1. MUSCULOSKELETAL BLOCK Pathology Disease of Joints
2013
Dr. Maha Arafah

2. Objectives Rheumatoid arthritis
1. Pathogenesis
2. Morphology
3. Major joints affected
4. Clinical course
Gout and gouty arthritis
2. Morphology of acute and chronic articular lesions
3. Clinical course
Osteoarthritis (degenerative joint disease)
1. The primary articular defect in osteoarthritis.
2. Pathogenesis
3. Morphology
4. Major joints affected
5. Clinical course

3. JOINTS TYPES Synovial joints: also called diarthroses
Nonsynovial joints: also called solid joint or synarthrosis

4. Inflammatory disease of joints (arthritis and synovitis)
has four main causes
Degeneration, e.g. osteoarthritis.
Autoimmity, e.g. rheumatoid arthritis, SLE, autoimmunity, rheumatic fever
Crystal deposition, e.g. gout and other crystalline arthropathies.
Infection, e.g. septic arthritis, tuberculous arthritis.

5. Clinical Manifestations of Joint Disease
Joint Pain (Arthralgia)
Joint Swelling
Joint Crepitus
Abnormal Joint Mobility

6. X-Ray Abnormalities
Articular cartilage, synovium, intra-articular ligaments, and synovial fluid are normally radiolucent
(1) an increase in the joint space (fluid, blood, or proliferation of the synovium)
(2) decreased joint space (degeneration of the articular cartilage)
(3) abnormalities in articular cartilage (opacification, and subchondral bone, such as erosion and cyst formation)
(4) the presence of abnormal loose bodies in the joint space.
Magnetic resonance imaging (MRI) permits visualization of all structures and is an excellent method of evaluation of joints

8. Changes in Synovial Fluid in Diseases of Joints

9. Osteoarthritis Definition and Incidence
Osteoarthritis is a nonneoplastic disorder of progressive erosion of articular cartilage.
Common and important degenerative disease, with both destructive and reparative components
Usually age 50+ years (present in 80% at age 65 years)

10. Osteoarthritis Aetiology
The main factors in the development of osteoarthritis are:
aging
abnormal load on joints
crystal deposition
inflammation of joints

11. Osteoarthritis Pathogenesis
In general, osteoarthritis affects joints that are constantly exposed to wear and tear.
It is an important component of occupational joint disease
e.g. osteoarthritis of
the fingers in typists
the knee in professional footballers

12. Osteoarthritis Types
Primary osteoarthritis
Secondary osteoarthritis

13. appears insidiously with age and without apparent initiating cause
Osteoarthritis Types
Primary osteoarthritis:
appears insidiously with age and without apparent initiating cause 
usually affecting only a few joints
Secondary osteoarthritis

14. Osteoarthritis Types
Primary osteoarthritis:
Secondary osteoarthritis:
some predisposing condition, such as previous traumatic injury, developmental deformity, or underlying systemic disease such as diabetes, ochronosis, hemochromatosis, or marked obesity
Secondary osteoarthritis affect young
often involves one or several predisposed joints
less than 5% of cases

15. Osteoarthritis Common sites
usually one joint or same joint bilaterally
Gender has some influence:
Women : knees and hands
Men : hips

16. Osteoarthritis The pathological changes involve: cartilage bone
synovium
joint capsule
with secondary effects on
muscle ( atrophy)

17. Osteoarthritis Pathogenesis
The early change: destruction of articular cartilage, which splits (fibrillation), becomes eroded, and leads to narrowing of the joint space on X ray
There is inflammation and thickening of the joint capsule and synovium

18. constant friction of bone surfaces, leading to a highly polished bony articular surface (eburnation)
Small cysts develop in the bone
osteophytes

19. Osteoarthritis. : Histologic demonstration of the characteristic fibrillation of the articular cartilage. 

20. Cracking and fibrillation of cartilage

21. Severe Osteoarthritis
Eburnated articular surface exposing subchondral bone
Subchondral cyst
Residual articular cartilage

22. Pathological changes in osteoarthritis
normal synovial joint
early change in osteoarthritis
'Heberden's nodes (osteophytes on the interphalangeal joints of the fingers)
Eburnation & osteophytes formation

