Nature Reviews Rheumatology

Published by Nature Publishing Group
Online ISSN: 1759-4804
Publications
Article
Osteoporosis is a major public health problem through associated fragility fractures. The most common sites of fracture are the hip, spine and wrist, and these have an enormous health and economic impact. All fractures result in some degree of morbidity, but fractures at the hip are associated with the worst outcomes. The worldwide direct and indirect annual costs of hip fracture in 1990 were estimated at US$34.8 billion, and are expected to increase substantially over the next 50 years. Fracture incidence varies between populations, and is set to increase over coming decades as the global population becomes more elderly. This effect will be particularly marked in the developing world, which is additionally assuming more-westernized lifestyles that predispose to increased fracture risk. Strategies to target those at high risk of fracture have been developed, but preventative measures at the public health level are also urgently needed to reduce the burden of this devastating disease.
 
Article
Familial Mediterranean fever (FMF) is the most common of the hereditary periodic fever syndromes. Although the typical clinical course of FMF is characterized by bouts of painful inflammation, this presentation represents only the tip of the iceberg. In many patients inflammation can persist in attack-free periods, as shown by high levels of acute-phase proteins, cytokines and inflammation-induced proteins. This subclinical inflammation puts patients at risk of developing complications such as anemia, splenomegaly, decreased bone mineral density, heart disease and life-threatening amyloid A amyloidosis, among others. In this article, we review the published data on markers and other factors involved in the persistence of inflammation in patients with FMF during attack-free periods, examine the risk factors for the development of this subclinical inflammation, summarize the complications of chronic inflammation in FMF and propose a new strategy for treatment, based on these data.
 
Article
Synovial fibroblasts are known to have a role in cartilage destruction in the setting of inflammatory arthritis, mainly via production of IL-6. Cadherin 11 (CDH11), which is selectively expressed on fibroblasts, has been implicated as an important mediator of inflammation: anti-CDH11 monoclonal antibodies reduced inflammation in a mouse model of arthritis, and mice deficient in CDH11 exhibited reduced damage to articular cartilage.
 
Article
Belimumab was recently shown to reduce disease activity in patients with systemic lupus erythematosus. This observation raises important questions about where belimumab might best fit into the treatment paradigm for this disease, and how the agent might compare to other biologic agents currently under investigation.
 
Article
A disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS-4, also known as aggrecanase-1) is a key proteinase involved in cartilage damage. New data suggest microRNAs (miRNAs) could mediate expression of this enzyme and development of osteoarthritis (OA).
 
Article
The main inflammatory myopathies within the myositis group include polymyositis, dermatomyositis and inclusion-body myositis (IBM). Although potentially treatable, various practical issues have an impact on the response of these conditions to therapy. The most common reason for therapeutic failure is that the treatment targets the wrong disease, often owing to poor distinction of polymyositis from difficult-to-treat mimics such as sporadic IBM, necrotizing myopathies and inflammatory dystrophies. Evidence from uncontrolled studies suggests that polymyositis and dermatomyositis respond to treatment with prednisone at least to some degree. Empirically, adding an immunosuppressive drug might offer a 'steroid-sparing' effect or perhaps additional benefit. Intravenous immunoglobulin is proven effective as a second-line agent in patients with dermatomyositis and also seems to be effective for those with polymyositis, but offers only minimal and transient benefit to a small proportion of patients with IBM. Small, uncontrolled series suggest other agents such as rituximab or tacrolimus might offer some benefit in disease refractory to the aforementioned therapies, although IBM is resistant to most therapies. Novel agents are emerging as potential treatment options for all forms of myositis. This Review highlights common pitfalls in therapy, discusses emerging new therapies, and provides a practical therapeutic algorithm.
 
Article
Targeting microRNA 155 (miR-155) might be a route to blocking aberrant cytokine expression in rheumatoid arthritis (RA). After studying mouse models and synovial biopsies from patients with RA or osteoarthritis, Iain McInnes and colleagues report in Proceedings of the National Academy of Sciences that this post-transcriptional regulator has a critical role in antigen-dependent arthritis and cytokine-driven joint inflammation.
 
