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Comparison of real-world treatment outcomes of systemic immunomodulating therapy in atopic dermatitis patients with dark and light skin types

Open AccessPublished:October 10, 2022DOI:https://doi.org/10.1016/j.jdin.2022.09.006

      Background

      Few data exist on differences in treatment effectiveness and safety in atopic dermatitis patients of different skin types.

      Objective

      To investigate treatment outcomes of dupilumab, methotrexate, and ciclosporin, and morphological phenotypes in atopic dermatitis patients, stratified by Fitzpatrick skin type.

      Methods

      In an observational prospective cohort study, pooling data from the Dutch TREAT (TREatment of ATopic eczema) NL (treatregister.nl) and UK-Irish A-STAR (Atopic eczema Systemic TherApy Register; astar-register.org) registries, data on morphological phenotypes and treatment outcomes were investigated.

      Results

      A total of 235 patients were included (light skin types [LST]: Fitzpatrick skin type 1-3, n = 156 [Ethnicity, White: 94.2%]; dark skin types [DST]: skin type 4-6, n = 68 [Black African/Afro-Caribbean: 25%, South-Asian: 26.5%, and Hispanics: 0%]). DST were younger (19.5 vs 29.0 years; P < .001), more often had follicular eczema (22.1% vs 2.6%; P < .001), higher baseline Eczema Area and Severity Index (EASI) scores (20.1 vs 14.9; P = .009), less allergic contact dermatitis (30.9% vs 47.4%; P = .03), and less previous phototherapy use (39.7% vs 59.0%; P = .008). When comparing DST and LST corrected for covariates including baseline EASI, DST showed greater mean EASI reduction between baseline and 6 months with only dupilumab (16.7 vs 9.7; adjusted P = .032). No differences were found for adverse events for any treatments (P > .05).

      Limitations

      Unblinded, non-randomized.

      Conclusion

      Atopic dermatitis differs in several characteristics between LST and DST. Skin type may influence treatment effectiveness of dupilumab.

      Key words

      Abbreviations used:

      AD (atopic dermatitis), AE (adverse event), DLQI (Dermatology Life Quality Index), DST (Dark Skin Type(s)), EASI (Eczema Area and Severity Index), IQR (interquartile range), LST (Light Skin Type(s)), NRS (Numerical Rating Scale), POEM (Patient-Oriented Eczema Measure), SD (Standard Deviation)
      • There is a lack of knowledge about differences in treatment effectiveness and safety in atopic dermatitis patients of different skin types.
      • Patients with atopic dermatitis differ in several characteristics between light and dark skin types, and skin type may influence treatment effectiveness of dupilumab in daily practice.

      Introduction

      Atopic dermatitis (AD), also known as atopic eczema, is a chronic pruritic inflammatory skin disorder which is among the most common dermatological conditions. AD is more prevalent in black and mixed race populations, and differences seem to exist between AD in darkly pigmented and light skin, including variations in genetics and immunology.
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      Eczema prevalence in the United States: data from the 2003 National Survey of Children's Health.
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      London-born black Caribbean children are at increased risk of atopic dermatitis.
      • Brunner P.M.
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      Racial differences in atopic dermatitis.
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      Atopic dermatitis in diverse racial and ethnic groups-variations in epidemiology, genetics, clinical presentation and treatment.
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      Endophenotypic variations of atopic dermatitis by age, race, and ethnicity.
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      Global differences in atopic dermatitis.
      Dark skin has been shown to have inherent structural properties that may trigger pruritus, such as higher transepidermal water loss and an increased size of mast cells.
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      Racial (ethnic) differences in skin properties: the objective data.
      Higher natural moisturizing factor levels and down-regulated keratinocyte differentiation have been shown in dark skin compared to light skin, suggesting differences in pathophysiological mechanisms.
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      A minimally invasive tool to study immune response and skin barrier in children with atopic dermatitis.
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      Reconstructed skin models revealed unexpected differences in epidermal African and Caucasian skin.
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      Variation in the activities of late stage filaggrin processing enzymes, calpain-1 and bleomycin hydrolase, together with pyrrolidone carboxylic acid levels, corneocyte phenotypes and plasmin activities in non-sun-exposed and sun-exposed facial stratum corneum of different ethnicities.
      This may imply a potential biological basis for differences in treatment response between light and dark skin. Clinically, AD can also present differently in a dark skin.
      • Kaufman B.P.
      • Guttman-Yassky E.
      • Alexis A.F.
      Atopic dermatitis in diverse racial and ethnic groups-variations in epidemiology, genetics, clinical presentation and treatment.
      • Nomura T.
      • Wu J.
      • Kabashima K.
      • Guttman-Yassky E.
      Endophenotypic variations of atopic dermatitis by age, race, and ethnicity.
      • Suaini N.H.A.
      • Tan C.P.T.
      • Loo E.X.L.
      • Tham E.H.
      Global differences in atopic dermatitis.
      Follicular eczema is an example of a morphological phenotype that is more frequently seen in African-American, Hispanic, and Asian patients.
      • Silverberg N.B.
      Typical and atypical clinical appearance of atopic dermatitis.
      A systematic review confirmed differences in morphological AD characteristics by study region.
      • Yew Y.W.
      • Thyssen J.P.
      • Silverberg J.I.
      A systematic review and meta-analysis of the regional and age-related differences in atopic dermatitis clinical characteristics.
      Nevertheless, studies investigating the effectiveness and safety of systemic therapy in AD patients of different skin types are lacking, and only a few studies focus on this topic.
      • Alexis A.F.
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      • et al.
      Efficacy of dupilumab in different racial subgroups of adults with moderate-to-severe atopic dermatitis in three randomized, placebo-controlled Phase 3 trials.
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      Effectiveness of dupilumab for the treatment of generalized prurigo nodularis phenotype of adult atopic dermatitis.
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      • Marzano A.V.
      • Ferrucci S.
      Efficacy of dupilumab on different phenotypes of atopic dermatitis: one-year experience of 221 patients.
      • Patruno C.
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      • Hansel K.
      • et al.
      Effectiveness of dupilumab for the treatment of nummular eczema phenotype of atopic dermatitis in adults.
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      • Qureshi A.A.
      Tapering cyclosporine after long-term treatment of atopic dermatitis.
      • Waxweiler W.T.
      • Agans R.
      • Morrell D.S.
      Systemic treatment of pediatric atopic dermatitis with azathioprine and mycophenolate mofetil.
      • Bhattacharya T.
      • Silverberg J.I.
      Efficacy of systemic treatments for atopic dermatitis in racial and ethnic minorities in the United States.
      Studies investigating treatments in AD patients are predominantly conducted on white patients.
      • Alexis A.F.
      • Rendon M.
      • Silverberg J.I.
      • et al.
      Efficacy of dupilumab in different racial subgroups of adults with moderate-to-severe atopic dermatitis in three randomized, placebo-controlled Phase 3 trials.
      In this study we aimed to investigate the effectiveness and safety of dupilumab, ciclosporin, and methotrexate in AD patients with different skin types. In addition, we wanted to investigate the association between morphological phenotypes and skin types. We hypothesized that AD patients with dark skin types (DST) have different treatment outcomes and morphological phenotypes compared to patients with light skin types (LST). We specifically focused on skin type instead of ethnicity or race, as skin type could be determined more objectively. Ethnicity or race are complex terminologies that, in addition to skin color may also cover country of origin, physical features, cultural traditions, and the concept of mixed ethnicity. We hypothesized skin type to be a proxy for genetic differences between patients, underlying potential differences in pathophysiology, and subsequently, morphology and treatment responses.

