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Key Points Tendon is a mechanosensitive tissue Abnormal loading leads to tendon injuries Mechanical forces are converted to biochemical signals that elicit cellular responses by tendon cells Similar mechanical and biological signals are involved in tendon development, homeostasis and repair A better understanding of the interaction between forces, intracellular pathways and gene transcription in the context of tendon biology is needed Understanding mechanobiology in tendon development, homeostasis and repair is critical to designing therapies for tendon injury Tendon disorders are common and are a major cause of musculoskeletal pain, but the development of effective therapies requires detailed knowledge of the biology of this mechanosensitive musculoskeletal tissue. As well as providing an overview of tendon physiology and pathology, this article reviews the mechanical and biological factors that contribute to tendon development, homeostasis and repair, drawing on evidence from experimental models and developmental biology. Tendon is a crucial component of the musculoskeletal system. Tendons connect muscle to bone and transmit forces to produce motion. Chronic and acute tendon injuries are very common and result in considerable pain and disability. The management of tendon injuries remains a challenge for clinicians. Effective treatments for tendon injuries are lacking because the understanding of tendon biology lags behind that of the other components of the musculoskeletal system. Animal and cellular models have been developed to study tendon-cell differentiation and tendon repair following injury. These studies have highlighted specific growth factors and transcription factors involved in tenogenesis during developmental and repair processes. Mechanical factors also seem to be essential for tendon development, homeostasis and repair. Mechanical signals are transduced via molecular signalling pathways that trigger adaptive responses in the tendon. Understanding the links between the mechanical and biological parameters involved in tendon development, homeostasis and repair is prerequisite for the identification of effective treatments for chronic and acute tendon injuries.

Key Points Getting therapeutics into joints in a targeted and sustained fashion is difficult Intra-articular injection solves the delivery problem and brings several additional advantages over systemic administration, including increased bioavailability, reduced systemic exposure, fewer off-target effects and lower costs Soluble drugs exit joints rapidly, via the capillaries (in the case of small molecules) and lymphatic system (for macromolecules) Strategies for extending the intra-articular half-lives of therapeutics include the use of small particles, drug modification and gene transfer Delivery of hyaluronate and corticosteroids accounts for the majority of intra-articular injections; additional therapeutics include recombinant proteins, autologous blood products and analgesics Clinical trials involving the intra-articular injection of mesenchymal stem cells have multiplied enormously in recent years If a drug is intended to work in a joint, then direct injection seems likely to be an appropriate route of delivery, to minimize adverse events and limit the amount of therapeutic agent required. Ensuring such a drug remains in the joint long enough to produce an effect, however, is another matter. Successes seen, lessons learned, and developmental prospects in intra-articular therapy are explored in this Review. Diarthrodial joints are well suited to intra-articular injection, and the local delivery of therapeutics in this fashion brings several potential advantages to the treatment of a wide range of arthropathies. Possible benefits over systemic delivery include increased bioavailability, reduced systemic exposure, fewer adverse events, and lower total drug costs. Nevertheless, intra-articular therapy is challenging because of the rapid egress of injected materials from the joint space; this elimination is true of both small molecules, which exit via synovial capillaries, and of macromolecules, which are cleared by the lymphatic system. In general, soluble materials have an intra-articular dwell time measured only in hours. Corticosteroids and hyaluronate preparations constitute the mainstay of FDA-approved intra-articular therapeutics. Recombinant proteins, autologous blood products and analgesics have also found clinical use via intra-articular delivery. Several alternative approaches, such as local delivery of cell and gene therapy, as well as the use of microparticles, liposomes, and modified drugs, are in various stages of preclinical development.

Key Points Allopurinol is a highly effective, cheap and simple therapy for gout if dosing is adequate and patients adhere to the therapy Serious allopurinol-related adverse events (for example, allopurinol hypersensitivity syndrome [AHS]) are rare, but are associated with high morbidity and mortality Risk factors for allopurinol-related serious adverse events include recent introduction of allopurinol, the presence of the HLA-B * 58:01 allele, a higher starting dose, renal impairment and the concomitant use of diuretics Allopurinol hypersensitivity is primarily mediated by an oxypurinol-specific T-cell response Although a generally safe and effective drug that is widely used in the treatment of gout, allopurinol can in rare instances be associated with severe adverse events. The presentation, risk factors and mechanisms of allopurinol-induced hypersensitivity are the focus of this Review, as well as strategies to avoid or minimize such reactions. Allopurinol is the most commonly prescribed urate-lowering therapy for the management of gout. Serious adverse reactions associated with allopurinol, while rare, are feared owing to the high mortality. Such reactions can manifest as a rash combined with eosinophilia, leukocytosis, fever, hepatitis and progressive kidney failure. Risk factors for allopurinol-related severe adverse reactions include the recent introduction of allopurinol, the presence of the HLA-B * 58:01 allele, and factors that influence the drug concentration. The interactions between allopurinol, its metabolite, oxypurinol, and T cells have been studied, and evidence exists that the presence of the HLA-B * 58:01 allele and a high concentration of oxypurinol function synergistically to increase the number of potentially immunogenic-peptide–oxypurinol– HLA-B * 58:01 complexes on the cell surface, thereby increasing the risk of T-cell sensitization and a subsequent adverse reaction. This Review will discuss the above issues and place this in the clinical context of reducing the risk of serious adverse reactions.

