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# Vol 17, No 3 (2020)

## Full Issue

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Access granted
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## Reviews

### Revisiting the safety of topical calcineurin inhibitors in patients with atopic dermatitis

Kalyuzhin O.V.

#### Abstract

Topical calcineurin inhibitors (TCI) have emerged from the shadow of topical corticosteroids as another first-line remedies for treating acute flares of atopic dermatitis (AD). The effectiveness of TCI in maintenance therapy is also undeniable. The wider use of TCI increases the relevance of the issue of their safety. The adherence of physicians and their patients to the treatment with TCI is constrained by a controversial FDA black box warning against these drugs based on the theoretical risk of skin tumors, especially lymphoma. This warning, formulated in 2005, has been repeatedly refuted. However, there have been studies that at least partially supported cautious use of TCI. In recent years, the results of large cohort prospective studies clarifying the issue of oncological safety of TCI have been published. The review highlights the results of various studies with optimistic, pessimistic and balanced conclusions regarding the safety of TCI, primarily their effect on tumorigenesis, in order to better inform physicians about the benefit/risk balance when using these drugs in AD patients. The data presented in this review indicate that there is no increased risk of melanoma and other forms of skin cancer in TCI users, but these data do not completely rule out the risk of skin lymphoma. However, the very low level of potential risk to an individual patient gives physicians the right to neglect this risk when choosing TCI as a treatment option for AD.

Russian Journal of Allergy. 2020;17(3):5-14
5-14

### Non-steroidal anti-inflammatory drugs (NSAIDs) – exacerbated respiratory disease: epidemiology, pathogenesis, clinical findings and management

Pavlova K.S., Dyneva M.E., Kurbacheva O.M.

#### Abstract

Non­-steroidal anti­-inflammatory drugs (NSAIDs) ­– exacerbated respiratory disease (N­-ERD) are characterized by non­-allergic hypersensitivity (intolerance) to NSAIDs and aspirin in patients with asthma and/or eosinophilic chronic rhinosinusitis with nasal polyps (CRSwNP). Asthma in N­-ERD patients is usually characterized by eosinophilic inflammation, tends to become severe and intractable, and needs chronic oral corticosteroid therapy. For some patients recurrent CSwNP is more significant problem due to nasal congestion, anosmia, and multiple repeated surgeries. Intolerance to aspirin and other NSAIDs limits the choice of pain relievers and antipyretics. Accidental use of these medications can lead to dangerous consequences, including anaphylaxis. This review presents the current understanding of the N­-ERD pathogenesis and perspective trends in therapy.

Russian Journal of Allergy. 2020;17(3):15-33
15-33

### T2 asthma and T2-associated diseases: a consolidated approach to biological therapy

Nenasheva N.M.

#### Abstract

This article is dedicated to the main characteristics of severe bronchial asthma (SBA) and its heterogeneity. In particular, it describes T2 asthma and the role of the main cytokines involved in T2 inflammation. It focuses on the role of IL-4 and IL-13 in the pathogenesis of asthma and other T2-associated diseases, as key cytokines in the initiation and maintenance of T2 inflammation. The article presents the results of experimental studies proving that the activation of IL-4/IL-13 can cause significant hyperresponsiveness of the human airway smooth muscles and the combined blockade of the activity of these cytokines using a human monoclonal antibody against the common IL-4/13 receptor á-subunit-dupilumab-determines the clinical efficacy not only in relation to exacerbations and control of asthma symptoms, but also an improvement of the lung function and a reduction in bronchial hyperresponsiveness. When type 2 helper cells (Th2) interact with antigen-presenting cells, IL-4 and IL-13 are simultaneously released, therefore, blocking IL-4Rá is more effective than blocking each of the ligands separately, which explains the high efficacy of dupilumab not only in T2 asthma, but also other T2-associated diseases: atopic dermatitis and chronic rhinosinusitis with nasal polyps. In addition to asthma and atopic dermatitis, a new indication for dupilumab, chronic rhinosinusitis with nasal polyps, has recently been approved.

