Rheumatic fever is the prototype of postinfectious autoimmune disease and is caused by untreated Streptococcus pyogenes throat infection in susceptible children. This review presents the major immune-mediated events leading to carditis, valvulitis and Sydenham’s chorea (SC). The role of genetic factors in susceptibility is also discussed. In the last 10–15 years, the pathogenesis of rheumatic autoimmune reactions has been clarified. A brief review on humoral immune response, focusing on crossreactive antibodies against laminin, vimentin and cardiac myosin, and the recent data on specific crossreactive antibodies against streptococcal antigens and lysogangliosides and tubulin from neuronal cells involved with the autoimmune reactions in SC is presented. T lymphocytes are the major effectors of crossreactivity between streptococcal and human proteins leading to rheumatic heart disease. Heart tissue T-cell infiltration is facilitated by adhesion molecules, myosin and laminin antibodies. A cytokine balance fa...
Tumor necrosis factor-α antagonists (anti-TNF agents) have been associated with increased risks of malignancies and serious infections in rheumatoid arthritis. However, available data on these risks remain sparse, and at times conflicting. Thus, at present, there are no precise and robust estimates of the risks of serious infections and malignancies with anti-TNF agents in rheumatoid arthritis. Discrepancies in data may be owing, in part, to methodological issues related to observational studies, including differences in study populations, comparison groups, definitions of outcomes and duration of follow-up, as well as possible channeling bias and precision error. Obtaining better estimates of uncommon risks with anti-TNF agents in rheumatoid arthritis will be challenging. Observational studies using large administrative databases, patient registries and postmarketing surveillance systems have the potential to add important information on the safety of these new therapies.
Abnormal innate and adaptive immune responses are critically involved in the pathogenesis of rheumatoid arthritis (RA). Anti-inflammatory and immunosuppressive therapies have been highly successful, but a cure for the disease has remained elusive, mostly due to lack of knowledge of disease instigators and the causative immune system abnormalities. RA is associated with premature aging of the immune system, which has been attributed to the chronic inflammatory milieu. However, recent data draw attention to processes of impaired immune regeneration as an underlying defect. Specifically, bone marrow hematopoietic stem cells (HSCs), permanently regenerating myeloid and lymphoid lineages, are functionally defective in RA, jeopardizing repopulation of the immune system. In RA, the pool of circulating HSCs is contracted and HSCs respond inadequately to hematopoietic growth factors. Most importantly, RA HSCs have age-inappropriate telomeric shortening, indicative of excessive proliferative stress. Defects in HSCs...
The mechanical performance of our skeleton is secured by the constant adaptation of bone to its mechanical loading environment. Mechanical adaptation of bone is brought about by the coordinated actions of osteoclasts and osteoblasts, which are orchestrated by the most mechano-sensitive cells in bone, the osteocytes. Loading on bone generates a flow of interstitial fluid through the lacuno-canalicular network in which the osteocytes are positioned. This flow is sensed by the osteocytes, which respond by the release of signaling factors such as nitric oxide, prostaglandins and Wnts, which alter the recruitment and activity of osteoblasts and osteoclasts, thereby affecting bone mass. Thus, any factor that alters the response of osteocytes to mechanical loading potentially affects bone mass. This paradigm could have implications for the field of rheumatology, where proinflammatory cytokines might affect bone mass by altering the response of osteocytes to mechanical loading.
