Several advances in 2013 have improved our understanding of how epigenetic mechanisms affect autoimmune disorders. Many new insights were made into the regulation of gene expression by DNA methylation in systemic lupus erythematosus. For rheumatoid arthritis, complex interrelationships between DNA methylation and microRNAs in regulating gene expression were described.
Degeneration of the intervertebral disc is the major contributor to back/neck and radicular pain. It is characterized by an elevation in levels of the inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1 α/β, IL-6 and IL-17 secreted by the disc cells themselves; these cytokines promote matrix degradation, chemokine production and changes in cell phenotype. The resulting imbalance between catabolic and anabolic responses leads to degeneration, as well as herniation and radicular pain. Release of chemokines from degenerating discs promote infiltration and activation of T and B cells, macrophages, neutrophils, and mast cells further amplifying the inflammatory cascade. Immunocyte migration into the disc is accompanied by the appearance of microvasculature and nerve fibers arising from the dorsal root ganglion (DRG). In this inflammatory milieu, neurogenic factors in particular nerve growth factor (NGF) and brain-derive neurotrophic factor (BDNF) generated by disc and immune cells induce expression of pain associated cation channels in DRGs. Depolarization of these channels is likely to promote discogenic and radicular pain and reinforce the cytokine-mediated degenerative cascade. Taken together, the enhanced understanding of the contribution of cytokines and immune cells to catabolic and nociceptive processes provide new targets for treating symptomatic disc disease.
Vasculitis of the medium and large arteries, most often presenting as giant cell arteritis (GCA), is an infrequent, but potentially fatal type of immune-mediated vascular disease. The site of the aberrant immune reaction, the mural layers of the artery, is strictly defined by vascular dendritic cells, endothelial cells, vascular smooth muscle cells and fibroblasts which engage in an interaction with T cells and macrophages to ultimately cause luminal stenosis or aneurysmal wall damage of the vessel. A multitude of effector cytokines, all known as critical mediators in host-protective immunity, has been identified in the vasculitic lesions. Two dominant cytokine clusters, one centering on the IL-6/IL-17 axis, the other on the IL-12/IFN-γ axis, have been connected with disease activity. These two clusters appear to serve different roles in the vasculitic process. The IL-6/IL-17 cluster is highly responsive to standard corticosteroid therapy, whereas the IL-12/IFN-γ cluster is resistant to steroid-mediated immunosuppression. The information exchange between vascular and immune cells and stabilization of the vasculitic process involves members of the NOTCH receptor and ligand family. Focusing on elements in the tissue context of GCA, instead of broadly suppressing host immunity, may allow for a more tailored therapeutic approach and spare patients the unwanted side-effects of aggressive immunosuppression.
The identification of modifiable risk factors for the development of rheumatic conditions and their sequelae is crucial for reducing the substantial worldwide burden of these diseases. However, the validity of such research can be threatened by sources of bias, including confounding, measurement and selection biases. In this Review, we discuss potentially major issues of selection bias—a type of bias frequently overshadowed by other bias and feasibility issues, despite being equally or more problematic—in key areas of rheumatic disease research. We present index event bias (a type of selection bias) as one of the potentially unifying reasons behind some unexpected findings, such as the ‘risk factor paradox’—a phenomenon exemplified by the discrepant effects of certain risk factors on the development versus the progression of osteoarthritis (OA) or rheumatoid arthritis (RA). We also discuss potential selection biases owing to differential loss to follow-up in RA and OA research, as well as those due to the depletion of susceptibles (prevalent user bias) and immortal time bias. The lesson remains that selection bias can be ubiquitous and, therefore, has the potential to lead the field astray. Thus, we conclude with suggestions to help investigators avoid such issues and limit the impact on future rheumatology research.
