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Derm Pharm 2020 > 3 - Interleukin 12/23 Inhibitors > Flashcards

3 - Interleukin 12/23 Inhibitors Flashcards

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Dermatology Board Prep flashcards
1
Q

Newly developed biological agents (TNF-alpha inhibitors, IL-12/23 inhibitors, IL-17 inhibitor) have grown increasingly popular for the treatment of moderate-to-severe psoriasis, as clinical studies have shown these agents to be free of the major organ toxicities of methotrexate and CsA

A

True
TNF-alpha inhibitors = etanercept, infliximab, adalimumab
IL-12/23 inhibitors = ustekinumab, briakinumab
IL-17 inhibitor = secukinumab

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2
Q

Biologic agents have been very successful in treating psoriasis patients who have been unresponsive or unable to tolerate traditional therapies

A

True
TNF-alpha inhibitors = etanercept, infliximab, adalimumab
IL-12/23 inhibitors = ustekinumab, briakinumab
IL-17 inhibitor = secukinumab

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3
Q

Progressive multifocal leukoencephalopathy is a serious neurologic adverse event that is associated with T-cell inhibitors

A

True (psoriasis is a T-cell mediated disease and the cytokines TNF-alpha, IL-12/23 and IL-17 are produced by T-helper cells)

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4
Q

Ustekinumab is a fully human IgG monoclonal antibody that inhibits both the IL-12 and IL-23 pathways

A

True

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5
Q

Secukinumab is a fully human IgG monoclonal antibody that selectively inhibits IL-17 (hence targets the IL-23 pathway downstream)

A

True

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6
Q

Briakinumab is a recombinant fully human IgG monoclonal antibody that inhibits both the IL-12 and IL-23 pathways

A

True

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7
Q

Both ustekinumab and briakinumab (IL-12/23 inhibitors) were developed with fully human sequences (fully human monoclonal antibody) to avoid anti-foreign protein constituents, as seen with the development of human anti-chimeric antibody formation after therapy with infliximab (chimeric human-mouse monoclonal antibody)

A

True

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8
Q

Briakinumab (IL-12/23 inhibitor) clinical trials were halted after phase III data suggested significant cardiovascular risk

A

True (although meta-analysis of randomised controlled trials demonstrated no significant difference in the rate of major adverse cardiac events observed in anti-IL-12/23 agents or anti-TNF-alpha treatments compared to placebo)

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9
Q

IL-12 and IL-23 have been implicated as key players in the pathogenesis of psoriasis, as these cytokines direct naive T-cells to differentiate into pro-inflammatory Th1 (signalled by IL-12) and Th17 (signalled by IL-23) cells

A

True

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10
Q

Growing evidence implicates IL-12 and IL-23 and Th17 (which is directed by IL-23 to produce IL-17 and IL-22) in the pathogenesis of psoriasis and other autoimmune inflammatory conditions

A

True

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11
Q

The 2 pathways that influence psoriasis pathogenesis are:

(1) IL-12 pathway (Th1 axis) - produce IL-2, TNF-alpha, IFN-gamma
(2) IL-23 pathway (Th17 axis) - produce IL-17, IL-22 and TNF-alpha

A

True

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12
Q

IL-22 (part of the IL-23/Th17 axis) is primarily a downstream mediator of IL-23 induced inflammation and a major cause of hyperproliferation and acanthosis

A

True

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13
Q

IL-22 has been shown to work synergistically with IL-17 (both part of the IL-23/Th17 axis) and may play a key role in the pathological findings of psoriasis

A

True

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14
Q

The IL-23/Th17 axis has more influence over the induction of autoimmune-mediated inflammation than the IL-12/Th1 axis, thus the IL-23/Th17 axis may be a predominant pathway in the induction of autoimmune disease and is an essential pathway to understand and to guide treatment of T-cell-influenced inflammatory conditions such as psoriasis

A

True

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15
Q

Th17 cell produce distinct cytokines (primarily IL-17 and IL-22) and are governed by IL-23

A

True

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16
Q

IL-23/Th17 axis is a major factor in the pathogenesis of T-cell mediated inflammation

A

True

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17
Q

Th1 cells require IL-12 to support their development, whereas Th17 cells depend on the presence of IL-23 to function properly

A

True

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18
Q

IL-23 stimulates the survival and proliferation of Th17 cells which regulate the production of other inflammatory cytokines (IL-17, IL-22, TNF-alpha)

A

True

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19
Q

Psoriasis is primarily due to a complex interaction of particular immune cells and inflammatory cytokines, with Th17 cells and IL-12 and IL-23 playing a critical role

A

True (more so IL-23/Th17 axis axis)

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20
Q

IL-23 is very important in the development of psoriasis

A

True

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21
Q

IL-17 is more proinflammatory than IL-22 (both produced by Th17 cells governed by IL-23)

A

True

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22
Q

IL-22 (produced by Th17 cells governed by IL-23) retards keratinocyte differentiation

