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    Home > Active Ingredient News > Infection > [Guideline consensus] Expert consensus on nasal glucocorticoid treatment of allergic rhinitis (2021, Shanghai)

    [Guideline consensus] Expert consensus on nasal glucocorticoid treatment of allergic rhinitis (2021, Shanghai)

    • Last Update: 2021-10-09
    • Source: Internet
    • Author: User
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    This article is an expert consensus on the treatment of allergic rhinitis with nasal glucocorticoids based on clinical experience and evidence-based medicine
    .
    This consensus systematically summarizes the role, clinical application and precautions of nasal glucocorticoids in the treatment of allergic rhinitis from the principle of action, pharmacological characteristics and clinical application of nasal glucocorticoids, aiming to further standardize allergy In the diagnosis and treatment of rhinitis, guide physicians to take reasonable medication to improve the curative effect of allergic rhinitis and the satisfaction of patients with medical treatment

    .

    01

    01

    Overview

    Overview

    Allergic rhinitis is a common non-infectious inflammation of the nasal mucosa
    .
    The global average prevalence rate of allergic rhinitis is as high as about 20%, and the prevalence rate in China is 4% to 38%

    .
    Allergic rhinitis is a chronic inflammatory disease of the nasal mucosa induced by allergens, which is dominated by specific immunoglobulin E (IgE) and participated by a variety of inflammatory cells

    .
    Allergens that cause allergic rhinitis include perennial allergens such as dust mites and fungi, as well as seasonal allergens such as pollen

    .
    The treatment of allergic rhinitis includes environmental control, drug therapy and immunotherapy.
    Among them, drug therapy can quickly, effectively and safely control the nasal symptoms such as nasal itching, sneezing, and runny nose in patients with allergic rhinitis.
    It is the current treatment The most important means of allergic rhinitis

    .
    Clinical guidelines recommend the first-line drug treatment of allergic rhinitis include: nasal corticosteroids, oral second-generation antihistamines, nasal antihistamines, leukotriene receptor antagonists

    .
    Nasal glucocorticoids play an important role in the treatment of allergic rhinitis and are currently the first-line medication for the treatment of allergic rhinitis.
    However, there are still some unclear points and irregularities in the current clinical use process.
    In view of this, China The Rhin Disease Research Cooperation Group convened young domestic rhinology experts to summarize and write an expert consensus on the treatment of allergic rhinitis with nasal glucocorticoids

    .
    The purpose of this consensus is to further clarify the clinical status and precautions of nasal glucocorticoids in the treatment of allergic rhinitis, so as to guide physicians in the rational use of drugs, and to improve the therapeutic effect of allergic rhinitis and the satisfaction of patients with medical treatment

    .

    02

    02

    Overview of the structure, physiology and biological receptors of the nasal mucosa

    Overview of the structure, physiology and biological receptors of the nasal mucosa

    The total area of ​​the bilateral mucosa of the human nasal cavity is about 150cm2, composed of epithelial layer, basement membrane and lamina propria
    .
    According to its organizational structure and physiological functions, the nasal mucosa can be divided into two parts, the olfactory zone and the respiratory zone

    .
    The respiratory mucosa occupies most of the nasal cavity.
    The first 1/3 part is pseudostratified columnar epithelium; the back 2/3 part is pseudostratified ciliated columnar epithelium

    .
    There are mucous glands and serous glands in the submucosa, and the mucous membranes are covered with a blanket of mucus by their secretions

    .
    Most of the epithelial cells of the nasal mucosa have a cilia structure on the surface, which cooperates with the mucus blanket to discharge foreign bodies in the secretion to the nasopharynx to remove foreign pathogenic microorganisms and other particulate matter

    .
    Nasal mucosal tissue contains a large number of secretory glands and goblet cells.
    In addition to glycoproteins, the serous or mucous secretions secreted by them also contain various immunoglobulins (the most IgA), albumin, lactoferric acid, and bacteriolysis Enzymes and other substances play an important role in maintaining normal nasal cavity function

    .
    The secretory function of the nasal mucosa is mainly regulated by the autonomic nervous system

    .
    Parasympathetic nerve excitement can enhance the secretory function of glands

    .
    Some inflammatory mediators (such as histamine, kinin or bradykinin, substance P) and some irritating substances (such as pepper), etc.
    , can directly act on secretory cells or submucosal blood vessels, resulting in increased glandular secretion or blood vessels such as leakage increases

    .

