Q2. What is the promising approach to induce tolerance in RA?
(iii) Reduction of antigen expression and prevention of the formation of pathogenic immune complexes in RA is another promising approach to induce tolerance [93].
Q3. What is the role of osteoclasts in the development of RA?
Osteoclasts as the main bone resorbing cells are highly responsive to antibodies and inflammatory cytokines in particular TNF, IL-1 and IL-6/IL-6R complexes, which all induce osteoclast differentiation either directly or by inducing the master differentiation factors of osteoclasts, RANKL [74].
Q4. What is the role of IL-6 in osteoclasts?
JAKi may indirectly affect osteoclast function through blocking the action of IL-6/IL-6R signalling in osteoclasts and hence preserve bone form resorptive damage.
Q5. What is the role of cytokine inhibitors in rheumatoi?
More recently, Janus kinase inhibitors have demonstrated that cytokine receptor families served by JAK/STAT dependent signaling are critical for disease, in part replicating the findings for IL-6 blockade but adding new knowledge as to the roles played by other cytokines e.g. the interferons.
Q6. What is the role of GM-CSF in RA?
Granulocyte-macrophage colony-stimulating factor (GM–CSF) is a pro-inflammatory soluble cytokine implicated by several previous studies in the pathogenesis of RA [24].
Q7. What is the important effect of IL-6R on the cardiovascular system?
Most importantly control of inflammation in RA has shown to affect cardiovascular risk: Methotrexate moderately lowers cardiovascular risk in RA [82].
Q8. What are the factors leading to increased cardiovascular risk in RA?
The duration and severity of inflammatory disease activity have been identified as factors leading to increased cardiovascular risk in RA.
Q9. What are the main approaches to reversing the proinflammatory microenvironment in RA?
targeting the epigenetic modifications of synovial fibroblasts in RA such as histone acetylation or bromodomain and extra-terminal (BET) proteins are interesting approaches, which may reverse the proinflammatory microenvironment, which continuously attracts immune cells to the joint [65-67].
Q10. What is the effect of IL-6R on the lipid metabolism in RA?
lipoprotein particles such as HDL change their composition with higher contents of acute phase proteins such as serum amyloid A (SAA) in RA patients.
Q11. What is the main reason for the cytokine inhibitors being used?
treatment with cytokine inhibitors is particularly effective in preventing structural damage even in the absence of full control of inflammation.
Q12. What are other approaches to reversing the proinflammatory microenvironment in RA?
Other approaches the can be envisioned is targeting molecules which are responsible for the proliferation of synovial fibroblasts such as synoviolin or Tyro-3 [63, 64].
Q13. What is the main reason for the elevation of cardiovascular risk in RA?
The intrinsic elevation of cardiovascular risk in RA may be considered to result from systemic immune activation and inflammation.
Q14. What is the significance of IL-6 in the pathogenesis of RA?
That synovial IL-6 levels can also predict subsequent responses to IL-6R blockade has also been suggested suggesting that the absolute local IL-6 concentration is of pathologic importance [23].
Q15. What is the main environmental factor inducing the citrullination of proteins?
Cessation of smoking, which is the main environmental factor inducing the citrullination of proteins, is most likely the easiest and most cost-effective approach in this respect but other targeted approaches such as small-molecule inhibitors of peptidyl deiminases, the enzymes responsible for protein citrullination, are in development [94].
Q16. What is the role of abatacept in RA?
Abatacept is a potent modulator of T cell activation in ex vivo studies though importantly it does not appear to enhance regulatory T cell responses.
Q17. What are the main factors that increase the risk of cardiovascular disease in RA?
other factors such disease-associated functional disability and glucocorticoid intakefurther increase the development of cardiovascular risk [79].
Q18. What are the main reasons for the lag in the development of cellular therapies inducing?
This lag in the development of cellular therapies inducing tolerance has several reasons, which are based on challenges related to (i) absence of a single autoantigen triggering immunity in RA, (ii) challenges in feasibility and standardization of cell-based therapy approaches targeting joint disease and (iii) the success of biologic and small-molecule drug approaches to treat RA.
Q19. What are the main findings of the study?
These studies have refreshed interest in targeting T cell dependent effector and regulatory pathways for the future development of therapeutics.
Q20. What is the role of IL-6 in RA?
As such it is timely to consider the invaluable opportunity offered by investigating the success and failure of specific targeted immune therapeutics in RA – in this sense they are serving as molecular scalpels to dissect mechanisms of disease.
Q21. What is the main effect of dendritic stem cells on RA?
a small trial showed that administration of allogeneic adipose-derived mesenchymal stem cells has an effect on treatment-resistant RA [70].
Q22. What is the role of ocrelizumab in RA?
Based on these encouraging pathologic insights, other CD20-targeted antibodies (e.g. obinutuzumab, ibrtumomab, ocaratuzumab) that could offer more potent depletion properties were considered but have either not started or advanced to larger scale trials in RA with the exception of the anti-CD20 antibody ocrelizumab which showed clinical efficacy in RA but was stopped due to increased infectious risk [55].
Q23. What are the key factors determining bone and cartilage damage in RA?
Presence of autoantibodies and duration of arthritis, resembling the exposure time of bone to inflammatory cytokines, therefore resemble the key factors determining bone and cartilage damage in RA.
Q24. What is the role of IL-6 in inflammatory response?
Taken together these studies suggest that IL-6 occupies a pivotal position in regulating both T cell migration, and activation but also in the downstream inflammatory response.