Showing papers in "Best Practice & Research: Clinical Rheumatology in 2014"
TL;DR: The purpose of this review is to illustrate how each of these factors interact together to instigate incident OA as well as to outline the need for ongoing epidemiologic studies for the future prevention of both incident and progressive OA.
Abstract: Osteoarthritis (OA) is a leading cause of disability and its incidence is rising due to increasing obesity and an ageing population. Risk factors can be divided into person-level factors, such as age, sex, obesity, genetics, race/ethnicity and diet, and joint-level factors including injury, malalignment and abnormal loading of the joints. The interaction of these risk factors is complex and provides a challenge to the managing physician. The purpose of this review is to illustrate how each of these factors interact together to instigate incident OA as well as to outline the need for ongoing epidemiologic studies for the future prevention of both incident and progressive OA. It is only by understanding the impact of this disease and the modifiable risk factors that we will be able to truly target public health prevention interventions appropriately.
1,504 citations
TL;DR: This chapter summarises the global and regional prevalence, disability and overall burden and costs for the common musculoskeletal disorders including low back and neck pain, hip and knee osteoarthritis, rheumatoid arthritis, gout and a remaining combined group of other MSK conditions.
Abstract: This chapter summarises the global and regional prevalence, disability (Years Lived with Disability (YLDs)) and overall burden (Disability Adjusted Life Years (DALYs)) and costs for the common musculoskeletal disorders including low back and neck pain, hip and knee osteoarthritis, rheumatoid arthritis, gout, and a remaining combined group of other MSK conditions. The contribution of the role of pain in disability burden is introduced. Trends over time and predictions of increasing MSK disability with demographic changes are addressed and the particular challenges facing the developing world are highlighted.
406 citations
TL;DR: An approach to biomarker validation and qualification for OA clinical trials that has recently commenced with the Foundation of NIH OA Biomarkers Consortium study cosponsored by the Osteoarthritis Research Society International (OARSI).
Abstract: Historically disease knowledge development and treatment innovation in osteoarthritis (OA) has been considered to be slow One of the many reasons purported as responsible for this slow pace has been the alleged lack of valid and responsive biomarkers to ascertain efficacy, which itself has been dependent upon the slow evolution of the understanding of the complex nature of joint tissue biology This narrative review outlines the rationale for why we need OA biomarkers with regard to biomarker validation and qualification The main biomarkers in current development for OA are biochemical and imaging markers We describe an approach to biomarker validation and qualification for OA clinical trials that has recently commenced with the Foundation of NIH OA Biomarkers Consortium study cosponsored by the Osteoarthritis Research Society International (OARSI) With this approach we endeavor to identify, develop, and qualify biological markers (biomarkers) to support new drug development, preventive medicine, and medical diagnostics for osteoarthritis
164 citations
TL;DR: It is important to note that while the magnitude of exercise benefits may be considered small to moderate, these effects are comparable to reported estimates for simple analgesics and oral nonsteroidal anti-inflammatory drugs for OA pain but exercise has much fewer side effects.
Abstract: Exercise is recommended for the management of osteoarthritis (OA) in all clinical guidelines irrespective of disease severity, pain levels, and functional status. For knee OA, evidence supports the benefits of various types of exercise for improving pain and function in the short term. However, there is much less research investigating the effects of exercise in patients with OA at other joints such as the hip and hand. It is important to note that while the magnitude of exercise benefits may be considered small to moderate, these effects are comparable to reported estimates for simple analgesics and oral nonsteroidal anti-inflammatory drugs for OA pain but exercise has much fewer side effects. Exercise prescription should be individualized based on assessment findings and be patient centered involving shared decision making between the patient and clinician. Given that patient adherence to exercise declines over time, appropriate attention should be pain as reduced adherence attenuates the benefits of exercise. Given this, barriers and facilitators to exercise should be identified and strategies to maximize long-term adherence to exercise implemented.
161 citations
TL;DR: The evidence for various cytokines in the initiation and pathogenesis of MAS are examined, how new biologic therapies may alter the risk of MAS is discussed and how cytokine-directed therapy could serve as novel treatment modalities.
