Showing papers in "Nature Reviews Rheumatology in 2013"
TL;DR: The dual behaviour of FLS in RA suggests that FLS- directed therapies could become a complementary approach to immune-directed therapies in this disease, and progress in targeting these cells is reviewed.
Abstract: 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.
669 citations
TL;DR: Investigations to determine the optimal treatment regimen required to minimize the likelihood of ADA formation might be an effective and practical way to deal with the immunogenicity of anti-TNF biologic agents for RA.
Abstract: Currently, five anti-TNF biologic agents are approved for the treatment of rheumatoid arthritis (RA): adalimumab, infliximab, etanercept, golimumab and certolizumab pegol. Formation of anti-drug antibodies (ADA) has been associated with all five agents. In the case of adalimumab and infliximab, immunogenicity is strongly linked to subtherapeutic serum drug levels and a lack of clinical response, but for the other three agents, data on immunogenicity are scarce, suggesting that further research would be valuable. Low ADA levels might not influence the efficacy of anti-TNF therapy, whereas high ADA levels impair treatment efficacy by considerably reducing unbound drug levels. Immunogenicity is not only an issue in patients treated with anti-TNF biologic agents; the immunogenicity of other therapeutic proteins, such as factor VIII and interferons, is well known and has been investigated for many years. The results of such studies suggest that investigations to determine the optimal treatment regimen (drug dosing, treatment schedule and co-medication) required to minimize the likelihood of ADA formation might be an effective and practical way to deal with the immunogenicity of anti-TNF biologic agents for RA.
356 citations
TL;DR: Mechanistically, paracrine signalling by MSCs might be more important than differentiation in stimulating repair responses; thus,Paracrine factors must be assessed as measures of MSC therapeutic potency, to replace traditional assays based on cell-surface markers and differentiation.
Abstract: Osteoarthritis (OA), a prevalent chronic condition with a striking impact on quality of life, represents an enormous societal burden that increases greatly as populations age. Yet no approved pharmacological intervention, biologic therapy or procedure prevents the progressive destruction of the OA joint. Mesenchymal stem cells (MSCs)-multipotent precursors of connective tissue cells that can be isolated from many adult tissues, including those of the diarthrodial joint-have emerged as a potential therapy. Endogenous MSCs contribute to maintenance of healthy tissues by acting as reservoirs of repair cells or as immunomodulatory sentinels to reduce inflammation. The onset of degenerative changes in the joint is associated with aberrant activity or depletion of these cell reservoirs, leading to loss of chondrogenic potential and preponderance of a fibrogenic phenotype. Local delivery of ex vivo cultures of MSCs has produced promising outcomes in preclinical models of joint disease. Mechanistically, paracrine signalling by MSCs might be more important than differentiation in stimulating repair responses; thus, paracrine factors must be assessed as measures of MSC therapeutic potency, to replace traditional assays based on cell-surface markers and differentiation. Several early-stage clinical trials, initiated or underway in 2013, are testing the delivery of MSCs as an intra-articular injection into the knee, but optimal dose and vehicle are yet to be established.
353 citations
TL;DR: Surprisingly, the same mechanisms underlie the inflammatory response to a number of irritant particles, many of which also cause disease, as well as pointing to potential new therapeutic targets for this and other sterile inflammatory diseases.
Abstract: 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 frequently suffer from a number of comorbid 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 into 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.
342 citations
TL;DR: The view that the modern concept of FJ OA is consonant with the concept of OA as a failure of the whole joint, and not simply of facet joint cartilage is presented.
Abstract: Osteoarthritis (OA) of the spine involves the facet joints, which are located in the posterior aspect of the vertebral column and, in humans, are the only true synovial joints between adjacent spinal levels. Facet joint osteoarthritis (FJ OA) is widely prevalent in older adults, and is thought to be a common cause of back and neck pain. The prevalence of facet-mediated pain in clinical populations increases with increasing age, suggesting that FJ OA might have a particularly important role in older adults with spinal pain. Nevertheless, to date FJ OA has received far less study than other important OA phenotypes such as knee OA, and other features of spine pathoanatomy such as degenerative disc disease. This Review presents the current state of knowledge of FJ OA, including relevant anatomy, biomechanics, epidemiology, and clinical manifestations. We present the view that the modern concept of FJ OA is consonant with the concept of OA as a failure of the whole joint, and not simply of facet joint cartilage.
