Showing papers in "Nature Reviews Rheumatology in 2019"

Anti-inflammatory and immune-regulatory cytokines in rheumatoid arthritis

Abstract: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by a failure of spontaneous resolution of inflammation. Although the pro-inflammatory cytokines and mediators that trigger RA have been the focus of intense investigations, the regulatory and anti-inflammatory cytokines responsible for the suppression and resolution of disease in a context-dependent manner have been less well characterized. However, knowledge of the pathways that control the suppression and resolution of inflammation in RA is clinically relevant and conceptually important for understanding the pathophysiology of the disease and for the development of treatments that enable long-term remission. Cytokine-mediated processes such as the activation of T helper 2 cells by IL-4 and IL-13, the resolution of inflammation by IL-9, IL-5-induced eosinophil expansion, IL-33-mediated macrophage polarization, the production of IL-10 by regulatory B cells and IL-27-mediated suppression of lymphoid follicle formation are all involved in governing the regulation and resolution of inflammation in RA. By better understanding these immune-regulatory signalling pathways, new therapeutic strategies for RA can be envisioned that aim to balance and resolve, rather than suppress, inflammation.

Surgical and tissue engineering strategies for articular cartilage and meniscus repair.

Abstract: Injuries to articular cartilage and menisci can lead to cartilage degeneration that ultimately results in arthritis. Different forms of arthritis affect ~50 million people in the USA alone, and it is therefore crucial to identify methods that will halt or slow the progression to arthritis, starting with the initiating events of cartilage and meniscus defects. The surgical approaches in current use have a limited capacity for tissue regeneration and yield only short-term relief of symptoms. Tissue engineering approaches are emerging as alternatives to current surgical methods for cartilage and meniscus repair. Several cell-based and tissue-engineered products are currently in clinical trials for cartilage lesions and meniscal tears, opening new avenues for cartilage and meniscus regeneration. This Review provides a summary of surgical techniques, including tissue-engineered products, that are currently in clinical use, as well as a discussion of state-of-the-art tissue engineering strategies and technologies that are being developed for use in articular cartilage and meniscus repair and regeneration. The obstacles to clinical translation of these strategies are also included to inform the development of innovative tissue engineering approaches.

Shared and distinct mechanisms of fibrosis

Abstract: Fibrosis is defined as an excessive deposition of connective tissue components and can affect virtually every organ system, including the skin, lungs, liver and kidney. Fibrotic tissue remodelling often leads to organ malfunction and is commonly associated with high morbidity and mortality. The medical need for effective antifibrotic therapies is thus very high. However, the extraordinarily high costs of drug development and the rare incidence of many fibrotic disorders hinder the development of targeted therapies for individual fibrotic diseases. A potential strategy to overcome this challenge is to target common mechanisms and core pathways that are of central pathophysiological relevance across different fibrotic diseases. The factors influencing susceptibility to and initiation of these diseases are often distinct, with disease-specific and organ-specific risk factors, triggers and sites of first injury. Fibrotic remodelling programmes with shared fibrotic signalling responses such as transforming growth factor-β (TGFβ), platelet-derived growth factor (PDGF), WNT and hedgehog signalling drive disease progression in later stages of fibrotic diseases. The convergence towards shared responses has consequences for drug development as it might enable the development of general antifibrotic compounds that are effective across different disease entities and organs. Technological advances, including new models, single-cell technologies and gene editing, could provide new insights into the pathogenesis of fibrotic diseases and the development of drugs for their treatment. A number of core pathways and mechanisms of fibrosis, outlined in this Review, are shared across different tissues and might therefore present targets for general antifibrotic strategies. Organ-specific and disease-specific differences in fibrotic diseases could also provide insights for drug development efforts.