In this Review, the phenotypic and genetic markers for common musculoskeletal pain conditions are discussed. Furthermore, the authors propose a heuristic approach to evaluation of the different kinds of markers associated with these conditions, which could enable greater understanding of the underlying pathophysiological processes. 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. Key Points Musculoskeletal pain conditions such as low back pain, chronic widespread pain, fibromyalgia and temporomandibular joint disorders are highly prevalent These conditions have measurable phenotypic signatures, which are heterogeneous in nature Musculoskeletal pain conditions have a genetic basis, with both common and rare genetic variants contributing to the conditions and associated endophenotypes Physical and psychological environmental exposures can produce epigenetic effects that alter gene expression, biological pathway activity, and thus the manifestation of clinical phenotypes of musculoskeletal pain conditions Genetic association studies combined with in vitro and in vivo follow-up studies can identify effective therapeutic agents for the treatment of large subpopulations of patients with musculoskeletal pain conditions

IL-1 has an important role in the pathogenesis of many hereditary and non-hereditary autoinflammatory diseases. This Review examines the biological functions of IL-1 and the use of IL-1-targeting agents in the treatment of various human diseases. Interleukin (IL)-1 was first cloned in the 1980s, and rapidly emerged as a key player in the regulation of inflammatory processes. The term IL-1 refers to two cytokines, IL-1α and IL-1β, which are encoded by two separate genes. The effects of IL-1 are tightly controlled by several naturally occurring inhibitors, such as IL-1 receptor antagonist (IL-1Ra), IL-1 receptor type II (IL-1RII), and other soluble receptors. Numerous IL-1 inhibitors have been developed and tested primarily in rheumatoid arthritis, with only modest effects. By contrast, the use of IL-1 antagonists has been uniformly associated with beneficial effects in patients with hereditary autoinflammatory conditions associated with excessive IL-1 signaling, such as cryopyrinopathies and IL-1Ra deficiency. Successful treatment with IL-1 blockers has also been reported in other hereditary autoinflammatory diseases, as well as in nonhereditary inflammatory diseases, such as Schnizler syndrome, systemic-onset juvenile idiopathic arthritis and adult Still disease. The role of microcrystals in the regulation of IL-1β processing and release has provided the rationale for the use of IL-1 inhibitors in crystal-induced arthritis. Finally, preliminary results indicating that IL-1 targeting is efficacious in type 2 diabetes and smoldering myeloma have further broadened the spectrum of IL-1-driven diseases. Key Points Interleukin (IL)-1, which includes IL-1α and IL-1β, exerts strong proinflammatory activities and has a major role in host responses to exogenous and endogenous noxious stimuli The proinflammatory activities of IL-1 are controlled by several endogenous inhibitors, such as IL-1 receptor antagonist (IL-1Ra), membrane-bound and soluble IL-1 receptor type II and IL-1 receptor accessory protein Numerous exogenous (for example, microbial components and asbestos) and endogenous (for example, monosodium urate and calcium pyrophosphate dihydrate crystals) agents can activate caspase 1, which induces release of bioactive IL-1β The role of IL-1 in disease is exemplified by the description of hereditary autoinflammatory diseases caused by excessive IL-1 signaling secondary to either IL-1β overproduction or IL-1Ra deficiency A beneficial effect of targeting IL-1 has been described in several hereditary and non-hereditary autoinflammatory diseases The potential role of IL-1 in the pathogenesis of type 2 diabetes and smoldering myeloma has been supported by the results of recent clinical trials

Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are inflammatory disorders that commonly occur in the elderly and whose disease patterns variably overlap. In this Review, Salvarani and colleagues describe the main clinical features of both PMR and GCA, detailing the pathogenesis, diagnosis, classification and management of these disorders, offering practical guidance to clinicians. Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are inflammatory diseases that typically affect white individuals >50 years. Women are affected ∼2–3 times more often than men. PMR and GCA occur together more frequently than expected by chance. The main symptoms of PMR are pain and stiffness in the shoulders, and often in the neck and pelvic girdle. Imaging studies reveal inflammation of joints and bursae of the affected areas. GCA is a large-vessel and medium-vessel arteritis predominantly involving the branches of the aortic arch. The typical clinical manifestations of GCA are new headache, jaw claudication and visual loss. PMR and GCA usually remit within 6 months to 2 years from disease onset. Some patients, however, have a relapsing course and might require long-standing treatment. Diagnosis of PMR and GCA is based on clinical features and elevated levels of inflammatory markers. Temporal artery biopsy remains the gold standard to support the diagnosis of GCA; imaging studies are useful to delineate large-vessel involvement in GCA. Glucocorticoids remain the cornerstone of treatment of both PMR and GCA, but patients with GCA require higher doses. Synthetic immunosuppressive drugs also have a role in disease management, whereas the role of biologic agents is currently unclear. Key Points Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are linked disorders that predominantly affect elderly white individuals The diagnosis of GCA and PMR is made on the basis of characteristic clinical features and elevated inflammatory markers, but temporal artery biopsy remains the diagnostic gold standard for GCA Early diagnosis is necessary to prevent ischaemic events in GCA; patients with GCA who suffer an ischaemic event are at high risk of developing another attack unless immediately treated Imaging studies are required to diagnose and monitor GCA with large-vessel involvement Glucocorticoids remain the mainstay of treatment for PMR and GCA

Key Points IgG4-related disease represents a chronic inflammatory disorder characterized by various systemic organ dysfunctions, such as IgG4-associated dacryoadenitis and sialadenitis (also called Mikulicz disease) and type 1 autoimmune pancreatitis The disease is associated with elevated serum levels of IgG4 and specific histopathological features, including abundant IgG4 + plasmacyte infiltration, and storiform fibrosis and obliterative phlebitis in the inflamed organs IgG4-related disease is also associated with a predominantly type 2 T-helper-cell cytokine profile, and infiltration of regulatory T cells is considered to be involved in the disease pathogenesis Comprehensive systemic and organ-specific diagnostic criteria have been defined for IgG4-related disease in Japanese populations, although criteria that classify the disease in other populations are not available at present Examination for systemic organ failure and screening for underlying malignancies is important during the diagnosis and follow-up of IgG4-related disease Glucocorticoids are effective in the treatment of IgG4-related disease, but the rate of relapse after tapering or discontinuing glucocorticosteroids is high Awareness of IgG4-related disease, which shares many clinical, and potentially pathogenetic, similarities with certain rheumatic disorders, is increasing worldwide. This Review provides an overview of this disease entity, with particular focus on pathogenesis, clinical features, diagnosis and treatment, for the benefit of rheumatologists, who are increasingly likely to be involved in the diagnosis and management of patients with IgG4-related disorders. Recognition of IgG4-related disease as an independent chronic inflammatory disorder is a relatively new concept; previously, the condition was thought to represent a subtype of Sjögren's syndrome. IgG4-related disease is characterized by elevated serum levels of IgG4 and inflammation of various organs, with abundant infiltration of IgG4-bearing plasma cells, storiform fibrosis and obliterative phlebitis representing the major histopathological features of the swollen organs. The aetiology and pathogenesis of this disorder remain unclear, but inflammation and subsequent fibrosis occur due to excess production of type 2 T-helper-cell and regulatory T-cell cytokines. The disease can comprise various organ manifestations, such as dacryoadenitis and sialadenitis (also called Mikulicz disease), type 1 autoimmune pancreatitis, kidney dysfunction and lung disease. Early intervention using glucocorticoids can improve IgG4-related organ dysfunction; however, patients often relapse when doses of these agents are tapered. The disease has also been associated with an increased incidence of certain malignancies. Increased awareness of IgG4-related disease might lead to consultation with rheumatologists owing to its clinical, and potentially pathogenetic, similarities with certain rheumatic disorders. With this in mind, we describe the pathogenic mechanisms of IgG4-related disease, and outline considerations for diagnosis and treatment of the condition.

