|Year : 2019 | Volume
| Issue : 1 | Page : 3-11
Advances in systemic treatment for adults with moderate-to-severe atopic dermatitis
Yung-Tsu Cho, Chia-Yu Chu
Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
|Date of Submission||05-Nov-2018|
|Date of Acceptance||23-Dec-2018|
|Date of Web Publication||28-Mar-2019|
Department of Dermatology, College of Medicine, National Taiwan University Hospital and National Taiwan University, Number 7, Chung-Shan South Road, Taipei 10002
Source of Support: None, Conflict of Interest: None
Atopic dermatitis (AD) is generally considered a T-helper type 2-dominated disease. Adult AD is often more severe and less manageable by topical therapies and may require systemic immunosuppressants that bear notable side effects and organ toxicities. There is an unmet need for safe and effective long-term therapy in this population. Dupilumab, a fully human monoclonal antibody, dually inhibits interleukin (IL) IL-4 and IL-13 signaling and has demonstrated promising efficacy and acceptable safety profile in several Phase III trials, followed by recent Food and Drug Administration approval for the treatment of moderate-to-severe AD in adults whose disease is inadequately controlled with topical therapies. Dupilumab may also serve as a new treatment option when other systemic medications have failed or are inadvisable. Nevertheless, long-term safety data beyond 1 year and comparison with the existing therapies remain to be investigated. Other emerging agents targeting pruritogenic proteins, chronic inflammation, and epidermal hyperplasia are under vigorous clinical development. In particular, nemolizumab, blocking IL-31-mediated pruritus, has been reported in Phase II trials to provide symptom relief by interrupting the itch-scratch cycle. Accompanied by thorough characterization of different phenotype and endotype subsets, the era of precision medicine could bring new prospects in the optimal treatment of AD.
Keywords: Atopic dermatitis, dupilumab, nemolizumab, pruritus, T-helper 1-T helper 2 balance
|How to cite this article:|
Cho YT, Chu CY. Advances in systemic treatment for adults with moderate-to-severe atopic dermatitis. Dermatol Sin 2019;37:3-11
| Introduction|| |
Atopic dermatitis (AD) is a chronic pruritic dermatosis presented with blotchy, reddening, and raised lesions resulting in erosion, excoriation, and lichenification of the inflicted sites., The lesions can span through the entire body and can occur in flexural or nonflexural regions of joints in the limbs. Flares of acute AD present as oozing, erosive, and inflammatory erythema, whereas chronic persistent lesions appear as pruritic plaques that are hyperkeratotic and lichenified. The itch and appearance of skin lesions can impact the patients' quality of life and psychosocial well-being, extending to limitations in lifestyle activities. The International Study of Asthma and Allergies in Childhood Phase One (mostly 1994–1995) and Three (mostly 2002–2003) repeat multicountry cross-sectional surveys reported the prevalence of eczema symptoms in Taiwan which has increased from 3.5% to 6.7% in the 6–7-year age group and from 1.4% to 4.1% in the 13–14-year age group. A recent international survey reported the estimated prevalence of adult AD ranges from 2.1% to 4.9% across countries. This adult patient population may comprise adult-onset AD together with a quarter of childhood-onset cases who did not grow out of the symptoms.
