Continuing Education Activity

Dupilumab is an injectable prescription medication administered subcutaneously to treat severe and refractory forms of atopic dermatitis (AD). It was approved by the US Food and Drug Administration (FDA) in April 2017 to treat moderate-to-severe, resistant, atopic dermatitis (AD) that is unresponsive to conventional therapy, including topical corticosteroids. Dupilumab is also used as maintenance treatment for asthma and chronic rhinosinusitis with nasal polyposis in both adults and children, in conjunction with other medications. Non-FDA-approved indications include allergic contact dermatitis, hand dermatitis, chronic spontaneous urticaria, prurigo nodularis, and alopecia areata. Extensive literature suggests the efficacy of dupilumab in treating conditions characterized by Th2-mediated inflammation. Clinical trials are currently in the pipeline to explore the potential of dupilumab in treating autoimmune blistering diseases, such as bullous pemphigoid. This activity describes dupilumab, including its mechanism of action, adverse event and safety profiles, eligible patient populations, and contraindications. It also highlights the interprofessional team's role in managing patients on dupilumab treatment.

Objectives:

• Describe the therapeutic mechanism of action of dupilumab.
• Identify the indications, both approved and off-label, for dupilumab.
• Review the adverse event and accompanying monitoring for dupilumab.
• Explain the importance of collaboration and communication among interprofessional team members to improve outcomes, treatment efficacy, and follow-up coordination for patients receiving dupilumab.

Indications

Dupilumab is a human monoclonal antibody administered subcutaneously to inhibit the interleukin-4 receptor subunit α (IL-4R α).[1] The drug was approved by the US Food and Drug Administration (FDA) in April 2017 for the treatment of moderate-to-severe atopic dermatitis (AD) in adults and pediatric patients six years and older and for chronic rhinosinusitis with nasal polyposis (CRSwNP) in adults.[1]

Since the incidence of AD has been consistently rising, especially in the developed and industrialized parts of the world, dermatologists must prescribe treatment regimens that are both efficacious and safe to use in the long-term management of this chronic skin condition.[2] Dupilumab is also used in treating adults with atopic dermatitis symptoms inadequately controlled with topical corticosteroid use.[3][4] 

Currently, no specific guidelines deem the drug safe for children under six years of age to treat atopic dermatitis.[4][5]

Dupilumab has shown to enhance lung function and reduce severe exacerbations in patients with uncontrolled persistent asthma, irrespective of baseline eosinophil count, and when used in addition to inhaled corticosteroids and long-acting beta-2 (β2) agonists, as compared to standard asthma therapy.[6][7]

Non-FDA Approved Indications

Non-FDA-approved indications include allergic contact dermatitis, hand dermatitis, chronic spontaneous urticaria, prurigo nodularis, and alopecia areata.[1] Extensive literature suggests the efficacy of dupilumab in treating conditions characterized by Th2-mediated inflammation.[8] Clinical trials are currently underway to explore the potential of dupilumab in treating autoimmune blistering diseases, such as bullous pemphigoid, eosinophilic esophagitis, and chronic obstructive pulmonary disease.[8]

Mechanism of Action

Dupilumab is a fully human monoclonal antibody of the immunoglobulin G4 subclass designed to inhibit receptor signaling downstream of the JAK-STAT pathway by blocking interleukin-4/interleukin-13 (IL-4/IL-13) receptors.[4]

As an IL-4Rα antagonist, dupilumab inhibits the signaling of pro-inflammatory cytokines, or interleukins, that induce inflammatory and immunological responses in several conditions, including eczema, asthma, allergic reactions, and rhinosinusitis.[9] Essentially, IL-4Rα is a component common to both IL-4 and IL-13 receptor complexes and is ubiquitously expressed on innate and adaptive immune cells to promote the signaling of IL-4 and IL-13.[10][11] 

By blocking this pathway, dupilumab affects three integral disease mechanisms of AD: the decrease of skin barrier function, the class switch to IgE, and the Th2-differentiation.[4][12]

Administration

The initial recommended dose of dupilumab comprises two subcutaneous injections at different injection sites, followed by one injection at different injection sites every two weeks or every four weeks, depending on the patient’s age and weight.[13]

