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1.  Duality of fibroblast-like synoviocytes in RA: passive responders and imprinted aggressors 
Nature reviews. Rheumatology  2012;9(1):24-33.
Rheumatoid arthritis (RA) is characterized by hyperplastic synovial pannus tissue, which mediates destruction of cartilage and bone. Fibroblast-like synoviocytes (FLS) are a key component of this invasive synovium and have a major role in the initiation and perpetuation of destructive joint inflammation. The pathogenic potential of FLS in RA stems from their ability to express immunomodulating cytokines and mediators as well as a wide array of adhesion molecule and matrix-modelling enzymes. FLS can be viewed as ‘passive responders’ to the immunoreactive process in RA, their activated phenotype reflecting the proinflammatory milieu. However, FLS from patients with RA also display unique aggressive features that are autonomous and vertically transmitted, and these cells can behave as primary promoters of inflammation. The molecular bases of this ‘imprinted aggressor’ phenotype are being clarified through genetic and epigenetic studies. The dual behaviour of FLS in RA suggests that FLS-directed therapies could become a complementary approach to immune-directed therapies in this disease. Pathophysiological characteristics of FLS in RA, as well as progress in targeting these cells, are reviewed in this manuscript.
PMCID: PMC3970924  PMID: 23147896
2.  Transforming growth factor-ß as a therapeutic target in systemic sclerosis 
Nature reviews. Rheumatology  2009;5(4):200-206.
Transforming growth factor-ß (TGF-ß) is a pleiotropic cytokine with vital homeostatic functions. Aberrant TGF-ß expression or activity is implicated in the pathogenesis of fibrosis in patients with systemic sclerosis (SSc), thus TGF-ß represents a molecular therapeutic target. Multiple strategies are available for blocking the TGF-ß pathway. A monoclonal antibody targeting TGF-ß has been evaluated in a small clinical trial for early SSc with disappointing results. Antibodies to the αvß6 integrin that prevent latent TGF-ß activation, however, show promise in preclinical studies. Small molecules inhibiting TGF-ß receptor activity are effective in animal models of fibrosis. Imatinib mesylate and related tyrosine kinase inhibitors that are currently used in cancer therapy also block TGF-ß pathways and abrogate fibrotic responses. Furthermore, some commonly used drugs have shown unanticipated anti-TGF-ß activity and, therefore, could have anti-fibrotic effects. Since TGF-ß has important physiologic functions for tissue homeostasis, blocking TGF-ß activity might lead to spontaneous immune activation, epithelial hyperplasia and impaired wound healing. Loss of immune tolerance is a potential concern in an autoimmune disease such as SSc. Novel insights from microarray-based gene expression analysis and studies of genetic polymorphisms in TGF-ß signaling could aid in identifying those patients who are most likely to respond to anti-TGF-ß treatment. Anti-TGF-ß interventions promise to have a major impact on the treatment of SSc. Significant concerns regarding efficacy, safety, questions regarding appropriate dosing and timing of therapy, identification of responders, and of biomarkers of safety and efficacy are critical challenges ahead.
PMCID: PMC3959159  PMID: 19337284
3.  Understanding fibrosis in systemic sclerosis: shifting paradigms, emerging opportunities 
Nature reviews. Rheumatology  2011;8(1):42-54.
Fibrosis in multiple organs is a prominent pathological finding and distinguishing hallmark of systemic sclerosis (SSc). Findings during the past 5 years have contributed to a more complete understanding of the complex cellular and molecular underpinning of fibrosis in SSc. Fibroblasts, the principal effector cells, are activated in the profibrotic cellular milieu by cytokines and growth factors, developmental pathways, endothelin 1 and thrombin. Innate immune signaling via Toll-like receptors, matrix-generated biomechanical stress signaling via integrins, hypoxia and oxidative stress seem to be implicated in perpetuating the process. Beyond chronic fibroblast activation, fibrosis represents a failure to terminate tissue repair, coupled with an expanded population of mesenchymal cells originating from bone marrow and transdifferentiation of epithelial cells, endothelial cells and pericytes. In addition, studies have identified intrinsic alterations in SSc fibroblasts resulting from epigenetic changes, as well as altered microRNA expression that might underlie the cell-autonomous, persistent activation phenotype of these cells. Precise characterization of the deregulated extracellular and intracellular signaling pathways, mediators and cellular differentiation programs that contribute to fibrosis in SSc will facilitate the development of selective, targeted therapeutic strategies. Effective antifibrotic therapy will ultimately involve novel compounds and repurposing of drugs that are already approved for other indications.
