Abstract
Identifying the characteristics of atopic dermatitis (AD) patients with its comorbidity has become increasingly crucial. We aimed to investigate the relevant factors associated with comorbidities in adults with AD. We analyzed cross-sectional data through univariate and multivariate regression analyses, encompassing 439 adult cases of AD from the Clinical Research and Homogenization Diagnosis and Treatment Project for Type 2 Inflammatory Dermatosis. It was found that 231 patients developed at least one comorbidity. 161 cases had a positive family history of atopy, 292 exhibited elevated IgE levels. A family history of allergic rhinitis or sinusitis was found to be associated with concurrent diseases (OR (95% CI): 2.92 (1.41–6.06) in model 1; 2.71 (1.27–5.77) in model 2; 3.59 (1.75–7.37) in model 3; 3.38 (1.62–7.05) in model 4; 3.60 (1.83–7.08) in model 5; 3.56 (1.78–7.12) in model 6). The linkage between elevated IgE levels and concurrent diseases with different classifications was negative (OR (95% CI): 0.51 (0.33–0.79) in model 1; 0.51 (0.33–0.80) in model 2; 0.51 (0.33–0.79) in model 3; 0.52 (0.33–0.81) in model 4; 0.45 (0.29–0.71) in model 5; 0.47 (0.30–0.73) in model 6). Scores for familial atopy (OR (95% CI): 1.56 (1.00-2.44) in model 2; 1.59 (1.03–2.48) in model 4; 1.84 (1.19–2.84) in model 6) were positively associated with comorbidities. Factors associated with comorbidity development in AD included a family history of allergic rhinitis or sinusitis, elevated IgE levels and scores indicating familial atopy. These relevant factors might contribute to improved discrimination and early intervention for comorbidities in individuals with AD.
Keywords: Atopic dermatitis, Comorbidity, Family health, Immunoglobulin E
Introduction
Atopic dermatitis (AD) is the most common recrudescent, chronic, inflammatory skin disorder that occurs with or without an increase in immunoglobulin E (IgE) and eosinophil levels; It is characterized by bothersome pruritus and polymorphic eczematous lesions. The prevalence of AD in children and adolescents ranges from 13.5 to 41.9%, while in adults, it varies from 3.4 to 33.7% [1, 2]. Therapy for AD includes basic moisturizers and emollients, and systemic and topical drugs [3, 4]. However, the treatment regimen is ineffective for the control and prediction of certain concurrent diseases associated with AD, whose significance is often underestimated.
The thorough exploration of AD, has shown that it often coexists with allergic rhinitis (AR), asthma, eosinophilic esophagitis and food allergy (FA), a phenomenon known as the atopic march. It is well-known that an individual with a family history of allergic asthma and allergic rhino-conjunctivitis is susceptible to AD or other atopic disorders, such as atopic diathesis [5]. Besides, researchers have discovered the link between AD and non-atopic illnesses, such as autoimmune diseases (including alopecia areata, vitiligo, chronic urticaria, inflammatory bowel disease, systemic lupus erythematosus, and rheumatoid arthritis), hypertension, diabetes mellitus, psychiatric diseases (including anxiety, depression, and attention hyperactivity disorder), infections (including cutaneous and extracutaneous infections), osteoporosis, nasal polyposis etc [6–9]. They may potentially share similar pathogenic factors, and pathways, and contribute to the development of certain illnesses.
Most research has focused on certain comorbidities in AD; and evidence regarding multiple concurrent diseases considered as an entity is limited. Usually, family atopy was categorized as being present or absent, and there is a scarcity of scoring systems. Also, there is insufficient clinical evidence on the relationship between relevant factors, such as initial onset site, elevated immunoglobulin E levels, and comorbidities associated with AD. Moreover, both dermatologists and patients probably underestimate the effects of these associations on the treatment and prevention of comorbidities in medical decision-making. Therapeutic approaches might vary slightly for various comorbidities [3, 4].
Thus, we analyzed the common features in the adult population to identify potential influential factors. Subsequently, we built clinical binomial logistic regression models to predict comorbidity development.
