Arthritis Handout[1]
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Transcript of Arthritis Handout[1]
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Cellular Pathology OptionArthritisDr Stephen Young
Rheumatologyext: 6480
Clinical picture of the two major forms of arthritis
Inflammation and the destructive process
The role of genes covered by Dr Wallace
Models and theories of aetiology
Arthritis
http://rheumb.bham.ac.uk/primer.htmlGeneral patient info on arthritis
http://rheumb.bham.ac.uk/teaching/immunology/index.htmlGeneral immunology course from 2002
http://webct.bham.ac.uk
WebCT site for BMedSci, Cell Path and Immunology
Rheumatology and Immunology Web pages
Inflammatory
arthritis15%
Back pain
35%
Soft tissue
diseases
30%
Osteoarthritis
20%
15% of people on a GPs list consult their doctor with arheumatic problem each year
This accounts for 20-25% of all GP consultations
Prevalence of the four main types of rheumatic disorder
Tibia
Interosseous membrane
Attachment ofjoint capsule
Acute poplitealligament
Head of fibula
Posterior ligamentof fibular head
Medial head of gastrocnemiusm. and bursa
Adductor magnus tendon
Plantaris m.
Lateral head ofgastrocnemius m. andbursa
Fibular collateralligament andbursa
Biceps femoristendon andbursa
Femur
Attachment of joint capsule
Tibial collateral ligament
Semimembranosus tendon
Oblique popliteal ligament
Bursa under tendon
Popliteus m.
Normal Knee joint
Articularisgenus m.
Suprapatellarfat body
Patella
Bursa underlateral head ofgastrocnemius m.
Synovialmembrane
Articularcartliages
Femur
Quadricepsfemoris tendon
Subcutaneous prepatellar bursa
Articular cavity
Intrapatellar fat body
Patellar ligament
Lateral meniscus
Suprapatellar bursa
Synovial membrane
Tuberosity oftibia
Deep infrapatellar bursa
Subcutaneous infrapatellar bursa
Normal Knee
joint cross-section
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The most common form of joint disease
Age related with focal damage to the articularcartilage surface of the joint and a reaction withthe underlying bone
Chiefly affects knees, hips and hands causingpain, stiffness and disability
Causes painful limitation of joint movement withbony swelling and crepitus (creaking) onmovement
Osteoarthritis
Bony enlargements ortenderness
MalalignmentNo inflammation
Subchondral cystsand sclerosis
Non-inflammatorysynovial fluid
Crepitus
Joint spacenarrowing
Rheumatoidfactor (RF) Titre< 1:40
Morning stiffness < 30min
OsteophytesErythrocytesedimentationrate (ESR) 50
RadiographyLaboratoryClinical
Osteoarthritis: General features
Heberdens node
Osteoarthritis Heberdens nodes
Osteophyte
Malalignment
Osteoarthritis radiographic changes
Normal joint cross-sectionOsteoarthritis joint cross-section
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Features of the osteoarthritic process
Osteophyte
CartilageSurfacedamage
Radiographic changes in OA
Distribution of OA of the hands Prevalence of radiographic OA
Strongly associated with age - may relate to accumulatedinsult to the joint, decline in neuromuscular function, orsenescence in homeostatic repair mechanism.
Uncommon < 45yr (and multi-joint rare)
Increases to age 65 when > 50% have at least one jointgroup involved from radiography - may be asymptomatic
Sex - more women have severe radiographic grades
Obesity
Osteoarthritis characteristicsSchematic representation of the pathogenesis
of OA
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OA as a balance of etiologic factors andtissue processes
A normal versus an Osteoarthritic Synovial Joint
Individual Risk Factors for OA The Pyramidal Approach to the treatment of OA
Juvenile arthritis
12,000 in UK
Most commoncause of disabilityin children
Inflammatory
arthritis Acute inflammation may be due to physical damage, chemicalsubstances, micro-organisms or other agents.
