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Pathophysiology Final > Rheumatoid Arthritis > Flashcards

Rheumatoid Arthritis Flashcards

1
Q

What is Rheumatoid Arthritis?

A
  • chronic inflammatory disease with possible periods of remission
  • symmetrically affects peripheral joints
  • immune system-mediated -> AUTOIMMUNE DISEASE
  • systemic disease -> there are often co-morbidities with it
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2
Q

What other co-morbidities can occur with Rheumatoid Arthritis?

A
  • can potentially affect the eyes, lungs, heart, NS, spleen, lymph system and blood cells
  • ie if feet are on “fire” might not want to exercise, become overweight therefore more at risk for HTN or heart failure or COPD…
  • why it is always important to ask about all other symptoms too (secondary complications)
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3
Q

Autoimmune Disease

A

body’s immune system attacks and destroys healthy body tissue by mistake:
cellular immunity- tcells
humoral immunity- antibodies
these act in positive feedback together

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4
Q

Signs of Rheumatoid Arthritis

A
  • early onset- swelling around the knuckles
  • inflammation of the episclera (protective lining covering sclera or “white” of eye)
  • RA nodules
  • RA joint swelling
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5
Q

Epidemiology of RA

A
  • 1 in 100
  • can occur as any age (most prevalent= 25-50)
  • female to male is 3:1
  • global variation in prevalence (likely genetic driven)
  • prevalence is growing (our society is obese as a whole which adds to the diagram)
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6
Q

Mortality of RA

A
  • mortality is 30% higher than in the general population with the same age and sex
  • if you have RA you have a 30% higher risk of dying than someone who doesn’t
  • risk increases as you age (more immobile, more prone to more diseases)
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7
Q

Etiology of RA

A
  • the exact cause(s) is unknown but it is know to involve:
    1) Genetics (non-modifiable) - twin condordance 15-35% therefore external factors also likely involved; may predispose an indiv as a result of an enviro triggers
    2) Smoking (known modifiable risk factor)
    3) Infection (inconclusive)- may activate inflammatory pathways that “prime” the development of RA; driving risk factor b/c it drives the IS (i.e. a bacterial or viral infection- Epstein Barr Virus)
    4) Autoimmunity
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8
Q

Explain how autoimmunity is involved in the etiology in RA.

A

-Ag-driven Ab’s [RF is an Ab detected in blood of 80% of adults with RF; anti-CCP - as sensitive of RF and more specific]
-ANA is a general test used to evaluate a person for autoimmune disorders such as lupus, MS, Sjogren’s syndrome, and RA
ESR reflects degree of inflammation in the body
-CRP also denotes inflammation but is a better indication of the amount of inflammation in the body than ESR
*first 2 are specific to RA, other 3 are general (if RA isn’t known yet, you can use the general test first and then go into specifics if you suspect RA)

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9
Q

Synovial Joint

A
  • joins bones with a fibrous joint capsule that is continuous with the periosteum of the joined bones, constitutes the outer boundary of a synovial cavity, and surrounds the bones’ articulating surfaces
  • the synovial cavity is filled with synovial fluid
  • joint capsule is made up of an outer layer, the articular capsule, which keeps the bones together structurally, and an inner layer, the synovial membrane, which seals in the synovial fluid
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10
Q

Normal Synovial Membrane

A

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

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11
Q

Normal Synovial Fluid

A
  • an ultra-filtrate of blood that diffuses across the synovial membrane and into the joint cavity
  • composed of hyaluronan and lubrican
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12
Q

What does hyaluronan do in the normal synovial membrane?

A

regulates cartilage viscosity

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13
Q

What does lubrican do in the normal synovial membrane?

A

lubricates surface of cartilage

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14
Q

What does fibronectin do in the normal joint?

A
  • it is a general cell adhesion molecule

- acts like “glue to hold collagen cells together (like the cross-meshing that gives it the strength)

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15
Q

What do synoviocytes do in a normal joint?

