3 - Interleukin 12/23 Inhibitors Flashcards
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
True
TNF-alpha inhibitors = etanercept, infliximab, adalimumab
IL-12/23 inhibitors = ustekinumab, briakinumab
IL-17 inhibitor = secukinumab
Biologic agents have been very successful in treating psoriasis patients who have been unresponsive or unable to tolerate traditional therapies
True
TNF-alpha inhibitors = etanercept, infliximab, adalimumab
IL-12/23 inhibitors = ustekinumab, briakinumab
IL-17 inhibitor = secukinumab
Progressive multifocal leukoencephalopathy is a serious neurologic adverse event that is associated with T-cell inhibitors
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)
Ustekinumab is a fully human IgG monoclonal antibody that inhibits both the IL-12 and IL-23 pathways
True
Secukinumab is a fully human IgG monoclonal antibody that selectively inhibits IL-17 (hence targets the IL-23 pathway downstream)
True
Briakinumab is a recombinant fully human IgG monoclonal antibody that inhibits both the IL-12 and IL-23 pathways
True
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)
True
Briakinumab (IL-12/23 inhibitor) clinical trials were halted after phase III data suggested significant cardiovascular risk
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)
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
True
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
True
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
True
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
True
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
True
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
True
Th17 cell produce distinct cytokines (primarily IL-17 and IL-22) and are governed by IL-23
True
IL-23/Th17 axis is a major factor in the pathogenesis of T-cell mediated inflammation
True
Th1 cells require IL-12 to support their development, whereas Th17 cells depend on the presence of IL-23 to function properly
True
IL-23 stimulates the survival and proliferation of Th17 cells which regulate the production of other inflammatory cytokines (IL-17, IL-22, TNF-alpha)
True
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
True (more so IL-23/Th17 axis axis)
IL-23 is very important in the development of psoriasis
True
IL-17 is more proinflammatory than IL-22 (both produced by Th17 cells governed by IL-23)
True
IL-22 (produced by Th17 cells governed by IL-23) retards keratinocyte differentiation
True (causing hyperproliferation of the keratinocytes in psoriasis)
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
True
Upregulated Th17 responses with resultant IL-17 production from T cells are evident in chronic inflammation
True (IL-17 is pro-inflammatory)
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
True (IL-23/Th17 axis)
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
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)
Partial responders to ustekinumab represent a distinct group and usually have increased body weight
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
Partial responders to ustekinumab represent a distinct group and usually have a longer history of psoriasis
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
Partial responders to ustekinumab represent a distinct group and usually have psoriatic arthritis
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
Partial responders to ustekinumab represent a distinct group and usually have a greater resistance to other biological agents
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
A high percentage of partial responders also had neutralising/anti drug antibodies against ustekinumab
True
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
True
Adverse events to ustekinumab have been relatively mild, with the majority being susceptibility to mild infections such as nasopharyngitis and upper respiratory tract infections
True (although rates were not higher in the ustekinumab patients than in placebo)
The incidence of serious infections with ustekinumab treatment are low
True
The incidence of malignancies (other than NMSCs) in ustekinumab patients are low
True
The incidence of NMSCs in ustekinumab patients are low
True
The incidence of neutralising/anti drug antibodies to ustekinumab are low
True
The incidence of injection-site reactions to ustekinumab are low
True
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
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
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
True
IL-2 and Th1 cells (the IL-12/Th1 axis) are important in fighting infections, especially those caused by mycobacteria and salmonella
True (IL-23 is also a key mediator for immunity against these infections)
Cytokines IL-12 and IL-23 are key mediators for immunity against certain infections such as mycobacteria and salmonella
True
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
True
Thus far no cases of TB, atypical mycobacteria or salmonella infections have been reported in patients treated with IL-12/23 antibodies
True (both cytokines are key mediators for immunity against mycobacteria and salmonella infections)
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
True (IL12/23 cytokines are key mediators for immunity against mycobacteria)
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
True (IL12/23 cytokines are key mediators for immunity against mycobacteria)
The role of IL-12/23 inhibitor therapy in the development of malignancies is not yet known
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)
In contrast to TNF-alpha inhibitors, ustekinumab did not cause any new onset or exacerbation of CNS demyelinating disorders
True
One of the most common adverse events with briakinumab is injection-site reaction
True
(1) injection site reaction
(2) nasopharyngitis
(3) upper respiratory tract infection
(4) headache
One of the most common adverse events with briakinumab is nasopharyngitis
True
(1) injection site reaction
(2) nasopharyngitis
(3) upper respiratory tract infection
(4) headache
One of the most common adverse events with briakinumab is upper respiratory tract infection
True
(1) injection site reaction
(2) nasopharyngitis
(3) upper respiratory tract infection
(4) headache
One of the most common adverse events with briakinumab is headache
True
(1) injection site reaction
(2) nasopharyngitis
(3) upper respiratory tract infection
(4) headache
Infrequent dosing schedules, ease of administration and long term remissions make the newer monoclonal antibodies convenient and economical treatment options
True
The efficacy of ustekinumab is affected by body weight and a weight of 100kg has been determined to best differentiate the dose response
True
In the clinical trials, body weight was found to be a significant cofactor regarding interpatient variability of systemic exposure to ustekinumab
True
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
True
Higher weight-based dosage of ustekinumab did not affect the safety profile of ustekinumab
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)
Flexibility of ustekinumab up to 90mg every 8 weeks might benefit the subgroup of patients who have treatment-resistant disease
True (frequency is usually every 12 weeks, dose for patents >100kg is 90mg whereas dose for patients <100kg is 45mg)
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
True
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
True
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
True
The risk of malignancy with the IL-12/23 inhibitors (and other biological therapies) remains unclear
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)
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
True
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
True
(1) multidose regimen at the beginning of treatment to induce immunological tolerance
(2) concomitant immunosuppressive therapy I.e. Methotrexate
(3) systematic maintenance dosing
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
True
(1) multidose regimen at the beginning of treatment to induce immunological tolerance
(2) concomitant immunosuppressive therapy I.e. Methotrexate
(3) systematic maintenance dosing
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
True
(1) multidose regimen at the beginning of treatment to induce immunological tolerance
(2) concomitant immunosuppressive therapy I.e. Methotrexate
(3) systematic maintenance dosing
