1. Kara Kliethermes Jim Shinaberry December 6, 2012

2.  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.  Chronic, inflammatory and often progressive autoimmune disease affecting joints  Frequently affects small joints  Symmetrical inflammation  Stiff/swollen, painful joints ¹

4.  Results in:  Deformity  Joint destruction  Nodules  Disability 2

5.  Joint space narrowing  Excessive tissue growth  High levels of synovial fluid Rheumatoid Joint Normal Joint 3

6.  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.  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.  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.  Commonly found in females  Remission during pregnancy (hormone surge)  Flare up after birth  Is there a link between RA and hormones? (estrogen/progesterone)

10.  Sex hormones  Estrogen ▪ Estrogen activates macrophages  Progesterone  Other Invovled Hormones ▪ Testosterone ▪ DHEA ▪ Prolactin ▪ Promotes survival of T-cell dependent autoreactive B-cells

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

13.  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.  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.  HRT (Hormone Replacement Therapy)  Initially successful  Controversial ▪ Shown to cause endometrial cancer  Prevent bone loss

16.  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=1604http://www.metrohealth.org/body.cfm?id=1611&oTopID=1604  2.http://images.rheumatology.org/viewphoto.php?imageId=2862487&albumId=7 5692  3. http://www.medicinenet.com/rheumatoid_arthritis/article.htmhttp://www.medicinenet.com/rheumatoid_arthritis/article.htm  4.http://images.rheumatology.org/viewphoto.php?imageId=2862491&albumId=7 5692

17.  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.  In patients with RA, what specific type of tissue is affected and why?

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