Article
Tumor necrosis factor (TNF) blockers are widely used to treat rheumatoid arthritis and other chronic inflammatory diseases. Many studies have demonstrated an increased risk of opportunistic infections such as tuberculosis and fungal infection in patients treated with TNF blockers, which is thought to be related to the primary role of TNF both in host defense and in the immune response. Little is known, however, about the association between TNF blockade and the development of viral infection. Owing to the critical role of TNF in the control of viral infection, depletion of this cytokine with TNF blockers could facilitate the development or reactivation of viral infection. A number of large observational studies have found an increased risk of herpes zoster in patients receiving TNF blockers for the treatment of rheumatoid arthritis. This Review draws attention to the risk of several viral infections, including HIV, varicella zoster virus, Epstein-Barr virus, cytomegalovirus, and human papillomavirus, in patients receiving TNF-blocking therapy for chronic inflammatory conditions. In addition, implications for clinical practice and possible preventative approaches are discussed.
 
Article
The role of tumor necrosis factor (TNF) in the development and progression of rheumatoid arthritis (RA), and the therapeutic benefits of blocking this proinflammatory cytokine, are well established. However, not all patients with RA respond to anti-TNF therapy, indicating that other cytokines are also involved in the inflammation, cartilage damage and joint destruction in this disease.
 
Article
The discovery that the IL-23-IL-17 immune pathway is involved in many models of autoimmune disease has changed the concept of the role of T-helper cell subsets in the development of autoimmunity. In addition to TH17 cells, IL-17 is also produced by other T cell subsets and innate immune cells; which of these IL-17-producing cells have a role in tissue inflammation, and the timing, location and nature of their role(s), is incompletely understood. The current view is that innate and adaptive immune cells expressing the IL-23 receptor become pathogenic after exposure to IL-23, but further investigation into the role of IL-23 and IL-17 at different stages in the development and progression of chronic (destructive) inflammatory diseases is needed. Rheumatoid arthritis (RA) and spondyloarthritis (SpA) are the two most common forms of chronic immune-mediated inflammatory arthritis, and the IL-23-IL-17 axis is thought to have a critical role in both. This Review discusses the basic mechanisms of these cytokines in RA and SpA on the basis of findings from disease-specific animal models as well as human ex vivo studies. Promising therapeutic applications to modulate this immune pathway are in development or have already been approved. Blockade of IL-17 and/or TH17-cell activity in combination with anti-TNF therapy might be a successful approach to achieving stable remission or even prevention of chronic immune-mediated inflammatory diseases.
 
Article
The discovery of interleukin (IL)-17 and its major cell source, the type 17 T-helper (TH17) lymphocyte, has been a major step in the understanding of erosive arthritis. This Review summarizes current knowledge of the role of IL-17 in this context derived from both animal models and studies in patients with rheumatoid arthritis. Evidence shows that IL-17 is present at sites of inflammatory arthritis and that, in synergistic interactions, it amplifies the inflammation induced by other cytokines, primarily tumor necrosis factor. In several animal models of arthritis, inhibition of IL-17 limits inflammation and joint erosion. Initial observations from phase I trials show that signs and symptoms of RA are significantly suppressed following treatment with anti-IL-17 antibodies, without notable adverse effects. The emergence of IL-17 blockade as a future therapy in rheumatoid arthritis is highlighted, along with the potential goals and limitations of this therapeutic approach.
 
Article
When searching for the cellular source of interleukin (IL)-17A in the inflamed synovium of patients with rheumatoid arthritis (RA), CD4⁺ type 17 T helper (TH17) cells are obvious possible culprits. However, research from the University of Glasgow, UK, published in the Journal of Immunology, identifies mast cells, not T cells, as the primary source of this proinflammatory cytokine in individuals with established disease.
 
