日本アレルギー学会、日本皮膚科学会、アトピー性皮膚炎診療ガイドライン作成員会編：アトピー性皮膚炎診療ガイドライン2021.アレルギー：70(10),1257-1342. 2021.
Elias PM.
Stratum corneum defensive functions: an integrated view.
J Invest Dermatol. 2005 Aug;125(2):183-200. doi: 10.1111/j.0022-202X.2005.23668.x.
Abstract/Text
Most epidermal functions can be considered as protective, or more specifically, as defensive in nature. Yet, the term "barrier function" is often used synonymously with only one such defensive function, though arguably its most important, i.e., permeability barrier homeostasis. Regardless of their relative importance, these protective cutaneous functions largely reside in the stratum corneum (SC). In this review, I first explore the ways in which the multiple defensive functions of the SC are linked and interrelated, either by their shared localization or by common biochemical processes; how they are co-regulated in response to specific stressors; and how alterations in one defensive function impact other protective functions. Then, the structural and biochemical basis for these defensive functions is reviewed, including metabolic responses and signaling mechanisms of barrier homeostasis. Finally, the clinical consequences and therapeutic implications of this integrated perspective are provided.
Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H, Lee SP, Goudie DR, Sandilands A, Campbell LE, Smith FJ, O'Regan GM, Watson RM, Cecil JE, Bale SJ, Compton JG, DiGiovanna JJ, Fleckman P, Lewis-Jones S, Arseculeratne G, Sergeant A, Munro CS, El Houate B, McElreavey K, Halkjaer LB, Bisgaard H, Mukhopadhyay S, McLean WH.
Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis.
Nat Genet. 2006 Apr;38(4):441-6. doi: 10.1038/ng1767. Epub 2006 Mar 19.
Abstract/Text
Atopic disease, including atopic dermatitis (eczema), allergy and asthma, has increased in frequency in recent decades and now affects approximately 20% of the population in the developed world. Twin and family studies have shown that predisposition to atopic disease is highly heritable. Although most genetic studies have focused on immunological mechanisms, a primary epithelial barrier defect has been anticipated. Filaggrin is a key protein that facilitates terminal differentiation of the epidermis and formation of the skin barrier. Here we show that two independent loss-of-function genetic variants (R510X and 2282del4) in the gene encoding filaggrin (FLG) are very strong predisposing factors for atopic dermatitis. These variants are carried by approximately 9% of people of European origin. These variants also show highly significant association with asthma occurring in the context of atopic dermatitis. This work establishes a key role for impaired skin barrier function in the development of atopic disease.
Nemoto-Hasebe I, Akiyama M, Nomura T, Sandilands A, McLean WH, Shimizu H.
FLG mutation p.Lys4021X in the C-terminal imperfect filaggrin repeat in Japanese patients with atopic eczema.
Br J Dermatol. 2009 Dec;161(6):1387-90. doi: 10.1111/j.1365-2133.2009.09406.x. Epub 2009 Aug 7.
Abstract/Text
BACKGROUND: Mutations in the gene encoding filaggrin (FLG) have been shown to predispose to atopic eczema (AE).
OBJECTIVES: Further to establish population genetics of FLG mutations in the Japanese population and to elucidate effects of FLG mutations to filaggrin biosynthesis in skin of patients with AE.
METHODS: We searched for FLG mutations in 19 newly recruited Japanese patients with AE. We then screened 137 Japanese patients with AE and 134 Japanese control individuals for a novel mutation identified in the present study. In addition, we evaluated FLG mRNA expression by real-time reverse transcription-polymerase chain reaction and profilaggrin/filaggrin protein expression by immunohistochemical staining in the epidermis of the patients carrying the novel mutation.
RESULTS: We identified a novel FLG nonsense mutation c.12069A>T (p.Lys4021X) in one patient with AE. Upon further screening, p.Lys4021X was identified in four patients with AE (2.9% of all the patients with AE). In total, there are at least eight FLG variants in the Japanese population. Here we show that about 27% of patients in our Japanese AE case series carry one or more of these eight FLG mutations and these variants are also carried by 3.7% of Japanese general control individuals. There is a significant statistical association between the eight FLG mutations and AE (chi(2) P = 6.50 x 10(-8)). Interestingly, the present nonsense mutation is in the C-terminal incomplete filaggrin repeat and is the mutation nearest the C-terminal among previously reported FLG mutations. Immunohistochemical staining for filaggrin revealed that this nonsense mutation leads to remarkable reduction of filaggrin protein expression in the patients' epidermis.
CONCLUSIONS: We clearly demonstrated that FLG mutations are significantly associated with AE in the Japanese population. The present results further support the hypothesis that the C-terminal region is essential for proper processing of profilaggrin to filaggrin.
De Benedetto A, Rafaels NM, McGirt LY, Ivanov AI, Georas SN, Cheadle C, Berger AE, Zhang K, Vidyasagar S, Yoshida T, Boguniewicz M, Hata T, Schneider LC, Hanifin JM, Gallo RL, Novak N, Weidinger S, Beaty TH, Leung DY, Barnes KC, Beck LA.
Tight junction defects in patients with atopic dermatitis.
J Allergy Clin Immunol. 2011 Mar;127(3):773-86.e1-7. doi: 10.1016/j.jaci.2010.10.018. Epub 2010 Dec 15.
Abstract/Text
BACKGROUND: Atopic dermatitis (AD) is characterized by dry skin and a hyperactive immune response to allergens, 2 cardinal features that are caused in part by epidermal barrier defects. Tight junctions (TJs) reside immediately below the stratum corneum and regulate the selective permeability of the paracellular pathway.
OBJECTIVE: We evaluated the expression/function of the TJ protein claudin-1 in epithelium from AD and nonatopic subjects and screened 2 American populations for single nucleotide polymorphisms in the claudin-1 gene (CLDN1).
METHODS: Expression profiles of nonlesional epithelium from patients with extrinsic AD, nonatopic subjects, and patients with psoriasis were generated using Illumina's BeadChips. Dysregulated intercellular proteins were validated by means of tissue staining and quantitative PCR. Bioelectric properties of epithelium were measured in Ussing chambers. Functional relevance of claudin-1 was assessed by using a knockdown approach in primary human keratinocytes. Twenty-seven haplotype-tagging SNPs in CLDN1 were screened in 2 independent populations with AD.
RESULTS: We observed strikingly reduced expression of the TJ proteins claudin-1 and claudin-23 only in patients with AD, which were validated at the mRNA and protein levels. Claudin-1 expression inversely correlated with T(H)2 biomarkers. We observed a remarkable impairment of the bioelectric barrier function in AD epidermis. In vitro we confirmed that silencing claudin-1 expression in human keratinocytes diminishes TJ function while enhancing keratinocyte proliferation. Finally, CLDN1 haplotype-tagging SNPs revealed associations with AD in 2 North American populations.
CONCLUSION: Collectively, these data suggest that an impairment in tight junctions contributes to the barrier dysfunction and immune dysregulation observed in AD subjects and that this may be mediated in part by reductions in claudin-1.
Copyright © 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.
厚生労働科学研究 河野陽一、山本昇壯監修 アトピー性皮膚炎治療ガイドライン2008.
河野陽一：アトピー性皮膚炎の発症および悪化因子の同定と発症予防・症状悪化防止のための生活環境整備に関する研究，平成18～20年度総合研究報告書，2009：1-11.
Roduit C, Frei R, Depner M, Karvonen AM, Renz H, Braun-Fahrländer C, Schmausser-Hechfellner E, Pekkanen J, Riedler J, Dalphin JC, von Mutius E, Lauener RP; the PASTURE study group; Hyvärinen A, Kirjavainen P, Remes S, Roponen M, Dalphin ML, Kaulek V, Ege M, Genuneit J, Illi S, Kabesch M, Schaub B, Pfefferle PI, Doekes G.
Phenotypes of Atopic Dermatitis Depending on the Timing of Onset and Progression in Childhood.
JAMA Pediatr. 2017 Jul 1;171(7):655-662. doi: 10.1001/jamapediatrics.2017.0556.
Abstract/Text
IMPORTANCE: Atopic dermatitis is an inflammatory, pruritic skin disease that often occurs in early infancy with a chronic course. However, a specific description of subtypes of atopic dermatitis depending on the timing of onset and progression of the disease in childhood is lacking.
OBJECTIVE: To identify different phenotypes of atopic dermatitis using a definition based on symptoms before age 6 years and to determine whether some subtypes are more at risk for developing other allergic diseases.
DESIGN, SETTING, AND PARTICIPANTS: The Protection Against Allergy Study in Rural Environments (PASTURE) is a European birth cohort where pregnant women were recruited between August 2002 and March 2005 and divided in 2 groups dependent on whether they lived on a farm. Children from this cohort with data on atopic dermatitis from birth to 6 years of age were included.
EXPOSURES: Atopic dermatitis, defined as an itchy rash on typical locations from birth to 6 years.
MAIN OUTCOMES AND MEASURES: The latent class analysis was used to identify subtypes of atopic dermatitis in childhood based on the course of symptoms. Multivariable logistic regressions were used to analyze the association between atopic dermatitis phenotypes and other allergic diseases.
RESULTS: We included 1038 children; of these, 506 were girls. The latent class analysis model with the best fit to PASTURE data separated 4 phenotypes of atopic dermatitis in childhood: 2 early phenotypes with onset before age 2 years (early transient [n = 96; 9.2%] and early persistent [n = 67; 6.5%]), the late phenotype with onset at age 2 years or older (n = 50; 4.8%), and the never/infrequent phenotype (n = 825; 79.5%), defined as children with no atopic dermatitis. Children with both parents with history of allergies were 5 times more at risk to develop atopic dermatitis with an early-persistent phenotype compared with children with parents with no history of allergies. Both early phenotypes were strongly associated with food allergy. The risk of developing asthma was significantly increased among the early-persistent phenotype (adjusted odds ratio, 2.87; 95% CI, 1.31-6.31). The late phenotype was only positively associated with allergic rhinitis.
CONCLUSIONS AND RELEVANCE: Using latent class analysis, 4 phenotypes of atopic dermatitis were identified depending on the onset and course of the disease. The prevalence of asthma and food allergy by 6 years of age was strongly increased among children with early phenotypes (within age 2 years), especially with persistent symptoms. These findings are important for the development of strategies in allergy prevention.
Yamamoto-Hanada K, Yang L, Saito-Abe M, Sato M, Inuzuka Y, Toyokuni K, Nishimura K, Irahara M, Ishikawa F, Miyaji Y, Fukuie T, Narita M, Saito H, Ohya Y.
Four phenotypes of atopic dermatitis in Japanese children: A general population birth cohort study.
Allergol Int. 2019 Oct;68(4):521-523. doi: 10.1016/j.alit.2019.02.010. Epub 2019 Mar 30.
Abstract/Text
Illi S, von Mutius E, Lau S, Nickel R, Grüber C, Niggemann B, Wahn U; Multicenter Allergy Study Group.
The natural course of atopic dermatitis from birth to age 7 years and the association with asthma.
J Allergy Clin Immunol. 2004 May;113(5):925-31. doi: 10.1016/j.jaci.2004.01.778.
Abstract/Text
BACKGROUND: Atopic dermatitis (AD) is considered to be one of the first manifestations in the atopic march. However, few prospective studies on AD and its association with childhood asthma exist.
OBJECTIVE: The aim of this study was to prospectively investigate the natural course of AD to determine factors influencing its prognosis and to analyze the relationship of AD with childhood asthma.
METHODS: The Multicenter Allergy Study, a German birth cohort, followed 1314 children from birth to age 7 years. Physical examinations, parental interviews on atopic symptoms and diagnoses, and determination of specific IgE levels were performed regularly.
RESULTS: The cumulative prevalence of AD in the first 2 years of life was 21.5%. Of these children with early AD, 43.2% were in complete remission by age 3 years, 38.3% had an intermittent pattern of disease, and 18.7% had symptoms of AD every year. Severity (adjusted cumulative odds ratio, 5.86; 95% CI, 3.04-11.29) and atopic sensitization (adjusted cumulative odds ratio, 2.76; 95% CI, 1.29-5.91) were major determinants of prognosis. Early wheeze and a specific sensitization pattern were significant predictors for wheezing at school age, irrespective of AD. Early AD without these cofactors constituted no increased risk of subsequent wheeze (adjusted odds ratio, 1.11; 95% CI, 0.56-2.20) or bronchial hyperreactivity.
CONCLUSION: AD is a common condition in infancy but disappears around age 3 years in a significant proportion of children. The prognosis is mostly determined by the severity and the presence of atopic sensitization. Early AD is associated with asthma at school age, but in many of these asthmatic children, wheezing manifests before or with the onset of AD. Children with AD and wheeze have a marked loss in lung function, suggesting a distinct phenotype rather than a progressive development from AD to asthma.
Ricci G, Patrizi A, Baldi E, Menna G, Tabanelli M, Masi M.
Long-term follow-up of atopic dermatitis: retrospective analysis of related risk factors and association with concomitant allergic diseases.
J Am Acad Dermatol. 2006 Nov;55(5):765-71. doi: 10.1016/j.jaad.2006.04.064. Epub 2006 Jun 27.
Abstract/Text
BACKGROUND: The association of atopic dermatitis (AD) with other allergic diseases has been extensively studied; however, there is a lack of reports focusing on long-term studies of the clinical and allergometric evaluations observed during the course of AD in respect to its evolution and association with allergic responses in affected patients.
OBJECTIVE: The aim of this study was to evaluate, with defined criteria of clinical diagnosis, severity assessment, and objective allergometric test at the time of inclusion, the natural course of AD, the factors influencing its healing or persistence, and the appearance of other allergic diseases with particular focus on asthma and the presence of specific immunoglobulin E at first observation.
METHODS: This study included only children, aged between 6 and 36 months, whose first clinical examination was made between 1981 and 1989. A total of 252 children satisfied these criteria. A semistructured interview was performed by the physician using a preformed questionnaire, which was completed for 205 children (104 boys and 101 girls).
RESULTS: AD had completely disappeared in 124 cases (60.5%). Other allergic manifestations that appeared included asthma in 70 cases (34.1%) and rhinoconjunctivitis (RC) in 118 cases (57.6%). Generally the average age of patients recovering from AD was higher in severe AD (6.0 +/- 3.5 years) than in its moderate or mild forms (5.8 +/- 4.5 and 5.5 +/- 3.9 years, respectively). This phenomenon was particularly evident in children with hen's egg sensitization, who show a longer persistence of the condition (Student t = 2.462 and P < .02). The initial severity score of AD was found to be associated with a high frequency of asthma appearance (Pearson chi2 = 14.225 and P < .001). Hen's egg sensitization was significantly related to the appearance of asthma (Fisher's exact test P < .007) and RC (Fisher's exact test P < .05). A retrospective analysis of related risks factors and their association with concomitant allergic diseases in our case studies shows that the egg sensitization, severity of AD, and onset of RC were positively related to the occurrence of asthma. In addition, our analysis shows that, although the appearance of RC was proportional to the incidence of atopy and asthma, it was inversely related to the persistence of AD (corrected odds ratio confidence intervals <1).
LIMITATIONS: The study includes children referred to the hospital. However, it is the practice of local national health pediatricians to send all patients with suspected AD, whatever the severity grade, to hospital specialists to perform allergometric assessment.
CONCLUSION: The use of defined criteria of clinical diagnosis for the determination of the condition's severity, along with the performance of objective allergometric tests at the time of inclusion, shows that the course of AD is significantly related to egg sensitivity. In addition, the average healing time is higher in egg-sensitive patients affected by the most severe form of AD than in mild or moderate cases.
Ohshima Y, Yamada A, Hiraoka M, Katamura K, Ito S, Hirao T, Akutagawa H, Kondo N, Morikawa A, Mayumi M.
Early sensitization to house dust mite is a major risk factor for subsequent development of bronchial asthma in Japanese infants with atopic dermatitis: results of a 4-year followup study.
Ann Allergy Asthma Immunol. 2002 Sep;89(3):265-70. doi: 10.1016/S1081-1206(10)61953-9.
Abstract/Text
BACKGROUND: Bronchial asthma (BA) often develops in children with atopic dermatitis (AD). Identification of factors that could predict the development of asthma in children with AD is useful for early intervention.
OBJECTIVE: We undertook a 4-year followup study to clarify the factors involved in the development of BA in infants with AD.
METHODS: We registered 169 infants with AD who were free of BA at registration and examined the prevalence and characteristics of the subsequent development of BA among these patients.
RESULTS: Among the patients followed for 4 years, approximately 45% experienced asthma-like respiratory symptoms, and 35% were diagnosed as asthmatic patients by pediatric allergologists. Patients who developed BA showed early appearance of house dust mite (HDM)-specific immunoglobulin E (IgE) and persistently high levels of food-specific IgE. Male sex, a positive family history of BA, and the appearance of HDM-specific IgE were identified as significant risk factors for the early development of BA, but the significance of these parameters decreased thereafter. A positive family history of AD, the outcome of skin lesions, and keeping furred pets were also identified as risk factors in a part of the followup period. Among the parameters examined, the early appearance of HDM-specific IgE was the most significant risk factor.
CONCLUSION: Appearance of HDM-specific IgE antibodies in early childhood, which seems to be mainly influenced by genetic factors, is a major risk factor for the subsequent development of BA in children with AD, but the influence decreases after longer followup.
Zhang Z, Li H, Zhang H, Cheng R, Li M, Huang L, Li C, Guo Y, Yao Z, Feng X.
Factors associated with persistence of early-onset atopic dermatitis up to the age of 12 years: a prospective cohort study in China.
Eur J Dermatol. 2021 Jun 1;31(3):403-408. doi: 10.1684/ejd.2021.4045.
Abstract/Text
Atopic dermatitis (AD) can remit as age increases. However, long-term follow-up studies evaluating disease evolution and related factors of persistence of early-onset AD are sparse. This study aimed to identify factors associated with the persistence of early-onset AD. In this prospective cohort study, 260 patients with onset of AD before age two years old were enrolled. Clinical examination was performed and a questionnaire survey completed at enrolment. In addition, the filaggrin gene (FLG) of all participants was sequenced to identify mutations within this gene. Patients were followed at age six and 12. The remission rate was 50.8% at age six and 70.3% at age 12. Persistent AD was associated with a higher SCORAD index at baseline (p < 0.001), a family history of asthma (p = 0.003) and food allergen sensitization (p = 0.033). However, the presence or absence of FLG mutation did not show any significant association with persistent AD. Prognostic factors for persistence of AD were analysed by logistic regression analysis. Disease severity according to SCORAD index at baseline (OR: 1.039; 95% CI: 1.018-1.059; p < 0.001) and family history of asthma (OR: 3.008; 95% CI: 1.297-7.007; p = 0.011) were risk factors that may predict persistent AD based on multivariate regression analysis. It is important to stratify early-onset AD according to severity and investigate family allergic history in order to establish appropriate individual management. Moreover, genetic factors other than FLG mutation may play more important roles in persistent early-onset AD.
Kakinuma T, Nakamura K, Wakugawa M, Mitsui H, Tada Y, Saeki H, Torii H, Asahina A, Onai N, Matsushima K, Tamaki K.
Thymus and activation-regulated chemokine in atopic dermatitis: Serum thymus and activation-regulated chemokine level is closely related with disease activity.
J Allergy Clin Immunol. 2001 Mar;107(3):535-41. doi: 10.1067/mai.2001.113237.
Abstract/Text
BACKGROUND: Atopic dermatitis (AD) is a chronic and relapsing inflammatory skin disease characterized by the predominant infiltration of TH2-type cells in lesional skin. Thymus and activation-regulated chemokine (TARC/CCL17) is a chemokine that attracts CC chemokine receptor 4-positive (CCR4+) or CCR8+ cells.
OBJECTIVE: The purpose of this study was to investigate the participation of TARC in AD.
METHODS: We measured serum TARC levels in 40 patients with AD, 20 healthy control subjects, and 20 patients with psoriasis. We also examined disease activity by using SCORAD score; serum soluble E-selectin, soluble IL-2 receptor, IgE, and GM-CSF levels; and eosinophil numbers in peripheral blood, as well as correlations between TARC levels and these factors. The positivity of CCR4 of CD4+CD45RO+ cells in PBMCs was examined by using FACS analysis. Immunohistochemical staining of TARC and GM-CSF was performed in the lesional skin of patients with AD.
RESULTS: The serum TARC levels of patients with AD were significantly higher than those of healthy control subjects and patients with psoriasis. The serum TARC levels significantly correlated with eosinophil number (r = 0.61), SCORAD score (r = 0.60), and serum soluble E-selectin levels (r = 0.58) and weakly correlated with serum soluble IL-2 receptor levels (r = 0.34) in patients with AD. The TARC levels of patients with AD decreased after the treatment in accordance with the improvement of clinical symptoms. The CCR4 positivity of CD4+CD45RO+ cells in PBMCs of patients with AD was also higher than that of healthy control subjects. Immunohistochemical staining revealed that TARC was positive in keratinocytes in the epidermis and in vascular endothelial cells, T cells, and dendritic cells in the dermis.
CONCLUSION: Serum TARC levels are associated with disease activity of AD, and TARC may play an important role in the pathogenesis of AD.
藤澤隆夫、長尾みづほ、野間雪子、他：小児アトピー性皮膚炎の病勢評価マーカーとしての血清TARC/CCL17の臨床的有用性．日本小児アレルギー学会誌, 2005;19：744-757．.
Nagao M, Inagaki S, Kawano T, Azuma Y, Nomura N, Noguchi Y, Ohta S, Kawaguchi A, Odajima H, Ohya Y, Fujisawa T, Izuhara K.
SCCA2 is a reliable biomarker for evaluating pediatric atopic dermatitis.
J Allergy Clin Immunol. 2018 May;141(5):1934-1936.e11. doi: 10.1016/j.jaci.2018.01.021. Epub 2018 Feb 5.
Abstract/Text
Takeuchi S, Furusyo N, Ono J, Azuma Y, Takemura M, Esaki H, Yamamura K, Mitamura Y, Tsuji G, Kiyomatsu-Oda M, Hayashi J, Izuhara K, Furue M.
Serum squamous cell carcinoma antigen (SCCA)-2 correlates with clinical severity of pediatric atopic dermatitis in Ishigaki cohort.
J Dermatol Sci. 2019 Aug;95(2):70-75. doi: 10.1016/j.jdermsci.2019.07.005. Epub 2019 Jul 24.
Abstract/Text
BACKGROUND: We sometimes encounter difficulties in assessing the severity of pediatric atopic dermatitis (AD) using currently available biomarkers such as thymus and activation-regulated chemokine (TARC) due to the higher baseline values in non-AD children. Recent case control studies have indicated the usefulness of squamous cell carcinoma antigens (SCCAs) in pediatric and adult AD. Notably, SCCAs are induced by IL-4 and IL-13, vital Th2 cytokines that play important roles in AD etiology.
OBJECTIVES: Relatively low prevalence and mild disease severity of pediatric AD are observed in our Ishigaki cohort presumably due to the moisturising subtropical climate, which could conversely mean possible higher allergic potential of non-AD subjects towards AD. Thus, the purpose of this study was to further investigate the feasibility of using SCCAs together with TARC and periostin as biomarkers for pediatric AD even in the Ishigaki cohort.
METHODS: We enrolled 1459 nursery school children and identified 96 as having AD through 2009-2011. As statistical analyses, we performed Student's t-test, correlation analysis, and receiver and operating characteristic (ROC) analysis.
RESULTS: Serum SCCA1, SCCA2, periostin and TARC levels were all significantly increased in AD compared with those in non-AD, but only serum SCCA2 showed a significant increase in AD when assessed in each age group or in subgroup analysis. Among the biomarkers tested, serum SCCA2 also showed the best correlations with clinical AD severity and TARC and showed the best diagnosability for AD in ROC analysis.
CONCLUSIONS: SCCA2 is a potent biomarker for pediatric AD in the Ishigaki cohort.
Copyright © 2019 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.
Ji J, Venderley J, Zhang H, Lei M, Ruan G, Patel N, Chung YM, Giesting R, Miller L.
Assessing nocturnal scratch with actigraphy in atopic dermatitis patients.
NPJ Digit Med. 2023 Apr 26;6(1):72. doi: 10.1038/s41746-023-00821-y. Epub 2023 Apr 26.
Abstract/Text
Nocturnal scratch is one major factor leading to impaired quality of life in atopic dermatitis (AD) patients. Therefore, objectively quantifying nocturnal scratch events aids in assessing the disease state, treatment effect, and AD patients' quality of life. In this paper, we describe the use of actigraphy, highly predictive topological features, and a model-ensembling approach to develop an assessment of nocturnal scratch events by measuring scratch duration and intensity. Our assessment is tested in a clinical setting against the ground truth obtained from video recordings. The new approach addresses unmet challenges in existing studies, such as the lack of generalizability to real-world applications, the failure to capture finger scratches, and the limitations in the evaluation due to imbalanced data in the current literature. Furthermore, the performance evaluation shows agreement between derived digital endpoints and the video annotation ground truth, as well as patient-reported outcomes, which demonstrated the validity of the new assessment of nocturnal scratch.
