Abstract
Background:
There still are few data on the long-term safety of sublingual immunotherapy (SLIT). The aim of this study was to assess the appearance of autoimmune diseases in patients before and after SLIT.
Materials & methods:
New cases of autoimmune diseases were monitored. Patients in the SLIT group (n = 816) were compared with controls (n = 1096).
Results:
The new incidences of autoimmune diseases in the SLIT group were lower compared with the control group: 18 (2.2%) versus 58 (5.3%); p < 0.05. Systemic lupus erythematosus, psoriasis and Hashimoto appeared much more often in the control group.
Conclusion:
SLIT had no significant effect on the induction of autoimmune diseases.
Keywords: allergy, autoimmune, IgE, lupus, psoriasis, sublingual immunotherapy
Plain language summary
The therapy for allergic people is named allergen-specific immunotherapy, and one of the ways of administering this therapy is sublingual immunotherapy (SLIT), which means that the medication is kept in the mouth under the tongue. The authors assessed the safety of SLIT in terms of the risk of inducing autoimmune diseases, which means that the immune system is overactive, causing it to attack and damage the body's own tissues. Analysis of medical history for autoimmune diseases, clinical examinations and laboratory diagnostic tests were performed. SLIT did not significantly increase the incidences of autoimmune disease in the study group. SLIT is a safe therapy in long-term observation.
The safety of allergen immunotherapy (AIT) has been confirmed by multiple observations. This treatment method is commonly used in many IgE-dependent diseases, such as allergic rhinitis, selected forms of allergic asthma and hymenoptera venom allergy [1,2]. The assessment of the long-term benefits of AIT is increasingly well documented. However, we still do not have many accurate observations regarding the long-term safety of AIT, including sublingual immunotherapy (SLIT), at the level of immunological assessment [1–3]. Among the potential long-term negative effects of AIT are autoimmune phenomena [4], where the induction of immune tolerance causes a “silencing” of the Th2 immune response and a shift toward Th1. Despite this, there is no evidence of negative clinical consequences of this phenomenon [4,5]. However, the studies supporting this hypothesis have been largely observational with few exceptions [6–8].
The aim of this study was to assess the immunological profile of autoantibodies in patients before and 5 years after the end of 3 years of any sublingual immunotherapy for various allergens and the clinical evaluation of patients for the appearance of autoimmune diseases.
Materials & methods
Patients
A total of 1011 patients were included in the study between January 2015 and December 2016. The inclusion criteria were as follows:
>12 years old;
A minimum of 3 years on a course of sublingual immunotherapy for house dust mites, grass or tree pollens due to allergic rhinitis and/or allergic asthma;
No autoimmune diseases, neoplasms or multiorgan failure at the start of SLIT.
A total of 195 participants were excluded due to dropouts or stopping SLIT due to a new contraindication (Figure 1). In total, 816 patients (405 women and 411 men) were enrolled in the study.
Figure 1. . Flowchart of the research process.
The process of obtaining patients through prescreening and final qualification based on the inclusion criteria and presentation of the reasons for excluding participants during observation.
SCIT: Subcutaneous immunotherapy; SLIT: Sublingual immunotherapy.
There was also a control group consisting of 1096 volunteers without allergic diseases. The characteristics of the groups are presented in Table 1. All patients were tested in the immunological laboratory at the Clinical Department of Internal Diseases, Dermatology and Allergology (Zabrze, Poland).