      Methods

      Study design

      We conducted a registry-embedded observational prospective cohort study, using real-world data from the Dutch TREAT (TREatment of ATopic eczema) NL (treatregister.nl) and UK-Irish A-STAR (Atopic eczema Systemic TherApy Register; astar-register.org) registries.

      Setting

      Patients were included at 2 centers in the Netherlands (November 2017 to June 2020), and 13 centers in the United Kingdom (October 2018 to April 2021). Study visits were at baseline, 4 weeks, and then approximately every 3 months, alongside routine clinic appointments.

      Participants

      Eligible patients were all children and adults with AD according to the U.K. working party’s diagnostic criteria, starting treatment with dupilumab, ciclosporin, and/or methotrexate in the context of routine clinical care. All dupilumab patients met the national criteria for dupilumab treatment, which stipulate prior treatment of at least 4 months with 1 or more conventional systemic therapies. Patients were allowed to use other systemic immunomodulating treatments and topical treatments concomitantly. The study size resulted from the inclusion of eligible patients in the abovementioned timeframes.

      Variables

      Data collection was based on the TREAT Registry Taskforce core dataset.
      • Gerbens L.A.A.
      • Apfelbacher C.J.
      • Irvine A.D.
      • et al.
      TREatment of ATopic eczema (TREAT) registry Taskforce: an international Delphi exercise to identify a core set of domains and domain items for national atopic eczema photo- and systemic therapy registries.
      ,
      • Vermeulen F.M.
      • Gerbens L.A.A.
      • Bosma A.L.
      • et al.
      TREatment of ATopic eczema (TREAT) registry Taskforce: consensus on how and when to measure the core dataset for atopic eczema treatment research registries.
      Data on Fitzpatrick skin type and morphological phenotype based on standardized proforma (eg, [non-]flexural eczema, palmar hyperlinearity, pompholyx, discoid eczema, nodular prurigo, follicular eczema, keratosis pilaris, erythroderma, and ichthyosis vulgaris; definitions included in Supplementary Material 1, available via Mendeley at https://doi.org/10.17632/s9y7fh7nbx.1) were collected. LST were defined as Fitzpatrick skin types 1 to 3 and DST as Fitzpatrick skin types 4 to 6. Effectiveness was analyzed using the Eczema Area and Severity Index (EASI),
      • Hanifin J.M.
      • Thurston M.
      • Omoto M.
      • Cherill R.
      • Tofte S.J.
      • Graeber M.
      The eczema area and severity index (EASI): assessment of reliability in atopic dermatitis. EASI Evaluator Group.
      Numerical Rating Scale (NRS) peak pruritus past 24 hours,
      • Yosipovitch G.
      • Reaney M.
      • Mastey V.
      • et al.
      Peak pruritus numerical rating scale: psychometric validation and responder definition for assessing itch in moderate-to-severe atopic dermatitis.
      Patient-Oriented Eczema Measure,
      • Charman C.R.
      • Venn A.J.
      • Williams H.C.
      The patient-oriented eczema measure: development and initial validation of a new tool for measuring atopic eczema severity from the patients' perspective.
      Dermatology Life Quality Index (DLQI), and Children's DLQI or Infants' Dermatitis Quality of Life Index.
      • Finlay A.Y.
      • Khan G.K.
      Dermatology Life Quality Index (DLQI)–a simple practical measure for routine clinical use.
      Safety was assessed through the reporting of adverse events at each visit (AEs, definitions are included in Supplementary Table IA, available via Mendeley at https://doi.org/10.17632/gfygbsw82y.1).

      Definition of treatment endpoint

      In previous studies, comparison of the effectiveness of methotrexate and ciclosporin at the same predefined treatment endpoint was considered a disadvantage due to differences in speed of action.
      • Goujon C.
      • Viguier M.
      • Staumont-Sallé D.
      • et al.
      Methotrexate versus cyclosporine in adults with moderate-to-severe atopic dermatitis: a Phase III randomized noninferiority trial.
      ,
      • Tsakok T.
      • Flohr C.
      Methotrexate vs. ciclosporin in the treatment of severe atopic dermatitis in children: a critical appraisal.
      Therefore, we defined appropriate treatment endpoints per treatment. Methotrexate has a relatively slow onset of action, and we, therefore, chose 6 months as treatment endpoint. To allow direct comparisons, we chose the same endpoint for dupilumab, even though the drug has a faster onset of action. In our dataset, ciclosporin was often terminated before 6 months of treatment, for instance because of side effects or ineffectiveness. As ciclosporin has a fast onset of action, we therefore analyzed the data at 3 months instead.

