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Learn more: PMC Disclaimer | PMC Copyright Notice Dermatol Ther (Heidelb) . 2026 Feb 22;16(4):2205–2211. doi: 10.1007/s13555-026-01690-5 Search in PMC Search in PubMed View in NLM Catalog Add to search Upadacitinib for Atopic Dermatitis Involving Special and Sensitive Areas: Real-World Multicenter Outcomes in Hand, Head/Neck, and Genital Involvement Francisco Javier Melgosa Ramos Francisco Javier Melgosa Ramos 1 Department of Dermatology, Hospital Universitario Doctor Peset, Av. de Gaspar Aguilar, 90, 46017 Valencia, Spain 2 Department of Dermatology, Hospital Lluís Alcanyís, Xátiva, Valencia Spain Find articles by Francisco Javier Melgosa Ramos 1, 2, ✉ , Santiago Guillén-Climent Santiago Guillén-Climent 3 Department of Dermatology, Hospital Universitario Virgen de los Lirios, Alcoy, Spain Find articles by Santiago Guillén-Climent 3 , Raquel Cavestany Rodriguez Raquel Cavestany Rodriguez 4 Department of Dermatology, Hospital Universitario, 12 de octubre, Madrid, Spain Find articles by Raquel Cavestany Rodriguez 4 , Javier Sabater-Abad Javier Sabater-Abad 5 Department of Dermatology, Hospital de la Ribera, Valencia, Spain Find articles by Javier Sabater-Abad 5 , Antonio Martorell Antonio Martorell 6 Department of Dermatology, Hospital de Manises, Valencia, Spain Find articles by Antonio Martorell 6 , Fátima Tous Romero Fátima Tous Romero 4 Department of Dermatology, Hospital Universitario, 12 de octubre, Madrid, Spain Find articles by Fátima Tous Romero 4 Author information Article notes Copyright and License information 1 Department of Dermatology, Hospital Universitario Doctor Peset, Av. de Gaspar Aguilar, 90, 46017 Valencia, Spain 2 Department of Dermatology, Hospital Lluís Alcanyís, Xátiva, Valencia Spain 3 Department of Dermatology, Hospital Universitario Virgen de los Lirios, Alcoy, Spain 4 Department of Dermatology, Hospital Universitario, 12 de octubre, Madrid, Spain 5 Department of Dermatology, Hospital de la Ribera, Valencia, Spain 6 Department of Dermatology, Hospital de Manises, Valencia, Spain ✉ Corresponding author. Received 2025 Dec 13; Accepted 2026 Feb 6; Collection date 2026 Apr. © The Author(s) 2026, modified publication 2026 Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/ . PMC Copyright notice PMCID: PMC13046934 PMID: 41723774 Abstract Introduction Atopic dermatitis (AD) involving special areas such as the hands, head and neck, and genital region poses important therapeutic challenges owing to distinct barrier fragility, environmental exposure, and mixed Th1/Th2/Th17 activation. These sites often drive treatment escalation despite limited overall body surface involvement. Evidence on the real-world effectiveness of upadacitinib in these anatomical locations remains limited. Methods A retrospective, observational multicenter study was conducted across five Spanish dermatology departments (November 2024 to November 2025). Adults and adolescents with moderate-to-severe AD and involvement of at least one special area treated with upadacitinib (15 or 30 mg) for ≥ 16 weeks were included. Disease severity was assessed using the Eczema Area and Severity Index (EASI), body surface area (BSA), pruritus numeric rating scale (NRS), Dermatology Life Quality Index (DLQI), Investigator’s Global Assessment (IGA), and local 0–4 Physician Global Assessment (PGA). Minimal disease activity (MDA) was defined as EASI ≤ 3 plus pruritus-NRS 0–1. Descriptive statistics were applied. Distribution-shift plots were used to analyze categorical changes in special areas. Results Overall, 57 patients were included (mean age 47.9 ± 17.6 years, 59.6% women). Facial/neck, hand, and genital involvement were present in 73.7%, 61.4%, and 21.1% of patients, respectively; 31.9% had ≥ 2 special areas affected. Upadacitinib induced rapid improvement, with EASI decreasing from 18.9 to 2.7 at week 16 and 2.4 at week 52. MDA was reached by 61% at week 16 and 69% at week 52. Special-area PGA improved markedly across all sites. Conclusions Upadacitinib provided rapid, sustained, and clinically meaningful improvement in AD involving special areas, supporting its use in anatomically sensitive areas. Keywords: Atopic dermatitis, Special areas, Sensitive areas, Upadacitinib Key Summary Points Atopic dermatitis (AD) involving special or anatomically sensitive areas (hands, head/neck, and genital region) represents a frequent cause of therapeutic failure and disproportionate impairment in quality of life, even when overall disease extent is limited. The