    Nasal contain a variety of biological receptors, including the glucocorticoid receptor (glucocorticoid receptor, GR), histamine receptors, adrenergic receptors, cholinergic receptors and the like
    .
    GR is mainly distributed in nasal mucosal epithelial cells, submucosal glands and inflammatory cells, and is expressed in cell membrane, cytoplasm and nucleus, respectively

    .
    Nasal glucocorticoids are the most common and effective drugs for the treatment of nasal inflammatory diseases.
    The fat-soluble glucocorticoid molecules pass through the target cell membrane and enter the cytoplasm, and combine with GR to exert biological effects

    .
    The two GR subtypes that humans have identified are GRa and GRβ.
    These two subtypes are derived from the same gene and are obtained by alternatively cutting the initial transcription product of GR

    .
    Fat-soluble glucocorticoids bind to GRa to initiate the process of enhancing anti-inflammatory or inhibiting the transcription of pro-inflammatory genes

    .
    The GRβ subtype does not directly bind to fat-soluble glucocorticoids, but studies have shown that it can interfere with the function of GRα

    .
    In patients with allergic rhinitis, long-term exposure to allergens may induce insensitivity or resistance to fat-soluble glucocorticoids

    .
    Fakhri et al.
    found that ragweed can induce an increase in the expression of GRβ in the inferior turbinate tissue of patients with allergic rhinitis

    .
    Barnes et al.
    reported that the expression level of GRβ mRNA in the nasal mucosa of the hormone-insensitive group of patients with allergic rhinitis was significantly higher than that of the hormone-sensitive group and the control group

    .
    The above research results indicate that the overexpression of GRβ in allergic rhinitis may play an important role in the insensitivity of fat-soluble glucocorticoid treatment

    .

    03

    03

    The principle of action of nasal glucocorticoids

    The principle of action of nasal glucocorticoids

    After nasal injection of corticosteroids in the nasal cavity, about 70% are swallowed or spit out naturally, and 30% can stay in the nasal cavity to form a high concentration to exert anti-inflammatory effects
    .
    In general, the principle of action of fat-soluble glucocorticoids can be divided into the following three aspects:

    ①Genomic effects: The classic way of action of fat-soluble glucocorticoids is the "genomic mechanism".
    The fat-soluble glucocorticoid-GR complex is transferred to the nucleus and responds to fat-soluble glucocorticoids in the form of homodimers.
    The glucocorticoid response element (GRE) is combined to play a role by directly or indirectly regulating gene transcription and translation, encoding many specific inflammatory mediator genes, including cytokines, chemokines, enzymes and adhesion factors related to inflammation

    .
    It usually takes effect after 7 to 8 hours, and the maximum effect time can be as long as 2 weeks

    .
    This effect mainly depends on the GR in the cytoplasm and nucleus to play its role in regulating gene activity;

    ② Non-genomic effects: The fat-soluble glucocorticoid-GR complex does not directly bind to GRE, but acts on transcription factors to inhibit the expression of inflammatory genes and perform post-transcriptional regulation, roughly activating a variety of cell signals through three ways The transduction pathway quickly exerts "non-genomic effects", and there may be a variety of receptors, kinases, and signaling molecules: The messenger system interacts with the centrifugal channel protein (G-coupled protein) to regulate the phosphorylation level of the intracellular protein and cause the cell to respond quickly to external stimuli; secondly, it is divided into non-specific and specific through the physical and chemical interaction with the cell membrane Non-genomic effects; Finally, through the specific interaction with the classical GR in the cytoplasm, the immunosuppressive effect occurs rapidly
    .
    The above three approaches are not isolated from each other, but there are certain interactive adjustments at certain levels

