bluuebunny/crossref_metadata_2025 huggingface dataset:
Polyarticular disease
Authors: Adebajo Ade , Dunkley Lisa
Published: February 2014

Polyarticular disease is a commonly encountered musculoskeletal problem which regularly confronts clinicians as a diagnostic dilemma. Polyarticular disease is a musculoskeletal presentation in which more than four joints are affected by the disease. The classical rheumatological condition which presents as polyarticular disease is rheumatoid arthritis, although even this condition can very occasionally present with a mono- or oligoarticular onset. Polyarticular disease includes a wide range of musculoskeletal conditions including such disorders as polyarticular gout, the seronegative spondyloarthropathies, rheumatic fever, and systemic lupus erythematosus. This chapter emphasizes how through a careful history, thorough clinical examination and appropriate investigations, a definitive diagnosis can be made in a patient presenting clinically with polyarticular disease. General management principles for patients with polyarticular disease are also provided.
Pain and fatigue
Authors: McCabe Candy , Haigh Richard , Cohen Helen , Hewlett Sarah
Published: February 2014

Pain and fatigue are the prominent problems for those with a rheumatic disease, and are often underestimated by clinicians. Symptoms may fluctuate in quality and intensity over time and commonly will vary over the course of a day. For pain, clinical signs and symptoms will be dependent on the source of the pain and whether causative underlying pathology is identifiable or not. Fatigue may range from mild effects to total exhaustion and may include cognitive and emotional elements, with a complex, probably multicausal, pathway. Theoretical knowledge of potential mechanistic pathways for pain and fatigue should be used to inform assessment and treatment approaches. Best practice recommends a multidisciplinary and holistic treatment approach with the patient an active participant in the planning of their care, and self-management. Many patients with chronic musculoskeletal conditions will not achieve a pain-free or fatigue-free status. Medication use must therefore balance potential benefit against short- and long-term side effects. Rheumatology centres should offer specific fatigue and pain self-management support as part of routine care. Emphasis should be given to facilitating self-management strategies for both pain and fatigue to help the patient optimize their quality of life over years or a lifetime of symptoms. Interventions should include behaviour change and cognitive restructuring of pain/fatigue beliefs, as well as access to relevant self-help groups and charitable organizations. Referral for specialist advice from regional or national clinics on pain relief and management should be considered if pain interferes significantly with function or quality of life despite local interventions.
The limping child
Authors: Kimura Yukiko , Southwood Taunton R.
Published: February 2014

This chapter presents a systematic approach to evaluating the limping child, beginning with a careful history, then the physical examination, and proceeding to the musculoskeletal examination followed by targeted investigations. Tables with useful tips for differential diagnosis based on age and laboratory testing, as well as diagnostic algorithms, are presented.
The systemically unwell child
Authors: Ramanan Athimalaipet V. , Akikusa Jonathan D.
Published: February 2014

The systemically unwell child is a common clinical problem in paediatrics. In most cases the cause is infection, and the child will usually improve spontaneously or following appropriate therapy. When routine investigations fail to reveal an aetiology and the child remains unwell, the differential diagnoses should be broadened to include, among others, paediatric rheumatic diseases. This chapter provides a brief overview of these conditions focusing on key clinical features, common diagnostic pitfalls, and investigations important in their diagnosis. The important rheumatologic differentials of systemic illness in children according to the age at which they typically occur and a summary of the key clinical and laboratory features of these conditions are presented. Once rheumatologic differentials relevant to the age of the child under evaluation are identified, they can be refined based on knowledge of the incidence and clinical and laboratory features of the diseases concerned.
Skin
Authors: Griffiths Christopher , Foulkes Amy
Published: February 2014

Optimal rheumatological care involves a holistic approach to the patient. As rheumatologists frequently see dermatological manifestations of rheumatological disease, as well as cutaneous signs of drug toxicity, knowledge of how to approach the diagnosis and management of the patient with skin disease is essential. With many successful examples of joint rheumatology/dermatology clinics, the subsequent shared knowledge and management will improve the quality of life of patients with combined skin and joint disease. This chapter includes basic skin anatomy and morphological definitions, which facilitate accurate description of skin disease. Common differential diagnoses and common dermatological manifestations of rheumatological disease are discussed with appropriate options for management.
Gastrointestinal system
Authors: Rogler Gerhard
Published: February 2014

