Interactions between environmental and genetic factors are proposed to explain why autoimmunity afflicts certain individuals and not others. Genes and genetic loci predisposing to autoimmunity are being identified, but theories as to how the environment contributes to autoimmunity still rely largely on examples such as drug-induced systemic lupus erythematosus (SLE) and epidemiologic evidence of occupational exposure, without clear mechanistic explanations or identification of specific environmental agents. Eukaryotic gene expression requires not only transcription factor activation but also regional modification of chromatin structure into a transcriptionally permissive configuration through epigenetic mechanisms, including DNA methylation and histone modifications. The realization that epigenetic mechanisms can alter gene expression and, therefore, cellular function has led to new insights into how environmental agents might contribute to the development of diseases in genetically predisposed individuals. The observation that some SLE-inducing drugs, such as procainamide and hydralazine, affect T cell DNA methylation and thereby cellular function, and that identical changes in T cell DNA methylation and cellular function are found in patients with SLE, implicates epigenetic mechanisms in the pathogenesis of human SLE, and perhaps other autoimmune diseases. In this Review we discuss how epigenetic mechanisms affect gene expression, how environmental agents can affect epigenetic mechanisms, and how epigenetic changes in gene expression can contribute to autoimmunity. Similar mechanisms might also contribute to the pathogenesis of other poorly understood human diseases.

The assessment of systemic inflammation by means of laboratory tests often complements the results of medical examination. Traditionally, the erythrocyte sedimentation rate and leukocytosis with left shift are diagnostic markers for inflammatory and infectious diseases. The levels of acute-phase proteins--especially C-reactive protein--are used to assess both the presence of inflammation and any response to treatment. The determination of C-reactive protein levels may be advised in three types of pathological situation: infection, acute or chronic inflammation, and evaluation of metabolic risk. Procalcitonin is useful as a marker of sepsis and severe infection. The concentration of serum amyloid A predicts the chances of survival of patients with secondary (AA) amyloidosis. Ferritin and its glycosylated form are of interest in the study of specific diseases such as adult-onset Still's disease. Markers of cartilage and bone turnover are complementary to these markers of inflammation. Although cytokine serum levels are transiently crucial to the generation of inflammation, their usefulness in the clinic is still under investigation. Serum concentrations of cytokine inhibitors or soluble cytokine receptors, as well as the clinical response of patients to treatment with cytokine antagonists, might generate important information for monitoring autoinflammatory diseases.

Regional soft-tissue complaints are commonplace, and they usually relate to a disease process, such as strain, inflammation or degeneration of a muscle, tendon or related muscle-tendon unit. The clinical features and investigations of the causative processes of these complaints are characteristic, and outcomes to treatments are usually predictable and satisfactory. Regional pain syndromes are different: these syndromes present with regional pain and tenderness, and other sensory symptoms unaccounted for by a simple musculoskeletal mechanistic explanation. Approved classification criteria for regional pain syndromes are lacking, and these syndromes are poorly understood and frequently misdiagnosed. Regional pain syndromes often occur after injury and overlap extensively with other musculoskeletal pain syndromes, in terms of clinical signs and symptoms. The clinician and patient are often confused about the nature of the problem and routine treatments directed to putative tissue damage will fail. Review of the epidemiology of regional pain syndromes combined with knowledge of other similar pain syndromes has enabled an evolving understanding of the condition. The musculoskeletal and central nervous systems both contribute to regional pain syndromes, through spine-related pain mechanisms and central sensitization, respectively. The patient's emotional state, particularly the effect on pain modulation, links these two systems.

Ankylosing Spondylitis (AS) is a chronic inflammatory arthritis that predominantly affects the axial skeleton in adolescent patients causing spinal pain and stiffness. There is a marked delay, on average 8 years, between onset of disease symptoms and clinical diagnosis. The distinction between the symptoms of mechanical and inflammatory back pain remains one of the main contributing factors for the delay in diagnosis. Several classification criteria exist to aid the diagnosis of AS, but their accuracy is poor. The Ankylosing Spondylitis Assessment Study group (ASAS) has defined a core set of domains for clinical outcome measurement in AS in order to assess the disease process in individual patients and to identify those with rapidly progressive disease. New therapies, such as the tumor necrosis factor (TNF) inhibitors, have transformed the treatment paradigm in AS, especially for those patients with aggressive disease. Thus, the definition of both patient selection criteria for these agents and the development of clinical methods to assess response to therapy have become a priority. This Review focuses on measuring the degree of disease activity, function and damage in patients with AS in an ambulatory care setting, and the assessment of suitability of various outcome measures for monitoring response to treatment with TNF inhibitors.

