Flare factors revisited: Correlation of serum immunoglobulin E and Vitamin D3 with atopic dermatitis severity

INTRODUCTION

Atopic dermatitis (AD) is a chronic and chronically relapsing, disabling dermatosis worldwide. “Dermatitis,” which includes AD, is ranked the highest among total global disability burden by the Global Disease Burden project.^[1] It accounts for 2–20% of the general population, with differences in age and ethnicity.^[2]

AD is characterized by itchy, papules, sometimes vesicles, which become lichenified and excoriated, typically involving the flexures that cause significant morbidity.^[3] This leads to deterioration in the quality of life (QOL) of the patient and that of the patient’s family, for which various indices have been used to measure how severely it affects the QOL of patients.^[4]

One of the least addressed areas of research is the serum level of vitamin D3 in AD.

The study aims to estimate the serum level of Immunoglobulin E (IgE) and vitamin D3 and to correlate their levels with the severity of AD. There are limited published data evaluating the combined role of serum IgE and vitamin D3 in AD severity from the Indian subcontinent; the present study contributes region-specific evidence to this growing body of literature.

MATERIALS AND METHODS

A cross-sectional observational study was conducted in the dermatology outpatient department over a period of 18 months.

The sample size was calculated using the standard formula for prevalence-based studies. Based on the study by Furue et al.,^[2] the prevalence of AD in the general population ranges from 2 to 20%. Considering a prevalence (p) of 20%, a 95% confidence level (Z = 1.96), and an allowable error (e) of 10%, the sample size was calculated using the formula: n = Z²p (1−p)/e².

Based on this calculation, the minimum required sample size was 62, and accordingly, 62 patients were included in the study. A total of 62 patients clinically diagnosed with AD, fulfilling the Hanifin and Rajka criteria, were consecutively recruited. The Institutional Ethics Committee approved the study protocol, and the study was registered with the Clinical Trials Registry of India (CTRI registration number: REF/2021/01/040412).

Clinically diagnosed cases of AD fulfilling the Hanifin and Rajka criteria and patients willing to participate in the study were included. Patients who had received antihistamines within the preceding 48 hours, vitamin D3 supplements, systemic corticosteroids, or immunosuppressive therapy were excluded. Additional exclusion criteria included patients with non-atopic eczemas, pregnant or lactating women, individuals with hyper-IgE syndrome, and patients unwilling to participate in the study. Patients of all ages meeting the inclusion criteria were informed about the study, and written informed consent was taken from the patients willing to participate in the study and from parent/legal guardians, along with assent if the patient is of the pediatric age group. A patient information sheet furnished with details was handed over to the subjects.

A detailed history and a visual examination were performed to confirm the diagnosis using Hanifin Rajka’s Criteria,^[5] and the severity of AD was assessed using the SCORing AD (SCORAD) index.^[6] Serum IgE and vitamin D3 levels were analyzed in the laboratory using the “Electrochemiluminescence Immunoassay” method with respective reference values for IgE and vitamin D3.^[7,8] Correlation between SCORAD scores and serum IgE and vitamin D3 levels was assessed using Spearman’s rank correlation coefficient. Correlation coefficients are presented with 95% confidence intervals (CIs). p < 0.05 was considered statistically significant.

RESULTS

The study recruited 62 cases of AD diagnosed using Hanifin and Rajka’s criteria. The results were analyzed using the Standard Statistical Package for the Social Sciences software. The mean patient age was 24.41 ± 18.82 (mean ± standard deviation [S.D]) years. The maximum number of patients (25.8%) was ≤9 years. The age of participants ranged from 9 months to 71 years, with a median age of 20.0 years (interquartile range [IQR]: 9.25–37.75 years), reflecting a wide age distribution.

Of the total 62 AD patients enrolled in the study, 17 (27.4%) were male, and 45 (72.6%) were female. The male-to-female ratio was 1:2.6.

Of the 53 who had a history of atopy, 41 (77.35%) had allergic rhinitis alone, 10 (18.86%) had asthma alone, and 2 (3.77%) had both. Among the study subjects, 48.4% (30) had a family history of atopy (Allergic rhinitis, 53.4%).

Most patients had flexural involvement (38.70%) [Figures 1-3]. Of the four major criteria, 61 (98.4%) patients fulfilled the criteria of pruritus.

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Figure 1: (a) Ill-defined excoriated scaly plaques over the trunk flexure and bilateral cubital fossa. (b) Excoriated scaly plaques over the bilateral popliteal fossa.

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Figure 2: (a) Shows diffuse scaling, xerosis, and exaggerated skin markings/hyperlinearity on bilateral hands suggestive of hand eczema. (b) Shows diffuse scaling, signs of lichenification over the foot dorsum, suggesting foot eczema.

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Figure 3: (a) Exaggerated skin markings and neck folds in a teenage girl. (b) Lichenified plaques over the anterior neck of a middle-aged female- dirty neck sign.