Abstract: Macrophage activation syndrome (MAS) is an episode of overwhelming inflammation that occurs most commonly in children with systemic juvenile idiopathic arthritis (SJIA). It is characterized by expansion and activation of T lymphocytes and hemophagocytic macrophages and bears great similarity to hemophagocytic lymphohistiocytosis (HLH). This disorder has substantial morbidity and mortality, and there is frequently a delay in recognition and initiation of treatment. Here, we will review what is known about the pathogenesis of MAS and, in particular, its similarities to HLH. The development of MAS is characterized by a cytokine storm, with the elaboration of numerous pro-inflammatory cytokines. We will examine the evidence for various cytokines in the initiation and pathogenesis of MAS and discuss how new biologic therapies may alter the risk of MAS. Finally, we will review current treatment options for MAS and examine how cytokine-directed therapy could serve as novel treatment modalities.
123 citations
TL;DR: It is critical that MSK initiatives in developing countries integrate well with health systems, rather than being stand-alone, and better inclusion of MSK conditions will avoid doubling of efforts and wasting of resources, and will help to promote a more streamlined, cost-effective approach.
Abstract: Musculoskeletal (MSK) conditions cause an enormous global burden, and this is dramatically increasing in developing countries, particularly due to rapidly ageing populations and increasing obesity. Many of the global non-communicable disease (NCD) initiatives need to expand beyond the traditional ‘top four’ NCD groups by incorporating MSK diseases. It is critical that MSK initiatives in developing countries integrate well with health systems, rather than being stand-alone. A better inclusion of MSK conditions will avoid doubling of efforts and wasting of resources, and will help to promote a more streamlined, cost-effective approach. Other key opportunities for action include the following: ensuring the principles of ‘development effectiveness’ are met; strengthening leadership and commitment; building the research, information and evidence base; and reducing the incidence and disability of MSK conditions through better prevention. Each of these elements is necessary to mitigate and reduce the growing burden from the MSKs.
107 citations
TL;DR: The roles and limitations of different imaging modalities for clinical practice and research in OA are described, with a focus on radiography and MRI and an emphasis on the knee joint.
Abstract: Osteoarthritis (OA) is the most prevalent joint disorder with no approved disease-modifying treatment available. The importance of imaging in assessing all joint structures involved in the disease process, including articular cartilage, meniscus, subarticular bone marrow, and synovium for diagnosis, prognostication, and follow-up, has been well recognized. In daily clinical practice, conventional radiography is still the most commonly used imaging technique for the evaluation of a patient with known or suspected OA and radiographic outcome measures are still the only approved end point by regulatory authorities in clinical trials. The ability of magnetic resonance imaging (MRI) to visualize all joint structures in three-dimensional fashion including tissue ultrastructure has markedly deepened our understanding of the natural history of the disease. This article describes the roles and limitations of different imaging modalities for clinical practice and research in OA, with a focus on radiography and MRI and an emphasis on the knee joint.
103 citations
TL;DR: Using the concept of frailty to identify older people with musculoskeletal problems as being at the risk of a poor outcome assists in treatment planning and is likely to become more important as effective pharmacological treatments for sarcopenia emerge.
Abstract: Frailty in older people is associated with a vulnerability to adverse events. While ageing is associated with a loss of physiological reserves, identifying those with the syndrome of frailty has the potential to assist clinicians to tailor treatments to those at the risk of future decline into disability with an increased risk of complications, morbidity and mortality. Sarcopenia is a key component of the frailty syndrome and on its own puts older people at risk of fragility fractures; however, the clinical syndrome of frailty affects the musculoskeletal and non-musculoskeletal systems. Hip fractures are becoming a prototype condition in the study of frailty. Following a hip fracture, many of the interventions are focused on limiting mobility disability and restoring independence with activities of daily living, but there are multiple factors to be addressed including osteoporosis, sarcopenia, delirium and weight loss. Established techniques of geriatric evaluation and management allow systematic assessment and intervention on multiple components by multidisciplinary teams and deliver the best outcomes. Using the concept of frailty to identify older people with musculoskeletal problems as being at the risk of a poor outcome assists in treatment planning and is likely to become more important as effective pharmacological treatments for sarcopenia emerge. This review will focus on the concept of frailty and its relationship with functional decline, as well as describing its causes, prevalence, risk factors, potential clinical applications and treatment strategies.
94 citations
TL;DR: Health system and local implementation strategies to improve consumer outcomes are outlined, including supporting access to multidisciplinary teams, improving access for vulnerable populations and levering digital technologies to support access and self-management.
