Acute arthritis

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Transcript Acute arthritis

L19
Infectious Arthritis
Infectious Arthritis

Infectious arthritis – the synovial inflammatory
reaction caused by invasion of the joint space by
various microorganisms

Acute (septic) arthritis – monoarticular arthritis of the
large synovial joints caused by pyogenic bacteria invading
via the hematogenous route
 Gonococcal
arthritis – caused by hematogenous spread of N.
gonorrhea to the joints in patients ages 18-35 with gonorrhea
 Non-gonococcal arthritis – commonly caused by S. aureus as the
most rapidly destructive form of joint disease, destroying the
cartilage within days of onset in children < 5 years and adults >
64 years


Predisposing factors in adults: prosthetic joint, rheumatoid arthritis,
malignancy, diabetes
Chronic arthritis – caused by slowly progressive organisms
that are difficult to eradicate
Non-gonococcal Arthritis

Source of invasion:

Hematogenous seeding (55%) of the synovium during bacteremia due to
high vascularization of the synovial membrane (which lacks a basement
membrane)

Sources of bacteremia: cutaneous, respiratory, or urinary infections; invasive
procedures; intravenous catheters, IV drug use
Direct inoculation (through surgery, trauma, or animal bites)
 Contiguous source (e.g., osteomyelitis)


Infants < 1 year: the metaphyseal blood vessels transverse the
epiphyseal growth plate, providing a channel for infections from
bone to joint space


In older children, infection of the bone can break the outer cortex and
cause secondary septic arthritis
Microorganisms: S. aureus (50%) in adults and children;
Streptococcus spp. (20%) in adults and children; Gram-negative
bacilli (13%) (e.g., P. aeruginosa, E. coli) in IV drug users, young
children, and immunocompromised
Non-gonococcal Arthritis





Pathogenesis: After adhesion and colonization of the joint space,
bacteria rapidly proliferate and activate an acute inflammatory
response, stimulating the release of pro-inflammatory from synovial
cells and, subsequently, metalloproteinases and proteolytic enzymes
from neutrophils → rapid degradation of the articular cartilage (and
damage of the joint even after clearance)
Risk factors: elderly, underlying joints disease, diabetes, skin infection
Symptoms: fever; malaise; warmth, redness, and severe pain with
swelling at the joint (e.g., knee)
Diagnosis:

Positive blood cultures (50%) with elevated erythrocyte sedimentation rate (ESR)
and C-reactive protein (CRP) levels

Positive synovial fluid (90%) aspirated from the joint with elevated WBC and
discoloration

CT / MRI for distinguishing joint effusions (and greater ability to image the soft
tissue with MRI)
Treatment: antibiotics, joint drainage, joint mobilization

Only 50% of patients with acute non-gonococcal arthritis fully recover
Gonococcal Arthritis

Possible pathogenesis: deposition of circulating gonococcal Ag/Ig complexes

Risk factors: virulence of N. gonorrhea, delay of diagnosis, complement deficiency,
SLE, female, menstruation / pregnancy, low socioeconomic / educational status

Symptoms: polyarticular asymmetric migratory arthralgias in the upper extremity
(e.g., wrist, elbow), generally resolving spontaneously (30-40%)

Forms:
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Tenosynovitis and dermatitis:

Tenosynovitis – asymmetric inflammation of the synovial sheath that surrounds the tendon is rare in
other forms of septic arthritis, generating pain with selling and limited ROM of the afflicted joint
(e.g., ankles, toes, wrists, hands)

Dermatitis – tiny maculopapular, pustular, or vesicular lesions on an erythematous base on the
extremities or the trunk in which the centers necrotize or hemorrhage (but are painless and
nonpruritic), disappearing within a few days
Purulent arthritis – polyarticular inflammation of the joints (e.g., knees, wrist, ankle,
elbow), generating redness and swelling with associated pain and limited ROM (and an
elevated WBC count that is lower than non-gonococcal arthritis)
Diagnosis: Gram-staining of gram-negative diplococcic and culture of N. gonorrhea
on Thayer-Martin agar (requiring both blood and synovial samples since synovial fluid
only allows 50 growth)
Tuberculosis Arthritis

Epidemiology: increasing due to expansion of the HIV
pandemic and increased antituberculous drug resistance

Pathogenesis:

