1. The Biochemistry of Rheumatoid Arthritis Cindy Zhang Yalda Pour Shahnazari Jessica Marcantonio Victoria Wong PHM142 Fall 2015 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson

2. What it is? 1  Chronic autoimmune condition  Inflammatory disease  Impacts the body systemically  causes polyarthritis of the joints.  Swelling and sensitivity of the joints; if left unchecked, can lead to deformation  Emerges between the ages of 30 to 50 generally

3. How common is it? 1  Most common inflammatory arthritis  25 men and 54 women out of 100,000 affected

4. What causes RA? 1  Exact cause unknown  Genetic predisposition and environmental factors play a role  A triggering event (e.g. infection) initiates joint inflammation  Cells of the immune system+ associated cytokines+ growth factors+ proteases facilitate destruction of the joints and other issues

5. Symptoms? 2  Symmetrical discomfort, stiffness, and inflammation of several joints  Symptoms emerge over the duration of weeks or even moths  Severe fatigue, weakness, loss of appetite and weight loss

6. Diagnosis (part 1) 2  Laboratory tests  Blood cell count with rheumatoid factor, erythrocyte sedimentation rate  Conclusive diagnosis not always practical, additional information is needed on each individual

7. Diagnosis (part 2) 1  Many other autoimmune disorders have symptoms that mimic R.A.

8. Diagnosis (part 3) 2  Physical symptoms: pain and inflammation in at least 3 joints, a positive squeeze test, prolonged stiffness of the joints in the morning  Blood test: presence of C-reactive protein, higher than normal erythrocyte sedimentation rate, rheumatoid factor.

9. Diagnosis (part 4) 1

10. Cytokines 6 A group of signalling proteins Able to act locally Functions – Regulate cellular functions – Tissue damage repair – Modulate immune reactions

11. Interleukins 5 A type of inflammatory cytokines Functions – Messengers among leukocytes – Play a role in differentiation and development of T and B lymphocytes and hematopoietic cells

12. Tumour Necrosis Factor (TNF) 4 A type of cytokines Able to induce apoptosis and cachexia in tumour cells

13. TNF and Interleukin-6 (IL-6) in RA 3 Reference: Choy, E. Understanding the dynamics: pathways involved in the pathogenesis of rheumatoid arthritis. Rheumatology. 51, v3-v11 (2012).

14. Pathophysiology of RA 3

15. Pathology of RA 3

16. Treatment Acute treatment: – pain reduction and anti-inflammation Chronic therapeutic choices 7 – Disease-modifying anti-rheumatic drugs (DMARDs) – Biologics Combination therapy 10

17. DMARD Example: Methotrexate 8 Neoplastic diseases 7.5mg once weekly Mechanism unclear 11 – Inhibit B-cell and T-cell – Inhibit cytokine production induced by T-cell activation

18. Biologics - Etanercept (Enbrel  ) 9 Treatment of moderately to severely active rheumatoid arthritis (RA) in adults 50mg bi-weekly SC injection Anti-TNF reagent 12 tmTNF-  vs sTNF-  13

19. Summary Rheumatoid Arthritis is a chronic autoimmune condition. It is an inflammatory disease that impacts the body systemically, and leads to the polyarthritis of the joints. Diagnosis based on several factors including pain and inflammation in at least 3 joints, a positive squeeze test, stiffness of the joints in the morning, the presence of C-reactive protein, higher than normal erythrocyte sedimentation rate, and rheumatoid factor. Cytokines are signalling molecules that regulate cellular functions and modulate immune responses The effects of Tumour Necrosis Factor alpha (TNFα) in RA include increasing monocyte activations and cytokine release and inducing T cell apoptosis. The effects of interleukin-6 (IL-6) in RA include activation of osteoclasts, B cell and T cell proliferation and osteoporosis. Activation of T- and B-cells leads to the release of pro-inflammatory cytokines, causing joint damage and the chronic state of the disease Acute treatment of symptoms such as pain and inflammation can include NSAIDs and corticosteroids. – Does not stop disease progression Two types of chronic therapy choices, disease-modifying anti-rheumatid drugs (DMARD) and biologics – Prevents progression and promotes remission – eg. MTX and etanercept (Enbrel  ) Methotrexate is an immunosuppressant that, at low doses, can also suppress RA activity and reduce further joint damage. The mechanism is unclear, but possible mechanisms include inhibition of T cell and B cell proliferation as well as inhibition of cytokine production induced by T-cell activation. – eg. of cytokines: IL-6 and TNF-  Etanercept (Enbrel  ) is semi-synthesized biological drug with the Fc of an IgG antibody with TNF receptor in place of the Fab region. The drug competitively inhibits TNF function by binding to TNF but disallowing biological activity. TNF-  is an transmembrane protein (tmTNF-  ) that can be cleaved by TACE (TNF-  converting enzyme) to release soluble TNF-  (sTNF-  ). Etanercept can bind to both tmTNF-  and sTNF- .

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