PMCID: PMC3954787  PMID: 22025123
4.  Genetics and epigenetics of rheumatoid arthritis 
Nature reviews. Rheumatology  2013;9(3):141-153.
Investigators have made key advances in rheumatoid arthritis (RA) genetics in the past 10 years. Although genetic studies have had limited influence on clinical practice and drug discovery, they are currently generating testable hypotheses to explain disease pathogenesis. Firstly, we review here the major advances in identifying RA genetic susceptibility markers both within and outside of the MHC. Understanding how genetic variants translate into pathogenic mechanisms and ultimately into phenotypes remains a mystery for most of the polymorphisms that confer susceptibility to RA, but functional data are emerging. Interplay between environmental and genetic factors is poorly understood and in need of further investigation. Secondly, we review current knowledge of the role of epigenetics in RA susceptibility. Differences in the epigenome could represent one of the ways in which environmental exposures translate into phenotypic outcomes. The best understood epigenetic phenomena include post-translational histone modifications and DNA methylation events, both of which have critical roles in gene regulation. Epigenetic studies in RA represent a new area of research with the potential to answer unsolved questions.
PMCID: PMC3694322  PMID: 23381558
5.  B cells as therapeutic targets in SLE 
Nature reviews. Rheumatology  2010;6(6):326-337.
The use of B-cell targeted therapies for the treatment of systemic lupus erythematosus (SLE) has generated great interest owing to the multiple pathogenic roles carried out by B cells in this disease. Strong support for targeting B cells is provided by genetic, immunological and clinical observations that place these cells at the center of SLE pathogenesis, as initiating, amplifying and effector cells. Interest in targeting B cells has also been fostered by the successful use of similar interventions to treat other autoimmune diseases such as rheumatoid arthritis, and by the initial promise shown by B-cell depletion to treat SLE in early studies. Although the initial high enthusiasm has been tempered by negative results from phase III trials of the B-cell-depleting agent rituximab in SLE, renewed vigor should be instilled in the field by the convergence of the latest results using agents that inhibit B-cell-activating factor (BAFF, also known as BLyS and tumor necrosis factor ligand superfamily, member 13b), further analysis of data from trials using rituximab and greatly improved understanding of B-cell biology. Combined, the available information identifies several new avenues for the therapeutic targeting of B cells in SLE.
PMCID: PMC3934759  PMID: 20520647
6.  Is HLA B genotyping the future of gout pharmacogenomics? 
Nature reviews. Rheumatology  2013;9(4):200-202.
Advances in pharmacogenomics have improved understanding of allopurinol hypersensitivity syndrome (AHS), and new research suggests HLA-B*5801 is a strong risk factor for this condition; in some populations, almost all patients who develop AHS carry this allele. This discovery could influence the treatment of gout, in particular, how allopurinol is used.
PMCID: PMC3899695  PMID: 23399693
Allopurinol; HLA-B*58:01; allopurinol hypersensitivity syndrome; severe cutaneous adverse reactions; adverse events; side effects; hypersensitivity reaction; Stevens-Johnson syndrome; toxic epidermal necrolysis; TEN; SJS; complications
7.  Cellular and molecular aspects of vascular dysfunction in systemic sclerosis 
Nature reviews. Rheumatology  2010;6(8):10.1038/nrrheum.2010.102.
Systemic sclerosis (SSc) is characterized by vascular alterations, activation of the immune system and tissue fibrosis. Vascular insufficiency manifests early in the disease, and although there is evidence of an active repair process, capillaries deteriorate and regress. Factors that contribute to the failure of vascular regeneration might include persistent injury, an imbalance between proangiogenic and antiangiogenic mediators, intrinsic abnormal properties of the cellular components of the vessels, and the presence of fibroblast-derived antiangiogenic factors. In addition, circulating dysfunctional endothelial progenitor cells might further exacerbate vessel deterioration. Abnormal expression of transcription factors, including Fra2 and Fli1, has been proposed to contribute to SSc vasculopathy. Fli1 regulates genes that are involved in vessel maturation and stabilization, suggesting that reduced levels of Fli1 in SSc vasculature could contribute to the development of unstable vessels that are prone to regression. Conversely, proliferating endothelial cells and pericytes, in the presence of an appropriate stimulus, might transdifferentiate into collagen-producing cells, and thus contribute to the initiation of fibrosis. Despite progress in treating the symptoms of vascular disease in SSc, the underlying mechanisms remain poorly understood. An improved knowledge of the molecular and cellular pathways that contribute to SSc vasculopathy could help in the design of effective therapies in the future.