Methods
Data source
Data from the AD population was randomly obtained from the database for the Clinical Research and Homogenization, Diagnosis and Treatment Project for Type 2 Inflammatory Dermatosis, National Clinical Research Center for Dermatological and immunologic Disease, which was established in April 2021, and is an ongoing, non-interventional, observational registry of patients with AD, eczema, bullous pemphigoid or prurigo nodularis in China. This project was approved by the Ethics Committee and informed consent was obtained from all the study participants.
In December 2022, we extracted data for over 600 cases using the nextlnt function of the SecureRandom library. After excluding data with obvious errors and inconsistencies, we screened 565 cases of AD, including 439 adults and 126 adolescents, during our analysis. We selected 439 adult cases of AD for further analyses, taking into account differences between adults and adolescents, for whom the collected information included the gender, birth date, onset sites, rash-distribution, comorbidities, elevated IgE (yes or no), serum IgE levels, mean pruritus scores, and pruritus severity, assessed weekly through the numerical rating scale(NRS), investigator’s global assessment (IGA) score, eczema area and severity index (EASI), affected body surface area (BSA) (%), dermatology life quality index (DLQI), AD control tool (ADCT), patient-oriented eczema measure (POEM), and hospital anxiety and depression scale (HADS), etc.
To assess the factors associated with comorbidity development, we defined 3 groups based on different outcome events. Outcome 1 (named as the ‘all comorbidities group’) referred to AD patients that developed at least one of con-current diseases, including asthma, AR or sinusitis, allergic conjunctivitis (AC), FA, drug allergy, xerodema or ichthyosis, chronic urticaria, contact dermatitis, psoriasis, alopecia areata, inflammatory bowel disease, coronary heart disease, diabetes, hypertension, depression or anxiety disorder, attention deficit hyperactivity disorder, and skin infections. Considering the internal associations between comorbidities, we reorganized outcome 2 based on whether the individual with AD had at least one of four allergic disorders, i.e., asthma, AR or sinusitis, AC, and FA. Furthermore, we defined outcome 3 based on whether patients suffered from at least one of three atopic diseases (asthma, AR or sinusitis, and AC) in this study, because the prevalence FA was lower in adults than in children.
Positive familial atopy was defined as a family history of at least one of following six diseases, eczema, asthma, AR or sinusitis, chronic urticaria, AC, and FA. In this study, family history was referred to as the medical history of collateral family members related by blood within three generations. Besides, we determined atopic family history scores, which were the sum of the familial atopy conditions described above (0–6 points) (Table 1). Disease inactivity is indicated by ADCT scores < 7 points; otherwise, it is considered that an individual has active disease. The severity of the EASI could be classified as mild when EASI scores were equal to or less than 7, moderate when EASI scores were between 7 and 21, and severe when scores exceeded 21. IGA scores less than or equal to 2 was mild, those equal to 3 was moderate, and those equal to 4 or 5 was severe. POEM scores below 7 were considered mild, those between 8 and 16 were considered moderate, and scores exceeding 16 were considered severe. Scores less than or equal to 5 were mild, those ranging from 6 to 10 were moderate, and those otherwise were considered severe in DLQI.
Table 1.
Atopic family history scores
| Scores | Description |
|---|---|
| 0 points | No family history of following diseases, eczema, asthma, AR or sinusitis, chronic urticaria, AC or FA |
| 1 point | Possessing a family history of one of above 6 diseases |
| 2 points | Possessing a family history of two of above 6 diseases |
| 3 points | Possessing a family history of three of above 6 diseases |
| 4 points | Possessing a family history of four of above 6 diseases |
| 5 points | Possessing a family history of five of above 6 diseases |
| 6 points | Possessing a family history of above all 6 diseases |
Family history was referred to a medical history of collateral relative by blood three generations
Statistical analysis
Categorical values were described as numbers and percentages, and continuous variables were described as medians and quartiles. Categorical variables were analyzed using the χ2 test. The non-parametric test was used for numerical variables. We analyzed the relationship between potential indicators and comorbidities of AD via univariable and multi-variable logistic regression analysis with SPSS 17.0. Results were presented as odds ratios (OR) with 95% confidence intervals (CIs). Results were defined as statistically significant if P < 0.05. Plyr, ggsci [10], ggplot2, rcompanion, ResourceSelection, VGAM, rms, reshape and cowplot packages in R (4.2.3) were used to plot and build binomial logistic regression models.
