BL 02-25-14 8-9 AM RA-Janson_Hirsh for flashcards
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
Location:
- 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.
- Continued MICROVASCULAR INJURY
- PANNUS
- SYNOVIAL FLUID contains primarily POLYMORPHONUCLEAR NEUTROPHILS now
Pannus
= 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
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
Genetic factors
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
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
- Arthritogenic peptide presentation to the immune system initiated/perpetuates RA
- Selection of T cell repertoire - either anti-arthritogenic protein T cells or T cells unable to clear etiologic agents
- 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:
- Fluid phase
- 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
OR
- 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
- Anti-inflammatory / analgesic drugs
- Disease-modifying anti-rheumatic drugs (DMARDs)
- Physical therapy
- Surgery (including total joint replacements)
Anti-inflammatory / Analgesic drugs in RA treatment
- palliative / symptomatic
- do NOT prevent tissue destruction
- inhibit production of inflammatory mediators
Include: - 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
Include:
- hydroxycloroquine
- sulfasalazine
- leflunomide
- methotrexate
Newer DMARDs in RA treatment - examples
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)