Table 1. . Characteristics of the groups.
| Study group (N = 816) | Control group (N = 1096) | p-value | |
|---|---|---|---|
| Female (%) | 405 (49.6) | 511 (46.6) | 0.05 |
| Mean age (± standard deviation) at study start, years | 28.4 ± 4.7 | 28.4 ± 4.7 | NS |
| Allergic rhinitis | 796 (97.5) | 988 (90.1) | <0.05 |
| Allergic asthma | 139 (17) | 211 (19.2) | NS |
| Hypersensitivity to: House dust mites Grass pollen Tree pollen Molds Mugwort Cat |
610 (74) 284 (34.8) 288 (35.3) 49 (6) 92 (11.3) 68 (8.3) |
||
| Mean duration of SLIT (± standard deviation), years | 3.4 ±1.8 | – | – |
| SLIT drops SLIT tablets |
538 278 |
– – |
– – |
| SLIT for: House dust mites Grass pollen Tree pollen |
387 251 238 |
– – – |
– |
| Concomitant diseases at study start† (%) Atopic dermatitis Diabetes Type 2 Arterial hypertension Heart failure including arrhythmia Obesity (BMI >26) Hashimoto |
43 (5.3) 11 (1.3) 34 (4.2) 20 (2.5) 22 (2.7) 31 (3.8) |
– 21 (1.9) 39 (3.6) 35 (3.2) 30 (2.7) 59 (5.4) |
NS NS NS NS <0.05 |
Detailed analysis of the studied patients, taking into account multimorbidity and allergy profiles.
Diseases occurring in at least 1% of the subjects.
NS: Not statistically significant; SLIT: Sublingual immunotherapy.
The following procedures were performed:
Analysis of medical history for autoimmune diseases according to the International Classification of Disease (10th revision);
Clinical examinations and laboratory diagnostic tests, including autoantibodies;
ELISA analysis (using EUROLineScan, EUROIMMUNE, Medizinische Labordiagnostika, Germany) of the following antibodies: dsDNA, histonic, U1-nRNP, Scl-70, ACA, Jo-1, Sm, U3-nRNP, RNA-polymerase I, PM-Scl (PM-1), Ro(SS-A/La [SS-B]), PCNA, Ku, Mi-1, Mi-2, Ribosomal-P-protein and AMA-M2; a positive result in serum was indicated by + to +++.
Additionally, pANCA (normal range <25.00 IU/ml), cANCA (normal range <20.0 IU/ml), antithyroglobulin (normal range <15.0 IU/ml), antiperoxidase (normal range <34 IU/ml) and anti-TRAb (normal range <1.8 IU/ml) were detected by the use electroluminescence (Roche, Katowice, Poland) based on a previous study [8].
Patient visits included the laboratory tests listed above and took place every year during the study period (7 years). The Bioethical Committee of the Medical University of Silesia approved the study in Katowice, Poland (NN-3111/92).
Statistics
The statistical analysis was performed by the use of the Statistica computer program, version 8.1 (SoftPol, Cracow, Poland). Besides descriptive statistics, one-way analysis of variance was used to compare the presence of autoimmune diseases or the type of autoantibodies between the groups. A hazard ratio was used to assess the risk of autoimmune disease in the population.
Results
The new cases of autoimmune diseases in the SLIT group were lower compared with the control group: 18 (2.2%) versus 58 (5.3%); p < 0.05. System lupus erythematosus (SLE), psoriasis and Hashimoto occurred much more often during the observation period in the control group. Additionally, after SLIT, patients had a low risk of developing selected autoimmune diseases (hazard ratio: 0.54; 95% CI: 0.29–0.65) despite the desensitized allergen. Details are presented in Table 2.
Table 2. . New incidence of autoimmune diseases over 7 years of observation.
| Autoimmune diseases and/or autoantibodies | Study group (N = 816) | Control group (N = 1096) | p-value |
|---|---|---|---|
| Systemic lupus erythematosus | 2 | 14 | <0.05† |
| Scleroderma | 1 | 2 | NS |
| Systemic vasculitis | 2 | 1 | NS |
| Rheumatoid arthritis | 1 | 3 | NS |
| Ankylosing spondylitis | 0 | 1 | NS |
| Psoriasis/psoriatic arthritis | 1 | 10 | <0.05† |
| Hashimoto | 5 | 19 | <0.05† |
| Ulcerative colitis | 2 | 2 | NS |
| Crohn disease | 1 | 2 | NS |
| Multiple sclerosis | 1 | 0 | NS |
| Others | 2 | 4 | NS |
| Total (%) | 18 (2.2) | 58 (5.3) | <0.05† |
Profile of the most frequently observed underlying autoimmune diseases based on the International Classification of Diseases, tenth revision, code (only new diagnoses).