Results
Clinical features
We analyzed 439 cases of AD and their clinical characteristics were as follows. Gender-based differences were not significant, with males accounting for 50.57% of the study population. Patients generally complained of pruritus (429), and a smaller number of patients experienced a burning sensation (65) and pain (59). The trunk (238), lower extremities (229), and upper extremities (220) were the most common initial onset sites in adults with AD. The top three areas where rashes were distributed included the upper extremities (338), lower extremities (326) and the trunk (324). 72 patients were positive for an allergen, 139 exhibited elevated eosinophils, and 292 had elevated IgE levels. Besides, most patients had the active disease (395, 89.98%). Over half the patients (231, 52.62%) were born in Spring and Autumn (i.e. born in SA) (Fig. 1a).
Fig. 1.
(a). Characteristics of AD patients. (b). The severity of AD population in different measurements. (c). The distribution of AD comorbidities. Some diseases didn’t show for zero case, such as alopecia areata, inflammatory bowel disease, coronary heart disease, depres-sion or anxiety disorder, attention deficit hyperactivity disorder. d. Multivariable logistic analysis in six models. Model 1, 3 and 5 corresponded to outcome 1, 2 and 3, encompassing variable of family atopy. Model 2, 4, 6 corresponded to outcome 1, 2 and 3 respectively, containing scores of familial atopy. * P < 0.05. y2y6Duration means that patients had AD presentation from 2 to 6 years old
The severity grade percentage varied with different assessments. The percentage of patients with mild, moderate, and severe EASI scores were 37.81% (166), 38.27% (168), and 23.92% (105), respectively. The percentage of patients with mild, moderate, and severe POEM scores accounted for 12.30% (54), 52.62% (231), and 35.08% (154) of the study population, respectively. In terms of IGA values, the percentage were 22.55% (99), 51.48% (226), and 25.97% (114) for the mild, moderate, and severe categories, respectively. The DLQIs were 33.03% (145), 19.13% (84), and 47.84% (210) for mild, moderate, and severe categories, respectively (Fig. 1b).
More than half the patients (231, 52.62%) developed at least one comorbidity. The percentage of patients with two concomitant comorbidities was 10.48% (46), while, 2.96% (13) had 3 or 4 comorbidities. The proportion of patients who had at least one comorbidity in the outcome 2 and outcome 3 groups accounted for 47.15% (207) and 38.50% (169) of the study population, respectively. The top 3 comorbidities health included AR or sinusitis (151, 34.40%), FA (59, 13.44%), and asthma (22, 5.01%) (Fig. 1c).
The differences in IgE levels and scores of individuals with familial atopy were statistically significant (Table 2). Categorical variables, including elevated IgE levels, familial atopy, and family history of AR or sinusitis showed statistical differences in different outcomes (Table 3).
Table 2.