More than 20 yrs ago, T-helper lymphocytes were divided into Th1 and Th2 subsets on the basis of their cytokine production. The pro-inflammatory Th1 subset was considered predominant in inflammatory arthritis, but evidence for this notion was incomplete, and some called into question the role of helper T cells. The identification of a novel T cell subset, Th17 cells, which appears to be critical for several forms of autoimmune inflammation, including arthritis, requires a reconsideration of arthritis pathogenesis and the role of T cells. This review deals with several of the newly described ('big number') cytokines which are involved in the differentiation and action of Th17 cells, and pays particular attention to the pathogenesis of spondyloarthritis because of the implication of the same cytokine networks in psoriasis and inflammatory bowel disease. The role of dendritic cells as coordinators of T cell differentiation in response to pathogen-derived signals in also emphasized.

Several chronic inflammatory disorders, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), and chronic infections that are associated with a chronic inflammatory state, such as human immunodeficiency virus (HIV) infection, are associated with an increased incidence of cardiovascular disease (CVD). Cardiovascular mortality is a major cause of death in patients with these disorders. Direct effects and indirect sequelae of systemic inflammation promote atherothrombotic vascular disease. Pathophysiological processes promoting atherogenesis can initiate years before the diagnosis of a chronic inflammatory disease is made, and since exposure to risk factors in this pre-clinical phase is widespread, early cardiovascular protection in these patients seems warranted.

There is mounting evidence that vascular pathology plays a role in the initiation and/or progression of the major disease of joints: osteoarthritis (OA). Potential mechanisms are: episodically reduced blood flow through the small vessels in the subchondral bone at the ends of long bones, and related to this, reduced interstitial fluid flow in subchondral bone. Blood flow may be reduced by venous occlusion and stasis or by the development of microemboli in the subchondral vessels. There are several likely effects of subchondral ischaemia: the first of these is compromised nutrient and gas exchange into the articular cartilage, a potential initiator of degradative changes in the cartilage. The second is apoptosis of osteocytes in regions of the subchondral bone, which would initiate osteoclastic resorption of that bone and at least temporarily reduce the bony support for the overlying cartilage. It may be important to recognize these potential aetiological factors in order to develop more effective treatments to inhibit the progression of OA.

Ocular manifestations of lupus are fairly common, may be the presenting feature of the disease and can be sight-threatening. Almost any part of the eye and visual pathway can be affected by inflammatory or thrombotic processes. Ocular pain and visual impairment require urgent assessment by an ophthalmologist. Infection should be excluded. Optic neuritis and ischaemic optic neuropathy may be difficult to distinguish. Scleritis and severe retinopathy require systemic immunosuppression but episcleritis, anterior uveitis and dry eyes can usually be managed with local eye drops. Vaso-occlusive disease, particularly in the presence of antiphospholipid antibodies, requires treatment with anticoagulation and proliferative retinopathy is treated with laser therapy. Hydroxychloroquine rarely causes ocular toxicity at doses under 6.5 mg/kg/day. When this has occurred, it has been associated with more than 5 years of drug exposure.

This review on joint aspiration and injection focuses on three common clinical problems: how to deal with 'dry taps', especially when a septic joint is suspected in the differential diagnosis; how to avoid rare complications associated with these techniques; and how to reduce pain in patients who are particularly sensitive. Solutions to these problems are proposed, and although no new data or insights are provided, this article could be used as a noncomprehensive check list for trainee rheumatologists. This review focuses on the knee, because of the common appearance of septic joints in the differential diagnosis of inflammatory knee effusion, and the paramount importance of septic joints in this setting. The five reasons for failing to aspirate fluid from a difficult knee joint that are discussed here could be applied to other more problematic joints, such as the elbow or ankle. Some additional time-consuming techniques involving more than one syringe and two operators might not be cost effective in many situations, but these should be taught for use in selected cases in which pain hinders aspiration. Training should also be provided to ensure that rheumatologists never inject against pressure, and that they switch to the lateral approach when aspirating the knee if their first attempt fails, especially if a septic joint is suspected and fluid must be obtained for diagnosis.

Rheumatologists with clinical expertise should perform clinical investigations of new molecules in an effort to discover therapies that could be of greater benefit or safety than those currently available for patients with chronic rheumatic diseases. Over the past few years, many studies have been conducted outside the United States and Europe because of the dearth of investigative sites in these countries. A clinician, whether in private practice or academia, who has the resources and desire to conduct clinical investigations, should be able to become involved in the process. The task of starting a new investigative unit is daunting, as it involves acquiring studies, hiring staff and obtaining space prior to any cash flow. If done properly, however, clinical investigation can be rewarding--both intellectually and financially.

