RA Pathophysiology - Postlethwaite/Gupta

Question 1

RA defined as? Hit me with them buzzwords

Answer 1

Chronic systemic autoimmune disease most associated with joint inflammation

Question 2

Joints commonly involved in RA? distribution of these joint involvement?

Answer 2

peripheral joints in a symmetrical distribution

Question 3

Epidemiology of RA:

Geographic Distribution?

Age range?

Prevalence in North America?

Prevalence/Age relationship?

Genetic role?

Sex?

Lifespan?

Answer 3

Mr. Worldwide distribution

30-50 years old

1% Prevalence in NA

Prevalence increases with age

Genetic predisposition and familial aggregation confirmed

Women 3x more common than men

Increased mortality, Women - decreases lifespan by 10 years, Men - by 4 years

Question 4

RA only affects joints, right?

Answer 4

No, multi system means multi system, not just joints

Question 5

What genetic marker is RA MOST associated with? What other genetic polymorphism is associated with RA?

Answer 5

• HLA-DR4 (aka HLA-DRB1) - 30% genetic risk
• PTPN22 - 5% genetic risk

Question 6

Describe the role of HLA-DR4 in the pathogenesis of RA?

Answer 6

Antigen presenting cells have HLA-DR4 on them. They will present Type II collagen (the antigen in this case) to auto reactive T cells. As a result, these auto reactive T cells attack the body’s own collagen.

Question 7

What are rheumatoid factors? In RA, what is the most common rheumatoid factor?

Answer 7

Rheumatoid factors = antibodies directed against the Fc portion of IgG

Usually IgM type, IgG and IgA have been described

Question 8

What 2 other antibodies are associated with RA?

Answer 8

Anti-CCP antibody, Antinuclear antibodies (ANA)

Question 9

Describe the relationship b/t evidence of autoimmunity and RA?

Answer 9

Evidence of autoimmunity can be present in RA many years before the onset of clinical arthritis

Question 10

In RA, autoantibodies can recognize what 2 types of antigens? (vague question)

Answer 10

Autoantibodies can recognize JOINT antigens, such as type II collagen, or SYSTEMIC antigens, such as glucose phosphate isomerase

Question 11

Complement involvement in inflammation seen in RA? What complements are involved

Answer 11

• Autoantibodies (such as RF) + IgG = immune complexes (IC).
• IC activate complement system, producing C3a and C5a, pulls neutrophils & leukocytes into the joint space, leading to inflammation.
• Rheumatic joint will also have decreased CH50, C3, and C4

Question 12

Low or high levels of T cell cytokines are present in RA synovium? What T cell cytokines are present? Whats their role?

Answer 12

Low levels of cytokines

IFN-gamma and IL-17 are produced, can activate macrophages within the synovium

Question 13

Regulatory T cell and its relationship with RA?

Answer 13

Low levels of regulatory T cells (FOXP3, CD24) in RA synovium, not enough to down regulate T cell cytokines.

Question 14

What cells/cytokines are abundant in the RA synovium? (vague question…i know)

Answer 14

Macrophage and fibroblast cytokines

Question 15

What cytokines are associated with macrophages and fibroblasts? Whats their role

Answer 15

IL-1, TNFalpha, IL-6, & IL-8 are the big ones.

Others include IL-15, IL-18, GM-CSF, and IL-33.

These cytokines recruit inflammatory cells into the synovial joint, causing further inflammation and pannus formation (that eats into cartilage).

Question 16

What 2 anti-inflammatory cytokines are associated with RA? Are they effective?

Answer 16

IL-1 receptor antagonists & IL-10 are produced in rheumatoid synovium; however, too few to suppress pro inflammatory cytokines.

Question 17

Does RA cause destruction of the bone?

Answer 17

Yes

Question 18

Walk me through how RA starts to destroy bone as well.

Answer 18

• Following the cytokine storm (IL-1, IL-6, IL-8, TNF-alpha), pannus formation starts in the periphery of synovium
• Pannus eventually starts eating into cartilage (chondrocytes)
• Osteoclasts get stimulated, causing bone resorption
• Fibroblasts and macrophages produce MMPS that further erode bone.

Question 19

What prostaglandin is seen in RA synovial fluid during inflammation? Role?

Answer 19

PGE2 and leukotrienes too. cause vasodilatation and pain of joint.

NSAIDs are great at attacking this

Question 20

Anti CCPs produced by what cells? What are they predictive of in RA?

Answer 20

• Produced by synovial tissue B cells (can be detected in synovial fluid)
• Predictors of more aggressive RA marked by bone and cartilage destruction

Question 21

What are some systemic features of RA? What is a fact you should know about all these features?

Answer 21

Fatigue, anorexia, weight loss, weakness, generalized aching and stiffness, low grade fever

• can appear before disease has been diagnosed, and are commonly worse with disease flares

Question 22

Does RA migrate to other joints?

Answer 22

No, usually involves a joint (symmetrically) and stays there

Question 23

Features of morning stiffness (…of the joint) in RA?

