Showing papers in "Nature Reviews Rheumatology in 2020"

Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology.

Abstract: Despite widespread clinical use of antimalarial drugs such as hydroxychloroquine and chloroquine in the treatment of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and other inflammatory rheumatic diseases, insights into the mechanism of action of these drugs are still emerging. Hydroxychloroquine and chloroquine are weak bases and have a characteristic ‘deep’ volume of distribution and a half-life of around 50 days. These drugs interfere with lysosomal activity and autophagy, interact with membrane stability and alter signalling pathways and transcriptional activity, which can result in inhibition of cytokine production and modulation of certain co-stimulatory molecules. These modes of action, together with the drug’s chemical properties, might explain the clinical efficacy and well-known adverse effects (such as retinopathy) of these drugs. The unknown dose–response relationships of these drugs and the lack of definitions of the minimum dose needed for clinical efficacy and what doses are toxic pose challenges to clinical practice. Further challenges include patient non-adherence and possible context-dependent variations in blood drug levels. Available mechanistic data give insights into the immunomodulatory potency of hydroxychloroquine and provide the rationale to search for more potent and/or selective inhibitors. Hydroxychloroquine and chloroquine are antimalarial drugs commonly used for the treatment of rheumatic diseases. Multiple mechanisms might explain the efficacy and adverse effects of these drugs, but further investigation could lead to the development of more specific and potent drugs.

Global epidemiology of gout: prevalence, incidence, treatment patterns and risk factors.

Abstract: Gout is the most common inflammatory arthritis and occurs when hyperuricaemia, sustained elevation of serum urate levels resulting in supersaturation of body tissues with urate, leads to the formation and deposition of monosodium urate crystals in and around the joints. Recent reports of the prevalence and incidence of gout vary widely according to the population studied and methods employed but range from a prevalence of <1% to 6.8% and an incidence of 0.58–2.89 per 1,000 person-years. Gout is more prevalent in men than in women, with increasing age, and in some ethnic groups. Despite rising prevalence and incidence, suboptimal management of gout continues in many countries. Typically, only a third to half of patients with gout receive urate-lowering therapy, which is a definitive, curative treatment, and fewer than a half of patients adhere to treatment. Many gout risk factors exist, including obesity, dietary factors and comorbid conditions. As well as a firmly established increased risk of cardiovascular disease and chronic kidney disease in those with gout, novel associations of gout with other comorbidities have been reported, including erectile dysfunction, atrial fibrillation, obstructive sleep apnoea, osteoporosis and venous thromboembolism. Discrete patterns of comorbidity clustering in individuals with gout have been described. Increasing prevalence and incidence of obesity and comorbidities are likely to contribute substantially to the rising burden of gout. Gout is a chronic crystal deposition disorder in which sustained hyperuricaemia leads to formation and deposition of monosodium urate crystals in the joints. The prevalence and incidence of gout are increasing globally, which may be related to changes in the prevalence of gout risk factors (such as obesity) and comorbidities.

Restoring synovial homeostasis in rheumatoid arthritis by targeting fibroblast-like synoviocytes

Abstract: Rheumatoid arthritis (RA) is a chronic immune-mediated disease that primarily affects the synovium of diarthrodial joints. During the course of RA, the synovium transforms into a hyperplastic invasive tissue that causes destruction of cartilage and bone. Fibroblast-like synoviocytes (FLS), which form the lining of the joint, are epigenetically imprinted with an aggressive phenotype in RA and have an important role in these pathological processes. In addition to producing the extracellular matrix and joint lubricants, FLS in RA produce pathogenic mediators such as cytokines and proteases that contribute to disease pathogenesis and perpetuation. The development of multi-omics integrative analyses have enabled new ways to dissect the mechanisms that imprint FLS, have helped to identify potential FLS subsets with distinct functions and have identified differences in FLS phenotypes between joints in individual patients. This Review provides an overview of advances in understanding of FLS biology and highlights omics approaches and studies that hold promise for identifying future therapeutic targets.

Autoimmune and inflammatory diseases following COVID-19.

