Rheumatoid Arthritis: Andreakos E

Sacre SM, Drexler SK, Andreakos E, Feldmann M, Brennan FM, Foxwell BM. · Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College London, 1 Aspenlea Road, Hammersmith, London W6 8LH, UK. · Ann Rheum Dis. · Pubmed #17934103 No free full text.

Abstract: In the last decade the development of a number of biological therapies has revolutionised the treatment of rheumatic diseases. The first and most widely used of these approaches, tumour necrosis factor (TNF) blockade (infliximab, entanercept, adalimumab), has now been administered to over a million patients. However, the success of these biological therapies has also highlighted their limitations. None of these treatments has shown a 100% patient response; normally responses are in the 50-70% range. As proteins, these drugs cannot be given orally and they are expensive to produce, a cost ultimately borne by the patient/health provider that can seriously limit the availability of these drugs. Lastly, these treatments, whether involving the systemic neutralisation of a cytokine (eg, TNF or IL6 receptor blockade (tocilizumab)), the ablation of a B cell population (anti-CD20, rituximab), or the potential disruption of important cellular interactions as with CTLA4-Ig (abatacept), can cause major perturbations of the immune system, the long-term effects of which are still unclear. At present, treatments such as TNF blockade can result in an increased infectious risk and the reactivation of tuberculosis can be a major issue in certain populations. As with all therapies, there is an increasing large refractory population over time. Therefore, despite the undoubted success of these therapies, there is room for improvement. Although it might be too much to expect any new treatment to affect a "cure" (all the current biological therapies require repeated administrations), there are definite gains to be made in terms of cost, oral bioavailability and a more selective interference with the immune-inflammatory response.

Sacre SM, Andreakos E, Taylor P, Feldmann M, Foxwell BM. · Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College of Science, Technology and Medicine, 1 Aspenlea Road, Hammersmith, London, W6 8LH, UK. · Expert Rev Mol Med. · Pubmed #16117838 No free full text.

Abstract: In an attempt to combat the pain and damage generated by rheumatoid arthritis (ra), new drugs are being developed to target molecular aspects of the disease process. Recently, a major development has been the use of biologicals (antibodies and soluble receptors) that neutralise the activity of tumour necrosis factor alpha (TNF-alpha) and interleukin 1 (IL-1), both of which are involved in disease progression. An increase in our understanding of cell and molecular biology has resulted in the identification and investigation of potential new targets, and also the refinement and improvement of current therapeutic modalities. This review describes therapies that are approved, in clinical trials or under pre-clinical investigation at the laboratory level, particularly focusing on cytokines, although other therapeutic targets of interest are mentioned.

Andreakos E, Sacre S, Foxwell BM, Feldmann M. · Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College of Science, Technology and Medicine, London, United Kingdom. · Front Biosci. · Pubmed #15970510 No free full text.

Abstract: The study of the role cytokines play in the pathogenesis of rheumatoid arthritis (RA) has provided a whole new range of targets for drug development. Many of them (e.g. TNF, IL-1, IL-6, IL-15 and IL-18) are already being targeted in the clinic with success using neutralizing monoclonal antibodies or soluble cytokine receptors. Targeting TNF, in particular, has shown great efficacy in controlling both the inflammation and structural damage of the joints, setting a new gold standard for the treatment of RA. However, what triggers the production of inflammatory cytokines such as TNF in RA remains to be determined. In this article, we review evidence suggesting that the transcription factor Nuclear Factor kappaB (NF-kappaB) is essential for the expression of both inflammatory cytokines and tissue destructive enzymes in RA. Also, we discuss whether Toll-like receptors (TLRs), major receptors involved in pathogen recognition and potent activators of the NF-kappaB pathway, are involved in triggering the inflammatory and joint destructive process in RA and whether they constitute sensible targets for monoclonal antibodies/soluble receptors and small molecule inhibitors. We conclude that although the TLR- NF-kappaB pathway offers ample opportunities for therapeutic intervention, future drugs to be approved will need to match or exceed the efficacy and safety of anti-TNF agents, with safety the most difficult aspect to predict.

