JOINT PATHOLOGYJOINT PATHOLOGY

FERDA ÖZKAN M.D.

YEDITEPE UNIVERSITY MEDICAL FACULTY

OBJECTIVESOBJECTIVES

Review joint structure

Explain inflammatory processes of Joints

Describe types of arthritis

JOINTSJOINTS

Nonsynovial- (solid)- synarhtoses: Lack joint space-fibrous synarthroses -synchondroses

Synovial- have joint space

Synovial JointSynovial Joint

Synovial JointsSynovial Joints

The boundry of the joint space is formed by the synovial membrane

Two types of synovial cells

Type A- (macrophage like) phagocytic and synthetize hyaluronic acid

Type B- (fibroblast like) produce various proteins

SYNOVIOCYTESSYNOVIOCYTES

ARTICULAR HYALINE ARTICULAR HYALINE

CARTILAGECARTILAGE

Articular hyaline cartilage is composed of type 2 collagen, water, proteoglycans and chonrocytes.

The water and proteoglycans give hyaline cartilage its turgor and elasticity and limit friction.

Chondrocytes synthetize the matrix as well as enzymatically digest it

Matrix turnover is controlled as chondrocytes secrete the degenerative enzymes in an inactive form and enrich the matrix with enzyme inhibitors

Cytokines such as IL-1 and TNF trigger degradative process

The source of cytokines include

-Chondrocytes-Synoviocytes-Inflammatory cells

CHRONIC INFLAMMATORY CHRONIC INFLAMMATORY SYNOVITIS SYNOVITIS

Arthritis - IntroductionArthritis - Introduction

Inflammation of joints - CommonCommon site for autoimmune

injury– Heart valves & Joints - damage –

Exposure of hidden antigens.Infections.Degeneration – Age/Stress/life

style

Use it or Loose it….!

Arthritis – Clinical features:Arthritis – Clinical features:

Pain Inflammation - capsule, synovium,

periosteum. Swelling:

inflammation, effusion, proliferation. Restricted movement

pain, fluid, synovial swelling, damage.

Deformity mal-alignment, erosion, ankylosis

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Arthritis Clinical Arthritis Clinical Classification:Classification:Monoarthritis:

– Local, asymmetric, secondary.– Acute: Bacterial, Trauma,

Crystal, Reactive– Chronic :Tuberculosis, Lyme,

Fungal, Trauma, Tumors.Polyarthritis:

– Chronic, symmetric, systemic.– Autoimmune, degenerative,

Crystal.– Rarely infective.

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Polyarthritis ClassificationPolyarthritis Classification::

Autoimmune: – Rheumatoid,Ankylosing

spondilitis, Psoriatic , Reiter’s syndrome, enteropathic

Degenerative: Osteroarthritis Crystal Deposition:

– Gout – Monosodium urate– CPPD - Pseudo Gout

Infective - Septic, TB, Lyme etc. rare.

Rheumatoid Arthritis

RHEUMATOID RHEUMATOID ARTHRITISARTHRITISAutoimmune chronic systemic

inflammatory disorder Attacks joints, causing a

nonsuppurative proliferative inflammatory synovitis

Destruction of articular cartilage and ankylosis of the joints

RHEUMATOID RHEUMATOID ARTHRITISARTHRITIS Symmetric, small joints Usually in hands

metacarpophalangeal and proximal interphalangeal joints

Feet, wrists,ankles, elbows and knees

Joints swollen, warm, painful particulary in the morning or following inactivity

Epidemiology of RAEpidemiology of RA

Prevalence about 1-3% of population

Female : Male ratio = 3-5:1

Concordance in identical twins 30%

Its pathogenesis is complex and incompletely understood, involving both type III (antigen-antibody complex) and type IV (T helper lymphocyte / macrophage-mediated) hypersensitivity reactions.

PathogenesisPathogenesis

Inciting agent activates immune system immunological reactions immune complexes in synovial fluid activate complement inflammatory response joint destruction.

Earliest change is inflammation and edema of synovium with increased vascularity and increased production of synovial fluid– shows evidence of CD4+ T helper cells

migrating into the joint.

