Coexistence of Allergic Diseases in Pediatric Systemic Lupus Erythematosus Patients: Prevalence, Clinical manifestation and Severity

Abstract

Objective. This study aimed to evaluate allergic diseases in pediatric patients with SLE and their association with SLE disease activity. Method. Patients with SLE aged ≤18 years were enrolled. Allergic diseases were screened using the International Study of Asthma and Allergies in Childhood questionnaire. Patients with a positive allergic disease screen were evaluated by a pediatric allergist for diagnostic confirmation and severity assessment. Results. Out of 118 patients, 16 patients (13.56%) were confirmed to have 1 or more allergic diseases; fourteen with allergic rhinitis, 4 with asthma, and 2 with atopic dermatitis. Two patients had severe-persistent allergic rhinitis and one patient had undiagnosed, uncontrolled severe asthma. No statistically significant correlations between the severity of allergic diseases and SLE disease activity were identified. Conclusions. The overall prevalence of allergic disease among pediatric patients with SLE is within the range of the general population. Severe and undiagnosed allergic diseases and SLE can coexist.

Introduction

Prevalence of allergic and autoimmune diseases are simultaneously rising.^1,2 This parallel increasing prevalence of these 2 disorders indicates a possibility of their association. Systemic lupus erythematosus (SLE) is a prototypical systemic autoimmune disease associated with multisystem organ involvement leading to significant morbidity and mortality. ³

The hallmark pathogenic mechanism of SLE is the production of autoantibodies via abnormalities of antigen stimulation, B-cell defects, and T-cell dysregulation. ⁴ Regarding T-cell dysregulation, the role of T-helper 1 (Th1) cells has been demonstrated in autoimmune diseases. ⁵ Meanwhile, allergy is a prototypic type 2 inflammatory disease that is mediated by cytokines that are primarily secreted by T-helper 2 (Th2) cells. ⁶

According to the aforementioned Th1/Th2 paradigm mechanistic theory, SLE, an autoimmune disease, and allergic diseases should be mutually exclusive or should confer some protection from 1 to the other. Prior studies investigating allergic diseases in adult patients with SLE and healthy controls, found that patients with SLE had a significantly lower incidence of allergic diseases.^7,8 However, more recent studies provide evidence that these 2 disorders can coexist. A retrospective cohort study using data from the National Health Insurance System found an increased risk of asthma in patients with SLE. ⁹ Another population-based case-control study included data from a national insurance claims dataset revealed that atopic disease to be a significant risk factor for SLE. ¹⁰ These studies suggest there may be shared genetic or environmental factors contributing to the development of autoimmune diseases and allergic diseases.

In addition to the conflicts in the previously reported data, most previous studies were conducted in adults. Moreover, previously evaluated data was collected via questionnaire, from patient records or diagnostic codes without details of clinical manifestations or severity of allergic diseases.

The aim of this study was to investigate prevalence, clinical manifestation, severity of coexisting allergic diseases. The secondary objective was to examine the association between severity of allergic diseases and SLE disease activity. As the quality of life of patients with SLE is negatively affected by disease activity, ¹¹ treating co-existing allergic diseases may lead to a positive outcome. Understanding the association between allergic disease and autoimmune diseases may have important implications for diagnosis, management and treatment and quality of life of the patients.

Method

Patients

This cross-sectional study enrolled pediatric patients with SLE aged ≤18 years who attended the pediatric departments of our University hospital, from 2020 to 2022. Patients with an overlapping syndrome or who were unwilling to participate were excluded. SLE was diagnosed according to Systemic Lupus International Collaborating Clinics (SLICC) classification criteria ¹² by pediatricians who subspecialize in rheumatology, nephrology, or dermatology. Baseline demographic data, personal history of food/drug allergy, family history of allergy, current medications were collected.

Diagnosis and Severity Assessment of Allergic Diseases

The most common allergic diseases with validated screening questionnaire and standardized diagnosis criteria ¹³ (ie, allergic rhinitis, asthma, and atopic dermatitis) were assessed in this study.

The International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire was used to screen for allergic rhinitis, asthma, and atopic dermatitis. ¹⁴ Patients with a positive screen on the ISAAC questionnaire were evaluated for diagnostic confirmation and assessment of disease severity by a pediatric allergist using clinical criteria and testing.

