Showing papers in "Best Practice & Research: Clinical Rheumatology in 2001"

Metalloproteases and inhibitors in arthritic diseases.

Abstract: Controlling degradation of the extracellular matrix is crucial in arthritic diseases such as osteoarthritis (OA) and rheumatoid arthritis (RA), as conventional treatments do not positively affect the structural properties of the articular tissues. Metalloproteases, a family of zinc-dependent enzymes, and more specifically the matrix metalloproteases (MMPs), play a premier role in joint articular tissue degeneration. Additional enzymes of the metalloprotease family, such as the membrane-type metalloproteases (MT-MMPs) and the adamalysins that include the ADAMs and the ADAMTS families, have also been found to be involved in these disease processes. At present, therapeutic intervention based on the inhibition of metalloproteases, and more particularly of the MMPs, is under intensive investigation, and several MMP inhibitors are in clinical development. Currently, MMP inhibitors are exemplified by several chemical classes: hydroxamic acids, carboxylic acids and thiols. One key issue in the clinical development of MMP inhibitors relates to whether broad-spectrum inhibitors active against a range of different enzymes or selective inhibitors targeted against a single enzyme or particular subset of the MMPs represents the optimal strategy. In this chapter, we address the different metalloprotease enzymes and sub-families and their implication in arthritic diseases. Furthermore, we assess physiological and chemical metalloprotease inhibitors, and for the latter, the current inhibitory classes of compounds being studied.

The balance of Th1/Th2 cytokines in rheumatoid arthritis

Abstract: It has been suggested that rheumatoid inflammation is mediated by activated pro-inflammatory T helper type I cells. In contrast, immunomodulatory T helper type 2 cells and their cytokines, in particular interleukin-4, are rarely found. This chapter reviews the concept of the Th1/Th2 dichotomy and summarizes the functions of the signature cytokines of the T helper subsets. We discuss current knowledge of the immunopathogenesis of rheumatoid arthritis and its related animal model, collagen induced arthritis, with regard to the Th1/Th2 paradigm. The accumulating evidence for a T helper type 1 driven inflammation and the implications for future therapy are delineated.

The role of nitric oxide in tissue destruction

Abstract: Nitric oxide (NO) is synthesized via the oxidation of arginine by a family of nitric oxide synthases (NOS), which are either constitutive (ie. endothelial (ec)NOS and neuronal (nc)NOS) or inducible (iNOS). The production of nitric oxide plays a vital role in the regulation of physiological processes, host defence, inflammation and immunity. Pro-inflammatory effects include vasodilation, oedema, cytotoxicity and the mediation of cytokine-dependent processes that can lead to tissue destruction. Nitric oxide-dependent tissue injury has been implicated in a variety of rheumatic diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis and osteoarthritis. Conversely, the production of NO by endothelial cell NOS may serve a protective, or anti-inflammatory, function by preventing the adhesion and release of oxidants by activated neutrophils in the microvasculature. In this chapter we describe the multifaceted role of nitric oxide in inflammation and address the potential therapeutic implications of NOS inhibition.

Injections in the treatment of osteoarthritis

Abstract: Injections, especially of corticosteroids but also of hyaluronan, are widely used in the treatment of osteoarthritis. The various joints - knee, hip, hand - affected by OA are accessible to these local treatments. This chapter concentrates on the evidence for efficacy of these treatments and attempts to delimit their respective indications and optimal doses. The side-effects of corticosteroid injections are reviewed, and the potential interest in post-injection rest is discussed. Finally, the potential structure-modifying effect of hyaluronan is investigated.

