1. + Rheumatoid Arthritis Jocelin Olmos & Matt Scroggy

2. + What is Rheumatoid Arthritis (RA)? Autoimmune disease : the result of the body attacking itself damaging healthy tissue and organs. Immune system makes antibodies that attack your own cells White blood cells travel to the joint lining, or synovium, and cause inflammation known as synovitis With time, the inflamed synovium invades and destroys the cartilage and bone within the joint.

3. + Histopathology Normal Joints The synovium is a thin lining that serves as Nutrients for cartilage Synthesize Joint Lubricants Collagens Fibronectin In a normal layer it contains 1-3 cells thick In RA it is 8-10 cells thick and filled with inflammatory cells and in chronic stages erode cartilage and bone. Synovium Is composed mainly of type II collagen and proteoglycans. This is a very resilient tissue that absorbs impact and stress In RA resilience and water content is impaired due to the increase catabolic pathways that inhibit new cartilage creation Cartilage Composed mainly of type I collagen Bone destruction is a main characteristic of RA due to the activation of osteoclasts. Bone

4. + Symptoms Symptoms include Fatigue Joint Pain Joint Tenderness Joint Swelling Joint Redness Joint Warmness Stiffness in joints : particularly in the morning Many joints are affected and both are sides affected symmetrically. o Rheumatoid arthritis is a chronic disease characterized by periods of disease flares and remissions. o Chronic inflammation of rheumatoid arthritis can cause permanent joint destruction and deformity.

5. + Understanding Rheumatoid Arthritis RA affects 1.3 million adults in the United States and it is 3x more common in women than men. In women it usually begins around 30-40 years old and in men it usually occurs much later in life. It does occur in children younger than 16 and it is called juvenile idiopathic arthritis. To get diagnosed : There is no singular test for diagnosing rheumatoid arthritis. rheumatoid arthritis is diagnosed based on a combination of the presentation of symptoms, Certain blood tests and X-Rays can help determine whether it is rheumatoid arthritis or another joint disease.

6. + Is there a cure? There is no cure for RA. With the combination of medication and non-medication you can manage it. Two classes of medications are used in treating rheumatoid arthritis fast-acting "first-line drugs" and slow-acting "second-line drugs" (also referred to as disease-modifying antirheumatic drugs or DMARDs). The first-line drugs, such as aspirin and cortisone (corticosteroids), are used to reduce pain and inflammation. The slow-acting second-line drugs, such as methotrexate promote disease remission and reduce progressive joint destruction. Treatment is customized according to many factors such as disease activity, types of joints involved, general health, age, and patient occupation. The EARLIER you treat it the better chances you to improve the outcome

7. + Standard Treatments “First-Line” Medications Side effects: stomach ulcers, kidney/liver problems, high blood pressure, and heart disease NSAIDs (non-steroidal, anti-inflammatory drugs) Over the counter treats temporary relief of pain and stiffness. Corticosteroid: suppresses immunity, anti-flammatory more potent than NSAIDs and should only be used when inflammation is severe Side effects: weight gain, mood change, infections, high blood pressure, cataracts

8. + Standard Treatments Slow- acting “second- line” drugs It reduces joint pain, swelling, and progression of joint damage DMARDs Binds to cells and molecules to stop inflammation, and autoimmune signaling Side effects: upset stomach, hair loss, oral ulcers, rash, low blood counts, inflammation of the liver, liver problems

9. + Stem Cells VS. RA and Autoimmune diseases Currently there are no “proven” stem cell therapies for RA. There are however numerous clinical studies and trials currently taking place in the U.S. Most of them in stage 1 and very few in stage 2. The main purpose of most of these studies and trials is to explore the safety and efficacy of stem cell transplantation as a treatment for rheumatoid arthritis. Most of these trials have ended inconclusive and results have not been posted for clinical trials yet.

10. + Mesenchymal Stem Cells Mesenchymal stem cells (MSC’s) are what most trials are revolving around right now because of: Anti-inflammatory properties (suppress effecter T cells) They act as local mediators and do not suppress the entire immune system of the patient like standard treatments do. Induce the production of T regulatory cells which function to protect the body against immunological self-attack. Repair bone and cartilage because they can turn into cartilage cells (chondrocytes), and bone cells (osteoblasts). All of these products combined seek to alleviate the progression of rheumatoid arthritis and possibly reverse and repair damaged cartilage and joints.

