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Ixekizumab
Indications
Psoriasis is a skin disease that affects about 2% of the US population. This condition has various subtypes, including inverse, guttate, and pustular; the most common form is plaque-type. Plaque-type psoriasis is a chronic inflammatory skin disease characterized by sharply demarcated, erythematous plaques that predominantly affect the elbows, knees, gluteal cleft, and scalp, often accompanied by mica-like scales. The skin plaques can be pruritic, slowly enlarging, and persist for a long time. Approximately 30% of patients with psoriasis develop psoriatic arthritis, which can be classified into 5 subtypes: arthritis mutilans, asymmetric, distal interphalangeal predominant, spondylitis, and symmetric.
Arthritis mutilans, which is present in fewer than 5% of psoriatic arthritis cases, is a severe condition characterized by the deformation of the small joints in the hands and feet. Asymmetric arthritis can affect any joint and may appear as sausage digits or dactylitis. Distal interphalangeal predominant can involve the fingers and toes, occurring in about 5% of psoriatic arthritis cases. Spondylitis or spondyloarthritis can affect the spine or pelvis, accounting for about 5% of psoriatic arthritis cases. Symmetrical arthritis can present as a milder form of rheumatoid arthritis.
The pathophysiology of psoriasis is not well understood. However, there is a genetic aspect to the disease, with about 50% of the patients having a family history. Activated T cells appear to produce cytokines, which lead to hyperproliferation of keratinocytes and endothelial cells. Interleukin 17A (IL-17A) is an example of a cytokine that ixekizumab selectively inhibits. This hyperproliferation of keratinocytes and endothelial cells causes the erythematous plaques with mica-like scales to form on the elbows, knees, or scalp. Interleukin 17 is a crucial mediator in the mammalian immune system. This mediator has 6 subtypes: IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, and IL-17F. Drugs that inhibit T cell activation, clonal expansion, or release (or activity) of proinflammatory cytokines can effectively treat psoriasis.[1]
FDA-Approved Indications
Ixekizumab is FDA-indicated for the adult treatment of moderate to severe plaque psoriasis, active psoriatic arthritis, active ankylosing spondylitis, and active non-radiographic axial spondyloarthritis with objective signs of inflammation.[2][3][4] These adult patients are also candidates for systemic therapy or phototherapy. Research has now determined the safety and effectiveness in pediatric patients for whom it is FDA-indicated.[5][6]
Ixekizumab should be used cautiously during breastfeeding, especially with newborns and preterm infants, because of limited clinical data.[7] Holding ixekizumab therapy for at least 2 weeks postpartum may minimize exposure to the baby. Ixekizumab is a large protein (146 KDa). The amount distributed to the breast milk is likely to be low, and the amount absorbed by the baby’s GI tract is also expected to be low, with some degradation of the protein in the GI tract.
Ixekizumab is safe and effective in treating axial spondylarthritis.[8] Future studies should compare ixekizumab to other biologic drugs and examine patient characteristics, such as sex, HLA-B27 status, baseline bone marrow edema, and disease duration.
Ixekizumab is safe and effective in treating non-radiographic axial spondyloarthritis, a condition that affects the spine, particularly the sacroiliac joints.[8] X-ray imaging studies might not be able to detect the degree of spinal damage.
Hawkes et al used multiple dynamic visualization techniques in several clinical trials, demonstrating that ixekizumab results in a rapid reduction in disease severity and sustained efficacy in treating skin and nail psoriasis.[9]
Landewé et al are conducting a Phase III clinical trial (COAST-Y) to examine the continuation or withdrawal of ixekizumab therapy in patients with axial spondyloarthritis who have achieved disease remission.[10]
Coates et al conducted a clinical trial on patients with psoriatic arthritis who received ixekizumab therapy.[11] The investigators examined the effect of withdrawing ixekizumab therapy in patients who achieved minimal disease activity. Continuing ixekizumab therapy was found to be superior to withdrawing therapy in sustaining minimal disease activity. Additionally, ixekizumab retreatment can restore disease control in patients who experienced relapse because of treatment interruption.