Pain is the defining symptom of osteoarthritis (OA), yet available treatment options, of which NSAIDs are the most common, provide inadequate pain relief and are associated with serious health risks when used long term. Chronic pain pathways are subject to complex levels of control and modulation, both in the periphery and in the central nervous system. Ongoing clinical and basic research is uncovering how these pathways operate in OA. Indeed, clinical investigation into the types of pain associated with progressive OA, the presence of central sensitization, the correlation with structural changes in the joint, and the efficacy of novel analgesics affords new insights into the pathophysiology of OA pain. Moreover, studies in disease-specific animal models enable the unravelling of the cellular and molecular pathways involved. We expect that increased understanding of the mechanisms by which chronic OA-associated pain is generated and maintained will offer opportunities for targeting and improving the safety of analgesia. In addition, using clinical and genetic approaches, it might become possible to identify subsets of patients with pain of different pathophysiology, thus enabling a tailored approach to pain management.
Systemic juvenile idiopathic arthritis (sJIA) has long been recognized as unique among childhood arthritides, because of its distinctive clinical and epidemiological features, including an association with macrophage activation syndrome. Here, we summarize research into sJIA pathogenesis. The triggers of disease are unknown, although infections are suspects. Once initiated, sJIA seems to be driven by innate proinflammatory cytokines. Endogenous Toll-like receptor ligands, including S100 proteins, probably synergize with cytokines to perpetuate inflammation. These and other findings support the hypothesis that sJIA is an autoinflammatory condition. Indeed, IL-1 is implicated as a pivotal cytokine, but the source of excess IL-1 activity remains obscure and the role of IL-1 in chronic arthritis is less clear. Another hypothesis is that a form of hemophagocytic lymphohistiocytosis underlies sJIA, with varying degrees of its expression across the spectrum of disease. Alternatively, sJIA with MAS might be a genetically distinct subtype. Yet another hypothesis proposes that inadequate downregulation of immune activation is central to sJIA, supporting evidence for which includes ‘alternative activation’ of monocyte and macrophages and possible deficiencies in IL-10 and T regulatory cells. Some altered immune phenotypes persist during clinically inactive disease, which suggests that this stage might represent compensated inflammation. Despite much progress being made, many questions remain, providing fertile ground for future research.
The molecular biology revolution coupled to the development of monoclonal antibody technology enabled remarkable therapeutic progress in rheumatology, comprising an array of highly effective biological agents. With advances in understanding of the molecular nature of immune cell receptors came elucidation of intracellular signaling pathways engaged by these receptors. These discoveries beg the question whether selectively targeting key intracellular molecules with small molecules would add to the rheumatologic armamentarium. In this review, we discuss several strategies that appear to be successful and ponder their implications for the future of immune targeted therapeutics. We focus on kinases inhibitors, primarily those targeting Janus kinase family members, and spleen tyrosine kinase (Syk) given their advanced status in clinical development and application. Thereafter we will summarize other signal targets that might offer promise in future.
Juvenile idiopathic arthritis (JIA) refers to a group of chronic childhood arthropathies, currently classified into subtypes primarily on the basis of clinical features. Research has focused on the hypothesis that these subtypes arise through distinct etiologic pathways. In this Review, we discuss four subtypes of JIA: persistent oligoarticular, extended oligoarticular, rheumatoid-factor positive polyarticular and rheumatoid-factor-negative polyarticular. These subtypes differ in prevalence between ethnic groups and are associated with different HLA alleles. Non-HLA genetic risk factors have also been identified, some of which reveal further molecular differences between these subtypes, while others suggest mechanistic overlap. Investigations of immunophenotypes also provide insights into subtype differences: adaptive immunity appears to have a prominent role in both polyarticular and oligoarticular JIA, and the more-limited arthritis observed in persistent oligoarticular JIA as compared with extended oligoarticular JIA may reflect more-potent immunoregulatory T-cell activity in the former. Tumor necrosis factor seems to be a key mediator of both polyarticular and oligoarticular JIA, especially in the extended oligoarticular subtype, although elevated levels of other cytokines also are observed. Limited data on monocytes, dendritic cells, B cells, natural killer T cells, and neutrophils suggest that the contributions of these cells differ across subtypes of JIA. Within each subtype, however, common pathways appear to drive joint damage.