© 2023. The Author(s).
Charman CR, Venn AJ, Ravenscroft JC, Williams HC.
Translating Patient-Oriented Eczema Measure (POEM) scores into clinical practice by suggesting severity strata derived using anchor-based methods.
Br J Dermatol. 2013 Dec;169(6):1326-32. doi: 10.1111/bjd.12590.
Abstract/Text
BACKGROUND: The Patient-Oriented Eczema Measure (POEM) is a validated, patient-derived assessment measure for monitoring atopic eczema severity, although further information on how different POEM scores translate into disease severity categories is needed for clinical trials, epidemiological research and audit.
OBJECTIVES: We sought to determine the relationship between Patient-Oriented Eczema Measure (POEM) scores (range 0-28) and two Global Questions (GQ1 and 2) concerning patients'/parents' views of the overall severity of their/their child's atopic eczema, in order to stratify POEM scores into five severity bands.
METHODS: POEM scores and GQs were completed by 300 patients from general practice and 700 patients from dermatology outpatient clinics, including 300 adults aged ≥ 16 years and 700 children.
RESULTS: The mean POEM score was 13·6 (range 0-28), and standard deviation (SD) was 7·2. Mean GQ1/GQ2 scores were 2·1/2·1, respectively (range 0-4 and SD 1·1 for both). The mean, mode and median of the GQ scores for each POEM score were used to devise possible POEM bandings. The proposed banding for POEM scores are: 0-2 (clear/almost clear); 3-7 (mild); 8-16 (moderate); 17-24 (severe); 25-28 (very severe), kappa coefficient 0·46.
CONCLUSIONS: Severity banding of the POEM will allow more clinically meaningful use in everyday clinical practice and as a core outcome measure in future atopic eczema research.
© 2013 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.
Gaunt DM, Metcalfe C, Ridd M.
The Patient-Oriented Eczema Measure in young children: responsiveness and minimal clinically important difference.
Allergy. 2016 Nov;71(11):1620-1625. doi: 10.1111/all.12942. Epub 2016 Jul 13.
Abstract/Text
BACKGROUND: The Patient-Oriented Eczema Measure (POEM) has been recommended as the core patient-reported outcome measure for trials of eczema treatments. Using data from the Choice of Moisturiser for Eczema Treatment randomized feasibility study, we assess the responsiveness to change and determine the minimal clinically important difference (MCID) of the POEM in young children with eczema.
METHODS: Responsiveness to change by repeated administrations of the POEM was investigated in relation to change recalled using the Parent Global Assessment (PGA) measure. Five methods of determining the MCID of the POEM were employed; three anchor-based methods using PGA as the anchor: the within-patient score change, between-patient score change and sensitivity and specificity method, and two distribution-based methods: effect size estimate and the one half standard deviation of the baseline distribution of POEM scores.
RESULTS: Successive POEM scores were found to be responsive to change in eczema severity. The MCID of the POEM change score, in relation to a slight improvement in eczema severity as recalled by parents on the PGA, estimated by the within-patient score change (4.27), the between-patient score change (2.89) and the sensitivity and specificity method (3.00) was similar to the one half standard deviation of the POEM baseline scores (2.94) and the effect size estimate (2.50).
CONCLUSIONS: The Patient-Oriented Eczema Measure as applied to young children is responsive to change, and the MCID is around 3. This study will encourage the use of POEM and aid in determining sample size for future randomized controlled trials of treatments for eczema in young children.
© 2016 The Authors. Allergy Published by John Wiley & Sons Ltd.
糸永宇慧, 柳田紀之, 西野誠, ほか. アトピー性皮膚炎の長期コントロール指標 Recap of atopic eczema（RECAP）の日本語版の作成と言語検証. アレルギー. 2023;72(10):1240-1247.
Lack G.
Epidemiologic risks for food allergy.
J Allergy Clin Immunol. 2008 Jun;121(6):1331-6. doi: 10.1016/j.jaci.2008.04.032.
Abstract/Text
This article reviews possible risk factors and theories for the development of food allergy. It is noted that previous strategies to prevent food allergy through allergen avoidance during pregnancy, breast-feeding, and infancy have more recently been called into question. Alternative hypotheses are examined with respect to food allergy, namely the hygiene hypothesis, the dietary fat hypothesis, the antioxidant hypothesis, and the vitamin D hypotheses. An alternative hypothesis is proposed, suggesting that sensitization to allergen occurs through environmental exposure to allergen through the skin and that consumption of food allergen induces oral tolerance. This hypothesis provides a possible explanation for the close link between eczema and the development of food allergies. It also suggests novel interventional strategies to prevent the development of food allergies.
Natsume O, Kabashima S, Nakazato J, Yamamoto-Hanada K, Narita M, Kondo M, Saito M, Kishino A, Takimoto T, Inoue E, Tang J, Kido H, Wong GW, Matsumoto K, Saito H, Ohya Y; PETIT Study Team.
Two-step egg introduction for prevention of egg allergy in high-risk infants with eczema (PETIT): a randomised, double-blind, placebo-controlled trial.
Lancet. 2017 Jan 21;389(10066):276-286. doi: 10.1016/S0140-6736(16)31418-0. Epub 2016 Dec 9.
Abstract/Text
BACKGROUND: Evidence is accumulating that early consumption is more beneficial than is delayed introduction as a strategy for primary prevention of food allergy. However, allergic reactions caused by early introduction of such solid foods have been a problematic issue. We investigated whether or not early stepwise introduction of eggs to infants with eczema combined with optimal eczema treatment would prevent egg allergy at 1 year of age.
METHODS: In this randomised, double-blind, placebo-controlled trial, we enrolled infants 4-5 months of age with eczema from two centres in Japan. Exclusion criteria were being born before 37 weeks of gestational age, experience of ingestion of hen's eggs or egg products, history of immediate allergic reaction to hen's eggs, history of non-immediate allergic reaction to a particular type of food, and complications of any severe disease. Infants were randomly assigned (block size of four; stratified by institution and sex) to early introduction of egg or placebo (1:1). Participants in the egg group consumed orally 50 mg of heated egg powder per day from 6 months to 9 months of age and 250 mg per day thereafter until 12 months of age. We aggressively treated participants' eczema at entry and maintained control without exacerbations throughout the intervention period. Participants and physicians were masked to assignment, and allocation was concealed. The primary outcome was the proportion of participants with hen's egg allergy confirmed by open oral food challenges at 12 months of age, assessed blindly by standardised methods, in all randomly allocated participants who received the intervention. This trial is registered with the University Hospital Medical Information Network Clinical Trials Registry, number UMIN000008673.
FINDINGS: Between Sept 18, 2012, and Feb 13, 2015, we randomly allocated 147 participants (73 [50%] to the egg group and 74 [50%] to the placebo group). This trial was terminated on the basis of the results of the scheduled interim analysis of 100 participants, which showed a significant difference between the two groups (four [9%] of 47 participants had an egg allergy in the egg group vs 18 [38%] of 47 in the placebo group; risk ratio 0·222 [95% CI 0·081-0·607]; p=0·0012). In the primary analysis population, five (8%) of 60 participants had an egg allergy in the egg group compared with 23 (38%) of 61 in the placebo group (risk ratio 0·221 [0·090-0·543]; p=0·0001). The only difference in adverse events between groups was admissions to hospital (six [10%] of 60 in the egg group vs none in the placebo group; p=0·022). 19 acute events occurred in nine (15%) participants in the egg group versus 14 events in 11 (18%) participants in the placebo group after intake of the trial powder.
INTERPRETATION: Introduction of heated egg in a stepwise manner along with aggressive eczema treatment is a safe and efficacious way to prevent hen's egg allergy in high-risk infants. In this study, we developed a practical approach to overcome the second wave of the allergic epidemic caused by food allergy.
FUNDING: Ministry of Health, Labour and Welfare, and National Centre for Child Health and Development, Japan.
Copyright © 2017 Elsevier Ltd. All rights reserved.
Yamamoto-Hanada K, Kobayashi T, Mikami M, Williams HC, Saito H, Saito-Abe M, Sato M, Irahara M, Miyaji Y, Ishikawa F, Tsuchiya K, Tamagawa-Mineoka R, Takaoka Y, Takemura Y, Sato S, Wakiguchi H, Hoshi M, Natsume O, Yamaide F, Seike M, Ohya Y; PACI Study Collaborators.
Enhanced early skin treatment for atopic dermatitis in infants reduces food allergy.
J Allergy Clin Immunol. 2023 Jul;152(1):126-135. doi: 10.1016/j.jaci.2023.03.008. Epub 2023 Mar 22.
Abstract/Text
BACKGROUND: Early-onset atopic dermatitis is a strong risk factor for food allergy, suggesting that early effective treatment may prevent transcutaneous sensitization.
OBJECTIVES: This study tested whether enhanced treatment of atopic dermatitis to clinically affected and unaffected skin is more effective in preventing hen's egg allergy than reactive treatment to clinically affected skin only.
METHODS: This was a multicenter, parallel-group, open-label, assessor-blind, randomized controlled trial (PACI [Prevention of Allergy via Cutaneous Intervention] study). This study enrolled infants 7-13 weeks old with atopic dermatitis and randomly assigned infants in a 1:1 ratio to enhanced early skin treatment or conventional reactive treatment using topical corticosteroids (TCSs). The primary outcome was the proportion of immediate hen's egg allergy confirmed by oral food challenge at 28 weeks of age.
RESULTS: This study enrolled 650 infants and analyzed 640 infants (enhanced [n = 318] or conventional [n = 322] treatment). Enhanced treatment significantly reduced hen's egg allergy compared with the conventional treatment (31.4% vs 41.9%, P = .0028; risk difference: -10.5%, upper bound of a 1-sided CI: -3.0%), while it lowered body weight (mean difference: -422 g, 95% CI: -553 to -292 g) and height (mean difference: -0.8 cm, 95% CI: -1.22 to -0.33 cm) at 28 weeks of age.
CONCLUSIONS: This study highlighted the potential of well-controlled atopic dermatitis management as a component of a hen's egg allergy prevention strategy. The enhanced treatment protocol of this trial should be modified before it can be considered as an approach to prevent hen's egg allergy in daily practice to avoid the adverse effects of TCSs. After remission induction by TCSs, maintenance therapy with lower potency TCSs or other topical therapies might be considered as alternative proactive treatments to overcome the safety concerns of TCSs.
Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Lebwohl M.
Efficacy and safety of fluticasone propionate ointment, 0.005%, in the treatment of eczema.
Cutis. 1996 Feb;57(2 Suppl):62-8.
Abstract/Text
The clinical efficacy and safety of fluticasone propionate ointment, 0.005%, were compared with those of its vehicle in the treatment of moderate-to-severe eczema of long duration in two multicenter, double-blind, vehicle-controlled, randomized studies. One of the two study medications (up to 100 gm/week) was applied topically to the affected areas of the body twice daily for up to four consecutive weeks. Drug efficacy was measured in terms of three variables: the physician's gross assessment of clinical response of the target lesion, severity scores of individual signs and symptoms, and the patient's subjective assessment of treatment effects. Efficacy and safety were evaluated after seven, fourteen, twenty-one, and twenty-eight days of treatment. The total number of patients in the two studies was 372 (203 in study 1 and 169 in study 2). Fluticasone propionate ointment, 0.005%, was more effective than vehicle at all postbaseline visits in both studies (study 1 P < or = 0.015, study 2 P < or = 0.018). In study 1, approximately 80% of the patients on fluticasone were rated as cleared, excellent, or good by the investigators at treatment endpoint, compared with 38% of those receiving vehicle. In study 2, the sum of 80% of the fluticasone-treated patients was rated as cleared, excellent, or good by the investigators at the end of the study, compared with 34% of those receiving vehicle. The beneficial effect of fluticasone ointment, 0.005%, was early and sustained and was particularly noticeable for pruritus, erythema, and skin thickening. In study 1, no drug-related adverse events were reported in the fluticasone group. Four patients (4.3%) in the vehicle group experienced a total of four drug-related adverse events. The most common was burning/stinging, reported by two patients. In study 2, two patients (2.4%) in the fluticasone-treated group and three (4.1%) in the vehicle group reported a total of five drug-related adverse events, the most common event being pruritus (fluticasone group one patient, vehicle group two patients). These findings show that fluticasone propionate ointment, 0.005%, applied twice daily, is therapeutically superior to the vehicle and is well tolerated.
Sears HW, Bailer JW, Yeadon A.
Efficacy and safety of hydrocortisone buteprate 0.1% cream in patients with atopic dermatitis.
Clin Ther. 1997 Jul-Aug;19(4):710-9. doi: 10.1016/s0149-2918(97)80095-1.
Abstract/Text
This multicenter, double-masked, placebo-controlled, randomized study evaluated the efficacy, safety, tolerability, and cosmetic acceptability of hydrocortisone buteprate 0.1% cream in the treatment of patients with atopic dermatitis. One hundred ninety-four adults with clinically diagnosed atopic dermatitis were randomized to treatment with hydrocortisone buteprate 0.1% cream or placebo (the cream base of the medication) applied topically once daily for 14 days. Investigators assessed the severity of dermatitis signs on a four-point scale at baseline and on days 3, 7, and 14. Overall improvement was also assessed at each study visit using a seven-point scale. In addition, overall treatment efficacy, tolerability, and cosmetic acceptability of both treatments were evaluated at the last study visit. At each study visit, patients treated with hydrocortisone buteprate showed significant improvement in mean total lesion scores and overall improvement compared with those receiving placebo. Investigators and patients rated hydrocortisone buteprate significantly more effective and significantly more tolerable than placebo at the end of the treatment period. In general, most adverse effects were mild to moderate, with a burning sensation (4% of patients using placebo, 2% of patients using hydrocortisone buteprate) being the most commonly reported. Patients judged both hydrocortisone buteprate and placebo cosmetically acceptable for daily use.
FK506軟膏研究会：FK506軟膏第Ⅲ相比較試験―アトピー性皮膚炎（躯幹・四肢）に対する吉草酸ベタメタゾン軟膏との群間比較試験. 西日皮膚, 1997;59:870-879.7.
Doss N, Kamoun MR, Dubertret L, Cambazard F, Remitz A, Lahfa M, de Prost Y.
Efficacy of tacrolimus 0.03% ointment as second-line treatment for children with moderate-to-severe atopic dermatitis: evidence from a randomized, double-blind non-inferiority trial vs. fluticasone 0.005% ointment.
Pediatr Allergy Immunol. 2010 Mar;21(2 Pt 1):321-9. doi: 10.1111/j.1399-3038.2009.00895.x. Epub 2009 Jun 26.
Abstract/Text
Tacrolimus 0.03% ointment is licensed for second-line treatment of children with atopic dermatitis (AD). Although data are available from clinical trials, no study has enrolled only second-line patients. This double-blind, non-inferiority study compared tacrolimus 0.03% and fluticasone 0.005% ointments in children with moderate-to-severe AD, who had responded insufficiently to conventional therapies. Children (aged 2-15 yr) were randomized to tacrolimus ointment (n = 240) or fluticasone ointment (n = 239), twice daily until clearance or for a maximum of 3 wk and, if lesions remained, once daily for up to 3 wk further. Primary end-point was week 3 response rate (improvement of >or=60% in modified Eczema Area and Severity Index and not withdrawn for lack of efficacy). Secondary end-points included pruritus and sleep quality, global assessment of clinical response, incidence of new flares and safety. Response rates were 86.3% with tacrolimus ointment and 91.5% with fluticasone. Lower limit of the 95% confidence interval was -11.8%, exceeding the non-inferiority limit of -15% and meeting the primary end-point. Moderate or better improvement on the physicians' global assessment occurred in 93.6% and 92.4% of patients in the tacrolimus ointment and fluticasone arms, respectively, while median pruritus scores improved by 84.0% and 91.5%. Sleep quality improved by approximately 92% in both treatment arms. After day 21, new flare-up occurred in 5.5% and 11.3% of patients receiving tacrolimus ointment and fluticasone, respectively; mean times to new flares were 6.5 +/- 5.0 and 8.6 +/- 5.2 days. Adverse events were similar between the two arms, with the exception of application-site skin burning sensation in the tacrolimus ointment group. In conclusion, efficacy of tacrolimus 0.03% ointment as second-line treatment was not inferior to that of fluticasone 0.005% ointment, with similar benefits on global disease improvement and quality of sleep.
Arellano FM, Wentworth CE, Arana A, Fernández C, Paul CF.
Risk of lymphoma following exposure to calcineurin inhibitors and topical steroids in patients with atopic dermatitis.
J Invest Dermatol. 2007 Apr;127(4):808-16. doi: 10.1038/sj.jid.5700622. Epub 2006 Nov 9.
Abstract/Text
Systemic use of immunosuppressant agents increases the risk of lymphoma in transplantation. We performed a nested case-control study in the PharMetrics database to evaluate the association between topical immunosuppressants and lymphoma in a cohort of patients with atopic dermatitis. We identified cases of lymphoma and randomly selected four controls for each case, matched by length of follow-up. We used conditional logistic regression to calculate odds ratio (OR) and 95% confidence intervals (CIs) of the association between topical immunosuppressants and lymphoma. Two hundred and ninety-four cases of lymphoma occurred in 293,253 patients, 81 in patients younger than 20 years. The adjusted analysis yielded the following OR (95%CI) for: severity (OR 2.4; 95% CI 1.5-3.8), oral steroids 1.5 (1.0-2.4), "super potent" topical steroids 1.2 (0.8-1.8) , "low potency" topical steroids OR 1.1 (0.7-1.6); pimecrolimus 0.8(0.4-1.6), tacrolimus OR 0.8 (0.4-1.7), and concomitant topical steroids, pimecrolimus, and tacrolimus 1.0 (0.3-4.1). We did not find an increased risk of lymphoma in patients treated with topical calcineurin inhibitors. It is difficult to disentangle the effects of severity of disease on outcome versus the true effects of drugs. However, in the adjusted analysis, severity of AD was the main factor associated with an increased risk of lymphoma.
Margolis DJ, Hoffstad O, Bilker W.
Lack of association between exposure to topical calcineurin inhibitors and skin cancer in adults.
Dermatology. 2007;214(4):289-95. doi: 10.1159/000100879.
Abstract/Text
BACKGROUND: Two topical calcineurin inhibitors (TCI) are available for the treatment of atopic dermatitis and there has been concern that their use could be associated with an increased risk of nonmelanoma skin cancer (NMSC).
OBJECTIVE: To determine if TCI exposure is associated with an increased risk of NMSC in adults.
METHODS: A case-control study using a questionnaire mailed to 5,000 adults with dermatitis.
RESULTS: We received responses from 70.7% of those surveyed by mail. Overall, 25.7% reported exposure to TCI. TCI exposure was 14.4% for the cases and 30.7% for the controls. Our primary analysis was a comparison between those with NMSC and those without. The unadjusted odds ratio was 0.38 (0.31-0.47) and the adjusted (age, gender, previous NMSC, history of atopic dermatitis) was 0.54 (0.41-0.69). The odds ratio of association for NMSC decreased as the number of tubes used and the potency of the agent increased.
CONCLUSION: This early study shows that TCI use is not associated with an increased risk of NMSC in adults.
2007 S. Karger AG, Basel
Legendre L, Barnetche T, Mazereeuw-Hautier J, Meyer N, Murrell D, Paul C.
Risk of lymphoma in patients with atopic dermatitis and the role of topical treatment: A systematic review and meta-analysis.
J Am Acad Dermatol. 2015 Jun;72(6):992-1002. doi: 10.1016/j.jaad.2015.02.1116. Epub 2015 Apr 1.
Abstract/Text
BACKGROUND: There is controversy regarding a potential increased risk of lymphoma in patients with atopic dermatitis (AD).
OBJECTIVE: To assess the risk of lymphoma and the role of topical treatments in patients with AD.
METHODS: A systematic literature search and a separate meta-analysis were performed on case control and cohort studies.
RESULTS: Of the 3979 articles retrieved, 24 references met the inclusion criteria. In cohort studies, the risk of lymphoma was slightly increased, with a relative risk (RR) of 1.43 (95% confidence interval [CI], 1.12-1.81). In case control studies, no significant increased risk of lymphoma was found, with an odds ratio (OR) of 1.18 (95% CI, 0.94-1.47). Severity of AD was a significant risk factor. Highly potent topical steroids were associated with an increased risk of lymphoma. For topical calcineurin inhibitors (TCIs), a significant association between tacrolimus and mostly skin lymphoma was found in 1 study.
LIMITATIONS: Confusion between severe AD and cutaneous T-cell lymphoma may account for part of the increased risk of lymphoma in patients with AD.
CONCLUSION: This systematic literature review shows a slightly increased risk of lymphoma in patients with AD. Severity of AD appears to be a significant risk factor. The role of topical steroids and TCIs is unlikely to be significant.
Copyright © 2015 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.
Siegfried EC, Jaworski JC, Kaiser JD, Hebert AA.
Systematic review of published trials: long-term safety of topical corticosteroids and topical calcineurin inhibitors in pediatric patients with atopic dermatitis.
BMC Pediatr. 2016 Jun 7;16:75. doi: 10.1186/s12887-016-0607-9. Epub 2016 Jun 7.
Abstract/Text
BACKGROUND: Many clinicians have concerns about the safety of atopic dermatitis (AD) treatments, particularly in children requiring long-term daily maintenance therapy. Topical corticosteroids (TCS) have been widely used for >5 decades. Long-term TCS monotherapy has been associated with adverse cutaneous effects including atrophy, rebound flares, and increased percutaneous absorption with potential for adverse systemic effects. Topical calcineurin inhibitors (TCIs), tacrolimus and pimecrolimus, available for 1-2 decades, are not associated with atrophy or increased percutaneous absorption after prolonged use and have much lower potential for systemic effects. However, since 2006 TCIs have carried a controversial Boxed Warning based on a theoretical risk of malignancy (eg, skin and lymphoma) that has limited TCI use for standard-of-care maintenance therapy.
METHODS: A comparative systematic search of PubMed was done for long-term (≥12 week) clinical trials of TCS or TCI treatment in patients <12 years with AD. Citations were reviewed for inclusion based on MeSH terms, abstracts, and relevant article text. Studies were excluded if they did not encompass subjects <12 years, or were <12 weeks' duration, retrospective, meta-analyses, or limited to anecdotal case reports.
RESULTS: Of 27 trials meeting criteria, 21 included 5825 pediatric patients treated with TCIs, and 6 included 1999 patients treated with TCS. TCS studies were limited to low- to mid-potency products, and all but one study lacked a vehicle control. Eight TCI studies were vehicle-controlled, and safety data were well reported, with ≤5 % of patients reporting discontinuation due to adverse effects (DAEs). Cutaneous and systemic adverse events (AEs) were similar in TCI and vehicle groups, with no reports of lymphoma. Safety data in TCS trials were less well reported. DAE incidence was addressed in just 2 trials, and systemic and cutaneous AEs were mostly unreported.
CONCLUSIONS: Data supporting long-term use of TCIs are robust, documenting safety and efficacy, while data supporting long-term TCS use are limited to low- to mid-potency products. Our review identifies a lack of information on the safety of commonly prescribed, long-term monotherapy with mid- to high-potency TCS in pediatric AD, and supports standard-of-care maintenance therapy with TCIs and intermittent use of low- to mid-potency TCS for flares.
Devasenapathy N, Chu A, Wong M, Srivastava A, Ceccacci R, Lin C, MacDonald M, Wen A, Steen J, Levine M, Pyne L, Schneider L, Chu DK; AAAAI/ACAAI Joint Task Force on Practice Parameters for Atopic Dermatitis Guideline Development Group.
Cancer risk with topical calcineurin inhibitors, pimecrolimus and tacrolimus, for atopic dermatitis: a systematic review and meta-analysis.
Lancet Child Adolesc Health. 2023 Jan;7(1):13-25. doi: 10.1016/S2352-4642(22)00283-8. Epub 2022 Nov 10.
Abstract/Text
BACKGROUND: Atopic dermatitis is a prevalent condition in children and can be effectively managed with medications such as topical calcineurin inhibitors (pimecrolimus or tacrolimus). A key unresolved safety concern is whether use of topical calcineurin inhibitors is associated with cancer. We systematically reviewed the risk of cancer in patients with atopic dermatitis exposed to topical calcineurin inhibitors.
METHODS: As part of the 2022 American Academy of Allergy, Asthma and Immunology and American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters atopic dermatitis guidelines, we searched MEDLINE, Embase, the Latin American and Caribbean Health Sciences Literature database, the Índice Bibliográfico Espanhol de Ciências da Saúde database, the Global Resource of Eczema Trials database, WHO's International Clinical Trials Registry Platform, the US Food and Drug Administration database, the European Medicines Agency database, company registers, and relevant citations from inception to June 6, 2022. We included randomised controlled trials and comparative and non-comparative non-randomised studies in any language addressing cancer risk in patients with atopic dermatitis using topical calcineurin inhibitors. We excluded split-body studies and studies with less than 3 weeks of follow-up. Paired reviewers independently screened records, extracted data, and assessed risk of bias in duplicate. We used Bayesian models to estimate the probability for cancer due to topical calcineurin inhibitor exposure and the GRADE approach to determine the certainty of the evidence. Patients, advocacy groups, and care providers set a priori thresholds of important effects. This study is registered with Open Science Framework, https://osf.io/v4bfc.