Baseline demographics and disease characteristics
| Characteristic | n | Classification | all | P value |
|---|---|---|---|---|
| Age (years, median[range]) | 439 | 34.00(24.00–48.00) | ||
| outcome 1 (yes) | 34.00(25.00–48.00) | 0.640 | ||
| outcome 2 (yes) | 34.00(25.00–48.00) | 0.554 | ||
| outcome 3 (yes) | 35.00(25.00–48.00) | 0.373 | ||
| Height (cm, median[range]) | 439 | 166.00(161.00-172.00) | ||
| outcome 1 (yes) | 165.00(160.00-172.00) | 0.475 | ||
| outcome 2 (yes) | 165.00(160.00-172.00) | 0.455 | ||
| outcome 3 (yes) | 165.00(160.00-172.00) | 0.401 | ||
| Weight (kg, median[range]) | 439 | 62.00(54.00–72.00) | ||
| outcome 1 (yes) | 63.00(55.00–72.00) | 0.888 | ||
| outcome 2 (yes) | 62.00(54.00–72.00) | 0.855 | ||
| outcome 3 (yes) | 63.00(53.00–72.00) | 0.808 | ||
| BMI (Kg/m2, median[range]) | 439 | 22.49(22.20-24.91) | ||
| outcome 1 (yes) | 22.55(20.24-24.91) | 0.525 | ||
| outcome 2 (yes) | 22.49(20.20–25.10) | 0.839 | ||
| outcome 3 (yes) | 22.27(20.07–25.13) | 0.932 | ||
| BSA (%, median[range]) | 439 | 18.00(8.00–36.00) | ||
| outcome 1 (yes) | 18.00(7.00–33.00) | 0.505 | ||
| outcome 2 (yes) | 19.00(7.00–33.00) | 0.533 | ||
| outcome 3 (yes) | 19.00(7.00-35.15) | 0.845 | ||
| ESAI (median[range]) | 439 | 10.00(4.50–20.60) | ||
| outcome 1 (yes) | 10.80(4.50–21.60) | 0.563 | ||
| outcome 2 (yes) | 10.80(4.40–21.60) | 0.459 | ||
| outcome 3 (yes) | 9.70(3.68–20.73) | 0.337 | ||
| ADCT (median[range]) | 439 | 14.00(11.00–18.00) | ||
| outcome 1 (yes) | 14.00(11.00–18.00) | 0.586 | ||
| outcome 2 (yes) | 14.00(11.00–18.00) | 0.917 | ||
| outcome 3 (yes) | 14.00(10.00–18.00) | 0.337 | ||
| POEM (median[range]) | 439 | 14.00(11.00–18.00) | ||
| outcome 1 (yes) | 13.00(10.00–18.00) | 0.262 | ||
| outcome 2 (yes) | 13.00(10.00–17.00) | 0.051 | ||
| outcome 3 (yes) | 13.00(9.50–18.50) | 0.576 | ||
| DLQI (median[range]) | 439 | 10.00(2.00–15.00) | ||
| outcome 1 (yes) | 11.00(1.00–16.00) | 0.964 | ||
| outcome 2 (yes) | 11.00(0.00–16.00) | 0.465 | ||
| outcome 3 (yes) | 10.00(0.00–16.00) | 0.391 | ||
| HADS (median[range]) | 439 | 12.00(6.00–18.00) | ||
| outcome 1 (yes) | 12.00(7.00–18.00) | 0.607 | ||
| outcome 2 (yes) | 12.00(7.00–17.00) | 0.989 | ||
| outcome 3 (yes) | 12.00(6.00–18.00) | 0.845 | ||
| Mean pruritus scores by weekly NRS (median[range]) | 437 | 6.00 (4.00–7.00) | ||
| outcome 1 (yes) | 6.00(5.00–7.00) | 0.373 | ||
| outcome 2 (yes) | 6.00(4.75-7.00) | 0.854 | ||
| outcome 3 (yes) | 6.00(4.00–7.00) | 0.879 | ||
| Pruritus severity by weekly NRS (median[range]) | 438 | 7.00(5.75-8.00) | ||
| outcome 1 (yes) | 7.00(6.00–8.00) | 0.765 | ||
| outcome 2 (yes) | 7.00(6.00–8.00) | 0.634 | ||
| outcome 3 (yes) | 8.00(5.00-8.75) | 0.660 | ||
| IgE (median[range]) | 438 | 315.50(86.49-842.45) | ||
| outcome 1 (yes) | 346.10(105.69–1180.00) | 0.007* | ||
| outcome 2 (yes) | 351.29(107.00-1221.80) | 0.003* | ||
| outcome 3 (yes) | 384.00(149.00-1388.45) | 0.000* | ||
| Scores of Familial Atopy (median[range]) | 438 | 0.00(0.00–1.00) | ||
| outcome 1 (yes) | 0.00(0.00–1.00) | 0.000* | ||
| outcome 2 (yes) | 0.50(0.00–1.00) | 0.000* | ||
| outcome 3 (yes) | 1.00(0.00–1.00) | 0.000* |
* P < 0.05, data were described as median and quartiles because these continuous variables were non-normal distribution. P value was calculated by non-parametric test with different outcomes
Table 3.