Secondary direct invasion from adjacent tuberculous
osteomyelitis

Hematogenous dissemination from a primary focus in the lungs or lymph nodes

Risk factors: elderly; poor and homeless;
immunocompromised; prisoners; alcoholics;
reactivation due to surgical and joint/bone trauma

Symptoms: chronic monoarthritis of the large and medium weight-bearing joints
(e.g., hip, knees) in men ages > 50, generating chronic progressive low-grade joint
pain and swelling (without warmth or erythema) and progressive loss of ROM


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Possible fever, night sweats, weight loss, anorexia
Diagnosis:

Radiograph: Phemister triad of periarticular osteoporosis, peripherally located osseous
erosion, and gradual diminution of the joint space (as opposed to joint narrowing)

Acid-fast stain (10-20%) of M. tuberculosis and culture (80%) of synovial fluid

Open biopsy technique positive for typical caseous granulomas (94%)
Treatment prevents complete joint obliteration with fibrous ankylosis
Lyme Arthritis

Lyme disease – caused by infection with spirochete
B. burgdorferi transmitted through deer ticks

Phases:
 Early
localized infection: skin lesion erythema migrans (80-90%)
within 1 month of the tick bite, beginning as a red macule that
expands uniformly with central clearing to produce a “bull’s
eye” (that is associated with flu-like symptoms)
 Early disseminated infection (weeks after onset): debilitating
fatigue, appearing ill, and development of multiple erythema
migrans lesions (e.g., trunk) with migratory muscle, joint, and
periarticular pain

Accompanied myopericarditis (1-3%) and meningitis (10%)
 Late
disease (months after onset): Lyme arthritis of the joints
and encephalomyelitis in untreated patients

Lyme arthritis – self-limited monoarticular or oligoarticular arthritis of
< 5 large joints (e.g., knee) in which the joints are warm with large
effusions and limited pain
Lyme Arthritis

Diagnosis:
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Nonspecific:
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Elevated WBC count predominated by neutrophils

Depending on the chronicity, synovial biopsy present with only
mononuclear cell infiltrates or pannus development in more advanced
cases
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Silver stains may reveal low numbers of organisms near the blood vessels (25%)
Specific: detection of B. burgdorferi antibodies (through ELISA or
indirect immunofluorescence followed by confirmation from
Western blot)
Treatment:
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“Antibiotic-refractory” lyme arthritis – persistent joint
inflammation and proliferative synovitis unresponsive to further
antimicrobials, causing synovial pannus that leads to destruction
of articular cartilage and permanent deformities

Possible cause: T cell cross-reaction to HLA-DR molecules bound to
surface protein A of B. burgdorferi (through molecular mimicry)
Viral Arthritis
Causes: parvovirus B19, hepatitis A-C, rubella,
alphaviruses, HIV, HTLV-1, Epstein-Barr, mumps,
varicella-zoster, HPV
 Symptoms: self-limited symmetrical small-joint
involvement of the periphery (e.g., hands, wrists,
knees, ankle) with morning stiffness and fusiform
swelling (and no erythema), progressively resolving
(and non-destructive)
 Diagnosis (based on symptomology and serology):
review of non-rheumatic symptoms and medical
history



PCR-based examination of synovial material (which may be
inconclusive)
Treatment: NSAIDs (with possible steroids or INF),
antiviral drugs
L20
Paget Disease of Bone
10
Review of Bone Cells

Osteoprogenitor Cells-pluripotent mesenchymal cells,
found on bone surface

differentiate into osteoblasts

by RUNX2/CBFA1 transcription factors and WNT/Bcatetin signaling pathway

Osteoblasts-surface of bones, synthesize, transport,
arrange matrix proteins, initiate mineralization
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Osteocytes
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Osteoclasts- bone resorption

