Rheumatoid arthritis (RA) is a chronic, debilitating autoimmune disease that results in inflammation and structural destruction of the joints. A hallmark of RA pathogenesis is an imbalance of the osteoblast-osteoclast axis driven by inflammatory processes, resulting in elevated bone resorption by osteoclasts. Current therapies used to treat this disease have focused on inhibition of synovitis, but such treatments do not adequately repair damaged bone. A key pathway of osteoclast formation involves the receptor activator of nuclear factor kappaB ligand (RANKL) pathway acting on myeloid progenitor cells. The Wnt pathway has been shown to be important for the differentiation of osteoblasts from mesenchymal lineage precursors, and endogenous Wnt inhibitors, such as Dickkopf1 and sclerostin, might have important roles in osteoclast dysregulation in RA. Inhibition of the RANKL pathway, or blockade of Dickkopf1 and sclerostin, might serve to restore the osteoblast-osteoclast balance and repair bone erosion in RA joints. Such treatments, in combination with anti-inflammatory therapies, could stabilize and repair damaged joints and have the potential to be valuable additions to the armory of RA treatments.

Few, if any, areas of medical therapeutics have witnessed such dramatic changes as those that have occurred in the therapy of rheumatoid arthritis (RA) during the past two decades. Improvements in clinical trials methodologies, the introduction of no fewer than nine biologic agents with distinct mechanisms of action, and the development of better strategies for the use of such agents have all contributed to the new age in RA therapeutics. Here, we review these developments and attempt to describe the current landscape of RA therapy in terms of available treatments, agreed-upon principles of RA management, as well as some important controversies in this field. Despite the great pace at which developments are moving, a treatment-free remission for patients with RA remains an elusive goal and unmet medical needs remain. The quest for better therapies for this potentially devastating disease is still as important as ever; research in this exciting area is ongoing, and it is reasonable to hope that, during the next decade, developments will lead to improved, rationally designed, targeted therapies for RA.

CNS or peripheral nervous system dysfunction sometimes occurs in Henoch-Schönlein patients.

Several advances have been made in the understanding of the pathogenesis, as well as in the clinical evaluation and treatment, of early inflammatory arthritis. The presence of anti-citrullinated protein antibodies (ACPAs) has emerged as a major new biomarker for use in clinical practice. The presence of ACPAs can be used to divide patients with early arthritis into subsets that are phenotypically similar but have varying pathogenetic and prognostic features. Although the detection of ACPAs is a major development in the diagnosis and prognosis of rheumatoid arthritis (RA), prediction of the outcome of arthritis at the individual level can still be much improved. For patients diagnosed with RA, and who have active polyarthritis, treatment is not dependent on the assessment of prognostic factors, as these patients are best treated with combination therapy; over 40% of these patients achieve remission with such treatment. In patients who present with oligoarthritis, however, management should be based on the assessment of prognostic factors. The success of early treatment of inflammatory arthritis and the recognition of a measurable preclinical phase of RA offer hope that treating the disease before it becomes clinically active might be possible.

Lesions in articular cartilage can result in significant musculoskeletal morbidity and display unique biomechanical characteristics that make repair difficult, at best. Several surgical procedures have been devised in an attempt to relieve pain, restore function, and delay or stop the progression of cartilaginous lesions. Advanced MRI and ultrasonography protocols are currently used in the evaluation of tissue repair and to improve diagnostic capability. Other nonoperative modalities, such as injection of intra-articular hyaluronic acid or supplementary oral glucosamine and chondroitin sulfate, have shown potential efficacy as anti-inflammatory and symptom-modifying agents. The emerging field of tissue engineering, involving the use of a biocompatible, structurally and mechanically stable scaffold, has shown promising early results in cartilage tissue repair. Scaffolds incorporating specific cell sources and bioactive molecules have been the focus in this new exciting field. Further work is required to better understand the behavior of chondrocytes and the variables that influence their ability to heal articular lesions. The future of cartilage repair will probably involve a combination of treatments in an attempt to achieve a regenerative tissue that is both biomechanically stable and, ideally, identical to the surrounding native tissues.

