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

Question 1

Rheumatoid arthritis (RA)

Answer 1

= 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

Question 2

RA – Joint distribution

Answer 2

• 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)

Question 3

RA – Signs/ Symptoms

Answer 3

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.

Question 4

RA – Serological findings

Answer 4

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

Question 5

Anti-cyclic citrullinated peptide (CCP) antibodies

Answer 5

• 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

Question 6

Why are anti-CCP antibodies so common in RA?

Answer 6

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

Question 7

RA – Synovial fluid analysis

Answer 7

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

Question 8

RA – Radiographic findings

Answer 8

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

Question 9

RA – Extra-articular manifestations

Answer 9

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

Question 10

Rheumatoid nodules

Answer 10

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

Location:

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

Question 11

End-organ involvement in RA

Answer 11

Numerous organ systems affected in ~20% of pts:

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

Pathophysiology: vasculitis, granulomatous infiltration

Question 12

Prevalence of RA

Answer 12

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

Question 13

Genetic factors in RA

Answer 13

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

HLA-DR4 in over 50%

Question 14

Pathology (overview)

Answer 14

Begins w/ inflammation in synovium.

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

Question 15

Early Findings in RA

Answer 15

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

Question 16

Later Findings in RA

Answer 16

• 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

Question 17

Pannus

Answer 17

= 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

Question 18

Etiology of RA

Answer 18

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

Question 19

Genetic factors

Answer 19

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

Question 20

Class II MHC (HLA DR) and RA

Answer 20

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)

Question 21

QKRAA sequence disease-associated alleles

Answer 21

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

Question 22

3 Theories on Mechanism whereby Genetic Factors influence RA disease process

Answer 22

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)

Question 23

Arthritogenic peptide theory

Answer 23

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)

Question 24

Model for Development of anti-CCP antibodies

Answer 24

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

Question 25

Selection of T cell repertoire theory

Answer 25

``` 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

Question 26

Class II peptide as an antigen itself in RA

Answer 26

- 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

Question 27

Pathogenesis in RA - way to conceptualize

Answer 27

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

Question 28

Pathogenesis in RA: Synovial fluid compartment

Answer 28

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

Question 29

Pathogenesis of RA: Synovial tissue compartment

Answer 29

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

Question 30

Pathogenesis of RA: Macrophages (in synovial tissue)

Answer 30

- 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

Question 31

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

Answer 31

- 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

Question 32

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

Answer 32

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

Question 33

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

Answer 33

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

Question 34

Receptor Activator of Nuclear Factor kB Ligand (RANKL)

Answer 34

- 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

Question 35

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

Answer 35

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

Question 36

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

Answer 36

- 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

Question 37

Pathogenesis of RA: Lymphocytes (in synovial tissue)

Answer 37

= 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

Question 38

T lymphocytes (in synovial tissue) Role in RA

Answer 38

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

Question 39

B lymphocytes (in synovial tissue) Role in RA

Answer 39

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 ?

Question 40

Pathogenesis of RA: Rheumatoid factors (in synovial tissue)

Answer 40

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

Question 41

Four elements of the therapeutic approach to RA

Answer 41

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

Question 42

Anti-inflammatory / Analgesic drugs in RA treatment

Answer 42

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

Question 43

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

Answer 43

- 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

Question 44

Variation of Arthritogenic peptide theory

Answer 44

- 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)

Question 45

Traditional DMARDs in RA treatment - examples

Answer 45

Include: - hydroxycloroquine - sulfasalazine - leflunomide - methotrexate

Question 46

Newer DMARDs in RA treatment - examples

Answer 46

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)