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Pathophysiology 2 > Feb 27 - Rheumatoid Arthritis > Flashcards

Feb 27 - Rheumatoid Arthritis Flashcards

1
Q

What is Rheumatoid Arthritis (RA)?

A

A chronic inflammatory disease with possible periods of remission
It symmetrically affects peripheral joints
It is immune system-mediated
It is a systemic disease, potentially affecting the eyes, lungs, heart, nervous system, spleen and lymph system and blood cells

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2
Q

When is RA onset?

A

Because it’s an immune response, it typically starts earlier in life (between the ages 25 and 50)

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3
Q

Is RA hereditary?

A

There is likely a genetic component for the development of RA, but it is not hereditary

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4
Q

Does RA affect mortality?

A

Mortality is 30% higher due to the systemic effects (heart, lungs and eyes) than in the general population with the same age and sex

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5
Q

The exact cause(s) of RA is unknown but it is known to involve what?

A

Genetics (non-modifiable)
Smoking (modifiable)
Infection (inconclusive)
Autoimmunity

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6
Q

How is genetics involved with RA?

A

It may predispose an individual as a result of environmental triggers. Twin concordance is 15-35%, therefore external factors are also likely involved

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7
Q

How is infection involved with RA?

A

An infection may activate inflammatory pathways that “prime” the development of RA

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8
Q

How is autoimmunity involved with RA?

A

Antigen-driven auto-antibodies - rheumatoid factor (RF) is an antibody detected in the blood of 80% of adults with RA. Anti-cyclic citrullinated peptide (anti-CCP) is an important surrogate marker for the diagnosis and prognosis of RA. It is as sensitive but more specific than RF. Anti-CCP is important in early detection even prior to RA

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9
Q

Besides RF and anti-CCP, what are other tests that can be used to diagnose RA?

A

Antinuclear antibody (ANA) is a general test used to evaluate a person for autoimmune disorders such as lupus, MS, Sjorgren’s syndrome (affects mucous membranes to cause dry eyes and dry mouth) and RA. Erythrocyte sedimentation rate (ESR) reflects the degree of inflammation in the body. C Reactive Protein (CRP) also denotes inflammation but it is a better indication of the amount of inflammation in the body compared to ESR levels

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10
Q

What is the synovial membrane?

A

A thin layer of connective tissue (1-3 cell layers thick) between the joint capsule and the synovial cavity

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11
Q

What is synovial fluid?

A

An ultra-filtrate of blood that diffuses across the synovial membrane and into the joint cavity

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12
Q

What composes the synovial fluid?

A

It is composed of hyaluronan (regulates cartilage viscosity) and lubrican (lubricates surface of cartilage)

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13
Q

What are cells responsible for the production of synovial fluid?

A

Fibroblast-like synoviocytes

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14
Q

Describe the normal synovial membrane

A

Normal synovial membrane is composed of a thin cellular lining (one to three cell layers thick) and an underlying interstitium, which contains blood vessels but few cells

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15
Q

What is fibronectin?

A

General cell adhesion molecule; it acts like “glue” to hold collagen cells together that make up the cartilage

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16
Q

What are hallmark characteristics of RA?

A 
Pannus formation (growth of fibrous tissue in the joint) causes loss of bone and erodes cartilage
Synovial fluid houses activated inflammatory immune system activated cells (there are all the mediators of infection but there is no infection)
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17
Q

What are the immune system activated cells present in RA?

A

Fibroblast-like synoviocytes
Macrophage-like synoviocytes
Macrophages (phagocytic cells)
T cells (part of cellular immunity; drive cytokines, interleukins, interferons, etc.)
B cells (part of humoral immunity; B cells differentiate into plasma cells, which produce antibodies)

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18
Q

How do the mediators of inflammation enter the joint?

A

Via the ultra-filtrate of the blood that diffuses from the synovial membrane and into the joint cavity (blood vessels supply the synovial membrane)

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19
Q

Describe the pathogenesis of the inflammatory immune system response that leads to RA

A

A foreign antigen (a protein, which resembles proteins that make up the collagen in the bone) is picked up by an antigen-presenting cell (APC). The APC presents the antigen to the T cells. This activates the T cells, which activate mediators of inflammation (cytokines, interleukins, etc.; cellular immunity). These mediators of inflammation activate B cells to differentiate into plasma cells, which production of antibodies against tissue in joints (RF, anti-CCP, ANA, ESR, CRP)

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20
Q

What do the antibodies of RA do?

