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Unit 3 B&L > BL 02-25-14 8-9 AM RA-Janson_Hirsh for flashcards > Flashcards

BL 02-25-14 8-9 AM RA-Janson_Hirsh for flashcards

1
Q

Rheumatoid arthritis (RA)

A

= peripheral, symmetric, inflammatory synovitis

  • -> often leads to cartilage / bone destruction & joint deformities
  • -> also, extra-articular manifestations (usually less extensive / severe than in other such diseases)

= autoimmune, but unknown etiology

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2
Q

RA – Joint distribution

A
  • peripheral synovial joints
  • symmetrical
  • esp. small joints of hands & feet (though medium & large joints also involved).
  • DIP often spared
  • Cervical spine commonly involved (esp. C1-2).
  • Other synovial joints (cricoarytenoid, inner ear ossicles, TMJ)
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3
Q

RA – Signs/ Symptoms

A

Morning stiffness
Soft tissue / joint swelling and warmth (from synovial tissue proliferation or excess synovial fluid)
Pain, tenderness to palpation
Deformities / Loss of function / Limited ROM possible.

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4
Q

RA – Serological findings

A
  • Rheumatoid factor (RF) in 85%
  • Elevated ESR &CRP often
  • Anemia & Hypergammaglobulinemia frequent
  • Anti-cyclic citrullinated peptide (CCP) antibodies in 70%
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5
Q

Anti-cyclic citrullinated peptide (CCP) antibodies

A
  • Highly specific for RA (>90% specific)
  • React w/ peptides containing citrulline (Arg residue modified by peptidyl arginine deiminase (PAD)), found in many sites of inflammation
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6
Q

Why are anti-CCP antibodies so common in RA?

A
  • Unknown
  • Strong association to smoking (risk factor for RA)
  • Shared epitope in HLA alleles observed in pts with RA who have anti-CCP antibodies
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7
Q

RA – Synovial fluid analysis

A
  • Inflammatory (>2000 WBC/microliter), predominantly neutrophils
  • LOW Complement & Glucose usually
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8
Q

RA – Radiographic findings

A
  • Soft tissue swelling
  • Juxta-articular osteopenia
  • Symmetric loss of joint space
  • Erosions in marginal distribution
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9
Q

RA – Extra-articular manifestations

A

Occurs in 20ish% of patients

  • Constitutional symptoms (common, may predominate over joint symptoms – fatigue, malaise, anorexia, weight loss, low-grade fever)
  • Rheumatoid nodules
  • End-organ involvement
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10
Q

Rheumatoid nodules

A
  • In 20-25% of RA cases
  • Associated w/ presence of serum RF

Location:

  • Extensor surfaces, tendon sheaths
  • Various internal organs, esp. lungs
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11
Q

End-organ involvement in RA

A

Numerous organ systems affected in ~20% of pts:

  • Eyes (scleritis)
  • Lungs (pulmonary fibrosis or nodules)
  • Peripheral nerves (neuropathy)

Pathophysiology: vasculitis, granulomatous infiltration

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12
Q

Prevalence of RA

A

1-2% of adult population
More in females (>2x)
Prevalence increases w/ age (~5% in >65yo)

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13
Q

Genetic factors in RA

A

Concordance rate ~30% in monozygotic twins, 3% in dizyogtic

HLA-DR4 in over 50%

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14
Q

Pathology (overview)

A

Begins w/ inflammation in synovium.

Later, destruction of articular cartilage, bone, and peri-articular structures.

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15
Q

Early Findings in RA

A
  • Mild inflammation w/MICROVASCULAR INJURY, subsynovial edema, fibrin, exudation, and minimal synovial lining cell proliferation.
  • SYNOVIAL FLUID at this stage is predominantly MONONUCLEAR CELLS.
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16
Q

Later Findings in RA

A
  • Increased cell proliferation in synovial lining (Macs [type A cells] from blood monocytes, Fibroblasts [type B cells] from local proliferation)
  • Normally acellular sublining region of synovium shows FIBROBLAST PROLIFERATION, growth of new blood vessels, and focal aggregates of CD4+ T lymphocytes, B cells, & plasma cells.
  • Continued MICROVASCULAR INJURY
  • PANNUS
  • SYNOVIAL FLUID contains primarily POLYMORPHONUCLEAR NEUTROPHILS now
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17
Q

Pannus

A

= organized mass of granulation tissue consisting of Macs, T cells, B cells, fibroblasts
= common in established RA
= arises from synovium under influence of numerous CYTOKINES
= covers & invades articular cartilage and juxta-articular bone
= leads to radiographic findings of loss of joint space & periarticular erosions

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18
Q

Etiology of RA

A

UNKNOWN

  • preclinical autoimmunity (RF or anti-CCP Abs) may exist for years before onset of clinical disease
  • various mechanisms of initiation & perpetuation of inflammation & tissue damage
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19
Q

Genetic factors

A 
POLYGENIC DISEASE 
Different sets of predisposing genes in different population groups, including...
- Class II MHC (HLA DR)
- PTPN22 gene
- STAT4 gene 
- TRAF1-C5 gene locus
20
Q