What is the natural history of rheumatoid arthritis

Abstract: Inflammatory polyarthritis can be a self-limiting disease, develop into rheumatoid arthritis (RA) or differentiate into another form of chronic arthritis. It remains a clinical and scientific challenge to understand the relationship between these phenotypes, determine their aetiologies and predict the course and outcome for individual patients. Even patients labelled as having RA show a wide spectrum of clinical phenotypes. Disease definition is a major problem in studying the aetiology of RA as currently used classification criteria were derived using patients with established disease. RA is thought to result from the combination of genetic susceptibility and exposure to an appropriate environmental trigger. The genetic component is probably oligogenic. The association with HLA has been known for over 25 years. RA is now thought to be associated with a conserved sequence of amino acids in a number of HLA-DRB1 alleles, called the RA shared epitope. However, the shared epitope appears to be associated with RA chronicity and severity more than with susceptibility. Other potential RA susceptibility genes include IL-1, aromatase, corticotropin-releasing hormone and a region on the X chromosome. Hormonal and reproductive factors also influence RA susceptibility and severity. RA is more common in women than men, especially before the menopause. Men may be protected by hormonal factors and require a stronger genetic component to develop disease. Although infectious triggers of RA have long been suspected, no definitive evidence has been obtained. Previous blood transfusion, smoking and obesity are also possible risk factors. Chronicity and remission are important aspects of the natural history of early RA. Although we can identify patients at risk of adverse prognosis with some accuracy, we remain unable to predict remission. Functional disability and radiological damage are the most studied outcomes in RA. Radiological damage often occurs early in the course of RA, but patients may show erosion for the first time several years after symptom onset. Many studies have demonstrated a relationship between HLA and features of severe RA in established patients. This appears to be related to gene dosage.

Vascular mechanisms in osteoarthritis

Abstract: Superficial injury and fibrillation of articular cartilage as a consequence of ageing, genetic, hormonal or mechanical factors are not necessarily associated with joint pain. However, failure of joint cartilage accompanied by synovitis and abnormalities in subchondral bone and its vasculature generally is, the syndrome being known as osteoarthritis. We suggest that the progression of early cartilage fibrillation to symptomatic OA arises initially as a consequence of the release into synovial fluid of cartilage-derived antigens that activate joint lining macrophages and circulating leukocytes, thereby establishing a synovitis. Pro-inflammatory mediators and pro-coagulant factors etc. not only perpetuate cartilage destruction but also promote a state of hypercoagulation, hypofibrinolysis, thrombosis and ischaemic bone necrosis at compromised sites such as in the subchondral vasculature. These events are augmented by ageing and associated hormonal changes. On the basis of this hypothesis we suggest that anti-thrombotic/anti-lipidaemic agents that also exhibit anti-inflammatory activity could be effective anti-osteoarthritic drugs. Experimental studies are described which support this proposal.

How does one assess early rheumatoid arthritis in daily clinical practice

Abstract: In past years, consensus has been reached on the assessment of rheumatoid arthritis in clinical trials. Next to a core set of disease activity variables, response criteria have been developed and validated. These criteria are, however, of limited value in daily clinical practice. In this situation, emphasis should be paid to accurate measurement of disease activity on a continuous scale using the lowest possible number of core set variables. Different studies have shown that the DAS28 is a valuable instrument for this purpose. Many factors have been identified to possess a prognostic value; however, the IgM rheumatoid factor is still the only one which is of any importance in daily clinical practice.

Gene therapy in rheumatic diseases.

Abstract: Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by joint inflammation as well as progressive cartilage and bone destruction. Advances in the understanding of the pathophysiology of RA have led to the development of new therapeutic strategies, including gene therapy. Gene therapy offers a new approach to deliver therapeutic proteins to the joints of arthritis patients. Local as well as systemic gene therapy can be envisaged for the treatment of arthritis. Several viral and non-viral vectors have been used in animal models for rheumatoid arthritis for ex vivo and in vivo delivery of therapeutic genes. Promising pre-clinical data have resulted from the application of these strategies. Using ex vivo gene delivery, successful and safe gene transfer has been demonstrated in the joints of RA patients. Although new insights into the role of cytokines and other mediators of chronic inflammation have provided novel targets for therapeutic intervention, the development of vectors that induce long-term and regulated gene expression remains a challenge.

Skeletal tissue engineering: opportunities and challenges.

Abstract: Tissue engineering is a field of biomedicine that is growing rapidly and is critically driven by scientific advances in the areas of developmental and cell biology and biomaterial sciences. Regeneration of skeletal tissues is among the most promising areas of biological tissue repair and is providing a broad spectrum of potential clinical applications, including joint resurfacing. The availability of novel tools such as pluripotent stem cells, morphogens, smart biomaterials and gene transfer technologies, makes us dream of many exciting novel therapeutic approaches. Despite these opportunities in regenerative medicine, good clinical practice requires the clinician to question the consistency, reproducibility, validation and appropriate regulation of these new biological treatments.

