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MSK/Derm > SM 227: Biologics and Therapeutics > Flashcards

SM 227: Biologics and Therapeutics Flashcards

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Dermatology Board Prep flashcards
1
Q

Is Rheumatoid Arthritis a chronic or acute condition?

A

Rheumatoid Arthritis is a chronic disease

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2
Q

Is Rheumatoid Arthritis a progressive condition?

A

Yes, Rheumatoid Arthritis is a progressive disease tht causes progressive physical disability

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3
Q

How does Rheumatoid Arthritis cause disability?

A

Rheumatoid Arthritis causes irreversible joint damage

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4
Q

What are the consequences of untreated or ineffectively managed Rheumatoid Arthritis?

A

Joint destruction and deformity
Progressive physical disability
Reduced Quality of Life

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5
Q

What is the new criteria for diagnosing Rheumatoid Arthritis and what is the cutoff score?

A

EULAR criteria that diagnoses with a score of 6 or more

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6
Q

What does the therapeutic approach to Rheumatoid Arthritis require?

A

Must be very comprehensive and consider:

Type of intervention
Timing
Follow-up management
Assessment of comorbid conditons

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7
Q

What was the traditional treatment pyramid for RA?

A

Involved sequential drug therapy (no longer used):

NSAIDS
Antimalarials
Methotrexate
Experimentals

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8
Q

What is the new approach to treating RA?

A

Primary target in treating RA is now defined as a state of clinical remission

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9
Q

What is a potential alternative to clinical remission in treating RA?

A

Low Disease Activity, if the Rheumatoid Arthritis has been long-standing

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10
Q

Describe the disease of Rheumatoid Arthritis?

A

Systemic inflammatory disease with unknown etiology

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11
Q

What are DMARDs and what do they do?

A

Disease modifying anti-rheumatic drugs, such as Methotrexate, which slow or stop progression of Rheumatoid Arthritis and may improve function

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12
Q

How do targeted biologics treat Rheumatoid Arthritis and do they replace traditional treatment?

A

Targeted biologics inhibit key cellular signaling pathways in Rheumatoid Arthritis

They may be used alone or in combination with DMARDs

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13
Q

How does Rheumatoid Arthritis alter the joints at a histological level?

A

Hyperplasia and hypertrophy of the synovial lining leading to destruction of cartilage and bone

A dense inflammatory infiltrate of Macropahges and lymphocytes develops beneath the synnovium leading to continued disease activity

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14
Q

What initiates Rheumatoid Arthritis at the molecular level?

A

Rheumatoid Arthritis is initiated when APC’s present an inciting antigen to an appropriate group of Tcells

Specific antigen remains unknown, but causes release of cytokines which mediate Rheumatoid Arthritis

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15
Q

How do cytokines effect the progression and treatment of Rheumatoid Arthritis?

A

Cytokines are released by Tcells after APC’s present a currently unknown inciting antigen

These cytokines drive the progression of Rheumatoid Arthritis and are targets for therapeutic agents

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16
Q

What cells produce the cytokines which drive Rheumatoid Arthritis?

A

More than a dozen cytokines produced by Macrophages, T and B lymphocytes drive Rheumatoid Arthritis

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17
Q

How do cytokines effect cellular signalling?

A

Cytokines are released by Macrophages, T + B lymphocytes which bind to complimentary receptors on target cells

Binding to receptor causes activation of cytoplasmsic messengers such as Protein Kinases, which activate transcription factors, turning a target cell “On” or “Off”

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18
Q

Are cytokines pro-inflammatory or anti-inflammatory?

A

Can be either or

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19
Q

What are the important pro-inflammatory cytokines in Rheumatoid Arthritis?

A

IL-1
IL-6
TNFalpha

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20
Q

Which pro-inflammatory target has responded the best to targeted treatment in Rheumatoid Arthritis?

A

TNFalpha, which acts upstream in the Rheumatoid Arthritis signaling pathway

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21
Q

What has been the effect of inhibiting TNFalpha in Rheumatoid Arthritis?

A

Inhibition of TNFalpha = decreased inflammation + decreased resporption of periarticular bone

Effect is mediated by IL-1 on osteoclasts

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22
Q

What cells are effected by TNFalpha inhibition in Rheumatoid Arthritis?

A

Osteoclasts, because inhibiting TNFalpha leads to less periarticular bone resorption

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23
Q

How do mAbs treat Rheumatoid Arthritis?

A

Monoclonal antibodies bind cytokines that drive Rheumatoid Arthritis

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24
Q

How can receptor antagonists treat Rheumatoid Arthritis?

A

Cytokine receptor antagonists can prevent pro-inflammatory effects that drive Rheumatoid Arthritis

25
Q

What is Infliximab?

A

Infliximab is a chimerac mAb with a high affinity and specificity for TNFalpha that treats Rheumatoid Arthritis

26
Q

What potential drawback of Inflximab arises from it’s structure?

A

The antigen binding site of Infliximab that targets TNFalpha is derived from Murine sequences, making the antibody itself potentially antigenic

27
Q

Why is Infliximab given with Methotrexate?

A

The Murine component of Infliximab is immunogenic and can result in the generation of HACA (Human anti-chimerica Antibodies)

To prevent the generation of HACA, Infliximab is given with immunosuppressants like Methotrexate

28
Q

Does Infliximab lead to sustained reduction in Rheumatoid Arthritis disease activity?

