Signal transduction pathways: new targets for treating rheumatoid arthritis.

Biotherapies and other new treatments introduced over the last few years have considerably enriched the therapeutic armamentarium for rheumatoid arthritis. Nevertheless, primary refractoriness or secondary escape phenomenon may occur, indicating a need for identifying new treatment targets. Promising candidates can be found among compounds involved in signal transduction pathways, most notably protein kinases (mitogen-activated protein kinase, MAPK and phosphatidylinositol-3 protein kinase, PI3) and transcription factors (nuclear factor kappa B, NF-kappaB; activating protein 1, AP-1; CCAAT/enhancer-binding protein, C/EBP and signal transducer and activator of transcription, STAT). Inhibition of signal transduction pathways may be achievable via three main strategies: pharmacological inhibitors, anti-sense or more specific inhibitors such as oligionucleotides or interfering mRNA, and induced overexpression of naturally occurring inhibitors. Clinical trials are under way to evaluate pharmacological inhibitors such as p38 MAPK. Although the preliminary results are promising, proof of safety has not yet been obtained. Signal transduction pathways are involved in normal processes, whose inhibition might produce untoward effects.