Intra-articular treatment options for knee osteoarthritis

Abstract: Intra-articular drug delivery has a number of advantages over systemic administration; however, for the past 20 years, intra-articular treatment options for the management of knee osteoarthritis (OA) have been limited to analgesics, glucocorticoids, hyaluronic acid (HA) and a small number of unproven alternative therapies. Although HA and glucocorticoids can provide clinically meaningful benefits to an appreciable number of patients, emerging evidence indicates that the apparent effectiveness of these treatments is largely a result of other factors, including the placebo effect. Biologic drugs that target inflammatory processes are used to manage rheumatoid arthritis, but have not translated well into use in OA. A lack of high-level evidence and methodological limitations hinder our understanding of so-called ‘stem’ cell therapies and, although the off-label administration of intra-articular cell therapies (such as platelet-rich plasma and bone marrow aspirate concentrate) is common, high-quality clinical data are needed before these treatments can be recommended. A number of promising intra-articular treatments are currently in clinical development in the United States, including small-molecule and biologic therapies, devices and gene therapies. Although the prospect of new, non-surgical treatments for OA is exciting, the benefits of new treatments must be carefully weighed against their costs and potential risks. Intra-articular therapies for knee osteoarthritis (OA) are causing excitement among clinicians and patients, but care should be taken when choosing which therapy to use. In this Review, Vangsness and colleagues critically appraise current and future intra-articular therapies for knee OA.

Pathogenesis and therapeutic interventions for ANCA-associated vasculitis

Abstract: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) affects systemic small vessels and is accompanied by the presence of ANCAs in the serum. This disease entity includes microscopic polyangiitis, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis and drug-induced AAV. Similar to other autoimmune diseases, AAV develops in patients with a predisposing genetic background who have been exposed to causative environmental factors. The mechanism by which ANCAs cause vasculitis involves ANCA-mediated excessive activation of neutrophils that subsequently release inflammatory cytokines, reactive oxygen species and lytic enzymes. In addition, this excessive activation of neutrophils by ANCAs induces formation of neutrophil extracellular traps (NETs). Although NETs are essential elements in innate immunity, excessive NET formation is harmful to small vessels. Moreover, NETs are involved not only in ANCA-mediated vascular injury but also in the production of ANCAs themselves. Therefore, a vicious cycle of NET formation and ANCA production is considered to be involved in the pathogenesis of AAV. In addition to this role of NETs in AAV, some other important discoveries have been made in the past few years. Incorporating these new insights into our understanding of the pathogenesis of AAV is needed to fully understand and ultimately overcome this disease.

The IL-1 family of cytokines and receptors in rheumatic diseases.

Abstract: More than any other cytokine family, the 11 members of the IL-1 family are associated with innate immune responses, which occur in acute inflammation and chronic inflammatory conditions such as rheumatic diseases. In many rheumatic diseases, the severity of the condition can result from the balance between the pro-inflammatory and anti-inflammatory members of the IL-1 family. Pro-inflammatory family members (IL-1α, IL-1β, IL-18, IL-33, IL-36α, IL-36β and IL-36γ) are found in the articular environment during arthritis and often correlate with the degree of inflammation present. IL-1β has emerged as pivotal for promoting inflammation, particularly in autoinflammatory diseases, whereas IL-1α and the IL-36 subfamily are associated with skin diseases. IL-33 regulates T helper 2 (TH2) cell-mediated diseases, in sharp contrast to IL-18, which mainly regulates TH1 cell-mediated responses. The IL-1 family also contains four members that suppress inflammation: two specific receptor antagonists (IL-1 receptor antagonist (IL-1Ra) and IL-36 receptor antagonist (IL-36Ra)), and two members that broadly suppress innate inflammation by non-specifically reducing several cytokines and chemokines (IL-37 and IL-38). In this Review, each of the eleven IL-1 family cytokines and their receptors are discussed, along with their putative roles in rheumatic disease and therapeutic options for targeting or promoting these cytokines. Cytokines from the IL-1 family perform important functions in innate immune reactions, but can also be involved in chronic inflammatory diseases. This Review highlights the roles of IL-1 family members in rheumatic diseases and potential therapeutic approaches to targeting them.

Therapeutic options for targeting inflammatory osteoarthritis pain.

Abstract: Pain is the major symptom of osteoarthritis (OA) and is an important factor in strategies to manage this disease. However, the current standard of care does not provide satisfactory pain relief for many patients. The pathophysiology of OA is complex, and its presentation as a clinical syndrome is associated with pathologies of multiple joint tissues. Inflammation is associated with both OA pain and disease outcome and is therefore a major treatment target for OA and OA pain. Unlike TNF inhibitors and IL-1 inhibitors, established drugs such as glucocorticoids and methotrexate can reduce OA pain. Although central nociceptive pathways contribute to OA pain, crosstalk between the immune system and nociceptive neurons is central to inflammatory pain; therefore, new therapies might target this crosstalk. Newly identified drug targets, including neurotrophins and the granulocyte–macrophage colony-stimulating factor (GM-CSF)–CC-chemokine ligand 17 (CCL17) chemokine axis, offer the hope of better results but require clinical validation. Pain management is presently the focus of osteoarthritis (OA) therapy, but traditional pain-relieving drugs such as NSAIDs and glucocorticoids have limited utility. In this Review, the next generation of OA analgesics and their potential mechanisms of action are discussed.