The involvement of autoreactive T cells in the pathogenesis of rheumatoid arthritis (RA) as well as in autoimmune animal models of arthritis has been well established; however, unanswered questions, such as the role of joint-homing T cells, remain. Animal models of arthritis are superb experimental tools in demonstrating how T cells trigger joint inflammation, and thus can help to further our knowledge of disease mechanisms and potential therapies. In this Review, we discuss the similarities and differences in T-cell subsets and functions between RA and mouse arthritis models. For example, various T-cell subsets are involved in both human and mouse arthritis, but differences might exist in the cytokine regulation and plasticity of these cells. With regard to joint-homing T cells, an abundance of synovial T cells is present in humans compared with mice. On the other hand, local expansion of type 17 T helper (TH17) cells is observed in some animal models, but not in RA. Finally, whereas T-cell depletion essentially failed in RA, antibody targeting of T cells can work, at least preventatively, in most arthritis models. Clearly, additional human and animal studies are needed to fill the gap in our understanding of the specific contribution of T-cell subsets to arthritis in mice and men.
Current classification criteria for rheumatoid arthritis allow its classification on the basis of the presence of erosions, in the absence of other indicators. Nevertheless, definition or quantitation of erosions was lacking. A European task force has now addressed this issue by analysing radiographic erosions in two cohorts of patients with early disease.
SLE nephritis is a challenging clinical condition for which current therapies are unsatisfactory with respect to both remission induction and unwanted toxicities. Despite intervention the rates of end stage renal disease appear to be increasing in the US. New discoveries over the last decade have greatly improved our understanding of immune activation and effector inflammatory pathways in SLE nephritis but these have not yet translated into an effective new approved therapeutic. An analysis of the mechanisms of new immunomodulatory drugs in multiple models of murine SLE shows clearly that interacting networks of immune and effector pathways are recruited as disease progresses. It is therefore difficult to reverse established disease by targeting a single cell population or inflammatory pathway once long-lived autoreactive lymphocyte populations are present and peripheral organs are inflamed. These data suggest that we need to consider new paradigms for the management of SLE that include earlier immune intervention, long-term maintenance therapies and protection of target organs.
Bone erosion is a central feature of rheumatoid arthritis and is associated with disease severity and poor functional outcome. Erosion of periarticular cortical bone, the typical feature observed on plain radiographs in patients with rheumatoid arthritis, results from excessive local bone resorption and inadequate bone formation. The main triggers of articular bone erosion are synovitis, including the production of proinflammatory cytokines and receptor activator of nuclear factor κB ligand (RANKL), as well as antibodies directed against citrullinated proteins. Indeed, both cytokines and autoantibodies stimulate the differentiation of bone-resorbing osteoclasts, thereby stimulating local bone resorption. Although current antirheumatic therapy inhibits both bone erosion and inflammation, repair of existing bone lesions, albeit physiologically feasible, occurs rarely. Lack of repair is due, at least in part, to active suppression of bone formation by proinflammatory cytokines. This Review summarizes the substantial progress that has been made in understanding the pathophysiology of bone erosions and discusses the improvements in the diagnosis, monitoring and treatment of such lesions.
Established and emerging data demonstrate that a ‘preclinical’ period of disease precedes the onset of clinical rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), as well as other autoimmune rheumatic diseases (ARDs).This preclinical stage of development of disease is characterized by abnormalities in disease-related biomarkers before the onset of the clinically apparent signs and symptoms. Numerous genetic and environmental risk factors for ARDs have also been identified, and many of these factors are likely to act before the clinical appearance of tissue injury to initiate and/or propagate autoimmunity and autoimmune disease. Thus, biomarkers representative of these autoimmune processes could potentially be used in conjunction with other clinical parameters during the preclinical period of ARDs to predict the future development of clinically apparent disease. This Review focuses on the preclinical stages of RA and SLE, as our current understanding of these diseases can be used to present an overall model of the development of ARDs that might ultimately be used to develop screening programmes and preventive strategies. Important considerations for the future development of such approaches, in particular, the issues that require additional research and how they might be addressed, are also discussed.