342 citations
TL;DR: Focusing on elements in the tissue context of GCA, instead of broadly suppressing host immunity, might enable a more tailored therapeutic approach that avoids unwanted adverse effects of aggressive immunosuppression.
Abstract: Vasculitis of the medium and large arteries, most often presenting as giant cell arteritis (GCA), is an infrequent, but potentially fatal, type of immune-mediated vascular disease. The site of the aberrant immune reaction, the mural layers of the artery, is strictly defined by vascular dendritic cells, endothelial cells, vascular smooth muscle cells and fibroblasts, which engage in an interaction with T cells and macrophages to, ultimately, cause luminal stenosis or aneurysmal wall damage of the vessel. A multitude of effector cytokines, all known as critical mediators in host-protective immunity, have been identified in vasculitic lesions. Two dominant cytokine clusters--the IL-6-IL-17 axis and the IL-12-IFN-γ axis--have been linked to disease activity. These two clusters seem to serve different roles in the vasculitic process. The IL-6-IL-17 cluster is highly responsive to standard corticosteroid therapy, whereas the IL-12-IFN-γ cluster is resistant to steroid-mediated immunosuppression. The information exchange between vascular and immune cells and stabilization of the vasculitic process involves members of the Notch receptor and ligand family. Focusing on elements in the tissue context of GCA, instead of broadly suppressing host immunity, might enable a more tailored therapeutic approach that avoids unwanted adverse effects of aggressive immunosuppression.
339 citations
TL;DR: The major advances in identifying RA genetic susceptibility markers both within and outside of the MHC are reviewed and current knowledge of the role of epigenetics in RA susceptibility is reviewed.
Abstract: 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.
330 citations
TL;DR: Understanding PRP in molecular terms could help to exploit its therapeutic potential, and aid the development of novel treatments and tissue-engineering approaches, for the different stages of joint degeneration.
Abstract: Platelet-rich plasma has anti-inflammatory properties and is an important source of molecules that are involved in the repair and regeneration of tissues. PRP therapy, therefore, has great potential for aiding the healing response and repairing joint damage in patients with osteoarthritis. In this comprehensive Review, the authors describe the biological processes of PRP tissue engineering as well as the novel applications and approaches of PRP therapy in the context of targeting joint degeneration. Osteoarthritis (OA) is a common disease involving joint damage, an inadequate healing response and progressive deterioration of the joint architecture. Autologous blood-derived products, such as platelet-rich plasma (PRP), are key sources of molecules involved in tissue repair and regeneration. These products can deliver a collection of bioactive molecules that have important roles in fundamental processes, including inflammation, angiogenesis, cell migration and metabolism in pathological conditions, such as OA. PRP has anti-inflammatory properties through its effects on the canonical nuclear factor κB signalling pathway in multiple cell types including synoviocytes, macrophages and chondrocytes. PRP contains hundreds of different molecules; cells within the joint add to this milieu by secreting additional biologically active molecules in response to PRP. The net results of PRP therapy are varied and can include angiogenesis, the production of local conditions that favour anabolism in the articular cartilage, or the recruitment of repair cells. However, the molecules found in PRP that contribute to angiogenesis and the protection of joint integrity need further clarification. Understanding PRP in molecular terms could help us to exploit its therapeutic potential, and aid the development of novel treatments and tissue-engineering approaches, for the different stages of joint degeneration.
329 citations
TL;DR: Recent findings regarding the pathogenic mechanisms involved in primary Sjögren's syndrome are summarized and lead to the development of promising novel therapeutic strategies.
Abstract: Primary Sjogren's syndrome (pSS) is a prototypic autoimmune disorder, management of which has long suffered from a lack of knowledge of the underlying pathophysiological mechanisms; however, over the past decade major advances have been made in understanding the pathogenesis of pSS. The innate immune system has been demonstrated to have an important role at the early stage of the disease, notably through activation of the type I interferon (IFN) system. In addition, mechanisms of B-cell activation in pSS have become clearer, particularly owing to recognition of the involvement of the TNF family cytokine B-cell-activating factor, production of which is highly dependent on expression of type I and type II IFNs. Moreover, key inroads have been made in understanding lymphomagenesis, the most severe complication of pSS. IL-12 production and subsequent T-cell activation, mainly IFN-γ-secreting type 1 T-helper cells, have also been implicated in disease pathogenesis. Furthermore, evidence implicates neuroendocrine system dysfunction in pSS pathogenesis. These pathophysiological advances open new avenues of investigation. Indeed, the increased understanding of pSS pathogenesis has already led to the development of promising novel therapeutic strategies. This article summarizes recent findings regarding the pathogenic mechanisms involved in pSS and their implications.
