Revolutionizing the management of patients with atopic dermatitis: practical considerations

KEYWORDS:

• Atopic dermatitis
• dupilumab
• tralokinumab
• upadacitinib
• baricitinib
• abrocitinib
• biological therapies
• small molecules drug
• management

1. Introduction

The introduction of new biological therapies and small-molecule drugs in the treatment of atopic dermatitis (AD) has brought about an era of unprecedented change in this field. Many of these novel therapies have proven to be very effective in suppressing the disease, although unfortunately none are curative [1].

The growing development and availability of target therapies for AD has dramatically improved patients’ quality of life and changed the prognosis of the disease. Indeed, the current therapeutic goal is represented by a complete or almost complete skin clearance, which was often not achieved with traditional systemic therapies. Clear demonstration of benefit in clinical trials with good safety profile provided strong evidence leading to subsequent approval of dupilumab in patients 6 months and older, upadacitinib for patients 12 years and older, and abrocitinib, tralokinumab, and baricitinib for adults 18 years and older.

2. Biological therapies

2.1. Dupilumab

Dupilumab is the first biological agent approved for atopic dermatitis in all its ages of onset, after the failure of traditional systemic therapies. It is a human immunoglobulin (Ig) G4 monoclonal antibody targeting the alpha subunit of the interleukin (IL)-4-Receptor (IL-4 Rα), inhibiting both the IL-13 and IL-4 pathways. It is also approved for moderate-to-severe asthma with an eosinophilic predominance, oral corticosteroid-dependent asthma, chronic rhinosinusitis with nasal polyposis, eosinophilic esophagitis, and prurigo nodularis. The most common side effects reported are injection-site reactions and conjunctivitis in all age groups [2]. In most randomized, placebo-controlled clinical trials in AD, patients treated with dupilumab had a higher incidence of conjunctivitis (8.6–22.1%) than patients treated with placebo (2.1–11.1%) [3]. In real-life experiences, paradoxical red face, arthritis, and psoriasis-like eruptions were also reported [4,5].

2.2. Tralokinumab

It is a fully human IgG4 monoclonal antibody that binds specifically to IL-13, inhibiting subsequent downstream signaling. Tralokinumab is not currently under development for other type 2 diseases and to date is only available for adults with AD. Overall, it is well tolerated, with a prevalence of conjunctivitis of 7.5%, possibly lower than that reported for dupilumab [6]. Other common side effects are headache, injection-site reaction, and upper respiratory tract infections [7].

3. Small molecule drugs

JAK inhibitors are small-molecule drugs administered orally and requiring laboratory exams due to their critical safety profile linked to recent box warning based on tofacitinib data (malignancy, thrombosis, cardiovascular issues, serious infections) [8,9]. In particular, while first-generation JAKi (tofacitinib and baricitinib) interfere with more than 50 cytokines, the second-generation inhibitors (upadacitinib and abrocitinib) have a narrower range of inhibition linked to a better safety profile and higher efficacy.

3.1. Upadacitinib

Upadacitinib is a selective JAK1 inhibitor (JAK1i) currently FDA-approved for the treatment of several inflammatory conditions (rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, non-radiographic ankylosing spondyloarthritis, and ulcerative colitis) other than AD in patients aging 12 years or older. Both the 30 mg and 15 mg doses are authorized in adult patients with moderate-to-severe AD, with only the lowest dose for adolescents. The most reported side effects include acne, nasopharyngitis, headaches, and herpes infection [7,8].

3.2. Abrocitinib

Abrocitinib, an orally administered selective JAK1i, is currently FDA approved for the treatment of moderate-to-severe AD of the adolescents (≥12 years old) and the adults [8].

The recommended dosage is 100 mg orally once daily that can be doubled to 200 mg in non-responders after 12 weeks of treatment. Side effects include nausea, nasopharyngitis, acne, and herpes infection [7].

3.3. Baricitinib

Baricitinib is a first-generation inhibitor of JAK1 and JAK2 FDA approved for the treatment of moderate-to-severe AD of adults, but also RA, juvenile idiopathic arthritis, and alopecia areata [10].

The recommended dosage for AD is baricitinib 4 mg that can be tapered to 2 mg in the maintenance phase [11]. In case of a patient at risk for malignancies and thrombosis, the initial dosage may be 2 mg daily. The most common side effects are nasopharyngitis, nausea, diarrhea, upper respiratory infections, headaches, herpes infection [7].

