Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Immunology, Endocrine and Metabolic Agents) - Volume 8, Issue 3, 2008

The last decade has seen profound improvements in the treatment and management of patients with autoimmune inflammatory diseases. This progress has been due, in large measures, to the development and application of new therapeutic agents that target selected molecules and cells. These agents are widely known as biological therapies. Success of biological therapies in the clinic and the development of new laboratory tests for early diagnosis brought with them new and progressive thinking on proactive disease management. Thus, treating patients with chronic inflammatory diseases at early stages with biological therapies and/or traditional disease modifying drugs are reducing disease severity and limiting damage. In addition to immeasurable health and economical benefits, successful application of biological therapies is providing new and direct insights into disease mechanisms superior to those previously provided by correlation studies. Such new insights, in turn, are providing new clues of further targets for treatment. However, this success has raised new challenges not least increased patient expectation. This is not a simple challenge considering the fact that not all patients with clinically similar manifestations respond to a given biological agent. In addition, lack of responses in some patients with similar clinical symptoms implies that alternative mechanisms of disease may be operating in different patient subsets. Therefore, much more work is still needed to understand disease mechanisms and identify new therapeutic targets.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that destroys joints and, if not appropriately controlled, severely limits life expectancy and quality of life. Such control can be achieved, even though cure is impossible for the time being. The mainstay of RA therapy are conventional disease-modifying drugs, (DMARDs), such as low dose methotrexate, sulfasalazine, and leflunomide, which should be started not later than 12 weeks after the onset of symptoms. Since these DMARDS need at least 6 weeks to control disease, the time interval is commonly bridged with corticosteroids. TNF blockers at this very early stage may be even more effective, but long-term impact of such therapy will yet have to be established. If, however, conventional DMARDs fail to achieve remission (or at least low disease activity), TNF blockade in combination with methotrexate is indicated and has a high rate of success, which extends to blocking erosions even in patients who still have active disease. At present, there are three TNF blockers (infliximab, etanercept, adalimumab) available, and two will be added shortly (certolizumab pegol, golimumab). If a first TNF blocker is not successful, other TNF blocking agents may still work. Alternatively, depletion of B cells with rituximab or costimulation blockade with abatacept, both in combination with methotrexate, are successful routine for many patients today, and interleukin-6 receptor blockade with tocilizumab will join this group shortly. Enforced peace thus is feasible for the vast majority of RA patients, but better understanding of RA pathophysiology and additional drugs are still needed.

Biological therapies, or biologics, are a class of medications that are specifically designed to target molecules from defined pathogenetic pathways for therapeutic purposes. Currently, the most widely used biological agents to treat inflammatory arthritides are mainly of the anti- tumour necrosis factor alpha (anti-TNFα) group. Other biological agents that are less widely used in the clinic include: interleukin-1 inhibitors (Anakinra), T cell co-stimulatory inhibitors, CTLA- 4 (Abatacept) and B lymphocyte depletion agents (Rituximab). TNFα blockers are more effective than conventional disease- modifying anti rheumatic drugs (DMARDs) and in combination with methotrexate induce remission in nearly half of the patients with rheumatoid arthritis (RA). Unlike conventional DMARDS, biological therapies specifically target molecular or cellular pathway central to disease development. Biological therapies are a true example of the translation of research from the laboratory bench to the bedside. At present, TNFα blockers are known to decrease joint inflammation and bone erosions but their effects on bone resorption are still being elucidated. Further, new emerging targets for biological therapy are being assessed, with several recent studies showing key roles played by various other cytokines and molecules in the pathophysiology of inflammatory joint damage. Importantly, in addition to the therapeutic benefits these studies reveal the importance of key cytokines and other target molecules in normal bone metabolism and homeostasis. This article will review current knowledge on the effects of disease processes and therapeutic agents on bone metabolism and homeostasis in arthritic diseases.

The immune system has highly evolved structured mechanisms to efficiently combat infections and cancers. However, its inbuilt complexicity creates a potential for causing diseases if not tightly regulated. Thus, autoimmune diseases could result from defects in the regulation of immune pathways resulting in the immune system's inability to distinguish self from non-self antigens (Ags), or the inability to suppress emerging autoreactive clones. This leads to immune responses to unlimited supplies of autoAgs, chronic inflammation and damage to tissues. Attempts to dissect the pathogenesis have shown that defects in T- and B-lymphocytes, innate immune cells and the complement system could trigger autoimmunity. Further, the level of involvement of different elements is varying in different diseases, and even within clinical subsets in the genetically diverse human population. The development of appropriate therapies has also been hampered by the need to delineate which mechanisms triggers a given disease and which ones sustain this same condition has been difficult because of the multiplicity of predisposing factors, susceptibility genes, and etiologies. A strategy to treat immune-mediated diseases in the clinic was initiated when the most evident abnormalities were targeted with inhibiting monoclonal antibodies or soluble receptors. Thus, tumor-necrosis factor α inhibitors were used for treating patients with rheumatoid arthritis and Crohn's diseases. The strategy proved to be successful, so that hundreds of thousand of patients are currently treated with these agents.

