1. New Treatments for Rheumatoid Arthritis
Brittany Salmon
Dur-E-Sameen Zahoor
Yuejia Liang
Jia Xin Jiang
October 24th 2017
PHM Fall 2016
Coordinator: Dr. Jeffrey Henderson
Instructor: Dr. David Hampson

2. What is Rheumatoid Arthritis?
Newman et. All, 2007
& Stats Canada
What is Rheumatoid Arthritis?
Chronic autoimmune disease which causes inflammation at joints
No foreign substance present but the immune system “revs” up
4.3 million Canadians aged 12 or older reported a diagnosis (in 2008)

3. History of Treatments Gold salts D-penicillamine
Zampeli, E. et al., 2017
History of Treatments
Gold salts
only effective in 1/3 of patients where as 2/3 of patients experience adverse effects
D-penicillamine
no advantages when used in combination with other medications
many side effects such as bone marrow suppression, vomiting and diarrhea
DMARDs - disease-modifying antirheumatic drugs
Examples: Sulfasalazine (SSZ); relatively low toxicity and fast acting, methotrexate
NSAIDS (Nonsteroidal anti-inflammatory drugs)
Example: ibuprofen (reduces symptoms)

4. Interleukin-6 cytokine blockade: Sirukumab
Choy et al., 2009
Interleukin-6 cytokine blockade: Sirukumab
Treatment for refractory patients
- IL-6  responsible for inflammatory
processes in joints in RA
MoA: selectively binds with high affinity to
IL-6 cytokine  direct inhibition of
messenger IL-6
Significant reduction in inflammatory action of disease  significant ARC20 response
Most common AE: injection site erythema and minor infections.

5. IL-6 Receptor Signal Blockade: Sarilumab
-On January 12, 2017, Health Canada issued a Notice of Compliance to Sanofi-Aventis Canada Inc. for the drug product Kevzara
-Approved for use in the management of adult patients with moderately to severe rheumatoid arthritis who have had an inadequate response or intolerance to one or more biologic or non-biologic Disease Modifying Anti-Rheumatic Drugs

6. Sarilumab Cont…
Human IgG1 monoclonal antibody that binds to both soluble and membrane-bound IL-6Rα with high affinity (antagonist)
Interferes with cis- and trans-IL-6-mediated inflammatory pathway
20X greater affinity to IL-6R than tocilizumab (first marketed anti-IL-6R monoclonal antibody)
Similar safety profile, longer half life, injection every other week instead of every week
Raimondo 2017

7. Treatments targeting the JAK-STAT pathway
O'Shea et al., 2004
Treatments targeting the JAK-STAT pathway
The Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) pathway mediates intracellular signal transduction of cytokines
Signaling pathway
Cytokine binding to cytokine receptor associated JAK dimerization and autophosphorylation
STAT phosphorylation and dimerization
STAT dimer localizes into the nucleus and starts transcription
JAK family: JAK1, JAK2, JAK3, TYK2
JAK3 signaling important for immune cell (haematopoietically derived) proliferation and activation  target for therapy
JAK3
T cells, natural killer cells, B cells proliferation & activation

8. JAK-STAT inhibitor: Tofacitinib
Patterson et al., 2017
JAK-STAT inhibitor: Tofacitinib
Drug by Pfizer (Xeljanz), FDA approved as a DMARD treatment for RA, targeting JAK3
ATP competitive inhibitor at the JAK ATP binding cleft
Inhibition of JAK autophosphorylation and STAT dimerization & nuclear localization: inhibition of gene transcription and leucocyte activation
Efficacy demonstrated in patients unresponsive to traditional DMARDs. However, unspecific bindings to JAK1 and Jak2 were discovered
Adverse effects include: infections, hyperlipidaemia and GI tract dysfunction

9. Summary
Rheumatoid Arthritis (RA) is an autoimmune disease which causes inflammation.
To reduce inflammation, NSAIDS (Nonsteroidal anti-inflammatory drugs) are useful.
To treat the condition, DMARDs (disease-modifying antirheumatic drugs) are useful.
There is a need for new treatments because these older drugs have high toxicity rates and high risk of adverse effects.
Sirukumab directly inhibits the pro-inflammatory cytokine IL-6 to reduce inflammation.
Sarilumab antagonizes the IL-6 receptor with high affinity which decreases RA symptoms.
JAK/STAT pathway inhibitor (e.g. Tofacitinib) inactivates JAK by competing with ATP. STAT dimerization and the downstream gene transcription are prevented.

10. REFERENCES
1. O'Shea JJ, Pesu M, Borie DC, Changelian PS. A new modality for immunosuppression: Targeting the JAK/STAT pathway. Nat Rev Drug Discov. 2004;3(7): Accessed Oct 9, doi: /nrd1441.
2. Tofacitinib-XELJANZ: Potential new treatment option for moderate to severe ulcerative colitis. Chemdiv Web site. Updated Accessed Oct 9, 2017.
3. Aittomäki S, Pesu M. Therapeutic targeting of the jak/STAT pathway. Basic Clin Pharmacol Toxicol. 2014;114(1): Accessed Oct 9, doi: /bcpt
4. Patterson H, Nibbs R, McInnes I, Siebert S. Protein kinase inhibitors in the treatment of inflammatory and autoimmune diseases. Clin Exp Immunol. 2014;176(1):1-10. Accessed Oct 9, doi: /cei
5. Aletaha D, Bingham CO, Tanaka Y, Agarwal P, Kurrasch R, Tak PP, Popik S. Efficacy and safety of sirukumab in patients with active rheumatoid arthritis refractory to anti-TNF therapy (SIRROUND-T): a randomised, double-blind, placebo-controlled, parallel-group, multinational, phase 3 study. The Lancet. 2017;389(10075): Accessed Sep 27, doi: /S (17)
6. Dayer JM, Choy E. Therapeutic targets in rheumatoid arthritis: the interleukin-6 receptor. Rheumatology. 2009;49(1): Accessed Sep 27, doi: /s
7.Newman E. Rheumatoid Arthritis FAQs. BC Decker; 2007.
8. Zampeli, E., Vlachoyiannopoulos, P. G., & Tzioufas, A. G. Treatment of rheumatoid arthritis: Unraveling the conundrum. Journal of Autoimmunity,  2015; 65, doi: /j.jaut
9. Raimondo M, Biggioggero M, Crotti C, Becciolini A, Favalli E. Profile of sarilumab and its potential in the treatment of rheumatoid arthritis. Drug Des Devel Ther. 2017;11: doi: /DDDT.S100302
10.Summary Basis of Decision-Kevzara-Health Canada. Government of Canada. Accessed Oct 19, 2017.
11. Arthritis. Statistics Canada Retrieved October 24, 2017, from