Class II MHC (HLA DR) and RA

A

QKRAA, or the “shared epitope”
= short sequence in 3rd hypervariable portion of DRB1 genes (RA-associated class II molecules)
- surrounds Ag-binding groove
- may interact both w/side chains of bound antigen & with T cell receptor
- citrullination of peptides enhances binding to shared epitope (anti-CCP Abs found)

21
Q

QKRAA sequence disease-associated alleles

A

Caucasians: HLA-DRB1 *0401, 0404, 0101
Asians: *0405
Indians: *1402
—> determines susceptibility & severity of disease

22
Q

3 Theories on Mechanism whereby Genetic Factors influence RA disease process

A
  1. Arthritogenic peptide presentation to the immune system initiated/perpetuates RA
  2. Selection of T cell repertoire - either anti-arthritogenic protein T cells or T cells unable to clear etiologic agents
  3. Class II peptide as antigen itself (cross-rxtive autoimmunity)
23
Q

Arthritogenic peptide theory

A

RA-associated Class II molecules may be able to bind & present arthritogenic peptides
- probably on DCs, Macs, B cells

Potential arthritogenic peptides:

  • exogenous infectious agents (EBV, other viruses, bacterial heat shock proteins)
  • modified endogenous molecules (collagen)
  • unlikely that a single arthritogenic peptide exists (either in a single pt or between pts)
24
Q

Model for Development of anti-CCP antibodies

A
  • Inflammation (from smoking, others) initially generates citrullinated proteins
  • In appropriate genetic background (& perhaps under influence of other inflammatory changes), anti-CCP antibodies develop
25
Q

Selection of T cell repertoire theory

A 
RA-associated class II molecules may help in  selection of particular T cell repertoire in the thymus
- These T cells may be able to amplify/perpetuate chronic inflammation after encountering multiple arthritogenic peptides (exogenous or endogenous)

-Alternatively, QKRAA motif might create a “hole” in the immune repertoire, preventing clearance of an etiologic agent

26
Q

Class II peptide as an antigen itself in RA

A
  • There is SEQUENCE HOMOLOGY between the “shared epitope” and sequences in common viral/bacterial peptides
  • Abs or (more likely) sensitized T cells against exogenous peptides potentially may CROSS-REACT w/ Class II peptide itself or w/ other endogenous Ags, producing autoimmune response
27
Q

Pathogenesis in RA - way to conceptualize

A

Conceptualize in 2 compartments:

  1. Fluid phase
  2. Synovial Tissue phase
    - Events taking place in TISSUE are more important in the disease process
28
Q

Pathogenesis in RA: Synovial fluid compartment

A

Major cellular component in synovial fluid: Neutrophils

  • emigrate from circulation under influence of cytokines (IL-8, TGF-beta) & of adhesion molecules expressed on endothelial cells
  • In fluid phase, may contribute to tissue damage through release of PGs, leukotrienes, cytokines, oxygen radicals, & enzymes
29
Q

Pathogenesis of RA: Synovial tissue compartment

A

Synovial tissue (in the form of pannus) is directly opposed to the articular cartilage & marginal bone

  • –> responsible for most joint tissue destruction
  • most infiltrating cells are mononuclear (lymphocytes & macs)
  • intense proliferation of local fibroblasts
  • Neutrophils are rare in synovial tissue (in contrast to synovial fluid)
  • Mast cells in synovium also may play role in release of enzymes & cytokines
30
Q

Pathogenesis of RA: Macrophages (in synovial tissue)

A
  • May play central role in RA through capacity to synthesize /secrete several pro-inflammatory cytokines (IL-1, TNFα, IL-6) & proteolytic enzymes
  • Major influence driving macrophages involves direct contact w/ lymphocytes
  • In chronic phase, macs & fibroblasts may experience autocrine & paracrine mechanisms of stimulation
  • -> tissue destruction becomes autonomous or self-perpetuating w/ time
  • Synovial macs may give rise to osteoclasts –> destruction of marginal bone
31
Q

Pathogenesis of RA: Proinflammatory Cytokines in synovial tissue) - EXAMPLES

A
  • EX: IL-1, TNFα, IL-6, IL-17
  • produced in synovial tissue by macs & Th17

IL-6 –> systemic effects

IL-1, IL-17, TNFalpha –> local effect

32
Q

Pathogenesis of RA: Proinflammatory Cytokines in synovial tissue) - SYSTEMIC EFFECTS

A

Systemic effects (mostly IL-6) include:

  • anorexia
  • fever
  • stimulation of hepatic synthesis of acute-phase proteins (CRP, serum amyloid A, etc.)
33
Q

Pathogenesis of RA: Proinflammatory Cytokines in synovial tissue) - LOCAL EFFECTS

A

Local effects in joints (mostly IL-1 & TNF) include:

  • chemotaxis of inflammatory cells
  • release of PGE2
  • induction of collagenase & neutral proteinase production by synovial fibroblasts & chondrocytes in superficial layer of articular cartilage
  • This latter mechanism is most important in the process of cartilage & bone destruction*