Abstract: Emerging reports show that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection precedes the appearance of various autoimmune and autoinflammatory diseases, including paediatric inflammatory multisystemic syndrome (PIMS) or multisystem inflammatory syndrome in children (MIS-C), thus adding to the growing mystery of this virus and raising questions about the nature of its link with autoimmune and autoinflammatory sequelae.

Translating IL-6 biology into effective treatments.

Abstract: In 1973, IL-6 was identified as a soluble factor that is secreted by T cells and is important for antibody production by B cells. Since its discovery more than 40 years ago, the IL-6 pathway has emerged as a pivotal pathway involved in immune regulation in health and dysregulation in many diseases. Targeting of the IL-6 pathway has led to innovative therapeutic approaches for various rheumatic diseases, such as rheumatoid arthritis, juvenile idiopathic arthritis, adult-onset Still's disease, giant cell arteritis and Takayasu arteritis, as well as other conditions such as Castleman disease and cytokine release syndrome. Targeting this pathway has also identified avenues for potential expansion into several other indications, such as uveitis, neuromyelitis optica and, most recently, COVID-19 pneumonia. To mark the tenth anniversary of anti-IL-6 receptor therapy worldwide, we discuss the history of research into IL-6 biology and the development of therapies that target IL-6 signalling, including the successes and challenges and with an emphasis on rheumatic diseases.

Evasion of apoptosis by myofibroblasts: a hallmark of fibrotic diseases.

Abstract: Organ fibrosis is a lethal outcome of autoimmune rheumatic diseases such as systemic sclerosis. Myofibroblasts are scar-forming cells that are ultimately responsible for the excessive synthesis, deposition and remodelling of extracellular matrix proteins in fibrosis. Advances have been made in our understanding of the mechanisms that keep myofibroblasts in an activated state and control myofibroblast functions. However, the mechanisms that help myofibroblasts to persist in fibrotic tissues remain poorly understood. Myofibroblasts evade apoptosis by activating molecular mechanisms in response to pro-survival biomechanical and growth factor signals from the fibrotic microenvironment, which can ultimately lead to the acquisition of a senescent phenotype. Growing evidence suggests that myofibroblasts and senescent myofibroblasts, rather than being resistant to apoptosis, are actually primed for apoptosis owing to concomitant activation of cell death signalling pathways; these cells are poised to apoptose when survival pathways are inhibited. This knowledge of apoptotic priming has paved the way for new therapies that trigger apoptosis in myofibroblasts by blocking pro-survival mechanisms, target senescent myofibroblast for apoptosis or promote the reprogramming of myofibroblasts into scar-resolving cells. These novel strategies are not only poised to prevent progressive tissue scarring, but also have the potential to reverse established fibrosis and to regenerate chronically injured tissues.

Methotrexate and its mechanisms of action in inflammatory arthritis.

Abstract: Despite the introduction of numerous biologic agents for the treatment of rheumatoid arthritis (RA) and other forms of inflammatory arthritis, low-dose methotrexate therapy remains the gold standard in RA therapy. Methotrexate is generally the first-line drug for the treatment of RA, psoriatic arthritis and other forms of inflammatory arthritis, and it enhances the effect of most biologic agents in RA. Understanding the mechanism of action of methotrexate could be instructive in the appropriate use of the drug and in the design of new regimens for the treatment of RA. Although methotrexate is one of the first examples of intelligent drug design, multiple mechanisms potentially contribute to the anti-inflammatory actions of methotrexate, including the inhibition of purine and pyrimidine synthesis, transmethylation reactions, translocation of nuclear factor-κB (NF-κB) to the nucleus, signalling via the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway and nitric oxide production, as well as the promotion of adenosine release and expression of certain long non-coding RNAs.

Fibromyalgia: an update on clinical characteristics, aetiopathogenesis and treatment

Abstract: Fibromyalgia is characterized by chronic widespread pain, fatigue, sleep disturbances and functional symptoms. The etiopathogenesis, diagnostic criteria and classification criteria of fibromyalgia are still debated and, consequently, so are the strategies for treating this condition. Fibromyalgia is the third most frequent musculoskeletal condition, and its prevalence increases with age. However, although diagnosis has improved with the evolution of more accurate diagnostic criteria, a considerable proportion of physicians still fail to recognize the syndrome. Many factors contribute to the development of fibromyalgia in a unique manner: genetic predisposition, personal experiences, emotional-cognitive factors, the mind-body relationship and a biopsychological ability to cope with stress. The multiple components of the pathogenesis and maintenance of the condition necessitate a multi-modal treatment approach. Individually tailored treatment is an important consideration, with the increasing recognition that different fibromyalgia subgroups exist with different clinical characteristics. Consequently, although an evidence-based approach to fibromyalgia management is always desirable, the approach of physicians is inevitably empirical, and must have the aim of creating a strong alliance with the patient and formulating shared, realistic treatment goals.

