Lecture 10: Joints

Normal Synovial Fluid

Hyaluronic acid (a non-sulfated proteoglycan) secreted by synovial cells acts as viscous lubricant

Clarity: Transparent

Color: Clear to pale yellow

0-150 WBC/mL

PMN < 25%

No RBCs

Glucose 0-10 mg/dL lower than blood glucose

Ankylosis

stiffening or immobility of a joint due to fusion of the bones

True intra-articular ankylosis is obliteration of the joint space by fibrosis or ossification between bony articular surfaces

Osteoarthritis (OA)

aka Degenerative Joint Disease (DJD)

Chronic, progressive degeneration of the articular cartilage → structural & functional failure of synovial joints

No systemic inflammatory response

usually Idiopathic (primary)

↑ after age 50

Secondary to previous injury, joint deformity, obesity

Joints affected: usually Oligoarticular, but may be polyarticular

Osteoarthritis Pathogenesis

Chondrocyte injury and death: wear & tear: Aging, metabolic (free radical damage, glycation) or mechanical injury (more common in weight bearing joints)

Chondrocyte reactive proliferation & secretion of inflammatory mediators activate degradative proteases

Early: Fibrillation (fraying & splitting) of cartilage

Chondrocyte reactive proliferation (“Cloning”) & secretion of inflammatory cytokines

Early attempts at repair

Proteolytic destruction of cartilage with full thickness sloughing

Dislodged pieces of cartilage & underlying subchondral bone tumble into the joint space → loose bodies” or “joint mice”

Friction of exposed bone with opposing surface “polishes” the bone giving it a smooth, ivory-like appearance (Eburnation) & underlying bone becomes thickened (sclerotic bone)

Synovial fluid leaks via cracks into the bone → fluid filled Subchondral bone cysts

Mushroom shaped bony outgrowths with cartilage caps form at edges of damaged articular surface (Osteophytes or “Bone Spurs”)

Osteoarthritis Morphology

Destruction of cartilage

Fraying/fibrillation followed by erosion

Detached cartilage fragments in joint space

Eburnation of Bone: sclerotic (dense) bone with polished ivory-like surface

Cystic changes in subchondral bone

New bone formation: increased density of subchondral bone → Osteophyte (bone spur) formation

Joint mice/loose joint bodies are detached fragments of bone & cartilage in the synovial fluid/joint space

Synovium shows congestion, variable fibrosis & few inflammatory cells

Osteoarthritis

Erosion of cartilage

Osteoarthritis

Eburnation

Osteoarthritis

Subchondral bone sclerosis

Osteoarthritis

Fibrillation

Osteoarthritis

Osteoarthritis

Osteoarthritis

Osteoarthritis

Osteoarthritis

Joint mice

Osteoarthritis

Joint mice

Osteoarthritis

Joint mice

Osteoarthritis

Joint mice

Osteoarthritis Distribution

Joints subjected to mechanical trauma ("wear & tear"): hips, knees; lower lumbar & cervical vertebrae & hands

In the Hands:

Bouchard’s nodes: Proximal interphalangeal (PIP)

Heberden’s nodes: Distal interphalangeal joints (DIP)

common in women (but not in men)

First carpal-metacarpal joint (1st CMC)

In the Feet: First metatarsal-phalangeal joint as a complication of bunions (Hallux Valgus)

Usually spares wrists, elbows, shoulders

Osteoarthritis

Joint space is narrowed, but fusion (Ankylosis) does not occur

Subchondral bone sclerosis (Osteosclerosis)

Peripheral Osteophytes

Faint scattered radiolucent Subchondral Bone Cysts

Patellofemoral OA: Patella normally slides in the trochlear groove of the femur; cartilage along the trochlear groove & underside of the patella wear down

Knee OA: loss of cartilage in the Patellofemoral compartment or in the Lateral or Medial Tibiofemoral compartments

