Association between allergic rhinitis and development of autoimmune thyroid diseases in Egyptian patients

Abstract

Background

Autoimmune thyroid diseases (AITD) and allergic rhinitis (AR) are prevalent conditions; however, limited research has investigated their association. This study aimed to evaluate whether AR can be considered a risk factor for developing AITD.

Methods

A retrospective cohort study analyzed the records of AITD patients who visited Alexandria University Students Hospital between January 2017 and December 2021. The parameters included in the study were thyroid-stimulating hormone (TSH), Free triiodothyronine (FT3), free thyroxine (FT4), thyroid peroxidase antibodies (TPOAb), thyrotropin receptor antibody (TRAb), eosinophils count, and IgE.

Results

Out of 4,515 eligible patients, 41.7% were diagnosed with AR in addition to AITD. Among the patients with both conditions, 81% were females, their mean age was 45.71 ± 24.14 years, and the mean duration of AITD was 7.32 ± 2.11 years. The Kaplan–Meier analysis revealed that the AR cohort had a higher cumulative incidence of AITD than did the non-AR cohort (log-rank test, p = 0.001). Multivariate-adjusted hazardous ratios showed that patients with AR, female sex, higher white blood cell count, and diagnosis in November had a higher risk of developing AITD.

Conclusions

Screening for AITD should be conducted at the time of diagnosis of AR as it could be a risk factor for AITD.

Introduction

Autoimmune thyroid diseases (AITD) encompassing Graves’ disease (GD) and Hashimoto’s thyroiditis (HT), are highly prevalent autoimmune conditions, affecting approximately 5% of the general population. This places them among the most commonly diagnosed autoimmune diseases [1]. Autoimmunity targeting the thyroid is characterized by the presence of antibodies against thyroid antigens. Apart from generating thyroid autoantibodies and disrupting thyroid hormone synthesis, AITD also entails the histological infiltration of self-directed T and B lymphocytes into the thyroid gland. [2]. The development of AITD is currently understood to be a result of various factors, both genetic and environmental, working in tandem. [3, 4]. Recent research, such as the National Health and Nutritional Examination Surveys (NHANES) study, has also highlighted racial variations in the prevalence of AITD, emphasizing the potential role of genetic differences and genetic susceptibility in the etiology of GD and HT [5].

HT is the most common cause of hypothyroidism in Egypt and is characterized by the destruction of thyroid cells by various cell- and antibody-mediated immune process. It is associated with thyroid autoantibodies production, the most common are thyroid peroxidase antibodies (anti-TPO) and thyroglobulin antibodies (anti-TG) with various degrees of thyroid hypofunction. GD is the most common cause of hyperthyroidism, typically presenting between 40 and 60 years. Auto-antibodies, primarily Thyroid stimulating hormone Receptor Antibodies (TRAb), are the driving force behind this disease, yet underlying mechanisms are still not completely understood [6].

Allergic rhinitis (AR) is a very common autoimmune disorder affecting people of all ages [7]. It is rarely found in isolation and is usually associated with numerous comorbid conditions, including asthma, chronic middle ear effusions, sinusitis, and lymphoid hypertrophy with obstructive sleep apnea, disordered sleep, consequent behavioral, educational effects, and a number of autoimmune diseases [8].

There is some evidence in the literature of an association between AITD and AR. A few studies addressed the relationship between them. Studies showed that there is a high incidence of HT among patients with AR [9]. Other studies showed that the prevalence of seasonal AR was significantly high in patients with GD [10]. In addition, a recent study showed that thyroid autoantibodies may be involved in the pathogenesis of AR). [11]

Despite the growing interest in the relationship between AR & AITD, most of these studies were designed as cross-sectional studies with small sample sizes, which is insufficient to establish such a relationship. We noticed in our endocrinology unit an increasing incidence of AITD among patients with AR. We hypothesized that there is a significant association between AITD and AR among Egyptian patients. Hence, our study aimed to investigate and describe the variables associated with this observed increased incidence.

