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RA Flashcards

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Dermatology Board Prep flashcards
1
Q

What are the three most important pro-inflammatory cytokines identified in RA?

A

IL-1, IL-6, and TNF-alpha

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2
Q

What is infliximab?

A

A chimeric monoclonal antibody with high affinity and specificity for TNF-alpha

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3
Q

What mad infliximab a problematic treatment?

A

The antigen binding site was murine, which makes the antibody antigenic

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4
Q

Which anti-TNF antibodies have fully human protein sequences?

A

Adalimumab and golimumab

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5
Q

What medication is often paired with biologics for RA?

A

Methotrexate

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6
Q

What is etanercept?

A

A fusion protein with two copies of the soluble TNF receptor that binds and inactivates TNF-alpha

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7
Q

What are biosimilars?

A

Drugs with the same protein sequences as the original drug that are made and can greatly reduce costs of biologic therapies

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8
Q

What is the mechanism of tocilizumab and sarilumab?

A

Monoclonal antibodies against the IL-6 receptor that prevent cytokines from binding to receptors

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9
Q

What do CTLA4:Igs do?

A

These drugs (ex. abatacept) bind CD80/86 (on APCs) and displace CD28 (on T-lymphocytes), which interrupts T-lymphocyte and APC signaling

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10
Q

What does rituximab do?

A

It is an anti-CD20 antibody that leads to B-lymphocyte depletion

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11
Q

What do small molecule JAK-inhibitors do?

A

They target JAK signaling kinases that transport surface signaling to the nucleus

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12
Q

What are three therapeutic goals for treatment with disease modifying anti-rheumatic drugs?

A
  • reduce symptoms - maintain or improve function - prevent further joint damage
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13
Q

What are three mechanics by which biologic response modifiers can block inter-cellular signaling?

A
  • antibodies to cytokines - antibodies to cytokine receptors - recombinant receptor antagonists
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14
Q

List three cytokines inhibited by approved therapies for RA?

A

TNF-alpha, IL-1, and IL-6

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15
Q

What are key differences between biologic therapies and targeted small molecule therapies?

A

Biologics: - inter-cellular - parenteral administration Small molecules: - intra-cellular - oral administration

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16
Q

What is the shared epitope hypothesis?

A

A hypothesis for the genetic risk of RA that states that the most potent genetic risk for RA is conveyed by certain major histocompatibility complex alleles

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17
Q

What is the shared epitope in RA?

A

A conserved amino acid sequence on the HLA that is over-represented in patients with RA (QKRAA)

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18
Q

Where does the RA shared epitope map to?

A

Third hypervariable region of DR beta chains at amino acids 70-74 (HLA DR4 and DR1)

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19
Q

What does the presence of the shared epitope suggest?

A

It is associated with increased susceptibility and severity of RA

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20
Q

What is the theory behind susceptibility alleles in RA?

A

Susceptibility alleles bind efficiently to arithrogenic peptides. Peptidylarginine deaminases convert arginine to an uncharged citrulline, which allows it to be loaded into the MHC and present to autoreactive T cells

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21
Q

What is the relationship of cigarette smoking to RA?

A

Smoking increases risk of developing anti-CCP autoantibody positive RA in patients with the shared epitope. It causes inflammation that activates innate immunity in the airway, leading to peptide citrullination, which causes immune hyperreactivity.

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22
Q

What is the structure of a normal synovial membrane?

A
  • 2 layers in intima:
    • type A: intimal lining layer that is bone marrow derived with macrophage-like synoviocytes
    • type B: fibroblast-like synoviocytes synthesize ECM proteins including collagen, fibronectin, hyaluronic acid
  • Sublining layer below intima: loose connective tissue with numerous blood vessels, lymphatics, nerves, fibrous connective tissue
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23
Q

What is a pannus?

A

Inflammatory synovial membrane

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24
Q

What changes occur in the inflammatory synovial membrane of RA?

A
  • Synovial membrane hyperplasia
  • Cellular infiltration into synovium (T and B lymphocytes, plasma cells, dendritic cells, NK cells, macrophages)
  • Neoangiogenesis
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25
Q

What is the function of the pannus in RA?

A

The thickened membrane forms projections that protrude into the joint cavity and destroys periarticular obne and cartilage. The inflammatory cytokines and proteases also cause joint destruction.

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26
Q

RA typically has a(n) _________ onset of _________ ____arthritis.

A

RA typically has an insidious onset of symmetrical polyarthritis.

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27
Q

What amount of morning stiffness is associated with RA?

A

> 1 hour of stiffness

28
Q

What constitutional symptoms are associated with RA?

A

low grade fevers, fatigue, malaise, myalgias, decreased appetite, weight loss

29
Q

What are the joint examination findings in RA?

A
  • symmetrical swelling and tenderness of joints
  • palpable swelling and “synovial bogginess,” enlargement due to swelling rather than bony hypertrophy
  • decreased range of motion and malalignment
  • synovial fluid WBC > 2000
30
Q

What is the joint distribution of early RA?

A

Wrists, MCPs, PIPs, MTPs (toes), interphalangeal joints of thumbs

31
Q

What is the jointdistribution of late RA?

A

Larger joints: ankles, knees, elbows, and shoulders

32
Q

What two joints are almost always spared in RA?

A

Distal interphalangeal joints, thoracocolumbar spine.

33
Q

What are two classic symptoms of RA?

A

1) worse in the morning
2) pain in the balls of feet upon first ambulating in the morning

34
Q

What are three classic (but late) signs of RA?