Andreakos E, Foxwell B, Feldmann M. · Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College of Science, Technology and Medicine, London, UK. · Immunol Rev. · Pubmed #15546398 No free full text.

Abstract: Cytokine-driven inflammation and tissue destruction is a common theme of chronic inflammatory diseases such as rheumatoid arthritis, Crohn's disease, ulcerative colitis, psoriasis, chronic obstructive pulmonary disease, and atherosclerosis. Research over the last two decades demonstrated the importance of cytokines that are not only expressed chronically but also are capable of signaling at sites of chronic inflammation. Cytokines thus regulate major pathological processes that include inflammation, angiogenesis, tissue remodeling, and fibrosis. This research led to the identification of key cytokines involved in these processes, two of which, tumor necrosis factor-alpha and interleukin-1, have also been successfully targeted in the clinic. However, what triggers and maintains cytokine gene expression in chronic inflammation remains a mystery. In this article, we review current progress in the understanding of cytokine-driven inflammation and discuss current evidence implicating Toll-like receptors (TLRs), recently identified as the receptors recognizing self versus non-self molecular patterns, in the regulation of cytokine-driven inflammation. Whether targeting TLRs and their downstream signaling pathway will prove to be a successful approach for the treatment of these devastating diseases remains to be determined.

Andreakos E. · Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College of Science, Technology and Medicine, London, UK. · Curr Drug Targets Immune Endocr Metabol Disord. · Pubmed #15180449 No free full text.

Abstract: Over the last decade it has become apparent that common pathogenic mechanisms are shared between many human chronic inflammatory diseases of unrelated pathology and manifestation. These mechanisms include common inflammatory networks that control tissue destructive and repair processes and their study is of major therapeutic potential as recently demonstrated for TNFalpha. Thus, early studies in rheumatoid arthritis defined TNFalpha as a major therapeutic target, the blockade of which was subsequently proved to be of great efficacy in the clinic. This paved the way for the successful blockade of TNFalpha in various other diseases including Crohn's disease, psoriasis, spondyloarthropathies and juvenile arthritis, although no similar networks with anti-TNFalpha at their apex had previously been demonstrated. In this article, we review the current knowledge of the pathogenic mechanisms involved in rheumatoid arthritis and chronic obstructive pulmonary disease with particular emphasis on the role of inflammatory cytokines, chemokines, and tissue degrading enzymes as revealed by studies in the laboratory and the clinic. Direct comparison of these mechanisms may provide clues for a future therapy for these painful and incurable diseases.

Monaco C, Andreakos E, Kiriakidis S, Feldmann M, Paleolog E. · Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College, London, UK. · Curr Drug Targets Inflamm Allergy. · Pubmed #15032640 No free full text.

Abstract: In the last decade, the understanding of the molecular mechanisms of regulation of the inflammatory process in chronic inflammatory diseases has moved remarkably forward. Recent evidence in various fields has consistently indicated that T-cells play a key role in initiating and perpetuating inflammation, not only via the production of soluble mediators but also via cell/cell contact interactions with a variety of cell types through membrane receptors and their ligands. Signalling through CD40 and CD40 ligand is a versatile pathway that is potently involved in all these processes. In this article, we review how T-cells become activated by dendritic cells or inflammatory cytokines, and how these T-cells activate, in turn, monocytes/macrophages, endothelial cells, smooth muscle cells and fibroblasts to produce pro-inflammatory cytokines (tumour necrosis factor alpha, interleukin-6), chemokines (interleukin-8, monocyte chemotactic protein-1), tissue factor, the main initiator of the coagulation cascade in vivo, and finally matrix metalloproteinases, responsible for tissue destruction. Moreover, we discuss how CD40 ligand at inflammatory sites stimulates fibroblasts and tissue monocyte/macrophage production of VEGF, leading to angiogenesis, which promotes and maintains the chronic inflammatory process. This cascade of events is discussed in the context of disease initiation/progression, with particular reference to atherosclerosis and rheumatoid arthritis, and to potential novel therapeutic targets for their treatment.

