalizumab has demonstrated efficacy in inflammatory bowel disease. The future of biological therapy for inflammatory bowel disease shows promise.     

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.     

Rheumatoid arthritis: an overview of new and emerging therapies

Rheumatoid arthritis (RA) is a chronic, inflammatory, systemic autoimmune disorder characterized by symmetric inflammation of synovial joints leading to progressive erosion of cartilage and bone. The aim of treatment is to mitigate joint destruction, preserve function, and prevent disability. The American College of Rheumatology guidelines for the treatment of RA recommend that newly diagnosed patients with RA begin treatment with disease-modifying antirheumatic drugs (DMARDs) within 3 months of diagnosis. Methotrexate remains the most commonly prescribed DMARD and is the standard by which recent new and emerging therapies are measured. Increasing knowledge regarding the immunologic basis of RA and advances in biotechnology have resulted in new, targeted biological therapies against proinflammatory cytokines that have dramatically changed the treatment paradigm and outcomes of patients with RA. This article reviews the pharmacological rationale underlying RA therapy, with a focus on currently available biological therapies and new therapies in development.     

Future treatments of allergic diseases and asthma

Recent advances in the understanding of the inflammatory and immunological mechanisms of allergic diseases have illuminated many potential therapeutic strategies that may prevent or even reverse the abnormalities of allergic inflammation. As the roles of effector cells, and of signalling and adhesion molecules are better understood, the opportunities to inhibit or prevent the inflammatory cascade have increased. In addition, there have been advances in the synthesis of proteins, monoclonal antibodies and new small molecule chemical entities, which provide further valuable flexibility in the therapeutic approach to asthma. Such new approaches are aimed at prevention of T-cell activation; redressing the imbalance of T helper cell populations thus inhibiting or preventing Th-2-derived cytokine expression; and the inhibition or blockade of the downstream actions of these cytokines such as effects on IgE and eosinophils. Approaches such as these allow both broad and highly specific targeting, and may pave the way towards the prevention and reversal of the immunological and inflammatory processes driving asthma, allergic rhinitis and atopic dermatitis. The development of effective agents with effects beyond those provided by current therapies coupled with lesser side-effects will further address the unmet needs of allergic disease.     

New prospects for the treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is a common inflammatory and destructive arthropathy. Current therapies fail to stop joint damage and reduce long-term disability. Greater understanding of disease pathogenesis has identified many inflammatory mediators as possible therapeutic targets. Novel therapeutic agents, such as monoclonal antibodies (mAbs), cytokine receptor-human immunoglobulin constructs, recombinant human proteins and antisense oligodeoxynucleotides targeting these inflammatory mediators have been tested in rheumatoid arthritis with some success. In particular, inflammation can be effectively suppressed using anticytokine therapies. However, the ideal treatment for RA, one that is immunomodulatory and induces prolonged disease remission after a single course of therapy, still eludes us. Strategies aiming to achieve this include TCR peptide vaccination and anti-CD4 mAbs, currently in clinical trials in RA.     

Juvenile rheumatoid arthritis: therapeutic perspectives

Juvenile rheumatoid arthritis (JRA) is the most common childhood chronic systemic autoimmune inflammatory disease. The therapeutic approach to JRA has, to date, been casual and based on extensions of clinical experiences gained in the management of adult rheumatoid arthritis (RA). The physiology of inflammation has been systemically studied and this has led to the identification of specific therapeutic targets and the development of novel approaches to the management of JRA. The classical treatments of the disease such as methotrexate, sodium aurothiomalate and sulfasalazine, are not always effective in controlling RA and JRA. 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. These biological therapeutic strategies in RA have proved successful and are being applied in the management of JRA. These developments have been facilitated by the advances in molecular biology which have heralded the advent of biodrugs (recombinant proteins) and gene therapy, in which specific genes can be introduced locally to enhance in vivo gene expression or suppress gene(s) of interest with a view to down-regulating inflammation. Some of these biodrugs, such as anti-tumor necrosis factor alpha (anti-TNFalpha), monoclonal antibodies (infliximab, adalimumab), TNF soluble receptor constructs (etanercept) and interleukin-1 receptor antagonist (IL-1Ra) have been tested and shown to be effective in RA. Etanercept has now been licensed for JRA. Clinical trials of infliximab in JRA are planned. Studies show that the clinical effects are transient, necessitating repeated treatments and the risk of vaccination effects. Anti-inflammatory cytokines such as IL-4, IL-10, transforming growth factor-beta and interferon-beta (IFN-beta) are undergoing clinical trials. Many of these agents have to be administered parenterally and production costs are very high; thus, there is a need, especially for pediatric use, to develop agents that can be taken orally. Long-term studies will be required to assess the tolerability and toxicity of these approaches in JRA, since cytokines and other mediators play important roles in host defenses, and the chronic inhibition, exogenous administration or constitutive over-expression of some cytokines/mediators may have undesirable effects.     