291 citations
TL;DR: Compartmentalized oxidative stress in self-reactive T cells, B cells and phagocytic cells might serve to limit autoimmunity and its inhibition could be detrimental, but antioxidant therapy might also be useful in ameliorating damage caused by other treatments.
Abstract: What is oxidative stress and how is it implicated in the pathogenesis of systemic lupus erythematosus (SLE)? Complex molecular pathways leading to and from redox imbalance in the context of SLE, including oxidative modification of autoantigens, are reviewed in this manuscript, alongside developmental approaches that aim to tackle and/or exploit oxidative stress in the clinical management of this disease.
258 citations
TL;DR: It is expected that increased understanding of the mechanisms by which chronic OA-associated pain is generated and maintained will offer opportunities for targeting and improving the safety of analgesia, and it might become possible to identify subsets of patients with pain of different pathophysiology, thus enabling a tailored approach to pain management.
Abstract: Pain is the defining symptom of osteoarthritis (OA), yet available treatment options, of which NSAIDs are the most common, provide inadequate pain relief and are associated with serious health risks when used long term. Chronic pain pathways are subject to complex levels of control and modulation, both in the periphery and in the central nervous system. Ongoing clinical and basic research is uncovering how these pathways operate in OA. Indeed, clinical investigation into the types of pain associated with progressive OA, the presence of central sensitization, the correlation with structural changes in the joint, and the efficacy of novel analgesics affords new insights into the pathophysiology of OA pain. Moreover, studies in disease-specific animal models enable the unravelling of the cellular and molecular pathways involved. We expect that increased understanding of the mechanisms by which chronic OA-associated pain is generated and maintained will offer opportunities for targeting and improving the safety of analgesia. In addition, using clinical and genetic approaches, it might become possible to identify subsets of patients with pain of different pathophysiology, thus enabling a tailored approach to pain management.
TL;DR: How the latest data on potential molecular targets for PTOA prevention and modification derived from studies in genetically modified mice are translated to humans is focused on, and the potential challenges to successful implementation of clinical trials of disease-modifying drugs for OA are identified.
Abstract: Osteoarthritis (OA), the most common of all arthropathies, is a leading cause of disability and has a large (and growing) worldwide socioeconomic cost. Despite its burgeoning importance, translation of disease-modifying OA therapies from the laboratory into clinical practice has slowed. Differences between the OA models studied preclinically and the disease evaluated in human clinical trials contribute to this failure. Most animal models of OA induce disease through surgical or mechanical disruption of joint biomechanics in young individuals rather than the spontaneous development of age-associated disease. This instability-induced joint disease in animals best models the arthritis that develops in humans after an injurious event, known as post-traumatic OA (PTOA). Studies in genetically modified mice suggest that PTOA has a distinct molecular pathophysiology compared with that of spontaneous OA, which might explain the poor translation from preclinical to clinical OA therapeutic trials. This Review summarizes the latest data on potential molecular targets for PTOA prevention and modification derived from studies in genetically modified mice, and describes their validation in preclinical therapeutic trials. This article focuses on how these findings might best be translated to humans, and identifies the potential challenges to successful implementation of clinical trials of disease-modifying drugs for PTOA.
TL;DR: Clinical terms, use of the total cholesterol to HDL-C ratio as the lipid component of CVD risk scoring in patients with RA would seem appropriate given that these lipid parameters generally change in parallel with inflammation and suppression of inflammation.