Foxwell B, Andreakos E, Brennan F, Feldmann M, Smith C, Conron M. · The Kennedy Institute of Rheumatology Division, Imperial College London, The Charing Cross Campus, ARC Building, 1 Aspenlea Road, London W6 8LH, UK. · Ann Rheum Dis. · Pubmed #14532159 links to  free full text

This publication has no abstract.

Andreakos E. · Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College of Science, Technology and Medicine, 1 Aspenlea Road, Hammersmith, London W6 8LH, UK. · Expert Opin Biol Ther. · Pubmed #12783612 No free full text.

Abstract: The increasing understanding of the pathophysiology of a number of human autoimmune diseases, and the realisation that cytokines play a major role, has provided the pharmaceutical industry with a wide array of new targets for therapeutic intervention. This has also resulted in a surge of interest for the development of ways of blocking cytokines and their actions in a specific and safe manner. This article reviews the current status of anticytokine therapy and the major efficacy that anti-TNF-a monoclonal antibodies (mAbs) and soluble TNF receptors have demonstrated in the clinic, which has led to their approval for the treatment of rheumatoid arthritis (RA), Crohn's disease (CD), juvenile arthritis and psoriatic arthritis. In addition, the development of novel approaches of cytokine blockade that are based on the characterisation of intracellular signalling pathways regulating cytokine expression (e.g., nuclear factor kappa B [NF-kB] and p38 mitogen activated protein kinase [MAPK]) and the use of small molecule inhibitors are discussed. Whether these approaches will keep up with their early promise and become a major and widespread treatment for several devastating autoimmune diseases will depend on specificity, safety, durability of the benefit, and pharmacoeconomic issues.

Andreakos E, Taylor PC, Feldmann M. · Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College of Science, Technology and Medicine, 1 Aspenlea Road, Hammersmith, W6 8LH, London, UK. · Curr Opin Biotechnol. · Pubmed #12482523 No free full text.

Abstract: The era of monoclonal antibody-based therapeutics has arrived. Monoclonal antibodies of high quality targeting almost any antigen can now be engineered and manufactured in large quantities. In the clinic, monoclonal antibodies are proving to be safe and effective for the treatment of a wide range of diseases including rheumatoid arthritis, Crohn's disease, spondyloarthropathies, psoriasis and allograft rejection.

Feldmann M, Andreakos E, Smith C, Bondeson J, Yoshimura S, Kiriakidis S, Monaco C, Gasparini C, Sacre S, Lundberg A, Paleolog E, Horwood NJ, Brennan FM, Foxwell BM. · Kennedy Institute of Rheumatology Division, Faculty of Medicine, Charing Cross Hospital Campus, Arthritis Research Campaign Building, 1 Aspenlea Road, London W6 8LH, UK. · Ann Rheum Dis. · Pubmed #12379614 links to  free full text

Abstract: There is increasing evidence that NF-kappaB is a major, if not the major transcription factor regulating inflammation and immunity. While this implies that blocking NF-kappaB might be therapeutically beneficial, it raises clear questions regarding the balance between efficacy and safety. In this brief review we discuss the effects of NF-kappaB blockade in rheumatoid arthritis, inflammation and immunity, and consider possible therapeutic targets within the NF-kappaB family.

Horwood NJ, Smith C, Andreakos E, Quattrocchi E, Brennan FM, Feldmann M, Foxwell BM. · Kennedy Institute of Rheumatology Division, Imperial College Faculty of Medicine, London, UK. · Arthritis Res. · Pubmed #12110141 No free full text.

