3 - Interleukin 12/23 Inhibitors

Question 1

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

Answer 1

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

Question 2

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

Answer 2

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

Question 3

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

Answer 3

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)

Question 4

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

Answer 4

True

Question 5

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

Answer 5

True

Question 6

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

Answer 6

True

Question 7

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)

Answer 7

True

Question 8

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

Answer 8

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)

Question 9

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

Answer 9

True

Question 10

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

Answer 10

True

Question 11

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

Answer 11

True

Question 12

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

Answer 12

True

Question 13

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

Answer 13

True

Question 14

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

Answer 14

True

Question 15

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

Answer 15

True

Question 16

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

Answer 16

True

Question 17

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

Answer 17

True

Question 18

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

Answer 18

True

Question 19

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

Answer 19

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

Question 20

IL-23 is very important in the development of psoriasis

Answer 20

True

Question 21

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

Answer 21

True

Question 22

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

Answer 22

True (causing hyperproliferation of the keratinocytes in psoriasis)

Question 23

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

Answer 23

True

Question 24

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

Answer 24

True (IL-17 is pro-inflammatory)

Question 25

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

Answer 25

True (IL-23/Th17 axis)

Question 26

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

Answer 26

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)

Question 27

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

Answer 27

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

Question 28

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

Answer 28

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

Question 29

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

Answer 29

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

Question 30

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

Answer 30

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

Question 31

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

Answer 31

True

Question 32

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

Answer 32

True

Question 33

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

Answer 33

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

Question 34

The incidence of serious infections with ustekinumab treatment are low

Answer 34

True

Question 35

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

Answer 35

True

Question 36

The incidence of NMSCs in ustekinumab patients are low

Answer 36

True

Question 37

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

Answer 37

True

Question 38

The incidence of injection-site reactions to ustekinumab are low

Answer 38

True

Question 39

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

Answer 39

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

Question 40

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

Answer 40

True

Question 41

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

Answer 41

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

Question 42

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

Answer 42

True

Question 43

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

Answer 43

True

Question 44

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

Answer 44

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

Question 45

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

Answer 45

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

Question 46

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

Answer 46

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

Question 47

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

Answer 47

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)

Question 48

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

Answer 48

True

Question 49

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

Answer 49

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

Question 50

One of the most common adverse events with briakinumab is nasopharyngitis

Answer 50

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

Question 51

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

Answer 51

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

Question 52

One of the most common adverse events with briakinumab is headache

Answer 52

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

Question 53

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

Answer 53

True

Question 54

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

Answer 54

True

Question 55

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

Answer 55

True

Question 56

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

Answer 56

True

Question 57

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

Answer 57

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)

Question 58

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

Answer 58

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

Question 59

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

Answer 59

True

Question 60

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

Answer 60

True

Question 61

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

Answer 61

True

Question 62

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

Answer 62

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)

Question 63

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

Answer 63

True

Question 64

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

Answer 64

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

Question 65

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

Answer 65

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

Question 66

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

Answer 66

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