23. Osteoarthritis Clinical features
An insidious disease predominantly affecting patients beginning in their 50s and 60s.
Characteristic symptoms include deep, aching pain exacerbated by use, morning stiffness and limited range of movement
swelling of affected joints
Osteophyte impingement on spinal foramina can cause nerve root compression with radicular pain, muscle spasms, muscle atrophy, and neurologic deficits.
Heberden nodes in fingers of women only (osteophytes at DIP joints)
Loose bodies: may form if portion of articular cartilage breaks off

24. Osteophyte

25. Course & Prognosis
Osteoarthrosis is a slowly progressive, chronic joint disability
Eventually, elderly sufferers may become confined to wheelchairs
Recent advancements in the technique of joint replacement with prostheses have improved the outlook of these patients

26. Osteoarthritis Summary
Incidence: common after 50 year
Primary and secondary types: underlying conditions
Pathogenesis: erosion of articular cartilage
Clinical features: pain and limitation of function

28. Rheumatoid arthritis
Definition aetiology pathological features clinical features radiological features

29. Rheumatoid arthritis Definition
Chronic systemic inflammatory disorder affecting synovial lining of joints, bursae and tendon sheaths; also skin, blood vessels, heart, lungs, muscles
Produces nonsuppurative proliferative synovitis, may progress to destruction of articular cartilage and joint ankylosis
1% of adults, 75% are women, peaks at ages years; also menopausal women

30. Extra-Articular Manifestations

31. Rheumatoid arthritis Aetiology
The joint inflammation in RA is immunologically mediated
Genetic and environmental variables

32. Rheumatoid arthritis Aetiology
triggered by exposure of immunogenetically susceptible host to arthitogenic microbial antigen
autoimmune reaction then occurs with T helper activation and release of inflammatory mediators, TNF and cytokines, that destroys joints
circulating immune complexes deposit in cartilage, activate complement, cause cartilage damage
Parvovirus B19 may be important in pathogenesis.

33. HLA-DR4, DR1 (65%)
are derived from proteins in which arginine residues are converted to citrulline residues posttranslationally
 Antibodies against cyclic citrullinated peptides (CCP protein antibodies) is the most specific for a diagnosis of rheumatoid arthritis

34. Rheumatoid arthritis Laboratory Findings:
80% have IgM autoantibodies to Fc portion of IgG (rheumatoid factor), which is not sensitive or specific;
synovial fluid has increased neutrophils (particularly in acute stage) & protein
Anti-CCP (cyclic citrullinated peptides)protein antibodies most specific for a diagnosis of rheumatoid arthritis
Other antibodies include antikeratin antibody (specific, not sensitive), antiperinuclear factor, anti-rheumatoid arthritis associated nuclear antigen (RANA)
Genetics: HLA-DR4, DR1 (65%)

35. Rheumatoid arthritis Pathologic Features
synovial cell hyperplasia and proliferation
dense perivascular inflammatory cell infiltrates (frequently forming lymphoid follicles) in the synovium composed of CD4+ T cells, plasma cells, and macrophages
increased vascularity due to angiogenesis
neutrophils and aggregates of organizing fibrin on the synovial surface
increased osteoclast activity in the underlying bone  bone erosion.

36. Rheumatoid arthritis Pathologic Features
Pannus
formed by proliferating synovial-lining cells admixed with inflammatory cells, granulation tissue, and fibrous connective tissue
Eventually the pannus fills the joint space, and subsequent fibrosis and calcification may cause permanent ankylosis.