PMCID: PMC3824624  PMID: 20585340
8.  SSc—fibrosis takes flight with Wingless inhibition 
Nature reviews. Rheumatology  2012;8(8):441-442.
Recent studies have highlighted a potentially important role for Wnts as profibrotic mediators, and implicated increased Wnt activity in systemic sclerosis and other fibrotic diseases. Strikingly, new data indicates that Wnts have a central role in the profibrotic activity of TGF-β.
PMCID: PMC3792167  PMID: 22751566
9.  The role of the immune system in atherosclerosis: molecules, mechanisms and implications for management of cardiovascular risk and disease in patients with rheumatic diseases 
Nature reviews. Rheumatology  2012;8(4):214-223.
Rapid-onset cardiovascular disease is a major concern for many patients suffering from SLE. Cardiovascular events are more frequent and occur much earlier in SLE patients compared to healthy controls. Traditional risk factors such as altered lipid levels, older age and smoking do not fully explain the increased risk of cardiovascular disease, strongly suggesting that autoimmunity contributes to accelerated atherosclerosis. Altered immune system function is recognized as the primary contributor to both the initiation and progression of atherosclerosis. Multiple manifestations of autoimmunity, including autoantibodies, altered cytokine levels and innate immunity response, adipokines, dysfunctional lipids, and oxidative stress appear to contribute to atherosclerotic risk. In addition, multiple SLE therapeutics appear to affect the development and progression of atherosclerosis both positively and negatively. SLE-specific biomarkers for identifying patients at risk of developing accelerated atherosclerosis are starting to be identified by multiple groups, and a comprehensive, clinically testable biomarker panel could be invaluable for identifying and treating these patients.
PMCID: PMC3765069  PMID: 22331061
10.  Mechanical signals as anabolic agents in bone 
Nature reviews. Rheumatology  2010;6(1):50-59.
Aging and a sedentary lifestyle conspire to reduce bone quantity and quality, decrease muscle mass and strength, and undermine postural stability, culminating in an elevated risk of skeletal fracture. Concurrently, a marked reduction in the available bone-marrow-derived population of mesenchymal stem cells (MSCs) jeopardizes the regenerative potential that is critical to recovery from musculoskeletal injury and disease. A potential way to combat the deterioration involves harnessing the sensitivity of bone to mechanical signals, which is crucial in defining, maintaining and recovering bone mass. To effectively utilize mechanical signals in the clinic as a non-drug-based intervention for osteoporosis, it is essential to identify the components of the mechanical challenge that are critical to the anabolic process. Large, intense challenges to the skeleton are generally presumed to be the most osteogenic, but brief exposure to mechanical signals of high frequency and extremely low intensity, several orders of magnitude below those that arise during strenuous activity, have been shown to provide a significant anabolic stimulus to bone. Along with positively influencing osteoblast and osteocyte activity, these low-magnitude mechanical signals bias MSC differentiation towards osteoblastogenesis and away from adipogenesis. Mechanical targeting of the bone marrow stem-cell pool might, therefore, represent a novel, drug-free means of slowing the age-related decline of the musculoskeletal system.
PMCID: PMC3743048  PMID: 20046206
11.  Genetics 
Nature reviews. Rheumatology  2010;6(12):678-679.
Genome-wide association studies of human diseases have uncovered large numbers of common genetic variants with low effect sizes; however, rare genetic variants with large effect sizes may have greater relevance with respect to disease heritability. The identification and characterization of rare variants such as SIAE is, therefore, likely to be a major endeavor in the field in the coming years.
PMCID: PMC3708796  PMID: 21119715
12.  Adult outcomes of childhood-onset rheumatic diseases 
Nature reviews. Rheumatology  2011;7(5):290-295.
