Rheumatoid Arthritis: Australia

Osborne RH, Jordan JE, Rogers A. · Centre for Rheumatic Diseases, Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Melbourne, Victoria 3050, Australia. · Nat Clin Pract Rheumatol. · Pubmed #18301410 No free full text.

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Hamilton JA, Tak PP. · Arthritis and Inflammation Research Centre, University of Melbourne and Department of Medicine, The Royal Melbourne Hospital, Parkville, Victoria, Australia. · Arthritis Rheum. · Pubmed #19404968 No free full text.

This publication has no abstract.

Anandacoomarasamy A, Fransen M, March L. · Institute of Bone and Joint Research, Royal North Shore Hospital, Sydney, New South Wales, Australia. · Curr Opin Rheumatol. · Pubmed #19093327 No free full text.

Abstract: PURPOSE OF REVIEW: To describe recent developments highlighting the effects and mechanisms of obesity and weight loss on the musculoskeletal system. RECENT FINDINGS: The global epidemic of obesity has far-reaching effects on the musculoskeletal system and associated conditions such as osteoarthritis, rheumatoid arthritis, spondyloarthropathy, and fibromyalgia. Obesity increases the need for, and reduces the health outcomes from, joint replacement surgery, which has enormous implications for societal economic burden. New insights have been gained into the possible mechanisms by which obesity is associated with musculoskeletal disease incidence, symptom severity and treatment outcomes particularly for osteoarthritis. Research exploring the role of adipocytokines provides a novel possible metabolic link for these diseases. SUMMARY: Obesity has a significant impact on the musculoskeletal system being associated with both degenerative and inflammatory conditions. Future research assessing the effects of obesity and weight loss as well as further elucidating the action of adipocytokines will aid in the assessment and management of this increasingly prevalent condition.

Lassere MN. · Department of Rheumatology, St George Hospital, University of NSW, Gray Street, Kogarah 2217, Sydney, Australia. · Best Pract Res Clin Rheumatol. · Pubmed #19041074 No free full text.

Abstract: The five stages in the evolution of a new method or measure are discovery (by design or inadvertent), development, testing, standardization and application. However, measures may be accepted, disseminated and used before they have been formally evaluated and standardized. This chapter describes the properties of measurement in the medical sciences and the process of standardization. It includes an example of the development and standardization of a magnetic resonance imaging rheumatoid arthritis score, and ends with a matrix that can serve as a guide for systematic appraisal and standardization of outcome measures, such as imaging outcomes. Using the matrix, one can determine the gaps in knowledge and what further evaluation is needed in one or more domains or metrics.

Pourgholami MH, Morris DL. · Cancer Research laboratories, University of New South Wales, Department of Surgery, St George Hospital (SESIAHS), Sydney, NSW 2217, Australia. · Cardiovasc Hematol Agents Med Chem. · Pubmed #18855647 No free full text.

Abstract: Angiogenesis is a complex process that is regulated by pro- and antiangiogenic factors. These factors can emanate from diverse sources including cancer cells, stromal cells, blood and extracellular matrix. Their relative contribution is likely to change with tumor type and tumor site. Vascular endothelial growth factor (VEGF) is now well confirmed as the primary and the most potent inducer of angiogenesis. To activate cellular signaling pathways, VEGF binds to receptor kinases VEGF-R1, R2 and R3. It then promotes several events required for the formation of new blood vessels, such as endothelial cell survival, proliferation, migration and vascular permeability. Activation of endothelial cells, leads to the secretion of enzymes which degrade the extracellular matrix (ECM) and hence promote metastasis. Similarly it promotes survival by inducing Bcl-2 expression on VEGF receptor positive leukemia. Besides being a potent mitogen for macrovascular cells derived from arteries, veins and lymphatics, it is also highly involved in a number of angiogenic related disorders including inflammatory diseases, rheumatoid arthritis, psoriasis, retinopathies and age related macular degeneration. Neovascularization and increased vessel permeability are being recognized as major causes of VEGF related pathogenesis. Therefore, inhibition of VEGF pathway is a strategy being widely pursued to provide new therapeutics for the treatment of VEGF related disorders. Over twenty compounds with anti-angiogenic properties ranging from VEGF neutralizing antibody, soluble receptors, receptor antagonists or tyrosine kinase inhibitors (TKIs) are either approved or are currently under clinical (phase I - III) study. This review aims to provide an updated account of how VEGF inhibitors are shaping up to become an important class of drugs used in the treatment of cancer.