38. increased vascularity
dense perivascular inflammatory cell infiltrates
increased vascularity
neutrophils and aggregates of organizing fibrin on the synovial surface
synovial cell hyperplasia and proliferation
Pannus formation
increased osteoclast activity in the underlying bone  bone erosion
swan neck finger

40. Rheumatoid arthritis Pathologic Features

41. Rheumatoid arthritis Clinical Feaures
morning stiffness, arthritis in 3+ joint areas
arthritis in hand joints,
symmetric arthritis,

43. Rheumatoid arthritis X-ray:
joint effusions, juxta- articular osteopenia, erosions
narrowing of joint space; destruction of tendons, ligaments and joint capsules produce radial deviation of wrist, ulnar deviation of digits, swan neck finger abnormalities

44. Rheumatoid arthritis Clinical course:
variable; malaise, fatigue, musculoskeletal pain and joint involvement
joints are warm, swollen, painful, stiff in morning
10% have acute onset of severe symptoms, but usually joint involvement occurs over months to years
50% have spinal involvement
rheumatoid nodules, rheumatoid factor, typical radiographic changes

45. Subcutaneous rheumatoid nodule
Palisading Granulomas

46. Rheumatoid arthritis Prognosis
Reduces life expectancy by 3-7 years
Death due to amyloidosis, vasculitis, GI bleeds from NSAIDs, infections from steroids.

47. Rheumatoid arthritis Summary
RA is a chronic inflammatory disease that affects mainly the joints, especially small joints, but can affect multiple tissues.
The disease is caused by an autoimmune response against an unknown self antigen(s)
This leads to T-cell reactions in the joint with production of cytokines that activate phagocytes that damage tissues and stimulate proliferation of synovial cells (synovitis).
The cytokine TNF plays a central role, and antagonists against TNF are of great benefit.

48. Comparison of the morphologic features of RA and osteoarthritis

49. Comparison of Osteoarthrosis & Rheumatoid Arthritis

50. Gout Gout is an inflammatory disease.
The first metatarsophalangeal joint is the site most commonly affected.
It is swollen, red, and, no doubt, very painful.
Sodium urate crystals have precipitated into the joint, producing an acute inflammatory response.

52. Hands, chronic gout - Clinical presentation
This is an example of chronic gout with gouty tophi. Note that there are numerous asymmetrical, periarticular swellings.
These represent inflammatory reaction to sodium urate crystals.
Tophi appear only after repeated attacks of gout in patients whose hyperuricemia has not been treated.

53. Tophus, gout - Low power
Histologically, tophi consist of crystals that are surrounded by macrophages, lymphocytes, and often foreign body giant cells. In routinely processed sections, the crystals are removed during processing.
Long, slender, needle-shaped monosodium urate crystals

54. Gout Besides joints, what other organ is affected in gout?
approximately 20% of patients die of renal failure.
Renal lesions are many:
precipitation of urates in the medulla forms tophi;
uric acid stones may form
acute renal failure due to precipitation of urates in the collecting tubes

55. Pseudogout Calcium pyrophosphate crystals
chondrocalcinosis

57. Scenario
A 40-year-old white woman presented to her physician with vague complaints of fatigue, anorexia, and generalized weakness for the previous six months. She complained that it was difficult to ambulate upon rising from bed, but after about 30 minutes she felt better and was able to move about the house. She also complained that stiffness and pain in her wrists and fingers made it difficult to do routine chores in the kitchen, because her manual dexterity was compromised. She was especially concerned about the recent swelling in the joints of her fingers.

60. Physical examination
her knees were swollen and tender, and motion in both her knees and hips waslimited. Her knees and both wrist joints were warm but not erythemic. The proximal interphalangeal joints of both hands were warm and enlarged by nonbony fusiform swelling. She had two small, nonpainful, subcutaneous (soft tissue) nodules along the proximal ulna of her left arm.

61. Radiographs of affected joints indicated soft tissue swelling, joint effusion, and juxtaarticular osteopenia.
Synovial fluid was aspirated and had the following characteristics:
Viscosity - low Color - translucent, yellow White blood cells cells per cu mm with 50% neutrophils No crystals Bacterial culture – negative
As well, the patient had the following clinical pathologic features:
HLA-DR4 - positive Rheumatoid factor - positive at a titer of 1:500 Erythrocyte sedimentation rate – increased

62. Acute rheumatoid arthritis
This is a classic presentation of acute rheumatoid arthritis. It is polyarthritic, affects the proximal interphalangeal joints, and has produced a fusiform swelling of the soft tissue. The lesion is usually symmetrical.

63. How does the distribution of affected joints in the hand differ from that seen in degenerative joint disease?  The lesions of degenerative joint disease in the hand are found in the distal interphalangeal joints, are bony, and are not symmetrical.

