ABSTRACT
In contrast to traditional disease-modifying antirheumatic drugs, biologics are novel agents that are developed specifi cally to target key pathophysiologic pathways in autoimmune diseases, such as rheumatoid arthritis (RA), with high specifi city. Success achieved so far in the blockade of tumor necrosis factor (TNF)-α in RA exemplifi es the feasibility and potential therapeutic application of antagonizing cytokine signaling. Identifi cation of additional pro-infl ammatory factors and an understanding of their eff ector function now off er major possibilities for the generation of additional novel biological therapeutics to address unmet clinical needs. Such interventions will ideally fulfi ll several of the following criteria: control of infl ammation, modulation of underlying immune dysfunction by promoting the re-establishment of immune tolerance, protection of targeted tissues such as bone and cartilage, and preservation of host immune capability to avoid profound immune suppression and amelioration of co-morbidity associated with underlying RA. A number of preclinical development programs are ongoing to target a variety of cytokines that are central to immune regulation and tissue-matrix destruction in RA. Considerable evidence has been presented to indicate that pro-infl ammatory cytokine network involving IL-6, IL-15 and IL-17 are suitable therapeutic targets for eff ective amelioration of infl ammation and bone destruction. In addition,
IL-7, IL-18, IL-19, IL-20, IL-22 and IL-32 are fascinating novel pro-infl ammatory cytokines, which should be targeted and off er new therapeutic options for RA. Th e quest for chemically amenable targets has recently led to the identifi cation and characterization of the intracellular signaling pathways associated with these infl ammatory cytokines. In particular, the mitogen-activated protein kinase (MAPK) pathways, which provide the essential link between receptor signals and nuclear transcription, off er several potential therapeutic opportunities for RA. Th is review provides an update on cytokine activities, MAPK signaling pathways activated, and novel strategies that represent, in our opinion, optimal utility as future therapeutic targets.