Chen J, Liu X. · Division of Immunology and Genetics, John Curtin School of Medical Research, Australian National University, ACT 2601, Australia. · Cell Immunol. · Pubmed #18848698 No free full text.

Abstract: Interferon gamma (IFNgamma) plays a central role in the immune response against infection and tumur immune surveillance. Its functions include not only activation of the host immune system to control microbial infections but also repression of autoimmune responses by turning on T-regulatory cells and increasing T effector cell apoptosis. Defects in IFNgamma and IFNgamma receptor genes have been associated with autoimmune diseases such as rheumatoid arthritis, type 1 diabetes and multiple sclerosis. However, treatment of autoimmune diseases by supplementing with IFNgamma has been satisfactory due to its broad biological effects. Instead, its target T-regulatory cells may be used for the clinical treatment of autoimmune diseases. Future study could also focus on promotion of the beneficial effects of IFNgamma and blocking those unwanted IFNgamma-induced activities.

Ding C. · University of Tasmania, Menzies Research Institute, Private Bag 23, Hobart, Tasmania 7000, Australia. · Expert Opin Biol Ther. · Pubmed #18847314 No free full text.

Abstract: BACKGROUND: B lymphocyte stimulator (BLyS) is a factor determining the survival of B cells, and elevated levels in serum or locally have been observed in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) patients. Belimumab (LymphoStat-B), a human monoclonal antibody that inhibits BlyS, was developed for the treatment of these diseases. OBJECTIVE: To summarize preclinical development, efficacy and safety of belimumab in treatment of RA and SLE. METHODS: Articles found in a PubMed search and data presented in abstract form at international conferences up to August 2008 are described. RESULTS/CONCLUSIONS: Belimumab was well tolerated in treatment of RA over 24 weeks and SLE over 3 years. It significantly decreased rheumatoid factor (RF) levels, and modestly reduced symptoms of RA, especially in some subgroups such as patients with high disease activity, positive RF and no anti-TNF treatment experience. It also significantly reduced symptoms of SLE, and decreased anti-double-stranded DNA autoantibodies among patients with positive baseline anti-double-stranded DNA or antinuclear antibodies during a long-period treatment. These results suggest that careful patient selection is necessary to achieve optimal outcomes.

Thomas R, Turner M, Cope AP. · Diamantina Institute for Cancer, Immunology and Metabolic Medicine, University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland 4102, Australia. · Arthritis Res Ther. · Pubmed #18710589 links to  free full text

Abstract: Self-reactive T cells with low signalling capacity through the T-cell receptor were recently observed in the SKG mouse model of rheumatoid arthritis (RA) and have been linked to a spontaneous mutation in the ZAP-70 signal transduction molecule. Here we hypothesize that similar mechanisms also drive RA, associated with an abnormal innate and adaptive immune response driven by nuclear factor-kappaB activation and tumour necrosis factor secretion. Similar to the essential role played by pathogens in SKG mice, we propose that HLA-associated immunity to chronic viral infection is a key factor in the immune dysregulation and joint inflammation that characterize RA.

Hawke F, Burns J, Radford JA, du Toit V. · School of Health Sciences, University of Newcastle, Health Precinct, PO Box 127, Ourimbah, NSW, Australia, 2258. · Cochrane Database Syst Rev. · Pubmed #18646168 No free full text.