Diagnosis of allergic rhinitis was modified from the International Consensus Report on the Diagnosis and Management of Rhinitis in which patients must have a history of 2 or more of the following symptoms: nasal discharge, nasal blockage, and/or sneeze/itch—with a duration of more than 1 hour on most days. ¹⁵ Skin prick tests for aeroallergens were also performed. Severity of allergic rhinitis was assessed using a visual analog scale (VAS), and was classified into intermittent/persistent and mild/moderate-severe. ¹⁶

The diagnosis of asthma was based on the patient’s history of characteristic symptom patterns and variable expiratory airflow limitation as documented by pulmonary function test. ¹⁷ The Childhood Asthma Control test (C-ACT) was used to determine the numerical asthma control score. ¹⁸ Asthma symptom control was classified as well-controlled, partly-controlled, or uncontrolled. ¹⁷

Atopic dermatitis was diagnosed based on Hanifin and Rajka’s diagnostic features of atopic dermatitis. Severity of atopic dermatitis was assessed using the Scoring Atopic Dermatitis (SCORAD) clinical tool. ¹⁹ SCORAD of <25, 25-50, >50 was classified as mild, moderate and severe atopic dermatitis, respectively.

SLE Disease Activity Assessment

SLE disease activity was assessed using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) ²⁰ by a pediatric rheumatologist. The SLEDAI-2K tool measures the global/overall disease activity of SLE. It comprises 24 clinical and laboratory variables that are weighted by the type of manifestation, and the total score reflects the sum of each of the 24 items. The higher SLEDAI-2k score represents worse disease activity.

Statistical Analysis

Patient demographic and clinical characteristics were analyzed using non-parametric descriptive statistics, as the data were mainly non-parametric or not normally distributed. Categorical data were compared using chi-square test or Fisher’s exact test. Continuous variables between the 2 groups were compared using Mann–Whitney U test. Correlation between severity of allergic diseases and SLE disease activity was assessed by Spearman rank-order correlation coefficient. Differences in the SLEDAI-2K score among the different severity classifications for allergic diseases were analyzed using the Kruskal–Wallis test. All data analyses were performed using Statistics SPSS version 19, and a P-value less than .05 was considered statistically significant.

Ethical Approval and Informed Consent

The protocol for this study complied with the 1964 Declaration of Helsinki and its later amendments and was approved by the Khon Kaen University Ethics Committee for Human Research (HE621327). Written informed consent was obtained from the parents and the patients.

Results

Patients

A total of 118 patients were included in this study. The patients’ baseline demographics and clinical characteristics, compared between those with and without confirmed allergic diseases are shown in Table 1. There were no statistically significant differences in any baseline characteristics or laboratory parameters between patients with and without confirmed allergic diseases except that a higher proportion of the patients with confirmed allergic diseases had a positive family history of allergic diseases in first-degree relatives.

Table 1.

Patient baseline Demographic, Clinical Characteristics and Laboratory Parameters, Compared Between Those With and Without Confirmed Allergic Disease.

Characteristics	All patients	Patients with confirmed allergic disease	Patients without confirmed allergic disease	P-value
Number of the patient	118 (100)	16 (13.56)	102 (86.44)	—
Female gender	108 (91.52)	14 (87.50)	94 (92.16)	.624
Age (years)	13.83 (11.71-15.90)	15.46 (12.69-16.34)	13.80 (11.41-15.65)	.216
Duration of disease (years)	1.54 (0.33-4.46)	0.82 (0.35-1.90)	1.58 (0.33-4.82)	.143
Personal history of drug and/or food allergy	11 (9.32)	2 (12.50)	9 (8.82)	.643
History of allergic disease in first degree relative	15 (12.70)	5 (31.25)	10 (9.80)	.017*
SLEDAI-2K	4 (2.00-8.25)	2 (0.00-10.00)	4 (2.00-8.00)	.305
ESR (mm/hour)	30 (14.00-43.00)	27 (18.76-42.50)	30 (13.50-44.50)	.694
C3 (mg/dL)	93.6 (73.70-117.10)	99.55 (88.38-118.45)	91 (72.43-117.08)	.233
C4 (mg/dL)	17.3 (11.50-23.90)	23.6 (12.10-29.23)	16.8 (11.13-22.88)	.126
Anti-dsDNA (IU/mL)	24.735 (0-425.52)	11.18 (0-318.28)	0 (27.82-424.65)	.585
Absolute eosinophil count (cells/mm3)	33.8 (11.62-117.90)	53.07(24.45-168.85)	31.36 (4.02-83.80)	0.293
Medication
Hydroxychloroquine	104 (88.14)	13 (81.25)	91 (89.22)	.704
Prednisolone	98 (83.05)	11 (68.75)	87 (85.29)	.101
Mycophenolate mofetil	69 (58.47)	6 (37.50)	63 (61.76)	.067
Azathioprine	12 (10.17)	2 (12.5)	10 (9.80)	.666
Methotrexate	2 (1.69)	1 (6.25)	1 (0.98)	.253
Cyclophosphamide	1 (0.85)	0 (0)	1 (0.98)	—

Continuous variables are reported as median (Interquartile range) and categorical and binary variables as n (%).