Methods

Study design and study setting

Following the STROBE checklist, we performed a retrospective cohort study using records of patients with AITD, specifically GD and HT. Our study included patients who sought treatment at the Endocrinology clinic of Alexandria University Students Hospital between 1st January 2017, and 31st December 2021.

Study population

All AR patients from 18 to 75 years old were included in the study. The case defined as AR based on a combination of medical history and physical examination findings. Symptoms such as clear rhinorrhea, pallor of the nasal mucosa, and red watery eyes were assessed. Additionally, at least one of the following symptoms was present: nasal congestion, nasal itching, or sneezing. The diagnosis was further confirmed through nasendoscopy [12] We excluded patients who met the following criteria: pregnant or lactating, taking medications that affect thyroid function (such as amiodarone, interferon, iodinated contrasts, and lithium), and having a history of thyroid treatment involving radioiodine or radiotherapy of the chest and neck. Based on the data collected during the initial visit, the patients were categorized into four groups:

Group 1:

Patients diagnosed with AR presenting with HT.

Group 2:

Patients without AR diagnosed presenting with HT.

Group 3:

Patients diagnosed with AR presenting with GD.

Group 4:

Patients without AR presenting with GD.

Data collection

All patients underwent comprehensive assessments, including thorough medical history interviews, physical examinations, and laboratory investigations. The laboratory tests included thyroid-stimulating hormone (TSH) levels ranging from 0.39 to 4.16 mIU/L, free triiodothyronine (FT3) levels ranging from 1.4 to 4.2 pg/mL, free thyroxine (FT4) levels ranging from 0.8 to 1.9 ng/dL, thyroid peroxidase antibody (TPOAb) levels less than 34 IU/m, and thyrotropin receptor antibody (TRAb) levels less than 1.75 IU/mL. Additionally, we assessed the peripheral blood eosinophils ratio (normal range 1–4%), and IgE levels (normal range 1.5 to 100 IU/mL). At the time of diagnosis, we performed an ultrasound (US) examination of the thyroid gland using a Kontron device with a linear probe and a 7.5–10 MHz transducer to evaluate its morphology.

Case definition

We identified autoimmune thyroid diseases as follows:

• HT: was diagnosed if patients tested positive for TPOAb, or exhibited a heterogeneous texture were diagnosed with US.

• Subclinical (mild) hypothyroidism was defined as increased levels of TSH alongside normal T4 or free T4 (FT4).

• Overt hypothyroidism was diagnosed when TSH levels were elevated and T4 or FT4 levels were below normal.

• GD is diagnosed when a patient tests positive for TRAb, with or without the presence of ophthalmopathy and dermopathy.

• Subclinical (mild) hyperthyroidism is diagnosed when there is a decrease in TSH levels accompanied by normal T4) or FT4 levels.

• Overt hyperthyroidism was diagnosed when TSH levels decreased and T4 or FT4 levels were elevated.

Statistical analysis

Quantitative variables were described using means, standard deviations (SD), and ranges. Qualitative variables were described using numbers and percentages. Unpaired t-tests and ANOVA tests were used to compare quantitative variables, while the Mann-Whitney and Wilcoxon test was used for non-parametric data analysis. The Spearman correlation coefficient was used to detect correlations between non normally distributed quantitative variables. The cumulative incidence curves of AITD were generated using the Kaplan-Meier method. Differences between the cumulative incidence curves were assessed using a log-rank test. The crude incidence rate of thyroid dysfunctions per 1000 person-years was calculated for various age and gender-specific groups. Poisson regression analysis was conducted to evaluate the adjusted incidence rate ratios of AITD in individuals with and without AR. We utilized univariate and multivariate Cox proportional hazards regression models to estimate hazard ratios (HRs) and assess the impact of AR on the risk of AITD. Additionally, we identified significant risk factors associated with the time to development of AITD in patients with AR, adjusting for age, gender, smoking, weight, and positive family history. The statistical analyses were performed using SPSS version 25 (SPSS Inc., an IBM company; Chicago, Ill). All statistical tests were two-tailed, and a significance level of < 0.05 was applied.