FINDINGS: We identified and analysed 110 unique studies (52 randomised controlled trials and 69 non-randomised studies [11 were non-randomised study extensions of randomised controlled trials]) including 3·4 million patients followed up for a mean of 11 months (range 0·7-120). The absolute risk of any cancer with topical calcineurin inhibitor exposure was not different from controls (absolute risk 4·70 per 1000 with topical calcineurin inhibitors vs 4·56 per 1000 without; odds ratio 1·03 [95% credible interval 0·94-1·11]; moderate certainty). For all age groups and using data from observational studies and randomised controlled trials, the use of pimecrolimus (OR 1·05 [95% credible interval 0·94-1·15]) or tacrolimus (0·99 [0·89-1·09]) is likely to have had little to no association with cancer compared with no topical calcineurin inhibitor exposure. For pimecrolimus versus tacrolimus, the finding was similar (0·95 [95% credible interval 0·83-1·07]). Findings were similar in infants, children, and adults, and robust to trial sequential, subgroup, and sensitivity analyses.
INTERPRETATION: Among individuals with atopic dermatitis, moderate-certainty evidence shows that topical calcineurin inhibitors do not increase the risk of cancer. These findings support the safe use of topical calcineurin inhibitors in the optimal treatment of patients with atopic dermatitis.
FUNDING: American Academy of Allergy, Asthma and Immunology and American College of Allergy, Asthma and Immunology via the Joint Task Force on Practice Parameters.
Copyright © 2023 Elsevier Ltd. All rights reserved.
Nakagawa H, Nemoto O, Igarashi A, Saeki H, Murata R, Kaino H, Nagata T.
Long-term safety and efficacy of delgocitinib ointment, a topical Janus kinase inhibitor, in adult patients with atopic dermatitis.
J Dermatol. 2020 Feb;47(2):114-120. doi: 10.1111/1346-8138.15173. Epub 2019 Dec 9.
Abstract/Text
Previous studies demonstrated that delgocitinib ointment, a novel topical Janus kinase inhibitor, rapidly improved clinical signs and symptoms of atopic dermatitis (AD) in Japanese adult patients. We sought to evaluate the long-term safety and efficacy of delgocitinib 0.5% ointment in a 52-week study (QBA4-2). Japanese patients aged 16 years or older with AD received delgocitinib 0.5% ointment b.i.d. for up to 52 weeks. Topical corticosteroids for the treatment of worsening of AD could be used at the investigators' discretion during the treatment period. Safety end-points included the incidence and severity of adverse events (AEs). Pooled safety analyses included the data from the other long-term study (QBA4-1). Efficacy end-points included the percentage change from baseline in the modified Eczema Area and Severity Index (mEASI). A total of 506 patients were included in the pooled safety population. Overall, AEs were reported in 69.0% of patients; most AEs were mild and unrelated to delgocitinib ointment. The most common AE was nasopharyngitis, followed by contact dermatitis, acne, and application site folliculitis. No skin atrophy or telangiectasia was found at the application sites of delgocitinib ointment. Application site irritation symptoms were infrequent (<2%) and mild. The incidence of AEs did not increase over time, except for seasonal diseases. The improvement effects on AD as assessed by mEASI were maintained throughout the treatment period. Delgocitinib 0.5% ointment was well tolerated and effective when administrated to Japanese adult patients with AD for up to 52 weeks.
© 2019 Japan Tobacco Inc. The Journal of Dermatology published by John Wiley & Sons Australia, Ltd.
Nakagawa H, Nemoto O, Igarashi A, Saeki H, Kaino H, Nagata T.
Delgocitinib ointment, a topical Janus kinase inhibitor, in adult patients with moderate to severe atopic dermatitis: A phase 3, randomized, double-blind, vehicle-controlled study and an open-label, long-term extension study.
J Am Acad Dermatol. 2020 Apr;82(4):823-831. doi: 10.1016/j.jaad.2019.12.015. Epub 2020 Feb 3.
Abstract/Text
BACKGROUND: Previous studies showed the potential effectiveness of delgocitinib ointment, a novel topical Janus kinase inhibitor, in atopic dermatitis (AD).
OBJECTIVE: This study aimed to evaluate the efficacy and safety of delgocitinib 0.5% ointment.
METHODS: In part 1, a 4-week double-blind period, Japanese patients aged 16 years or older with moderate or severe AD were randomly assigned in a 2:1 ratio to delgocitinib 0.5% ointment or vehicle ointment. Eligible patients entered part 2, a 24-week extension period, to receive delgocitinib 0.5% ointment.
RESULTS: At the end of treatment in part 1, the least-squares mean percent changes from baseline in the modified Eczema Area and Severity Index score, the primary efficacy endpoint, were significantly greater in the delgocitinib group than in the vehicle group (-44.3% vs 1.7%, P < .001). The improvement in modified Eczema Area and Severity Index score was maintained in part 2. Most adverse events were mild and unrelated to delgocitinib across the study periods.
LIMITATIONS: Only Japanese patients were included. The vehicle-controlled period lasted only 4 weeks. In part 2, topical corticosteroids were allowed for the treatment of worsening of AD.
CONCLUSION: Delgocitinib ointment was effective and well tolerated in Japanese adult patients with moderate to severe AD for up to 28 weeks.
Copyright © 2019 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.
Nakagawa H, Nemoto O, Igarashi A, Saeki H, Kabashima K, Oda M, Nagata T.
Delgocitinib ointment in pediatric patients with atopic dermatitis: A phase 3, randomized, double-blind, vehicle-controlled study and a subsequent open-label, long-term study.
J Am Acad Dermatol. 2021 Oct;85(4):854-862. doi: 10.1016/j.jaad.2021.06.014. Epub 2021 Jun 10.
Abstract/Text
BACKGROUND: Delgocitinib 0.5% ointment, a topical Janus kinase inhibitor, has been approved in Japan for adult patients with atopic dermatitis (AD).
OBJECTIVE: To evaluate the efficacy and safety of delgocitinib ointment in pediatric patients with AD.
METHODS: Part 1 of this study was a 4-week double-blind period in which Japanese patients aged 2 through 15 years were randomized in a 1:1 ratio to delgocitinib 0.25% ointment or vehicle ointment. Part 2 was a 52-week extension period. Eligible patients entered part 2 to receive 0.25% or 0.5% delgocitinib ointment.
RESULTS: At the initiation of the study, approximately half of the patients had moderate AD. At the end of treatment in part 1, the least-squares mean percent change from baseline in modified Eczema Area and Severity Index score, the primary efficacy endpoint, was significantly greater for delgocitinib ointment than for vehicle (-39.3% vs +10.9%, P < .001). In part 2, improvements in AD were also seen through week 56. Most adverse events were mild and unrelated to delgocitinib across the study periods.
LIMITATIONS: Only Japanese patients were included. In part 2, no control group was included and rescue therapy was allowed.
CONCLUSION: Delgocitinib ointment was effective and well tolerated when applied to Japanese pediatric patients with AD for up to 56 weeks.
Copyright © 2021 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.
Nakagawa H, Igarashi A, Saeki H, Kabashima K, Tamaki T, Kaino H, Miwa Y.
Safety, efficacy, and pharmacokinetics of delgocitinib ointment in infants with atopic dermatitis: A phase 3, open-label, and long-term study.
Allergol Int. 2024 Jan;73(1):137-142. doi: 10.1016/j.alit.2023.04.003. Epub 2023 Apr 24.
Abstract/Text
BACKGROUND: Delgocitinib ointment, a topical Janus kinase inhibitor, is used as treatment of patients with atopic dermatitis (AD) aged ≥2 years in Japan. Although initiating appropriate and early treatment upon the onset of AD in childhood is important, the safety and efficacy of delgocitinib ointment in infants with AD have not been established.
METHODS: This phase 3 study was conducted from October 2020 to June 2022 (number JapicCTI-205412). Eligible Japanese infants with AD aged 6 to <24 months received 0.25% or 0.5% of delgocitinib ointment twice daily for 52 weeks in an open-label uncontrolled manner. Topical corticosteroids were allowed to apply for worsening AD during the treatment period at the investigators' discretion.
RESULTS: A total of 22 infants were enrolled. Adverse events (AEs) were reported in 21 (95.5%) infants and were mostly mild. No treatment-related AEs were reported. The Modified Eczema Area and Severity Index (mEASI) score continuously decreased until week 4, and the score reduction was maintained until week 52. The mean percent changes in the mEASI score from baseline were -73.5% at week 4, -81.7% at week 28, and -81.9% at week 52. Delgocitinib was not detected in the plasma of most infants (68.2%-95.2%).
CONCLUSIONS: Delgocitinib ointment is well tolerated and effective for up to 52 weeks when applied to Japanese infants with AD.
Copyright © 2023 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.
Saeki H, Baba N, Ito K, Yokota D, Tsubouchi H.
Difamilast, a selective phosphodiesterase 4 inhibitor, ointment in paediatric patients with atopic dermatitis: a phase III randomized double-blind, vehicle-controlled trial.
Br J Dermatol. 2022 Jan;186(1):40-49. doi: 10.1111/bjd.20655. Epub 2021 Nov 1.
Abstract/Text
BACKGROUND: In atopic dermatitis (AD), phosphodiesterase 4 (PDE4) inhibition reduces proinflammatory mediators and cytokines. Difamilast is a new selective PDE4 inhibitor.
OBJECTIVES: To demonstrate the superiority of topical difamilast to vehicle in Japanese paediatric patients with AD.
METHODS: This was a phase III randomized, double-blind, vehicle-controlled trial. Patients aged 2-14 years with an Investigator Global Assessment (IGA) score of 2 or 3 received difamilast 0·3% (n = 83), difamilast 1% (n = 85) or vehicle (n = 83) ointment twice daily for 4 weeks.
RESULTS: The primary endpoint was the percentage of patients with an IGA score of 0 or 1 with improvement by at least two grades at week 4. The success rates in IGA score at week 4 were 44·6%, 47·1% and 18·1% in the difamilast 0·3%, difamilast 1% and vehicle groups, respectively. Both difamilast groups demonstrated significantly higher success rates in IGA score compared with vehicle at week 4 [difamilast 0·3% (P < 0·001); difamilast 1% (P < 0·001)]. Regarding secondary endpoints, improvements in Eczema Area and Severity Index (EASI; improvement of ≥ 50%, ≥ 75% and ≥ 90% in overall score) at week 4 were significantly higher in patients in the difamilast 0·3% and 1% groups than those in the vehicle group. EASI score in the difamilast 0·3% and 1% groups was significantly reduced compared with that of patients in the vehicle group at week 1. The significant difference between both the difamilast groups and the vehicle groups was maintained from week 1 through to week 4. Most treatment-emergent adverse events were mild or moderate, and no serious events or deaths were reported.
CONCLUSIONS: Difamilast 0·3% and 1% ointments are superior to vehicle and well tolerated in Japanese paediatric patients with AD.
© 2021 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.
Saeki H, Imamura T, Yokota D, Tsubouchi H.
Difamilast Ointment in Japanese Adult and Pediatric Patients with Atopic Dermatitis: A Phase III, Long-Term, Open-Label Study.
Dermatol Ther (Heidelb). 2022 Jul;12(7):1589-1601. doi: 10.1007/s13555-022-00751-9. Epub 2022 Jun 18.
Abstract/Text
INTRODUCTION: Phosphodiesterase 4 (PDE4), which regulates inflammatory cytokine production leading to atopic dermatitis (AD), is selectively inhibited by difamilast. The objective of this phase III, long-term, open-label study was to evaluate the safety and efficacy of topical difamilast in Japanese adult and pediatric patients with AD.
METHODS: Adult patients (n = 166) began treatment with difamilast 1% ointment, and pediatric patients began treatment with difamilast 0.3% ointment (n = 144) or difamilast 1% ointment (n = 56). Treatment was continued twice daily for 52 weeks. All patients had an Investigator's Global Assessment (IGA) score of 2 (mild), 3 (moderate), or 4 (severe/very severe), and an AD-affected body surface area (BSA) of ≥ 5% before treatment, with no restriction on the upper limit for the AD-affected BSA.
RESULTS: During therapy, 120 adult patients (72.3%) and 178 pediatric patients (89.0%) experienced treatment-emergent adverse events (TEAEs), most of which were mild or moderate in severity. Discontinuation due to TEAEs was reported in 13 adult patients (7.8%) and in 7 pediatric patients (3.5%). Treatment-related adverse events were reported in 14 adult patients (8.4%) and 16 pediatric patients (8.0%), most frequently dermatitis atopic (1.8%) and acne (1.2%) in adult patients and dermatitis atopic and pigmentation disorder (each 2.0%) in pediatric patients. The cumulative success rates in Eczema Area and Severity Index (EASI)-75 in adult and pediatric patients were 55.4% and 73.5%, respectively, at week 52, and the cumulative success rates increased from week 4 to week 52. The cumulative success rates in IGA score showed the same trend as those in EASI -75.
CONCLUSIONS: This study demonstrates that difamilast ointments are well tolerated and effective in Japanese adult and pediatric patients with AD when applied twice daily for 52 weeks, and are expected to be used for a long-term treatment for AD.
CLINICAL TRIAL REGISTRATION: Clinical Trials.gov identifier: NCT03961529.
© 2022. The Author(s).
Lu LC, Chao CM, Chang SP, Lan SH, Lai CC.
Clinical efficacy and safety of topical difamilast in the treatment of patients with atopic dermatitis: a systematic review and meta-analysis of randomized controlled trials.
Expert Rev Clin Pharmacol. 2022 Dec;15(12):1471-1478. doi: 10.1080/17512433.2022.2134114. Epub 2022 Oct 11.
Abstract/Text
OBJECTIVE: To investigate the clinical efficacy and safety of topical difamilast in mild-to-moderate atopic dermatitis (AD).
METHODS: Only randomized controlled trials (RCTs) that compared topical difamilast with vehicle treatment for patients with AD were included. PubMed, Web of Science, Ovid Medline, Cochrane Library, ClinicalTrials.gov and JapicCTI were searched to 10 April 2022.
RESULTS: Five studies enrolling a total of 1009 patients with mild-to-moderate AD were identified. Compared with the topical vehicle, topical difamilast was associated with a significantly higher success rate according to the Investigator's Global Assessment score at week 4 (relative risk, 2.82; 95% confidence interval [CI]: 2.11-3.77). Compared with the vehicle, difamilast was associated with a significant decrease in day 28 eczema area and severity index scores (mean difference [MD], -4.10; 95% CI: -5.32 to -2.87), verbal rating scale scores (MD, -0.51; 95% CI: -0.71 to -0.32), visual analog scale scores (MD, -12.15; 95% CI: -19.70 to -4.61), patient-oriented eczema measure values (MD, -3.99; 95% CI: -4.91 to -3.07), and total affected body surface area (MD, -6.48; 95% CI: -8.09 to -4.87). No difference in treatment-related adverse events was identified.
CONCLUSIONS: This meta-analysis suggests that topical difamilast is an effective and safe treatment for mild-to-moderate AD.
Saeki H, Ohya Y, Baba N, Imamura T, Yokota D, Tsubouchi H.
An Interim Report of a Phase 3, Long-Term, Open-Label Study to Evaluate Efficacy and Safety of Difamilast Ointment in Japanese Infants with Atopic Dermatitis.
Dermatol Ther (Heidelb). 2024 Sep;14(9):2443-2455. doi: 10.1007/s13555-024-01236-7. Epub 2024 Jul 29.
Abstract/Text
INTRODUCTION: Difamilast is the first selective phosphodiesterase 4 inhibitor approved for atopic dermatitis (AD) in Japan. A phase 3, 52-week, open-label study is ongoing to establish efficacy and safety of difamilast ointments in infants with AD aged 3 to < 24 months because a clinical study has not been conducted in this population.
METHODS: This study consisted of a 4-week primary evaluation period in which difamilast 0.3% ointment was applied twice daily to Japanese infants aged 3 to < 24 months (n = 41) and an ongoing 48-week long-term extension period in which difamilast 0.3% or 1% ointment was applied based on existing symptoms. The data on efficacy and safety of difamilast were obtained as of an interim report in the study period.
RESULTS: The response rate in Investigator's Global Assessment score was 45.0% at week 1, which was maintained at 56.1% at week 4 and 63.4% at the interim report. Infants achieved the response rate in Eczema Area and Severity Index 75 (improvement of ≥ 75%) of 47.5% at week 1, which further improved to 82.9% at week 4 and 78.1% at the interim report. Adverse events (AEs) were reported in 22 (53.7%) infants in the primary evaluation period: of those the most frequent AE was nasopharyngitis (19.5%) followed by dermatitis contact (7.3%). As of the interim report, 36 (87.8%) infants experienced AEs: of those, nasopharyngitis (70.7%) and gastroenteritis (22.0%) were most frequently observed. The total AEs were mostly mild or moderate in severity. No investigational medicinal product-related AEs and no AEs leading to discontinuation were reported.
CONCLUSION: Difamilast ointments applied twice daily to Japanese infants with AD aged 3 to < 24 months is effective and well tolerated as of the interim report in the study period. The final results will be reported in the near future.
CLINICAL TRIAL REGISTRATION: Clinical Trials. gov identifier: NCT05372653.
© 2024. The Author(s).
Silverberg JI, Eichenfield LF, Hebert AA, Simpson EL, Stein Gold L, Bissonnette R, Papp KA, Browning J, Kwong P, Korman NJ, Brown PM, Rubenstein DS, Piscitelli SC, Somerville MC, Tallman AM, Kircik L.
Tapinarof cream 1% once daily: Significant efficacy in the treatment of moderate to severe atopic dermatitis in adults and children down to 2 years of age in the pivotal phase 3 ADORING trials.
J Am Acad Dermatol. 2024 Sep;91(3):457-465. doi: 10.1016/j.jaad.2024.05.023. Epub 2024 May 20.
Abstract/Text
BACKGROUND: Tapinarof cream 1% once daily (QD), a topical aryl hydrocarbon receptor agonist, downregulates pro-inflammatory Th2 cytokines, upregulates skin-barrier components, and reduces oxidative stress.
OBJECTIVE: To assess tapinarof efficacy and safety in adults and children down to 2 years of age with atopic dermatitis (AD).
METHODS: Eight hundred and thirteen patients were randomized to tapinarof or vehicle QD in two 8-week phase 3 trials.
RESULTS: The primary efficacy endpoint, Validated Investigator Global Assessment for Atopic Dermatitis score of 0 or 1 and ≥2-grade improvement from baseline at Week 8, was met with statistical significance in both trials: 45.4% versus 13.9% and 46.4% versus 18.0% (tapinarof vs vehicle; both P < .0001). Significantly superior Eczema Area and Severity Index 75 (EASI75) responses were also observed with tapinarof versus vehicle at Week 8: 55.8% versus 22.9% and 59.1% versus 21.2% (both P < .0001). Rapid improvements in patient-reported pruritus were also significant with tapinarof versus vehicle. Common adverse events (≥5%) of folliculitis, headache, and nasopharyngitis were mostly mild or moderate, with lower discontinuations due to adverse events in the tapinarof groups than with vehicle.
LIMITATIONS: Long-term efficacy was not assessed.
CONCLUSION: Tapinarof demonstrated highly significant efficacy and favorable safety and tolerability in a diverse population of patients with AD down to 2 years of age.
Copyright © 2024 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.
Igarashi A, Tsuji G, Fukasawa S, Murata R, Yamane S.
Tapinarof cream for the treatment of atopic dermatitis: Efficacy and safety results from two Japanese phase 3 trials.
J Dermatol. 2024 Nov;51(11):1404-1413. doi: 10.1111/1346-8138.17451. Epub 2024 Sep 13.
Abstract/Text
Tapinarof is a nonsteroidal, topical, aryl hydrocarbon receptor agonist. We evaluated the efficacy and safety of tapinarof cream 1% in Japanese patients aged ≥12 years with atopic dermatitis (AD) in two phase 3 trials, ZBB4-1 and ZBB4-2. ZBB4-1 (N = 216) consisted of an 8-week, double-blind, vehicle-controlled treatment period (period 1) and a 16-week extension treatment period (period 2). Patients were randomized 2:1 to tapinarof or vehicle in period 1; subsequently, all patients who enrolled in period 2 received tapinarof. ZBB4-2 (N = 291) was a 52-week, open-label, uncontrolled trial in which all patients received tapinarof. In period 1 of ZBB4-1, the proportion of patients who achieved an Investigator's Global Assessment (IGA) score of 0 (clear) or 1 (almost clear) with ≥2-grade improvement from baseline at week 8 (IGA treatment success, the primary end point) was 20.24% in the tapinarof group and 2.24% in the vehicle group (p = 0.0007). The proportion of patients with ≥75% improvement from baseline in Eczema Area and Severity Index (EASI) score at week 8 (EASI-75 response, the key secondary end point) was 40.3% in the tapinarof group and 4.3% in the vehicle group (p < 0.0001). In ZBB4-2, IGA treatment success rate was 28.1% at week 16, 32.3% at week 24, and 41.3% at week 52, and EASI-75 response rate was 53.3% at week 16, 63.7% at week 24, and 76.6% at week 52, indicating that efficacy responses improved over time and were maintained over 52 weeks. Across the two trials, most adverse events (AEs) were mild or moderate; common AEs included folliculitis, acne, and headache. In summary, tapinarof cream 1% was effective and generally safe for up to 52 weeks of treatment in Japanese patients with AD.
© 2024 The Author(s). The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.
Bleehen SS, Chu AC, Hamann I, Holden C, Hunter JA, Marks R.
Fluticasone propionate 0.05% cream in the treatment of atopic eczema: a multicentre study comparing once-daily treatment and once-daily vehicle cream application versus twice-daily treatment.
Br J Dermatol. 1995 Oct;133(4):592-7. doi: 10.1111/j.1365-2133.1995.tb02711.x.
Abstract/Text
The aim of this study was to compare the efficacy and safety of once-daily with twice-daily application of a 0.05% cream formulation of fluticasone propionate in the treatment of atopic eczema in adults and children. Two hundred and seventy patients with moderate to severe atopic eczema were enrolled in the study, and randomized to receive either once-daily or twice-daily fluticasone propionate 0.05% cream for 4 weeks. Patients randomized to the once-daily group also received the vehicle cream to ensure that the study remained blinded. The clinical response of a preselected target area of affected skin was assessed by investigators at weekly intervals and compared with the baseline. Analysis of the investigators' overall assessment of the response of the target area for both the 'intent-to-treat' population and the per protocol population showed that 79-85% of patients were judged a clinical success. For both populations, there was no statistically significant difference between the response to once-daily and twice-daily active treatment (intent-to-treat; P = 0.35; 95% confidence interval for difference -14.2 to +5.0 percentage points: per protocol; P = 0.42; 95% confidence interval for difference -14.7 to +6.2 percentage points.) The improvement in the signs and symptoms was judged a success in 95-97% of patients. There was an equal reduction in severity scores for disease activity in both groups, and the speed of symptom relief was similar.(ABSTRACT TRUNCATED AT 250 WORDS)
Green C, Colquitt JL, Kirby J, Davidson P.
Topical corticosteroids for atopic eczema: clinical and cost effectiveness of once-daily vs. more frequent use.
Br J Dermatol. 2005 Jan;152(1):130-41. doi: 10.1111/j.1365-2133.2005.06410.x.
Abstract/Text
BACKGROUND: Topical corticosteroids remain the mainstay of treatment for atopic eczema, yet there is uncertainty over the frequency of their use in terms of clinical and cost effectiveness.
OBJECTIVES: To assess the clinical and cost effectiveness of once-daily vs. more frequent use of same-potency topical corticosteroids in atopic eczema.
METHODS: A systematic review of the clinical and cost-effectiveness literature was undertaken, together with a cost-minimization analysis.
RESULTS: The review identified a sparse literature, comprising one previous systematic review and 10 randomized controlled trials (RCTs). No published cost-effectiveness studies were identified. RCTs were focused on potent topical corticosteroids (eight RCTs), with no trials (RCTs/controlled clinical trials) identified on mild potency products. There was broad heterogeneity in trial methods, and therefore we considered outcomes according to: (i) at least a good response or 50% improvement, and (ii) eczema rated as cleared or controlled. Studies found little difference between once-daily and more frequent use of topical corticosteroids. The literature on moderately potent and potent corticosteroids offered no basis for favouring once-daily or more frequent use, although some significant differences favouring twice-daily treatment were identified. One RCT on very potent products favoured three times daily use on the basis of clinical response, but reported no difference in the numbers with at least a good response. Given the similar outcomes seen in clinical effectiveness a cost-minimization approach was adopted to consider cost effectiveness, in order to identify the least-cost option. However, cost-minimization analysis proved complex due to wide variations in product price, with the relative cost of product comparisons by frequency proving the most important factor in determining the least-cost alternative.