derived from macrophage and monocyte hematopoietic
cells
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macrophage colony stimulating factor (M-CSF, IL-2,
TNF) regulate differentiation and maturation
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Review of Bone Cells
 regulate
bone homeostasis with signaling
pathways:
 1.
transmembrane RANK receptor
(activates NF-kB)
 2.
RANK ligand (RANNKL) on osteoblasts
and stromal cells
 3.
Osteoprotegrin (OPG)- “decoy”
receptor from osteoblasts
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Osteoclast Formation
 1.
RANKL (osteoblast) binds to RANK
(osteoclast)
 2. M-CSF causes precursor cells to produce
osteoclasts by activating NF-kB
 3. stromal cells (osteoblasts) secrete
osteoprotegrin (OPG) to prevent it from binding
to RANK receptor on osteoclast precursors
 4. OPG also prevents bone resorption: inhibits
osteoclast differentiation
 RANKL: OPG ratio determines bone
resorption/formation
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Paget Disease of Bone
 Paget
disease of bone is a localized
disorder of bone remodeling
 2nd
most common bone disease in the
world
 was
termed “osteitis deformans” but is
now disease of the osteoclast
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Paget Disease of Bone
 disorder
of increased, but disordered and
structurally unsound bone mass
 1.
initial osteolytic stage
 2.
mixed osteoclastic/osteoblastic stage,
ends in predominance of osteoblastic
activity
 3.
burnt out quiescent osteosclerotic
stage
 net
effect: gain in bone mass; however
newly formed bone is disordered and
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Paget Disease: Epidemiology
 begins
in late adulthood (avg. age 70)
 common
in whites in europe, new zealand
and america
 many
 1%
people asymptomatic
over 40 in US affected
 2.5%
men, 1.6% women in England
 fall
in cases over 20-30 years and declined
severity
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Paget Disease: Pathogenesis
 cause
is uncertain, evidence suggests
genetic and environmental factors
 mutation
in SQSTM1 gene present in
familial and sporadic cases
 mutation
enhance NF-kB by RANK, leads
to increased osteoclast activity
 chronic
infection of osteoclast precursors by
measles or other RNA viruses
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Paget Disease: Morphology
 mosaic
pattern of lamellar bone in sclerotic
phase
 “jigsaw”
pattern
 initial
lytic phase has wave of osteoclastic
activity
 large
osteoclasts
 osteoclasts
persist in mixed phase, but bone
surface lined by osteoblasts
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Paget Disease: Clinical Course
 variable
 cases
are mild, discovered by accidental radiographic
finding
 15% monostatic, the rest polystatic
 axial skeleton or proximal femur- 80% of cases
 pain localized to affected bone
 microfractures or bone overgrowth: compress
nerve roots
 enlargement
of craniofacial skeleton: heavy head
 invagination of skull base by weakened bone
 chalk-stick type fractures long bones, compression
fractures spine
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Paget Disease: Clinical Course
 weight
bearing causes anterior bowing of the
femur and tibiae distorts femoral head
 results
 diagnosis
in severe secondary osteoarthritis
from radiographic findings
 pagetic
bone is enlarged with coarsened
cortices and cancellous bone
 elevated
 tumor
serum alkaline phosphatase
and tumor like conditions
 benign
lesions: giant cell tumor
 sarcomas
(osteosarcomas/fibrosarcomas):0.70.9% of cases
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L21
Osteoporosis
Osteoporosis
 Osteopenia
– decreased bone mass (with 1
to 2.5 STDEV below mean peak bone mass)
 Osteoporosis
– localized (through disuse) or
generalized (due to a metabolic bone disease)
osteopenia characterized by porous bones and a
reduced bone mass that significantly increases
the risk of fracture (with atleast -2.5 STDEV
below mean peak bone mass)
 Signified
by the presence of an atraumatic or
vertebral compression
 Typically
refers to senile and postmenopausal forms
Pathogenesis
Peak bone mass is
achieved during young
adulthood (with its
magnitude receiving
influence from
hereditary factors,
physical activity,
muscle strength, diet,
and hormonal state)
 Once maximal skeletal
mass is reached, a small
deficit in bone
formation accrues with
every resorption and
formation cycle
(average 0.7% per year)

Pathogenesis

Senile (Type II) osteoporosis – age-related changes in
bone cells and matrix strongly impact bone metabolism
 Low-turnover
form: Osteoblasts in the elderly have reduced
proliferative and biosynthetic potential and proteins bound to
the extracellular matrix (e.g., growth factors) lose their biologic
activity over time, generating an overall diminished capacity to
make bone

Postmenopausal (Type I) osteoporosis – hormonal
influences after menopause cause yearly reductions in
bone mass ( < 2% of cortical bone and < 9% of cancellous
bone), causing postmenopausal women to suffer more
osteoporotic fractures than men of similar age
 Strongly
influenced by estrogen deficiency (in which estrogen
replacement can protect against bone loss)