Results

Demographic data & epidemiology

Over 5 years, out of 27,374 patients presented with thyroid problems, 4515 newly diagnosed patients with AITDs of both sexes. Figure 1 Among the eligible patients, 41.7% were found to have AR in addition to AITDs. Of them, 81% were females, their mean age was 45.71 ± 24.14 years, and the mean duration of AITDS was 7.32 ± 2.11 years. The age and sex distribution of AR patients with AITDs were like that of non-AR patients with AITDs. Among AR patients, the prevalence of HT was 83.7%, while the prevalence of GD was 16.4%. In non-AR patients, the prevalence of HT was 67.6%, and the prevalence of GD was 32.37%. Table 1.

Fig. 1

The flow chart of the study participants

In terms of the comparison of baseline characteristics between the studied groups, the following findings were observed. Group 1 (AR and HT) were significantly younger at the time of HT diagnosis compared to those with group 2. However, there was no significant difference in terms of gender distribution. The mean period between the diagnosis of AR and the development of HT was 6.08 ± 0.34 years. Similarly, group 3 (AR and GD), were significantly younger compared to group 4. However, no significant difference was found in terms of gender distribution. Patients in group 3 had a significantly higher eosinophil count and IgE level compared to those in group 4. The mean period between the diagnosis of AR and the development of GD was 5.61 ± 1.04 years.

There was no significant difference observed between the studied groups in terms of family history. For patients diagnosed with HT, the seasonal peak of diagnosis was primarily in winter, with higher frequencies in February and December. On the other hand, for patients diagnosed with GD, the seasonal peak of diagnosis was mainly in summer, particularly in May and August, with a smaller peak observed in February. Figure 2 In HT patients, allergic skin diseases, bronchial asthma, and connective tissue diseases were primarily associated with AR diseases. Similarly, allergic skin diseases and bronchial asthma were higher in the AR diseases group. Figure 3.

Fig. 2

The seasonal peak of diagnosis of AITDs in relation to allergic rhinitis status

Fig. 3

Past medical history of autoimmune diseases in patients with AITDs and the relation to AR status

Group 1 had a higher gland volume on thyroid ultrasonography compared to those with group 2. The increased volume was predominantly seen as isoechoic diffuse goiter. Among patients with group 1, associated pseudo nodular/nodular patterns were primarily isoechoic single nodules. These nodules were often accompanied by. Group 3 and the GD group also exhibited a higher gland volume on thyroid ultrasonography compared to those with GD only. The increased volume was mainly observed as the diffuse isoechoic pattern. Among group 3, associated pseudo nodular/nodular patterns were predominantly isoechoic multinodular. Also, the reactive cervical lymph nodes were significantly higher in AR patients versus nonAR patients with GD or HT within in group interestingly, the thyroid nodules detected by the US were frequently associated with the presence of reactive cervical lymph nodes. Table 2.

Cumulative incidence of autoimmune thyroid diseases in allergic rhinitis patients:

After adjusting for age, sex, family history of thyroid diseases, and comorbidities, the results of the Kaplan-Meier analysis demonstrated that the AR cohort had a significantly higher cumulative incidence of overall AITDs, HT, and GD compared to the non-AR cohort (log-rank test, P = 0.001). Specifically, the AR cohort exhibited a 50% increased risk of developing AITDs and HT after 1 year of follow-up, and a 2-year follow-up period was associated with a 50% increased risk of developing GD. The incidence rate ratios for overall AITDs, HT, and GD were as follows: 1.51 (95% CI [1.261–1.71]) for AITDs, 2.64 (95% CI [1.66–1.97]) for HT, and 1.73 (95% CI [0.69–3.75]) for GD, respectively. Figure 4.