Mechanism of Action
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Mechanism of Action
Ixekizumab is a humanized monoclonal antibody (IgG) that selectively binds to interleukin-17A (IL-17A), thereby preventing it from binding to the IL-17 receptor. This attenuates an inflammatory response mediated by interleukin-17A.[12] Psoriasis is caused by upregulated immune-related mechanisms that activate myeloid dendritic cells, which release interleukin-17A and other cytokines to activate T cells, including helper T cells of the T17 subtype. Along with other immune cells, T17 produces interleukin 17A. This proinflammatory cascade triggers the proliferation of keratinocytes, angiogenesis, and the migration of immune cells in psoriatic skin lesions. Thus, ixekizumab disrupts the pathogenic inflammatory cascade of psoriasis.
Ixekizumab was studied in 3 clinical phase trials: UNCOVER-1, UNCOVER-2, and UNCOVER-3.[13] UNCOVER-1 compared ixekizumab treatment in 1296 patients with psoriasis. Researchers randomly assigned patients to 1 of 3 groups. The 2-week group initially received a 160-mg starting dose, followed by 80 mg every 2 weeks for 12 weeks. The 4-week group initially received a 160 mg starting dose, 80 mg every 4 weeks for 12 weeks. The placebo group received a placebo for 12 weeks. The measurement of therapeutic efficacy was assessed using the Psoriasis Area and Severity Index (PASI) score. A psoriasis area and severity index (PASI) score of 90 indicates a 90% reduction in the psoriasis skin lesion area. At the end of 12 weeks, the 2-week, 4-week, and placebo groups had the following psoriasis area and severity index (PASI) 90 scores: 70.9%, 64.6%, and 0.5%, respectively. These scores were statistically significant when researchers compared the 2 treatment groups to the placebo.
UNCOVER-2 compared ixekizumab treatment in 1224 patients with psoriasis. The same UNCOVER-1 treatment regimens were used, with the additional treatment group receiving etanercept 50 mg twice a week for 12 weeks. At the end of 12 weeks, the 2-week, 4-week, etanercept, and placebo groups had the following psoriasis area and severity index (PASI) 90 scores: 70.7%, 59.7%, 18.7%, and 0.6%, respectively, which were statistically significant when researchers compared the ixekizumab treatment groups to etanercept and placebo.[14]
UNCOVER-3 compared ixekizumab treatment in 1346 patients with psoriasis. The study used the same treatment regimens as in UNCOVER-2. At the end of 12 weeks, the 2-week, 4-week, etanercept, and placebo groups had the following psoriasis area and severity index (PASI) 90 scores: 68.1%, 65.3%, 25.7%, and 3.1%, respectively, which were statistically significant when researchers compared the ixekizumab treatment groups to etanercept and placebo.[15] Etanercept is a synthetic TNF receptor that binds to and inhibits the inflammatory cytokine tumor necrosis factor (TNF).[16]
Herrera-Acosta et al reported a case involving a 50-year-old man with multiple sclerosis and chronic plaque psoriasis.[17] The patient received treatment with ixekizumab for his plaque psoriasis. Multiple sclerosis and plaque psoriasis share a common pathophysiological pathway, characterized by the overexpression of the Th17 pathway. Ixekizumab treatment led to complete skin clearance with no adverse side effects. Additionally, there appeared to be no progression of the patient’s multiple sclerosis.
Berman et al conducted a clinical trial on 23 patients with psoriatic arthritis.[18] The patients were initially taking secukinumab but did not experience an adequate response to therapy. The patients then received treatment with ixekizumab. The majority of the patients experienced a positive response to ixekizumab therapy. However, the response at 6 months of treatment was better than at 12 months of therapy.
Administration
Ixekizumab is administered subcutaneously. This drug should be stored at 2 °C to 8 °C (36 °F to 46 °F). The ixekizumab dosage form should not be frozen, and it requires protection from light. The patient should discard the unused portion of the dosage. The patient should remove ixekizumab from the refrigerator and let it warm to room temperature, which will take approximately 30 minutes. Next, the patient should visually inspect the ixekizumab liquid, which should be free of particles and have a clear to slightly yellow color. The patient should not shake the autoinjector or prefilled syringe. Lastly, the patient should inject ixekizumab subcutaneously at the directed dose. Recommended injection sites are the thighs, upper arms, or abdomen, which the patient should rotate to prevent damage to the skin. The patient should avoid injecting sites that are affected by psoriasis, are bruised, or are damaged.
