key: cord-0902483-h6uzrnz2
authors: Naik, Piyu Parth
title: Treatment-resistant atopic dermatitis: novel therapeutics, digital tools, and precision medicine
date: 2022-04-28
journal: Asia Pac Allergy
DOI: 10.5415/apallergy.2022.12.e20
sha: dd6129bc83e9310228cef76e56dbccc9e503e8c4
doc_id: 902483
cord_uid: h6uzrnz2

Atopic dermatitis (AD) is a prevalent condition impacting up to 25% of children and 8% of adults worldwide. An estimated 20% of those with AD comprise a subset of patients with treatment-resistant AD, for whom traditional therapeutics and management strategies are unsuccessful. Physical symptoms significantly impact quality of life for patients and caregivers. The condition is chronic and may persist throughout the lifespan with recurrent episodes. Novel AD therapeutics offer new opportunities to resolve symptoms of treatment-resistant more effectively AD. Recently developed pharmacological agents were developed with an appreciation of AD as a heterogeneous condition. New advances include topical, oral, and injectable therapeutics with novel mechanisms of action. In addition, advances in clinical practice, including the application of digital tools, can promote a personalized medicine approach. For example, teledermatology for chronic conditions such as AD have been embraced by clinicians and patients; communicating symptoms via photographs can augment patient symptom trackers and aid trigger identification. Digital tools can also be used to increase medication adherence and improve patient/caregiver engagement. Integrating the above is a personalized medicine approach. Advanced therapeutics with novel mechanisms of action, integrated with digital tools, and trends toward patient-centered medicine can assist this chronic, heterogeneous condition via precision medicine and better treat treatment-resistant AD.

Atopic dermatitis (AD) is a prevalent condition, impacting approximately 10%-25% of children and 2%-8% of adults worldwide [1, 2] . Signs and symptoms of AD may include cutaneous erythema, inflammation, pruritus, and xerosis [3] [4] [5] . Many individuals with AD experience childhood onset which may persist into adulthood, subside, or recur intermittently throughout the lifespan [6] . Other individuals experience adult-onset AD, which may occur at any age, including after the age of 60 years [6] . AD often impacts quality of life for patients and caregivers, causing sleep disturbance, fatigue, and emotional distress, in addition to the physical manifestations [3, [7] [8] [9] ]. more therapeutic agents to treat moderate-to-severe AD ( Table 2 ). Significant research is ongoing to explore treating AD through the off-label use of medications approved for other atopic conditions.

Baricitinib Baricitinib is an oral selective Janus kinase (JAK)1/JAK2 inhibitor studied for moderate-tosevere AD in children and adolescents (aged 2-17 years) and in adults [17] [18] [19] , with U.S. Food and Drug Administration (FDA) approval for the treatment of AD anticipated in near future. However, Baricitinib is already approved by many regulatory bodies and countries including European Medicines Agency (EMA), Korea, and Japan for adult cases with moderate-tosevere AD who are candidates for systemic therapy. It is already FDA approved for moderately to severely active rheumatoid arthritis in adults [17] [18] [19] .

Abrocitinib is an orally administered JAK1 inhibitor employed for moderate-to-severe AD in adolescents (aged 12-17 years) and in adults [20, 21] . Abrocitinib was safe and effective in adults and adolescents with moderate-to-severe AD when used as solitary agent in once daily dosing [21] . Even a recent study assessed the efficacy of abrocitinib in patients who received prior dupilumab [20] . This study bolsters the safety and efficacy vignette of abrocitinib for moderate-to-severe cases of AD notwithstanding previous dupilumab response status [20] . Abrocitinib is approved by FDA for the treatment of refractory, moderate-to-severe AD whose disease is not adequately controlled with other systemic agents, including biologics or when use of those therapies is not advisable.

