Introduction to Rheumatologic Disease Art Weiss August 31, 2011

Definition: Rheumatologic (or Rheumatic) Disease: diseases characterized by pain and inflammation in joints and connective tissues, often referred to as “collagen-vascular diseases”.

Diversity of Rheumatologic Diseases: Common and Uncommon Diseases Involving Inflammatory and Immune Responses Inflammatory Diseases (innate immunity) Osteoarthritis* Gout* Pseudogout Immunologically-Mediated Diseases (adaptive immunity) Rheumatoid Arthritis* Systemic Lupus Erythematosus* Spondyloarthropathies* Ankylosing spondylitis Reactive Arthritis (Reiter’s Syndrome) Psoriatic Arthritis Spondylitis associated with IBD Sjogren’s Syndrome Polymositis/Dematomyositis Lyme Disease Rheumatic Fever Behcet’s Syndrome Systemic Sclerosis (Scleroderma) Wegener’s Granulomatosis Giant Cell Arteritis* * Diseases that will be covered in depth later in lecture of this course.

Introduction to Rheumatology: Historical Perspective The Virgin with Canon van Der Paele, 1436 Jan van Eyck (1385-1440) Evidence of: Temporal (Giant Cell) Arteritis The Painter’s Family Jacob Jordaens (1593-1678) Evidence of: Rheumatoid Arthritis

Importance and Impact of Rheumatologic Disease Prevalence (per 100,000) Male Female Rheumatoid Arthritis 440 1,100 Ankylosing Spondylitis 197 73 Gout 980 230 SLE 7 32 Scleroderma 1 5 Osteoarthritis 3,470 5,870 All Musculoskeletal conditions 15,510 20,720

CDC: Census Bureau 2004

Enormous Impact of Arthritis In 2003, the total cost of arthritis was $128 billion—nearly $81 billion in direct costs and $47 billion in indirect costs, equal to 1.2% of the 2003 U.S. gross domestic product. Arthritis is not just an old person’s disease. Nearly two-thirds of people with arthritis are younger than 65. Although arthritis affects children and people of all racial and ethnic groups, it is more common among women and older adults. - CDC

The Normal Joint

The Normal Synovium Function of Normal Synovium: maintenance of intact non-adherent tissue surface lubrication of cartilage control of synovial fluid volume and composition (plasma and hyaluronan) nutrition of chondrocytes within joints

Arthralgia vs Arthritis Arthralgia: Joint pain (there may not be any inflammation) Arthritis: Inflammation of the Joint - Pain - Redness - Swelling - Increased warmth - Fluid accumulation (synovial effusion) - Stiffness (especially in the AM)

Pathogenesis of Rheumatoid Arthritis Choy, E. H.S. et al. N Engl J Med 2001;344:907-916 Inflammed synovial tissue (synovitis) Villous hyperplasia Intimal cell proliferation Inflammatory cell infiltration T cells, B cells, macrophages and plasma cells Production of cytokines and proteases Increased vascularity Self-amplifying process

Multiple Cell Types and Cytokine Signaling Pathways Involved in Chronic Inflammatory Arthritis Modified from Choy, E. H.S. et al. N Engl J Med 2001;344:907-916 Key cytokines in Chronic Inflammatory Arthritis: TNF-a IL-1 IFN-g IL-6 OPGL (RANK-ligand) IL-17 Naïve T cell

Multiple T cell Subsets Contribute to the Development of Arthritis adapted from McInnes and Schett, Nat. Rev. Immunol., 7:429-442, 2007 CD4 CD28

Key Factors that Regulate Osteoclast Differentiation in Arthritis Nature Reviews Immunology, 2007

Th17 Cells Contribute to Cartilage Distruction in Additional Ways Nature Reviews Immunology, 2007

Progressive Chronic Inflammation Can Lead to Joint Destruction in the joint leads to bone destruction evident as erosions Prolonged severe chronic arthritis leads to deformity and disability. Early Arthritis - soft tissue swelling, especially around the PIP joints

What is the Immune Response Directed Against? Very Diverse Autoantigens Lyme Disease: Residual Organisms Cross-reactive antigens Rheumatoid Arthritis: Type II collagen IgG (rheumatoid factor) Citrullinated proteins (arginine residues modified) Systemic Lupus Erythematosus (intra- and extra-cellular antigens): Nuclear antigens: Ribonuclear proteins Histones dsDNA Leukocyte cell surface antigens Cardiolipin

Rheumatoid Factors: An Auto-antibody to Self IgG Fc

Multiple Nuclear Antigens Can be Detected by Autoantibodies in Sera of Patients with Rheumatic Diseases Homogeneous ANA Nucleolar Speckled ANA Centriolar

Why does tolerance fail? Why do people develop auto-immune rheumatologic diseases?