Baseline demographics and disease characteristics (categorical variables)
| Characteristic | Percentage | Outcome 1 | Outcome 2 | Outcome 3 | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| no | yes | χ2 | P value | no | yes | χ2 | P value | no | yes | χ2 | P value | ||
| Gender, male, yes, n |
50.57% (222/439) |
110 | 112 | 0.848 | 0.357 | 123 | 99 | 1.179 | 0.277 | 140 | 82 | 0.461 | 0.497 |
| Ig E elevation, yes, n |
66.67% (292/438) |
153 | 139 | 8.464 | 0.004* | 168 | 124 | 7.332 | 0.007* | 197 | 95 | 12.558 | 0.000* |
| Lower Limb Onset, yes, n |
53.01% (229/432) |
94 | 135 | 7.454 | 0.006* | 112 | 117 | 2.928 | 0.087 | 135 | 94 | 1.416 | 0.234 |
| y2y6 Duration, yes, n |
9.74% (41/421) |
12 | 29 | 6.214 | 0.013* | 18 | 23 | 1.579 | 0.209 | 24 | 17 | 0.264 | 0.607 |
| Family history of AR or sinusitis, yes, n |
18.49% (81/438) |
17 | 64 | 27.988 | 0.000* | 17 | 64 | 40.799 | 0.000* | 22 | 59 | 49.979 | 0.000* |
| Familial Atopy, yes, n |
36.76% (161/438) |
51 | 110 | 25.523 | 0.000* | 58 | 103 | 29.336 | 0.000* | 66 | 95 | 45.913 | 0.000* |
| Family history of eczema, yes, n |
17.12% (75/438) |
28 | 47 | 3.743 | 0.053 | 33 | 42 | 2.922 | 0.087 | 36 | 39 | 7.125 | 0.008* |
*P < 0.05. Categorical variables were described as numbers. P value was calculated by χ2 test. y2y6 Duration indicated patients ever had rashes when they were from 2 to 6 years old
Evaluating potentially associated factors via logistic regression analysis
In order to investigate the potential were differences between familial atopy and its scores, we categorized them into different subgroups for each outcome. In the multi-variable logistic regression analysis, we built models 1, 3, and 5, corresponding to outcomes 1, 2, and 3, respectively, and encompassing the variable of family atopy. Models 2, 4, and 6 corresponded to outcomes 1, 2, and 3 encompassing the scores for familial atopy.
Univariate and multivariate regression analysis with outcome 1
In the univariable analysis, 8 variables were significantly associated with the development of AD-associated comorbidities (Table 4). In the multivariable analysis, only a few variables remained statistically significant. These included elevation of IgE (OR (95% CI): 0.51 (0.33–0.79) in model 1; 0.51 (0.33–0.80) in model 2), onset in the lower extremities (OR (95% CI): 1.85 (1.22–2.81) in model 1; 1.86 (1.23–2.82) in model 2), scores for familial atopy (OR (95% CI): 1.56 (1.00-2.44)), and family history of AR or sinusitis (OR (95% CI): 2.92 (1.41–6.06) in model 1; 2.71 (1.27–5.77) in model 2), y2y6 duration (OR (95% CI): 3.38 (1.58–7.25) in model 1; 3.38 (1.58–7.25) in model 2) (Fig. 1d; Table 4). However, no statistical differences were observed for familial atopy (OR (95% CI): 1.67 (0.98–2.86)) in this multivariable analysis.
Table 4.