Abstract: The elucidation of the signalling pathways involved in inflammatory diseases, such as rheumatoid arthritis, could provide long sought after targets for therapeutic intervention. Gene regulation is complex and varies depending on the cell type, as well as the signal eliciting gene activation. However, cells from certain lineages, such as macrophages, are specialised to degrade exogenous material and consequently do not easily transfect. Methods for high-efficiency gene transfer into primary cells of various lineages and disease states are desirable, as they remove the uncertainties associated with using transformed cell lines. Significant research has been undertaken into the development of nonviral and viral vectors for basic research, and as vehicles for gene therapy. We briefly review the current methods of gene delivery and the difficulties associated with each system. Adenoviruses have been used extensively to examine the role of various cytokines and signal transduction molecules in the pathogenesis of rheumatoid arthritis. This review will focus on the involvement of different signalling molecules in the production of tumour necrosis factor alpha by macrophages and in rheumatoid synovium. While the NF-kappaB pathway has proven to be a major mediator of tumour necrosis factor alpha production, it is not exclusive and work evaluating the involvement of other pathways is ongoing.

Sacre SM, Andreakos E, Kiriakidis S, Amjadi P, Lundberg A, Giddins G, Feldmann M, Brennan F, Foxwell BM. · Kennedy Institute of Rheumatology, Imperial College London, and the Department of Orthopedics, Royal United Hospital, Bath, UK. · Am J Pathol. · Pubmed #17255320 links to  free full text

Abstract: The widespread distribution of Toll-like receptors (TLRs) and their ligands raises the question whether they contribute to the production of inflammatory and tissue destructive molecules in rheumatoid arthritis (RA). We examined the expression and function of TLR2 and TLR4 and their downstream signaling adaptors MyD88 and Mal/TIRAP in synovial membrane cultures from RA tissue. Both TLR2 and TLR4 were detected by flow cytometry, and stimulation with TLR2 and TLR4 ligands augmented the spontaneous production of tumor necrosis factor-alpha, interleukin (IL)-6, and IL-8, indicating that TLR2 and TLR4 are functional in these cultures. In addition, overexpression of dominant-negative forms of MyD88 and Mal/TIRAP significantly down-regulated the spontaneous production of cytokines tumor necrosis factor-alpha, IL-6, and vascular endothelial growth factor, and enzymes MMP-1, MMP-2, MMP-3, and MMP-13 in RA synovial membrane cell cultures. Because TLR2 and TLR4 require both MyD88 and Mal/TIRAP for signaling, this study suggests that TLR function may regulate the expression of these factors in the RA synovium. Conditioned media from synovial membrane cell cultures stimulated human macrophages in a MyD88- and Mal-dependent manner, suggesting the release of a TLR ligand(s) from these cells. Thus, TLRs not only protect against infection but may also promote the inflammatory and destructive process in RA.

Andreakos E, Rauchhaus U, Stavropoulos A, Endert G, Wendisch V, Benahmed AS, Giaglis S, Karras J, Lee S, Gaus H, Bennett CF, Williams RO, Sideras P, Panzner S. · Biomedical Research Foundation, Academy of Athens, Athens, Greece. · Arthritis Rheum. · Pubmed #19333921 No free full text.

Abstract: OBJECTIVE: Mediation of RNA interference by oligonucleotides constitutes a powerful approach for the silencing of genes involved in the pathogenesis of inflammatory disease, but in vivo application of this technique requires effective delivery to immune cells and/or sites of inflammation. The aim of the present study was to develop a new carrier system to mediate systemic administration of oligonucleotides to rheumatoid arthritis (RA) joints, and to develop an antisense oligonucleotide (ASO)-based approach to interfere with CD40-CD154 interactions in an experimental model of RA. METHODS: A novel liposomal carrier with amphoteric properties, termed Nov038, was developed and assessed for its ability to systemically deliver an ASO directed against CD40 (CD40-ASO). Male DBA/1 mice with collagen-induced arthritis were treated with Nov038-encapsulated CD40-ASO, and the effects of treatment on various parameters of disease activity, including clinical score, paw swelling, lymph node responses, and inflammatory cytokine production in the joints, were assessed. RESULTS: Nov038 was well tolerated, devoid of immune-stimulatory effects, and efficacious in mediating systemic oligonucleotide delivery to sites of inflammation. In mice with collagen-induced arthritis, Nov038 enabled the therapeutic administration of CD40-ASO and improved established disease, while unassisted CD40-ASO was ineffective, and anti-tumor necrosis factor alpha (anti-TNFalpha) treatment was less effective in this model. Nov038/CD40-ASO efficacy was attributed to its tropism for monocyte/macrophages and myeloid dendritic cells (DCs), resulting in rapid down-regulation of CD40, inhibition of DC antigen presentation, and reduction in collagen-specific T cell responses, as well as decreased levels of TNFalpha, interleukin-6 (IL-6), and IL-17 in arthritic joints. CONCLUSION: Amphoteric liposomes represent a novel carrier concept for systemic and antigen-presenting cell-targeted oligonucleotide delivery with clinical applicability and numerous potential applications, including target validation in vivo and inflammatory disease therapeutics. Moreover, Nov038/CD40-ASO constitutes a potent alternative to monoclonal antibody-based approaches for interfering with CD40-CD40L interactions.