According to the recommendations of the European Academy of Allergy and Clinical Immunology (EAACI) for the biological therapy of SBA 2020, dupilumab is recommended as an add-on maintenance therapy in adults and children aged 12–17 years old with uncontrolled severe T2 asthma, including asthma with the allergic and eosinophilic phenotype, as well as mixed (when there are signs of both phenotypes) and steroid-dependent asthma. At the same time, dupilumab is well tolerated.

Russian Journal of Allergy. 2020;17(3):34-49
34-49

### Modern view on LRBA deficiency

Latysheva T.V., Latysheva E.A., Setdikova N.K., Esaulova D.R.

#### Abstract

Facilities of molecular genetic methods allow to distinguish several monogenic deficiencies in the general group of primary immunodeficiencies, including common variable immune deficiency (CVID), which have peculiarities of the natural course, therapy, and prognosis. One of these nosologies is LRBA deficiency. In this article a number of foreign sources were reviewed, systematized and classified to define a comprehensive understanding of the LRBA deficiency phenomenon . The most relevant scientific studies of North America and Europe and publications from various ranking medical journals were analyzed.

LRBA deficiency is a PID caused by mutations in LRBA gene that disrupt the immune system regulation. It is characterized by lymphoproliferation, autoaggression, hypogammaglobulinemia and recurrent infections. Sometimes LRBA deficiency is called LATAIE disease (LRBA deficiency with autoantibodies, regulatory T-cell defects, autoimmune infiltration, and enteropathy).

Special attention was given to the mutation of LRBA gene and the connection to the defects caused in T-­ and B­-lymphocytes, the clinical picture and diagnostics. It was suggested that LRBA protein reduces the level of autophagy, leading to increased apoptosis, impared T-­ and B-­cell immune response, lymphoproliferation and autoimmune disorders. LRBA protein is especially expressed in the immune cells, its deficiency leads to defects of B-­cells differentiation. However, LRBA deficiency does not affect T-regulatory cells differentiation. Main approaches to the treatment of patients with LRBA deficiency are presented in the article.

Methods of systemic and content analysis of Russian and foreign sources were used when writing the article.

Russian Journal of Allergy. 2020;17(3):50-56
50-56

## Original studies

### The features of the pollen sensitization in seasonal allergic rhinitis patients with gastrointestinal tract inflammatory diseases comorbidity

Iraklionova N.S., Belan E.B., Turkina S.V., Panina A.A., Sadchikova T.L., Klyausov A.S.

#### Abstract

BACKGROUND: Allergic diseases and gastrointestinal tract diseases can influence on the natural course of each other.

AIM: To study the sensitization profile in patients with comorbidity of seasonal allergic rhinitis (SAR) and upper gastrointestinal tract inflammatory diseases (UGITID).

MATERIALS AND METHODS: 112 adult residents of Volgograd city suffering from SAR but without perennial symptoms and sensitization to indoor allergens have been included in the study. 31/112 patients had H. pylori­-negative and 38/112 H. pylori­-positive UGITID. Control group consisted of 43/112 patients without gastrointestinal diseases. Skin prick-­testing with 3 groups of pollen allergens have been carried out.

RESULTS: 75.9% of patients were sensitized to weed pollen; sensitization to grass pollen was in 1.5–3 times less, and 10.5% of patients (4/38) had positive tests with birch pollen. The sensitization to quinoa and ragweed in SAR and H. pylori«–»­-UGITID patients was comparable with control group but less common with wormwood, sumpfweed allergens. The sensitization in SAR patients and H. pylori«+»­-UGITID was similar to the control group, but positive SPT with sunflower and corn allergens were rare then in control group.

CONCLUSION: Weed pollen allergens prevail in sensitization spectrum of adult Volgograd residents with SAR. Sensitization to goose-foot and ragweed is common less in SAR patients and H. pylori«–»­-UGITID but to graminea grass and birch pollen is more often. It may be supposed that the UGITID are predisposing factors to the sensitization to cross-­reacting plant food allergens. At the same time supposed immunomodulating action of H. pylori make the differences between AR patients with H. pylori«+»­-UGITID or H. pylori«–»­-UGITID minor.