Repair of bone erosions in rheumatoid arthritis has been considered a difficult goal to achieve. However—with better therapies at hand to control synovial inflammation—sensitive μCT imaging techniques now available confirm that repair of bone erosion is possible, and begins at the base of erosive lesions.
Oxidative stress is increased in systemic lupus erythematosus (SLE), and it contributes to immune system dysregulation, abnormal activation and processing of cell-death signals, autoantibody production and fatal comorbidities. Mitochondrial dysfunction in T cells promotes the release of highly diffusible inflammatory lipid hydroperoxides, which spread oxidative stress to other intracellular organelles and through the bloodstream. Oxidative modification of self antigens triggers autoimmunity, and the degree of such modification of serum proteins shows striking correlation with disease activity and organ damage in SLE. In T cells from patients with SLE and animal models of the disease, glutathione, the main intracellular antioxidant, is depleted and serine/threonine-protein kinase mTOR undergoes redox-dependent activation. In turn, reversal of glutathione depletion by application of its amino acid precursor, N-acetylcysteine, improves disease activity in lupus-prone mice; pilot studies in patients with SLE have yielded positive results that warrant further research. Blocking mTOR activation in T cells could conceivably provide a well-tolerated and inexpensive alternative approach to B-cell blockade and traditional immunosuppressive treatments. Nevertheless, compartmentalized oxidative stress in self-reactive T cells, B cells and phagocytic cells might serve to limit autoimmunity and its inhibition could be detrimental. Antioxidant therapy might also be useful in ameliorating damage caused by other treatments. This Review thus seeks to critically evaluate the complexity of oxidative stress and its relevance to the pathogenesis and treatment of SLE.
Osteoarthritis (OA) of the spine involves the facet joints, which are located in the posterior aspect of the vertebral column and, in humans, are the only true synovial joints between adjacent spinal levels. Facet joint osteoarthritis (FJ OA) is widely prevalent in older adults, and is thought to be a common cause of back and neck pain. The prevalence of facet-mediated pain in clinical populations increases with increasing age, suggesting that FJ OA might have a particularly important role in older adults with spinal pain. Nevertheless, to date FJ OA has received far less study than other important OA phenotypes such as knee OA, and other features of spine pathoanatomy such as degenerative disc disease. This Review presents the current state of knowledge of FJ OA, including relevant anatomy, biomechanics, epidemiology, and clinical manifestations. We present the view that the modern concept of FJ OA is consonant with the concept of OA as a failure of the whole joint, and not simply of facet joint cartilage.
Musculoskeletal pain conditions, such as fibromyalgia and low back pain, tend to coexist in affected individuals and are characterized by a report of pain greater than expected based on the results of a standard physical evaluation. The pathophysiology of these conditions is largely unknown, we lack biological markers for accurate diagnosis, and conventional therapeutics have limited effectiveness. Growing evidence suggests that chronic pain conditions are associated with both physical and psychological triggers, which initiate pain amplification and psychological distress; thus, susceptibility is dictated by complex interactions between genetic and environmental factors. Herein, we review phenotypic and genetic markers of common musculoskeletal pain conditions, selected based on their association with musculoskeletal pain in previous research. The phenotypic markers of greatest interest include measures of pain amplification and ‘psychological’ measures (such as emotional distress, somatic awareness, psychosocial stress and catastrophizing). Genetic polymorphisms reproducibly linked with musculoskeletal pain are found in genes contributing to serotonergic and adrenergic pathways. Elucidation of the biological mechanisms by which these markers contribute to the perception of pain in these patients will enable the development of novel effective drugs and methodologies that permit better diagnoses and approaches to personalized medicine.