Results of univariable and multivariable logistic analysis
| Univariable logistic analysis | Multivariable logistic analysis | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Outcome 1 | Outcome 2 | Outcome 3 | Model 1 [OR (95%CI)] |
Model 2 [OR (95%CI)] |
Model 3 [OR (95%CI)] |
Model 4 [OR (95%CI)] |
Model 5 [OR (95%CI)] |
Model 6 [OR (95%CI)] |
|
| Lower Limb Onset |
1.70* (1.16-2.49) |
1.39 (0.95-2.04) |
1.27 (0.86-1.87) |
1.85* (1.22-2.81) |
1.86* (1.23-2.82) |
||||
| y2y6 Duration |
2.39* (1.19-4.83) |
1.51 (0.79-2.90) |
1.19 (0.62-2.29) |
3.38* (1.58-7.25) |
3.38* (1.58-7.25) |
||||
| IgE elevation |
0.55* (0.37-0.82) |
0.58* (0.39-0.86) |
0.48* (0.32-0.72) |
0.51* (0.33-0.79) |
0.51* (0.33-0.80) |
0.51* (0.33-0.79) |
0.52* (0.33-0.81) |
0.45* (0.29-0.71) |
0.47* (0.30-0.73) |
| Family history of AR or sinusitis |
4.33* (2.44-7.69) |
5.70* (3.21-10.13) |
6.10* (3.56-10.46) |
2.92* (1.41-6.06) |
2.71* (1.27-5.77) |
3.59* (1.75-7.37) |
3.38* (1.62-7.05) |
3.60* (1.83-7.08) |
3.56* (1.78-7.12) |
| Onset Age |
0.80* (0.68-0.94) |
0.83* (0.71-0.98) |
0.90 (0.77-1.06) |
0.81* (0.68-0.97) |
0.81* (0.68-0.97) |
||||
| Perineum |
0.29* (0.09-0.90) |
0.25* (0.07-0.88) |
0.35 (0.10-1.26) |
0.29 (0.08-1.05) |
0.29 (0.08-1.05) |
||||
| Familial Atopy |
2.82* (1.88-4.25) |
3.00* (2.00-4.49) |
4.02* (2.66-6.08) |
1.67 (0.98-2.86) |
1.71* (1.01-2.90) |
2.22* (1.31-3.76) |
|||
| Familial Atopy scores |
2.35* (1.67-3.30) |
2.51* (1.80-3.52) |
3.02* (2.15-4.26) |
1.56* (1.00-2.44) |
1.59* (1.03-2.48) |
1.84* (1.19-2.84) |
|||
| Family history of eczema |
1.65 (0.99-2.75) |
1.54 (0.94-2.55) |
1.97* (1.19-3.24) |
||||||
| Birth in SA |
0.95 (0.65-1.38) |
0.78 (0.53-1.13) |
0.63* (0.43-0.93) |
0.62* (0.41-0.96) |
0.62* (0.41-0.95) |
||||
*P < 0.05. Model 1, 3 and 5 corresponded to outcome 1, 2 and 3, encompassing variable of family atopy. Model 2, 4, 6 corresponded to outcome 1, 2 and 3 respectively, containing scores of familial atopy. Birth in SA: birth in spring or autumn; y2y6 Duration indicated patients ever always had rashes when they were from 2 to 6 years old. Perineum: Patients had a rash-distribution in perineum when they go to a doctor
Univariate and multivariate regression analysis with outcome 2
The results of univariable analysis are shown in Table 4. Notably, elevated IgE levels (OR (95% CI): 0.51 (0.33–0.79) in model 3; 0.52 (0.33–0.81) in model 4), age of onset (OR (95% CI): 0.81 (0.68–0.97) in model 3; 0.81 (0.68–0.97) in model 4), scores of familial atopy (OR (95% CI): 1.59 (1.03–2.48)), familial atopy (OR (95% CI): 1.71 (1.01–2.90)), and family history of AR or sinusitis (OR (95% CI): 3.59 (1.75–7.37) in model 3; 3.38 (1.62–7.05) in model 4) were statistically significant in multivariable analysis (Fig. 1d).
Univariate and multivariate regression analysis with outcome 3
The results of univariable analysis are shown in Table 4. In the multivariable analysis, elevated IgE levels (OR (95% CI): 0.45 (0.29–0.71) in model 5; 0.47 (0.30–0.73) in model 6), familial atopy (OR (95% CI): 2.22 (1.31–3.76)) or scores of familial atopy (OR (95% CI): 1.84 (1.19–2.84)), family history of AR or sinusitis (OR (95% CI): 3.60 (1.83–7.08) in model 5; 3.56 (1.78–7.12) in model 6) and birth in spring and autumn (OR (95% CI): 0.62 (0.41–0.96) in model 5; 0.62 (0.41–0.95) in model 6) exhibited statistical differences (Fig. 1d; Table 4). Notably, both univariable and multivariable logistic regression analysis results showed that birth in the spring and autumn (birth in SA) seasons was related to comorbidities from outcome 3.