Rheumatic diseases and diseases of the gastrointestinal (GI) tract are connected in two ways. The extraintestinal manifestations of inflammatory GI diseases such as inflammatory bowel disease affect joints in up to one-third of patients. On the other hand, several rheumatic diseases such as vasculitis or systemic lupus erythematosus (SLE) induce a wide spectrum of gastrointestinal manifestations. The GI tract constitutes a huge area in contact with the environment. It is exposed to billions of food antigens, commensal bacteria, and potential pathogens. Some of those antigens are thought to play a role in the pathogenesis of rheumatic diseases. The intestinal barrier function and the gut immune system are tightly regulated, as on one hand tolerance for food antigens and the resident commensal flora needs to be maintained, and on the other hand pathogens need to be rapidly and effectively eliminated. Non-infectious, chronic inflammatory diseases of the small and large intestine with rheumatic manifestations have been well known for decades. Among the susceptibility genes for Crohn's disease and ulcerative colitis are some that also cause susceptibility to rheumatoid arthritis or SLE, indicating a shared susceptibility and overlapping pathological mechanisms. Subsequently, similar therapeutic principles have successfully been applied in autoimmune GI and rheumatological diseases such as steroids, immunosuppressants, and anti-TNF (tumour necrosis factor) antibodies.
Malignancy
Authors: Hamilton Jennifer , Kelly Clive
Published: February 2014

This chapter addresses the links between malignancy and rheumatic disease. It begins with a summary of rheumatological conditions associated with an increased risk of malignancy, and describes and discusses specific neoplasms associated with each rheumatic disorder. The present knowledge base is summarized in tabular form, describing the relative risks of different malignancies for each relevant rheumatic disease. The diseases featured include rheumatoid arthritis, primary Sjögren’s syndrome, scleroderma, dermatomyositis and systemic lupus.
The next section reviews the drugs used in present rheumatological practice known to be associated with malignancy, describing the specific established risks linked to each of the following agents: azathioprine, cyclophosphamide, ciclosporin, anti-tumour necrosis factor alpha (TNFα‎‎) agents, and mycophenolate mofetil. The evidence base and strength of these associations are summarized.
Finally we describe the musculoskeletal manifestations that arise as a consequence of underlying malignancy, considering bone pain, polymyalgia, arthropathy, and vasculitis as clinical presentations or complications of underlying neoplasia. This section also includes descriptions of less common rheumatic disorders that may also be associated with cancer, including erythema nodosum, Sweet’s syndrome, and pyoderma gangrenosum.
The eye
Authors: Petrushkin Harry , Stanford Miles
Published: February 2014

The ophthalmologist has a large part to play in the management of many rheumatological diseases. These diseases can cause a number of symptoms from mild ocular discomfort to sudden blindness. In addition, many rheumatological diseases have helpful ophthalmic signs, which can aid diagnosis.
This chapter has been written to help rheumatologists identify these signs and symptoms. We have started by summarizing the common pathology found in patients with rheumatological diseases (dry eye syndromes, conjunctivitis, episcleritis, scleritis, uveitis, and optic neuropathy). This has been arranged working backwards from the front of the eye towards the retina and optic nerve. The rheumatological conditions that give rise to ophthalmic signs (giant cell arteritis, systemic lupus erythematosus, polyarteritis nodosa, Wegner's granulomatosis, systemic sclerosis, rheumatoid arthritis, seronegative arthropathies, sarcoidosis, and Behçet’s disease) have then been summarized, including a section of paediatric conditions (juvenile idiopathic arthritis, spondyloarthropathies, and multisystemic illness). Finally, treatment regimes and recent guidelines have been covered for the screening of uveitis in juvenile idiopathic arthritis and the management of patients taking hydroxychloroquine.
We hope that both rheumatologists in training and consultants find this chapter a useful clinical aid, and that it encourages them to look closely for subtle signs that will help improve the management of their patients.
The kidney
Authors: Little Mark , Salama Alan
Published: February 2014

Kidney dysfunction is common in patients with rheumatological disease, be it secondary to renal (usually glomerular) involvement by a multisystem rheumatological disorder, renal impairment due to nephrotoxic medication use, or incidentally noted during a rheumatological work-up. It is therefore important for the rheumatologist to know how to assess kidney function biochemically and radiologically, to appreciate when an organ-threatening process is present, and to understand the basic steps to take in the event of acute kidney injury. This chapter reviews assessment of kidney function with respect to estimating excretory function, and the degree of proteinuria and haematuria. It provides an in-depth review of the causes, assessment, and management of acute kidney injury as encountered in rheumatological practice, and a summary of the causes and approach to chronic kidney disease.
Psychology
Authors: McBain Hayley , Cleanthous Sophie , Newman Stanton
Published: February 2014

Most chronic rheumatological conditions require major psychological adaptation, both at the time of diagnosis and throughout the illness. Patients have to take regular medications and may face major surgery. Not only do individuals have to come to terms with symptoms and varying treatments, but they have to adapt to altered life plans, reduced employment prospects, and uncertainty about the future course of the disease and its impact on their lives. It is therefore not surprising that rheumatic disease does not only affect a person’s psychological well-being but that these psychological factors can also impact upon the disease itself. Treatment, although primarily pharmacological and sometimes surgical, also includes a range of non-medical interventions including physiotherapy, pain management, weight-loss regimens, and self-management.
Design of clinical trials in rheumatology
Authors: Strand Vibeke , Sokolove Jeremy , Chu Alvina D.
Published: February 2014