Preventing psoriatic arthritis: focusing on patients with psoriasis at increased risk of transition

Abstract: Psoriasis is one of the most common chronic inflammatory skin diseases, affecting 3% of the world's population, and approximately one-third of patients with psoriasis will eventually transition to having psoriatic arthritis (PsA). The evolution from cutaneous to synovio-entheseal inflammation in these patients presents an opportunity to investigate the critical events linked to arthritis development. The events responsible for progression to PsA are currently unclear. Genetic and clinical-demographic risk factors (most notably familial aggregation and psoriasis sub-phenotypes) provide relevant insights into the variables that promote transition. The specific underlying molecular and cellular mechanisms, however, remain poorly defined. Intriguingly, although targeting the IL-23-IL-17 axis substantially improves psoriasis outcomes, this strategy is not more effective than TNF inhibitors in improving musculoskeletal symptoms in PsA. Major unmet needs in the field of PsA include defining those patients with psoriasis at increased risk of developing arthritis, improving our understanding of the natural history of disease and characterizing the immune, environmental and molecular subclinical events preceding PsA onset. Improving our knowledge of this transition is essential for designing clinical trials with treatments that can delay, attenuate or even prevent the development of PsA in patients with psoriasis.

Neuropsychiatric lupus: new mechanistic insights and future treatment directions.

Abstract: Patients with systemic lupus erythematosus (SLE) frequently show symptoms of central nervous system (CNS) involvement, termed neuropsychiatric SLE (NPSLE). The CNS manifestations of SLE are diverse and have a broad spectrum of severity and prognostic implications. Patients with NPSLE typically present with nonspecific symptoms, such as headache and cognitive impairment, but might also experience devastating features, such as memory loss, seizures and stroke. Some features of NPSLE, in particular those related to coagulopathy, have been characterized and an evidence-based treatment algorithm is available. The cognitive and affective manifestations of NPSLE, however, remain poorly understood. Various immune effectors have been evaluated as contributors to its pathogenesis, including brain-reactive autoantibodies, cytokines and cell-mediated inflammation. Additional brain-intrinsic elements (such as resident microglia, the blood-brain barrier and other neurovascular interfaces) are important facilitators of NPSLE. As yet, however, no unifying model has been found to underlie the pathogenesis of NPSLE, suggesting that this disease has multiple contributors and perhaps several distinct aetiologies. This heterogeneity presents a challenge for clinicians who have traditionally relied on empirical judgement in choosing treatment modalities for patients with NPSLE. Improved understanding of this manifestation of SLE might yield further options for managing this disease.

Inclusion body myositis: clinical features and pathogenesis.

Abstract: Inclusion body myositis (IBM) is often viewed as an enigmatic disease with uncertain pathogenic mechanisms and confusion around diagnosis, classification and prospects for treatment. Its clinical features (finger flexor and quadriceps weakness) and pathological features (invasion of myofibres by cytotoxic T cells) are unique among muscle diseases. Although IBM T cell autoimmunity has long been recognized, enormous attention has been focused for decades on several biomarkers of myofibre protein aggregates, which are present in <1% of myofibres in patients with IBM. This focus has given rise, together with the relative treatment refractoriness of IBM, to a competing view that IBM is not an autoimmune disease. Findings from the past decade that implicate autoimmunity in IBM include the identification of a circulating autoantibody (anti-cN1A); the absence of any statistically significant genetic risk factor other than the common autoimmune disease 8.1 MHC haplotype in whole-genome sequencing studies; the presence of a marked cytotoxic T cell signature in gene expression studies; and the identification in muscle and blood of large populations of clonal highly differentiated cytotoxic CD8+ T cells that are resistant to many immunotherapies. Mounting evidence that IBM is an autoimmune T cell-mediated disease provides hope that future therapies directed towards depleting these cells could be effective.

New therapies for systemic lupus erythematosus - past imperfect, future tense.