Fig. 4

Cumulative incidence of AITDs, HT, and GD in patients with AR

Highlighting the higher incidence of AITDs, HT, and GD in the AR cohort compared to the non-AR cohort over a median follow-up period of 62.5 months. The incidence rate of AITDs was further stratified based on age at diagnosis and sex. The incidence rate proved significantly higher for patients with associated AR, female sex, aged between 30 and 50 years. Table 3.

The risk factors and comorbidities could be associated with the progress of autoimmune thyroid diseases among patients with allergic rhinitis.

The results of the multivariable Cox proportional hazard regressions showed the following associations between various factors and the risk of developing AITDs, HT, and GD in patients with allergic rhinitis. Higher risk group AITDs were female sex, higher WBCs, and diagnosis in November. In contrast, lower risk groups included older age at AR onset, no medical history of AITDs, use of Azathioprine and Methotrexate as medications, and higher vitamin D levels. Higher risk for HT includes female sex, higher WBCs, higher eosinophils, a history of combined bronchial asthma and skin allergy, and diagnosis in November. The lower-risk population included those older age at AR onset, medical history of skin allergy, and higher levels of IgE and vitamin D. Higher risk group for GD included female sex and higher WBCs, while lower risk included those with higher eosinophils and higher levels of IgE. Figure 5.

Fig. 5

The risk factors & comorbidities associated with the progress to AITD in AR

Discussion

The main finding of our study is that AR increases the risk of AITD. The risk for HT is increased after 1 year of AR diagnosis and that for GD is increased after 2 years of AR diagnosis.

AR is prevalent in more than one-third to two-thirds of Egyptians [4]. The rapid increase in AITD prevalence cannot be explained only by genetic factors. It is suggested that environmental factors may play a role in this development, especially in cases with seasonal patterns. [12] Consistent with our findings, a retrospective cohort study found that the patients with AR had higher incidence-AITD compared with patients without allergic disease, [1.18 (95% CI 1.08–1.29)]. [13] Amino et al. studied the prevalence of AR in GD and HT patients. They found that the prevalence of AR was significantly higher in patients with GD (42.9%, p = 0.05), and lower in patients with indolent thyroiditis (13.0%, p = 0.01), but no difference in patients with HT (26.1%) compared to healthy controls (32.6%) [10].

Contrary to our results, Gürlek et al., [14] showed that among a total of 319 patients with AR, there is no history of thyroid disease. However, a higher prevalence of thyroid antibodies in patients with AR was found. Another study by El-Aziz et al. [15] showed that there was no significant difference in FT4, FT3, and TSH and anti-TG and anti-TPO values between AR and healthy groups. Also, Akkoca et al. could not find any significant difference between the AR group and the healthy group in terms of the thyroid function tests. However, Subclinical hyperthyroidism and hypothyroidism in patients with and without AR were detected in 4.8%,and 33.8% versus 9.5%, and 22.2% of patients, respectively [15]. The difference in the incidence rate of thyroid dysfunction originated from the difference between the small sample size and the variable median ages of these studies. Also, the prevalence and incidence rates of thyroid disorders were associated with several factors including geographic areas, senility, ethnicity, and the amount of iodine intake [16].

The environmental factors may induce AR that may precipitate AITD [3]. The association between AR and AITD could be explained by the main pathogenesis for the development of both, being resulted from T cell-mediated organ-specific autoimmune effect, (especially T1 helper cell upregulations and T2 helper cell downregulations by T regulatory cells). [1, 17] Molecular mimicry theory may also play a role in the association between AR and AITD as thyroid hormone receptors are localized in the nasal mucosa [18, 19].

The current results showed that in patients with AR, the peak season of diagnosis of HT was October and November, while the peak season of diagnosis of GD was April and May. In agreement with our results, Takeoka et al. found that the level of anti-TPO was significantly increased with a peak of eosinophils levels in October and a peak of IgE and TSH receptor antibodies in April. [20]

Combined bronchial asthma and AR together increase the risk for HT in patients with AR. Lindberg et al. [21] found high anti-TPO levels in patients with bronchial asthma. This finding is concordant with the increase in the incidence of thyroid autoantibodies in AR and/or bronchial asthma patients defined by Amino et al. [10] In the study by El Aziz et al., [15] both anti-TPO and anti-TG antibodies were statistically higher in patients with bronchial asthma and AR when compared to the healthy group (p < 0.01).