Abstract: With musculoskeletal conditions now identified as the second highest cause of the morbidity-related global burden of disease, models of care for the prevention and management of disability related to musculoskeletal conditions are an imperative. Musculoskeletal models of care aim to describe how to operationalise evidence-based guidelines for musculoskeletal conditions and thus support implementation by clinical teams and their health systems. This review of models of care for musculoskeletal pain conditions, osteoarthritis, rheumatoid arthritis, osteoporosis and musculoskeletal injuries and trauma outlines health system and local implementation strategies to improve consumer outcomes, including supporting access to multidisciplinary teams, improving access for vulnerable populations and levering digital technologies to support access and self-management. However, the challenge remains of how to inform health system decision-makers and policy about the human and fiscal benefits for broad implementation across health services. Recommendations are made for potential solutions, as well as highlighting where further evidence is required.
93 citations
TL;DR: In this article, the effects of α7nAChR activation in an animal model of rheumatoid arthritis was studied and it was shown that stimulation of the cholinergic anti-inflammatory pathway by vagus nerve stimulation improved experimental arthritis.
Abstract: There has been a marked improvement in the treatment of rheumatoid arthritis (RA), but most patients do not achieve disease remission. Therefore, there is still a need for new treatments. By screening an adenoviral short hairpin RNA library, we discovered that knockdown of the nicotinic acetylcholine receptor type 7 (α7nAChR) in RA fibroblast-like synoviocytes results in an increased production of mediators of inflammation and degradation. The α7nAChR is intimately involved in the cholinergic anti-inflammatory pathway (CAP). This led us to study the effects of α7nAChR activation in an animal model of RA, and we could show that this resulted in reduced arthritis activity. Accordingly, stimulation of the CAP by vagus nerve stimulation improved experimental arthritis. Conversely, we found aggravation of arthritis activity after unilateral cervical vagotomy as well as in α7nAChR-knockout mice. Together, these data provided the basis for exploration of vagus nerve stimulation in RA patients as a novel anti-inflammatory approach.
83 citations
TL;DR: A historical evolution of the concept of SpA is provided, from the Rome Criteria to the ASAS criteria, current issues and barriers with the use of AS AS criteria, and the work that still needs to be done moving forward are provided.
Abstract: The term spondyloarthritis (SpA) encompasses a group of diseases characterized by inflammation in the spine and in the peripheral joints, and other clinical features such as uveitis, dactylitis, psoriasis, inflammatory bowel disease, and association with human leukocyte antigen (HLA) B27. The spectrum of SpA encompasses axial spondyloarthritis (axSpA) and peripheral spondyloarthritis including psoriatic arthritis (PsA), reactive arthritis (ReA), and inflammatory bowel disease-associated arthritis. In recent years, there has been tremendous progress in understanding the natural history and pathogenetic mechanisms underlying SpA leading to the development of effective treatments. It has become imperative to identify the disease early, and accurately, to avail patients of effective treatments in a safe manner. The development of the Assessment of SpondyloArthritis International Society (ASAS) classification criteria has been a welcome advance in this regard. This article provides a historical evolution of the concept of SpA, from the Rome Criteria to the ASAS criteria, current issues and barriers with the use of ASAS criteria, and the work that still needs to be done moving forward.
TL;DR: The complex relationship between SpA pathogenesis and gut microbes is considered, with a discussion of how manipulation of the gut microbiota itself may be a promising future target for SpA therapy.
Abstract: The intestinal microbiota is firmly implicated not only in the pathogenesis of inflammatory bowel disease (IBD) but increasingly also in the development of inflammation at extraintestinal tissue sites. Significant clinical, genetic, immunological, and microbiological overlap exists between IBD and spondyloarthritis (SpA), which indicates that pathophysiological mechanisms are shared between these diseases and may center on the intestinal microbiota. Recently, culture-independent techniques have enabled the microbiota in health and disease to be described in increasing detail. Moreover, functional studies have identified myriad host effector and regulatory pathways that shape or are shaped by this microbial community. We consider the complex relationship between SpA pathogenesis and gut microbes, with a discussion of how manipulation of the gut microbiota itself may be a promising future target for SpA therapy.
TL;DR: Clinically, the contribution of mechanical stress to SpA including psoriatic arthritis (PsA) helps conceptualize the disease in a new way and provides obvious mechanistic links to skin and nail Koebner responses and molecularly, the monogenic forms of SpA have site-specific expression of mutated proteins in the skin, thus offering a direct molecular link between local inflammation-related pathway dysregulation and local stress or injury in disease causation.