Abstract: The failure of many new, mostly biologic, drugs to meet their primary end points in double-blind clinical trials in patients with systemic lupus erythematosus (SLE) has caused a profound sense of disappointment among both physicians and patients. Arguably, the success of B cell depletion with rituximab in open-label clinical trials, the approval of belimumab (which blocks B cell-activating factor (BAFF)) for use in patients with lupus nephritis in the USA and in difficult-to-treat patients with SLE in the UK and the recognition that clinical trial design can be improved have given some cause for hope. However, changes to therapies in current use and the development of new approaches are urgently needed. The results of the latest studies investigating the use of several new approaches to treating SLE are discussed in this Review, including: fully humanized anti-CD20 and anti-CD19 monoclonal antibodies; inhibition of tyrosine-protein kinase BTK; CD40 ligand blockade; interfering with the presentation of antigen to autoreactive T cells using a peptide approach; a receptor decoy approach using an analogue of Fcγ receptor IIB; dual blockade of IL-12 and IL-23; and inhibition of Janus kinases.

Cutaneous lupus erythematosus: new insights into pathogenesis and therapeutic strategies.

Abstract: Cutaneous lupus erythematosus (CLE) is an autoimmune disease that can present as an isolated skin disease or as a manifestation within the spectrum of systemic lupus erythematosus. The clinical spectrum of CLE is broad, ranging from isolated discoid plaques to widespread skin lesions. Histologically, skin lesions present as interface dermatitis (inflammation of the skin mediated by anti-epidermal responses), which is orchestrated by type I and type III interferon-regulated cytokines and chemokines. Both innate and adaptive immune pathways are strongly activated in the formation of skin lesions owing to continuous re-activation of innate pathways via pattern recognition receptors (PRRs). These insights into the molecular pathogenesis of skin lesions in CLE have improved our understanding of the mechanisms underlying established therapies and have triggered the development of targeted treatment strategies that focus on immune cells (for example, B cells, T cells or plasmacytoid dendritic cells), as well as immune response pathways (for example, PRR signalling, Janus kinase (JAK)–signal transducer and activator of transcription (STAT) signalling and nuclear factor-κB signalling) and their cytokines and chemokines (for example, type I interferons, CXC-chemokine ligand 10 (CXCL10), IL-6 and IL-12). Cutaneous lupus erythematosus encompasses a broad spectrum of skin lesions that can occur in isolation or as a manifestation of systemic lupus erythematosus. Insights into the cellular and molecular pathogenesis of cutaneous lupus erythematosus have triggered the development of new therapeutic strategies.

Machine-learning-based patient-specific prediction models for knee osteoarthritis

Abstract: Osteoarthritis (OA) is an extremely common musculoskeletal disease. However, current guidelines are not well suited for diagnosing patients in the early stages of disease and do not discriminate patients for whom the disease might progress rapidly. The most important hurdle in OA management is identifying and classifying patients who will benefit most from treatment. Further efforts are needed in patient subgrouping and developing prediction models. Conventional statistical modelling approaches exist; however, these models are limited in the amount of information they can adequately process. Comprehensive patient-specific prediction models need to be developed. Approaches such as data mining and machine learning should aid in the development of such models. Although a challenging task, technology is now available that should enable subgrouping of patients with OA and lead to improved clinical decision-making and precision medicine.

T follicular helper cells and T follicular regulatory cells in rheumatic diseases.

Abstract: As a hallmark of autoimmune rheumatic diseases, autoantibodies have been used in diagnosis for decades. However, the immunological mechanism underlying their generation has only become clear following the identification of T follicular helper (TFH) cells and T follicular regulatory (TFR) cells. TFH cells are instrumental in supporting antibody affinity maturation in germinal centre reactions and humoral memory formation, whereas TFR cells suppress TFH cell-mediated antibody responses. Evidence indicates that patients with autoimmune rheumatic diseases have increased numbers of TFH cells that can be hyperactive, and also potentially have altered numbers of TFR cells with reduced function, suggesting a conceivable dysregulation in the balance between TFH cells and TFR cells in these diseases. Therefore, by identifying the molecular mechanisms underlying the development and function of these cell populations, new opportunities have emerged to develop novel therapeutic targets. An increased knowledge of TFH cells and TFR cells has inspired, and hopefully will inspire more, approaches to reinstate the balance of these cells in the prevention and treatment of rheumatic diseases. T follicular helper cells and T follicular regulatory cells tightly control the production of (auto)antibodies by B cells. Understanding their phenotypes and how the function of these cells is dysregulated in rheumatic diseases will aid future therapeutic development.

