Inflammatory joint diseases

1. JOINT PATHOLOGY

2. Aim
To discuss pathogenesis, morphology and
clinical course of common diseases of joint
Osteoarthritis
rheumatoid arthritis
gouty arthritis
infectious arthritis

3. OBJECTIVE
Students should be able to:
• Define and identify osteoarthritis, rheumatoid arthritis,
gouty arthritis and infectious arthritis
• Explain the pathogenesis of osteoarthritis, rheumatoid
arthritis, gouty arthritis and infectious arthritis
• Describe the morphology of osteoarthritis, rheumatoid
arthritis, gouty arthritis and infectious arthritis
• Outline the clinical course of osteoarthritis,
rheumatoid arthritis, gouty arthritis and infectious
arthritis

4. SYNOVIAL JOINTS

6. Normal articular cartilage performs two functions:
(1) Along with the synovial fluid, it provides virtually
friction-free movement within the joint
(2) in weight-bearing joints, it spreads the load across the
joint surface
These functions require the cartilage to be elastic and to
have high tensile strength provided by proteoglycans and
type II collagen produced by chondrocytes
articular cartilage constantly undergoes matrix degradation
and replacement
Normal chondrocyte function is critical to maintain cartilage
synthesis and degradation

7. JOINT DISEASES
Joints are subject to a wide variety of disorders
 Degeneration
 Infections
 immune-mediated injury
 metabolic derangements
 neoplasms

8. JOINT DISEASES
ARTHRITIS
– Degenerative (OSTEOARTHRITIS)
– Rheumatoid
– Infectious: Supp., TB, Lyme, Viral
– Gout (URATE)
– Pseugout (PYROPHOSPHATE)
TUMORS
– Ganglion (Synovial Cyst)
– Giant Cell Tumor (Pigmented VilloNodular Synovitis[PVNS])
– Synovial Sarcoma

9. OSTEOARTHRITIS
(degenerative joint disease)
characterized by
degeneration of cartilage that results in
structural and functional failure of
synovial joints
an intrinsic disease of cartilage in which
chondrocytes respond to biochemical &
mechanical stresses resulting in breakdown of the
matrix

10. OSTEOARTHRITIS
Primary osteoarthritis
Onset - insidiously with age and
without apparent initiating cause
Most commonly affected joints:
joints of the hands, knees, hips, and spine

11. Secondary osteoarthritis
 strikes in youth
 predisposing conditions
- previous trauma
- developmental deformity
- systemic disease : diabetes, ochronosis,
hemochromatosis
- marked obesity
OSTEOARTHRITIS

12. PATHOGENESIS
Risk Factors
A wear-and-tear phenomenon
 Mechanical stresses
 Aging
 Genetic factors : polymorphisms and mutations
in genes encoding components of the matrix and
signaling molecules
sustained high estrogen levels
increased bone density

13. Imbalance in the expression, activity, and signalling
of cytokines and growth factors involved in synthesis
and degradation of matrix
PATHOGENESIS
Aging
Mechanical Stress
Degradation and loss of matrix
 degenerating cartilage containing more water and less
proteoglycan
 diminished type II collagen network

14. MORPHOLOGY
early changes in osteoarthritis include
alterations in the composition and structure of
the matrix
Microscopic :
vertical and horizontal fibrillation and
cracking of the matrix
occur as the superficial layers of the cartilage
are degraded

15. MORPHOLOGY
fibrillation of the articular cartilage

16. Gross morphology
Chondromalacia: at early stage - a soft granular-
appearing articular cartilage surface
bone eburnation: Eventually full-thickness portions
of the cartilage are lost and the subchondral bone plate
is exposed and is smoothened and burnished by
friction, giving it the appearance of polished ivory
 underlying cancellous bone becomes sclerotic and
thickened
 subchondral cyst: fracture gaps allow synovial fluid
to be forced into the subchondral regions to form
fibrous walled cysts
MORPHOLOGY

17. residual articular cartilage
subchondral cyst
eburnated articular surface
exposing subchondral
bone
Advanced subchondral degenerative
cyst in femoral head

18. joint mice: Small fractures can dislodge pieces
of cartilage and subchondral bone into the
joint, forming loose bodies
MORPHOLOGY

19. Osteophytes: Mushroom-shaped bony outgrowths
develop at the margins of the articular surface
• pannus: a fibrous synovial pannus covers the
peripheral portions of the articular surface in severe
disease
MORPHOLOGY
The synovium is
usually only mildly
congested and
fibrotic, and may
have scattered
chronic
inflammatory cells