definition and clinical characterization of “special areas” in AD remain heterogeneous and poorly standardized in literature, limiting the comparability of available evidence. In this multicenter real-world cohort, upadacitinib provided rapid and sustained improvement in both global disease severity and local involvement of hands, head/neck, and genital areas. Clinically meaningful responses were observed across all special areas, including in patients with prior biologic exposure and overlap eczema–psoriasis phenotypes. Broad JAK1 inhibition may be particularly advantageous in anatomically sensitive areas characterized by mixed Th2, Th1, and Th17 inflammatory pathways. These findings support the use of upadacitinib as an effective therapeutic option in patients whose disease burden is driven by involvement of special or sensitive sites. Open in a new tab Introduction AD is a chronic inflammatory skin disease that imposes a substantial burden on patients’ quality of life [ 1 ]. Although advanced targeted therapies have significantly improved the management of AD [ 2 , 3 ], an elevated proportion of patients still fail to achieve complete or sustained disease control, particularly when inflammation affects anatomically sensitive regions. The terms “special areas” or “difficult-to-treat areas” are not uniformly defined in AD and are partly extrapolated from psoriasis [ 4 ]. Anatomical AD phenotypes such as facial/head-and-neck dermatitis, hand eczema, nipple involvement, and genital AD demonstrate distinct barrier vulnerability, environmental susceptibility, and mixed Th1/Th2/Th17 inflammatory signatures, all of which contribute to therapeutic challenges, heterogeneous responses, and disproportionate psychosocial burden [ 1 – 3 ]. Even limited inflammation in areas such as the face/neck, hands, or genital region can impair fine motor skills, work performance, intimacy, social interaction, and self-image, often prompting treatment escalation despite relatively small surface involvement. Upadacitinib, a selective JAK1 inhibitor, has demonstrated strong global efficacy in moderate-to-severe AD owing to its mechanisms of action, which enable broad-spectrum immunomodulation and control of all immunological pathways activated in these locations, it could be a highly effective treatment for special areas. Post hoc analyses from clinical trials have been published; however, real-world data remain scarce [ 5 – 7 ]. For this reason, we conducted a study specifically designed to evaluate the effectiveness of upadacitinib in these anatomically sensitive locations. Methods A retrospective, observational multicenter study was conducted across five Spanish dermatology departments between November 2024 and November 2025. It included adult and adolescent patients with moderate-to-severe AD and active involvement of at least one anatomically sensitive or “special” area (face/neck, hands, or genital region) who were treated with upadacitinib (15 or 30 mg) in routine clinical practice for a minimum of 16 weeks. Dosing was individualized on the basis of age, disease severity, and comorbidities. Disease severity was evaluated using Eczema Area and Severity Index (EASI), body surface area (BSA), pruritus numeric rating scale (NRS), Dermatology Life Quality Index (DLQI), and the Investigator’s Global Assessment (IGA). Local severity in each special area was independently assessed using the 0–4 Physician Global Assessment (PGA; 0 = clear, 4 = severe). EASI75 and EASI90 response rates were calculated, and minimal disease activity (MDA) [2] was defined as EASI ≤ 3 together with a pruritus-NRS of 0–1. Continuous variables were expressed as means ± standard deviations (SD) or medians (interquartile range), as appropriate. Changes in continuous outcomes over time were analyzed using paired t -tests or Wilcoxon signed-rank tests, depending on data distribution. Categorical variables were expressed as frequencies and percentages. Data from special areas were evaluated using distribution-shift plots to illustrate transitions between severity categories at baseline, week 16, and week 52. Changes in the distribution of PGA categories over time (baseline versus week 16, 24, and 52) were assessed using the Stuart–Maxwell test. Statistical significance was defined as p < 0.05. Missing data were handled using available-case analysis, and no imputation methods were applied. Analyses at later time points were on based on patients with available follow-up data. The primary objective was to assess the real-world