Emerging evidence of a COVID-19 thrombotic syndrome has treatment implications.

Abstract: Reports of widespread thromboses and disseminated intravascular coagulation (DIC) in patients with coronavirus disease 19 (COVID-19) have been rapidly increasing in number. Key features of this disorder include a lack of bleeding risk, only mildly low platelet counts, elevated plasma fibrinogen levels, and detection of both severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and complement components in regions of thrombotic microangiopathy (TMA). This disorder is not typical DIC. Rather, it might be more similar to complement-mediated TMA syndromes, which are well known to rheumatologists who care for patients with severe systemic lupus erythematosus or catastrophic antiphospholipid syndrome. This perspective has critical implications for treatment. Anticoagulation and antiviral agents are standard treatments for DIC but are gravely insufficient for any of the TMA disorders that involve disorders of complement. Mediators of TMA syndromes overlap with those released in cytokine storm, suggesting close connections between ineffective immune responses to SARS-CoV-2, severe pneumonia and life-threatening microangiopathy.

Emerging pharmaceutical therapies for osteoarthritis.

Abstract: The prevalence of osteoarthritis (OA) and the burden associated with the disease are steadily increasing worldwide, representing a major public health challenge for the coming decades. The lack of specific treatments for OA has led to it being recognized as a serious disease that has an unmet medical need. Advances in the understanding of OA pathophysiology have enabled the identification of a variety of potential therapeutic targets involved in the structural progression of OA, some of which are promising and under clinical investigation in randomized controlled trials. Emerging therapies include those targeting matrix-degrading proteases or senescent chondrocytes, promoting cartilage repair or limiting bone remodelling, local low-grade inflammation or Wnt signalling. In addition to these potentially disease-modifying OA drugs (DMOADs), several targets are being explored for the treatment of OA-related pain, such as nerve growth factor inhibitors. The results of these studies are expected to considerably reshape the landscape of OA management over the next few years. This Review describes the pathophysiological processes targeted by emerging therapies for OA, along with relevant clinical data and discussion of the main challenges for the further development of these therapies, to provide context for the latest advances in the field of pharmaceutical therapies for OA.

COVID-19 revisiting inflammatory pathways of arthritis.

Abstract: Coronavirus disease 2019 (COVID-19) is an infectious disease, caused by severe acute respiratory syndrome coronavirus 2, which predominantly affects the lungs and, under certain circumstances, leads to an excessive or uncontrolled immune activation and cytokine response in alveolar structures The pattern of pro-inflammatory cytokines induced in COVID-19 has similarities to those targeted in the treatment of rheumatoid arthritis Several clinical studies are underway that test the effects of inhibiting IL-6, IL-1β or TNF or targeting cytokine signalling via Janus kinase inhibition in the treatment of COVID-19 Despite these similarities, COVID-19 and other zoonotic coronavirus-mediated diseases do not induce clinical arthritis, suggesting that a local inflammatory niche develops in alveolar structures and drives the disease process COVID-19 constitutes a challenge for patients with inflammatory arthritis for several reasons, in particular, the safety of immune interventions during the pandemic Preliminary data, however, do not suggest that patients with inflammatory arthritis are at increased risk of COVID-19

IgG4-related disease: an update on pathophysiology and implications for clinical care.