    .
    This effect requires large doses of fat-soluble glucocorticoids to occur in a very short period of time (minutes or even seconds), and because it does not require gene transcription and protein synthesis, transcription inhibitors or protein synthesis inhibition Neither drug can block the rapid effect of fat-soluble glucocorticoids;

    ③Total effect: There are many differences between genomic effects and non-genomic effects, but there are interactions between them, so the two cannot always be directly distinguished
    .

    04

    04 04

    Pharmacological characteristics of nasal glucocorticoids

    Pharmacological characteristics of nasal glucocorticoids Pharmacological characteristics of nasal glucocorticoids

    4.
    1 Pharmacological characteristics

    4.
    1 Pharmacological characteristics

    The anti-inflammatory effect of nasal glucocorticoids is mainly by reducing the infiltration of eosinophils and mast cells to the nasal mucosal epithelium, affecting the metabolism of arachidonic acid, significantly reducing the production and release of inflammatory mediators and cytokines, and inhibiting cells The effect of factors; significantly inhibit the local recruitment of basophils, eosinophils, neutrophils and monocytes to the nasal mucosa; inhibit the synthesis of chemokines or adhesion molecules in the nasal mucosa and polyp epithelial cells, thereby indirectly intervening Eosinophil function; exerts immunomodulatory effect through non-genomic mechanism, quickly inhibits neutrophil degranulation; reduces the expression of vascular endothelial growth factor and reduces nasal congestion; in addition, it can also reduce the high response of nasal mucosa to antigen and histamine , Reduce the inflammatory edema and vasodilation of the nasal mucosa, and play a direct anti-inflammatory effect
    .

    4.
    2
    Pharmacokinetics

    4.
    2
    Pharmacokinetics

    ①Hepatic first-pass metabolism: There are certain differences in liver first-pass metabolism of different nasal glucocorticoids.
    Theoretically, the higher the liver's first-pass metabolism, the lower the systemic bioavailability of the drug, and the possibility of systemic side effects of the drug is also Will be smaller

    .
    However, in fact, liver first-pass metabolism is not the only factor that determines systemic bioavailability.
    Although the proportion of drugs absorbed locally from the nasal cavity is small (about 30%), it has become a middle-nasal system because there is no first-pass metabolism.
    The main source of glucocorticoids is more important for systemic bioavailability than drugs absorbed from the gastrointestinal tract;

    ②Fat solubility: Fat solubility is one of the important indicators that determine the degree of local absorption of drugs
    .
    In general, nasal glucocorticoids with high fat-soluble properties are more easily absorbed by the nasal mucosa, so that they stay locally in the nasal cavity for a longer time, and enter the target cells to combine with GR to exert their pharmacological effects

    .
    The fat solubility of nasal glucocorticoids in descending order is: mometasone furoate>fluticasone propionate>budesonide>triamcinolone acetonide

    .
    Drugs with too high or low fat solubility are not easily absorbed, and the difference in lipophilicity is the main reason for the difference in the pharmacokinetic properties of nasal glucocorticoids

    .
    Highly lipophilic nasal glucocorticoids such as fluticasone propionate and mometasone furoate have high receptor affinity, long nasal mucosal retention time, high first pass metabolic rate, low bioavailability, more pharyngeal drugs, and better onset Slowness, wide distribution in the body, long half-life, and strong systemic effects after repeated medication;

    ③Bioavailability: Bioavailability is a key indicator that determines the safety of nasal glucocorticoids.
    It depends on the residual drugs that still have pharmacological activity after the first pass metabolism of the liver and are absorbed into the blood circulation through the nasal mucosa to avoid the liver.
    Metabolic drugs

