Current Pharmaceutical Design - Volume 11, Issue 5, 2005

We wish to thank all the authors for their contribution to this year's edition on Rheumatoid Arthritis in Current Pharmaceutical design. Rheumatoid arthritis (RA) is a complex autoimmune disease of unknown etiology. The authors assembled in this review will help shed new light on the recent molecular advances in RA at the basic science level and at the clinical level. Meinecke et al. [1] will review the impact that synovial fibroblasts have on joint inflammation and bone erosion. These authors will focus on the various transcription factors and anti-apoptotic genes that are expressed in RA synovial fibroblasts. Ma et al. [2] will review the role of macrophages in RA. Due to their ability to produce TNF and IL-1, macrophages have come to the forefront of investigations in RA. These authors will expand on the novel concept that antiapoptotic proteins in addition to suppressing death also regulate cytokine production. Tas et al. [3] will review the recent advances in signal transduction molecules in RA. These authors will detail the significance of the MAPK, NF-kB, Akt, and the STAT pathways in RA. Rudolph et al. [4] will review the role of angiogenesis in RA. The authors will also focus on the contribution of chemokines to RA pathogenesis. Dr. Michael Volin [5] will review the function of soluble adhesion molecules in inflammatory RA. The impact of individual soluble adhesion molecules in RA will be discussed in great detail. Low et al. [6] will review the contribution of B-cells, specifically autoantibody production in RA. Additionally, these authors will detail the role that the complement pathways play in RA pathogenesis. In the last review Dr. Eric Ruderman [4] will expand on the recent advances in RA therapy including the biologics.

Rheumatoid arthritis (RA) is a chronic, inflammatory joint disease with systemic involvement that affects about 1% of the Western population. The progressive destruction of affected joints is a major characteristic of the disease and distinguishes RA from other acute and chronic arthritides. The etiology of RA is unknown, and a variety of genetic and environmental factors are being discussed as potential causes of the disease. However, in contrast to our incomplete understanding of the etiology, the knowledge about molecular mechanisms leading to joint destruction has advanced considerably over the past years. Thus, a large number of studies have investigated the presence and interplay of several types of cells in rheumatoid synovium, such as lymphocytes, macrophages and fibroblasts. They have led to the understanding that cells in the rheumatoid synovium form a network, which interacts through direct cell-to cell contacts as well as the release of a multitude of cytokines. The use of novel molecular techniques together with the development of new animal models has revised our concept on the pathogenesis of RA and specifically on the role of fibroblasts in initiation and progression of joint destruction. This article will review current data and hypotheses on disease mechanisms by which fibroblasts are involved in the destruction of joints in RA.

Rheumatoid arthritis (RA) is a common autoimmune chronic inflammatory joint disease, characterized by macrophage and lymphocyte infiltration, proliferation of synovial fibroblasts, and joint destruction. Macrophages are critically involved in the pathogenesis of RA. Not only do they produce a variety of pro-inflammatory cytokines and chemokines, but they also contribute to the cartilage and bone destruction in RA through multiple mechanisms. Macrophage activation by several distinct mechanisms is crucial for their function. This review will discuss several aspects of macrophage function in RA, including the mechanisms for macrophage activation, the signaling pathways in activated macrophages, and the mechanisms that inhibit apoptosis in macrophages in the rheumatoid joints.

Many chronic inflammatory diseases are associated with deregulated intracellular signal transduction pathways. Resultant pathogenic interactions between immune and stromal cells lead to changes in cell activation, proliferation, migratory capacity, and cell survival that all contribute to inflammation. Increasing efforts are now being made in the design of novel therapeutic compounds to interfere with signaling pathways in inflammatory diseases like rheumatoid arthritis (RA). In this review we will outline the major signal transduction pathways involved in the pathogenesis of RA. We will assess advances in targeting a number of key intracellular pathways, including nuclear factor-κB (NF-κB), mitogen-associated protein kinases (MAPKs), phosphoinositide 3-kinase (PI3K) / Akt, signal transducers and activators of transcription (STATs), and reactive oxygen species (ROS) production. Finally, we will discuss recently identified lead molecules and the progress of selected compounds towards becoming new drugs for the treatment of inflammatory diseases.