Article
Type 17 T helper (TH17) cells are a population of CD4+ effector T cells that are distinct from TH1 and TH2 cells owing to their ability to produce interleukin (IL)-17. Although TH1 and TH2 cells are similar in mice and humans, TH17 cells differ in several ways. The differentiation of mouse TH17 cells requires transforming growth factor beta and IL-6, whereas human naive T cells can develop into TH17 cells in the presence of IL-1beta and IL-23 alone, transforming growth factor beta having an indirect role in their development via the selective inhibition of TH1 cell expansion. in both mice and humans, a late developmental plasticity of TH17 cells towards the TH1 lineage has been shown. Mainly based on mouse gene knockout studies, TH17 lymphocytes have been found to have a pathogenic role in several autoimmune disorders; however, whether human autoimmune disorders, including rheumatoid arthritis (RA) and psoriasis, are prevalently TH1-mediated or TH17-mediated, is still unclear. research suggests that both TH1 and TH17 cells are involved in RA pathogenesis, raising the possibility that interventions that target both the IL-23-IL-17 (TH17) and the IL-12-interferon gamma (TH1) axes might be successful future therapeutic approaches for RA.
 
Article
The proinflammatory cytokine IL-17 has an important role in pathogenesis of several inflammatory diseases. In immune-mediated joint diseases, IL-17 can induce secretion of other proinflammatory cytokines such as IL-1, IL-6 and TNF, as well as matrix metalloproteinase enzymes, leading to inflammation, cartilage breakdown, osteoclastogenesis and bone erosion. In animal models of inflammatory arthritis, mice deficient in IL-17 are less susceptible to development of disease. The list of IL-17-secreting cells is rapidly growing, and mast cells have been suggested to be a dominant source of IL-17 in inflammatory joint disease. However, many other innate sources of IL-17 have been described in both inflammatory and autoinflammatory conditions, raising questions as to the role of mast cells in orchestrating joint inflammation. This article will critically assess the contribution of mast cells and other cell types to IL-17 production in the inflammatory milieu associated with inflammatory arthritis, understanding of which could facilitate targeted therapeutic approaches.
 
Network of comparisons for RCTs in psoriasis, PsA, and AS. Each therapeutic agent is represented as a node (blue circle), and links between the nodes (lines) indicate that RCTs exist comparing the two connected treatments. The number on each link indicates the number of RCT comparisons recorded to date. Data are shown for all registered trials (published and unpublished) in the left panels, and for published trials only in the right panels. These networks indicate that comparisons with placebo are the norm in clinical trials in these diseases, consistently comprising >90% of the published evidence; this trend seems to be generally consistent across other rheumatic diseases. Abbreviations: AS; ankylosing spondylitis; NB–UVB, narrowband ultraviolet B; PsA, psoriatic arthritis; RCTs, randomized controlled trials.
| Total and published RCTs of anti-TNF agents in each rheumatic disease indication*
Published meta-analyses of trials of biologic agents in psoriasis and RA. a | Cumulative number of meta-analysis publications on trials of biologic therapies in psoriasis. b | Cumulative number of meta-analysis publications on trials of biologic agents in RA. We identified 23 and 104 meta-analyses that were published by the end of 2012 in psoriasis and RA, respectively, with a rapid increase in the number of such publications observed in the preceding 2 years. See 'Review criteria' section for a description of the literature search used to obtain the data shown. Abbreviation: RA, rheumatoid arthritis.
Article
Anti-TNF agents and other biologic therapies are widely prescribed for a variety of indications, with total sales that exceed $200 billion to date. In rheumatic diseases, biologic agents have now been studied in more than 200 randomized clinical trials and over 100 subsequent meta-analyses; however, the information obtained does not always meet the needs of patients and clinicians. In this Review, we discuss the current issues concerning the evidence derived from such studies: potential biases favouring positive results; a paucity of head-to-head comparisons between biologically active agents; overwhelming involvement of manufacturer sponsors in trials and in the synthesis of the evidence; the preference for trials with limited follow-up; and the potential for spurious findings on adverse events, leading to endless debates about malignancy risk. We debate the responsibilities of regulatory authorities, the pharmaceutical industry and academia in attempting to solve these shortcomings and challenges. We propose that improvements in the evidence regarding biologic treatments that are continually being added to the therapeutic armamentarium for rheumatic diseases might require revisiting the design and conduct of studies. For example, trials with long-term follow-up that are independent of the pharmaceutical industry, head-to-head comparisons of therapeutic agents and the use of rigorous clinical outcomes should be considered, and public availability of raw data endorsed.
 