Diagnosis of AD is primarily clinical, based on validated diagnostic standards such as the Hanifin and Rajka's criteria and the American Academy of Dermatology guideline, as no definitive laboratory or pathology markers have been confirmed., The clinical presentation of AD is known to be heterogeneous. Several AD phenotypes have been noted with categorization by age, lesion presentation, concurrent allergic diseases, serum immunoglobulin E (IgE), inflammatory cytokines, genetic mutation, and race. Acute, erythematous lesions are commonly seen in pediatric AD, whereas adult AD may show prominent epidermal hyperplasia with chronicity. The differences in lesion presentations are associated with the corresponding cytokine profiles. Based on the status of IgE-mediated allergic sensitization, patients can be categorized into “extrinsic” AD, with high levels of total IgE and environmental or food allergen-specific IgE, and “intrinsic” AD, which exhibits normal total IgE without allergen-specific IgE. With regard to racial differences, Asian AD lesions have shared features between European-American AD and psoriasis, with more recognizable demarcation and lichenification, as well as higher variations in filaggrin mutation. Although the majority of adult AD lesions share typical flexural distribution and lichenified/exudative patterns as seen in pediatric AD, some may have a nonflexural distribution and atypical morphologic variants, such as nummular, follicular, prurigo-like, and seborrheic dermatitis-like patterns., AD disease severity is highly correlated with therapy selection and treatment outcome. The severity of AD can be assessed by using the Eczema Area Severity Index (EASI) and the Scoring Atopic Dermatitis (SCORAD) index, both of which are validated instruments for scoring the extent and severity of AD lesions.
| Etiology – Multifactorial With an Underlying Immune Dysregulation|| |
To date, the complete etiology of AD is not yet conclusive, though the prevailing view is that both genetic susceptibility to barrier dysfunction and environmental factors are involved in the pathogenesis., Indeed, a pro-inflammatory microenvironment can be observed even in nonlesional AD skin, characterized by increase number of T-helper (Th) type 2, Th22, and to a lesser degree, Th17 cells. In addition, the breach of epidermal barrier by allergens, irritants, and microbes are considered the triggering event of local inflammation and subsequent cascade of the immune response [Figure 1]. The growing knowledge of AD pathomechanisms has pointed toward the idea that AD is an immune-mediated disease characterized by an imbalanced Th1/Th2 paradigm and increased levels of Th2 signature cytokines, such as interleukin (IL) IL-4 and IL-13, have been identified to correlate with AD disease activity., Th2 response is also prominently activated in asthma and chronic rhinitis with nasal polyps, which are linked to AD as major comorbidities., During local assault in the skin, nonlymphoid cells secrete chemokines such as thymus- and activation-regulated chemokine (also known as CCL17), as well as cytokines including IL-25, IL-33, and thymic stromal lymphopoietin (TSLP). Activated by these mediators, Th2 cells secrete IL-4, IL-5, IL-13, and IL-31 and trigger Th2 proximal effector events, including accumulation of IL-5-dependent eosinophils and IgE class switching, leading to inflammation and damage of barrier integrity. Moreover, IL-31 induces itch via sensory neuron activation, which triggers scratching behavior and in turn aggravates inflammation. On the other hand, recent research revealed the significant role of innate lymphoid cells (ILC) in enhancing Th2 immunity. Upon activation by mediators from keratinocytes, ILC type 2 can release IL-5 and IL-13, perpetuating Th2 response. The progression of acute AD to chronic stage has been characterized by intensified Th2 and Th22 axes and Th1 activation. In addition, cytokine IL-17 released by Th17 has been shown to synergistically contribute to epidermal hyperplasia with IL-22 released by Th22. Although the involvement of the Th17 axis is less significant in AD than in psoriasis, it appears to play a more important role in Asian AD than in European-American AD.,,
|Figure 1: Pathomechanisms of atopic dermatitis. B: B cell, EoS: Eosinophil, FLG: Filaggrin, ILC2: Type II innate lymphoid cell, IDEC: Inflammatory dendritic epidermal cell, IFNγ: Interferon gamma, IL: Interleukin, LC: Langerhans cells, TARC: Thymus- and activation-regulated chemokine, Th: T helper cell, TSLP: Thymic stromal lymphopoietin|
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| Unmet Needs of Current Treatments|| |
Adult AD is more severe with poor long-term prognosis compared with pediatric AD, and is often inadequately managed by patient education, emollients/moisturizers, and topical corticosteroids (TCS)., Therefore, topical calcineurin inhibitors, burst systemic corticosteroids, phototherapy, and systemic immunosuppressants, including cyclosporine, azathioprine, methotrexate, and mycophenolate mofetil, may be opted in treating moderate-to-severe and recalcitrant AD. However, due to associated toxicities with each immunosuppressive agent, the consensus recommendation is to use the lowest dose and duration possible with monitoring of potential adverse events (AE). In a recent cross-sectional study involving 1519 adults with AD, 55% of the cohort had moderate/severe disease, reporting more severe itching and pain, greater sleep problems, higher prevalence of anxiety and depression, and greater health-related quality-of-life impairment compared to those with mild disease. Among these patients who assessed their diseases as inadequately controlled by systemic immunomodulators or phototherapy, more than half (55.7%) reported higher burdens of itch and sleeping problems. Taken together, there is an unmet need for a safe and effective long-term therapy for AD patients whose disease is inadequately controlled or are intolerant to topical treatments.
