Section 3: Systemic autoimmunity - Rheumatoid Arthritis

Question 1

Rheumatic diseases

Answer 1

-relating to joint inflammation, swelling and pain of muscles, joints and fibrous tissues

Question 2

Rheumatic diseases caused by autoimmunity

Answer 2

1. systematic lupus erythematosus (SLE)
2. Rheumatoid arthritis
3. Juvenile arthritis
4. Sjogren’s syndrome
5. scleroderma (progressive systemic sclerosis)
6. polymyositis
7. Behcet’s disease
8. ankylosing spondylitis
9. Reiter’s syndrome
10. Psoriatic arthritis

Question 3

Rheumatoid arthritis epidemiology

Answer 3

-most common rheumatic disease (1-3% of US pop)
-more common in women to men (3:1)
-onset of symptoms 20-40 years of age

Question 4

Rheumatoid arthritis: Key symptoms

Answer 4

-chronic and episodic inflammation of the joints (synovium-lining of joint)
-chronic pain, loss of function, and disability)

Question 5

Rheumatoid arthritis: pathogenesis

Answer 5

-leukocyte infiltration in affected joints (T-cell, B-cell, lymphoblast, plasma cells, neutrophils and macrophages)
-80% of patients produce rheumatoid factor
-there is a strong association with particular class II of HLA-DR alleles which suggest that T-cells are involved in pathogenesis
-autoreactive T cells: type II collagen, proteoglycans, aggrecan, cartilage, etc..
-yet, T-cell directed therapies have failed while treatments targeting TNF-a and B-cells have been very successful
-complex disease with a definitive cause yet to be determined

Question 6

Rheumatoid factor

Answer 6

-IgM, IgG, and IgA antibodies specific for the fc region of human IgG
-suggest that this disease is driven by B-cells
-but Rheumatoid factor can be found in healthy patients and not all RA suffers produce this antibody (-30% in SLE patients)

Question 7

Rheumatoid arthritis graph

Answer 7

1. unknown trigger sets up initial focus of inflammation in synovial membrane, attracting leukocytes into the tissue
2. autoreactive CD4 T-cells activate macrophages, resulting in production of pro-inflammatory cytokines and sustained inflammation
3. cytokines induce production of MMP and RANK ligands by fibroblasts
4. MMPs attack tissue, activation of bone-destroying osteoclasts, resulting in joint destruction

Question 8

RA treatment

Answer 8

-combination of physiotherapy, anti-inflammatory and immunosuppressive drugs

Question 9

Infliximab

Answer 9

-anti-TNF-a monoclonal antibody (inactivates TNF-a)

Question 10

Rituximab

Answer 10

• anti-CD20 monoclonal antibody (depletes B-cells by antibody dependent cytotoxicity- ADCC)

Question 11

Methotrexate

Answer 11

-inhibits folic acid and metabolism

Question 12

RA diagnosis

Answer 12

-no definitive lab test
-must have a number of associated symptoms (criteria for classification) to be diagnosed
-morning stiffness in and around joints
-swelling or fluid around three or more joints
-at least one swollen area in the hand, wrist, or finger
-arthritis involving the same joint on both sides
-Rheumatoid nodules
-Rheumatoid factor
-X ray changes in joints

Question 13

Classification criteria for RA

Answer 13

> 6 = definite RA compared to chart numbers
-if the score is less than 6, the patient might fulfill the criteria prospectively (over time cumulatively) or retrospectively (if data on all four domains have been adequately recorded in the past)

Question 14

RA testing

Answer 14

Latex agglutination test for RF
-15-20% of RA patients are negative for RF
-RF can be found in a number of other autoimmune disease (SLE and Sjogren’s syndrome) as well as healthy patients)

Question 15

Process of antibody-dependent cytotoxicity

Answer 15

-add an anti-CD 20 to our B cells or a patient which binds to its B cells. You tag it to be bound by fc receptors. This allows NK cells (innate cytotoxic lymphocytes) to come in and bind and then kill B cells. Removing patients B-cells in vivo will help reduce symptoms