Development of new therapies for rheumatic diseases requires a series of randomized controlled trials (RCTs) progressing from phase 1, 'first-in-human' to generate initial safety, pharmacokinetic (PK) and pharmacodynamic (PD) data; to phase 2, proof of concept for efficacy with safety and PK/PD data; and phase 3, designed to demonstrate definitive efficacy and safety to support regulatory approval. Important aspects of RCT designs include sample size estimations, treatment allocation, rescue, blinding, and statistical analyses of prespecified endpoints to preserve trial integrity. Over the past 15 years, significant progress has been made in the design of RCTs in rheumatoid arthritis (RA). Similarly, development and validation of composite outcome measures in psoriatic arthritis, ankylosing spondylitis, gout, and osteoarthritis have furthered trial design and treatment approvals. RCTs in systemic lupus erythematosus and other multisystem, heterogeneous diseases pose more challenges. Trial design will continue to evolve as promising therapies are introduced into the clinic.
Health economics
Authors: Merkesdal Sonja , Mau Wilfried
Published: February 2014

The economic burden of rheumatic diseases for society, various payers, and last but not least the individual patient has been increasingly recognized. In addition to the well-known impact of back pain and osteoarthritis, the upcoming new and expensive therapies have made this issue especially intriguing in the treatment of rheumatoid arthritis (RA). A mean international estimate of the total annual costs of RA, mainly consisting of direct resource consumption and indirect costs due to productivity losses relating to paid work, comes to about €5600. Other inflammatory rheumatologic diseases (ankylosing spondylitis, psoriatic arthritis, lupus erythematosus) generate similar costs.
The implementation of expensive biological drugs in rheumatic care has also led to the pressing need to determine the relation of their costs and clinical outcome (e.g. quality-adjusted life-years, QALYs) in order to compare different treatment strategies in defined patient groups. In RA the health-economic evidence for the cost-effectiveness of biologicals is already quite substantial in terms of treatment of early and advanced RA, as last option treatment of patients refractory to TNF inhibitors. Their cost-effectiveness as first line treatment is less clear. All biologicals have proved their cost-effectiveness in various settings depending on patient selection. It has been clearly demonstrated that adherence to the current guidelines, including monitoring of their effectiveness. leads to cost-effective scenarios. In TNF-refractory RA, abatacept and rituximab have proved to be economically favourable strategies.
Economic data on other inflammatory rheumatic entities is relatively sparse. Incomplete long-term and observational data are still the most prominent gaps in health-economic evidence relating to rheumatic disorders.
Comorbidities of rheumatic disease
Authors: Sokka Tuulikki , Puolakka Kari , Turesson Carl
Published: February 2014

All other diseases that coexist with a disease of interest are called comorbidities. Comorbidities in inflammatory rheumatic diseases may be associated with persistent inflammatory activity or disease-related organ damage, or may be related to medications. Lifestyle choices such as smoking or physical inactivity contribute to comorbidity. Patients with rheumatic diseases meet health professionals regularly and are more often tested for osteoporosis or cholesterol levels than individuals without rheumatic disease, which may contribute to a higher prevalence of some comorbidities. Comorbidities can also be unrelated to rheumatic diseases or their treatments. In this chapter, we discuss the impact of comorbidities to the patient. We emphasize the importance to review and manage comorbidities in usual daily rheumatology clinic, to improve outcomes of patients with rheumatic diseases.
Biologics registries
Authors: Isenberg David , Zink Angela
Published: February 2014

Double-blind controlled trials undertaken over the past two decades have established the short-term effectiveness and side-effect profile of biologic drugs for patients with rheumatoid arthritis and related diseases. However, the development of biologics registers to capture 'real-life experience' and explore long-term effectiveness and complications is equally important. In this chapter, we demonstrate how these registers have identified long-term joint benefits, a reduction in cardiovascular mortality, reassurance concerning fears about cancer development, and a balanced view of the risk of infection.
Environment
Authors: Holroyd Christopher R. , Harvey Nicholas C. , Edwards Mark H. , Cooper Cyrus
Published: February 2014

Musculoskeletal disease covers a broad spectrum of conditions whose aetiology comprises variable genetic and environmental contributions. More recently it has become clear that, particularly early in life, the interaction of gene and environment is critical to the development of later disease. Additionally, only a small proportion of the variation in adult traits such as bone mineral density has been explained by specific genes in genome-wide association studies, suggesting that gene-environment interaction may explain a much larger part of the inheritance of disease risk than previously thought. It is therefore critically important to evaluate the environmental factors which may predispose to diseases such as osteorthritis, osteoporosis, and rheumatoid arthritis both at the individual and at the population level. In this chapter we describe the environmental contributors, across the whole life course, to osteoarthritis, osteoporosis and rheumatoid arthritis, as exemplar conditions. We consider factors such as age, gender, nutrition (including the role of vitamin D), geography, occupation, and the clues that secular changes of disease pattern may yield. We describe the accumulating evidence that conditions such as osteoporosis may be partly determined by the early interplay of environment and genotype, through aetiological mechanisms such as DNA methylation and other epigenetic phenomena. Such studies, and those examining the role of environmental influences across other stages of the life course, suggest that these issues should be addressed at all ages, starting from before conception, in order to optimally reduce the burden of musculoskeletal disorders in future generations.
Epigenetics
Authors: Gay Steffen , Neidhart Michel
Published: February 2014

