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 InvolvingInflammatory and Immune ResponsesInflammatory Diseases (innate immunity)Osteoarthritis*Gout*Pseudogout

Immunologically-Mediated Diseases (adaptive immunity)Rheumatoid Arthritis*Systemic Lupus Erythematosus*Spondyloarthropathies*Ankylosing spondylitisReactive Arthritis (Reiters Syndrome)Psoriatic ArthritisSpondylitis associated with IBDSjogrens SyndromePolymositis/DematomyositisLyme DiseaseRheumatic FeverBehcets SyndromeSystemic Sclerosis (Scleroderma)Wegeners GranulomatosisGiant Cell Arteritis*

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

The Painters FamilyJacob Jordaens (1593-1678)

Evidence of: Rheumatoid ArthritisThe Virgin with Canon vanDer Paele, 1436Jan van Eyck (1385-1440)

Evidence of:Temporal (Giant Cell) ArteritisIntroduction to Rheumatology: Historical Perspective

Importance and Impact of Rheumatologic DiseasePrevalence (per 100,000)

MaleFemaleRheumatoid Arthritis440 1,100Ankylosing Spondylitis197 73Gout980 230SLE 7 32Scleroderma 1 5Osteoarthritis 3,470 5,870

All Musculoskeletal conditions 15,510 20,720

CDC: Census Bureau 2004

Enormous Impact of ArthritisIn 2003, the total cost of arthritis was $128 billionnearly $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 persons 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 SynoviumFunction 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 ArthritisArthralgia: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;344:907-916Pathogenesis of Rheumatoid ArthritisInflammed 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;344:907-916Multiple Cell Types and Cytokine Signaling Pathways Involved in Chronic Inflammatory ArthritisKey cytokines in ChronicInflammatory Arthritis:

TNF-a IL-1IFN-gIL-6OPGL (RANK-ligand)IL-17Nave T cell

Multiple T cell Subsets Contribute to the Development of Arthritis adapted from McInnes and Schett, Nat. Rev. Immunol., 7:429-442, 2007CD4CD28

Key Factors that Regulate Osteoclast Differentiationin ArthritisNature Reviews Immunology, 2007

Th17 Cells Contribute to Cartilage Distructionin Additional WaysNature Reviews Immunology, 2007

Progressive Chronic Inflammation Can Lead to Joint DestructionEarly Arthritis - soft tissue swelling,especially around the PIP joints Chronic inflammationin the joint leads to bone destructionevident as erosionsProlonged severechronic arthritisleads to deformity anddisability.

What is the Immune Response Directed Against?Very Diverse AutoantigensLyme 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 proteinsHistonesdsDNALeukocyte cell surface antigensCardiolipin

Rheumatoid Factors: An Auto-antibody to Self IgG Fc

HomogeneousANA

NucleolarANASpeckled ANA

CentriolarANAMultiple 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 ComponentDisease Concordance (%) Concordance (%) Explained by HLA (%)

Rheumatoid Arthritis 15-340-6 35

SLE 25-570-3

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 RAPlenge et al. NEJM. 357:1199 (2007)A common polymorphism in PTPN22 confers susceptibility to multiple autoimmune diseases - RA, Lupus, T1 diabetes, Hashimotos Thyroiditis

Whole genome scan for RAPTPN22 is #2 hitOdds ratio < 2

II. Environmental Factors

A. Viral infections (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 Target Organ/Tissue

A. Visibility 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 PolyarticularMonoPolyGoutRAInfectionSLEReactive

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 PathogenesisDiseaseOrgan System Involvement

Rheumatoid ArthritisJoints (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 DiseaseJoints (arthritis)Skin (Erythema chronicum migrans)Heart (carditis)CNS (meningo-encephalitis)

Rheumatoid Arthritis is Systemic Inflammatory Disease

SLE is a Systemic Inflammatory Disease

Therapeutic StrategiesReagents that blunt inflammation but dont 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:MethotrexateHydroxychloroquinAzathoprineCyclophosphamideCyclosporinMore 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;344:907-916Methods of Blocking the Activity of an Inflammatory Cytokine

Blocking CD28-dependent CostimulationAbatacept 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

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