Abstract: Dyslipidaemia is commonly observed in patients with active rheumatoid arthritis (RA), with lower total cholesterol levels as well as lower levels of high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) reported in these patients than in individuals without RA. This pattern is mirrored in sepsis and other inflammatory states, suggesting systemic inflammation has the general effect of lowering circulating lipid levels. In line with such observations, suppressing inflammation with DMARDs, biologic therapies and small-molecule Janus kinase inhibitors seems to elevate levels of lipid fractions in RA, albeit in a variable manner dependent presumably upon the mechanism of action of the different agents. In addition, limited epidemiological data in patients with RA suggest increased cardiovascular disease (CVD) risk at relatively low cholesterol levels, a pattern contrasting with that observed in the population without RA. Our understanding of the potential mechanisms behind these inflammation-associated lipid changes remains suboptimal and requires further study. In clinical terms, however, use of the total cholesterol to HDL-C ratio as the lipid component of CVD risk scoring in patients with RA would seem appropriate given that these lipid parameters generally change in parallel with inflammation and suppression of inflammation. Whether alternative lipid or lipoprotein measures (or simple markers of inflammation) could improve stratification of CVD risk in RA beyond the established risk factors requires future investigation.
TL;DR: The phenotypic markers of greatest interest include measures of pain amplification and 'psychological' measures (such as emotional distress, somatic awareness, psychosocial stress and catastrophizing) and genetic polymorphisms reproducibly linked with musculoskeletal pain are found in genes contributing to serotonergic and adrenergic pathways.
Abstract: Musculoskeletal pain conditions, such as fibromyalgia and low back pain, tend to coexist in affected individuals and are characterized by a report of pain greater than expected based on the results of a standard physical evaluation. The pathophysiology of these conditions is largely unknown, we lack biological markers for accurate diagnosis, and conventional therapeutics have limited effectiveness. Growing evidence suggests that chronic pain conditions are associated with both physical and psychological triggers, which initiate pain amplification and psychological distress; thus, susceptibility is dictated by complex interactions between genetic and environmental factors. Herein, we review phenotypic and genetic markers of common musculoskeletal pain conditions, selected based on their association with musculoskeletal pain in previous research. The phenotypic markers of greatest interest include measures of pain amplification and 'psychological' measures (such as emotional distress, somatic awareness, psychosocial stress and catastrophizing). Genetic polymorphisms reproducibly linked with musculoskeletal pain are found in genes contributing to serotonergic and adrenergic pathways. Elucidation of the biological mechanisms by which these markers contribute to the perception of pain in these patients will enable the development of novel effective drugs and methodologies that permit better diagnoses and approaches to personalized medicine.
TL;DR: This Review discusses the three main types of cytokine blockers used in knee and hand OA, which target β-nerve growth factor, IL-1β or TNF, and inhibitors of nitrogen oxide production and the use of growth factors to treat OA.
Abstract: New treatment options are needed for osteoarthritis (OA) to slow down the structural progression of the disease; current therapies mostly target pain and function with minimal effectiveness. OA results from an imbalance between catabolic and anabolic factors, and biologic agents either target specific catabolic proinflammatory mediators, such as cytokines, nitric oxide synthesis, or affect anabolism more generally. Biologic agents have dramatic effects in other rheumatic inflammatory diseases such as rheumatoid arthritis; they were hoped to have similar effects in the treatment of OA. In this Review, we will discuss the three main types of cytokine blockers used in knee and hand OA, which target β-nerve growth factor (β-NGF), IL-1β or TNF. We will also discuss inhibitors of nitrogen oxide production and the use of growth factors to treat OA. Among the targeted agents, anti-β-NGF therapy has shown promising results, although cases of rapid destructive arthropathy caution against its widespread use. The future of therapies targeting cytokines, nitrogen oxide synthesis and growth factors in OA is questionable, as results from clinical trials have been repeatedly negative. Strategies in OA therapy need to be reconsidered. New molecules emerging from preclinical data should focus on treating the early phase of the disease where damage may be reversible, and treatment should be modified to fit each patient.
TL;DR: Evidence suggests that a subpopulation of patients with acute inflammation derive intermediate-term benefit from this therapy, and enhancing diagnostic specificity and phenotyping, as well as techniques that increase the likelihood of successful nerve ablation, such as maximizing lesion size.