Russian Journal of Allergy. 2020;17(3):57-63
57-63

### Patient management plan for sublingual allergen specific immunotherapy with birch pollen allergen and the maintenance of patient compliance

Trusova O.V., Kamaev A.V., Makarova I.V.

#### Abstract

BACKGROUND: Sublingual allergen­-specific immunotherapy (SLIT) inefficiencie is mainly caused by non-­compliance with the treatment regimen and premature treatment termination.

AIM: Frequency and causes of dropouts determination in children receiving SLIT with birch pollen according to the pre­-coseasonal protocol, and approbation of the developed visit-­to-­visit patient management plan (Plan).

MATERIALS AND METHODS: 332 cases of treatment with birch pollen in children are analyzed. 290 patients (72.1% boys, aged 5–18 years (9.82 years [5.93; 14.67]), received SLIT with birch pollen in 2012–2019. 42 patients received SLIT according to the Plan (69% boys, 8.95 years old [5.38; 11.79]) in 2017–2019.

RESULTS: A low dropout frequency was noted in the 1st and 2nd year of therapy (2 years after the start of treatment, 85% patients continue it). However, only 63.1% complete 3 years of therapy, and 11% ­– 4 years of therapy. It has been shown that experienced allergists have more efficient patient retention. The implementation of the Plan increased patient retention in treatment at the 3rd year of treatment up to 82.9% (p=0.02).

CONCLUSION: The study confirmed the main reasons for the withdrawal of patients from SLIT: doubts about the effectiveness, cost and side effects. A low dropout frequency was shown according to the results of the 1st and 2nd years of therapy, but only a small proportion of patients (11%) receive 4 or more courses of therapy. Visit-­to-­visit Plan optimizes the patient’s management, reduces patients’ withdrawal from treatment and can be recommended for practical healthcare.

Russian Journal of Allergy. 2020;17(3):64-73
64-73

### The effectiveness of omalizumab in patients with severe chronic spontaneous urticaria (results of own clinical experience)

Skorokhodkina O.V., Klyucharova A.R., Luntsov A.V.

#### Abstract

BACKGROUND: Urticaria is one of the most common dermatoses and affects 15–25% of the population; chronic spontaneous urticaria occur in 1.8% of adults and in 0.1–3% of children. Second generation antihistamines are effective only in 45–77% of patients. The next steps of treatment include increase antihistamines dose and their combination with omalizumab.

AIM: To analyze own clinical experience and assess effectiveness of omalizumab in severe chronic spontaneous urticaria.

MATERIALS AND METHODS: Effectiveness of biological treatment with omalizumab was analyzed in 14 patients with severe chronic spontaneous urticaria.

RESULTS: The prescription of omalizumab in the basic therapy of patients with severe chronic spontaneous urticaria (CSU) allowed to reduce significantly the severity of clinical symptoms in 78.6% of patients, to abandon the use of systemic glucocorticosteroids and to achieve partial or complete control of the disease. It should be noted, that 28.5% of patients during the immunobiological therapy stopped taking second-generation antihistamines and the dosage was reduced to therapeutic in 35.7% of patients.

CONCLUSION: Omalizumab is a highly effective in patients with severe chronic spontaneous urticaria.

Russian Journal of Allergy. 2020;17(3):74-81
74-81

### Molecular allergodiagnostics capabilities in determining the indications for allergen-specific immunotherapy with house dust mites allergen and its effectiveness in atopic dermatitis patients

Shtyrbul O.V., Dvornikov A.S., Khaitov M.R., Elisyutina O.G., Fedenko E.S.