Heberden & Bouchard "nodes" are due to presence of Osteophytes

Osteoarthritis

Osteoarthritis

Subchondral Bone Cysts

Osteoarthritis

Osteoarthritis Gender variation

Females: knees & hands more often involved

knees (tibiofemoral & patellofemoral)

hands include Distal interphalangeal joints (DIP)

Males: hips more commonly involved

Osteoarthritis Clinical course

Insidious onset; usually asymptomatic until 50’s

Morning stiffness (“gel”) that usually lasts < 30 minutes; stiffness/pain after periods of inactivity

Joint crepitus (grating sound or sensation); limitation of motion

Deep achy pain that “worsens with use”; worse at end of day

Spinal foramina stenosis with nerve root impingement by osteophytes: radicular pain; muscle spasm; neurologic deficits; muscle atrophy

Usually slowly progressive; produces disability

X-rays are characteristic & definitive but do not correlate well with Sx severity

Charcot Joint

Neuropathic Joint Disease

Progressive joint destruction from peripheral neuropathy

Foot joints in Diabetic Neuropathy

Knees in Tabes Dorsalis (tertiary syphilis)

Extremity joints in persons with Leprosy

Shoulder in Syringomyelia (most due to Chiari malformation)

Pathogenesis: lack of pain & proprioception leads to abnormal mechanics/repeated joint trauma

Rapidly progressive severe OA-like with joint fragmentation

Osteoarthritis Synovial Fluid

Group I; no crystals

Non-inflammatory

Clarity: Transparent

Color: Clear to pale yellow

WBC < 3000

PMN% < 20%

No RBCs

Glucose: blood/SF difference: 0 - 20

Rheumatoid Arthritis (RA)

Chronic systemic Autoimmune inflammatory disorder that primarily affects joints

Polyarthritis involves diarthrodial joints symmetrically & bilaterally

Most commonly involves: Small joints of the Hands & Feet: PIP & MCP in the hands & corresponding joints in the feet

Also, the Wrists, Elbows, Knees, Ankles & Cervical Spine

Produces a nonsuppurative chronic inflammatory proliferative synovitis which progresses to destruction of the articular cartilage & ankylosis of the joint

Rheumatoid Arthritis Risk Factors

Age: cumulative incidence ↑ with age; typical onset age 30-50

Women

HLA-DRB1 alleles of MHC II with similar binding sites to arthritogenic antigens

Smoking, including children of mothers who smoke

Nulliparity

Obesity

Rheumatoid Arthritis Pathogenesis

Autoimmune with genetic susceptibility

HLA allele variants of MHC II Ag presenting cells (APC) preferentially bind to neoautoantigens

Risk linked to a few genetic HLA-DRB1 alleles of MHC II on APCs

Endogenous neoantigen CCP (Cyclic Citrullinated Peptide), which are proteins that have had Arginine post-translationally converted to Citrulline via a Converting Enzyme that is activated by ↑ intracellular Ca++ during Necrosis or Apoptosis & normally marks proteins for destruction

In joints, Citrullination of extracellular structural proteins unfolds the proteins making them neoantigens

APC binding to Citrullinated proteins & presentation to Th cells activate of CD4+ Th cells (Th1 & Th2)

HLA-DR4

Rheumatoid Arthritis Labs

Rheumatoid factor (RF) is an IgM (or IgA) anti-IgG Fc

Often negative in early disease or at presentation

High titers associated with more severe disease & extra-articular manifestations

Not specific; High “False positive” rate: chronic infection, TB, aging

Anti-Citrullinated Peptide Antibodies (ACPAs/Anti-CCP)

May be negative in first months or may precede (predict) development of RA

More specific

Presence at disease onset is the strongest predictor of later radiographic joint damage

↑ C-reactive protein (CRP) or Erythrocyte Sedimentation Rate (ESR)

No RF or Anti CCP → Seronegative

Rheumatoid Arthritis Pathogenesis Model

Apoptosis/Necrosis results in activation of a Converting enzyme that Citrullinates extracellular proteins to form CCP → HLA-DRB1 allele of MHC II of APCs then binds CCP →