A

They eat away the collagen

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21
Q

What are osteoclasts? How do they become involved in RA?

A

Osteoclasts are responsible for bone resorption - breaking down of bone. Osteoclast formation is stimulated by the immune response (the mediators of inflammation)

22
Q

How are fibroblasts involved in RA?

A

Fibroblast formation is stimulated by the immune system. This causes pannus formation leading to the loss of cartilage and bone, activation for matrix metalloproteinases (degrade bone matrix) and the production of pro-inflammatory cytokines (tumor necrosis factor alpha, interferon gamma and IL-6)

23
Q

How many T cells are found in the RA synovium?

A

T cells make up 30-50% of lymphocytes in the RA synovium

24
Q

The activation of T cells by some unknown auto-antigen leads specifically to what?

A

Production of cytokines, prostaglandins, cytotoxines
The release of inflammatory cytokines, matrix metalloproteinases (degrade bone), osteoclasts (break down bone), and B cells lead to antibodies that are involved in the phagocytosis of bone cartilage

25
Q

What are some examples of pro-inflammatory cytokines? Anti-inflammatory cytokines? How are these cytokines involved in RA?

A

Pro-inflammatory: TNF-alpha, IL-1, IL-6, IL-7
Anti-inflammatory: Il-4, IL-10
In RA, IL-6 is the most abundant cytokine in the synovium. It stimulates the synthesis of acute-phase reactants from the liver osteoclasts, T-lymphocytes and B lymphocytes. Serum IL-6 positively correlates with increased disease activity and it is also involved in causing anemia of chronic disease

26
Q

How do B cells affect RA?

A

B cells are thought to affect RA in 3 ways:

  1. Production of auto-antibodies (RF, anti-CCP, ANA)
  2. Stimulation of cytotoxins and free radical release
  3. Activation of T cells
27
Q

Explain how B cells affect RA via the production of auto-antibodies, and the stimulation of cytotoxins and free radical release

A

Antibodies are involved in the phagocytosis of the cartilage and bone creating more inflammation of the joints. Cytotoxins and free radical release damage synovium and bone.

28
Q

Explain how B cells affect RA via the activation of T cells

A

There is a positive feedback loop between the humoral and cellular immune response. Activation of T cells by B cells in turn promotes the release of pro-inflammatory cytokines (IL-1, IL-6, TNF-alpha)

29
Q

Describe the clinical presentation of patients with RA

A

Symptoms usually develop and progress over months. RA usually begins early
Often pain or stiffness begins in 1 or 2 joints; usually progresses to poly-articular presentation (5+ joints)
Hot, swollen joints
Pain persists for over an hour upon waking; often lasts all day
May have systemic complaints: fatigue, weakness, low-grade fever, loss of appetite, and depression (can precede articular symptoms)
Symptoms can vary day-to-day

30
Q

What are the criteria for the diagnosis of RA?

A

Must present with 4 or more of the following for over 6 weeks (time is critical):

  • morning stiffness in and around the joints lasting over an hour
  • soft tissue swelling of 3 or more joints observed by an MD
  • symmetric presentation
  • subcutaneous nodules
  • positive for RF and/or anti-CCP
  • radiologic evidence
31
Q

What are the areas (joints) affected in RA?

A 
Proximal interphalangeal joints (very common)
Metacarpophalangeal joints (very common)
Wrists (common)
Elbows (common)
Knees (common)
Ankle (very common)
Metatarsophalangeal joints (very common)
32
Q

What are some of the clinical characteristics of RA?

A

The joints affected most frequently by RA are the small joints of the hands, wrists and feet
Elbows, shoulders, hips, knees, and ankles may be involved
Joint stiffness is typically worse in the morning
Duration of stiffness tends to be correlated directly with disease activity, usually exceeds 30 minutes, and may persist all day
Chronic inflammation with lack of an adequate exercise program results in loss of range of motion, atrophy of muscles, weakness, and deformity

33
Q

What are some of the laboratory tests used for the diagnosis of RA?

A

Rheumatoid factor
Antic-cyclic citrullinated peptide (anti-CCP)
Elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)
Antinuclear activity (ANA)
Iron (Fe): absorption correlated inversely with ESR and CRP resulting in normocytic normochromic anemia
Blood platelets: thrombocytosis common in RA resulting in too many platelets, resulting in an elevated risk of blood clots and CV events

34
Q

What is CCP? Why is anti-CCP important?