The inflammatory response consist of changes in blood flow,increased permeability of blood vessels and escape of cells from theblood into the tissues.
The changes are essentially the same whatever the cause andwherever the site.
Acute inflammation is short-lasting, lasting only a few days. If it islonger lasting however, then it is referred to as chronicinflammation.
Various examples of acute inflammation that you may be aware ofare sore throat, reactions in the skin to a scratch or a burn or insectbite.
Inflammation
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The four principal effects of acute inflammation were described nearly2,000 years ago by Celcus:
Redness (rubor)An acutely inflamed tissue appears red, for example skin affected bysunburn, cellulitis due to bacterial infection or acute conjunctivitis. Thisis due to dilatation of small blood vessels within the damaged area.
Heat (calor)Increase in temperature is seen only in peripheral parts of the body,such as the skin. It is due to increased blood flow (hyperaemia) throughthe region, resulting in vascular dilatation and the delivery of warmblood to the area.
Swelling (tumor)Swelling results from oedema, the accumulation of fluid in the extravascular space as part of the fluid exudate, and to a much lesser extent,from the physical mass of the inflammatory cells migrating into thearea.
Clinical Aspects of Acute Inflammation
Pain (dolor)
For the patient, pain is one of the best known features of acuteinflammation. It results partly from the stretching and distortion oftissues due to inflammatory oedema and, in particular, from pus underpressure in an abscess cavity. Some of the chemical mediators of acuteinflammation, including bradykinin, the prostaglandins and serotonin, areknown to induce pain.
Loss of function
Loss of function, a well-known consequence of inflammation, wasadded by Virchow (1821-1902) to the list of features drawn up byCelsus. Movement of an inflamed area is consciously and reflexlyinhibited by pain, while severe swelling may physically immobilise thetissues.
Clinical Aspects of Acute Inflammation
A group of conditions, which include systemicconditions, that target joints (e.g. rheumatoidarthritis) as well as purely local inflammatorydisorders (e.g. septic arthritis)
The most severe, painful and disabling chronicdiseases, which may have their onset in
children and young adults
Inflammatory arthropathiesCan be sub-classified as follows:
Rheumatoid arthritis (RA) and related disorders
Juvenile chronic arthritis (JCA)
Sero-negative spondoarthropathies (eg ankylosing
spondylitis)
Crystal arthritis (eg gout)
Connective tissue disease (eg systemic lupuserythrematosus)
Septic arthritis
Inflammatory arthropathy subclasses
Is an inflammatory disease of the synovium (jointsurface) which results in erosion, deformity anddestruction of the joints.
Predominantly in women (ratio of 1:3) in young adultlife or middle age, although it has been recorded in allage groups, and recent surveys suggest that it may bemore common in older people than previously thought.
Can affect children (Juvenile chronic arthritis) whichis the most common cause of disability in children inthe UK.
Prevalence is about 1-3% of the population
Rheumatoid arthritis
Early RA Expanded synovial membrane
Rheumatoid arthritis joint features
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Characteristically starts in the small joints of thehands and feet with metacarpophalangeal (knuckle)
joints often being affected first
The destruction of the joints begins as a vasculitisassociated with increased capillary permeability,oedema and inflammatory cell infiltrates into the
joint
Hypertrophy (massive growth) of the synovial tissueseating into the cartilage as pannus, probably as resultof activation of macrophages and neutrophils whichcause erosion of cartilage and bone
Clinical featuresRA can be very aggressive
Normal Knee joint
Normal joint
OsteoarthritisDestruction of cartilageOvergrowth of subchondral bone
Inflammatory arthritisInflammation of the synoviumErosion/destruction of boneand cartilage
RA and OA compared
One third of patients have systemic problems ofthree types:
1. Fibrosing alveolitis - lung inflammation andoedema leading to fibrosis
2. Vasculitis of the skin, nerves or eyes
3. Granuloma formation - foci of necrosissurrounded by macrophages and lymphocytes
Extra-articular disease Perivascular cuffing is a common pattern of lymphocytic infiltration inchronic inflammmatory reactions. Lymphocytes emerge from thecirculating blood mostly through the walls of small venules and tend toaggregate around the vessels.