In higher eukaryotic organisms epigenetic modifications are crucial for proper chromatin folding and thereby proper regulation of gene expression. Epigenetics include DNA methylation, histone modifications, and microRNAs. First described in tumors, the involvement of aberrant epigenetic modifications has been reported also in other diseases, i.e. metabolic, psychiatric, inflammatory, and autoimmune. Deregulation of epigenetic mechanisms occurred in patients with rheumatoid arthritis, systemic lupus erythematosus, and scleroderma. Many questions remain: e.g. what is the cause of these epigenetic changes and how can we interfere in the pathological process? Here we discuss whether supplementation with methyl donors could represent a novel therapeutic concept for such diseases.
Genetics of spondyloarthropathies
Authors: Brown Matthew
Published: February 2014

Spondyloarthropathies are a diverse group of conditions, of which ankylosing spondylitis is the prototypic disease, with shared clinical features, genetic risk factors, and histopathological characteristics. These conditions are highly familial and heritable. Several genes have been associated with spondyloarthropathies, with genes in the IL-23 signalling pathway being shared by the major types of spondyloarthritis. These discoveries have already led to the development and successful clinical introduction of novel treatments for psoriasis and psoriatic arthritis, and major advances in our understanding of the pathogenesis of the conditions. Many more genes remain to be identified which are involved in these common conditions; identifying these genes is likely to be highly informative as to their causes.
Genetics of connective tissue diseases
Authors: Lewis Myles , Vyse Tim
Published: February 2014

The advent of genome-wide association studies (GWAS) has been an exciting breakthrough in our understanding of the genetic aetiology of autoimmune diseases. Substantial overlap has been found in susceptibility genes across multiple diseases, from connective tissue diseases and rheumatoid arthritis (RA) to inflammatory bowel disease, coeliac disease, and psoriasis. Major technological advances now permit genotyping of millions of single nucleotide polymorphisms (SNPs). Group analysis of SNPs by haplotypes, aided by completion of the Hapmap project, has improved our ability to pinpoint causal genetic variants. International collaboration to pool large-scale cohorts of patients has enabled GWAS in systemic lupus erythematosus (SLE), systemic sclerosis and Behçet's disease, with studies in progress for ANCA-associated vasculitis. These 'hypothesis-free' studies have revealed many novel disease-associated genes. In both SLE and systemic sclerosis, identified genes map to known pathways including antigen presentation (MHC, TNFSF4), autoreactivity of B and T lymphocytes (BLK, BANK1), type I interferon production (STAT4, IRF5) and the NFκ‎B pathway (TNIP1). In SLE alone, additional genes appear to be involved in dysregulated apoptotic cell clearance (ITGAM, TREX1, C1q, C4) and recognition of immune complexes (FCGR2A, FCGR3B). Future developments include whole-genome sequencing to identify rare variants, and efforts to understand functional consequences of susceptibility genes.
Putative environmental triggers for connective tissue diseases include infectious agents, especially Epstein-Barr virus; cigarette smoking; occupational exposure to toxins including silica; and low vitamin D, due to its immunomodulatory effects. Despite numerous studies looking at toxin exposure and connective tissue diseases, conclusive evidence is lacking, due to either rarity of exposure or rarity of disease.
Genetics of osteoarthritis
Authors: MacGregor Alex , Valdes Ana , Williams Frances M. K.
Published: February 2014

In this chapter we outline the approaches which have been adopted to identify genetic variants predisposing to osteoarthritis (OA), a condition long recognized as having a heritable component. Such routes to their identification include examining mendelian traits in which OA is a feature, candidate gene studies based on knowledge of OA pathobiology, linkage analysis in related individuals, and, more recently, genome-wide association studies in large samples of unrelated individuals. It is increasingly evident that the main symptom deriving from OA—notably joint pain—also has a genetic basis but this is differs from that underlying OA. Variants convincingly shown to predispose to OA lie in the GDF5 and MCF2L genes and in the chr7 cluster mapping to the COG5 gene, in addition to the ASPN gene in Asian populations. Those associated with pain in OA include TRPV1 and PACE4. Epigenetic influences are also being explored in both the pathogenesis of OA and the variation of pain processing.
Genetics of chronic musculoskeletal pain
Authors: Holliday Kate L. , Thomson Wendy , McBeth John
Published: February 2014