#### Abstract

BACKGROUND: Atopic dermatitis (AD) is a widespread chronic inflammatory skin disease, in the development of which complex genetic and immune mechanisms, environmental factors, allergens, are involved. An effective method of treating IgE­-mediated allergic diseases is allergen-­specific immunotherapy (ASIT), which affects all pathogenetically significant links of the allergic process. It is known that as a result of ASIT tissue sensitivity to an allergen, nonspecific tissue hyperreactivity and the intensity of allergic inflammation decrease, which testifies to the rearrangement of the cellular response from Th2 to Th1 with a corresponding change in the cytokine profile. Currently, dozens of scientific papers on the efficacy and safety of subcutaneous and sublingual ASIT in AD have been published; however, the question of the advisability of its appointment still remains unresolved.

AIM: To investigate the ASIT with house dust mite (HDM) allergens efficacy in AD patients, considering the results of molecular allergy diagnosis.

MATERIALS AND METHODS: The study was conducted as a prospective comparative open study, including 32 patients with AD (20 children and 12 adults), 90.6% were diagnosed with concomitant respiratory allergic diseases. Molecular allergodiagnostics was performed using microchip technology with purified natural or recombinant allergen components immobilized in the solid phase (Immuno­-Solid phase Allergen Chip, ISAC) to quantify allergen-­specific IgE (asIgE) against 112 allergen molecules from 51 allergen sources in one study (ImmunoCAP ISAC (Thermofisher, Phadia, Uppsala, Sweden). Patients were divided into two groups depending on the profile of molecular sensitization: with the presence or absence of asIgE to the major allergens of D. farinae and/or D. pteronyssinus Der p 1 (p 2) and/or Der f 1 (f 2). All patients passed three consecutive courses of subcutaneous ASIT with water­-salted HDM allergens produced by I.I. Mechnikov Biomed (Russia) under an accelerated scheme for 3 years. To assess the severity of the disease, the SCORAD indices, the Investigator’s Global Assessment (IGA), and the dermatological quality of life index (DLQI) were used.

RESULTS: Patients with sensitization to major allergens of D. farinae and/or D. pteronyssinus Der p 1 (f 1) and/or Der p 2 (f 2) more often achieved a significant improvement of AD symptoms according to the SCORAD index (OR 3.929, 95% CI: 0.879; 17.56), as well as they more often achieved IGA values of 1 or 0 after three courses of ASIT (OR 3.556, CI 95% 0.730–17.324) and more often assessed the effectiveness of ASIT as excellent and good in comparison with patients without sensitization to these components. The median and interquartile range of the DLQI index before treatment in group 1 was 17 [14; 20] points, in group 2 – 14 [12; 18], after the 3rd course of ASIT: 6 [2; 10] and 8 [3; 10] points in groups 1 and 2, respectively. Adverse events were rare, their frequency did not significantly differ in both groups.

CONCLUSION: ASIT with HDM allergens is an effective and safe method of treatment of AD patients. Determination of the molecular spectrum of sensitization to HDM allergens components allows to justify the indications and predict the effectiveness of ASIT.

Russian Journal of Allergy. 2020;17(3):82-92
82-92

## Case reports

### A case of hereditary angioedema with late adulthood onset

Pokalyukhina J.P., Abramova N.N.

#### Abstract

Over the last years, high attention is given to the hereditary angioedema (HAO). Practitioners can identify the disease by clinical manifestations and family history even before specific laboratory testing. More than 95% of HAO cases are associated with C-1­inhibitor deficiency/dysfunction caused by a mutation in SERPING1 gene. In 25% of patients without C1-inhibitor deficiency HAO is associated with heterozygous mutations in gene F12 coding Hageman XII factor. In 2017–2018 years two more genes responsible for normal C1-inhibitor HAO were discovered: genes PLG and ANGPT1. In clinical practice patients do not always meet typical HAO diagnosis criteria. Diagnostic difficulties appear when clinical picture is not confirmed by related genetic testing results, for example, mutations in genes not described earlier are detected. It should be noted that app. 25% of patients do not have any HAO family history, i.e. have so called de novo mutations. Normally HAO onset takes place within 2 first life decades. 40% of patients have disease progress before the age of 5, and 75% of patients – before the age of 15 y.o. However, it can appear in elderly age, which means certain diagnostic difficulties. It is important to analyze thoroughly patient’s comorbidity and make differential diagnosis with a secondary angioedema.

