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Rheumatology > 1 - What is Rheumatology and Phenotype of Systemic Inflammation > Flashcards

1 - What is Rheumatology and Phenotype of Systemic Inflammation Flashcards

1
Q

What is Rheumatology a subspecialty of?

A

Internal Medicine

Pediatrics

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2
Q

What are the key areas of expertise of a Rheumatologist?

A

Musculoskeletal Medicine

Systemic Auto-immune and Auto-inflammatory Conditions

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3
Q

What is the overlap between musculoskeletal medicine and auto-immune/auto-inflammtory diseases?

A

Arthritis/Arthralgia

Myalgia/Myopathy

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4
Q

The bright side of having a systemic inflammatory response

A

Defense against infection
Cancer surveillance
Hemostasis/Homeostasis after acute tissue damage/injury
Wound healing

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5
Q

The dark side of having a systemic inflammatory response

A

Overly excessive inflammatory response
Chronic expression
Pleiotropic effects of inflammatory mediators

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6
Q

Septic Arthritis

A

Inflammation is NECESSARY to clear the infection
Prevent entrenchment or dissemination (bacteremia has high mortality rate)
Inflammation CAUSES most of the irreparable damage to the joint. UGH

This also happens in ARDS and post-inflammatory changes after encephalitis or CVA

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7
Q

Lymphotoxin

A

TNF-β

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8
Q

Systemic Inflammatory Response - Immune Effectors

A

Macrophages
Neutrophils
T-Cells

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9
Q

Systemic Inflammatory Response - Cytokines

A 
TNF-α
IL-6
IL-1
IFN
Lymphotoxin
Chemokines
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10
Q

Cytokine Targets

A 
Bone Marrow
CNS
Liver
Muscle
Adipose
Blood Vessels
ReticuloEndothelial System
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11
Q

Cytokines - Effect on Bone Marrow

A

Leukocytosis

Thrombocytosis

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12
Q

Cytokines - Effect on CNS

A

Fever
Somnolence
Lethargy

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13
Q

Cytokines - Effect on Liver

A 
Synthesis of Acute Phase Reactants
Complement
Hepcidin
Triglycerides
Reduced glycogenesis
Reduced albumin synthesis
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14
Q

Cytokines - Effect on Muscle

A

Reduced glucose uptake

Sarcopenia

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15
Q

Cytokines - Effect on Adipose

A

Lipolysis
Free Fatty Acid Release
Adipokines

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16
Q

Cytokines - Effect on Blood Vessels

A

Endothelium primed for leukocyte transmigration
Plaque rupture
Atherogenesis

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17
Q

Cytokines - Effect on ReticuloEndothelial System

A

Migration of dendritic cells to lymph nodes

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18
Q

Acute Phase Reactants - Induced in response to

A

Cytokines and other extra-cellular signals

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19
Q

Acute Phase Reactants - Importance in systemic inflammatory response

A

Varies depending on reactant

Pro-inflammatory vs. Anti-inflammatory

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20
Q

Acute Phase Reactants - Test characteristics

A

Circulate in much higher concentrations than cytokines, easily identified as markers for disease processes.

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21
Q

Examples of Acute Phase Reactants

A 
Complement
CRP
Fibrinogen
Serum Amyloid A
Haptoglobin
Ferritin
Mannose binding lectin
Others

Macrophages produce TNF-α and IL-1
These induce IL-6
This induces the liver to produce the above.

22
Q

Lab Measures of Acute Phase Reactants

A

C-Reactive Protein (CRP)

Erythrocyte Sedimentation Rate (ESR)

23
Q

C-Reactive Protein

A

Pentamer of 23kDa subunits
Synthesized by hepatocytes under cytokine (primarily IL-6) stimulation
Fixes complement
Binds to macrophages to induce inflammatory cytokines
Binds to endothelial cells to expose tissue factor
May have putative anti-inflammatory effects

Primarily used to measure the inflammatory response in patients

24
Q

Erythrocyte Sedimentation Rate

A

The rate at which RBCs will migrate over an hour, the distance they will travel in an upright tube in that time.

25
Q

What increases the ESR?

A 
Older Age
Female Sex
Temperature of sample
Smoking
Increase in plasma proteins(immunoglobulins, fibrinogen, etc)
Microcytic anemia or variable RBC size
Increase in plasma viscosity
26
Q

What decreases the ESR?

A

Polycythemia
Extreme leukocytosis
Sickle cell anemia

27
Q

You see an elevated or depressed ESR. What do you ask?

A

Is this because of a response to cytokines?

Is this because of another factor unrelated to inflammation?

28
Q

Proposed benefits of fever during infection

A

Inhibition of bacterial growth
Facilitates killing by macrophages and PMNs
Sequesters iron
Other

29
Q

How do exogenous pyrogens and microbes cause a fever?