How to use education as an intervention in osteoarthritis

Abstract: Definitions of health education and patient education form the starting point for an overview of patient education interventions for people with osteoarthritis (OA). Recipients, tutors and the key messages that education can deliver are considered, followed by a review of the methods used and the typical content of current educational provision for OA. The theoretical and empirical basis for interventions is illustrated using examples from the somewhat limited field. The outcomes used to evaluate education and the evidence for effectiveness is presented. The issues of which patients benefit most, adherence, length of interventions, optimal timing and frequency are raised. The chapter concludes with a brief discussion of the best health care system is needed to underpin educational provision and suggestions for a research agenda that will go some way towards addressing the many questions that remain unanswered.

Clinical assessment of the osteoarthritis patient.

Abstract: It is becoming apparent that the disease process of osteoarthritis should be regarded separately from the clinical syndrome of joint pain, use-related stiffness and disability. The latter may best be approached as a chronic regional pain disorder that requires attention to physical, psychological and social factors as well as those related to the disease process. This chapter sets out to look at some of the practical implications of taking this view for the clinical assessment. Starting with the syndrome of hip, knee or hand pain in older adults in the community, we consider what leads people to consult, what the important features to assess might be, the role of imaging in the clinical assessment of osteoarthritis, and finally how a management plan could be formulated. The usefulness of assessing clinical osteoarthritis as a regional pain disorder is uncertain. Even if this were demonstrated, the concept of osteoarthritis as a structural disease should be retained as an integral part.

Barriers to the effectiveness of any intervention in OA.

Abstract: One of the main barriers to the effectiveness of interventions in osteoarthritis (OA) is adherence to treatment interventions and advice. Estimates suggest that adherence to any intervention in OA is between 50 and 95% but many of these estimates are derived from clinical trials and the real levels in clinical practice may be much lower. The factors influencing adherence are complex and multifactorial and, although information is available from other diseases, little is known about the relative contribution of these factors in adherence to treatment in OA. Few interventions to improve adherence have been evaluated in OA, and such studies would be limited by the lack of an accurate method for assessing adherence.

The evidence that exercise during growth or adulthood reduces the risk of fragility fractures is weak

Abstract: There has never been, and will never be, a randomized double-blind placebo-controlled trial demonstrating that exercise in youth, adulthood or old age reduces fragility or osteoporosis-related fractures in old age. The next level of evidence, a randomized, controlled but unblinded study with fractures as an end-point is feasible but has never been done. The basis for the belief that exercise reduces fractures is derived from lower levels of 'evidence', namely, retrospective and prospective observation cohort studies and case-control studies. These studies are at best hypothesis generating, never hypothesis testing. They are all subject to many systematic biases and should be interpreted with extreme scepticism. Surrogate measures of anti-fracture efficacy are the next level of evidence, such as the demonstration of a reduction in risk factors for falls, a reduction in falls, a reduction in fractures due to falls, an increase in peak bone size and mass, prevention of bone loss in midlife and restoration of bone mass and structure in old age.

What is the impact of early rheumatoid arthritis on the individual

Abstract: Rheumatoid arthritis has a significant impact on patients’ physical, emotional and social functioning that often occurs very early in the disease with the onset of symptoms. Patients therefore come to their consultation with the rheumatologist, having often experienced these symptoms over a period of some months, with specific expectations (for reassurance and diagnosis) and their own understanding and beliefs about the aetiology and prognosis of their symptoms. Information and advice given by rheumatologists will be rejected by patients if it cannot be accommodated within these lay beliefs. The diagnosis itself can cause a variety of reactions, including relief, disbelief, anger, fear and devastation. Following diagnosis, patients are faced with the problems of adapting to a new self-concept, managing their symptoms and trying to assimilate the large amount of information that they are given about their disease, its treatment, preferred health behaviours, prognosis and so on. There are a number of ways in which health professionals can reduce this impact in early disease. Eliciting patients’ lay beliefs about the cause of their symptoms will ensure that information given in the consultation is relevant to individual patients and is presented in a way that has meaning for them. Determining patients’ expectations of the rheumatologist will ensure that patients’ needs for information and reassurance are met and that unrealistic or inappropriate expectations can be discussed and re-negotiated. Understanding patients’ attitudes towards treatment interventions will inform shared clinical decision-making and promote adherence. Obtaining this information in the context of a time-limited consultation can be assisted by the use of validated clinical tools, presented as self-completed questionnaires. Further research is needed to determine the content, frequency, timing and methodology of educational interventions in early rheumatoid arthritis and to improve the understanding of the complex interaction between lay beliefs and disease outcome.