CONCLUSIONS: This review has not identified any clear differences in outcomes between once-daily and more frequent application of topical corticosteroids. We would encourage prescribing clinicians to consider the once-daily use of topical corticosteroids when making treatment decisions for patients with atopic eczema. However, we find that the literature on clinical effectiveness is limited and a broader understanding of compliance and phobia associated with topical steroids is needed to inform on this issue.
Hanifin J, Gupta AK, Rajagopalan R.
Intermittent dosing of fluticasone propionate cream for reducing the risk of relapse in atopic dermatitis patients.
Br J Dermatol. 2002 Sep;147(3):528-37. doi: 10.1046/j.1365-2133.2002.05006.x.
Abstract/Text
BACKGROUND: One of the most troublesome features of atopic dermatitis (AD) is its chronic relapsing nature, and there is a lack of published evidence on the best treatment strategy for long-term management of the disease.
OBJECTIVE: To compare an intermittent dosing regimen of fluticasone propionate (FP) cream 0.05% (twice per week) with its vehicle base in reducing the risk of relapse when added to regular daily emollient in adult and paediatric subjects with stabilized AD.
METHODS: Subjects (aged 3 months to 65 years) with moderate or severe AD were enrolled into an open-label Stabilization Phase of up to 4 weeks on daily emollients plus FP twice daily. Those subjects who achieved 'treatment success' (Global Assessment Score RESULTS: A total of 372 (247 paediatric, 125 adult) subjects were enrolled into the Stabilization Phase. Of these, 348 (231 children, 117 adults) were randomized into the Maintenance Phase. Analysis of the primary efficacy parameter showed that subjects receiving intermittent FP cream (twice per week), in addition to regular daily emollients in the Maintenance Phase, were 7.7 times less likely to have an AD relapse than subjects receiving intermittent vehicle cream/emollients [Mantel-Haenszel (MH) estimate of the odds ratio, 95% confidence interval (CI) 4.6, 12.8; P < 0.001]. Paediatric subjects were 8.1 times less likely to have an AD relapse (95% CI 4.3, 15.2; P < 0.001) and adult subjects were 7.0 times less likely to have an AD relapse (95% CI 3.0, 16.7; P < 0.001). For subjects receiving intermittent FP cream/emollient, the median time to relapse could not be estimated as the majority remained controlled at 20 weeks. For those receiving intermittent vehicle/emollient, the median time to relapse was 4.7 weeks. For paediatric and adult groups, this was 5.1 and 4.1 weeks, respectively. Median exposure to FP for all subjects was 337 days. There was only one study drug-related adverse event (acne) and there were no reports of skin thinning or atrophy associated with the use of FP cream in paediatric or adult subjects.
CONCLUSIONS: In paediatric and adult subjects, once stabilized with regular FP treatment, the risk of relapse of AD can be significantly reduced by extended intermittent dosing with FP cream in addition to regular emollient therapy.
Peserico A, Städtler G, Sebastian M, Fernandez RS, Vick K, Bieber T.
Reduction of relapses of atopic dermatitis with methylprednisolone aceponate cream twice weekly in addition to maintenance treatment with emollient: a multicentre, randomized, double-blind, controlled study.
Br J Dermatol. 2008 Apr;158(4):801-7. doi: 10.1111/j.1365-2133.2008.08436.x. Epub 2008 Feb 16.
Abstract/Text
BACKGROUND: The relapsing nature of atopic dermatitis (AD) presents a challenge for its long-term treatment. Efficacy and safety of corticosteroids have been proven in the acute treatment of active AD, but their long-term efficacy and potential to reduce or prevent relapses have only partially been addressed.
OBJECTIVES: To investigate long-term management (16 weeks) of AD with methylprednisolone aceponate (MPA) 0.1% cream twice weekly in addition to an emollient (Advabase((R))) after stabilization of an acute severe or very severe flare of AD with MPA cream.
METHODS: Patients > or = 12 years of age with a > or = 2-year history of moderate to severe AD were eligible for this multicentre, randomized, double-blind, controlled study if they presented with an acute flare of severe or very severe AD [Investigator's Global Assessment (IGA) score > or = 4]. After successful treatment of the flare in an acute phase (AP), patients received either MPA twice weekly plus emollient or emollient alone over a 16-week maintenance phase (MP). The primary study endpoint was time to relapse of AD. Secondary endpoints included relapse rate and disease status, the patient's assessment of intensity of itch, the Eczema Area and Severity Index, the IGA score, affected body surface area, Dermatology Life Quality Index (DLQI) and children's DLQI (CDLQI), patient's and investigator's global assessment of response and patient's assessment of quality of sleep.
RESULTS: Two hundred and forty-nine patients entered the AP and 221 continued into the MP. Time to relapse was longer in the MPA group than in the emollient group. The probability of remaining free from relapse after 16 weeks was 87.1% in the MPA group compared with 65.8% for the emollient. Patients treated with MPA twice weekly had a 3.5-fold lower risk of experiencing a relapse than patients treated with emollient alone (hazard ratio 3.5, 95% confidence interval 1.9-6.4; P < 0.0001). MPA was also superior to emollient for all other efficacy endpoints. Therapy with both treatments was well tolerated.
CONCLUSIONS: MPA twice weekly plus an emollient provides an effective maintenance treatment regimen to control AD. Once stabilized, treatment with MPA significantly reduces the risk of relapse and the intensity of itching, and improves the overall patient status.
Glazenburg EJ, Wolkerstorfer A, Gerretsen AL, Mulder PG, Oranje AP.
Efficacy and safety of fluticasone propionate 0.005% ointment in the long-term maintenance treatment of children with atopic dermatitis: differences between boys and girls?
Pediatr Allergy Immunol. 2009 Feb;20(1):59-66. doi: 10.1111/j.1399-3038.2008.00735.x. Epub 2008 Feb 22.
Abstract/Text
Treatment of atopic dermatitis (AD) in children tends to stabilize the condition in the short term. 'Maintenance' treatment options in children are limited. To assess the efficacy and safety of twice daily treatment with fluticasone propionate 0.005% (FP) ointment during 4 wk and the efficacy and safety of twice weekly maintenance treatment with FP in preventing exacerbations or remissions of AD during a 16 wk follow-up period. Ninety children (aged 4-10 yr) with moderate to severe AD were included in a randomized, multi-centre study and received FP ointment twice daily during the acute phase. Children whose AD was in remission after 4 wk of treatment, entered the maintenance phase. In addition to twice daily emollient, children were randomly allocated to receive FP or placebo ointment twice weekly on consecutive days. Efficacy was assessed by the objective SCORAD. Eighty-seven (97%) completed the 4-wk acute study period. Extensive remission was achieved in 78 (87%) children, and 75 children entered the maintenance phase. Intermittent treatment with FP resulted in less severe AD and significantly reduced risk of further relapse as compared with placebo. The risk of an exacerbation of AD was more than twice as high in the placebo group as in the FP group (hazard ratio 2.182, 95% CI). AD in girls was better controlled than in boys. This long-term study shows that the addition of twice weekly FP to standard maintenance therapy significantly reduces the risk of relapse in children with moderate severe AD.
Eichenfield LF, Basu S, Calvarese B, Trancik RJ.
Effect of desonide hydrogel 0.05% on the hypothalamic-pituitary-adrenal axis in pediatric subjects with moderate to severe atopic dermatitis.
Pediatr Dermatol. 2007 May-Jun;24(3):289-95. doi: 10.1111/j.1525-1470.2007.00405.x.
Abstract/Text
Desonide, a low potency corticosteroid, has been used widely as a topical treatment for inflammatory dermatoses for over 30 years. A recent formulation advance has enabled the development of desonide 0.05% into a novel moisturizing aqueous gel (hydrogel) that is free of alcohol and surfactants. This multicenter, open-label study evaluated the hypothalamic-pituitary-adrenal axis suppression potential, tolerability, and efficacy of this new Class VI topical steroid formulation in pediatric subjects with moderate-to-severe atopic dermatitis (mean body surface area = 51%). Forty children, aged 6 months to 6 years were enrolled and treated twice daily for 4 weeks. Desonide hydrogel 0.05% was well tolerated and no treatment-related adverse events were reported. No suppression of adrenal function was observed in subjects who completed the study without protocol violations related to cosyntropin administration or cortisol testing (n=34). Of the subjects who completed the study with complications in cortisol testing (n=3), there was one subject (1/37=3%) who had a low poststimulation cortisol level at week 4. Efficacy was demonstrated by marked improvement in overall disease state and in the signs and symptoms of atopic dermatitis. This study validates the systemic safety of a novel desonide hydrogel formulation in young pediatric patients and confirms the longstanding tolerability and efficacy profile of desonide.
Hebert AA, Friedlander SF, Allen DB.
Topical fluticasone propionate lotion does not cause HPA axis suppression.
J Pediatr. 2006 Sep;149(3):378-82. doi: 10.1016/j.jpeds.2006.05.008.
Abstract/Text
OBJECTIVE: To establish the absence of adrenal suppression of fluticasone propionate (FP) 0.05% lotion when applied extensively to children (3 months to 6 years), with moderate to severe atopic dermatitis (AD).
STUDY DESIGN: Open-label, conducted at 6 US centers; 44 subjects (3 to 71 months) with widespread AD (mean body surface area treated, 65%) received FP lotion twice daily for up to 4 weeks.
RESULTS: No significant differences in mean cortisol levels were detected before or after treatment. At baseline, mean (+/-standard deviation) cortisols before and after cosyntropin (CST) stimulation were 13 +/- 6 microg/dL and 35 +/- 6 microg/dL, respectively. End-treatment, pre-CST, and post-CST cortisols were 12 +/- 6 microg/dL and 33 +/- 8 microg/dL, respectively. All 42 subjects with end-treatment post-CST cortisols demonstrated a normal adrenal response to CST (>18.0 microg/dL). FP lotion was well tolerated. Subjects who had blood drawn for bioavailability showed no correlation between FP levels and end-treatment post-CST cortisols.
CONCLUSIONS: In patients as young as 3 months, FP lotion had no effect on HPA axis function and did not cause skin thinning even when used extensively over widespread, severe inflammatory disease. These results, together with others from studies using cream and ointment, provide further evidence of the safety of FP.
Paller AS, Nimmagadda S, Schachner L, Mallory SB, Kahn T, Willis I, Eichenfield LF.
Fluocinolone acetonide 0.01% in peanut oil: therapy for childhood atopic dermatitis, even in patients who are peanut sensitive.
J Am Acad Dermatol. 2003 Apr;48(4):569-77. doi: 10.1067/mjd.2003.174.
Abstract/Text
BACKGROUND: Fluocinolone acetonide 0.01% in a blend of refined peanut and mineral oils has been used as treatment for scalp psoriasis for several years, but only more recently for atopic dermatitis.
OBJECTIVE: We sought to study the effectiveness for atopic dermatitis, potential for adrenal axis suppression, and safety of the fluocinolone acetonide 0.01% in oil in children with atopic dermatitis, including children with atopic dermatitis and peanut allergic sensitivity.
METHODS: Three separate studies were performed in children aged 2 to 12 years with atopic dermatitis: multicenter double-blind, randomized, and vehicle-controlled trial; cortisol stimulation testing; and prick testing, patch testing, and monitored medication use in children with peanut allergic sensitivity.
RESULTS: Improvement of >/=50% was demonstrated within 2 weeks in 81% to 87% of 81 patients treated with active medication versus 39% of 45 children treated with vehicle oil alone. No adrenal suppression occurred after 4 weeks of therapy in 32 patients. None of 9 patients who were peanut sensitive reacted to either the full formulation or vehicle in prick or patch testing; 20 children who were peanut sensitive showed no allergic reactions after application of the medication.
CONCLUSION: Fluocinolone 0.01% in peanut oil is an effective alternative to the use of topical corticosteroid agents in ointment, cream, and lotion forms in children. No evidence of adrenal suppression or adverse local effects were demonstrated in these studies. The medication was well tolerated in patients with peanut allergic sensitivity.
Ellison JA, Patel L, Ray DW, David TJ, Clayton PE.
Hypothalamic-pituitary-adrenal function and glucocorticoid sensitivity in atopic dermatitis.
Pediatrics. 2000 Apr;105(4 Pt 1):794-9. doi: 10.1542/peds.105.4.794.
Abstract/Text
OBJECTIVES: Topical glucocorticoids (GCs) fail to produce a clinical response in some children with atopic dermatitis (AD), suggesting that GC resistance may be present. To determine whether such resistance is generalized or specific to diseased skin, hypothalamic-pituitary-adrenal (HPA) axis function has been assessed in children with moderate to severe AD, who showed a variable response to treatment with topical GC.
STUDY DESIGN: Thirty-five patients (.7-18.7 years old; median: 9.3 years) with AD requiring topical GCs from infancy underwent a low-dose adrenocorticotrophin hormone (ACTH; Synacthen) test (LDST) (500 ng/1.73 m(2) ACTH). Groups 1 (7 patients), 2 (17 patients), and 3 (4 patients) used mild, moderate, or potent/very potent topical preparations, respectively. Group 4 (7 boys with severe, treatment-resistant disease) had received GC in at least 1 form (inhaled +/- intranasal +/- oral) in addition to varying potencies of topical GC. Fourteen healthy subjects (3.8-17.3 years old) served as control subjects. Group 4 patients had a daytime plasma cortisol profile and 08.00 hours measurement of plasma ACTH and its precursors.
RESULTS: The response to ACTH for groups 1 and 2 did not differ from that of control subjects. Group 3 had lower peak, increment, and area under curve cortisol responses than those in controls, whereas group 4 had lower baseline, peak, and area under curve cortisol responses. Eight patients failed the LDST (peak cortisol <500 nmol/L and increment <200 nmol/L): controls = 0/14, group 1 = 0/7, group 2 = 1/17, group 3 = 4/4, and group 4 = 3/7. Treatment score (based on GC potency, area treated, and duration) was the only factor to influence peak cortisol response on LDST (r(2) = 24%). In group 4, only 1 of 7 patients had a cortisol profile within the normal range but he failed the LDST. In the 5 subjects with an 08.00 hours cortisol <300 nmol/L, the matched ACTH level was inappropriately low.
CONCLUSIONS: HPA suppression was rarely found in children or adolescents with moderate to severe AD who used mild or moderately potent topical GCs over many years. However, HPA suppression was common in those receiving potent topical GC preparations or a combination of GC routes of administration. In those with severe AD, evidence of HPA suppression but lack of clinical response to GC treatment excluded significant generalized GC resistance. This would suggest that localized resistance to GCs within the diseased skin may be part of the aetiopathogenesis of severe AD.
Schlessinger J, Miller B, Gilbert RD, Plott RT; Vanos Study Group.
An open-label adrenal suppression study of 0.1% fluocinonide cream in pediatric patients with atopic dermatitis.
Arch Dermatol. 2006 Dec;142(12):1568-72. doi: 10.1001/archderm.142.12.1568.
Abstract/Text
OBJECTIVE: To assess the potential of a superhigh-potency 0.1% fluocinonide cream to suppress the hypothalamic-pituitary-adrenal (HPA) axis in pediatric patients with atopic dermatitis.
DESIGN: A multicenter, multiple-dose, open-label safety study in 4 age cohorts with 0.1% fluocinonide cream applied once or twice daily for 2 weeks.
SETTING: Clinical outpatient setting.
PATIENTS: Patients with moderate to severe atopic dermatitis with 20% or more of the body surface area involved were included in the study. Each cohort began only after evaluation of the preceding cohort: ages 12 to younger than 18 years (cohort 1); 6 to younger than 12 years (cohort 2); 2 to younger than 6 years (cohort 3); and 3 months to younger than 2 years (cohort 4).
MAIN OUTCOME MEASURES: Assessment of HPA axis suppression, local and systemic adverse events, and change in disease status from baseline.
RESULTS: Suppression of the HPA axis was not observed in any patient treated once daily for the 2 youngest cohorts. Suppression was observed in 1 (7%) of 15 and 2 (12%) of 16 patients in the fluocinonide twice-daily group in cohorts 1 and 2, respectively. In all 4 cohorts, more than 90% of patients in the fluocinonide once-daily and twice-daily groups showed improvement in their disease status.
CONCLUSIONS: Once-daily treatment with 0.1% fluocinonide cream for 2 weeks does not result in HPA axis suppression under the conditions of this study. Once-daily applications provided similar or better efficacy as twice-daily applications with a lower risk of HPA axis suppression. The frequency of HPA axis suppression is no greater in younger children than in older children.
TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN71227633.
中村晃一郎, 二村昌樹, 常深祐一郎, 種瀬啓士, 加藤則人：デルゴシチニブ軟膏（コレクチム®軟膏0.5％）安全使用マニュアル．日皮会誌, 130（7）; 1581-1588, 2020.
常深祐一郎, 井川健, 石氏陽三, ほか. ジファミラスト軟膏（モイゼルト®軟膏0.3％, 1％）安全使用マニュアル. 日皮会誌. 2022;132(7):1627-1635.
Kawashima M, Tango T, Noguchi T, Inagi M, Nakagawa H, Harada S.
Addition of fexofenadine to a topical corticosteroid reduces the pruritus associated with atopic dermatitis in a 1-week randomized, multicentre, double-blind, placebo-controlled, parallel-group study.
Br J Dermatol. 2003 Jun;148(6):1212-21. doi: 10.1046/j.1365-2133.2003.05293.x.
Abstract/Text
BACKGROUND: Fexofenadine, a nonsedating, H1-receptor selective antihistamine, exhibits consistent efficacy and safety in the treatment of allergic rhinitis and urticaria. The pruritus associated with atopic dermatitis is considered to be induced, in part, by histamine. Therefore, we thought that fexofenadine may be useful in the relief of pruritus associated with atopic dermatitis.
OBJECTIVE: To compare the efficacy of twice-daily fexofenadine hydrochloride (HCl) 60 mg vs. placebo in reducing the pruritus associated with atopic dermatitis.
METHODS: In this randomized, multicentre, double-blind, placebo-controlled study, patients (aged >or= 16 years) with atopic dermatitis underwent a 1-week placebo lead-in period, followed by randomization to fexofenadine HCl 60 mg twice daily or placebo for 1 week. All patients also received topical treatment with 0.1% hydrocortisone butyrate twice daily throughout the study. The primary efficacy endpoint was mean change in pruritus score from baseline. Patients reflectively recorded pruritus scores twice daily (day and night) using a five-point scale (0 = none; 4 = very severe).
RESULTS: Fexofenadine (n = 201) significantly decreased the severity of pruritus compared with placebo (n = 199) (mean change in score -0.75 (unadjusted 95% confidence interval [-0.88, -0.62]) vs. -0.5 [-0.62, -0.38], respectively; P = 0.0005). This improvement was seen after just 1 day of treatment (P = 0.039) and was maintained throughout the treatment period (P = 0.019). Compared with placebo, fexofenadine significantly improved both diurnal (P = 0.0001) and nocturnal pruritus (P = 0.013). In addition, significantly more patients in the fexofenadine group experienced a reduction in the ratio of pruritus area to body surface area compared with those in the placebo group (P = 0.007). The incidence of adverse events was low and similar across all treatment groups.
CONCLUSIONS: Fexofenadine HCl 60 mg twice daily demonstrated a rapid, significant improvement in the pruritus associated with atopic dermatitis, with a safety profile equivalent to that of placebo.
川島眞, 原田昭太郎：抗アレルギー薬を併用した標準的薬物療法がアトピー性皮膚炎患者の痒みとQuality of life(QOL)に及ぼす影響に関する調査．臨皮, 2006;60:661-667.
谷内一彦, 田代学, 岡村信行：中枢に移行しない第2世代抗ヒスタミン薬：PETによる脳内移行性に関する研究. 西日皮膚, 2009;71: 3-6.
田代学, 谷内一彦：抗ヒスタミン薬の鎮静作用評価に関するPET研究. 小児科, 2009;50(9): 1469.
谷内一彦, 岡村信行, 田代学：脳内に移行する抗ヒスタミン薬の小児に与える影響. 小児科, 2007;48: 1435-1443.
川島眞、古江増隆、秀道広、佐藤伸一、宮地良樹：鎮静性および非鎮静性抗ヒスタミン薬のかゆみ抑制効果と眠気の発現に関する比較検討(ACROSS trial). 臨床医薬，2011；27：563-573．.
Matterne U, Böhmer MM, Weisshaar E, Jupiter A, Carter B, Apfelbacher CJ.
Oral H1 antihistamines as 'add-on' therapy to topical treatment for eczema.
Cochrane Database Syst Rev. 2019 Jan 22;1(1):CD012167. doi: 10.1002/14651858.CD012167.pub2. Epub 2019 Jan 22.
Abstract/Text
BACKGROUND: The symptoms of eczema can lead to sleeplessness and fatigue and may have a substantial impact on quality of life. Use of oral H1 antihistamines (H1 AH) as adjuvant therapy alongside topical agents is based on the idea that combining the anti-inflammatory effects of topical treatments with the blocking action of histamine on its receptors in the skin by H1 AH (to reduce the principal symptom of itch) might magnify or intensify the effect of treatment. Also, it would be unethical to compare oral H1 AH alone versus no treatment, as topical treatment is the standard management for this condition.
OBJECTIVES: To assess the effects of oral H1 antihistamines as 'add-on' therapy to topical treatment in adults and children with eczema.
SEARCH METHODS: We searched the following databases up to May 2018: the Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, and the GREAT database (Global Resource of EczemA Trials; from inception). We searched five trials registers and checked the reference lists of included and excluded studies for further references to relevant randomised controlled trials (RCTs). We also searched the abstracts of four conference proceedings held between 2000 and 2018.
SELECTION CRITERIA: We sought RCTs assessing oral H1 AH as 'add-on' therapy to topical treatment for people with eczema compared with topical treatment plus placebo or no additional treatment as add-on therapy.
DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. Primary outcome measures were 'Mean change in patient-assessed symptoms of eczema' and 'Proportion of participants reporting adverse effects and serious adverse events'. Secondary outcomes were 'Mean change in physician-assessed clinical signs', 'Mean change in quality of life', and 'Number of eczema flares'.
MAIN RESULTS: We included 25 studies (3285 randomised participants). Seventeen studies included 1344 adults, and eight studies included 1941 children. Most studies failed to report eczema severity at baseline, but they were conducted in secondary care settings, so it is likely that they recruited patients with more severe cases of eczema. Trial duration was between three days and 18 months. Researchers studied 13 different H1 AH treatments. We could not undertake pooling because of the high level of diversity across studies in terms of duration and dose of intervention, concomitant topical therapy, and outcome assessment. Risk of bias was generally unclear, but five studies had high risk of bias in one domain (attrition, selection, or reporting bias). Only one study measured quality of life, but these results were insufficient for statistical analysis.Although this review assessed 17 comparisons, we summarise here the results of three key comparisons in this review.Cetirizine versus placeboOne study compared cetirizine 0.5 mg/kg/d against placebo over 18 months in 795 children. Study authors did not report patient-assessed symptoms of eczema separately for pruritus. Cetirizine is probably associated with fewer adverse events (mainly mild) (risk ratio (RR) 0.68, 95% confidence interval (CI) 0.46 to 1.01) and the need for slightly less additional H1 AH use as an indication of eczema flare rate (P = 0.035; no further numerical data given). Physician-assessed clinical signs (SCORing Atopic Dermatitis index (SCORAD)) were reduced in both groups, but the difference between groups was reported as non-significant (no P value given). Evidence for this comparison was of moderate quality.One study assessed cetirizine 10 mg/d against placebo over four weeks in 84 adults. Results show no evidence of differences between groups in patient-assessed symptoms of eczema (pruritus measured as part of SCORAD; no numerical data given), numbers of adverse events (RR 1.11, 95% CI 0.50 to 2.45; mainly sedation, other skin-related problems, respiratory symptoms, or headache), or physician-assessed changes in clinical signs, amount of local rescue therapy required, or number of applications as an indicator of eczema flares (no numerical data reported). Evidence for this comparison was of low quality.Fexofenadine versus placeboCompared with placebo, fexofenadine 120 mg/d taken in adults over one week (one study) probably leads to a small reduction in patient-assessed symptoms of pruritus on a scale of 0 to 8 (mean difference (MD) -0.25, 95% CI -0.43 to -0.07; n = 400) and a greater reduction in the ratio of physician-assessed pruritus area to whole body surface area (P = 0.007; no further numerical data given); however, these reductions may not be clinically meaningful. Results suggest probably little or no difference in adverse events (mostly somnolence and headache) (RR 1.05, 95% CI 0.74 to 1.50; n = 411) nor in the amount of 0.1% hydrocortisone butyrate used (co-intervention in both groups) as an indicator of eczema flare, but no numerical data were given. Evidence for this comparison was of moderate quality.Loratadine versus placeboA study of 28 adults compared loratadine 10 mg/d taken over 4 weeks versus placebo. Researchers found no evidence of differences between groups in patient-assessed pruritus, measured by a 100-point visual analogue scale (MD -2.30, 95% CI -20.27 to 15.67); reduction in physician-assessed clinical signs (SCORAD) (MD -4.10, 95% CI -13.22 to 5.02); or adverse events. Study authors reported only one side effect (folliculitis with placebo) (RR 0.25, 95% CI 0.01 to 5.76). Evidence for this comparison was of low quality. Number of eczema flares was not measured for this comparison.
