For many years, non-steroidal anti-inflammatory agents, steroids and immunosuppressive drugs have been the mainstay of treatment for rheumatological disorders. Over the last few years, the emergence of biologic treatments has dramatically changed the management of numerous rheumatological diseases. However, immunoglobulin treatment has been used for decades and its use has still not been superseded in certain rheumatological diseases. In fact, despite the introduction of newer immunomodulatory drugs, there has been an ever-increasing number of clinical indications for which intravenous immunoglobulin (IVIG) has been tried. Immunoglobulins are plasma proteins secreted by plasma cells, forming a major component of the adaptive immune system. IVIG is a blood product prepared from plasma, each batch prepared from a pool of 10,000-20,000 donations. Multiple purification steps during the manufacturing process aim to eliminate all known transmissible pathogens, but cannot completely exclude the risk from unknown pathogens. It should be noted that there has been the transmission of hepatitis C in one batch of immunoglobulin, reported in 1994, resulting in more than 200 patients in the USA and Europe being affected. Nevertheless, IVIG remains relatively safe compared with other immunosuppressive drugs. Headaches and fatigue are common side effects but fortunately the more severe problems such as aseptic meningitis, venous thromboembolism and acute renal failure remain rare. High-dose immunoglobulin when administered i.v. has immunomodulatory properties. The precise mechanism of action of IVIG is complex and not yet fully understood.

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-1alpha and IL-1beta, 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-1beta 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.

Examples of naturally occurring musculoskeletal disorders are extremely common in veterinary species and provide a valuable comparative research resource, which can provide compelling comparative data on the aetiopathogenesis and treatment of many common human musculoskeletal diseases. In particular, orthopaedic diseases are a common morbidity in both dogs and horses. In this review, we give an overview of the common musculoskeletal diseases encountered in these species: for instance, tendon and ligament injuries, arthropathies and stress fractures, as well as an insight into the basic biology of these conditions. In doing so, we aim to demonstrate the similarities and differences between these disorders and similar conditions in man.

Chronic fatigue is one of the most prevalent and debilitating symptoms in primary SS (pSS). Approximately 70% of pSS patients suffer from disabling fatigue, which is associated with reduced health-related quality of life. In this article, we review the instruments used for evaluating pSS-related fatigue, our current understanding of the underlying psychosocial and physiological mechanisms of fatigue in pSS and the therapeutic strategies that have been studied in the management of fatigue in pSS.

Autoimmunity has been a topic of intensive research for several decades, yet amazingly, no uniform hypothesis exists to explain the basis for the spectrum of autoantibody specificities seen in autoimmune diseases. It therefore seems appropriate to consider whether our current framework for understanding tolerance, and thus the mechanisms controlling the initiation and perpetuation of autoimmunity, may be faulty. Adapting the paradigm of Matzinger-the 'danger model', a case can be made for a perspective that appreciates the fundamental role of the tissues in controlling immune response, favouring a shift of focus in studies on the initiation of autoimmunity. Applying the elements of this model, I set forth a number of scenarios for how autoreactivity could emerge, with emphasis on the likely sources of the involved autoantigens and the functional basis of their appearance. The emerging picture is one in which disruption of tissue homeostasis takes centre stage, with the antigen-presenting cells as the key players.

Rheumatoid arthritis (RA) is a prototypical immune-mediated inflammatory disease that is characterized by increased cardiovascular morbidity and mortality, independent of the traditional risk factors for cardiovascular disease. The chronic inflammatory state--a hallmark of RA--is considered to be a driving force for accelerated atherogenesis. Consequently, aggressive control of RA disease activity is thought to be instrumental for cardiovascular risk reduction. Currently, statin-mediated reduction of LDL-cholesterol levels is considered to be the cornerstone of cardiovascular disease prevention. In addition to their lipid-lowering capabilities, statins exert immunomodulatory effects, which could be of dual benefit in the treatment of RA. Guidelines on the reduction of cardiovascular risk in patients with RA are lacking, however, largely owing to the absence of data from randomized controlled trials. This Review focuses on the pathophysiology of cardiovascular events in RA, as well as the need to adjust cardiovascular risk engines to better-accommodate the impact of chronic inflammatory disease over and above the established risk factors to predict cardiovascular risk in patients with RA.