Abstract: Given that entheses are sites of high mechanical stress that concentrate the forces of large contracting muscles down onto a small footprint of bone contact, it was recognized nearly 60 decades ago that stress and injury at such sites may play a role in the pathogenesis of mechanically related enthesopathy. In recent years, the role of mechanical stress and its related consequences on inflammatory enthesitis have also been recognized. Clinical imaging studies and experimental animal models of spondyloarthropathy including tumor necrosis factor (TNF) transgenic models and interleukin (IL)-23 overexpression systems are associated with a primary enthesitis with disease subsequently spreading to adjacent joint structures including the synovium and bone. Joint mechanical stress, without discernible microdamage or injury, leads to spondyloarthritis (SpA) in a TNF transgenic model. Normal-aged human entheses often demonstrate microdamage, but it is unclear whether an abnormal response to mechanical stress alone or the need for stress-induced microdamage is involved in human disease initiation. Clinically, the contribution of mechanical stress to SpA including psoriatic arthritis (PsA) helps conceptualize the disease in a new way and provides obvious mechanistic links to skin and nail Koebner responses. It also offers novel epidemiological explanations for why PsA develops in subjects with high body mass indices most typically in the fourth and fifth decades. Molecularly, the monogenic forms of SpA including caspase recruitment domain-containing protein 14 (CARD14) and IL36RN mutations have site-specific expression of mutated proteins in the skin, thus offering a direct molecular link between local inflammation-related pathway dysregulation and local stress or injury in disease causation. Given that many of the pathways that govern both immunity and mechanical stress including extracellular-signal-regulated kinase (ERK) and mitogen-activated protein kinase (MAPK) are shared, it may be difficult to develop strategies that selectively target mechanical stress-related pathways. However, occupational- and obesity-related factors may be potentially modifiable in susceptible individuals to prevent or ameliorate disease.
TL;DR: Clinical flow-charts useful for a correct diagnosis of children with suspected autoinflammatory syndromes are presented and a brief clinical description of these conditions is provided.
Abstract: Autoinflammatory diseases are characterized by the presence of chronic or recurrent systemic inflammation secondary to abnormal activation of innate immunity pathways. Many of these diseases have been found to have mutations in the genes within these pathways. Due to their rarity, non-specific symptoms and the very recent genetic and phenotypic identification and recognition, a delay in diagnosis is common. Nevertheless, some specific clin- ical features should help the clinician to make the diagnosis. The purpose of this article is to provide a brief clinical description of these conditions and to present clinical flow-charts useful for a correct diagnosis of children with suspected autoinflammatory syndromes.
TL;DR: Until significant improvements are made, however, in identifying patients most at risk for developing PTOA--and therefore those who are candidates for therapy--primary prevention programmes will remain the most effective current management tools.
Abstract: Post-traumatic osteoarthritis (PTOA) subsequent to joint injury accounts for over 12% of the overall disease burden of OA, and higher in the most at-risk ankle and knee joints. Evidence suggests that the pathogenesis of PTOA may be related to inflammatory processes and alterations to the articular cartilage, menisci, muscle and subchondral bone that are initiated in the acute post-injury phase. Imaging of these early changes, as well as a number of biochemical markers, demonstrates the potential for use as predictors of future disease, and may help stratify patients on the likelihood of their developing clinical disease. This will be important in guiding future interventions, which will likely target elements of the inflammatory response within the joint, molecular abnormalities related to cartilage matrix degradation, chondrocyte function and subchondral bone remodelling. Until significant improvements are made, however, in identifying patients most at risk for developing PTOA--and therefore those who are candidates for therapy--primary prevention programmes will remain the most effective current management tools.
TL;DR: The various causative agents of infective arthritis are discussed and emphasize on the approach to each type of arthritis, highlighting the diagnostic tests, along with their statistical accuracy.
Abstract: Bacteria, viruses, fungi, and parasites can all cause arthritis of either acute or chronic nature, which can be divided into infective/septic, reactive, or inflammatory. Considerable advances have occurred in diagnostic techniques in the recent decades resulting in better treatment outcomes in patients with infective arthritis. Detection of emerging arthritogenic viruses has changed the epidemiology of infection-related arthritis. The role of viruses in the pathogenesis of chronic inflammatory arthritides such as rheumatoid arthritis is increasingly being recognized. We discuss the various causative agents of infective arthritis and emphasize on the approach to each type of arthritis, highlighting the diagnostic tests, along with their statistical accuracy. Various investigations including newer methods such as nucleic acid amplification using polymerase chain reaction are discussed along with the pitfalls in interpreting the tests.