Abstract: Facetogenic pain, also known as zygapophysial joint pain, is a frequent cause of mechanical spine pain. Diagnostic blocks (for example, medial branch blocks [MBBs]) are the only reliable approach to identify facet joints as the source of neck or back pain. In the absence of a reference standard, MBBs actually serve more of a prognostic than diagnostic role, enabling the selection of patients who might respond to radiofrequency denervation treatment--the standard treatment for facet joint pain. Using double blocks reduces the false-positive rate of MBBs, but will invariably reduce the overall treatment success rate. No studies have evaluated non-interventional treatments for confirmed facetogenic pain, but data from studies in non-specific back pain suggest a modest, short-term beneficial effect for pharmacotherapy and some non-traditional treatments. Trials of intra-articular steroid injections for lumbar and cervical facet joint pain have yielded disappointing results, but evidence suggests that a subpopulation of patients with acute inflammation derive intermediate-term benefit from this therapy. Radiofrequency denervation provides some benefit for up to a year in approximately 60% of individuals. Increasing this success rate might involve enhancing diagnostic specificity and phenotyping, as well as techniques that increase the likelihood of successful nerve ablation, such as maximizing lesion size.
TL;DR: In this Review, the reader is provided with an up-to-date discussion of the epidemiological, aetiological and clinical aspects of DISH, together with the need for modified criteria that enable timely identification of early phases in the development of DISh.
Abstract: Diffuse idiopathic skeletal hyperostosis (DISH) is a systemic condition characterized by the ossification and calcification of ligaments and entheses. DISH is observed on all continents and in all races, but most commonly in men over 50 years of age. Although DISH is asymptomatic in most individuals, the condition is often an indicator of underlying metabolic disease, and the presence of spinal or extraspinal ossifications can sometimes lead to symptoms including pain, stiffness, a reduced range of articular motion, and dysphagia, as well as increasing the risk of unstable spinal fractures. The aetiology of DISH is poorly understood, and the roles of the many factors that might be involved in the development of excess bone are not well delineated. The study of pathophysiological aspects of DISH is made difficult by the formal diagnosis requiring the presence of multiple contiguous fully formed bridging ossifications, which probably represent advanced stages of DISH. In this Review, the reader is provided with an up-to-date discussion of the epidemiological, aetiological and clinical aspects of DISH. Existing classification criteria (which, in the absence of diagnostic criteria, are used to establish a diagnosis of DISH) are also considered, together with the need for modified criteria that enable timely identification of early phases in the development of DISH.
TL;DR: The complexity of the Wnt signalling cascades and the potential secondary effects of drug interventions targeting them highlight the need for further research and suggest that the understanding of this exciting pathway is still in its infancy.
Abstract: The Wnt signalling cascades have essential roles in development, growth and homeostasis of joints and the skeleton. Progress in basic research, particularly relating to our understanding of intracellular signalling cascades and fine regulation of receptor activation in the extracellular space, has provided novel insights into the roles of Wnt signalling in chronic arthritis. Cartilage and bone homeostasis require finely tuned Wnt signalling; both activation and suppression of the Wnt-β-catenin cascade can lead to osteoarthritis in rodent models. Genetic associations with the Wnt antagonist encoded by FRZB and the transcriptional regulator encoded by Dot1l with osteoarthritis further corroborate the essential part played by Wnts in the joint. In rheumatoid arthritis, inhibition of Wnt signalling has a role in the persistence of bone erosions, whereas Wnts have been associated with the ankylosing phenotype in spondyloarthritis. Together, these observations identify the Wnt pathway as an attractive target for therapeutic intervention; however, the complexity of the Wnt signalling cascades and the potential secondary effects of drug interventions targeting them highlight the need for further research and suggest that our understanding of this exciting pathway is still in its infancy.
TL;DR: The current understanding of FAI is discussed, focusing on cam abnormalities and their association with OA, and preventative treatments aiming to reduce the incidence ofcam abnormalities and subsequent OA could be developed.
Abstract: Femoroacetabular impingement (FAI) is characterized by abnormal contact between the proximal femur and the acetabulum. Two subtypes have been described: pincer impingement, caused by an overcovered acetabulum; and cam impingement, which occurs as a result of an aspherical femoral head (cam abnormality). A strong correlation exists between cam impingement and the subsequent development of hip osteoarthritis (OA). Major cam abnormalities confer a high risk of OA. However, the association between cam abnormalities and the pathology of OA has been difficult to compare between studies, as different methods have been used to define the abnormality. Cam abnormalities are acquired during skeletal growth and could be influenced by high impact sporting activities. Preventative treatments aiming to reduce the incidence of cam abnormalities and subsequent OA could, therefore, be developed. In this Perspective, we discuss the current understanding of FAI, focusing on cam abnormalities and their association with OA.