    .
    After intranasal administration, nasal glucocorticoids that enter the systemic circulation come from two parts: about 30% of them are nasal glucocorticoids that are directly absorbed in the nose through capillaries to exert pharmacological effects, and are absorbed into the blood through the nasal venous system Circulation; another part of about 70% is the nasal glucocorticoid that is cleared by the nasal cilia and absorbed through the gastrointestinal tract after swallowing and enters the blood circulation

    .
    Although the former accounts for a small proportion (about 30%), it is the main source of nasal glucocorticoids in the systemic circulation because there is no first pass metabolism

    .
    There is little difference in absorption between the two, which is mainly because the first pass metabolism of the liver of the second part of nasal glucocorticoids is higher (99%), so its higher nasal cilia clearance rate increases the amount of drugs swallowed into the intestines.
    However, it does not increase the total absorbed drug amount, but also reduces the amount of drug directly absorbed into the blood from the nasal capillaries, and its bioavailability is low

    .
    The currently used second-generation nasal glucocorticoids have good pharmacokinetic characteristics and further reduce system bioavailability (<1%);

    ④ Potency intensity: At present, the best indicator for evaluating the potency intensity of nasal glucocorticoid drugs is the affinity of different nasal glucocorticoids to GR
    .
    Receptor affinity is also positively correlated with the lipophilicity of nasal glucocorticoids.
    Drugs with high receptor affinity can be used in a smaller dose to produce the same strength as drugs with low receptor affinity

    .
    Clinical trials have proved that: after budesonide nasal spray with lower receptor affinity but longer local retention, the effect of treating allergic rhinitis is the same as that of mometasone furoate nasal spray with higher receptor affinity

    .
    But it needs to be clear that the results of in vitro drug tests do not fully represent the role of the drug in the body

    .

    05

    05 05

    Clinical effects of nasal glucocorticoids

    Clinical effect of nasal glucocorticoids Clinical effect of nasal glucocorticoids

    Nasal glucocorticoids have powerful anti-inflammatory effects and are currently the first-line drug choice for the treatment of allergic rhinitis
    .
    The clinically widely used nasal glucocorticoids include budesonide, fluticasone propionate, mometasone furoate and so on

    .
    A number of clinical controlled trials have shown that nasal glucocorticoids can effectively improve the nasal symptoms of patients with allergic rhinitis, including sneezing, nasal itching, runny nose and nasal congestion

    .
    Once the nasal symptoms are improved, sleep and quality of life will increase accordingly

    .
    Most nasal corticosteroids also improve the symptoms of allergic conjunctivitis, including itchy eyes, tearing, conjunctival congestion, and eyelid swelling

    .
    Some studies have shown that nasal glucocorticoids can also effectively improve the symptoms of patients with allergic rhinitis and asthma

    .
    In multiple clinical studies, nasal glucocorticoids are superior to antihistamines and leukotriene receptor antagonists in controlling nasal symptoms including nasal congestion, runny nose, sneezing, nasal itching, and postnasal drip

    .
    For the adverse reactions of nasal glucocorticoids, the current literature reports mostly mild or moderate local reactions, including local irritation, nasal dryness, nasal burning, nasal itching, nose bleeding, pharyngitis, taste changes, nausea or diarrhea

    .
    One of the rarer serious complications is perforation of the nasal septum

    .
    It is clear that the use of nasal glucocorticoids does not increase the incidence of common bacterial infections or Candida infections, and therapeutic doses of nasal glucocorticoids have no significant effect on adrenal cortex function, bone metabolism and growth, and nasal mucosal atrophy.

    .
    See Table 1 for specific instructions

    .

    Table 1 Indications, contraindications, usage and adverse reactions of commonly used nasal glucocorticoids

    Table 1 Indications, contraindications, usage and adverse reactions of commonly used nasal glucocorticoids Table 1 Indications, contraindications, usage and adverse reactions of commonly used nasal glucocorticoids

     

    06

    06

    Principles of application of nasal glucocorticoids

    Principles of application of nasal glucocorticoids

    In view of the fact that nasal glucocorticoids can effectively improve sneezing, nasal itching, runny nose and nasal congestion and some ocular symptoms in patients with allergic rhinitis, this consensus recommends nasal glucocorticoids as the current first-line treatment of allergic rhinitis Medication
    .