Next steps:– synovial villi hypertrophy, – synovial cells proliferation, – increased vascularisation

(angiogenesis) – pannus form (granulation tissue

that grows across surface of articular cartilage from adjacent synovium).

Marked synovial hypertrophy Marked synovial hypertrophy with formation of villi.with formation of villi.

Subsynovial tissue containing Subsynovial tissue containing a dense lymphoid aggregatea dense lymphoid aggregate

Synovial angiogenesis

Tissue section of rheumatoid synovial pannus showing prominent new blood vessel formation

Hyperplastic synovium may spread over and erode into cartilage and bone.

This destructive proliferation of synovium is known as pannus.

Large numbers of inflammatory cells (T and B lymphocytes, plasma cells and macrophages) take up residence within the synovium.

These secrete inflammatory mediators (cytokines, prostaglandins etc.) into the synovial fluid.

This figure demonstrates – destruction of

articular cartilage (open arrow; osteoclastic cells)

– by synovial pannus (solid arrow).

It is thought that the pannus destroys the cartilage by production of metalloproteinases.

Pannus can also destroy bone by recruiting osteoclasts to resorb bone matrix (open arrow).

Osteoclasts are very sensitive to IL1 and TNF, resorbing bone in response to production of these cytokines by the inflammatory cells infiltrating the pannus (solid arrow).

Production of metalloproteinases by synovial cells is induced by the inflammatory cytokines IL1 and TNF- which are both produced by chronically inflamed synovium.

These cytokines also cause synovial cells to proliferate and are probably responsible for the development of pannus.

The muscles waste around the joint Hyperemia develops The joint capsule is distended Destruction of unprotected bone at

joint margin and subchondral bone by pannus

Later leading to marked joint damage and capsular laxity

Leading to deformity and fibrous ankylosis

Eventually bony ankylosis of the joint.

N.Synovium - - R.Arthritis:N.Synovium - - R.Arthritis:

RA - Pannus:RA - Pannus:

Hyperplastic Hyperplastic inflammed inflammed synoviumsynovium

Skin RA Nodule:Skin RA Nodule:

Skin RA Nodule:Skin RA Nodule:

Rheumatoid Nodule (skin):Rheumatoid Nodule (skin):

PalisadingPalisadingMacrophagesMacrophages

CentralCentralFibrinoidFibrinoidNecrosisNecrosis

Subcutaneous rheumatoid nodule with an Subcutaneous rheumatoid nodule with an area of necrosis surrounded by a palisade area of necrosis surrounded by a palisade of macrophages and scattered chronic of macrophages and scattered chronic inflammatory cells.inflammatory cells.

Joint involvement in RA:Joint involvement in RA:

Swan Neck Deformity in RA:Swan Neck Deformity in RA:

Joint Destruction in RA:Joint Destruction in RA:

Swan NeckDeformity

RA Joint destruction, RA Joint destruction, ankylosis:ankylosis:

EExtraarticular manifestationsxtraarticular manifestations Weight loss, malaise and fever; Lymphadenopathy Skin (rheumatoid nodules – in 50%, at

periarticular positions subject to high external pressure; inflammatory granulomatous lesions; vasculitis (leukocytoclastic vasculitis and palpable purpura)

Eye (keratoconjunctitis, scleritis, episcleritis) Respiratory (pleurisy, pleural effusions,

interstitial fibrosis, rheumatoid nodules, bronchiolitis)

Cardiac (pericardial effusion, pericarditis, myocarditis, endocarditis, valvular heart disease)

Peripheral nerves: nerve compression by synovitis or tenosynovitis, syndrome of mononeuritis multiplex.

Gastrointestinal (adverse effects from drugs)

Renal (amyloidosis, drug induced nephropathy, renal tubular acidosis)

Neurologic (entrapment syndromes – especially carpal tunnel, peripheral neuropathy from vasculitis – sensory and motor, mononeuritis multiplex)

Hematologic (anemia, leucopenia, lymphoma, thrombocytosis)

Hand deformities (fusiform swelling spindle shape to fingers)

Cervical spine involvement.

Juvenile Rheumatoid Juvenile Rheumatoid Arthritis:Arthritis:

Before age 16 Multisystem involement -

Spleenomegaly, Starts with systemic involvement

unlike RA. No serum RA Factor – Seronegative Antinuclear Antibody (ANA) +ve

autoimmune.

