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Abstract: Diagnosing patients with immune-mediated rheumatic diseases has many facets to be considered, but early and rapid diagnosis is an important prerequisite for correct and straight-forward future management of the patients. For optimal results physicians should not miss any diagnosis (assuring high sensitivity of the diagnostic process), and high specificity is needed in view of future therapeutic interventions. This review focuses on select principal aspects of diagnosis in clinical practice: Challenges of diagnostic approaches in immune-mediated rheumatic diseases include the frequent lack of diagnostic criteria (with subsequent misuse of classification criteria), the urgent need for diagnostic values of history and further examinations to support diagnosis-finding strategies, and differential diagnoses to be excluded (e.g., infections during early disease and follow-up). First, pure application of classification criteria without expert's experience as diagnostic criteria may lead to inappropriate diagnoses in 4-32% of all patients with immune-mediated rheumatic diseases. Second, sensitivity and specificity data for history and clinical examination are necessary not only for routine clinical work, but also for purposes of teaching students and learning physicians. Third, conditions to be excluded before classification of a certain disease are not necessarily excluding a certain diagnosis. Specific interest is given to differentiate infections from early onset or relapse of immune-mediated rheumatic diseases. ... Read more

Advances in the Evaluation and Classification of Chronic Inflammatory Rheumatic Diseases

Abstract: The challenges of diagnosing rheumatic diseases are the high prevalence of certain rheumatic diseases, the existence of orphan disease, and the different pathophysiological backgrounds including infection and autoimmune mechanisms. During recent decades, more and more attention has been drawn to early diagnosis and achievement of full remission. Accordingly, new classification criteria have been developed and more biomarkers introduced into clinical practice. Specific laboratory parameters as well as wider use of functional imaging tools like ultrasound and magnetic resonance further support the early diagnostic process. Besides diagnosis early after disease onset, achievement of remission during follow-up is another important clinical aim of rheumatologists. In parallel with the development of new therapeutic approaches, both quality of life and treatment outcome especially of chronic inflammatory diseases could be improved. Both specific outcome parameters and global disease activity assessments are important to verify treatment goals of (full) remission, and at the same time may also predict response to treatment regimens. ... Read more

Advances in Pathogenesis and Treatment of ANCA-associated Vasculitis

Abstract: Anti-neutrophil cytoplasmic autoantibodies (ANCA) directed to proteinase 3 (PR3-ANCA) and myeloperoxidase (MPO-ANCA) are sensitive and specific markers for their associated diseases, granulomatosis with polyangiitis (GPA, formerly Wegener's granulomatosis) and microscopic polyangiitis (MPA), respectively. Clinical observations suggest but do not prove that ANCA are involved in the pathogenesis of GPA and MPA. In vivo and in vitro experimental data strongly suggest if not prove that MPO-ANCA underlie the pathological lesions seen in MPO-ANCA associated MPA. This is less clear for PR3-ANCA associated GPA in which, besides small-vessel vasculitis, granulomatous inflammation is apparent. Here, cellular immunity appears to play an additional role. Insight into the pathogenetic events involved in these diseases has resulted in new ways of treatment that target the specific pathways that underlie the development of the lesions. ... Read more

Scleritis: Challenges in Immunopathogenesis and Treatment

Abstract: Scleritis is an uncommon disease characterized by inflammation of the sclera and adjacent ocular structures. Recent studies have led to significant progress in understanding the epidemiology, immunopathogenesis, severity assessment, treatment, and prognosis of this potentially sight threatening disease. Despite these advances, significant challenges remain regarding our understanding of the mechanisms of scleral destruction and inflammation, and the rational approach to treatment. Information from studies in associated systemic diseases and vasculitis and a small number of studies of ocular tissue has revealed the prominent role of T and B cells, autoantibodies, immune complexes, and cytokines, such as TNF-alpha. These studies have prompted clinical trials that have demonstrated the effectiveness of anti-TNF, anti-B cell therapy, systemic immunosuppression, and more recently the use of local sub-conjunctival steroid treatment. ... Read more

The Quest for Better Understanding of HLA-Disease Association: Scenes from a Road Less Travelled By

Abstract: Dozens of human diseases and health traits are significantly more common among individuals carrying particular human leukocyte antigens (HLA) alleles. The underlying mechanism of this phenomenon, commonly referred to as "HLA-disease association," has been the subject of a decades-long debate. The prevailing hypotheses implicate an auto-aggressive immune response due to aberrant presentation of self-, self-mimicking-, or altered self-antigens by HLA molecules. However, the identity of such putative antigens remains elusive in the vast majority of HLA-associated diseases. Moreover, antigen presentation-based hypotheses are difficult to reconcile with epidemiologic data and functional characteristics of HLA molecules. To provide better answers to these inconsistencies an alternative theory involving allele-based, antigen presentation-independent mechanism is proposed here. Recent research findings in rheumatoid arthritis, an emblematic HLA-associated disease, lend support to the proposed theory. ... Read more

Personalized Medicine: Theranostics (Therapeutics Diagnostics) Essential for Rational Use of Tumor Necrosis Factor-alpha Antagonists

