Vascular endothelial injury in SSc leads to a host of pathological changes in the blood vessels that adversely impact the physiology of many organ systems and eventually results in a state of chronic tissue ischaemia. Current hypotheses in SSc vascular disease pathogenesis suggest a possible infectious or chemical trigger(s) that activates both cellular and humoral immunity. Products of immune activation may lead to vascular injury possibly through the production of autoantibodies and the release of products of activated T cells that can directly damage the endothelium. Knowledge of the initial trigger of immune activation in SSc may offer an opportunity to develop a multiple step strategy for therapeutic intervention.

Tissue fibrosis is a major cause of morbidity and mortality in SSc. An increasing number of promising molecular targets for anti-fibrotic therapies have been described recently. However, the number of patients eligible for clinical trials is limited in SSc. The present article discusses criteria to select the most promising molecular targets for clinical trials in SSc. Based on consensus among experts, important criteria for the selection of molecular-based therapies were as follows: First, there should be strong experimental evidence that targeting the molecule of interest inhibits fibrosis. Optimally, the anti-fibrotic effects should be confirmed in at least two complementary animal models of SSc. Second, inhibitors of the molecule of interest should be clinically available. Third, clinical experience with the drug of interest in other diseases hastens the initiation of clinical trials and reduces the risk of unexpected side-effects. Finally, funding for clinical trials with the drug of interest in SSc should be available. We propose that the priority of novel targets for evaluation in clinical trials in SSc might be selected based on these consensus criteria.

Tissue fibrosis is a major cause of death in SSc, but therapies that target selectively fibrosis are not yet available for routine clinical use. Recent pre-clinical studies suggest that selective tyrosine kinase inhibitors that target c-Abl, PDGF receptor or Src kinases might be promising targets for anti-fibrotic approaches. Dual inhibition of c-Abl and PDGF receptor by imatinib and nilotinib, and inhibition of Src kinases either selectively by SU6656 or in combination with c-Abl and PDGF by dasatinib exerted potent anti-fibrotic effects. Imatinib, nilotinib, dasatinib and SU6656 reduced dose-dependently the synthesis of extracellular matrix protein in human dermal fibroblasts in vitro and prevented fibrosis in the mouse model of bleomycin-induced skin fibrosis. Clinical data from patients with chronic myelogenous leukaemia suggest that imatinib, nilotinib and dasatinib are well tolerated. Based on the promising pre-clinical data, imatinib is currently evaluated in clinical trials for the treatment of fibrosis in SSc and trials with other tyrosine kinase inhibitors are in preparation.

The strong anti-inflammatory and immunosuppressive effects of glucocorticoids are mediated primarily by the cytosolic glucocorticoid receptors. These receptors are members of the steroid hormone receptor family, a superfamily of ligand-inducible transcription factors, and exert genomic effects that can result in increased expression of regulatory-including anti-inflammatory-proteins (transactivation), or decreased production of proinflammatory proteins (transrepression). Transactivation is thought to be responsible for numerous adverse effects of glucocorticoids; transrepression is thought to be responsible for many of the clinically desirable anti-inflammatory and immunosuppressive effects of glucocorticoids. Optimized glucocorticoids, such as selective glucocorticoid receptor agonists, are being developed to try to minimize the adverse effects many patients experience. Glucocorticoids also exert their effects via rapid, nongenomic mechanisms that can be classified as involving nonspecific interactions of glucocorticoids with cellular membranes, nongenomic effects that are mediated by cytosolic glucocorticoid receptors, or specific interactions with membrane-bound glucocorticoid receptors. Increased understanding of these mechanisms of glucocorticoid action could enable the development of novel drugs with which to treat patients with inflammatory and autoimmune disease.