Abstract: IgG4-related disease (IgG4-RD) has only existed as a unique disease entity since 2003, yet remarkable progress has already been achieved in describing the essential features of the disease. A framework for systematic clinical studies has been created by the development of a quantitative disease activity tool (the IgG4-RD Responder Index) and the validation of classification criteria, both of which were the products of international, multi-centre investigations. In addition, substantial strides have been made in understanding the pathophysiology of IgG4-RD. In particular, the central role of B cells in the disease has been demonstrated by both the robust clinical responsiveness of IgG4-RD to B cell depletion and by the identification of multiple self-antigens that promote B cell expansion. CD4+ T cells have also been investigated in detail; CD4+ cytotoxic T lymphocytes (suspected of promoting disease) and a specific T follicular helper cell subset that contributes to IgG4 isotype switching have both been defined by multiple groups. The mechanisms by which these immune cells converge on target tissues, interact with fibroblasts and promote tissue remodelling are beginning to be understood and will be an important research focus in the coming years. Over the past few years, considerable advances have been made in understanding the pathogenesis of IgG4-related disease. Our increased knowledge of the important roles of B cells and T cells is now starting to make its way into the clinic.

T cell metabolism: new insights in systemic lupus erythematosus pathogenesis and therapy.

Abstract: T cell subsets are critically involved in the development of systemic autoimmunity and organ inflammation in systemic lupus erythematosus (SLE). Each T cell subset function (such as effector, helper, memory or regulatory function) is dictated by distinct metabolic pathways requiring the availability of specific nutrients and intracellular enzymes. The activity of these enzymes or nutrient transporters influences the differentiation and function of T cells in autoimmune responses. Data are increasingly emerging on how metabolic processes control the function of various T cell subsets and how these metabolic processes are altered in SLE. Specifically, aberrant glycolysis, glutaminolysis, fatty acid and glycosphingolipid metabolism, mitochondrial hyperpolarization, oxidative stress and mTOR signalling underwrite the known function of T cell subsets in patients with SLE. A number of medications that are used in the care of patients with SLE affect cell metabolism, and the development of novel therapeutic approaches to control the activity of metabolic enzymes in T cell subsets represents a promising endeavour in the search for effective treatment of systemic autoimmune diseases. The activity of various metabolic pathways can influence the function and differentiation of T cells. T cell metabolism is dysfunctional in systemic lupus erythematosus (SLE) and targeting metabolic pathways in SLE could be a promising therapeutic avenue.

Kawasaki disease: pathophysiology and insights from mouse models.

Abstract: Kawasaki disease is an acute febrile illness and systemic vasculitis of unknown aetiology that predominantly afflicts young children, causes coronary artery aneurysms and can result in long-term cardiovascular sequelae. Kawasaki disease is the leading cause of acquired heart disease among children in the USA. Coronary artery aneurysms develop in some untreated children with Kawasaki disease, leading to ischaemic heart disease and myocardial infarction. Although intravenous immunoglobulin (IVIG) treatment reduces the risk of development of coronary artery aneurysms, some children have IVIG-resistant Kawasaki disease and are at increased risk of developing coronary artery damage. In addition, the lack of specific diagnostic tests and biomarkers for Kawasaki disease make early diagnosis and treatment challenging. The use of experimental mouse models of Kawasaki disease vasculitis has considerably improved our understanding of the pathology of the disease and helped characterize the cellular and molecular immune mechanisms contributing to cardiovascular complications, in turn leading to the development of innovative therapeutic approaches. Here, we outline the pathophysiology of Kawasaki disease and summarize and discuss the progress gained from experimental mouse models and their potential therapeutic translation to human disease.

Mycophenolate mofetil, azathioprine and tacrolimus: mechanisms in rheumatology

Abstract: The introduction of biologic DMARDs into rheumatology has resulted in a substantial reduction of the burden of many rheumatic diseases. In the slipstream of the success achieved with these biologic DMARDs, some conventional immunosuppressive drugs have also found use in new indications. Notably, mycophenolate mofetil, azathioprine and tacrolimus have made their way from solid organ transplantation drugs to become useful assets in rheumatology practice. Mycophenolate mofetil and azathioprine inhibit the purine pathway and subsequently diminish cell proliferation. Both drugs have a pivotal role in the treatment of various rheumatic diseases, including lupus nephritis. Tacrolimus inhibits lymphocyte activation by inhibiting the calcineurin pathway. Mycophenolate mofetil and tacrolimus are, among other indications, increasingly being recognized as useful drugs in the treatment of interstitial lung disease in systemic rheumatic diseases and skin fibrosis in systemic sclerosis. A broad array of trials with mycophenolate mofetil, azathioprine and/or tacrolimus are ongoing within the field of rheumatology that might provide further novel avenues for the use of these drugs. In this Review, we discuss the historical perspective, pharmacodynamics, clinical indications and novel avenues for mycophenolate mofetil, azathioprine and tacrolimus in rheumatology.