High-turnover form: Decreased estrogen levels (through increased
stimulation of inflammatory cytokines by monocytes and bone marrow
cells) stimulate osteoclast recruitment and activity, thereby
increasing RANKL levels and decreasing OPG expression, and
compensatory osteoblastic activity cannot keep pace
Pathogenesis
 Reduced
physical activity increases the rate of bone
loss since mechanical forces stimulate normal bone
remodeling (in which the type of exercise and
associated load magnitude plays an important role)
 Genetic factors (60-80% of bone density variation):
 Genome-wide
association studies (GWAS) – conclude
RANKL, OPG, and RANK play key roles (as regulators of
osteoclasts)
 MHC locus (through the effects of inflammation on calcium
metabolism) and estrogen receptor gene
 Variants of Vitamin D receptor and LRP5 as risk factors
 Calcium
nutritional state of the body: The
insufficient intake of dietary calcium in girls during
periods of rapid bone growth ultimately stunts peak
bone mass, increasing the risk of osteoporosis
Morphology

Postmenopausal osteoporosis –
increased osteoclast activity
affects bones with increased
surface areas (e.g., cancellous
compartment of the vertebral
bodies)


Effect: The trabecular plates
become perforated, thinned, and
lose their interconnection, leading
to progressive microfractures →
vertebral collapse
Senile osteoporosis – thinning of
the cortex by subperiosteal and
endosteal resorption with widening
of the haversian systems
In advanced osteoporosis,
both the trabecular bone of
the medulla (bottom) and
the cortical bone (top) are
markedly thinned.
Clinical Presentation

Vertebral fractures commonly in the thoracic and lumbar regions:
painful, contributing to significant loss of height and spinal
curvature deformities


Complications of femoral neck, pelvis, and spine fractures: pulmonary
embolism, pneumonia
Remains asymptomatic until advancement of skeletal fragility:

Cannot be reliably detected from x-rays until 30-40% of bone mass is
lost


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Blood levels of calcium, phosphorus, and alkaline phosphatase are not diagnostic
Specialized imaging techniques for the measurement of bone density:
Dual-energy X-ray Absorptiometry (DEXA) / Quantitative CT
Prevention and treatment: exercise, relative calcium and Vitamin
D intake, pharmacologic agents (e.g., bisphosphonates) that bind
to bone and inhibit osteoclasts
L22
Osteoarthritis
Joints

Joints allow movement while providing mechanical stability


Solid joints (synarthroses) – nonsynovial joints that lack a joint space,
providing structural integrity while allowing only minimal movement

Fibrous synarthroses: cranial sutures and the bonds between the roots of
teeth/jawbones

Cartilaginous synarthroses: the symphyses (e.g., manubriosternalis, pubic)
Cavitated joints – synovial joints with a wide space that allows for a wide range
of motion between the ends of bones formed via endochondral ossification

Fibrous capsule – strengthens the joint with reinforcement by ligaments and muscles

Synovial membrane – the boundary of the joint space that is anchored to the
underlying capsule, appearing smooth (except near the osseous insertion where it
possesses numerous villous folds), and lacks a basement membrane, allowing for the
exchange of nutrients and wastes between the blood and synovial fluids


Type A synoviocytes – specialized macrophages

Type B synoviocytes – fibroblast-like cells that synthesize hyaluronic acid and various proteins
Synovial fluid – a plasma filtrate containing hyaluronic acid that acts as a lubricant
and provides nutrition for the articular hyaline cartilage
Joints

Hyaline cartilage – a unique connective tissue suited for
shock absorption and wear-resistance, lacking a blood
supply, innervation, and lymphatic drainage

Composition: 70% water, 10% Type II collagen, 8%,
proteoglycans, chondrocytes

Collagen fibers grant resistance to tensile stresses and transmit vertical
loads

Water and proteoglycans grant resistance to compression and limit
friction

Chondrocytes synthesize and enzymatically digest the matrix, secreting
degradative enzymes in inactive forms and enriching the matrix with
enzyme inhibitors


Diseases that destroy articular cartilage (by IL-1/TNF) activate the catabolic
enzymes and decrease the production of inhibitors in order to accelerate matrix
breakdown
Articular cartilage – contributes to frictionless movement
of the joint with resistance to tension and compression
Synovial Joint
Osteoarthritis