      Statistical analyses

      Patient characteristics, safety, and treatment discontinuation data were summarized using descriptive statistics and assessed during the entire follow-up period of this study. For univariate comparisons, Mann–Whitney tests and chi-squared tests were used as appropriate.
      Baseline scores were compared to treatment endpoint scores using paired t-tests. To investigate differences between treatment groups in delta scores and the course of scores over time, we used linear mixed-effects models with an interaction between time and treatment. We modeled the change in scores over time, using natural cubic splines with the optimal degrees of freedom based on the minimal Bayesian Information Criterion. To test if there is a difference between skin types in scores during treatment, an ANOVA (Analysis of variance) test was conducted to assess the difference between the model with skin type and a model where this interaction term was removed. We included a random intercept for each patient and, in addition to skin type, included variables for which we found a significant difference between DST and LST in the models as potential confounders (including age, baseline severity score, follicular eczema, allergic contact dermatitis, and previous phototherapy use). Missing values for the covariates were included as unknown.
      Effects were considered statistically significant if P < .05. Analyses were performed using SPSS 24.0 (IBM) and R version 3.4.1 (Foundation for Statistical Computing).
      We have included a RECORD/STROBE checklist as Supplementary Material 2, available via Mendeley at https://doi.org/10.17632/6zrg834255.1.

      Results

      Baseline patient characteristics

      In total, 235 patients were included (Table I). The majority of patients were male (59.1%), 67.7% were white, 156 patients (66.4%) had LST, and 68 patients (28.9%) had DST. Skin types of 11 patients were missing, and were excluded from analyses comparing skin types.
      Table IBaseline patient characteristics
      Study cohort (n = 235)aLight skin type (n = 156, 66.4%)Dark skin type (n = 68, 28.9%)P value
      Sex—no. (%): Male/Female139 (59.1)/96 (40.9)93 (59.6)/63 (40.4)40 (58.8)/28 (41.2).91
      Age, median (IQR)—years26.0 (14.0-45.0)29.0 (17.3-48.0)19.5 (13.0-32.3)<.001
      Age of onset AD, median (IQR)—years10 (0-3)0 (0-3)0 (0-4).92
      EASI, median (IQR)217.0 (9.175-27.325)14.9 (7.6-25.8)20.1 (10.8-30.6).009
      NRS pruritus past 24h, median (IQR)37 (6-8)7 (6-8)7 (4-9).38
      POEM, median (IQR)421 (16-24)21 (16-24)20 (13-24).67
      DLQI, mean ± SD514.1 ± 7.013.8 ± 6.914.8 ± 7.2.32
      Patients per treatment group—no. (%)
       Dupilumab168 (71.5)121 (77.6)42 (61.8)
       Methotrexate65 (27.7)37 (23.7)22 (32.4)
       Ciclosporin26 (11.1)19 (12.2)7 (10.3)
      BMI—median (IQR)b24.7 (22.6-27.8)24.7 (22.6-27.3)24.8 (21.8-30.1).63
      Educational statusc,6.28
       ISCED 0-2: Early childhood, primary and lower secondary education57 (24.3)38 (24.4)14 (20.6)
       ISCED 3-5: Upper secondary to short cycle tertiary education103 (43.8)73 (46.8)27 (39.7)
       ISCED 6-8: Bachelor’s, Master’s, Doctoral or equivalent level64 (27.2)40 (25.6)21 (30.8)
      Ethnicity—no. (%)7<.001
       White (Europe, Russia, Middle East, North Africa, USA, Canada, Australia)159 (67.7)147 (94.2)4 (5.9)
       Black African, Afro-Caribbean18 (7.7)0 (0)17 (25.0)
       Asian-Chinese5 (2.1)0 (0)5 (7.4)
       South-Asian (India, Pakistan, Sri Lanka, Nepal, Bhutan, Bangladesh)23 (9.8)4 (2.6)18 (26.5)
       Asian-other (Korea, China north of Huai River)8 (3.4)0 (0)7 (10.3)
       Hispanic or Latino1 (0.4)1 (0.6)0 (0)
       Mixed19 (8.1)4 (2.6)d15 (22.0)e
       Other1 (0.4)0 (0)1 (1.5)
      Fitzpatrick skin type—no. (%)6<.001
       I/II17 (7.2)/87 (37.0)17 (10.9)/87 (55.8)0 (0)/0 (0)
       III/IV52 (22.1)/29 (12.3)52 (33.3)/0 (0)0 (0)/29 (42.6)
       V/VI29 (12.3)/10 (4.3)0 (0)/0 (0)29 (42.6)/10 (14.7)
      Fitzpatrick skin type—median (IQR)3 (2-4)2 (2-3)5 (4-5)<.001
      Morphological phenotypes—no. (%)
       Flexural eczema8169 (71.9)113 (72.4)49 (72.0).96
       Non-flexural eczema8173 (73.6)116 (74.4)51 (75.0).31
       Palmar hyperlinearity964 (27.2)45 (28.8)18 (26.5).29
       Pompholyx1013 (5.5)10 (6.4)3 (4.4).84
       Discoïd (syn. nummular) eczema117 (3.0)4 (2.6)3 (4.4).41
       Prurigo nodularis1214 (6.0)6 (3.8)7 (10.3).13
       Follicular eczema1319 (8.0)4 (2.6)15 (22.1)<.001
       Keratosis pilaris1412 (5.1)5 (3.2)7 (10.3).09
       Erythroderma1514 (6.0)9 (5.8)3 (4.4).58
       Ichthyosis vulgaris1611 (4.7)6 (3.8)5 (7.4).34
       Infraorbital Dennie-Morgan skin folds1713 (9.8)10 (10.5)3 (7.9).53
       Infra-auricular fissure(s)1814 (10.5)11 (11.6)3 (7.9).29
       Skin infection1917 (7.2)11 (7.1)4 (5.9).95
      Allergic co-morbidities—no. (%)
       Asthmaf,7128 (54.5)87 (55.8)41 (60.3).68
       Allergic rhinoconjunctivitisf,7129 (54.9)92 (59.0)37 (54.4).69
       Atopic eye diseasef,2018 (7.7)13 (8.3)5 (7.4).53
       Eosinophilic esophagitisf,202 (0.8)1 (0.6)1 (1.5).86
       Allergic contact dermatitisg97 (41.3)74 (47.4)21 (30.9).026
       Food allergy118 (50.2)h/93 (39.6)i76 (48.7)h/63 (40.4)i42 (61.8)h/30 (44.1)i.18/.14
      Family history of AD and allergic diseasesj,21- no. (%)140 (59.6)98 (62.8)42 (61.8).84
      Previous use of systemic therapies for AD—no. (%)5190 (80.9)134 (85.9)50 (73.5).052
       Ciclosporin127 (54.0)89 (57.1)35 (51.5).57
       Azathioprine38 (16.2)29 (18.6)6 (8.8).14
       Methotrexate96 (40.9)64 (41.0)28 (41.2).80
       Mycophenolic acid/mycophenolate mofetil30 (12.8)19 (12.2)10 (4.7).71
       Systemic corticosteroids99 (42.1)76 (48.7)23 (33.8).09
       Dupilumabk2 (0.9)0 (0)1 (1.5).26
       Other medicationl2 (0.9)2 (1.3)0 (0).52
       Investigational medication14 (6.0)11 (7.1)3 (4.4).60
      Previous use of phototherapy—no. (%)122 (51.9)92 (59.0)27 (39.7).008
      Concomitant immunomodulating therapy—no. (%)37 (15.7)24 (15.4)13 (19.1).49
       Systemic corticosteroidsm/Othern30 (12.8)/7 (3.0)20 (12.8)/4 (2.6)10 (14.7)/3 (4.4).70/.47
      AD, Atopic dermatitis; BMI, body mass index; DLQI, Dermatology Life Quality Index; EASI, Eczema Area Severity Index; IQR, interquartile range; ISCED, International Standard Classification of Education; No., number; NRS, Numerical Rating Scale; POEM, Patient-Oriented Eczema Measure; SD, standard deviation.
      Significant P values displayed in bold. Missing data: 1n = 15, 2n = 5, 3n = 33, 4n = 14, 5n = 16, 6n = 11, 7n = 1, 8n = 51-57, 9n = 25, 10n = 59, 11n = 62,12n = 59, 13n = 64, 14n = 22, 15n = 20, 16n = 58, 17n = 53, analysis of NL data, 18n = 56, analysis of NL data, 19n = 16, 20n = 2, 21n = 10.
      aAD based on the U.K. Working Party’s Diagnostic Criteria: n = 133 (NL), n = 102 (UK), bExcluding patients <18 years, c<18 years: ISCED of parents, fphysician-diagnosed, gpositive patch test; never tested (n = 24), tested negative (n = 15), unknown (n = 12) or missing (n = 87), hpatient-reported, ipatient-reported food allergy was confirmed by a physician diagnosis; patient-reported food allergy (n = 131), jfirst degree family member with at least one of the following allergic diseases: AD, asthma, allergic rhinoconjunctivitis, atopic eye disease or other, kopen-label extension study, ldimethyl fumarate (n = 1), rituximab (n = 1), mpredniso(lo)ne, nciclosporin (n = 3), long-term clarithromycin (n = 1), methotrexate (n = 1), mycophenolate mofetil (n = 1), ciclosporin and dupilumab concomitantly (n = 1).
      DSTs were on average younger when entering the registries compared to LSTs (median age 19.5 vs 29.0 years; P < .001). Higher baseline EASI scores were recorded in DST (20.1 vs 14.9; P = .009). Allergic contact dermatitis and previous use of phototherapy were more prevalent in LST (47.4% vs 30.9%; P = .026 and 59.0% vs 39.7%; P = .008, respectively). We also found a correlation between ethnicity and skin type (P < .001).