AUTHORS' CONCLUSIONS: Based on the main comparisons, we did not find consistent evidence that H1 AH treatments are effective as 'add-on' therapy for eczema when compared to placebo; evidence for this comparison was of low and moderate quality. However, fexofenadine probably leads to a small improvement in patient-assessed pruritus, with probably no significant difference in the amount of treatment used to prevent eczema flares. Cetirizine was no better than placebo in terms of physician-assessed clinical signs nor patient-assessed symptoms, and we found no evidence that loratadine was more beneficial than placebo, although all interventions seem safe.The quality of evidence was limited because of poor study design and imprecise results. Future researchers should clearly define the condition (course and severity) and clearly report their methods, especially participant selection and randomisation; baseline characteristics; and outcomes (based on the Harmonising Outcome Measures in Eczema initiative).
Cuello-Garcia CA, Brożek JL, Fiocchi A, Pawankar R, Yepes-Nuñez JJ, Terracciano L, Gandhi S, Agarwal A, Zhang Y, Schünemann HJ.
Probiotics for the prevention of allergy: A systematic review and meta-analysis of randomized controlled trials.
J Allergy Clin Immunol. 2015 Oct;136(4):952-61. doi: 10.1016/j.jaci.2015.04.031. Epub 2015 Jun 2.
Abstract/Text
BACKGROUND: Allergic diseases are considered a health burden because of their high and constantly increasing prevalence, high direct and indirect costs, and undesirable effects on quality of life. Probiotics have been suggested as an intervention to prevent allergic diseases.
OBJECTIVE: We sought to synthesize the evidence supporting use of probiotics for the prevention of allergies and inform World Allergy Organization guidelines on probiotic use.
METHODS: We performed a systematic review of randomized trials assessing the effects of any probiotic administered to pregnant women, breast-feeding mothers, and/or infants.
RESULTS: Of 2403 articles published until December 2014 identified in Cochrane Central Register of Controlled Trials, MEDLINE, and Embase, 29 studies fulfilled a priori specified inclusion criteria for the analyses. Probiotics reduced the risk of eczema when used by women during the last trimester of pregnancy (relative risk [RR], 0.71; 95% CI, 0.60-0.84), when used by breast-feeding mothers (RR, 0.57; 95% CI, 0.47-0.69), or when given to infants (RR, 0.80; 95% CI, 0.68-0.94). Evidence did not support an effect on other allergies, nutrition status, or incidence of adverse effects. The certainty in the evidence according to the Grading of Recommendation Assessment Development and Evaluation approach is low or very low because of the risk of bias, inconsistency and imprecision of results, and indirectness of available research.
CONCLUSION: Probiotics used by pregnant women or breast-feeding mothers and/or given to infants reduced the risk of eczema in infants; however, the certainty in the evidence is low. No effect was observed for the prevention of other allergic conditions.
Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Zuccotti G, Meneghin F, Aceti A, Barone G, Callegari ML, Di Mauro A, Fantini MP, Gori D, Indrio F, Maggio L, Morelli L, Corvaglia L; Italian Society of Neonatology.
Probiotics for prevention of atopic diseases in infants: systematic review and meta-analysis.
Allergy. 2015 Nov;70(11):1356-71. doi: 10.1111/all.12700. Epub 2015 Aug 13.
Abstract/Text
Growing evidence underlines the pivotal role of infant gut colonization in the development of the immune system. The possibility to modify gut colonization through probiotic supplementation in childhood might prevent atopic diseases. The aim of the present systematic review and meta-analysis was to evaluate the effect of probiotic supplementation during pregnancy and early infancy in preventing atopic diseases. PubMed, Embase and Cochrane Library were searched for randomized controlled trials evaluating the use of probiotics during pregnancy or early infancy for prevention of allergic diseases. Fixed-effect models were used, and random-effects models where significant heterogeneity was present. Results were expressed as risk ratio (RR) with 95% confidence interval (CI). Seventeen studies, reporting data from 4755 children (2381 in the probiotic group and 2374 in the control group), were included in the meta-analysis. Infants treated with probiotics had a significantly lower RR for eczema compared to controls (RR 0.78 [95% CI: 0.69-0.89], P = 0.0003), especially those supplemented with a mixture of probiotics (RR 0.54 [95% CI: 0.43-0.68], P < 0.00001). No significant difference in terms of prevention of asthma (RR 0.99 [95% CI: 0.77-1.27], P = 0.95), wheezing (RR 1.02 [95% CI: 0.89-1.17], P = 0.76) or rhinoconjunctivitis (RR 0.91 [95% CI: 0.67-1.23], P = 0.53) was documented. The results of the present meta-analysis show that probiotic supplementation prevents infantile eczema, thus suggesting a new potential indication for probiotic use in pregnancy and infancy.
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Li L, Han Z, Niu X, Zhang G, Jia Y, Zhang S, He C.
Probiotic Supplementation for Prevention of Atopic Dermatitis in Infants and Children: A Systematic Review and Meta-analysis.
Am J Clin Dermatol. 2019 Jun;20(3):367-377. doi: 10.1007/s40257-018-0404-3.
Abstract/Text
BACKGROUND: Probiotic supplementation in early life may be effective in preventing atopic dermatitis (AD); however, results regarding efficacy have been controversial.
OBJECTIVE: The aim of our study was to investigate the effect of probiotic supplementation on the risk of AD.
METHODS: We systematically searched PubMed, EBSCO, Embase and Web of Science databases up to 8 March 2018 for potentially relevant studies regarding probiotic supplementation and AD. Included infants and children were those with probiotic exposure in utero and/or after birth who were not previously diagnosed with AD. We calculated the odds ratios (ORs) and 95% confidence intervals (CIs) and used the Jadad and Newcastle-Ottawa scales to assess methodologic quality.
RESULTS: A total of 28 studies met the inclusion criteria. Compared with controls, probiotic treatment was associated with a reduced risk of AD (OR 0.69; 95% CI 0.58-0.82, P < 0.0001). The use of probiotics during both the prenatal and the postnatal period significantly reduced the incidence of AD (OR 0.67; 95% CI 0.54-0.82); however, analysis of studies of probiotics given prenatally only or postnatally only did not reach statistical significance.
CONCLUSIONS: Our meta-analysis showed that probiotic supplementation during both the prenatal and the postnatal period reduced the incidence of AD in infants and children. Our findings suggest that starting probiotic treatment during gestation and continuing through the first 6 months of the infant's life may be of benefit in the prevention of AD.
Simpson EL, Chalmers JR, Hanifin JM, Thomas KS, Cork MJ, McLean WHI, Brown SJ, Chen Z, Chen Y, Williams HC. Emollient enhancement of the skin barrier from birth offers effective atopic dermatitis prevention. J Allergy Clin Immunol [Internet]. 2014 Oct [cited 2018 Dec 11];134(4):818–823. Available from: https://linkinghub.elsevier.com/retrieve/pii/S009167491401118X
Horimukai K, Morita K, Narita M, Kondo M, Kitazawa H, Nozaki M, Shigematsu Y, Yoshida K, Niizeki H, Motomura KI, Sago H, Takimoto T, Inoue E, Kamemura N, Kido H, Hisatsune J, Sugai M, Murota H, Katayama I, Sasaki T, Amagai M, Morita H, Matsuda A, Matsumoto K, Saito H, Ohya Y. Application of moisturizer to neonates prevents development of atopic dermatitis. J Allergy Clin Immunol [Internet]. 2014 Oct [cited 2018 Dec 11];134(4):824-830.e6. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0091674914011609
Chalmers JR, Haines RH, Bradshaw LE, Montgomery AA, Thomas KS, Brown SJ, Ridd MJ, Lawton S, Simpson EL, Cork MJ, Sach TH, Flohr C, Mitchell EJ, Swinden R, Tarr S, Davies-Jones S, Jay N, Kelleher MM, Perkin MR, Boyle RJ, Williams HC; BEEP study team.
Daily emollient during infancy for prevention of eczema: the BEEP randomised controlled trial.
Lancet. 2020 Mar 21;395(10228):962-972. doi: 10.1016/S0140-6736(19)32984-8. Epub 2020 Feb 19.
Abstract/Text
BACKGROUND: Skin barrier dysfunction precedes eczema development. We tested whether daily use of emollient in the first year could prevent eczema in high-risk children.
METHODS: We did a multicentre, pragmatic, parallel-group, randomised controlled trial in 12 hospitals and four primary care sites across the UK. Families were approached via antenatal or postnatal services for recruitment of term infants (at least 37 weeks' gestation) at high risk of developing eczema (ie, at least one first-degree relative with parent-reported eczema, allergic rhinitis, or asthma, diagnosed by a doctor). Term newborns with a family history of atopic disease were randomly assigned (1:1) to application of emollient daily (either Diprobase cream or DoubleBase gel) for the first year plus standard skin-care advice (emollient group) or standard skin-care advice only (control group). The randomisation schedule was created using computer-generated code (stratified by recruiting centre and number of first-degree relatives with atopic disease) and participants were assigned to groups using an internet-based randomisation system. The primary outcome was eczema at age 2 years (defined by UK working party criteria) with analysis as randomised regardless of adherence to allocation for participants with outcome data collected, and adjusting for stratification variables. This trial is registered with ISRCTN, ISRCTN21528841. Data collection for long-term follow-up is ongoing, but the trial is closed to recruitment.
FINDINGS: 1394 newborns were randomly assigned to study groups between Nov 19, 2014, and Nov 18, 2016; 693 were assigned to the emollient group and 701 to the control group. Adherence in the emollient group was 88% (466 of 532) at 3 months, 82% (427 of 519) at 6 months, and 74% (375 of 506) at 12 months in those with complete questionnaire data. At age 2 years, eczema was present in 139 (23%) of 598 infants with outcome data collected in the emollient group and 150 (25%) of 612 infants in the control group (adjusted relative risk 0·95 [95% CI 0·78 to 1·16], p=0·61; adjusted risk difference -1·2% [-5·9 to 3·6]). Other eczema definitions supported the results of the primary analysis. Mean number of skin infections per child in year 1 was 0·23 (SD 0·68) in the emollient group versus 0·15 (0·46) in the control group; adjusted incidence rate ratio 1·55 (95% CI 1·15 to 2·09).
INTERPRETATION: We found no evidence that daily emollient during the first year of life prevents eczema in high-risk children and some evidence to suggest an increased risk of skin infections. Our study shows that families with eczema, asthma, or allergic rhinitis should not use daily emollients to try and prevent eczema in their newborn.
FUNDING: National Institute for Health Research Health Technology Assessment.
Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.
Skjerven HO, Rehbinder EM, Vettukattil R, LeBlanc M, Granum B, Haugen G, Hedlin G, Landrø L, Marsland BJ, Rudi K, Sjøborg KD, Söderhäll C, Staff AC, Carlsen KH, Asarnoj A, Bains KES, Carlsen OCL, Endre KMA, Granlund PA, Hermansen JU, Gudmundsdóttir HK, Hilde K, Håland G, Kreyberg I, Olsen IC, Mägi CO, Nordhagen LS, Saunders CM, Skrindo I, Tedner SG, Værnesbranden MR, Wiik J, Jonassen CM, Nordlund B, Carlsen KCL.
Skin emollient and early complementary feeding to prevent infant atopic dermatitis (PreventADALL): a factorial, multicentre, cluster-randomised trial.
Lancet. 2020 Mar 21;395(10228):951-961. doi: 10.1016/S0140-6736(19)32983-6. Epub 2020 Feb 19.
Abstract/Text
BACKGROUND: Skin emollients applied during early infancy could prevent atopic dermatitis, and early complementary food introduction might reduce food allergy in high-risk infants. The study aimed to determine if either regular skin emollients applied from 2 weeks of age, or early complementary feeding introduced between 12 and 16 weeks of age, reduced development of atopic dermatitis by age 12 months in the general infant population.
METHODS: This population-based 2×2 factorial, randomised clinical trial was done at Oslo University Hospital and Østfold Hospital Trust, Oslo, Norway; and Karolinska University Hospital, Stockholm, Sweden. Infants of women recruited antenatally at the routine ultrasound pregnancy screening at 18 weeks were cluster-randomised at birth from 2015 to 2017 to the following groups: (1) controls with no specific advice on skin care while advised to follow national guidelines on infant nutrition (no intervention group); (2) skin emollients (bath additives and facial cream; skin intervention group); (3) early complementary feeding of peanut, cow's milk, wheat, and egg (food intervention group); or (4) combined skin and food interventions (combined intervention group). Participants were randomly assigned (1:1:1:1) using computer- generated cluster randomisation based on 92 geographical living area blocks as well as eight 3-month time blocks. Carers were instructed to apply the interventions on at least 4 days per week. Atopic dermatitis by age 12 months was the primary outcome, based on clinical investigations at 3, 6 and 12 months by investigators masked to group allocation. Atopic dermatitis was assessed after completing the 12-month investigations and diagnosed if either of the UK Working Party and Hanifin and Rajka (12 months only) diagnostic criteria were fulfilled. The primary efficacy analyses was done by intention-to-treat analysis on all randomly assigned participants. Food allergy results will be reported once all investigations at age 3 years are completed in 2020. This was a study performed within ORAACLE (the Oslo Research Group of Asthma and Allergy in Childhood; the Lung and Environment). The study is registered at clinicaltrials.gov, NCT02449850.
FINDINGS: 2697 women were recruited between Dec 9, 2014, and Oct 31, 2016, from whom 2397 newborn infants were enrolled from April 14, 2015, to April 11, 2017. Atopic dermatitis was observed in 48 (8%) of 596 infants in the no intervention group, 64 (11%) of 575 in the skin intervention group, 58 (9%) of 642 in the food intervention group, and 31 (5%) of 583 in the combined intervention group. Neither skin emollients nor early complementary feeding reduced development of atopic dermatitis, with a risk difference of 3·1% (95% CI -0·3 to 6·5) for skin intervention and 1·0% (-2·1 to 4·1) for food intervention, in favour of control. No safety concerns with the interventions were identified. Reported skin symptoms and signs (including itching, oedema, exanthema, dry skin, and urticaria) were no more frequent in the skin, food, and combined intervention groups than in the no intervention group.
INTERPRETATION: Neither early skin emollients nor early complementary feeding reduced development of atopic dermatitis by age 12 months. Our study does not support the use of these interventions to prevent atopic dermatitis by 12 months of age in infants.
FUNDING: The study was funded by several public and private funding bodies: The Regional Health Board South East, The Norwegian Research Council, Health and Rehabilitation Norway, The Foundation for Healthcare and Allergy Research in Sweden-Vårdalstiftelsen, Swedish Asthma and Allergy Association's Research Foundation, Swedish Research Council-the Initiative for Clinical Therapy Research, The Swedish Heart-Lung Foundation, SFO-V at the Karolinska Institute, Freemason Child House Foundation in Stockholm, Swedish Research Council for Health, Working Life and Welfare-FORTE, Oslo University Hospital, the University of Oslo, and Østfold Hospital Trust.
Copyright © 2020 Elsevier Ltd. All rights reserved.
Kelleher MM, Cro S, Van Vogt E, Cornelius V, Lodrup Carlsen KC, Ove Skjerven H, Rehbinder EM, Lowe A, Dissanayake E, Shimojo N, Yonezawa K, Ohya Y, Yamamoto-Hanada K, Morita K, Cork M, Cooke A, Simpson EL, McClanahan D, Weidinger S, Schmitt J, Axon E, Tran L, Surber C, Askie LM, Duley L, Chalmers JR, Williams HC, Boyle RJ.
Skincare interventions in infants for preventing eczema and food allergy: A cochrane systematic review and individual participant data meta-analysis.
Clin Exp Allergy. 2021 Mar;51(3):402-418. doi: 10.1111/cea.13847. Epub 2021 Feb 25.
Abstract/Text
OBJECTIVE: Eczema and food allergy start in infancy and have shared genetic risk factors that affect skin barrier. We aimed to evaluate whether skincare interventions can prevent eczema or food allergy.
DESIGN: A prospectively planned individual participant data meta-analysis was carried out within a Cochrane systematic review to determine whether skincare interventions in term infants prevent eczema or food allergy.
DATA SOURCES: Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase and trial registries to July 2020.
ELIGIBILITY CRITERIA FOR SELECTED STUDIES: Included studies were randomized controlled trials of infants <1 year with healthy skin comparing a skin intervention with a control, for prevention of eczema and food allergy outcomes between 1 and 3 years.
RESULTS: Of the 33 identified trials, 17 trials (5823 participants) had relevant outcome data and 10 (5154 participants) contributed to IPD meta-analysis. Three of seven trials contributing to primary eczema analysis were at low risk of bias, and the single trial contributing to primary food allergy analysis was at high risk of bias. Interventions were mainly emollients, applied for the first 3-12 months. Skincare interventions probably do not change risk of eczema by age 1-3 years (RR 1.03, 95% CI 0.81, 1.31; I2 =41%; moderate certainty; 3075 participants, 7 trials). Sensitivity analysis found heterogeneity was explained by increased eczema in a trial of daily bathing as part of the intervention. It is unclear whether skincare interventions increase risk of food allergy by age 1-3 years (RR 2.53, 95% CI 0.99 to 6.47; very low certainty; 996 participants, 1 trial), but they probably increase risk of local skin infections (RR 1.34, 95% CI 1.02, 1.77; I2 =0%; moderate certainty; 2728 participants, 6 trials).
CONCLUSION: Regular emollients during infancy probably do not prevent eczema and probably increase local skin infections.
© 2021 John Wiley & Sons Ltd.
Perkin MR, Logan K, Marrs T, Radulovic S, Craven J, Boyle RJ, Chalmers JR, Williams HC, Versteeg SA, van Ree R, Lack G, Flohr C; EAT Study Team.
Association of frequent moisturizer use in early infancy with the development of food allergy.
J Allergy Clin Immunol. 2021 Mar;147(3):967-976.e1. doi: 10.1016/j.jaci.2020.10.044.
Abstract/Text
BACKGROUND: Food allergy is thought to develop through transcutaneous sensitization, especially in the presence of skin barrier impairment and inflammation. Regular moisturizer application to infant skin could potentially promote transcutaneous sensitization and the development of food allergy.
OBJECTIVES: We tested this hypothesis in the Enquiring About Tolerance (EAT) study population.
METHODS: The EAT study was a population-based randomized clinical trial conducted from January 15, 2008, to August 31, 2015, and recruited 1303 exclusively breastfed 3-month-old infants and their families from England and Wales. At enrollment at 3 months, families completed a questionnaire that included questions about frequency and type of moisturizer applied, use of corticosteroid creams, and parental report of dry skin or eczema. Infants were examined for visible eczema at the enrollment visit.
RESULTS: A statistically significant dose-response relationship was observed between parent-reported moisturization frequency at 3 months of age and the subsequent development of food allergy. Each additional moisturization per week was associated with an adjusted odds ratio of 1.20 (95% CI, 1.13-1.27; P < .0005) for developing food allergy. For infants with no visible eczema at the enrollment visit, the corresponding adjusted odds ratio was 1.18 (95% CI, 1.07-1.30; P = .001) and for those with eczema at the enrollment visit, 1.20 (95% CI, 1.11-1.31; P < .0005). Moisturizer frequency showed similar dose-response relationships with the development of both food and aeroallergen sensitization at 36 months.
CONCLUSIONS: These findings support the notion that regular application of moisturizers to the skin of young infants may promote the development of food allergy through transcutaneous sensitization.
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
Zhong Y, Samuel M, van Bever H, Tham EH.
Emollients in infancy to prevent atopic dermatitis: A systematic review and meta-analysis.
Allergy. 2022 Jun;77(6):1685-1699. doi: 10.1111/all.15116. Epub 2021 Oct 12.
Abstract/Text
BACKGROUND: Several studies have evaluated prophylactic emollients as a preventive strategy against atopic dermatitis (AD) and food allergy (FA). We aimed to synthesize the evidence on efficacy and safety of prophylactic emollients started during the first 6 weeks of infancy for prevention of AD and FA.
METHODS: MEDLINE, Embase, CINAHL, BIOSIS, and the Cochrane Library databases were searched systematically for randomized controlled trials published between January 2000 and July 2020, which assessed the effects of prophylactic emollients initiated within the first 6 weeks of life on the development of AD within 24 months of age, compared to no treatment. Risk of bias and certainty of evidence were assessed using the Cochrane Collaboration's tool and GRADE process, respectively.
RESULTS: Of the 1486 articles identified, 10 studies fulfilled inclusion criteria. In infants given emollients, there was no significant reduction on the development of AD (risk ratio (RR) 0.84, 95% confidence interval (CI) 0.64, 1.10) compared to the control group. However, there was significant benefit of prophylactic emollients (RR 0.75, 95% CI 0.62-1.11) in the high-risk population (n = 8 studies). There was also significant benefit (RR 0.59, 95% CI 0.43, 0.81) in studies (n = 6) where emollients were used continuously to the point of AD assessment; but not when treatment was ceased for an interval before AD assessment. There were no protective effects on FA found.
CONCLUSION: The prophylactic application of emollients initiated in early infancy may prevent AD, especially in high-risk populations and when used continuously. We hypothesize that emollients may delay rather than prevent AD.
© 2021 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.
Breneman D, Fleischer AB, Abramovits W, Zeichner J, Gold MH, Kirsner RS, Shull TF, Crowe AW, Jaracz E, Hanifin JM. Intermittent therapy for flare prevention and long-term disease control in stabilized atopic dermatitis: A randomized comparison of 3-times-weekly applications of tacrolimus ointment versus vehicle. J Am Acad Dermatol [Internet]. 2008 Jun [cited 2018 Dec 11];58(6):990–999. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0190962208002399
Wollenberg A, Reitamo S, Girolomoni G, Lahfa M, Ruzicka T, Healy E, Giannetti A, Bieber T, Vyas J, Deleuran M; European Tacrolimus Ointment Study Group.
Proactive treatment of atopic dermatitis in adults with 0.1% tacrolimus ointment.
Allergy. 2008 Jul;63(7):742-50.
Abstract/Text
BACKGROUND: Long-term treatment for atopic dermatitis (AD) using low dose, intermittent, topical anti-inflammatory agents may control acute disease and prevent relapses. This 12-month, European, multicentre, randomized study investigated whether the proactive use of 0.1% tacrolimus ointment applied twice weekly can keep AD in remission and reduce the incidence of disease exacerbations (DE).
METHODS: During the initial open-label period, 257 adults with AD applied 0.1% tacrolimus ointment twice daily (b.i.d.) for up to 6 weeks to affected areas. When an Investigator Global Assessment (IGA) score of RESULTS: Proactive tacrolimus 0.1% ointment application significantly reduced the number of DEs requiring substantial therapeutic intervention (median difference 2; P < 0.001; Wilcoxon rank sum test), the percentage of DE treatment days (median difference: 15.2%; P < 0.001; Wilcoxon rank sum test) and increased the time to first DE (median 142 vs 15 days; P < 0.001; stratified log-rank test). The adverse event profile was similar for the two treatment approaches.
CONCLUSION: A 12-month, twice weekly proactive tacrolimus ointment application was an effective treatment in most study patients which prevented, delayed and reduced the occurrence of AD exacerbations
Schmitt J, von Kobyletzki L, Svensson A, Apfelbacher C.
Efficacy and tolerability of proactive treatment with topical corticosteroids and calcineurin inhibitors for atopic eczema: systematic review and meta-analysis of randomized controlled trials.
Br J Dermatol. 2011 Feb;164(2):415-28. doi: 10.1111/j.1365-2133.2010.10030.x. Epub 2010 Nov 23.
Abstract/Text
BACKGROUND: Long-term low-level topical anti-inflammatory therapy has been suggested as a new paradigm in the treatment of atopic eczema (AE).
OBJECTIVES: To determine the efficacy and tolerability of topical corticosteroids and calcineurin inhibitors for flare prevention in AE.
METHODS: Systematic review of randomized controlled trials reporting efficacy of topical corticosteroids and/or topical calcineurin inhibitors for flare prevention in AE. Identification of relevant articles by systematic electronic searches (Cochrane Library, Medline) supplemented by hand search. Primary efficacy endpoint: proportion of participants experiencing at least one flare during proactive anti-inflammatory treatment. Relative risks (RRs) and corresponding 95% confidence intervals (CIs) were calculated and pooled by pharmaceutical agent using random-effects meta-analysis. Sensitivity analysis included meta-regression to explore the influence of study-specific covariates.