A

They stimulate leukocytes to produce endogenous pyrogens
Mostly monocytes/macrophages and neutrophils
IL-1
TNF-α
Lymphotoxin (TNF-β)
Interferons
IL-6

30
Q

Fever during Infection - Mechanism

A

Endogenous pyrogens circulate
Endogenous pyrogens signal the CNS (multiple redundant mechanisms)
Prostaglandins (PGE2) are synthesized
This elevates the thermostatic set point of the hypothalamus (No PGE receptor = no fever)
Fever is dampened by poorly-understood endogenous anti-pyrogens

31
Q

Fever during Chronic Inflammatory Diseases - Mechanism

A

Same process as during infection, except instead of endogenous pyrogens triggering it, we have exogenous pyrogens:

Synovitis
Activated leukocytes
Etc

32
Q

Anemia of Inflammation

A

Anemia of Chronic Disease (previous name)
Associated with chronic infections, inflammatory diseases, neoplastic disorders
Affects Iron, Erythropoietin, RBC survival
NOT resolved by exogenous Fe or Erythropoietin.

33
Q

Anemia of Inflammation - Levels

A

Circulating iron is normal (Lecturer said normal, slide said decreased)
Iron binding capacity is decreased
Whole body iron stores are normal or increased
Blunted response to endogenous and exogenous erythropoietin
RBC life span is reduced

NOT resolved by exogenous Fe or Erythropoietin

34
Q

Anemia of Inflammation - Mechanism

A

IL-6 levels are high
This raises hepcidin levels
This destroys ferroportin
This causes less iron to be absorbed, and for iron to get trapped in hepatocytes and macrophages.

Treat with an IL-6 inhibitor!

35
Q

Hepcidin

A

Small peptide/hormone (25aa)
Synthesized in liver
Expressed primarily in liver (less in kidney, heart, muscle, brain)
Negative regulator of iron homeostasis
Mutations in hepcidin lead to severe juvenile hemochromatosis

36
Q

Hepcidin knockout leads to

A

Multi-organ iron overload

37
Q

Hepcidin overexpression leads to

A

Severe Fe deficiency anemia

38
Q

How does Hepcidin regulate iron?

A

In the duodenum, where iron is absorbed, hepcidin destroys ferroportin channels in the setting of iron excess.
This prevents the basal translocation of further iron into the bloodstream, when we already have too much.
This means iron is trapped in the hepatocytes, rather than allowed into the bloodstream.
Iron can also be trapped in macrophages due to this process.

39
Q

What are the regulators of Hepcidin?

A 
Serum Iron (low serum iron suppresses hepcidin, high serum iron induces hepcidin)
Inflammation (IL-6 via NF-κB) - THIS IS THE PRIMARY REGULATOR
40
Q

Cachexia - Definition

A

Loss of lean (non-fat) mass in the setting of systemic inflammation
Distinct from frank wasting (not associated with malnutrition, the fat is unaffected or even INCREASED)
Related to, but distinct from aging-associated sarcopenia

41
Q

Cachexia - Mechanism

A

Multifactorial:

Cytokine-driven (TNF-α, IL-6, IL-1)
Degradation mediated through NF-κB
Reduced physical activity
Effects of altered hormone signaling/insulin not well studied

42
Q

Energy Metabolism - Normal

A

Glucose & Free Fatty Acids are essential sources of energy during infection, acute injury, healing

43
Q

Energy Metabolism - Acute Inflammation

A

Cytokines facilitate release of glucose & free fatty acids into circulation
These target liver, adipose & skeletal muscle

44
Q

Energy Metabolism - Chronic exposure to the cytokines of acute inflammation leads to:

A 
Diabetes
Insulin resistance
Atherogenic lipid profile
Atherogenesis
(particularly in the setting of energy excess and other CV risk factors)
45
Q

TNF-α and Glucose Metabolism

A

Adipose - Acts through p55 receptor:
Lipolysis
Free Fatty Acid Release

Liver
Increased hepatic gluconeogenesis
Increased triglyceride production (synergized under IL-1, IL-6)
Increased VLDL production, enriched with triglyceride, decreased clearance

Skeletal Muscle - Acts through the p55 receptor in combination with the free fatty acids released from the adipose tissue:
Altered insulin-signaled glucose uptake

46
Q

TNF-α and reduced insulin-stimulated glucose uptake in skeletal muscle - Mechanism

A

Inhibition of auto-phosphorylation of the insulin receptor

47
Q

Pro-Inflammatory HDL

A

Apo A-1 (a component of HDL) promotes reverse cholesterol process
Inflammation results in accumulation of oxidants in HDL
This inactivates Apo A-1
This also facilitates the formation of oxidized LDL

48
Q

Chronic Inflammation - Steps of Atherogenesis/Thrombosis

A

Chronic inflammation is linked to all stages of atherogenesis/thrombosis

Endothelial dysfunction (earliest stage)
Atheroma formation (potentiated by other CVD risk factors)
Plaque instability and rupture (results in MI)
49
Q

Atherogenesis/Thrombosis - Effects (direct or indirect) of cytokines on the vasculature

A 
Up-regulate vascular adhesion molecules
Activate and recruit macrophages
Upregulate other pro-inflammatory cytokines
Remodel vascular matrix (MMPs, TIMPs)
Regulate the apoptosis of vascular SMCs
Induce pro-coagulant state (PAI-1)
Modulate glucose metabolism
Modulate fat/lipid metabolism
Antagonize anti-inflammatory pathways
50
Q

Vulnerable Plaque

A

“Thin capped fibroatheroma”
Rupture is prone to a plaque weak at the “shoulders”
Shoulders with few SMC, PG, collagen
More macrophages and infiltrating t-cells

51
Q

Cardio - Long term exposure to inflammtory cytokines leads to

A

Higher rates of cardiovascular events

Rheumatology (16 decks)

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