A number of studies published over the past 10 years have examined the long-term health, functional and quality of life outcomes of adults with childhood-onset rheumatic diseases such as juvenile idiopathic arthritis, systemic lupus erythematosus, juvenile dermatomyositis and localized scleroderma. As increasing numbers of patients with these conditions survive into adulthood, understanding the adult outcomes of these pediatric conditions has become ever-more important. Identifying modifiable risk factors for poor outcomes is vital to improving care for these patients. In addition, as these conditions and their treatments can affect cardiovascular health, bone health and fertility, particular attention needs to be paid to these outcomes. Preparing patients and their families for a successful transition from pediatric to adult rheumatology care is an important first-step in the long-term management strategy for this expanding patient population.
PMCID: PMC3705738  PMID: 21487383
13.  Mechanistic biomarkers for clinical decision making in rheumatic diseases 
Nature reviews. Rheumatology  2013;9(5):267-276.
The use of biomarkers is becoming increasingly intrinsic to the practice of medicine and holds great promise for transforming the practice of rheumatology. Biomarkers have the potential to aid clinical diagnosis when symptoms are present or to provide a means of detecting early signs of disease when they are not. Some biomarkers can serve as early surrogates of eventual clinical outcomes or guide therapeutic decision making by enabling identification of individuals likely to respond to a specific therapy. Using biomarkers might reduce the costs of drug development by enabling individuals most likely to respond to be enrolled in clinical trials, thereby minimizing the number of participants required. In this Review, we discuss the current use and the potential of biomarkers in rheumatology and in select fields at the forefront of biomarker research. We emphasize the value of different types of biomarkers, addressing the concept of ‘actionable’ biomarkers, which can be used to guide clinical decision making, and ‘mechanistic’ biomarkers, a subtype of actionable biomarker that is embedded in disease pathogenesis and, therefore, represents a superior biomarker. We provide examples of actionable and mechanistic biomarkers currently available, and discuss how development of such biomarkers could revolutionize clinical practice and drug development.
PMCID: PMC3673766  PMID: 23419428
14.  Evidence for a genetic component to disease severity in RA 
Nature reviews. Rheumatology  2012;8(6):312-313.
Rheumatoid arthritis (Ra) is partly heritable; genetic and serological markers are known to confer risk of developing pathology. But given clinical heterogeneity in Ra, can we predict who will develop severe disease? Substantial heritability of erosive progression rates has now been identified, but better prognostic biomarkers remain wanting.
PMCID: PMC3668790  PMID: 22647779
15.  Fat Targets for Skeletal Health 
Nature reviews. Rheumatology  2009;5(7):365-372.
Emerging evidence points to a critical role for the skeleton in several homeostatic processes including energy balance. The connection between fuel utilization and skeletal remodeling begins in the bone marrow with lineage allocation of mesenchymal stromal cells into adipocytes or osteoblasts. Mature bone cells secrete factors that influence insulin sensitivity and fat cells synthesize cytokines that regulate osteoblast differentiation. The emerging importance of the bone-fat interaction suggests that novel molecules could be used as targets to enhance bone formation and possibly prevent fractures. In this review, we discuss three pathways that could favor pharmacologic intervention with the ultimate goal of enhancing bone mass and reducing osteoporotic fracture risk. Not surprisingly, because of the complex interactions across homeostatic networks, other pathways will likely be activated by this targeting and these could prove to be beneficial or detrimental for the organism. Hence a more complete picture of energy utilization and skeletal remodeling will be required to bring these potential agents into any future clinical armamentarium.
PMCID: PMC3661210  PMID: 19468288
16.  Uric acid as a danger signal in gout and its comorbidities 
Nature reviews. Rheumatology  2012;9(1):13-23.