The term 'growing pains' has been used for almost 200 years to refer to the often severe, generally bilateral lower-extremity nocturnal pains experienced by up to one-third of all children at some time during early childhood. No clear mechanism has yet been identified that explains these pains, but there is an increasing body of evidence indicating that several factors, individually or in combination, might be responsible for this phenomenon. These include mechanical factors, such as joint hypermobility and flat feet, decreased pain thresholds, reduced bone strength, and emotional factors involving the patient's family and other social stressors. Correct diagnosis of growing pains requires a thorough patient history and physical examination. The diagnosis can be safely established without unnecessary laboratory investigations or imaging; however, identification of one or more clinical cautionary signs, such as unilateral pain, morning stiffness, joint swelling and systemic symptoms (e.g. fever, weight loss and malaise), should trigger an extended evaluation to exclude other more serious conditions that might also present with limb pain. Once the diagnosis has been established, conservative management, using symptomatic pain medications, massage and other supportive measures, should be employed until the syndrome self-resolves with time.

Antibodies that react with self-molecules occur in healthy individuals and are referred to as natural antibodies or autoantibodies. Natural autoantibodies are mainly IgM, are encoded by unmutated V(D)J genes and display a moderate affinity for self-antigens. They provide a first line of defense against infections, probably serve housekeeping functions and contribute to the homeostasis of the immune system. By contrast, high-affinity, somatically mutated IgG autoantibodies reflect a pathologic process whereby homeostatic pathways related to cell clearance, antigen-receptor signaling or cell effector functions are disturbed. In some autoimmune disorders, autoantibodies might be present before disease onset, show remarkable specificity and serve as biomarkers providing an opportunity for diagnosis and therapeutic intervention. In organ-specific autoimmune diseases, such as myasthenia gravis or pemphigus, autoantibodies directly bind to and injure target organs. In systemic autoimmune diseases, autoantibodies react with free molecules, such as phospholipids, as well as cell surface and nucleoprotein antigens, forming pathogenic antigen-antibody (immune) complexes. These autoantibodies injure tissues and organs through engagement of Fc gammaR activation of complement as well as internalization and activation of Toll-like receptors. Activation of intracellular Toll-like receptors in plasmacytoid dendritic cells leads to the production of type I interferon, whereas engagement of intracellular Toll-like receptors on antigen-presenting cells stimulates cell activation and the production of other inflammatory cytokines. Thus, immune complexes might perpetuate a positive feedback loop amplifying inflammatory responses.

Wnt proteins regulate organ development, tumorigenesis and bone homeostasis, among other functions. The binding of Wnt proteins to plasma membrane receptors on mesenchymal cells induces the differentiation of these cells into the osteoblast lineage and thereby supports bone formation. Wnts are also key signaling proteins in joint remodeling processes. Active Wnt signaling contributes to osteophyte formation and might have an essential role in the anabolic pattern of joint remodeling that is observed in ankylosing spondylitis and osteoarthritis. By contrast, blockade of Wnt signaling facilitates bone erosion and contributes to catabolic joint remodeling, a process that is observed in rheumatoid arthritis. This Review summarizes current knowledge of the molecular regulation of joint remodeling associated with chronic arthritis, focusing on the role of the Wnt proteins and their inhibitors. It also addresses the role of Wnt in determining the differences in clinical presentation of inflammatory arthropathies and discusses implications for future therapy.

The introduction of new therapeutic modalities, such as biologic agents, for the treatment of lupus nephritis has re-energized research into this disorder, enabling investigators to formulate evidence-based recommendations. Thus, it is now widely accepted that the management of lupus nephritis involves a period of intensive induction therapy, followed by a longer period of less-intensive maintenance therapy. Risk stratification, based on histologic, demographic, clinical and laboratory characteristics, allows the identification of patients at high risk of renal dysfunction, for whom aggressive therapy is likely to be the most beneficial. New studies and meta-analyses comparing mycophenolate mofetil with cyclophosphamide have confirmed the efficacy of the former for induction and maintenance therapy--particularly induction therapy, owing to its favorable toxicity profile; however, claims of efficacy superior to that of cyclophosphamide require additional documentation. Nonetheless, an increasing number of physicians use mycophenolate mofetil as induction therapy for most cases of proliferative lupus nephritis, while reserving cyclophosphamide for the most severe cases. No evidence yet indicates that mycophenolate mofetil is better than azathioprine for the maintenance of remission. For patients who relapse or who are unable to be treated with these agents, rituximab seems to offer some benefit with an acceptable toxicity profile. This article summarizes the advances in the management of lupus nephritis since our 2005 Review.