effectiveness and safety of upadacitinib in AD involving special areas. Secondary objectives included evaluating the evolution of global outcomes (EASI, pruritus-NRS, and IGA) at weeks 16, 24, and 52. Adverse events were collected retrospectively from electronic medical records and routine follow-up visits. Laboratory parameters were reviewed according to standard clinical practice at each participating center. The study protocol was reviewed in accordance with institutional ethics policies and was considered exempt from formal approval in accordance with Spanish Law 14/2007 on Biomedical Research and EU General Data Protection Regulation (GDPR) 2016/679, owing to its retrospective design and the use of fully anonymized data. In accordance with institutional policies, the requirement for written informed consent was waived. Patients were informed through institutional privacy notices and had the opportunity to opt out from the use of their anonymized data for research purposes. Data were collected and processed in compliance with GDPR standards, and no identifiable personal information was accessible to the investigators. When required, specific consent for publication was obtained. Results A total of 57 patients were included in the study. The mean age was 47.9 ± 17.6 years, and 59.6% were women. Patients presented a mean diagnostic delay from symptom onset to diagnosis of 4.0 ± 4.4 years, and 40.4% had cardiovascular risk factors. AD comorbidities and family history of AD were identified in 31.6% of patients. Five patients presented an overlap psoriasis–eczema phenotype. The baseline sociodemographic and clinical characteristics are detailed in Table 1 . Table 1. Baseline characteristics of the study population N = 57 Age, years (mean ± SD) 47.9 ± 17.6 Women, % 59.6 Men, % 41.4 BMI, kg/m 2 (mean ± SD) 27.8 ± 6.9 Family history of AD, % 31.6 Diagnostic delay, years (mean ± SD) 4.05 ± 4.42 EASI baseline (mean ± SD) 18.9 ± 11.1 IGA baseline (median [IQR]) 3 [3, 4] Pruritus NRS baseline (median [IQR]) 7 [6–9] BSA baseline (mean ± SD) 29.1 ± 18.7 Subtype of AD Generalized, % 24.6% Flexural/classical % 57.9% Prurigo, % 12.3% Palmoplantar, % 7.0% Cardiovascular risk factors (FRCV), % 40.4% Hypertension (HTA), % 28.1% Diabetes mellitus (DM), % 14.0% Dyslipidemia (DL), % 33.3% Baseline involvement of special areas Hands, % 61.4% Face/neck, % 73.7% Genital region, % 21.1% Number of prior systemic treatments (mean ± SD) 1.8 ± 1.0 Prior dupilumab exposure, % 45.6% Prior tralokinumab exposure, % 10.5% Upadacitinib dose 15 mg/day, % 35.1% 30 mg/day, % 64.9% Open in a new tab AD atopic dermatitis, BMI body mass index, EASI Eczema Area and Severity Index, IGA Investigator’s Global Assessment, IQR interquartile range, NRS numeric rating scale, BSA body surface area, FRCV cardiovascular risk factors, HTA arterial hypertension, DM diabetes mellitus, DL dyslipidemia Regarding AD subtypes, 57.9% of patients presented with classical/flexural AD, 24.6% with generalized disease (including erythrodermic phenotypes), 12.3% with prurigo, and 7.0% had only palmoplantar involvement. Special-area disease was common: 73.7% had facial or neck involvement, 61.4% had hand eczema, and 21.1% had genital AD. A total of 31.9% of patients (23/57) presented involvement of at least two special areas. Patch testing was performed in 33.3% of patients. Prior to upadacitinib initiation, patients had received a mean of 1.8 ± 1.0 systemic treatments. For 53.5% of the cohort, upadacitinib represented their first advanced systemic therapy. In total, 20 patients (35.1%) received upadacitinib 15 mg and 37 (64.9%) received 30 mg. Patients treated with 30 mg showed higher baseline disease severity (mean baseline EASI: 20.2 versus 16.0). Rates of minimal disease activity were comparable between dose groups, with no statistically significant differences observed at week 16 (45% versus 43%). Categorical improvement in special areas was pronounced. The Stuart–Maxwell test for marginal homogeneity confirmed a statistically significant reduction in PGA scores from baseline to week 52 in hands ( p < 0.001), head/neck ( p < 0.001), and the genital area ( p < 0.001). Shift-plot analyses showed that most patients transitioned from IGA 3–4 at baseline to IGA 0–1 at weeks 16 and 52 across the hands, face/neck, and genital regions, confirming consistent benefit in the anatomical sites traditionally considered more challenging to manage (Fig. 1 ). Fig. 1. Open in a new tab Distribution-shift plots of local PGA severity in hands, head/neck, and