21. Clinical Course
insidious disease
predominantly affecting patients beginning in
their 50s and 60s
Characteristic symptoms and signs
1. deep, aching pain exacerbated by use
2. morning stiffness
3. crepitus (grating or popping sensation in the
joint)
4. limitation in range of movement

22. Clinical Course
5. Osteophyte impingement on spinal foramina
can cause nerve root compression with
radicular pain, muscle spasms,muscle atrophy,
and neurologic deficits
6. Heberden nodes in the fingers, representing
prominent osteophytes at the distal
interphalangeal joints are characteristic in
women
7. significant joint deformity

23. 1. Hips
2. Knees
3. lower lumbar
4. cervical vertebrae
5. proximal and distal
interphalangeal joints of
the fingers
6. first carpometacarpal
joints
7. first tarsometatarsal joints
of the feet are commonly
involved

24. RHEUMATOID ARTHRITIS
 systemic chronic inflammatory disorder that
 affect many tissues and organs—skin, blood
vessels, heart, lungs, and muscles but principally
attacks the joints
 causing a non suppurative proliferative synovitis
 progresses to destruction of the articular
cartilage and underlying bone resulting ankylosis
of the joints

25. RHEUMATOID ARTHRITIS
Pathogenesis
RA is an autoimmune disease involving complex
interactions of
- genetic risk factors
- environment
- immune system
genetic and environmental factors contribute to
the breakdown of tolerance to self-antigens

26. Pathogenesis
Genetic susceptibility
50% of the risk of developing RA is related to
genetic factors
Specific HLA-DRB1 alleles have been shown to
be associated with rheumatoid arthritis
Another gene associated with rheumatoid
arthritis is PTPN22 gene which encodes a
tyrosine phosphatase that is postulated to
inhibit T cell activation
RHEUMATOID ARTHRITIS

27. Pathogenesis
Environmental factors:
Many infectious agents whose antigens may
activate T or B cells have been considered
Inflammatory and environmental insults such as
smoking and infections may induce the
citrullination of some self proteins
creating new epitopes that trigger autoimmune
reactions
RHEUMATOID ARTHRITIS

28. Pathogenesis
Environmental factors:
Cyclic citrullinated peptides are derived from
proteins in which arginine residues are
converted to citrulline residues post
translationally
70% of patients the blood contains anti-CCP
antibody (antibodies against cyclic citrullinated
peptides) which may be produced during
inflammation
RHEUMATOID ARTHRITIS

29. Pathogenesis
Autoimmunity
Pathologic changes are caused mainly by
antibodies against self-antigens & cytokine-
mediated inflammation (with CD4+ T cells
princinpal source of the cytokines)
In RA, antibodies to citrullinated fibrinogen, type II
collagen, α-enolase, and vimentin
immune complexes that deposit in the joints
These antibodies are a diagnostic marker for the disease
and may be involved in tissue injury
RHEUMATOID ARTHRITIS

30. About 80% of individuals with rheumatoid arthritis
have
autoantibodies to the Fc portion of autologous
IgG (rheumatoid factors)
Rheumatoid factor, however, is not present in some
individuals with the disease (seronegative)
and is sometimes found in other disease states and
even in otherwise healthy people

31. Pathogenesis
RHEUMATOID ARTHRITIS
disease is initiated in a genetically predisposed
person by activation of CD4+ helper T cells
responding to some arthritogenic agent, possibly
microbial,or to a self-antigen such as CCP

32. IL-1, IL-8, TNF, IL-6, IL-17, У interferon

33. IL-1, IL-8, TNF, IL-6, IL-17, У interferon

35. Morphology
RA typically manifests as symmetric arthritis
principally affecting
small joints of the hands and feet, ankles, knees,
wrists, elbows & shoulders
Most often - proximal interphalangeal &
- metacarpophalangeal joints
distal interphalangeal joints are spared
Axial involvement, when it occurs is limited to the
upper cervical spine
RHEUMATOID ARTHRITIS

36. Morphology
Joints
Gross
synovium becomes
 Thickened
 Transforming thin, smooth synovial membrane is
into lush, edematous, frondlike (villous)
projections
RHEUMATOID ARTHRITIS

37. Morphology
Affected joints show chronic papillary synovitis
The characteristic histologic features include
1. synovial cell hyperplasia and proliferation
2. infiltration of synovial stroma by a dense perivascular
inflammatory infiltrate composed of lymphoid aggregates
(mostly CD4+ helper T cells), B cells, plasma cells, dendritic cells,
and macrophages
3. increased vascularity due to vasodilation and
angiogenesis - with superficial hemosiderin deposits
4. aggregation of organizing fibrin - covering portions of the
synovium and floating in the joint space as rice bodies
RHEUMATOID ARTHRITIS