Chronic pain disorders are prevalent and a large burden on health care resources. Around 10% of the general population report chronic widespread pain, which is the defining feature of fibromyalgia. Fibromyalgia is a poorly understood idiopathic disorder which is also characterized by widespread tenderness and commonly occurs with comorbid mood disorders, fatigue, sleep disturbance, and cognitive dysfunction.
A role for genetics in chronic pain disorders has been identified by twin studies, with heritability estimates of around 50%. Susceptibility genes for chronic pain are likely to be involved in pain processing or the psychological component of these disorders. A number of genes have been implicated in influencing how pain is perceived due to mutations causing monogenic pain disorders or an insensitivity to pain from birth. The role of common variation, however, is less well known. The findings from human candidate gene studies of musculoskeletal pain to date are discussed. However, the scope of these studies has been relatively limited in comparison to other complex conditions.
Identifying susceptibility loci will help to determine the biological mechanisms involved and potentially new therapeutic targets; however, this is a challenging research area due to the subjective nature of pain and heterogeneity in the phenotype. Using more quantitative phenotypes such as experimental pain measures may prove to be a more fruitful strategy to identify susceptibility loci. Findings from these studies and other potential approaches are discussed.
Measuring movement and gait
Authors: Hooper Lindsey , Taylor Mark , Edwards Christopher
Published: February 2014

Measuring movement and gait is an important part of assessing the effect of rheumatological disorders on a patient’s ability to perform tasks of daily living and to record changes of function associated with treatment. Movement requires a coordinated set of actions, the study of which is termed biomechanics. The way in which joints and related soft tissues function together affects how movement is achieved. Impaired movement can therefore be an important indication of joint or tissue pathology, or can itself lead to pathology. This chapter presents the principles of movement assessment and discusses how these can be applied within rheumatology. A number of assessment methods for the lower limb and gait are discussed, ranging from the clinical evaluation of movement to digital three-dimensional motion analysis. An accompanying reference guide of normal ranges of motion for the lower limb is presented. The relevance and interpretation of biomechanical findings within a rheumatological context is discussed, with osteoarthritis of the knee considered as a clinical example throughout.
Innate vs acquired immunity
Authors: Voll Reinhard E. , Bröker Barbara M.
Published: February 2014

The innate and the adaptive immune system efficiently cooperate to protect us from infections. The ancient innate immune system, dating back to the first multicellular organisms, utilizes phagocytic cells, soluble antimicrobial peptides, and the complement system for an immediate line of defence against pathogens. Using a limited number of germline-encoded pattern recognition receptors including the Toll-like, RIG-1-like, and NOD-like receptors, the innate immune system recognizes so-called pathogen-associated molecular patterns (PAMPs). PAMPs are specific for groups of related microorganisms and represent highly conserved, mostly non-protein molecules essential for the pathogens' life cycles. Hence, escape mutants strongly reduce the pathogen's fitness. An important task of the innate immune system is to distinguish between harmless antigens and potentially dangerous pathogens. Ideally, innate immune cells should activate the adaptive immune cells only in the case of invading pathogens.
The evolutionarily rather new adaptive immune system, which can be found in jawed fish and higher vertebrates, needs several days to mount an efficient response upon its first encounter with a certain pathogen. As soon as antigen-specific lymphocyte clones have been expanded, they powerfully fight the pathogen. Importantly, memory lymphocytes can often protect us from reinfections. During the development of T and B lymphocytes, many millions of different receptors are generated by somatic recombination and hypermutation of gene segments making up the antigen receptors. This process carries the inherent risk of autoimmunity, causing most inflammatory rheumatic diseases. In contrast, inadequate activation of the innate immune system, especially activation of the inflammasomes, may cause autoinflammatory syndromes.
Cellular side of acquired immunity (T cells)
Authors: Eljaafari Assia , Miossec Pierre
Published: February 2014

The adaptive T-cell response represents the most sophisticated component of the immune response. Foreign invaders are recognized first by cells of the innate immune system. This leads to a rapid and non-specific inflammatory response, followed by induction of the adaptive and specific immune response. Different adaptive responses can be promoted, depending on the predominant effector cells that are involved, which themselves depend on the microbial/antigen stimuli. As examples, Th1 cells contribute to cell-mediated immunity against intracellular pathogens, Th2 cells protect against parasites, and Th17 cells act against extracellular bacteria and fungi that are not cleared by Th1 and Th2 cells. Among the new subsets, Th22 cells protect against disruption of epithelial layers secondary to invading pathogens. Finally these effector subsets are regulated by regulatory T cells. These T helper subsets counteract each other to maintain the homeostasis of the immune system, but this balance can be easily disrupted, leading to chronic inflammation or autoimmune diseases. The challenge is to detect early changes in this balance, prior to its clinical expression. New molecular tools such as microarrays could be used to determine the predominant profile of the immune effector cells involved in a disease process. Such understanding should provide better therapeutic tools to counteract deregulated effector cells.
Synovial pathology
Authors: Pitzalis Costantino , Humby Frances , Seed Michael P.
Published: February 2014

