Introduction to Rheumatologic Disease

Art Weiss

August 31, 2011

Definition:

Rheumatologic (or Rheumatic) Disease: diseases characterized by pain and inflammationin joints and connective tissues, often referred toas “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 spondylitisReactive Arthritis (Reiter’s Syndrome)Psoriatic ArthritisSpondylitis associated with IBD

Sjogren’s SyndromePolymositis/DematomyositisLyme DiseaseRheumatic FeverBehcet’s SyndromeSystemic Sclerosis (Scleroderma)Wegener’s GranulomatosisGiant Cell Arteritis*

* Diseases that will be covered in depth later in lecture of this course.

The Painter’s FamilyJacob Jordaens (1593-1678)

Evidence of: Rheumatoid Arthritis

The Virgin with Canon vanDer Paele, 1436Jan van Eyck (1385-1440)

Evidence of:Temporal (Giant Cell) Arteritis

Introduction to Rheumatology: Historical Perspective

Importance and Impact of Rheumatologic Disease

Prevalence (per 100,000)

Male FemaleRheumatoid Arthritis 440 1,100Ankylosing Spondylitis 197 73Gout 980 230SLE 7 32Scleroderma 1 5Osteoarthritis 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)

Choy, E. H.S. et al. N Engl J Med 2001;344:907-916

Pathogenesis of Rheumatoid Arthritis

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

Modified from Choy, E. H.S. et al. N Engl J Med 2001;344:907-916

Multiple Cell Types and Cytokine Signaling Pathways Involved in Chronic Inflammatory Arthritis

Key cytokines in ChronicInflammatory Arthritis:

TNF- IL-1

IFN-IL-6OPGL (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 Differentiationin Arthritis

Nature Reviews Immunology, 2007

Th17 Cells Contribute to Cartilage Distructionin Additional Ways

Nature Reviews Immunology, 2007

Progressive Chronic Inflammation Can Lead to Joint Destruction

Early Arthritis - soft tissue swelling,especially around the PIP joints

Chronic inflammationin the joint leads to bone destructionevident as erosions

Prolonged severechronic arthritisleads to deformity anddisability.

What is the Immune Response Directed Against?Very Diverse Autoantigens

Lyme Disease:Residual OrganismsCross-reactive antigens

Rheumatoid Arthritis:Type II collagenIgG (rheumatoid factor)Citrullinated proteins (arginine residues modified)

Systemic Lupus Erythematosus (intra- and extra-cellular antigens):Nuclear antigens:

Ribonuclear proteinsHistonesdsDNA

Leukocyte cell surface antigensCardiolipin

Rheumatoid Factors: An Auto-antibody to Self IgG Fc

HomogeneousANA

NucleolarANA

Speckled ANA

CentriolarANA

Multiple Nuclear Antigens Can be Detected by Autoantibodies in Sera of Patients with Rheumatic Diseases

Why does tolerance fail?

Why do people develop auto-immunerheumatologic diseases?

Factors that Predispose an Individual to Rheumatologic Diseases

I. Susceptibility Genes

A. MHC class I (i.e., HLA-B27 in spondyloarthropathies) B. MHC class II (i.e. HLA-DR4 in RA) C. Complement deficiency states (i.e., C2 or C4 deficiency in SLE) D. Fc Receptor Polymorphisms (i.e., FcR deficiency in SLE) E. PTPN22, a tyrosine phosphatase, polymorphism associated with rheumatoid arthritis, SLE, others F. Gender (female:male cases of SLE are 9:1) G. Others (48 susceptibility loci for SLE in the genome)

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 certaingenotype predisposes an individual to a disease, but does not make disease development a certainty.

Genome Wide Scan of SNPs Associated with RA

Plenge et al. NEJM. 357:1199 (2007)

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

II. Environmental Factors

A. Viral infect ions (hepatitis B, hepatitis C, others) B. Bacterial infections (Shigella, Salmonella, gp A strep., etc.) C. Drugs (procainamide, dilantin, others) D. Toxins (heavy metals, others) E. UV-light (i.e., in SLE)

III. Status of the Immune System

A. Relative state of activation B. Relative balance of Th1 and Th2 C. History of previous responses

IV. Status of Targ et Organ/Tissue

A. Visibi lity of autoantigen (privileged sites, intra- vs extra-cellular, etc) B. Expression level of autoantigen C. Expression level of MHC D. Costimulatory molecules E. Ongoing inflammation

Multiple Factors Contribute to the Development of ArthritisNature Reviews Immunology, 2007

Clinical Features

Acute vs Chronic Inflammatory Arthritis

Acute ArthritisRapid onset (hours or days)Severe symptomsMediated by components of innate immune response, especially neutrophils (proteases, leukotrienes, prostaglandins, etc.)Can result in rapid joint destruction Can also evolve into chronic diseaseExamples: Gout and Infectious Arthritis

Chronic ArthritisMore gradual onset (days to weeks)Symptoms are more moderate, AM stiffness is a prominent symptomMediated by the adaptive immune response, especially T cells

and macrophages - a Th1 diseaseCytokines and chronic inflammation lead to joint remodeling and destruction via erosionsExamples: Rheumatoid Arthritis, Ankylosing Spondylitis, SLE, Lyme Disease

Pattern of Joint Involvement is Distinct in Different Diseases

Monoarticular vs PolyarticularMono PolyGout RAInfection SLEReactive

Joint distributionPIPs and MCPs: RA, SLEDIPs: Osteoarthritis, PsoriaticMTP: Gout

Symmetrical vs AsymmetricalSymmetrical: RA, SLEAsymmetrical: Psoriatic, Reactive

Rheumatic Disease Are Systemic Inflammatory Diseases withan 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:AspirinNonsteroidal anti-inflammatory drugs (NSAIDs)

Non-selective and selective COX-2 antagonistsSteroids (prednisone)

Disease Modifying Anti-Rheumatic Drugs (DMARDs):Broad Acting:

MethotrexateHydroxychloroquinAzathoprineCyclophosphamideCyclosporin

More selective biologics:TNF antagonistsIL-6R antagonistsIL-1R antagonistsanti-B cell (CD20) therapycostimulatory inhibitors (CTLA4-Ig)Intravenous Immunoglobulin (iv Ig)

Choy, E. H.S. et al. N Engl J Med 2001;344:907-916

Methods of Blocking the Activity of an Inflammatory Cytokine

Blocking CD28-dependent Costimulation

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)

From: Morelandhttp://www.medscape.com/viewprogram/3415_pnt

Biological TherapeuticsTargets, Rationale, Status