In most clinical trials, the steady-state concentrations were reached by week 16 following the administration of 600 mg starting dose and 300 mg dose every other week.[13] Dupilumab injection comes as a 300 mg/2 mL solution in a single-dose pre-filled syringe with a needle shield.[13]

More recently, two large phase 3 trials - including adults with symptoms inadequately suppressed by topical medications commonly used to manage atopic dermatitis - demonstrated the role of dupilumab in treating the condition. Patients were treated with either placebo or 300 mg dupilumab administered every week or every two weeks over a span of 16 weeks. A significant reduction of 75% in eczema area and severity index (EASI) was observed in patients on dupilumab in both weekly and 2-weekly interval dosing regimens.[13]

Adverse Effects

Although not common, dupilumab may cause serious adverse effects, including joint aches, eyelid swelling and inflammation, and allergic reactions such as shortness of breath and wheezing.[14] However, the most common side effects noted in AD patients on dupilumab include injection site reactions and eye and eyelid inflammation, including redness, swelling, itching, blurred vision, and cold sores in the mouth or on the lips.[14][15] Most adverse events seen in clinical trials performed in patients aged 18 or above are mild or moderate in severity.[14]

Nasopharyngitis and headache have also been reported at a higher frequency among patients receiving dupilumab than among those receiving placebo.[14] The occurrence of herpes viral infections has also been observed in some cases.[16]

It is postulated that dupilumab may possibly induce various forms of arthropathy, enthesitis, and tendinopathy in certain highly atopic individuals by enhancing an IL-17-mediated peripheral spondyloarthritis/psoriatic arthritis pattern of inflammatory enthesitis.[17] Further research must be done to establish a causal link and determine the exact mechanism.[17]

Contraindications

A number of contraindications to dupilumab have been noted in the literature, some of which are listed below. However, insufficient scientific data or research-based evidence exists to back up most of these contraindications. For the most part, the contraindications to dupilumab are few, and it is considered relatively safe for use in pregnancy when compared to most other medications for AD. The most serious contraindication to using dupilumab is hypersensitivity to any of its excipients.[17]

Hamster Protein Hypersensitivity

Dupilumab is contraindicated in patients with hamster protein hypersensitivity, as this drug is produced in Chinese hamster ovary cells. Hypersensitivity reactions, including rash and allergic conjunctivitis, have occurred after dupilumab administration.[17]

Vaccination

Current FDA recommendations caution only against the use of live virus vaccines in dupilumab recipients, although no concrete date is available on the ability of live vaccines to trigger an immune response.[17] It is suggested to complete all age-appropriate immunizations prior to beginning dupilumab treatment. Limited data are available regarding the coadministration of non-live vaccines with dupilumab.[16]

Acute Bronchospasm, Asthma, Corticosteroid Withdrawal, and Status Asthmaticus

While dupilumab is approved as an adjuvant or maintenance therapy to treat eosinophilic and glucocorticoid-dependent moderate-to-severe asthma, it should not be used by itself to treat episodes of asthma exacerbations or acute bronchospasm.[16]

Patients with comorbid asthma who start dupilumab therapy for atopic dermatitis or chronic rhinosinusitis with nasal polyposis should be advised to stay on their asthma medications to prevent the onset of any adverse event.[16] However, a study by Rabe et al. revealed that for patients on oral glucocorticoid therapy for moderate-to-severe asthma or acute asthma exacerbations, adding dupilumab not only led to an overall reduction in the glucocorticoid use but also alleviation of symptoms associated with acute asthmatic episodes or exacerbations over the course of 24 weeks. The only notable but transient adverse effect seen was reversible eosinophilia in about 14% of the patients.[18]

Eosinophilic Pneumonia and Vasculitis

Rare cases of eosinophilic pneumonia and vasculitis consistent with eosinophilic granulomatosis with polyangiitis have been reported in asthmatic patients on dupilumab.[17]

Helminth Infection

It is advised to treat patients with a preexisting helminthic infection with anti-helminthic therapy prior to initiating dupilumab.[16] However, in the event that a patient becomes infected while receiving dupilumab and fails to respond to treatment with anti-helminthic medicine, dupilumab should be discontinued until the infection resolves.[16] Complete resolution of helminthic infection before starting dupilumab therapy for AD is of utmost importance and should take precedence.