Article
Few, if any, areas of medical therapeutics have witnessed such dramatic changes as those that have occurred in the therapy of rheumatoid arthritis (RA) during the past two decades. Improvements in clinical trials methodologies, the introduction of no fewer than nine biologic agents with distinct mechanisms of action, and the development of better strategies for the use of such agents have all contributed to the new age in RA therapeutics. Here, we review these developments and attempt to describe the current landscape of RA therapy in terms of available treatments, agreed-upon principles of RA management, as well as some important controversies in this field. Despite the great pace at which developments are moving, a treatment-free remission for patients with RA remains an elusive goal and unmet medical needs remain. The quest for better therapies for this potentially devastating disease is still as important as ever; research in this exciting area is ongoing, and it is reasonable to hope that, during the next decade, developments will lead to improved, rationally designed, targeted therapies for RA.
 
Article
The term spondyloarthritis (SpA) encompasses conditions including ankylosing spondylitis (AS), reactive arthritis, arthritis and/or spondylitis associated with inflammatory bowel disease (IBD), some forms of psoriatic arthritis and undifferentiated SpA. The newly developed ASAS (Assessment of SpondyloArthritis International Society) classification scheme proposes to split the spondyloarthritides according to the leading clinical manifestations, that is, either predominantly axial or predominantly peripheral, with or without the presence of associated diseases such as psoriasis, IBD or previous infections.
 
| Criteria sets for the classification of fibromyalgia published before 1990
Article
Fibromyalgia is a disorder characterized by chronic widespread pain in the presence of widespread tenderness, and multiple somatic symptoms. Since the publication of the American College of Rheumatology (ACR) 1990 classification criteria for fibromyalgia, research has proliferated and, in a relatively short period, investigators have begun to unravel the etiology and long-term impact of this complex condition. Although the ACR 1990 criteria have been central to fibromyalgia research during the past two decades, a number of practical and philosophical objections have been raised in relation to them. Principally these objections have centered on the use (or lack thereof) of the tender point examination, the lack of consideration of associated symptoms, and the observation that fibromyalgia might represent the extreme end of a pain continuum. In developing the ACR 2010 criteria, experts have sought to address these issues and to simplify clinical diagnosis. An implicit aim was to facilitate more rigorous study of etiology. The purpose of this Review is to summarize research to date that has described the epidemiology, pathology and clinical course of fibromyalgia, and to assess the probable impact of the ACR 2010 criteria on future research efforts.
 
Article
In several areas of investigation, the results of a bumper year in osteoporosis research are set to stoke rather than settle debate. From the origins of bone health to the use of established and experimental therapies, the new findings will be discussed into 2011 and beyond.
 
Article
Important advances have been made in gout therapeutics in 2010. In addition to the development of novel biologic agents, progress has been made in the safe prescribing of colchicine. However, colchicine also became the subject of considerable controversy in the USA when one brand of this drug was granted exclusivity.
 
Article
In 2010, important research into the systemic autoinflammatory diseases has confirmed and extended the role of IL-1 inhibition in hereditary autoinflammatory disorders, demonstrated a novel treatment for a dangerous complication, and expanded the spectrum of systemic autoinflammatory diseases while further implicating autoinflammation in the complications of the metabolic syndrome.
 
Article
How can we optimize the management of osteoarthritis? Recent studies into the efficacy and mechanisms of interventions that target nociceptive mechanisms, lower-extremity musculature and ligament integrity reflect the progress being made in this field.
 
Article
The 1987 ACR classification criteria for rheumatoid arthritis were criticized for their lack of sensitivity in early disease. To overcome this limitation, new criteria have now been developed. The question is how will these criteria be implemented in clinical and basic research, and in daily clinical practice?
 
