1 Background

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by recurrent pruritus and eczematous lesions and is influenced by various factors, including genetics, the environment, and immunity [1]. The clinical manifestations of AD vary across different age groups, leading to the categorization of distinct subtypes based on age. Alongside the established subtypes for infants, children, adolescents, and adults, recent research has identified unique subtypes specific to the older population [2, 3]. Older patients with AD exhibit distinctive clinical phenotypes and immunologic endotypes [4,5,6]. Furthermore, managing this subtype poses challenges owing to the presence of multiple comorbidities and medication regimens in older patients. The prevalence of AD in the older population is approximately 2–4% [4]. With the global aging trend and increasing life expectancy, the overall number of older AD cases, including those aged over 80 years, is expected to rise [7, 8]. Notably, individuals above 80 years of age experience heightened immunosenescence, leading to a higher incidence of age-related conditions such as cardiovascular disease, diabetes mellitus, and Alzheimer’s disease [9,10,11]. Moreover, those aged older than 80 years demonstrate decreased resilience against severe diseases and infections [12, 13]. Therefore, the treatment of older patients with AD necessitates thoughtful deliberation, with treatment outcomes exhibiting potential variations.

Dupilumab, a systemic targeted drug used in the treatment of AD, has shown long-term efficacy and safety in treating pediatric, adult, and older patients [14,15,16,17]. However, the inclusion of older subjects aged 80 years and above in previous reports has been limited. To address this gap, we conducted a retrospective analysis of 28 patients with AD aged 80 years and above who received dupilumab treatment. Our objective was to provide real-world evidence regarding the effectiveness and safety of dupilumab in this specific age group.

2 Methods

2.1 Study Area and Study Population

The study included patients with AD who fulfilled the diagnostic criteria set by Hanifin and Rajka [18] and who visited the Dermatology Clinic of Sichuan Provincial People’s Hospital between May 2022 and February 2023. The study was specifically focused on patients aged 80 years and above with a SCORing Atopic Dermatitis (SCORAD) score greater than 35, indicating severe AD. Eligible patients had previously received at least one systemic therapy (such as traditional Chinese medicine, glucocorticoids, immunosuppressants, or phototherapy) with limited effectiveness. Patients with concurrent tumors, active tuberculosis, immunodeficiency, or other relevant diseases were excluded from the study.

2.2 Study Methods and Data Collection

All patients received regular injections of dupilumab (Sanofi, France) as per the prescribed treatment regimen, which was determined after an independent diagnostic evaluation by two experienced dermatologists. The initial dose administered was 600 mg, followed by subsequent doses of 300 mg administered subcutaneously every 2 weeks. Follow-up observations were conducted every 2–4 weeks.

Demographic and clinical characteristics of the patients were recorded, including age, sex, time of onset, previous medications, changes in coexisting conditions (comorbidities and underlying diseases), concomitant medications used with dupilumab, a family history of allergic disease, and the morphology and distribution of skin lesions. Relevant scoring systems, such as the Atopic Dermatitis Control Tool (ADCT), Pruritus Numeric Rating Scale (NRS), Eczema Area and Severity Index (EASI), and Dermatology Life Quality Scale (DLQI), were employed to assess disease severity before treatment and during the follow-up. Any adverse events that occurred during the medication period were also documented.

The levels of eosinophils and total serum immunoglobulin E (IgE) were measured at the initial presentation and at 16 weeks to evaluate their changes. Additionally, the efficacy of dupilumab was assessed by monitoring changes in the aforementioned scoring systems. A safety evaluation was conducted by monitoring the incidence of adverse reactions and their impact on comorbidities and infections.

2.3 Statistical Analysis

Statistical analysis was conducted using SPSS 27.0 statistical software, and graphical representations were generated using GraphPad Prism 7.0. Descriptive analysis was employed to examine demographic data and clinical characteristics. The paired t test or rank-sum test was utilized to compare scale scores before and after treatment. A significance level of α = 0.05 (two sided) was applied, with p < 0.05 considered statistically significant.