Significant differences in the occurrence of autoimmune diseases between analyzed groups in one-way analysis of variance.
NS: Not statistically significant.
Laboratory tests
After 3 years of SLIT, the detected autoantibodies in patients were less frequently observed than in controls. These findings were independent of the kind of immunotherapy. There was also no relationship between the types of allergies and the presence of autoantibodies. Detailed data are presented in Table 3. The autoantibodies dsDNA, Scl70, anti-TG, anti-TPO and anti-TRAb were significantly more prevalent in nonallergic patients than in the SLIT group.
Table 3. . Detected new autoantibodies in the sera of patients (regardless of a diagnosis of autoimmune disease) during observation.
| Autoantibodies | Study group (N = 816) | Control group (N = 1096) | p-value |
|---|---|---|---|
| dsDNA | 2 | 11 | >0.05† |
| Scl-70 | 3 | 8 | >0.05† |
| ACA | 2 | 2 | NS |
| Jo-1 | 2 | 1 | NS |
| U3-nRNP | 2 | 1 | NS |
| RNA-polymerase | 1 | 1 | NS |
| PM-Scl | 1 | 1 | NS |
| PCNA | 3 | 4 | NS |
| C1q | 4 | 7 | NS |
| Mi-1 | 2 | 2 | NS |
| Mi-2 | § | 1 | NS |
| Ribosomal-P-protein | 0 | 1 | NS |
| AMA-M2 | 1 | 2 | NS |
| pANCA | 0 | 1 | NS |
| cANCA | 0 | 1 | NS |
| Antithyroglobulin | 5 | 15 | >0.05† |
| Antiperoxidase | 7 | 18 | >0.05† |
| Anti-TRAb | 5 | 11 | >0.05† |
Assessment of the presence of autoantibodies in blood serum using the polyquantitative immunoenzymatic method.
Significant differences in the occurrence of autoantibodies between analyzed groups in one-way analysis of variance.
NS: Not statistically significant.
The hazard ratio for the appearance of any new autoantibodies in patients after SLIT was 0.78 (95% CI: 0.55–0.88).
Discussion
These results support the safety of SLIT in the assessment of autoimmune activity during and after treatment. A few cases of autoimmune diseases in the desensitized group were significantly less frequent compared with the control group. This is consistent with other similar observations, mainly of patients desensitized by injection immunotherapy [9,10]. Lindelof et al. [10] performed an observational study on the Swedish population, including more than 140,000 patients who were tested for total serum IgE, or Phadiatop. Simultaneously, they assessed the risk of autoimmune diseases in them. Participants with a positive Phadiatop test were at a statistically decreased risk of subsequent autoimmune disease compared with patients with a negative test [10]. There was no similar correlation between the total serum IgE level and the risk of autoimmune diseases.
The novelty of this observation is the focus on patients desensitized by the sublingual method, which is newer and shorter than the injection method. However, there are isolated case reports of autoimmune diseases associated with immunotherapy [11–13]. Based on the data obtained, the authors do not confirm a relationship in desensitized patients who developed the autoimmune diseases presented.