Juvenile Rheumatoid Juvenile Rheumatoid ArthritisArthritis

Still (1887) : rheumatoid arthritis in children

Common connective tissue disease in children age 15 or less, 65% male.

Either oligoarticular (<5 joints), polyarticular (5 or more joints) or systemic.

Compared to classic rheumatoid arthritis, oligoarthritis is more common; – systemic large joints are affected more than

small joints, – no rheumatoid nodules are present, – no rheumatoid factor is present, – ANA positive.

Associated with HLA-DRB1, infections by mycobacteria, bacteria, viruses.

70% recover– 10% have residual severe joint deformities

Symptoms: systemic onset with fever, rash, hepatosplenomegaly, generalized lymphadenopathy, serositis; also warm and swollen joints; pericarditis, myocarditis, pulmonary fibrosis, glomerulonephritis, uveitis, growth retardation.

Sites: knees, wrists, elbows, ankles. Micro: similar morphologic changes as

rheumatoid arthritis.

Seronegative Seronegative spondyloarthropathyspondyloarthropathy Inflammatory joint diseases that all

share a common pathology and strong association to the HLA-B27 antigen and are negative for rheumatoid factor (seronegative).

Used to be referred to as variants of rheumatoid arthritis as they share many pathologic and radiologic features with rheumatoid arthritis. – ‘Spondylos’ is Greek for vertebrae.

Ankylosing Spondylitis (Marie-Strumpell’s disease)

Psoriatic Arthritis (PsA)Reactive Arthritis (ReA)

(Reiter’s syndrome)Enteropathic Spondylitis

(Enteropathic synovitis)Undifferentiated spondylitis

Ankylosing SpondylitisAnkylosing Spondylitis (Marie-Strumpell’s disease)(Marie-Strumpell’s disease) Chronic inflammatory disorder primarily affecting

the axial skeleton Affected joints tend to fibrosis and ankylosis. Cause unknown,

– Strongly associated with HLA-B27 histocompatibility antigen (90%)

Affects up to 1% of population– Affects teenage boys

Chronic synovitis destroys articular cartilage and causes bony ankylosis

Inflammation of tendinoligamentous insertion sites cause osteophytes.

Symptoms: low back pain that gets progressively.

AS - fusion of vertebral AS - fusion of vertebral bodies due to bridging bodies due to bridging ssyndesmophytes.yndesmophytes.

Scoliosis in Ankylosing Scoliosis in Ankylosing SpondylitisSpondylitis

Psoriatic Arthritis (PsA)Psoriatic Arthritis (PsA)

Inflammatory arthritis in 2-7% of those with psoriasis (psoriasis affects 1-2% of population).

Most have previous long history of psoriasis– all forms of psoriasis can develop

arthritis. High association with HLA-B27

and HIV infection.

Reactive Arthritis (ReA)Reactive Arthritis (ReA) (Reiter’s syndrome)(Reiter’s syndrome)

Post-infectious disorder (not a local infection, but a reaction).

Classic triad (Reiter – 1916) of arthritis, urethritis and conjunctivitis following infection. – Reiter’s syndrome is now

not the preferred name (Reiter was involved with Nazi politics and medical experiments).

Syndrome now considered consisting of:1) Arthritis (asymmetric) 2) Urethritis(mild)3) Conjunctivitis (mild)4) Mucocutaneous lesions (oral erosions/ulcers).

Reiter’s Syndrome: Reiter’s Syndrome: conjunctivitisconjunctivitis

Reiter’s Reiter’s Syndrome Syndrome ::IritisIritis

Reiter’s SyndromeReiter’s Syndrome : Urethritis : Urethritis

Organisms in Reiter’sOrganisms in Reiter’s

Shigella FlexneriSalmonellaS.typimurium – othersYersinia enterocoliticaCampylobacter JejuniChlamydia trachomatisUreaplasma urealyticum

Enteropathic Spondylitis Enteropathic Spondylitis (Enteropathic synovitis)(Enteropathic synovitis) Joint manifestations associated with

chronic inflammatory bowel diseases:– ulcerative colitis– Crohn’s disease.