38. 5. accumulation of neutrophils - in the synovial fluid and
along the surface of synovium but usually not deep in the
synovial stroma
6. osteoclastic activity in underlying bone - allowing the
synovium to penetrate into the bone and cause and periarticular
bone erosion s, subchondral cysts, and osteoporosis
7. pannus formation
- pannus is a mass of synovium and synovial stroma consisting of
proliferating synovial lining cells admixed with inflammatory cells,
granulation tissue, and fibrous connective tissue
- overgrowth of this tissue is so exuberant that thin, smooth
synovial membrane is transformed into lush, edematous, frondlike
(villous) projections

39. In time, after the cartilage has been destroyed,
the pannus bridges the apposing bones to form
a fibrous ankylosis which eventually ossifies and
results in bony ankylosis
Inflammation in the tendons, ligaments, and
occasionally the adjacent skeletal muscle
frequently accompanies the arthritis

40. Skin
Rheumatoid nodules are firm, non tender, and round to
oval, in the skin arise in the subcutaneous tissue
the most common cutaneous lesion
in approximately 25% of affected individuals
Sites:
arise in regions of the skin that are subjected to pressure,
including the ulnar aspect of the forearm, elbows,
occiput, and lumbosacral area
Less commonly
they form in the lungs, spleen, pericardium, myocardium,
heart valves, aorta, and other viscera

41. Microscopically
A central zone of fibrinoid necrosis
surrounded by
a prominent rim of epithelioid histiocytes
(activated macrophages) and
numerous lymphocytes and plasma cells

42. The rheumatoid “nodule” shows “palisading”
fibroblasts
HANDSWRISTELBOWS

44. Blood Vessels
 with severe erosive disease
 rheumatoid nodules
 high titers of rheumatoid factor
are at risk of developing vasculitic syndromes
Rheumatoid vasculitis is a potentially catastrophic
complication of rheumatoid arthritis,
particularly when it affects vital organs

45. Frequently, segments of small arteries such as
vasa nervorum and digital arteries are
obstructed by an obliterating endarteritis
resulting in peripheral neuropathy, ulcers, and
gangrene
Leukocytoclastic venulitis produces purpura,
cutaneous ulcers, and nail bed infarction

46. Clinical Course
Symmetric polyarticular arthritis
Constitutional symptoms (weakness, malaise,
and low-grade fever)
Subcutaneous rheumatoid nodules
Vasculitic involvement of the extremities may
give rise to Raynaud phenomenon and chronic
leg ulcers
RHEUMATOID ARTHRITIS

47. Symmetric polyarticular arthritis
The arthritis first appears insidiously with
aching and stiffness of the joints, particularly in the
morning
As the disease advances the joints become
- swollen, painful
- Limited movement (minimal or no range of motion)
- complete ankylosis
characteristic deformities
- radial deviation of the wrist
- ulnar deviation of the fingers
- flexion-hyperextension abnormalities of the fingers (swan
neck, boutonnière)
Large synovial cysts

48. Hand, acute rheumatoid arthritis
This is a classic presentation of acute rheumatoid arthritis
It is polyarthritic, affects the proximal interphalangeal joints
has produced a fusiform swelling of the soft tissue
The lesion is usually symmetric

50. Chronic RA

51. The radiographic hallmarks are
 joint effusions
juxta-articular osteopenia
erosions and narrowing of the joint space
loss of articular cartilage

52. Diffuse osteopenia
Narrow joint spaces
Periarticular bony erosions
Ulnar drift of the fingers

53. The disease course may be slow or rapid, and
fluctuates over the years, with the greatest
damage occurring in the first 4 or 5 years
Approximately 20% of affected individuals enjoy
periods of partial or complete remission

54. Juvenile Rheumatoid Arthritis
 A group of multifactorial disorders with
environmental and genetic components
 unknown etiology
 classified according to their presentation into
oligoarthritis, polyarthritis & systemic (Still’s
disease) variants
 Large joints often are affected
 begin before the age of 16 years and persist for
more than 6 weeks
 Extraarticular inflammatory manifestations
such as uveitis also may be present

55. GOUT
Crystal-Induced Arthritis
 affects about 1% of the population & shows a
predeliction for males
 caused by excessive amounts of uric acid within
tissues and body fluids
 Monosodium urate crystals precipitate from
supersaturated body fluids and induce an acute
inflammatory reaction