Beech JT, Andreakos E, Ciesielski CJ, Green P, Foxwell BM, Brennan FM. · Kennedy Institute of Rheumatology Division, Imperial College School of Medicine, 1 Aspenlea Road, Hammersmith, London W6 8LH, UK. · Arthritis Res Ther. · Pubmed #17101049 links to  free full text

Abstract: We and others have reported that rheumatoid arthritis (RA) synovial T cells can activate human monocytes/macrophages in a contact-dependent manner to induce the expression of inflammatory cytokines, including tumour necrosis factor alpha (TNFalpha). In the present study we demonstrate that RA synovial T cells without further activation can also induce monocyte CC and CXC chemokine production in a contact-dependent manner. The transcription factor NFkappaB is differentially involved in this process as CXC chemokines but not CC chemokines are inhibited after overexpression of IkappaBalpha, the natural inhibitor of NFkappaB. This effector function of RA synovial T cells is also shared by T cells activated with a cytokine cocktail containing IL-2, IL-6 and TNFalpha, but not T cells activated by anti-CD3 cross-linking that mimics TCR engagement. This study demonstrates for the first time that RA synovial T cells as well as cytokine-activated T cells are able to induce monocyte chemokine production in a contact-dependent manner and through NFkappaB-dependent and NFkappaB-independent mechanisms, in a process influenced by the phosphatidyl-inositol-3-kinase pathway. Moreover, this study provides further evidence that cytokine-activated T cells share aspects of their effector function with RA synovial T cells and that their targeting in the clinic has therapeutic potential.

Andreakos E, Smith C, Kiriakidis S, Monaco C, de Martin R, Brennan FM, Paleolog E, Feldmann M, Foxwell BM. · Kennedy Institute of Rheumatology, Imperial College of Science, Technology and Medicine, London, UK. · Arthritis Rheum. · Pubmed #12847684 links to  free full text

Abstract: OBJECTIVE: To investigate the potential role of IkappaB kinase 1 (IKK-1) and IKK-2 in the regulation of nuclear factor kappaB (NF-kappaB) activation and the expression of tumor necrosis factor alpha (TNFalpha), as well as interleukin-1beta (IL-1beta), IL-6, IL-8, vascular endothelial growth factor (VEGF), and matrix metalloproteinases (MMPs), in rheumatoid arthritis (RA). METHODS: Recombinant adenoviruses expressing beta-galactosidase, dominant-negative IKK-1 and IKK-2, or IkappaBalpha were used to infect ex vivo RA synovial membrane cultures and synovial fibroblasts obtained from patients with RA undergoing joint replacement surgery, or human dermal fibroblasts, human umbilical vein endothelial cells (HUVECs), and monocyte-derived macrophages from healthy volunteers. Then, their effect on the spontaneous or stimulus-induced release of inflammatory cytokines, VEGF, and MMPs from RA synovial membrane cells was examined. RESULTS: IKK-2 was not required for lipopolysaccharide (LPS)-induced NF-kappaB activation or TNFalpha, IL-6, or IL-8 production in macrophages, but was essential for this process in response to CD40 ligand, TNFalpha, and IL-1. In synovial fibroblasts, dermal fibroblasts, and HUVECs, IKK-2 was also required for LPS-induced NF-kappaB activation and IL-6 or IL-8 production. In RA synovial membrane cells, IKK-2 inhibition had no effect on spontaneous TNFalpha production but significantly reduced IL-1beta, IL-6, IL-8, VEGF, and MMPs 1, 2, 3, and 13. CONCLUSION: Our study demonstrates that IKK-2 is not essential for TNFalpha production in RA. However, because IKK-2 regulates the expression of other inflammatory cytokines (IL-1beta, IL-6, and IL-8), VEGF, and MMPs 1, 2, 3, and 13, which are involved in the inflammatory, angiogenic, and destructive processes in the RA joint, it may still be a good therapeutic target.