Gene therapy is not for the faint of heart. Since its launch in 1989 [1], human gene therapy has been variously cast as visionary, feckless, a panacea and a dangerous folly. One of its pioneers is in jail, and another was sued successfully in civil court following the death of a clinical trial subject. Skeptics like to point out that it has killed approximately as many people as it has cured and, apart from two cancer gene therapies approved recently in China, there is little to show for nearly two decades of promises and expensive research. Against these headwinds, arthritis gene therapy has made laudable progress. Proof of principle is well established in animal models, and a small number of clinical trials have been implemented (Table 1). However, we have reached the stage of diminishing returns with preclinical research. Pivotal clinical trials are needed to maintain momentum and confirm promise in human disease [2]. These will require a considerable injection of funding, without which research will stagnate and become largely condemned to re-inventing the wheel in animal models. Arthritis gene therapy emerged in the early 1990s (Figure 1) and made quite rapid progress, leading, within a few years, to proof of concept in animal models of rheumatoid arthritis and osteoarthritis, and a Phase I clinical trial – remarkable achievements for a new area of research. As reflected in the publication history shown in Figure 1, the number of investigators remains limited, with approximately 30 papers appearing in the refereed literature each year at a remarkably constant rate since 1999. The fact that almost half of these publications are review articles is telling. Arthritis was the subject of the first human gene-therapy protocol for a nonlethal disease [3], and consequently attracted much scrutiny from the regulatory agencies. The data from this trial confirmed that genes could be safely transferred to human joints and expressed within them [4]. Moreover, in a similar small, German study, each of two subjects treated with this gene therapy appeared to mount a clinical response, one of them dramatically so [5] [Wehling et al., Unpublished Data]. Nevertheless, the ex vivo, retrovirus-based approach used in these two studies is unlikely to find wide clinical application; ex vivo gene transfer using autologous cell culture is too cumbersome and costly, and concerns regarding insertional mutagenesis with retrovirus vectors have resurfaced. Subsequent clinical trials (Table 1) based on this approach have used allogeneic cells lines to reduce costs and, in one case, irradiation of cells to prevent cell division and thus tumorigenicity. In the search for an efficient vector that can be introduced safely into joints by intra-articular injection, most investigators have converged on adeno-associated virus (AAV). Recombinant AAV has risen in popularity as a gene therapy vector because it is perceived to be safe and new technologies permit easier production of clinical-grade material [6]. Wild-type AAV causes no known disease and recombinant AAV vectors have been used safely in gene therapy trials of a number of single-gene disorders, as well as Parkinson’s disease, Alzheimer’s disease and cancer. Two large Phase III trials for prostate cancer using AAV are underway, and orphan drug status has been granted by the EU for AAV-mediated gene therapy for familial lipoprotein lipase deficiency.
Rheumatoid arthritis is a chronic inflammatory systemic autoimmune disease that destroys cartilage and peri-articular bone. Recent therapeutic advances for this disease have yielded promising results, the most notable of which have been pharmacologic agents that block tumor necrosis factor (TNF)-α. Despite these advances, the search for new therapies continues, amongst which stem cells are being developed for potential applications in cartilage- and bone-tissue engineering. Given the large clinical demand for such stem-cell applications, muscle-derived stem cells are being heavily investigated due to their ease of isolation and ability to differentiate into multiple lineages, including osteogenic and chondrogenic lineages. Furthermore, when genetically modified ex vivo to express growth factors, these cells can repair bone and cartilage in animal models. Accordingly, regenerative therapies and tissue engineering that are based on muscle-derived stem cells are emerging with promising experimental results t...
Febuxostat is a novel, nonpurine, selective inhibitor of xanthine oxidase (NP-SIXO), recently approved in the European Union. Febuxostat shows high, long-term efficacy for the reduction of serum urate (SU) levels, showing linear pharmacokinetics at approved doses, and its pharmacokinetics are not clinically significantly influenced by the presence of mild-to-moderate renal or liver function impairment. The clinical applicability of febuxostat should have a significant impact in patients with the highest baseline SU levels, the most severe gout, previous adverse events with other urate-lowering drugs or no availability of alternative urate-lowering drugs after failure to properly control SU levels during urate-lowering therapy. Febuxostat may become an interesting choice in our use of xanthine oxidase inhibitors.
In the last two decades, there has been an explosive interest in the role of oxidative stress in experimental and clinical medicine. Oxidative stress is strongly correlated with a number of age-related diseases, such as rheumatoid arthritis, osteoarthritis, osteoporosis and atherosclerosis. Repeated intra-articular injections of the antioxidant enzyme superoxide dismutase (SOD) have slowed down progression of rheumatoid arthritis. Unfortunately, none of the native human SODs possess attractive pharmacological properties to make them a clinically useful therapeutic drug, owing to their rapid renal clearance. To overcome these limitations, several synthetic low-molecular-weight compounds that mimic the effects of SOD were developed and have been shown to be efficient in vivo. The use of SOD for clinical application still receives great interest and attention. However, the limitation to the injection route of drug administration has not yet been overcome. Current research continues to investigate new strateg...