      Effectiveness according to skin type

      In total, 168 patients were treated with dupilumab (LST: n = 121 [72.0%], DST: n = 42 [25.0%]), 65 patients with methotrexate (LST: n = 37 [56.9%], DST: n = 22 [33.8%]), and 26 patients with ciclosporin (LST: n = 19 [73.1%], DST: n = 7 [26.9%]).
      For dupilumab and methotrexate, an ANOVA test revealed a significant P value for skin type as interaction term for EASI (P < .001 and P = .04, respectively), indicating that the course of EASI over time differs between DST and LST. Results of the linear mixed-effects models displaying the course of the scores over time according to skin type are shown for EASI only (Fig 1). Both skin type groups show improvement over time. Other scores are shown in Supplementary Figs 1-3, available via Mendeley at https://doi.org/10.17632/4khfjgm2n7.1, https://doi.org/10.17632/hscd3ysgvd.1, https://doi.org/10.17632/dcxtdbg86k.1.
      Figure thumbnail gr1
      Fig 1Difference in Eczema Area and Severity Index (EASI) from baseline (delta EASI) over time for each treatment group. Estimated mean differences in EASI scores from baseline (including 95% confidence interval) for our linear mixed-effects models with continuous values for time, and time displayed in weeks and corrected for age, baseline EASI scores, follicular eczema, allergic contact dermatitis, and previous use of phototherapy, in patients with atopic dermatitis. Higher delta scores indicate greater improvement of disease activity and/or burden. The median follow-up duration for the outcome measurements varied from 38 to 46 weeks (IQR: 14-74 weeks) for dupilumab, from 17 to 19 weeks (IQR: 1-47 weeks) for methotrexate, and from 15 to 17 weeks (IQR: 0-32 weeks) for ciclosporin. Dupilumab: n = 168 at baseline (light skin types [LST]: n = 121; dark skin types [DST]: n = 42), n = 125 at 6 months (LST: n = 90; DST: n = 35). Methotrexate: n = 65 at baseline (LST: n = 37; DST: n = 22), n = 25 at 6 months (LST: n = 15; DST: n = 10). Ciclosporin: n = 26 at baseline (LST: n = 19; DST: n = 7), n = 15 at 3 months (LST: n = 11; DST: n = 4). EASI, Eczema Area and Severity Index.
      To get insight into how DST and LST are different, we compared baseline scores to treatment endpoint scores (Table II). Significant improvement over time was observed for all outcome measures in both skin type groups when treated with dupilumab (eg ΔEASI for DST: 16.7; P < .001 and ΔEASI for LST: 9.7; P < .001). LST also showed significant improvements in all outcome measures for methotrexate (eg ΔEASI: 11.0; P = .019) and ciclosporin (eg ΔEASI: 13.1; P < .001). In DSTs treated with methotrexate and ciclosporin, EASI showed significant improvements for methotrexate (Δ5.7; P = .048) and borderline significant improvements were found for DLQI (Δ4.9; P = .051) for methotrexate, and EASI for ciclosporin (Δ12.9; P = .054). Both groups reached the minimal clinically important difference (MCID)
      • Schram M.E.
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      EASI, (objective) SCORAD and POEM for atopic eczema: responsiveness and minimal clinically important difference.
      • Basra M.K.
      • Salek M.S.
      • Camilleri L.
      • Sturkey R.
      • Finlay A.Y.
      Determining the minimal clinically important difference and responsiveness of the Dermatology Life Quality Index (DLQI): further data.
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      • et al.
      Itch assessment with visual analogue scale and numerical rating scale: determination of minimal clinically important difference in chronic itch.
      for all outcomes with dupilumab. For methotrexate, patients with DST did not reach the MCID for EASI, Patient-Oriented Eczema Measure, and NRS pruritus. For ciclosporin, DST did not reach the MCID for NRS pruritus. When comparing DST and LST, DST showed a significantly greater improvement in EASI when treated with dupilumab, even after adjustment for age, baseline severity, follicular eczema, allergic contact dermatitis, and previous phototherapy use (Δ16.7 vs Δ9.7; P = .032; Table II). We found no difference in EASI improvement between DST and LST for methotrexate and ciclosporin, as well as no difference in any of the other scores for all treatments.
      Table IIEffectiveness of dupilumab, methotrexate, and ciclosporin according to skin type
      Baseline scoreFollow-up scoreP value
      Paired t-tests for comparison between baseline and follow-up. Number of patients per treatment group: dupilumab: dark: n = 35, light: n = 90; methotrexate: dark: n = 10, light: n = 15; ciclosporin: dark: n = 4, light: n = 11.
      Δ score
      Dupilumab
       EASI
      Mean score dark skin type (SD)24.2 (13.0)7.5 (7.1)<.00116.7 (13.0)
      Mean score light skin type (SD)18.0 (13.0)8.3 (7.5)<.0019.7 (11.0)
      P-value Δ difference
      The P-value Δ difference between the Δ-scores for light and dark skin type was assessed according to a multivariable linear model, corrected for age, baseline score, follicular eczema, allergic contact dermatitis and previous use of phototherapy.
      .032
       POEM
      Mean score dark skin type (SD)20.2 (6.0)10.1 (6.0)<.00110.1 (6.4)
      Mean score light skin type (SD)19.9 (5.7)10.5 (6.8)<.0019.4 (6.8)
      P-value Δ difference
      The P-value Δ difference between the Δ-scores for light and dark skin type was assessed according to a multivariable linear model, corrected for age, baseline score, follicular eczema, allergic contact dermatitis and previous use of phototherapy.
      .33
       DLQI
      Mean score dark skin type (SD)15.6 (6.8)6.2 (7.6)<.0019.4 (8.5)