Article
From evidence pointing to a possible etiologic role for microbes to the development of new strategies and agents to treat early and established disease, 2010 has seen the publication of several interesting findings in the field of rheumatoid arthritis.
 
Article
Advances in therapy mean a state of remission is increasingly an achievable goal in rheumatoid arthritis. However, using remission as a target of treatment begs the question of how this state should be defined. The fruits of a transcontinental collaboration have brought a uniform definition a step closer.
 
Article
Findings from ongoing studies of imatinib in systemic sclerosis (SSc) were eagerly awaited in 2011, but results from these clinical trials have so far been disappointing. However, progress in the understanding of the mechanisms that underlie SSc pathogenesis could provide clues to novel targets for 2012 and beyond.
 
Article
From neutrophil extracellular traps to genetic networks that underlie the disease and new targeted therapies, important advances in 2011 improve our understanding of the pathogenesis of systemic lupus erythematosus and mark the beginning of our ability to treat it effectively.
 
Article
In 2011, the year that subtypes of ANCA-associated vasculitis (AAV) were officially renamed according to key pathological characteristics, important progress was made not only in differentiating these subtypes, but also in understanding—and treating—their eponymous manifestations.
 
Article
Evidence presented in 2011 suggests that rheumatoid arthritis might comprise two separate diseases—each with different etiological underpinnings—and that kinase inhibitors could soon be added to the therapeutic armamentarium. Together with new definitions of remission, these advances could aid the development of personalized, treat-to-target strategies.
 
Article
That primary osteoarthritis (OA) is an age-related disorder is undoubted, but how aging contributes to OA is poorly understood. New insights from 2011 offer potential explanations, novel models for study, and the suggestion that a deeper understanding of what 'aging' actually is might pave the way to everlasting joints.
 
Article
In 2011, new treatment recommendations for juvenile idiopathic arthritis (JIA) were proposed, inroads were made towards understanding the heterogeneity of this disease, and data were presented demonstrating the potential efficacy of DMARD combination therapies for JIA treatment. These advances hold promise for improved management of JIA in 2012 and beyond.
 
Article
Advances in 2012 have helped to solve several established mysteries in spondyloarthritis (SpA) - why T-cell-directed therapies have not delivered the expected efficacy and how the IL-23-IL-17 cytokine axis is linked to the specific pathology of SpA. The opportunity to influence disease progression at inflammatory lesions using anti-TNF agents may be fleeting.
 
Article
Tissue engineering and regenerative medicine have advanced rapidly towards the development of therapeutic solutions for musculoskeletal disorders. In 2012, breakthroughs have been made in the guidance of adult stem cell homing, the tissue regenerative activity of stem-cell-derived extracellular matrix has been tested, and novel, mechanically superior biomaterials have been fabricated.
 
Article
A number of microRNAs have been implicated in the pathogenesis of various rheumatic diseases, and evidence in support of the therapeutic potential of microRNA-based strategies for these conditions is growing, as demonstrated by several new findings published in 2012.
 
Article
In 2012, several new concepts emerged that widen our view of the regulation of bone mass in health and disease. Three key studies outline these discoveries, which affect our understanding of the skeletal system, particularly its physiological function and the changes it undergoes during inflammatory disease.
 
Article
Several advances in 2013 have improved our understanding of how epigenetic mechanisms affect autoimmune disorders. Many new insights were made into the regulation of gene expression by DNA methylation in systemic lupus erythematosus. For rheumatoid arthritis, complex interrelationships between DNA methylation and microRNAs in regulating gene expression were described.
 
Article
Clinical, basic and translational research in systemic lupus erythematosus are fast-moving fields. 2013 has seen the publication of some potentially landmark papers, which not only explore the potential of novel agents but also glean new insights from past trials.
 
Article
With every passing year, research on the pathogenesis of rheumatoid arthritis benefits from discoveries in other scientific fields. Three of the best examples that illustrate the benefit of such interdisciplinary bridges and the effects they have on our understanding of rheumatoid arthritis are presented here.
 