New insights into the role of antinuclear antibodies in systemic lupus erythematosus

Abstract: Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by antinuclear antibodies (ANAs) that form immune complexes that mediate pathogenesis by tissue deposition or cytokine induction. Some ANAs bind DNA or associated nucleosome proteins, whereas other ANAs bind protein components of complexes of RNA and RNA-binding proteins (RBPs). Levels of anti-DNA antibodies can fluctuate widely, unlike those of anti-RBP antibodies, which tend to be stable. Because anti-DNA antibody levels can reflect disease activity, repeat testing is common; by contrast, a single anti-RBP antibody determination is thought to suffice for clinical purposes. Experience from clinical trials of novel therapies has provided a new perspective on ANA expression during disease, as many patients with SLE are ANA negative at screening despite previously testing positive. Because trial results suggest that patients who are ANA negative might not respond to certain agents, screening strategies now involve ANA and anti-DNA antibody testing to identify patients with so-called ‘active, autoantibody-positive SLE’. Evidence suggests that ANA responses can decrease over time because of the natural history of disease or the effects of therapy. Together, these findings suggest that, during established disease, more regular serological testing could illuminate changes relevant to pathogenesis and disease status. Antinuclear antibodies (ANAs), characteristic features of systemic lupus erythematosus (SLE), are a requirement for disease classification and trial enrolment. In this Review, the authors re-examine the role of ANAs in SLE and discuss changing attitudes towards using ANAs as biomarkers.

Asymptomatic hyperuricaemia: a silent activator of the innate immune system

Abstract: Asymptomatic hyperuricaemia affects ~20% of the general population in the USA, with variable rates in other countries. Historically, asymptomatic hyperuricaemia was considered a benign laboratory finding with little clinical importance in the absence of gout or kidney stones. Yet, increasing evidence suggests that asymptomatic hyperuricaemia can predict the development of hypertension, obesity, diabetes mellitus and chronic kidney disease and might contribute to disease by stimulating inflammation. Although urate has been classically viewed as an antioxidant with beneficial effects, new data suggest that both crystalline and soluble urate activate various pro-inflammatory pathways. This Review summarizes what is known about the role of urate in the inflammatory response. Further research is needed to define the role of asymptomatic hyperuricaemia in these pro-inflammatory pathways.

Therapeutic glucocorticoids: mechanisms of actions in rheumatic diseases.

Abstract: Therapeutic glucocorticoids have been widely used in rheumatic diseases since they became available over 60 years ago. Despite the advent of more specific biologic therapies, a notable proportion of individuals with chronic rheumatic diseases continue to be treated with these drugs. Glucocorticoids are powerful, broad-spectrum anti-inflammatory agents, but their use is complicated by an equally broad range of adverse effects. The specific cellular mechanisms by which glucocorticoids have their therapeutic action have been difficult to identify, and attempts to develop more selective drugs on the basis of the action of glucocorticoids have proven difficult. The actions of glucocorticoids seem to be highly cell-type and context dependent. Despite emerging data on the effect of tissue-specific manipulation of glucocorticoid receptors in mouse models of inflammation, the cell types and intracellular targets of glucocorticoids in rheumatic diseases have not been fully identified. Although showing some signs of decline, the use of systemic glucocorticoids in rheumatology is likely to continue to be widespread, and careful consideration is required by rheumatologists to balance the beneficial effects and deleterious effects of these agents. Glucocorticoids are anti-inflammatory therapies commonly used in rheumatology, but have wide-ranging adverse effects. Understanding the pharmacokinetic properties and mechanisms of action of glucocorticoids could inform in the development of novel therapies with fewer adverse effects.

Immune monitoring using mass cytometry and related high-dimensional imaging approaches.