Bone changes in early rheumatoid arthritis

Abstract: Bone disease in rheumatoid arthritis affects the peri-articular and axial skeleton and is a major cause of disability Recent studies have shown that pro-inflammatory cytokines stimulate the expression of osteoprotegerin ligand, a transmembrane protein of the tumour necrosis factor ligand superfamily, on synoviocytes and activated T cells Osteoprotegerin ligand stimulates osteoclast formation and activation, membrane-bound and soluble osteoprotegerin ligand leading to osteoporosis as well as erosions Bone densitometry using dual energy X-ray absorptiometry is an objective and precise method for monitoring this bone disease Bone loss is more rapid in patients with early rheumatoid arthritis and correlates well with measures of inflammation and function Data are emerging that monitoring bone loss of the hands in early rheumatoid arthritis could be an outcome measure and a prognostic indicator of future functional disability Suppressing inflammation effectively and the use of bone active agents can reduce the rate of loss In animal models, osteoprotegerin—a decoy receptor of osteoprotegerin ligand—blocks osteoporosis and erosions without affecting inflammation The use of new biological agents could in future effectively prevent and treat rheumatoid bone disease

Surgical approaches for osteoarthritis.

Abstract: Patients with osteoarthritis (OA) often benefit from properly performed surgical procedures. However, the scientific database from studies investigating appropriate timing of surgery, patient morbidity, quality of life before and after the intervention, and cost utility of different procedures is insufficient. In order to allow a fair allocation of resources in future health care systems, randomized controlled trials (RCTs) with defined entry criteria, sufficient number of patients, and valid outcome measures should be performed for different surgical approaches. They should especially include control groups with conservative treatment in order to allow an evidence based comparison between different therapeutic approaches. At present, however, optimal management of OA as a dynamic disease process must include a combination of conservative as well as operative treatment modalities. In case of malalignment, instability and intra-articular causes of mechanical dysfunction, correction of these abnormalities and relief of symptoms can be achieved with properly indicated and performed osteotomies. Debridement by arthroscopy and arthotomy probably does not alter the natural history of OA and true clinical outcomes are difficult to determine, but it can provide transient relief of symptoms. Joint replacement has to be considered for refractory pain associated with disability and radiological deterioration. As the pre-operative functional status seems to influence the outcome not only in joint replacement but also in joint-preserving osteotomies, the indication for these procedures might be expanded in the future.

Is early rheumatoid arthritis the same disease process as late rheumatoid arthritis

Abstract: Thoughts on treatment for the early control of synovitis have stimulated research on pathobiological events at the site of inflammation in patients with early rheumatoid arthritis. Several studies have thus been conducted to examine synovial biopsy samples at various stages of the disease. The most important conclusion from these studies is that all features of chronic synovial inflammation can be observed in so-called early rheumatoid arthritis. This suggests that no arguments exist for the effect of therapeutic intervention on synovitis varying in different phases of rheumatoid arthritis. In end-stage rheumatoid arthritis, factors that are secondary to the disease may contribute to the perpetuation of synovial inflammation. Mutations in key regulatory genes could play a role in the autonomous progression of the disease. In addition, it is conceivable that the release of bone and cartilage fragments might elicit an inflammatory response in patients with destructive rheumatoid arthritis.