Upadacitinib is an orally administered JAK1 inhibitor utilized for moderate-to-severe AD in 3/14 adolescents (aged 12-17 years) and adults [22, 23] . It is recently FDA approved for refractory, moderate-to-severe cases of AD in adults and children 12 years and older whose disease process was not responding to previous treatments or AD is not controlled by other systemic medications including biologics or when those other medications are not recommended [22, 23] . A favorable benefit-risk profile and efficacy were observed in recently concluded 2 longterm, randomized clinical trials of upadacitinib's efficacy and safety in moderate-to-severe AD [22] . Clinicians should be encouraged to use upadacitinib in adults as well as adolescent resistant cases of AD in view of these recent encouraging results.

Ruxolitinib Ruxolitinib in the cream form has been approved by FDA for the short-term and noncontinuous treatment of mild-to-moderate AD in nonimmunocompromised patients aged 12 years and older whose AD is not adequately controlled with other topical medications or when those medicines are not advisable. It is the first and only FDA approved topical form JAK inhibitor [24] . Tofacitinib Tofacitinib is a topically administered JAK inhibitor studied for moderate-to-severe AD in adults [25] . It is currently FDA and EMA approved to treat juvenile idiopathic arthritis in children and adolescents (aged 2-17 years) and rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis in adults [26] .

Delgocitinib is a topically administered JAK inhibitor studied for moderate-to-severe AD in children and adolescents (aged 2-17 years) and adults [27, 28] . It is approved for the treatment of AD in adults in Japan, with FDA and EMA approval for the treatment of AD anticipated [27, 28] .

Lebrikizumab Lebrikizumab (subcutaneous injection) is an anti-interleukin 13 (IL-13) antibody studied for moderate-to-severe AD in adolescents (aged 12-17 years) and adults [29, 30] . It is not yet FDA approved, while phase 3 clinical trials have been promising [29, 30] .

Nemolizumab (subcutaneous injection) is monoclonal antibody that targets interleukin 31 (IL-31), studied for moderate-to-severe AD in adolescents (aged 12-17 years) and in adults. It is not yet FDA approved, while phase 3 clinical trials have been promising [31] .

Tralokinumab (subcutaneous injection) is fully human, high-affinity monoclonal antibody that selectively blocks the signaling of IL-13. Tralokinumab is approved by FDA for moderateto-severe AD in adults whose AD is not controlled with topical remedies or when those therapies are not advisable [32] .

Ustekinumab (subcutaneous injection) is human interleukin 12 (IL-12) and interleukin 23 (IL-23) antagonist studied for the treatment of severe and/or chronic AD in adults [33] . Ustekinumuab is FDA approved for the treatment of moderate-to-severe psoriasis in children and adolescents (aged 6-17 years), and adults with psoriasis, psoriatic arthritis, Crohn disease, and ulcerative colitis [34] .

Risankizumab (subcutaneous injection) is monoclonal antibody that blocks IL-23 that is FDA approved for the treatment of moderate-to-severe plaque psoriasis in adults [35] . Phase 2 studies are underway to evaluate risankizumab for the treatment of moderate-to-severe AD in adolescents (aged 12-17 years) and in adults [36] .

Omalizumab (subcutaneous injection) is a biologic that targets immunoglobulin E (IgE) production, studied for the treatment of AD in children and adolescents (aged 4-17 years) as well as in adults [37] . Omalizumab is FDA approved to treat allergic asthma in children and adolescents (aged 6-17 years) and in adults; chronic idiopathic urticaria in adolescents (aged 12-17 years) and in adults, and nasal polyps in adults [38] . Patients with AD may have coexisting atopic conditions such allergic asthma for which omalizumab can be

Treatment-resistant atopic dermatitis administered. While the potential efficacy of omalizumab to treat AD in such patients is noteworthy, the use of omalizumab to treat AD is presently controversial [39] .

The clinical evaluation for treatment-resistant AD involves confirming the diagnosis of AD, classifying it as treatment resistant, and selecting appropriate treatment and prevention strategies. Patient/caregiver engagement and education are essential, particularly for treatment adherence, trigger avoidance, and trigger identification [40] .

