Rheumatoid Arthritis Flashcards

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1
Q

What is rheumatodi arthritis?

A

disease of an aberrant immune response that leads to chornic progressive synovial inflammation and joint destruction

has the potential to cause severe pain, joint damage, disability, and increased mortality

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2
Q

What is the epidemiology of RA?

A

female > male (2.5:1)

worldwide distribution

0.5-1% disease prevalence in European and North American populations

peak incidence is 40-60 years of age

prevalence increases with age (7% at 75 years)

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3
Q

What are the possible causes of premature mortality in individuals with RA?

A

infection

GI bleed

lymphoproliferative disorders

CVD

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4
Q

What is the primary lesion in RA?

A

inflammation of the synovium

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5
Q

What are the two layers of synoviocytes in the intima, and what do they do?

A

type A - bone marrow derived with macrophage like synoviocytes that is 1-2 cells thick

type B - fibroblast-like synoviocytes synthesize extracellular matrix proteins (collagen, fibronectin, hyaluronic acid, molecules that facilitate the lubrication of the cartilage surface)

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6
Q

What is the composition of the sublining layer below the intima of the synovium?

A

loose connective tissue with numerous blood vessels, lymphatics, nerves, fibrous connective tissue

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7
Q

What happens to the synovium in RA?

A

hyperplasia of the synovialmembrane, up to 10 cells thick (both type A and B)

cellular infiltration into the synovium sublining - T and B lymphocytes, plasma cells, interdigitating and follicular dendritic cells, NK cells, macrophages

diffuse or organized cellular infiltrates into lymphoid aggregates and secondary lymphoid follicles

neoangiogenesis

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8
Q

What is the pannus?

A

inflammatory synovial membrane in RA

thickened synovial membrane forms villous projections that protrude into the joint space, and extend to cartilage and bone

pannus invades and destroys periarticular bone and cartilage -> marginal erosions (juxta-articular lesions)

lining produces inflammatory cytokines and proteases that work with activated chondrocytes and osteoclasts to cause joint destruction

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9
Q

What is the pathogenesis of RA?

A

aberrant immune response in a genetically predisposed host

genetic susceptibility + trigger -> autoimmune disease (RA)

peristence and progression of RA are regulated by immune mediators

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10
Q

What is the shared epitope hypothesis?

A

the genetic system conferring the most risk is thought to be certain major histocompatibility complex alleles (MHC, or HLA for human leukocyte antigen)

conserved amino acid sequence on the HLA is high in RA (QKRAA)

third hypervariable region of DRbeta chains at amino acids 70-74

presence of SE is associated with increased susceptibility and severity of RA

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11
Q

How does the shared epitope cause increased susceptibility of RA?

A

epitope borders the antigen binding cleft of the HLA-DR molecule

the theory is that MHC molecules with the shared epitope could bind efficiently to arthritogenic peptides

it is possible that SE confers a positive charge to the peptide binding cleft of the class II MHC that prevents the binding of peptides containing arginine

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12
Q

What is the rol eof petidylarginine deaminases (PADIs)?

A

convert arginine to an uncharged citrulline thereby permitting hte citrullinated protein to be loaded on the MHC and presented to autoreactive T cells

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13
Q

What is PADI4?

A

a functional variant of tyrosine phosphatase N22 (PTPN22) and is an RA susceptibility gene

intracellular tyrosine phosphatase that negatively regulates T cell activity

defect could generate autoimmunity by modulating negative selection in the thymus

2-fold increased risk of RA for heterozygotes PTPN22 polymorphism

4-fold increased risk RA for homozygotes PTPN22

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14
Q

What are some potential environmental triggers of RA?

A

hormal influences

cigarette smoking - best characterized, increases risk of anti-CCP autoantibody (has the shared epitope)

bacterial or viral infectious agents could be potential initiating factors - increased EBV load, which can lead ot RF productino

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15
Q

What are the classical symptoms of RA?

A

insiduous onset symmetric polyarthritis

joint swelling

eventual decreased range of motion

morning stiffness > 1 hour

stiffness after rest (gelling)

pain and swelling worse in the morning

pain in the balls of the feet upon first ambulating in the morning

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16
Q

What are common findings of the joint exam in RA?

A

inflammatory synovitis

symmetric joint swelling and tenderness

palpable swelling and synovial bogginess as opposed to joint enlargement due to bony hypertrophy (osteophytes)

later in course can have deformity, decreased ROM, and malalignment

synovial fluid WBC > 2000

nodules at pressure points

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17
Q

What joints are affected in early RA?

A

wrists affected, MCPs, PIPs, MTPs, thumb interphalangeal joints

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18
Q

What joints are affected in later RA?

A

larger joints

ankles, knees, elbows, shoulders, and occasionally sternoclavicular, temporomandibular, and cervical spine

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19
Q

What joints are almost always spared in RA?

A

DIP joints

thoracolumbar spine

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20
Q

What are physical findings commonly found in RA?

A

swan neck and Boutenniere’s deformities

hand nodules with ulnar deviation and subluxation

nodules on tendon sheath

extra-articular manifestations

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21
Q

What patients are more often affected by extra-articular manifestations?

A

RF+ patients

rheumatoid nodules

more severe articular disease

MHC class II HLA-DR4 allele

22
Q

Swan-neck deformity

A

flexion at DIP

hyperextension of PIPs

23
Q

Boutenniere deformity

A

flexion at PIP and hyperextension of DIP

24
Q

What are cardiac manifestations of RA?

A

pericardial effusions

pericarditis (rarely)

nodules in the myocardium or valve leaflets

coronary heart diseaes - mortality rates CVD in RA 50-100% higher than in the general population

25
Q

What are skin mainfestations of RA?

