Atopic dermatitis (AD) is a chronic, recurrent inflammatory skin disease with an estimated prevalence of 10% in adults and 20% in children.1 Recent advances in our understanding of the pathogenic mechanisms underlying this disease have led to significant improvements in treatment options.2 Thus, a total of 6 novel systemic therapies have emerged for the management of moderate-to-severe AD in recent years, namely 3 Janus kinase [JAK] inhibitors—baricitinib, upadacitinib, and abrocitinib—and 3 biologics—dupilumab, tralokinumab, and lebrikizumab.3 Lebrikizumab was approved in just 2023. Because AD often requires long-term systemic therapy, safety is a critical consideration.

Although the safety and efficacy profile of novel treatments for AD is supported by data from clinical trials, these typically apply strict inclusion and exclusion criteria,4 limiting the generalizability of their findings. Patients with moderate-to-severe AD who do not meet these criteria, for example, but who are eligible for advanced systemic treatments might experience different adverse effects and responses.

Real-world registries are important sources of pharmacovigilance data that can be very useful for monitoring long-term safety and efficacy in diverse patient populations. They may be more representative of the overall population with a given disease as they do not exclude patients based on factors such as age, comorbidities, and concomitant treatments.5,6

The primary endpoint of this study was to quantify the proportion of patients with AD on advanced systemic therapy who are underrepresented in randomized clinical trials (RCTs). Secondary endpoints were to describe the clinical characteristics and treatments in underrepresented patients and compare the risk of adverse events between RCT-eligible and -ineligible patients.

Data for this study were obtained from the Spanish national BIOBADATOP registry, which is a real-world registry that collects information on patients of all ages with AD started on a new systemic therapy (conventional or advanced).7 The registry is supported by the Spanish Group for Research in Contact Dermatitis and Cutaneous Allergy (GEIDAC) and the Spanish Group of Pediatric Dermatology (GEDP)—both working groups of the Spanish Academy of Dermatology and Venereology (AEDV). BIOBADATOP is aligned with the TREatment of ATopic eczema (TREAT) Registry Taskforce, an international initiative aimed at harmonizing the collection of observational data of patients on systemic therapy.8,9 The objective of BIOBADATOP is to characterize the safety and efficacy profile of systemic therapies for AD in Spanish hospitals.7,10 A total of 14 dermatology departments currently contribute to this registry. We analyzed all data recorded in the registry from its launch in March 2020–March 2024.

The registry contains information on baseline demographics, clinical characteristics, diagnosis, changes in AD severity, atopic and non-atopic comorbidities, and previous and current treatments. It also records start and discontinuation dates and reasons for discontinuation for all new treatments. Adverse events that occurred since the patient's last visit are reported using the Medical Dictionary for Drug Regulatory Activities (MedDRA) terminology (https://www.meddra.org). Patient data are coded with a unique identifier and entered using the Research Electronic Data Capture (REDCap) system,11 hosted by AEDV Healthy Skin Foundation.

All adults patients who started an advanced systemic therapy (biologic or JAK inhibitor) during the study period were included. To identify RCT-ineligible patients, we reviewed the eligibility criteria from 74 RCTs included in a recent network analysis of conventional and novel systemic treatments for AD. A total of 58 of these trials specified at least one eligibility criterion.12 We selected the most frequently applied exclusion factors as safety criteria. Trial ineligibility was defined as meeting at least one of the following 8 exclusion factors: advanced age (≥65 years) (applied in 7/58 RCTs); pregnancy, breastfeeding, or desire to become pregnant, (16 RCTs); uncontrolled comorbidities, including hypertension, cardiovascular disease, and diabetes mellitus (14 RCTs); chronic kidney disease (11 RCTs); present or past history of cancer (11 RCTs); liver disease (10 RCTs); history of tuberculosis, human immunodeficiency virus or hepatitis B or C infection (9 RCTs); and active or acute infection, including superinfection of AD lesions (7 RCTs).