2.4 Ethics Statement

The study adhered to the ethical standards outlined in the Declaration of Helsinki. Approval was obtained from the Ethics Committee of Sichuan Provincial People’s Hospital (Protocol 2022-327), and written informed consent was obtained from participants or their legal guardians. This cross-sectional study follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines.

3 Results

3.1 Clinical Demographics and Characteristics

A total of 28 patients were included in the study (Table 1), consisting of 27 male individuals (96.4%) and one female individual. The age range was 80–93 years, with an average age of 85 ± 3.56 years. Among the participants, five cases were classified as adult onset (17.9%), while 23 cases (82.1%) involved onset at age 60 years or above. Type 2 inflammatory comorbidities were observed, with eight cases of allergic rhinitis (28.6%), three cases of chronic obstructive pulmonary disease (10.7%), two cases of asthma (7.1%), and one case of food allergy (3.6%). Sixteen patients had comorbidities related to hypertension or cardiovascular disease (57.1%), 12 patients had genitourinary disease (42.9%), nine patients had endocrine disease (32.1%), and six patients had neurological disease (21.4%). Sixteen patients had combined diseases involving two or more systems (57.1%). In terms of the clinical phenotype, 15 patients exhibited flexor involvement (53.6%), 21 patients had generalized involvement (75%), 14 patients had head and neck involvement (50.0%), and 14 patients had hand and foot involvement (50.0%). Twelve patients (42.6%) had serum total IgE levels greater than 400 IU/mL, and 13 patients (46.4%) had eosinophils greater than 0.5 × 109/L. Three patients died during the treatment period, with causes of death including cardiovascular disease, neurological disease, and new coronavirus infection.

Table 1 Clinical characteristics of 28 older (aged ≥ 80 years) patients with AD
Full size table

3.2 Efficacy Evaluation

A total of 28 patients were treated for a duration range from 4 weeks to 42 weeks (Table 2). During the follow-up period, 23 patients discontinued the treatment, while five patients were still undergoing treatment. Among the patients, 92.9% (26 patients) completed a 16-week treatment, 45.6% (13 patients) completed 28 weeks of treatment, and two patients were treated for a duration of 36 weeks or longer. Reasons for discontinuation included significant relief of rash in seven patients (25.0%), poor treatment response in six patients (21.4%), inconvenience to visit in three patients (10.7%), adverse events in three patients (10.7%), serious medical illness or death in three patients, and economic reasons in one patient.

Table 2 Treatment with dupilumab and the follow-up in 28 older (aged ≥80 years) patients with atopic dermatitis
Full size table

Among the 26 patients who completed 16 weeks of treatment and the follow-up, all scores showed significant reductions compared with the baseline scores (p < 0.0001). The EASI score decreased from a mean of 40.52 ± 14.80 points at baseline to 20.71 ± 13.89 points, representing a mean reduction of 43.60%. EASI-50 was achieved in 53.85% (14/26) of patients. Notably, the EASI scores exhibited an average reduction of 50.8% in the head, face, and neck region and a reduction of 45.8% in the hands and feet. The NRS score for pruritus decreased from 8.46 ± 1.05 at baseline to 3.73 ± 2.36 at the follow-up, with a mean reduction of 55.20%. Eighteen of 26 (69.23%) patients had a decrease in NRS score of ≥4. Patients experienced a reduction in NRS score of ≥3 within a range of 2–84 days; the mean duration was 14.94 ± 20.46 days. The DLQI score decreased from 15.08 ± 7.09 at baseline to 6.42 ± 6.59, representing a mean reduction of 56.56%. The ADCT score decreased from a baseline value of 19.19 ± 2.95 to 9.23 ± 6.05, with an average reduction of 49.80%. Furthermore, 50.00% (13/26) of patients achieved disease control with an ADCT score of < 7 (Fig. 1).

