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

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Flashcards in BL 02-25-14 8-9 AM RA-Janson_Hirsh for flashcards Deck (46):

Rheumatoid arthritis (RA)

= 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


RA – Joint distribution

- 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)


RA – Signs/ Symptoms

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.


RA – Serological findings

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


Anti-cyclic citrullinated peptide (CCP) antibodies

- 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


Why are anti-CCP antibodies so common in RA?

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


RA – Synovial fluid analysis

- Inflammatory (>2000 WBC/microliter), predominantly neutrophils
- LOW Complement & Glucose usually


RA – Radiographic findings

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


RA – Extra-articular manifestations

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


Rheumatoid nodules

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

- Extensor surfaces, tendon sheaths
- Various internal organs, esp. lungs


End-organ involvement in RA

Numerous organ systems affected in ~20% of pts:
- Eyes (scleritis)
- Lungs (pulmonary fibrosis or nodules)
- Peripheral nerves (neuropathy)

Pathophysiology: vasculitis, granulomatous infiltration


Prevalence of RA

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


Genetic factors in RA

Concordance rate ~30% in monozygotic twins, 3% in dizyogtic
HLA-DR4 in over 50%


Pathology (overview)

Begins w/ inflammation in synovium.
Later, destruction of articular cartilage, bone, and peri-articular structures.


Early Findings in RA

-Mild inflammation w/MICROVASCULAR INJURY, subsynovial edema, fibrin, exudation, and minimal synovial lining cell proliferation.

-SYNOVIAL FLUID at this stage is predominantly MONONUCLEAR CELLS.


Later Findings in RA

- 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.



= 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


Etiology of RA

- 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


Genetic factors

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


Class II MHC (HLA DR) and RA

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)


QKRAA sequence disease-associated alleles

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


3 Theories on Mechanism whereby Genetic Factors influence RA disease process

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)


Arthritogenic peptide theory

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)


Model for Development of anti-CCP antibodies

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


Selection of T cell repertoire theory

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


Class II peptide as an antigen itself in RA

- 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


Pathogenesis in RA - way to conceptualize

Conceptualize in 2 compartments:
1. Fluid phase
2. Synovial Tissue phase
- Events taking place in TISSUE are more important in the disease process


Pathogenesis in RA: Synovial fluid compartment

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


Pathogenesis of RA: Synovial tissue compartment

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


Pathogenesis of RA: Macrophages (in synovial tissue)

- 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


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

- 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


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

Systemic effects (mostly IL-6) include:
- anorexia
- fever
- stimulation of hepatic synthesis of acute-phase proteins (CRP, serum amyloid A, etc.)


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

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


Receptor Activator of Nuclear Factor kB Ligand (RANKL)

-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


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

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


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

- 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


Pathogenesis of RA: Lymphocytes (in synovial tissue)

= 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


T lymphocytes (in synovial tissue) Role in RA

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

May explain, in part, the chronicity of the disease


B lymphocytes (in synovial tissue) Role in RA

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 ?


Pathogenesis of RA: Rheumatoid factors (in synovial tissue)

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


Four elements of the therapeutic approach to RA

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


Anti-inflammatory / Analgesic drugs in RA treatment

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


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

- 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


Variation of Arthritogenic peptide theory

-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)


Traditional DMARDs in RA treatment - examples

- hydroxycloroquine
- sulfasalazine
- leflunomide
- methotrexate


Newer DMARDs in RA treatment - examples

- 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)