Abbreviations: SLEDAI-2K, Systemic Lupus Erythematosus Disease Activity Index 2000; ESR, Erythrocyte sedimentation rate; C3, Complement component 3; C4, Complement component 4; Anti-dsDNA, Anti-double-stranded deoxyribonucleic acid.

^*indicated a significant P value (< 0.05).

Twenty-one patients (17.80%) were disease-positive for allergic diseases via questionnaire. Sixteen patients (13.56%) were confirmed to have 1 or more allergic diseases. Three patients had both asthma and allergic rhinitis. One patient had atopic dermatitis along with allergic rhinitis. The median duration from the SLEDAI-2K assessment to the onset of allergic diseases was 1.49 years (IQR: 1.07-4.13).

Details specific to the patients who were disease-positive via questionnaire and the patients who were confirmed to have allergic diseases and their disease severity are shown in Figure 1.

Figure 1.

Patients with disease-positive via questionnaire and patients with confirmed and not confirmed with allergic diseases.

Patients Who Were Disease-Positive via Questionnaire, and Were Confirmed to Have Allergic Diseases

Fourteen patients were confirmed to have allergic rhinitis. All of them reported having had sneezing, a runny nose, and/or a plugged nose while not having a cold or the flu. They currently had symptoms in the past 12 months which interfere with their daily activities. Our study newly diagnosed 4 patients with mild intermittent allergic rhinitis, for which an antihistamine was started. Ten patients were previously diagnosed with allergic rhinitis and were on treatment. Of these, 5 patients had mild-intermittent allergic rhinitis, 1 patient had moderate-intermittent allergic rhinitis, 2 patients had mild-persistent allergic rhinitis, and 2 patients had severe-persistent allergic rhinitis. The patients with mild persistent allergic rhinitis were already using an as needed antihistamine, and then an intranasal steroid was added to their treatment regimen. The rest of the patients were educated regarding the correct technique of intranasal steroid administration and allergens avoidance according to their skin test results.

Four patients were confirmed to have asthma. All of them reported having had wheezing and/or whistling in the chest at any point in the past. One patient who was first diagnosed in our study reported a severe wheeze, limiting her ability to talk between breaths within the last 12 months. She also had sleep disturbance, wheezing during or after exercise and nocturnal cough. She never previously reported the symptoms to her physician as she thought they were a part of her SLE. Her pulmonary function test was compatible with asthma. Her asthma was uncontrolled. A combination of inhaled corticosteroid/long-acting beta agonist was started. The rest of the patients were known to have physician-diagnosed asthma and under treatment. Of these patients, 1 patient had partly controlled and her asthma medications were optimized.

Two patients were confirmed to have atopic dermatitis. Both of them reported having had an itchy rash which was coming and going for at least 6 months and experienced symptoms within the past 12 months with night awakening symptoms. One patient, who had been previously diagnosed with atopic dermatitis and not on current treatment, had a mild severity score. The other patient, who had not been previously diagnosed with atopic dermatitis had a moderate severity score. Both were advised on optimal skin care and prescribed moisturizers.

Patients Who Were Disease-Positive via Questionnaire But Were Not Confirmed to Have Allergic Diseases

For the one patient who was disease-positive for allergic rhinitis via questionnaire, she reported having had a blocked nose when she did not have a cold or the flu in the past 12 months. Upon further evaluation, she did not show any other symptoms of allergic rhinitis. She was found to have adenotonsillar hypertrophy with obstructive symptoms. A pediatric pulmonologist was consulted.

For the patients who were disease-positive for asthma, 2 of them reported a history of wheezing but not including the past 12 months. Their pulmonary function tests were normal. The wheezing events occurred after having a respiratory tract infection and subsided before the age of 5, compatible with viral-induced wheezing. Two patients reported wheezing with symptoms in the past 12 months, including sleep disturbance. Their pulmonary function tests were compatible with restrictive lung disease. One patient who was confirmed to have allergic rhinitis also reported wheezing in the past 12 months. However, she did not have any other characteristic symptom patterns of asthma. Her pulmonary function test was normal. Upon further evaluation, the patient misreported nasal congestion as wheezing symptoms.