Can also be associated with intestinal bypass surgery (bypass arthritis-dermatitis syndrome), infectious gastroenteritis, pancreatic disease, biliary cirrhosis, coeliac disease (gluten sensitive enteropathy) and Whipple’s disease.

Undifferentiated spondylitisUndifferentiated spondylitis

Patients who have some of the features of seronegative spondyloarthropathy, but do not meet the criteria for the well recognised conditions.

They may be an early stage of a known spondyloarthropathy, an atypical variant of a known spondyloarthropathy or an unknown type of spondyloarthropathy.

Hemophilic arthropathyHemophilic arthropathy Common feature of hemophilia

– more common in knee, ankle and elbow Hemorrhage induces a synovial proliferation,

chronic inflammation release of degradative proteinases joint damage.

Recurrent bleeding irreversible damage.Stages of the disease: Stage 1 – acute hemoarthrosis in child when

begin to walk Stage 2 – subacute or chronic arthritis Stage 3 – end-stage arthropathy (chronic

destructive arthropathy with joint instability, fibrous ankylosis, osteophytic overgrowth)

OsteoarthritisOsteoarthritis

Degenerative joint disease (osteoarthritis) Progressive erosion of articular cartilage

associated with aging, trauma, occupational injury

Usually age 50+ years (present in 80% at age 65 years)

Cartilage degradation may be mediated by IL-1 Sites: men in hips, women in knees and hands;

usually one joint or same joint bilaterally, at least initially

Symptoms: pain worse with use of joint, crepitus, limited range of motion, nerve root compression; Heberden nodes in fingers of women only (osteophytes at DIP joints).

OsteoarthritisOsteoarthritis

OsteoarthritisOsteoarthritis

Degenerative joint disease ( wear and tear)

Insidious disease affecting elderly

Deep achy pain worsen with use, morning stiffness, crepitus, and limitation of movement

Xray: deformity of joint with loss of

bone substance and cartilage, loss of joint space, migration of joint, osteophyte formation, sclerosis of subchondral bone, subchondral bone cysts.

Gross: – sloughing of cartilage, – bone eburnation (friction smooths and burnishes

the exposed bone to resemble ivory), – joint mice (dislodged pieces of cartilage and

subchondral bone), – cysts (synovial fluid forced into fractures via ball-

valve-like mechanism), – osteophytes (bony outgrowths at margins of

articular surface), – pannus (fibrous synovium that covers periphery

of articular surface) Loose body: may form if portion of articular

cartilage breaks off; has the tide mark of articular cartilage,

normally loose body is nourished by synovium and continues to grow, has a tree ring appearance; no clumped atypical chonodrocytes; no unevenly distributed chondrocytes.

Severe osteoarthritis with small islands of residual articular cartilage next to exposed subchondral bone.

1, Eburnated articular surface.2, Subchondral cyst. 3, Residual articular cartilage.

Micro: – ghost chondrocytes (no nuclei) or

necrotic chondrocytes; – irregular thinning, fragmentation

and fibrillation of thinned cartilage; – subchondral cysts with mucoid fluid

surrounded by sclerotic bone; – advanced cases have synovial

hyperplasia with lymphoid follicles.

NormalNormal -- Femur Head -- -- Femur Head -- OAOA

Normal Osteoarthritis

Femur Osteroarthritis:Femur Osteroarthritis:

Joint Mice or Loose Bodies:Joint Mice or Loose Bodies:

Spine Osteophytes (OA):Spine Osteophytes (OA):

OsteoarthritiOsteoarthritis:s:•Narrow joint space•Lipping – osteophyte

•Dislocation•Osteoporosis.

Osteophyte formation:Osteophyte formation:

Bone cysts in OA:Bone cysts in OA:

Osteoarthritis: AnkylosisOsteoarthritis: Ankylosis

varus deformity of the knee and collapse of the joint space with destruction of the medial cartilage and the subchondral cortex (open arrowheads).

Osteoarthritis:Osteoarthritis:

Lateral view of the left knee shows sclerosis with marked osteophyte formation (arrows). The osteophytes are best seen in this view.