Chronic anterior uveitis is the most important extra-articular complication of juvenile idiopathic arthritis. It is more frequent in the early-onset forms, with a higher prevalence in the oligoarticular subtype, and bilateral in most cases. The risk for visual impairment is still relevant due to sight-threatening complications, such as band keratopathy, cataract, glaucoma and cystoid macular edema. To date, treatment is not standardized and involves a complex decision-making process. Among several steroid-sparing immunosuppressive options, low-dose methotrexate is still the most diffuse treatment. Mycophenolate mofetil is another potential choice, although it is less effective in chronic anterior uveitis than in posterior or intermediate uveitis. TNF-α antagonists, the new generation of agents increasingly frequently used in autoimmune and rheumatic conditions, have demonstrated effectiveness in open-label studies, although no large, randomized, controlled trials have been reported so far. Although inflix...
Evaluation of: van der Heijde D, Schiff MH, Sieper J et al.: Adalimumab effectiveness for the treatment of ankylosing spondylitis is maintained for up to 2 years: longterm results from the ATLAS trial. Ann. Rheum. Dis. (2008) (Epub ahead of print). In contrast to the situation in rheumatoid disease where a variety of inexpensive disease-modifying agents exist (e.g., methotrexate), no such agent modifies disease in ankylosing spondylitis. Therefore, the arrival of anti-TNF drugs has been an enormous contribution. All the anti-TNF agents are efficacious in this condition, and this article reviews data regarding adalimumab in ankylosing spondylitis. In the future, we will need to define which anti-TNF agent should be considered the drug of choice for which type of disease. Important outstanding issues exist, such as should anti-TNF be given very early, following symptom onset, in order to turn off the disease process rather than merely suppress symptoms? The long-term will certainly see more anti-TNF agents,...
The main goal of therapy for systemic lupus erythematosus is to achieve remission, as this has a major impact on patient and renal survival. Furthermore, early treatment success has been shown to improve long-term prognosis. Treatment has traditionally followed a standardized schematic therapy. However, studies have shown that treatment response may depend on age, gender, ethnicity and other genetic factors. In addition, data show that mycophenolate mofetil is effective in the treatment of lupus nephritis, and research focusing on the pathogenesis of lupus is ongoing with emerging treatment targets. Thus, the treatment of systemic lupus erythematosus and, in particular, lupus nephritis, is evolving from standardized therapy to an individualized therapeutic approach based on analysis of organ involvement, the patient’s background, risk factors and, possibly, cytokine, antibody or cell profiles.
Dr Stuart Silverman was born in Chicago (IL, USA) and graduated from Princeton University (NJ, USA) cum laude in biology with an interest in art history. He received his MD from Johns Hopkins (MD, USA) in 1973. He was an intern and resident in the Boston University Hospital System (MA, USA) and was a rheumatology fellow at Boston University under Dr Alan Cohen. Following his rheumatology fellowship he was a Thorndike research fellow. He is board-certified in internal medicine, rheumatology and allergy-immunology, and has served as a lecturer in rheumatology at Tufts University, assistant professor at University of Pennsylvania (PA, USA) and is currently Clinical Professor of Medicine at University of California, Los Angeles (UCLA, CA, USA). He has served as acting chief of rheumatology at Greater Los Angeles VA Medical Center where he currently holds a research appointment. His clinical practice is based at Cedars-Sinai (CA, USA). Dr Silverman is medical director of the OMC Clinical Research Center, a non...
Josef S Smolen† & Daniel Aletaha †Author for correspondence Medical University of Vienna, Division of Rheumatology, Internal Medicine III, Waehringer Guertel 18-20, A-1090, Vienna, Austria Tel.: +43 140 400 4300 Fax: +43 140 400 4331 josef.smolen@wienkav.at ‘While existing and imminent new therapies have improved and will continue to improve the situation of patients with rheumatoid arthritis, we will still need further treatment modalities to achieve optimal success in all patients.’
Kawasaki disease is the leading cause of multisystem vasculitis in childhood. The coronary arteries are targets of long-term inflammation and damage, making Kawasaki disease the leading cause of acquired heart disease in children from the developed world. The link between the systemic immune response seen in the acute phase of Kawasaki disease and subsequent damage to the coronary arteries is not clearly understood. Recent work points to TNF-α and its downstream effector molecules as the key players in mediating coronary artery damage. In this article, we will review the evidence pointing to TNF-α in the pathogenesis of disease and the implications for therapy.