Combined skin allergy and AR together increase the risk for HT in patients with AR. In line with our results, for both bronchial asthma and eczema, a retrospective cohort study employing data extracted from the UK primary care database showed that in patients with asthma, the adjusted incidence rate ratios for autoimmune thyroiditis were 1.23 (95% CI 1.14–1.33) whereas eczema is 1.13 (95% CI 1.05–1.22) [13] Amino et al. [10] found that the prevalence of thyroid autoantibody positivity was increased in patients with atopic eczema, and with allergic asthma and/or AR. On the contrary, in a retrospective study conducted by Reisacher et al., [22] skin prick test positivity was found in only 10.4% of patients diagnosed with autoimmune thyroiditis. Also, the relationship between thyroid disease in patients with atopic eczema was not confirmed in studies conducted by Raffle and Hal [23].

Our results showed that IgE seems to be a risk factor for GD and not for HT. In line with this, Takeoka et al., [20] demonstrated that Japanese cedar wood pollen/ ragweed-related pollen affects the clinical course of GD. They have shown that allergic rhinitis has increased the serum antithyroid autoantibody and pollen-specific immunoglobulin E (IgE) concentrations. Moreover, IgE was found to be high with an increased incidence of elevated levels of IgE in autoimmune thyroid disease patients, particularly in GD [24]. A study was conducted on Albanian patients comparing GD and HT for IgE. The study found that there was an increase in IgE levels in the GD group. While no differences were recorded regarding the HT group versus the control group, the anti-TPO antibody level was significantly negatively correlated with the total IgE. The difference between these results and ours was thought to be due to the result of the low prevalence of genetic and environmental factors associated with allergic diseases. [25] Similarly, in asthmatic Egyptian women serum anti-TPO autoantibodies showed a negative correlation with serum IgE. [26]

In the current study, reactive cervical lymph nodes were detected by ultrasound neck in AITD patients with AR versus patients without AR. In line with our results, a retrospective study of 417 patients with HT was conducted to evaluate the size and number of cervical lymph nodes in HT, showed that HT was associated with an ultrasonographic pattern of enlarged cervical lymph nodes. [27] Importantly, regional lymph nodes are known to be involved in early AITD; activation of T cells in thyroid draining nodes. [28, 29] The proposed mechanism may be due to the local allergic reactions in the respiratory mucosa, including local thyroid receptors, by IgE-presenting cells which migrate and begin processing the T cell zone of the regional lymph node. The ific T cells will cause either production of cytotoxic Th1 cytokines or the production of Th2 cytokines in lymph nodes and can activate the production of autoantibodies to the thyroid gland by B cells. [30]

The limitation of our study is the retrospective nature; however, all the analyses and estimates were adjusted for the cohort effect, which is a variable summarizing both the effect of the generation and that of the recall bias.

Conclusions

In conclusion, this comprehensive study has yielded valuable insights into the relationship between AR and ATIDs, specifically HT and GD. Patients with AR have a potential for the development of HT & GD. The duration between the diagnosis of AR and the development of HT or GD was relatively consistent, emphasizing a link between AR and the subsequent onset of these ATIDs. The environmental triggers and the development of ATIDs were revealed by the seasonal variations in the diagnosis of HT and GD. HT diagnosis was more common in winter months, particularly February and December, while GD diagnosis peaked during the summer, with May and August being the predominant months.

Table 1 Sociodemographic factors and comorbidity according to AITDs and AR status

Table 2 Thyroid gland function and ultrasound parameters in the studied groups

Table 3 Incidence rate ratios (IRR) and 95% confidence intervals (CI) for AITDs in AR and non-AR patients