TL;DR: An overview of biologic therapies currently available for patients with rheumatoid arthritis is provided, and why certain immunological regulators represent potential targets for intervention is discussed.
Abstract: The introduction of biologic agents to clinical practice has had a major bearing on the treatment of patients with chronic inflammatory diseases such as rheumatoid arthritis. These drugs have the potential to improve the outcome of disease and the quality of life for patients. However, clinical criteria alone are inadequate for determining which therapy is most appropriate for an individual patient. Furthermore, why a particular drug is effective in a particular patient, or indeed in any patient, but is ineffective for other individuals, is often unknown. In this Review, we provide an overview of biologic therapies currently available for patients with rheumatoid arthritis, and discuss why certain immunological regulators represent potential targets for intervention. Current agents can be clustered into three major types: cytokine blockers, lymphocyte-targeting agents, and small-molecule inhibitors of signal transduction pathways. We differentiate among the modes of action of each of these types of therapy and consider the challenges associated with their use in clinical practice.
TL;DR: Although knee OA presents intrinsic barriers to weight management, weight loss is possible at all stages of disease and the degree of weight loss required might be greater with increasing disease severity.
Abstract: Obesity and knee osteoarthritis (OA), two of the most common chronic diseases, are often comorbid. Obesity increases the risk of knee OA by a variety of mechanisms, such as increased joint loading and changes in body composition, with detrimental effects related to metainflammation and behavioural factors, including diminished physical activity and subsequent loss of protective muscle strength. These complex interactions present a challenge to the managing physician. The risk of knee OA related to weight gain and obesity begins from an early age. Weight loss reduces the risk of incident knee OA, and, in established disease, reduces symptoms, improves function and is likely to reduce disease progression. We review strategies to facilitate weight loss, with particular reference to their application in people with knee OA. Although knee OA presents intrinsic barriers to weight management, weight loss is possible at all stages of disease. Exercise or muscle strengthening are desirable for general health and to improve function, but are not essential to achieve weight loss and a successful symptomatic result. The degree of weight loss required to achieve benefit might be greater with increasing disease severity. Finally, we outline the need for a societal approach to tackle obesity-related OA.
TL;DR: Interest in MRI-based semiquantitative scoring systems has led to the development of several novel scoring systems that can be applied to different joints: a knee synovitis scoring system based on contrast-enhanced MRI; the MRI Osteoarthritis Knee Score (MOAKS); the Hip OsteOarthritis MRI Score (HOAMS); and the Oslo Hand Osteosarthritis MRI score (OHOA-MRI).
Abstract: The use of MRI techniques to investigate tissue pathology has become increasingly widespread in osteoarthritis (OA) research. Semiquantitative assessment of the joints by expert interpreters of MRI data is a powerful tool that can increase our understanding of the natural history of this complex disease. Several reliable and validated semiquantitative scoring systems now exist and have been applied to large-scale, multicentre, cross-sectional and longitudinal observational epidemiological studies. Such approaches have advanced our understanding of the associations of different tissue pathologies with pain and improved the definition of joint alterations that lead to disease progression. Semiquantitative MRI outcome measures have also been applied in several clinical trials in OA. Indeed, interest in MRI-based semiquantitative scoring systems has led to the development of several novel scoring systems that can be applied to different joints: a knee synovitis scoring system based on contrast-enhanced MRI; the MRI Osteoarthritis Knee Score (MOAKS); the Hip Osteoarthritis MRI Score (HOAMS); and the Oslo Hand Osteoarthritis MRI score (OHOA-MRI). Although these new scoring systems offer theoretical advantages over pre-existing systems, whether they offer actual superiority with regard to reliability, responsiveness and validity remains to be seen.
TL;DR: Three approaches for cartilage tissue repair at the rheumatology–orthopaedics interface are described: disease-modifying osteoarthritis (OA) drug (DMOAD) treatment; cell-based therapies, and intrinsic cartilage repair by joint distraction.