56. GOUT
Definition
Gout is marked by
 transient attacks of acute arthritis initiated by
crystallization of monosodium urate within and
around joints
 sometime accompanied by the formation of
large crystalline aggregates called tophi, and
eventual permanent joint deformity

57. Gout is divided into primary and secondary forms
Primary gout - 90% of cases
designates cases in which the basic cause is
unknown or (less commonly) in which the disorder
is due to an inborn metabolic defect that causes
hyperuricemia
Secondary gout - 10% of cases
cause of the hyperuricemia is known, but gout is
not necessarily the main or even dominant clinical
disorder
GOUT

59. PATHOGENESIS
 elevated level of uric acid is an essential
component of gout, not all such persons develop
gout, and genetic and environmental factors also
contribute to its pathogenesis
 elevated uric acid levels can result from
overproduction or reduced excretion of uric
acid, or both
GOUT

60. Uric acid synthesis -end product of purine
catabolism
increased urate synthesis typically reflects some
abnormality in purine nucleotide production
synthesis of purine nucleotides involves two
different but interlinked pathways:
the de novo - involved in the synthesis of purine
nucleotides from nonpurine precursors.
salvage pathways - involved in the synthesis of
purine nucleotides from free purine bases, derived
from dietary intake and by catabolizing nucleic
acids and purine nucleotides
GOUT

61. PATHOGENESIS
Uric acid excretion
Circulating uric acid is freely filtered by the
glomerulus and virtually completely resorbed in
the proximal tubules of the kidney
A small fraction of the resorbed uric acid is
subsequently secreted by the distal nephron and
excreted in the urine
GOUT

62. PATHOGENESIS
Primary gout - cause of excessive uric acid biosynthesis
is unknown in most cases
 rare patients have identifiable enzymatic defects [e.g.
complete lack of HGPRT in Lesch-Nyhan syndrome]
Secondary gout - hyperuricemia can be caused by
 increased urate production[e.g.rapid cell lysis during
chemotherapy for lymphoma or leukemia)
 decreased excretion [chronic renal insufficiency or
reduced renal excretion caused by drugs such as
thiazide diuretics]
GOUT

63. increased levels of uric acid in the blood & body fluids ( synovium)
precipitation of monosodium urate crystals
chain of events that culminate in joint injury
Activation of complement system leading to
production of chemotactic and pro-inflammatory mediators
Phagocytosis of crystal by macrophages, stimulates the
production of the cytokine IL-1
local accumulation of neutrophils & macrophages in the joints &
synovial membranes
release of chemokines, cytokines, toxic free radicals, leukotriene B &
destructive lysosomal enzymes from activated inflammatory cells
Cytokines activate synovial cells & cartilage cells to release proteases

65. MORPHOLOGY
Major morphologic manifestations of gout are
acute arthritis
chronic tophaceous arthritis
tophi in various sites
gouty nephropathy
GOUT

66. MORPHOLOGY
Acute arthritis : characterized by
 a dense neutrophilic infiltrate permeating the
synovium and synovial fluid
 presence of long, slender, needle-shaped monosodium
urate crystals in the cytoplasm of the neutrophils & in
small clusters in the synovium
 synovium is edematous and congested & contains
scattered mononuclear inflammatory cells
when the episode of crystallization abates and the crystals
resolubilize, the attack remits
GOUT

67. MORPHOLOGY
Chronic tophaceous arthritis - evolves from
 Repetitive precipitation of urate crystals during acute
attacks
 urates can heavily encrust the articular surfaces and
form visible deposits in the synovium
 synovium becomes hyperplastic, fibrotic, and thickened
by inflammatory cells, forming a pannus that destroys
the underlying cartilage, leading to juxtaarticular bone
erosions
 In severe cases, fibrous or bony ankylosis ensues,
resulting in loss of joint function
GOUT

68. MORPHOLOGY - Tophi in various sites
Tophi are pathognomonic for gout
 formed by large aggregations of urate crystals
surrounded by an intense inflammatory
reaction of lymphocytes, macrophages, &
foreign-body giant cells, attempting to engulf
the masses of crystals
 Sites - articular cartilage of joints
- periarticular ligaments, tendons, & soft tissues
- ear lobes, nasal cartilages, skin of the fingertips
[Superficial tophi can lead to large ulcerations of the overlying
skin]
GOUT