For the patients who were disease-positive for atopic dermatitis, 2 patients reported having had an itchy rash and experienced symptoms within the past 12 months. However, the Hanifin and Rajka’s diagnostic features of atopic dermatitis were not met. The rashes presented during physical examination were compatible with discoid lupus and the patients were prescribed appropriate topical steroids.

Causative Allergens

Skin prick testing for common allergens was performed in patients confirmed to have allergic diseases and was positive for house dust mites in 46.15%, grasses in 30.77%, cockroach in 15.38 %, cat in 7.69% of the patients.

Correlation Between Severity of Allergic Diseases and SLE Disease Activity

As shown in Table 2, there was no significant correlation between SLEDAI-2K and VAS, C-ACT, or SCORAD. There were no significant differences in the SLEDAI-2K score among the different severity classifications for allergic disease. There was also no significant association between severity of allergic diseases and laboratory parameters of SLE.

Table 2.

Correlation Between Severity of Allergic Diseases and Disease Activity of SLE.

Score	Severity score	SLEDAI-2K	Correlation coefficient	P-value
VAS	2.00 (1.00-4.25)	3 (0-10)	−0.283	.327
C-ACT	23.00 (18.25-26.25)	1 (0-8)	0.211	.789
SCORAD	19.25 (2.40-36.10)	6 (2-10)	−1.000	—

Data presented as median and interquartile range.

Abbreviations: SLE, systemic lupus erythematosus; SLEDAI-2K, Systemic Lupus Erythematosus Disease Activity Index 2000; VAS, visual analog scale; C-ACT Childhood Asthma Control Questionnaire; SCORAD, Scoring Atopic Dermatitis.

Discussion

Systemic lupus erythematosus (SLE) is one of the most common pediatric systemic autoimmune diseases ³ which can coexist with other conditions that could worsen the disease. ²¹ In this study, we evaluated the coexistence of SLE and allergic diseases. We found that the prevalence of allergic diseases is within the range of the general population. Moreover, the patients could present with severe manifestations and could be previously undiagnosed, that is, one of the patients who was first diagnosed in our study, had episodes of severe wheeze that affected her ability to talk, sleep and exercise due to her uncontrolled asthma.

The prevalence of confirmed allergic diseases in pediatric patients with SLE in our study was 13.56%, comparable to general population which was 10%-30%. ¹³ Therefore, SLE does not confer protection from allergic diseases.

Comparing to the studies in patients with SLE, the prevalence of allergic diseases in those studies was 23.00%-43.75%.^8,10,22 However, those studies used questionnaire, ⁸ diagnosis codes ¹⁰ or serum specific immunoglobulin E (IgE)/skin prick tests ²² to diagnose allergic diseases, which could lead to overestimation of allergic diseases. In our study, allergic diseases were diagnosed by a pediatric allergist using standardized clinical criteria and testing. Therefore, true prevalence of allergic disease in patients with SLE could be reflected more accurately.

Our study demonstrated that allergic diseases and SLE can co-exist which contradict the Th1 /Th2 paradigm mechanistic theory of autoimmune diseases and allergic diseases. More evidence shows that SLE, is indeed characterized by decreased function of Th1 and hyperfunction of Th2.^23,24 The levels of Th2 cytokines are mostly increased in patients with SLE esp. during active disease. ²⁵ In addition, IL-33 which is one of the known innate cytokines that initiate type 2 responses ²⁶ and IgE in which its role in pathogenesis of allergic diseases has been well established, ²⁷ are also demonstrated to participate in SLE pathogenesis. Over 50% of patients with SLE produce autoantibodies of the IgE isotype (autoreactive IgE) and is associated with increased disease activity. ²⁸ IL-33 and autoreactive Ig-E activate plasmacytoid dendritic cells and basophils in patients with SLE. These activated basophils migrate to lymphnodes and promote T cell differentiation into Th2 and T follicular helper type 2. T follicular helper type 2 further induce B cells to differentiate into plasma cells, which produce autoreactive IgE that subsequently activate plasmacytoid dendritic cells and basophils, leading to amplification loop of autoantibodies production. ²⁴ Concurrently, autoreactive IgE containing immune complexes deposit in vessels and tissues, contributing to pathogenesis of SLE. ²⁹ Moreover, therapeutic targeting of IgE improved SLE disease activity in a clinical trial. ³⁰