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Of the 23 minor criteria, the most frequently found criterion was xerosis in 100% patients [Figure 4].

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Figure 4: Hyperlinear palms in a child.

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The mean value of SCORAD was 49.84 ± 21.18 (Mean ± S.D), that falls under the moderate SCORAD category. The minimum value was 21.18, and the maximum value was 94.70. The median SCORAD score was 44.7 (IQR: 33.65–69.46).

The patients belonging to mild, moderate, and severe SCORAD scores were 24 (38.70%), 32 (51.61%), and 6 (9.67%), respectively; the majority being in the moderate grade.

Serum IgE levels

In our study, serum IgE levels were raised (≥120 kIU/L^[7]) in 57/62 (91.93%) patients. The mean ± SD was 4404.01 ± 7264.38 kIU/L. The minimum level was 28.49 kIU/L, and the maximum was 42,380 kIU/L. Serum IgE levels showed marked variability with a median of 1425.0 IU/L (IQR: 531.4–5378.0 IU/L). The patient with the maximum IgE level had a SCORAD score of 88.6.

The Spearman’s correlation coefficient (r-value) was used to ascertain the relationship between serum IgE and the severity of AD using the SCORAD index. The r-value was 0.603, the Confidence interval (CI) being 0.416–0.741, and p = 0.0001, indicating a positive and significant correlation between the two entities [Tables 1 and 2]. This means that the severity of AD is directly proportional to serum IgE levels [Figure 5].

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Figure 5: Shows that the severity of atopic dermatitis is directly proportional to serum immunoglobulin E levels.

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Table 1: Correlation of serum IgE with the severity of atopic dermatitis.

Correlation between severity and serum IgE	Mean	Standard deviation	r-value	p-value
SerumIgE	4404.01	7264.38	0.603 (CI: 0.416– 0.741)	0.0001
TotalSCORing atopic dermatitis index(severity)	49.84	21.18

CI: Confidence interval, IgE: Immunoglobulin E. p-value significant at: p-value (<0.05).

Table 2: Correlation analysis performed using Spearman’s rank correlation coefficient with 95% CIs.

Parameter	Spearman’s R (95% CI)	p-value
SerumIgEversusSCORAD	0.603 (0.416–0.741)	0.0001 (<0.001)
SerumVitaminD3versusSCORAD	−0.234 (–0.457–0.017)	0.045

CI: Confidence interval, IgE: Immunoglobulin E, SCORAD: SCORing atopic dermatitis index. p-value significant at: p-value (<0.05).

Serum vitamin D3 level

The mean serum vitamin D3 levels as shown in Table 3. Measured among 62 AD patients were 17.9 (±8.56) ng/mL. The highest serum level of vitamin D3 was 54.26 ng/mL, and the lowest vitamin D3 was 7 ng/mL. The median serum vitamin D3 level was 15.85 ng/mL (IQR: 12.59–20.86 ng/mL).

Table 3: Serum Vitamin D3 levels range.

Range of Vitamin D3 levels	Frequency (n)	Percentage (%)
<20 ng/mL (deficiency)	44	71
20–29.9 ng/mL (insufficiency)	12	19.4
>30 ng/mL (normal)	6	9.7

The patient with the lowest vitamin D3 values was a 27-year-old male with a serum IgE value of 10,239 and a SCORAD of 69.5. He had alopecia areata associated, while the patient with the highest vitamin D3 value was a 71-year-old female with a serum IgE level of 28.49 kIU/L and a SCORAD index of 14.5.

For determining the relation between serum vitamin D3 and the severity of AD using the SCORAD index, the Spearman’s correlation coefficient (r-value) was used. The r-value was -0.234, CL being -0.457-0.017, and p = 0.045, suggesting that the correlation between the two entities was negative, but weak [Tables 2 and 4, Figure 6].

Table 4: Correlation of serum Vitamin D3 with the severity of atopic dermatitis.

Correlation between severity and serum Vitamin D3 levels	Mean	Standard deviation	r-value	p-value
SerumVitaminD3levels	17.9	8.56	−0.234 (CI: −0.457–0.017)	0.045
TotalSCORing atopic dermatitis index(severity)	49.84	21.18

CI: Confidence interval. p-value significant at: p-value (<0.05).

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Figure 6: Shows that the severity of atopic dermatitis is inversely proportional to serum Vitamin D3 levels.

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DISCUSSION

AD has been increasingly discussed in the past decade, especially in developing countries like India. The increasing prevalence of AD has been hypothesized to be influenced by lifestyle and environmental changes associated with urbanization and westernization; however, current evidence remains limited and inconclusive. In addition, Vitamin D plays a crucial role in immune regulation and skin barrier homeostasis.^[9] The treatment of AD involves using topical and systemic immunosuppressants to minimize the triggers, improve skin moisture, manage and address aggravating factors, and reduce inflammation, thus improving the QOL and alleviating the social embarrassment of the individual.^[10] Due to significant methodological heterogeneity, which includes variations in study design, age groups studied, diagnostic criteria, severity assessment tools, laboratory assays used for IgE and vitamin D estimation, and population characteristics, direct comparisons of findings across studies should be interpreted cautiously. The observed similarities and differences between research may be partially explained by these changes.