Uric acid is a waste product of purine catabolism. This molecule comes to clinical attention when it nucleates to form crystals of monosodium urate (MSU) in joints or other tissues and thereby causes the inflammatory disease of gout. Patients with gout also frequently suffer from a number of co-morbid conditions including hypertension, diabetes mellitus and cardiovascular disease. Why MSU crystals trigger inflammation and are associated with comorbidities of gout has been unclear, but recent studies provide new insights these issues. Rather than simply being a waste product, uric acid could serve a pathophysiological role as a local alarm signal that alerts the immune system to cell injury and helps to trigger both innate and adaptive immune responses. The inflammatory component of these immune responses is caused when urate crystals trigger both inflammasome-dependent and independent pathways to generate the proinflammatory cytokine IL-1. The resulting bioactive IL-1 stimulates the inflammation of gout and might contribute to the development of other comorbidities. Surprisingly, the same mechanisms underlie the inflammatory response to a number of irritant particles, many of which also cause disease. These new insights help to explain the pathogenesis of gout and point to potential new therapeutic targets for this and other sterile inflammatory diseases.
PMCID: PMC3648987  PMID: 22945591
17.  [No title available] 
PMCID: PMC3645862  PMID: 22945592
18.  Type I interferons: crucial participants in disease amplification in autoimmunity 
Nature reviews. Rheumatology  2010;6(1):40-49.
A significant body of data implicates the type I interferon (IFN) pathway in the pathogenesis of autoimmune rheumatic diseases. In these disorders, a reinforcing cycle of IFN production can contribute to immunopathology through multiple mechanisms. The type I IFN cytokines are pleiotropic in their effects, mediating anti-viral and anti-tumor activities, and possessing numerous immunomodulatory functions for both the innate and adaptive immune responses. A key principle of the type I IFN system is rapid induction and amplification of the signaling pathway, which generates a feed-forward loop of IFN production, ensuring that a vigorous anti-viral immune response is mounted. While such feed-forward pathways are highly adaptive when it comes to rapid and effective virus eradication, this amplification can be maladaptive in immune responses directed against host tissues. Such feed-forward loops, however, create special opportunities for therapy.
PMCID: PMC3622245  PMID: 20046205
19.  Skin and Bones (and Cartilage): The Dermal Fibroblast Connection 
Nature reviews. Rheumatology  2009;5(9):471-472.
PMCID: PMC3612427  PMID: 19710666
20.  Follicular helper T cells in immunity and systemic autoimmunity 
Nature reviews. Rheumatology  2012;8(6):337-347.
Follicular helper T (TFH) cells are essential for B-cell maturation and immunoglobulin production after immunization with thymus-dependent antigens. Nevertheless, the development and function of TFH cells have been less clearly defined than classic CD4+ effector T-cell subsets, including T-helper-1 (TH1), TH2 and TH17 cells. As such, our understanding of the genesis of TFH cells in humans and their role in the development of autoimmunity remains incomplete. However, evidence from animal models of systemic lupus erythematosus (SLE) and patients with systemic autoimmune diseases suggests that these cells are necessary for pathogenic autoantibody production, in a manner analogous to their role in promotion of B-cell maturation during normal immune responses. In this Review, I discuss the findings that have increased our knowledge of TFH-cell development and function in normal and aberrant immune responses. Such information might improve our understanding of autoimmune diseases, such as SLE, and highlights the potential of TFH cells as therapeutic targets in these diseases.
PMCID: PMC3604997  PMID: 22549246
21.  Macro view of microRNA’s function in Osteoarthritis 
Nature reviews. Rheumatology  2012;8(9):543-552.
Osteoarthritis (OA) is the most common musculoskeletal disorder. It is a complex and multifaceted disease, characterized by the degradation of articular cartilage and joint inflammation. Although few pathogenesis pathways have been characterized, current knowledge is incomplete and has not led to effective approaches for prevention or treatment. These limitations can be overcome by advances in the understanding of molecular mechanisms that are involved in the maintenance and destruction of articular cartilage. Understanding extracellular regulators and intracellular signaling mechanisms in joint cells that control cartilage homeostasis has the potential to lead to the identification of new therapeutic targets for OA. Recently, non-coding RNAs, miRNAs, was noted to act as novel regulatory molecules that regulated the expression of several target genes. The major role of miRNAs is to control development and tissue homeostasis through the ‘fine-tuning’ of the gene expression. Several miRNAs exhibit a tissue- or developmental stage-specific expression pattern and have been associated with diseases such as cancer and cardiovascular disorders. This review is based on our observations that miRNAs play an important role in cartilage homeostasis, and is to summarize the information on miRNA involved in OA pathogenesis, and its clinical approach.