      Mean score light skin type (SD)14.1 (6.7)5.7 (5.7)<.0018.4 (7.3)
      P-value Δ difference
      The P-value Δ difference between the Δ-scores for light and dark skin type was assessed according to a multivariable linear model, corrected for age, baseline score, follicular eczema, allergic contact dermatitis and previous use of phototherapy.
      .54
       NRS
      Mean score dark skin type (SD)6.9 (1.8)3.5 (2.2)<.0013.4 (2.3)
      Mean score light skin type (SD)7.2 (2.3)3.4 (2.7)<.0013.7 (3.0)
      P-value Δ difference
      The P-value Δ difference between the Δ-scores for light and dark skin type was assessed according to a multivariable linear model, corrected for age, baseline score, follicular eczema, allergic contact dermatitis and previous use of phototherapy.
      .99
      Methotrexate
       EASI
      Mean score dark skin type (SD)12.9 (9.2)7.2 (3.9).0485.7 (7.4)
      Mean score light skin type (SD)19.0 (13.2)7.9 (5.8).01911.0 (14.7)
      P-value Δ difference
      The P-value Δ difference between the Δ-scores for light and dark skin type was assessed according to a multivariable linear model, corrected for age, baseline score, follicular eczema, allergic contact dermatitis and previous use of phototherapy.
      .52
       POEM
      Mean score dark skin type (SD)13.8 (9.5)10.5 (7.8).323.2 (8.5)
      Mean score light skin type (SD)18.5 (9.6)10.9 (6.8).0077.5 (8.4)
      P-value Δ difference
      The P-value Δ difference between the Δ-scores for light and dark skin type was assessed according to a multivariable linear model, corrected for age, baseline score, follicular eczema, allergic contact dermatitis and previous use of phototherapy.
      .19
       DLQI
      Mean score dark skin type (SD)9.9 (6.9)5.0 (3.5).051
      Borderline significant.
      4.9 (5.9)
      Mean score light skin type (SD)12.6 (8.3)7.0 (7.5).0115.6 (6.0)
      P-value Δ difference
      The P-value Δ difference between the Δ-scores for light and dark skin type was assessed according to a multivariable linear model, corrected for age, baseline score, follicular eczema, allergic contact dermatitis and previous use of phototherapy.
      .26
       NRS
      Mean score dark skin type (SD)5.2 (3.1)3.8 (2.3).171.3 (2.1)
      Mean score light skin type (SD)5.9 (2.9)3.2 (2.2).0372.7 (3.2)
      P-value Δ difference
      The P-value Δ difference between the Δ-scores for light and dark skin type was assessed according to a multivariable linear model, corrected for age, baseline score, follicular eczema, allergic contact dermatitis and previous use of phototherapy.
      .74
      Ciclosporin
       EASI
      Mean score dark skin type (SD)23.2 (14.7)10.3 (14.4).054
      Borderline significant.
      12.9 (8.3)
      Mean score light skin type (SD)21.3 (8.5)8.2 (11.4)<.00113.1 (6.9)
      P-value Δ difference
      The P-value Δ difference between the Δ-scores for light and dark skin type was assessed according to a multivariable linear model, corrected for age, baseline score, follicular eczema, allergic contact dermatitis and previous use of phototherapy.
      .98
       POEM
      Mean score dark skin type (SD)19.8 (9.3)13.5 (8.4).296.2 (9.7)
      Mean score light skin type (SD)19.6 (6.4)8.0 (9.3).00811.6 (9.9)
      P-value Δ difference
      The P-value Δ difference between the Δ-scores for light and dark skin type was assessed according to a multivariable linear model, corrected for age, baseline score, follicular eczema, allergic contact dermatitis and previous use of phototherapy.
      .39
       DLQI
      Mean score dark skin type (SD)16.2 (9.0)6.8 (7.3).129.5 (8.7)
      Mean score light skin type (SD)13.8 (5.7)3.1 (2.4)<.00110.7 (5.9)
      P-value Δ difference
      The P-value Δ difference between the Δ-scores for light and dark skin type was assessed according to a multivariable linear model, corrected for age, baseline score, follicular eczema, allergic contact dermatitis and previous use of phototherapy.
      .36
       NRS
      Mean score dark skin type (SD)7.2 (2.2)5.0 (2.9).252.2 (3.2)
      Mean score light skin type (SD)7.1 (2.2)2.4 (2.5).0054.7 (3.7)
      P-value Δ difference
      The P-value Δ difference between the Δ-scores for light and dark skin type was assessed according to a multivariable linear model, corrected for age, baseline score, follicular eczema, allergic contact dermatitis and previous use of phototherapy.
      .63
      Mean scores (SD) for dark and light skin type at baseline and follow-up (6 months dupilumab, 6 months methotrexate, 3 months ciclosporin), and the corresponding differences for each skin type. Δ-score: reduction in score between baseline and follow-up.
      Significant P values displayed in bold.
      The minimal clinically important difference for improvement is a decrease of 6.6 points for EASI, 3.4 points for POEM, 3.3 points for DLQI, and 2.7 points for NRS pruritus.
      DLQI, Dermatology Life Quality Index (0-30); EASI, Eczema Area and Severity Index (0-72); NRS, Numerical Rating Scale (0-10); POEM, Patient-Oriented Eczema Measure (0-28).
      Borderline significant.
      Paired t-tests for comparison between baseline and follow-up. Number of patients per treatment group: dupilumab: dark: n = 35, light: n = 90; methotrexate: dark: n = 10, light: n = 15; ciclosporin: dark: n = 4, light: n = 11.
      The P-value Δ difference between the Δ-scores for light and dark skin type was assessed according to a multivariable linear model, corrected for age, baseline score, follicular eczema, allergic contact dermatitis and previous use of phototherapy.

