Transcript Rheumatoid Arthritis

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 Painter’s Family
Jacob Jordaens (1593-1678)
Evidence of:
Rheumatoid Arthritis
The Virgin with Canon van
Der Paele, 1436
Jan van Eyck (1385-1440)
Evidence of:
Temporal (Giant Cell)
Arteritis
Importance and Impact of Rheumatologic Disease
Prevalence (per 100,000)
Rheumatoid Arthritis
Ankylosing Spondylitis
Gout
SLE
Scleroderma
Osteoarthritis
All Musculoskeletal conditions
Male
440
197
980
7
1
3,470
Female
1,100
73
230
32
5
5,870
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
Naïve T cell
Key cytokines in Chronic
Inflammatory Arthritis:
TNF-a
IL-1
IFN-g
IL-6
OPGL (RANK-ligand)
IL-17
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
Chronic inflammation
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
Speckled
ANA
Nucleolar
ANA
Centriolar
ANA
Why does tolerance fail?
Why do people develop auto-immune
rheumatologic 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
associatedwith 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
Concordance (%)
Concordance (%)
Disease
Rheumatoid Arthritis
15-34
0-6
SLE
25-57
0-3
Genetic Component
Explained by HLA (%)
35
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)
II. Environmental Factors
A. Viral infect ions (hepatitis B, hepatitis C, others)
B. Bacterial infecti ons (Shigella , Salmonella,
gp A strep., etc.)
C. Drugs (procainamide, dilan tin, others)
D. Toxin s (heavy metals, others)
E. UV-light (i.e., in SLE)
III. Status of the ImmuneSystem
A. Relative state of activation
B. Relative balance of Th1 and Th2
C. History of previous responses
IV. Status of Target Organ/Tissue
A. Visibi lity of autoantige n (privilege d sites,
intra- vs extra-cellular, etc)
B. Expression level of autoantigen
C. Expression level of MHC
D. Costim ulato ry molecules
E. Ongoing inflamma tion
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
Gout
Infection
Reactive
Poly
RA
SLE
Joint distribution
PIPs and MCPs: RA, SLE
DIPs:
Osteoarthritis, Psoriatic
MTP:
Gout
Symmetrical vs Asymmetrical
Symmetrical:
Asymmetrical:
RA, SLE
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