genital areas at baseline and during follow-up. All areas demonstrated progressive and sustained improvement, with most patients reaching PGA 0–1 by week 52 Upadacitinib induced a rapid and sustained improvement in disease severity. The mean baseline EASI was 18.9 ± 11.1, decreasing to 2.7 at week 16, with sustained control at week 52 (2.4). Pruritus showed a parallel reduction, from 7 (6–9) at baseline to 1 (1–2) at week 16. IGA also improved markedly, decreasing from a baseline median of 3 (IQR 3–4) to 1 by week 4 and maintaining this level through week 52. At week 16, 79.5% of patients achieved EASI75, and 59.1% reached EASI90. At week 52, response rates increased to 86.1% for EASI75 and 66.7% for EASI90. Using a composite definition of MDA, defined as EASI < 3 plus pruritus-NRS of 0–1, 61% of patients met criteria for MDA at week 16 and 69% at week 52. Notably, two patients maintained mild residual erythema in hand and facial areas, although without fissures or functional impairment, and both continued the treatment without adjustments. No serious adverse events were observed during follow-up. No cases of herpes zoster were reported. Two patients developed mild treatment-related acne. Five patients presented asymptomatic lymphopenia (800–1000 cells/mm 3 ), which did not lead to treatment discontinuation. Discussion Management of AD involving special or anatomically sensitive areas presents unique clinical challenges and disproportionately affects quality of life owing to the combination of barrier fragility, environmental exposure, and mixed immunologic activation, including Th2, Th1, and Th17 pathways [ 1 , 5 – 8 ]. These distinctive characteristics set it apart from classic flexural AD and likely underlie its well-recognized refractoriness to conventional therapies. Persistent inflammation in the hands, face/neck, or genital region is a common driver of treatment escalation, even when global disease severity appears controlled, and may negatively affect long-term drug survival, as patients often perceive ongoing activity in visible or functionally important sites as insufficient response [ 8 – 10 ]. Owing to their negative impact on patients’ quality of life, involvement of these areas may prompt initiation of advanced therapies even when overall body surface involvement is limited [ 3 ]. Previous studies evaluating targeted therapies in difficult anatomical locations have highlighted the complexity of these phenotypes [ 1 ]. The mixed cytokine profiles described in hand eczema where type 2 cytokines, interferon-mediated signaling, and keratinocyte stress responses coexist partially explain the suboptimal outcomes sometimes observed with therapies selectively blocking interleukin (IL)−4/IL-13 pathways. Similarly, facial and cervical AD frequently show Th2/Th1/Th17 activation and microbiome dysbiosis, mechanisms linked to paradoxical facial erythema and conjunctivitis in patients treated with IL-4/IL-13 inhibitors. Several patients initiated upadacitinib after suboptimal response to dupilumab or tralokinumab, highlighting the therapeutic difficulty posed by special-area involvement [ 9 , 10 ]. In this context, JAK1 inhibition provides a broader immunologic blockade, modulating multiple converging cytokines including IL-4, IL-13, IL-22, IL-23, IL-31, IFN-γ, and TSLP [ 1 ]. This mechanism aligns with the rapid and consistent categorical improvements observed in our cohort across all special areas, including patients with prior exposure to biologics. Our findings suggest that persistent involvement of special areas may represent a potential barrier to achieving complete disease control in some patients, although dedicated comparative analyses are needed to confirm this observation. Even when EASI and pruritus scores improved globally, persistent activity in the hands, face/neck, or genital region could limit the perception of full disease control. Patients with overlap syndrome (eczema–psoriasis) and those with more inflammatory hand or facial phenotypes also experienced meaningful improvement over time. Recent multicenter data involving 74 adults with sensitive-area AD also demonstrated substantial clinical benefit with upadacitinib, with improvements maintained through 52 weeks and and supporting its use as a first-line therapy in this setting. Our results align closely with those observations, despite a broader age distribution and the inclusion of patients with overlap phenotypes or previous biologic failure, further confirming the consistency and reliability of JAK1 