Differentiating Differentiating Features:Features:

Rheumatoid Arthritis:Rheumatoid Arthritis: Young, small joints Autoimmune. Synovial Inflammation synovium Cartilage

Osteoarthritis:Osteoarthritis: Old, Large joints Degenerative. Cartilage

degeneration. Cartilage Synovium

GoutGout Arthritis Arthritis

Gout is a chronic disease, but it is characterised by episodes of acute inflammation of affected joints.

These episodes cause often dramatic pain and swelling of the affected joint and surrounding soft tissues

In gout the inflammatory stimulus is deposition of urate crystals in joints in individuals who have raised serum levels of urate due to a variety of causes.

Deposits of monosodium urate crystals surrounded by inflammatory cells (mainly macrophages) which produce IL-1 in response to these crystals.

Pathogenesis of Gouty Pathogenesis of Gouty ArthritisArthritis

Big Toe in Gout:Big Toe in Gout:

Joint Destruction in Gout:Joint Destruction in Gout:

Big Toe in GoutBig Toe in Gout

Gout Tophi:Gout Tophi:

Gouty TophusGouty Tophus

Urate Crystals (Gout):Urate Crystals (Gout):

Pseudo GoutPseudo Gout

• Calcium PyroPhosphate Deposition diseaseCalcium PyroPhosphate Deposition disease• CPPDCPPD• Chondrocalcinosis.Chondrocalcinosis.

Calcium pyrophosphate crystal Calcium pyrophosphate crystal deposition diseasedeposition disease

Pseudogout, chondrocalcinosis. Common finding in arthritic joints (age 50+ years,

30% of patients are at least 85 years old) Calcium pyrophosphate crystals (chalky white

deposits) develop first in menisci and intervertebral discs, may seed the joint and elicit neutrophilic response.

- Knee is common site; 50% have involvement of several joints at diagnosis

50% get significant joint damage. Secondary to the prior joint damage:

hyperparathyroidism, hemochromatosis, hypomagnesemia, hypothyroidism, ochronosis, diabetes mellitus

Microscopy: small rectangular (rhomboid) crystals that are weakly positive birefringent; may have histiocytic and giant cell reaction around these crystals.

CPPD-Arthritis (pseudo gout):CPPD-Arthritis (pseudo gout):

Pseudo Gout–Pseudo Gout–Calcium Calcium pyrophoshatepyrophoshate

Synovial fluid containing Synovial fluid containing calcium pyrophosphate calcium pyrophosphate crystalscrystals

Arthritis Comparison:Arthritis Comparison:

BursitisBursitis

Bursae are closed, round, flattened sacs that are lined by synovium and separate bare areas of bone from overlapping muscles (deep bursae) or skin and tendons (superficial bursae).

They occur at areas of friction or possible impingement.

When inflamed, – the synovial cells increase in thickness and may

show villous hyperplasia. – Bursal lining eventually may be replaced by

granulation tissue prior to fibrous tissue formation. – The bursa becomes filled with fluid, which is often

rich in fibrin. Hemorrhage sometimes occurs.

Pigmented villonodular synovitisPigmented villonodular synovitis

A benign proliferative disorder of uncertain etiology that affects synovial lined joints, bursae, and tendon sheaths.

Two Forms:– The diffuse form typically involves the large

joints, while the localized form typically occurs around the small joints of the hands and feet.

– The localized form often occurs around tendon sheaths and is then termed giant cell tumor of the tendon sheath.

Pathologic featuresPathologic features

Gross Thickened synovium, with a combination of

villous and nodular proliferation. Two types of villi are present in the diffuse

form, – coarse villi with a "shag carpet" appearance – fine or fernlike villi.

The nodular component is seen predominantly in tendinous or extra-articular lesions.– The nodules are well demarcated and may be

sessile or pedunculated, although they lack a true capsule.

Microscopy Characterized by the presence of

hemosiderin-laden multinucleated giant cells. In addition, lipid-laden macrophages,

fibroblasts, and other large polyhedral-shaped mononuclear cells are present, have abundant cytoplasm, and possess oval nuclei.

Hemosiderin also is found within the surrounding tissues (characteristic pigmented appearance).

The lesions tend to be hypervascular and demonstrate synovial hyperplasia.

"The gem cannot be polished without friction, nor man

perfected without trials or problems (or exams)…!."

--Chinese proverb