Nutripharmaceuticals for osteoarthritis

Abstract: What is the level of evidence for current symptomatic agents (SYSADOA) in patients with osteoarthritis? Existing publications which met the inclusion criteria were rated by calculating the effect size of the compounds and applying a quality assessment score of the study methodology. This produced a median effect size for the primary outcome measure, pain, of 1.37 (range 0.37-1.50) for chondroitin-sulphate and 0.57 (range 0.26-1.02) for glucosamine-sulphate in patients with knee osteoarthritis. These effect sizes were strongly diminished when only recent high-quality studies were considered (effect size of pain for chondroitin-sulphate 0.37 and for glucosamine-sulphate 0.26). Effect sizes for functional improvement and overall WOMAC index (pain, stiffness and function) were in the same range for both compounds. So far, and in contrast to recent claims, there is no reliable scientific evidence that these two substances have structure-modifying actions with respect to prohibiting, healing or restoring cartilage lesions. There is only scarce or no scientific evidence for the effects of nutrients in patients with knee, hip or hand osteoarthritis. Several large company-sponsored and independent trials with several of these nutripharmaceuticals are ongoing in Europe and the USA.

Imaging the joints in early rheumatoid arthritis.

Abstract: Radiography is the most widely utilized imaging modality for early rheumatoid arthritis, determination of radiographic progression remaining a crucial part of the evaluation of therapy. Conventional radiography is, however, insensitive for showing bone damage in early disease and is totally unsuitable for assessing synovial inflammation. The recognition of these limitations has led to intense interest in the multiplanar imaging capabilities of magnetic resonance imaging in rheumatoid arthritis and to an increasing use of ultrasonography for assessing synovitis and bone damage. This chapter discusses the role of radiography in early rheumatoid arthritis and the emerging use and role of magnetic resonance imaging and ultrasonography in evaluating synovitis and bone damage. The relationship between synovitis and bone damage is also addressed in the light of recent magnetic resonance imaging observations.

Epidemiology of osteoporosis.

Abstract: The epidemiology of osteoporosis is reviewed in this article. Attempts were made to answer the following questions: How should osteoporosis be defined? How can risk factors and bone mineral density (BMD) measurements be applied to diagnose osteoporosis? How do the rates for osteoporotic fractures vary by country, sex, age and time? What are the costs for osteoporosis in terms of direct and indirect cost, morbidity and mortality? According to the WHO criteria, osteoporosis can be defined as a BMD of 2.5 standard deviations or more below the young normal mean. BMD measurements are predictive of fracture risks. Hip fracture is by far the most costly of osteoporotic fractures, and the rates are highest in Caucasians, intermediate in Asians and lowest in Blacks. Risk factors could be used to assist in the decision to measure BMD.

Neuroendocrine mechanisms in fibromyalgia-chronic fatigue.

Abstract: Fibromyalgia and chronic fatigue syndrome are poorly understood disorders that share similar demographic and clinical characteristics. Because of the clinical similarities between both disorders it was suggested that they share a common pathophysiological mechanism, namely, central nervous system dysfunction. This chapter presents data demonstrating neurohormonal abnormalities, abnormal pain processing and autonomic nervous system dysfunction in fibromyalgia and chronic fatigue syndrome. The possible contribution of the central nervous system dysfunction to the development and symptomatology of these conditions is discussed. The chapter concludes by reviewing the effect of current treatments and emerging therapeutic modalities in fibromyalgia and chronic fatigue syndrome.

How can the risk of long-term consequences of rheumatoid arthritis be reduced?

Abstract: The long-term natural history of rheumatoid arthritis includes early radiographic damage and progression, severe functional declines, work disability and increased mortality rates. Emerging evidence suggests that this natural history may be favourably affected by disease-modifying anti-rheumatic drugs (DMARDs), which slow the radiographic progression and functional decline. It is necessary to document both the efficacy of these drugs in randomized controlled clinical trials and their long-term effectiveness in clinical observational studies. Although a 20% improvement in inflammatory measures in the American College of Rheumatology Core Data Set (ACR20) distinguishes DMARDs from placebo in clinical trials, it is not clear that a control of inflammation at this level, or even at 50%, is sufficient to prevent long-term damage. There is limited financial support for long-term observational studies, which depend on data from the clinical experience of rheumatologists. Quantitative databases from clinical care, can be developed to document long-term outcomes in patients with early rheumatoid arthritis to include additional physical, radiographic, laboratory and patient questionnaire quantitative data. Patient self-report questionnaires appear to provide the least expensive and most effective measures toward this goal.