Osteoarthritis (OA) – most common degenerative joint disease
characterized by the degeneration of articular cartilage resulting in
structural and functional failure of the synovial joints (due to
chondrocyte-induced breakdown of the matrix), appearing
asymptomatic until age 50

Primary (idiopathic) osteoarthritis – oligoarticular OA that appears insidiously
without an apparent initiating cause (by aging)

Secondary osteoarthritis (5%) – OA in younger individuals arising from previous
joint injuries, a congenital developmental deformity of the joints, or a systemic
disease (e.g., diabetes, obesity)
Symptoms: deep and achy pain that worsens with use, morning
stiffness, limited ROM → joint deformity without fusion

Involvement of 1+ joints (e.g., hips, knees, lower lumbar and cervical
vertebrae, proximal and distal IP joints)


Heberden nodes – prominent osteophytes at the DIP joints
No effective means to prevent or halt progression of primary OA

Therapy includes pain management, activity modification, and arthroplasty
Pathogenesis




Phases of chondrocytic changes:

Chondrocyte injury due to genetic and biochemical factors

Early OA: proliferation of chondrocytes and secretion of inflammatory
mediators, collagens, proteoglycans, and proteases, acting to remodel the
matrix and initiate secondary inflammatory changes in the synovium and
subchondral bone

Late OA: repetitive injury and chronic inflammation, leading to chondrocyte
drop out, loss of cartilage, and extensive subchondral bone changes
Extracellular components: Degradation of type II collagen by matrix
metalloproteinases and proteoglycans during disease progression
Increased counts of cytokines and diffusible factors (e.g., TGF-β),
TNF, prostaglandins, NO
Environmental and genetic influences: Aging and biomechanical
stress

Genetically heterogeneous: Risk is associated with the additive effect of
multiple genes
Morphology

In the early stages during chondrocyte proliferation, the
chondrocytes cluster as the water content increases and
proteoglycan concentration decreases,

The horizontally-arranged type II collagen fibers in the
superficial zone are cleaved into fissures and clefts at
the articular surface, generating a granular soft
articular surface

In the later stage, the chondrocytes die and the thick
portions of the cartilage are sloughed, tumbling into the
joint to form lose bodies (or joint mice)

The newly exposed subchondral plate becomes the new
articular surface, and friction with the opposing surface
smooths and burnishes the exposed bone, polishing it
during bone eburnation

Small fractures develop through the articulating bone,
creating gaps that allow synovial fluid into the
subchondral regions to form fibrous walled cysts

Mushroom-shaped osteophytes (or bony outgrowths)
develop at the margins of the articular surface (which
are capped by fibrocartilage and hyaline cartilage,
gradually ossifying)
L23
Crystal-induced Arthritis
Crystal-induced Arthritis


Crystals produce disease by triggering a cytokine-mediated
cascade that destroys cartilage

Endogenous crystals: monosodium urate → gout; calcium
pyrophosphate dehydrate → pseudogout; basic calcium
phosphate

Exogenous crystals: corticosteroid ester crystals; talcum;
polyethylene; methyl methacrylate
Gout / gouty arthritis – marked by transient attacks
of acute arthritis caused by crystallization of
monosodium urate within and around the joints

Primary (90%) – increased uric acid biosynthesis
(manifesting as gout) due to unknown causes

Secondary – increased uric acid (and urinary excretion) due
to a dominant/known underlying disease
Uric Acid

Hyperuricemia ( > 6.8 g/dL of plasma urate levels) is not
sufficient for the development of gout (since elevated uric acid
can result from overproduction or reduced excretion of uric
acid)

Uric acid – the final product of purine catabolism (by xanthine oxidase)

De novo pathway: purine nucleotides are synthesized from nonpurine precursors

Salvage pathways: purine nucleotides are synthesized from free purine bases
from dietary sources or recycled purine nucleotides



Possible cause of primary gout: deficiency of HGPRT inhibits the recycling of purine
metabolites, degrading into uric acid instead
Excretion: uric acid is filtered from circulation by the glomerulus and
resorbed by the proximal tubule of the kidneys
Contributing factors for gout: age of the patient and associated
duration of hyperuricemia; genetic predisposition; heavy
alcohol consumption; obesity; drugs that reduce the excretion
of urate (e.g., thiazides); lead toxicity
Gout – Pathogenesis

