RA Pathophysiology - Postlethwaite/Gupta Flashcards by Jacob McMillan

RA defined as? Hit me with them buzzwords

Chronic systemic autoimmune disease most associated with joint inflammation

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

peripheral joints in a symmetrical distribution

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Epidemiology of RA:

Geographic Distribution?

Age range?

Prevalence in North America?

Prevalence/Age relationship?

Genetic role?

Sex?

Lifespan?

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

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RA only affects joints, right?

No, multi system means multi system, not just joints

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

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

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

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.

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

Rheumatoid factors = antibodies directed against the Fc portion of IgG

Usually IgM type, IgG and IgA have been described

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What 2 other antibodies are associated with RA?

Anti-CCP antibody, Antinuclear antibodies (ANA)

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

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

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

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

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

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

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

Low levels of cytokines

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

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Regulatory T cell and its relationship with RA?

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

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

Macrophage and fibroblast cytokines

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

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).

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

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

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Does RA cause destruction of the bone?

Yes

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

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.

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

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

NSAIDs are great at attacking this

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

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

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

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

Does RA migrate to other joints?

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

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

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

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

Swelling, warmth, and erythema around joint

Synovial fluid of RA will have what 3 features

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

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

Symmetrical wrist and proximal hand joint involvement

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

No DIP involvement No lumbar spine involvement

What joint in the head is involved in RA?

temporomandibular joint

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

- 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)

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

Wrist: Volar subluxation with radial ward rotation MCP joints: Ulnar deviation PIP and DIP joints: Swan neck and Boutonniere deformities

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

Skin, eyes, mouth, CV, Lungs, Neurologic

What skin probs are seen in RA?

- Rheumatoid nodules - Vasculitis

What eye/mouth probs are see in RA?

- Keratoconjunctivitis sicca - "dry eyes" - Xerostomia - "dry mouth" - Episcleritis and scleritis

What lung probs are seen in RA? Which is "HUGEEEE"

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

What cardiac probs are seen in RA?

- Pericarditis (common but largely asymptomatic) - Valve nodules

What neurologic probs are seen in RA?

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

Immune complexes of RA manifest as chronic \_\_\_\_?

polyarticular arthritis

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

Acute stage - Neutrophils + mononuclear cells Chronic - mononuclear cells (plasma cells and lymphocytes)

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

Acute stage. I just said this.

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

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

Path. Describe synovial villi.

Hyperplastic synovial villi eroding and replacing cartilage at the joint margin

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

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

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

Fibrin deposition and fibrinoid change Necrosis can be present as well.

Path. What is a pannus?

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

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

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

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

Rheumatoid nodules (found in 25% of RA patients) Skin usually over bony prominence, like the elbow

Path. Histologically describe a rheumatoid nodule?

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

Triad seen in Felty's Syndrome?

RA Palpable Splenomegaly Manifestations of hypersplenism (such as leukopenia)

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

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