    Nasal glucocorticoids can be used clinically for the treatment of all types of allergic rhinitis (including mild and moderate to severe, intermittent and persistent) allergic rhinitis
    .
    The course of treatment of nasal glucocorticoids for allergic rhinitis is usually no less than 4 weeks.
    In the course of treatment, in principle, the frequency and dosage of medication should be gradually reduced according to the condition of symptom control, and finally adjusted to the minimum dosage required to control clinical symptoms It can be maintained or the drug can be discontinued for a short time, but the drug should be continued once the symptoms return and the disease recurs

    .

    In order to facilitate clinical operation, this consensus divides the treatment of perennial allergic rhinitis into an attack period and a maintenance period, and introduces the concept of chemical "titration"
    .

    ①Continuous treatment is recommended during the onset period.
    For mild allergic rhinitis, nasal glucocorticoid can be used alone, spray the nose 1 to 2 times a day according to the recommended dose, and the course of treatment is not less than 2 weeks, with nasal glucocorticoid Whether to control nasal symptoms is the standard to determine whether to add other types of anti-inflammatory drugs (drug type titration); for moderate to severe allergic rhinitis, nasal corticosteroids can be used alone, or nasal corticosteroids and other anti-inflammatory drugs Combined use, nasal glucocorticoids should be sprayed 1 to 2 times a day according to the recommended dose, and the course of treatment is not less than 2 weeks; then reduce to 1/2 or 1/4 of the dose, and the standard is sufficient to control nasal symptoms Carry out fine-tuning of the dose (drug dose titration), the treatment course is not less than 2 weeks, that is, the total treatment course is more than 4 weeks;

    ②In the maintenance period, on-demand treatment is recommended.
    Nasal glucocorticoids can be used alone, or nasal glucocorticoids can be used in combination with other anti-inflammatory drugs.
    Nasal glucocorticoids can be sprayed 1 to 2 times a day at the recommended dose, and the course of treatment is 1 About weeks, fine-tune the course of treatment (drug treatment titration) based on the standard of sufficient medicine to control nasal symptoms; for seasonal allergic rhinitis, it is recommended to take preventive use 1 to 2 weeks before the season, which can effectively reduce or even avoid Onset of clinical symptoms

    .

    Medication time: When you only need to use it once a day, nasal glucocorticoids are best used in the morning, because the morning medication is relatively consistent with the endogenous hormone secretion time, so that even long-term repeated use will not inhibit the patient's own hormone secretion.
    , Can greatly reduce side effects

    .
    Children with asthma tend to have symptoms at night, because the body's own hormone levels are the lowest at night.
    At this time, spraying or inhaling hormones has a great effect on preventing asthma attacks

    .

    Medication: Mastering the correct use of nasal glucocorticoids not only helps to improve the efficacy, but also reduces the occurrence of adverse reactions
    .
    Before each spraying, the liquid should be shaken to ensure effective spray

    .
    When in use, the patient’s head is tilted back slightly in an upright position, and the spray nozzle is slightly facing the outside of the nasal cavity to avoid direct spraying of the medicine to the nasal septum

    .
    Generally use the left hand to spray the right nose and the right hand to spray the left nose

    .
    After spraying, the head can be raised for 2 to 3 minutes to allow the liquid to flow backwards into the nasal cavity, and finally spit out the liquid that has entered the pharynx

    .
    Avoid breathing hard when spraying the nose

    .
    Mastering the correct nasal spray method can reduce the possibility of nasal mucosal erosion, bleeding, ulcers and even nasal septum perforation

    .

