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Evolving Treatment Strategies in Type 2 Inflammatory Disease

Treatment of atopic conditions, such as atopic dermatitis (AD), asthma, and chronic rhinosinusitis with nasal polyps (CRSwNP), has traditionally encompassed several treatment modalities and delivery mechanisms to reduce inflammatory response. In recent years, increased knowledge regarding the role of type 2 inflammation in these conditions has coincided with the development of therapies that target specific inflammatory mediators and pathways. These targeted therapies provide new opportunities to optimize care and reduce adverse events (AEs). Specifically, agents targeting various interleukin (IL) pathways offer the potential to halt the type 2 inflammatory process. This article reviews the current treatment paradigms for AD, asthma, and CRSwNP, with an emphasis on the role of IL-based therapies in their management.

Atopic Dermatitis

AD is a skin disease defined by chronic and pruritic inflammation; it follows a relapsing course. It is associated with elevated serum immunoglobulin (IgE) levels and a genetic and environmental history of type I allergies, allergic rhinitis, and asthma.1,2 AD occurs most frequently in children, with a prevalence of 10% to 20% in the United States. Children with AD often present with symptoms within the first year of life.1

Treatment Overview

Multiple guidelines are available for the treatment of atopic dermatitis, the broader goals of which are to provide symptom relief and decrease the severity of itching.1-3 In addition to potentially improving quality of life, appropriate therapy can also help prevent significant complications, such as infection, sleep disturbance, behavioral problems, and growth impairment.1-3

Topical Agents

Topical agents are used frequently in the treatment of AD, even in severe cases, in which they are used in combination with systemic therapy or phototherapy.2 Topical corticosteroids are recommended in adult and pediatric patients with AD who have not responded to proper skin care regimens and regular use of emollients.2 Topical corticosteroids act on different immune cells, including T lymphocytes, monocytes, macrophages, and dendritic cells. Moreover, these agents have been employed to manage active inflammatory disease and prevent relapse in AD for 60 years.2

Topical calcineurin inhibitors (TCIs) are second-line antiinflammatory therapies used to treat AD. TCIs can be used in more sensitive areas or as an alternative to steroids, such as in situations of steroid recalcitrance or steroid-induced atrophy. TCIs inhibit calcineurin-dependent T-cell activation and block the production of proinflammatory cytokines and of mediators of the AD inflammatory reaction. Topical tacrolimus ointment (0.03% and 0.1% strengths) and pimecrolimus cream (1% strength) have shown to be effective in adults and children with active disease in the short term (3-12 weeks) and long term (up to 12 months).2

Patients with AD have a compromised physical barrier on the skin and thus are prone to infections. If an infection is present, the use of topical antimicrobials may be warranted. For instance, bleach baths and intranasal mupirocin may be used in patients with moderate to severe disease who have signs of a secondary bacterial infection to reduce the severity of the AD.2

Phototherapy and Systemic Immunomodulatory Agents

According to guidelines from the American Academy of Dermatology, phototherapy is a second-line treatment and can be used in maintenance therapy of chronic disease.4 Several factors affect the utility of phototherapy as a viable modality in AD, such as availability, cost, patient skin type, skin cancer history, and patient use of photosensitizing medications.4 Phototherapy treatments must be administered under the guidance of a physician who has knowledge of phototherapy.

Systemic immunomodulatory agents are reserved for the subset of adult and pediatric patients who have uncontrolled disease that is having a significant negative physical, emotional, or social impact. These agents are best used for limited time periods, such as for acute, severe exacerbations of the disease, or as short-term bridge therapy to other systemic, steroid-free therapy.4

IL Inhibitors

Many of the available treatment options for AD offer symptom relief rather than addressing the core pathways through which the inflammatory cascade takes place. The FDA approval of the IL-4/IL-13 inhibitor dupilumab in 2017 for the treatment of adults with AD represented a new step in the management of AD, prompting the development of multidisciplinary consensus recommendations focused on novel therapies for the diagnosis and treatment of disease.3

Dupilumab binds to the α subunit of the IL-4 receptor, which modifies the signaling of both the IL-4 and IL-13 pathways.5-7 It is currently the only monoclonal antibody approved for the treatment of AD. The initial approval of dupilumab in adults with moderate to severe AD was based on findings from three phase 3 trials: SOLO 1, SOLO 2, and CHRONOS.5,6 SOLO 1 and SOLO 2 were identical in design and enrolled adults with moderate to severe AD whose disease was inadequately controlled by topical treatment. Patients with AD were randomized 1:1:1 and received 300 mg doses of weekly dupilumab subcutaneously, placebo weekly, or a 300-mg dose of dupilumab every other week alternating with placebo for 16 weeks. The proportion of patients who had both an Investigator’s Global Assessment (IGA) score of 0 or 1 (clear or almost clear) and a score that had gone down at least 2 points between baseline and week 16 was the primary outcome of the study.5