Discrepancies between clinical trial and real-world patients pose a significant challenge when applying trial findings to routine clinical practice. In this study, we found that 18.3% of patients on advanced systemic therapies for AD in Spain are underrepresented in RCTs. This proportion went up to 22.1% when patients with EASI<16 were included in the analyses (22.1% of the patients treated in real life had EASI<16). While an EASI cutoff value of 16 is widely used to denote severe AD in clinical trials, it is an arbitrary selection criterion. Special site involvement, for instance, is assigned relatively little weight in the EASI tool, meaning that patients with significant facial, hand, or genital lesions may be inaccurately classified as having mild disease, despite having moderate-to-severe symptoms and quality of life impairment.13,14 In other words, this disproportionate weighting can result in an underestimation of disease, potentially excluding patients from participation in clinical trials or access to new treatment if additional assessments are not performed.15,16 Supplementary evaluations are critical for gaining a broader understanding of how AD affects different aspects of the patients’ lives, including work and social functioning. Furthermore, since real-world patients do not typically undergo washout therapy before switching to a new treatment, they may have low baseline EASI scores, even when their treatment is not working.

The proportion of patients deemed eligible or ineligible for a given RCT varies according to the eligibility criteria applied. To identify underrepresented patients in this study, we applied the most common eligibility criteria used by RCTs in an extensive network analysis of AD trials. Most criteria were exclusion criteria related to safety, and, as expected, patients deemed ineligible were significantly more likely to have comorbidities that would exclude them from RCTs evaluating the safety and efficacy profile of advanced systemic therapies for AD.

When comparing the use of individual treatments within our cohort, no significant differences were observed between patients who were eligible or ineligible for RCTs, possibly reflecting clinicians’ confidence in the safety profiles established in those trials. However, when treatments were analyzed by drug class, Janus kinase (JAK) inhibitors were significantly less likely to be prescribed to patients who did not meet RCT eligibility criteria. This finding is consistent with the European Medicines Agency recommendation to avoid prescribing JAK inhibitors to patients aged>65 years, those with cardiovascular risk, smokers or former smokers, patients with thromboembolic risk, and those with a high risk of cancer, unless no suitable alternatives are available.17 The rationale behind this recommendation is to reduce the risks associated with JAK inhibitors in patients with comorbidities.18,19

Although serious adverse events were significantly more common in RCT-ineligible patients in the univariate analysis, there were no differences after adjusting for age, sex, and Charlson comorbidity index. This suggests that the increased risk of SAEs in ineligible patients has been causally mediated by these variables. Age is a strong predictor of serious adverse events for many drugs and, like comorbid conditions, must be taken into account when taking treatment decisions. Treatments should be chosen only after thoroughly discussing and weighing up the risks and benefits for each patient.18

National and international population-based registries provide important additional information on the safety and efficacy profile of new treatments for AD and other immune-mediated diseases. These registries enable long-term follow-up of a broader, more diverse, patient population, thereby addressing some of the limitations of RCTs, which typically represent a more select population. While RCTs are crucial for evaluating interventions due to their controlled, randomized design, their external validity is often constrained by strict eligibility criteria that do not reflect real-world clinical practice.6,20,21 Additional analyses of registry data can yield more realistic, generalizable insights into treatment outcomes, help identify rare or very rare adverse events and associated risk factors, and be used to evaluate real-world efficacy across diverse patient groups, including patients with special site involvement and those who have switched treatments.

Finally, we observed no differences in drug survival between RCT-eligible and -ineligible patients, suggesting that the exclusion criteria applied in RCTs of novel systemic AD treatments do not significantly affect treatment efficacy or duration.

Our study has some limitations. First, AD research is evolving rapidly, with numerous drugs in the pipeline and clinical trials underway. Most patients in this real-world cohort were treated with dupilumab, the first biologic to be approved for moderate to severe AD in adults. Second, although the use of MedDRA terminology to classify serious adverse events improves the detection of relevant differences and events, it does not distinguish between the mechanisms underlying these events. Finally, the limited statistical power of this study may have prevented us from detecting certain differences or drawing broader conclusions. However, this limitation is intrinsic to studies based on evolving registries such as BIOBADATOP. The value of this registry lies in its ability to deliver real-world evidence that complements insights from controlled clinical trials. As the registry continues to grow, it holds the potential to improve the detection of nuanced differences and provide robust answers to clinically relevant questions that emerge from routine practice.