Binomial logistic regression models
After excluding missing data using the R language, we proceeded with the data for 401 individuals model development. Additionally, we analyzed and identified important factors from various elements through a step-by-step approach using R language, and the results were similar to those calculated using SPSS. Then, we plotted nomograms displaying 100% of the developing comorbidities (outcome 1), allergic comorbid conditions (outcome 2) and atopic comorbidities (outcome 3). The nomograms included points assigned to factors in different models (Fig. 2). Notably, no statistical differences in familial atopy were observed in patients with allergic comorbid conditions (outcome 1). Elevated IgE levels and family history of AR or sinusitis were statistically different statistically in all models. Models were verified via calibration.
Fig. 2.
Nomogram (on the left) and calibration curve (on the right) in different models. Both a and b, d and e were respectively analyzed with outcome of AD comorbidity and atopic diseases, corresponding to different forms of familial atopy. C was built by results of allergic disease in adults with AD
Discussion
The increasing prevalence of AD, has gradually attracted the attention of dermatologists towards concurrently occurring diseases. Thus, it is necessary to design appropriate preventive strategies for understanding the factors associated with concurrent disease development in individuals with AD. In this article, we indicated the presence or absence of familial atopy, scores of familial atopy, and family history of AR or sinusitis, and showed that these factors were positively associated with concurrent disease development. However, there was a negative association between elevated IgE levels and comorbidities. Binomial logistic regression models indicated that AD subjects with a family history of AR or sinusitis, who had higher scores of family atopy or familial atopy, non-elevated IgE levels, and onset in the lower limbs were more likely to have comorbid disorders. These patients, characterized by higher scores for family atopy, IgE levels within normal ranges, and positive allergen and family history of AR or sinusitis, had a higher likelihood of development of one of the conditions in outcome 2. Individuals in the outcome 3 group, exhibiting the development of disorders, showed certain features, including not being born in spring and autumn, having normal IgE levels, familial atopy or higher scores of family atopy, and a positive family history of AR or sinusitis.
Consistent with other studies [11, 12], this article identifies AR (151, 34.4%) as the most common comorbidity. Increasingly, scientific research indicates an increased risk of developing AD and AR in a population with a positive parental history of AD or other atopic diseases [13–15]. In comparison to health individuals, the prevalence of AD in a population in which the relatives had atopic dermatitis was about 3.1 times higher (12.4% vs. 4.0%) [16]. Besides, Ćosićkić Almira et al. [17] observed in a cohort study that familial atopy was a risk factor for both asthma and AR OR values were 7.0 (95%CI 2.8–17.0) and 4.0 (95%CI 1.6–9.5). Nevertheless, evidence regarding the relationship between familial atopy and individuals with AD and other comorbidities is limited.
In this study, we retrospectively investigated the connection between familial atopy and comorbidities, treating them as a collective entity. First, we introduced the concept of atopic family history scores, representing the sum of all positive family histories of 6 other atopic diseases. Significant differences were observed in the multi-variable logistic regression analysis of outcome 1. While family atopy, indicated by a yes or no showed no statistical differences, a similar trend was observed. However, this phenomenon was not evident in multi-variable logistic models of outcome 2 and outcome 3. The inconsistency may be attributed to the small sample size and inclusion familial history of partial atopic diseases in this context. Consequently, we hypothesized that atopic family history scores may be a unique and potentially superior factor contributing to the evaluation of the risk of comorbid diseases compared to simple family atopy classification. This may provide new clues for further research by refining the level and weight of familial atopy based on the degree of the relationship. Also, its authenticity and effectiveness need to be verified by more large-scale, multi-center, and prospective studies.
FA, AD, and asthma are commonly accompanied by strong familial clustering [18–20]. However, we only observed that a family history of AR or sinusitis was positively associated with comorbid diseases in all 6 models. These results can be attributed to a certain genetic background, similar external environment, and lifestyle. Notably, FA, AD, AR, and asthma are clinically considered as different but genetically interlinked disorders involving at least 16 common genes (IL5, IL4, TSLP, IL10, RNASE3, IGHG4, IL13, CCL11, IFNG, RNASE2, FCER2, CD4, FOXP3, IL4R, KCNE4, and CCL26) [21]. The relevance estimate value for AD and AR, was 0.62 [22]. Herein, a family history of AR or sinusitis could be used as a predictor of co-morbidity in AD patients.