A
  • they are fibroblast-like
  • are located on the inner surface of the capsule
  • produce synovial fluid
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16
Q

RA Synovial Membrane

A
  • the synovium has a greatly expanded expanded lining layer (8-10 cells thick) composed of activated cells and a highly inflammatory interstitial (Bcells, Tcells, macrophages, and vascular changes (thrombosis and neovascularization)
  • pannus formation causes loss of bone and erosion of cartilage (hallmark characteristic of RA)
  • the synovial fluid houses the activated inflammatory IS activated cells
  • destruction of synoviocytes leads to the bone on bone
  • key pathologic hallmarks seen peripherally in joint spaces in RA
  • *in RA, self/non-self confusion results in destruction of synovial tissue
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17
Q

pannus

A
  • thickened cellular membrane of fibrovascular tissue that invades the underlying cartilage bone
  • at sites where synovium and cartilage are contiguous, RA synovial tissue (AKA PANNUS) invades and destroys adjacent cartilage and bone
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18
Q

Inflammation of the Synovium

A
  • your immune system attacks your synovium (lining of membranes that surrounds your joints)
  • immune system activated cells
    a) fibroblast-like synoviocytes
    b) macrophage-like synoviocytes
    c) macrophages
    d) t and b cells
  • mediators of inflammation enter the joint via the ultra-filtrate of blood that diffuses across the synovial membrane and into the joint cavity (blood vessels supply the synovial membrane)
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19
Q

Neutrophils

A
  • recruited to the rheumatoid cavity
  • in an activated state, releasing free radicals that damage hyaluronic acid and inactivate endogenous inhibitors of proteases, thus promoting damage to the joint
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20
Q

Osteoclasts

A
  • responsible for bone resorption
  • bone resoprtion= breaking down of the bone
  • their formation is stimulated by the immune response
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21
Q

Fibroblast

A
  • formation is stimulated by the IS, causes:
    a) pannus formation leading to loss of cartilage and bone
    b) matrix metalloproteinases –> degrade bone matrix
    c) pro-inflammatory cytokines (tumor necrosis factor alpha, interferon gamma, and interleukin 6)
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22
Q

Pathogenesis of the Inflammatory Response

A

(see slide 13)

  • mechanism involves both humeral and cellular immunity
  • the processed antigen is recognized by major histocompatibility complex proteins on the lymphocyte –> activates it to stimulate the production of T and B cells
  • APCs present Ag to Tcell to activate the Tcell, cause its proliferation, and secretion of cytokines (IL-17)
  • activated Bcells produce plasma cells which produce self-ag’s (RF and ACPA)
  • macrophages are responsible for the major damage to bone/synovium (major producers of pro-inflammatory cytokines)
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23
Q

Tcells and RA

A
  • Tcells make up 30-50% of lymphocytes in the RA synovium
  • activation by some auto-antigen leads to:
    a) production of prostaglandins, cytotoxins, and cytokines
    b) release of inflammatory cytokines, matrix metalloproteinases, osteoclasts, and Bcells
  • this activation requires 2 steps:
    1) presentation of an APC to the Tcell receptor
    2) CD28 (on T cell) binds to CD80/CD86 (on APC) - “co-stim” (CD28 acts as on switch)
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24
Q

Cytokine balance

A 
Pro-inflammatory cytokines:
 a) TNF
 b) IL-1
 c) IL-6
d) IL-7
Anti-inflammatory cytokines:
 a) IL-4
 b) IL-10
-during RA, pro-inflammatory cytokines are released (balance shifts to excess of pro, which leads to clinically evident inflammation)
25
Q

What cytokine is most important during RA?

A

IL-6

  • most abundant cytokine in the synovium
  • stimulates the synthesis of acute-phase reactants from the liver, osteoclasts, T and B lymphocytes
  • IL-6 positively correlates with increased disease activity
  • IL-6 also involved in causing anemia of chronic disease
26
Q

Bcells and RA

A

affect RA in 3 ways:

1) produce auto-Ab’s (RF, anti-CCP, ANA)
2) Stimulate cytotoxin and free radical release (damages synovium and bone -> Ab’s involved in the phagocytosis of the cartilage and bone creating more inflammation of the joints)
3) Activate T cells (positive feedback loop between humeral and cellular immune responses) which in turn promotes release of pro-inflammatory cytokines

27
Q

Clinical presentation of RA

A
  • symptoms usually develop and progress over months
  • symmetrical disease (both sides of joint)
  • often pain/stiffness begins in 1 or 2 joints; progresses to poly-acicular presentation (5+) —Hot Swollen Joints
  • pain persists for over 1 hour upon waking (often all day)
  • may have systemic complaints (fatigue, weak, low-grade fever) that can precede articular symptoms
  • symptoms can very day-to-day
28
Q

Rheumatology Classification Criteria

A

Need 4 or more of the following for over 6 weeks:
1) morning stiffness in and around joints (hour or more)
2) soft tissue swelling of 3 or more joints
3) symmetric presentation
4) subcutaneous nodules
5) positive for RF and/or anti-CPP
6) radiologic evidence
(criticized for lack of sensitivity in early disease)

