The Most Common Autoimmune Disease: Rheumatoid Arthritis. Bonita S. Libman, M.D.

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1 The Most Common Autoimmune Disease: Rheumatoid Arthritis Bonita S. Libman, M.D.

2 Disclosures Two googled comics

3

4 The Normal Immune System Network of cells and proteins that work together Goal: protect against disease by fighting against infections and cancerous cells

5 Autoimmune Definition Immunitas (Latin): exempt from public service; resistant to disease Auto- (Greek): self, one s own Autoimmune: immune system acting against oneself

6 Allergy or Autoimmune? Allergy Reaction to external substance that the body would normally ignore Autoimmune Reaction to normal internal body tissues that the body would normally ignore

7 Foreign (or self) antigen How Immune System Works MHC antigenpresenting complex T cell receptor T cell Activated T cell Cytokines Antigen presenting cell Cytokine receptor B cell T cell Cell death Infected cell (or displays self antigen) Some antibodies help T cells Antibodies recognize pathogen (or self antigen) Antibodies clear the pathogen

8 Autoimmune Disease: Scope of Problem 5-8% of US population (15-24 million people), majority are female More than 80 diseases Among the top 10 common causes of death in people younger than 65 years old

9 Autoimmune Disease in USA Rheumatoid Arthritis: > 2 million Diabetes Mellitus Type I: >1.5 million Inflammatory Bowel Disease: >1.4 million

10 Systemic vs Organ Specific Systemic: multiple body tissues affected RA, SLE, Scleroderma, Myositis Organ/Tissue Specific: one tissue or organ affected Hashimoto s, Diabetes Mellitus Type I, Multiple Sclerosis, Myasthenia Gravis

11 Top 10 Autoimmune Diseases Graves Disease Rheumatoid Arthritis (1% of world s population) Hashimoto s Thyroiditis Vitiligo Diabetes Mellitus Type I Pernicious Anemia Multiple Sclerosis Glomerulonephritis Systemic Lupus Erythematosus Sjogren s Syndrome

12 Rheumatoid Arthritis History Evidence in American skeletons years ago First convincing description in 1800 by Landré-Beauvais Was RA transmitted by explorers returning to Europe from America?

13 Rheumatoid Arthritis More frequent in women (F:M = 2-3:1) Positive familial/genetic associations, especially HLA-DR4 All ages affected

14 Rheumatoid Arthritis - Symptoms Joint pain and swelling that improves with use Profound stiffness after inactivity (more than one hour) Loss of motion Others: fever, weight loss, fatigue, inflammation in other organs (eye, lung, blood cell abnormalities)

15 Rheumatoid Arthritis - Signs Joint inflammation (swelling, warmth, tenderness) Deformities Boutonnière, Swan Neck, Ulnar Deviation Rheumatoid Nodules Typical pattern of joint involvement

16 Rheumatoid Arthritis Pattern of Joint Involvement

17 Osteoarthritis Pattern of Joint Involvement

18 (Insert picture of rheumatoid hands: 2-4)

19 (Insert picture of rheumatoid hand: 2-6)

20 (Insert picture of rheumatoid feet: 2-31)

21 (Insert picture of elbow rheumatoid nodule: 2-18)

22 (Insert picture of x-ray of fingers: 2-9)

23 (Insert picture of x-ray of hands: 2-10)

24 Rheumatoid Arthritis - Pathophysiology Marked inflammation in the joint (promoted by immune cells and proteins such as TNF alpha) Proliferation (growth) of the synovium (the lining made of connective tissue that surrounds the joint) Invasion of synovium into cartilage and bone, resulting in erosions/joint damage

25 (Insert picture of knee arthroscopy: 2-43)

26 Diagnosis of RA Symptoms of joint pain, swelling and stiffness Signs of joint swelling, deformity, nodules Positive blood test for RF and/or CCP X-ray findings