The recommended dosing is discussed below.
For moderate to severe plaque psoriasis: 160 mg as a single initial dose, followed by 80 mg every 2 weeks for 12 weeks, then 80 mg every 4 weeks thereafter
For psoriatic arthritis or ankylosing spondylitis: 160 mg once initially, then 80 mg every 4 weeks
For nonradiographic axial spondyloarthritis: 80 mg SQ every 4 weeks
There are no documented maximum doses for indicated use. No studies have shown the need for dose adjustment in patients with renal or hepatic impairment.[19][20]
Adverse Effects
Commonly observed (>10%) adverse drug reactions in patients who have treatment with ixekizumab include neutropenia, hypersensitivity reactions (eg, urticaria and angioedema), infections, and injection site reactions (eg, pain). Less commonly observed (<10%), adverse drug reactions are fungal skin infections (tinea), nausea, thrombocytopenia, and antibody development. Antibody development can decrease the concentrations of ixekizumab and decrease drug efficacy. Less than 1% of observed adverse drug reactions include Crohn disease, ulcerative colitis, oral candidiasis (Candida albicans infection), influenza, conjunctivitis, and rhinitis. Crohn disease and ulcerative colitis include exacerbations in susceptible patients.[21][22]
Miller et al conducted research on the safety and efficacy of ixekizumab in treating psoriatic arthritis based on several clinical trials.[23] Ixekizumab caused greater injection site reactions compared to placebo or adalimumab. Ixekizumab had fewer serious adverse events than adalimumab. Ixekizumab was efficacious in treating psoriatic arthritic disease and slowed radiographic disease progression. The researchers cite a need for more African Americans to be included in future studies.
Romozzi et al reported that a 28-year-old man with psoriatic arthritis developed cervical myelitis during ixekizumab treatment.[24] A T2 hyperintense lesion was noted on a spinal MRI at the C4-C5 level. However, the brain MRI was nonspecific. Ixekizumab re-exposure caused similar neurological effects.
Some patients may experience ixekizumab-induced urticaria, which is believed to be mediated by mast cell activation.[25] This can cause early psoriasis relapse after completing ixekizumab therapy.
A 62-year-old woman is reported to have ixekizumab-induced interstitial lung disease. The patient received treatment with ixekizumab for psoriasis, and she presented with symptoms of pulmonary embolism, which were consistent with interstitial lung disease.[26]
Contraindications
Patient contraindications include severe hypersensitivity reactions, such as anaphylaxis, resulting from ixekizumab itself or any excipients in the dosage form.[27] Contraindications also include active infection, particularly with TB.
Monitoring
It is recommended that patients receiving ixekizumab be monitored for signs of infection, including tuberculosis, as well as for new or worsening symptoms of inflammatory bowel disease.
Toxicity
There are no specific antidotes for an overdose of ixekizumab.
Enhancing Healthcare Team Outcomes
The interprofessional healthcare team must collaborate to ensure the safety and efficacy of ixekizumab therapy. The patient requires training on the correct self-administration and storage of ixekizumab; the clinician, nurse, or pharmacist provide this education. Patients may benefit well from hearing it from multiple providers to optimize therapy. Notably, the interprofessional team needs to monitor for signs of severe infection and exacerbation of inflammatory bowel disease. The pharmacist should verify the dosing and perform a drug interaction check. Nurses can monitor adverse events, assess treatment effectiveness on subsequent visits, and verify patient adherence to pharmacotherapy.
Both nurses and pharmacists must maintain an open line of communication with the prescribing clinician to report or discuss any concerns regarding ixekizumab therapy or the patient's medication regimen. Open interprofessional communication within healthcare teams is necessary to optimize patient outcomes and minimize adverse events.