Fig. 1
figure 1

Changes in score measures and laboratory parameters in 26 dupilumab-treated patients who completed 16 weeks. a–d Eczema Area and Severity Index (EASI), Numeric Rating Scale (NRS), Dermatology Life Quality Index (DLQI), and Atopic Dermatitis Control Tool (ADCT) scores decreased significantly at 16 weeks, and 13 patients who adhered to treatment continued to improve through 28 weeks. e, f A total of 20 patients had their eosinophil (EOS) count and total serum immunoglobulin E (IgE) levels compared before treatment and at the 16-week follow-up. Eosinophil count decreased in 16 patients (e). A total of 19 patients exhibited a decrease in IgE levels at 16 weeks, with one patient showing levels below 100 IU/mL despite a slight increase. Eight patients (40.0%) had IgE levels exceeding 400 IU/mL (f)

Full size image

Thirteen patients continued treatment for 28 weeks, and all of them demonstrated a significant reduction in scores by the 16-week mark. At 16 weeks, ten patients achieved EASI-50, and 12 patients achieved a decline of ≥ 4 points on the NRS score. All scores continued to decrease in these 13 patients, all of whom achieved EASI-75 and nine (69.2%) of whom achieved EASI-90. Additionally, all patients experienced a reduction of ≥ 4 points on the pruritus NRS score, and 92.30% (12/13) of patients showed a DLQI reduction of ≥ 4 points. Among them, 92.30% (12/13) achieved disease control with an ADCT score of < 7 (Fig. 1).

A total of 20 patients had their eosinophil count and total serum IgE levels compared before treatment and at the 16-week follow-up (Fig. 1). At the 16-week mark, eosinophil count decreased in 16 patients. Two patients experienced a decrease below 0.5 × 109/L, while one patient showed an increase from 0.499 × 109/L to 0.523 × 109/L, and another patient showed an increase from 0.84 × 109/L to 2.222 × 109/L. A total of 19 patients exhibited a decrease in IgE levels at 16 weeks, with one patient showing levels below 100 IU/mL despite a slight increase. Eight patients (40.0%) had IgE levels exceeding 400 IU/mL.

3.3 Safety Evaluation

No malignant tumors or impairment of liver and kidney function were found in any patients during the follow-up. Four patients experienced adverse events, and one of them developed redness and swelling at the injection site within 2–3 days after the initial injection as well as at weeks 28 and 32 of the treatment. Another patient experienced gastrointestinal discomfort following the first, second, and fourth injections. These adverse events resolved spontaneously without the need for specific treatment. The patients who experienced injection-site reactions discontinued the medication. One patient experienced a recurrence of pulmonary tuberculosis approximately 4 months after the first injection and subsequently discontinued dupilumab to receive antituberculosis treatment (Table 2). The patient had tuberculosis more than 20 years previously and recovered after treatment. Fever and cough occurred again, and pulmonary tuberculosis was diagnosed in the local centers for disease control and prevention. The sputum smear was negative for Mycobacterium tuberculosis. Additionally, one patient developed a psoriasis-like rash after a single injection and switched to cyclosporine, discontinuing dupilumab.

Furthermore, special attention was given to patients with concurrent diseases (Table 2). No abnormal fluctuations in the indicators of these concurrent diseases were observed during the treatment period. All patients continued to be managed and controlled according to their original treatment regimens and measurements. The concomitant medications used alongside dupilumab included amlodipine, nifedipine, traditional Chinese medicine, metoprolol, metformin, insulin, anti-anxiety drugs, aspirin, trimetazidine, atorvastatin, and finasteride.

During the COVID-19 outbreak in Sichuan in December 2022, seven patients remained uninfected (21.4%), while nine patients developed pulmonary symptoms with abnormal chest computed tomography findings, with six of them requiring hospitalization. Additionally, ten patients experienced mild symptoms (35.7%) (Table 2).

