The mechanism, causes, symptoms, susceptibility, diagnosis and treatments of Rheumatoid Arthritis

1. Autoimmunity
RHEUMATOID ARTHRITIS
By: Seok Shin Law (27527026)
Chi Vo (28733703)
Nash Tapan (28185986)
Sayuri Kakishima (28753402)

2. Mechanism and Target

3. AGE (Advanced glycation endproducts)
modified IgG
Citrullinated
Type II collagen and Vimentin
Immune cells
Unrecognized Self-antigen and proteins
Adapted from:
https://www.slideshare.net/mntmntmint/dendritic-cell
Adapted from:
https://www.prosci-inc.com/blog/Isotypes/
Adapted from:
https://www.omicsonline.org/optimizing-the-identification-of-citrullinated-peptides-by-mass-spectrometry-
jpb.1000293.php?aid=21308

4. Helper T cell Activation B cell activation
Autoantibody production
Antigens presentation
Adapted from:
https://www.immunology.org/public-information/bitesized-immunology/systems-and-processes/t-cell-activation Adapted from: http://www.biology-pages.info/B/B_and_Tcells.html

5. Migrations to the joint
T Helper Cells Autoantibodies

6. T helper cells:
- IFNγ
- IL-17
T Helper Cells
Macrophage:
- TNFα
- IL-1
- IL-6
Synovial cell proliferation
Adapted from:
https://healthychocolatez.com/knee-pain/swollen-knee-without-pain/

7. Pannus formation Protease secretion
Fibroblast-like synoviocytes
Adapted from: https://medical-dictionary.thefreedictionary.com/pannus Adapted from: https://www.sciencedirect.com/science/article/pii/S1063458414011029#fig1

8. Upregulation of RANKL Expression
Osteoclast maturation
Adapted from: https://openi.nlm.nih.gov/detailedresult.php?img=PMC4176903_JIR2014-263625.001&req=4

9. Autoantibodies
Target:
Modified IgG Fc domain
IgM Rheumatoid Factor Anti-cyclic citrullinated peptide
antibody (CCP)
Target:
Citrullinated protein
Immune complexes formations
Joint inflammation and injuries
Complement activation
Adapted from:
https://laboratoryinfo.com/rheumatoid-facto
r-rf-test/
Adapted from:
http://autoimmunityblog.com/2011/03/24/diagno
stic-value-antibodies-mutated-citrullinated-vime
ntin-rheumatoid-arthritis-orgentec/

10. Chronic Inflammation
Angiogenesis
● More inflammatory cells arrive
Adapted from
https://www.slideserve.com/alexis-woodard/angiogenesis

11. SUSCEPTIBILITY

12. Shared epitope is associated with RA
● HLA-DRB1*04 and DRB*01 loci
● Share the same amino acid sequence at peptide binding site, located in the
third hypervariable region of HLA-DB beta chain positions 70-74
● At position 70 of HLA-DB beta chain:
+ Glutamine or Arginine increase the susceptibility for RA
+ Aspartic acid protects individual from RA
Available at:
http://www.jrheum.org/content/41/2/27
0.tab-figures-data

13. Posttranslational events vastly contribute to RA
susceptibility
● Autoantibodies: antibodies directed against self antigens
● Autoantibodies directed against citrullinated proteins have a high specificity
for RA.
● In this family, Anti-cyclic citrullinated peptide (anti-CCP) antibodies is
associated with RA susceptibility → recognise citrulline.
● Citrulline: product of the citrullination of arginine by peptidyl arginine
deiminase (PAD) enzyme

14. Environmental factor acts as a trigger
● Smoking triggers RA regardless of the presence of anti-CCP antibody →
stronger response in presence of anti-CCP and SE.
● Citrullinated proteins were found in lung cells of smokers

15. SYMPTOMS AND
DIAGNOSIS

16. Rheumatoid arthritis (RA) is generally characterised
by swelling of the joints
INFLAMMATION
- leukocyte infiltration into the
synovial membrane
- induce inflammatory response
via cytokine secretion (TNF and
IL-6)
- persistent inflammation
leading to joint destruction Fig.1 Normal vs. Inflamed synovial membrane;
adapted from: Rheumatoid arthritis (Smolen et al., 2016)

17. Joint inflammation may also give rise to other
symptoms
Including:
- Pain, restricted movement, lumps development, tightness, and prolonged
stiffness on the affected areas.
Environmental triggers and symptoms also suggested to influence RA’s risk of
comorbidity with cardiovascular problems
- Smoking, Atherosclerosis

18. Inflammatory autoantibodies secreted against
peptide mutations and are indicative of RA onset
- Autoantigens induce immune response via secretion of autoantibodies
- Particular autoantibodies are noted as good indicators of Rheumatoid arthritis
pathogenesis.
Some of the indicators include:
1. Anti‐cyclic citrullinated peptide (anti‐CCP) antibodies
2. IgM rheumatoid factors (RF)
3. Anti‐keratin antibodies (AKA)

19. Assessing autoantibody levels is essential in
diagnosing Rheumatoid arthritis (RA)
- Patient samples obtained through
synovial tissue biopsy
- Autoantibodies tested in the serum
via ELISA
(enzyme-linked immunosorbent assay).
Fig.2 ELISA plate;
adapted from: Tek Image at FineArtAmerica; accessed 23 Aug 2018

20. Radiology procedures are also recommended as
diagnostic tools
1. Ultrasonography - degraded joints, inflammatory fluid and swelling rate
2. Bone scintigraphy - swelling of multiple joints and tenderness in a short
duration for the whole body
3. MRI imaging - progression of RA and effectiveness of DMARD treatments

21. Treatment

22. What can people do?
● Heating/ Cooling affected area
● Stretching
● Physical therapies
● Exercise
● Pain killers (over the counter)
● Non steroidal anti-inflammatory drugs
● Immunosuppressing drugs
● Joint replacement surgery
Photograph Title: none available at:
https://ajp.com.au/news/rheumatoid-arthritis-treatment-in-new-cla
ss-of-medicines/

23. First Drug used to treat Rheumatoid Arthritis
Methotrexate
● Disease-modifying antirheumatic drug
(DMARD)
● High toxicity
● Not for prolonged use
Image Title: Methotrexate C20
H22
N8
O5
available at:
https://en.wikibooks.org/wiki/Structural_Biochemistry/Meth
otrexate
Methotrexate
Type of antimetabolites that are able to inhibit cell
growth by competing with the folic acid that is
essential in purine development.
Phtograph Title: none available at:
https://www.rheumatoidarthritis.org/treatment/methotrexate/

24. Low Risk Treatments
BIOLOGICAL Disease-modifying antirheumatic drugs
More targeted
- Effective
- Efficient
- Fast
- Less side effects
Anti- TNF
→ inhibit secretion of
IL-33
→ Less action from NK
and T cells
‘Abatacept’ inhibits
T cell activation

25. Thankyou