Survival rates in pulmonary arterial hypertension (PAH) associated with rheumatic diseases, in particular connective tissue diseases such as systemic sclerosis, are even lower than in idiopathic PAH. These low survival rates highlight the need for early diagnosis and treatment in these patients. Transthoracic Doppler-echocardiography is most often used for diagnostic screening of patients at risk. Other screening tests are serum pro-brain-natriuretic peptide (pro-BNP) and diffusion capacity for carbon monoxide (DLCO), which appear to be changed early in the course of the PAH associated with connective tissue diseases. The diagnosis needs to be confirmed by right heart catheterization, which is recommended in all patients with suspected PAH. Besides the conventional background therapy, a number of specific therapies have been evaluated in randomized controlled trials in the recent years. These therapies include prostacyclins and prostacyclin analogues, endothelin-receptor antagonists and phosphodiesterase-5 inhibitors. Response to treatment can be measured by exercise capacity (e.g. 6 min walk distance) and pro-BNP, although certain aspects of validation for these outcome measures are lacking in PAH associated with connective tissue diseases.

Cardiovascular manifestations constitute a major cause of death in myositis. Despite this, clinically manifest cardiac involvement in polymyositis and dermatomyositis is relatively rare. In contrast, subclinical manifestations are frequently reported and are predominated by conduction abnormalities and arrhythmias detected by ECG. The most frequently reported clinically overt manifestations are congestive heart failure, conduction abnormalities, that may lead to complete heart block, and coronary artery disease. The underlying pathophysiological mechanisms that may cause cardiac manifestations involve myocarditis and coronary artery disease as well as involvement of the small vessels of the myocardium.

Systemic sclerosis (SSc) is a connective tissue disease characterized by diffuse vascular lesions and fibrosis. Primary myocardial involvement is common in SSc and, when clinically evident, appears as a poor prognostic factor. An increasing body of evidence suggests that myocardial involvement is due, at least in part, to microcirculation impairment with abnormal vasoreactivity, with or without associated structural abnormalities of the small coronary arteries or arterioles. Using conventional methods, myocardial perfusion impairment, systolic and diastolic left ventricular dysfunction and right ventricular dysfunction have been reported in SSc. Recently, tissue Doppler echocardiography and magnetic resonance imaging have confirmed these results. Vasodilators, such as calcium channel blockers and angiotensin converting enzyme inhibitors, improve both myocardial perfusion and function abnormalities.

Recent studies have highlighted the functional capacity of neutrophils as powerful mediators of tissue inflammation. Granule-packaged proteases and reactive oxygen intermediates, which are important for intracellular digestion during phagocytosis, are released from neutrophils during inflammation. In the extracellular environment, neutrophil-derived proteases can cause local tissue damage, but also regulate the activity of cytokines, cytokine receptors and chemokines. Neutrophils can themselves produce an array of inflammatory mediators, including cytokines, chemokines and complement; these cells also express Fc receptors, which can bind and possibly transport immune complexes into the extravascular compartment, as well as activating neutrophils at opsonised surfaces. Blood-borne neutrophils interact with, and then exit through, the endothelium of blood vessels, after which these cells die and must be removed safely. The balance between neutrophil survival and clearance is crucial to the resolution of inflammation. A major regulator of neutrophil production and survival is the cytokine granulocyte colony-stimulating factor (G-CSF). Treatment with G-CSF can exacerbate underlying inflammatory diseases in humans and mice, and G-CSF deficiency is profoundly protective against collagen-induced arthritis in mice. These findings implicate G-CSF as an important proinflammatory cytokine. This article discusses the roles of neutrophils and G-CSF during chronic inflammatory diseases.

The creation of specific immune tolerance has often been referred to as the ultimate goal of immunotherapy, because it would allow autoimmune disease to be reversed without the need for nonspecific and potentially harmful immunosuppressive therapy. Studies performed during the past decade have been immensely fruitful in terms of advances in our understanding of the cellular and molecular mechanisms of immune tolerance, and have paved the way for successful exploitation of these mechanisms for therapeutic purposes. Important developments include an increased understanding of central and peripheral tolerance, and treatment strategies that mimic the mechanisms behind deletion of self-reactive cells, the identification of crucial gene products that are involved in the induction of anergy, and the characterization of regulatory T cells and protocols for their induction and expansion for therapeutic applications. These landmarks of immune-tolerance research are summarized and their potential use in the immunotherapy of autoimmune disease discussed.

