title: Beyond TNF: TNF superfamily cytokines as targets for the treatment of rheumatic diseases.
abstract: TNF blockers are highly efficacious at dampening inflammation and reducing symptoms in rheumatic diseases such as rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis, and also in nonrheumatic syndromes such as inflammatory bowel disease. As TNF belongs to a superfamily of 19 structurally related proteins that have both proinflammatory and anti-inflammatory activity, reagents that disrupt the interaction between proinflammatory TNF family cytokines and their receptors, or agonize the anti-inflammatory receptors, are being considered for the treatment of rheumatic diseases. Biologic agents that block B cell activating factor (BAFF) and receptor activator of nuclear factor-κB ligand (RANKL) have been approved for the treatment of systemic lupus erythematosus and osteoporosis, respectively. In this Review, we focus on additional members of the TNF superfamily that could be relevant for the pathogenesis of rheumatic disease, including those that can strongly promote activity of immune cells or increase activity of tissue cells, as well as those that promote death pathways and might limit inflammation. We examine preclinical mouse and human data linking these molecules to the control of damage in the joints, muscle, bone or other tissues, and discuss their potential as targets for future therapy of rheumatic diseases.
authors.affiliation: Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, and Department of Medicine, University of California San Diego, La Jolla, California 92037, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Croft
authors.affiliation: Immunoregulation Section, Autoimmunity Branch, NIAMS, NIH, Bethesda, Maryland, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Siegel
mesh_terms: D053330:4-1BB Ligand / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D053282:CD27 Ligand / Q000037:antagonists & inhibitors / Q000378:metabolism; D023201:CD40 Ligand / Q000037:antagonists & inhibitors / Q000378:metabolism; D016923:Cell Death; D000074049:Cytokine TWEAK; D003713:Dendritic Cells / Q000276:immunology; D053222:Fas Ligand Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance; D008213:Lymphocyte Activation; D008233:Lymphotoxin-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D058990:Molecular Targeted Therapy; D053278:OX40 Ligand / Q000037:antagonists & inhibitors / Q000378:metabolism; D012216:Rheumatic Diseases / Q000188:drug therapy* / Q000276:immunology*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000037:antagonists & inhibitors / Q000378:metabolism; D000079424:Tumor Necrosis Factor Inhibitors; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14 / Q000037:antagonists & inhibitors / Q000378:metabolism; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000276:immunology / Q000378:metabolism*
chemical_list: D053330:4-1BB Ligand; D053282:CD27 Ligand; D000074049:Cytokine TWEAK; D053222:Fas Ligand Protein; D008233:Lymphotoxin-alpha; D053278:OX40 Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C109743:TNFSF12 protein, human; C478967:TNFSF18 protein, human; D000079424:Tumor Necrosis Factor Inhibitors; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15; D048069:Tumor Necrosis Factors; D023201:CD40 Ligand