Abstract: BACKGROUND: Custom foot orthoses are commonly recommended for the treatment of foot pain. OBJECTIVES: To evaluate the effectiveness of custom foot orthoses for different types of foot pain. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2007, Issue 2), MEDLINE (from January 1966), EMBASE (from January 1980), CINAHL (from January 1982) and the Physiotherapy Evidence Database (PEDro) (to June 2007). We also contacted authors of included trials and known researchers in the field and checked the reference lists of included trials to identify trials. No language or publication restrictions were applied. SELECTION CRITERIA: Randomised controlled trials and controlled clinical trials evaluating custom-made foot orthoses for any type of foot pain. Outcomes included quantifiable levels of foot pain, function, disability, health-related quality of life, participant satisfaction, adverse effects and compliance. DATA COLLECTION AND ANALYSIS: Two authors independently selected trials, rated methodological quality and cross checked data extraction. Data were analysed separately for different diagnoses of foot pain and follow-up time points. MAIN RESULTS: Eleven trials involving 1332 participants were included: five trials evaluated custom-made foot orthoses for plantar fasciitis (691 participants); three for foot pain in rheumatoid arthritis (231 participants); and one each for foot pain in pes cavus (154 participants), hallux valgus (209 participants) and juvenile idiopathic arthritis (JIA) (47 participants). Comparisons to custom-made foot orthoses included sham orthoses; no intervention; standardised interventions given to all participants; non-custom (prefabricated) foot orthoses; combined manipulation, mobilisation or stretching; night splints; and surgery. Follow up ranged from one week to three years. Custom-made foot orthoses were effective for painful pes cavus (NNTB:5), rearfoot pain in rheumatoid arthritis (NNTB:4), foot pain in JIA (NNTB:3) and painful hallux valgus (NNTB:6); however, surgery was even more effective for hallux valgus and non-custom foot orthoses appeared just as effective for JIA but the analysis may have lacked sufficient power to detect a difference in effect. It is unclear if custom-made foot orthoses were effective for plantar fasciitis or metatarsophalangeal joint pain in rheumatoid arthritis. Custom-made foot orthoses were a safe intervention in all studies. AUTHORS' CONCLUSIONS: There is limited evidence on which to base clinical decisions regarding the prescription of custom-made foot orthoses for the treatment of foot pain. Currently, there is gold level evidence for painful pes cavus and silver level evidence for foot pain in JIA, rheumatoid arthritis, plantar fasciitis and hallux valgus.

Jackson C, Whitmont K, Tritton S, March L, Sambrook P, Xue M. · Institute of Bone and Joint Research, Kolling Institute, Sutton Arthritis Research Laboratories, Department of Rheumatology, University of Sydney at Royal North Shore Hospital, 2065 Australia. · Expert Opin Biol Ther. · Pubmed #18613763 No free full text.

Abstract: BACKGROUND: Activated protein C (APC) is derived from its precursor, protein C (PC). Originally thought to be synthesised exclusively by the liver, recent reports have shown that PC is also produced by endothelial cells, smooth muscle cells, keratinocytes and some leukocytes. OBJECTIVE: To provide an update on the emerging therapeutic effects of APC. RESULTS/CONCLUSION: APC functions as an anticoagulant with cytoprotective, anti-inflammatory and antiapoptotic properties. In vitro and preclinical data have revealed that APC exerts its protective effects via an intriguing mechanism requiring endothelial protein C receptor and protease activated receptor-1. Approved as a therapeutic agent for severe sepsis, APC is emerging as a potential treatment for a number of autoimmune and inflammatory diseases including spinal cord injury, asthma, chronic wounds and possibly rheumatoid arthritis. The future therapeutic uses of APC look very promising.

Dass CR, Choong PF. · Department of Orthopaedics, St. Vincent's Hospital, Peter MacCallum Cancer Centre, Melbourne, Australia. · Pharmazie. · Pubmed #18604982 No free full text.

Abstract: Recent studies have demonstrated the potential of DNAzymes for therapy of various diseases via mRNA target-specific cleavage. One such target, the basic region-leucine zipper protein c-Jun, has been targeted and efficacy seen in such pathologies as cancer, ocular neovascularisation, arterial thickening, acute inflammation, and rheumatoid arthritis. This review discusses these cases in turn, and presents some new data on the applicability of a c-jun DNAzyme against a panel of cancer cells. Importantly, downregulation of c-jun is noted to cause apoptotic death of cancer cells. These studies collectively demonstrate the potential of this DNAzyme as a lead candidate for DNAzyme therapeutics.

Ralph JA, Morand EF. · Monash University, Department of Medicine, Centre for Inflammatory Diseases, Monash Medical Centre, 246 Clayton Road, Clayton, Melbourne 3168, Australia. · Expert Opin Ther Targets. · Pubmed #18554149 No free full text.

Abstract: BACKGROUND: Rheumatoid arthritis (RA) represents a challenge for therapeutic interventions due to complex inflammatory signalling pathways underlying its pathogenesis. The MAPK signalling network, a major effector limb of the inflammatory lesion, is an attractive therapeutic target. MAPK phosphatases (MKPs), endogenous negative regulators of MAPK signalling, have received increasing recognition as modulators of inflammatory and immune responses, and hence as a potential therapeutic avenue for RA. OBJECTIVE: To present the rationale for therapeutically targeting MAPK signalling and explore the case for addressing MKP1 as a novel therapeutic strategy for RA. METHODS: We summarise literature describing the importance of MAPK signalling in RA and review reports describing the roles of MKPs in modulating innate and adaptive immune responses. Finally we expand on the role of MKP1 in RA pathogenesis and explore data defining MKP1 as a mediator of glucocorticoid action. CONCLUSION: MKP1 constitutes an exciting, novel potential therapeutic target for RA.