In conclusion, 18.3% of patients on advanced systemic therapies for AD are misrepresented in clinical trials evaluating the safety and efficacy profile of these therapies. This represents a significant proportion of real-world patients and highlights the need for more pragmatic clinical trials that address treatment outcomes based on frequent clinical questions. Our findings suggest that future trials should be designed to include older patients, those with atypical disease patterns, and those with severe AD defined by criteria other than absolute EASI scores, such as those with facial, hand, or genital involvement.

The BIOBADATOP project is managed by the Fundación Piel Sana of the Spanish Academy of Dermatology and Venereology (AEDV) and receives funding from the pharmaceutical companies Sanofi, AbbVie, Pfizer, and Leo-Pharma. None of these companies had any involvement in study design or conduct; data collection, management, analysis, or interpretation; manuscript preparation, revision, or approval; or the decision to submit this manuscript for publication. The collaborating companies did not participate in the analysis or interpretation of the results.

M. Munera-Campos declared to have received fees for consultancy services, presentations, and related activities from AbbVie, Leo-Pharma, Janssen, Sanofi, and Galderma. She has also served as a principal or sub-investigator in clinical trials sponsored by Lilly, Leo-Pharma, Novartis, Janssen, Sanofi, Pfizer, AbbVie, Almirall, UCB, and Galderma.

A. González Quesada declared to have received fees for consultancy services, presentations, and related activities from AbbVie, Leo-Pharma, Sanofi, UCB, and Pfizer. She has also served as a principal or sub-investigator on clinical trials sponsored by Lilly, Leo-Pharma, Novartis, Janssen, Sanofi, Pfizer, AbbVie, Almirall, UCB, and Galderma.

M. Espasandín Arias has led and/or been involved in training activities and attended courses and conferences sponsored by AbbVie, Sanofi, Almirall, Viatris, Pfizer, and Leo-Pharma.

M.A. Lasheras Perez declared no conflicts of interest whatsoever.

P. de la Cueva Dovao has been involved as a researcher and/or advisor and/or speaker for AbbVie, Almirall, BMS, Boehringer, Celgene, Janssen, Leo-Pharma, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi, and UCB.

T. Montero-Vilchez declared to have received consultancy and speaker's fees and been involved in clinical trials sponsored by AbbVie, Almirall, Incyte, Leo-Pharma, Lilly, Novartis, Sanofi, Pfizer-Wyeth, and UCB, and Instituto de Salud Carlos III.

R. Ruiz Villaverde declared to have served as an advisor for Sanofi, Janssen, Almirall, and Novartis, given presentations for Almirall, Sanofi, Lilly, AbbVie, Novartis, and Pfizer, and been involved in research projects with Almirall, Sanofi, Pfizer, AbbVie, and Leo-Pharma.

P. Chicharro declared to have provided consultancy services for and been involved in presentations and clinical trials organized by Janssen Pharmaceuticals, Almirall, Sanofi Genzyme, Lilly, AbbVie, Novartis, Leo-Pharma, and Pfizer-Wyeth.

Y. Gilaberte declared to have served as an advisor for Isdin, Roche Posay, and Galderma, given presentations for Almirall, Sanofi, Avene, Rilastil, Lilly, Uriage, Novartis, and Cantabria Labs, and been involved in research projects with Almirall, Sanofi, Pfizer, AbbVie, and Leo-Pharma.

M. Elosua-González declared to have participated as a research and/or speaker for AbbVie, Lilly, Galderma, Leo-Pharma, Pfizer, UCB Pharma, and Sanofi Genzyme.

L. Curto-Barredo declared to have received fees for scientific consulting, presentations, and related activities from AbbVie, Leo Pharma, Sanofi, Lilly, Novartis, Pfizer, Almirall, and Menarini. She has also been involved as a principal or sub-investigator in clinical trials sponsored by Lilly, Leo Pharma, Novartis, Sanofi, AbbVie, and Almirall.

J. J. Pereyra Rodríguez declared to have received fees for scientific consulting, presentations, and other activities from AbbVie, Almirall, Galderma, Janssen, Gebro-Pharma, Leo-Pharma, Novartis, Lilly, Pfizer, Sanofi, Incyte, UCB, IFC. He has also been involved as a researcher in studies by Novartis, AbbVie, Sanofi, Almirall, Lilly, Galderma, Leo-Pharma, and Argenx.