RESULTS: Nine articles reporting on eight vehicle-controlled trials were included. Three, four and one trial(s) evaluated proactive therapy with topical tacrolimus, fluticasone propionate and methylprednisolone aceponate, respectively. Each agent under study was more efficacious to prevent flares than vehicle. Meta-analysis suggested that topical fluticasone propionate (RR 0·46, 95% CI 0·38-0·55) may be more efficacious to prevent disease flares than topical tacrolimus (RR 0·78, 95% CI 0·60-1·00). Meta-regression indicated robustness of these findings. Proactive anti-inflammatory therapy was generally well tolerated. The trials identified, however, do not allow firm conclusions about long-term safety.
CONCLUSIONS: Vehicle-controlled trials indicate efficacy of proactive treatment with tacrolimus, fluticasone propionate and methylprednisolone aceponate to prevent AE flares. Indirect evidence from vehicle-controlled trials suggests that twice weekly application of the potent topical corticosteroid fluticasone propionate may be more efficacious to prevent AE flares than tacrolimus ointment. Head to head trials should be conducted to confirm these results. Future studies are also needed to evaluate the long-term safety of proactive treatment of AE.
© 2010 The Authors. BJD © 2010 British Association of Dermatologists.
厚生労働省：最適使用推進ガイドライン. ウパダシチニブ水和物（販売名：リンヴォック錠7.5mg、リンヴォック錠15mg、リンヴォック錠30mg）～アトピー性皮膚炎～（2022年4月16日閲覧）.
厚生労働省：最適使用推進ガイドライン. アブロシチニブ（販売名：サイバインコ錠200mg、サイバインコ錠100mg、サイバインコ錠50mg）～アトピー性皮膚炎～（2022年4月16日閲覧）.
Guttman-Yassky E, Teixeira HD, Simpson EL, Papp KA, Pangan AL, Blauvelt A, Thaçi D, Chu CY, Hong HC, Katoh N, Paller AS, Calimlim B, Gu Y, Hu X, Liu M, Yang Y, Liu J, Tenorio AR, Chu AD, Irvine AD.
Once-daily upadacitinib versus placebo in adolescents and adults with moderate-to-severe atopic dermatitis (Measure Up 1 and Measure Up 2): results from two replicate double-blind, randomised controlled phase 3 trials.
Lancet. 2021 Jun 5;397(10290):2151-2168. doi: 10.1016/S0140-6736(21)00588-2. Epub 2021 May 21.
Abstract/Text
BACKGROUND: Upadacitinib is an oral Janus kinase (JAK) inhibitor with greater inhibitory potency for JAK1 than JAK2, JAK3, and tyrosine kinase 2. We aimed to assess the efficacy and safety of upadacitinib compared with placebo for the treatment of moderate-to-severe atopic dermatitis.
METHODS: Measure Up 1 and Measure Up 2 were replicate multicentre, randomised, double-blind, placebo-controlled, phase 3 trials; Measure Up 1 was done at 151 clinical centres in 24 countries across Europe, North and South America, Oceania, and the Asia-Pacific region; and Measure Up 2 was done at 154 clinical centres in 23 countries across Europe, North America, Oceania, and the Asia-Pacific region. Eligible patients were adolescents (aged 12-17 years) and adults (aged 18-75 years) with moderate-to-severe atopic dermatitis (≥10% of body surface area affected by atopic dermatitis, Eczema Area and Severity Index [EASI] score of ≥16, validated Investigator's Global Assessment for Atopic Dermatitis [vIGA-AD] score of ≥3, and Worst Pruritus Numerical Rating Scale score of ≥4). Patients were randomly assigned (1:1:1) using an interactive response technology system to receive upadacitinib 15 mg, upadacitinib 30 mg, or placebo once daily for 16 weeks, stratified by baseline disease severity, geographical region, and age. Coprimary endpoints were the proportion of patients who had achieved at least a 75% improvement in EASI score from baseline (EASI-75) and the proportion of patients who had achieved a vIGA-AD response (defined as a vIGA-AD score of 0 [clear] or 1 [almost clear] with ≥2 grades of reduction from baseline) at week 16. Efficacy was analysed in the intention-to-treat population and safety was analysed in all randomly assigned patients who received at least one dose of study drug. These trials are registered with ClinicalTrials.gov, NCT03569293 (Measure Up 1) and NCT03607422 (Measure Up 2), and are both active but not recruiting.
FINDINGS: Between Aug 13, 2018, and Dec 23, 2019, 847 patients were randomly assigned to upadacitinib 15 mg (n=281), upadacitinib 30 mg (n=285), or placebo (n=281) in the Measure Up 1 study. Between July 27, 2018, and Jan 17, 2020, 836 patients were randomly assigned to upadacitinib 15 mg (n=276), upadacitinib 30 mg (n=282), or placebo (n=278) in the Measure Up 2 study. At week 16, the coprimary endpoints were met in both studies (all p<0·0001). The proportion of patients who had achieved EASI-75 at week 16 was significantly higher in the upadacitinib 15 mg (196 [70%] of 281 patients) and upadacitinib 30 mg (227 [80%] of 285 patients) groups than the placebo group (46 [16%] of 281 patients) in Measure Up 1 (adjusted difference in EASI-75 response rate vs placebo, 53·3% [95% CI 46·4-60·2] for the upadacitinib 15 mg group; 63·4% [57·1-69·8] for the upadacitinib 30 mg group) and Measure Up 2 (166 [60%] of 276 patients in the upadacitinib 15 mg group and 206 [73%] of 282 patients in the upadacitinib 30 mg group vs 37 [13%] of 278 patients in the placebo group; adjusted difference in EASI-75 response rate vs placebo, 46·9% [39·9-53·9] for the upadacitinib 15 mg group; 59·6% [53·1-66·2] for the upadacitinib 30 mg group). The proportion of patients who achieved a vIGA-AD response at week 16 was significantly higher in the upadacitinib 15 mg (135 [48%] patients) and upadacitinib 30 mg (177 [62%] patients) groups than the placebo group (24 [8%] patients) in Measure Up 1 (adjusted difference in vIGA-AD response rate vs placebo, 39·8% [33·2-46·4] for the upadacitinib 15 mg group; 53·6% [47·2-60·0] for the upadacitinib 30 mg group) and Measure Up 2 (107 [39%] patients in the upadacitinib 15 mg group and 147 [52%] patients in the upadacitinib 30 mg group vs 13 [5%] patients in the placebo group; adjusted difference in vIGA-AD response rate vs placebo, 34·0% [27·8-40·2] for the upadacitinib 15 mg group; 47·4% [41·0-53·7] for the upadacitinib 30 mg group). Both upadacitinib doses were well tolerated. The incidence of serious adverse events and adverse events leading to study drug discontinuation were similar among groups. The most frequently reported treatment-emergent adverse events were acne (19 [7%] of 281 patients in the upadacitinib 15 mg group, 49 [17%] of 285 patients in the upadacitinib 30 mg group, and six [2%] of 281 patients in the placebo group in Measure Up 1; 35 [13%] of 276 patients in the upadacitinib 15 mg group, 41 [15%] of 282 patients in the upadacitinib 30 mg group, and six [2%] of 278 patients in the placebo group in Measure Up 2), upper respiratory tract infection (25 [9%] patients, 38 [13%] patients, and 20 [7%] patients; 19 [7%] patients, 17 [16%] patients, and 12 [4%] patients), nasopharyngitis (22 [8%] patients, 33 [12%] patients, and 16 [6%] patients; 16 [6%] patients, 18 [6%] patients, and 13 [5%] patients), headache (14 [5%] patients, 19 [7%] patients, and 12 [4%] patients; 18 [7%] patients, 20 [7%] patients, and 11 [4%] patients), elevation in creatine phosphokinase levels (16 [6%] patients, 16 [6%] patients, and seven [3%] patients; nine [3%] patients, 12 [4%] patients, and five [2%] patients), and atopic dermatitis (nine [3%] patients, four [1%] patients, and 26 [9%] patients; eight [3%] patients, four [1%] patients, and 26 [9%] patients).
INTERPRETATION: Monotherapy with upadacitinib might be an effective treatment option and had a positive benefit-risk profile in adolescents and adults with moderate-to-severe atopic dermatitis.
FUNDING: AbbVie.
Copyright © 2021 Elsevier Ltd. All rights reserved.
Reich K, Teixeira HD, de Bruin-Weller M, Bieber T, Soong W, Kabashima K, Werfel T, Zeng J, Huang X, Hu X, Hendrickson BA, Ladizinski B, Chu AD, Silverberg JI.
Safety and efficacy of upadacitinib in combination with topical corticosteroids in adolescents and adults with moderate-to-severe atopic dermatitis (AD Up): results from a randomised, double-blind, placebo-controlled, phase 3 trial.
Lancet. 2021 Jun 5;397(10290):2169-2181. doi: 10.1016/S0140-6736(21)00589-4. Epub 2021 May 21.
Abstract/Text
BACKGROUND: Systemic therapies are typically combined with topical corticosteroids for the management of moderate-to-severe atopic dermatitis. Upadacitinib is an oral Janus kinase (JAK) inhibitor with greater inhibitory potency for JAK1 than JAK2, JAK3, or tyrosine kinase 2 that is being tested for atopic dermatitis. We aimed to assess the efficacy and safety of upadacitinib plus topical corticosteroids compared with placebo for the treatment of moderate-to-severe atopic dermatitis.
METHODS: In this randomised, double-blind, placebo-controlled, phase 3 trial (AD Up) adults (aged 18-75 years) and adolescents (aged 12-17 years) with chronic atopic dermatitis that was moderate to severe (≥10% of body surface area affected, Eczema Area and Severity Index [EASI] score of ≥16, validated Investigator's Global Assessment for atopic dermatitis [vIGA-AD] score of ≥3, and weekly average Worst Pruritus Numerical Rating Scale score of ≥4 at baseline) were enrolled at 171 clinical centres across 22 countries in the Asia-Pacific region, Europe, the Middle East, North America, and Oceania. Patients were randomly assigned (1:1:1) to receive upadacitinib 15 mg, upadacitinib 30 mg, or placebo once daily, all in combination with topical corticosteroids for 16 weeks. Randomisation was done using an interactive response technology system, stratified by baseline disease severity, geographical region, and age. Study investigators, study site personnel, and patients were masked to study treatment. The coprimary endpoints were the proportion of patients who had achieved at least a 75% reduction in EASI score from baseline (EASI-75) and the proportion of patients who had achieved a vIGA-AD response (defined as a vIGA-AD score of 0 [clear] or 1 [almost clear] with ≥2 grades of improvement from baseline) at week 16. Efficacy was analysed in the intention-to-treat population and safety was analysed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03568318, and is active, but not recruiting.
FINDINGS: Between Aug 9, 2018, and Dec 20, 2019, 901 patients were randomly assigned to receive upadacitinib 15 mg plus topical corticosteroids (n=300), upadacitinib 30 mg plus topical corticosteroids (n=297), or placebo plus topical corticosteroids (n=304). At week 16, the proportion of patients who had achieved EASI-75 was significantly higher in the upadacitinib 15 mg plus topical corticosteroid group (194 [65%] of 300 patients) and the upadacitinib 30 mg plus topical corticosteroids group (229 [77%] of 297 patients) than the placebo group (80 [26%] of 304 patients; adjusted difference in EASI-75 response rate vs placebo, 38·1% [95% CI 30·8-45·4] for the upadacitinib 15 mg group and 50·6% [43·8-57·4] for the upadacitinib 30 mg group; p<0·0001 for both doses). The proportion of patients who had achieved a vIGA-AD response at week 16 was significantly higher in the upadacitinib 15 mg plus topical corticosteroid group (119 [40%] patients) and upadacitinib 30 mg plus topical corticosteroid group (174 [59%] patients) than the placebo group (33 [11%] patients; adjusted difference in vIGA-AD response vs placebo, 28·5% [22·1-34·9] for the upadacitinib 15 mg group and 47·6% [41·1-54·0] for the upadacitinib 30 mg group; p<0·0001 for both doses). During the double-blind period, upadacitinib 15 and 30 mg were well tolerated in combination with topical corticosteroids. The most frequently reported treatment-emergent adverse events (≥5% in any treatment group) were acne, nasopharyngitis, upper respiratory tract infection, oral herpes, elevation of blood creatine phosphokinase levels, headache, and atopic dermatitis. The incidence of acne was higher in the upadacitinib 15 mg (30 [10%] of 300 patients) and upadacitinib 30 mg (41 [14%] of 297 patients) groups than the placebo group (six [2%] of 304 patients). The incidence of adverse events leading to discontinuation of study drug (four [1%] patients in the upadacitinib 15 mg plus topical corticosteroids group, four [1%] patients in the upadacitinib 30 mg plus topical corticosteroids group, and seven [2%] patients in the placebo plus topical corticosteroids group) and serious adverse events (seven [2%] patients, four [1%] patients, and nine [3%] patients) were similar among treatment groups. No deaths were reported in any treatment group.
INTERPRETATION: Upadacitinib plus topical corticosteroids was well tolerated and superior to placebo plus topical corticosteroids. Upadacitinib as combination therapy had a positive benefit-risk profile in adults and adolescents with moderate-to-severe atopic dermatitis.
FUNDING: AbbVie.
Copyright © 2021 Elsevier Ltd. All rights reserved.
Katoh N, Ohya Y, Murota H, Ikeda M, Hu X, Ikeda K, Liu J, Sasaki T, Raymundo EM, Teixeira HD, Saeki H.
Safety and Efficacy of Upadacitinib for Atopic Dermatitis in Japan: 2-Year Interim Results from the Phase 3 Rising Up Study.
Dermatol Ther (Heidelb). 2023 Jan;13(1):221-234. doi: 10.1007/s13555-022-00842-7. Epub 2022 Nov 19.
Abstract/Text
INTRODUCTION: Upadacitinib, an oral, selective Janus kinase inhibitor, is approved in Japan for the treatment of moderate-to-severe atopic dermatitis (AD), a chronic inflammatory skin disease characterized by eczematous morphology and intense itch.
METHODS: Rising Up is an ongoing phase 3, randomized, multicenter study evaluating the long-term safety and efficacy of upadacitinib in Japan. Patients with moderate-to-severe AD were randomized 1:1:1 to topical corticosteroids plus upadacitinib 15 mg (UPA15), upadacitinib 30 mg (UPA30), or placebo at baseline; at week 16, placebo patients were rerandomized 1:1 to UPA15 or UPA30 (plus topical corticosteroids per investigator discretion). This 2-year interim analysis evaluated safety and efficacy through 112 weeks (data cutoff date: 11 August 2021). Adverse events (AEs), AEs of special interest (AESIs), and laboratory data were assessed. Efficacy assessments included ≥ 75% and ≥ 90% improvement from baseline in Eczema Area and Severity Index (EASI 75/90), achievement of clear or almost clear on the validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD 0/1), and ≥ 4-point improvement in the Worst Pruritus Numerical Rating Scale (WP-NRS).
RESULTS: A total of 272 patients were enrolled and 242 were ongoing at data cutoff (UPA15, n = 120; UPA30, n = 122). After 112 weeks of treatment, serious AEs, AEs leading to discontinuation, and most AESIs were generally infrequent, and rates were similar between the two upadacitinib groups. One event each of rectal cancer and cerebellar hemorrhage was reported in the UPA15 group; no thrombosis events were observed. The most common AEs included acne, nasopharyngitis, and herpes zoster. EASI 75, EASI 90, vIGA-AD 0/1, and WP-NRS response rates were maintained through week 112.
CONCLUSION: UPA15 and UPA30 were well tolerated through 112 weeks of treatment with similar safety profiles to short-term studies and demonstrated durable long-term efficacy for the treatment of moderate-to-severe AD in adults and adolescents.
TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03661138.
© 2022. The Author(s).
Simpson EL, Sinclair R, Forman S, Wollenberg A, Aschoff R, Cork M, Bieber T, Thyssen JP, Yosipovitch G, Flohr C, Magnolo N, Maari C, Feeney C, Biswas P, Tatulych S, Valdez H, Rojo R.
Efficacy and safety of abrocitinib in adults and adolescents with moderate-to-severe atopic dermatitis (JADE MONO-1): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial.
Lancet. 2020 Jul 25;396(10246):255-266. doi: 10.1016/S0140-6736(20)30732-7.
Abstract/Text
BACKGROUND: Abrocitinib, an oral selective Janus kinase 1 inhibitor, was effective and well tolerated in adults with moderate-to-severe atopic dermatitis in a phase 2b trial. We aimed to assess the efficacy and safety of abrocitinib monotherapy in adolescents and adults with moderate-to-severe atopic dermatitis.
METHODS: In this multicentre, double-blind, randomised phase 3 trial (JADE MONO-1), patients (aged ≥12 years) with moderate-to-severe atopic dermatitis (Investigator Global Assessment score ≥3, Eczema Area and Severity Index [EASI] score ≥16, percentage of body surface area affected ≥10%, and Peak Pruritus Numerical Rating Scale score ≥4) with a bodyweight of 40 kg or more, were enrolled at 69 sites in Australia, Canada, Europe, and the USA. Patients were randomly assigned (2:2:1) to oral abrocitinib 100 mg, abrocitinib 200 mg, or placebo once daily for 12 weeks. Randomisation was done using an interactive response technology system, stratified by baseline disease severity and age. Patients, investigators, and the funder of the study were masked to study treatment. The coprimary endpoints were the proportion of patients who had achieved an Investigator Global Assessment response (score of 0 [clear] or 1 [almost clear] with a ≥2-grade improvement from baseline), and the proportion of patients who achieved at least a 75% improvement in EASI score from baseline (EASI-75) score, both assessed at week 12. Efficacy was assessed in the full analysis set, which included all randomised patients who received at least one dose of study medication. Safety was assessed in all randomised patients. This study is registered with ClinicalTrials.gov, NCT03349060.
FINDINGS: Between Dec 7, 2017, and March 26, 2019, 387 patients were enrolled: 156 were assigned to abrocitinib 100 mg, 154 to abrocitinib 200 mg, and 77 to placebo. All enrolled patients received at least one dose of study treatment and thus were evaluable for 12-week efficacy. Of the patients with available data for the coprimary endpoints at week 12, the proportion of patients who had achieved an Investigator Global Assessment response was significantly higher in the abrocitinib 100 mg group than in the placebo group (37 [24%] of 156 patients vs six [8%] of 76 patients; p=0·0037) and in the abrocitinib 200 mg group compared with the placebo group (67 [44%] of 153 patients vs six [8%] of 76 patients; p<0·0001). Of the patients with available data for the coprimary endpoints at week 12, compared with the placebo group, the proportion of patients who had achieved an EASI-75 response was significantly higher in the abrocitinib 100 mg group (62 [40%] of 156 patients vs nine [12%] of 76 patients; p<0·0001) and abrocitinib 200 mg group (96 [63%] of 153 patients vs nine [12%] of 76 patients; p<0·0001). Adverse events were reported in 108 (69%) of 156 patients in the abrocitinib 100 mg group, 120 (78%) of 154 patients in the abrocitinib 200 mg group, and 44 (57%) of 77 patients in the placebo group. Serious adverse events were reported in five (3%) of 156 patients in the abrocitinib 100 mg group, five (3%) of 154 patients in the abrocitinib 200 mg group, and three (4%) of 77 patients in the placebo group. No treatment-related deaths were reported.
INTERPRETATION: Monotherapy with oral abrocitinib once daily was effective and well tolerated in adolescents and adults with moderate-to-severe atopic dermatitis.
FUNDING: Pfizer.
Copyright © 2020 Elsevier Ltd. All rights reserved.
Bieber T, Simpson EL, Silverberg JI, Thaçi D, Paul C, Pink AE, Kataoka Y, Chu CY, DiBonaventura M, Rojo R, Antinew J, Ionita I, Sinclair R, Forman S, Zdybski J, Biswas P, Malhotra B, Zhang F, Valdez H; JADE COMPARE Investigators.
Abrocitinib versus Placebo or Dupilumab for Atopic Dermatitis.
N Engl J Med. 2021 Mar 25;384(12):1101-1112. doi: 10.1056/NEJMoa2019380.
Abstract/Text
BACKGROUND: The oral Janus kinase 1 (JAK1) inhibitor abrocitinib, which reduces interleukin-4 and interleukin-13 signaling, is being investigated for the treatment of atopic dermatitis. Data from trials comparing JAK1 inhibitors with monoclonal antibodies, such as dupilumab, that block interleukin-4 receptors are limited.
METHODS: In a phase 3, double-blind trial, we randomly assigned patients with atopic dermatitis that was unresponsive to topical agents or that warranted systemic therapy (in a 2:2:2:1 ratio) to receive 200 mg or 100 mg of abrocitinib orally once daily, 300 mg of dupilumab subcutaneously every other week (after a loading dose of 600 mg), or placebo; all the patients received topical therapy. The primary end points were an Investigator's Global Assessment (IGA) response (defined as a score of 0 [clear] or 1 [almost clear] on the IGA [scores range from 0 to 4], with an improvement of ≥2 points from baseline) and an Eczema Area and Severity Index-75 (EASI-75) response (defined as ≥75% improvement from baseline in the score on the EASI [scores range from 0 to 72]) at week 12. The key secondary end points were itch response (defined as an improvement of ≥4 points in the score on the Peak Pruritus Numerical Rating Scale [scores range from 0 to 10]) at week 2 and IGA and EASI-75 responses at week 16.
RESULTS: A total of 838 patients underwent randomization; 226 patients were assigned to the 200-mg abrocitinib group, 238 to the 100-mg abrocitinib group, 243 to the dupilumab group, and 131 to the placebo group. An IGA response at week 12 was observed in 48.4% of patients in the 200-mg abrocitinib group, 36.6% in the 100-mg abrocitinib group, 36.5% in the dupilumab group, and 14.0% in the placebo group (P<0.001 for both abrocitinib doses vs. placebo); an EASI-75 response at week 12 was observed in 70.3%, 58.7%, 58.1%, and 27.1%, respectively (P<0.001 for both abrocitinib doses vs. placebo). The 200-mg dose, but not the 100-mg dose, of abrocitinib was superior to dupilumab with respect to itch response at week 2. Neither abrocitinib dose differed significantly from dupilumab with respect to most other key secondary end-point comparisons at week 16. Nausea occurred in 11.1% of the patients in the 200-mg abrocitinib group and 4.2% of those in the 100-mg abrocitinib group, and acne occurred in 6.6% and 2.9%, respectively.
CONCLUSIONS: In this trial, abrocitinib at a dose of either 200 mg or 100 mg once daily resulted in significantly greater reductions in signs and symptoms of moderate-to-severe atopic dermatitis than placebo at weeks 12 and 16. The 200-mg dose, but not the 100-mg dose, of abrocitinib was superior to dupilumab with respect to itch response at week 2. Neither abrocitinib dose differed significantly from dupilumab with respect to most other key secondary end-point comparisons at week 16. (Funded by Pfizer; JADE COMPARE ClinicalTrials.gov number, NCT03720470.).
Copyright © 2021 Massachusetts Medical Society.
Reich K, Silverberg JI, Papp KA, Deleuran M, Katoh N, Strober B, Beck LA, de Bruin-Weller M, Werfel T, Zhang F, Biswas P, DiBonaventura MD, Chan G, Johnson S, Farooqui SA, Kerkmann U, Clibborn C.
Abrocitinib efficacy and safety in patients with moderate-to-severe atopic dermatitis: Results from phase 3 studies, including the long-term extension JADE EXTEND study.
J Eur Acad Dermatol Venereol. 2023 Oct;37(10):2056-2066. doi: 10.1111/jdv.19280. Epub 2023 Jul 11.
Abstract/Text
BACKGROUND: Abrocitinib improved signs and symptoms of moderate-to-severe atopic dermatitis (AD) at 12 or 16 weeks in phase 3 studies with a manageable safety profile. Further understanding of the abrocitinib long-term efficacy and safety profile is important for its appropriate use in treating chronic AD.
OBJECTIVE: To evaluate the abrocitinib efficacy up to 48 weeks and long-term safety in patients with moderate-to-severe AD.
METHODS: JADE EXTEND (NCT03422822) is an ongoing, phase 3, long-term extension study that enrolled patients from previous abrocitinib AD trials. This analysis focusses on patients from the phase 3 JADE MONO-1 (NCT03349060), JADE MONO-2 (NCT03575871) and JADE COMPARE (NCT03720470) studies who completed the full treatment period of placebo or abrocitinib (200 mg or 100 mg once daily) and subsequently entered JADE EXTEND. Efficacy endpoints included the proportion of patients achieving skin clearance (Investigator's Global Assessment [IGA] 0/1 [clear/almost clear]; ≥75% improvement in Eczema Area and Severity Index [EASI-75]) and itch response (Peak Pruritus Numerical Rating Scale [PP-NRS] severity ≥4-point improvement). Safety endpoints included treatment-emergent adverse events (TEAEs), serious TEAEs and TEAEs leading to discontinuation. Data cut-off: April 22, 2020.