27 Rheumatoid Arthritis and Rheumatoid Factor Antibody a protein produced by the immune system to help fight off infections Rheumatoid Factor an antibody directed against other antibodies Rheumatoid Factor not the cause of rheumatoid arthritis

28 Rheumatoid Arthritis and Rheumatoid Factor Some healthy people have a rheumatoid factor Many other diseases (infections, other autoimmune diseases) can produce a rheumatoid factor 20-30% of patients with rheumatoid arthritis are negative for rheumatoid factor

29 Other Laboratory Tests and RA CCP: Antibody to Cyclic Citrullinated Peptide Specific (highly diagnostic) for RA ESR: Erythrocyte Sedimentation Rate Measures inflammation in the body Elevated in many diseases (infections, cancers, other autoimmune diseases) and sometimes in healthy people CBC: Complete Blood Count Inflammation leads to anemia and elevated platelet count

30 Rheumatoid Arthritis - Treatment Principles of Treatment Education Relief of symptoms Prevention of joint damage/preservation of function Early treatment is essential

31 Rheumatoid Arthritis Treatment Adjuncts to medications Exercise to preserve muscle strength and joint flexibility Orthotics (canes, splints or other assistive devices) Joint injection (corticosteroid) Surgery for severe end-stage joint involvement

32 Rheumatoid Arthritis - Treatment NSAIDs (Non-Steroidal Anti-Inflammatory drugs) Mildly helpful for pain and swelling Do not prevent joint damage Corticosteroids More potent than NSAIDs Side effects preclude long term use Immunosuppressive/Immunomodulatory Drugs Methotrexate Biological Drugs

33 Methotrexate Best first choice for treatment of rheumatoid arthritis Helps prevent joint damage Anchor Drug Often used in combination with other drugs Well tolerated Laboratory tests must be done to monitor for side effects

34 Biological Drugs Selectively target certain parts of the immune system that promote rheumatoid arthritis Very effective Prevent joint damage

35 Foreign (or self) antigen How Immune System Works MHC antigenpresenting complex T cell receptor T cell Activated T cell Cytokines Antigen presenting cell Cytokine receptor B cell T cell Cell death Infected cell (or displays self antigen) Some antibodies help T cells Antibodies recognize pathogen (or self antigen) Antibodies clear the pathogen

36 Biological Drugs are antibodies directed at different parts of the immune system Antibody directly targeting a cytokine Antibody targeting a receptor for a cytokine Antibody blocking co-stimulation required for cell activation Antibody directly targeting a B cell

37 Targets for Biological Drugs Pro-inflammatory cytokines Tumor Necrosis Factor alpha (TNFα) Interleukin 1 (IL-1) Interleukin 6 (IL-6) B cells CD 20 (B cell marker) T cells (via co-stimulation blockade) CTLA4 (modulator of T cell activation via CD 80/86 and CD28 co-stimulatory pathway)

38 Anti-cytokine Antibody TNFα Antibody against TNFα TNFα TNFα receptor WBC

39 Anti-Cytokine receptor fusion protein TNFα receptor TNFα WBC

40 Anti-Cytokine receptor antagonist IL-1ra IL-1 receptor IL-1 WBC

41 APC = antigen presenting cell (B cell, macrophage, dendritic cell) Co-stimulatory blockade APC Co-stimulatory molecule (e.g. CD 80) MHC Antigen Co stimulatory blocker Co-stimulatory receptor (e.g. CD 28) T cell receptor T cell

42 Antibody to B cell B cell Anti-B cell antibody

43 Biological Drugs Given by injection Subcutaneous Intravenous May cause serious infections May cause other side effects: cancer, autoimmune disease Changing one part of the immune system may impact other parts of the immune system

44 Summary Autoimmunity: immune system acts against oneself Autoimmune diseases are common; RA is the most common systemic (i.e. may affect other areas besides joints) autoimmune disease Biological treatments for RA Target certain parts of the immune system Illustrate how the immune system works

45 Autoimmunity in action?

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