Activate Th1 cells make IFN-Ƴ → activates Macrophages → IL-1 & TNF

IL-1 & TNF → synovial cells & chondrocytes to secrete/activate proteases that destroy hyaline cartilage

IL-17 from Th17 cells recruits neutrophils & macrophages

RANKL (expressed by activated Th cells) → activates RANK receptor of osteoclasts → Bone Resorption/lysis

activation of Th2 cells → B-cell Humoral Ab response (anti-CCP, RF) with joint deposition of immune complexes

Rheumatoid Arthritis Morphology

Hyperplastic synovium creeps over the surface of the articular cartilage & is thrown into Papillary folds → PANNUS

Synovial cell hyperplasia, stromal edema, chronic inflammation (lymphocytes, lymphoid follicles & plasma cells)

Angiogenesis & fibroblastic proliferation (granulation tissue)

↑ Osteoclastic activity in underlying bone → juxta-articular erosions (lytic bone)

Fibrinopurulent exudate in joint surfaces & synovial fluid

Pannus grows over cartilage → fibrotic, followed by bony fusion (Ankylosis) & destructive inflammation of joint capsule, ligaments, tendons & bursae

Rheumatoid Arthritis

Hyperplastic Synovium forming frond-like papillary folds

Rheumatoid Arthritis

Hyperplastic Synovium forming frond-like papillary folds

Rheumatoid Arthritis

Rheumatoid Arthritis

Rheumatoid Arthritis

Joint Fusion = Ankylosis

Subcutaneous Rheumatoid nodules

Rheumatoid Arthritis

Immune Complex activation of Macrophages

Occur in mostly “pressure areas” such as elbows, ulnar forearm, lumbosacral region, or periarticular; less commonly in visceral organs

Firm, freely moveable, nontender

more frequent in those with severe disease

Histology: palisaded granuloma with central fibrinoid necrosis

Rheumatoid nodules

Rheumatoid nodules

Rheumatoid nodules

Osteoarthritis

Sclerotic, dense bone

Joint space narrowed, but preserved

Rheumatoid Arthritis

Juxta-articular erosions (lysis of bone/osteopenia)

Joint ankylosis

Rheumatoid Arthritis

Juxta-articular bone erosions

Rheumatoid Arthritis

Juxta-articular bone erosions

Rheumatoid Arthritis

Late dislocations

Ulnar deviation

Rheumatoid Arthritis joint contractures & deformities

Ulnar deviation of the fingers

Radial deviation of wrist

Swan-neck, Boutonniere deformities of the fingers

Synovial cysts: Baker cyst (Popliteal Cyst) is a synovial lined herniation from the back of the knee into popliteal fossa 2° weakened joint capsule

Joint instabilities & restricted range of motion

Rheumatoid Arthritis Extra-articular manifestations

Lymphadenopathy; Thymic hyperplasia; Splenomegaly

Felty's Syndrome: RA + Splenomegaly with Neutropenia

Risk for Lymphoma; Multiple Myeloma

Anemia of chronic disease

Pulmonary involvement

Rheumatoid nodules; interstitial fibrosis, Caplan syndrome (RA + a Pneumoconiosis)

Vasculitis (RF immune complex or cryoglobulinemia) of small vessels of skin

Neurologic abnormalities due to vasculitis of vasa nervorum

Secondary reactive Amyloidosis (SAA type)

“Serositis”: pleural; pericardial effusions with fibrinous pleuritis/pericarditis

Eye: Scleritis/corneal perforation; uveitis

Heart: accelerates Atherosclerosis & ↑ risk CAD & cardiovascular mortality

Rheumatoid Arthritis Synovial Fluid

Inflammatory-noninfectious (Group II)

Clarity: transparent/opaque

Color: Cloudy, Pale yellow or white/bloody

3000-75,000 WBC/mL

PMN%: 50-90%

No RBCs

Glucose (blood/SF difference, mg/dL): 0-40

Rheumatoid Arthritis Clinical

Fatigue, malaise, anorexia, weight loss, fever, myalgia with joint involvement

Swelling of joints & stiffness, especially in morning or after inactivity → lasts at least 1 hour