Apoptotic defects and impaired clearance of cellular debris are considered key events in the development of autoimmunity, as they can contribute to autoantigen overload and might be involved in the initiation of an autoimmune response. The C1q protein and mannose-binding lectin are activators of the complement system. The pentraxins are a group of highly conserved proteins including the short pentraxins, C-reactive protein and serum amyloid P, and the long pentraxin family member, pentraxin 3, all of which are involved in innate immunity and in acute-phase responses. In addition to their role in innate immunity and inflammation, each of these proteins participates in the removal of damaged and apoptotic cells. In this article, we discuss the clinical significance of different levels of these proteins, their role in the induction of or protection against autoimmunity, and the presence of specific autoantibodies against them in various autoimmune diseases.

The normal course of aging is associated with gradual declines in a number of functional abilities. Patients who are at high risk of functional decline are described as frail or vulnerable. A screening tool to identify such patients is needed, as it has been shown that intervention can delay the onset and/or slow the progression of functional decline. This Review describes the methods currently available for nonspecialist evaluation of aging individuals, including behavioral, interview and questionnaire assessments. Such assessments can be undertaken during routine physician visits. In recognition of the time pressures on physicians, this article focuses on those measurements that are fairly comprehensive yet concise, easy to administer in an office setting, and available in English.

To evaluate the evidence for the effectiveness of acupuncture in peripheral joint osteoarthritis (OA).

Reactive arthritis (ReA) in tuberculosis (TB) is known as Poncet's disease. It is a rare aseptic form of arthritis observed in patients with active TB. We present two such patients and review the literature on Poncet's disease.

A variety of retinal signs can occur in patients who have systemic vasculitides, or who experience complications of these diseases or their treatment. Although treatment of these retinal manifestations is usually the treatment of the systemic disease, specific treatment is occasionally indicated to preserve vision. The more prevalent of the systemic vasculitides are giant cell arteritis, polyarteritis nodosa, Wegener's granulomatosis, Churg-Strauss syndrome, relapsing polychondritis and systemic lupus erythematosus. Less frequently occurring vasculitides include Takayasu's arteritis, Goodpasture's disease, microscopic polyangiitis and Henoch-Schönlein purpura, as well as vasculitis secondary to scleroderma and rheumatoid arthritis. This article describes the pathogenesis, clinical features and treatment of retinal manifestations of systemic vasculitides.

Studies on the pathogenesis of inflammatory arthritides have begun to delve into the molecular and cellular mechanisms behind the development of these diseases, and transcription factors, as key regulators of immune-effector-cell development and function, have received growing attention. Their involvement in immune cells, such as T and B lymphocytes, macrophages and neutrophils, and cells from diseased tissues, such as synoviocytes, has been investigated, revealing dominant roles for members of the nuclear factor kappaB family, signal-transducer and activator of transcription family, and activator protein 1 family. This review summarizes recent findings and current knowledge regarding the roles of transcription factors in inflammatory arthritis, as evidenced by both biological and genetic studies, and discusses the relevance of these findings for anti-inflammatory therapies.

Rheumatoid arthritis (RA) is a complex disease in which environmental agents are thought to interact with genetic factors that influence susceptibility. This interaction triggers immunologic events that eventually result in the clinical signs of arthritis. Knowledge of the chain of etiological events that lead to the development of RA is incomplete. In this review, we describe the experimental approaches that are used to address the issue of gene-environment interactions in the etiology of RA, and discuss relevant examples of such interactions. We focus on how smoking, the best-known environmental risk factor for RA, interacts with HLA-DR shared epitope genes, the main genetic risk factors for RA, and result in a high risk of RA in individuals exposed to both of these risk factors. From these and other related findings, we can begin to define the distinct environmental risk factors (such as smoking) that in certain genetic contexts (for example, the presence of HLA-DR shared epitope alleles) can trigger immune reactions (such as autoantibodies to citrullinated peptides) many years before onset of RA, and consider how these immune reactions might contribute to clinical symptoms in a subset of affected patients. Increased knowledge about these and other events involved in the development of RA should enable the design of new tools for suppressing RA pathogenesis before the onset of disease.

Cognitive behavioral therapy (CBT) techniques offer short-term, goal-oriented psychotherapy. In this respect, it differs from classical psychoanalysis in emphasizing changes in thought patterns and behaviors rather than providing 'deep insight'. Importantly, the beneficial effects of CBT can be achieved in 10-20 sessions, compared with the many years required for classical psychoanalysis. Although CBT is often done on a one-to-one basis, it also lends itself to a group therapeutic setting. CBT was initially used in the treatment of mood disorders, but its use has subsequently been expanded to include various other medical conditions, including chronic pain states. Over the past 18 years, several chronic pain treatment programs have used CBT techniques in the management of fibromyalgia. In this review, the results from 13 programs using CBT, alone or in combination with other treatment modalities, are analyzed. In most studies, CBT provided worthwhile improvements in pain-related behavior, self-efficacy, coping strategies and overall physical function. Sustained improvements in pain were most evident when individualized CBT was used to treat patients with juvenile fibromyalgia. The current data indicate that CBT, as a single treatment modality, does not offer any distinct advantage over well-planned group programs of education or exercise, or both. Its role in the management of fibromyalgia patients needs further research.