References
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Blegvad C, Skov L, Zachariae C. Ixekizumab for the treatment of psoriasis: an update on new data since first approval. Expert review of clinical immunology. 2019 Feb:15(2):111-121. doi: 10.1080/1744666X.2019.1559730. Epub 2018 Dec 27 [PubMed PMID: 30589394]
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Atzeni F, Carriero A, Boccassini L, D'Angelo S. Anti-IL-17 Agents in the Treatment of Axial Spondyloarthritis. ImmunoTargets and therapy. 2021:10():141-153. doi: 10.2147/ITT.S259126. Epub 2021 May 3 [PubMed PMID: 33977094]
Libon F, Lebas E, De Schaetzen V, Sabatiello M, De Schepper S, Nikkels AF. Biologicals for moderate-to-severe plaque type psoriasis in pediatric patients. Expert review of clinical immunology. 2021 Sep:17(9):947-955. doi: 10.1080/1744666X.2021.1958675. Epub 2021 Jul 30 [PubMed PMID: 34328370]
Cather JC, Young CT, Young MS, Cather JC. Ixekizumab for the treatment of pediatric patients with moderate to severe plaque psoriasis. Expert opinion on biological therapy. 2021 Aug:21(8):983-990. doi: 10.1080/14712598.2021.1931679. Epub 2021 Jun 9 [PubMed PMID: 34106794]
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Harrison SR, Marzo-Ortega H. Ixekizumab: an IL-17A inhibitor for the treatment of axial Spondylarthritis. Expert review of clinical immunology. 2021 Oct:17(10):1059-1071. doi: 10.1080/1744666X.2021.1970534. Epub 2021 Aug 26 [PubMed PMID: 34407705]
Hawkes JE, See K, Burge R, Strakbein S, McKean-Matthews M, Saure D, Gooderham M, Leonardi C. Dynamic Visual Representation of Clinical Efficacy of Ixekizumab in Psoriasis. Dermatology and therapy. 2021 Aug:11(4):1107-1118. doi: 10.1007/s13555-021-00548-2. Epub 2021 May 29 [PubMed PMID: 34050899]
Landewé RB, Gensler LS, Poddubnyy D, Rahman P, Hojnik M, Li X, Liu Leage S, Adams D, Carlier H, Van den Bosch F, COAST-Y study group. Continuing versus withdrawing ixekizumab treatment in patients with axial spondyloarthritis who achieved remission: efficacy and safety results from a placebo-controlled, randomised withdrawal study (COAST-Y). Annals of the rheumatic diseases. 2021 Aug:80(8):1022-1030. doi: 10.1136/annrheumdis-2020-219717. Epub 2021 May 6 [PubMed PMID: 33958326]
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Level 1 (high-level) evidenceDong J, Goldenberg G. New biologics in psoriasis: an update on IL-23 and IL-17 inhibitors. Cutis. 2017 Feb:99(2):123-127 [PubMed PMID: 28319618]
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Level 1 (high-level) evidenceDeodhar A, Poddubnyy D, Pacheco-Tena C, Salvarani C, Lespessailles E, Rahman P, Järvinen P, Sanchez-Burson J, Gaffney K, Lee EB, Krishnan E, Santisteban S, Li X, Zhao F, Carlier H, Reveille JD, COAST-W Study Group. Efficacy and Safety of Ixekizumab in the Treatment of Radiographic Axial Spondyloarthritis: Sixteen-Week Results From a Phase III Randomized, Double-Blind, Placebo-Controlled Trial in Patients With Prior Inadequate Response to or Intolerance of Tumor Necrosis Factor Inhibitors. Arthritis & rheumatology (Hoboken, N.J.). 2019 Apr:71(4):599-611. doi: 10.1002/art.40753. Epub 2019 Mar 8 [PubMed PMID: 30343531]
Level 1 (high-level) evidencePhilipose J, Ahmed M, Idiculla PS, Mulrooney SM, Gumaste VV. Severe de novo Ulcerative Colitis following Ixekizumab Therapy. Case reports in gastroenterology. 2018 Sep-Dec:12(3):617-621. doi: 10.1159/000493922. Epub 2018 Oct 17 [PubMed PMID: 30483039]
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Level 3 (low-level) evidence