Joints warm & painful

Small bones of hands & feet first

Swelling of the same joints on both sides of the body

Rheumatoid nodules of the skin

+ for RF and/or Anti-citrullinated Peptide Antibodies (ACPA)

Progressive joint involvement:

Deformity, greatest joint damage occurs during the first 4-5 years

Increasing numbers of joints involved

Rheumatoid Arthritis labs and Px

Clinical course tends to have remission/flare cycles

ESR & CRP elevated during active inflammation

Positive RF, anti-CCP ("Seropositive") predicts a more severe, progressive disease

Without therapy, life expectancy decreased by 10 years

Top causes of death are:

Ischemic heart disease (Atherosclerotic CAD)

Pulmonary Interstitial Fibrosis

Other causes of death include:

Vasculitis

Systemic amyloidosis, SAA type

Lymphoma

Juvenile Idiopathic Arthritis (JIA)

Arthritis before age 16 of unknown cause that persists > 6 weeks

Large joints more often affected than small joints

Usually Seronegative: Rheumatoid nodules, RF & anti-CCP are absent

Systemic disease is more frequent (serositis, myocarditis, growth retardation, glomerulonephritis, uveitis)

Seronegative Spondyloarthropathies

Seronegative

HLA-B27 (an HLA Class I Ag on all nucleated cells that present cytosolic peptides to CD8+ T Cells)

Sacroiliac joints & Spine

Inflammation of the Entheses (tendinous & ligamentous insertions)

Axial oligoarthritis or asymmetric peripheral arthritis

Achilles tendon involvement & Plantar Fasciitis

Immune mediated Pathogenesis (T-cell response to cross reacting arthritogen)

Ankylosing Spondylitis

AKA Axial Spondyloarthritis

Entheses of the Spine & the joint where sacrum joins the pelvis (Sacroiliac joint)

HLA-B27 positive

Late adolescence or early adulthood, in males

Inflammation of the sacroiliac joints (Sacroiliitis) → progressive low back pain or pain in gluteal region

Enthesitis of peripheral Annulus Fibrosus of discs & anterior/posterior Longitudinal ligaments (Spondylitis) damage tissue → calcifies → Syndesmophytes → vertebral fusion (Ankylosis or “bamboo spine”)

Affect the joints between spine & ribs, restricting breathing; prone to vertebral fractures

Acute Iritis → eye pain & photophobia

↑ incidence in inflammatory bowel disease (IBD)

Diagnose early with MRI of Sacroiliac joint

Ankylosing Spondylitis

Ankylosis or “bamboo spine”

Ankylosing Spondylitis

Ankylosis or “bamboo spine”

Reactive Arthritis

Seronegative Polyarthritis

urethritis/cervicitis

Conjunctivitis/Uveitis

males in 20s, 30s

Post-Infectious Arthritis after an infection elsewhere in the body, from which the patient has recovered

Pathogenesis: Immune cross-reactivity reaction after infection with GU Chlamydia, GI Dysenteric infections (Salmonella, Shigella, Yersinia, Campylobacter, Clostridium difficile), Chlamydia pneumonia, or HIV related infections

Reactive Arthritis Clinical

Early: low back pain, joint stiffness, asymmetric oligoarthritis, usually of lower extremity

“Sausage” fingers or toes (synovitis of digital tendon sheath)

Enthesitis of Achiles tendon & plantar fascial insertions of calcaneous (swelling of heel)

chronic cases develop calcaneal bone spurs; ossification of other tendoligamentous insertion sites

Arthritic episodes wax & wane; most remit

Conjunctivitis/Uveitis/Urethritis/Balanitis/Cervicitis

Cardiac valvular disease (aortic regurgitation)

Erythematous, scaly plaques, usually affecting the palms, soles & toes (Keratoderma Blennorrhagicum)

Sausage left second toe in reactive arthritis

Erythematous, scaly plaques, usually affecting the palms, soles & toes (Keratoderma Blennorrhagicum) in Reactive Arthritis