Evidence strongly suggests that excessive or protracted signaling, or both, by cell-surface or intracellular innate immune receptors is central to the pathogenesis of most autoimmune and autoinflammatory rheumatic diseases. The initiation of aberrant innate and adaptive immune responses in autoimmune diseases can be triggered by microbes and, at times, by endogenous molecules--particularly nucleic acids and related immune complexes--under sterile conditions. By contrast, most autoinflammatory syndromes are generally dependent on germline or de novo gene mutations that cause or facilitate inflammasome assembly. The consequent production of proinflammatory cytokines, principally interferon-alpha/beta and tumor necrosis factor in autoimmune diseases, and interleukin-1beta in autoinflammatory diseases, leads to the creation of autoamplification feedback loops and chronicity of these syndromes. These findings have resulted in a critical reappraisal of pathogenetic mechanisms, and provide a basis for the development of novel diagnostic and therapeutic modalities for these diseases.

Tumor necrosis factor (TNF) blockers are widely used to treat rheumatoid arthritis and other chronic inflammatory diseases. Many studies have demonstrated an increased risk of opportunistic infections such as tuberculosis and fungal infection in patients treated with TNF blockers, which is thought to be related to the primary role of TNF both in host defense and in the immune response. Little is known, however, about the association between TNF blockade and the development of viral infection. Owing to the critical role of TNF in the control of viral infection, depletion of this cytokine with TNF blockers could facilitate the development or reactivation of viral infection. A number of large observational studies have found an increased risk of herpes zoster in patients receiving TNF blockers for the treatment of rheumatoid arthritis. This Review draws attention to the risk of several viral infections, including HIV, varicella zoster virus, Epstein-Barr virus, cytomegalovirus, and human papillomavirus, in patients receiving TNF-blocking therapy for chronic inflammatory conditions. In addition, implications for clinical practice and possible preventative approaches are discussed.

Sciatica is a set of symptoms rather than a specific diagnosis, and is caused by a herniated lumbar disc in the vast majority of cases. The most important symptom is lower limb pain radiating below the knee and into the foot and toes. The clinical course of acute sciatica is generally favorable, with most pain and related disability improving within 2-4 weeks with or without treatment. Diagnosis mainly involves history taking and physical examination. Imaging is warranted if there is evidence of an underlying pathology other than disc herniation, such as infection or malignancy, and in patients with severe symptoms that do not improve after 6-8 weeks of conservative treatment. MRI is the preferred imaging modality, as it can visualize soft tissues better than CT and does not expose the patient to ionizing radiation. Conservative treatment is generally the first-line option in patients with sciatica; however, the currently available evidence does not show any intervention--including a broad range of conservative and surgical approaches--to have clearly superior outcomes. Thus, patient preference seems to be an important factor in the clinical management of sciatica.

The pathogenetic role of autoantibodies in systemic sclerosis (SSc) remains unclear, but these autoantibodies have been established as strong predictors of disease outcome and the pattern of organ complications in patients with this condition. The three most frequently observed types of SSc-specific autoantibody-anti-centromere antibodies, anti-topoisomerase antibodies and anti-RNA polymerase III antibodies-are found in over 50% of patients; the presence of each is generally exclusive of the others. Although a lot less frequently observed, antibodies directed against U3RNP and Th/To are also specific for scleroderma, whereas anti-Pm/Scl, anti-Ku and anti-U1RNP antibodies are seen mainly in patients with overlap syndromes. Up to 11% of patients with SSc can test negative for antinuclear antibodies. Strong links exist between autoantibody specificities and disease presentation and outcome, which make autoantibodies essential assessment tools in patients with SSc.

