Researchers are uncovering new drugs with new mechanisms of action that span the distance between the basic science of immunology and the clinic. It is important that clinicians understand the underlying background and targets of these new drugs in order to apply these advances in treating rheumatoid arthritis (RA). RA researchers are approaching the onset of a new era of therapeutic agents that combine the ease of oral administration with therapeutic efficacy that may be as effective as antibody-based therapy for RA. These new agents, kinase inhibitors, target activity in intracellular signaling pathways responsible for the activation of pathogenic immune cells. This has led to increased attention to signaling pathways to evaluate their potential for generating more specific and high-affinity small organic molecules.
This research and its application were addressed in the ACR Immunology Updates for the Clinician, “New Targets in Rheumatoid Arthritis: SYK, JAKs, BTK,” at the 2011 ACR/ARHP Annual Scientific Meeting in November. [Editor’s note: This session was recorded and is available via ACR SessionSelect at www.rheumatology.org.] Leading the session, Iain B. McInnes, FRCP, PhD, FRSE, professor of experimental medicine and rheumatology and director of the Institute of Infection, Immunity, and Inflammation at the University of Glasgow in Scotland, said he is speaking to those clinicians “who are trying to set themselves up for the new generation” of treatment. Dr. McInnes said, “What we need in the way of therapeutics should be at least as good if not better than what is available for us within our current best strategy.” Fortunately, Dr. McInnes continued, “therapeutic options in treatment of rheumatoid arthritis are expanding rapidly with the advent of novel strategies of treatment together with arrival of new therapeutic agents including biologics.”
Pathological Landscape of the Rheumatoid Process
RA is a three-phase process, a multi-hit phenomenon in which environmental factors, including but not confined to smoking, periodontal disease, and changes in gut microbiology, bring about epigenetic modifications in the structure of some cell proteins. These epigenetic changes cause the immune system to find the affected cells interesting, which leads to autosensitivity of the cell and the body’s inability to tolerate the cell’s altered makeup. This phase of intolerance may occur for several years before the patient develops RA. Therefore, the patient is often an immunological patient before becoming a rheumatoid patient.
The immunological underpinning of the RA process supports the early breach of tolerance and perpetual chronicity, and therefore some may assume that a one-size-fits-all drug approach is adequate. However, the clinical implication of that is immunologically and clinically naive. The immunological patient moves through four stages to reach the condition of RA:
- Pre RA
- Early RA
- Breach of tolerance
- Established chronic phase
Rheumatologists need to understand each stage in order to make informed decisions about treatment. Dr. McInnes thinks that “one of the big advances of the next decade is going to be understanding the distinct pathophysiology of the processes that dominate at distinct stages of disease development and to thereby design our clinical strategies and use of drugs to match the pathology that predominates at that disease stage.”
New Immunology?
New therapeutic treatment options and agents tailored to immunological mechanisms do not require researchers and clinicians to learn anything new about immunology. Dr. McInnes reassured his audience that “the immune system we are talking about in the context of kinase targeting is identical to the one we have already learned about in the past ten years when thinking about biologic therapies.” What is new is that the “new classes of drugs allow us to pick in very specific ways the different parts of the immunological cascade we wish to modify,” explained Dr. McInnes. In other words, physicians “are looking for new targets in the same old immune system.” To do that, they need to understand signaling pathways.
Signaling Pathways
Signaling pathways are interactions between molecules on the outside or on the surface of a cell that in turn lead to interaction with a receptor that will change its properties. In many cases, the interaction is responsible for activation of pathogenic immune cells. Signaling pathways work by changing shape, conformation, or state of cells by exchanging phosphate molecules. The binding of phosphate changes allows kinases to change shape. Signaling pathways then transmit signals via cascades of protein kinases. Thus, kinases are efficient ways of entering a cell and discovering or rediscovering targets inside the cell.
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.
Ann Kepler is a medical journalist based in Chicago.