TL;DR: For example, this paper showed that patients who underwent arthroscopic partial meniscectomy for a degenerative meniscal tear generally did not show more improvement than those who underwent sham meniscal resection or an intensive course of physical therapy.
Abstract: Technological advances throughout the 20th century enabled an increase in arthroscopic knee surgery, particularly arthroscopic debridement for osteoarthritis (OA) and arthroscopic partial meniscectomy for symptomatic meniscal tear in the setting of OA. However, evaluation of the outcomes of these procedures lagged behind their rising popularity. Not until the early 2000s were rigorous outcomes studies conducted; these showed that arthroscopic debridement for OA was no better than a sham procedure in relieving knee pain or improving functional status, and that patients who underwent arthroscopic partial meniscectomy for a degenerative meniscal tear generally did not show more improvement than those who underwent sham meniscal resection or an intensive course of physical therapy. Though the number of arthroscopic knee procedures for OA performed each year has begun to decline, there remains a significant gap between the evidence and actual practice. Further investigation is needed to shore up the evidence base and bring policy and practice in line with rigorous research.
TL;DR: This review considers the role of circulating autoantibodies in the development of seronegative RA, and the implications for the management of patients with this challenging, though sometimes overlooked, condition.
Abstract: Rheumatoid arthritis (RA) has long been recognised as a highly heterogeneous disease of immune dysregulation. Despite an ever-growing appreciation of the role of circulating autoantibodies in the development of 'seropositive' disease, the pathogenesis of seronegative RA remains poorly understood. Accumulating evidence suggests that RA 'serotypes', in fact, reflect distinct disease entities that, despite their clinical overlap, diverge in respect of genetic architecture, cellular pathology and even therapeutic responsiveness. Focussing on seronegative RA, this review considers these concepts and their implications for the management of patients with this challenging, though sometimes overlooked, condition.
TL;DR: The tools available to assist with assessing appropriateness for TJR are examined; the modifiable risk factors associated with poor outcome are investigated; and areas for future research in selecting those appropriate for joint replacement are identified.
Abstract: Osteoarthritis (OA) is one of the 10 most disabling diseases in developed countries and worldwide estimates are that 10% of men and 18% of women aged over 60 years have symptomatic OA, including moderate and severe forms. Total joint replacement (TJR) is considered the most effective treatment for end-stage OA in those who have exhausted available conservative interventions. The demand for TJR is continually rising due to the ageing population; in the United States, more than 1 million TJRs were performed in 2010 and the number of procedures is projected to exceed 4 million in the US by 2030. It has been estimated that of all hip and knee replacements performed, approximately one quarter of the patients may be considered inappropriate candidates. Predicting who will benefit from TJR and who will not would seem critical in terms of containing the current and projected expenditure as well as improving satisfaction in TJR recipients. Few formal predictive tools are available to aid referring clinicians to determine those likely to be good or poor responders to surgery and current available tools tend to focus on disease severity alone with little consideration of risk factors that may predict a poor outcome or impede an effective response to surgery. This review examines the tools available to assist with assessing appropriateness for TJR; investigates the modifiable risk factors associated with poor outcome; and identifies areas for future research in selecting those appropriate for joint replacement.
TL;DR: While GWAS studies have yielded great insights into the genes that contribute to the pathogenesis of PsV and PsA, replication in large cohorts, fine-mapping and resequencing efforts, together with functional studies of genetic variants identified, are warranted to better understand susceptibility to and progression of these diseases.