Research into the pathogenesis of the spondyloarthropathies has examined the role of HLA-B27 and other genes in susceptibility to these diseases. Novel characteristics of HLA-B27 have been discovered, which have allowed hypotheses for an influence of HLA-B27 on disease to be developed that do not reflect its ability to present arthritogenic peptides to CD8(+) T cells. Although a role for CD8(+) T cells has not been excluded, they are not required in the HLA-B27 transgenic rat model, and do not dominate at sites of disease in humans. Studies have also focused on the consequences of the (rather inefficient) intracellular folding of the HLA-B27 heavy chain, the ability of cells to deal with intracellular infection, and their expression of unusual forms of HLA-B27 on cell surfaces (including free heavy chains and dimers). Unusual surface forms of HLA-B27 interact with a different set of receptors from those that recognize conventional class I MHC molecules and thus can be implicated in driving inflammatory responses. Additional candidate susceptibility genes are being identified, either using gene-targeting technology in mice, or genomic screening approaches in humans. In several cases, as with HLA-B27, the evidence suggests that these genes influence the response of the host to bacteria, including pathogens and commensal organisms of the skin and gastrointestinal tract. The concept that spondyloarthropathies are the result of interactions between susceptibility genes, bacteria and the immune system remains a useful model for the pathogenesis of these diseases.

Articular cartilage, the load-bearing tissue of the joint, has limited repair and regeneration potential. The scarcity of treatment modalities for large chondral defects has motivated attempts to engineer cartilage tissue constructs that can meet the functional demands of this tissue in vivo. Cartilage tissue engineering requires three components: cells, scaffold, and environment. Adult stem cells, specifically multipotent mesenchymal stem cells, are considered the cell type of choice for tissue engineering, because of the ease with which they can be isolated and expanded and their multilineage differentiation capabilities. Successful outcome of cell-based cartilage tissue engineering ultimately depends on the proper differentiation of stem cells into chondrocytes and the assembly of the appropriate cartilaginous matrix to achieve the load-bearing capabilities of the natural articular cartilage. Multiple requirements, including growth factors, signaling molecules, and physical influences, need to be met. Adult mesenchymal stem-cell-based tissue engineering is a promising technology for the development of a transplantable cartilage replacement to improve joint function.

In the past decade, we have made tremendous progress in our understanding of fibromyalgia, which is now recognized as one of many 'central' pain syndromes that are common in the general population. Specific genes that might confer an increased risk of developing fibromyalgia syndrome are beginning to be identified and the environment (in this case exposure to stressors) might also have a significant effect on triggering the expression of symptoms. After developing the syndrome, the hallmark aberration noted in individuals with fibromyalgia is augmented central pain processing. Insights from research suggest that fibromyalgia and related syndromes require a multimodal management program that is different from the standard used to treat peripheral pain (i.e. acute or inflammatory pain). Instead of the nonsteroidal anti-inflammatory drugs and opioids commonly used in the treatment of peripheral pain, the recommended drugs for central pain conditions are neuroactive compounds that downregulate sensory processing. The most efficacious compounds that are currently available include the tricyclic drugs and mixed reuptake inhibitors that simultaneously increase serotonin and norepinephrine concentrations in the central nervous system. Other compounds that increase levels of single monoamines (serotonin, norepinephrine or dopamine), and anticonvulsants also show efficacy in this condition. In addition to these pharmacologic therapies, which are useful in improving symptoms, nonpharmacologic therapies such as exercise and cognitive behavioral therapy are useful treatments for restoring function to an individual with fibromyalgia.

Complement activation is common in patients with systemic lupus erythematosus (SLE), resulting in hypocomplementemia and deposition of complement at sites of tissue damage. The availability of mice with specific deficiencies of components of the complement system has provided new insights into the mechanisms by which complement might be involved in autoimmunity and tissue injury in SLE. In humans, deficiencies of early components of the classical complement pathway are strongly associated with SLE. Mice lacking C1q or C4 are also predisposed to autoimmunity, which is associated with the failure of normal clearance of apoptotic cells bearing on their surfaces many of the autoantigens involved in SLE. Antiphospholipid syndrome is common in patients with SLE and studies in an animal model of fetal loss caused by antiphospholipid syndrome have shown that injury is dependent on activation of complement with subsequent neutrophil influx and synthesis of tumor necrosis factor. Insights from animal models might enable the design of more rational therapeutic approaches for manipulating the complement system in human SLE.