DISH is a condition characterized by calcification and/or ossification of soft tissues, mainly entheses, ligaments and joint capsules. Its prevalence increases with age and, therefore, DISH is a relatively common entity in the elderly. The classical site of involvement is the spinal column with right anterolateral soft tissue ossification being the most characteristic feature. However, DISH is not limited to the spine, and may affect multiple peripheral sites independently. Extraspinal entheseal ossifications are common and observing their isolated presence may lead to the diagnosis of DISH. Furthermore, hypertrophic or atypical OA observed in joints usually not affected by primary OA has frequently been reported in DISH. Several metabolic derangements and concomitant diseases have been suggested to be associated with DISH including obesity, increased waist circumference, hypertension, dyslipidaemia, diabetes mellitus (DM), hyperuricaemia, metabolic syndrome and an increased risk for cardiovascular diseases. Witnessing the present increase in lifespan, obesity, DM and metabolic syndrome in the Western population, the prevalence of DISH should be expected to rise. In order to increase the awareness for DISH, this review focuses on the extraspinal features of the condition.

Cyclooxygenase (COX) inhibitors remain a major class of drugs in rheumatology and their widespread use is expected to continue. The view that a prothrombotic effect explains the increase in myocardial infarction (MI) associated with both COX-2 selective and traditional NSAIDs (tNSAIDs) has been increasingly questioned. We review the evidence that prostanoids direct the immune response away from a Th1 response and that consequently inhibition of prostaglandin synthesis results in augmentation of the Th1 response by limiting prostanoid synthesis. Although the role of prostanoids as mediators of inflammation in the periphery is well understood, the systemic immunomodulatory role of prostanoids shifting the immune response away from a Th1 type is less appreciated. Atherosclerosis is an inflammatory arterial disease driven by a Th1 type immune response. Moreover, the vulnerable phenotype of atheroma is associated with the cellular Th1 immune response in contrast to the stable plaque phenotype associated with a Th2 type response. We propose a class effect of COX-2 selective and tNSAIDs, which results in augmentation of Th1-mediated atherogenesis/ production of pro-atherogenic cytokines associated with detrimental plaque remodeling, instability, rupture and embolization resulting in MI. Understanding of the Th1 mediated immunity, which underlies the cardiovascular, and the non-Th1, which underlies gastrointestinal adverse effects associated with the use of COX inhibitors, should lead to better risk assessment and the development of anti-inflammatory treatments with improved safety. Our explanation also emphasizes the pharmacological effects and consequences of immunomodulation in the inflammation associated with atherosclerosis and other Th1- as well as non-Th1-driven diseases.

Genetic factors, in addition to the HLA-B27, could play a role in the pathogenesis of AS. TNF-alpha promoter polymorphisms have been reported to be associated with AS susceptibility, but the results of these previous studies have been inconsistent. The aim of this study was to explore whether TNF-alpha promoter polymorphisms confer susceptibility to AS.

Geographic or ethnic differences in the occurrence of disease often provide insights into causes of disease and possible opportunities for disease prevention. A wide variation on the incidence and prevalence of PsA was reported in different countries. The prevalence in China was similar to the rest of the world, whereas the incidence and prevalence of PsA was much lower in Japan. Among patients with psoriasis, 6-42% of the Caucasians were reported to have PsA, but figures were lower from Asian countries (1-9%). Divergent distribution of HLA in different ethnic groups and other genetic determinants may account for these differences in prevalence. PsA affects men and women almost equally in Chinese, Japanese and Iranians, which is similar to their Caucasian counterparts. Polyarthritis developing in the fourth decade was the commonest pattern of arthritis among Chinese, Indians, Iranians, Kuwaiti Arabs and Malays. Arthritis mutilans and eye lesions have rarely been reported in Asian countries. Chinese patients with nail disease and DIP joints involvement have a significantly higher risk of developing deformed joints. More data are required on the safety, efficacy and cost effectiveness of TNF blockers for the treatment of PsA in Asia. Premature atherosclerosis has been recognized as an important co-morbidity in Asian patients with PsA. Increased prevalence of traditional cardiovascular risk factors associated with PsA suggested that the two conditions may share the same inflammatory pathway. Carotid intima-media thickness can identify PsA patients with subclinical atherosclerosis who may benefit from early intervention.

