arthritis handout[1]

7/30/2019 Arthritis Handout[1]

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Cellular Pathology OptionArthritisDr Stephen Young

Rheumatologyext: 6480

[email protected]

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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