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

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

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

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

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

Abstract: Arthritic disease is one of the most common age-related pathologies worldwide. The erosion of cartilaginous tissues from articular surfaces within the joint and the failure to efficiently repair and regenerate this region with age lead to debilitating joint destruction, severe pain, and a crippling loss of function. In addition to the accumulative damage brought about by years of mechanical forces acting upon this region of tissue, there are also defects in underlying biological mechanisms which predispose the older population to excessive joint erosion. This occurs as aberrations in normal chondrocyte biology lead to a reduction in crucial matrix proteins and inhibitory molecules, and elevated production of destructive enzymes. The end result is an accelerated loss of articular cartilage and increased erosion of the joint. As a significant global link exists between aging and the onset of arthritis, this review will consider whether factors known to affect lifespan may also play a role in arthritic disease. ... Read more

Abstract: Vitamin D deficiency is highly prevalent in the general population including individuals with rheumatoid arthritis (RA). Autocrine regulation of vitamin D modulates important biologic processes including immune responses. Vitamin D deficiency has been implicated in the pathogenesis of several autoimmune diseases including RA. Vitamin D regulates both the innate and adaptive immune responses. Recent evidence indicates that vitamin D's effects on the innate immune system are predominantly through the toll-like receptors (TLR) and on the adaptive immune system through T cell differentiation, particularly the Th17 response. As Th17 cells are critical in the pathogenesis of RA, this has led to an interest in the effects of vitamin D deficiency in RA. Several studies have looked at the association of vitamin D deficiency with markers of disease activity in RA with somewhat mixed results. Based on these results, although the role of vitamin D in mediating various biological processes is well defined, this has not translated into meaningful clinical associations in RA. Herein, we review the immune-modulatory role of vitamin D and its effects on pathogenesis, disease activity, and cardiovascular risk in RA. ... Read more

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

Abstract: There have been numerous chemoprevention trials in the past 10 years, but the number of approved chemoprevention drugs is still quite small. This is likely due to a number of factors, but two consistent problems in the field of chemoprevention have been the lack of efficacy with or without unacceptable toxicity, and unexpected toxicity or fear of it associated with most of the approaches. This review intends to describe the types of chemoprevention as well as highlight recent successes and failures. We will also discuss potential solutions for the problems of limited efficacy and toxicity. ... Read more

Abstract: There is a significant association between rheumatoid arthritis (RA) and periodontal disease (PD). Patients with longstanding active RA have been found to have a substantially increased frequency of PD compared with healthy subjects. Further, patients with PD have been shown to have a higher prevalence of RA than patients without periodontitis. Antibodies to Gram-negative, anaerobic periodontal pathogens such as Porphyromonas gingivalis, Prevotella intermedia, Prevotella melaninogenica, and Tannerella forsythia have been detected in the serum and synovial fluid of RA patients. These pathogens have also been identified in the synovial fluid of RA patients, with higher levels of bacterial DNA in RA patients than in controls. This review examines the association between periodontopathic bacteria and the etiology of RA. ... Read more