| Recent Advances in Systemic Treatment of Moderate-To-Severe Atopic Dermatitis in Adults|| |
The emerging therapeutics for AD focuses on the intervention of the Th2 pathway or associated proximal events by target-specific biologics., To this point, monoclonal antibodies against IgE, IL-4 receptor subunit alpha (IL-4Rα), IL-5, IL-13, IL-31 receptor A (IL31RA), IL-33, and TSLP have been evaluated clinically for adult AD. Encouraging results have come from many of the biologics, of which the most exciting being dupilumab, an IL-4Rα antagonist that received Food and Drug Administration approval in 2017 for moderate-to-severe adult AD whose disease is inadequately controlled with topical therapies. Meanwhile, a number of Th2 pathway-blocking biologics are also being tested in asthma or chronic rhinitis with nasal polyps, which are known to exhibit Th2 association.
Dupilumab (Dupixent®, Sanofi-aventis US LLC, Bridgewater, NJ, USA) and Regeneron (Pharmaceuticals, Inc., Tarrytown, NY, USA.) is the first biologic approved for the treatment of adult patients with moderate-to-severe AD whose disease is inadequately controlled with topical therapies or when those therapies are not advisable. Dupilumab is given as subcutaneous injections every other week with or without TCS. It is a human monoclonal antibody against IL-4Rα, a shared component of functional IL-4 and IL-13 receptor complexes, and therefore blocks the signals triggered by IL-4 and IL-13 concurrently. In the following sections, data from Phase III trials of dupilumab are summarized.
SOLO1 and SOLO2
The two Phase III, randomized, placebo-controlled trials (RCT) with identical design were performed in North America, Europe, and Asia to evaluate dupilumab monotherapy in adults with moderate-to-severe AD. Eligible patients were randomized in the ratio of 1:1:1 to groups treated with placebo, 300 mg dupilumab once a week (qw), or 300 mg dupilumab once every other week (q2w) for 16 weeks. The primary end point was the proportion of patients with Investigator's Global Assessment (IGA) of 0 or 1 (clear or almost clear) and reduction of ≥2 scores from baseline. The proportion of patients with ≥75% improvement in EASI score (EASI-75) was a co-primary end point. Improvements in pruritus, quality of life, and symptoms of anxiety or depression were also evaluated. A total of 671 and 708 patients were enrolled in SOLO1 and SOLO2 trials, respectively. At the end of SOLO1, the proportion of patients achieving IGA score of 0 or 1 and improvement ≥2 points was 37% and 38% in those who received dupilumab qw and q2w, respectively, as compared with 10% in the placebo group (P < 0.001) [Table 1]. Similarly, in SOLO2, higher proportion of patients achieved IGA score of 0 or 1 and improvement ≥2 points in both of the treatment groups, compared with the placebo group (36% qw and 36% q2w vs. 8% placebo, P < 0.001). Moreover, significant improvements in co-primary (i.e., EASI-75) and major secondary end points were observed in the treatment groups compared with placebo. As for quality of life measure, 58%‒73% of patients who received dupilumab qw and q2w had ≥4-point improvement in the Dermatology Life Quality Index (DLQI) score (i.e., the minimal clinically important difference), significantly higher than that in the placebo group (28%‒31%, all P < 0.001). The total incidence of nonserious or serious AE did not significantly differ among the groups, although the incidence of injection-site reactions and conjunctivitis occurred at a higher rate in the treatment groups. It was concluded that dupilumab monotherapy given qw or q2w for 16 weeks improved the signs and symptoms of disease in adult with moderate-to-severe AD that was inadequately controlled with topical medications.
