More than just B-cell inhibition

Despite tremendous advances in the therapy of rheumatoid arthritis (RA), there remains interest in oral agents that may offer benefits that are similar to, or better than, those of biologic therapies. In their paper, Chang and colleagues demonstrate the effectiveness of a Bruton tyrosine kinase (Btk) inhibitor in two models of RA. Btk inhibition impacts several pathways affecting both B-cell and macrophage activation, making it a promising target in RA. However, other kinase inhibitors have failed to transition from animal models to human therapy, so it remains to be seen whether a Btk inhibitor will have a role in the RA treatment armamentarium.

Th erapy for rheumatoid arthritis (RA) has advanced tremendously over the past 10 years. Biologic therapy employing recombinant antibodies and receptors has become the standard of care. Neutralization of cytokines (tumor necrosis factor-alpha and interleukin-6), inhibition of co-stimulatory pathways (CTLA4Ig), and B-cell depletion (anti-CD20) have all been shown to be eff ective therapies. However, each requires parenteral adminis tration, is expensive, and may result in undesired side eff ects. Over the last several years, there have been intensi fi ed eff orts to develop small-molecule inhibitors that can be taken orally and that may result in less expensive, safer, and more conveniently administered therapy. In this issue of Arthritis Research & Th erapy, Chang and colleagues [1] present data demon strating the eff ectiveness of a selective Bruton tyrosine kinase (Btk) inhibitor, PCI-32765, in two experimental models of RA.
Btk was originally identifi ed as defective in patients who had X-linked agammaglobulinemia and who exhi bited a profound reduction of B cells. Btk is a non-receptor tyrosine kinase within the Tec family of kinases and contains six domains: pleckstrin homogy (PH), Btk homology, polyproline region, two Src homology (SH2 and SH3), and a tyrosine kinase. Th ough originally identifi ed in B cells (identifying it as a potential B-cell target), it has been found more recently in myeloid cells, including monocytes, macrophages neutrophils, and mast cells [2]. Btk is activated by crosslinking immuno globulins on the surface of B cells and by the ligation of Fc receptors and integrins on myeloid cells, mediated through Src kinases, including Lyn and Syk [3,4], the latter a promising therapeutic target in RA. Src kinase activation of plasma membrane-bound (through the PH domain) Btk results in tyrosine phosphorylation of tyrosine 551 (in the tyrosine kinase domain), which leads to autophosphorylation at tyrosine 223 (in the SH3 domain), resulting in full kinase activity. Activated Btk drives phosphorylation of PLCγ and subsequent PKC activation, which in turn results in the calcium fl ux and the activation of trans cription factors, including nuclear factor-kappa-B (NF-κB) and NF-AT, regulating the expression down stream genes controlling proliferation, survival, and chemokine and cytokine gene expression [2]. PCI-32765, like other Btk inhibitors, was designed to inhibit the activation by select ively interacting with an ATP-binding site in the tyrosine kinase domain, preventing Btk phos phorylation and activation [5][6][7].
Adding to their previously published observations in collagen-induced arthritis [8], Chang and colleagues [1] convincingly demonstrate the therapeutic eff ectiveness of PCI-32765 in collagen-induced arthritis, documenting marked reduction of joint swelling, destruction, and infl am matory mediators. However, their prior publication demonstrated that the improvement was due in part to suppression of the anti-collagen antibody response [8], consistent with the results observed with another Btk inhibitor [5]. However, suppression of the collagen antibody-induced arthritis (CAIA) model, which employed anti-collagen antibodies plus the Toll-like receptor 4 (TLR4) ligand lipopolysaccharide (LPS), by both Btk inhibitors demonstrates an eff ect beyond just suppression of autoantibody production [1,5]. Th e in vitro studies demonstrate the ability to inhibit B-cell activation and proliferation and to inhibit activation Abstract Despite tremendous advances in the therapy of rheumatoid arthritis (RA), there remains interest in oral agents that may off er benefi ts that are similar to, or better than, those of biologic therapies. In their paper, Chang and colleagues demonstrate the eff ectiveness of a Bruton tyrosine kinase (Btk) inhibitor in two models of RA. Btk inhibition impacts several pathways aff ecting both B-cell and macrophage activation, making it a promising target in RA. However, other kinase inhibitors have failed to transition from animal models to human therapy, so it remains to be seen whether a Btk inhibitor will have a role in the RA treatment armamentarium.
through IgG and IgE Fc receptors but not TLR4 [1]. Th e inability to suppress TLR4 signaling confounds the interpretation of the CAIA model, which employs LPS. In contrast, other studies have documented a role for Btk in macrophage activation through TLR4 [9,10]. Th e ability to suppress TLR signaling might be benefi cial in RA since TLR signaling may contribute to the progression of RA mediated by endogenous TLR ligands [11].
How might Btk inhibitors, given their eff ectiveness in animal models, fi t into the armamentarium of therapies for RA? Th at depends on a number of factors. Th e fi rst, and most important, is whether success in animal models will translate to effi cacy in human disease. Th e p38 mitogen-activated protein (MAP) kinase experience, in which a number of compounds that demonstrated promising effi cacy in preclinical animal models failed to deliver on that promise in clinical studies in patients with RA, taught us a valuable lesson in this regard [12,13]. Th e p38 experi ence taught us another important lesson as well: the ubiquitous nature of the kinase family, and its presence in so many diff erent cell types, increases the likelihood of off -target eff ects of inhibitors of these proteins. Th e similarity of the Btk ATP-binding site to other kinase-binding sites makes this concern relevant. For some of the p38 MAP kinase inhibitors that advanced into clinical trials, this resulted in central nervous system eff ects and elevated liver enzymes that threatened to overshadow their modest clinical effi cacy.
Th e two kinase inhibitors that have moved farthest into clinical development -tofacitinib, a JAK kinase inhibitor, and fostamatinib, a Syk kinase inhibitor -have successfully bridged the gap between animal models and human clinical effi cacy. Moreover, early evidence suggests that they have done so with off -target toxicity that is likely to be acceptable in light of their clinical effi cacy. Although this is promising, it remains to be seen whether Btk inhibitors will meet this promise in patients with RA.
Competing interests EMR has received consulting fees from Pfi zer Inc (New York, NY, USA). RMP declares that he has no competing interests.