Genetic Basis of Rheumatic Diseases: Genotype contributes to rheumatic disease susceptibility ________ Twin Studies____________ Monozygotic Dizygotic Genetic Component Disease Concordance (%) Concordance (%) Explained by HLA (%) Rheumatoid Arthritis 15-34 0-6 35 SLE 25-57 0-3 Ankylosing Spondylitis 50-75 13-18 37 ______________________________________________________________________________ Most often rheumatic diseases are polygenic. A certain genotype predisposes an individual to a disease, but does not make disease development a certainty.

Genome Wide Scan of SNPs Associated with RA A common polymorphism in PTPN22 confers susceptibility to multiple autoimmune diseases - RA, Lupus, T1 diabetes, Hashimoto’s Thyroiditis Whole genome scan for RA PTPN22 is #2 hit Odds ratio < 2 Plenge et al. NEJM. 357:1199 (2007)

Multiple Factors Contribute to the Development of Arthritis Nature Reviews Immunology, 2007

Clinical Features

Acute vs Chronic Inflammatory Arthritis Acute Arthritis Rapid onset (hours or days) Severe symptoms Mediated by components of innate immune response, especially neutrophils (proteases, leukotrienes, prostaglandins, etc.) Can result in rapid joint destruction Can also evolve into chronic disease Examples: Gout and Infectious Arthritis Chronic Arthritis More gradual onset (days to weeks) Symptoms are more moderate, AM stiffness is a prominent symptom Mediated by the adaptive immune response, especially T cells and macrophages - a Th1 disease Cytokines and chronic inflammation lead to joint remodeling and destruction via erosions Examples: Rheumatoid Arthritis, Ankylosing Spondylitis, SLE, Lyme Disease

Pattern of Joint Involvement is Distinct in Different Diseases Monoarticular vs Polyarticular Mono Poly Gout RA Infection SLE Reactive Joint distribution PIPs and MCPs: RA, SLE DIPs: Osteoarthritis, Psoriatic MTP: Gout Symmetrical vs Asymmetrical Symmetrical: RA, SLE Asymmetrical: Psoriatic, Reactive

Rheumatic Disease Are Systemic Inflammatory Diseases with an Underlying Immune or Inflammatory Pathogenesis Disease Organ System Involvement Rheumatoid Arthritis Joints (arthritis) Vessels (vasculitis) Eyes (scleritis and episcleritis) Hematologic (anemia, thrombocytosis) Pulmonary (plueritis, alveolitis, etc,) Systemic Lupus Erythematosus (SLE) Joints (arthritis) Skin (photosensitive rash) Serosa (pericardium & pleura) Hematology (anemia, thrombocytopenia) Kidneys (glomerulonephritis) Lungs (interstitial disease, alveolitis, etc.) CNS (cognitive dysfunction, seizures, etc.) Lyme Disease Joints (arthritis) Skin (Erythema chronicum migrans) Heart (carditis) CNS (meningo-encephalitis)

Rheumatoid Arthritis is Systemic Inflammatory Disease

SLE is a Systemic Inflammatory Disease

Therapeutic Strategies Reagents that blunt inflammation but don’t have effects on disease progression: Aspirin Nonsteroidal anti-inflammatory drugs (NSAIDs) Non-selective and selective COX-2 antagonists Steroids (prednisone) Disease Modifying Anti-Rheumatic Drugs (DMARDs): Broad Acting: Methotrexate Hydroxychloroquin Azathoprine Cyclophosphamide Cyclosporin More selective biologics: TNF antagonists IL-6R antagonists IL-1R antagonists anti-B cell (CD20) therapy costimulatory inhibitors (CTLA4-Ig) Intravenous Immunoglobulin (iv Ig)

Methods of Blocking the Activity of an Inflammatory Cytokine Choy, E. H.S. et al. N Engl J Med 2001;344:907-916

Blocking CD28-dependent Costimulation From: Moreland http://www.medscape.com/viewprogram/3415_pnt Abatacept is a fusion of the extracellular domain of CTLA-4 (similar to CD28 but with higher affinity for CD80 and CD86) with the Fc fragment of IgG1 (for effector function and to prolong half-life)

Biological Therapeutics Targets, Rationale, Status