New therapeutic strategies in systemic lupus erythematosus management

Abstract: The current treatment approach for systemic lupus erythematosus (SLE), as outlined in the recommendations by international medical associations including EULAR and the ACR, is mostly eminence-based rather than evidence-based. However, knowledge on SLE is growing quickly, and such new advances need to be translated into clinical practice. Questions remain regarding the choice and timing of drug administration and tapering until withdrawal, which both can affect the balance between the control of disease activity and damage to organs triggered by long-standing and/or disproportionate immunosuppression. Currently, the treating physicians of patients with SLE are required to weigh the present with the future situation of their patients in an optimized balance between therapeutic harm and benefit. In this Review, the available therapeutic strategies and main challenges in the approach to SLE treatment are discussed. Remission and low disease activity are desirable therapeutic goals. Although the drug armamentarium for SLE has not expanded much in the past few decades, there are nonetheless opportunities to make better choices and explore combination therapies; such opportunities offer the potential of a personalized medicine strategy. The treatment of systemic lupus erythematosus involves a balance between control of disease activity and prevention of therapeutic harm that requires careful optimization. In this Review, the authors discuss available and emerging therapeutic strategies that exploit the current drug armamentarium.

Rheumatic manifestations of chikungunya: emerging concepts and interventions

Abstract: The largest epidemic ever recorded for chikungunya, a disease caused by infection with the chikungunya virus (CHIKV), began in Africa in 2004 and spread to >100 countries on four continents. The epidemic caused >10 million cases of often debilitating rheumatic disease, classically involving rapid onset of fever and polyarthralgia, often with polyarthritis. The clinical diagnosis of chikungunya is often complicated by infections with dengue or Zika virus. For many individuals with chikungunya, the disease is benign and self-limiting; however, some patients have a complex spectrum of atypical and severe manifestations. Many patients also experience a chronic phase of the disease, primarily involving arthralgia (which can be protracted (>1 year)), and a number of sequelae are also recognized. CHIKV-induced arthropathy arises from infection of multiple cell types in the joint and the infiltration of mainly mononuclear cells. Innate responses (primarily involving type I interferon responses and natural killer cells) and cognate responses (primarily involving CD4 T helper 1 cells), alongside activation of macrophages and monocytes, mediate CHIKV-induced arthritic immunopathology. Ideally, improved anti-inflammatory treatments should not compromise antiviral immunity. New concepts in mosquito control are being field tested and a number of CHIKV vaccines are being developed. Chikungunya can be a mild and self-limiting disease, but can also involve a complex spectrum of atypical, severe and/or chronic rheumatic manifestations that place a considerable burden on individuals. New strategies are under development to help treat and prevent this disease.

The immunobiology of MIF: function, genetics and prospects for precision medicine

Abstract: The role of macrophage migration inhibitory factor (MIF) in autoimmunity is underscored by data showing that common functional polymorphisms in MIF are associated with disease susceptibility or clinical severity. MIF can regulate glucocorticoid-mediated immunosuppression and has a prominent function in cell survival signalling. Further specific functions of MIF are now being defined in different autoimmune diseases and MIF-targeted biologic therapeutics are in early-stage clinical trials. The unique structure of MIF is also directing the development of small-molecule MIF antagonists. Together, these efforts could provide a means of selectively intervening in pathogenesis and overcoming MIF-related genetic susceptibility to many rheumatic diseases. The pleiotropic cytokine macrophage migration inhibitory factor (MIF) is involved in the pathogenesis of autoimmune inflammatory disorders. This Review discusses MIF biology and signalling, its mechanisms of action and its involvement in rheumatic diseases, including opportunities for targeted therapies.

IVD progenitor cells: a new horizon for understanding disc homeostasis and repair

Abstract: Intervertebral disc (IVD) degeneration is associated with low back pain. In IVDs, a high mechanical load, high osmotic pressure and hypoxic conditions create a hostile microenvironment for resident cells. How IVD homeostasis and function are maintained under stress remains to be understood; however, several research groups have reported isolating native endogenous progenitor-like or otherwise proliferative cells from the IVD. The isolation of such cells implies that the IVD might contain a quiescent progenitor-like population that could be activated for IVD repair and regeneration. Increased understanding of endogenous disc progenitor cells will improve our knowledge of IVD homeostasis and, when combined with tissue engineering techniques, might hold promise for future therapeutic applications. In this Review, the characteristics of progenitor cells in different IVD compartments are discussed, as well as the potency of different cell populations within the IVD. The stem cell characteristics of these cells are also compared with those of mesenchymal stromal cells. On the basis of existing evidence, whether and how IVD degeneration and the hostile microenvironment might affect endogenous progenitor cell function are considered, and ways to channel the potential of these cells for IVD repair are suggested.