Inflammation is triggered by the precipitation of
monosodium urate (MSU) crystals in the joints, resulting
in the production of cytokines that recruit leukocytes
Macrophages phagocytose MSU and subsequently produce
cytokines (e.g., IL-1), promoting the accumulation of neutrophils
and macrophages at the joint (pro-inflammatory)
 Newly recruited leukocytes release cytokines, free radicals,
proteases, and arachidonic acid metabolites to ultimately recruit
more leukocytes and damage the joint



The cascades trigger acute arthritis (which spontaneously regresses)
Modulated solubility of MSU in the joint:
Synovial fluid is a poor solvent for MSU (compared to plasma)
 Lower temperatures of the peripheral joints favor precipitation

Gout – Pathogenesis

Repeated episodes of acute arthritis eventually
leads to chronic tophaceous arthritis, forming tophi
Tophi – large aggregates of urate crystals with associated
inflammation in the synovial membranes and periarticular
tissue, appearing in articular cartilage, ligaments/tendons,
softer tissue, kidneys
 Severe damage to the cartilage develops, compromising the
function of the joints

Simultaneous development of urate nephropathy
 Phases of development: ① Asymptomatic
hyperuricemia → ② Acute arthritis → ③
Asymptomatic intercritical period → ④ Chronic
tophaceous arthritis → ⑤ Tophi in various sites →
⑥ Gouty nephropathy

Gout – Morphology


Acute arthritis: dense neutrophilic
infiltrate in the synovium and synovial fluid
with clusters of MSU crystals within the
cytoplasm of the neutrophils

Crystals: long, slender, needle-shaped with
negative birefringent (or polarity)

Synovium: edematous and congested,
containing scattered lymphocytes, plasma
cells, and macrophages
Chronic tophaceous arthritis: encrusting
of MSU at the articular surface, forming
visible deposits in the synovium

Synovium: hyperplastic, fibrotic, and
thickened with inflammatory cells, forming a
pannus that destroys the underlying cartilage
and leads to juxta-articular bone erosions


Pannus – membrane of granulation tissue
Fibrous or bony ankylosis (or union) can
develop to hinder joint function
Gout – Clinical Presentation

Acute arthritis presents with sudden onset of excruciating joint
pain (and associated localized hyperemia and warmth)
First presentations are monoarticular (with 50% occurring at the 1st
metatarsophalangeal joint) and progress to other locations (e.g.,
ankles, knees, wrists, fingers, elbows)
 If untreated, it may last for days to weeks but will gradually resolve
(before recurring polyarticularly at shorter intervals without therapy)


Chronic tophaceous gout develops years after the initial acute
attack, progressing to a severely crippling disease

Radiograph: juxta-articular bone erosion (due to osteoclastic bone
resorption and joint space loss)

Renal manifestations: renal colic associated with the passage of
gravel and stones, progressing to chronic gouty nephropathy (in
which 20% die of renal failure)

Treatment acts to stop or prevent acute attacks and mobilize
tophaceous deposits
CPPD Disease

Calcium pyrophosphate crystal deposition (CPPD) disease
(or pseudogout) – accumulation of crystals that stimulates
inflammation at the joints, occurring in patients > 50 years
(which becomes more prevalent with increasing age)


Possible cause: degradation of cartilage proteoglycans (that
normally inhibit mineralization), allowing crystallization around
chondrocytes
Types:
Sporadic (idiopathic)
 Hereditary – autosomal dominant germline mutations in the
pyrophosphate channel that cause the development of crystals
early in life
 Secondary – associated with various disorders (e.g., previous
joint damage, diabetes, hyperparathyroidism, ochonosis,
hemochromatosis, hypomagnesemia, hypothyroidism)

CPPD Disease

Crystals first develop in the articular
matrix, menisci, and IV discs, enlarging
and rupturing the joint
Seeding allows for phagocytosis by
macrophages, triggering pro-inflammatory
cascades
 The crystals form chalky white, crumbly
deposits, appearing as blue-purple oval
clusters (that are weakly polarized)