      Concomitant therapy during follow-up

      In total, 31 (18%), 13 (20%), and 7 (27%) patients used conventional systemic therapy concomitantly with dupilumab, methotrexate, and ciclosporin, respectively (Supplementary Table IIA-C, available via Mendeley at https://doi.org/10.17632/9v46888y3v.1). No differences were found for usage of concomitant systemic therapy or mean usage duration between DST and LST (P > .05).

      Safety

      In total, 79 potentially related adverse events were reported during the study (Supplementary Table IA-C). No serious adverse events were reported. In none of the treatment groups, differences were found in the total number of adverse events when comparing DST and LST (P > .05).

      Treatment discontinuation

      A significant difference in treatment discontinuation was found between treatments, with most discontinuation for ciclosporin (n = 12/26, 46.2%), followed by methotrexate (n = 20/65, 30.8%), and dupilumab (n = 23/168, 13.7%) (P < .001). The most frequent reasons for discontinuation were side-effects and/or treatment ineffectiveness (Supplementary Table III, available via Mendeley at https://doi.org/10.17632/kfz4sb8sbt.1). However, no differences in treatment discontinuation were found between DST and LST (P > .05).

      Differences in morphological phenotypes

      We found a higher prevalence of follicular eczema in DST (22.1% vs 2.6%; P < .001) (Table I). No differences were found between skin types for the other morphological features ([non-]flexural eczema, palmar hyperlinearity, pompholyx, discoid eczema, nodular prurigo, keratosis pilaris, erythroderma, ichthyosis vulgaris, infraorbital Dennie–Morgan skin folds, and infra-auricular fissure[s]). No analyses could be performed to investigate, if the morphological phenotypes respond differently to treatment due to low numbers.