Autoimmune chronic inflammatory diseases are thought to have a prevalence of one in 30 people in the Western world. Understanding how environmental factors can eventually lead to such a burden is of crucial importance. In a recent meeting held in Milan, Italy, the cellular and molecular basis of autoimmunity arising following infection, and protection against autoimmunity induced by infection, were discussed by more than 100 scientists from around the world.
The metabolic syndrome is a cluster of cardiovascular risk factors that are of metabolic origin and include atherogenic dyslipidemia, hypertension and hyperglycemia. This syndrome is generally considered to develop as a consequence of excess adiposity- mediated insulin resistance. In rheumatoid arthritis (RA), apart from excess adiposity, high-grade inflammation, routine glucocorticoid use and subclinical hypothyroidism are further implicated in insulin resistance. Several more recently uncovered metabolic risk factors including microalbuminuria, hypercoagulability, autonomic dysfunction, hyperuricemia, renin–angiotensin activation and raised aminotransferase concentrations prior to methotrexate use are also more prevalent in RA subjects as compared with non-RA subjects, linked to other metabolic syndrome components and/or related to RA characteristics. Suppression of RA disease activity improves metabolic cardiovascular risk. Systemic inflammation, glucocorticoid therapy, hypothyroidism, insulin resistan...
Environmental factors have long been suspected to affect the pathogenesis and incidence of inflammatory diseases. Epidemiological research has demonstrated that sunlight, or rather ultraviolet radiation exposure, is one such environmental factor that can affect inflammatory diseases. Increased exposure levels of ultraviolet radiation have been shown to decrease the incidence of autoimmune diseases – including rheumatoid arthritis, Type 1 diabetes, multiple sclerosis and colitis. The immunomodulatory effects of ultraviolet radiation are mimicked by administration of vitamin D, suggesting that photosynthesized vitamin D is the mediator involved in the biological effects of sunlight. Vitamin D has a variety of roles in the body, including regulation of the immune system predominantly affecting Th1 immunity, increasing T-cell apoptosis, reducing immune-cell infiltration, decreasing cytokine/chemokine production and suppressing proinflammatory transcription-factor activation and protein expression. Our group h...
The Scandinavian Congress of Rheumatology has been held every other year since 1946 in one of the five Scandinavian countries: Sweden, Norway, Denmark, Iceland and Finland. These congresses focus on clinical and basic research in Scandinavian countries, with a strong history of research in epidemiology, diagnosis and treatment of rheumatic diseases. The 32nd Scandinavian Congress of Rheumatology, named ‘Northern HighLights in Rheumatology’, was held in Levi, Lapland. The meeting covered important clinical topics such as diagnostics, monitoring, imaging modalities and treatment strategies for rheumatic diseases. Work disability and its prevention, chronic widespread pain, updates of rheumatologic ‘emergencies’ and pediatric rheumatology were discussed. Topics in the basic science lessons included the role of T cells in chronic inflammation, lymphocyte tracking in arthritis and other autoimmune diseases, gene polymorphisms and the role of adipokines in inflammation and rheumatic diseases. More than 50 abstracts were selected for oral presentations. Some of the highlights of the congress are presented in this report.
‘…some modalities of Traditional Chinese medicine are effective and should be included as part of a multidisciplinary integrative approach to management of patients with OA.’ Current recommendations for the management of patients with symptomatic osteoarthritis (OA) emphasize a multidisciplinary approach focused on the reduction of pain, functional limitation and disability [1–4]. This approach incorporates the use of nonpharmacologic modalities, including patient education, occupational and physical therapy, aerobic exercise, social support and weight loss, as well as pharmacologic therapies, including simple and opioid analgesics, NSAIDs including COX-2-selective inhibitors, and injectable agents including glucocorticoids and hyaluronan preparations. In patients whose symptoms are not adequately controlled with this approach, or who prefer not to take prescription medications because of fear of side effects, the use of traditional Chinese medicine (TCM) has been recommended as part of an integrated approach to care [5]. TCM can be defined as a range of traditional practices that originated in China and developed over a period of several thousand years [101]. Several treatment methods are considered to be part of TCM; these include herbal medicine, acupuncture (with or without moxibustion or electrical stimulation), food therapy, massage therapy, physical exercise such as T’ai Chi, mental exercise such as Feng Shui, and breathing and meditation exercise such as Qi Gong. This editorial will review the published evidence that supports the use of some TCM modalities as part of an integrative approach to the holistic management of patients with symptomatic OA. Herbal compounds