Confirming the diagnosis of AD involves assessing for a personal/family history of atopy; the physical examination; ruling out coexisting or mimicking conditions; and reviewing trigger exposures [40] . The diagnosis of AD is based on clinical decision-making as there is no biomarker to distinguish AD from other diseases. An elevated serum IgE level is present in some, but not all individuals with AD [40, 41] . Patients with AD typically experience pruritus, xerosis, inflammation, erythema, and characteristic morphological patterns [40, 41] . Several disease severity and clinical outcome scales are available, including: body surface area of AD involvement; Eczema Area and Severity Index; Investigator's Global Assessment; and SCORing Atopic Dermatitis (SCORAD). The application of these instruments in clinical settings is limited, however, assessments such as the SCORAD index may be useful for assessing disease states and treatment efficacy [40, 41] .

Possible coexisting and mimicking conditions include psoriasis, seborrheic dermatitis, atopic contact dermatitis, nummular dermatitis, scabies, or other conditions [3, 41] . It is important to rule out the presence of infections such as Staphylococcus aureus, impetigo, and tinea [41] . Finally, is important to rule out hypersensitivity reactions to medications, irritation from topical formulations, or drug allergies which may stem from active or inactive ingredients, such as drug dyes [42] .

The condition may be classified as treatment-resistant AD if the patient's symptoms and clinical score are unchanged or aggravated after 2 weeks of treatment, provided that the patient has been treatment adherent and symptoms are not caused by ongoing trigger exposures [40] .

It is recommended that clinicians seek information on the duration and relapsing/remitting nature of symptoms [40, 41] , as this can be correlated with treatment adherence and trigger avoidance to establish causal associations. AD that is persistent or recurrent due to ongoing or intermittent trigger exposure may respond to treatment after the patient adheres to triggers avoidance strategies [40, 41] . Similarly, non-adherence or partial adherence with treatment may explain the frequent recurrence or persistence of symptoms.

AD triggers are found in many environments, including the home, workplace, school, automobiles, mass transit, medical settings, fitness facilities, and recreational settings. The patient may experience exposure to one or more AD trigger(s). In the home, AD triggers may be found in grooming products such as soaps, hair care products, moisturizers, sunscreens, cosmetics, or perfumes, laundry detergents and/or household cleaners. Fabrics such as clothing, bedding, and towels may themselves trigger AD, or harbor allergic triggers such as pet dander or dust mites. Aeroallergens have sources such as animal dander/saliva from pets

Treatment-resistant atopic dermatitis or rodents. Animals, including house pets (cats, dogs) or those found in agriculture/farming environments (pigs, horses), may transmit allergens via contact or inhalation of aeroallergens.

Certain foods, milk, alcoholic beverages, and infant formula may also cause AD, however, the role of food allergies in AD remains controversial [40] . While dietary restrictions to prevent AD are burdensome, they are typically within the control of the patient/caregiver. AD may be triggered by medications, as well as inactive ingredients such as dyes, compounding agents, or the vehicle for topical formulations [42] . Medical supplies or over the counter health care products may also be implicated, such as gloves, face masks, or tape/adhesives.

AD symptoms may be caused by ongoing, intermittent, or recurrent exposure(s) to one or multiple trigger(s). In a given AD patient, recurrent skin rashes may follow a pattern of recurrent trigger exposure(s). Trigger avoidance includes proactively identifying new triggers in addition to avoiding known triggers. Patient/caregiver education should provide information that AD as a chronic condition; that a patient may develop reactions to new triggers which were not previously problematic; and that latency-a delay from the time of exposure to the appearance of the skin rash-may obscure trigger attribution [43] . Many environments may harbor a wide range of triggers such as aeroallergens, cleansers, fabrics, foods, and grooming products [43] [44] [45] .

Patient symptom trackers and trigger exposure diaries may enhance patient engagement, prompt trigger identification, and promote adherence. As AD is a chronic, relapsing/remitting condition, recurrent or persistent rashes are common. Similarly, identifying new triggers that underly an outbreak is not uncommon, and proactive trigger identification is an important component of prevention. Trigger diaries may be organized by environment (e.g., home, school, workplace, fitness center, swimming pool) or suspected causative agents (e.g., foods, cleansers, animals). Exposures should be recorded with date and time; the trigger exposure diary should be correlated with a symptom tracker to assess for a causative association.