Monaco C, Andreakos E, Young S, Feldmann M, Paleolog E. · Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College of Science, Technology & Medicine, London, United Kingdom. · J Leukoc Biol. · Pubmed #11927653 links to  free full text

Abstract: Adhesion of leukocytes to the vascular endothelium is an early event in inflammation. Since cell-cell signaling may be an important stimulus for endothelial activation, we focused in this study on the role of contact-mediated activation by T lymphocytes of endothelial cells (EC). T lymphocytes were cultured with anti-CD3 monoclonal antibody or in the presence of a combination of TNF-alpha, interleukin (IL)-6, and IL-2, prior to fixation and coculture with human umbilical vein EC. Fixed, activated (anti-CD3- or cytokine-stimulated), but not unstimulated T cells, induced release of monocyte chemotactic protein-1, IL-8, and IL-6 by EC in a contact-dependent manner. Moreover, expression of tissue-factor antigen and activity was also significantly increased. Addition of anti-CD40 ligand antibody abolished T cell-induced activation of EC. Our data suggest that contact-mediated activation of EC by T cells, involving ligand:counter ligand interactions such as CD40:CD40 ligand, may represent a novel pathogenic mechanism of progression in inflammatory diseases such as atherosclerosis or rheumatoid arthritis.

Smith C, Andreakos E, Crawley JB, Brennan FM, Feldmann M, Foxwell BM. · Kennedy Institute of Rheumatology Division, Imperial College School of Medicine, Hammersmith, London, United Kingdom. · J Immunol. · Pubmed #11698466 links to  free full text

Abstract: The transcription factor NF-kappaB is of major importance in the biology of pro-inflammatory cytokines, such as TNF-alpha and IL-1alpha, and thereby is intimately involved in the process of inflammation. Understanding the mechanisms by which NF-kappaB is activated in response to inflammatory stimuli has become a major goal of inflammation research. The discovery of NF-kappaB-inducing kinase (NIK) as a TNFR-associated factor-interacting enzyme and a potential activator of the IkappaBalpha-kinase complex appeared to have identified an important element of the NF-kappaB activation pathway, a view that was supported by several subsequent studies. However, recent experiments in the alymphoplasia (aly/aly) mouse, which has missense point mutation (G885R) in NIK, has challenged that view. The reasons for the discrepancy between the different studies is unclear and could be due to multiple factors, such as cell type, species of cell, or primary vs transformed cell lines. One system that has not been investigated is primary human cells. Using an adenoviral vector encoding kinase-deficient NIK, we have investigated the role of NIK in LPS, IL-1, TNF-alpha, and lymphotoxin (LT) betaR signaling in primary human cells and TNF-alpha expression from rheumatoid tissue. These data show that, in the primary systems tested, NIK has a restricted role in LTbetaR signaling and is not required by the other stimuli tested. Also, there is no apparent role for NIK in the process of TNF-alpha production in human rheumatoid arthritis. These data also highlight the potential problems in extrapolating the function of signaling pathways between primary and transfected cell lines.