4 Discussion

Atopic dermatitis in older individuals presents unique clinical characteristics and treatment challenges compared with other types of AD, primarily owing to compromised skin barrier function and an immunoregulatory imbalance [4]. Common manifestations include skin dryness and lichenification, with a slightly lower incidence on the flexor side and head and face [5]. In a study focusing on older patients with AD in China, it was observed that the trunk and extensor sides of the extremities were more affected, and approximately 49.8% of patients had involvement of the head, face, neck, hands, and feet [19]. Notably, the proportion of affected hands and feet was higher than previously reported. A study investigating epidermal barrier function in older individuals (> 80 years of age) suggested that the recovery of skin barrier function after stimulation takes longer in older individuals, indicating that age plays a crucial role in the restoration of skin barrier function [20]. However, further research with a larger sample size is needed to determine whether the high prevalence of hand and foot involvement in older patients is indeed a consequence of further deterioration in skin barrier function, which is a distinctive feature of AD in octogenarians and older individuals.

Previous research has indicated that T helper-2 and T helper-22 immune signals in the skin lesions and serum of patients with AD tend to decrease with age, while T helper-1/T helper-17 immune mediators increase. Additionally, serum IgE levels and eosinophil counts show a negative correlation with age in patients with AD [21]. Studies have demonstrated that older patients with AD have lower levels of IgE and eosinophils than patients in other age groups [6, 21]. The proportion of patients with IgE levels exceeding 400 IU/mL is typically approximately 60% [22]. However, in our dataset, the proportion of patients with IgE levels exceeding 400 IU/mL was only 40.0%. This suggests that there may be a further decline in IgE levels with increasing age, leading to a reduced proportion of older patients with AD with elevated IgE levels.

The use of dupilumab, a fully human monoclonal antibody targeting interleukin (IL)-4Rα, has revolutionized the treatment of AD by blocking IL-4 and IL-13 signaling [23]. The findings of this study demonstrate the significant efficacy of dupilumab in controlling symptoms in older patients aged 80 years and above. At 16 weeks, there were notable reductions in EASI, NRS, DLQI, and ADCT scores. While the proportion of score reductions in this study was slightly higher than that in previous studies focusing on AD in older patients aged over 60 years [24, 25], further investigations are necessary to assess the differences in efficacy specifically for individuals aged 80 years and above. Remarkably, notable improvements were observed in specific sites, including the head, face, neck, and hands and feet, consistent with the overall findings. Older individuals aged 80 years and above are a distinct group characterized by multiple comorbidities, polypharmacy, mobility difficulties, and other challenges in treatment. In China, the population of individuals aged 80 years and above has been steadily increasing, making it essential to address their specific healthcare needs [7, 8, 26]. In this study, most older patients had multiple systemic diseases, faced difficulties in adhering to treatment, and exhibited poor family compliance. Less than half of the patients were able to complete 28 weeks of treatment, with many discontinuing treatment after 16 weeks because of satisfactory efficacy. Therefore, the 16-week therapeutic effect may be crucial for ensuring drug adherence in older patients receiving AD treatment. Improving treatment strategies for older patients with AD is of utmost importance, necessitating careful consideration of factors such as patient convenience and self-administration. It has now been shown that dupilumab injections can be extended to 4–8 weeks after AD symptoms are effectively controlled [27]. Using the smallest dose avoids drug overuse and is also a measure to facilitate elderly individuals. Such approaches have the potential for broad application in this population.

The safety profile of dupilumab in our study aligns with previously reported results, demonstrating an overall favorable safety profile [28]. Interestingly, we did not observe the occurrence of the most commonly reported adverse reactions associated with dupilumab, such as ocular complications (e.g., conjunctivitis, ocular pruritus, ocular hyperaemia, and dry eye) [29]. These 28 patients did not experience facial and neck erythema during treatment and the follow-up. The original rash on the head and face also substantially improved. During dupilumab treatment in patients with AD aged 80 years and above, there were no significant fluctuations in blood pressure, blood glucose levels, uric acid values, or other parameters, and the original treatment regimens were maintained.