A

1) swan neck deformity: flexion at DIP and hyperextension of PIP
2) boutonniere deformity: flexion at PIP and hyperextension of DIP
3) ulnar deviation at MCPs

35
Q

What are extra-articular manifestations of RA?

A
  • secondary sjogren’s syndrome (dry eyes and mouth)
  • rheumatoid nodules on pressure areas
  • pleuropulmonary problems
  • cardiovascular events
  • anemia
  • Felty’s syndrome
  • ophthamologic findings
36
Q

What autoantibodies are found in RA?

A
  • rheumatoid factor (autoantibodies with specificity for the Fc fragmet of IgG)
  • Anti-cyclic citrullinated peptide (anti-CCP) antibodies
37
Q

What are rheumatoid factor antibodies?

A

Autoantibodies with specificity for the Fc fragments of IgG

38
Q

What are high titer positive rheumatoid factor values suggestive of in RA?

A

Poor prognosis, more aggressive erosive disease, poorer long-term function, extra-articular disease

39
Q

What are non-RA causes of positive RF?

A

aging, chronic infection, viral disease, parasitic disease, chronic inflammatory disease, hypergammaglobulinemia

40
Q

What are anti-CCP antibodies?

A

They are auto-antibodies directed against citrullinated residues of proteins

41
Q

What is associated with high titer positive anti-CCP in RA?

A

poor prognosis, more aggressive disease, functional disability, extra-articular disease

42
Q

What are the erythrocyte sedimentation rate and c-reactive protein findings associated with RA?

A

They are elevated inactive disease and decline with disease treatment

43
Q

What are the x-ray findings of RA?

A

Juxta-articular bone erosions, diffuse symmetrical joint space narrowing, periarticular osteopenia (less specific), degenerative changes

44
Q

What are the general goals of RA therapy?

A
  • reduce or eliminate joint pain/swelling
  • prevent joint damage
  • minimize disability/maintain function
  • early diagnosis/treatment
  • accurate assessment of disease activity
45
Q

What is the gold standard, first-line treatment for moderate to severe RA?

A

Methotrexate

46
Q

What does methotrexate do?

A

A variety of mechanisms including inhibition of B and T cell functions, inhibition of IL-1 beta, and inhibition of purine metabolism

47
Q

What are the side effects of methotrexate?

A

Nausea, stomatitis, fatigue, alopecia, elevated liver enzymes, increased infection. Contraindicated in renal disease.

48
Q

What is the mechanism of leflunomide?

A

Inhibits an enzime in pyrimidine synthesis (orotic acid dehydrogenase)

49
Q

What are the side effects of leflunomide?

A

Nausea, elevated liver enzymes, teratogenicity, long half-life

50
Q

What is the mechanism of hydroxychloroquine?

A

Antimalarial that interferes with presentation of auto-antigenic peptides

51
Q

What are the side effects of hydroxychloroquine?

A

Retinal toxicity

52
Q

What is the mechanism of sulfasalazine?

A

It is an antibiotic combined with an anti-inflammatory agent that suppresses lymphocyte and leukocyte functions

53
Q

Which RA mediciations have been shown to reduce radiographic progression?

A

Methotrexate, leflunomide, and sulfasalazine

54
Q

What do tumor necrosis factor antagonists do?

A

They are antagonists for TNF, which is a proinflammatory cytokien that regulates the production of other proinflammatory cytokines in RA

55
Q

What are teh side effects of TNF antagonists?

A

Injection site reactions, infusion reactions, opportunistic infections (especially reactivation of latent TB), increased risk of lymphoproliferative disorders. Can also cause drug induced lupus.

56
Q

What is the mechanism of abatacept?

A

It is a CTLA-4 immunoglobulin that binds to CD80/86 on the surface of antigen preventing cells preventing binding to CD28 on T cells, which prevents T-cell activation.

57
Q

What does rituximab do?

A

Chimeric anti-CD20 monoclonal antibody that depletes B cells with CD20 on their surface.

58
Q

What are the side effects of rituximab?

A

infusion reaction, chronic hypogammaglobulinemia, and infection

59
Q

What do IL-6 inhibitors do?

A

They are humanized anti-human IL-6 receptor antibodies that bind to soluble and membrane bound IL-6 and inhibit IL-6 signal transduction.

60
Q

What are side effects of IL-6 inhibitors?

A

Mycobacterial infections, liver function test abnormalities, neutropenia, thrombocytopenia, hyperlipidemia, and GI perforations

61
Q

What do JAK inhibitors do?

A

They decrease signaling by several cytokine and growth factor receptors.

62
Q

What are the side effects of JAK inhibitors?

A

Infections such as herpes zoster, liver function test abnormalities, neutropenia, hyperlipidemia, GI perforators, venous thromboembolism.

63
Q

Compare hand and wrist joint distribution of RA vs. OA

A

RA: all MCPs, PIP, IP of the thumbs, all carpal bones

OA: PIP, DIP, IP thumb, 1st MCP, 1st carpal metacarpal joint very commonly involved

64
Q

All of the following lab abnormalities might be seen in RA except:

a) normochromic normocytic anemia
b) positive anti-CCP antibodies
c) microcytic anemia
d) positive anti-dsDNA
e) positive antinuclear antibody (ANA)
f) positive rheumatoid factor
g) neutropenia
h) thrombocytopenia

A

d) anti-dsDNA

this is more associated with SLE

65
Q
A

msk-derm (41 decks)

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