Abstract: The cellular complexity and functional diversity of the human immune system necessitate the use of high-dimensional single-cell tools to uncover its role in multifaceted diseases such as rheumatic diseases, as well as other autoimmune and inflammatory disorders. Proteomic technologies that use elemental (heavy metal) reporter ions, such as mass cytometry (also known as CyTOF) and analogous high-dimensional imaging approaches (including multiplexed ion beam imaging (MIBI) and imaging mass cytometry (IMC)), have been developed from their low-dimensional counterparts, flow cytometry and immunohistochemistry, to meet this need. A growing number of studies have been published that use these technologies to identify functional biomarkers and therapeutic targets in rheumatic diseases, but the full potential of their application to rheumatic disease research has yet to be fulfilled. This Review introduces the underlying technologies for high-dimensional immune monitoring and discusses aspects necessary for their successful implementation, including study design principles, analytical tools and future developments for the field of rheumatology.

Combating physical inactivity during the COVID-19 pandemic.

Abstract: Physical inactivity is common during periods of self-isolation, but for patients with rheumatic diseases, there are crucial benefits to be gained from maintaining an active lifestyle throughout the COVID-19 pandemic. Patients should be provided with support to maintain physical activity and avoid prolonged periods of time spent sitting.

Immune-mediated necrotizing myopathy: clinical features and pathogenesis.

Abstract: Immune-mediated necrotizing myopathy (IMNM) is a group of inflammatory myopathies that was distinguished from polymyositis in 2004. Most IMNMs are associated with anti-signal recognition particle (anti-SRP) or anti-3-hydroxy-3-methylglutaryl-coA reductase (anti-HMGCR) myositis-specific autoantibodies, although ~20% of patients with IMNM remain seronegative. These associations have led to three subclasses of IMNM: anti-SRP-positive IMNM, anti-HMGCR-positive IMNM and seronegative IMNM. IMNMs are frequently rapidly progressive and severe, displaying high serum creatine kinase levels, and failure to treat IMNMs effectively may lead to severe muscle impairment. In patients with seronegative IMNM, disease can be concomitant with cancer. Research into IMNM pathogenesis has shown that anti-SRP and anti-HMGCR autoantibodies cause weakness and myofibre necrosis in mice, suggesting that, as well as being diagnostic biomarkers of IMNM, they may play a key role in disease pathogenesis. Therapeutically, treatments such as rituximab or intravenous immunoglobulins can now be discussed for IMNM, and targeted therapies, such as anticomplement therapeutics, may be a future option for patients with refractory disease.

Raynaud phenomenon and digital ulcers in systemic sclerosis.

Abstract: Raynaud phenomenon is a symptom complex caused by impaired digital perfusion and can occur as a primary phenomenon or secondary to a wide range of underlying causes. Raynaud phenomenon occurs in virtually all patients with systemic sclerosis (SSc) and is often the earliest clinical manifestation to occur. Careful assessment is required in patients with Raynaud phenomenon to avoid missing secondary causes such as SSc. Digital ulcers are a painful and disabling visible manifestation of digital vascular injury in patients with SSc. Progress has been made in the classification and assessment of digital ulcers and in understanding ulcer pathogenesis, and there are a wide range of treatments available to both prevent and heal digital ulcers, some of which are also used in Raynaud phenomenon management. In this Review, the assessment of patients with Raynaud phenomenon is discussed, including 'red flags' that are suggestive of SSc. The pathogenesis, classification and assessment of SSc-associated digital ulcers are also covered, alongside an overview of management approaches for SSc-associated Raynaud phenomenon and digital ulcers. Finally, unmet needs are discussed and the concept of a unified vascular phenotype in which therapies that affect the vasculature to support disease modification strategies is introduced.

Tendon and ligament mechanical loading in the pathogenesis of inflammatory arthritis.

Abstract: Mechanical loading is an important factor in musculoskeletal health and disease. Tendons and ligaments require physiological levels of mechanical loading to develop and maintain their tissue architecture, a process that is achieved at the cellular level through mechanotransduction-mediated fine tuning of the extracellular matrix by tendon and ligament stromal cells. Pathological levels of force represent a biological (mechanical) stress that elicits an immune system-mediated tissue repair pathway in tendons and ligaments. The biomechanics and mechanobiology of tendons and ligaments form the basis for understanding how such tissues sense and respond to mechanical force, and the anatomical extent of several mechanical stress-related disorders in tendons and ligaments overlaps with that of chronic inflammatory arthritis in joints. The role of mechanical stress in 'overuse' injuries, such as tendinopathy, has long been known, but mechanical stress is now also emerging as a possible trigger for some forms of chronic inflammatory arthritis, including spondyloarthritis and rheumatoid arthritis. Thus, seemingly diverse diseases of the musculoskeletal system might have similar mechanisms of immunopathogenesis owing to conserved responses to mechanical stress.