An overview of immunomodulatory intervention in rheumatoid arthritis

In recent years there has been exceptional progress in the development of immunomodulatory interventions for the treatment of rheumatoid arthritis (RA). Part of the impetus for the creation of novel therapies for RA has come from a growing appreciation of the substantial morbidity and mortality that this chronic, progressive disease causes for affected patients. In addition, there has been the realization that currently available therapeutics are suboptimal as regards both their efficacy and tolerability. The development of newer therapies has been facilitated by two factors; a greater understanding of the immunopathogenesis of RA and progress in biotechnology that has allowed the creation of specific inhibitors and other agents. Myriad studies performed by investigators throughout the world have helped delineate the immunologic basis of RA. It appears that various components of the immune system are involved in the initiation and propagation of this systemic inflammatory disease. T-cells, and in particular activated CD4(+) 'memory' T-cells, serve a central role in orchestrating the immune response that underlies rheumatoid inflammation. Other cells, including monocytes, fibroblasts, B-cells, dendritic cells, mast cells and neutrophils also contribute significantly to various aspects of disease. Adhesion molecules mediate many intercellular interactions, thus contributing to activities such as the accrual of cells within the synovium and the activation of cells. Cytokines, small peptides that exert numerous inflammatory activities and cause many of the signs and symptoms of RA, play a crucial role. Indeed, RA may be considered a disorder of 'cytokine dysregulation' in that the activity of proinflammatory cytokines such as TNF-alpha and IL-1 is enhanced, and overwhelms the effects of antiinflammatory factors. Finally, a host of other inflammatory mediators are involved in the disease process. Thus, many components of the immune response may be attractive therapeutic targets for immunomodulatory intervention in RA. Advances in biotechnology have permitted the creation of specific inhibitors of distinct components of the immune system. Monoclonal antibodies (MAbs) have been created to target various cell surface molecules and cytokines. At first, most MAbs were murine in origin, which can present problems as regards immunogenicity. More recently, progress in molecular biologic techniques has allowed the synthesis of hybrid antibodies that are partly human. Such techniques have also allowed the creation of cytokine receptors coupled to immunoglobulin molecules, and other constructs. These agents can be modified to provide optimal characteristics in terms of half-life, immunogenicity and specificity, and this is an exciting area of new development. Progress has also been made in molecular-based agents that directly modify the genes or gene products for specific targets. To date, a number of trials assessing novel immunomodulatory therapies have been undertaken. In some cases, such as with inhibitors of TNF-alpha, the results have been dramatic and exciting. Further development and refinement may allow the introduction of these agents into the clinic in the foreseeable future, and will provide an important area for further research. In other cases, for example with therapies targeting CD4(+) molecules, the results have not been as promising as was hoped. Nevertheless, critical analysis of the results of these studies has provided insights into the pathogenesis of RA which may prove quite valuable for future trials. A number of agents are being studied actively at the present time, and it is hoped that they too may generate novel therapies for, and a greater understanding of, this difficult disease. The future for immunomodulatory intervention in RA looks very promising. Greater understanding of the intricacies of the immune response that underlie this disease should continue to yield viable, specific targets for novel therapies. Advances in biopharmaceuticals should generate treatments that maximize efficacy while minimizing toxicity. This should allow the clinician truly to modify the disease and achieve tangible improvements in the lives of RA patients.     

Annotated Patent Selections

Inflammatory conditions such as rheumatoid arthritis (RA) and other autoimmune diseases represent a very active area of research for the development of novel therapeutics. In the past few years, the research focus of many pharmaceutical companies and other organisations has resulted in the identification of various novel biological targets for the development of new therapies for the treatment of inflammatory diseases such as RA. This has resulted in the identification of biological agents such as infliximab (Remicade^®, Centocor, Inc.), etanercept (Enbrel^®,Immunex Corp.), adalimumab (Humira^®,Abbott Lab.) and kineret (Anakinra^®, Amgen, Inc.) that affect the TNF-α or IL1 associated pathways, for the treatment of RA and other inflammatory diseases such as psoriasis and inflammatory bowel disease (IBD). Ongoing research continues to expand the application of these agents for additional therapeutic use. In addition to the biological agents above, cyclooxygenase-2 (COX-2) inhibitors such as rofecoxib (Vioxx^®, Merck &; Co., Inc.) and celecoxib (Celebrex^®, Pharmacia) have also shown some efficacy for the treatment of RA. The approval of these agents for the treatment of RA has provided a validation of the role of TNF-α, IL-1 and COX-2 in the pathogenesis of RA. Although the biologicals and COX-2 inhibitors are effective, they are however limited in that they modulate a single cytokine or pathway. It is recognised that the alternate pathway delineated by p38 mitogen-activated protein kinase (MAPK) provides for a more combinatorial path for treatment of RA, as an inhibitor of p38 MAPK would not only affect TNF-α, IL-1 and other related cytokines, but also the expression of COX-2. The efforts to develop small molecule agents for p38 MAPK have not yet yielded an agent ready for the market, but several inhibitors are presently under investigation in clinical trials. While details of these studies have yet to be formally reported, two recently published studies have evaluated the effect of p38 inhibitors on the suppression of pro-inflammatory cytokines and other markers of inflammation in healthy human volunteers exposed to endotoxaemia, caused by exposure to lipopolysaccharide (LPS) [1,2].     

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.     

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.     

Therapeutic options for rheumatoid arthritis

Background: Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder primarily targeting the synovium. Unchecked disease activity is associated with significant morbidity and an increased mortality. Recent advances in the understanding of the pathogenesis of RA and the capability of biologically engineered treatments for RA have expanded the armamentarium of antirheumatic agents. Methods: A systematic literature review was conducted through PubMed. Results/conclusions: At present, a common strategy for the treatment of RA uses methotrexate either as monotherapy or in combination with a variety of conventional and/or biologic disease-modifying antirheumatic drugs (DMARDs), with the goal of inducing remission of active disease. The choice of which agent(s) to use is based upon patient-specific criteria (activity of disease, comorbidities, patient preferences, costs etc.). Emerging therapies that target specific cytokines and growth factors in the inflammatory cascade of RA offer a potent new means of modifying disease activity, but many questions regarding their use remain unanswered.     

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.     

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.