11. +  In RA, the FLS and MSCs are activated by T-cells to secrete pro inflammatory cytokines like tumor necrosis factor. These intern stimulate the immune response that causes damage to the joints. Regulate T cell proliferation = Cure for RA. Healthy MSC and FLS produce Indoleamine 2, 3- dioxygenase(IDO). To catalyse tryptophan into kynurenine. Which inhibits cell proliferation.

12. + Pre Clinical Trials Mice immunized to cause collagen induced arthritis( CIA, or RA) were injected with MSC’s. They found that the MSC’s induced hypo responsiveness of T cells in the mice which served as a type of immunosuppressant to protect the joints in the mice. However at the end of the experiment the MSCs were undetectable in the joints suggesting that they did not restore tissue integrity via tissue repair. MSC’s circulated throughout mice for about 7 days and then disappeared.

13. + In conclusion the pre trial discovered a few things. MSC’s did not improve any tissue repair MSC’s did show anti inflammatory properties and act as a modulator for T cells in response to CIA. Effects were only short term and would need to last long term for any real therapeutic value. Overall, it was fairly inconclusive.

14. + Therapeutic potential of MSC’s in treatment for RA was controversial in preclinical studies. Which lead to slow start in clinical trials. Most Pre-Trials suggested either the efficacy of MSC s, or that MSC’s alone are ineffective in suppressing mediated joint inflammation caused by RA. There is not enough known yet about the immunomodulatory mechanisms of MSC’s. New clinical trials combining DMARDs and transplantation of MSC’s into patients could lead to effective treatment of RA through MSCs.

15. + Goals for new trials In new clinical trials these are the 4 factors that companies are looking to change. As they are all indicators of RA. 1) Reduce C-reactive protein levels (CRP) 2) Reduce erythrocyte sedimentation rate 3) Reduce anti-citrulline antibody measure 4) Reduce Rheumatoid Factor (RF)

16. + Still a long ways to go MSCs are very effective when they are transplanted. The problem is getting them to stay, or to replicate and teach other cells. Has not shown effective repair to damaged cartilage. All trials are in stage one or two. New combinations of stem cell treatment and standard treatments are being tested for effectiveness. Other autoimmune diseases have shown much more success.

17. + fdg Thank you!

18. + Sources http://www.webmd.com/rheumatoid-arthritis/features/autoimmune- disease-and-ra?page=3 http://www.webmd.com/rheumatoid-arthritis/features/autoimmune- disease-and-ra?page=3 http://www.mayoclinic.org/diseases-conditions/rheumatoid- arthritis/basics/symptoms/con-20014868 http://www.mayoclinic.org/diseases-conditions/rheumatoid- arthritis/basics/symptoms/con-20014868 http://www.medicinenet.com/rheumatoid_arthritis_early_symptoms/ views.htm http://www.medicinenet.com/rheumatoid_arthritis_early_symptoms/ views.htm http://www.medicinenet.com/rheumatoid_arthritis/page4.htm#how_ do_physicians_diagnose_rheumatoid_arthritis http://www.medicinenet.com/rheumatoid_arthritis/page4.htm#how_ do_physicians_diagnose_rheumatoid_arthritis http://www.hopkinsarthritis.org/arthritis-info/rheumatoid-arthritis/ra- pathophysiology-2/ http://www.hopkinsarthritis.org/arthritis-info/rheumatoid-arthritis/ra- pathophysiology-2/ http://www.slideshare.net/smgnj/living-with-rheumatoid-arthritis- 29965719 http://www.slideshare.net/smgnj/living-with-rheumatoid-arthritis- 29965719

19. + Sources cont…. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3712145/ http://clinicaltrials.gov/ct2/show/NCT01873625?term=Rheumatoid+ arthritis+stem+cell+treatments&rank=3 http://clinicaltrials.gov/ct2/show/NCT01873625?term=Rheumatoid+ arthritis+stem+cell+treatments&rank=3 http://clinicaltrials.gov/show/NCT01547091 http://onlinelibrary.wiley.com/doi/10.1002/art.22511/full http://rheumatology.oxfordjournals.org/content/47/1/22.short