Pai S, Thomas R. · Diamantina Institute for Cancer, Immunology and Metabolic Medicine, University of Queensland, Queensland, 4102, Australia. · J Autoimmun. · Pubmed #18539434 No free full text.

Abstract: Nuclear factor (NF)-kappaB is a transcription factor family which transmits signals from the cell surface to the nucleus, resulting in transcriptional effects on genes involved in inflammation, cell differentiation and survival. The signaling of NF-kappaB and mitogen-activated protein (MAP) kinases through adapter molecules is of critical importance to survival and activation of all cells in the body, including those regulating innate and adaptive immunity. Here we review the individual and intersecting roles played by the alternate and classical NF-kappaB pathways in the pathogenesis of autoimmune disease. Understanding the differences in classical and alternate NF-kappaB function has greatly assisted the development of models of their contribution to different autoimmune diseases. To exemplify these concepts, we consider the contribution of NF-kappaB to rheumatoid arthritis and type 1 diabetes pathogenesis and approaches to immunotherapy.

Rowley MJ, Nandakumar KS, Holmdahl R. · Department of Biochemistry and Molecular Biology, Monash University, Wellington Rd, Clayton, VIC, 3800, Australia. · Mod Rheumatol. · Pubmed #18521704 No free full text.

Abstract: This review examines evidence that rheumatoid arthritis (RA) depends on autoimmunity to articular collagen, and mechanisms whereby autoantibodies to type II collagen contribute to disease development. Three major autoantigenic reactants have been identified in RA; the corresponding autoantibodies are rheumatoid factor (RF), antibodies to citrullinated peptide antigens (ACPA), citrullinated peptides (anti-CCP), and anti-type II collagen (anti-CII). Both RF and ACPA are well-validated and predictive markers of severe erosive RA, but cannot be linked to pathogenesis. By contrast, in various animal species immunized with CII there occurs an erosive inflammatory arthritis resembling that seen in human RA, together with antibodies to CII with an epitope specificity similar to that in RA. We discuss the well-known role of immune complexes in the induction of inflammation within the joint, and present recent data showing, additionally, that antibodies to CII cause direct damage to cartilage in vitro. The close resemblances between human RA and collagen-induced arthritis in animals suggest that autoimmunity, and particularly autoantibodies to CII, are important for both the initiation and perpetuation of RA in a dual manner: as contributors to the inflammation associated with immune complex deposition, and as agents with direct degradative effects on cartilage integrity and its repair.

Vitetta L, Cicuttini F, Sali A. · Unit of Health Integration, School of Medicine, University of Queensland, Level 2, Centres for Health Research, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Brisbane, Queensland 4102, Australia. · Best Pract Res Clin Rheumatol. · Pubmed #18519102 No free full text.

Abstract: The use of complementary and alternative medicine is complex and nuanced. Patterns of use of complementary and alternative medicine differ among racially and ethnically different groups. Multivariate models of utilization indicate that ethnicity plays an independent role in the implementation of these modalities, in seeking practitioners and in health problems for which assistance is required. Moreover, there are many reasons why people use complementary and alternative medicine: conventional treatment may not be working as well as they would like; they want greater relief of symptoms and/or disability; they have issues with side-effects of pharmaceutical treatment; they wish to reduce some of the stress that comes from living with a chronic illness and want to cope better; they believe that complementary and alternative therapies are safer and 'natural'; and they are influenced by the widespread advertising and attractive claims that are made for many natural products. Although there are more than 150 different kinds of syndromes and conditions associated with arthritis, this review will focus on currently available evidence-based medicine for the two most common conditions diagnosed in Western countries - osteoarthritis and rheumatoid arthritis - for which people seek and then implement complementary and alternative medicine modalitites.

Vogelzang A, King C. · Department of Immunology, The Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, NSW 2010, Australia. · Front Biosci. · Pubmed #18508588 No free full text.