Russian Journal of Allergy. 2020;17(3):93-96
93-96

## Help to the practitioner

### Federal clinical guidelines. Primary immunodeficiency: severe combined immunodeficiency

Rodina Y.A., Deripapa E.V., Laberko A.L., Pershin D.E., Kalinina E.V., Raikina E.V., Roppelt A.A., Yukhacheva D.V., Burlakov V.I., Balashov D.N., Rumiantsev A.G., Shcherbina A.Y.

#### Abstract

Severe combined immunodeficiency (SCID) is the most life-threatening form of primary immunodeficiency, fatal within the first years of life if hematopoietic stem cell transplantation (HSCT) is not performed. Early diagnosis is crucial for prevention of multiple life-threatening complications, which in turn allows for successful HSCT. Current publication contains clinical recommendations for diagnosis of SCID and its complications, complex treatment, including HSCT, prenatal diagnostics and genetic family counselling.

Russian Journal of Allergy. 2020;17(3):97-114
97-114

### Biological therapy of allergic diseases during the COVID-19 pandemic

Fedenko E.S., Elisyutina O.G., Ilina N.I.

#### Abstract

The outbreak of the SARS-CoV-2-induced Coronavirus Disease 2019 (COVID-19) pandemic started in December 2019 in Wuhan, China, continued to spread across the globe and spanned 188 countries. Under the new circumstances treatment approach for T2 allergic diseases such as asthma, chronic hives, atopic dermatitis, and sinusitis with polyps has been changed. In the past years, new biological therapies – monoclonal antibodies for these diseases have been developed targeting different aspects of the type 2 immune response. New knowledge on the COVID-19 disease course raises many issues around the safety of biologicals in patients with active infection, as well as their interactions with antiviral medications. In Russia new biological therapies entered clinical practice but it’s effectiveness and safety still are not known.

This newsletter is based on “Considerations on Biologicals for Patients with allergic disease in times of the COVID-19 pandemic: an EAACI Statement” and the latest scientific data.

Russian Journal of Allergy. 2020;17(3):115-120
115-120

### Efficacy and safety of the antileukotriene drugs: relevant data. RAACI experts conclusion

Ilina N.I., Kurbacheva O.M., Nenasheva N.M., Astafieva N.G., Beltyukov E.K., Demko I.V., Zhestkov A.V., Osipova G.L.

#### Abstract

In many countries of the world and in Russia, in particular, the pharmacological use of antagonists of cysteinyl receptors LT1 (CysLTR) is a long­-proven and well­-proven pharmacotherapy of bronchial asthma (BA) and allergic rhinitis (AR) in adults and children.

Among antileukotriene drugs the most commonly used medication for the treatment of these diseases is the original montelukast, which is considered a safe drug associated with the appearance of only a few adverse reactions, usually not differing in type and frequency from those that occur with placebo. Currently, there are a large number of generics of montelukast, therefore, practitioners have many questions regarding the benefits and risks of montelukast therapy for patients with BA and AR.

In 2020 FDA (Food and Drug Administration USA) analyzed the risk of adverse events during Montelukast treatment and indicated them on the packaging of the drug (original montelukast and its generics). This contributed to the creation of an expert commission to study this issue and form an expert opinion, which is demonstrated in our publication.

Russian Journal of Allergy. 2020;17(3):121-129
121-129

## Short communications

### Иван Иванович Балаболкин

#### Abstract

To the 85th anniversary of the birth

Russian Journal of Allergy. 2020;17(3):132-133
132-133

### Veronika Igorevna Skvortsova

#### Abstract

For the anniversary

Russian Journal of Allergy. 2020;17(3):134-136
134-136

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