Garden of therapeutic delights: new targets in rheumatic diseases

Advances in our understanding of the cellular and molecular mechanisms in rheumatic disease fostered the advent of the targeted therapeutics era. Intense research activity continues to increase the number of potential targets at an accelerated pace. In this review, examples of promising targets and agents that are at various stages of clinical development are described. Cytokine inhibition remains at the forefront with the success of tumor necrosis factor blockers, and biologics that block interleukin-6 (IL-6), IL-17, IL-12, and IL-23 and other cytokines are on the horizon. After the success of rituximab and abatacept, other cell-targeted approaches that inhibit or deplete lymphocytes have moved forward, such as blocking BAFF/BLyS (B-cell activation factor of the tumor necrosis factor family/B-lymphocyte stimulator) and APRIL (a proliferation-inducing ligand) or suppressing T-cell activation with costimulation molecule blockers. Small-molecule inhibitors might eventually challenge the dominance of biologics in the future. In addition to plasma membrane G protein-coupled chemokine receptors, small molecules can be designed to block intracellular enzymes that control signaling pathways. Inhibitors of tyrosine kinases expressed in lymphocytes, such as spleen tyrosine kinase and Janus kinase, are being tested in autoimmune diseases. Inactivation of the more broadly expressed mitogen-activated protein kinases could suppress inflammation driven by macrophages and mesenchymal cells. Targeting tyrosine kinases downstream of growth factor receptors might also reduce fibrosis in conditions like systemic sclerosis. The abundance of potential targets suggests that new and creative ways of evaluating safety and efficacy are needed.     

Cytokines in rheumatic diseases

IL-1 and related cytokines have multiple biologic activities relevant to the rheumatic diseases. In addition to mediating inflammatory and immune responses, these proteins regulate many aspects of connective tissue metabolism. The cytokines interact in complex cascades: because of this, and various technical reasons, the exact role of cytokines in the pathogenesis of rheumatic diseases remains uncertain. However, considerable experimental data suggest that the abnormal regulation of cytokines contributes to such siseases as inflammatory arthritis, systemic lupus erythematosus, scleroderma, and dermatomyositis. Animal models of these diseases have contributed to understanding the role of cytokines in pathogenesis. Furthermore, drugs useful in treating these diseases affect cytokine pathways; some cytokines, their antagonists, or related substances have been used therapeutically to treat rheumatic diseases. The therapeutic use of these agents will likely increase as knowledge about the role of cytokines in the pathogenesis of rheumatic diseases expands.Abbreviations CSF colony stimulating factor - ELAM endothelial leukocyte adherence molecule - FGF fibroblast growth factor - ICAM intercellular adhesion molecule - IFN interferon - IL interleukin - LFA lymphocyte function-associated antigen - LIF leukemia inhibitory factor - MCAF monocyte chemotactic/activitating factor - MCP monocyte chemoattractant protein - MDP muramyl dipeptide - PAI plasminogen activator inhibitor - PBMC peripheral blood mononuclear cells - PDGF platelet derived growth factor - PG prostaglandin - PHA phytohemagglutinin - Ra receptor antagonist - SLE systemic lupus erythematosus - SSc systemic sclerosis - TGF transforming growth factor - TNF tumor necrosis factor     

Osteoimmunology in rheumatic diseases

This review summarizes the recent advances of osteoimmunology, a new research field that investigates the interaction of the immune system with the skeleton. Osteoimmunology has contributed significantly to the understanding of joint destruction in rheumatoid arthritis and other forms of arthropathies. In particular, the molecular regulation of osteoclast formation and its control by proinflammatory cytokines have helped investigators to understand the mechanisms of bone erosion in rheumatic diseases. Osteoimmunology has also allowed an improvement in our knowledge of the structure-sparing effects of antirheumatic drug therapy. Moreover, recent advances in the understanding of the molecular regulation of osteophyte formation are based on the characterization of the regulation of bone formation by inflammation. This review highlights the key insights into the regulation of bone destruction and formation in arthritis. Moreover, concepts of how bone influences the immune system are discussed.     