Psoriatic Arthritis

Age 30-50

HLA-B27 & HLA-Cw6

Gradual onset of joint involvement, concurrent with or following skin disease

Conjunctivitis

Iritis

Asymmetric involvement of hands & feet

DIP joints most involved: “sausage” digits

Radiograph: "Pencil in cup deformity"

Sacroiliac & spinal disease

Histology like RA but Joint destruction less frequent

Psoriatic Arthritis

Dactylitis of third & fourth toes

Psoriatic Arthritis

Enthesitis of right Achilles' tendon

Psoriatic Arthritis

Dactylitis of middle finger

Psoriatic Arthritis

Psoriatic Arthritis

Pencil in cup deformity

Psoriatic Arthritis

Pencil in cup deformity

Psoriatic Arthritis

Sausage Digits (nail changes)

Psoriatic Arthritis

Sausage Digits

Psoriatic Arthritis

Pencil in cup deformity

Septic (bacterial) arthritis

Pathogenesis: Hematogenous or direct inoculation

Sudden onset of painful swollen joint with decreased range of motion

Fever, leukocytosis, elevated ESR

Most monoarticular; knee most common

Septic (bacterial) arthritis Synovial Fluid

Group III: Septic joint

Clarity: opaque

Color: White

< 50,000 WBCs/mL

PMN%: >90%

RBCs

Glucose (blood/SF difference, mg/dL): 20-100

Lyme Arthritis

Infection by spirochete Borrelia (“Borreliosis”)

Inoculation via bite of deer tick

Erythema Migrans skin lesions

Erythematous margins with central fading +/- central “bull’s eye”

Untreated develop arthritis

Arthritis develops within weeks to up to 2 years after infection (main feature of late-stage disease)

Joint swelling- knees are affected most often

Involves large joints

Attacks last for weeks to months, then migrating to new sites

Usually, one or two joints affected at a time

Pathology: Synovitis, papillary

Viral Arthritis

Rubella; Parvovirus B19; Chronic hepatitis B, C; mosquito borne Alphaviruses

Pathogenesis: infection, autoimmune x-reactivity or immune complex deposition

Parvovirus B19 infection (Fifth Disease; Erythrovirus) in adults → self-limited arthritis (lasts days to weeks) that mimics RA

Gout

Precipitation of Monosodium Urate crystals, within & around joints → Arthritis

Uric acid: nitrogenous waste product from breakdown of DNA Purine nucleotides (Adenine & Guanine) & is excreted in Urine (2/3) & Feces (1/3)

Deficiency of HGPRT → cannot salvage → purines degraded into uric acid (↑ serum Uric Acid)

Value of > 7 = Hyperuricemia

Primary gout: idiopathic

Secondary gout:

↑ production due to nucleic acid turnover, as in acute Leukemia/Lymphoma, or release after chemotherapy (Tumor Lysis Syndrome)

↓ excretion in chronic renal disease

Congenital HGPRT deficiency (Lesch-Nyhan syndrome)- X-linked; manifests with neurologic symptoms, intellectual disability, self mutilation; some develop gout

Causes of Secondary Hyperuricemia/Gout

Drugs: Loop, Thiazide, & Thiazide-like Diuretics (↓ renal excretion)

Saturnine gout due to Lead poisoning

Gout Pathogenesis

Inflammatory arthritis triggered by the precipitation of MSU crystals in the joint

Macrophages phagocytose the crystals & produce cytokines that recruit additional Macrophages & neutrophils

Complement is also activated by the crystals

Transient attack of arthritis that typically remits spontaneously in days to weeks

Repeated attacks of acute arthritis eventually lead to chronic Tophaceous arthritis with severe cartilage damage & joint dysfunction

loss of joint space & juxta-articular bone erosions

Acute Gouty arthritis, clinical

Most common in older men

Sudden onset of joint pain with localized hyperemia, warmth

1st attack generally monoarticular:

1st metatarsophalangeal joint "Podagra”

Flare lasts hours to weeks if untreated

Acute Gouty Arthritis Morphology

Dense neutrophilic infiltrate of synovium

Monosodium Urate crystals in neutrophils

Synovial fluid shows long, slender, needle- shaped, negatively birefringent crystals by polarized light

Acute Gouty Arthritis Synovial Fluid

Group II: Inflammatory-noninfectious

Clarity: transparent/opaque

Color: Cloudy, Pale yellow or white/bloody

3000-75,000 WBC/mL

PMN%: 50-90%

No RBCs

Glucose (blood/SF difference, mg/dL): 0-40

Chronic Tophaceous gout

Chronic gout: Tophaceous gout develops (chronic chalky white deposits of urate crystals in joints, around joints or in soft tissue)

>10 years after 1st attack

Podagra

Bone erosion, loss of joint spaces

Associated with hypertension; Renal disease

↑ risk of cardiovascular disease

Morphology of Chronic Tophaceous gout

Urates heavily encrust articular surfaces

form visible whitish, chalky deposits

Synovium hyperplastic, fibrotic & thickened

Pannus forms; destroys cartilage

Tophi are the microscopic hallmark

Bone erosions develop adjacent to joints

Ankylosis occurs in severe cases

Chronic Tophaceous gout

Chronic Tophaceous gout

Tophi

Tophi are Pathognomonic of gout

Deposits of chalky white Uric acid crystals surrounded by giant cells

Joints: intra-articular, periarticular in soft tissues or bone

Helix & antihelix of the ear

Achilles tendon

Olecranon & prepatellar bursae

Skin may ulcerate over tophi

Tophi

Tophi

Tophi

Urate/Uric Acid Nephropathy

Obstruction of collecting tubules by crystals in Tumor Lysis Syndrome → Acute Renal Failure

Formation of Uric Acid & calcium oxalate Kidney Stones

Hyperuricosuria increases risk of calcium oxalate stone formation

Chronic Kidney Disease

Tenosynovial Giant Cell Tumors

Related neoplasms of the Synovium lining Joints, Tendon Sheaths or Bursae

Clonal neoplastic proliferations (Benign, but can be locally destructive)

Giant Cell Tumor of Tendon Sheath

Diffuse type/Pigmented Villonodular Synovitis

Age 20-40; Male = female

Pathogenesis: Reciprocal chromosomal translocation, t(1;2) → fusion of type VI collagen promoter with coding sequence of Monocyte CSF gene → Overexpression of M-CSF stimulates production of macrophages

Neoplastic cells are minority of neoplasm

Majority of tumor is infiltrates of macrophages, with hemosiderin; foamy lipid; multinucleated giant cells; fibrosis may occur

Giant cell tumor of Tendon Sheath

Most common mesenchymal neoplasm of the hand

Localized type of Tenosynovial Giant cell tumor

Involves tendon sheath of wrist, fingers, toe

Presents as a slow-growing, painless mass

May erode underlying bone

Can recur

Solid, golden/yellow nodule attached to synovium

Giant cell tumor of Tendon Sheath

Giant cell tumor of Tendon Sheath

Diffuse Tenosynovial Giant Cell Tumor (Pigmented Villonodular Synovitis)

monoarticular arthritis: pain, locking & swelling of joint

Diffuse growth limits range of motion

Knee, Hip, Ankle

Benign, but tends to aggressive local growth with recurrence after excision

"Pigmented" due to Hemosiderin deposition

Diffuse Tenosynovial Giant Cell Tumor (Pigmented Villonodular Synovitis)

Diffuse Tenosynovial Giant Cell Tumor (Pigmented Villonodular Synovitis)

Diffuse Tenosynovial Giant Cell Tumor Synovial Fluid

Group IV: Hemorrhagic

Clarity: Opaque

Color: Red-brown or Xanthochromic

50-10,000 WBC/mL

PMNs, % < 50%

RNCs predominate

Glucose (blood/SF difference, mg/dL): 0-20