Synovial pathology is seen in a variety of disease states, including rheumatoid arthritis (RA), osteoarthritis (OA), psoriatic arthritis, and systemic lupus erythmatosus (SLE). This chapter highlights recent advances that characterize the cellular composition of these tissues according to surface markers and chemokine and cytokine expression, and describes synovial functional status and response to therapeutics. In RA, after initiation, pannus migrates over and under cartilage, and into subchondral bone, in a destructive process. Cartilage-pannus junction (CPJ) is characterized as invasive or 'quiescent' or 'indistinct'. Invasive CPJ can comprise macrophages, fibroblast-like synoviocytes (FLS), mast cells, and/or neutrophils. CPJ activity is related to the state of activation of the overlying subintima. Subintimal inflammation can be graded to a variety of degrees (I–IV) according to established criteria and is illustrated. In some RA synovia, cellular aggregates organize into ectopic lymphoid structures (ELS) through the expression of lymphorganogenic signals, to exhibit T- or B-cell zones accompanied by dendritic cells and lymphangiogenesis. ELS synthesize rheumatoid factor (RF) and anti-citrullinated peptide antibodies (ACAP), considered to be indicative of aggressive disease. The selective cellular expression of macrophage and dendritic cell chemokines and cytokines such as TNF, GMCSF, TGFβ‎, IL-1, IL-6, IL-23, and chemokines can be seen in synovia, to form a regulated and cooperative environment that sustains the cellular organization and pathological function. Important to this process are FLS and CD68+ macrophages. CD68 expression correlates with disease severity and can be useful as a surrogate marker of disease modifying activity of therapeutics, such as anti-TNF and anti-B-cell biologics.
Enthesitis
Authors: Rudwaleit Martin
Published: February 2014

Enthesitis is one of the key manifestations of spondyloarthritides (SpA) including ankylosing spondylitis (AS) and psoriatic arthritis. Enthesitis can occur alone or in combination with peripheral arthritis, sacroiliitis, or spondylitis. The inflammatory process is typically located at the insertion of the enthesis or ligament to bone, often resulting in osteitis as well. Because of its anatomical and functional complexity the term 'enthesis organ' has been coined. Biomechanical stress applied to the enthesis seems to play an important role for the occurrence of enthesitis in genetically predisposed individuals. Ultrasound imaging of peripheral entheses reveals enthesis abnormalities including entheseal calcification, bony erosion, or bony proliferation. Power Doppler signals demonstrating increased vascularization of inflamed entheses at the insertional site appear to be the most characteristic finding for enthesitis, yet study results are conflicting. Enthesitis-related osteitis and enthesitis at the spine is best visualized by MRI. Enthesitis may resolve spontaneously or may run a chronic course. Standard treatment includes local steroid injections, non-steroidal anti-inflammatory drugs (NSAIDs), and physical therapy. There is little evidence for the efficacy of disease-modifying anti-rheumatic drugs (DMARDs) in enthesitis. In contrast, anti-TNF agents have proven efficacy, and their use in treatment-resistant enthesitis is recommended in the Assessment of SpondyloArthritis international Society (ASAS)/European League Against Rheumatism (EULAR) recommendations for the management of AS and axial SpA and in the EULAR recommendations for psoriatic arthritis.
Joint biochemistry
Authors: Pap Thomas , Korb Adelheid , Heitzmann Marianne , Bertrand Jessica
Published: February 2014

Synovial joints are composed of different morphological structures that have their distinct cellular and biochemical properties. Articular cartilage and synovial membrane are key components of synovial joints and show a number of peculiarities that makes them different from other tissues in our body. An in-depth knowledge of these structural and biochemical peculiarities is not only important for understanding key features of articular function but also provides explanations for important characteristics of both degenerative and inflammatory joint diseases. This chapter reviews the structure and biochemical composition of cartilage and synovium and points to important links between physiology and pathological conditions, particularly arthritis.
Pain neurophysiology
Authors: Schaible Hans-Georg , Straub Rainer H.
Published: February 2014

Physiological pain is evoked by intense (noxious) stimuli acting on healthy tissue functioning as a warning signal to avoid damage of the tissue. In contrast, pathophysiological pain is present in the course of disease, and it is often elicited by low-intensity stimulation or occurs even as resting pain. Causes of pathophysiological pain are either inflammation or injury causing pathophysiological nociceptive pain or damage to nerve cells evoking neuropathic pain. The major peripheral neuronal mechanism of pathophysiological nociceptive pain is the sensitization of peripheral nociceptors for mechanical, thermal and chemical stimuli; the major peripheral mechanism of neuropathic pain is the generation of ectopic discharges in injured nerve fibres. These phenomena are created by changes of ion channels in the neurons, e.g. by the influence of inflammatory mediators or growth factors. Both peripheral sensitization and ectopic discharges can evoke the development of hyperexcitability of central nociceptive pathways, called central sensitization, which amplifies the nociceptive processing. Central sensitization is caused by changes of the synaptic processing, in which glial cell activation also plays an important role. Endogenous inhibitory neuronal systems may reduce pain but some types of pain are characterized by the loss of inhibitory neural function. In addition to their role in pain generation, nociceptive afferents and the spinal cord can further enhance the inflammatory process by the release of neuropeptides into the innervated tissue and by activation of sympathetic efferent fibres. However, in inflamed tissue the innervation is remodelled by repellent factors, in particular with a loss of sympathetic nerve fibres.
Autoimmune serology
Authors: Hamann Philip , McHugh Neil
Published: February 2014

