Rheumatoid Arthritis: Basic Facts
Here is a video created by Pfizer that is also useful to gain a little more knowledge about rheumatoid arthritis as well as providing some good visual sources of what the disease looks like.
The mechanism of how rheumatoid arthritis develops is understood to some extent but there are large areas of uncertainty too. For example, the trigger that sets off this autoreactivity to self in the joints is unknown. However, it is known that the process is dependent on both T and B cells as knock-out mice who are deficient of both these lymphocytes have shown to be resistant to the disease. The diagram below shows the progression though which the mechanism of rheumatoid arthritis was discovered.
It is now known that CD4+ T cells contribute to the intiation of the disease and macrophages cause perpetuation of the disease. The animation below shows how this process works.
So, we can see that CCL2 and therefore its receptor CCR2 play a role in the early initiation stages of the disease and also the progression towards a chronic inflammatory state. For this reason, it has been and still is a major topic of research as a therapeutic target. At the moment, the ‘gold-standard’ treatment for rheumatoid arthritis is anti-TNF-α treatment (involving antibodies targeted towards this cytokine) alongside steroids and methotrexate (Disease Modifying Anti-Rheumatic Drugs or DMARDS). Whist this treatment is effective in around 40% of patients, there is still a need to develop new therapies to tackle this disease in patients who are non-responders in cases of secondary and tertiary resistance (1).
Table showing how these potential therapeutic interventions have been studied
This table demonstrates the importance of CCR2 targeting for rheumatoid arthritis treatment although it does highlight some discrepancies as to how effective inhibition can be achieved. Also, it is worth noting that some studies using genetic approaches with knock-out mice have showed contradictory evidence as to whether CCR2 is an effective target for ameliorating this disease. A worsening of arthritis was seen with CCR2-deficient mice which can be explained by activation-induced cell death due to CCR2 deficiency. This raises the issue of safety and where it is plausible to knock-out these receptors in the clinical setting (1).
Is CCR2 the Correct Receptor to Target?
In light of the failings of clinical trials using CCR2 blockade in rheumatoid arthritis, it has to be questioned whether CCR2 is worth targeting in this disease. As shown in the mechanism of the disease profile and the studies done in animal models, CCR2 definitely contributes to rheumatoid arthritis incidence or progression in some way. However, it is now noted that other synovial fluids may be acting as the ligand to CCR2 to induce monocyte chemotaxis, rather than MCP-1/CCL2. This may be why failure of CCR2 therapeutics in rheumatoid arthritis has occurred. It has been suggested that CCR1 is a more useful target. Although it has failed in clinical trials, an increase in receptor occupancy of CCR1 may prove to be successful in vivo (3).
Conclusions
1) CCR2 is involved in rheumatoid pathogenesis
2) It has been researched extensively in mice with some successful results using mainly antagonists to the receptor
3) Clinical trials so far have failed
4) It may be more feasible to look at targeting a different chemokine receptor in this disease or looking at targeting a variety of chemokine receptors at once
I hope I've shown you how current a topic CCR2 blockade is with regards to rheumatoid arthritis. Whilst many developments have been made in the area of research, it is quite clear that more work needs to be done in order to transfer the findings into the clinic.
No comments:
Post a Comment