MicroRNAs (miRNAs) are short noncoding RNA molecules that modulate the expression of multiple target genes at the post-transcriptional level and are implicated in a wide array of cellular and developmental processes. In hematopoietic cells, miRNA levels are dynamically regulated during lineage differentiation and also during the course of the immune response. Mouse models have provided good evidence for miRNAs being key players in the establishment of hematopoietic lineages. Furthermore, miRNA-dependent alterations in gene expression in hematopoietic cells are critical for mounting an appropriate immune response to a wide range of pathogens, spontaneously emerging tumors, and autoimmune cells. Deregulation of hematopoietic-specific miRNA expression results in defects in both central and peripheral tolerance, hematopoietic malignancies, and sometimes both. Abnormal expression of miRNAs-which is implicated in inflammation-has also been found in patients with rheumatoid arthritis. These findings identify miRNAs as critical targets for immunomodulatory drug development.

The aim of this systematic review is to evaluate the available evidence, from randomized clinical trials (RCTs), of acupuncture for treating patients with RA. Systematic searches were conducted on 17 databases up to April 2008 without the language restriction. All RCTs of acupuncture, with or without electrical stimulation or moxibustion, for patients with RA were considered for inclusion. A total of 236 potentially relevant studies were identified and eight RCTs were included. Four RCTs compared the effects of manual or electro-acupuncture with penetrating or non-penetrating sham acupuncture and failed to show specific effects of acupuncture on pain [n = 88; weighted mean differences (WMD), 10 cm VAS -0.46; 95% CI -1.70, 0.77; P = 0.46; heterogeneity: tau(2) = 0.19; chi(2) = 2.38; P = 0.30; I (2) = 16%] or other outcome measures. One RCT compared manual acupuncture with indomethacin and suggested favourable effects of acupuncture in terms of total response rate. Three RCTs tested acupuncture combined with moxibustion, vs conventional drugs and failed to show that acupuncture plus moxibustion was superior to conventional drugs in terms of response rate (n = 345; RR 1.12; 95% CI 0.99, 1.28; P = 0.08; heterogeneity: tau(2) = 0.00; chi(2) = 1.34; P = 0.51; I(2) = 0%), pain reduction (n = 105; WMD, 10 cm VAS 1.53; 95% CI -0.57, 3.63; P = 0.15; heterogeneity: tau(2) = 1.18; chi(2) = 1.81; P = 0.18; I(2) = 45%) or joint swelling index (n = 105; WMD, 10 cm VAS 0.25; 95% CI -1.31, 1.82; P = 0.75; heterogeneity: tau(2) = 0.18;chi(2) = 1.14; P = 0.28; I(2) = 13%). In conclusion, penetrating or non-penetrating sham-controlled RCTs failed to show specific effects of acupuncture for pain control in patients with RA. More rigorous research seems to be warranted.

There are no studies of fatigue levels in patients with SSc. The objective of this study was to compare fatigue in SSc to general population samples and patients with rheumatic diseases and cancer, where fatigue has been researched extensively.