Patients/caregivers may have experience using these tools, particularly if they suffer coexisting conditions of atopy (e.g., asthma) for which such tools are common. Digital versions of these tools may increase engagement and the ability to capture detail. Photos diaries depicting skin rashes may demonstrate discoloration, body surface area impacted, changes over time, and be correlated in time and place to trigger exposures [3] . Photo diaries may be particularly useful in demonstrating the presence or absence of a response to treatment. As AD is a heterogeneous, chronic condition, ongoing patient/caregiver engagement is important, and can be enhanced with digital tools.

Precision medicine involves patient engagement to develop treatment strategies, including prescribing therapeutics, targeted to the individual patient's condition [46] . Clinicians and patients have embraced telemedicine for the treatment of AD [47] . Virtual visits, combined with face-to-face consultations and lab tests when needed, have been found to provide health care for AD that is equally effective to onsite visits at a lower cost [46, 47] . Referrals may be appropriate for more specialized consultations (e.g., oncology) or diagnostic testing (e.g., biopsy) [47, 48] .

The expansion of telemedicine visits amid the coronavirus disease 2019 (COVID-19) pandemic has included teledermatology utilization when clinics were closed [49] . A retrospective records analysis conducted by the department of dermatology at Massachusetts General Hospital of Harvard University, Boston, USA found that after clinics reopened, the proportion of telehealth visits declined by less than 50%, with telehealth engagement remaining particularly high for patients with common dermatoses such as AD [49] . The fact that teledermatology utilization levels remained high despite the availability of onsite visits demonstrates strong provider and patient acceptance that will likely endure beyond the pandemic [47] [48] [49] .

Patient/caregiver adherence with treatment generally includes preventive skin care (moisturizers, emollients) and prescribed therapeutics. Obstacles to adherence may include AEs, cost, steroid phobia, inconvenience, and/or cognitive/physical limitations. Notably, a significant cause of treatment failure is the practice of applying topicals too sparingly; this may be due to cost or insufficient knowledge on the part of the patient/caregiver. The onset of AD often occurs during childhood, and a significant proportion of patients are children and adolescents. While it may be practical for caregivers to monitor medication adherence, a significant element of a patient's treatment plan involves trigger identification and avoidance, which is more difficult to monitor. Caregivers must be aware of potential triggers in the child or adolescent's environments (e.g., home, school, recreational facilities), as well as trigger avoidance habits.

A patient-centered approach may be effective in removing adherence obstacles and developing a treatment plan with alternatives better suited to the patient/caregiver abilities and preferences. Additionally, increased patient/caregiver education may stress the relationship of consistent adherence to improved outcomes, and thereby gain increased adherence. Only when the patient is adherent with both treatment recommendations and trigger avoidance strategies can a determination be made as to whether the AD is truly treatment resistant. A patient-centered approach may incorporate self-administered tools that increase patient/caregiver engagement. Such tools include the Patient Oriented Eczema Measure; Patient Oriented SCORing Atopic Dermatitis; Atopic Dermatitis Control Tool [47] .

Telemedicine encounters may be synchronous, asynchronous, or hybrid virtual visits [47, 48] . Synchronous virtual visits offer the advantage of real-time, spontaneous clinician/patient interactions that are similar to onsite clinic visits. They may occur via video platforms that allow clinicians and patients to see and hear one another, or via an audio only connection [47, 48] . One disadvantage is that synchronous virtual visits must be scheduled at a mutually convenient time for provider and patient, as occurs with traditional office visits. Asynchronous virtual visits, also called "store-and-forward," offer scheduling freedom, yet do not allow the clinician to obtain additional information from the patient spontaneously [47, 48] . Hybrid virtual visits allow clinicians and patients to supplement synchronous or asynchronous appointments with further questions, information, or the transmission of images [47, 48] . This is particularly useful for devices such as smart phones which may preclude the transfer of images during the call [47, 48] .

Most patients/caregivers can use cameras, phones, or other devices to capture and transmit clear digital images efficiently. Photos can document the appearance of AD skin rashes. A

Treatment-resistant atopic dermatitis photos series can document changes over time and be correlated with a symptom tracker, trigger exposure diary, and treatment adherence diary to evaluate the impact of trigger exposures or treatments.

