Allergen Immunotherapy in Autoimmune Terrain: A Case Study

Abstract

Allergen immunotherapy (AIT), or specific immunotherapy (SIT), is an effective treatment for inducing immune tolerance to specific allergens. It is widely used for allergic rhinitis, conjunctivitis, asthma, and Hymenoptera venom allergies, with recent applications to food allergies and atopic dermatitis. Despite its benefits, the use of SIT in patients with autoimmune diseases is controversial due to concerns about its potential to induce or exacerbate autoimmune conditions. This report examines a case of autoimmune hypothyroidism developing during AIT and the management decisions involved. A 26-year-old female with a history of moderate to severe persistent allergic rhinitis and childhood asthma presented with severe malaise, weakness, and fatigue over the past three months. She had a family history of asthma and allergic rhinitis. The patient had been on AIT for six months and was using intranasal fluticasone furoate nasal spray daily. Initial laboratory investigations prior to AIT showed normal thyroid function. Three months into AIT, she developed hypothyroidism, confirmed by elevated TSH levels and positive anti-TPO antibodies. A causality assessment suggested a “possible” link between AIT and hypothyroidism. However, a risk-benefit analysis favored the continuation of AIT along with the initiation of L-thyroxine therapy. After six months of thyroid hormone replacement, her TSH levels normalized, and her allergic rhinitis symptoms significantly improved. This case underscores the complexity of managing coexisting allergic and autoimmune conditions. The decision to continue AIT, despite the onset of hypothyroidism, was based on a thorough risk-benefit analysis, emphasizing the need for personalized treatment plans. Understanding the immunological mechanisms, particularly the balance between Th17 and Treg cells, is crucial. Neutrophils play a significant role as both effectors and modulators of immune responses. The clinical pharmacologist’s recommendation was informed by these factors and the manageable nature of hypothyroidism with hormone replacement therapy. The continuation of AIT was justified by its benefits in managing allergic rhinitis and the manageable nature of hypothyroidism with hormone therapy. This case highlights the importance of personalized medicine and continuous monitoring in treatment decisions for patients with coexisting conditions.

Introduction

Allergen immunotherapy (AIT), also known as specific immunotherapy (SIT), is a treatment modality aimed at inducing immune tolerance to specific allergens. SIT has been widely recognized for its efficacy in treating allergic rhinitis, conjunctivitis, asthma, and allergies to Hymenoptera venom, with recent expansions to food allergies and atopic dermatitis​ [1]​. One of the major advantages of SIT is its ability to modify the natural history of allergic diseases, potentially preventing the progression to more severe conditions and reducing the incidence of new sensitizations, thus attempting to halt the “allergic march” commonly seen in children​ [2].

However, the application of SIT in patients with autoimmune diseases remains a topic of debate due to concerns about its potential to induce or exacerbate autoimmune conditions. The safety profile of SIT is continuously monitored, with particular attention to its long-term effects on the immune system. While some guidelines suggest that autoimmune diseases, especially when active, may be contraindications for SIT, others advocate for a careful evaluation of the risks and benefits on a case-by-case basis​ [2, 3].

Pitsios et al. have highlighted that the coexistence of autoimmune disease is considered a relative contraindication for SIT, advising caution particularly when the autoimmune condition is in remission​ [​4]. Zuberbier et al. further emphasized that all serious autoimmune diseases might contraindicate SIT, though without specifying the nature of these diseases​ [5]​. On the other hand, Linneberg et al. have supported a more balanced view, suggesting that SIT could be considered in patients with established autoimmune diseases, provided that a thorough risk-benefit analysis is conducted​ [6]​.

The literature on SIT’s potential to induce autoimmune diseases is limited, with most evidence derived from case reports. There are isolated instances of autoimmune diseases such as systemic lupus erythematosus, scleroderma, vasculitis, and Sjögren’s syndrome appearing during SIT, though causality remains uncertain due to the possibility of these conditions being present subclinically before the initiation of SIT​ [7–11]​.

This case report discusses a 26-year-old female patient with persistent allergic rhinitis and a family history of asthma and allergic rhinitis, who developed autoimmune hypothyroidism during SIT. The report aims to evaluate the potential causality between SIT and the onset of autoimmune hypothyroidism and to discuss the management decisions regarding the continuation of SIT in light of this new diagnosis.

Case Description

A 26-year-old female with a history of moderate to severe persistent allergic rhinitis for the past five years and childhood asthma presented with severe malaise, weakness, and fatigue over the past three months. She had a family history of asthma and allergic rhinitis, with both her mother and maternal grandmother affected. The patient had been on allergen immunotherapy (AIT) for the past six months and was also using intranasal fluticasone furoate nasal spray (27.5 mcg per spray) once daily.

The patient was on Subcutaneous Immunotherapy (SCIT) with a composition of 50% Dermatophagoides farinae (DF) and 50% Dermatophagoides pteronyssinus (DP), administered at a strength of 1:5000. At the time of assessment, the patient was in the build-up phase of immunotherapy. This phase involves gradually increasing the dose of allergens until a maintenance dose is reached. The allergen composition and strength were tailored to address her sensitization to house dust mites, a common trigger for allergic rhinitis and asthma.

Initial laboratory investigations prior to the initiation of AIT revealed the following results:

TSH: 4.2 µIU/ml.

Free T4: 0.98 ng/dl.

Hemoglobin: 11.3 gm/dl.

Absolute eosinophil count: 320/µL.

Total IgE: 234 U/L.