The objective of this study was to assess the efficacy and safety of amitriptyline as a treatment of FM. A comprehensive computerized search in Medline (Pubmed), EMBASE and The Cochrane Library was performed. Randomized controlled trials (RCTs) comparing amitriptyline vs placebo in adult patients suffering from FM were identified, the methodological quality was assessed and the results of the main outcomes were evaluated. Ten RCTs were identified. Large clinical variability and statistical heterogeneity precluded quantitative meta-analysis. Overall, the study quality was moderate to high. Amitriptyline 25 mg/day (six RCTs) demonstrated a therapeutic response compared with placebo in the domains of pain, sleep, fatigue and overall patient and investigator impression. This benefit was generally seen at 6-8 weeks of treatment but no effect was noted at 12 weeks. Amitriptyline 50 mg/day (four RCTs) did not demonstrate a therapeutic effect compared with placebo. Neither dose of amitriptyline had an effect on tender points count. No clear statements on adverse events with amitriptyline can be made due to inconsistencies in data among the studies. A definitive clinical recommendation regarding the efficacy of amitriptyline for FM symptoms cannot be made. There is some evidence to support the short-term efficacy of amitriptyline 25 mg/day in FM. There is no evidence to support the efficacy of amitriptyline at higher doses or for periods >8 weeks. More stringent RCTs with longer follow-up periods are required to determine the long-term efficacy and safety of the amitriptyline and define its role in the multidisciplinary management of FM.

There is an increasing interest in the role of vitamin D as a potential treatment for a number of disparate diseases. In addition to its role in calcium homeostasis, vitamin D has a plethora of effects including immunomodulation, pleiotropic effects, modulating propensity to infection and blood pressure regulation. Detection and treatment of vitamin D deficiency in selected patients with RA is relevant as deficiency is common. Vitamin D therapy may modify the increased risk of falls and fracture in this group, and possibly exert additional immunomodulatory effects on disease onset and activity although data are largely epidemiological. Currently, there is no consensus view on vitamin D replacement regimens, nor an agreed optimal level of serum 25-hydroxyvitamin D [25(OH)D] for health. Indeed levels may vary for different organ systems and the concept of 'tissue specific vitamin D deficiency' needs to be considered. Therefore, there is clinical uncertainty regarding both when and how to correct vitamin D deficiency. Older patients, particularly post-menopausal women, and others at high risk of vitamin D deficiency should be preferentially targeted since they are likely to benefit most from supplementation. Clinicians should be aware of the technical difficulties associated with measuring and interpreting 25(OH)D levels. The administration of high-dose vitamin D as an oral weekly bolus is safe and can rapidly correct vitamin D deficiency followed by regular lower doses to maintain adequate levels.

Cryopyrinopathies are a group of rare autoinflammatory diseases that includes familial cold autoinflammatory syndrome, Muckle-Wells syndrome and chronic infantile neurologic cutaneous articular syndrome (also termed neonatal-onset multisystemic inflammatory disease). These syndromes were initially considered to be distinct disease entities despite some clinical similarities; however, mutations of the same gene have since been found in all three cryopyrinopathies. These diseases, therefore, are not separate but represent a continuum of subphenotypes. The gene in question, CIAS1 (now renamed NLRP3) encodes NALP3 (also known as cryopyrin). NALP3 is an important mediator of inflammation and interleukin 1beta processing. New therapies based on biologic agents that specifically target interleukin 1beta are currently being developed. These new agents have provided very encouraging results for patients with these long-lasting inflammatory conditions--which used to be considered refractory to treatment. The development of therapeutic options for these cryopyrinopathies illustrates effective translation of basic science to clinical practice and the convergence of human genetics and targeted therapies.

To determine the prevalence, characteristics and long-term outcome of psychosis due to SLE defined according to the ACR nomenclature for neuropsychiatric (NP) syndromes.

