There are key features of a complex signaling pathway:
- It transmits signals (information) from the membrane to the nucleus of the cell.
- There are multiple pathways that may exert functions for one molecule.
- Information is usually mediated via phosphorylation of kinases of tyrosine, threonine, and serine residues.
- It allows the cell to “sense” its extracellular environment.
- It integrates varied external stimuli.
- It allows cross regulation of signals within cells.
Signaling pathways are complex and require ongoing study to identify redundancy and to look for potential problems.
Kinases as Targets in RA Therapy
Kinases are implicated in each phase of pathogenesis of RA. There are questions rheumatologists should ask, however, before starting a patient on a kinase inhibitor. First, he or she should explore the biological plausibility: Is the pathway to be targeted present in relevant tissues (synovium, lymph node, metabolic tissues, vasculature) where it needs to be to affect function in RA?
Second, does the pathway mediate relevant biologic effects? An antiinflammatory pathway, for example, is not useful.
Third, what happens to the target when it is manipulated in vitro or in vino? Do data exist?
In addition, the kinase needs to be amenable to small molecule inhibition. Kinases have been found to be tractable to small molecule inhibition, which often allows for oral administration.
Which kinases should be targeted? There is good clinical evidence that JAK (Janus) kinases and SYK (spleen tyrosine) kinases are good targets. JAK pathway signaling is important for immune cell development, survival, proliferation, and differentiation. Physicians are now finding the JAK inhibitor tofacitanib effective in suppressing collagen-induced arthritis. SYK inhibitors mediate function for the B-cell receptor and regulate the way a B cell reacts to a given antigen. The SYK inhibitor fostamatinib inhibits osteoclastogenesis of murine bone marrow precursor cells. There is enough published research to validate these choices. BTK (Bruton tyrosine) kinases also affect the immune response that is part of the RA picture.
Benefits Versus Disadvantages
Despite the fact that rheumatology is stepping forward into an era of new drugs to treat RA, clinicians and researchers alike have to look at the effectiveness and benefits in light of possible problems and side effects.
Questions remain about the efficacy, safety, clinical effectiveness, cost, convenience, and predictability of these drugs. Long-term effects are always a concern as well. Changes in the immune system, liver function, creatine levels, hemopoiesis, lipid biology, and elevated low-density lipoprotein C must be monitored.
Final Thoughts
There are several factors to consider when looking at new targets in RA. This is plausible and enticing biology, “a new look at an established immunopathology,” said Dr. McInnes. The preliminary data for the use of some of these small molecules is encouraging. However their precise role and placement into the therapeutic regimen is not clear. Further long-term data on their efficacy and safety will help to resolve these issues. Although there is work still to be done, RA therapy has entered a new domain.