|Table 1: Clinical efficacy of Phase III trials of dupilumab for adult with moderate-to-severe atopic dermatitis|
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Liberty AD Chronos
This 52-week RCT assessed the efficacy of dupilumab with concomitant medium-potency TCS with or without topical calcineurin inhibitor in adults with moderate-to-severe AD. Patients with AD for ≥3 years and IGA score ≥3 plus EASI ≥16 score were enrolled. Responders were defined as those who achieved IGA score of 0 or 1 with improvement ≥2 score from baseline or ≥75% improvement in EASI. In line with SOLO1 and SOLO2, the IGA responder rates in the dupilumab qw and q2w groups at 16 weeks were both 39%, compared with 12% in the placebo group (P < 0.0001). The EASI-75 responder rate at 16 weeks was 64% and 69% in the qw and q2w treatment groups, respectively, compared with 23% in the placebo group (P < 0.0001). At 52 weeks, the IGA and the EASI-75 responder rates were maintained at similar levels across all treatment groups [Table 1], suggesting that the optimal treatment response was achieved early on during the study period. Furthermore, dupilumab significantly reduced the incidence of flares (i.e., proportion of patients with AD flares, dupilumab qw and q2w vs. placebo, 13% and 14% vs. 41%; P < 0.0001) and improved quality of life (i.e., proportion of patients achieving ≥ 4-point improvement in DLQI, dupilumab qw and q2w vs. placebo, 63% and 80% vs. 30%; P < 0.0001). The safety profile evaluated at 52 weeks was not much different from that in SOLO1 and SOLO2. These results demonstrated the long-term safety and efficacy of dupilumab for the management of moderate-to-severe AD with concomitant TCS.
Liberty AD Café
The CAFÉ study focused on the adult difficult-to-treat AD population who are intolerant, unresponsive, or ineligible to cyclosporine, which is approved in Europe and Japan for AD. In this study, patients were randomly assigned to dupilumab or placebo with concomitant TCS treatment for 16 weeks. The EASI-75 responder rates were 59% and 63% in the dupilumab qw and q2w plus TCS groups as compared with 30% in the placebo plus TCS group (P < 0.001) [Table 1]. In addition, dupilumab reduced the mean weekly dose of TCS and the number of patients requiring rescue medication, including potent or very potent TCS, topical calcineurin inhibitors, or systemic medication. With regard to quality of life, the proportion of patients achieving ≥4-point improvement in DLQI was 78% and 88% in the dupilumab qw and q2w plus TCS groups as compared with 44% in the placebo plus TCS group (P < 0.001), respectively. Higher rates of mild or moderate conjunctivitis were observed in the dupilumab plus TCS groups than the placebo plus TCS group, but most events were recovered or recovering by the end of treatment. These results supported the use of dupilumab in adults with difficult-to-treat AD.