69. MORPHOLOGY
Gouty nephropathy
 refers to renal complications associated with
urate deposition, variously forming medullary
tophi, intratubular precipitations, or free uric
acid crystals and renal calculi
 Secondary complications such as pyelonephritis
can occur, especially when there is urinary
obstruction
GOUT

70. GOUT

71. Clinical Features
more common in men than in women
not usually cause symptoms before the age of 30
Risk factors :
- obesity
- excess alcohol intake
- consumption of purine-rich foods
- diabetes
- metabolic syndrome
- renal failure
GOUT

72. Clinical Features
Four stages are classically recognized:
(1)asymptomatic hyperuricemia:
around puberty in males and after menopause in
women
(2) acute gouty arthritis
(3) “intercritical”gout (asymptomatic intercritical period)
(4) chronic tophaceous gout
GOUT

73. (2) acute gouty arthritis :
after a long interval of years appear as
sudden onset, excruciating joint pain with
localized erythema & warmth mostly
monoarticular
50% occur in the first metatarsophalangeal joint
(great toe) & 90% in ankle, heel, or wrist
last for hours to weeks & gradually completely
resolves, and the patient enters an
asymptomatic intercritical period
GOUT

74. GOUT
(4) chronic tophaceous gout
At this stage, radiographs show characteristic
- juxtaarticular bone erosion caused by the
crystal deposits and loss of the joint space
Progression leads to chronic gouty nephropathy
- renal colic associated with the passage of
gravel and stones

75. Pseudogout
calcium pyrophosphate crystal deposition disease
(also known as chondrocalcinosis )
 crystal deposits first appear in structures composed of
cartilage such as menisci, intervertebral discs, and
articular surfaces
 When the deposits enlarge enough, they may rupture,
inducing an inflammatory reaction
 typically first occurs in persons 50 years of age or older
becoming more common with increasing age, and
eventually reaching a prevalence of 30% to 60% in those
age 85
 no gender or race predilection

76. Infectious Arthritis
 Mode of entry: hematogenous dissemination &
direct inoculation or by contiguous spread from
osteomyelitis or a soft tissue abscess
 Infectious arthritis is serious because it can
cause rapid joint destruction and permanent
deformities

77. Suppurative Arthritis
Aetiology (causative agent )
 In children < 2 years of age - Haemophilus influenzae
 In older children and adults - S. aureus & gonococcus
 Patients with sickle cell disease - Salmonella infection
at any age
 Both genders are affected equally except for
gonococcal arthritis, which occurs mainly in sexually
active women
 In this group, those with deficiency of complement
proteins (C5, C6, C7) are particularly susceptible to
disseminated gonococcal infections
Infectious Arthritis

78. Suppurative Arthritis
Clinical presentation
 sudden onset with cardinal signs of acute
inflammation
 Fever, leukocytosis, and elevated ESR
 involves only a single joint—usually the knee—
followed in order by hip, shoulder, elbow, wrist,
and sternoclavicular joints
 Joint aspiration typically yields a purulent fluid
in which the causal agent can be identified
Infectious Arthritis

79. Lyme Arthritis
Aetiology - spirochete Borrelia burgdorferi
Mode of transmission : arthropod-borne disease
deer ticks of the Ixodes ricinus complexin
Clinical course - involves multiple organ systems
and in its classic form progresses through three
successive stages
Stage 1 - multiply at the site of the tick bite and cause
an expanding area of redness, often with an indurated or
pale center (erythema chronicum migrans) with fever
&lymphadenopathy last for few weeks’time
Infectious Arthritis

80. Stage 2 - early disseminated stage ,spread
hematogenously &cause secondary annular skin
lesions, lymphadenopathy, migratory joint and
muscle pain, cardiac arrhythmias, and meningitis,
often with cranial nerve involvement
- Diagnostically useful antibodies (usually both IgM
and IgG) against Borrelia antigens appear in the
serum at this stage of the disease
Infectious Arthritis

81. Infectious Arthritis
Stage 3 - late disseminated stage, which occurs 2
or 3 years after the initial bite
chronic arthritis, with severe damage to large
joints, and an encephalitis that ranges in
severity from mild to debilitating disease
 The arthritis may be caused by immune
responses against Borrelia antigens that cross-
react with proteins in the joints
disease tends to be migratory, with remissions
&relapses

82.  involves mainly large joints, especially the
knees, shoulders, elbows, and ankles, in
descending order of frequency
Infectious Arthritis

83. Morphology
Histologic examination reveals a
Chronic papillary synovitis with synoviocyte
hyperplasia fibrin deposition, mononuclear cell
infiltrates, onion-skin thickening of arterial
walls
Infectious Arthritis