Pregnancy

It is unknown whether dupilumab use during pregnancy may cause harm to the fetus, including congenital defects or other adverse outcomes.[19] Since IgG antibodies can cross transplacentally, the possibility of dupilumab's transmission from the mother to the fetus exists.[19]

Animal research studies have shown no adverse effects on the growth or development of offspring at birth or later after IL-4R alpha antibody injection.[19] Several case reports in which dupilumab was either discontinued prior to conception or a few weeks after conception demonstrated no fetal harm.[19] However, more research is required to analyze the harmful effect of dupilumab on a fetus when used continually during pregnancy.[19]

Breast-feeding

It is unknown whether dupilumab is excreted in breast milk or whether systemic absorption occurs after ingestion.[19] The amount of dupilumab in breast milk is expected to be low, given its large size, and absorption is unlikely because it is destroyed in the infant's gastrointestinal tract.[19] It is crucial to assess the importance of breast milk, along with the mother's medical indication and urgency for dupilumab use.[19]

Monitoring

Given the potential interaction of dupilumab with other drugs that are substrates of the cytochrome P450 (CYP450), the FDA suggests monitoring those patients on medications like warfarin which are also CYP450 substrates and can alter the activity of dupilumab.[19] Interestingly, this may be uncertain speculation as a study conducted by Davis et al. in 2018 failed to reveal any effect of dupilumab on the pharmacokinetics of CYP450 drugs.[16]

Patients must monitor for serious and sudden onset reactions when on dupilumab therapy. It is strongly advised to discontinue dupilumab if a systemic hypersensitivity reaction is noted.[19] Additionally, patients must report to their healthcare provider any worsening eye symptoms leading to conjunctivitis and/or keratitis. Patients with comorbid asthma must be monitored periodically to ensure that they continue their usual asthma treatment without attempting to adjust it on their own.[19]

Healthcare providers are advised to monitor asthmatic patients with vasculitic rash, worsening pulmonary symptoms, cardiac complications, and neuropathy in the presence of eosinophilia as dupilumab use in asthmatics may be associated with eosinophilic pneumonia or vasculitis.[19] Additionally, all healthcare team personnel must actively participate in patient counseling and provide access to resources and contacts if the need to reach out to the interprofessional team arises.[19]

It may be helpful to involve social workers to identify reasons for the lack of treatment adherence leading to less than satisfactory outcomes. Sometimes, prior authorization by insurance companies may take longer than anticipated, in which case the patient may not start the medication promptly. Having a nurse or medical assistant from the office follow up with the patient may help drive a positive outcome for patients.

Toxicity

Dupixent has no black box warning, unlike the relatively newer topical and oral Janus kinase (JAK) inhibitors used for treating AD.[20] Patients on JAK inhibitor treatment should be monitored closely for the onset of any infection. The possible emergence of serious adverse events may result from synergistic effects of JAK inhibitors with other immunomodulating agents, such as Vitamin D, which also act on the JAK-STAT pathway.[20] 

No serious or frequent toxicity was reported. Clinicians must be careful when using dupilumab with substrates of CYP450, as it utilizes the same enzyme for its degradation. There have been rare instances of vasculitis and pneumonia in patients using dupilumab along with CYP450 substrates.[20]

Enhancing Healthcare Team Outcomes

Dupilumab is the most effective and safe immunomodulating therapy available for treating moderate-to-severe symptoms associated with atopic dermatitis, including itching, poor sleep quality, anxiety, and depression. The evidence from an increasing number of trials suggests that the benefits of dupilumab far outweigh its side effects.

Since no concrete literature-based evidence suggest that dupilumab is contraindicated during pregnancy or lactation, shared decision-making among healthcare team members and patients is paramount for ensuring safe and effective treatment plans. It is crucial that patients receive significant education on their treatment options, including discussing the benefits and risks to maternal and fetal health, and that patient's individual values and preferences are taken into consideration.

Both pharmacists and nurses need to have easy and direct access to the prescriber so any patient concerns regarding dupilumab use can be addressed immediately. Uniform communication among healthcare team members is pivotal to obtaining optimal therapeutic results for dupilumab use with minimal adverse events. [Level 1]