Abstract: Spondyloarthritis (SpA) represents a group of inflammatory rheumatic diseases that cluster within families and possess overlapping clinical features. The pathogenesis of SpA encompasses a complex array of genetic, immunological and environmental factors. In this article, we will briefly review the genetics of PsA, and then focus on the genes that may be potentially linked either directly or indirectly to the immunopathology of the Th-17 pathway. The most consistent and dominant genetic effect of PsV and PsA is located on chromosome 6p21.3 within the major histocompatibility complex (MHC) region, which accounts for approximately one-third of the genetic contribution of PsV and PsA. To date, 36 genes have reached genome-wide significance, accounting for approximately 22% of psoriasis (PsV) heritability. Prominent genes identified via GWAS include HLA-Cw6, IL12B, IL23R, IL23A, TNIP1, TNFAIP3, LCE3B-LCE3C, TRAF3IP2, NFkBIA, FBXL19, TYK2, IFIH1, REL, and ERAP1. Genes identified in psoriatic arthritis (PsA) has largely echoed those in PsV and include HLA-B/C, HLA-B, IL-12B, IL-23R, TNIP1, TRAF3IP2, FBXL19, and REL. The lack of identified genetic susceptibility loci is largely attributed to the much smaller number of PsA patients and the greater clinical heterogeneity of PsA. Searching for different types of genetic variants such as small CNVs and/or insertions/deletions has also led to the identification of several genes with a function relative to PsV in particular including DEFB4, LCE3C_LCE3B, and IL-22 gene (exon 1). The candidate genes identified in PsV/PsA have highlighted pathways of critical importance to psoriatic disease including distinct signaling pathways comprised of barrier integrity, innate immune response and adaptive immune response, mediated primarily by Th-17 and Th-1 signalling. While GWAS studies have yielded great insights into the genes that contribute to the pathogenesis of PsV and PsA, replication in large cohorts, fine-mapping and resequencing efforts, together with functional studies of genetic variants identified, are warranted to better understand susceptibility to and progression of these diseases. That searching solely for common variants by GWAS will identify only a fraction of the entire genetic burden of disease, a concerted effort is underway to search for highly penetrant but rare disease alleles in families with PsV and PsA, using next-generation sequencing and through epigenetic investigations.
TL;DR: Long-term data with tumor necrosis factor (TNF) inhibitors also suggest that some window of opportunity may exist to inhibit structural disease progression, and new discoveries such as a masterswitch T cell population that carries the IL23 receptor are contributing to innovative insights into the pathophysiology of disease.
Abstract: The success of targeted therapies directed against tumor necrosis factor for patients with spondyloarthritis has shifted the focus of physicians and scientists towards the prevention of structural damage to the involved structures, in particular the sacroiliac joints and the spine, to avoid loss of function and disability. Structural damage to the skeleton as witnessed by radiography mainly consists of new bone formation potentially progressively leading to spine or joint ankylosis. This important long-term outcome parameter has been difficult to study, not alone because the time window for change may be long but also because human tissues with direct translational relevance are rarely available. Data from rodent models have identified growth factor signaling pathways as relevant targets. Both human and animal studies have tried to understand the link between inflammation and new bone formation. At the current moment, most evidence points towards a strong link between both but with the question still lingering about the sequence of events, disease triggers, and the interdependence of both features of disease. New discoveries such as a masterswitch T cell population that carries the IL23 receptor and the analysis of auto-antibodies directed again noggin and sclerostin are contributing to innovative insights into the pathophysiology of disease. Long-term data with tumor necrosis factor (TNF) inhibitors also suggest that some window of opportunity may exist to inhibit structural disease progression. All these data provide support for a further critical analysis of the available datasets and boost research in the field. The introduction of novel disease definitions, in particular the characterization of non-radiographic axial spondyloarthritis patients, will likely be instrumental in our further understanding of structural damage.
TL;DR: This chapter reviews concepts and determinants associated with health inequity, and the effect of interventions to minimize their impact, and discusses examples of interventions designed for reducing health inequities.
Abstract: Even in most egalitarian societies, disparities in care exist to the disadvantage of some people with chronic musculoskeletal (MSK) disorders and related disability. These situations translate into inequality in health and health outcomes. The goal of this chapter is to review concepts and determinants associated with health inequity, and the effect of interventions to minimize their impact. Health inequities are avoidable, unnecessary, unfair and unjust. Inequities can occur across the health care continuum, from primary and secondary prevention to diagnosis and treatment. There are many ways to define and identify inequities, according for instance to ethical, philosophical, epidemiological, sociological, economic, or public health points of view. These complementary views can be applied to set a framework of analysis, identify determinants and suggest targets of action against inequity. Most determinants of inequity in MSK disorders are similar to those in the general population and other chronic diseases. People may be exposed to inequity as a result of policies and rules set by the health care system, individuals' demographic characteristics (e.g., education level), or some behavior of health professionals and of patients. Osteoarthritis (OA) represents a typical chronic MSK condition. The PROGRESS-Plus framework is useful for identifying the important role that place of residence, race and ethnicity, occupation, gender, education, socioeconomic status, social capital and networks, age, disability and sexual orientation may have in creating or maintaining inequities in this disease. In rheumatoid arthritis (RA), a consideration of international data led to the conclusion that not all RA patients who needed biologic therapy had access to it. The disparity in care was due partly to policies of a country and a health care system, or economic conditions. We conclude this chapter by discussing examples of interventions designed for reducing health inequity.