Overall, trials of dupilumab have shown promising clinical efficacy and patient-reported outcomes with acceptable safety profiles. Together with the lack of suitable options in treating moderate-to-severe chronic AD, a multidisciplinary committee in the U.S. recommended that dupilumab should be used as a first-line systemic treatment in adults with moderate-to-severe AD who are uncontrolled with topical therapies. Similarly, the consensus-based European guidelines also recommended dupilumab as a disease-modifying drug when topical treatment is insufficient and other systemic treatments are inadvisable. However, long-term data on the safety and efficacy of dupilumab beyond 1 year, as well as trials that comparing dupilumab with existing systemic therapies, remain to be reported. Additional costs also need to be taken into consideration. Based on the above concerns, other experts recommended using dupilumab in patients with uncontrolled AD despite the adequate use of TCS and treatment failure with one or more oral immunosuppressive drugs. Similarly, recent guidance from the National Institute for Health and Care Excellence also recommended dupilumab as an option for treating moderate-to-severe AD in adults only if the disease has not responded to at least one other systemic therapy, or the systemic therapies are contraindicated or not tolerated.
| Emerging Systemic Targeted Therapies for Adults With Moderate-To-Severe Atopic Dermatitis|| |
Based on the growing understanding of the pathomechanisms for AD, several biologics and small molecules targeting various AD-related pathways are being investigated in Phase II or III clinical trials., Those that are in or beyond Phase III trials include baricitinib (Janus kinase [JAK] 1/2 antagonist), tradipitant (neurokinin-1 receptor antagonist), tralokinumab (anti-IL-13), upadacitinib, and PF-04965842 (JAK1 antagonist) [Table 2]. Baricitinib with TCS in a Phase II trial (NCT02576938) showed significantly more patients (61% vs. 37%) achieving EASI-50 compared with placebo. A Phase III monotherapy clinical trial is ongoing. Tradipitant has completed Phase II trial (NCT02651714) for adult AD with treatment-resistant pruritus with results yet to be reported. The Phase IIb trial of tralokinumab (NCT02347176) reported that the Dose 3 group had a significant absolute reduction in EASI score at week 12 (adjusted mean difference – 4.94, 95% confidence interval: −8.76 to − 1.13) compared with placebo. The Phase II results for upadacitinib (NCT02925117) has not yet been reported, but a Phase IIb proof-of-concept study of PF-04965842 (NCT02780167) demonstrated that significantly higher proportion of patients achieved IGA of 0 or 1 and a reduction of ≥2 scores from baseline at week 12 in the highest dose group compared with placebo (44.5% vs. 6.3%).
|Table 2: Trials of systemic targeted therapies for adult with moderate-to-severe atopic dermatitis|
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| Insights into the Mechanisms of Pruritus|| |
Pruritus is the itching sensation triggered by activated sensory neurons, leading to scratching behavior and thereby causing scaling and even wounding of the skin., Irritants, allergens, and pathogens could induce local inflammatory response. The inflammatory cascades further exacerbate tissue damage and pruritus, perpetuating the vicious “itch-scratch cycle” [Figure 1]. Pruritus not only exacerbates disease manifestation of the skin, but can also disrupt daily activities and sleep quality. Alleviating itchiness is one of the major goals in treating AD and causes major improvements in quality of life for patients. Therapeutic approaches for pruritus that directly intervene itch-specific pathways have been rigorously developed in recent years. Local sensory neurons can be activated by molecules including histamine, reactive oxygen species, acetylcholine, and various neuropeptides. Cytokines such as IL-4, IL-13, IL-31, and TSLP that are secreted by a range of immune and nonimmune cells have also been known to exert pruritogenic effect via stimulation of sensory neurons.,,
Currently, the timing and nature of the first event that ignites the itch-scratch cycle in AD remain inconclusive. Interruption in the itch-scratch cycle is nevertheless considered beneficial in improving inflammation, pruritus, and quality of life. It has been known that the pro-inflammatory cytokine, IL-31, plays a specific role in the occurrence of pruritus associated with AD. Nemolizumab, an anti-IL31RA antibody, was shown to reduce pruritus in patients with moderate-to-severe AD., In the recently published 64-week Phase II results, the improvement of pruritus and sleep disturbance scores by 50% was observed in the first 8 weeks, while that of EASI occurred later in the study [Table 3]. Furthermore, the maximal improvements in EASI, pruritus score, and quality of life occurred after 24 weeks, suggesting a steady and progressive response induced by the intervention. This supports the notion that ameliorating pruritus induced by IL-31 may ultimately improve skin lesions.