Abstract: In this review, we discuss recent progress from studies on the biology of IL-21 and the role of this cytokine in the pathogenesis of autoimmunity. Recent studies have demonstrated that IL-21 plays an important and non-redundant role in a number of autoimmune animal models indicating that IL-21 could be a common modulator of the adaptive immune response towards self-tissue constituents in diseases such as systemic lupus erythematosus, models of rheumatoid arthritis, multiple sclerosis and type-1 diabetes. Also, the studies on the production of IL-21 in human autoimmune diseases and its behaviour on human cells in vitro are revealing the potential of IL-21 to exacerbate cellular processes that determine the course of autoimmune diseases.

Ding C, Jones G. · Menzies Research Institute, Hobart, Tasmania, Australia. · Rev Recent Clin Trials. · Pubmed #18473972 No free full text.

Abstract: Tocilizumab (namely MRA), a humanized anti-interleukin (IL)-6 receptor monoclonal antibody, is under development by Roche for the treatment of inflammatory autoimmune diseases such as rheumatoid arthritis (RA), systemic onset juvenile idiopathic arthritis (JIA), adult-onset Still's disease, Castleman's disease and Crohn's disease. Tocilizumab has a long plasma half-life, so it can be administered intravenously biweekly or monthly. Phase I and II clinical trials showed that tocilizumab (2, 4, 5, 8 or 10 mg/kg) reduced disease activity significantly in a dose-dependent manner. Tocilizumab not only improved signs and symptoms, but also normalized inflammatory markers such as C-reactive protein, erythrocyte sedimentation rate (ESR), fibrinogen and serum amyloid A, and reversed joint damage of RA. The efficacy of tocilizumab in the treatment of RA was at least as good as methotrexate. Tocilizumab was generally safe and well tolerated. Some adverse events such as significant rises in total cholesterol and triglyceride levels, liver function disorders, decreases in white blood cell counts, diarrhoea and infection were observed. In summary, preliminary clinical results suggest that tocilizumab is effective and generally well tolerated in the treatment of IL-6-related inflammatory autoimmune diseases. Like other anti-cytokine immunotherapies, caution and close monitoring for the adverse events, especially infection, are necessary in subsequent clinical trials.

Massy-Westropp N, Johnston RV, Hill C. · University of South Australia, Health Sciences, City East Campus, North Terrace, Adelaide, South Australia, Australia, 5000. · Cochrane Database Syst Rev. · Pubmed #18254021 No free full text.

Abstract: BACKGROUND: Metacarpophalangeal (MCP) arthroplasty with implants, which is the replacement of painful knuckle joints with artificial knuckle joints, has been performed for people with rheumatoid arthritis (RA) since the 1960s. The surgery is done because RA can cause damage of the knuckle joints making them unable to straighten out (flexion deformity) and causing them to lean over toward the small finger (flexion or ulnar deviation deformity). For eight to 12 weeks following surgery, patients wear hand splints and perform exercises to maintain and increase motion in the healing hand. Post-operative therapy regimes share common aims of encouraging MCP flexion and extension without the recurrence of flexion or ulnar deviation deformity. OBJECTIVES: To compare the effectiveness of post-operative therapy regimes for increasing hand function after MCP arthroplasty in adults with rheumatoid arthritis. SEARCH STRATEGY: The Cochrane Musculoskeletal Group Register, MEDLINE (January 1950 to August 2006), EMBASE (January 1993 to August 2006), CINAHL (January 1982 to August 2006), Digital Dissertations (January 1960 to August 2006), DARE (The Cochrane Library 2006, Issue 3), Current Contents Connect (January 1998 to August 2006), and AMED (January 1985 to August 2006) were searched for randomised controlled trials and controlled clinical trials using rheumatoid arthritis and hand as the search terms. The bibliographies of all trials identified by this strategy were also searched and primary authors were contacted for unpublished data and also clarification regarding study protocols.We performed handsearches of all relevant society conference proceedings and reference lists of retrieved articles. No language limits were applied, although searches were only relevant after the 1950s when MCP arthroplasty began to be performed. SELECTION CRITERIA: Randomised controlled trials and controlled clinical trials were accepted if they evaluated the efficacy of a post-operative therapy regime for MCP arthroplasty. DATA COLLECTION AND ANALYSIS: No data analyses were performed as only one controlled clinical trial was found. The data from that study are described. MAIN RESULTS: Our search only identified one controlled clinical trial involving 22 participants. The majority of the evidence for various splinting and exercise regimes consisted of case series and case studies. Results from the one (poor quality) trial suggest that the use of continuous passive motion is not effective in increasing motion or strength after MCP arthroplasty. AUTHORS' CONCLUSIONS: Well-designed randomised controlled trials which compare the efficacy of different therapeutic splinting programmes following MCP arthroplasty are required. At this time, the results of one study (silver level evidence) suggest that continuous passive motion alone is not recommended for increasing motion or strength after MCP arthroplasty.

