Rheumatoid Arthritis

Question 1

What is RA?

Answer 1

1) Autoimmune disease
2) multifactorial
3) chronic systemic
4) inflammatory disease mostly affect peripheral small joint in a symmetrical manner

Question 2

What are the unique changes in joints of RA patients?

Answer 2

1- Radial deviation of the wrists
2- Ulnar deviation of the fingers
3- Swan neck deformity: hyperextension of PIP and flexion of DIP joints
4- Boutonnier deformity: flexion of PIP and extension of DIP joints

Question 3

RA is characterized by what?

Answer 3

Proliferative synovitis > Pannus
that causes:
1- Destruction of articular cartilage 
2- Ankylosis (fusion) of joint
3- Joint deformity & disability

Question 4

What are SF findings in RA?

Answer 4

1) Gross: Yellow white
2) WBC count: 2000-100,000 cells / mm3
3) Neutrophils: >50% of the total count.
4) Crystals : absent

Question 5

Population affected in RA

Answer 5

Females , 30-50 years of age

Question 6

What are the manifestations of RA?

Answer 6

1) Articular manifestations:
- Changes in joints
2) Extra-articular manifestations: circulating immune complexes
- Changes in skin
- Changes in blood vessels
- Changes in other tissues and organs

Question 7

Describe stiffness in RA

Answer 7

As a result of overnight rest of the joint this will result in deposition of water in the periarticular area > edema > as a result of movement after waking up the accumulated fluid overnight will go back into vessels which is known as Reverse Third Spacing & this will improve the morning stiffness

Question 8

Human Leukocyte Antigens involved in RA

Answer 8

HLA-DR4/DR1

Question 9

What triggers RA?

Answer 9

Smoking

Genetics

Question 10

RA autoantibodies (RF & ACPA) are against which antigens?

Answer 10

Citrullinated proteins (Autoantigens)

Question 11

What is citrullination and what is the process called?

Answer 11

Normal physiologic process. A “post-translational modification” of A.A arginine to neutral citrulline which alters the structure of a protein

Question 12

Explain Citrullination in RA

Answer 12

In RA, patients shows an exaggerated response to citrullinated proteins as foreign bodies

Question 13

What does citrullination mean to the cell?

Answer 13

A process related with apoptosis & terminal differentiation of cells

Question 14

What proteins that are normally citrullinated?

Answer 14

• Keratin
• Basic myelin protein of CNS
• Triton hyaline of hair follicle

Question 15

Citrullination is catalyzed by which enzyme?

Answer 15

calcium-dependent enzyme PAD

Question 16

In RA, PAD can be secreted by which cells?

Answer 16

granulocyte & macrophage

Question 17

ACPA occurs as a result of an abnormal antibody response to a range of citrullinated proteins which are?

Answer 17

• Fibrin
• Vimentin
• Fibronectin
• Epstein-Barr Nuclear Antigen 1
• α-enolase
• Type II collage
• Histones

Question 18

When there is immune complex deposition, it is what kind of necrosis?

Answer 18

Fibrinoid necrosis

Question 19

What are the pathologic joint changes in RA?

Answer 19

1) Chronic synovitis (proliferative synovitis)
2) Pannus formation
3) Fibrous and bony ankylosis (joint fusion)
4) Development of Joint deformities

Question 20

Discuss joint pathology in RA & what happens as a result

Answer 20

1) Synovium is 1/2 layer in thickness. In RA there is proliferation of the synovium > proliferative synovitis > more inflammation > Lymphocytes, Plasma cells, Mast cells & eventually Neutrophils & Macrophages in the synovial membrane.
2) This proliferation of the synovium leads to loss of space & can’t grow anymore & the only way to be accumulated in small joints is to twist and turn on itself creating a finger-like projection > Pannus
3) Also there will be influx of inflammatory cells to the site of action & will be organized in a pseudo-lymphoid follicles.
4) RANKL on surface of CD4+ T cells will get detached under the effect of MMPs > activate osteoclasts > resorb subchondral bone > bony erosion

Result:
1) Due to many layers of the synovial membrane the synovial fluid will be blocked from the articular cartilage leading to death of Chondrocytes

2) M1 Macrophages that promotes inflammation will be dominant than the anti-inflammatory M2 macrophages. So, ratio will be high > activating the osteoclasts > Osteoclastogenesis

Question 21

What is the source of Nutritional supply to the articular cartilage?

Answer 21

Synovial Fluid

Question 22

What does pannus lead to?

Answer 22

1) It extends over the articular surface and causes erosion of : Articular cartilage and Subarticular bone
2) Undergoes fibrosis and calcification to cause
fibrous ankylosis which ossifies > bony ankylosis (joint fusion)

Question 23

What cause Joint deformities?

Answer 23

Due to destruction of tendons, ligaments and joint capsule

Question 24

What is the cause of Fatigue, Weight loss, Low-grade fever in RA?

Answer 24

Due to release of IL-1 and TNF from macrophages (in the joint) into circulation

Question 25

What Changes in SKIN of RA patient?

Answer 25

Rheumatoid nodules (most common lesion)

Question 26

What are Rheumatoid nodules & how do they look?

Answer 26

• Fibrinoid necrosis, surrounded by epithelioid/palisading histiocytes, plasma cells and lymphocytes
• Firm, nontender and round to oval

Question 27

Where are Rheumatoid nodule located?

Answer 27

forearm
elbow
lungs
spleen
heart

Question 28

What is an associated condition with RA?

Answer 28

Sjogren’s syndrome

Question 29

What is Sjogren’s syndrome?

Answer 29

Autoimmune destruction of lacrimal and minor salivary glands

Question 30

What are the Clinical findings of Sjogren’s syndrome?

Answer 30

• Keratoconjunctivitis Sicca

- Xerostomia

Question 31

What is RF?

Answer 31

An IgM auto-antibody that targets the Fc portion of IgG

Question 32

State Laboratory Findings in RA

Answer 32

Elevated ESR
Positive rheumatoid factor (70%)
ACPA (high specificity, 97%)

Question 33

What are the radiographic findings in RA?

Answer 33

• Erosions at articular surface
• Narrow joint space
• Fusion of joints (ankylosis)
• Joint deformity

Question 34

Explain Pathogenesis of RA briefly

Answer 34

Autoimmune reaction results in:
1) Activation of CD4+ T cells
2) Release of chemical mediators (IL-1 and TNF)
3) Formation of autoantibodies (RF and ACPA)
These cause joint changes and extraarticular manifestations

Question 35

Detailed Explaination of RA Pathogenesis

Answer 35

1) Injury > Influx of CD4 T cells/macrophages into synovial tissue > Local stimulation of B cells to produce IgM autoantibodies directed against Fc receptor of IgG (RF) and against citrullinated antibodies
2) Formation of immune-complexes that activate the complement system > Production of C5a > Chemotaxis of neutrophils into joint space > Neutrophils produce acute inflammation of synovial tissue causing > Joint injury
3) Phagocytosis of immune-complexes produces Ragocytes > Release of inflammatory mediators by macrophages (IL-1, TNF alpha) > Induce synovial cells to release inflammatory mediators that destroy connective tissue, cartilage and bone > Chronically inflammed synovial tissue begins to proliferate (forms a pannus)
4) Pannus obstructs diffusion of SF to the hyaline cartilage
5) RANK L is released from CD4+ T cells and activate the osteoclasts > Destruction of joint from within, from above and from below
6) Pannus undergo fibrosis > contracture of the joint.
7) Then dystrophic calcification will result in fusion of the joint (ankylosis)