Early aggressive treatment of rheumatoid arthritis is associated with improved disease control, slower radiological progression and improved functional outcomes. Tumor necrosis factor blocking therapy is effective but there remain concerns about long-term risks. Combining disease-modifying antirheumatic drugs (DMARDs) is a widely used therapeutic alternative; however, there is uncertainty surrounding the most effective regimen. A popular combination is methotrexate plus sulfasalazine, but each of these DMARDs can also be used in combination with other DMARDs and in triple therapy regimens. However, wide variations in study size, design, steroid usage and approaches to combination therapy have made it difficult to form firm conclusions regarding their efficacy. Generally, combination therapy is well tolerated and associated with no significant increase in the rate of adverse events compared with monotherapy. Methotrexate-sulfasalazine, methotrexate-chloroquine, methotrexate-cyclosporin, methotrexate-leflunomide, methotrexate-intramuscular-gold and methotrexate-doxycycline are effective combination regimens. Triple DMARD therapy is better than various DMARD monotherapy and dual therapy regimens. Methotrexate and hydroxychloroquine may have synergistic anti-inflammatory properties. Clinical trial evidence to support the use of other methotrexate and sulfasalazine combinations is often weak or lacking. Further investigation is required to determine the most effective regimen and approach to combination therapy.

Gout is one of the most common inflammatory arthritides, which is considered to be a true crystal deposition disorder caused by the formation of monosodium urate crystals in and around joints. A number of epidemiological studies from a diverse range of countries suggest that gout has increased in prevalence and incidence in recent years and that the clinical pattern of gout is becoming more complex. In particular, the greatest increase has been observed in primary gout in older men. Robust epidemiological studies have established risk factors for gout including genetic factors, excess alcohol consumption, purine-rich diet, the metabolic syndrome (obesity, hypertension, hyperlipidemia and insulin resistance), use of diuretics and chronic renal failure. Trends in alcohol use, diet, obesity and the metabolic syndrome in the general population might explain changes in the prevalence and incidence of gout in the community. Osteoarthritis, which is thought to predispose patients to monosodium urate crystal deposition in their joints, is becoming more prevalent as a consequence of increased longevity. In hospital settings, widespread diuretic use, increasing prevalence of end-stage renal failure and the success of organ transplant programmes have led to an increase in clinical complexity. Suboptimal management of gout is likely to have contributed to the rise in the prevalence of clinically overt, symptomatic, chronic gout.

Angiogenesis inhibition, long studied in the treatment of malignancies, has begun to emerge as a potential therapeutic approach in managing inflammatory arthritis, particularly rheumatoid arthritis. The growth of new vessels is required for the development of the rheumatoid pannus, which then leads to extensive synovial inflammation and joint destruction. Vascular endothelial growth factor is the best studied mediator of angiogenesis, and several therapies have been developed that specifically target this molecule. Several other angiogenesis mediators, such as the angiopoietin-TIE system, hypoxia inducible factor and integrin alpha(V)beta(3), as well as naturally occurring inhibitors of angiogenesis, are also being investigated as potential therapeutic targets. Additionally, there are a number of drugs, including paclitaxel, 2-methoxyestradiol and fumagillin analogs, that might have a role in inhibiting angiogenesis and, thus, in treating proliferative synovitis.

There has been renewed interest in the treatment of gout with recent reported intervention studies of new agents such as etoricoxib, febuxostat and pegylated-uricase. However, these studies have highlighted the relative paucity of validated outcome measures with which to judge efficacy. This review outlines the published information regarding which endpoints have been measured in randomized clinical trials, what should be measured, what tools or instruments are available for this and the technical properties of such instruments. It highlights recent work that validates measures of tophi, radiographic damage and patient-reported outcomes. The absence of a valid definition of gout-flare or how flare reduction defines response is problematic; this forms the basis for a current ACR-EULAR sponsored project.

To study the abdominal manifestations of the antiphospholipid syndrome (APS).

The objective of this systematic review is to evaluate data from controlled clinical trials testing the effectiveness of tai chi for treating rheumatoid arthritis (RA). Systematic searches were conducted on Medline, Pubmed, AMED, British Nursing Index, CINAHL, EMBASE, PsycInfo, The Cochrane Library 2007, Issue 1, the UK National Research Register and ClinicalTrials.gov, Korean medical databases, Qigong and Energy Medicine Database and Chinese databases up to January 2007. Hand-searches included conference proceedings and our own files. There were no restrictions regarding the language of publication. All controlled trials of tai chi for patients with RA were considered for inclusion. Methodological quality was assessed using the Jadad score. The searches identified 45 potentially relevant studies. Two randomized clinical trials (RCTs) and three non-randomized controlled clinical trials (CCTs) met all inclusion criteria. The included RCTs reported some positive findings for tai chi on disability index, quality of life, depression and mood for RA patients. Two RCTs assessed pain outcomes and did not demonstrate effectiveness on pain reduction compared with education plus stretching exercise and usual activity control. The extent of heterogeneity in these RCTs prevented a meaningful meta-analysis. Currently there are few trials testing the effectiveness of tai chi in the management of RA. The studies that are available are of low methodological quality. Collectively this evidence is not convincing enough to suggest that tai chi is an effective treatment for RA. The value of tai chi for this indication therefore remains unproven.