64. In this case, there is marked destruction of the epiphyseal bone
In this case, there is marked destruction of the epiphyseal bone. The joint spaces are narrowed, because of the destruction of the articular cartilage. In severe cases, the joints become fused by bony ankylosis.

65. What is the significance of the radiologic findings in rheumatoid arthritis (RA)? 
In RA, there is diffuse narrowing of the joint space. The cartilage is destroyed by the release of IL-1 and TNF, which depresses the synthesis of proteoglycans, and by proteases released from neutrophils. As well, proliferation of the synovial membrane leads to pannus formation, which isolates the cartilage from the synovial fluid, its source of nutrients. The severe, extensive damage of RA often leads to ankylosis.

66. What is the significance of the radiologic findings in rheumatoid arthritis (RA)? 
In chronic RA, the periarticular bone is osteoporotic, a change secondary to disuse of the affected limbs, to the stimulation of osteoclasts by corticosteroid therapy, or to the release of RANK-L by activated lymphocytes in the synovium.

67. List two important histologic changes found in the synovial membrane in joints affected by rheumatoid arthritis.  The synovium is proliferative and is infiltrated by numerous lymphocytes and plasma cells.

68. Which class of lymphocytes predominates in the inflammatory infiltrate
Which class of lymphocytes predominates in the inflammatory infiltrate?  An autoimmune reaction in which T cells play the pivotal role accounts for the inflammation and joint destruction. CD4+ cells accumulate in affected joints, where they stimulate monocyte- macrophages to release cytokines and recruit B cells, which produce antibody - most importantly, the autoantibody rheumatoid factor (IgM against the Fc portion of IgG). During active inflammation, the synovial tissue generates a plethora of cytokines/growth factors. It is now generally accepted that IL-1 and TNF are key mediators in the cytokine cascade.

69. What is the significance of the clinical signs of anorexia, fatigue, and generalized weakness in the first patient?  It is important to realize that RA is a chronic, relapsing, inflammatory disease that includes the joints. While the principal target is the synovial lining of joints, the disease also affects many organ systems - skin, heart, lungs, blood vessels, and muscle. The release of inflammatory cytokines, such as IL-1 and TNF, from the joints into the circulation can lead to the generalized systemic signs and symptoms. As well, 80% of individuals with RA have autoantibodies (usually IgM) to the Fc portion of IgG. These circulating complexes contribute to the extra-articular signs of RA.

70. What is the significance of finding inflammatory cells in the joint fluid?  Quantitation of white blood cells is an important part of synovial fluid analysis, especially because it is the major basis for classification of an effusion as septic, inflammatory, or noninflammatory. 

71. Hands, chronic rheumatoid arthritis - Clinical presentation
The destructive nature of chronic, severe rheumatoid arthritis:
Subluxation and fusion of joints
Ulnar deviation of the digits
Note that the lesion is polyarticular and symmetrical.
The most common deformity of the thumb is flexion with hyperextension at the interphalangeal joint.

72. Rheumatoid nodule - Low power
Rheumatoid nodules consist of a central zone of fibrinoid necrosis surrounded by a prominent rim of epithelioid histiocytes and numerous lymphocytes and plasma cells.
Rheumatoid nodules occur in approximately 20% to 25% of patients with definitive or classic rheumatoid arthritis. Nodules generally are associated with severe articular and systemic disease and with high titers of rheumatoid factor.

73. Rheumatoid nodules occur in approximately 20% to 25% of patients with definitive or classic rheumatoid arthritis. Nodules generally are associated with severe articular and systemic disease and with high titers of rheumatoid factor.

74. Where do rheumatoid nodules typically develop
Where do rheumatoid nodules typically develop?  The nodules typically appear on the extensor surface of the forearm below the elbow, or at sites of local pressure, such as the Achilles tendon. Less commonly, they form in the lungs, spleen, myocardium, and heart valves. The subcutaneous nodules are firm, nontender, and round to oval.

75. degenerative joint disease is the formation of osteophytes at the margin of affected joints.
What is the common name of osteophytes that develop at the distal interphalangeal joints of women?  These osteophytes are called Heberden nodes.