IL-1, IL-17, TNFalpha –> expression of Receptor Activator of Nuclear Factor kB Ligand (RANKL) in osteocytes

34
Q

Receptor Activator of Nuclear Factor kB Ligand (RANKL)

A
  • TNFα, IL-1, and IL-17 induce osteocyte lineage cells to express this factor
  • interacts w/ RANK receptor on osteoclast precursors
  • –> activation & osteoclastic resorption of bone
35
Q

Osteoprotegerin (OPG) vs. Receptor Activator of Nuclear Factor kB Ligand (RANKL)

A

In normal bone:
- Osteoprotegerin (OPG) competitively binds RANKL & modulates its activity

In RA bone:
-elevated RANKL/OPG ratio –> bony resorption

Anti-TNF therapies

  • -> decrease this ratio & bone resorption
  • mAb against RANKL (denosumab) used for osteoporosis
36
Q

Pathogenesis of RA: Anti-inflammatory Cytokines & Substances (in synovial tissue)

A
  • EX: IL-1Ra (IL-1 receptor antagonist), and soluble receptors for IL-1 and TNFα
  • Also produced in rheumatoid synovium

Net inflammatory response depends on local balance btwn pro- & anti-inflammatory molecules

37
Q

Pathogenesis of RA: Lymphocytes (in synovial tissue)

A

= mostly CD4+ memory T cells in RA synovium
= also a variable number of B & plasma cells

Despite their predominance, T cells aren’t activated & T cell cytokines IL-2 & IFN-beta are sparse

  • Th17 T cells play significant role IL-17 secretion
  • Deficient Th2 & regs

Synovial tissue T & B cells are involved in disease process & probably vary in importance btwn pts or over time

38
Q

T lymphocytes (in synovial tissue) Role in RA

A

T cells may recognize…
- citrullinated peptides
OR
- proteoglycan / collagen molecules altered by enzymatic digestion w/ presentation of neoepitopes

May explain, in part, the chronicity of the disease

39
Q

B lymphocytes (in synovial tissue) Role in RA

A

B cells make RF & anti-CCP Abs
–> may lead to production of immune complexes, further enhancing local inflammation

Probably have further roles, as suggested through benefit of anti-B cell Ab (rituximab) therapy…

  • roles as APCs ?
  • roles in sustaining local T cell function ?
40
Q

Pathogenesis of RA: Rheumatoid factors (in synovial tissue)

A

Anti-IgG IgM (also may be IgG or IgA)

  • recognize epitopes present w/in Fc portion of IgG
  • made locally in synovial tissue in many pts w/ RA
  • associated w/ more severe disease
  • present on B cell surface (may bind immune complexes & function as APCs)

RF+IgG Immune complexes present in both synovial tissue & fluid
–> complement activation via classical pathway, producing inflammatory consequences

Not specific for RA
- found in low levels in normal individuals & in other infectious/inflammatory diseases

41
Q

Four elements of the therapeutic approach to RA

A
  1. Anti-inflammatory / analgesic drugs
  2. Disease-modifying anti-rheumatic drugs (DMARDs)
  3. Physical therapy
  4. Surgery (including total joint replacements)
42
Q

Anti-inflammatory / Analgesic drugs in RA treatment

A
  • palliative / symptomatic
  • do NOT prevent tissue destruction
  • inhibit production of inflammatory mediators
    Include:
  • NSAIDS, acetaminophen, prednisone (PO or intra-articular injection)
43
Q

Disease-modifying anti-rheumatic drugs (DMARDs) in RA treatment

A
  • instituted early after Dx to PREVENT tissue destruction
  • Traditional agents inhibit macs / lymphocytes
  • Newer agents inhibit cytokine effects & T cell co-stimulator molecules, modify T cell activation, and deplete B cells
  • Under investigation: Agents that inhibit cytokines; deplete particular cells; or inhibit intracellular tyrosine kinases (oral “small molecules”)
    = Tofacitinib (novel oral JAK inhibitor) recently FDA-approved
44
Q

Variation of Arthritogenic peptide theory

A
  • predisposing MHC class II preferentially binds & presents citrulllinated peptides, leading to production of anti-CCP antibodies
  • these antibodies then lead to joint disease by direct targeting of citrullinated proteins w/in joint (Type II immune rxn) OR through formation of immune complexes which then deposit in joint & cause inflammation (Type III)
45
Q

Traditional DMARDs in RA treatment - examples

A

Include:

  • hydroxycloroquine
  • sulfasalazine
  • leflunomide
  • methotrexate
46
Q

Newer DMARDs in RA treatment - examples

A

Include:

  • Anakinra (inhibit IL-1)
  • Etanercept (inhibit TNFalpha)
  • Infliximab (inhibit TNFalpha)
  • Adalimumab (inhibit TNFalpha)
  • Certolizumab (inhibit TNFalpha)
  • Golimumab (inhibit TNFalpha)
  • Tocilizumab (inhibit IL-6)
  • Abatacept (inhibit T cell costimulator molecule & modulate T cell activation)
  • Ritiximab (deplete T cells)

Unit 3 B&L (18 decks)

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