Pregnancy is an issue that should be discussed with all patients with rheumatic diseases who are in the reproductive age group. Infertility is rarely due to the disease but can be associated with cyclophosphamide therapy. Most rheumatic diseases that are well controlled prior to pregnancy do not deteriorate in pregnancy, providing that the patient continues with appropriate disease-modifying therapy. Some patients with inflammatory arthritis go in to remission during pregnancy. Patients with renal involvement may be at increased risk of disease flare. This needs to be distinguished from pre-eclampsia. Intrauterine growth restriction is more likely in patients with active systemic disease, hypertension, a history of thrombosis and renal involvement. Premature delivery may need to be planned to reduce the risks of stillbirth and can be associated with a variety of neonatal complications. Post-partum flare is common in all the rheumatic diseases.

The identification of subgroups of patients from randomized clinical trials that are of specific interest for guiding clinical decisions can be an attractive idea; however, since such trials are designed for the comparison of groups of patients, performing subgroup analyses can result in misinterpretation of the data. Such analyses must, therefore, be performed and evaluated with caution: these should be pre-planned and included in the design of a suitably powered trial. Data obtained should be analyzed using formal statistical tests of interaction on proper subgroups rather than improper subgroups of patients, the results obtained should be delineated carefully, and details of how these analyses were performed, and how the data should be interpreted, should be reported in the trial paper. The caveats associated with this approach, such as the occurrence of false positive or false negative effects, chance differences in observed effects, lack of power to perform the analysis, floor or ceiling effects, issues relating to multiple statistical testing, and over-reporting and under-reporting are discussed in this review. Subgroup analyses can, however, provide valuable, albeit predominantly exploratory, information on which to base clinical decisions if they are performed in accordance with recommendations and guidelines, and do, therefore, have a legitimate place in rheumatology clinical trials.

In 90% of cases, women with rheumatoid arthritis suffer a disease flare within 3 months of delivery of their baby. Drug treatment is, therefore, required; however, such therapies have implications for mothers who decide to nurse their infants. Unfortunately, because of a paucity of data, little is known about the transfer of antirheumatic drugs into breast milk, and even less is known about whether small amounts of these agents ingested during nursing could harm the infant. Our review of the literature indicates that paracetamol, prednisone, antimalarial agents, sulfasalazine and most NSAIDs can safely be used by lactating mothers. Expert opinions differ regarding the use of azathioprine, ciclosporin, and methotrexate during lactation because of varying views on the potential for short-term and long-term adverse effects. Evidence regarding the transfer of leflunomide and biologic drugs into breast milk is insufficient; therefore, until more studies are conducted, the use of these drugs in breastfeeding mothers should be restricted. At present, many patients feel they have to choose between postpartum disease control and lactation. Extended studies of the transfer of antirheumatic drugs into breast milk and the resulting consequences are, therefore, urgently needed.

Innate immunity achieves our primary host defense by recognizing invading microorganisms through pathogen-associated molecular patterns (PAMPs) and by reacting to tissue damage signals called damage-associated molecular patterns (DAMPs). DAMP molecules, including high mobility group box 1 protein (HMGB-1), heat-shock proteins (HSPs), uric acid, altered matrix proteins, and S100 proteins, represent important danger signals that mediate inflammatory responses through the receptor for advanced glycation end-products (RAGE, also known as AGER) and Toll-like receptors, after release from activated or necrotic cells. The terms 'alarmins' and 'endokines' have also been proposed for DAMP molecules. A prototypic DAMP molecule, the nuclear protein HMGB-1, is either passively released by necrotic cells or actively secreted with delay by activated cells. S100A8, S100A9, and S100A12 are calcium-binding proteins expressed in the cytoplasm of phagocytes. They are rapidly secreted by activated monocytes or neutrophils, which are abundant in inflamed synovial tissue. HSPs are involved in the crosstalk between innate and adaptive immune systems, and primarily mediate immune regulatory functions. Multiple positive feedback loops between DAMPs and PAMPs and their overlapping receptors temporally and spatially drive these processes and may represent the molecular basis for the observation that infections, as well as nonspecific stress factors, can trigger flares in rheumatic diseases.