Key Points Diffuse idiopathic skeletal hyperostosis (DISH) is characterized by entheseal ossification and/or calcification involving mainly the thoracic spine Peripheral joints and adjacent entheses can also be involved The pathogenesis of DISH is not clear, but several factors may promote the differentiation of mesenchymal cells into bone-forming cells DISH is often associated with a variety of metabolic derangements, which may increase cardiovascular morbidity Patients with DISH also have an increased risk of complicated spinal fractures, with associated morbidities Diffuse idiopathic skeletal hyperostosis (DISH) is a poorly understood condition characterized by ossification of ligaments and entheses. This comprehensive Review explains the epidemiology and clinical manifestations of DISH, as well as highlighting the latest insights into pathogenic mechanisms. The authors also argue for the development of new classification criteria that can identify early disease. 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.

Key Points On B cells, CD22 and Siglec-G mediate inhibition of B-cell antigen receptor-induced signalling; Siglec-G is an inhibitory receptor for B1 cells Ligand-binding of CD22 and Siglec-G to other membrane glycoproteins in cis regulate their association to the B-cell receptor and the degree of inhibition CD22-deficiency or Siglec-G-deficiency does not result in autoimmunity, whereas CD22 and Siglec-G double-deficient mice develop a systemic lupus erythematosus (SLE)-like disease The immunomodulatory CD22-specific antibody, epratuzumab, reduces disease activity in patients with SLE, although the exact mechanism is unknown Attaching CD22-specific or Siglec-G-specific sialic acids with antigens on liposomes induces antigen-specific tolerance in mice and could be a new autoantigen-specific treatment strategy The sialic-acid-binding immunoglobulin-type lectins (Siglecs) CD22 and Siglec–G (or the human orthologue Siglec–10) are expressed on B-cell surfaces. Here, the authors detail the involvement of CD22 and Siglec–G in maintaining B-cell tolerance, and their contribution to the prevention of autoimmune diseases. In addition, the authors describe therapeutic targeting of CD22, with antibodies and synthetic CD22 ligands, in autoimmune disease. A high proportion of peripheral human B cells produce polyreactive or autoreactive antibodies, which indicates that they have escaped the elimination of self-reactive B cells in the bone marrow. CD22 and Siglec-G are two inhibitory receptors of the sialic-acid-binding immunoglobulin-like lectin (Siglec) family that inhibit the B-cell antigen receptor (BCR) signal. The ability of these two receptors to bind sialic acids is crucial for regulating inhibition and inducing tolerance to self-antigens. Sialylated glycans are usually absent on microbes (although several pathogenic microorganisms have evolved strategies to mimic self by decorating their surfaces with sialic acids) but abundant in higher vertebrates and might, therefore, provide an important tolerogenic signal. Combined Siglec-G deficiency and CD22 deficiency leads to spontaneous autoimmunity in mice, and mutations in an enzyme that modifies Siglec ligands are directly linked to several autoimmune diseases in humans. New data show that high-affinity ligands for CD22 and Siglec-G can be used to induce antigen-specific B-cell tolerance, which might be one strategy for the treatment of autoimmune diseases in the future.

Familial Mediterranean fever (FMF) is characterized by episodes of acute inflammation; however, in approximately 30% of patients with FMF inflammation persists even during the attack-free periods. In this Review, the authors discuss the markers and risk factors for persistent chronic inflammation in these patients, summarize the clinical outcomes of such inflammation, and suggest a new potential treatment strategy. Familial Mediterranean fever (FMF) is the most common of the hereditary periodic fever syndromes. Although the typical clinical course of FMF is characterized by bouts of painful inflammation, this presentation represents only the tip of the iceberg. In many patients inflammation can persist in attack-free periods, as shown by high levels of acute-phase proteins, cytokines and inflammation-induced proteins. This subclinical inflammation puts patients at risk of developing complications such as anemia, splenomegaly, decreased bone mineral density, heart disease and life-threatening amyloid A amyloidosis, among others. In this article, we review the published data on markers and other factors involved in the persistence of inflammation in patients with FMF during attack-free periods, examine the risk factors for the development of this subclinical inflammation, summarize the complications of chronic inflammation in FMF and propose a new strategy for treatment, based on these data. Key Points The hallmark feature of familial Mediterranean fever (FMF) is acute, painful episodes of inflammation, but chronic subclinical inflammation may persist between attacks Chronic subclinical inflammation in patients with FMF might lead to complications, including amyloid A amyloidosis, anemia, splenomegaly and decreased bone density In addition to the prevention of acute attacks, treatment of FMF should be aimed at decreasing the chronic subclinical inflammation and impeding its deleterious clinical outcome Serum amyloid A protein is a sensitive marker of chronic inflammation in FMF that should be measured and the levels taken into account in treatment decisions