However, we observed a recurrence of pulmonary tuberculosis in one patient after 4 months of using dupilumab. According to previous studies, immunosuppressive drugs, Janus kinase inhibitors, and biological agents that may be selected when treating skin diseases may increase the chance of systemic infection, including tuberculosis infection [30,31,32,33]. This mainly occurs with biological agents that affect the type 1 immune response in host immunity, such as tumor necrosis factor-α and interleukin-17 inhibitors [34]. Dupilumab targets and blocks important cytokines in the type 2 immune pathway and is not important for the host’s defense mechanism against most infectious pathogens, except for internal parasites [35, 36]. In a summary analysis of the incidence of infection in 2932 patients with AD who received dupilumab treatment, no tuberculosis infection or reactivation was reported in any studies [37]. In addition, previous studies have also suggested that older people have many risk factors for developing pulmonary tuberculosis [38]. Being older than 75 years of age can increase the risk of active tuberculosis [39]. In the management of older patients with AD, determining whether opportunistic infections should be screened before using dupilumab treatment will still require a large sample of data.

In addition, one 80-year-old patient in our study developed psoriasiform lesions after 1 week of treatment. Similar psoriatic or psoriasis-like rashes have been reported previously with the use of dupilumab and are believed to be associated with dysregulation of immune responses involving the Th2 and Th1/Th17 pathways [40]. Notably, these occurrences have predominantly been observed in older patients [41]. On average, the rashes occurred approximately 3.9–4.3 months after dupilumab use [41, 42]. The occurrence time in our patient was significantly shorter than previously reported, and further research is needed to determine whether this is related to advanced age. Furthermore, although the patient had eczematous changes on a pathological biopsy performed 4 years prior to treatment, no recent biopsy was conducted before initiating treatment. These findings suggest the importance of exercising caution when treating older individuals, emphasizing the need to assess skin pathology before initiating therapy.

Given the global COVID-19 pandemic, it is noteworthy to mention that IL-13 levels have been found to be significantly increased in plasma samples from COVID-19-positive patients; IL-13 has been implicated in promoting hyaluronic acid deposition in the lungs, thereby exacerbating lung injury based on mouse model experiments [43]. As dupilumab acts as an immunomodulatory agent primarily by inhibiting IL-13 signaling, it may potentially exert beneficial effects in patients infected with COVID-19. Consequently, we paid additional attention to the occurrence of novel coronavirus pneumonia in the subjects included in this study. More than half of the patients (17 out of 26) remained uninfected or experienced milder symptoms. These findings are consistent with previous reports by Ungar et al. demonstrating that the incidence and severity of COVID-19 symptoms were lower in the group treated with dupilumab than in other systemic treatment groups or the limited/no treatment group among 1237 patients with moderate-to-severe AD [44]. However, importantly, our study had a small sample size, and factors such as the vaccination status of patients, the relationship between dupilumab use/discontinuation and novel coronavirus infection, and the impact of other underlying diseases were not specifically considered. Currently, with the ongoing global threat of the novel coronavirus, investigating the protective effects of dupilumab on antiviral immune responses may be an avenue worth exploring in future in-depth studies.

Given the limitations of our study, larger multi-center randomized controlled trials with a long-term follow-up are still necessary to further evaluate the therapeutic value of dupilumab in this unique population of older patients with AD. Additionally, almost all of our patients are male. According to our previous reports and our general observations, there is no sex difference in AD in older patients, based on criteria including the age of onset, location of skin lesions, and the efficacy and safety of treatments. However, the inclusion criteria for this study may have led to a higher representation of male AD patients aged 80 years and above.

5 Conclusions

Dupilumab treatment yielded a significant improvement in symptoms and achieved satisfactory clinical efficacy in much older patients with AD after 16 weeks. Furthermore, it did not have a notable impact on the control of underlying diseases or medication in these patients, indicating a high level of safety. These findings emphasize that age should not be a limiting factor for clinicians when considering the use of biological agents, such as dupilumab, in the treatment of moderate-to-severe AD in older patients. The results of this study provide valuable guidance for the appropriate utilization of dupilumab in this specific population.