Rheumatoid arthritis (RA) is characterized by hyperplastic synovial pannus tissue, which mediates destruction of cartilage and bone. Fibroblast-like synoviocytes (FLS) are a key component of this invasive synovium and have a major role in the initiation and perpetuation of destructive joint inflammation. The pathogenic potential of FLS in RA stems from their ability to express immunomodulating cytokines and mediators as well as a wide array of adhesion molecule and matrix-modelling enzymes. FLS can be viewed as ‘passive responders’ to the immunoreactive process in RA, their activated phenotype reflecting the proinflammatory milieu. However, FLS from patients with RA also display unique aggressive features that are autonomous and vertically transmitted, and these cells can behave as primary promoters of inflammation. The molecular bases of this ‘imprinted aggressor’ phenotype are being clarified through genetic and epigenetic studies. The dual behaviour of FLS in RA suggests that FLS-directed therapies could become a complementary approach to immune-directed therapies in this disease. Pathophysiological characteristics of FLS in RA, as well as progress in targeting these cells, are reviewed in this manuscript.
Transforming growth factor-ß (TGF-ß) is a pleiotropic cytokine with vital homeostatic functions. Aberrant TGF-ß expression or activity is implicated in the pathogenesis of fibrosis in patients with systemic sclerosis (SSc), thus TGF-ß represents a molecular therapeutic target. Multiple strategies are available for blocking the TGF-ß pathway. A monoclonal antibody targeting TGF-ß has been evaluated in a small clinical trial for early SSc with disappointing results. Antibodies to the αvß6 integrin that prevent latent TGF-ß activation, however, show promise in preclinical studies. Small molecules inhibiting TGF-ß receptor activity are effective in animal models of fibrosis. Imatinib mesylate and related tyrosine kinase inhibitors that are currently used in cancer therapy also block TGF-ß pathways and abrogate fibrotic responses. Furthermore, some commonly used drugs have shown unanticipated anti-TGF-ß activity and, therefore, could have anti-fibrotic effects. Since TGF-ß has important physiologic functions for tissue homeostasis, blocking TGF-ß activity might lead to spontaneous immune activation, epithelial hyperplasia and impaired wound healing. Loss of immune tolerance is a potential concern in an autoimmune disease such as SSc. Novel insights from microarray-based gene expression analysis and studies of genetic polymorphisms in TGF-ß signaling could aid in identifying those patients who are most likely to respond to anti-TGF-ß treatment. Anti-TGF-ß interventions promise to have a major impact on the treatment of SSc. Significant concerns regarding efficacy, safety, questions regarding appropriate dosing and timing of therapy, identification of responders, and of biomarkers of safety and efficacy are critical challenges ahead.
Fibrosis in multiple organs is a prominent pathological finding and distinguishing hallmark of systemic sclerosis (SSc). Findings during the past 5 years have contributed to a more complete understanding of the complex cellular and molecular underpinning of fibrosis in SSc. Fibroblasts, the principal effector cells, are activated in the profibrotic cellular milieu by cytokines and growth factors, developmental pathways, endothelin 1 and thrombin. Innate immune signaling via Toll-like receptors, matrix-generated biomechanical stress signaling via integrins, hypoxia and oxidative stress seem to be implicated in perpetuating the process. Beyond chronic fibroblast activation, fibrosis represents a failure to terminate tissue repair, coupled with an expanded population of mesenchymal cells originating from bone marrow and transdifferentiation of epithelial cells, endothelial cells and pericytes. In addition, studies have identified intrinsic alterations in SSc fibroblasts resulting from epigenetic changes, as well as altered microRNA expression that might underlie the cell-autonomous, persistent activation phenotype of these cells. Precise characterization of the deregulated extracellular and intracellular signaling pathways, mediators and cellular differentiation programs that contribute to fibrosis in SSc will facilitate the development of selective, targeted therapeutic strategies. Effective antifibrotic therapy will ultimately involve novel compounds and repurposing of drugs that are already approved for other indications.