Asia is home to more than half of the world's population and is a region of diverse ethnicity, culture, microbial endemicity, and economic backgrounds. This diversity is also reflected in the heterogeneity among Asian patients with rheumatic diseases in terms of clinical manifestations, disease courses, treatment responses and outcomes, which provides opportunities for researchers to conduct some unique studies. Several disease entities, such as Behçet syndrome, Takayasu arteritis, Kawasaki disease, and immunological disorders associated with human T-lymphotropic virus type 1 (HTLV-1), were first observed and defined in Asia. In addition, the region's researchers have been at the forefront of research in some interesting scientific topics, which has opened up new research avenues in rheumatology, such as the direct targeting of synovial cells in patients with rheumatoid arthritis via activation of the agonistic Fas pathway, establishment of the field of osteoimmunology, the discovery of regulatory T cells and synoviolin, and the development of tocilizumab, a humanized monoclonal antibody against interleukin-6 receptor.

Osteoporosis is a major public health problem through associated fragility fractures. The most common sites of fracture are the hip, spine and wrist, and these have an enormous health and economic impact. All fractures result in some degree of morbidity, but fractures at the hip are associated with the worst outcomes. The worldwide direct and indirect annual costs of hip fracture in 1990 were estimated at US$34.8 billion, and are expected to increase substantially over the next 50 years. Fracture incidence varies between populations, and is set to increase over coming decades as the global population becomes more elderly. This effect will be particularly marked in the developing world, which is additionally assuming more-westernized lifestyles that predispose to increased fracture risk. Strategies to target those at high risk of fracture have been developed, but preventative measures at the public health level are also urgently needed to reduce the burden of this devastating disease.

Invariant natural killer T (iNKT) cells are an innate T-cell lineage known to recognize a range of endogenously derived and exogenously derived glycolipid antigens. Advances in our understanding of this T-cell subset have enabled researchers to investigate the immunomodulatory activity of iNKT cell ligands in experimental models of diseases such as cancer, allergy and chronic inflammatory joint disease. To a large extent, the ability of iNKT cells to regulate such disease models has been ascribed to their capacity to promote a polarized cytokine environment, which is understood to skew adaptive immune responses. In this Review, we discuss the current understanding of how iNKT-cell polarization is regulated and relate this basic theory to the proposed role for iNKT cells in models of rheumatologic disease.

Glucocorticoid-induced osteoporosis is a common condition that results in significant morbidity and mortality. The skeletal effects of glucocorticoids include both direct and indirect actions on bone that result in an early, transient increase in bone resorption accompanied by a decrease in bone formation, which is maintained for the duration of glucocorticoid therapy. Rapid bone loss and increased fracture risk occur soon after the initiation of glucocorticoid therapy and are dose dependent. The increase in fracture risk is partly independent of bone mineral density, probably as a result of changes in bone material properties and an increased risk of falling. Bisphosphonates are the front-line choice for prevention of fracture in glucocorticoid-treated patients, with teriparatide as the second-line option; calcium and vitamin D supplements should be co-prescribed in the majority of individuals. Future guidelines for the management of glucocorticoid-induced osteoporosis should recognize the limitations of FRAX in assessing fracture risk in glucocorticoid-treated patients, and should include recently approved interventions, such as zoledronate and teriparatide.

The concept of disease modification in ankylosing spondylitis (AS) incorporates aspects of inflammation, bone destruction and new bone formation. The degree to which inflammation and new bone formation are linked remains conjectural, but data from MRI studies of spinal inflammation support the concept of such coupling; however, these studies also suggest a role for the involvement of noninflammatory pathways, such as those involving bone morphogenetic proteins, wingless proteins and Dickkopf-1, in the formation of new bone. The main clinical outcome that reflects disease modification is the modified Stoke Ankylosing Spondylitis Spine Score, which assesses abnormalities in the anterior vertebral corners of the cervical and lumbar spine. However, radiographic progression can only be reliably detected using this method after at least 2 years, and this delay precludes the conduct of placebo-controlled trials on ethical grounds. Preliminary data using this scoring tool suggest that cyclooxygenase-2-selective NSAIDs might reduce disease progression if used continuously over 2 years. By contrast, three different anti-tumor necrosis factor therapies have shown no impact on radiographic progression. Therapeutic trials recruiting patients early in their disease course and at high risk of radiographic progression constitute a high priority for clinical research in AS.