Osteoarthritis (OA) is a leading cause of pain and disability worldwide. Evidence-based guidelines and recommendations for the treatment of OA consider non-pharmacological modalities as the cornerstone of modern OA management. Nonetheless, research evidence from clinical trials on non-pharmacological interventions for the treatment of hand and hip OA is scarce and considerably less than that for knee OA. In addition, research on non-pharmacological interventions for OA appears highly on the list of patients' research priorities. Thus, there is a clear mismatch between the available research evidence for non-pharmacological interventions for hip and hand OA and both the treatment guidelines and the interests of patients.

RA is known to be associated with a high cardiovascular (CV) risk. Longitudinal data suggest that RA disease course may have become milder over the past decades. Thus, we set out to estimate the magnitude of the overall increase in CV mortality associated with RA and to determine whether it has decreased over the past 50 years.

Sexual impairment in women with SSc has received little attention. The objective of this study was to compare levels of sexual impairment in women with SSc with samples of women with medical illnesses for which sexual impairment has been researched more extensively.

Paget disease of bone is a focal disorder of the skeleton that can affect one or more bones. Many patients are discovered accidentally because of elevated serum alkaline phosphatase activity or an abnormal skeletal radiograph intended to evaluate an unrelated condition. Patients are often asymptomatic, but a subset experience considerable morbidity that can include bone pain and skeletal deformity, as well as a variety of regional complications, such as hearing loss associated with cranial involvement, degenerative arthritis of the hip or knee, fractures of the lower extremities and, rarely, sarcoma or giant cell tumors. Bisphosphonates have proven to be effective in controlling disease activity because they inhibit osteoclast function. Administration of these agents can relieve bone pain, decrease biochemical markers of bone resorption and bone formation, and retard or reverse the early osteolytic phase of the disease. Future studies are needed to determine whether these drugs, if used in an early stage of the disease, can prevent complications in asymptomatic patients.

Acute or progressive sensorineural hearing loss, with or without vertigo and tinnitus, has a considerable impact upon an individual's quality of life. Sensorineural hearing disorders are more commonly observed in patients with rheumatic disease than in the general population, are more likely to be accompanied by the presence of serum autoantibodies, and might respond to steroid therapy. A subgroup of these disorders seem to be immune mediated, but audiologic presentation and serologic testing do not enable this subgroup to be further defined. Rheumatologists should be prepared to manage patients with known rheumatic disease who develop acute hearing loss and to evaluate referred patients without known rheumatic illness experiencing progressive or refractory sensorineural hearing loss. In this article, we summarize the literature and outline a rational approach for the evaluation and treatment of such patients.

It is well established that risk of developing SLE is higher among women compared with men but only very little is understood about the underlying mechanisms. Oestrogen and their catechol metabolites seem to play an important role in SLE but the exact patho-aetiology remains elusive. The evidences concerning the possibility of catecholoestrogens (CEs) in the development of SLE are very limited and preliminary. The possible mechanism involves quinone-semiquinone redox cycling of CEs to generate the free radical that can cause DNA damage. This would probably alter its immunogenicity leading to the induction and elevated levels of SLE autoantibodies cross-reacting with native DNA. The data demonstrate the possible role of CE in presenting unique neo-epitopes that might form one of the factors in induction of SLE autoantibodies. However, the role of oestrogen in immune modulation cannot be rule out as a mediator of various immune-related diseases.