A

Yes, as proven by long-term trials

29
Q

What potential complication can arise from Infliximab and other TNFalpha antagonists?

A

Opportunistic nifections

30
Q

Name two anti-TNF antibodies other than Infliximab?

A

Adalimunab and Golimumab

31
Q

What are the 3 anti-TNF antibodies?

A

IAN

Infliximab
Adalimunab
Golimumab

32
Q

What are the potential advantages of Adalimunab and Golimumab over Infliximab?

A

Adalimunab and Golimumab have entirely human protein sequences which may make them less antigenic than the partially murine Infliximab

Still give them with Methotrexate tho

33
Q

What is Certolizumab pegol?

A

A recombinant molecule made of the Fab of a human anti-TNF antibody and a PEG moiety, which is also FDA-approved for the treatment of Rheumatoid Arthritis

34
Q

Is there a soluble version of the TNF receptor?

A

Yes, and it’s found in excess in the serum and synovial fluid of patients with RA

35
Q

What is Etanercept?

A

A fusion protein containing 2 copies of the soluble portion of the TNF receptor bound to the Fc fragment from human IgG

36
Q

How does Etanercept work?

A

It binds and inactivates TNFalpha leading to reduced disease activity in patients with long standing Rheumatoid Arthritis

37
Q

What drug should be given to patients who have long standing, drug-resistant Rheumatoid Arthritis?

A

Etanercept

38
Q

Should Etanercept be given alone or wtih Methotrexate?

A

Give Etanercept with Methotrexate

39
Q

What are biosimilars?

A

Copies of existing biologic agents that share the same protein sequences as the original molecule but with different folding and quaternary structure

40
Q

What is the advantage of biosimilars?

A

They may result in less expensive treatment options than the branded treatment

41
Q

Do biosimilars need to go through clinical trials?

A

Unlike small molecule generics, biosimilars must undergo abbreviated clinic trials prior to approval

42
Q

Are there any biosimilars approved and available in the US for the treatment of Rheumatoid Arthritis?

A

Biosimilars have been approved for Inflixiamb but are not widely available

Around the world, they have helped lower costs of therapy

43
Q

What are the IL-6 inhibitors?

A

6 = ST

Tocilizumab
Sarilumab

44
Q

How do the IL-6 inhibitors work?

A

They’re mAb’s trageted against the IL-6 receptor, blocking IL-6 signalling

45
Q

What advantage do IL-6 inhibitors have over TNFalpha inhibitors?

A

IL-6 inhibitors may be effective even without concomitant Methotrexate - can be monotherapies

46
Q

What evidence is there that Macrophages are supposedly the primary drives of Rheumatoid Arthritis?

A

The success of TNFalpha inhibitors in managing RA suggests that Macrophages are producing TNFalpha in inflamed joints, leading to RA

Runs counter to the evidence that APC/T-cell interactions initiate RA

47
Q

How do T-cells and APCs interact, and what is required for a T-cell to be successfully activated?

A

Need 2 signals:

APC presents antigen leading to interaction between TCR and MHCII

Costimulatory molecules on T-cells and APCs create a second signal, not specific to a particular antigen, to activate the T-cell

48
Q

What is the nature of the second signal involved in T-cell activation by APC’s, and how can this effect the T-cell?

A

Second signal (after MHCII-TCR) is non-specific to an antigen, unlike the MHCII-TCR interaction

Required to activate the T-cell, and in its absence, the T-cell dies or becomes anergic

49
Q

Name an example of a second signal interaction between APC’s and T-cells?

A

CD80 (APC) interacts with CD28 (T-cell)

50
Q

What is Abatacept?

A

Abatacept binds CD80 on APC and prevents the interaction with CD28 on the T-cells, disrupting the second signal and leading to T-cell death

51
Q

Which cells express CD28?

A

T-cells

52
Q

Which cells express CD80?

A

APC’s like Macrophages

53
Q

Is Abatacept effecive in managing Rheumatoid Arthritis and when?

A

Yes, but only late in the disease as opposed to early on, where you would expect it to disrupt T-cell activation

Suggests ongoing T-cell activation in Rheumatoid Arthritis

54
Q

Do B-cells play a role in Rheumatoid Arthritis?

A

Yes - Rituximab helps manage RA

55
Q

How does Rituximab work?

A

Rituximab is a mAb directed against CD20 on B cells, leading to profound decreases in B-cell counts

Effective in TNFalpha resistant Rheumatoid Arthritis

56
Q

When should Rituximab be given in Rheumatoid Arthritis?

A

Give Rituximab if Rheumatoid Arthritis does not respond to TNFalpha inhibitors like Infliximab

57
Q

What are the major limitations of biologics in treating any disease?

A

Biologics require parenteral adminstration

Produced in expensive mammalian cell-culture

58
Q

What is the next-next generation of targeted therapy in Rheumatoid Arthritis?

A

Targeted small molecules that can be administered orally and target intracellular proteins/signaling pathways

59
Q

How should potential small molecule and biologic therapeutics for Rheumatoid Arthritis be used in a patient?

A

Determine which is more likely to be more effective in each unique patient

MSK/Derm (46 decks)

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