RESULTS: As of the data cut-off, ~70% and ~45% of patients received abrocitinib for ≥36 and ≥48 weeks, respectively. Nasopharyngitis, atopic dermatitis, nausea and upper respiratory tract infections were the most frequent TEAEs. Serious TEAEs occurred in 7% and 5% and TEAEs leading to study discontinuation occurred in 9% and 7% of patients receiving abrocitinib 200 mg and 100 mg, respectively. Week 48 efficacy responses with abrocitinib 200 mg and 100 mg were as follows: IGA 0/1 52% and 39%; EASI-75 82% and 67%, and PP-NRS severity ≥4-point improvement 68% and 51%.
CONCLUSIONS: In patients with moderate-to-severe AD, long-term abrocitinib treatment resulted in clinically meaningful skin and pruritus improvement. The long-term safety profile was manageable and consistent with previous reports.
© 2023 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.
Simpson EL, Lacour JP, Spelman L, Galimberti R, Eichenfield LF, Bissonnette R, King BA, Thyssen JP, Silverberg JI, Bieber T, Kabashima K, Tsunemi Y, Costanzo A, Guttman-Yassky E, Beck LA, Janes JM, DeLozier AM, Gamalo M, Brinker DR, Cardillo T, Nunes FP, Paller AS, Wollenberg A, Reich K.
Baricitinib in patients with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids: results from two randomized monotherapy phase III trials.
Br J Dermatol. 2020 Aug;183(2):242-255. doi: 10.1111/bjd.18898. Epub 2020 Mar 5.
Abstract/Text
BACKGROUND: Baricitinib, an oral selective Janus kinase 1 and 2 inhibitor, effectively reduced atopic dermatitis (AD) severity in a phase II study with concomitant topical corticosteroids.
OBJECTIVES: To evaluate the efficacy and safety of baricitinib in patients with moderate-to-severe AD who had an inadequate response to topical therapies.
METHODS: In two independent, multicentre, double-blind, phase III monotherapy trials, BREEZE-AD1 and BREEZE-AD2, adults with moderate-to-severe AD were randomized 2 : 1 : 1 : 1 to once-daily placebo, baricitinib 1 mg, 2 mg, or 4 mg for 16 weeks.
RESULTS: At week 16, more patients achieved the primary end point of Validated Investigator's Global Assessment of AD (0, 1) on baricitinib 4 mg and 2 mg compared with placebo in BREEZE-AD1 [N = 624; baricitinib 4 mg 16·8% (P < 0·001), 2 mg 11·4% (P < 0·05), 1 mg 11·8% (P < 0·05), placebo 4·8%], and BREEZE-AD2 [N = 615; baricitinib 4 mg 13·8% (P = 0·001), 2 mg 10·6% (P < 0·05), 1 mg 8·8% (P = 0·085), placebo 4·5%]. Improvement in itch was achieved as early as week 1 for 4 mg and week 2 for 2 mg. Improvements in night-time awakenings, skin pain and quality-of-life measures were observed by week 1 for both 4 mg and 2 mg (P ≤ 0·05, all comparisons). The most common adverse events in patients treated with baricitinib were nasopharyngitis and headache. No cardiovascular events, venous thromboembolism, gastrointestinal perforation, significant haematological changes, or death were observed with any baricitinib dosage.
CONCLUSIONS: Baricitinib improved clinical signs and symptoms in patients with moderate-to-severe AD within 16 weeks of treatment and induced rapid reduction of itch. The safety profile remained consistent with prior findings from baricitinib clinical development in AD, with no new safety concerns.
© 2020 British Association of Dermatologists.
Reich K, Kabashima K, Peris K, Silverberg JI, Eichenfield LF, Bieber T, Kaszuba A, Kolodsick J, Yang FE, Gamalo M, Brinker DR, DeLozier AM, Janes JM, Nunes FP, Thyssen JP, Simpson EL.
Efficacy and Safety of Baricitinib Combined With Topical Corticosteroids for Treatment of Moderate to Severe Atopic Dermatitis: A Randomized Clinical Trial.
JAMA Dermatol. 2020 Dec 1;156(12):1333-1343. doi: 10.1001/jamadermatol.2020.3260.
Abstract/Text
IMPORTANCE: Baricitinib, an oral selective Janus kinase 1 and 2 inhibitor, effectively reduced disease severity in moderate to severe atopic dermatitis (AD) in 2 phase 3 monotherapy studies.
OBJECTIVE: To assess the efficacy and safety of 4 mg and 2 mg of baricitinib in combination with background topical corticosteroid (TCS) therapy in adults with moderate to severe AD who previously had an inadequate response to TCS therapy.
DESIGN, SETTING, AND PARTICIPANTS: This double-blind, placebo-controlled, phase 3 randomized clinical trial, BREEZE-AD7 (Study of Baricitinib [LY3009104] in Combination With Topical Corticosteroids in Adults With Moderate to Severe Atopic Dermatitis) was conducted from November 16, 2018, to August 22, 2019, at 68 centers across 10 countries in Asia, Australia, Europe, and South America. Patients 18 years or older with moderate to severe AD and an inadequate response to TCSs were included. After completing the study, patients were followed up for up to 4 weeks or enrolled in a long-term extension study.
INTERVENTIONS: Patients were randomly assigned (1:1:1) to receive 2 mg of baricitinib once daily (n = 109), 4 mg of baricitinib once daily (n = 111), or placebo (n = 109) for 16 weeks. The use of low-to-moderate potency TCSs was allowed.
MAIN OUTCOMES AND MEASURES: The primary end point was the proportion of patients achieving a validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) score of 0 (clear) or 1 (almost clear), with a 2-point or greater improvement from baseline at week 16.
RESULTS: Among 329 patients (mean [SD] age, 33.8 [12.4] years; 216 [66%] male), at week 16, a vIGA-AD score of 0 (clear) or 1 (almost clear) was achieved by 34 patients (31%) receiving 4 mg of baricitinib and 26 (24%) receiving 2 mg of baricitinib compared with 16 (15%) receiving placebo (odds ratio vs placebo, 2.8 [95% CI, 1.4-5.6]; P = .004 for the 4-mg group; 1.9 [95% CI, 0.9-3.9]; P = .08 for the 2-mg group). Treatment-emergent adverse events were reported in 64 of 111 patients (58%) in the 4-mg group, 61 of 109 patients (56%) in the 2-mg group, and 41 of 108 patients (38%) in the placebo group. Serious adverse events were reported in 4 patients (4%) in the 4-mg group, 2 (2%) in the 2-mg group, and 4 (4%) in the placebo group. The most common adverse events were nasopharyngitis, upper respiratory tract infections, and folliculitis.
CONCLUSIONS AND RELEVANCE: A dose of 4 mg of baricitinib in combination with background TCS therapy significantly improved the signs and symptoms of moderate to severe AD, with a safety profile consistent with previous studies of baricitinib in AD.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03733301.
Silverberg JI, Simpson EL, Wollenberg A, Bissonnette R, Kabashima K, DeLozier AM, Sun L, Cardillo T, Nunes FP, Reich K.
Long-term Efficacy of Baricitinib in Adults With Moderate to Severe Atopic Dermatitis Who Were Treatment Responders or Partial Responders: An Extension Study of 2 Randomized Clinical Trials.
JAMA Dermatol. 2021 Jun 1;157(6):691-699. doi: 10.1001/jamadermatol.2021.1273.
Abstract/Text
IMPORTANCE: Baricitinib, an oral selective Janus kinase inhibitor, improved the clinical signs and symptoms of moderate to severe atopic dermatitis in the 16-week, phase 3 monotherapy studies, BREEZE-AD1 and BREEZE-AD2. Long-term efficacy has not yet been examined.
OBJECTIVE: To evaluate the long-term (68-week) efficacy of baricitinib in adults with moderate to severe atopic dermatitis who were treatment responders or partial responders in BREEZE-AD1 and BREEZE-AD2.
DESIGN, SETTING, AND PARTICIPANTS: Patients completing BREEZE-AD1/BREEZE-AD2 entered the ongoing, multicenter, double-blind, long-term extension study BREEZE-AD3. The study was initiated on March 28, 2018. Data were analyzed on December 13, 2019.
INTERVENTIONS: Responders and partial responders (patients achieving validated Investigator Global Assessment for Atopic Dermatitis [vIGA-AD] score of 0 or 1 [0,1], or 2) at BREEZE-AD1/BREEZE-AD2 completion remained on originally assigned treatment for 52 weeks (68 total weeks of continuous therapy).
MAIN OUTCOMES AND MEASURES: The primary end point was the proportion of patients achieving a vIGA-AD score of 0,1 at weeks 16, 36, and 52 of BREEZE-AD3. Secondary end points included the proportion of patients achieving 75% or more improvement in the Eczema Area and Severity Index [EASI75] score and 4-point or more improvement in the itch numeric rating scale (NRS), using originating study baseline data. Itch data were collected during the first 16 weeks in BREEZE-AD3. The last originating study visit was the first BREEZE-AD3 visit; therefore, data are presented for continuous weeks of therapy, including the 16-week originating study period. Missing data were imputed by last observation carried forward. Modified intention-to-treat analysis was used.
RESULTS: Of the responder/partial responder population, the proportion of patients treated with baricitinib, 4 mg (n = 70) (mean [SD] age, 36.7 [15.5] years; 42 [60%] were men), achieving vIGA-AD (0,1) at week 16 was 45.7% (BREEZE-AD3 baseline) and, at week 68, 47.1%. Improvement of 75% or more in the EASI score was 70.0% at week 16 and 55.7% at week 68. The proportion of patients achieving an itch NRS improvement greater than or equal to 4 points at week 16 was 52.5% and, at week 32, 45.9%. Of the responder/partial responder population, the proportion of patients treated with baricitinib, 2 mg (n = 54) (mean [SD] age, 32.8 [12.7] years; 28 [51.9%] were men), achieving vIGA-AD (0,1) at week 16 was 46.3% and, at week 68, 59.3%. Improvement in the EASI75 score was 74.1% at week 16 and 81.5% at week 68. The proportion of patients achieving an itch NRS improvement greater than or equal to 4 points at week 16 was 44.2% and, at week 32, 39.5%.
CONCLUSIONS AND RELEVANCE: In this long-term double-blind extension study of 2 randomized clinical trials, baricitinib, 4 and 2 mg, demonstrated sustained long-term efficacy in patients with moderate to severe atopic dermatitis.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03334435.
Torrelo A, Rewerska B, Galimberti M, Paller A, Yang CY, Prakash A, Zhu D, Pontes Filho MAG, Wu WS, Eichenfield LF.
Efficacy and safety of baricitinib in combination with topical corticosteroids in paediatric patients with moderate-to-severe atopic dermatitis with an inadequate response to topical corticosteroids: results from a phase III, randomized, double-blind, placebo-controlled study (BREEZE-AD PEDS).
Br J Dermatol. 2023 Jul 7;189(1):23-32. doi: 10.1093/bjd/ljad096.
Abstract/Text
BACKGROUND: Baricitinib, an oral selective Janus kinase (JAK)1/JAK2 inhibitor, is approved in many countries for moderate-to-severe atopic dermatitis (AD) in adults who are candidates for systemic therapy.
OBJECTIVES: To evaluate the efficacy and safety of three doses of baricitinib in combination with low-to-moderate potency topical corticosteroids in paediatric patients with moderate-to-severe AD.
METHODS: Patients (aged 2 to < 18 years) were randomized (1 : 1 : 1 : 1) to once-daily baricitinib low dose (1 mg equivalent), medium dose (2 mg equivalent), high dose (4 mg equivalent) or placebo for 16 weeks. The primary endpoint was the proportion of patients achieving a validated Investigator Global Assessment® (vIGA-AD) of 0/1 with a ≥ 2-point improvement at week 16. Key secondary endpoints included the proportions of patients achieving ≥ 75% and ≥ 90% improvement in the Eczema Area and Severity Index (EASI-75 and EASI-90, respectively), ≥ 75% improvement in the SCORing Atopic Dermatitis (SCORAD 75), mean change from baseline in EASI score and proportion of patients achieving a 4-point improvement in the Itch Numeric Rating scale (NRS) for patients aged ≥ 10 years. Primary and key secondary efficacy analyses were conducted on the intent-to-treat population and adjusted for multiplicity. Safety analyses included all randomized patients who received ≥ 1 dose of study treatment.
RESULTS: A total of 483 patients were randomized (mean age 12 years). The baricitinib 4 mg equivalent achieved a statistically significant (P < 0.05) improvement vs. placebo on all 16-week endpoints (vIGA 0/1 with ≥ 2-point improvement, EASI-75, EASI-90, SCORAD 75, mean change in EASI score and Itch NRS 4-point improvement for patients aged ≥ 10 years). Improvement (P < 0.05, non-multiplicity adjusted) was also observed for baricitinib 4 mg equivalent vs. placebo in the ability to fall asleep and in reduction of topical corticosteroid use. Few patients discontinued due to adverse events (1.6% for placebo and 0.6% for those treated with baricitinib). There were no deaths, venous thromboembolic events, arterial thrombotic events, major adverse cardiovascular events, malignancies, gastrointestinal perforations or opportunistic infections seen.
CONCLUSIONS: The results indicate that baricitinib offers a potential therapeutic option with a favourable benefit-risk profile for paediatric patients with moderate-to-severe AD who are candidates for systemic therapies.
© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists.
Simpson EL, Bieber T, Guttman-Yassky E, Beck LA, Blauvelt A, Cork MJ, Silverberg JI, Deleuran M, Kataoka Y, Lacour JP, Kingo K, Worm M, Poulin Y, Wollenberg A, Soo Y, Graham NM, Pirozzi G, Akinlade B, Staudinger H, Mastey V, Eckert L, Gadkari A, Stahl N, Yancopoulos GD, Ardeleanu M; SOLO 1 and SOLO 2 Investigators.
Two Phase 3 Trials of Dupilumab versus Placebo in Atopic Dermatitis.
N Engl J Med. 2016 Dec 15;375(24):2335-2348. doi: 10.1056/NEJMoa1610020. Epub 2016 Sep 30.
Abstract/Text
BACKGROUND: Dupilumab, a human monoclonal antibody against interleukin-4 receptor alpha, inhibits signaling of interleukin-4 and interleukin-13, type 2 cytokines that may be important drivers of atopic or allergic diseases such as atopic dermatitis.
METHODS: In two randomized, placebo-controlled, phase 3 trials of identical design (SOLO 1 and SOLO 2), we enrolled adults with moderate-to-severe atopic dermatitis whose disease was inadequately controlled by topical treatment. Patients were randomly assigned in a 1:1:1 ratio to receive, for 16 weeks, subcutaneous dupilumab (300 mg) or placebo weekly or the same dose of dupilumab every other week alternating with placebo. The primary outcome was the proportion of patients who had both a score of 0 or 1 (clear or almost clear) on the Investigator's Global Assessment and a reduction of 2 points or more in that score from baseline at week 16.
RESULTS: We enrolled 671 patients in SOLO 1 and 708 in SOLO 2. In SOLO 1, the primary outcome occurred in 85 patients (38%) who received dupilumab every other week and in 83 (37%) who received dupilumab weekly, as compared with 23 (10%) who received placebo (P<0.001 for both comparisons with placebo). The results were similar in SOLO 2, with the primary outcome occurring in 84 patients (36%) who received dupilumab every other week and in 87 (36%) who received dupilumab weekly, as compared with 20 (8%) who received placebo (P<0.001 for both comparisons). In addition, in the two trials, an improvement from baseline to week 16 of at least 75% on the Eczema Area and Severity Index was reported in significantly more patients who received each regimen of dupilumab than in patients who received placebo (P<0.001 for all comparisons). Dupilumab was also associated with improvement in other clinical end points, including reduction in pruritus and symptoms of anxiety or depression and improvement in quality of life. Injection-site reactions and conjunctivitis were more frequent in the dupilumab groups than in the placebo groups.
CONCLUSIONS: In two phase 3 trials of identical design involving patients with atopic dermatitis, dupilumab improved the signs and symptoms of atopic dermatitis, including pruritus, symptoms of anxiety and depression, and quality of life, as compared with placebo. Trials of longer duration are needed to assess the long-term effectiveness and safety of dupilumab. (Funded by Sanofi and Regeneron Pharmaceuticals; SOLO 1 ClinicalTrials.gov number, NCT02277743 ; SOLO 2 ClinicalTrials.gov number, NCT02277769 .).
Blauvelt A, de Bruin-Weller M, Gooderham M, Cather JC, Weisman J, Pariser D, Simpson EL, Papp KA, Hong HC, Rubel D, Foley P, Prens E, Griffiths CEM, Etoh T, Pinto PH, Pujol RM, Szepietowski JC, Ettler K, Kemény L, Zhu X, Akinlade B, Hultsch T, Mastey V, Gadkari A, Eckert L, Amin N, Graham NMH, Pirozzi G, Stahl N, Yancopoulos GD, Shumel B.
Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomised, double-blinded, placebo-controlled, phase 3 trial.
Lancet. 2017 Jun 10;389(10086):2287-2303. doi: 10.1016/S0140-6736(17)31191-1. Epub 2017 May 4.
Abstract/Text
BACKGROUND: Dupilumab (an anti-interleukin-4-receptor-α monoclonal antibody) blocks signalling of interleukin 4 and interleukin 13, type 2/Th2 cytokines implicated in numerous allergic diseases ranging from asthma to atopic dermatitis. Previous 16-week monotherapy studies showed that dupilumab substantially improved signs and symptoms of moderate-to-severe atopic dermatitis with acceptable safety, validating the crucial role of interleukin 4 and interleukin 13 in atopic dermatitis pathogenesis. We aimed to evaluate the long-term efficacy and safety of dupilumab with medium-potency topical corticosteroids versus placebo with topical corticosteroids in adults with moderate-to-severe atopic dermatitis.
METHODS: In this 1-year, randomised, double-blinded, placebo-controlled, phase 3 study (LIBERTY AD CHRONOS), adults with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids were enrolled at 161 hospitals, clinics, and academic institutions in 14 countries in Europe, Asia-Pacific, and North America. Patients were randomly assigned (3:1:3) to subcutaneous dupilumab 300 mg once weekly (qw), dupilumab 300 mg every 2 weeks (q2w), or placebo via a central interactive voice/web response system, stratified by severity and global region. All three groups were given concomitant topical corticosteroids with or without topical calcineurin inhibitors where inadvisable for topical corticosteroids. Topical corticosteroids could be tapered, stopped, or restarted on the basis of disease activity. Coprimary endpoints were patients (%) achieving Investigator's Global Assessment (IGA) 0/1 and 2-point or higher improvement from baseline, and Eczema Area and Severity Index 75% improvement from baseline (EASI-75) at week 16. Week 16 efficacy and week 52 safety analyses included all randomised patients; week 52 efficacy included patients who completed treatment by US regulatory submission cutoff. This study is registered with ClinicalTrials.gov, NCT02260986.
FINDINGS: Between Oct 3, 2014, and July 31, 2015, 740 patients were enrolled: 319 were randomly assigned to dupilumab qw plus topical corticosteroids, 106 to dupilumab q2w plus topical corticosteroids, and 315 to placebo plus topical corticosteroids. 623 (270, 89, and 264, respectively) were evaluable for week 52 efficacy. At week 16, more patients who received dupilumab plus topical corticosteroids achieved the coprimary endpoints of IGA 0/1 (39% [125 patients] who received dupilumab plus topical corticosteroids qw and 39% [41 patients] who received dupilumab q2w plus topical corticosteroids vs 12% [39 patients] who received placebo plus topical corticosteroids; p<0·0001) and EASI-75 (64% [204] and 69% [73] vs 23% [73]; p<0·0001). Week 52 results were similar. Adverse events were reported in 261 (83%) patients who received dupilumab qw plus topical corticosteroids, 97 (88%) patients who received dupilumab q2w, and 266 (84%) patients who received placebo, and serious adverse events in nine (3%), four (4%), and 16 (5%) patients, respectively. No significant dupilumab-induced laboratory abnormalities were noted. Injection-site reactions and conjunctivitis were more common in patients treated with dupilumab plus topical corticosteroids-treated patients than in patients treated with placebo plus topical corticosteroids.
INTERPRETATION: Dupilumab added to standard topical corticosteroid treatment for 1 year improved atopic dermatitis signs and symptoms, with acceptable safety.
FUNDING: Sanofi and Regeneron Pharmaceuticals Inc.
Copyright © 2017 Elsevier Ltd. All rights reserved.
Berdyshev E, Goleva E, Bissonnette R, Bronova I, Bronoff AS, Richers BN, Garcia S, Ramirez-Gama M, Taylor P, Praestgaard A, Agueusop I, Jurvilliers P, Boguniewicz M, Levit NA, Rossi AB, Zhang A, Leung DYM.
Dupilumab significantly improves skin barrier function in patients with moderate-to-severe atopic dermatitis.
Allergy. 2022 Nov;77(11):3388-3397. doi: 10.1111/all.15432. Epub 2022 Jul 21.
Abstract/Text
BACKGROUND: Atopic dermatitis (AD) is characterized by abnormal skin lipids that are largely driven by hyperactivated type 2 immune responses. The antibody to the α-subunit of interleukin (IL)-4 receptor, dupilumab, was recently approved to treat AD and demonstrated strong efficacy. However, the role of dupilumab therapy in the regulation of skin barrier structure and function has not been fully explored.
METHODS: We have evaluated the content of lipids and transepidermal water loss (TEWL) in lesional and non-lesional skin of adults and adolescents with moderate-to-severe AD over the course of 16-week treatment with dupilumab and compared those values with that of matched healthy volunteers.
RESULTS: Dupilumab treatment provided a significant decrease in TEWL in AD lesions, lowering it almost to the levels seen in the skin of healthy subjects. Blocking IL-4/IL-13 signaling with dupilumab normalized lipid composition (decreased levels of ceramides with non-hydroxy fatty acids and C18-sphingosine and increased the level of esterified omega-hydroxy fatty acid-containing ceramides) and increased ceramide chain length in lesional as well as non-lesional stratum corneum of AD patients. Partial changes for these parameters were already observed after 2 weeks, with a full response achieved after 8 weeks of dupilumab treatment.
CONCLUSIONS: Inhibition of IL-4/IL-13 signaling by dupilumab allows restoration of skin lipid composition and barrier function in patients with moderate-to-severe AD.
© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.
Worm M, Simpson EL, Thaçi D, Bissonnette R, Lacour JP, Beissert S, Kawashima M, Ferrándiz C, Smith CH, Beck LA, Chan KC, Chen Z, Akinlade B, Hultsch T, Staudinger H, Gadkari A, Eckert L, Davis JD, Rajadhyaksha M, Graham NMH, Pirozzi G, Stahl N, Yancopoulos GD, Ardeleanu M.
Efficacy and Safety of Multiple Dupilumab Dose Regimens After Initial Successful Treatment in Patients With Atopic Dermatitis: A Randomized Clinical Trial.
JAMA Dermatol. 2020 Feb 1;156(2):131-143. doi: 10.1001/jamadermatol.2019.3617.
Abstract/Text
IMPORTANCE: The dupilumab regimen of 300 mg every 2 weeks is approved for uncontrolled, moderate to severe atopic dermatitis (AD).
OBJECTIVE: To assess the efficacy and safety of different dupilumab regimens in maintaining response after 16 weeks of initial treatment.
DESIGN, SETTING, AND PARTICIPANTS: The Study to Confirm the Efficacy and Safety of Different Dupilumab Dose Regimens in Adults With Atopic Dermatitis (LIBERTY AD SOLO-CONTINUE) was a randomized, double-blind, phase 3 clinical trial conducted from March 25, 2015, to October 18, 2016, at 185 sites in North America, Europe, Asia, and Japan. Patients with moderate to severe AD who received dupilumab treatment and achieved an Investigator's Global Assessment score of 0 or 1 or 75% improvement in Eczema Area and Severity Index scores (EASI-75) at week 16 in 2 previous dupilumab monotherapy trials (LIBERTY AD SOLO 1 and 2) were rerandomized in SOLO-CONTINUE. After completing SOLO-CONTINUE, patients were followed up for up to 12 weeks or enrolled in an open-label extension. Data were analyzed from December 5 to 12, 2016.
INTERVENTIONS: High-responding patients treated with dupilumab in SOLO were rerandomized 2:1:1:1 to continue their original regimen of dupilumab, 300 mg, weekly or every 2 weeks or to receive dupilumab, 300 mg, every 4 or 8 weeks or placebo for 36 weeks.
MAIN OUTCOMES AND MEASURES: Percentage change in EASI score from baseline during the SOLO-CONTINUE trial, percentage of patients with EASI-75 at week 36, and safety.