A

Citrullination (i.e., deamination) of arginine residues
Normal process for skin formation and other physiological functions
During inflammation results in the production of antigenic epitope
Antibodies to citrullinated proteins (anti-CCP) become elevated, and can be used as the most sensitive and specific test for RA
May be detected up to 15 years before onset of clincial symptoms of RA

35
Q

Besides laboratory tests (anti-CCP, RF, ESR, ANA, etc.), what are other tests used for the diagnosis of RA?

A

Joint fluid aspiration may show increased white blood cell counts without infection crystals
Joint radiographs may show peri-articular osteoporosis, joint space narrowing, or erosions

36
Q

What are the systemic effects of RA?

A 
Rheumatoid nodules
Cardiopulmonary disease
Eye diseases
Sjogren's syndrome (dry eyes and dry mouth)
Rheumatoid vasculitis
37
Q

RA can cause rheumatoid nodules. Elaborate.

A

20% of cases
Extensor surface of the arm
Can also affect the lungs, heart or sclera of the eyes
Fibrous cells surround necrotic tissue centre
Often painless

38
Q

RA can cause cardiopulmonary disease. Elaborate.

A

Can cause pericarditis (inflammation of the lining of the heart)
Can cause atherosclerosis (leading cause of death in RA) - may be causes by chronic inflammation

39
Q

RA can cause eye diseases. Elaborate.

A

Reduced tear production can result in chronic eye irritation (episcleritis)
In severe cases, can lead to corneal ulceration (which can lead to blindness)

40
Q

RA can cause Sojgren’s syndrome. Elaborate.

A

10-15% of all RA patients will develop Sjogren’s syndrome
Affects exocrine gland function (chronic xerostomia (bad breath due to dry mouth), keratoconjunctivitis sicca (dry eyes))
Plus dental complications and eye damage

41
Q

RA can cause rheumatoid vasculitis. Elaborate.

A

Commonly seen as digital nail bed infarcts

Usually after long-standing disease

42
Q

Describe the clinical course of RA

A

The majority of patients (75-80%) have cyclic-type of disease course (flares followed by periods of remission/control)
10% have mild disease which is stable and easily controlled
15% have severe/aggressive disease which responds poorly to treatments and leads to significant morbidity/premature mortality

43
Q

What are some non-pharmacological treatment options for RA?

A

Rest
-important component of treatment plan
-fatigue is a major factor in RA
-also reduces pain (but must avoid excessive rest as it makes RA worse)
Occupation/physical therapy
Assistive devices (canes, walkers, splints, etc.)
Weight loss (reduce joint stress)
Surgery (for severe diseases; tendon repair, joint replacements)

44
Q

What are the major pharmacological treatment classes

A

NSAIDs
Corticosteroids (i.e. prednisone)
Disease-modifying anti-rheumatic drugs (DMARDs)

45
Q

What is the role of NSAIDs in RA?

A

For analgesia and inflammation (decrease prostaglandin synthesis); rarely used as monotherapy - no effect on disease progression

46
Q

What is the role of corticosteroids in RA?

A

They decrease inflammation and immunosuppression

47
Q

What can the overuse of corticosteroids cause?

A

The overuse cause the depletion of calcium in the bones (calcium resporption) - the bones become very brittle

48
Q

What can the overuse of NSAIDs cause?

A

NSAIDs can aggrevate the stomach and can aggrevate asthma symptoms

49
Q

What is the role of DMARDs in RA?

A

These agents modify the course of disease and improve prognosis
They include non-biologic and biologic agents
They suppress cellular and humoral immune system responses

50
Q

Describe the DMARD treatment guidelines

A

All individuals with early RA (<6 months) should start DMARD
Early treatment reduces mortality and long-term complications of RA
Should start with non-biologic agents (e.g., NSAIDs, steroids, methotrexate, leflunomide, sulfasalazine, hydroxychloroquine)
Biologics indicated when poor disease response to non-biological DMARDs or advanced progression of RA

51
Q

How do biologics work?

A

All biologics work by one of 3 mechanisms:
1. Interfere with cytokine function
2. Inhibit the “second signal” or “co-stimulation” required for T cell activation
3. Depleted B cells (reduce self-antibodies)
They are relatively well-tolerated - caution with immunosuppression and opportunistic infections
Increased risk of infection and tuberculosis (TB skin test for all)

Pathophysiology 2 (15 decks)

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