What are the costs to society and the potential benefits from the effective management of early rheumatoid arthritis

Abstract: Rheumatoid arthritis is a chronic disabling condition associated with a significant long-term loss of function and a significant socio-economic impact on individual sufferers and their families, as well as on society as a whole. There is a suggestion that the incidence and severity of the disease may be abating slightly, which has been attributed to the trend to 'invert the pyramid' and to diagnose and treat rheumatoid disease earlier and more aggressively. Studies have confirmed that the erosions, which lead to subsequent joint damage, occur early in the course of the disease. Ongoing disease activity, both clinically and serologically, has now been linked to increasing morbidity, loss of function and mortality. New agents have been developed and, together with combinations of old and new agents, have been shown to be more effective if used earlier in the course of the disease. The better the early control of the disease, the better the long-term outcome. Early and more vigorous treatment, particularly of those patients with a high joint count, early loss of function and an elevated titre of inflammatory markers, has potential to reduce the twofold increase in mortality seen among rheumatoid arthritis patients. The scene is set to have a greater impact on the long-term disability and associated cost to the individual and society by treating early and treating often. Combination therapy and the new 'biologicals' are, however, far more expensive than the previously available agents, and the direct medical costs associated with medication, as well as the monitoring costs for rheumatoid arthritis, are increasing. It is difficult to value the long-term prevention of pain and suffering, and the maintenance of productivity. However, if the disease were effectively controlled early, there would be long-term benefits to be offset against the higher treatment cost. It behooves the rheumatological community to use the new agents wisely to gain the greatest advantage for all patients as well as to monitor the long-term benefits and drawbacks so that cost-effectiveness can be comprehensively evaluated.

Role of biochemical markers in the management of osteoporosis

Abstract: Several serum and urine biochemical markers of bone resorption and formation have been developed. Biochemical bone markers have been used as intermediate end-points in all major studies of anti-osteoporotic therapies. Bone resorption markers, in particular, may add an independent, predictive value to the assessment of bone loss and fracture risk. There are also potential advantages in monitoring anti-osteoporotic treatment in the short-term in addition to bone densitometry, to rapidly identify non-responders to therapy, or non-compliance. Despite these recent advances, until now bone markers have simply been very useful research tools, with their clinical utility being limited by intra-individual and diurnal variability. However, the probability of the true bone mineral density response to hormone replacement therapy for the individual patient may be predicted using algorithms based on a spectrum of cut-off bone marker levels with varying false positive and negative rates. Thus, the transition of biochemical bone markers into everyday clinical practice may be rapidly approaching.

Lifestyle changes in the management of osteoarthritis

Abstract: Lifestyle changes are gaining increasing recognition in the management of osteoarthritis. In most guidelines advice on exercise and weight reduction is now given priority over pharmacological therapies. In view of the face validity, safety and cost-effectiveness of such measures this would seem appropriate. This chapter discusses the role of exercise therapy, weight reduction and footwear. The emphasis is on evidence for effectiveness, comparison of techniques available and maintenance of adherence with each lifestyle change. Because most of our knowledge surrounds management of knee osteoarthritis, this is the focus of our discussion, with reference being made to other sites as appropriate.

Stem cells in the aetiopathogenesis and therapy of rheumatic disease

Abstract: Animal models of autoimmune disease and case reports of patients with these diseases who have been involved in bone marrow transplants have provided important data implicating the haemopoietic stem cell in rheumatic disease pathogenesis. Animal and human examples exist for both cure and transfer of rheumatoid arthritis, systemic lupus erythematosus (SLE) and other organ-specific diseases using allogeneic haemopoietic stem cell transplantation. This would suggest that the stem cell in these diseases is abnormal and could be cured by replacement of a normal stem cell although more in vitro data are required in this area. Given the morbidity and increased mortality in some patients with severe autoimmune diseases and the increasing safety of autologous haemopoietic stem cell transplantation (HSCT), pilot studies have been conducted using HSCT in rheumatic diseases. It is still unclear whether an autologous graft will cure these diseases but significant remissions have been obtained which have provided important data for the design of randomized trials of HSCT versus more conventional therapy. Several trials are now open to accrual under the auspices of the European Bone Marrow Transplant Group/European League Against Rheumatism (EBMT/EULAR) registry. Future clinical and laboratory research will need to document the abnormalities of the stem cell of a rheumatic patient because new therapies based on gene therapy or stem cell differentiation could be apllied to these diseases. With increasing safety of allogeneic HSCT it is not unreasonable to predict cure of some rheumatic diseases in the near future.