The other plausible explanations of coexisting between allergic diseases and SLE are as follow: firstly, the hygiene hypothesis in which the development of strong immune responses against antigens from infection could inhibit responses to autoantigens and allergen which are weaker antigens via antigenic competition.^30,31 Secondly, the shared genetic variants of pathways in allergy and SLE, evidenced from genome-wide association studies.^32,33 Lastly, reduced number and function of regulatory T-cells have been demonstrated in both allergy and SLE.^34,35 Regulatory T-cells cells mediate tolerance to allergens and self-antigens by diverse suppressive mechanisms. ³⁶

Patients may underreport symptoms of allergic diseases because they assume them to be symptoms of SLE, and vice versa. This could lead to difficulty in management as the treatment of these 2 groups of disease is different. Several of our patients received new diagnosis of allergic disease, regardless of their severities. One newly diagnosed asthma patient presented with a severe and disabling wheeze. She had never reported her symptoms as she thought it was due to SLE. Pulmonary involvement in SLE is reported in a majority of patients ³⁷ in which one of the most common findings is restrictive lung disease. ³⁸ However, wheezing is an uncommon manifestation in restrictive lung disease and most are characterized by an insidious progression of dyspnea. ³⁹ Careful history taking could initially differentiate between asthma and restrictive lung disease before confirming with pulmonary function test. The main treatment of asthma and restrictive lung disease are disparate in which inhaled corticosteroid is the main treatment for treatment asthma ¹⁷ and immunosuppressive drugs are for the latter. ⁴⁰ If left untreated, both diseases could lead to severe complications including respiratory failure.

Two patients were disease-positive via questionnaire for atopic dermatitis but were diagnosed as having discoid lupus. Discoid lupus tends to occur around the eyes, ears and sun exposed areas but can be distributed over the face, neck and sun protected areas. Most are asymptomatic but patients may complain of pruritus, which could be mistaken with atopic dermatitis. ⁴¹ Therefore, physicians should be cautiously aware that patients may mistakenly assume their symptoms to be unrelated to SLE.

The majority of our patients with confirmed allergic diseases were previously diagnosed and had been under treatment by their general pediatricians. However, significant amount of them had moderate-severe or not controlled disease and required adjustment to their treatment regimens. Therefore, subspecialists involved in the care of patients with SLE should regularly review these conditions as a holistic approach. In addition, patients and their parents/caregivers should be educated to report their symptoms, even though they think they were unrelated to SLE.

The quality of life of patients with SLE is known to be adversely affected by several factors, including coexisting diseases. ⁴² Although a correlation between severity of allergic diseases and SLE disease activity was not found in our study, it was well established that allergic diseases impact the quality of life of children and their parents.^43,44 Therefore, coexisting uncontrolled allergic diseases undoubtedly have an effect on the already impaired quality of life in children with SLE.

This study has some limitations. Firstly, our second objective to identify association between severity of allergic diseases and SLE disease activity was performed using data that were collected at 1 point in time. SLE disease activity is dependent on other factors, such as previous treatment and the time of assessment during the clinical course of the disease. Secondly, there were no statistically significant differences in either characteristics or disease activity between patients with and without confirmed allergic diseases which could be due to the limited sample size. Thirdly, we enrolled all of the patients who met the inclusion criteria during the study period, but a sample size calculation was not performed. Lastly, the prevalence of allergic diseases was compared to the existing literature but not to healthy controls. However, the strengths of this study are that all the diagnoses, severity of allergic diseases and SLE disease activity were confirmed and assessed by a board-certified pediatric allergist/rheumatologist using standardized clinical criteria, scores and testing. In addition to addressing the specific details of each patient which could be adapted to use in real-life practice, the study was also conducted in the pediatric population in which the data is still scarce.

Conclusion

This study demonstrated than allergic diseases and SLE can coexist. The prevalence of allergic diseases in pediatric patients with SLE is within the range of the general population Patients may underreport symptoms of allergic diseases because they assume them to be symptoms of SLE, and vice versa. Several of our patients were first diagnosed allergic disease in our study, regardless of their severities. Significant amount of the patients who were previously diagnosed allergic diseases had moderate-severe or not controlled disease and required adjustment to their treatment. Therefore, physicians involved in the care of patients with SLE should be aware of the coexistence of allergic diseases and diagnosis of these allergic diseases should be investigated and confirmed in patients that present with allergic disease-compatible clinical manifestations. Patients and their parents should be educated to report any unusual symptoms, even if they don’t seem to be related to SLE.