RESULTS: Among the 422 patients (mean [SD] age, 38.2 [14.5] years; 227 [53.8%] male), continuing dupilumab treatment once weekly or every 2 weeks maintained optimal efficacy, with negligible change in percent EASI improvement from SOLO 1 and 2 baseline during the SOLO-CONTINUE trial (-0.06%; P < .001 vs placebo); percent change with the other regimens dose-dependently worsened (dupilumab every 4 weeks, -3.84%; dupilumab every 8 weeks, -6.84%; placebo, -21.67%). More patients taking dupilumab weekly or every 2 weeks (116 of 162 [71.6%]; P < .001 vs placebo) maintained EASI-75 response than those taking dupilumab every 4 weeks (49 of 84 [58.3%]) or every 8 weeks (45 of 82 [54.9%]) or those taking placebo (24 of 79 [30.4%]). Overall adverse event incidences were 70.7% in the weekly or every 2 weeks group, 73.6% in the every 4 weeks group, 75.0% in the every 8 weeks group, and 81.7% in the placebo group. Treatment groups had similar conjunctivitis rates. Treatment-emergent antidrug antibody incidence was lower with more frequent dupilumab dose regimens (11.3% in the placebo group and 11.7%, 6.0%, 4.3%, and 1.2% in the dupilumab every 8 weeks, every 4 weeks, every 2 weeks, and weekly groups, respectively).
CONCLUSIONS AND RELEVANCE: In this trial, continued response over time was most consistently maintained with dupilumab administered weekly or every 2 weeks. Longer dosage intervals and placebo resulted in a diminution of response for both continuous and categorical end points. No new safety signals were observed. The approved regimen of 300 mg of dupilumab every 2 weeks is recommended for long-term treatment.
TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02395133.
Beck LA, Bissonnette R, Deleuran M, Nakahara T, Galus R, Coleman A, Gherardi G, Xiao J, Dingman R, Xu C, Avetisova E, Dubost-Brama A, Shabbir A.
Dupilumab in Adults With Moderate to Severe Atopic Dermatitis: A 5-Year Open-Label Extension Study.
JAMA Dermatol. 2024 Aug 1;160(8):805-812. doi: 10.1001/jamadermatol.2024.1536.
Abstract/Text
IMPORTANCE: Moderate to severe atopic dermatitis (AD) is a chronic inflammatory skin disease that often requires continuous long-term systemic management. Long-term safety and efficacy data for treatment options are critically important.
OBJECTIVE: To assess the safety and efficacy of dupilumab treatment for up to 5 years in adults with moderate to severe AD.
DESIGN, SETTING, AND PARTICIPANTS: The 5-year LIBERTY AD open-label extension study was conducted from September 2013 to June 2022 at 550 sites in 28 countries. The study enrolled adult patients with moderate to severe AD who had participated in previous dupilumab clinical trials. Data were analyzed from August 2022 to February 2023.
EXPOSURES: At enrollment, patients initiated a regimen of subcutaneous dupilumab, 200 mg, weekly (400-mg loading dose). The regimen was amended in June 2014 to dupilumab, 300 mg, weekly (600-mg loading dose) based on a dose-ranging study and again in November 2019 to dupilumab, 300 mg, every 2 weeks to align with the regulatory regimen approvals.
MAIN OUTCOMES AND MEASURES: The primary end points were the incidence and rate of treatment-emergent adverse events (TEAEs). Key secondary end points included incidence and rate of serious TEAEs and adverse events of special interest, proportion of patients achieving an Investigator's Global Assessment (IGA) score of 0 or 1 (clear or almost clear), and proportion of patients with 75% or more improvement in the Eczema Area and Severity Index (EASI) from the parent study baseline.
RESULTS: A total of 2677 patients were enrolled and treated in the open-label extension study; 1611 (60.2%) were male, and the mean (SD) age was 39.2 (13.4) years. A total of 334 patients (12.5%) completed treatment up to week 260. The most common reasons for withdrawal were due to regulatory approval of dupilumab in compliance with the study protocol (810 of 1380 [58.7%]), patient withdrawal (248 of 1380 [18.0%]), and adverse events (116 of 1380 [8.4%]). Exposure-adjusted rates of TEAEs were generally stable or declined throughout the study. Common TEAEs (incidence of 5% or greater) included nasopharyngitis, worsening AD, upper respiratory tract infection, conjunctivitis, conjunctivitis allergic, headache, oral herpes, and injection-site reaction. At week 260, 220 of 326 patients (67.5%) achieved an IGA score of 0 or 1 and 288 of 324 (88.9%) achieved 75% or greater improvement in the EASI. The mean (SD) EASI score was 16.39 (14.60) at baseline and 2.75 (5.62) at end of study.
CONCLUSIONS AND RELEVANCE: In this study, there was sustained safety and efficacy of continuous long-term dupilumab treatment for adults with moderate to severe AD.
Ebisawa M, Kataoka Y, Tanaka A, Nagao M, Laws E, Mortensen E, Nawata H, Arima K, Watanabe D, Lu X, Maloney J, Dubost-Brama A, Bansal A, Yahata K.
Efficacy and safety of dupilumab with concomitant topical corticosteroids in Japanese pediatric patients with moderate-to-severe atopic dermatitis: A randomized, double-blind, placebo-controlled phase 3 study.
Allergol Int. 2024 Oct;73(4):532-542. doi: 10.1016/j.alit.2024.04.006. Epub 2024 May 11.
Abstract/Text
BACKGROUND: We investigated the efficacy and safety of dupilumab in Japanese patients aged ≥6 months to <18 years old with moderate-to-severe atopic dermatitis not adequately controlled with existing therapies.
METHODS: In this randomized, double-blind, phase 3 study, patients received dupilumab (n = 30) or placebo (n = 32) with concomitant topical corticosteroids for 16 weeks, then all patients received dupilumab from 16 to 52 weeks. The primary endpoint was the proportion of patients with ≥75% improvement in Eczema Area and Severity Index (EASI) score from baseline (EASI-75) to Week 16. Key secondary endpoints included changes in EASI score, proportion of patients with investigator global assessment (IGA) scores of 0/1, and changes in worst daily itch numerical rating scale (NRS) scores (evaluated in patients aged ≥6 to <12 years [n = 35]).
RESULTS: At Week 16, more patients achieved EASI-75 with dupilumab than placebo (43.3% vs 18.8%; P = 0.0304), and the least squares mean (LSM) difference in percent change in EASI scores at Week 16 of dupilumab vs placebo was -39.4% (P = 0.0003). However, no significant difference in the proportion of patients achieving IGA scores of 0/1 at Week 16 with dupilumab versus placebo were seen (10.0% vs 9.4%; P = 0.8476). The percent change in worst daily itch NRS scores at Week 16 was higher with dupilumab (LSM difference: -33.3%; nominal P = 0.0117). Dupilumab was well tolerated; no new safety signals were identified.
CONCLUSIONS: Dupilumab showed consistent efficacy and was well tolerated in Japanese patients aged ≥6 months to <18 years with moderate-to-severe atopic dermatitis previously insufficiently controlled with existing therapies.
Copyright © 2024 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.
Kabashima K, Matsumura T, Komazaki H, Kawashima M; Nemolizumab-JP01 Study Group.
Trial of Nemolizumab and Topical Agents for Atopic Dermatitis with Pruritus.
N Engl J Med. 2020 Jul 9;383(2):141-150. doi: 10.1056/NEJMoa1917006.
Abstract/Text
BACKGROUND: Nemolizumab is a subcutaneously administered humanized monoclonal antibody against interleukin-31 receptor A, which is involved in pruritus and inflammation in atopic dermatitis. In phase 2 studies, nemolizumab lessened the severity of atopic dermatitis.
METHODS: In a 16-week, double-blind, phase 3 trial, we randomly assigned Japanese patients with atopic dermatitis and moderate-to-severe pruritus and an inadequate response to topical agents in a 2:1 ratio to receive subcutaneous nemolizumab (60 mg) or placebo every 4 weeks until week 16, with concomitant topical agents. The primary end point was the mean percent change in the visual-analogue scale (VAS) score for pruritus (range, 0 to 100, with higher scores indicating worse pruritus) from baseline to week 16. Secondary end points included the time course of change in the VAS score for pruritus up to week 4, the change in the Eczema Area and Severity Index (EASI) score (range, 0 to 72, with higher scores indicating greater severity), a score of 4 or less on the Dermatology Life Quality Index (DLQI; range, 0 to 30, with higher scores indicating a greater effect on daily life), a score of 7 or less on the Insomnia Severity Index (ISI; range, 0 to 28, with higher scores indicating greater severity), and safety.
RESULTS: A total of 143 patients were randomly assigned to receive nemolizumab and 72 to receive placebo. The median VAS score for pruritus at baseline was 75. At week 16, the mean percent change in the VAS score was -42.8% in the nemolizumab group and -21.4% in the placebo group (difference, -21.5 percentage points; 95% confidence interval, -30.2 to -12.7; P<0.001). The mean percent change in the EASI score was -45.9% with nemolizumab and -33.2% with placebo. The percentage of patients with a DLQI score of 4 or less was 40% in the nemolizumab group and 22% in the placebo group; the percentage of patients with an ISI score of 7 or less was 55% and 21%, respectively. The incidence of injection-related reactions was 8% with nemolizumab and 3% with placebo.
CONCLUSIONS: In this 16-week trial, the use of subcutaneous nemolizumab in addition to topical agents for atopic dermatitis resulted in a greater reduction in pruritus than placebo plus topical agents. The incidence of injection-site reactions was greater with nemolizumab than with placebo. Longer and larger trials are necessary to determine whether nemolizumab has a durable effect and is safe for atopic dermatitis. (Funded by Maruho; JapicCTI number, 173740.).
Copyright © 2020 Massachusetts Medical Society.
Kabashima K, Matsumura T, Komazaki H, Kawashima M; Nemolizumab JP01 andJP02 Study Group.
Nemolizumab plus topical agents in patients with atopic dermatitis (AD) and moderate-to-severe pruritus provide improvement in pruritus and signs of AD for up to 68 weeks: results from two phase III, long-term studies.
Br J Dermatol. 2022 Apr;186(4):642-651. doi: 10.1111/bjd.20873. Epub 2021 Dec 21.
Abstract/Text
BACKGROUND: Interleukin (IL)-31 affects the inflammatory response, is involved in epidermal barrier disruption in atopic dermatitis (AD) and plays a key role in pruritus. Nemolizumab, a humanized monoclonal antibody against IL-31 receptor A, reduced pruritus in patients with AD after a 16-week administration period.
OBJECTIVES: To examine the long-term effectiveness and safety of nemolizumab in patients aged ≥ 13 years with AD and inadequately controlled moderate-to-severe pruritus.
METHODS: In two long-term phase III studies, nemolizumab 60 mg every 4 weeks (Q4W) was administered subcutaneously, concomitantly with topical treatments. Study-JP01 patients received double-blind nemolizumab or placebo for 16 weeks, and then entered a 52-week extension period in which all patients received nemolizumab (nemolizumab/nemolizumab and placebo/nemolizumab groups). Study-JP02 patients received nemolizumab for 52 weeks. Both studies included an 8-week follow-up period.
RESULTS: Study-JP01 nemolizumab/nemolizumab and placebo/nemolizumab, and Study-JP02 nemolizumab groups comprised 143, 72 and 88 patients, respectively. In the nemolizumab/nemolizumab group, there were clinically meaningful improvements from the start of treatment to week 68 in the pruritus visual analogue scale (66% decrease) and Eczema Area and Severity Index (78% decrease). Quality of life (QoL) indicators improved after the first nemolizumab dose; improvements were maintained during the follow-up period. The long-term safety profile was consistent with previous studies, with no unexpected late-onset adverse events.
CONCLUSIONS: Nemolizumab 60 mg Q4W with concomitant topical treatments in patients with AD and inadequately controlled moderate-to-severe pruritus produced a continuous improvement in pruritus, signs of AD, and QoL for up to 68 weeks, with a favourable safety profile.
© 2021 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.
Igarashi A, Katsunuma T, Matsumura T, Komazaki H; Nemolizumab-JP04 Study Group.
Efficacy and safety of nemolizumab in paediatric patients aged 6-12 years with atopic dermatitis with moderate-to-severe pruritus: results from a phase III, randomized, double-blind, placebo-controlled, multicentre study.
Br J Dermatol. 2023 Dec 20;190(1):20-28. doi: 10.1093/bjd/ljad268.
Abstract/Text
BACKGROUND: Atopic dermatitis (AD) is a chronic, inflammatory skin condition affecting up to one-quarter of children. Uncontrolled pruritus associated with childhood AD, and the accompanying scratching, negatively impacts quality of life (QoL), sleep and development. The humanized monoclonal antibody nemolizumab, used concomitantly with topical agents, was shown to reduce pruritus and improve QoL in patients with AD aged ≥ 13 years. However, data relating to its efficacy and safety in younger children (aged < 13 years) have been lacking.
OBJECTIVES: To evaluate the efficacy and safety of nemolizumab, administered concomitantly with topical agents, in Japanese paediatric patients (aged 6-12 years) with AD and inadequately controlled moderate-to-severe pruritus.
METHODS: This was a randomized, placebo-controlled, double-blind, parallel-group, multicentre, 16-week, phase III study. Patients aged ≥ 6 and < 13 years, with confirmed AD, and an inadequate pruritic response despite treatment with topical agents and oral antihistamines were randomly assigned (1 : 1) to receive nemolizumab 30 mg or placebo every 4 weeks (Q4W). The primary efficacy endpoint was the change in the weekly mean 5-level itch score from baseline to week 16; secondary efficacy endpoints were related to pruritus, indicators for AD and QoL. Safety was assessed via adverse events (AEs) and laboratory test results.
RESULTS: In total, 89 patients were enrolled, received either nemolizumab 30 mg (n = 45) or placebo (n = 44) Q4W, and completed the study. The mean patient age was 9.1 (SD 1.9) years, and mean duration of AD was 8.5 (2.7) years. The change in 5-level itch score from baseline to week 16 showed a statistically significant difference in the nemolizumab treatment group (-1.3) compared with placebo (-0.5; least-squares mean difference -0.8, 95% confidence interval -1.1 to -0.5; P < 0.0001). Improvements with nemolizumab were observed from the second day of administration. Secondary endpoints were in favour of nemolizumab. No AEs resulted in discontinuation, and the overall safety profile in patients aged 6-12 years was comparable with that in older patients (aged ≥ 13 years) with AD.
CONCLUSIONS: Nemolizumab is a potential new treatment option for paediatric patients with AD whose pruritus has not been sufficiently improved with topical treatments and antihistamines.
© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists.
Silverberg JI, Guttman-Yassky E, Thaçi D, Irvine AD, Stein Gold L, Blauvelt A, Simpson EL, Chu CY, Liu Z, Gontijo Lima R, Pillai SG, Seneschal J; ADvocate1 and ADvocate2 Investigators.
Two Phase 3 Trials of Lebrikizumab for Moderate-to-Severe Atopic Dermatitis.
N Engl J Med. 2023 Mar 23;388(12):1080-1091. doi: 10.1056/NEJMoa2206714. Epub 2023 Mar 15.
Abstract/Text
BACKGROUND: Lebrikizumab, a high-affinity IgG4 monoclonal antibody targeting interleukin-13, prevents the formation of the interleukin-4Rα-interleukin-13Rα1 heterodimer receptor signaling complex.
METHODS: We conducted two identically designed, 52-week, randomized, double-blind, placebo-controlled, phase 3 trials; both trials included a 16-week induction period and a 36-week maintenance period. Eligible patients with moderate-to-severe atopic dermatitis (adults [≥18 years of age] and adolescents [12 to <18 years of age, weighing ≥40 kg]) were randomly assigned in a 2:1 ratio to receive either lebrikizumab at a dose of 250 mg (loading dose of 500 mg at baseline and week 2) or placebo, administered subcutaneously every 2 weeks. Outcomes for the induction period were assessed up to 16 weeks and are included in this report. The primary outcome was an Investigator's Global Assessment (IGA) score of 0 or 1 (indicating clear or almost clear skin; range, 0 to 4 [severe disease]) with a reduction (indicating improvement) of at least 2 points from baseline at week 16. Secondary outcomes included a 75% improvement in the Eczema Area and Severity Index score (EASI-75 response) and assessments of itch and of itch interference with sleep. Safety was also assessed.
RESULTS: In trial 1, the primary outcome was met in 43.1% of 283 patients in the lebrikizumab group and in 12.7% of 141 patients in the placebo group (P<0.001); an EASI-75 response occurred in 58.8% and 16.2%, respectively (P<0.001). In trial 2, the primary outcome was met in 33.2% of 281 patients in the lebrikizumab group and in 10.8% of 146 patients in the placebo group (P<0.001); an EASI-75 response occurred in 52.1% and 18.1%, respectively (P<0.001). Measures of itch and itch interference with sleep indicated improvement with lebrikizumab therapy. The incidence of conjunctivitis was higher among patients who received lebrikizumab than among those who received placebo. Most adverse events during the induction period were mild or moderate in severity and did not lead to trial discontinuation.
CONCLUSIONS: In the induction period of two phase 3 trials, 16 weeks of treatment with lebrikizumab was effective in adolescents and adults with moderate-to-severe atopic dermatitis. (Funded by Dermira; ADvocate1 and ADvocate2 ClinicalTrials.gov numbers, NCT04146363 and NCT04178967, respectively.).
Copyright © 2023 Massachusetts Medical Society.
Blauvelt A, Thyssen JP, Guttman-Yassky E, Bieber T, Serra-Baldrich E, Simpson E, Rosmarin D, Elmaraghy H, Meskimen E, Natalie CR, Liu Z, Xu C, Pierce E, Morgan-Cox M, Garcia Gil E, Silverberg JI.
Efficacy and safety of lebrikizumab in moderate-to-severe atopic dermatitis: 52-week results of two randomized double-blinded placebo-controlled phase III trials.
Br J Dermatol. 2023 May 24;188(6):740-748. doi: 10.1093/bjd/ljad022.
Abstract/Text
BACKGROUND: Lebrikizumab is a novel, high-affinity monoclonal antibody that selectively binds to interleukin (IL)-13.
OBJECTIVES: To evaluate the efficacy and safety of lebrikizumab monotherapy in adolescent and adult patients with moderate-to-severe atopic dermatitis (AD) over 52 weeks of treatment in ADvocate1 (NCT04146363) and ADvocate2 (NCT04178967).
METHODS: Patients who responded to lebrikizumab 250 mg every 2 weeks (Q2W) at the end of the 16-week induction period were re-randomized 2 : 2 : 1 to receive lebrikizumab Q2W, lebrikizumab 250 mg every 4 weeks (Q4W) or placebo Q2W (lebrikizumab withdrawal) for 36 additional weeks. Response at week 16 was defined as achieving a 75% reduction in Eczema Area Severity Index (EASI 75) or an Investigator's Global Assessment (IGA) of 0 or 1, with a ≥ 2-point improvement and no rescue medication use. Multiple imputation was used to handle missing data. Intermittent use of topical therapy was permitted during the maintenance period.
RESULTS: After 52 weeks, an IGA of 0 or 1 with a ≥ 2 point improvement was maintained by 71.2% of patients treated with lebrikizumab Q2W, 76.9% of patients treated with lebrikizumab Q4W and 47.9% of patients in the lebrikizumab withdrawal arm. EASI 75 was maintained by 78.4% of patients treated with lebrikizumab Q2W, 81.7% of patients treated with lebrikizumab Q4W and 66.4% of patients in the lebrikizumab withdrawal arm at week 52. Across treatment arms, proportions of patients using any rescue therapy were 14.0% (ADvocate1) and 16.4% (ADvocate2). During the combined induction and maintenance periods of ADvocate1 and ADvocate2, 63.0% of lebrikizumab-treated patients reported any treatment emergent adverse event, with most events (93.1%) being mild or moderate in severity.
CONCLUSIONS: After a 16-week induction period with lebrikizumab Q2W, lebrikizumab Q2W and Q4W maintained similar improvement of the signs and symptoms of moderate-to-severe AD, with a safety profile consistent with previously published data.
© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists.
Simpson EL, Gooderham M, Wollenberg A, Weidinger S, Armstrong A, Soung J, Ferrucci S, Lima RG, Witte MM, Xu W, ElMaraghy H, Natalie CR, Pierce E, Blauvelt A; ADhere Investigators.
Efficacy and Safety of Lebrikizumab in Combination With Topical Corticosteroids in Adolescents and Adults With Moderate-to-Severe Atopic Dermatitis: A Randomized Clinical Trial (ADhere).
JAMA Dermatol. 2023 Feb 1;159(2):182-191. doi: 10.1001/jamadermatol.2022.5534.
Abstract/Text
IMPORTANCE: Lebrikizumab (LEB), a high-affinity monoclonal antibody targeting interleukin (IL)-13, demonstrated efficacy and safety in patients with moderate-to-severe atopic dermatitis (AD) during 16 weeks of monotherapy in a phase 2b trial, and two 52-week phase 3 trials.
OBJECTIVE: To evaluate efficacy and safety of LEB combined with low- to mid-potency topical corticosteroids (TCS) in patients with moderate-to-severe AD.
DESIGN, SETTING, AND PARTICIPANTS: The ADhere trial was a 16-week randomized, double-blinded, placebo (PBO)-controlled, multicenter, phase 3 clinical trial conducted from February 3, 2020, to September 16, 2021. The study was conducted at 54 outpatient sites across Germany, Poland, Canada, and the US and included adolescent (aged ≥12 to <18 years weighing ≥40 kg) and adult patients with moderate-to-severe AD. The treatment allocation ratio was 2:1 (LEB:PBO).
INTERVENTIONS: Overall, 211 patients were randomized to subcutaneous LEB (loading dose of 500 mg at baseline and week 2, followed by 250 mg every 2 weeks [Q2W] thereafter) or PBO Q2W in combination with TCS for 16 weeks.
MAIN OUTCOMES AND MEASURES: Efficacy analyses at week 16 included proportions of patients achieving Investigator's Global Assessment score of 0 or 1 (IGA [0,1]) with 2 or more points improvement from baseline, and 75% improvement in the Eczema Area and Severity Index (EASI-75). Key secondary end points included evaluation of itch, itch interference on sleep, and quality of life. Safety assessments included monitoring adverse events (AEs).
RESULTS: The mean (SD) age of patients was 37.2 (19.3) years, 103 (48.8%) patients were women, 31 (14.7%) patients were Asian, and 28 (13.3%) patients were Black/African American. At week 16, IGA (0,1) was achieved by 145 (41.2%) patients in the LEB+TCS group vs 66 (22.1%) receiving PBO+TCS (P = .01); corresponding proportions of patients achieving EASI-75 were 69.5% vs 42.2% (P < .001). The LEB+TCS group showed statistically significant improvements in all key secondary end points. Most treatment-emergent adverse events (TEAEs) were nonserious, mild or moderate in severity, and did not lead to study discontinuation. The TEAEs frequently reported in the LEB+TCS group included conjunctivitis (7 [4.8%]), headache (7 [4.8%]), hypertension (4 [2.8%]), injection site reactions (4 [2.8%]), and herpes infection (5 [3.4%]) vs 1.5% or less patient-reported frequencies in the PBO+TCS group. Similar frequencies of patient-reported serious AEs following LEB+TCS (n = 2, 1.4%) and PBO+TCS (n = 1, 1.5%).
CONCLUSIONS AND RELEVANCE: In this randomized phase 3 clinical trial, LEB+TCS was associated with improved outcomes in adolescents and adults with moderate-to-severe AD compared with TCS alone, and safety was consistent with previously reported AD trials.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04250337.
川島眞, 林伸和, 乃木田俊辰, 他：アトピー性皮膚炎の寛解維持における保湿剤の有用性の検討．日皮会誌, 2007;117: 1139-1145.
Lodén M, Andersson AC, Anderson C, Bergbrant IM, Frödin T, Ohman H, Sandström MH, Särnhult T, Voog E, Stenberg B, Pawlik E, Preisler-Häggqvist A, Svensson A, Lindberg M.
A double-blind study comparing the effect of glycerin and urea on dry, eczematous skin in atopic patients.
Acta Derm Venereol. 2002;82(1):45-7. doi: 10.1080/000155502753600885.
Abstract/Text
Moisturizing creams have beneficial effects in the treatment of dry, scaly skin, but they may induce adverse skin reactions. In a randomized double-blind study, 197 patients with atopic dermatitis were treated with one of the following: a new moisturizing cream with 20% glycerin, its cream base without glycerin as placebo, or a cream with 4% urea and 4% sodium chloride. The patients were asked to apply the cream at least once daily for 30 days. Adverse skin reactions and changes in skin dryness were assessed by the patient and a dermatologist. Adverse skin reactions such as smarting (a sharp local superficial sensation) were felt significantly less among patients using the 20% glycerin cream compared with the urea-saline cream, because 10% of the patients judged the smarting as severe or moderate when using glycerin cream, whereas 24% did so using urea-saline cream (p < 0.0006). No differences were found regarding skin reactions such as stinging, itching and dryness/irritation. The study showed equal effects on skin dryness as judged by the patients and the dermatologist. In conclusion, a glycerin containing cream appears to be a suitable alternative to urea/sodium chloride in the treatment of atopic dry skin.