    07

    07

    Application of nasal glucocorticoid in special population

    Application of nasal glucocorticoid in special population

    7.
    1 Application of
    nasal glucocorticoids in children with allergic rhinitis

    7.
    1 Application of
    nasal glucocorticoids in children with allergic rhinitis

    In general, nasal glucocorticoids have little effect on children's growth in short-term (several weeks) use at the recommended dose, but long-term high-dose inhaled corticosteroids may inhibit the growth of children, but this inhibitory effect is in the first year of treatment Most notably, it showed a weakening trend with the extension of treatment, suggesting that the inhibitory effect of topical glucocorticoid therapy on children's growth may be transient
    .
    The results of current long-term studies have not found that nasal glucocorticoids can affect the final height of children

    .
    The 2010 revised version of allergic rhinitis and its impact on asthma (allergic rhinitis and its impact on asthma, ARIA) guidelines gave high-strength recommendations for nasal glucocorticoids.
    This recommendation is also applicable to pediatric patients and has an impact on growth and development.
    No adverse reactions

    .
    However, this consensus recommends that the medication time for pediatric patients should be controlled within 6 weeks as much as possible

    .
    For children who use nasal glucocorticoids for a long time, the growth status should be assessed every 4 months in the first year of treatment, and follow-up every 6 months from the second year

    .

    7.
    2 The application of
    nasal glucocorticoids in elderly patients with allergic rhinitis

    7.
    2 The application of
    nasal glucocorticoids in elderly patients with allergic rhinitis

    Compared with children with allergic rhinitis, the current academic circles have not paid enough attention to elderly patients with allergic rhinitis
    .
    But in fact, there are more elderly patients with allergic rhinitis, especially those aged 60 to 75 years, than usually expected, and the literature suggests that the incidence is 3% to 12%

    .
    Nasal glucocorticoids are also first-line drugs for elderly patients over 60 years old, and they are well tolerated by the elderly

    .
    The local injection of nasal glucocorticoids produces a wide range and powerful anti-inflammatory effect, which plays a "full net" effect on the inflammatory response of the nasal mucosa, and can quickly control allergic symptoms.
    Long-term use can smooth the nasal cavity and improve the sense of smell.
    Improving the quality of life of the elderly plays an important role

    .
    There are currently no reports of side effects after long-term use, but considering the physiological characteristics of old age, this consensus recommends the use of nasal hormones with low bioavailability, such as mometasone and ciclesonide

    .

    7.
    3 Application of
    nasal glucocorticoids in patients with allergic rhinitis during pregnancy

    7.
    3 Application of
    nasal glucocorticoids in patients with allergic rhinitis during pregnancy

    For patients with allergic rhinitis during pregnancy, there are insufficient clinical trials for the use of nasal glucocorticoids.
    At present, only budesonide is a Class B drug approved by the US Food and Drug Administration

    .
    Studies have shown that the systemic absorbed dose of nasal administration of budesonide is much lower than that of oral inhalation of budesonide, indicating that its safety is at least equivalent to that of oral inhalation of budesonide

    .
    This consensus believes that if fluticasone furoate, mometasone, and budesonide are used at the recommended therapeutic doses in the middle and late stages of pregnancy, it should be safe to use them intranasally

    .
    However, during pregnancy, clinicians should consider the risk-benefit ratio and communicate effectively with patients before prescribing any nasal corticosteroids

    .

    08

    08

    summary

    summary

    Nasal glucocorticoids have powerful anti-inflammatory effects and are currently the first-line drugs for the treatment of allergic rhinitis
    .
    Nasal glucocorticoids can effectively relieve the nasal symptoms of patients with allergic rhinitis, including sneezing, nasal itching, runny nose, nasal congestion and some eye symptoms, and improve sleep and quality of life

    .
    Nasal glucocorticoids can be used clinically for the treatment of all types (including mild and moderately severe, intermittent and persistent) allergic rhinitis

    .
    The adverse reactions of nasal glucocorticoids are mostly mild or moderate local reactions

    .
    Children, the elderly, and patients with allergic rhinitis during pregnancy should be given proper attention when using nasal glucocorticoids

    .



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