A

True (causing hyperproliferation of the keratinocytes in psoriasis)

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23
Q

IL-22 (produced by Th17 cells governed by IL-23) is increased in psoriatic lesions and in plasma, and these levels correlate with disease severity

A

True

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24
Q

Upregulated Th17 responses with resultant IL-17 production from T cells are evident in chronic inflammation

A

True (IL-17 is pro-inflammatory)

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25
Q

In psoriasis, the predominant T-cell population isolated from skin lesions has a Th17 phenotype and has been correlated to the attraction of inflammatory cells to epithelial tissues

A

True (IL-23/Th17 axis)

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26
Q

Factors influencing variation in apparent clearance of psoriasis in patients treated with ustekinumab include:

(1) body weight
(2) diabetes
(3) auto drug antibodies to ustekinumab

A

True (the most significant of these is body weight with the cut off of 100kg, therefore it is important to adjust the dose in those who have body weight >100kg to achieve similar efficacy)

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27
Q

Partial responders to ustekinumab represent a distinct group and usually have increased body weight

A

True
Key characteristics of this distinct group:
(1) increased body weight
(2) longer history of psoriasis
(3) have psoriatic arthritis
(4) have greater resistance to other biological agents

28
Q

Partial responders to ustekinumab represent a distinct group and usually have a longer history of psoriasis

A

True
Key characteristics of this distinct group:
(1) increased body weight
(2) longer history of psoriasis
(3) have psoriatic arthritis
(4) have greater resistance to other biological agents

29
Q

Partial responders to ustekinumab represent a distinct group and usually have psoriatic arthritis

A

True
Key characteristics of this distinct group:
(1) increased body weight
(2) longer history of psoriasis
(3) have psoriatic arthritis
(4) have greater resistance to other biological agents

30
Q

Partial responders to ustekinumab represent a distinct group and usually have a greater resistance to other biological agents

A

True
Key characteristics of this distinct group:
(1) increased body weight
(2) longer history of psoriasis
(3) have psoriatic arthritis
(4) have greater resistance to other biological agents

31
Q

A high percentage of partial responders also had neutralising/anti drug antibodies against ustekinumab

A

True

32
Q

Ustekinumab gives a rapid, clinically significant improvement in patients with moderate-to-severe psoriasis including those who have failed prior biological or conventional systemic therapies

A

True

33
Q

Adverse events to ustekinumab have been relatively mild, with the majority being susceptibility to mild infections such as nasopharyngitis and upper respiratory tract infections

A

True (although rates were not higher in the ustekinumab patients than in placebo)

34
Q

The incidence of serious infections with ustekinumab treatment are low

A

True

35
Q

The incidence of malignancies (other than NMSCs) in ustekinumab patients are low

A

True

36
Q

The incidence of NMSCs in ustekinumab patients are low

A

True

37
Q

The incidence of neutralising/anti drug antibodies to ustekinumab are low

A

True

38
Q

The incidence of injection-site reactions to ustekinumab are low

A

True

39
Q

There has been an imbalance in the number of major adverse cardiac events in the first 12 weeks of the trial involving ustekinumab patients, although a high proportion of patients recruited into psoriasis clinical trials had cardiovascular risk factors such as obesity, smoking, hypertension and diabetes

A

True (there are confounding factors) - increased major adverse cardiac events seen in the first 12 weeks of anti-IL-12/23 therapy is not due to the medication itself, as the risk appears to be due to disease status I.e. Severe inflammatory condition, and/or the patient population I.e. Associated comorbidities predisposing to cardiovascular events

40
Q

Overall compared to placebo, there is no significant difference in the rate of major adverse cardiac events observed in patients receiving anti-IL-12/23 antibodies or anti-TNF-alpha treatments

A

True

41
Q

IL-2 and Th1 cells (the IL-12/Th1 axis) are important in fighting infections, especially those caused by mycobacteria and salmonella

A

True (IL-23 is also a key mediator for immunity against these infections)

42
Q

Cytokines IL-12 and IL-23 are key mediators for immunity against certain infections such as mycobacteria and salmonella

A

True

43
Q

Patients diagnosed with latent TB upon screening were allowed into ustekinumab trials as along as they had received appropriate anti-TB therapy and active disease had been ruled out

A

True

44
Q

Thus far no cases of TB, atypical mycobacteria or salmonella infections have been reported in patients treated with IL-12/23 antibodies

A

True (both cytokines are key mediators for immunity against mycobacteria and salmonella infections)

45
Q

Patients with a history of active or latent TB which had been treated prior to starting IL-12/23 inhibitors should be closely monitored with yearly TB screening and/or CXR whilst on IL-12/23 inhibitor treatment

A

True (IL12/23 cytokines are key mediators for immunity against mycobacteria)

46
Q

Prior to treatment with an IL12/23 inhibitor, patients with active or latent TB should be treated with appropriate anti-TB therapy as the risk of TB infections and the targeting of proinflammatory cytokines involved have not been completely elucidated