Management of systemic vasculitis

Abstract: The systemic vasculitides are a wide-ranging group of diseases that are characterized by the presence of blood vessel inflammation. Despite this common feature, each type of vasculitis has a unique variety of clinical manifestations that influences its degree of disease severity and ultimately its management. Immunosuppressive therapy forms the foundation of treatment for almost all forms of systemic vasculitis. Because of this, treatment can be associated with its own risk of morbidity, or even mortality, related to specific medication side-effects or infections which occur as a result of impaired host defences. This chapter seeks to review the approach to management in selected forms of systemic vasculitis. Questions examined include the following. When should one treat systemic vasculitis? How does the nature of the disease and its severity affect treatment decisions? What are the data regarding the effectiveness of individual therapeutic regimens?

Signal transduction in rheumatoid arthritis

Abstract: Extracellular signals are transduced intracellularly by multiple pathways, resulting in alterations in the transcription and translation of specific proteins. The end result of some of these signalling pathways is the production of proteins, including cytokines and matrix metalloproteinases, that are implicated in the pathogenesis of rheumatoid arthritis. This chapter includes a discussion of these signal transduction pathways, including tumour necrosis factor receptor signalling, interleukin-1, -4, and -6 receptor signalling, stress- and mitogen-activated protein kinase pathways, CD14 and Toll-like receptor signalling, and T cell signal transduction. The known effects of currently available rheumatoid arthritis (RA) therapeutics on these signalling pathways are also reviewed. In addition, potential future targets for therapeutic intervention in RA are discussed.

On the organization of an early arthritis clinic.

Abstract: Early active treatment with disease-modifying anti-rheumatic drugs has become standard management for patients with recent-onset rheumatoid arthritis. A number of questions, however, remain unresolved for practising clinicians, for example how early and how actively to treat and what the treatment goals should be. This chapter summarizes some recent data that have added important empirical evidence on these issues. It has thus been demonstrated that the formal organization of an early arthritis clinic shortens the referral time from primary care, that a delay in the institution of disease-modifying drug treatment leads to decreased long-term function and that early active treatment with pharmacotherapy as well as team-based care may increase occupational capacity. It is argued that adopting a day care approach in the initial encounter with specialist care may increase the possibility for patients actively to understand the disease and their own potentials to diminish and cope with its effects. The further development of care for early arthritis patients with new, potentially efficient but also expensive drugs will increase the requirement for a structured documentation of outcomes, systems for such documentation being discussed in the chapter.

Introduction to, and classification of, the systemic vasculitides

Abstract: This overview serves as an introduction to the systemic vasculitides, which are a group of heterogeneous disorders sharing a common pathophysiological mechanism leading to blood vessel inflammation and tissue necrosis. Our lack of understanding of the aetiology for most forms of vasculitis has resulted in the development of a classification system, which is primarily based on vessel size. Such a system assists in the grouping together of similar conditions for the purposes of multi-centre studies. Difficulties arise in classification of the vasculitides due to considerable overlap of clinico-pathological features; for example, microscopic polyangiitis (MPA), Wegener's granulomatosis (WG) and Churg–Strauss syndrome (CSS) may all cause the identical renal lesion of necrotizing glomerulonephritis. The rationale for treatment often depends on the type of vasculitis and on the extent of organ involvement. Treatment may be similar for different types of disease. The lack of validated diagnostic criteria has, however, resulted in the application of classification criteria in their place, and has highlighted the limited usefulness of classification criteria in clinical practice. Classification systems should assist in the determination of therapy and prediction of outcomes, but have many limitations, which are discussed further in this review.