Regulation of angiogenesis occurs in the context of particular microenvironments and is governed by a sensitive balance between angiogenic and anti-angiogenic mediators. Under normal physiologic conditions, the expansion of existing blood vessels is held in check suggesting that homeostasis is maintained by a predominance of angiostatic factors. In the rheumatoid arthritis joint, it is probable that the expansive and tumor-like synovial pannus that invades cartilage requires additional nutrients and oxygen. In the face of these demands, there is likely a shift in the balance such that angiogenic mediators predominate leading to neovascularization, a hallmark of rheumatoid arthritis. Chemokines are a subset of cytokines that primarily mediate physiologic and pathophysiologic leukocyte trafficking during inflammation and immune cell differentiation. Chemokines are also fundamental participants, along with a variety of other factors, which regulate angiogenesis. Within the CXC family of chemokines, there is functional discrepancy, where some family members are angiogenic and others are angiostatic. Moreover, the expression of several chemokines has been well documented in rheumatoid arthritis synovial tissues and fluids. This review will discuss what is known about the role of specific chemokines in the regulation of angiogenesis with particular emphasis on those chemokines likely to participate in rheumatoid arthritis.

Rheumatoid arthritis is chronic systemic inflammatory disease that is characterized by joint swelling and leukocyte recruitment into synovial tissue. Within the peripheral blood and synovial fluid of patients with rheumatoid arthritis there are many soluble mediators that function together to create an inflammatory environment ultimately responsible for the synovial pannus formation and subsequent joint destruction. One such group of soluble mediators present in the peripheral blood and synovial fluid of rheumatoid arthritic patients are soluble adhesion molecules. Soluble adhesion molecules are commonly formed as the result of cell surface adhesion molecule shedding due to cell stimulation, but may also be the result of de novo synthesis of truncated soluble forms of adhesion molecules. There has been debate over the function of soluble adhesion molecules in the inflammatory process. Soluble adhesion molecules have been shown to both enhance and inhibit different aspects of the inflammatory process. However, the preponderance of research studying rheumatoid arthritis has shown soluble adhesion molecules to be important regulators of leukocyte recruitment into the synovial tissue. This review will focus on the soluble adhesion molecules that have been studied in peripheral blood and synovial fluids of patients with rheumatoid arthritis. The role of different soluble adhesion molecules in the pathogenesis of rheumatoid arthritis will be discussed, as will the effects of common disease modifying anti-rheumatic therapies on their production.

The production of autoreactive antibodies from self-reactive B cells results in the formation of immune complexes that deposit in tissue and fix complement, contributing to the pathogenesis of rheumatoid arthritis (RA). Earlier mouse models emphasize the importance of autoreactive antibodies formed against “self” proteins that serve as a source for T cell-mediated immune response, stemming from cross-reactivity and resulting in B cell activity. However, more recent models suggest the need for both autoantibodies and the initiation of the inflammatory cascade via the alternative complement pathway, which is unbridled as the cartilage lacks the usual regulatory proteins of the complement system. Furthermore, deficiencies in specific complement proteins could lead to an escape from negative selection by these selfreactive B cells. Moreover, the classical complement pathway establishes chemotactic gradients by which inflammatory cells follow and accumulate in the synovial fluid where they engulf immune complexes and release proteolytic enzymes. In addition, the processing of circulating immune complexes either via Fc receptor or CR1 and opsonization by complement fragments plays a key role in determining the fate of immune status. In addition, complement proteins are a major determinant in the size and solubility of an immune complex, which also affects clearance. The evidence regarding intra-articular activation of the complement system in RA provides the possibility to pharmacologically manipulate various parts of the complement system for therapeutic purposes and potential therapeutic targets for the control of inflammation and the prevention of joint destruction.

Rheumatoid arthritis (RA) is a chronic, inflammatory arthritis with a population prevalence of approximately 1%. Pharmaceutical treatment includes both anti-inflammatory medications and disease modifying drugs (DMARDs) that impact the course of the damage associated with this disease. Traditional DMARD therapy includes immunomodulatory agents such as methotrexate, used both alone and in combination. Recently available biologic response modifiers are very effective at reducing both the clinical symptoms of disease and the radiographic damage that accompanies them. This manuscript describes the clinical assessments used to measure response to therapy in RA and reviews the results seen with the various treatment strategies in this disease. In addition, the clinical and structural outcomes seen in trials of newly available and pending biologic therapies are reviewed, along with the specific toxicity issues associated with these agents. Clinical trial data is reviewed for the TNF antagonists, which have become the standard of care in RA patients with an inadequate response to methotrexate. RA has been clearly shown to be a destructive and disabling disease. The widespread use of newer agents, however, along with more aggressive use of existing therapies, appears to limit disease progression very effectively, and should lead to better long-term outcomes for these patients.