Ayoub S, Hickey MJ, Morand EF. · Monash Medical Centre and Monash University, Melbourne, Victoria, Australia. · Nat Clin Pract Rheumatol. · Pubmed #18235539 No free full text.

Abstract: The past decade has seen the emergence of two new paradigms in inflammatory disease: first, cardiovascular complications of atherosclerosis are markedly increased in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE); and second, inflammatory mechanisms are important in the pathogenesis of atherosclerosis. These concurrent developments have lead to the concept that inflammatory mediators operative in RA and SLE might be causal in the accelerated atherosclerosis observed, a concept supported by clinical studies showing that this acceleration is not fully explained by traditional vascular risk factors. Separate lines of evidence implicate the cytokine macrophage migration inhibitory factor (MIF) in RA, SLE, and atherosclerosis. Several reports have revealed definitive in vivo evidence of the activity of MIF in a model of SLE, demonstrated a novel role for MIF in monocyte/macrophage recruitment, and showed that MIF regulates a key mediator of inflammatory cell activation. Together with evidence that MIF circulates in increased concentrations in patients with RA and SLE, this information suggests that in addition to contributing to each disease, MIF might contribute directly to the acceleration of atherosclerosis in RA and SLE.

Lee H, Whitfeld PL, Mackay CR. · Immunology and Inflammation Department, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia. · Immunol Cell Biol. · Pubmed #18227853 No free full text.

Abstract: Complement component C5a is one of the most potent inflammatory chemoattractants and has been implicated in the pathogenesis of numerous inflammatory diseases. C5a binds two receptors, C5aR and C5L2. Most of the C5a functional effects occur through C5aR, and the pharmaceutical industry has focused on this receptor for the development of new anti-inflammatory therapies. We used a novel approach to generate and test therapeutics that target C5aR. We created human C5aR knock-in mice, and used neutrophils from these to immunize wild-type mice. This yielded high-affinity blocking mAbs to human C5aR. We tested these anti-human C5aR mAbs in mouse models of inflammation, using the human C5aR knock-in mice. These antibodies completely prevented disease onset and were also able to reverse established disease in the K/B x N arthritis model. The physiological role of the other C5a receptor, C5L2 is still unclear, and our studies with blocking mAbs to human C5L2 have failed to demonstrate a clear functional role in signaling to C5a. The development of effective mAbs to human C5aR is an alternative approach to drug development, for this highly attractive target.

Alderuccio F, Siatskas C, Chan J, Field J, Murphy K, Nasa Z, Toh BH. · Department of Immunology, Monash University, Commercial Road, Prahran, Victoria 3181, Australia. · Curr Stem Cell Res Ther. · Pubmed #18220873 No free full text.

Abstract: Autoimmune diseases affect approximately 6% of the population and are characterised by a pathogenic immune response that targets self-antigens. Well known diseases of this nature include type 1 diabetes, systemic lupus erythematosus, rheumatoid arthritis and multiple sclerosis. Treatment is often restricted to replacement therapy or immunosuppressive regimes and to date there are no cures. The strategy of utilising autologous or allogeneic haematopoietic stem cell transplantation to treat autoimmunity and induce immunological tolerance has been trailed with various levels of success. A major issue is disease relapse as the autoimmune response is reinitiated. Cells of the immune system originate from bone marrow and have a central role in the induction of immunological tolerance. The ability to isolate and genetically manipulate bone marrow haematopoietic stem cells therefore makes these cells a suitable vehicle for driving ectopic expression of defined autoantigens and induction of immunological tolerance.

Groom J, Mackay F. · The Autoimmunity Research Unit, The Garvan Institute of Medical research, Darlinghurst, New South Wales, Australia. · Immunol Cell Biol. · Pubmed #18172443 No free full text.