The incidence of rheumatoid arthritis (RA) is decreasing, and rheumatologists perceive that their patients are presenting with less-disabling disease. This impression coincides with the availability of improved therapeutic options, including biologic agents. In RA, the term 'disease severity' can be defined from various perspectives: that of the patient, or by measures of disease activity and damage. This Perspectives article examines the scientific basis for a perceived decrease in RA severity over time, as determined by patient-reported outcomes and measures of disease severity and structural damage. An improved health care system and better treatment strategies with access to new therapeutic modalities are likely to have contributed to a milder RA disease course in more-recent years. The focus needs to be kept on these issues to further improve disease severity in patients with RA.

Fractures are a clinical consequence of osteoporosis, and represent a major cause of morbidity and mortality worldwide. Several treatments have been shown to decrease the risk of fracture, but problems arise in identifying individuals at high fracture risk so that treatments can be effectively targeted. The case for widespread population screening using bone mineral density testing is weak, as these tests lack sensitivity. Case-finding algorithms are available in many countries, but differ markedly in their approaches. Recent developments in fracture risk assessment include the availability of the FRAX (WHO Collaborating Center for Bone Metabolic Disease, Sheffield, UK) tool, which integrates the weight of clinical risk factors for fracture risk with or without information on bone mineral density, and computes the 10-year probability of fracture. The tool increases sensitivity without trading specificity, and is now being used in the reappraisal of clinical guidelines.

The lifetime risk of experiencing a fracture in 50-year-old men is lower (20%) than the risk in women (50%). Consequently, much less research has been carried out on osteoporosis and fracture risk in men. Differences in the risk and incidence of fractures between men and women are related to differences in bone-related and fall-related factors between the sexes. During the past decade, progress has been achieved in case finding and fracture prevention in men. Epidemiology studies have better specified the prevalence and incidence of fractures, and insight into the pathophysiology of osteoporosis and fractures in men has progressed considerably. Case finding for men and women at the highest risk of fracture is now possible using the FRAX algorithm, which includes clinical risk factors, with and without bone mineral density, and allows calculation of an individual's 10-year fracture risk. Although strategies to prevent fractures are much less common in men than in women, several treatment options are now available for this purpose. Bisphosphonates, in particular, consistently demonstrate a positive effect on bone mineral density, and some data also indicate decreased rates of vertebral fractures. For men with severe osteoporosis, treatment with the anabolic agent teriparatide might be an effective option.

The management of patients with rheumatoid arthritis (RA) has changed dramatically in recent years, largely because of the unrivaled efficacy of biologic agents in ameliorating clinical disease activity and in preventing joint damage; however, the use of biologic agents is associated with medical risks and socioeconomic costs. Guidance is, therefore, needed to identify those patients who might benefit most from this intensive treatment approach--and to identify those individuals who can be spared the potential adverse effects of such treatment without risking disease progression. As reviewed here, a variety of serological, clinical, immunological, radiological, and genetic markers have been proposed to predict clinical outcome in RA. These markers can all be determined without difficulty; however, with the notable exception of the genetic markers and erosions, these parameters are for the most part indicative of inflammatory disease activity and, therefore, subject to variation. As tight control of disease activity dissociates the prognostic markers from the clinical course, these predictive parameters should be assessed at baseline for every patient and used to guide individualized treatment strategies.

Iron is critical in nearly all cell functions and the ability of a cell, tissue and organism to procure this metal is obligatory for survival. Iron is necessary for normal immune function, and relative iron deficiency is associated with mild immunosuppression. Concentrations of this metal in excess of those required for function can present both an oxidative stress and elevate risks for infection. As a result, the human has evolved to have a complex mechanism of regulating iron and limiting its availability. This homoeostasis can be disrupted. Autoimmune diseases and gout often present with abnormal iron homoeostasis, thus supporting a participation of the metal in these injuries. We review the role of iron in normal immune function and discuss both clinical evidence of altered iron homoeostasis in autoimmune diseases and gout as well as possible implications of both depletion and supplementation of this metal in this patient population. We conclude that altered iron homoeostasis may represent a purposeful response to inflammation that could have theoretical anti-inflammatory benefits. We encourage physicians to avoid routine iron supplementation in those without depleted iron stores.