Complex regional pain syndrome (CRPS), a fairly common problem in rheumatological and orthopaedic practice, is an allodynic pain state of uncertain pathology often variably and unpredictably responsive to treatments. Although published diagnostic criteria are available, in the reality of clinical practice these do not appear to encompass the wide variety of symptoms that a patient may present with. This leads to scepticism on the part of the clinician and confusion for the sufferer. This article aims to provide some explanations for an often bewildering clinical picture. We provide a construct for the plethora of symptoms that we have entitled 'the embarrassment of pain perceptions'. With the aid of a case report we examine recent research that suggests how peripherally based symptoms and signs arise from changes within the central nervous system, with particular attention given to the control function of the motor-proprioceptive integrative system. We speculate how these changes within the central nervous system may provide the patient with CRPS the ability to access complex layers of lower level perceptions that are normally suppressed. We propose that such a system may explain some of the clinical puzzlements seen in this condition and suggest that the complexities of CRPS may provide an insight into brain development through evolution, which is a fruitful area for interdisciplinary clinical and scientific research.

Systemic lupus erythematosus (SLE) is typically associated with hypergammaglobulinaemia but has been described in the setting of hypogammaglobulinaemia as well. The purpose of this article is to describe various cases of SLE and hypogammaglobulinaemia, review the literature and present management strategies for hypogammaglobulinaemia in SLE.

Several cytokines are involved in the complex processes ultimately leading to autoimmune diseases. In a preceding review, we have already discussed the role of the IL-12 and -17 families of cytokines. This review is focused on IL-15 and -18. Both these molecules have pro-inflammatory activity and act on many cell types and because of their broad spectrum of activity they play an important role in autoimmunity and disease pathogenesis. Their biological activity is ultimately regulated by the signalling cascades set into motion within their target cells. In this second review, we will, once again, describe the signal transduction pathways activated by these two cytokines and focus on how this relates to the pathogenesis of autoimmune diseases. We will also describe some of the therapeutic approaches that are being investigated to curtail the pro-inflammatory activities of these two molecules.

Understanding the pathogenesis of SLE remains a considerable challenge. Multiple abnormalities of both the innate and adaptive immune system have been described and, furthermore, immunological dysfunction precedes clinical presentation by many years. There is a strong genetic basis to SLE, which means that genetic studies can play a key role in furthering our understanding of this disease. Since susceptibility variants are present from birth and are unaffected by the course of the disease, or by its treatment, genetic analysis is, perhaps uniquely, capable of identifying fundamental, causative, disease mechanisms. Over the last 12 months, there has been a staggering increase in our understanding of SLE genetics. We have seen the identification of new and important SLE susceptibility genes through candidate gene studies, and we have seen the publication of two whole-genome association analyses. The 'hypothesis free' whole-genome studies have provided additional evidence in support of a number of existing susceptibility genes and have identified novel gene candidates. In this article, we review the current SLE genetics literature in the light of these recent advances and we discuss our current understanding of the functional role of the key susceptibility genes. By considering how these genes fall into clusters with shared function we can begin to understand how dysregulation at a number of key immunological steps may predispose to the development of SLE.

1,25-Dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], the biologically active form of vitamin D(3), is a secosteroid hormone essential for bone and mineral homeostasis. It regulates the growth and differentiation of multiple cell types, and displays immunoregulatory and anti-inflammatory properties. Cells involved in innate and adaptive immune responses--including macrophages, dendritic cells, T cells and B cells--express the vitamin D receptor (VDR), and can both produce and respond to 1,25(OH)(2)D(3). The net effect of the vitamin D system on the immune response is an enhancement of innate immunity coupled with multifaceted regulation of adaptive immunity. Epidemiological evidence indicates a significant association between vitamin D deficiency and an increased incidence of several autoimmune diseases, and clarification of the physiological role of endogenous VDR agonists in the regulation of autoimmune responses will guide the development of pharmacological VDR agonists for use in the clinic. The antiproliferative, prodifferentiative, antibacterial, immunomodulatory and anti-inflammatory properties of synthetic VDR agonists could be exploited to treat a variety of autoimmune diseases, from rheumatoid arthritis to systemic lupus erythematosus, and possibly also multiple sclerosis, type 1 diabetes, inflammatory bowel diseases, and autoimmune prostatitis.