4. Expert opinion

In recent years, new therapies, both biological and small-molecule drugs, i.e. JAK inhibitors, have improved the management of atopic dermatitis in both the short- and long-term compared to traditional systemic drugs.

The use of traditional drugs such as ciclosporin, methotrexate, mycophenolate mofetil, and azathioprine requires screening of eligible patients and monitoring of blood tests during treatment that result to be unsuitable for patients belonging to the so-called special categories, i.e. those affected by serious systemic infections, neoplasms, renal failure, myelodysplastic syndrome, etc. Indeed, the side effects related to the use of these drugs may outweigh the benefit of the AD management, leading to a down treatment with poor patients’ quality of life. As a result, traditional systemic treatments may not adequately meet the treatment needs of moderate and severe AD in the elderly and may even pose certain safety risks [12]. Furthermore, the treatment duration of traditional AD drugs usually does not correspond to the AD course, being employed for a limited period of time (cyclosporin may be administered for up to 2 years) that contrasts with the chronic and then long-lasting character of the disease.

With the advent of biological and small molecules, AD course has been revolutionized, with increased patients’ quality of life. The first approved biological agent was dupilumab and represented a milestone in the treatment of AD given its highly favorable efficacy and safety profiles that led to its approval in patients from 6 months of age, including the elderly population. Moreover, it provided several benefits in clinical practice: starting from the lack of need for screening and laboratory monitoring tests up to the possibility of treating multiple type 2 diseases with a single treatment. The main side effects reported in clinical studies (for example, conjunctivitis and injection site reactions) almost never led to discontinuation of the drug and were mainly transient and/or easy to manage. Another new monoclonal antibody in AD treatment was represented by tralokinumab, which is well tolerated and not currently under development for other type 2 diseases. A recent network meta-analysis highlighted its efficacy, although slightly lower than dupilumab at 16 weeks [13]. Biologicals provide effective and safe treatment with no need for laboratory monitoring and a very low risk of drug interaction given their peculiar and selective mechanism of action against cytokines or cell surface receptors. However, there are practical limitations on the use of biologicals: drug refrigeration (with consequent issues in storage and transportation), potentially reduced compliance due to needle phobia, immunological issues (anti-drug antibodies which may lead to a loss of efficacy), phenotype-dependent efficacy (recalcitrant head and neck dermatitis). Compared to monoclonal antibodies, JAKi has demonstrated a greater speed in achieving itch improvement, seen in some cases after the first doses, and greater efficacy after 16 weeks of therapy, especially with regard to upadacitinib at a 30 mg dose daily [12]. The tablet formulation and the storage at room temperature allow to overcome the practical limitations associated with biological therapy. By contrast, their use implies screening and monitoring tests posing limitations in some categories of patients such as those affected by concomitant or recent neoplasm, cardiological and thromboembolic comorbidities, and chronic infections.

Anyway, the key point in AD management is the selection of patients according to the disease presentation (involved body areas and severity), symptoms, and their impact on patients’ quality of life, comorbidities, disease history (previous treatment failure), and patients’ compliance. Hence, with the increasing number of options for the treatment of moderate-to-severe atopic dermatitis, clinicians need guidance on a practical approach to select a systemic agent for specific patient populations [14]. Different phenotypes of AD, defined according to the patient age at onset, race, and ethnic background, disease duration, immune-polarization have been recently described, underlying the need for a personalized treatment approach. The vision that certain well-defined phenotypes and endotypes may guide the future treatment of AD is appealing, but not yet a reality. In recent years, a growing body of evidence suggests race-specific alterations in the epidermal structure and related immune pathways. To date, ethnicity data on most new agents for AD are largely not available and future investigations could hopefully stratify AD populations more precisely to achieve a better tailored therapeutic approach [15].

The real challenge for the clinician will be to select the most suitable therapy for each patient, considering as main objectives not only the control of the severity and symptoms of AD but also the recovery of quality of life. Furthermore, given the chronicity of the disease, patient compliance, and safety profiles represent other relevant aspects in long-term management.

Declaration of interest

F Russo acted as speaker and consultant for Sanofi, AbbVie, and Novartis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

A reviewer on this manuscript has disclosed receipt of personal honoraria from Pfizer (makes abrocitinib) and Sanofi (in part makes dupilumab). Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Author contributions

All authors contributed to the article conception and design. Material preparation, data collection, and analysis were performed by E Camela and F Russo. The first draft of the manuscript was written by E Camela and F Russo. All authors read and approved the final manuscript.

Additional information

Funding

This paper was not funded.