Our study recruited 62 cases of AD that fulfilled the inclusion criteria, with a mean age of 24.41 years. The youngest patient was 9 months old, and the oldest was 71 years old. A nationwide population-based study^[11] showed that the age group of 1–6 years (21.76%) had the largest number of cases, almost comparable with our study, further strengthening the fact that AD is predominantly a disease of childhood. Somani reported an age range from 1 to 24 years in his study, which is discordant with our study, primarily due to the low sample size.^[7] Our study showed a predominance of females (72.6%) affected by AD the most. Tania González-Mendoza et al.^[12] and Fuxench et al.^[13] showed the prevalence of AD to be higher in females than in males, which was consistent with our study. Interestingly, a study in children showed a male preponderance of the disease.^[14] The sociocultural factors and referral bias, including healthcare-seeking behavior, may have contributed to the observed female predominance. Furthermore, the present study was hospital-based and included both adult and pediatric patients, which may account for variations in age distribution and disease features. A number of the mentioned studies were population-based or pediatric-focused.

Our study found a personal history of atopic diathesis in 53/62 patients (85.5%). In contrast, a study by Hong et al.^[15] showed the presence of atopic diathesis in AD to be very low, that is, 4.7%. In another cohort of 529 children with atopic parents, 60% (316) had a history of atopy, comparable with our study.^[16] Differences in reported prevalence of atopic diathesis across studies may be influenced by variations in definitions of atopy, reliance on self-reported history versus objective testing, and differences in sample size and study populations.

In our study, 41 (77.35%) had allergic rhinitis, 10 (18.86%) had asthma, and 2 (3.77%) had a history of both. Kiiski et al.^[17] showed a 13.95% presence of asthma in patients of AD, while Wang Xin et al.^[18] showed 19.2% of patients had asthma, which is consistent with our study. The latter study^[18] further showed a 21.4% prevalence of allergic rhinitis in AD patients, which was lower than our study.

Our study showed a family history of atopy to be 48.4%, which is on par with a survey by Tariq et al.^[19] that showed the history of atopy in first-degree relatives to be 58.5%, while Vaneckova and Bukač^[20] showed a 66% familial atopic history. Hence, overall, the family history in AD patients ranges between 48 and 66%.

Our study further showed the most common atopic family history to be allergic rhinitis (53.4%), which has not yet been evaluated like this in the literature.

Our study revealed that most lesions were present over the flexures (38.70%), consistent with a study by Lochav et al.^[21]

In our study, the most common Hanifin and Rajka’s minor criterion was xerosis, consistent with Lochav and Gupta.^[21] Dutta et al.^[22] portrayed the consistency of occurrence of the early age of onset (83%) as one of the most common minor features, followed by xerosis (71%), while the study in children by Parthasarathy et al.^[14] showed Dennie-Morgan infraorbital fold (71.8%) as the most common minor criterion presentation, contrasting our study.

The mean of SCORAD in our study is 49.84 ± 21.18. The same research by Dutta et al. showed the mean SCORAD index to be 23.5 ± 11.4.^[22]

The severity categorization according to SCORAD showed 38.70%, 51.61%, and 9.67% being in mild, moderate, and severe categories, respectively. Our study is on par with a study done by Lee et al.^[23] where among 157 patients, mild, moderate, and severe AD was found in 30 (11.1%), 87 (55.4%), and 40 (25.5%) patients, respectively. The above study by Dutta et al. showed mild, moderate, and severe SCORAD to be in 66%, 26%, and 8% of the study subjects, respectively.^[22] In addition, variations in disease severity at presentation, assessment timing, and prior therapy exposure, all of which were not consistently controlled across studies, may account for variations in SCORAD distribution.

CONCLUSION

The condition and spectrum of AD are physically, mentally, financially, and socially exhausting to the patient and their family members. This is an observational cross-sectional study conducted in a tertiary care facility to correlate serum IgE and vitamin D3 levels with the severity of AD. Our findings revealed a positive and negative correlation between serum IgE and vitamin D3 levels, respectively, with the severity of AD, implying that the higher the level of serum IgE, the greater the severity, and the lower the serum vitamin D3, the greater the severity. Although the correlation of serum IgE and vitamin D levels with AD severity has been separately studied in the past, studies on the correlation of both serum IgE and vitamin D3 with AD severity are seldom available in the literature. This study adds to the existing body of evidence by demonstrating an association between serum IgE, vitamin D3 levels, and disease severity in patients with AD in our study population. When considered together, our results are generally in line with previous research; nonetheless, the observed differences underscore the necessity of standardized procedures and more extensive, long-term investigations to better clarify the correlation between IgE, vitamin D status, and the severity of AD.