**Acknowledgments**

also inhibited the expression of macrophage CD40 suggesting that interference with CD40-mediated signaling by macrophages may be the mechanism responsible for the at‐

The medical therapy of RA was revolutionized with the introduction of biological drugs, in‐ cluding TNF antagonists, the IL-6R antagonist, tocilizumab, the T-cell co-stimulatory factor inhibitor, abatacept, the B-cell inhibitor, rituximab and the IL-1 receptor antagonist, anakin‐ ra as well as the use of first-line therapy with disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate and anti-malarial drugs [223]. Nevertheless, the long-term and chronic use of these drugs for treating RA patients is not without potential deleterious consequences for those RA patients who use them. Thus, RA patients prescribed DMARDs and/or biological drugs need to be continuously monitored for changes in liver enzyme lev‐ els, ocular and/or kidney toxicities, infections and to a lesser extent malignancies such as lymphoma [224]. Just as important is the fact that some RA patients fail to respond to one or

Development of JAK-specific SMIs was originally predicated on their use as a treatment for suppressing organ transplant rejection. However, JAK-SMIs were also considered as a po‐ tential adjunctive therapy for overcoming issues of long-term use of biological drugs for the therapy of RA [7, 11, 16, 17]. Now only time will tell whether or not the JAK-specific SMI, tofacitinib [218, 225], will be aggressively employed in the treatment of RA, or whether tofa‐ citinib will be used in RA patients who only have exhibited a moderate or inadequate re‐

Presently, there has been little attention paid, comparatively speaking, on acquiring data from RA patients in the general population who have been treated over several years with biological drugs to determine the extent to which the pro-inflammatory and/or anti-inflam‐ matory cytokine repertoires have been altered from baseline. In addition, there are hardly any systematic studies, with the exception of some analyses conducted (often as a minor component of an RA clinical trial) with respect to which of several biological drugs restore the imbalance between Th1 and Th2 cytokines, suppress the activity of Th17-producing cyto‐ kines, or improve the biological activity of dysfunctional Treg cells [225]. Truly, the possibili‐ ty exists that treating RA patients with biological drugs only partially inhibit overexpression of the pro-inflammatory cytokines that have been shown to mainly contribute to the progression of RA, namely, IL-6, IFN-γ and TNF-α (Table 1). This 'take-home' point ap‐ pears to adequately justify a continual search for alternative cellular mechanisms that are ac‐ tive in determining whether clinical remission in RA patients is sustained or not. In conclusion, determining how STAT-responsive cytokine genes are regulated at the molecu‐ lar and cellular level offers the potential going forward for developing yet another treatment

modality designed to suppress the clinical activity and progression of RA pathology.

several of these biological drugs or become refractory to their action [225].

tenuation of arthritis by the STAT-1 decoy ODN.

sponse to biological drugs or DMARDs.

**10. Conclusion**

394 Drug Discovery

The Arthritis Research Laboratory at Case Western Reserve University School of Medicine was supported by an investigator-initiated project grant from Takeda Pharmaceuticals of North America (Deerfield, IL) and is presently supported by an investigator-initiated project grant from Genentech/Roche Group, (South San Francisco, CA).