Revisiting the gut-joint axis: links between gut inflammation and spondyloarthritis.

Abstract: Gut inflammation is strongly associated with spondyloarthritis (SpA), as exemplified by the high prevalence of inflammatory bowel disease (IBD) and the even higher occurrence of subclinical gut inflammation in patients with SpA. The gut-joint axis of inflammation in SpA is further reinforced by similarities in immunopathogenesis at both anatomical sites and by the clinical success of therapies blocking TNF and IL-23 in IBD and in some forms of SpA. Many genetic risk factors are shared between SpA and IBD, and changes in the composition of gut microbiota are seen in both diseases. Current dogma is that inflammation in SpA initiates in the gut and leads to joint inflammation; however, although conceptually attractive, some research does not support this causal relationship. For example, therapies targeting IL-17A are efficacious in the joint but not the gut, and interfering with gut trafficking by targeting molecules such as α4β7 in IBD can lead to onset or flares of SpA. Several important knowledge gaps remain that must be addressed in future studies. Determining the true nature of the gut-joint axis has real-world implications for the treatment of patients with co-incident IBD and SpA and for the repurposing of therapeutics from one disease to the other.

Atherosclerotic cardiovascular disease prevention in rheumatoid arthritis.

Abstract: Patients with rheumatoid arthritis (RA) are at high risk of developing cardiovascular disease (CVD). Inflammation has a pivotal role in the pathogenesis of CVD. RA is an inflammatory joint disease and, compared with the general population, patients with RA have approximately double the risk of atherosclerotic CVD, stroke, heart failure and atrial fibrillation. Although this high risk of CVD has been known for decades, patients with RA receive poorer primary and secondary CVD preventive care than other high-risk patients, and an unmet need exists for improved CVD preventive measures for patients with RA. This Review summarizes the evidence for atherosclerotic CVD in patients with RA and provides a contemporary analysis of what is known and what needs to be further clarified about recommendations for CVD prevention in patients with RA compared with the general population. The management of traditional CVD risk factors, including blood pressure, lipids, diabetes mellitus and lifestyle-related risk factors, as well as the effects of inflammation and the use of antirheumatic medication on CVD risk and risk management in patients with RA are discussed. The main aim is to provide a roadmap of atherosclerotic CVD risk management and prevention for patients with RA. Atherosclerotic cardiovascular disease is a major cause of morbidity and mortality in patients with rheumatoid arthritis. In this Review, Semb and colleagues outline atherosclerotic cardiovascular disease risk management and prevention for patients with rheumatoid arthritis.

The COVID-19 Global Rheumatology Alliance: collecting data in a pandemic.

Abstract: The global COVID-19 pandemic has the potential to severely affect those with rheumatic diseases or who are taking immunosuppressive therapies. Information is lacking as to how these groups will fare if they become infected. A global alliance has rapidly formed to try to address this information deficit.

Digital health technologies: opportunities and challenges in rheumatology.

Abstract: The past decade in rheumatology has seen tremendous innovation in digital health technologies, including the electronic health record, virtual visits, mobile health, wearable technology, digital therapeutics, artificial intelligence and machine learning. The increased availability of these technologies offers opportunities for improving important aspects of rheumatology, including access, outcomes, adherence and research. However, despite its growth in some areas, particularly with non-health-care consumers, digital health technology has not substantially changed the delivery of rheumatology care. This Review discusses key barriers and opportunities to improve application of digital health technologies in rheumatology. Key topics include smart design, voice enablement and the integration of electronic patient-reported outcomes. Smart design involves active engagement with the end users of the technologies, including patients and clinicians through focus groups, user testing sessions and prototype review. Voice enablement using voice assistants could be critical for enabling patients with hand arthritis to effectively use smartphone apps and might facilitate patient engagement with many technologies. Tracking many rheumatic diseases requires frequent monitoring of patient-reported outcomes. Current practice only collects this information sporadically, and rarely between visits. Digital health technology could enable patient-reported outcomes to inform appropriate timing of face-to-face visits and enable improved application of treat-to-target strategies. However, best practice standards for digital health technologies do not yet exist. To achieve the potential of digital health technology in rheumatology, rheumatology professionals will need to be more engaged upstream in the technology design process and provide leadership to effectively incorporate the new tools into clinical care. Digital health technologies (DHTs) have a variety of interesting current and possible future applications in rheumatology. In this article, the authors describe some of the key barriers that prevent DHT integration into rheumatology care and discuss ways in which these barriers could be addressed.