Biomaterial-guided delivery of gene vectors for targeted articular cartilage repair

Abstract: Articular cartilage defects are prevalent and are potentially involved in the initiation of osteoarthritis, yet the lack of efficient therapeutic options to treat cartilage defects represents a substantial challenge. Molecular treatments that require the delivery of therapeutic gene vectors are often less effective that specific, targeted approaches, and the scientific evidence for acellular biomaterial-assisted procedures is limited. Controlled delivery of gene vectors using biocompatible materials is emerging as a novel strategy for the sustained and tuneable release of gene therapies in a spatiotemporally precise manner, thereby reducing intra-articular vector spread and possible loss of the therapeutic gene product. Controlled, biomaterial-guided delivery of gene vectors could be used to enhance intrinsic mechanisms of cartilage repair while affording protection against potentially damaging host immune responses that might counteract the gene therapy component. This Review provides an overview of advances in gene vector-loaded biomaterials for articular cartilage repair. Such systems enable the sustained release of gene therapies while maintaining transduction efficacy. Strategies that harness these properties are likely to result in improved in situ cartilage tissue regeneration that could be safely translated into clinical applications in the near future.

Emerging targets of disease-modifying therapy for systemic sclerosis

Abstract: Systemic sclerosis (SSc) has the highest cause-specific mortality of all the connective tissue diseases, and the aetiology of this complex and heterogeneous condition remains an enigma. Current disease-modifying therapies for SSc predominantly target inflammatory and vascular pathways but have variable and unpredictable clinical efficacy, and none is curative. Moreover, many of these therapies possess undesirable safety profiles and have no appreciable effect on long-term mortality. This Review describes the most promising of the existing therapeutic targets for SSc and places them in the context of our evolving understanding of the pathophysiology of this disease. As well as taking an in-depth look at the immune, inflammatory, vascular and fibrotic pathways implicated in the pathogenesis of SSc, this Review discusses emerging treatment targets and therapeutic strategies. The article concludes with an overview of important unanswered questions in SSc research that might inform the design of future studies of treatments aimed at modifying the course of this disease.

Cell migration: implications for repair and regeneration in joint disease

Abstract: Connective tissues within the synovial joints are characterized by their dense extracellular matrix and sparse cellularity. With injury or disease, however, tissues commonly experience an influx of cells owing to proliferation and migration of endogenous mesenchymal cell populations, as well as invasion of the tissue by other cell types, including immune cells. Although this process is critical for successful wound healing, aberrant immune-mediated cell infiltration can lead to pathological inflammation of the joint. Importantly, cells of mesenchymal or haematopoietic origin use distinct modes of migration and thus might respond differently to similar biological cues and microenvironments. Furthermore, cell migration in the physiological microenvironment of musculoskeletal tissues differs considerably from migration in vitro. This Review addresses the complexities of cell migration in fibrous connective tissues from three separate but interdependent perspectives: physiology (including the cellular and extracellular factors affecting 3D cell migration), pathophysiology (cell migration in the context of synovial joint autoimmune disease and injury) and tissue engineering (cell migration in engineered biomaterials). Improved understanding of the fundamental mechanisms governing interstitial cell migration might lead to interventions that stop invasion processes that culminate in deleterious outcomes and/or that expedite migration to direct endogenous cell-mediated repair and regeneration of joint tissues.

Establishing outcome measures in early knee osteoarthritis

Abstract: The classification and monitoring of individuals with early knee osteoarthritis (OA) are important considerations for the design and evaluation of therapeutic interventions and require the identification of appropriate outcome measures. Potential outcome domains to assess for early OA include patient-reported outcomes (such as pain, function and quality of life), features of clinical examination (such as joint line tenderness and crepitus), objective measures of physical function, levels of physical activity, features of imaging modalities (such as of magnetic resonance imaging) and biochemical markers in body fluid. Patient characteristics such as adiposity and biomechanics of the knee could also have relevance to the assessment of early OA. Importantly, research is needed to enable the selection of outcome measures that are feasible, reliable and validated in individuals at risk of knee OA or with early knee OA. In this Perspectives article, potential outcome measures for early symptomatic knee OA are discussed, including those measures that could be of use in clinical practice and/or the research setting.

Mouse models for human hyperuricaemia: a critical review.