TL;DR: The limits of current classification criteria, their use and abuse in clinical practice, and how they should be used with caution when applied in clinics are presented.
Abstract: In rheumatic diseases, classification criteria have been developed to identify well-defined homogenous cohorts for clinical research. Although they are commonly used in clinical practice, their use may not be appropriate for routine diagnostic clinical care. Classification criteria are being revised with improved methodology and further understanding of disease pathophysiology, but they still may not encompass all unique clinical situations to be applied for diagnosis of heterogenous, rare, evolving rheumatic diseases. Diagnostic criteria development is challenging primarily due to difficulty for universal application given significant differences in the prevalence of rheumatic diseases based on geographical area and clinic settings. Despite these shortcomings, the clinician can still use classification criteria for understanding the disease as well as a guide for diagnosis with a few caveats. We present the limits of current classification criteria, their use and abuse in clinical practice, and how they should be used with caution when applied in clinics.
TL;DR: Targeting pathogenic stromal cells has the potential to provide a cure for chronic inflammatory disorders such as rheumatoid arthritis.
Abstract: Biological therapies for the management of immune mediated inflammatory diseases such as rheumatoid arthritis have proven to be extremely successful in recent years. Despite these successes, even the most effective of therapies do not lead to cure. Why chronic inflammation persists indefinitely within the rheumatoid synovium despite an absence of continuous stimulation, and why some patients with early synovitis progress to persistent disease whilst others do not, has remained unexplained. In contrast to the paradigm that stromal cells are biochemically active but immunologically passive, there is now growing evidence that stromal components from the rheumatoid synovium play a crucial part in the immunopathology of rheumatoid arthritis. Stromal cells play a central role in the transformation of an acute, resolving to a chronic inflammatory process, and to the persistence of synovial inflammation and joint destruction through a variety of immune mechanisms. Therapeutic manipulation of the stroma is a largely unexplored, yet potentially vital area of research. Targeting pathogenic stromal cells has the potential to provide a cure for chronic inflammatory disorders such as rheumatoid arthritis.
TL;DR: It is important for a clinician to know the method used, its sensitivity and specificity to help in the proper interpretation of the laboratory results, and this review will address these issues.
Abstract: Autoantibodies are the serological hallmark of autoimmune disease. Though their pathogenic role is debatable, they play an important role in the management of a patient with rheumatic disease. However, due to their presence in the general population as well as in multiple autoimmune diseases, the presence of an autoantibody alone does not make a diagnosis; the result has to be interpreted along with clinical findings. Similarly, the absence of autoantibody does not exclude a disease. The common autoantibodies used in clinical practice include rheumatoid factor, anti-CCP antibodies, antinuclear antibodies (ANAs), anti-neutrophil cytoplasmic antibodies (ANCA) and anti-phospholipid antibodies. Once an autoantibody to a broad antigen is detected in a patient, sub-specificity analysis can improve the utility of the antibody. Autoantibodies are detected in the serum using different assays and results of which can vary; thus, it is important for a clinician to know the method used, its sensitivity and specificity to help in the proper interpretation of the laboratory results. This review will address these issues.
TL;DR: The chequered history of kinase inhibitor development in RA is summarized, describing successes and failures alike, and future trends in this exciting field are examined.
Abstract: Rheumatoid arthritis (RA) remains a formidable clinical challenge. This is despite remarkable recent advances in our understanding of pathogenesis and the introduction of a variety of novel agents, particularly biologic therapeutics that are potent inhibitors of extracellular immune pathways. Whereas the latter have brought substantial improvements in efficacy and thus outcomes, there remain significant numbers of non- or partial responders to current standard of care. The discovery of key intracellular pathways, particularly kinases that subserve the function of these pivotal cytokine and immune cell receptors implicated in RA pathogenesis, has facilitated the advent of a new phase of RA drug development. Thus, a range of kinase inhibitors has entered clinical trials and one agent has been licenced for use in some regions. Herein we summarise the chequered history of kinase inhibitor development in RA, describing successes and failures alike, and thereafter examine future trends in this exciting field.