      Discussion

      In this study we investigated treatment outcomes and morphological phenotypes in AD patients with DST versus LST receiving treatment with dupilumab, methotrexate, and ciclosporin in a daily practice setting. Patients with DST had significantly more severe disease at baseline, indicated by higher EASI. We found that EASI scores improved in both DST and LST when treated with dupilumab, methotrexate, and ciclosporin, although this change did not reach statistical significance in DST ciclosporin patients, probably related to the small sample size. When comparing treatment effectiveness between DST and LST, DST patients showed a significantly greater EASI improvement in comparison to LST when treated with dupilumab after correction for baseline differences, but not with methotrexate or ciclosporin. No differences were found between DST and LST for total number of adverse events. Taken together, skin type may potentially influence treatment effectiveness of dupilumab, but does not seem to affect safety. Concerning morphological phenotypes, follicular eczema was significantly more common in DST.
      DST patients had significantly higher baseline EASI scores, indicating more severe disease at the time of inclusion. DSTs were also significantly younger. Higher disease severity in DST has been reported previously,
      • Shaw T.E.
      • Currie G.P.
      • Koudelka C.W.
      • Simpson E.L.
      Eczema prevalence in the United States: data from the 2003 National Survey of Children's Health.
      • Williams H.C.
      • Pembroke A.C.
      • Forsdyke H.
      • Boodoo G.
      • Hay R.J.
      • Burney P.G.
      London-born black Caribbean children are at increased risk of atopic dermatitis.
      • Brunner P.M.
      • Guttman-Yassky E.
      Racial differences in atopic dermatitis.
      • Kaufman B.P.
      • Guttman-Yassky E.
      • Alexis A.F.
      Atopic dermatitis in diverse racial and ethnic groups-variations in epidemiology, genetics, clinical presentation and treatment.
      and a retrospective study showed that children with treatment resistant AD more often had DST.
      • Bosma A.L.
      • Ouwerkerk W.
      • Middelkamp-Hup M.A.
      Children with atopic eczema experiencing increased disease severity in the pollen season more often have hay fever at a young age and a dark skin type.
      Patients with skin type IV were also found to have higher scores of EASI, DLQI, and Investigator Global Assessment, compared to patients with Fitzpatrick skin type II.
      • Bosma A.L.
      • de Wijs L.E.M.
      • Hof M.H.
      • et al.
      Long-term effectiveness and safety of treatment with dupilumab in patients with atopic dermatitis: results of the TREAT NL (TREatment of ATopic eczema, The Netherlands) registry.
      Nonetheless, our registries contain more patients with LST than DST. This may result from the geographical location of the including centers, or it may reflect a potential disparity in receiving systemic therapies amongst the subgroups. Other studies showed racial and ethnic disparities in receiving therapies for AD and other diseases.
      • Bell M.A.
      • Whang K.A.
      • Thomas J.
      • Aguh C.
      • Kwatra S.G.
      Racial and ethnic disparities in access to emerging and frontline therapies in common dermatological conditions: a cross-sectional study.
      ,
      • Alexander T.
      • Maxim E.
      • Cardwell L.A.
      • Chawla A.
      • Feldman S.R.
      Prescriptions for atopic dermatitis: oral corticosteroids remain commonplace.
      Black psoriasis patients are reported to be less likely to receive biologics than white patients due to potential financial and racial barriers in the United States.
      • Takeshita J.
      • Gelfand J.M.
      • Li P.
      • et al.
      Psoriasis in the US medicare population: prevalence, treatment, and factors associated with biologic use.
      More research on disparities in receiving systemic AD therapies and potential causal factors of differences in severity amongst subgroups would be of interest.
      • de Lusignan S.
      • Alexander H.
      • Broderick C.
      • et al.
      Epidemiology and management of atopic dermatitis in England: an observational cohort study protocol.
      • de Lusignan S.
      • Alexander H.
      • Broderick C.
      • et al.
      Patterns and trends in eczema management in UK primary care (2009-2018): a population-based cohort study.
      • de Lusignan S.
      • Alexander H.
      • Broderick C.
      • et al.
      The epidemiology of eczema in children and adults in England: a population-based study using primary care data.
      We found that allergic contact dermatitis was more prevalent in LST versus DST. Dark skin has been shown to be less permeable compared to light skin,
      • Reed J.T.
      • Ghadially R.
      • Elias P.M.
      Skin type, but neither race nor gender, influence epidermal permeability barrier function.
      ,
      • Wedig J.H.
      • Maibach H.I.
      Percutaneous penetration of dipyrithione in man: effect of skin color (race).
      and this could be a possible explanation. Another explanation could be that allergic contact dermatitis is more difficult to diagnose in DST. However, it may also be possible that LST are more commonly investigated for contact allergy, for example because they have better access to health care. The higher numbers of previous phototherapy in LST could be explained by a higher age in this subgroup. No statistically significant differences were found between DST versus LST for other characteristics, such as age of onset, body mass index, educational status, family AD history and allergic diseases, and concomitant therapy use.
      Regarding morphology, we found significantly more follicular eczema in DST. Others have described follicular eczema in Hispanic and Asian populations,
      • Silverberg N.B.
      Typical and atypical clinical appearance of atopic dermatitis.
      ,
      • Kulthanan K.
      • Boochangkool K.
      • Tuchinda P.
      • Chularojanamontri L.
      Clinical features of the extrinsic and intrinsic types of adult-onset atopic dermatitis.
      • Julián-Gónzalez R.E.
      • Orozco-Covarrubias L.
      • Durán-McKinster C.
      • Palacios-Lopez C.
      • Ruiz-Maldonado R.
      • Sáez-de-Ocariz M.
      Less common clinical manifestations of atopic dermatitis: prevalence by age.
      • Dhar S.
      • Kanwar A.J.
      Epidemiology and clinical pattern of atopic dermatitis in a North Indian pediatric population.
      rather than directly comparing populations or focusing on skin type as was done in this study. Follicular eczema is characterized by follicular prominence clinically and follicular spongiosis histopathologically.
      • Silverberg N.B.
      Typical and atypical clinical appearance of atopic dermatitis.
      Remarkably, the investigated morphological characteristics (eg pompholyx, discoid eczema, nodular prurigo, keratosis pilaris, erythroderma, and ichthyosis vulgaris) were only present in a small minority of patients. Due to limited numbers, we were not able to investigate treatment effects within morphological phenotypes.
      In our registries, dupilumab was most frequently prescribed (71%), followed by methotrexate (28%), and ciclosporin (11%). Interestingly, prescription of methotrexate was more common than ciclosporin, despite the latter being an on-label treatment option for adults. For all treatments, side-effects were the main reason for discontinuation of treatment, followed by ineffectiveness.
      Several limitations result from the daily practice setting. Due to the absence of randomization for treatment allocation, differences may arise in treatment groups because of selection bias. Dupilumab treatment requires previous use of conventional systemics. Also, bias may have been induced by the non-blinded observational nature of the study, including for severity assessments, with erythema being particularly difficult to assess in DST. We also had relatively low numbers of DST, especially in the methotrexate and ciclosporin groups. We did not stratify patients based on treatment dosage and included patients on combined systemic therapies. Only severe AEs were registered in the Netherlands as part of the TREAT core dataset.
      • Vermeulen F.M.
      • Gerbens L.A.A.
      • Bosma A.L.
      • et al.
      TREatment of ATopic eczema (TREAT) registry Taskforce: consensus on how and when to measure the core dataset for atopic eczema treatment research registries.
      In summary, we found significant differences between AD patients with DST and LST, such as more severe disease at baseline and more follicular eczema in DST. Importantly, skin type may also influence treatment effectiveness of dupilumab in AD, as DST showed significantly greater EASI improvement than LST. Larger studies are needed to confirm these results, and skin type should therefore be considered a confounder in future AD intervention studies. Moreover, further research investigating whether morphological phenotypes respond differently to treatments is needed.