A

subcutaneous nodule

vasculitis

gangrene

26
Q

What are pulnoary manifestations of RA?

A

pleural thickening, pleural effusions, pulmonary nodules

diffuse intersitial lung diseae, BOOP, Caplan’s syndrome, corcoarytenoid arthritis

27
Q

What are manifestations of RA in the eye?

A

epicscleritis

scleritis

scleromalacia

28
Q

episcleritis

A

abrupt onset of inflammation in the episclera of the eye

29
Q

scleritis

A

painful, destructive, and potentially blinding disorder that may also involve the cornea, adjacent episclera, and underlying uveal tract

scleritis has striking, highly symptomatic clinical presentation

30
Q

scleromalacia

A

marked scleral thinning and adjacent scleral and conjunctival injection

darker pigmented uveal tissue has herneated through the softened sclera, and perforation is imminent

nonconcentric pupil

31
Q

What are general radiographic features of initial RA?

A

diffuse joint space narrowing of RA (asymmetric joint space narrowing in OA)

32
Q

What are early radiologic findings of RA?

A

soft tissue swelling

periarticular osteopenia

no erosions

progresses to thinning of cortex and loss of bone with marginal erosion and joint space narrowing

33
Q

What are radiologic findings of late RA?

A

MCP narrowing, subluxation, ulnar deviation

erosions at MCPs

joint space narrowing

demineralization

carpal bones - narrowed spaces and erosions

34
Q

What are the cervical findings in RA?

A

posterior displacement of the odontoid process

preodontoid space 8mm

change in the distance with flexion and extension and indicates instability

measurement made at the base of the anterior aspect of the dens with th eneck held in flexion

35
Q

What are laboratory abnormalities in RA?

A

anemia from chronic disease

elevated acute phase reactants (ESR, CRP)

thrombocytosis

rheumatoid factor

anti-cyclic citrullinated peptide antibodies (anti-CCP)

antinuclear antibody (ANA) can be present in 20-30% of RA

36
Q

What is rheumatoid factor?

A

any antibody that targets the Fc region of IgG

high titer positive RF leads to a poor prognosis (more aggressive and erosive disease, poorer long-term function, extra-articular disease)

sensitivity 66% and specificity 82%

37
Q

What are some reasons for a false positive RF?

A

aging

chronic bacterial infection

viral diseases

parasitic diseases

chronic inflammatory diseases

hypergammaglobulinemia

38
Q

What is peptidylarginine deaminase?

A

peptidylarginine deiminase (PAD) converts arginine into citrulline

PAD2 and PAD4 are abundant in RA synovium

carries out local citrullination of synovial proteins, such as fibrin

39
Q

anti-cyclic citrunillated peptide antibody

A

antibodies to synthetic citrullinated peptides is 75% ssensitive and 95% specific for RA

poor prognostic marker for erosive disease

40
Q

What is the theory behind the shared epitope hypothesis of rheumatoid arthritis?

A

HLA only binds peptides that fits into the groove

citrillunation helps the protein bind to the groove and makes it more likely for the antigen to be presented to the immune system

41
Q

What are the goals of treatment in RA?

A

reduce joint pain and swelling, fatigue

prevent joint damage and minimize disability and maintain employability

emphasis on diagnosing and treating RA early and intensively in order to prevent joint damage

therefore, recognition and early referral by primary care physicians is essential

42
Q

How is disease activity assessed in RA?

A

the number of tender and swollen joints is the dominant determinant of disease activity

the patient’s rating of pain and functional disability

serum levels of acute phase reactants

radiographic progression of disease

43
Q

What are the treatment options for RA?

A

NSAIDs

corticosteroids

DMARDs

44
Q

What is the role of NSAIDs in RA treatment?

A

symptomatic relief, improved function

no change in disease progression

GI and renal toxicity

45
Q

What is the role of corticosteroids in RA treatment?

A

low-dose prednisone (<10 mg daily) - may substitute for NSAID and used as bridge therapy

intra-articular steroids - useful for flares

46
Q

What is the role of DMARDs in RA?

A

diverse group of drugs that reduce signs/symptoms of RA and slow radiographic progression

DMARDs are the cornerstone of RA therapy

47
Q

What are the common DMARDs used in RA therapy?

A

methotrexate (most effective single DMARD)

sulfasalazine

hydroxychloroquine

leflunomide

minocycline

gold (rarely used now)

48
Q

What are the biologic response modifiers used in the treatment of RA?

A

subset of DMARDs

TNF antagonists

CTLA-4Ig

anti-CD20 monoclonal antibody

Janus kinase (JAK kinase) inhibitor

humanized anti-human interleukin (IL)-6 receptor antibody

49
Q

methotrexate

A

most effective single DMARD, most often used initially

usually continued as other DMARD or biologics added

mechanism: inhibits dihydrofolate reductase, an enzyme needed for DNA synthesis, lymphocyte proliferation but possibly mechanism is anti-inflammatory

  • inhibits neovascularization
  • inhibits neutrophil activation and adherence
  • inhibits IL-1 and IL-8 production by mononuclear cells
  • inhibits TNF production by T cells

administered orally or subcutaneously once weekly

50
Q

sulfasalazine

A

links an antibiotic, sulfapyridine, with an anti-inflammatory agent, 5-aminosalicylic acid

suppresses lymphocyte and leukocyte functions

has been shown to reduce the development of joint damage

taken 2-4 times daily

can cause reaction in sulfa allergic individuals

51
Q

hydroxychloroquine

A

antimalarial

may be effective due to interference with presentation of autoantigenic peptides

has not been shown to reduce radiographic progression

SE - retinal toxicity requires eye exam every 6-12 months

administered orally twice dialy