Symptoms: asymptomatic → acute,
subacute, or chronic arthritis


Joint involvement may involve 1+ joints
for several days to weeks at the wrists,
elbows, shoulders, and ankles (with 50% of
patients suffering from significant joint
damage)
Treatment: none (with supportive
therapy)
L24
Rheumatoid Arthritis
Rheumatoid Arthritis
 Rheumatoid
arthritis – a chronic systemic
inflammatory autoimmune disorder that
produces a non-suppurative proliferative and
inflammatory synovitis, progressing to
destructions of the articular cartilage and
ankylosis of the joints
 Epidemiology:
 Risk
affects mostly women ages 20-50
factors:
 Genetic
susceptibility (50%): HLA-DRB1 / PTPNN2
 Environmental arthritogen-activation of T and B cells:
certain environmental influences promote citrullination of
self-proteins, creating new epitopes that trigger
autoimmune reactions

Citrullinated peptides (CCPs) – post-translational modification of
arginine residues to citrulline
Pathogenesis

Initiation of autoimmune responses
by CD4+ TH cells + arthritogenic
agents (e.g., microbial or selfantigen), producing cytokines that
stimulate tissue injury


Rheumatoid factors – Fc portion of
autologous IgM / IgG that generates
immune complexes of
autoantibodies in the sera, synovial
fluid, and synovial membranes


TNF from macrophages stimulate
synovial cells to secrete proteases,
destroying hyaline cartilage
Act as a marker for disease (but can
be seronegative)
Manifests as a symmetric arthritis
of the small joints of the hand and
feet
Morphology

Initially, the synovium becomes grossly
edematous, thickened, and hyperplastic,
developing delicate and bulbous fronds

Pannus – a mass of edematous synovium,
inflammatory cells, granulation tissues, and
fibroblasts that grows over the articular cartilage
and causes erosion

After destruction of the cartilage, the pannus
bridges the apposing bones to form a fibrous
ankylosis, ossifying and resulting in fusion of the
bones as a bony ankylosis

Characteristics:
1.
Synovial cell hyperplasia and proliferation
2.
Dense inflammatory infiltrates of CD4+ TH cells,
B cells, plasma cells, APCs
3.
Increased vascularity due to angiogenesis
4.
Fibrinopurulent exudate on the synovial and
joint surfaces
5.
Osteoclastic activity in the underlying bone,
allowing the synovium to penetrate into the
bone and cause periarticular erosions and
subchondral cysts
Morphology

Rheumatoid subcutaneous nodules – severe
cutaneous lesions characterized by firm,
nontender, round-to-oval nodules that arise
in regions of the skin subjected to pressure
(e.g., ulnar aspect of the forearm, elbows,
occiput, lumbosacral area)


Microscopically resemble necrotizing granulomas with a central zone of
fibrinoid necrosis surrounded by a rim of activated macrophages and
lymphocytes
Affected individuals with severe RA are at-risk of developing
vasculitis:
Acute necrotizing vasculitis involves small and large arteries and can
evolve into chronic fibrosing processes (with involvement in the pleura
and pericardium)
 Obstruction of the small arteries by obliterating endarteritis can lead to
peripheral neuropathy, ulcers, and gangrene
 Leukocytoclastic vasculitis produces purpura, cutaneous ulcers, and nail
be infections

Clinical Presentation


Symptoms of malaise, fatigue, and generalized MSK pain develop
slowly and insidiously through cytokine-mediation (e.g., TNF, IL-1)
before involving the joints (in a symmetrical patterns progressing from
smaller to larger joints)

The affected joints are swollen, warm, painful, and stiff following inactivity and
progressively enlarge (which decreases ROM until complete ankylosis)

Swan-neck/boutonniere deformity – characteristic radial deviation of the wrist
and ulnar deviation / flexion-hyperextension of the fingers → no stability and
minimal ROM

Baker’s cyst – large synovial cyst of the posterior knee that develops with
increasing intra-articular pressure, causing herniation of the synovium
Multisystem involvement for definitive diagnosis:

Characteristic radiographic findings: joint effusions and juxta-articular
osteopenia with erosions and narrowing of the joint space and loss of cartilage

Sterile, turbid synovial fluid with decreased viscosity, poor mucin clot
formation, and inclusion-bearing neutrophils

Presence of rheumatoid factor and anti-CCP antibody (80%)
Clinical Presentation
 Treatment
is aimed at relieving pain and
inflammation while slowing/stopping joint
destruction: corticosteroids, synthetic and
biologic disease-modifying drugs (e.g.,
methotrexate), TNF antagonists
 Biologic
agents that interfere with T and B cell
lymphocyte responses
 Longterm
complications: systemic
amyloidosis (5-10%), opportunistic
infections (in patients who receive longterm
immunosuppressive agents)
Juvenile Idiopathic Arthritis