Current evidence regarding the association between IgE, severity, and comorbidity in individuals with AD has been inconsistent. Unlike previous studies [23], this study found no notable associations between AD severity, as measured by various clinical indicators, and comorbidities. For instance, Nora Laske et al. [24] reported that extremely high levels of IgEs (over 10,000 kU/L) resulted in a higher proportion of individuals exhibiting allergy reactions (20% vs. 7%) and hypersensitivity to both airborne and food allergens (80% vs. 32%), compared to individuals with the moderate IgE levels (400-1000kU/L). However, elevated cord-blood IgE levels have been found to correlate negatively with AD in infants who were less than 12 months old [25]. In our study, raised IgE levels were similarly found to negatively correlated with comorbidity presence in the adult AD population. Several factors may explain the inconsistency in IgE associations. First, this study focused on adults, whose IgE levels may differ in stability from those in children. Additionally, the IgE data collected across three generations relied on self-reporting and family-reported information, which may introduce potential recall bias and limitations in data accuracy, especially for historical records lacking precise medical documentation. Future studies could benefit from a prospective design or standardized multigenerational medical records to obtain more reliable data. Moreover, IgE levels are also easily influenced by various external factors, such as air pollution, parasite infections, gender, and genetic factors, complicating consistent associations with AD comorbidities. Furthermore, our study classified IgE elevation simply as “yes” or “no”, without stratifying by degree of elevation, potentially overlooking nuanced relationships. This limitation leads us to speculate on whether IgE may play a dual regulatory role in AD. IgE may play a transient protective role when its levels are within a certain range, and act as a risk factor for individuals with AD with comorbidities when present at levels beyond this range. This hypothesis offers a novel perspective for future research to investigate IgE’s threshold effects in AD comorbidities.
Lio Peter A et al. [26] suggested that patient quality of life is affected by lesion sites, particularly in visible areas such as the head and neck (68%), hands (58%), and upper extremities (22%). Unfortunately, no statistical differences were observed between rash-distribution, other onset sites of the human body, and comorbidities apart from onset in the lower limbs. These differences might stem from variations in ethnicity, environmental exposure, or study design.
The identified indicators in our study may assist with early identification and intervention of comorbid conditions in AD patients, which is especially important for personalized precision medicine. Dermatologists need to consider these factors, particularly family history of AR or sinusitis and familial atopy scores, when making clinical decisions to prevent comorbidities in AD patients. In summary, factors associated with comorbidity development in AD patients included a family history of AR or sinusitis, elevated IgE levels, and familial atopy scores, all of which may improve discrimination and early intervention in AD patients with comorbidities.
Acknowledgements
We express our gratitude to the Clinical Research and Homogenization Diagnosis and Treatment Project for Type 2 Inflammatory Dermatosis, at the National Clinical Research Center for Skin and Immune Disease for providing data.
Author contributions
L.J.: Methodology, Data curation, Formal Analysis, Writing-original draft, Writing-review & editing. S.P.: Data curation, Methodology, Investigation, Visualization, Writing-review & editing. J.G.: Data curation, Methodology, Investigation, Visualization, Writing-review & editing. A.W.: Methodology, Project Administration, Supervision, Writing-review & editing. All authors have read and agreed to the published version of the manuscript.
Funding
None.
Data availability
Research data is available upon request under reasonable request.
Declarations
Ethical approval
Additional ethical approval was not required for this study because data were obtained from studies conducted by the Clinical Research and Homogenization Diagnosis and Treatment Project for Type 2 Inflammatory Dermatosis. These studies were performed in accordance with the Declaration of Helsinki and approved by the Ethics Committee (2021 scientific research 223).
Consent to participate
Informed consent was obtained from all subjects.
Consent to publish
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
The original online version of this article was revised to correct the References 10 and 13.
Publisher’s note
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Change history
1/9/2025
The original online version of this article was revised to correct the References 10 and 13.
Change history
1/10/2025
A Correction to this paper has been published: 10.1007/s00403-024-03766-8
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Data Availability Statement
Research data is available upon request under reasonable request.