Abstract: Hyperuricaemia (increased serum urate concentration) occurs mainly in higher primates, including in humans, because of inactivation of the gene encoding uricase during primate evolution. Individuals with hyperuricaemia might develop gout - a painful inflammatory arthritis caused by monosodium urate crystal deposition in articular structures. Hyperuricaemia is also associated with common chronic diseases, including hypertension, chronic kidney disease, type 2 diabetes and cardiovascular disease. Many mouse models have been developed to investigate the causal mechanisms for hyperuricaemia. These models are highly diverse and can be divided into two broad categories: mice with genetic modifications (genetically induced models) and mice exposed to certain environmental factors (environmentally induced models; for example, pharmaceutical or dietary induction). This Review provides an overview of the mouse models of hyperuricaemia and the relevance of these models to human hyperuricaemia, with an emphasis on those models generated through genetic modifications. The challenges in developing and comparing mouse models of hyperuricaemia and future research directions are also outlined.

Cardiometabolic comorbidities in RA and PsA: lessons learned and future directions.

Abstract: Cardiometabolic comorbidities present a considerable burden for patients with rheumatoid arthritis (RA) or psoriatic arthritis (PsA) Both RA and PsA are associated with an increased risk of cardiovascular disease (CVD) PsA more often exhibits an increased risk of metabolically linked comorbidities such as obesity, insulin resistance, type 2 diabetes mellitus and non-alcoholic fatty liver disease Although both RA and PsA are characterized by a state of chronic inflammation, the mechanisms that contribute to CVD risk in these conditions might not be identical In RA, systemic inflammation is thought to directly contribute to CVD risk, whereas in PsA, adiposity is thought to contribute to a notable metabolic phenotype that, in turn, contributes to CVD risk Hence, appropriate management strategies that consider the increased risk of cardiometabolic comorbidities in patients with inflammatory arthropathy are important In RA, such strategies should focus on the prediction of CVD risk and its management through targeting chronic inflammation and traditional CVD risk factors In PsA, management strategies should additionally focus on targeting metabolic components, including weight management, which might not only help improve disease activity in the joints, entheses and skin, but also reduce the risk of metabolic comorbidities and improve the quality of life of patients

Treat-to-target in rheumatoid arthritis - are we there yet?

Abstract: Treat-to-target has been established as a guiding principle for the treatment of rheumatoid arthritis (RA) and encompasses several distinct elements: choosing a target and a method for measuring it; assessing the target at a pre-specified time point; a commitment to change the therapy if the target is not achieved; and shared decision-making. A treat-to-target approach yields superior outcomes to standard care in RA, and the ACR, EULAR and other professional organizations have endorsed treat-to-target as a fundamental therapeutic strategy for RA. Nevertheless, data on the degree to which treat-to-target is employed in the clinic are scarce; it seems that although some elements of treat-to-target are widely used, full implementation remains uncommon. Outstanding knowledge gaps to be addressed include how to select the right target for each patient, how often to assess whether the target has been achieved and the selection of each subsequent therapy in an evidence-based manner.

The IL-23-IL-17 pathway as a therapeutic target in axial spondyloarthritis.

Abstract: The cytokines IL-23 and IL-17 have an important role in the pathogenesis of, and as a therapeutic target in, both animal models of chronic inflammation and some human chronic inflammatory diseases. The traditional view is that a main source of IL-17 is T cells and that IL-17 production is under the control of IL-23. IL-17 inhibition has shown good efficacy in clinical trials for ankylosing spondylitis (AS), a subtype of axial spondyloarthritis (axSpA) characterized by radiographic evidence of sacroiliitis. On the basis of data from animal models, genetic studies and the investigation of tissue and blood samples from patients with AS, IL-23 had also been predicted to be important in the pathogenesis of this disease and was therefore considered a potential therapeutic target for axSpA. However, two placebo-controlled, double-blind clinical trials in axSpA of monoclonal antibodies directed against either the p40 protein or the p19 protein of the IL-23 molecule had clear negative results. These findings indicate that IL-23 and IL-17 are at least partly uncoupled in axSpA. Reasons as to why, when and how such an uncoupling might occur are discussed in this Review, with special reference to the unique microenvironment of the subchondral bone marrow in axSpA.

Systemic effects of IL-17 in inflammatory arthritis.