inhibition in difficult-to-treat anatomical regions [ 7 , 8 ]. The safety profile in our cohort was favorable, with no severe adverse events reported during follow-up. This is consistent with previous real-world studies and clinical trial extension data evaluating JAK inhibition in moderate-to-severe AD. The absence of treatment-limiting events supports the suitability of upadacitinib in scenarios where rapid onset of action and reliable control of anatomically sensitive areas are priorities [ 5 – 9 ]. This study has several limitations, including its retrospective design, the absence of a comparator group (therefore, no direct comparative conclusions with biologic therapies can be drawn from the present study), and the relatively small number of patients with genital involvement. A further limitation arises from the fact that there is no strict or standardized definition of “special areas” in atopic dermatitis, which supports the need for cautious terminology in this field. Current classifications are largely adapted from psoriasis, and validated AD-specific criteria for difficult anatomical locations are still lacking, which may affect comparability between studies Despite these limitations, the present work represents one of the largest real-world cohorts specifically evaluating the performance of a JAK inhibitor in AD affecting special anatomical sites. Conclusions Upadacitinib demonstrated rapid, clinically meaningful, and sustained effectiveness in moderate-to-severe AD with involvement of special areas. Its rapid onset of action, broad coverage of relevant cytokine pathways, and consistent responses in hand, face/neck, and genital disease support its use as a valuable therapeutic option in patients whose disease burden is disproportionately driven by special-area involvement or in whom these sites hinder attainment of minimal disease activity. Acknowledgements We thank the participants of the study. Author Contributions Francisco Javier Melgosa Ramos, Santiago Guillén Climent, Raquel Cavestany Rodriguez, Javier Sabater Abad, Antonio Martorell, and Fatima Tous Romero have equally contributed to the conception and design of the study, data collection, data interpretation, drafting of the manuscript, and critical revision of the content. All authors approved the final version of the manuscript to be published Funding No funding or sponsorship was received for this study or publication of this article Data availability The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Declarations Conflict of Interest Francisco Javier Melgosa Ramos has received honoraria and/or travel grants and/or has acted as an advisory board member for Novartis, Abbvie, Janssen Cilag, UCB, Lilly, LEO Pharma, L’Oreal, Sanofi, Almirall, and Amgen. Antonio Martorell has acted as a consultant, advisory board member, and investigator, and has received honoraria from Novartis, AbbVie, Janssen Cilag, UCB, Lilly, LEO Pharma, L’Oréal, Sanofi, Sandoz, Boehringer Ingelheim, and Amgen. Fátima Tous Romero has received honoraria and/or travel grants and/or has acted as an advisory board member for Novartis, Abbvie,, Lilly, LEO Pharma, Sanofi, Almirall, and Pfizer. Santiago Guillén Climent, Raquel Cavestany, and Javier Sabater Abad declare no conflicts of interest in relation to this manuscript. Ethical Approval The study protocol was reviewed in accordance with institutional ethics policies and was considered exempt from formal approval in accordance with Spanish Law 14/2007 on Biomedical Research and EU General Data Protection Regulation (GDPR) 2016/679, owing to its retrospective design and the use of fully anonymized data. In accordance with institutional policies, the requirement for written informed consent was waived. Patients were informed through institutional privacy notices and had the opportunity to opt out from the use of their anonymized data for research purposes. Data were collected and processed in compliance with GDPR standards, and no identifiable personal information was accessible to the investigators. When required, specific consent for publication was obtained. Footnotes Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Change history 3/15/2026 Given name and family name of author Fátima Tous Romero updated. References 1. Meledathu S, Naidu MP, Brunner PM. Update on atopic dermatitis. J Allergy Clin Immunol. 2025;155(4):1124–32. [ DOI ] [ PubMed ] [ Google Scholar ] 2. Silverberg JI, Gooderham M, Katoh N, Aoki V, Pink AE, Binamer Y, et al. 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