Autoimmune serology has become central in the characterization of many rheumatic conditions and in many cases the presence of an autoantibody (e.g. anti-citrullinated peptide, rheumatoid factor, ANCA, ANA, ENA, anti-phospholipid antibody), may form part of the diagnostic criteria. Increasingly, as pathogenic mechanisms are derived, the role of these autoantibodies is becoming better understood. This chapter covers the key techniques (immunoflourescence, immunodiffusion, ELISA, immunoblotting, immunoprecipitation) used in autoantibody detection as well as the clinico-pathological significance of a positive result.
Limb anatomy and medical imaging
Authors: Benjamin Mike , McGonagle Dennis , Miguel Maribel I. , Bong David A. , Möller Ingrid
Published: February 2014

This chapter provides a generalized framework for helping the clinician to understand basic principles of functional anatomy in the limbs in relation to medical imaging, particularly ultrasonography (US). Certain basic design principles that are evident in the limbs are explained: for example, that larger muscles lie proximally, and that tendons are more numerous and longer distally. While the upper limb is ultimately geared to moving the hand with ease and precision in three-dimensional space, the lower limb is both an organ of propulsion and a column supporting body weight. It is important to note that when the foot is on the ground this has an important influence on muscle function. Fundamental principles of muscle design and action are explained, including the distinction between prime movers, antagonists, synergists, and fixators; the fact that movements and not muscles are represented in the cerebral cortex; the all-or-nothing principle of fibre contraction; the modifying influence of gravity on muscle action; and issues relating to fibre architecture. The less appreciated functions of tendons are included and the difference between an enthesis and an enthesis organ is explained. The similar appearance of nerves and tendons in dissections and even in MRI and US images is explained and the importance of fascia is highlighted—particularly its role as an 'ectoskeleton'. Brief mention is made of adipose tissue and blood vessels, and planes of movement between adjacent structures are described in order to inform the ultrasonographer who deals with structures in real time.
Ultrasound
Authors: Kane David , Platt Philip
Published: February 2014

Musculoskeletal ultrasound (MSUS) is rapidly becoming a standard part of many rheumatologists' daily clinical practice. MSUS is safe, increasingly widely available, relatively low cost, non-invasive, and hence very acceptable to the patient. Current problems with availability of training, mentoring, and accreditation procedures need to be overcome for MSUS to reach its full potential for rheumatologists.
MSUS is capable of improving clinical diagnosis and the accuracy of intervention. MSUS is more sensitive than clinical examination in the detection of synovitis and effusion and is capable of rapid targeted assessment of widely spaced joints coupled with clinical correlation.
MSUS has advantages over other imaging modalities; the ability to display dynamic real-time movement makes it the imaging modality of choice for tendon problems. It is significantly more sensitive than plain radiology in the demonstration of early erosive changes, and although its sensitivity is less than that of MRI for the detection of erosions it is far more practical, timely, and available. The combination of sensitivity in detection of synovitis, tenosynovitis, and erosions makes it an ideal imaging modality in the context of an early arthritis clinic. Power Doppler has been shown to be an effective way of evaluating synovitis and hence is of value in early diagnosis and monitoring of inflammatory arthritides.
The accuracy of placement of local injection therapies is enhanced by MSUS, and it significantly increases the diagnostic success rate of aspiration of joints and bursas. The flexibility of ultrasound as a tool for rheumatologists is shown by its application in the assessment of vasculitides, peripheral nerve pathology, salivary glands, and skin lesions.
Magnetic resonance imaging
Authors: Balamoody S. , Marzo-Ortega Helena , O’Connor Philip J.
Published: February 2014

Magnetic resonance imaging (MRI) is a highly valuable tool in the assessment of the musculoskeletal disorders, complementing other modalities such as plain radiography and ultrasound. This chapter provides an overview of the different utilities of MRI, both in the clinical management of rheumatic conditions and in the setting of a research study. A simplified description of the major principles of MRI is provided for the rheumatologist. The features of the major arthritides are discussed, including a description of how MRI has helped to increase understanding of the pathogenesis of these diseases. New concepts for disease classification are now being defined to include MRI criteria in conditions such as spondyloarthropathy. There is increasing scope for the role of MRI in detecting early arthritis, the assessment of undifferentiated arthritis, and as a biomarker for disease incidence and progression within the research setting. Ongoing technological advances in MRI, including functional and whole-body MRI, will no doubt further our understanding of arthritis and play an increasing role in guiding the management of rheumatological conditions.
Computed tomography
Authors: Hide Geoff , Humphries Jennifer
Published: February 2014