      Conflicts of interest

      A. L. Bosma, S. J. Brown, P. I. Spuls, C. Flohr, and M. A. Middelkamp-Hup are investigators on the European Union Horizon 2020-funded BIOMAP Consortium (http://www.biomap-imi.eu/). M. R. Ardern-Jones has undertaken consultancy or received sponsorship or his department has received funding from Abbvie, Almirall, Ducentis, Janssen, Leo, Lilly Pfizer, and Sanofi Genzyme. S. J. Brown holds a Wellcome Trust Senior Research Fellowship (220875/Z/20/Z) and has received research funding but no personal payments from Pfizer, Abbvie, Janssen, Sosie-Heptares, and the European Lead Factory. J. R. Ingram receives a stipend as Editor-in-Chief of the British Journal of Dermatology and an authorship honorarium from UpToDate. He is a consultant for Boehringer Ingelheim, ChemoCentryx, Novartis, and UCB Pharma and has served on advisory boards for Insmed, Kymera Therapeutics, and Viela Bio, all in the field of hidradenitis suppurativa (HS). He is co-copyright holder of HiSQOL, Investigator Global Assessment and Patient Global Assessment instruments for HS. His department receives income from copyright of the Dermatology Life Quality Instrument (DLQI) and related instruments. A. D. Irvine received consulting fees from Arena, Amirall, Pfizer, Regenron, Sanofi, Novarti, Abbvie, Benevolent Ai, and Lilly; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Leo, Abbvie, Lilly, and Sanofi; participation on a Data Safety Monitoring Board or Advisory Board for Novartis (paid); leadership or fiduciary role in other board, society, committee, or advocacy group at International Eczema Council (unpaid) and Irish Hospital Consultants Association (unpaid). G. Ogg is funded by the Medical Research Council and NIHR Oxford Biomedical Research Centre and has received research awards or undertaken advisory roles for Sanofi, Leo Pharma, Eli Lilly, UCB, Novartis, Janssen, and BMS. N. J. Reynolds has performed consultancy work/lectures for Almirall UK LTD, Abbvie, LEO Pharma, Lilly UK, and Novartis UK Sanofi Genzyme though Newcastle University. Income to Newcastle University, no personal income (over last 5 years). R. B. Warren has received research grants from AbbVie, Almirall, Amgen, Celgene, Janssen, Lilly, Leo, Medac, Novartis, Pfizer, and UCB and consulting fees from AbbVie, Almirall, Amgen, Arena, Astellas, Avillion, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, DiCE, GSK, Janssen, Lilly, Leo, Medac, Novartis, Pfizer, Sanofi, Sun Pharma, UCB, and UNION. R. T. Woolf is principal or co-investigator in clinical trials—Abbvie, Amgen, Anaptys Bio, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Galderma, Janssen-Cilag, Kymab, Leo Pharma, Pfizer, Sanofi, and UCB; received honoraria from and consultancy work for Abbvie, Eli Lilly, Janssen-Cilag, Leo Pharma, Novartis, Sandoz, Sanofi, and UCB; and received honoraria from NICE (clinical expert). P. I. Spuls has done consultancies in the past for Sanofi 111017 and AbbVie 041217 (unpaid), received a departmental independent research grants for TREAT NL registry from Pharma since December 2019, is involved in performing clinical trials with many pharmaceutical industries that manufacture drugs used for the treatment of, for example, psoriasis and atopic dermatitis, for which financial compensation is paid to the department/hospital and is chief investigator (CI) of the systemic and phototherapy atopic eczema registry (TREAT NL) for adults and children. C. Flohr is Chief Investigator of the UK National Institute for Health Research-funded TREAT (ISRCTN15837754) and SOFTER (Clinicaltrials.gov: NCT03270566) trials as well as the UK-Irish Atopic eczema Systemic Therapy Register (A-STAR; ISRCTN11210918) and a principle investigator in the European Union (EU) Horizon 2020-funded BIOMAP Consortium (http://www.biomap-imi.eu/). He also leads the EU Trans-Foods Consortium. His department has received funding from Sanofi-Genzyme for skin microbiome work. M. A. Middelkamp-Hup has done consultancies for Sanofi, Pfizer, and Leo Pharma and is one of the main investigators of the TREAT NL registry.
      The authors would like to acknowledge Manja Bloem for her support in preparing the data for analysis. NJR is a National Institute for Health and Care Research (NIHR) Senior Investigator and by the NIHR Newcastle Biomedical Research Center. RBW is supported by the Manchester NIHR Biomedical Research Centre .

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