The use of TNF inhibitors has been associated with a number of cases of TB, mostly through reactivation. Part of the explanation for the link between TB and TNF inhibition is the presence of a defect in cell-mediated immunity in active RA. Indeed, peripheral blood mononuclear cells from patients with RA respond poorly to the synergistic interactions between IL-12 and IL-18 to produce IFNγ, the key cytokine for protection against intracellular pathogens. Such a defect is related to disease activity as it is partially reversible in responders. IL-17 expression, which is linked to RA disease activity, has an enhancing effect on this immune defect through a specific down-regulation of the IL-12–specific chain of the IL-12 receptor. Lack of a functional receptor leads to reduced response to IL-12 and production of IFNγ, increasing the risk of TB reactivation.
An important limitation of TNF inhibitors is the necessity for continuous therapy. In general, disease recurs a few months after stopping treatment. This indicates that mechanisms upstream or downstream of TNF are still activated and reemerge when TNF inhibition is stopped. IL-17 may have a role in this setting through its effect on synoviocyte survival. Treatment of synoviocytes with IL-17 inhibits activation-induced apoptosis. Furthermore, arthritic mice with chronic streptococcal cell wall arthritis where the IL-17 receptor (IL-17R) has been inactivated have reduced disease activity with increased synoviocyte apoptosis. This is in part related to the enhancing effect of IL-17 on synoviolin expression. Synoviolin is an anti-apoptotic molecule, and elevated levels of synoviolin in RA blood have been associated with lack of response to infliximab.16
Long-lasting remission and even a cure for RA is the next goal of therapy. My friend Vijay Kuchroo, DVM, PhD, professor of neurology at Harvard Medical School in Boston, has established a key point by showing that inflammation itself is able to induce defects in regulatory T cells.17 As indicated above, the classical proinflammatory cytokines IL-6, IL-1, and TNF interact with IL-23 to promote the Th17 pathway. Chronicity follows when IL-17, in turn, inhibits the T regulatory pathway. Inhibition of TNF, which also affects IL-17 production, can partially correct these regulatory defects. It is suggested that control of IL-17, either directly with IL-17–specific inhibitors or upstream by acting on IL-23, may be needed to restore a full regulatory function. This could lead to a reactivation of repair mechanisms, which are completely depressed by inflammation.
Plans for Use of IL-17 Inhibitors
One may ask why it took so much time to consider the use of IL-17 inhibitors in the treatment of RA. In 1995 and 1996, Schering-Plough had a blocking anti–IL-17 antibody and a patent on the protein. Immunex had a soluble IL-17 receptor and a patent for the IL-17 receptor. Since neither company had the full rights to the development of IL-17 inhibitors for RA, it is likely they were unwilling to plan a clinical trial, possibly afraid of a lawsuit from the other competitor. It took 20 years to administer a biological inhibitor of IL-17 to humans. Strangely, this was performed in 2007 by another company, Novartis, without longstanding interests in IL-17.