The main inflammatory myopathies within the myositis group include polymyositis, dermatomyositis and inclusion-body myositis (IBM). Although potentially treatable, various practical issues have an impact on the response of these conditions to therapy. The most common reason for therapeutic failure is that the treatment targets the wrong disease, often owing to poor distinction of polymyositis from difficult-to-treat mimics such as sporadic IBM, necrotizing myopathies and inflammatory dystrophies. Evidence from uncontrolled studies suggests that polymyositis and dermatomyositis respond to treatment with prednisone at least to some degree. Empirically, adding an immunosuppressive drug might offer a 'steroid-sparing' effect or perhaps additional benefit. Intravenous immunoglobulin is proven effective as a second-line agent in patients with dermatomyositis and also seems to be effective for those with polymyositis, but offers only minimal and transient benefit to a small proportion of patients with IBM. Small, uncontrolled series suggest other agents such as rituximab or tacrolimus might offer some benefit in disease refractory to the aforementioned therapies, although IBM is resistant to most therapies. Novel agents are emerging as potential treatment options for all forms of myositis. This Review highlights common pitfalls in therapy, discusses emerging new therapies, and provides a practical therapeutic algorithm.

To systematically review the efficacy of acupuncture in fibromyalgia syndrome (FMS).

The HLA-B27 molecule is one of the most fascinating in medicine. Its contribution to the aetiopathogenesis of SpA and other diseases, and its protective action in certain infections, continue to challenge our understanding of its immunobiology and physiological roles. Animal studies have helped to cast light on ways in which HLA-B27 exerts its effects. Subtle variations in structure and behaviour between B27 subtypes that are strongly associated with SpA, compared with those whose association is neutral or weak, are helping to elucidate its pathogenetic mechanisms. However, none of the current hypotheses fully explains the observed actions of HLA-B27. Consequently, attention is turning to how haplotype linkages and genetic networks involving other MHC and non-MHC genes influence the penetrance and clinical expression of B27. HLA-B27 gives an intriguing insight into the connection between heredity and disease. As well as its close links with SpA, various other associations have been reported between B27 and diseases of different organs and systems. Evidence is also accumulating that it mitigates the virulence of HIV and other viral infections. The role of HLA-B27 as an aid to diagnosis, prognosis and disease management is gradually becoming clearer.

In the past decade, fat-suppression MRI techniques have been increasingly used for the assessment of axial-SpA. Indeed, newly proposed classification criteria have suggested the inclusion of fat-suppression MRI for the evaluation of the SI joint in inflammatory back pain (IBP) of suspected axial-SpA. However, recent data on the whole spine have identified certain MRI spinal lesions to be highly diagnostic of axial-SpA; that the SI joint can be spared in axial-SpA; and that IBP may originate in the lumbar spine rather than SI joint. Therefore, it is proposed that MRI of the whole spine and not just the SI joint should now become a routine part of the assessment of axial-SpA. Not only is spinal MRI of great diagnostic utility in axial-SpA but there is also increasing evidence to suggest that it can play a significant role in the management, in particular directing anti-TNF therapy in AS, and also it may be prognostically useful in axial-SpA. With the wider availability, improving technology and falling cost of MRI, and the difficulty that clinical assessment of axial-SpA poses, especially in early disease, there is now a strong case for the use of whole-spine MRI in the diagnosis and management of axial-SpA.

Meta-analysis of pregabalin trials in FM using company trial reports, which provide more detailed information about trials than published papers. FM is a common condition with a significant impact on quality of life.