J.F. Silvestre Salvador declared to have collaborated as a speaker, advisor, and/or researcher for AbbVie, Almirall, Amgen, Astra Zeneca, Bristol Myers Squibb, Eli Lilly, Galderma, Incyte, Leo Pharma, Novartis, Pfizer, Regeneron, and Sanofi Genzyme.

A. Batalla declared to have participated in training activities and attended courses and conferences sponsored by AbbVie, Celgene, Faes Farma, Isdin, Janssen, Leo-Pharma, Lethipharma, Lilly, Mylan, Novartis, Pierre Fabre, and Sanofi. She has also worked as a sub-investigator in clinical trials sponsored by AbbVie, Celgene, Leo-Pharma, Lilly, Novartis, Pfizer, and Sanofi and provided consultancy services for AbbVie and Sanofi.

S. Arias-Santiago declared to have been provided consultancy services for and been involved in talks and clinical trials sponsored by AbbVie, Leo-Pharma, Lilly, Sanofi, and Pfizer-Wyeth.

F. J. Navarro Triviño has collaborated in scientific advisory capacities, participated in medical meetings, and contributed to training courses sponsored by Almirall, Sanofi, Leo-Pharma, Lilly, Pfizer, Galderma, Pierre Fabre, Cantabria Labs, La Roche-Posay, Leti Labs, Genové Labs, ISDIN Labs, and Rilastil Labs. He has also worked as a principal investigator or collaborator in clinical trials or research studies for Leo-Pharma and Novartis.

A. Navarro-Bielsa declared to have served as an advisor and/or researcher and/or speaker for AbbVie, Almirall, Janssen, Leo-Pharma, Sanofi, and Galderma.

G. Roustan Gullón declared to have received consultancy and training fees from Sanofi, AbbVie, Lilly, Pfizer, and Leo-Pharma.

M. Bertolín declared no conflicts of interest whatsoever.

I. Betlloch-Mas declared no conflicts of interest whatsoever.

I. Castaño declared no conflicts of interest whatsoever.

C. Couselo-Rodríguez declared to have been involved as a sub-investigator or speaker in projects sponsored by AbbVie, Sanofi, Leo-Pharma, Lilly, UCB, Novartis, Pierre Fabre, and Janssen.

M. Rodríguez-Serna declared to have been involved in advisory roles for Sanofi, Pfizer, Leo, Novartis, and AbbVie.

R. Sanabria de la Torre declared to have been involved in clinical trials for AbbVie, Sanofi, and Instituto de Salud Carlos III.

J. Carlos Ruiz Carrascosa declared no conflicts of interest whatsoever.

J. Sánchez declared no conflicts of interest whatsoever.

Á. Rosell Díaz declared to have received speaker's fees from Sanofi and Leo-Pharma and worked as a sub-investigator in studies for Sanofi and Pfizer.

A. M. Gimenez Arnau declared to have served as a medical advisor for Uriach Pharma/Neucor, Genentech, Novartis, FAES, GSK, Sanofi-Regeneron, Amgen, Thermo Fisher Scientific, Almirall, Celldex, and Leo-Pharma. She has also been involved as an investigator in projects sponsored by Uriach Pharma, Novartis, and Instituto de Salud Carlos III-ERDF, and has conducted training activities sponsored by Uriach Pharma, Novartis, Genentech, Menarini, Leo-Pharma, GSK, MSD, Almirall, Sanofi, and Avene.

S. Martínez Fernández declared to have conducted training activities and attended courses and conferences sponsored by AbbVie, Janssen, Leo Pharma, Lilly, Novartis, La Roche-Posay, Pierre Fabre, and Sanofi. She has also been involved as a sub-investigator in clinical trials sponsored by AbbVie, Pfizer, Sanofi, and Novartis.

I. García-Doval declared to have received travel and training grants for scientific conferences sponsored by AbbVie, MSD, Pfizer, and Sanofi.

M. Á. Descalzo-Gallego declared no conflicts of interest whatsoever.

J. M. Carrascosa Carrillo declared to have served as a principal investigator/sub-investigator and/or received speaker's fees, and/or served on expert or steering committees for AbbVie, Novartis, Janssen, Lilly, Sandoz, Amgen, Almirall, BMS, Boehringer Ingelheim, Biogen, and UCB.