Juvenile idiopathic arthritis (JIA) – a heterogeneous
group of disorders of unknown cause that present
with arthritis before age 16 (due to cytokinemediated inflammation by IL-1, IL-17, TNF, and IFN-γ
released by TH cells)

Risk factors: HLA / PTPN22 variants

Compared to RA: more common oligoarthritis, more
frequent systemic disease, affliction of larger joints,
absence of rheumatoid nodules and rheumatoid factor,
presence of antinuclear antibody (ANA) seropositivity
 Subclassifications

are based on clinical and laboratory variables
Treatment is aimed at relieving pain and
inflammation while slowing/stopping joint
destruction: IL-6 receptor antibody in systemic form
L25
Ankylosing Spondylitis
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Seronegative Spondyloarthropathies
• family of related disorders with back pain, uveitis, peripheral joint
inflammarion, and gastrointestinal symptoms
• HLA-B27
• negative rheumatoid factor
• chronic inflammatory disease





Lesions consists of enthesitis rather than synovitis
There is a tendency to affect spinal joints: sacroiliitis, spondylitis
Peripheral joints are affected less frequently (approximately in 30% of cases)
There is a tendency for extra-articular manifestations (such as: eye, heart, lung, kidney)
There is a strong familial aggregation
53
Ankylosing Spondylitis
 sacroiliac
 back
joints, axial skeleton
pain and stiffness of spine
 oligoarthritis
of hips and shoulders,
enthesopathy, and anterior uveitis
 men>women:
 most
20-30 yrs old
common HLA-B27 subtypes
 HLA-B*2705,
B*2702, B*2704, B*2707
54
Ankylosing Spondylitis
 involvement
of entheses
 point at which tendon, fascia or ligament or
joint capsule inserts into bone
 annulus fibrosis of intervertebral disk
(central) and the achilles tendon (peripheral)
 sacroiliitis is hallmark
 ultimately there is metaplasia of articular
cartilage and bone fusion
 synovial joint involvment: thorax is “rigid cage”
 diaphragmatic respiration
55
Ankylosing Spondylitis
End stage: bamboo spine
The end-result of ankylosing spondylitis is a rigid spine, so called
from its radiographic appearance.
 In this stage both the anterior and posterior longitudinal
ligament, and annulus fibrosus are ossified.
 Intervertebral discs are present but bridged over at the ends by
ossified bars (syndesmophytes).
 Intervertebral discs may have disappeared and the vertebral
bodies may be completely fused together
 Apophyseal joints are ossified
 There is total ankylosis, which is associated with osteoporosis
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Reiter Syndrome
Reactive arthritis – involves the triad of arthritis
nongonococcal urethritis or cervicitis and conjunctivitis,
commonly affecting men ages 20-30 years, which is
associated with HLA-B27
◦ Causes: autoimmune reaction triggered by a prior infection of the
GI tract or GU system, developing within several weeks of
urethritis or diarrhea
◦ Symptoms: initial joint stiffness and lower back pain with
asymmetric involvement of the ankles, knees, and feet; “sausage”
finger or toe due to synovitis of a digital tendon sheath;
ossification of tendonoligamentous insertion sites that leads to
calcaneal spurs and bony outgrowths; indistinguishable
involvement of the spine
◦ Extra-articular involvement: inflammatory conjunctivitis, cardiac
conduction abnormalities, aortic regurgitation
57
◦ Recurrent episodes fluctuate over a period of weeks to 6 month
Psoriasis Arthritis
• chronic inflammatory arthropathy that affects the
peripheral and axial joints with associated
psoriasis in which the symtpoms manifest by ages
30-50
◦ Susceptibility is determined by HLA-B27 and HLA-Cw6
alleles
◦ Progression: the distal interphalangeal joints of the
hands and feet are asymmetrically affected, producing
a “pencil in cup” deformity with possible remission
and minimal joint destruction
58
Enteropathic Arthropathies
•Inflammatory bowel disease (IBD) is a group of idiopathic
inflammatory conditions of the colon and small intestine.
• 5–10% of ankylosing spondylitis patients have IBD.
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