The humanized anti-interleukin (IL)-6 receptor antibody Tocilizumab is currently in Phase III clinical trials for use in autoimmune conditions such as rheumatoid arthritis and Crohn's disease. However do we fully appreciate the regulation of IL-6 responses in vivo, and understand the wider implications of IL-6 bioactivity in general physiology and inflammation? In the context of this review we will explore how IL-6 affects arthritis progression, and discuss the inflammatory mechanism governing IL-6 responsiveness. Specific attention will be given to the role of the soluble IL-6 receptor and we will discuss the merit of selectively targeting this soluble receptor as an alternative therapeutic strategy for clinically blocking IL-6 involvement in disease.

In addition to TNF and IL-1, IL-17 derived from Th17 cells is a leading cytokine target and has an established key role in adaptive and autoimmune disease such as rheumatoid arthritis (RA). A recent explosion in the literature in the last few years has lead to a renewal of interest in IL-17 as a key causative cytokine implicated in autoimmunity. This review will focus on IL-17 and its receptor as emerging therapeutic targets in RA.

Inflammation is a primordial response that organisms set up to counteract the invasion of pathogens and attack by any other xenobiotic; the symptoms characteristic of inflammation are well known, the classic rubor, dolor, calor, tumor and functio laesa being described since ancient times. This response of the host is complex and multifactorial, and crucial for survival: abnormal inflammation, as in the case of patients affected by leukocyte adhesion deficiency, a genetic disease whereby specific adhesion molecules are absent, is associated with poor life quality and precocious death. Fighting inflammation is a common problem that physicians have to face when dealing with a wide variety of diseases. Hence, understanding the molecular and cellular mechanism responsible for it is important for the design of a better therapy. Modern theories in this field of research have suggested that one way to achieve a better and more efficient antiinflammatory therapy is to exploit the body's own arsenal of endogenous antinflammatory mediators. One such protein is Annexin-1 (AnxA1): an endogenous anti-inflammatory protein whose activity correlates to the pharmacological effects of glucocorticoids. In this review we will summarize the most recent studies on the biological effects of AnxA1 and in particular we will be focusing on the differential and yet complementary role of this protein in the innate and adaptive immune systems.

The introduction of statins and drugs blocking the renin angiotensin aldosterone system in the treatment of cardiovascular diseases (CVD) in the general population has led to substantial reductions in morbitity and mortality. Recent evidence suggests multiple actions of these agents, including modulation of the immune response and attenuation of inflammation. Even though several studies have addressed the anti-inflammatory properties of these drugs in the general population, only few studies have focused on their potential benefit when administered to patients with rheumatoid arthritis (RA), a chronic systemic disease characterised by both inflammatory joint damage and excess cardiovascular mortality. The present review focuses on the potential role of these agents in reducing the excess CVD (by controlling cardiovascular risk factors, improving endothelial dysfunction, reducing size and increasing stability of atheromatous plaques, activating the fibrinolytic system and reducing systemic inflammation) and in controlling the disease itself (both systemic and localised joint inflammation), in RA patients. Overall, the review has strong evidence to support the effects of statins on reducing cardiovascular risk, however by comparison the evidence supporting their efficacy in RA is relatively weak.

As for any disease, unravelling the underlying mechanisms involved in the pathogenicity of rheumatoid arthritis is key to providing clues for designing effective therapeutic strategies that can ultimately translate from the laboratory to the clinic. Here, we provide an overview of rheumatoid arthritis and discuss experimental evidence suggesting how genetic and environmental factors, such as MHC genes, smoking and female sex hormones, can contribute to disease susceptibility. In established disease, the role of T cells is discussed in light of increased numbers of T cells in the arthritic versus healthy joint and the observed therapeutic effects of T cell modifying agents such as anti-CD4, anti-TCR and anti- IL2R antibodies in animal models of rheumatoid arthritis. As a vital tool, crucial to furthering our understanding of disease mechanisms, we elaborate on various animal models of rheumatoid arthritis being extensively exploited in arthritis research, including adjuvant-induced arthritis, collagen-induced arthritis, and transgenic mice expressing TNFα or IL-1β genes. Such experimental disease models have led to significant discoveries relating to the importance of proinflammatory cytokines in the pathogenesis of rheumatoid arthritis, resulting from a disregulation of the normally finely tuned balance of pro- and anti-inflammatory cytokine signalling. Indeed, the most successful therapeutic to date for rheumatoid arthritis, anti-TNFα, was initially studied in collagen-induced arthritis. It is concluded that mechanistic based research is essential to elucidate and evaluate new candidate therapies for the treatment of rheumatoid arthritis, and other autoimmune diseases.