  • -there is also a point scale to diagnose RA:
    1) Joint (number or joints affects, their size)
    2) Serology (negative or positive tests, i.e. RF, anti-CCP)
    3) Acute-phase reactants (normal or abnormal CRP or ESR)
    4) Duration (under 6 weeks in 0, over 6 weeks is 1)
  • it is defined as definite RA if they have a score of 6 or over (slide 20)
29
Q

Joints Affected by RA

A

-the joints affected most frequently by RA are the small joints of the hands (PIP, MCP), wrists and feet
-in addition, elbows, shoulders, hips, knees, ankles, and MTP may be involved (usually later on)
(skeleton on slide 21)

30
Q

Clinical Characteristics of RA

A
  • most frequently: hands, wrists, feet
  • maybe: elbows, shoulders, hips, knees, ankles (later on)
  • stiffness worse in morning
  • duration of stiffness is correlated directly with disease activity, usually excess 30 mins and me persist all day (this is a major diff from OA)
  • chronic inflammation with lack of an adequate exercise program results in loss of range of motion, atrophy or muscles, weakness, and deformity
31
Q

Lab Tests

A

1) Rheumatoid factor (RF)
2) Anti-cyclic citrullinated peptide (anti-ACC)
3) Erythrocyte Sedimentation Rate (ESR)
4) C-reactive protein (CRP)
5) Antinuclear Antibody (ANA)
6) Iron
7) Blood platelets

32
Q

RF test

A
  • RF is detectable in 60-70%
  • is specific to RA (although can be found in other conditions)
  • if (+), prognosis is worse for severity of inflammation and rate of joint destruction
33
Q

anti-CCP test

A
  • # 1 pre-diagnostic test (may be detected up to 15 years before onset of clinical symptoms of RA); most sensitive and specific test for RA
  • these antibodies have similar sensitivity to RF (50-85%) but are more specific (90-95%) and are present earlier in the disease
  • (+) test also leads to worse prognosis for severity of inflammation and rate of joint destruction
  • citullination (ie deamination) of arginine residues is a normal process for skin formation and other physiological functions
  • during inflammation, production of antigenic epitope therefore Ab’s to citrullinated proteins (anti-CCP) elevated
34
Q

ESR and CRP tests

A
  • elevated ESR and CRP are markers for the degree of inflammation
  • CRP is better
35
Q

ANA test

A

general marker for inflammation and autoimmune disorders

36
Q

Iron test

A
  • absorption correlated inversely with ESR and CRP resulting in normocytic normochromic anemia
  • this means is ESR and CRP are high, Fe will be low therefore low iron can be another diagnostic test
37
Q

blood platelet test

A
  • thrombocytosis is common in RA
  • too many platelets -> risk of blood clots and CDV events
  • with too many platelets, they become sticky and form a clot
  • ppl with RA prone to developing pulmonary embolisms
38
Q

Other diagnostic tests

A
  • joint fluid aspiration may show increased WBC counts w/o infection, crystals
  • joint radiographs may show peri-articular osteoporosis, joint space narrowing, or erosions
  • *DO BLOOD TESTS FIRST**
  • can also do radiologic (show bony changes, but its not useful in early disease as it doesn’t display soft tissue change) or aspiration (analysis of oedematous fluid useful for exclusion)
39
Q

extra-articular involvement

aka systemic effects of RA

A

1) Rheuatoid Nodules
2) Cardiopulmonary Diseases
3) Eye Diseases
4) Sjogren’s Syndrome
5) Rheumatoid Vasculitis

40
Q

Explain the systemic effects of RA on Rheumatoid Nodules

A
  • 20% of cases
  • extensor surface of arm
  • can also affect lungs, heart, or sclera of eyes
  • fibrous cells surround nerotic tissue centre
  • often painless
  • commonly found on pressure points
41
Q

Explain the systemic effects of RA on Cardiopulmonary Diseases

A

1) Pericarditis
2) Atherosclerosis
- may be caused by chronic inflammation
- leading cause of death in RA

42
Q

Explain the systemic effects of RA on Eye Diseases

A

1) Reduced tear production can result in chronic eye irritation (episcleritis)
2) In severe cases corneal ulceration

43
Q

Explain the systemic effects of RA on Sjogren’s Syndrome

A
  • dry eyes and dry mouth
  • 10-15% of all RA will develop
  • affects exocrine gland function:
    • chronic xerostomia- bad breath due to dry mouth
    • keratoconjunctivitis sicca (dry eyes)
  • plus dental complications and eye damage

Sjogrens – exocrine glands that produce tears and saliva are destroyed
-Keratoconjunctivitis sicca = Dry, itchy eyes that result from atrophy of the lacrimal ducts, which can be seen in inflammatory arthritis.