The analyzed allergic patients seemed to be less prone to autoimmunity. It was confirmed in other studies [14,15]. Allergen immunotherapy induces immunotolerance to some allergens based on altered allergen-specific T and B responses and decreased IgE, and increased IgG4 production. As a consequence, allergic reactions were suppressed, moving the Th2 response toward Th1 [16]. During AIT, increasing IL-10 and TGF-B concentrations, inducing lymphocyte tolerance and changes in the Th1/Th2 balance, could lead to autoimmune problems in such patients [17,18]. Assessing the relationship between IgE-mediated allergies and autoimmune diseases from a balanced profile of Th1/Th2 seems overly simplistic [19,20]. It is possible that mast cells play a critical role not only in allergic disease but also in many autoimmune diseases such as rheumatoid arthritis, psoriasis, autoimmune thyroiditis, scleroderma and multiple sclerosis. Allergens activate mast cells and contact other active immunocompetent cells involved in the immune response, such as T lymphocytes. Activated mast cells, in turn, are a source of TNF-α, which is an essential proinflammatory factor in many autoimmune diseases [21,22]. The role of Th17 cells involved in chronic inflammation, such as IL-17, in allergic asthma and in some systemic diseases (e.g., psoriasis) is well documented. However, there still is not much evidence of it in other autoimmune systemic diseases [23]. The authors also observed that patients with low levels of total serum IgE in the control group probably had a greater predisposition to autoimmune diseases. However, the study was not published due to the small number of patients with low-level IgE (10 kU/l). The most common disease occurring in this study was Hashimoto thyroiditis, which is consistent with other studies. This disease is common, particularly in women in the examined age group. It was similarly observed in the present study but was slightly less common in desensitized subjects. These data may indicate the lack of a simple relationship between SLIT and the induction of this disease. New recommendations for using AIT are less restrictive in excluding patients with autoimmune diseases. This document allows AIT to be performed in many patients with clinical remission of an autoimmune disease, such as psoriasis and autoimmune thyroiditis, if the benefits of desensitization are indisputable [24,25].
The limitations of this study were the short observation time and the evaluation of only the most common autoantibodies. It could be interesting to evaluate the family history of autoimmune diseases and their impact on analyzed patients.
The results suggested that allergic patients with or without SLIT showed a significant relationship between rare occurrences of autoantibodies and autoimmune diseases. However, further studies with double-blind and placebo control regimens are required to precisely evaluate the potential risk of allergen immunotherapy inducing autoimmune diseases. A sufficiently long observation period is crucial.
Conclusion
In this prolonged observational study, SLIT did not increase the prevalence of selected autoimmune diseases or result in a significant presence of the most frequently marked autoantibodies in serum compared with the control group.
Summary points.
There is no information on whether sublingual immunotherapy (SLIT) increases the risk of autoimmune diseases.
New cases of autoimmune diseases in allergic patients in the SLIT group and the controls (without SLIT) were monitored.
In the group undergoing SLIT, 18 (2.2%) new cases of autoimmune diseases were observed compared with 58 (5.3%) in the control group.
dsDNA Scl-70 and antithyroid lesions occurred more often in the control group without desensitization.
SLIT is safe because patients have a low risk of developing autoimmune disease: hazard ratio = 0.54 (95% CI: 0.55–0.88).
The obtained results suggested that allergic patients with or without SLIT showed a significant relationship between rare occurrences of autoantibodies and autoimmune diseases.
Footnotes
Author contributions
A Bozek: substantial contributions to the conception of the work and acquisition and analysis of data for the work, validation, data curation and methodology. S Mucka: substantial contributions to the design of the work and the acquisition and interpretation of data for the work, conceptualization and supervision. M Miodonska: acquisition and interpretation of data. A Zlik: analysis of data for the work and validation. M Mroz-Dybowska: acquisition and interpretation of data.
Financial disclosure
The authors have no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.
Competing interests disclosure
The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, stock ownership or options and expert testimony.
Writing disclosure
No writing assistance was utilized in the production of this manuscript.
Ethical conduct of research
The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Ethics Committee of the Medical University of Silesia in Katowice, Poland (KNW-1-131/N/9/K). In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.
Data availability statement
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to ethical restrictions.
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Papers of special note have been highlighted as: • of interest; •• of considerable interest
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