Abstract: Inflammatory arthritis occurs in many diseases and is characterized by joint inflammation and damage. However, the inflammatory state in arthritis is commonly associated with systemic manifestations, which are generally linked to a poor prognosis. The pro-inflammatory cytokine IL-17 functions within a complex network of cytokines and contributes to the pathogenesis of various inflammatory diseases. Three IL-17 inhibitors have already been approved for the treatment of psoriasis, psoriatic arthritis, and ankylosing spondylitis. After a brief description of IL-17 and its local effects on joints, this Review focuses on the systemic effects of IL-17 in inflammatory arthritis. Increased circulating concentrations of bioactive IL-17 mediate changes in blood vessels, liver and cardiac and skeletal muscles. The effects of IL-17 on vascular and cardiac cells might contribute to the increased risk of cardiovascular events that occurs in all patients with inflammatory disorders. In the liver, IL-17 contributes to the high circulating concentrations of acute-phase proteins, such as C-reactive protein, and the appearance of liver lesions. In skeletal muscle, IL-17 contributes to muscle contractibility defects and weakness. Thus, targeting IL-17 might have beneficial effects at both local and systemic levels, and could also be proposed for the treatment of a wider range of inflammatory diseases.

Mechanisms of lung disease development in rheumatoid arthritis

Abstract: Rheumatoid arthritis (RA) is a chronic autoimmune disorder that causes joint inflammation and damage. Extra-articular manifestations occur in many patients and can include lung involvement in the form of airway or parenchymal inflammation and fibrosis. Although the pathophysiology of articular RA has been extensively investigated, the mechanisms causing airway and parenchymal lung disease are not well defined. Infections, cigarette-smoking, mucosal dysbiosis, host genetics and premature senescence are all potentially important contributors to the development of lung disease in patients with RA. RA-associated lung disease (which can predate the onset of articular disease by many years) probably originates from chronic airway and alveolar epithelial injury that occurs in an individual with a genetic background that permits the development of autoimmunity, leading to chronic inflammation and subsequent airway and lung parenchymal remodelling and fibrosis. Further investigations into the specific mechanisms by which lung disease develops in RA will be crucial for the development of effective therapies. Identifying mechanisms by which environmental and host factors cooperate in the induction of autoimmunity in the lung might also help to establish the order of early events in RA.

Spontaneous dog osteoarthritis — a One Medicine vision

Abstract: Osteoarthritis (OA) is a global disease that, despite extensive research, has limited treatment options. Pet dogs share both an environment and lifestyle attributes with their owners, and a growing awareness is developing in the public and among researchers that One Medicine, the mutual co-study of animals and humans, could be beneficial for both humans and dogs. To that end, this Review highlights research opportunities afforded by studying dogs with spontaneous OA, with a view to sharing this active area of veterinary research with new audiences. Similarities and differences between dog and human OA are examined, and the proposition is made that suitably aligned studies of spontaneous OA in dogs and humans, in particular hip and knee OA, could highlight new avenues of discovery. Developing cross-species collaborations will provide a wealth of research material and knowledge that is relevant to human OA and that cannot currently be obtained from rodent models or experimentally induced dog models of OA. Ultimately, this Review aims to raise awareness of spontaneous dog OA and to stimulate discussion regarding its exploration under the One Medicine initiative to improve the health and well-being of both species.

Antiresorptive and anabolic agents in the prevention and reversal of bone fragility.

Abstract: Bone volume, microstructure and its material composition are maintained by bone remodelling, a cellular activity carried out by bone multicellular units (BMUs). BMUs are focally transient teams of osteoclasts and osteoblasts that respectively resorb a volume of old bone and then deposit an equal volume of new bone at the same location. Around the time of menopause, bone remodelling becomes unbalanced and rapid, and an increased number of BMUs deposit less bone than they resorb, resulting in bone loss, a reduction in bone volume and microstructural deterioration. Cortices become porous and thin, and trabeculae become thin, perforated and disconnected, causing bone fragility. Antiresorptive agents reduce fracture risk by reducing the rate of bone remodelling so that fewer BMUs are available to remodel bone. Bone fragility is not abolished by these drugs because existing microstructural deterioration is not reversed, unsuppressed remodelling continues producing microstructural deterioration and unremodelled bone that becomes more mineralized can become brittle. Anabolic agents reduce fracture risk by stimulating new bone formation, which partly restores bone volume and microstructure. To guide fracture prevention, this Review provides an overview of the structural basis of bone fragility, the mechanisms of remodelling and how anabolic and antiresorptive agents target remodelling defects.