Investigators have made key advances in rheumatoid arthritis (RA) genetics in the past 10 years. Although genetic studies have had limited influence on clinical practice and drug discovery, they are currently generating testable hypotheses to explain disease pathogenesis. Firstly, we review here the major advances in identifying RA genetic susceptibility markers both within and outside of the MHC. Understanding how genetic variants translate into pathogenic mechanisms and ultimately into phenotypes remains a mystery for most of the polymorphisms that confer susceptibility to RA, but functional data are emerging. Interplay between environmental and genetic factors is poorly understood and in need of further investigation. Secondly, we review current knowledge of the role of epigenetics in RA susceptibility. Differences in the epigenome could represent one of the ways in which environmental exposures translate into phenotypic outcomes. The best understood epigenetic phenomena include post-translational histone modifications and DNA methylation events, both of which have critical roles in gene regulation. Epigenetic studies in RA represent a new area of research with the potential to answer unsolved questions.
The use of B-cell targeted therapies for the treatment of systemic lupus erythematosus (SLE) has generated great interest owing to the multiple pathogenic roles carried out by B cells in this disease. Strong support for targeting B cells is provided by genetic, immunological and clinical observations that place these cells at the center of SLE pathogenesis, as initiating, amplifying and effector cells. Interest in targeting B cells has also been fostered by the successful use of similar interventions to treat other autoimmune diseases such as rheumatoid arthritis, and by the initial promise shown by B-cell depletion to treat SLE in early studies. Although the initial high enthusiasm has been tempered by negative results from phase III trials of the B-cell-depleting agent rituximab in SLE, renewed vigor should be instilled in the field by the convergence of the latest results using agents that inhibit B-cell-activating factor (BAFF, also known as BLyS and tumor necrosis factor ligand superfamily, member 13b), further analysis of data from trials using rituximab and greatly improved understanding of B-cell biology. Combined, the available information identifies several new avenues for the therapeutic targeting of B cells in SLE.
Advances in pharmacogenomics have improved understanding of allopurinol hypersensitivity syndrome (AHS), and new research suggests HLA-B*5801 is a strong risk factor for this condition; in some populations, almost all patients who develop AHS carry this allele. This discovery could influence the treatment of gout, in particular, how allopurinol is used.
Allopurinol; HLA-B*58:01; allopurinol hypersensitivity syndrome; severe cutaneous adverse reactions; adverse events; side effects; hypersensitivity reaction; Stevens-Johnson syndrome; toxic epidermal necrolysis; TEN; SJS; complications
Systemic sclerosis (SSc) is characterized by vascular alterations, activation of the immune system and tissue fibrosis. Vascular insufficiency manifests early in the disease, and although there is evidence of an active repair process, capillaries deteriorate and regress. Factors that contribute to the failure of vascular regeneration might include persistent injury, an imbalance between proangiogenic and antiangiogenic mediators, intrinsic abnormal properties of the cellular components of the vessels, and the presence of fibroblast-derived antiangiogenic factors. In addition, circulating dysfunctional endothelial progenitor cells might further exacerbate vessel deterioration. Abnormal expression of transcription factors, including Fra2 and Fli1, has been proposed to contribute to SSc vasculopathy. Fli1 regulates genes that are involved in vessel maturation and stabilization, suggesting that reduced levels of Fli1 in SSc vasculature could contribute to the development of unstable vessels that are prone to regression. Conversely, proliferating endothelial cells and pericytes, in the presence of an appropriate stimulus, might transdifferentiate into collagen-producing cells, and thus contribute to the initiation of fibrosis. Despite progress in treating the symptoms of vascular disease in SSc, the underlying mechanisms remain poorly understood. An improved knowledge of the molecular and cellular pathways that contribute to SSc vasculopathy could help in the design of effective therapies in the future.
Recent studies have highlighted a potentially important role for Wnts as profibrotic mediators, and implicated increased Wnt activity in systemic sclerosis and other fibrotic diseases. Strikingly, new data indicates that Wnts have a central role in the profibrotic activity of TGF-β.