A

True (IL12/23 cytokines are key mediators for immunity against mycobacteria)

47
Q

The role of IL-12/23 inhibitor therapy in the development of malignancies is not yet known

A

True (there is some evidence that IL-12 has anti-tumour activity, and IL-23 and IL-17 are favourable to the growth of tumours)

48
Q

In contrast to TNF-alpha inhibitors, ustekinumab did not cause any new onset or exacerbation of CNS demyelinating disorders

A

True

49
Q

One of the most common adverse events with briakinumab is injection-site reaction

A

True

(1) injection site reaction
(2) nasopharyngitis
(3) upper respiratory tract infection
(4) headache

50
Q

One of the most common adverse events with briakinumab is nasopharyngitis

A

True

(1) injection site reaction
(2) nasopharyngitis
(3) upper respiratory tract infection
(4) headache

51
Q

One of the most common adverse events with briakinumab is upper respiratory tract infection

A

True

(1) injection site reaction
(2) nasopharyngitis
(3) upper respiratory tract infection
(4) headache

52
Q

One of the most common adverse events with briakinumab is headache

A

True

(1) injection site reaction
(2) nasopharyngitis
(3) upper respiratory tract infection
(4) headache

53
Q

Infrequent dosing schedules, ease of administration and long term remissions make the newer monoclonal antibodies convenient and economical treatment options

A

True

54
Q

The efficacy of ustekinumab is affected by body weight and a weight of 100kg has been determined to best differentiate the dose response

A

True

55
Q

In the clinical trials, body weight was found to be a significant cofactor regarding interpatient variability of systemic exposure to ustekinumab

A

True

56
Q

In the clinical trials, body weight was found to be the reason for lower efficacy of the low dose compared with the high dose in heavier patents

A

True

57
Q

Higher weight-based dosage of ustekinumab did not affect the safety profile of ustekinumab

A

True (thus in overweight psoriasis patients, ustekinumab may provide increased efficacy as compared to the fixed-dose biologics that may be compromised by high body weight)

58
Q

Flexibility of ustekinumab up to 90mg every 8 weeks might benefit the subgroup of patients who have treatment-resistant disease

A

True (frequency is usually every 12 weeks, dose for patents >100kg is 90mg whereas dose for patients <100kg is 45mg)

59
Q

Although ustekinumab is appealing because of its long half-life allowing for improved patient adherence and infrequent dosing as well as improved efficacy and safety profile, this advantage could prove detrimental in patients with infection or any issues necessitating discontinuation of treatment in which a drug with a shorter half-life may be preferred

A

True

60
Q

Ustekinumab (and similar IL-12/23 agents) is especially beneficial for patients with refractory psoriasis who have failed or are intolerant of other systemic and/or biologic therapies

A

True

61
Q

Although IL-12 deficiency is associated with increased susceptibility to intracellular pathogens/infections, the risk of increased infections have not been a significant issue with IL-12/23 inhibitors such as Ustekinumab

A

True

62
Q

The risk of malignancy with the IL-12/23 inhibitors (and other biological therapies) remains unclear

A

True (studies have shown that TNF-alpha inhibitors may cause a slightly increased risk of cancer including NMSCs and haematologic malignancies, although this data is derived from treatment of patients with rheumatoid arthritis which is a systemic inflammatory disorder that has a greater risk of carcinogenesis than psoriasis)

63
Q

Human-derived monoclonal antibodies is theoretically less immunogenic than chimeric monoclonal antibodies such as infliximab, therefore the risk of infusion reactions and loss of treatment efficacy over time due to development of neutralising anti-drug antibodies is less likely

A

True

64
Q

To circumvent the development of neutralising/anti-drug antibodies and possible loss of efficacy, the following 1 of 3 strategies can be considered:
(1) multidose regimen at the beginning of treatment to induce immunological tolerance

A

True

(1) multidose regimen at the beginning of treatment to induce immunological tolerance
(2) concomitant immunosuppressive therapy I.e. Methotrexate
(3) systematic maintenance dosing

65
Q

To circumvent the development of neutralising/anti-drug antibodies and possible loss of efficacy, the following 1 of 3 strategies can be considered:
(2) concomitant immunosuppressive therapy I.e. Methotrexate

A

True

(1) multidose regimen at the beginning of treatment to induce immunological tolerance
(2) concomitant immunosuppressive therapy I.e. Methotrexate
(3) systematic maintenance dosing

66
Q

To circumvent the development of neutralising/anti-drug antibodies and possible loss of efficacy, the following 1 of 3 strategies can be considered:
(3) systematic maintenance dosing

A

True

(1) multidose regimen at the beginning of treatment to induce immunological tolerance
(2) concomitant immunosuppressive therapy I.e. Methotrexate
(3) systematic maintenance dosing

Derm Pharm 2020 (47 decks)

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