Article
2013 has witnessed the maturation of imaging science with rheumatology research, in part due to large, public databases. Using imaging in osteoarthritis (OA) as an example, breakthroughs include further elucidation of the relationship between obesity and OA, and identification of the importance of bone and meniscus shape in OA development.
 
Article
In 2013, much progress has occurred in gout research. Imaging continues to help elucidate aspects of pathophysiology and now suggests that healing of erosions could occur when urate levels are reduced dramatically. New genetic loci associated with hyperuricaemia have been identified and management strategies for prophylaxis of gout flares continue to evolve.
 
Autoinflammatory and autoimmune features of three new monogenic diseases. Distinguishing features can be used to classify these conditions as either autoinflammatory or autoimmune. Some features overlap both categories, and AGS7 has the potential to progress from being driven by innate immunity to being an antibody-mediated disease. Abbreviations: ADA2, adenosine deaminase 2; AGS7, Aicardi–Goutières syndrome 7; CTLA-4, cytotoxic T-lymphocyte protein 4; dsRNA, double-stranded RNA; IFN, interferon; TREG cell, T regulatory cell.
Article
Three monogenic diseases, with features of both autoinflammation and autoimmunity, were described for the first time in 2014. As well as providing insights into the molecular basis of several rare immunological disorders, the discoveries have implications for their diagnosis and treatment.
 
Article
Even though activation of immunity is associated with bone destruction, new mechanisms have been described in 2014 through which immunology-associated pathways can cooperate to support osteogenesis. These advances support the view of the immune system as a central mechanism which can regulate bone homeostasis, regeneration and destruction.
 
Article
The treatment and study of systemic sclerosis (SSc) is entering a new era with the reporting and preparation of several randomized controlled trials according to an improved understanding of SSc pathogenesis. Advances in trial designs reported in 2014 should now be built upon with further improvements to patient selection to enable targeting of therapies to specific subgroups of patients with SSc.
 
Article
2014 saw the emergence of a novel rheumatoid arthritis therapy to rival methotrexate, as well as advances in our understanding of mouse T-cell biology and of the cross-talk between the nervous system and the immune system. How will these advances affect the future of rheumatoid arthritis research and therapy?
 
Article
Important advances in 2014 foster new perspectives on definitions of early and end-stage disease, and promote a shift in the clinical management of osteoarthritis (OA) through implementing treatment algorithms intended to minimize strain on current health-care models. Collectively, these changes shed new light on developing and optimizing approaches to OA treatment.
 
Article
Optimizing the management of childhood arthritis requires detailed knowledge of the disease in an individual patient. Advances in 2014 show how in-depth genetic studies and insights into immunopathogenesis could translate into clinical biomarkers and, eventually, individualized therapy.
 
Article
Despite advances in our understanding of the pathogenesis of giant cell arteritis (GCA), in terms of the involvement of type 1 T helper (TH1) and type 17 T helper (TH17) cell responses, the cytokines that control these pathways remain unknown. A paper in Arthritis & Rheumatism now identifies a key regulatory role for IL-21 in this process.
 
Article
Advances in our understanding of the pathogenesis of primary Sjögren syndrome (pSS) characterize it as a highly complex process encompassing both the initiation of innate immunity and subsequent adaptive immune responses. IL-21 is receiving attention as a potential key player in the pathogenesis of pSS owing to its pleiotropic effects on the type I interferon signalling pathway, and newly identified roles in generation of follicular and IL-17-producing subtypes of helper T cells, as well as plasma-cell differentiation and B-cell activation. Taking into consideration the diverse biological functions of IL-21 and its clinical relevance to pSS, we propose that this cytokine has a central role in orchestrating the complex immune response in pSS. This hypothesis might provide new insight into the pathogenesis of pSS and facilitate the development of effective therapeutic strategies.
 
Top-cited authors
Mohit Kapoor
  • St. Francis Xavier University
Jean-Pierre Pelletier
  • Université de Montréal
Daniel Lajeunesse
  • Université de Montréal
Francis Berenbaum
  • Sorbonne Université
Michael Doherty
  • University of Nottingham