Abstract: Systemic autoimmunity such as systemic lupus erythematosus (SLE) is associated with the loss of B-cell tolerance, B-cell dysregulation and autoantibody production. While some autoantibodies may contribute to the pathology seen with SLE, numerous studies have shown that dysregulation of T-cell function is another critical aspect driving disease. The positive results obtained in clinical trials using T-cell- or B-cell-specific treatments have suggested that cooperation between T and B cells probably underlies disease progression in many patients. A similar cooperative mechanism seemed to explain SLE developing in mice overexpressing the B-cell-activating factor from the tumor necrosis factor family (BAFF). However, surprisingly, T-cell-deficient BAFF transgenic (Tg) mice develop SLE similar to T-cell-sufficient BAFF Tg mice, and the disease was linked to innate activation of B cells and production of proinflammatory autoantibody isotypes. In conclusion, dysregulated innate activation of B cells alone can drive disease independently of T cells, and as such this aspect represents a new pathogenic mechanism in autoimmunity.

Chang J, Girgis L. · Rheumatology Department, St Vincent's Hospital, Sydney, New South Wales. · Aust Fam Physician. · Pubmed #18075630 links to  free full text

Abstract: BACKGROUND: Tumour necrosis factor-alpha (TNF-alpha) inhibitors are a new class of injectable drugs, under the umbrella term 'biological agents', now available for the treatment of rheumatoid arthritis and other chronic inflammatory conditions including juvenile idiopathic arthritis, Crohn disease, psoriasis and psoriatic arthritis. OBJECTIVE: The aim of this review is to provide an overview of TNF-alpha inhibitors and highlight the key practical issues of relevance to general practitioners. DISCUSSION: TNF-alpha inhibitors may have a potent effect in reducing inflammation and possibly inducing remission where conventional disease modifying drugs have failed to do so. These drugs are associated with an increased risk of infection as well as other potentially serious side effects. Their use is restricted to the relevant specialist prescribing the drug and are only available on the Pharmaceutical Benefits Scheme under strict prescribing criteria. The role of the GP is critical in identifying patients suitable for referral to consider commencing treatment and in monitoring patients on long term therapy.

Nik Tavakoli N, Hambly BD, Sullivan DR, Bao S. · Discipline of Pathology, School of Medical Sciences and Bosch Institute, University of Sydney, New South Wales 2006, Australia. · Int J Biochem Cell Biol. · Pubmed #18037337 No free full text.

Abstract: CD4+CD25+ regulatory T (Treg) cells play a crucial role in maintaining self-tolerance and preventing autoimmune disease. The transcription factor forkhead box protein 3 (Foxp3) has been identified as a molecular marker for Treg cells. Foxp3 is highly expressed in lymphoid tissue and several signalling pathways influence its expression. It plays an essential role in the development and function of Treg cells. Mutations in Foxp3 are responsible for the scurfy (sf) mutant mouse, and for autoimmune human diseases including the X-linked fatal "immune dysregulation, polyendocrinopathy, enteropathy, X-linked" (IPEX), autoimmune colitis and rheumatoid arthritis. Recent studies have also revealed an important and novel anti-atherogenic role for Treg cells and consequently for Foxp3. These data open up potential novel therapeutic avenues for the management of atherosclerosis.

Duffy DL. · Genetic Epidemiology Laboratory, Queensland Institute of Medical Research, Herston, Queensland, Australia. · Curr Opin Allergy Clin Immunol. · Pubmed #17989522 No free full text.

Abstract: PURPOSE OF REVIEW: I discuss the increasing number of genes discovered to exert pleiotropic action on susceptibility to diabetes and simultaneously to other immune-mediated diseases. While a genetic correlation between type 1 diabetes and autoimmunity is not surprising, the mechanism of a relationship to other conditions such as atopy is less obvious. The recent wave of genome-wide association studies offers confirmation of previously recognized risk loci, but also novel loci that also are likely to act via multiple pathogenetic pathways. I will review this material more in a genetical than an immunological way. RECENT FINDINGS: Identification of IFIH1, an RNA helicase involved in the innate immune response to viral infection as a risk factor for type 1 diabetes and rheumatoid arthritis. Confirmation of the roles of CTLA4 and PTPN22 as general immune function modulators with a nonlinear dose-response effect on autoimmunity, and confirmation of the role of IL2RA, which may act via a regulatory T cell subset on immune disease risk. Expansion of the role of PPARG in immunity. SUMMARY: The wave of genome-wide association studies already experienced in the last 2 years has solidified what we thought we knew and added a list of genes in new pathways. The association of IFIH1 with type 1 diabetes may offer a real window into early events in the development of that disease.