Answer 23

Lasts AT LEAST 30 minutes, and may persist for several hours

As compared to OA that would only last for AT MOST 20-30 minutes

Question 24

Since this is a inflammatory disease, what superficial skin findings would you observe around an RA joint? (Cant spoon feed this one any better)

Answer 24

Swelling, warmth, and erythema around joint

Question 25

Synovial fluid of RA will have what 3 features

Answer 25

• exudative yellow fluid
• Increased # WBCs
• Decreased viscosity (b/c hyaluronic acid is destroyed)

Question 26

Joint involvement: Symmetrical or asymmetrical? Most characteristic pattern of joint involvement?

Answer 26

Symmetrical

wrist and proximal hand joint involvement

Question 27

What joint(s) are not involved in RA (distinguishing it from OA)

Answer 27

No DIP involvement

No lumbar spine involvement

Question 28

What joint in the head is involved in RA?

Answer 28

temporomandibular joint

Question 29

RA patient starts complaining of neck pain. Why? Is this an early or later stage of RA? Risks associated?

Answer 29

• Cervical spine involved. C1 “slips” relative to C2.
• Damage usually occurs after several years of disease
• Risk of spinal cord compression (sensory loss to sudden death)

Question 30

4 hand deformities associated in RA? Name them and what bones associated with.

Answer 30

Wrist: Volar subluxation with radial ward rotation

MCP joints: Ulnar deviation

PIP and DIP joints: Swan neck and Boutonniere deformities

Question 31

List common sites of extra-articular involvement seen with RA?

Answer 31

Skin, eyes, mouth, CV, Lungs, Neurologic

Question 32

What skin probs are seen in RA?

Answer 32

• Rheumatoid nodules
• Vasculitis

Question 33

What eye/mouth probs are see in RA?

Answer 33

• Keratoconjunctivitis sicca - “dry eyes”
• Xerostomia - “dry mouth”
• Episcleritis and scleritis

Question 34

What lung probs are seen in RA? Which is “HUGEEEE”

Answer 34

• Interstitial fibrosis
• Pulmonary nodules
• Pleuritis with Pleural Effusion (Mr. Monotone said these are HUGEEEE)

Question 35

What cardiac probs are seen in RA?

Answer 35

• Pericarditis (common but largely asymptomatic)
• Valve nodules

Question 36

What neurologic probs are seen in RA?

Answer 36

• Cervical myelopathy
• Compressive peripheral neuropathy (carpal tunnel, ulnar tunnel)

Question 37

Immune complexes of RA manifest as chronic ____?

Answer 37

polyarticular arthritis

Question 38

Path question. Except for the acute stage, what cells are not generally present in RA? What cells are?

Answer 38

Acute stage - Neutrophils + mononuclear cells

Chronic - mononuclear cells (plasma cells and lymphocytes)

Question 39

If you see neutrophils, what stage of RA are you in?

Answer 39

Acute stage. I just said this.

Question 40

Path. Earliest changes of RA include? Proliferation of what cells?

Answer 40

hyperemia of synovium with proliferation of synovial lining cells with infiltration by plasma cells and lymphocytes

Question 41

Path. Describe synovial villi.

Answer 41

Hyperplastic synovial villi eroding and replacing cartilage at the joint margin

Question 42

Path. Following synovial villi hypertrophy, what characteristic cells develop (think similar to lymph nodes)

Answer 42

• Multinucleated giant cells underlying the synovial lining begin to develop
• Eventual formation of germinal centers

Question 43

Path. In synovium, after multinucleated cells/germinal centers develop, what gets deposited?

Answer 43

Fibrin deposition and fibrinoid change

Necrosis can be present as well.

Question 44

Path. What is a pannus?

Answer 44

Pannus occurs when synovial inflammatory and granulation tissue adjacent to the margin of the joint begins to cover and adhere to the cartilage as a membrane

• The articular cartilage under the pannus undergoes degradation and disappears, beginning at the joint margin and extending centrally

Question 45

What characteristic feature regarding joint mobility is different between OA and RA?

Answer 45

Fibrous ankylosis (fusion) of the joint occurs in RA (after pannus formation and destruction by MMPs/osteoclasts,etc)

OA - is NOT associated with ankylosis of the joint

Question 46

Path. Most common extra-articular manifestation of RA? What organ? Where in the organ?

Answer 46

Rheumatoid nodules (found in 25% of RA patients)

Skin

usually over bony prominence, like the elbow

Question 47

Path. Histologically describe a rheumatoid nodule?

Answer 47

Granulomatous lesion consisting of:

• a central zone of collagen necrosis and fibrinoid change
• Middle zone of epitheliod cells and macrophages
• Outer zone of granulation tissue infiltrated by lymphocytes, plasma cells and macrophages

Question 48

Triad seen in Felty’s Syndrome?

Answer 48

RA

Palpable Splenomegaly

Manifestations of hypersplenism (such as leukopenia)

Question 49

Fun fact. Splenomegaly and its relation to a blood component?

Answer 49

Platelets will get sequestered in the spleen. Large ass spleen = platelets in between