In a different scenario, where the Th2 immune dominance is the main target of dupilumab, a 50% improvement in EASI score was observed within 4 weeks, whereas steady but significant improvement in pruritus was found starting from week 2. The data from dupilumab indicated that signs and symptoms could be improved early on and maintained by interrupting Th2 signaling. Activation of neuronal IL-4Rα has been shown to sensitize sensory neurons to multiple other pruritogens. Other than inhibiting IL-4's direct pruritogenic properties, it is also likely that dupilumab improved pruritus by blocking downstream signaling of IL-4Rα.
| Heterogeneity of Atopic Dermatitis|| |
The current trend in treating chronic diseases is moving toward a precision medicine approach, which relies on thorough characterization of disease endotypes for targeted treatment development. In comparison to treatment and diagnosis paradigms in asthma and rhinitis, the endotype characterization approach in AD is currently lacking. A recently published observational study focusing on serum biomarkers of AD in the Netherlands proposed 4 endotype clusters of AD [Table 4]. Clusters 1 and 4 had higher levels of Th2 cytokines and higher frequency of the erythematous phenotype compared to cluster 2 and 3. In addition, cluster 4 patients showed distinctively high levels of epithelial cytokine TSLP than cluster 1. In contrast, clusters 2 and 3 had predominantly lichenified phenotype and low Th2 cytokines. Notably, serum IgE levels were not significantly different among the clusters, and comorbid atopic diseases did not correlate with level of Th2 markers. This coincides with the clinical findings that IgE and IL-5 did not present as pan-effective targets in AD., Future interventional studies are needed to confirm the reliability of the endotyping approach and to support the development of precision medicine.
|Table 4: Four distinct patient clusters of atopic dermatitis based on serum biomarker analysis|
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| Conclusion|| |
To date, there remains an unmet need for safe and effective long-term therapy in adults with moderate-to-severe AD. The growing knowledge of immune-mediated pathomechanisms of AD has led to the development of several new, targeted systemic agents. Dupilumab is a newly approved systemic biologic with promising efficacy and acceptable safety in the adult AD population, and future real-world studies will provide long-term evidence. While dupilumab is already clinically available to adults, its clinical trials for children and adolescents AD are underway (NCT02612454, NCT03345914), including positive Phase III results released for adolescents with inadequately controlled moderate-to-severe AD. Emerging biologics and small molecules targeting various AD-related pathomechanisms are currently under investigation and may provide further benefit in disease control. Nemolizumab, an anti-IL31RA antibody, has been shown to significantly reduce AD pruritus in two phase II clinical trials. Meanwhile, it is hoped that evolving biomarker assessments in the future could provide accurate characterization of AD endotypes and guide treatment planning. The evolution in precision medicine could bring new prospects in the optimal treatment of AD.
Writing and editorial assistance in the preparation of this manuscript was provided by Chian-Yi Liu at EMD Asia Scientific Communication (Taiwan branch) Co., Ltd. Support of this assistance was funded by Sanofi Taiwan Co., Ltd. The content of this article was expressed according to the opinions of authors and the manuscript submission for publication was completed with the final approval of all authors. Sanofi reviewed this article for medical accuracy only.
Financial support and sponsorship
Conflicts of interest
One author received consulting fees from Sanofi and has also served as an investigator for AbbVie, Eli Liliy, Pfizer, and Novartis. The other author received consulting fees, travel support, and payment for lectures from Novartis, Pfizer, and Sanofi and has also served as an investigator for AbbVie, Eli Lilly, Novartis, Pfizer, and Sanofi.
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[Table 1], [Table 2], [Table 3], [Table 4]