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Rheumatoid Arthritis

Kara Kliethermes Jim Shinaberry December 6, 2012. Rheumatoid Arthritis. Overview. What is rheumatoid arthritis? What are the underlying mechanisms? Epidemiology Triggers and risk factors What leads to the development of RA? Can RA be effectively treated? References Study Questions.

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Rheumatoid Arthritis

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  1. Kara Kliethermes Jim Shinaberry December 6, 2012 Rheumatoid Arthritis

  2. Overview • What is rheumatoid arthritis? • What are the underlying mechanisms? • Epidemiology • Triggers and risk factors • What leads to the development of RA? • Can RA be effectively treated? • References • Study Questions

  3. What is Rheumatoid Arthritis? • Chronic, inflammatory and often progressive autoimmune disease affecting joints • Frequently affects small joints • Symmetrical inflammation • Stiff/swollen, painful joints ¹

  4. What are additional symptoms? • Results in: • Deformity • Joint destruction • Nodules • Disability 2

  5. What occurs within the joints? Rheumatoid Joint • Joint space narrowing • Excessive tissue growth • High levels of synovial fluid Normal Joint 3

  6. Pathophysiology • Begins with inflammation of synovial joints • Leads to excessive synovial fluid production • Fluid contains metalloproteinase enzyme • Attacks and erodes cartilage • Inflammation caused by infiltration of macrophages, T-helper cells and B-plasma cells

  7. Epidemiology • Worldwide prevalence  roughly 1-2% (2012) • Occurs most often between 50-60 years of age • May begin around 30 years of age • Life expectancy of RA patients reduced 5-10 years • Often resulting from CVD risk factors

  8. What are some risk factors? • Human leukocyte antigen (HLA) • HLA-DRB1 is a significant risk factor gene • Viruses may be causative agents • Epstein Barr Virus (EBV) • High levels of EBV in synovial fluid of RA patients • The epitope polypeptide sequence of HLA-DBR1 (or DBR4) is similar to that of EBV and E-coli

  9. Risk Factors (cont.) • Commonly found in females • Remission during pregnancy (hormone surge) • Flare up after birth • Is there a link between RA and hormones? (estrogen/progesterone)

  10. Hormones as Risk Factors • Sex hormones • Estrogen • Estrogen activates macrophages • Progesterone • Other Invovled Hormones • Testosterone • DHEA • Prolactin • Promotes survival of T-cell dependent autoreactive B-cells

  11. What leads to the development of RA? • Unknown causes • Genetic predisposition hypothesized • Influenced by environmental risk factors • Rheumatoid Factor • Autoantibody produced against Fc region of IgG • The Fc regions of free IgG molecules are accessed easily by these autoantibodies

  12. Treatment • No cure • Treatments aim to: • Achieve remission/ Control symptoms • Preserve structure of joints (prevent damage/deformity) • Improve/maintain quality of life

  13. Treatment (cont.) • Rituximab (intravenous injection) • Targets CD 20 on surface of B cells • Results in destruction of B cells • both normal and dysfunctional • Tocilizumab • Monoclonal Ab that blocks interleukin-6 receptors • IL-6 is responsible for activating inflammatory cells

  14. Treatment (cont.) • Disease-modifying antirheumatic drugs (DMARDS) • Alleviates symptoms caused by inflammation • Lessen joint distruction • Methotrexate (DMARD) • Most widely used drug of choice • Adenosine (active metabolite)-suppresses expression of inflammatory cytokines • Used in low doses to control inflammation • Reduces cytokine production

  15. Treatment (cont.) • HRT (Hormone Replacement Therapy) • Initially successful • Controversial • Shown to cause endometrial cancer • Prevent bone loss

  16. References • Babushetty V, Sultanpur CM. 2012. The role of sex hormones in rheumatoid arthritis. International Journal of Pharmacy and Pharmaceutical Sciences 4(1): 15-21. • Clancy J, Hasthorpe H. 2011. Pathophysiology of rheumatoid arthritis: nature or nurture? Primary Health Care 21(9): 31-38. • Holroyd CR, Edwards CJ. 2009. The effects of hormone replacement therapy on autoimmune disease: rheumatoid arthritis and systemic lupus erythematosus. Climacteric 2: 378-386. • Islander U, Jochems C, Lagerquist MK, Forsblad-d’Elia H, Carlsten H. 2011. Estrogens in rheumatoid arthritis; the immune system and bone. Molecular and Cellular Endocrinology 335: 14-29. • 1. http://www.metrohealth.org/body.cfm?id=1611&oTopID=1604 • 2.http://images.rheumatology.org/viewphoto.php?imageId=2862487&albumId=75692 • 3. http://www.medicinenet.com/rheumatoid_arthritis/article.htm • 4.http://images.rheumatology.org/viewphoto.php?imageId=2862491&albumId=75692

  17. Study Question • Why does estrogen inhibit Treg cells? • A) Treg cells have a greater proportion of ERα/ERβ receptors causing Treg cell function to be suppressed • B) Estrogen blocks the CD4 receptor on the surface of the Treg cell • C) Estrogen inhibits successful Treg development within the bone marrow • D) Estrogen blocks the binding of B7 on autoreactive T cells to Treg cells, thus inhibiting necessary suppression

  18. Short Answer Question • In patients with RA, what specific type of tissue is affected and why?

  19. Questions from the audience??? 4

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