Continuing Education Activity

Psoriasis is a common skin disease that affects about 2% of the US population. The most common form is plaque-type. Ixekizumab is FDA-indicated for the adult treatment of moderate to severe plaque psoriasis. These adult patients are also candidates for systemic therapy or phototherapy. Safety and effectiveness have been determined in pediatric patients. Psoriasis will be briefly discussed to become familiar with ixekizumab's mechanism of action and its therapeutic use. This activity highlights the role of the interprofessional team in managing patients prescribed ixekizumab for psoriasis.

Objectives:

• Describe the mechanism of action of ixekizumab.
• Review the therapeutic uses of ixekizumab.
• Explain the potential side effects of ixekizumab.
• Outline the importance of collaboration and coordination among the interprofessional team to enhance patient care when dosing and monitoring ixekizumab treatment for psoriasis.

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.[1][2][3] 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.[4][5]

Ixekizumab should be used cautiously during breastfeeding, especially with newborns and preterm infants.[6]

Ixekizumab is safe and effective in treating axial spondylarthritis.[7] Future studies should compare ixekizumab to other biologic drugs and examine patient characteristics like sex, HLA-B27 status, baseline bone marrow edema, and disease duration.

Hawkes J. et al. used multiple dynamic visualization techniques in several clinical trials, demonstrating that ixekizumab has a rapid reduction in disease severity and sustained efficacy in treating skin and nail psoriasis.[8]

Landewé R. et al. are conducting a phase III clinical trial (COAST-Y) to examine continuing or withdrawing ixekizumab therapy in axial spondyloarthritis patients who have attained disease remission.[9]

Coates L. et al. conducted a clinical trial on psoriatic arthritis patients receiving ixekizumab therapy.[10] The investigators were examining the effect of withdrawing ixekizumab therapy in patients who achieved minimal disease activity. Continuing ixekizumab therapy was found to be superior when compared to withdrawing therapy in sustaining minimal disease activity. Also, in patients who experienced relapse because of treatment interruption, ixekizumab retreatment can restore disease control.

Next, a brief discussion of psoriasis will follow to understand better the mechanism of action of ixekizumab and its therapeutic use. 

Psoriasis is a common skin disease that affects about 2% of the US population. The most common form is plaque-type. Examples of types of psoriasis are inverse, guttate, and pustular. Plaque-type psoriasis is a chronic inflammatory skin disease with the following clinical characteristics: erythematous plaques with mica-like scales, sharply demarcated, predominately affecting the elbows, knees, gluteal cleft, and scalp. The skin plaques can be pruritic, slowly enlarge, and last long periods. Approximately 30% of psoriasis patients have psoriatic arthritis in five subtypes: arthritis mutilans, asymmetric, distal interphalangeal predominant, spondylitis, and symmetric.

Arthritis mutilans, which account for less than 5% of psoriatic arthritis cases, is severe and can deform the small joints of 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. Symmetric arthritis can present as a milder form of rheumatoid arthritis. The pathophysiology of psoriasis is not well understood.

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. It has six 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.[11]

Mechanism of Action

Ixekizumab is a humanized monoclonal antibody (IgG) that selectively binds to interleukin 17A (IL-17A); this prevents interleukin 17A from binding to the IL-17 receptor. Thus, 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 cell T17. Along with other immune cells, T17 produces interleukin 17A. This proinflammatory cascade causes the proliferation of keratinocytes, angiogenesis, and movement of immune cells in psoriatic skin lesions. Thus, ixekizumab disrupts the pathogenic inflammatory cascade of psoriasis.

Ixekizumab was the object of study in three 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 one of three groups. The two-week group received a 160 mg starting dose at week zero and 80 mg every two weeks for 12 weeks. The four-week group received 160 mg starting dose at week zero, 80 mg every four weeks for 12 weeks. The placebo group received a placebo for 12 weeks. The measurement of therapeutic efficacy was via 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 two-week, four-week, and placebo groups had the following psoriasis area and severity index (PASI) 90 scores: 70.9%, 64.6%, and 0.5%, respectively, which were statistically significant when researchers compared the two treatment groups to 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 two-week, four-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 two-week, four-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 binds to and inhibits the inflammatory cytokine tumor necrosis factor (TNF). It is a synthetic TNF receptor.[16]

Herrera-Acosta E et al. reported on 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 which is overexpression of the Th17 pathway. Ixekizumab treatment led to complete skin clearance with no adverse side effects. Also, there appeared to be no progression of the patient’s multiple sclerosis.

Berman J. 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 six months of treatment was better than at 12 months of therapy.

Administration

Ixekizumab administration is subcutaneous. Storage should be at 2 to 8 degrees Celsius (36 to 46 degrees Fahrenheit). 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 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 the following (all doses administered subcutaneously).

For moderate to severe plaque psoriasis:

• 160 mg once on week 0, then 80 mg every 2 weeks for 12 weeks
• 80 mg every four weeks thereafter

For psoriatic arthritis or ankylosing spondylitis:

• 160 mg once on week 0, then 80 mg every four weeks

For non-radiographic axial spondyloarthritis:

• 80 mg SQ every 4 weeks

There are no documented maximum doses for indicated use. There are no studies for dose adjustment in patients with renal or hepatic impairment.[19][20]

Adverse Effects

Commonly observed (over 10%) adverse drug reactions in patients who have treatment with ixekizumab are: neutropenia, hypersensitivity reactions, e.g., urticaria and angioedema, infections, injection site reactions, e.g., pain. Less commonly observed (less than 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 are 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 J. et al. conducted research from several clinical trials on the safety and efficacy of ixekizumab in treating psoriatic arthritis.[23] Ixekizumab caused greater injection site reactions when compared to placebo or adalimumab. Ixekizumab had fewer serious adverse events when compared to adalimumab. Ixekizumab was efficacious in treating psoriatic arthritic disease and slowed radiographic disease progression. The researchers cite a need for more African Americans in future studies.

Romozzi M. 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 unspecific. Ixekizumab re-exposure caused similar neurological effects.

Contraindications

Patient contraindications include a severe hypersensitivity reaction, for example, anaphylaxis resulting from ixekizumab itself or any excipients in the dosage form.[25] Contraindications also include active infection, particularly with TB.

Monitoring

Recommendations are that patients receiving treatment with ixekizumab receive monitoring for signs of infection, such as tuberculosis and inflammatory bowel disease, including exacerbations. 

Toxicity

There are no specific antidotes for an overdose of ixekizumab.

Enhancing Healthcare Team Outcomes

The entire interprofessional healthcare team, e.g., clinicians (MDs, DOs, PAs, NPs), specialists (e.g., rheumatologists), nurses, pharmacists, etc., need to work together to ensure the safety and efficacy of ixekizumab therapy. The patient needs training on how to correctly self-administer and store ixekizumab; the clinician, nurse, or pharmacist can perform this education. In fact, it may serve the patient well to hear 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. Nursing can monitor adverse events, make preliminary assessments of treatment effectiveness on subsequent visits, and verify patient adherence to pharmacotherapy.

Both nurses and pharmacists need to have an open communication line with the prescribing clinician to report or discuss any concerns regarding ixekizumab therapy or the patient drug regimen. This type of open interprofessional healthcare team communication is necessary to optimize patient outcomes with minimal adverse events. [Level 5]