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Medical Specialties / Rheumatology / Rheumatoid Arthritis


Novel Insight into the Role of Alpha-actinin-1 in Rheumatoid Arthritis

Abstract: The knowledge of rheumatoid arthritis (RA) pathology is rapidly advancing and becoming more and more complex, and a simple fact is that the major organ targeted by RA pathogenic factors is the synovium. It is well known that fibroblast-like synovial (FLS) cell is the major cell-type for constructing synovium. Following stimulation by pro-inflammatory cytokines, FLS cells are phenotypically changed to have the capability to proliferate abnormally. Recently we demonstrated that α-actinin-1 (ACTN1) gene is significantly increased in synovial tissues obtained from RA, as compared to osteoarthritis (OA). We therefore reviewed the literature about α-actinins (ACTNs) and we now propose that ACTN1 may function as a "terminal effector" of intracellular signalings initiated by tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1) in RA. Future research on ACTN1 may help to improve the current therapeutic and diagnostic strategies of RA. ... Read more

Pharmacogenomics in Childhood Rheumatic Disorders: A Foundation for Future Individualized Therapy

Abstract: Investigating the effect of genotype on drug response in children is an evolving field, with many challenges, but there is great potential to optimize safe and effective use of drugs in children. An exponential increase in available medications for use in children with rheumatic disease has opened seemingly endless genotype/phenotype relationships to explore, but challenges inherent in studying rare diseases and the often overlooked role of ontogeny contribute to limitations in pharmacogenomic studies in this population. With careful recognition of the importance of development, improved phenotyping with the incorporation of biomarkers, and expanding collaborative efforts on a national and even international scale, the field of pediatric rheumatology has the opportunity to strategically study the new therapeutic armamentarium available and provide individualized safe and effective therapies to our population of patients. ... 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

Novel Therapeutic Approaches for Corneal Disease

Abstract: Congenital and acquired corneal opacities, and diseases of the ocular surface, are blinding conditions that impose physical, psychological, and financial constraints upon the sufferer. In the past, corneal and corneal epithelial stem cell transplantation have been the major treatment for severe corneal and ocular surface disease, respectively, but the sequelae of neovascularization and inflammatory eye disease cause many grafts to undergo irreversible immunological rejection. Furthermore, in the case of corneal dystrophies, the original disease may recur in the graft. New therapeutic options for diseases of the cornea and ocular surface are now being actively explored in experimental animals and in clinical trials. Antibody-based biologics are being tested for their ability to reduce blood and lymphatic vessel ingrowth into the cornea, and to reduce inflammation. Many new biomaterials are being examined for their capacity to transfer drugs and corneal epithelial cell progenitor cells to the ocular surface and anterior segment of the eye. New component-cell corneal transplantation procedures that may reduce the risk of immunological rejection have been developed and are already in clinical practice. Finally, gene therapy is being tested in experimental animals to improve the outcomes of corneal transplantation, and to halt or reverse the pathophysiology of some corneal dystrophies. ... 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

Challenges in the Diagnosis of Chronic Immune-mediated Rheumatic Diseases

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

Current Concepts in Diagnosing and Managing Primary Vitreoretinal (Intraocular) Lymphoma

Abstract: Primary vitreoretinal lymphoma (PVRL), previously called primary intraocular lymphoma (PIOL), is a rare and fatal ocular malignancy. PVRL is a subset of primary central nervous system lymphoma (PCNSL), mostly a diffuse large B-cell lymphoma. The diagnosis of PVRL is often challenging as it often masquerades as chronic uveitis. PVRL requires invasive procedures for tissue diagnosis. Cytology/pathology, molecular pathology (immunoglobulin or T-cell receptor gene rearrangement), immunohistochemistry, biophysical technology (flow cytometry), and cytokine analysis (interleukine-10) are often required. The therapies that have been successful in systemic lymphomas have not been reliably effective in PVRL and PCNSL. Current management of PVRL involves aggressive chemotherapy (methotrexate and rituximab) and radiation therapy. PVRL normally responds well to initial treatment; however, relapse rate and CNS involvement are high, resulting in poor prognosis and limited survival. A professional team of medical experts in ophthalmology, oncology (particularly neuro-oncology), and pathology is essential for optimizing patient management. ... Read more

Adipokines: Novel Players in Rheumatic Diseases

Abstract: A large body of evidence from clinical and experimental studies is aiding to understand the close relationships between obesity and rheumatic diseases. For instance, it is generally accepted that obesity contributes to the development of osteoarthritis by increasing mechanical load of the joints, at least in weight bearing joints. However, besides mechanical effects, recent studies demonstrated that white adipose tissue is able to secrete a plethora of soluble factors, called adipokines, which have a critical role in the development and progression of some rheumatic diseases such as osteoarthritis and rheumatoid arthritis. In this article, we summarize the recent findings on the interaction of certain adipokines with the two most common rheumatic diseases: osteoarthritis and rheumatoid arthritis. ... Read more

Rheumatoid Arthritis and Alzheimer's Disease: Genetic and Epigenetic Links in Inflammatory Regulation

Abstract: Controversial data are available about the relationship between Alzheimer's disease (AD) and rheumatoid arthritis (RA). An inverse relationship between AD and RA, due to different factors, was previously described. Similarly to RA, AD pathogenesis is multifactorial and different findings support the inflammatory pathogenetic hypothesis. Several inflammatory mediators are involved in the disease onset and progression regulated by genetic and epigenetic mechanisms. Among them, inteleukin-6 (IL-6) and interleukin-1 (IL-1) as pro-inflammatory soluble factors produced by monocytes-macrophages and tumor necrosis factor alpha (TNF-α) produced by activated macrophages and mononuclear cells represent key molecules in the induction and maintenance of chronic inflammation in RA. In particular a link with the T allele of the SNP 3953 T/C in the IL-1 gene and an overexpression of miR-146a appears to be common to both RA and AD. In this review we will discuss the genetic and epigenetic regulation of the inflammatory cascade in RA and AD to find out the possible links between RA and AD onset. ... Read more

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