What's new in gastroenterology

The philosophy of treatment in eclampsia cannot rest upon the principle of combatting every symptom with many therapeutic weapons until the symptom, and occasionally the patient, fades away. It should rest rather upon assisting the maternal organism to keep its own compensatory efforts within the bounds of safety, preventing damage to vital organs where possible, and removing the cause of the disease by termination of the pregnancy whenever that may be done with safety to both mother and child. Such assistance must necessarily be based upon current understanding of the disturbances which underlie each symptom.     

What's new in surgery

Anesthesia entails some risk of morbidity. This morbidity can be minimized by adequate preoperative preparation of the patient, by judicious selection and proper administration of anesthetic agents and by proper care in the early postoperative period. Properties of various anesthetic agents are discussed with regard to their systemic effects, with emphasis upon the effect on patients with impaired function of internal organs.     

MicroRNAs in systemic rheumatic diseases

MicroRNAs (miRNAs) are endogenous, non-coding, single-stranded RNAs about 21 nucleotides in length. miRNAs have been shown to regulate gene expression and thus influence a wide range of physiological and pathological processes. Moreover, they are detected in a variety of sources, including tissues, serum, and other body fluids, such as saliva. The role of miRNAs is evident in various malignant and nonmalignant diseases, and there is accumulating evidence also for an important role of miRNAs in systemic rheumatic diseases. Abnormal expression of miRNAs has been reported in autoimmune diseases, mainly in systemic lupus erythematosus and rheumatoid arthritis. miRNAs can be aberrantly expressed even in the different stages of disease progression, allowing miRNAs to be important biomarkers, to help understand the pathogenesis of the disease, and to monitor disease activity and effects of treatment. Different groups have demonstrated a link between miRNA expression and disease activity, as in the case of renal flares in lupus patients. Moreover, miRNAs are emerging as potential targets for new therapeutic strategies of autoimmune disorders. Taken together, recent data demonstrate that miRNAs can influence mechanisms involved in the pathogenesis, relapse, and specific organ involvement of autoimmune diseases. The ultimate goal is the identification of a miRNA target or targets that could be manipulated through specific therapies, aiming at activation or inhibition of specific miRNAs responsible for the development of disease.     

What's new in cardiovascular surgery

Advances in the treatment of congenital cardiovascular lesions have led to a renewed interest in the treatment of acquired heart disease. Although this field could best be served by the perfection of the extracorporal heart, such devices are as yet not ready for human application. Meanwhile, various approaches through the ventricles and left atrium have been developed to treat valvular stenosis. Refinements in diagnostic tests and in methods of physiological investigation are of great aid in the proper evaluation of patients.     

Tissue engineering in the rheumatic diseases

Diseases such as degenerative or rheumatoid arthritis are accompanied by joint destruction. Clinically applied tissue engineering technologies like autologous chondrocyte implantation, matrix-assisted chondrocyte implantation, or in situ recruitment of bone marrow mesenchymal stem cells target the treatment of traumatic defects or of early osteoarthritis. Inflammatory conditions in the joint hamper the application of tissue engineering during chronic joint diseases. Here, most likely, cartilage formation is impaired and engineered neocartilage will be degraded. Based on the observations that mesenchymal stem cells (a) develop into joint tissues and (b) in vitro and in vivo show immunosuppressive and anti-inflammatory qualities indicating a transplant-protecting activity, these cells are prominent candidates for future tissue engineering approaches for the treatment of rheumatic diseases. Tissue engineering also provides highly organized three-dimensional in vitro culture models of human cells and their extracellular matrix for arthritis research.     

Outcome measures in inflammatory rheumatic diseases

Inflammatory rheumatic diseases are generally multifaceted disorders and, therefore, measurement of multiple outcomes is relevant to most of these diseases. Developments in outcome measures in the rheumatic diseases are promoted by the development of successful treatments. Outcome measurement will increasingly deal with measurement of low levels of disease activity and avoidance of disease consequences. It is an advantage for patient management and knowledge transfer if the same outcomes are used in practice and in trials. Continuous measures of change are generally the most powerful and, therefore, are preferred as primary outcomes in trials. For daily clinical practice, outcome measures should reflect the patients' state and have to be easily derivable. The objective of this review is to describe recent developments in outcome measures for inflammatory rheumatic diseases for trials and clinical practice, with an emphasis on rheumatoid arthritis.