Abstract
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.
Highlights
The development of new therapies for rheumatic diseases was mainly empiric until recently
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
The new biologics are ineffective in many individuals; in some situations, like systemic lupus erythematosus (SLE), no new effective therapies have been approved for decades
Summary
The development of new therapies for rheumatic diseases was mainly empiric until recently. APRIL, a proliferation-inducing ligand; BAFF, B-cell activation factor of the tumor necrosis factor family; BLyS, B-lymphocyte stimulator; ERK, extracellular regulating kinase; GPCR, G-protein coupled receptor; IL, interleukin; JAK, Janus kinase; LIGHT, lymphotoxin-related inducible ligand that competes for glycoprotein D binding to herpes virus entry mediator on T cells; LT, lymphotoxin; mAb, monoclonal (therapeutic) antibody; MEK, mitogen-activated protein kinase; P13K, phosphatidylinositol 3-kinase; PDGF-R, platelet-derived growth factor receptor; RA, rheumatoid arthritis; RANKL, receptor activator of nuclear factor-kappa B ligand; sJIA, systemic juvenile idiopathic arthritis; SLE, systemic lupus erythematosus; SMIP, small modular immunopharmaceutical; Syk, spleen tyrosine kinase Both benefits and side effects of kinase inhibitors are often observed because of structural similarities between enzymes, especially in the ATP site where most small compounds bind. PI3Kγ deficiency decreases disease activity in murine lupus models [69]
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