Pulmonary function test: Normal ventilatory pattern.

FeNO: 67 ppb.

Skin prick test: Sensitization to dust mite (Dermatophagoides pteronyssinus and Dermatophagoides farinae), cockroach, coconut, and milk allergens with good positive and negative controls.

Fasting plasma glucose: 90 mg/dl.

Creatinine: 0.85 mg/dl.

SGPT: 51 U/L.

SGOT: 36 U/L.

Three months into AIT, she developed severe malaise, weakness, and fatigue. Follow-up laboratory investigations showed:

TSH: 11.2 µIU/ml.

Free T4: 0.84 ng/dl.

Vitamin D (25-OH): 12.3 ng/ml.

Hemoglobin: 11.3 gm/dl.

Fasting plasma glucose: 87 mg/dl.

Creatinine: 0.9 mg/dl.

SGPT: 43 U/L.

SGOT: 38 U/L.

Anti-TPO antibodies: 98 U/ml (positive).

Given the elevated TSH and positive anti-TPO antibodies, the patient was diagnosed with autoimmune hypothyroidism. The case was reviewed by an endocrinologist and referred to a clinical pharmacologist for a causality assessment regarding the potential link between hypothyroidism and AIT.

Using the WHO-UMC causality assessment scale and the Naranjo Causality Assessment Scale, a score of 1 was determined, indicating a “possible” causality. However, considering the lack of pharmacological plausibility for AIT causing hypothyroidism and the patient’s need for continued AIT, a risk-benefit assessment was performed.

The clinical pharmacologist recommended continuing AIT and initiating L-thyroxine replacement therapy. The patient started on L-thyroxine 50 mcg daily. After six months of thyroid hormone replacement, her TSH levels normalized to 2.4 µIU/ml, and her allergic rhinitis symptoms significantly improved. The frequency of intranasal fluticasone furoate nasal spray usage was reduced to one spray in each nostril twice weekly or on alternate days.

Discussion

The presented case of a 26-year-old female with a history of persistent allergic rhinitis and childhood asthma who developed autoimmune hypothyroidism during allergen immunotherapy (AIT) highlights the complex interplay between therapeutic interventions and autoimmune conditions. The decision to continue AIT despite the onset of hypothyroidism was based on a thorough risk-benefit analysis, emphasizing the necessity of integrating clinical pharmacological principles in treatment decision-making.

Risk-Benefit Analysis

AIT is well-established for its efficacy in managing allergic conditions by modulating immune responses to specific allergens​ [1, 3]. The patient had shown significant sensitization to multiple allergens and had been receiving AIT alongside intranasal corticosteroids. The introduction of AIT was aimed at achieving long-term control of her allergic rhinitis, with a potential reduction in the overall medication burden and improvement in quality of life.

However, during the course of AIT, the patient developed symptoms indicative of hypothyroidism, confirmed by elevated TSH levels and positive anti-TPO antibodies, suggesting autoimmune thyroiditis. This raised concerns about the potential causal relationship between AIT and the development of autoimmune hypothyroidism.

Causality assessments using the WHO-UMC scale and the Naranjo score yielded a score of 1, indicating a “possible” association. This assessment, while useful, does not provide definitive evidence of causality. As highlighted in the literature, the development of autoimmune diseases during AIT is rare and often coincidental​ [6, 12]​.

Immunological Mechanisms and Clinical Pharmacological Principles

Understanding the underlying immunological mechanisms is crucial. The balance between Th17 and Treg cells plays a significant role in maintaining immune homeostasis and preventing autoimmunity. Dysregulation of this balance, characterized by an increased Th17 response and a decreased Treg function, has been implicated in the pathogenesis of autoimmune thyroid diseases (AITDs)​ [13]​. The therapeutic strategies targeting Th17/Treg equilibrium, such as the use of IL-6 inhibitors and JAK inhibitors, are being explored to manage AITDs​ [13].

Neutrophils, as both effectors and modulators of immune responses, contribute to autoimmune pathogenesis through various mechanisms, including the release of cytokines and the formation of neutrophil extracellular traps (NETs), which can present autoantigens and perpetuate autoimmunity​ [14–16]​. The role of neutrophils and their interaction with adaptive immune cells further underscores the complexity of immune-mediated diseases.

Clinical Pharmacological Decision-Making

The clinical pharmacologist’s recommendation to continue AIT while initiating L-thyroxine replacement was based on a comprehensive evaluation of the patient’s clinical status, the benefits of AIT in managing her allergic condition, and the manageable nature of hypothyroidism with appropriate thyroid hormone replacement. This decision aligns with the principles of personalized medicine, where treatment plans are tailored to the individual patient’s needs, considering both the efficacy and safety of the interventions.

The risk of discontinuing AIT included potential worsening of allergic rhinitis symptoms and increased reliance on symptomatic treatments, which could adversely affect the patient’s quality of life. Conversely, the introduction of L-thyroxine provided a straightforward and effective means of managing hypothyroidism, thus mitigating the risk associated with continued AIT.

Conclusion

This case underscores the importance of a nuanced approach to managing patients with coexisting allergic and autoimmune conditions. While causality assessments provide valuable insights, they must be complemented by a thorough understanding of immunological mechanisms and clinical pharmacological principles. The decision to continue AIT in this patient was justified by the overall benefit to her allergic condition and the manageable nature of her hypothyroidism with hormone replacement therapy. This approach highlights the importance of personalized medicine and the need for continuous monitoring and adjustment of treatment plans based on patient-specific factors and evolving clinical evidence.