Totals of 671 and 708 patients were enrolled in SOLO 1 and SOLO 2, respectively. At 16 weeks, 38% of patients in SOLO 1 and 36% in SOLO 2 who received dupilumab 300 mg every 2 weeks achieved clear or almost clear skin.5 Among patients who received either regimen of dupilumab, 51% and 44% in SOLO 1 and SOLO 2, respectively, achieved 75% or greater reduction in the Eczema Area and Severity Index (EASI) score. Patients who received dupilumab saw such improvements as reduction in pruritus, decreased symptoms of anxiety or depression, and improvement in quality of life. However, patients in the dupilumab group saw more injection-site reactions and conjunctivitis than those in the placebo group.5

The CHRONOS study examined the use of dupilumab with topical steroids in patients with AD.6 At 16 weeks, 39% of patients receiving dupilumab 300 mg every 2 weeks, along with topical corticosteroids, achieved clear or almost clear skin, and 69% of patients receiving that combination achieved EASI-75. Additionally, 59% of patients receiving the dupilumab/topical corticosteroid combination achieved a ≥4-point improvement in patient-reported daily itch intensity. At 52 weeks, 36% of patients receiving the dupilumab/topical corticosteroid combination every 2 weeks achieved clear or almost clear skin.

Findings from the LIBERTY AD SOLO trials, presented in March 2018, indicated that dupilumab was effective for adults with AD, even those with comorbid asthma.8 Results from a 16-week study showed that more patients with comorbid asthma receiving dupilumab 300 mg once or twice weekly achieved IGA 0/1 versus placebo (34.1%/31.9% vs 9.3%), EASI-75 (50.0%/47.4% vs 13.7%), and Peak Pruritus Numerical Rating Scale (NRS) improvement ≥4 (37.9%/37.8% vs 9.3%; P <.0001 for all). Patients without comorbid asthma showed similar results. The investigators noted that dupilumab-treated patients with and without comorbid asthma had comparable and significant improvements in AD signs and symptoms. More studies are needed to evaluate the benefits of dupilumab in patients with severe AD with comorbid type 2 inflammatory conditions.

Although the 2017 FDA approval of dupilumab for adults with moderate to severe AD was significant, an unmet need for new monotherapies in the pediatric population persisted until March 2019, when dupilumab was approved to treat children aged 12 to 17 years with moderate to severe AD.7 Prior to that approval, a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial included patients of those ages with moderate to severe AD. Eligible patients also had an Eczema Area Severity Index score of at least 16 (on a scale of 0 to 72), a minimum of 10% body surface area involvement, and previous inadequate response to topical medication. Patients in the study with a baseline weight of less than 60 kg received an initial dose of 400 mg followed by doses of 200 mg for 16 weeks. Those with a baseline weight of at least 60 kg received an initial dose of 600 mg, followed by weekly doses of 300 mg for 16 weeks. Patients were considered nonresponders if they received rescue treatment at the discretion of the investigator. The primary outcome was the proportion of participants with an IGA score of clear or almost clear and at least a 2-point improvement from baseline to week 16. Other end points were the proportion of subjects with EASI-75 or EASI-90 and a reduction in itch as measured by the Peak Pruritus NRS (≥4-point improvement).

After 16 weeks, results were similar to those evaluating dupilumab in adults with AD. Average improvement in EASI was 66% in those treated with dupilumab, compared with 24% for placebo.7 Additionally, 42% of patients treated with dupilumab achieved at least a 75% improvement in skin improvement, compared with 8% of those receiving placebo. Also of note, 24% of patients with an IGA score of clear or almost clear who received dupilumab based on their weight reached the primary outcome, compared with 2% of the placebo arm. Dupilumab was also shown to significantly reduce itch in 37% of those treated, compared with 5% for placebo.

Long-term safety and efficacy of the drug in adolescents was assessed in an open-label extension study. These results were consistent through 52 weeks, with common AEs being injection-site reactions, eye and eyelid inflammation, throat pain, and cold sores in or on the mouth and lips.7

The new indication for dupilumab for adolescents aged 12 to 17 years represents a significant step in the trajectory of AD care. Additionally, investigations continue for a potential indication in patients aged 6 to 11 years with severe AD not well controlled by topical medications9; in 2016, dupilumab was granted breakthrough designation by the FDA for this indication. See Table 1 lists ongoing clinical trials evaluating dupilumab in atopic dermatitis.9-13
 
Investigational IL Inhibitors for Atopic Dermatitis

 
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