Interplay between genetics and epigenetics in osteoarthritis.

Abstract: Research into the molecular genetics of osteoarthritis (OA) has been substantially bolstered in the past few years by the implementation of powerful genome-wide scans that have revealed a large number of novel risk loci associated with the disease. This refreshing wave of discovery has occurred concurrently with epigenetic studies of joint tissues that have examined DNA methylation, histone modifications and regulatory RNAs. These epigenetic analyses have involved investigations of joint development, homeostasis and disease and have used both human samples and animal models. What has become apparent from a comparison of these two complementary approaches is that many OA genetic risk signals interact with, map to or correlate with epigenetic mediators. This discovery implies that epigenetic mechanisms, and their effect on gene expression, are a major conduit through which OA genetic risk polymorphisms exert their functional effects. This observation is particularly exciting as it provides mechanistic insight into OA susceptibility. Furthermore, this knowledge reveals avenues for attenuating the negative effect of risk-conferring alleles by exposing the epigenome as an exploitable target for therapeutic intervention in OA.

PAD enzymes in rheumatoid arthritis: pathogenic effectors and autoimmune targets

Abstract: Peptidylarginine deiminases (PADs) have an important role in the pathogenesis of rheumatoid arthritis (RA) owing to their ability to generate citrullinated proteins - the hallmark autoantigens of RA. Of the five PAD enzyme isoforms, PAD2 and PAD4 are the most strongly implicated in RA at both genetic and cellular levels, and PAD inhibitors have shown therapeutic efficacy in mouse models of inflammatory arthritis. PAD2 and PAD4 are additionally targeted by autoantibodies in distinct clinical subsets of patients with RA, suggesting anti-PAD antibodies as possible biomarkers for RA diagnosis and prognosis. This Review weighs the evidence that supports a pathogenic role for PAD enzymes in RA as both promoters and targets of the autoimmune response, as well as discussing the mechanistic and therapeutic implications of these findings in the wider context of RA pathogenesis. Understanding the origin and consequences of dysregulated PAD enzyme activity and immune responses against PAD enzymes will be important to fully comprehend the pathogenic mechanisms involved in this disease and for the development of novel strategies to treat and prevent RA.

Protecting the kidney in systemic lupus erythematosus: from diagnosis to therapy.

Abstract: Lupus nephritis (LN) is a common manifestation of systemic lupus erythematosus that can lead to irreversible renal impairment. Although the prognosis of LN has improved substantially over the past 50 years, outcomes have plateaued in the USA in the past 20 years as immunosuppressive therapies have failed to reverse disease in more than half of treated patients. This failure might reflect disease complexity and heterogeneity, as well as social and economic barriers to health-care access that can delay intervention until after damage has already occurred. LN progression is still poorly understood and involves multiple cell types and both immune and non-immune mechanisms. Single-cell analysis of intrinsic renal cells and infiltrating cells from patients with LN is a new approach that will help to define the pathways of renal injury at a cellular level. Although many new immune-modulating therapies are being tested in the clinic, the development of therapies to improve regeneration of the injured kidney and to prevent fibrosis requires a better understanding of the mechanisms of LN progression. This mechanistic understanding, together with the development of clinical measures to evaluate risk and detect early disease and better access to expert health-care providers, should improve outcomes for patients with LN. Lupus nephritis is a serious and currently irreversible complication of systemic lupus erythematosus that is a leading cause of mortality. New biomarkers and therapies are being developed to improve the monitoring and treatment of this disease.