PMCID: PMC3572197  PMID: 22890245
Osteoarthritis; Cartilage; Chondrocytes; microRNA; miR-140
22.  Inherited human diseases of heterotopic bone formation 
Nature reviews. Rheumatology  2010;6(9):518-527.
Human disorders of hereditary and nonhereditary heterotopic ossification are conditions in which osteogenesis occurs outside of the skeleton, within soft tissues of the body. The resulting extraskeletal bone is normal. The aberration lies within the mechanisms that regulate cell-fate determination, directing the inappropriate formation of cartilage or bone, or both, in tissues such as skeletal muscle and adipose tissue. Specific gene mutations have been identified in two rare inherited disorders that are clinically characterized by extensive and progressive extraskeletal bone formation—fibrodysplasia ossificans progressiva and progressive osseous heteroplasia. In fibrodysplasia ossificans progressiva, activating mutations in activin receptor type-1, a bone morphogenetic protein type I receptor, induce heterotopic endochondral ossification, which results in the development of a functional bone organ system that includes skeletal-like bone and bone marrow. In progressive osseous heteroplasia, the heterotopic ossification leads to the formation of mainly intramembranous bone tissue in response to inactivating mutations in the GNAS gene. Patients with these diseases variably show malformation of normal skeletal elements, identifying the causative genes and their associated signaling pathways as key mediators of skeletal development in addition to regulating cell-fate decisions by adult stem cells.
PMCID: PMC3551620  PMID: 20703219
23.  Connective tissue diseases: Predicting death in SSc: planning and cooperation are needed 
Nature reviews. Rheumatology  2011;7(11):628-630.
Systemic sclerosis is associated with a high level of patient mortality. A promising prognostic model that could enable more effective management and improve survival was recently validated; however, the results demonstrate that choosing the best cohorts for development and validation of predictors of mortality is essential.
PMCID: PMC3544157  PMID: 21971285
24.  Neutrophils in the pathogenesis and manifestations of SLE 
Nature reviews. Rheumatology  2011;7(12):691-699.
Systemic lupus erythematosus (SLE) is an autoimmune disease of unclear etiology that affects mostly women of childbearing age. Profound abnormalities in both innate and adaptive immunity triggered by genetic and environmental factors are well documented to play an important part in the pathogenesis of SLE. Nonetheless, the role of neutrophils—the most abundant immune cell type—in the pathology of this disease has been unclear. Over the past decade, compelling evidence has emerged that implicates neutrophils in the initiation and perpetuation of SLE and also in the resultant organ damage frequently observed in patients with this disease. SLE-derived low-density granulocytes (LDGs) induce vascular damage and synthesize increased amounts of type I interferons and, as such, could play a prominent part in the pathogenesis of SLE. Furthermore, increased cell death and enhanced extracellular trap formation observed in SLE-derived neutrophils might have key roles in the induction of autoimmunity and the development of organ damage in patients with SLE. Together, these events could have significant deleterious effects and promote aberrant immune responses in this disease. This Review highlights the role of neutrophils in the pathogenesis of SLE, with a particular focus on the putative deleterious effects of LDGs and neutrophil extracellular trap formation.
PMCID: PMC3243068  PMID: 21947176
25.  Validation of new biomarkers in systemic autoimmune diseases 
Nature reviews. Rheumatology  2011;7(12):708-717.
Biomarkers have an important influence on the clinical decision-making processes involved in diagnosis, assessment of disease activity, allocation of treatment, and determining prognosis. The clinical usefulness of a biomarker is dependant on demonstration of its validity. Ideally, biomarkers should provide information not available from currently available tests and should be tested as they would be used in clinical practice; however, potential biomarkers could be affected by many different clinical or patient variables—such as disease activity, therapeutic intervention, or the presence of comorbidities—and validation studies might not include all the design features that are required to ensure that the biomarker is a true measure of the clinical process it is intended to reflect. In this Review, we appraise studies that have been conducted to validate six promising new biomarkers for diagnosis, disease activity assessment, or prognosis in patients with systemic autoimmune diseases. We discuss the validity of these six biomarkers with particular reference to the features of the studies that lend weight to or distract from their findings. The intent of this discussion is to draw attention to elements of validation study design that should be considered when evaluating the robustness of a biomarker, which differ according to the marker's intended use.
PMCID: PMC3441180  PMID: 22045310

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