Computed tomography (CT), along with its cross-sectional partner MRI, continues to evolve apace. Although MRI retains the larger role in the musculoskeletal system due to its unparalleled soft tissue contrast and, not least, its lack of ionizing radiation, CT offers significant advantages in many areas. Imaging acute trauma is more rapid with CT, allowing 'whole body' assessment of patients following polytrauma, and CT is more useful than MRI in demonstrating the configuration of fractures, aiding surgical planning. CT can clearly identify cortical bone and areas of calcification, making the diagnosis of tarsal coalitions straightforward and facilitating the diagnosis and characterization of bone tumours such as osteoid osteoma and chondroid lesions. CT arthrography supplements standard imaging with intra-articular contrast to allow the detection of subtle joint abnormalities, and CT can demonstrate needles precisely within bone and soft tissue to enable the performance of complex image-guided procedures. Developments in CT have been especially rapid in the past decade and although this has particularly impacted on cardiac imaging, other areas of medicine, including rheumatology, have benefited. High multislice scanners can obtain data for a volume of tissue allowing reconstruction of slices with exceptional detail in any plane, and can rapidly image large areas of the body such as the spine. CT is responsible for a large proportion of the population's medical radiation exposure. Although techniques allowing reduction in dose continue to advance, radiologists and referrers retain responsibility to ensure that requests for CT examinations are necessary and justifiable.
Cyclooxygenase inhibitors
Authors: Hinz Burkhard , Brune Kay
Published: February 2014

Cyclooxygenase (COX) inhibitors are widely used to relieve musculoskeletal pain. COX inhibitors are a group of heterogenous substances including non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol (acetaminophen). Moreover, various selective cyclooxygenase-2 (COX-2) inhibitors with improved gastrointestinal tolerability as compared with conventional NSAIDs have been established for symptomatic pain treatment in recent years. This chapter addresses the pharmacology of all of these drugs with particular emphasis on their rational use based on their diverse pharmacokinetic characteristics and adverse drug reaction profiles. Referring to the current debate, cardiovascular side effects associated with the long-term use of COX-2 inhibitors and NSAIDs as well as novel insights into the safety profile of paracetamol are discussed.
Immunosuppressants
Authors: Ledingham Joanna , Westlake Sarah
Published: February 2014

A variety of immunosuppressants and disease-modifying anti-rheumatic drugs (DMARDs) with beneficial effects on inflammatory rheumatic diseases have been identified over the last 50 years. Their use for these conditions is now well established and has led to considerable improvements in disease management. Their use earlier in the inflammatory disease process and the use of combination therapies have also led to significantly improved patient outcomes.
This chapter provides an overview of the immunosuppressants and DMARDs used to treat rheumatic disease, focusing particularly on those in common use and with the best evidence for efficacy. The mechanism of action, toxicity, and clinical indications are outlined. Tips for practical prescribing and for monitoring for potential complications are also included.
Anti-cytokine biologics
Authors: Östör Andrew J. K.
Published: February 2014

Following the introduction of biologic disease-modifying agents into the therapeutic armoury against rheumatoid arthritis (RA) a dramatic shift has occurred in the natural history of the condition. Improvements have been seen not only in the signs and symptoms of disease but also in radiographic progression, functionality, quality of life, and productivity. Anti-cytokine biologics have been at the forefront of this management ’revolution’ as tumour necrosis factor (TNF) antagonists were the first to be trialled in this setting, leading to a profound alteration in the treatment paradigm. In addition to the five anti-TNF biologics (infliximab, etanercept, adalimumab, certolizumab, golimumab), IL-6 blockade with tocilizumab has also been shown to be effective in RA. Antagonism of IL-1 with anakinra, however, has not been as successful.
In order to optimize outcomes anti-cytokine biologics are being used earlier in the management of RA. Trial data has shown that they work as well, if not better, in early disease, to achieve disease remission. Safety remains of paramount importance, particularly the increased risk of infection, which has been seen in clinical trials and in biologic registries. The side-effect profile is favourable overall, however. A number of novel anti-cytokine biologics are currently being trialled potentially paving the way for ’individualized’ therapy.
Rituximab and abatacept
Authors: Isaacs John D. , Brown Philip M.
Published: February 2014

Two biologics that target cells have been licensed to treat rheumatoid arthritis (RA). Rituximab is a chimeric monoclonal antibody (mAb) against CD20 that depletes B cells; abatacept is a soluble form of CTLA-4 that blocks costimulation and interferes with T-cell function. Both drugs alleviate signs and symptoms of RA and have been shown to retard radiographic progression. Rituximab is licensed for use following failure of tumour necrosis factor (TNF) blockade whereas abatacept's licence permits it use as a first-line biologic. In the United Kingdom, however, the National Institute for Health and Clinical Excellence (NICE) restricts the use of abatacept to patients who develop adverse effects with rituximab or in whom rituximab is contraindicated. As with other biologics, the use of either drug is associated with an enhanced risk of serious infections; additionally, rituximab in particular can cause infusion reactions, requiring prophylaxis. By targeting cells that are central to RA pathogenesis, these drugs provide important additional therapeutic options for patients with RA.