Blood cellsin vessel
Lymphocytes
Lymphocytes around a blood vessel
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Synovial membrane expansion in RA Micrograph of hyperplasia
Type A and B synoviocytes
CartilageSynovial membrane
Immunecomplexes
Capsule
PMN Pannus
Inflammed synovialmembrane
Plasmacell
Macrophage
Interdigitatingcell
Changes in synovium in RA
Soluble factors?T cells?B cells?Neutrophils?Macrophages?Fibroblasts?The joint environment?
Factors involved in driving the destructiveprocess in RA
RF (rheumatoid factor) - anti-IgG Fc
Anti-calpastatin
inhibitor of calpains, cysteine proteases able todegrade extracelluar matrix
Abs inhibit these so allowing unopposedproteolysis
Auto-antibodies
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Self-associated IgGRF
IgG
Antigen
+IgM RF
+ complement
Immunecomplex
Immunecomplex
Immunecomplexes
can promoteinflammation
Professional APC - dendritic cells (DC), B cells and macrophagesNon-professional APC - fibroblasts and endothelial cellsNeutrophils
Clusters of T cells around high endothelial venules with DC andactivated macrophages - likely site of antigen presentation
T cells mainly CD4+ but some CD8+
Memory phenotype CD45RA-RObright Rbdull
End-stage cells - bystander activated?
Cells in joint
Other changes in vivo
Increase in erythrocyte sedimentation rate (ESR)
Decrease in serum metalsCopper, zinc and iron all diminish. Again there are multiple reasons.Copper is used for synthesis of ceruloplasmin and both Cu and Zn arewithdrawn into the liver as the intracellular levels of the metal bindingprotein metallothionein increase. Iron is held back in macrophages asan attempt at bacteriostasis.
Anaemia of chronic disease
As a result of the iron withholding, as well as direct effects ofcytokines on bone marrow erythropoeisis, blood haemoglobin levelscan fall very dramatically
This is a composite of various blood changes, including effectsof fibrinogen, erthrocyte surface and shape changes, anaemia,dietary lipids.
Generation of oxidants by neutrophils
Oxygen radical effects in arthritis
V VDJJ
MHC
T cell
Antigen presenting cell
Ca flux
Cytokines
Antigen
Processing
Signal
Accessory molecules
(signal 2)
Signal 1
PiTNF, radicals
Invariant chain,
HLA-DM
T cell/APCinteractions
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T cell keeps things going althoughfibroblast and macrophages destroy
joint
Non-T cell hypothesis:
Need T cell response to Ag (?) toset things going but thenmesenchymal cells (Fibroblast andmacrophages) perpetuateindefinitely
T cell hypothesis:
MHC association
Large T cell infiltrate into the synoviumEvidence for antigen-driven arthritisT-cell therapies work e.g. total lymph nodeirradiation, thoracic duct drainage, anti-CD4 therapy,cyclosporin
Anti-TNF therapy may workDisease transfer with T cells in animal models
Evidence for a role for T cells
1) Responds to arthritogenic peptide on MHC
2) Susceptibility through thymic selection
3) Molecular mimicry - sequence homologybetween self and common pathogen eg gp110glycoprotein of EBV or dna J of E coli
Possible roles for T cell:Initiation
Reactive arthritisLyme diseaseViruses
RubellaParvovirushepatitis B
Mechanisms unknownPersistent low level virus or bacterial infection
results in continuous release of arthritogenic peptide
Infection releases cytokines allowing self T cellsto break tolerance
Molecular mimicry
Infectious agents
Type II collagen - specific to cartilage- suggested by animal models
- 10% of patients have Ab- but DR3/7 suggesting not a
primary role
- oral collagen - results conflictingin suppressing disease
