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'Rac'-ing upstream to treat rheumatoid arthritis

DOI: 10.1186/ar2924

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Protein-based therapeutics for rheumatoid arthritis have limitations despite improved clinical outcomes. In addition to expense and the need for parenteral administration, a significant percentage of patients do not have robust responses. Intracellular signaling molecules, such as members of the Rho family [1], represent an attractive alternative because the compounds are often orally bioavailable and can block numerous proinflammatory mediators simultaneously.Targeting signal transduction, however, has been an exercise in frustration until recently. The p38 mitogen-activated protein kinase saga is emblematic of these problems [2]. Despite abundant preclinical data supporting the utility of p38 inhibitors, benefit has been marginal at best [3]. It is important to recognize that success in biologics also did not come with the first attempt. Numerous failures preceded the advent of TNF blockers, including anti-CD4, anti-CD5 and anti-CD52 antibodies, IL-2-diphtheria toxin fusion protein, IFNγ, IL-2, and several others. Clinical efficacy for JAK and Syk inhibitors demonstrated in recent years crossed the Rubicon for signaling-directed therapeutics [4,5]. The question now is not whether some of these agents can be effective; rather, it is whether the toxicity and side effects will be acceptable in a world where biologics have an advantageous therapeutic index.A distinguishing feature of the encouraging interventions (Syk, JAK, and perhaps c-Kit) compared with p38 inhibitors is that the former targets are proximal in the signaling cascade. Going upstream can be risky, since each enzyme casts a broader penumbra of effects than a downstream target. This increases the potential for both benefit and toxicity. Risk, however, can be managed; lack of efficacy cannot.This lesson is being exploited by going far upstream using therapeutics that inhibit the Rac proteins. These signaling enzymes, unlike the classical protein kinases that phosphorylate various transcription factors, a


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