Pain Exam 2: Witt-Enderby OA and RA (p1-9)

Osteoarthritis (OA):

-degenerative ___ disease (articular cartilage) of hands, fingertips, knees, hips, feet, spine (neck/lower back) with no effect on internal organs

joint

Rheumatoid Arthritis (RA):

-chronic ____ and ___ disease

inflammatory, systemic

Rheumatoid Arthritis (RA):

-starts in smaller joint and eventually reaches ___

circulation

Rheumatoid Arthritis (RA):

-peripheral polyarthritis (means affects ≥ ___ joints)

5

symmetry?

OA: Asymmetrical and _____

RA: Symmetrical and ____

unilateral, bilateral

number of joints targeted?

OA: generally ___

RA: 5+

1

systemic disease?

OA: ___

RA: ___

no, yes

prolonged stiffness?

OA: ____

RA: ____

no, yes

targets internal organs?

OA: ____

RA: ___

no, yes

is OA or RA more prevalent?

OA

interior part of joint = ____

synovium

OA Progression

1. loss of ____

2. ___ of joint space

3. bone-on-bone contact

cartilage, narrowing

OA Progression

4. bone-on-bone contact induces ____

5. production of ____/spurs

6. joint deterioration

inflammation, osteophytes

RA Progression

1. protein/peptide ____

2. auto antibody formation (___, ___)

citrullination, ACPA, RF

RA Progression

3. enhances ____

4. synovium ___ is induced

hyperplasia

RA Progression

5. immune cell ____

6. MMPs escape joint → enter ____ circulation

infiltration, systemic

MMPs = ____ ____

matrix metalloproteinases

OA Etiology

-age-related

-____ predominate <45 years (sports/work related), ____ predominate >45 years (menopause related)

men, womrn

OA Etiology

mechanical damage → ____ → physical deformities → physical debilitation, pain, poor qulity of life

inflammation

RA Etiology

-autoimmune

-involves ___ ____ (RF) and __-___ ___ ___ (ACPA)

rheumatoid factor, anti-citrullinated peptide antibody

OA Risk Factors

-joint injury or ___

-age

-gender

-obesity

-genetics

-race

overuse

RA Risk Factors

-60% = ____ (2-10x greater risk with 1st degree relative, HLA-DRB1 gene, epigenetics)

-40% = ____ (western diet, microbiome), ____ (smoking), female gender, ethnicity

familial, diet, lifestyle

OA Molecular Pathology

Synovium → releases ____ & ___ ___

cytokines, inflammatory mediators

OA Molecular Pathology

Synovium → releases cytokines & inflammatory mediators → activates ___ ____

catabolic chondrocytes

OA Molecular Pathology

Synovium → releases cytokines & inflammatory mediators → activates catabolic chondrocytes → chondrocytes release IL-1α, IL-1β, TNF-α, NO, prostaglandins → these stimulate ____ release

MMP

OA Molecular Pathology

Synovium → releases cytokines & inflammatory mediators → activates catabolic chondrocytes → chondrocytes release IL-1α, IL-1β, TNF-α, NO, prostaglandins → these stimulate MMP release → ____ cartilage

dissolves

OA Treatment

A. ____ blocks Na+ channels

-site of action = synovium

lidocaine

OA Treatment

B. ____ inhibits COX to decrease prostaglandins

-site of action = synovium + the cells that release inflammatory mediators

NSAIDs

OA Treatment

C. _____ work through mu opioid receptors

-site of action = cells that release inflammatory mediators + CNS

Opioids

OA Treatment

D. ____ (inhibit A-delta and C-fibers)

-site of action = CNS

SNRIs

RA Treatment (general list of drug targets)

-Inhibit B cells

-Inhibit T-cell ___-____

-Inhibit macrophages /___ signaling

-Inhibit TNF-α

-Inhibit IL-1, IL-6, IL-17

co-stimulation, JAK

OA Pharmacological Goals

-reduce ___ (lidocaine, opioids, SNRIs, capsaicin, APAP)

-reduce ____ (NSAIDs)

pain, inflammation

RA Pharmacological Goals

-reduce ___

-reduce ____ (suppress T-cell activation, suppress macrophage mediated release of TNF-α, IL-1, and IOL-6, suppress B-cell mediated release of autoantibodies)

pain, inflammation

RA Molecular Pathology

-a complex disease that involves numerous immune system regulatory pathways and organ. It is an interplay between _____ and ___ ___

genotype, environmental factors

RA-Genotype

-there is 15-30% concordance between monozygotic twins

-HLA-DRB1 has a "shared epitope" = QKRAA (strongly associated with increased RA risk)

-the R (____) is the key “RA risk” amino acid

arginine

RA-Genotype

-HLA-DRB1 is strongly associated with the production of ____

ACPAs

Arginine is a strong target for citrullination because it is a ____ amino acid with a ____ charged side chain

basic, positively

Citrullination refers to converting arginine (positively charged) into citrulline (____)

neutral

Citrullination

____ (peptidylarginine deiminases) convert arginine, which is positively charged, into citrulline, which is neutral

PADs

Why is citrullination bad?

1. because the citrullinated proteins are recognized as foreign by the immune system (ie loss of tolerance), leading to the production of ____ and ____, which trigger the immune system

ACPAs, RF

Why is citrullination bad?

consequence of triggering immune system = Synoviocytes and chondrocytes respond produce ___ (which degrade cartilage)

MMPs

Why is citrullination bad?

2. arginine also normally functions to keep ____ tightly bound to DNA. When PADs are overactive, they convert histone arginine residues to citrulline, causing histones to ____ from DNA.

histones, detach

Why is citrullination bad?

consequence of histones detaching from DNA = increases gene ___, leading to excessive synoviocyte ____

transcription, proliferation

RA-Environmental Factors

-Lungs: ____ and ____ exposure can cause inflammation that promotes protein citrullination

smoking, silica

RA-Environmental Factors

-Tonsils: Chronic ____ or bacterial ____ may activate peptidylarginine deiminases (PADs), leading to citrullination.

inflammation, infection

RA-Environmental Factors

-Gums: Periodontitis-Infection with Porphyromonas gingivalis, which expresses ____, can citrullinate proteins and trigger autoantibody formation.

PAD4

What is the gold standard in RA autoantibody testing?

CCP2

CCP2 = ____ ____ ____ ___

cyclic citrullinated peptide test

Criteria for diagnosis of RA = positive for ___

ACPAs

ACPA-positive RA → ___ severe disease course

more

ACPA-negative RA → ____ severe disease course

less

Since the body is inflammed in RA, there is potential involvement of the ___/___/___ axis

CRH, ACTH, cortisol

1. body is inflammed

2. ____ CRH

3. ____ ACTH

4. ____ cortisol (which is ___-inflammatory)

increased, increased, increased, anti

The autoantibodies and citrullinated antigens trigger a chronic inflammatory response, including the release of inflammatory cytokines (____, ___, ___)

TNF-α, IL-1, IL-6

The autoantibodies and citrullinated antigens trigger a chronic inflammatory response, including the release of inflammatory factors (____, ___ ___)

ROS, inducible NOS

JAKs act inside ____ to amplify cytokine signaling

macrophages