Abstract: In this Review we describe three approaches for cartilage tissue repair at the rheumatology–orthopaedics interface: disease-modifying osteoarthritis (OA) drug (DMOAD) treatment; cell-based therapies, and intrinsic cartilage repair by joint distraction. DMOADs can slow the progression of joint damage. Cell-based therapies have evolved to do the same, through selection of the most potent cell types (and combinations thereof), as well as identification of permissive boundary conditions for indications. Joint distraction techniques, meanwhile, have now demonstrated the capacity to stimulate actual intrinsic tissue repair. Although this progress is promising, true biological joint reconstruction remains distant on the developmental pathway of 'regenerative medicine'. Prolonged functional repair—that is, cure of diseases such as OA—remains an unmet medical need and scientific challenge, for which comparative and constructive interaction between these physical, chemical and cellular approaches will be required. Careful selections of patients and combinations of approaches will need to be made and tested to demonstrate their cost-effectiveness. Only with such rational and integrated assessment of outcomes will the promising results of these approaches be consolidated in clinical practice.
TL;DR: This Review discusses several examples of selective targeting of key intracellular factors with small molecules in rheumatology therapy, primarily those targeting Janus kinase family members and spleen tyrosine kinase, given their advanced status in clinical development and application.
Abstract: The molecular biology revolution coupled with the development of monoclonal antibody technology enabled remarkable progress in rheumatology therapy, comprising an array of highly effective biologic agents. With advances in understanding of the molecular nature of immune cell receptors came elucidation of intracellular signalling pathways downstream of these receptors. These discoveries raise the question of whether selective targeting of key intracellular factors with small molecules would add to the rheumatologic armamentarium. In this Review, we discuss several examples of this therapeutic strategy that seem to be successful, and consider their implications for the future of immune-targeted treatments. We focus on kinase inhibitors, primarily those targeting Janus kinase family members and spleen tyrosine kinase, given their advanced status in clinical development and application. We also summarize other targets involved in signalling pathways that might offer promise for therapeutic intervention in the future.
TL;DR: Evidence for neuroimmune regulation in autoimmune arthritis with a focus on the sympathetic nervous system is discussed and changes of the peripheral nervous system lead to an unfavourable situation with ongoing energy reallocation and continuous local destruction.
Abstract: The peripheral nervous system takes an active part in inflammatory processes by regulating effector cell function and reallocation of energy to the immune system. During acute inflammation, rapid neuronal reorganization and change of activity takes place. The hallmarks of this process are an increase in systemic sympathetic activity, a decrease in systemic parasympathetic activity and loss of sympathetic nerve fibres from sites of inflammation concomitant with increased innervation with sensory nerve fibres and increased sensory nerve fibre activity. On a systemic level, the increase in sympathetic activity (and decrease in parasympathetic activity) is necessary to provide enough energy to nourish the activated immune system. In locally inflamed tissue, the decrease in sympathetic nerve fibre density results in reduced anti-inflammatory signalling and, together with neuropeptides released from sensory nerve fibres, promotes local inflammation. In acute inflammation, this 'inflammatory configuration' of the peripheral nervous system favours the rapid clearance of antigenic threats. However, in chronic autoimmune inflammation, these changes of the peripheral nervous system lead to an unfavourable situation with ongoing energy reallocation and continuous local destruction. As an example of a chronic inflammatory condition, we discuss evidence for neuroimmune regulation in autoimmune arthritis with a focus on the sympathetic nervous system.
TL;DR: While eagerly awaiting diagnostic criteria for this disease, interim potential solutions to facilitate its diagnosis are proposed.
Abstract: Systemic lupus erythematosus (SLE) is a multiorgan disease with protean manifestations. Because SLE is uncommon and heterogeneous, its diagnosis can pose a considerable challenge, especially for clinicians with limited expertise of the disease. This is particularly true at the early stages of SLE, when an inadequate number of features to secure the diagnosis might be present, and for patients presenting with uncommon features, which can nonetheless be severe and require prompt treatment. Furthermore, the suboptimal performance of immunological testing in patients referred for possible SLE has been highlighted. As a result, SLE remains largely a clinical diagnosis that is made after excluding alternative diagnoses. Diagnostic criteria can expedite diagnosis and treatment, but are not available for SLE. Thus, SLE classification criteria are often used, but strict adherence to these criteria could delay diagnosis. Therefore, while eagerly awaiting diagnostic criteria for this disease, we propose interim potential solutions to facilitate its diagnosis.