Other Ags - Proteogylcans - not normallyinvolved in T cell responses since epitopes hidden bygycosaminoglycans
But T cells can be activated by revealing crypticepitopes by proteolysis or de-glycosylation
Autoantigens
Involved in destructive process- produce many inflammatory
cytokines, - most of which found in the joint
TNF, IL1, IL6 and IL8, metalloproteinases,prostaglandins, leukotrienes, oxygen radicalsand nitrous oxides
Anti-TNF works (?) as therapy
Macrophages
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Major cell of the expanded synovial membraneSecrete matrix degrading enzymes especiallyMMPs eg collagenase and stromolysin
Secrete cytokines e.g IL6, TGFActivated by TNFEvidence for partial transformation through p53mutations e.g. c-myc upregulated
synovial fibroblasts transplanted into SCID micejoints invade the cartilage
Fibroblasts? Cytokines
Most cytokines have been found in RA
synovium or synovial fluidIL1 and TNF are the predominant pro-inflammatory mediators
TNF-
IL-1
IL-8 IL-6GM-CSF
INFLAMMATION
CYTOKINE HEIRACHYCYTOKINE HEIRACHY EFFECTS OF TNFEFFECTS OF TNF--
TNF-
Adhesion molecule
expressionCollagenase + PG
production
Bone and Cartilageresorption
Cytokine production
TNF receptor expression
Fibroblast growth
Privileged site - apoptosis of T cells andfibroblast inhibited
Anaerobic - re-perfusion injury - oxidative stressDeposition of gut mucosal antigens?Angiogenesis - increased blood vessels formedUp-regulation of adhesion molecules
Attraction and retention of T cells.
Joint environment?Candidate antigens for driving the immune
response in RA
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Infection
Innate
responsespecific
response
Initiation of RA?
Innate
responsespecific
response
Perpetuation of RA?
The synovium in RA is marked by expansion of the intimal liningcell population and massive infiltration of the sub-lining by T-cells,macrophages and B-cells.
Products of macrophages and fibroblasts are abundant in therheumatoid joint, while T-cell products are absent or present in lowconcentrations.
Cytokines regulate and perpetuate many aspects of RA, includingproduction of metalloproteinases, recruitment of new cells to the
joint, expression of small molecule mediators of inflammation, and
cell proliferation.The initiation and perpetuation of RA are distinct events andmight be regulated by different cell types.
Chronicity appears to involve complex interactions betweenfibroblasts, macrophages and T-cells.
Summary of immune events in RA Therapy of RA relates to the stage of disease
Role of T cells in development of arthritis
JSH Gaston (1998) Clinical Science 95, 19-31.
Invasive fibroblast-like synoviocytes in RAGS Firestein Arthritis and Rheumatism (1996) 39, 1781-1790
Joint destruction in RA: biological basesG Kingsley and GS Panayi (1997) Clin Exp Rheumatology 15 (suppl 17) S3-S14.
Role of cytokines in RA
M Feldman, FM Brennan and RN Maini (1996) Ann Rev Immunol 14, 397-440
Accelerated atherogenesis in autoimmune rheumatic diseasesPA Bacon. Autoimmunity Reviews 1 (6):338-347, 2002.
Cytokine regulation in RA synovial tissue: role of T cell/macrophage contact-dependentinteractionsBrennan FM, Foey ADArthritis Res 2002, 4(Suppl 3):S177-S182 (9 May 2002)
Pathogenesis of arthritis: recent research progress.
M Feldmann. Nature Immunology 2 (9):771-773, 2001.
Is osteoarthritis a systemic disorder of bone?Rogers J, Shepstone L, Dieppe P ARTHRITIS RHEUM 50 (2): 452-457 FEB 2004
Osteoarthritis: time to shift the paradigmDieppe P BRIT MED J 318 (7194): 1299-1300 MAY 15 1999
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