44
Q

Explain the systemic effects of RA on Rheumatoid Vasculitis

A
  • commonly seen as digital nail bed infarcts

- usually after long-standing disease

45
Q

Clinical Course of RA

A
  • majority of patients 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
46
Q

Differences between OA and RA

A

OA: no inflammation, in big joints, affects older people (wear and tear), the repeated use wears down the cartilage leading to bone on bone, short range of pain
RA: inflammation and hot to touch, small joints, could be at any age (b/c it is autoimmune therefore chronic), pain all day long
(more in table on slide 33)

47
Q

Non-Pharm treatment of RA

A
  • rest -> important in treatment b/c fatigue is major factor in RA. This reduces pain, but must avoid excessive rest b/c it makes RA worse)
  • OT/PT -> water exercises; help keep range of motion
  • assistive devices -> canes, walkers, splints
  • weight loss -> reduce joint stress
  • surgery -> for serious disease -> tendon repair, joint replacements
48
Q

Major treatment classes

A

1) NSAIDS
2) Corticosteroids
3) Disease-modifying anti-rheumatic drugs (DMARDS)
* use these treatments in this order as the drug progresses and worsens

49
Q

Use of NSAIDS

A
  • for analgesia and inflammation by decreasing prostaglandin synthesis
  • rarely used as mono therapy as it has no effect on disease progression
  • they balance out the TNF alpha and interluekins
  • dont use these for ppl with high bp, ulcers or COPD
  • This is one of the drugs used for symptomatic management
50
Q

Use of Corticosteroids

A
  • decreases inflammation and immunosuppression
  • ie prednisone
  • The other drug used in symptomatic management
51
Q

Use of DMARDS

A
  • agents that modify course of disease and improve prognosis
  • include non-biologic and biologic agents
  • suppress cellular and humoral system responses
52
Q

DMARD Treatment Guidelines

A
  • all indivs with early RA (under 6m) should start
  • early treatment reduces mortality and long-term complications
  • start with non-bio ($$)- NSAID, steroid, methotrexate
  • biologics indicated when poor disease response to non biologics or advanced progression of RA
53
Q

Biologics

A

all work by 1 of 3 mechs:

1) interfere with cytokine function
2) inhibit the “second signal” or “co-stim” required for T-cell activation
3) Deplete B cells (reduce self-Ab’s)
- relatively well tolerated-caution with immunosupression and opportunistic infections
- increased risk of infection and TB

54
Q

what is the term arthritis used to describe?

A

> 100 conditions that affect joints, tissues which surround joints, and other connective tissue
-joint pain and musculoskeletal pain is the common denominator
-it is the leading cause of disability in Canada
(athro= joint, itis= inflammation)

55
Q

What is the earliest pathogenic process in RA?

A

Activated T-cells stimulate the release of inflammatory cytokines, matrix metalloproteinases (recall MMPs from OA lecture), osteoclasts, and B lymphocytes

56
Q

describe the process that the Antigen- Presenting Cell goes through at eh beginning of RA

A
  • APCs process and present antigens to T cells which may stimulate B cells to produce antibodies and osteoclasts to destroy and remove bone.
  • Macrophages stimulated by the immune response can stimulate T cells and osteoclasts to promote inflammation. They also can stimulate fibroblasts which produce matrix metalloproteinases to degrade the bone matrix and produce proinflammatory cytokines.
  • Activated T cells and macrophages release factors that promote tissue destruction, increase blood flow, and result in cellular invasion of synovial tissue and joint fluid. (APC, antigen-presenting cell; MMP, matrix metalloproteinase; IL, interleukin; TNF-, tumor necrosis factor .)
  • Once activated, RASFs produce a variety of cytokines, chemokines and matrix-degrading enzymes that mediate the interaction with neighbouring inflammatory and endothelial cells and are responsible for the progressive destruction of articular cartilage and bone
57
Q

what are the signs and symptoms of the inflammation in RA

A

-redness, swelling, heat, pain  loss of function of joint

+/- Low grade fever (high fever must rule out infectious cause)

58
Q

if you get a negative lab test result back does that mean you do not have RA?

A
  • no, while abnormal values help w the diagnosis of RA, neg values cannot be used to rule out RA
  • RF or ACPA (+) patients: prognosis worse for severity of inflammation and rate of joint destruction (i.e. more severe, aggressive disease and potentially poorer outcomes)

Pathophysiology Final (10 decks)

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