TL;DR: Select examples of genes whose products have distinctly altered function in SLE and contribute to the pathogenic process are discussed and epigenetic modifications, which are abundantly present and might alter gene expression in the presence or absence of susceptibility variants, are considered.
Abstract: The aetiology of systemic lupus erythematosus (SLE) is complex and is known to involve both genetic and environmental factors. In a small number of patients, single-gene defects can lead to the development of SLE. Such genes include those encoding early components of the complement cascade and the 3'-5' DNA exonuclease TREX1. In addition, genome-wide association studies have identified single-nucleotide polymorphisms that confer some susceptibility to SLE. In this Review, we discuss selected examples of genes whose products have distinctly altered function in SLE and contribute to the pathogenic process. Specifically, we focus on the genes encoding integrin αM (ITGAM), IgG Fc receptors, sialic acid O-acetyl esterase (SIAE), the catalytic subunit of protein phosphatase PP2A (PPP2CA) and signalling lymphocytic activation molecule (SLAM) family members. Moreover, we highlight the changes in epigenetic signatures that occur in SLE. Such epigenetic modifications, which are abundantly present and might alter gene expression in the presence or absence of susceptibility variants, should be carefully considered when deconstructing the contribution of individual genes to the complex pathogenesis of SLE.
TL;DR: This Review will summarize epidemiological data on anaemia in inflammatory rheumatic diseases, along with a detailed description of underlying pathophysiological pathways, available diagnostic tools and practical diagnostic strategies.
Abstract: Anaemia is frequently observed in patients with inflammatory rheumatic diseases. Depending on its severity, anaemia negatively affects cardiovascular performance, physical activity and the quality of life of patients. However, anaemia is considered to be a symptom of the underlying inflammatory disease and, thus, neglected as a complex medical condition that warrants specific diagnosis and treatment. Although inflammation-induced alterations in iron homeostasis and erythropoiesis have a dominant role in the pathogenesis of this type of anaemia, multiple other factors such as chronic blood loss, haemolysis, disease and treatment-associated adverse effects or vitamin deficiencies can also take part in the development of anaemia. Accordingly, the prevalence of anaemia is positively associated with the severity of the underlying disease. This Review will summarize epidemiological data on anaemia in inflammatory rheumatic diseases, along with a detailed description of underlying pathophysiological pathways, available diagnostic tools and practical diagnostic strategies. Discussion of established and newly emerging treatment regimens, as well as the need for further research in this clinically relevant field, will also be included.
TL;DR: The value of different types of biomarkers is emphasized, addressing the concept of 'actionable' biomarkers, which can be used to guide clinical decision making, and 'mechanistic' biomarker, a subtype of actionable biomarker that is embedded in disease pathogenesis and, therefore, represents a potentially superior biomarker.
Abstract: 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.
TL;DR: How mechanisms that normally regulate TREG cells are affected in the inflamed joints of patients with arthritis are focused on and have important clinical implications and will affect the development of new therapeutic strategies for autoimmune arthritis.
Abstract: Since the discovery of FOXP3+ regulatory T (T(REG)) cells over 15 years ago, intensive research has focused on their presence, phenotype and function in autoimmune disease. Whether deficiencies in T(REG) cells underlie autoimmune pathology and whether, or how, therapeutic approaches based on these cells might be successful is still the subject of debate. The potential role of T(REG)-cell extrinsic factors, such as proinflammatory cytokines and resistance of effector T cells to suppression, as the cause of regulatory defects in chronic autoimmune inflammation is an intensive area of research. It is now clear that, at the site of inflammation, antigen presenting cells (APCs) and proinflammatory cytokines drive effector T cell skewing and plasticity, and that these T cells can become unresponsive to regulation. In addition, expansion and function of T(REG) cells is affected by the inflammatory environment; indeed, new data suggest that, in certain conditions, T(REG) cells promote inflammation. This Review summarizes the latest findings on changes in effector T cell homeostasis in autoimmune disease and focuses on how mechanisms that normally regulate these cells are affected in the inflamed joints of patients with arthritis. These findings have important clinical implications and will affect the development of new therapeutic strategies for autoimmune arthritis.