Abstract: With the discovery of the central pathogenic role of tumor necrosis factor (TNF)-α in many immunoinflammatory diseases, specific inhibition of this pleiotropic cytokine has revolutionized the treatment of patients with several non-infectious inflammatory disorders. As a result, genetically engineered anti-TNF-α antibody constructs now constitute one of the heaviest medicinal expenditures in many countries. All currently used TNF antagonists may dramatically lower disease activity and, in some patients, induce remission. Unfortunately, however, not all patients respond favorably, and safety can be severely impaired by immunogenicity, i.e., the ability of a drug to induce anti-drug antibodies (ADA). Assessment of ADA is therefore an important component of the evaluation of drug safety in both pre-clinical and clinical studies and in the process of developing less immunogenic and safer biopharmaceuticals. Therapeutics diagnostics, also called theranostics, i.e., monitoring functional drug levels and neutralizing ADA in the circulation, is central to more effective use of biopharmaceuticals. Hence, testing-based strategies rather than empirical dose-escalation may provide more cost-effective use of TNF antagonists as this allows therapies tailored according to individual requirements rather than the current universal approach to diagnosis. The objective of the present review is to discuss the reasons for recommending theranostics to implement an individualized use of TNF antagonists and to highlight some of the methodological obstacles that have obscured cost-effective ways of using these therapies. ... Read more

Autoimmunity, End Organ Damage, and the Origin of Autoantibodies and Autoreactive T Cells in Systemic Lupus Erythematosus

Abstract: Systemic lupus erythematosus (SLE) is a prototype of systemic autoimmunity affecting many systems. Both antibodies and autoreactive T cells play significant roles in its pathogenesis. Experimental data and clinical observations indicate that autoimmunity and end organ damage are under separate genetic controls and that there are significant interactions between these two pathways. Experimental evidence has been obtained to support the hypothesis that autoantibodies and autoreactive T effector cells may be initiated by environmental factors through molecular mimicry and the inherent polyreactive nature of antigen receptors. A unified hypothesis has been postulated for the pathogenesis of SLE that has practical implications. ... Read more

B-cell Lymphomagenesis in Autoimmune Diseases: the Missing Links

Abstract: Patients with autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and Sjögren's syndrome have an increased risk of developing B-cell non-Hodgkin's lymphomas but the mechanisms behind this phenomenon remain unknown. By focusing on recent research reports we explore and discuss some of the proposed mechanisms that contribute to this link. The complexity is enormous and can involve genetic and environmental factors, chronic immune stimulation by antigens, and even the treatment for these autoimmune diseases. These mechanisms can be combined in different ways causing great variability in one's predisposition to lymphomagenesis. Knowing more about these pathways is urgent. The more we know about autoimmune diseases the better we can treat our patients effectively and the more we can prevent lymphomas from developing. ... Read more

Environmental Triggers and Epigenetic Deregulation in Autoimmune Disease

Abstract: The study of epigenetic mechanisms in the pathogenesis of autoimmune diseases is receiving unprecedented attention from clinicians and researchers in the field. Autoimmune disorders comprise a wide range of genetically complex diseases, including systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, and multiple sclerosis. Together they affect a significant proportion of the population and have a great economic impact on public health systems. Epigenetic mechanisms control gene expression and are influenced by external stimuli, linking environment and gene function. A variety of environmental agents, such as viral infection, hormones, certain drugs, and pollutants, have been found to influence the development of autoimmune diseases. On the other hand, there is considerable evidence of epigenetic changes, particularly DNA methylation alterations, in diseases like systemic lupus erythematosus, rheumatoid arthritis, or multiple sclerosis. However, the gap in our understanding between the specific effects of external agents and the influence on epigenetic profiles has not yet been filled. Here we review a number of studies describing epigenetic alterations in autoimmune diseases and a range of environmental factors that influence the development of autoimmune diseases. We also discuss potential mechanisms linking environment and epigenetics, consider the prospects for future epigenetic studies addressing the relationship between environment and epigenetics, and comment on the use of drugs with an epigenetic-reversing effect in the clinical management of these diseases. ... Read more

Bromodomain Coactivators in Cancer, Obesity, Type 2 Diabetes, and Inflammation

Abstract: Double bromodomain proteins bind to acetylated lysines in histones, bringing associated histone modification and nucleosome remodeling activity to chromatin. The ability of bromodomain regulators to alter chromatin status and control gene expression has long been appreciated to be important in the development of certain human cancers. However, bromodomain proteins have now been found also to be critical, non-redundant players in diverse, non-malignant phenotypes, directing transcriptional programs that control adipogenesis, energy metabolism and inflammation. The fact that such different processes are functionally linked by the same molecular machinery suggests a common epigenetic basis to understand and interpret the origins of several important co-morbidities, such as asthma or cancer that occurs in obesity, and complex inflammatory diseases like cardiovascular disease, systemic lupus erythematosus, rheumatoid arthritis and insulin resistance that may be built on a common pro-inflammatory foundation. ... Read more

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