Photographic images can be taken by the patient/caregiver, or by an allied health professional in the community, e.g., a physician's assistant or nurse practitioner in a nursing facility, school nurse, or corporate nurse. Photos can be transmitted digitally from patient/caregiver to physician, and onward to a specialist (e.g., oncologist) if needed. Photo image quality is important: photos should have clear focus, high resolution, and good lighting. Several pictures should be taken to depict detail and body surface area impacted [47, 48] .

Telemedicine may indeed be inadequate for some evaluations, for example, examining body areas that are hair-bearing or conditions requiring palpation. However, if clinics are closed due to COVID-19, or a patient requires specialty care unavailable locally, telemedicine may offer clinical access that would otherwise be unavailable [47] [48] [49] .

Digital tools may enhance patient and caregiver engagement and promote adherence. Comprehensive databases and registries with patient demographics, clinical traits, triggers, symptoms, and responses to treatment could facilitate research to further improve management strategies for AD. There remain many gaps in knowledge and unmet needs, for example, there are needs for uniform definitions and standardized terminology to facilitate database analyses. There are also no comprehensive multinational databases for AD presently [3, 50] . Developing digital tools for AD research and surveillance may build on the success of other conditions of atopy (e.g., asthma) for which registries and retrospective records analyses are useful.

These digital tools and patient engagement methods are particularly useful for clinicians managing AD with a shared decision-making model, by which doctor, and patient consider clinical evidence together with patient priorities to develop a treatment plan [51]. This patient-centered approach is well-suited to AD treatment plans, as AD is a heterogeneous, chronic condition heavily impacted by lifestyle and environmental factors, with multiple treatment options available [50] .

Although this article has thrown light on every aspect of treatments for AD, finding the ultimate reason of treatment failure is an integral portion of therapeutic strategy in these cases. Poor adherence to prescribed treatment has been identified as the most common reason of treatment failure and hence the resistance [40] . Other crucial things to address in treatmentresistance patients of AD are psychosomatic aspects as pruritis-scratch cycle negatively impact the quality of life. Regular clinical dermatological examination can identify any secondary cutaneous infection in atopic skin. Early identification of infection can help in targeting microbes to prevent deterioration. Comprehensive allergy work-up will help in focusing on allergens which were not considered in prior management. Widening the vision with targeted histories of occupational setting, cosmetic utilization, soap and diet will benefit the clinician in closing on the ultimate culprit allergen [40] . Once treatment resistance is addressed, SCORAD recounting and recategorization are recommended. In extremely rare circumstances, even after correcting all possible causes of resistance and employing medications; if patient is not responding then clinicians should consider second line immunosuppressive medicines, biopsy, and second opinion with dermato-immunologist (Fig. 1) . • Tralokinumab (adults) Choice between these medications depends on AD severity, patient age, comorbidities, availability, and cost.

• Avoidance of relevant allergens and irritants (dust mite control, avoid animal contact, detergent/soap/heat/preservatives)

• Allergen-specific immunotherapy Fig. 1 . Flowchart for the management of atopic dermatitis. * Oral glucocorticoids have largely unfavorable benefit/risk ratio in the treatment of atopic dermatitis. Short-term treatment up to 1 week may be an option for severe exacerbation in exceptional cases). AD, Atopic dermatitis; SCORAD, SCORing Atopic Dermatitis.

Recent advances in the development of targeted therapeutics offer new promise for patients with treatment-resistant AD. These therapeutics were developed with recognition of the heterogeneity of AD and enable a precision medicine approach to optimize patient outcomes. Patient and caregiver engagement as essential components of developing an efficacious treatment plan tailored to the individual patient. Digital tools and telemedicine may also be employed to enhance patient and caregiver engagement. Progress toward standardized terminology and developing databases and registries will facilitate research to enhance scientific understanding of AD and patient subgroups. Emerging therapeutics currently under development are expected to offer improved outcomes for treatment-resistant AD.

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The author acknowledges the medical writing, and editorial work of Dr. Daniel Bennett and Dr. Parth Naik.

Treatment-resistant atopic dermatitis