TL;DR: There are numerous trial designs and modifications that can be made to improve efficiency and maximise what little data may be available in a rare disease clinical trial, as well as examples from paediatric rheumatology.
Abstract: Evidence from clinical trials, ideally using randomisation and allocation concealment, is essential for informing clinical decisions regarding the benefits and harms of treatments for patients. Where diseases are rare, such as in paediatric rheumatic diseases, patient recruitment into clinical trials can be a major obstacle, leading to an absence of evidence and patients receiving treatments based on anecdotal evidence. There are numerous trial designs and modifications that can be made to improve efficiency and maximise what little data may be available in a rare disease clinical trial. These are discussed and illustrated with examples from paediatric rheumatology. Regulatory incentives and support from research networks have helped to deliver these trials, but more can be done to continue this important research.
TL;DR: Identifying the pathomechanics and clinical characteristics of individuals with patellofemoral osteoarthritis that respond to treatment may assist in the development of individualised treatment strategies that alleviate symptoms and slow structural damage.
Abstract: Patellofemoral joint integrity is maintained by an optimal interaction of passive, dynamic and structural restraints. Disruption of these mechanics can lead to structural joint damage and subsequent patellofemoral osteoarthritis, which is a prevalent and disabling condition with few effective conservative management strategies. Due to the influential role of biomechanics in this disease, targeting the specific pathomechanics exhibited by an individual is logical to improve their likelihood of a positive treatment outcome. This review summarises the effect of different pathomechanical factors on the presence and progression of patellofemoral osteoarthritis. It then presents a synthesis of mechanical effect of treatment strategies specifically addressing these pathomechanics. Identifying the pathomechanics and clinical characteristics of individuals with patellofemoral osteoarthritis that respond to treatment may assist in the development of individualised treatment strategies that alleviate symptoms and slow structural damage.
TL;DR: Preliminary proof-of-concept studies with ustekinumab and interleukin-17 targeting therapies suggest that these agents could become the first new treatment options, not targeting TNF, for axial spondyloarthritis.
Abstract: The advent of biologics targeting tumor necrosis factor-alpha (TNF-alpha) has revolutionized the field of rheumatology in general and the treatment of spondyloarthritis (SpA) in particular, since - apart from non-steroidal anti-inflammatory agents - no disease modifying treatments are available for this frequent, inflammatory rheumatic condition. The significant improvements in signs and symptoms observed with TNF-blockers in this group of diseases, have raised the bar with regard to treatment goals, including clinical remission. Even if treatment failure with TNF-blocking agents may be a relatively rare phenomenon, cases of primary non-responders, secondary loss-of-efficacy and intolerance, have been described. Results with abatacept, rituximab and tocilizumab - all effective in the treatment of rheumatoid arthritis - were disappointing, especially in patients that had previously failed anti-TNF therapy. On the other hand, there is increasing evidence that targeting the cytokines of the Th-17 axis is associated with major improvements of skin psoriasis and its associated arthritis. In axial spondyloarthritis, preliminary proof-of-concept studies with ustekinumab and interleukin-17 targeting therapies suggest that these agents could become the first new treatment options, not targeting TNF. Finally, the advent of small molecules targeting inflammatory, intracellular signalling pathways, may further change our future therapeutic approach.
TL;DR: Novel developments in which clinical innovations go hand in hand with basic discoveries are described, mainly in severe forms of JIA, most notably systemic JIA and polyarticular JIA.
Abstract: Despite the enormous progress in the treatment of juvenile idiopathic arthritis (JIA), innovations based on true bench-to-bedside research, performed in JIA patients, are still scarce. This chapter describes novel developments in which clinical innovations go hand in hand with basic discoveries. For the purpose of this review, we will mainly focus on developments in severe forms of JIA, most notably systemic JIA and polyarticular JIA. However, also in less severe forms of JIA, such as oligoarticular JIA, better insight will help to improve diagnosis and treatment. Facilitating the transition from bench to bedside will prove crucial for addressing the major challenges in JIA management. If successful, it will set new standards for a safe, targeted and personalized therapeutic approach for children with JIA.